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Medicine Update 2018
My wife
Dr (Mrs) Sushma Gupta
Being so tolerant, cooperative and supportive to all my life
and
Dr Ankur Gupta, Dr Preeti Gupta, Parth Gupta
Dr Rajat Gupta, Dr Deepti Gupta, Ishan and Shanaya
The prestigious conference ‘APICON 2018’ is going to be held in the last week of February, 2018
at Bengaluru, the city of digital technology. This Annual Scientific Program is much awaited by
students, teachers and practitioners with equal zeal and enthusiasm. The proceedings of this
Scientific Program are compiled in the form of a book titled Medicine Update. This year the Medicine
Update is edited by the President Elect, Dr Pritam Gupta, a very senior practitioner of medicine in
North India. The theme chosen by Dr Pritam Gupta is Dawn of New Era in Medicine which truly reflects
the spirit and advancement in the field of medicine.
Dr Pritam Gupta has been successful in getting the contributions from the doctors all over the country and they
are all experts in their own field and have command over the subject matter. This book has covered all the newer
advancements in the field of diagnosis and management of diseases. The book covers the global context of medicine
and has also been very successful being relevant to the Indian context. This book is a multiauthored compilation so
there is a variation in the style of presentation and conveying the message. However, the Editor—Dr Pritam Gupta and
his team of editorial board have tried to present the data in a precise and uniform pattern. Moreover, these publications
of API have a very useful supplementary role to the Textbook of Medicine which is published once in three years.
We are grateful to the authors for having spared their valuable time and expertise by contributing to this book. Dr
Pritam Gupta deserves our thanks and appreciation for having compiled the book which provides a concise, easy-to-
read and knowledge for gearing up the clinicians of India for practice of medicine in future as well. The book is appealing
to the eye, the style and formatting are easy-to-read and the language is simple and easy to understand. I am sure this
effort of Dr Pritam Gupta will find place on the desk of all doctors who can lay their hands on this useful compilation for
ready reference, and learning the new trend, and thought in changing medicine. These topics will be discussed by the
masters during the forthcoming APICON by themselves in person. So, you will have an opportunity to interact with them
to clarify your doubts from the book. Before I close, I am inspired to quote Swami Vivekananda
Education is the manifestation of the perfection already in man.
Change is the law of nature and so is with the medical science. The whole perception of the medicine has changed.
Many early impressions, personal experiences, options, dogmas and axons of the past years have been challenged and
proven to be wrong in the present era of evidence-based medicine. Modern imaging has transformed the approach to
anatomy. Molecular biology and genetics can predict various diseases, which can occur in future. Interventions have
blurred the boundary between the physicians and surgeons. Robots are conducting various surgeries and targeted
interventions. Target therapy is being done for cancers, and is a part of protocol. Today we are living in digital world.
Moreover, the society and media have easy access to Internet and the expectations of the patients are too high from the
treating doctors. Therefore, it is essential for the treating physicians to update themselves with the latest developments
in the field of medicine. With that view I have kept the theme of my scientific program as “Dawn of a New Era in Medicine”.
For a good doctor, three things are essential, i.e. competence, communication and compassion. Competence, i.e.
skill is achieved through conferences, literatures, journals, books and Internet. Conference provides a means of updating
knowledge in the context of changing scenarios of Medical Sciences. There is one-to-one interaction between the
attendees and the experts, and they can exchange and share their views. APICON is a multidisciplinary conference,
where all disciplines of medicine are being discussed at one common platform. Medicine Update 2018 a very popular
book read by postgraduate students and internists, which contain the preceding of APICON-2018. It contains common
topics, clinical problems and approach and management of various disorders, especially in Indian context. The intention
is not to replace textbooks or journals but to complement them.
This book contains 159 chapters in 17 sections written by the experts in their fields meant for Indian population. The
emphasis has been laid on clinical approach to medical problems, case-based discussions and algorithmic approach to
various diseases. I am sure that this book will be very handy and useful not only for postgraduates but also as a reference
guide for busy practicing physicians.
I do hope you find the book stimulating for, in the words of Alan Bennett, “A book is a device to ignite the
imagination”. The book belongs as much to the reader as it does to me as the editor. I have enjoyed editing this. I hope
you enjoy reading this.
I would like to acknowledge the contribution of the galaxy of eminent academicians, physicians and experts from India
and abroad in contributing the chapters. At times due to limitations of time, I pushed them hards and would like to
apologize for the same.
I am extremely thankful to Dr YP Munjal, my mentor, a role model for guidance who has been helping at every step
for preparing a good scientific program and editing this book. His commitment to academics and passion to achieve
perfection in scientific pursuits, whether it is a session, guidelines or book has been guiding us to move a step forward.
Whenever I needed his help even at midnight, he was ever fresh and encouraging me for the whole year. Drs Siddharth
N Shah and BB Thakur deserve the special thanks for inspiring me to bring out a good scientific program and the book,
Medicine Update 2018.
Drs Ghan Shyam Pangtey and Anupam Prakash made my job easy for free papers and poster presentation. Our past
president Drs Rajesh Upadhyay, Shashank Joshi, Sandhya Kamath, A Muruganathan were always helping me time to
time in preparing scientific program. Dr BR Bansode, President of API, an ever smiling personality, helped me a lot and
was always inspiring me.
Scientific committee members Drs NK Soni, Rita Sood, Sandeep Garg and Sekhar Chakraborty were instrumental in
finalizing the scientific program. Drs RM Chhabra, MPS Chawla, AK Agarwal, RK Singal and JR Chugh were kind enough
in providing their valuable opinion and guidance for the publication of this book.
Drs Rohini Handa, Jyotirmoy Pal, Girish Mathur, GS Wander and KK Pareek were very generous in discussing the
scientific material and program. My heartfelt thanks to Dr Milind Y Nadkar, Editor-in-chief, JAPI, and Dr Mangesh
Tiwaskar, Secretory, API, who had always been a great support to me and guiding regularly. I would like to pay thanks to
whole staff of API Headquarter especially Mrs Sunita Shukla and other for their support.
For every success, there is always a lady behind it; she is Dr Sushma Gupta, my beloved wife. She had always been
cooperative, tolerant and source of inspiration to me. Drs Ankur Gupta and Rajat Gupta my sons had been a great
support of help for me, especially in planning and execution of this project including the publication of Medicine Update
2018.
I thank my all well wishers, friends and staff of Sunder Lal Jain Hospital especially Dr Sunil Mangla, who had been
looking after the patients in my absence.
Organizing committee members from Bengaluru, Dr P Chandrasekhra and their team-mates were always generous
and cooperative during the whole year. My special thanks to them.
I would like to thank the team of Evangel Publishing, especially Mr Tarun Duneja (Director) and Mr Mohit Bhargava
(Production Head), for printing this book in time.
Scientific committee of APICON-2018 is grateful to unconditional educational grant from Mankind Pharma, USV
Pharma, Merck Ltd, Abbott Pharma, Dr Reddy’s Laboratories Ltd, Novo Nordisk, Aristo Pharma, Sun Pharma, Alkem
Pharmaceuticals, Maxcare and Sanetra Pharma, etc.
I thank Mr Tapas Thakur my secretary and other members of staff especially, Mr Devender Kumar, without their help
it was not possible for me to bring out the scientific program and Medicine Update 2018 in time.
CONTENTS
SECTION 1 HYPERTENSION
1. Pitfalls in Hypertension Management..........................................................................................................3
K Tewary
Errors in Examination 3
Diagnostic Errors 3
Treatment Errors 4
Errors by Patients 4
Surgical Revascularization 31
Angioplasty 31
SECTION 2 CARDIOLOGY
12. Atherosclerosis: Can We Tame it?................................................................................................................ 75
Harendra Kumar
Methods are Carotid Intima-Media Thickness (CIMT) 75
Cholesterol Absorption Inhibitor 77
19. How did Fractional Flow Reserve Change My Clinical Decisions? Case-based Discussions.......... 110
Nagendra Boopathy Senguttuvan
Fractional Flow Reserve 110
Characteristics of FFR 110
Functional PCI 111
Deferred PCI 112
Assessment of Serial Lesions 112
26. Heart Failure with Reduced Ejection Fraction: Treatment Strategy................................................... 144
Amal Kumar Banerjee
Classifiction 144
Diagnosis 145
Pharmacologic Treatment 147
Nonsurgical Device Treatment 147
Mechanical Circulatory Support and Heart Transplantation 148
Heart Failure and Comorbidities 149
Arrhythmias and Conductance Disturbances 149
Monitoring 149
SECTION 3 DIABETES
29. ADA Standards of Care: An Update........................................................................................................... 173
Abhishek Pandey
Section Changes 173
Staging of Type 1 Diabetes 174
Pharmacologic Therapy for Diabetes 175
30. Can Medical Care Change the Natural History of T2DM: Turning Fiction into Reality?.................. 181
Rajesh Rajput
Contents xxix
31. Are all Gliptins the Same: How to Decide and Choose?........................................................................ 186
Harbir Kaur Rao, Rajinder Singh Gupta
Pathogenesis of Type 2 Diabetes Mellitus 186
Ideal Antihyperglycemic Drug 187
Dipeptidyl Pepitidase-4 Inhibitors 187
Efficacy 188
Safety 189
48. Novel Therapeutic Approaches to Preserve Beta Cell Function in Diabetes Mellitus..................... 290
Vijay Negalur
Pancreatic Beta Cell Mass Function in Diabetes 290
Therapeutic Approaches to Preserve Beta Cell Function in T1D 291
Tumor Necrosis Factor-Α (TNF-Α) Agonist 293
Therapeutic Approaches to Preserve Beta Cell Function in T2D 293
51. Nonhigh–Density Lipoprotein Cholesterol: Primary Target for Lipid Lowering.............................. 305
SN Narasingan
Non-HDL-C as an Indicator of ASCVD Risk 305
Other Advantages of Non-HDL-C 307
SECTION 4 ENDOCRINOLOGY
52. Growth Hormone Replacement Therapy: Current Recommendations.............................................. 313
Minal Mohit
Differences Between COGHD and AOGHD 314
Consequences of Untreated GHD 314
Metabolic Complications 314
Osteopenia/Osteoporosis 314
Quality of Life 315
Transitional Care of GHD 315
Diagnosis of GHD in Adults 315
Factors Affecting GH Dosing 316
Dosing Strategies 317
Safety Issues with GH Replacement Therapy 318
Unapproved Uses of GH in Adults 319
SECTION 5 NEUROLOGY
59. Headache: Headache for Physician........................................................................................................... 355
Gurubax Singh
Every Head has its Own Headache 355
First Severe Headache 355
Chronic Daily Headache 356
Headache in Elderly 357
Status Migranosus 357
Menstrual Migraine 357
Headache with Comorbidities 357
64. An Overview and Practical Clinical Hints in the Diagnosis of Temporal Lobe Epilepsy.................. 376
Venkataraman Nagrajan
Definition 376
Etiology 376
Pathology 376
Pathophysiology 376
Clinical Features 377
International Classifciation of the CPS 377
Seizure Phenomena 377
Eeg Phenomenon in TLE or CPS 378
Imaging Studies CT vs MRI 378
Differential Diagnosis 378
Management 379
Prognosis 379
66. Present Status of Thrombolysis in Acute Ischemic Stroke: Indian Scenario..................................... 386
V Shankar
Rates of Thrombolysis 386
Thrombolysis Outcomes 386
Thrombolysis Dosage 387
Sonothrombolysis 387
Tenecteplase 387
Telestroke 387
Complications and Other Observations 387
Intraarterial TPA 388
Thrombolysis and Endovascular Therapy 388
SECTION 6 GASTROENTEROLOGY/HEPATOLOGY
69. Acute Upper Gastrointestinal Bleeding .................................................................................................. 415
Rajesh Upadhyay, Deepak Sharma
Etiology 415
Risk Factors 415
Clinical Presentation 416
Management 416
Contents xxxvii
SECTION 8 INFECTIONS
87. Infections Causing Cancer.......................................................................................................................... 539
Anupam Dey
Pathogenesis 539
International Agency for Research on Cancer (WHO) Classification 539
Mechanisms by which Common Agents Cause Cancers 540
Detection and Proving Association of the Infectious Agent in Cancer 540
90. MDR-TB and XDR-TB: What are the Options? ......................................................................................... 553
Bidita Khandelwal
Epidemiology 553
Defining MDR-, Pre-XDR- and XDR-TB 553
Management Options in M/XDR-TB 553
Regimes 554
Newer Drugs Options 554
High-Dose Isoniazid 555
Duration of Treatment M/XDR-TB 555
Surgical Options 555
118. Arterial Blood Gas Analysis: Simple Steps for Understanding............................................................ 705
Ravindra Kumar Das
Collection of Blood Samples and Transportation 705
Method of Analyisis 705
Case History/Provisional Diagnosis 710
119. Superbugs in ICU and the Need for Antibiotic Stewardship................................................................ 716
Pankaj Kumar
SECTION 11 TOXICOLOGY
122. Clinical Approach to Patient of Coma...................................................................................................... 733
Geeta Kampani, Umashankar US, Munish Prabhakar
Etiology and Pathogenesis 733
Assessment of COMA 733
History 733
General Physical Examination 733
Neurologic Examination 734
Brainstem Reflexes 735
Respiratory Patterns 735
Investigations 735
Prognosis 736
SECTION 12 HEMATOLOGY/ONCOLOGY
125. Stem Cell Therapy in Various Diseases: Dawn of a New Era................................................................. 759
Sunita Aggarwal, Jahnvi Dhar, Sandeep Garg
Stem Cell 759
Methods for Stem Cells Transplantation 759
Hematopoietic Stem Cell Transplantation (HSCT) 759
Scope of Stem Cell Therapy in India 761
Contents li
126. Basics of Hematopoietic Stem Cell Transplant: Autologous and Allogeneic.................................... 763
Punit L Jain
Principles of HSCT 763
SECTION 13 RHEUMATOLOGY
136. Asymptomatic Hyperuricemia: What to Do?........................................................................................... 811
Arup Kumar Kundu, Shyamashis Das
Epidemiology 811
Definitions 811
Why Hyperuricemia Occurs? 811
Clinical Consequences of Persistent Hyperuricemia 812
Evaluation of Patients with Asymptomatic Hyperuricemia 813
When to Treat Asymptomatic Hyperuricemia? 813
SECTION 14 NEPHROLOGY
141. Recipient and Donor Selection for Renal Transplantation in India: Current Status........................ 837
Sanjay Kumar Agarwal
Advantages of Renal Transplant over Maintenance Dialysis 837
Contraindication of Renal Transplantation 837
Recipient Evaluation 837
Donor Evaluation 839
SECTION 17 MISCELLANEOUS
154. Changing Trends in Medicine: Past, Present and Future...................................................................... 909
Pritam Gupta, Ghan Shyam Pangtey, Sujata Mangla
Medicine Before the 20th Century 909
Medicine in the 20th Century 911
Medical Science and Technology in 21st Century 913
Future Medical Inventions 915
lviii Medicine Update 2018
Index........................................................................................................................................................... 941
SECTION
1
Hypertension
Pitfalls in Hypertension Management High Altitude Systemic Hypertension:
K Tewary Unraveling the Mystery
VA Kothiwale, Deebanshu Gupta
Ambulatory Blood Pressure Monitoring
in Clinical Practice Management of Isolated Systolic Hypertension:
Narayan G Deogaonkar, Viplav N Deogaonkar Current Concepts
Girish Mathur, Shrikant Chaudhary
Azilsartan: A New Baby in Old Horizon
BA Muruganathan Blood Pressure Control with Changing Time
BR Bansode
Hypertension and Menopause
Anuj Maheshwari, Shipra Kunwar Management of Hypertension in Diabetes
BB Thakur, Smita Thakur
Renovascular Hypertension: Current Status
Puneet Rijhwani Grey Areas in Diagnosis and
Management of Hypertension
Diuretics for Hypertension: Review and Update
Anita Jaiswal
R Rajasekar
CHAPTER
1
Pitfalls in Hypertension Management
K Tewary
Hypertension is one of the most commonly encountered TABLE 1: Average changes in blood pressure associated with
cardiovascular disease (CVD) in the outpatient depart common activities*
ment (OPD). It is a silent killer associated with high Change in blood pressure, mm Hg
morbidity and mortality. More than 1 billion people Activity Systolic Diastolic
suffer from hypertension worldwide. Although it looks Attending a meeting +20.2 +15.0
very simple to diagnose and treat hypertension, a lot of Working +16.0 +13.0
practical challenges are there in real life management of Commuting +14.0 +9.2
hypertension. Following types of errors are commonly Walking +12.0 +5.5
seen in routine management of hypertension. Dressing +11.5 +9.7
1. Errors in examination Doing chores +10.7 +6.7
2. Diagnostic errors Talking on telephone +9.5 +7.2
3. Treatment errors Eating +8.8 +9.6
4. Patient errors (Compliance Issues) Talking +6.7 +6.7
Doing desk work +5.9 +5.3
ERRORS IN EXAMINATION Reading +1.9 +2.2
In countries like India where crowded OPDs are very Doing business (at home) +1.6 +3.2
common, it is not unusual to see that clinicians do not Watcing television +0.3 +1.1
have sufficient time to discuss patient’s history. Many Sleeping –10.0 –7.6
important points such as quantitative assessment of *Changes are shown relative to BP while relaxing
salt intake, calorie intake and daily exercise time are
missed. These points help to provide overall assessment 10–15 minute physical and mental rest. As shown in
of patient. Modest education and encouragement to the Table 1 many mild physical activities can increase
patient can help the patient to control BP and multiple blood pressure significantly. Patient should avoid
other risk factors. smoking or drinking tea/coffee just before blood
pressure measurement. Crossing the legs is known to
DIAGNOSTIC ERRORS increase systolic blood pressure by 2–8 mm Hg. Patients
It is important to prepare and relax the patient in proper arm should not be hanging in air and resting at the
position before measurement of blood pressure. Patient heart level. No tight clothing should constrict the arm
should be in either supine or sitting position with minimum while BP measurement. The BP cuff should remain to
4 SECTION 1: Hypertension
the level of heart. American Heart Association (AHA) and Indian hypertension guidelines recommend
publishes guidelines for blood pressure measurement usage of either indapamide or chlorthalidone,
recommends that the bladder length and width (the whenever diuretics are required to control BP.
inflatable portion of the cuff ) should be 80% and 40% Combined Use of 2 RAAS (renin angiotensin aldos
respectively, of arm circumference (Table 1). terone system) blockers : in ONTARGET study,
Korotkoff V is the commonly recommended combined use of telmisartan and ramipril did not
measuring point except in pregnant patients as It is provide any extra-cardiovascular benefits while
associated with less interobserver variations and It is increasing risk of adverse events such as diarrhea,
easier to detect by most observers. Korotkoff IV is on hypotension and renal impairment. Similarly in
average 8 mm Hg above the invasively measured diastolic ALTITUDE trial, addition of aliskiren to ACEI or ARB
blood pressure. Korotkoff V is on average 2 mm Hg above in diabetic nephropathy patients did not provide
the invasively measured diastolic blood pressure. cardiovascular benefits and increased risk of non-
fatal stroke, renal complications, hyperkalemia
TREATMENT ERRORS and hypotension. Based on these studies, US-FDA
Targeting low BP goal in elderly: Previously, low BP and other regulatory agencies have advised not to
levels (< 130/80 mmHg or < 120/80 mm Hg) were combine two RAAS blockers in same patients.
recommended in elderly population. Such low levels
can lead to falls and fractures in elderly population
ERRORS BY PATIENTS
As hypertension requires a lifelong disease, patient
who have high prevalence of osteoporosis. As per
compliance is an important issue in long-term therapy.
recent JNC-8 guidelines, ESC (European Society
Various studies have shown that compliance to anti-
of Cardiology) and ASH (American Society of
hypertensive therapy is around 20–70%. Sudden
Hypertension) guidelines, BP targets in elderly (age
withdrawal of antihypertensive drugs can lead to
> 60 years or 80 years) should be < 150/80 mm Hg. In
serious complications due to shoot up in BP. Fixed dose
some selected elderly patients, BP targets of < 140/90
combination (FDCs) of different antihypertensive drugs
mm Hg can be tried, if it is tolerated well by patients
can help to improve patient compliance. Use of FDCs
without adverse events.
can also minimize adverse effects of different drugs,
Selection of wrong drugs for management of
e.g. when ARBs/ACE inhibitors are used as FDCs with
hypertension : Drugs such as atenolol and
thiazide diuretics, there is reduced risk of imbalance in
hydrochlorothiazide are still very commonly used in
serum potassium (either hypokalemia or hyperkalemia).
India and other developing countries despite lack of
Similarly, use of CCBs (calcium-channel blockers) with
evidence of cardiovascular benefits in randomized ARBs can reduce the risk of CCB-induced pedal edema.
clinical trials. In a meta-analysis published in Lancet Proper patient education regarding compliance to
in 2004 (which included data from 5 clinical trials of therapy is essential.
atenolol comparing it with other antihypertensives;
total 17671 patients were followed up for mean 4–6 BIBLIOGRAPHY
years), atenolol significantly increased risk of stroke, 1. 2013 ESH/ESC Guidelines for the management of arterial
all-cause mortality and cardiovascular mortality. 2013 hypertension. The Task Force for the management of arterial
Indian guidelines for hypertension recommended hypertension of the European Society of Hypertension (ESH)
and of the European Society of Cardiology (ESC). European
to use newer (3rd generation) beta-blockers in
Heart Journal. 2013;34:2159-219.
hypertension in young patients. In ACCOMPLISH 2. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH
trial, HCTZ was shown to be inferior to amlodipine Fixed-dose combinations improve medication compliance:
for cardiovascular risk reduction. So, NICE guidelines a meta-analysis. Am J Med. 2007;120(8):713-9.
CHAPTER 1: Pitfalls in Hypertension Management 5
3. Carlberg B, Samuelsson O, Lindholm LH. Atenolol in 6. Littlejohn TW, Majul CR, Olvera R, Seeber M, Kobe M,
hypertension: is it a wise choice? Lancet. 2004;364(9446): Guthrie R, Oigman W; Study Investigators. Results of
1684-9. treatment with telmisartan-amlodipine in hypertensive
4. Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, patients. J Clin Hypertens (Greenwich). 2009;11(4):207-13.
Hester A, Gupte J, Gatlin M, Velazquez EJ. Benazepril plus 7. Weber MA, Schiffrin, EL, Whilte WB, et al. Clinical Practice
amlodipine or hydrochlorothiazide for hypertension in high- Guidelines for the Management of Hypertension in the
risk patients. ACCOMPLISH Trial Investigators. N Engl J Med. Community. A Statement by the American Society of
2008;359(23):2417-28. Hypertension and the International Society of Hypertension.
5. James PA, Oparil S, Carter BL, et al. 2014 Evidence-based The Journal of Clinical Hypertension. 2014;16(1):14-26.
guideline for the management of high blood pressure 8. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both
in adults: report from the panel members appointed in patients at high risk for vascular events. N Engl J Med.
to the Eighth Joint National Committee (JNC 8). JAMA. 2008;358(15):1547-59.
2014;311:507-20.
CHAPTER
2
Ambulatory Blood Pressure
Monitoring in Clinical Practice
Narayan G Deogaonkar, Viplav N Deogaonkar
INTRODUCTION
Hypertension (HTN) is a significant global health
problem, responsible for 7.5 million deaths each year
worldwide. 1 It is a common cardiovascular disease
(CVD) risk factor, usually diagnosed and treated based
on blood pressure readings obtained in the clinic setting.
Traditionally, BP in the office or clinic has been assessed
with the auscultatory technique, which was introduced
into clinical medicine at the beginning of the twentieth
Fig. 1: Factors involved in 24-hour blood pressure (BP) variability
century, and which has survived to this day in clinical (Mancia G. Journal of Cardiovascular
practice. Although the technique is inherently accurate, Pharmacology. 1990;16(6):S1-S6)
it is dependent on observer attention to detail, which
is often lacking, and it provides only a momentary progressively gaining recognition as the gold standard for
measurement of BP, usually under circumstances diagnosing hypertension.
that can influence the level of BP being measured. To
overcome these serious methodological problems, Blood Pressure Variability (Fig. 1)
techniques for obtaining automated profiles of BP over Blood pressure (BP) measurements are highly variable.
24 hours and measures of BP in the home setting have Measured blood pressure varies due to a various factors
been developed. such as measurement technique, accuracy of equipment,
Five decades ago, Kain et al. 2 demonstrated the and multiple patient factors such as anxiety. Even though
benefits of ambulatory blood pressure monitoring these factors are controlled, blood pressure is subject to
(ABPM), and the attractive possibility of measuring blood biological variation (circadian variation) from beat-to-
pressure during patients’ daily activities. ABP monitoring beat, minute-to-minute, and day-to-day.
was developed initially to study the circadian changes The circadian blood pressure profile is similar in both
in BP and to determine the influence of BP-lowering normotensive and essential hypertensives (mild-severe).
drugs on the 24-h profile. ABPM gives information on The profile is deranged only in malignant hypertension,
circadian variations in blood pressure, and documents complicated hypertension, and some secondary
blood pressure responses to different behaviors. ABPM is hypertension which are characterized by the reduction
CHAPTER 2: Ambulatory Blood Pressure Monitoring in Clinical Practice 7
or loss of nocturnal hypotension. 3 In hypertensive daytime average (reverse dippers). Other important
patients, 24-h blood pressure (BP) variability (V) shows parameters of blood pressure assessment facilitated by
a positive relationship with organ damage, organ ambulatory blood pressure monitoring are the morning
damage progression and cardiovascular morbidity. 4 surge, when blood pressure increases rapidly from
Understanding the extent of BP variability is very nighttime levels to daytime levels, and blood pressure
important since it impacts diagnosis of hypertension, variability.7
clinical management of elevated BP and number of drugs The advantages of ABPM stated in comprehensive
prescribed to achieve ‘‘BP control’’.5 reviews are briefly summarized as follows:
The technique of ambulatory blood pressure Gives a larger number of readings than office blood
on 24-hour ABPM is generally reported using two patient’s usual daily environment
metrics, day-night standard deviation which captures Allows identification of white-coat and masked
variability which captures variability in blood pressure Assesses blood pressure variability over the 24-h
home BP monitoring (HBPM) done before prescribing events including death. Nondipping is common in
antihypertensive drug therapy (ESH 2014 guidelines). diabetic patients and may reach a prevalence of ~30%.
For diagnosis of nondipping, it is important to relate
Masked Hypertension nighttime readings with the patient’s’ diary to confirm
Masked hypertension is the phenomenon whereby their reliability. A decrease in heart rate, which is typical
certain individuals who are not on antihypertensive in sleep time, may indicate that the patient was asleep.
medication show non-elevated blood pressure in a Extreme fall of 0–20% in BP during sleep time is known
clinical setting but show high blood pressure when out as extreme dipping. This pattern is not necessarily
of the office, typically assessed by ambulatory blood benign, since it may be associated with mild cognitive
pressure monitoring: approximately 15–30% of adults impairment in the elderly.
with non-elevated office blood pressure have masked
hypertension. Since masked hypertension is associated Prediction of CV Events
with increased risks of cardiovascular morbidity and Blood pressure (BP) is an established prognostic factor
mortality, clinic readings may therefore underestimate for cardiovascular disease. But, are all BP values created
an individual’s cardiovascular risk. Antihypertensive equal? Multiple cross-sectional and cohort studies
treatment may be warranted in patients with masked have demonstrated that home (BP measured regularly
hypertension, but there are currently no randomized trials at rest by the patient at home) and ambulatory (BP
that have evaluated this strategy, and the best method to measured automatically regardless of activity or time
identify people with masked hypertension has not been of day) BP readings are superior to traditional office BP
established. There is a substantial diagnostic overlap values in predicting end-organ damage and incident
between prehypertension and masked hypertension. cardiovascular disease. Home BP fails to provide
overnight readings, which correlate highly with disease
Night-time Blood Pressure: ‘‘Dippers’’ Versus events, and it is also subject to selection bias. Ambulatory
‘‘Nondippers’’ (Table 1) blood pressure (ABP) has long been recognized as
The possibility of noninvasive measurement of blood a superior predictor of cardiovascular disease and
pressure at night and during sleep by ambulatory mortality, independent of clinic measurements.8-10
monitoring devices has stimulated interest in the No matter the level of office BP, it is the out-of-office
pathophysiological significance of night-time blood BP that best predicts events by 17–39% (home BP) and
pressure. Physiologically, BP falls by >10% during 17–31% (ABPM) per 10 mm Hg increase in systolic BP.11,12
nighttime (asleep). When BP falls by <10% during Diagnostic and predictive accuracy of blood pressure
nighttime, it is defined as nondipping. screening methods with consideration of rescreening
Nocturnal nondipping is associated with increased intervals: a systematic review for the U.S. Preventive
risk of stroke, end-organ damage, and cardiovascular Services Task Force.
TABLE 1: Blood pressure patterns that can be determined by means of ABPM and other methods (N Engl J Med. 2006;354:2368-74)
Variable Ambulatory blood-pressure Clinical blood-pressure Home blood-pressure
monitoring monitoring monitoring
zz True, or mean, blood pressure Yes Questionable Yes
zz Diurnal blood pressure rhythm Yes No No
—— Dipping status Yes No No
—— Morning surge Yes No Questionable
zz Blood pressure variability Yes No Questionable
zz Duration of drug effects Yes No Yes
CHAPTER 2: Ambulatory Blood Pressure Monitoring in Clinical Practice 9
Studies have reported that ABP measurements However, unlike ABPM it does not allow the assessment of
give better prediction of clinical outcomes compared BP during sleep or at work or the quantification of short-
with conventional clinic or office blood pressure term BP variability. In addition, the recommendation to
measurements.13,14 measure BP at home may induce anxiety that leads to
The first involved 1542 subjects of Ohasama, Japan, excessive measurements and treatment changes made
who were followed up for a mean of 6.2 years. ABP on the basis of erroneous measurements. HBPM should
measurements better predicted mortality than did be used in conjunction with ABPM as a complementary
casual blood pressure measurements. In another study method of BP assessment. When there is a concordance
of 808 older participants (aged over 60 years) with between the methods, HBPM may be appropriate for
isolated systolic hypertension followed up for a mean long-term follow-up of treated HTN patients.
of 4.4 years, ambulatory systolic blood pressure was a
significantly better predictor of cardiovascular events ABPM Guiding Management of HTN
than conventional blood pressure measurement. ‘‘Smooth’’ or uniform blood pressure control is an
There are several potential explanations for the better obvious goal of antihypertensive therapy, but it is
prognostication afforded by out-of-office BP levels. First, difficult to measure by the traditional clinic blood
both methods include a larger number of readings, thus pressure measurements. Ambulatory blood pressure
increasing their reliability and reproducibility compared monitoring, therefore, is used increasingly to evaluate
with office readings. Second, both home BP and ABPM new antihypertensive drugs and to assess the adequacy
are able to diagnose white coat hypertension (high office of treatment. This application is based on the assumption
BP, normal ambulatory BP) and masked hypertension that treatment must be continuously adequate and
(normal office BP < high ambulatory BP). By identifying that more frequent blood pressure measurements
these two conditions, home BP and ABPM allow more during treatment, particularly at different times and
accurate determination of overall BP burden and its during various types of activity or mental states, may
associated risk. Third, ABPM, but not home BP, is able to lead to a more accurate assessment than infrequent
quantify BP during sleep. Sleep BP is marginally better measurements in the clinic.
than daytime BP in the prediction of hypertension- Progressive decrease in sleep BP in nondipping
related outcomes. Moreover, reverse dippers have patients reduces cardiovascular morbidity and mortality
increased cardiovascular risk compared with all other and therefore should be a therapeutic target. Achieving
types of circadian BP patterns. There is also increased this target requires proper patient evaluation by 24-h
risk among non-dippers (compared to dippers) and ABPM. Bedtime treatment will be clearly indicated in
perhaps a protective effect from extreme dipping. patients with a nondipping pattern, whereas in extreme
dippers evening dosing should be avoided. ABPM may
Comparison of Ambulatory BP Measurements also identify patients with morning BP surge. Several
with Home Measurements studies showed an association between morning BP
Home BP monitoring (HBPM) offers an attractive surge and cardiovascular morbidity and mortality.18-20
alternative to 24-h ABPM. Several studies have reported Drugs that are given once daily in the morning but
that target organ damage and cardiovascular outcomes do not provide adequate BP control during the night
are more strongly correlated with HBPM than with clinic and early morning may be less protective than drugs
BP measurements.15-17 HBPM provides measurements providing 24-h BP control. Pareek et al (J Am Coll Cardiol
over a much longer period, is cheaper, more widely 2016;67:379–89) showed that Treatment with low-dose
available, more convenient for patients (particularly for chlorthalidone, 6.25 mg daily, significantly reduced
repeated measurements), and has been shown to improve mean 24-h ABP as well as daytime and nighttime BP.
patients’ compliance with treatment and HTN control. Due to its short duration of action, no significant 24-h
10 SECTION 1: Hypertension
ABP reduction was seen with HCTZ, 12.5 mg daily, which TABLE 2: Thresholds of hypertension diagnosis based on ABPM
merely converted sustained hypertension into masked 24-h average ≥130/80 mm Hg
hypertension. Awake (daytime) average ≥135/85 mm Hg
The threshold values in NICE 2003 guidelines, the Asleep (night-time) average ≥120/70 mm Hg
JNC 7 2007 guideline, the ESH/ESC 2013 guidelines and (ESH guidelines)
the results of outcome studies have contributed to the
definition of consensus values summarized in following
TABLE 3: Additional information derived from ABPM
Table 2.
Compelling indications
ABPM may help to identify secondary HTN. Lack of zz White-coat hypertension in untreated individuals
nocturnal fall in BP may suggest the existence of sleep zz White-coat effect in treated or untreated individuals
apnea. Performing ABPM is indicated in all patients with zz False resistant hypertension due to white-coat effet in treated
individuals
resistant HTN to exclude white coat effect as a cause of
Identifying masked hypertension phenomena
apparent resistance. Data derived from 24-h ABPM can
zz Masked hypertension in untreated individuals
be useful to diagnose the cause of syncope. It is useful
zz Masked uncontrolled hypertension in treated individuals
to document fluctuating BP in patients with orthostatic
Identifying anbnormal 24-h BP patients
hypotension, autonomic failure, or asymptomatic
postprandial hypotension (Table 3).
zz Daytime dipping/post-prandial hypotension
effects of ischemic and hemorrhagic stroke and in zz Dipping status/isolated nocturnal hypertension
the day and night, and set without the readings being
displayed to the patient. Although ABPM occurs while
individuals go about their normal daily activities, they
are asked to keep their arm still while the cuff is inflating,
and to avoid excessive motion, which is associated
with unobtainable or artifactual readings. At the end
of the recording period, the readings are downloaded
into a computer for processing. Individuals can fill out
a diary during the monitoring period to document any
symptoms, awakening and sleeping times, naps, periods
of stress, timing of meals, and medication ingestion.22
Average BP values (over 24 h, daytime, and night-
A B time) are undoubtedly the most important parameters
obtained from ABPM recordings, based on outcome
data. However, a large number of additional indices with
promising clinical evidence may be derived from ABPM
recordings.
Fig. 3: Clinically blood pressure followed by 24-hour ambulatory blood pressure monitor device
ABPM is particularly useful in pregnancy for detecting pressure measurement has been reported, causing a
white-coat and nocturnal hypertension. ABPM is higher prevalence of white-coat phenomenon.31
particularly helpful in hypertensive patients who for
various considerations are regarded as being at high risk Patients with Atrial Fibrillation
of cardiovascular disease. BP measurement in patients with atrial fibrillation is less
An example of an ABP report and its interpretation is precise as this type of arrhythmia is accompanied by
shown in Figure 5. increased beat-to-beat BP variability due to variations in
ventricular filling time, stroke volume, and contractility.
Position of ABPM in Hypertension Unfortunately, published evidence regarding the role of
Guidelines (Table 4) ABPM in patients with arrhythmias and, specifically in
ABPM has an increasingly defined and appropriate patients with atrial fibrillation, is scarce. Inspite of these
position within some, but not all, guidelines. limitations, and although larger trials in patients on atrial
NICE, CHEP and NHFA guidelines recommend that fibrillation are needed, there is no reason at present to
ABPM is useful to exclude white-coat hypertension. exclude such patients from ABPM procedures.32
However, the guidelines of the American Joint National
Committee (JNC) 8 did not mention either ABPM or Children and Adolescents
HBPM based on the fact that these techniques have not In children and adolescents, ABPM is indicated for
been evaluated by randomized controlled trials.24 suspected white-coat hypertension, evaluation and
follow-up of primary and secondary hypertension or
Challenges in using ABPM in conditions with associated risk of arterial hypertension,
Special Population such as diabetes mellitus, chronic pyelonephritis, chronic
Obese Patients renal failure and autosomal dominant polycystic kidney
Obesity is a well-established major risk factor for disease because it shows better correlation with the
hypertension with higher prevalence in specific development of target organ damages than office blood
population groups. In obese persons some technical pressure measurement (Degree of Recommendation IIa
difficulties, such as miscuffing may be present but – Evidence Level C). Only a few ABPM devices have been
these should not prevent them from undergoing this validated for use in children. Applicability, however,
investigation. is promising, and there have been reports of good
In such cases, conically shaped cuffs might be used, precision and reproducibility. The success percentage
when available. In patients with very obese arms in whom in obtaining measurements increases with age. The
ABPM cannot be performed, ABPM carried out with the primary limitation to its use in children and adolescents
cuff placed on the forearm may be the only means of is the lack of normative pediatric values.32
obtaining a 24-h recording, with an instruction that the
wrist must be kept at heart level during measurement, Elderly Patients
although this possibility requires further investigation.30 ABPM can provide valuable clinical support for
In obese patients with arm circumference above 20.5 suspected orthostatic, postprandial, drug-related
inches or short arms, the examination is contraindicated, and situational arterial hypotension, as well as for
because ABPM devices do not have appropriate cuffs evaluation of patients with dysautonomia and syncope
(Degree of Recommendation III – Evidence Level D). (Degree of Recommendation IIa – Evidence Level D). In
It should also be emphasized that in obese patients, elderly individuals with isolated systolic hypertension,
particularly those with visceral fat distribution, an ABPM is useful to rule out white-coat effect (Degree
increased frequency of alert reactions to casual blood of Recommendation IIa – Evidence Level A). Some
14 SECTION 1: Hypertension
SBP: Grade 2
Summary
hypertension
Min Mean Max STD BP load (>20%) ≥148 mm Hg
Systolic 125 151 183 13.4 94%
Diastolic 71 90 115 11.9 57%
Heart rate 54 79 94 9.5 DBP: Grade 1
Day summary 6:00 to 22:00 hypertension
≥84 mm Hg
Min Mean Max STD BP load (>20%)
Systolic 125 152 176 12.2 91%
Diastolic 73 91 111 10.9 65%
Heart rate 54 71 90 8.7
Night summary 22:00 to 6:00
Min Mean Max STD BP load
Night SBP Systolic 129 146 183 14.7 100%
dipping Diastolic 71 96 115 135 70%
abnormal
Heart rate 57 69 94 11.1 Night DBP
% Night SBP dip 3.9% % Night DBP dip 5.5% dipping
(>10%) (>10%) abnormal
Awake summary 7:00 to 1:30
Min Mean Max STD BP load
Systolic 132 155 183 11 100%
Diastolic 75 92 115 11 55%
Heart rate 55 73 94 9
Asleep summary 1:30 to 7:00
Min Mean Max STD BP load
Systolic 125 134 143 5 100%
Asleep SBP
dipping Diastolic 71 76 85 5 55%
normal Heart rate 54 60 67 5 Asleep DBP
% Night SBP dip 14% % Night DBP dip 28% dipping
(>10%) (>10%) normal
Interpretation: Patient ABP day, night, awak, asleep BP, BP load values are
all above hypertension grade 1 threshold (shown in red). While night summary
suggests nondipping (<10%) this is due to very late sleep onset. The nocturnal
dipping based on awake and asleep values are satisfactory (>10%)
Conslusion: Confirmed grade 1 hypertension
European Society of Hypertension (ESH)28 2013 zz Marked discordance between office BP and home BP
zz Assessment of dipping status
zz Suspicion of nocturnal hypertension or absence of dipping,
National Institute for Health and Care Excellence (NICE)29 2011 If clinic BP is ≥140/90 mm Hg, offer ABPM to confirm the diagnosis
of hypertension
limitations must be emphasized in this age group. Age- antihypertensive treatments and should be included in
related arterial stiffening underestimates blood pressure studies designed to compare the effects of various drugs.
measurement obtained by the oscillometric method Night-time blood pressure can be assessed only with
and thus, ABPM is subject to errors in the presence of ambulatory blood-pressure monitoring, and evidence
pseudo-hypertension.32 suggests that a failure of blood pressure to decrease at
night may be associated with an adverse prognosis.
Pregnant Women
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Monitoring in Clinical Practice: A Review, The American
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CHAPTER
3
Azilsartan: A New Baby in Old Horizon
BA Muruganathan
TABLE 1: Pharmacokinetic profile of azilsartan in comparison to other available angiotensin II receptor blockers
Primary Cytochrome CYP-2C9 and Conjugation De- Unknown CYP 2C9 O-demethyla- Glucoronide
metabolic P450 (CYP) 3A4 eserifictation tion conjugation
pathway 2C9
Elimination 55 feces, 35 renal, 60 >97 biliary 8–12 renal and 10 renal, 20 renal, 33 renal and 67 7 renal and
(%) 42 urine, hepatic hepatic >80 80 hepatic hepatic 90 hepatic
15 hepatic
unchanged
Dose in No initial Initial dosage Use with No change in No No change No change in No change in
chronic liver dose caution dose change in in dose* dose* dose
disease adjustment dose*
ANGIOTENSIN RECEPTOR drugs for clinical effects beyond blood pressure control,
BLOCKERS: BEYOND BLOOD PRESSURE potentially counteracting cardiac hypertrophy, cardiac
fibrosis and insulin resistance, along with enhanced
LOWERING EFFECTS
renoprotection and atherosclerotic plaque stabilization.
ARBs could decelerate the progression of diabetic
nephropathy, independently of their BP lowering effect.
ARBs may be more effective clinical utility over other class TOLERABILITY
of drugs in reducing proteinuria in patients with diabetic Azilsartan at dosages of 20, 40 or 80 mg once daily,
nephropathy despite similarly induced reductions in are, in general favorably tolerated by adults, for the
BP. AT1R blockade may help to modulate diabetes- management of hypertension, over a period of up to 24
induced vascular remodeling, probably independently weeks, as indicated by the results of three RCTs. Studies
of BP lowering. Very high affinity and slow dissociation suggested that the tolerability profile of azilsartan was
from the angiotensin 1 receptor (AT1R) combined with like that of placebo in the two 6-week trials, the most
its inverse agonistic properties make them promising frequently encountered adverse events were headache
CHAPTER 3: Azilsartan: A New Baby in Old Horizon 19
and dizziness. Increase in serum creatinine of ≥50% angiotensin (1–7) which acts on the Mas receptors
above baseline was observed in ≤1.1% of patients, which (present in cardiac muscles) resulting into vasodilatation,
was reversible upon discontinuation. No elevations in antihypertrophy thus cardioprotection with BP
serum potassium levels (>6.0 mmol/L) was detected in lowering. Azilsartan even reduces levels of 20-HETE (a
any of the study participants.1,2 prostaglandin metabolite) thus leading to vasodilatation,
BP lowering and renoprotection. Azilsartan reduces
DIRECT AT1R EFFECTS OF AZILSARTAN expression of NHE3 sodium transporter in proximal
Azilsartan possesses a very high selectivity 39,000 times tubules and improves salt sensitivity.
greater for the AT1 receptor than for the AT2 receptor. Azilsartan, could likely be the very potent AT1
It also depicted a potent ability to inhibit the binding receptor blocker known till date, due to strong binding
of angiotensin II to human AT1 receptors (IC50 values properties, which allows it tooffer 24-hour BP lowering
>30–1000-fold lower for azilsartan compared to other effect; this seems to be significantly more than maximum
ARBs including telmisartan, olmesartan, valsartan and approved doses of other ARBs such as olmesartan,
irbesartan. Time course studies of the ability of different valsartan, and candesartan; however, it remains to be
ARBs to persistently block angiotensin II binding to AT1 determined whether azilsartan will offer further clinical
receptors after drug washout have also indicated that benefits beyond those afforded by its robust ability to
azilsartan dissociates from AT1 receptors more slowly inhibit the renin angiotensin system and lower BP.
than other ARBs including olmesartan, telmisartan, and
valsartan. As azilsartan bound tightly to and dissociated AZILSARTAN: PLEIOTROPIC EFFECTS
slowly from AT1 receptors compared with conventional BEYOND BP LOWERING
ARBs, azilsartan is expected to be a desirable ARB,as it Several recent preclinical studies indicated that azilsartan
not only shows superior BP control compared with other may have beneficial effects on cellular mechanisms
ARBs but also improves insulin resistance in preclinical related of morbid cardiometabolic processes, through
studies. Study even demonstrated that azilsartan induces actions mediated beyond just blockade of AT1 receptors
stronger inverse agonism than candesartan, and this and/or reduction in BP.4
ability of azilsartan may be associated with its unique Azilsartan, when compared with conventional ARB,
moiety, a 5- oxo-1,2,4-oxadiazole, in place of a tetrazole including candesartan, valsartan or olmesartan, in a
ring.3,4 study that compared the efficacy and tolerability of
azilsartan to candesartan, 622 Japanese patients with
AZILSARTAN: POTENT AT grade I-II essential hypertension were included. Blood
1 RECEPTOR BINDING reduction was superior with azilsartan medoxomil,
Major International and Indian guidelines on compared with candesartan. Similarly, azilsartan was
hypertension recommended ARB as a 1st line treatment found to be more effective than candesartan for its effect
for hypertension. Azilsartan a long-acting and more on ambulatory blood pressure at 14 weeks, particular
potent ARB provides a 24-hour potent and sustained improvements in diastolic and systolic BP over a 24-h
antihypertensive effect, which plays a role in its greater period. Azilsartan indicated to possess maximal pressor
blood pressure lowering efficacy. Novel Sartan azilsartan, effect of angiotensin II by approximately 90% when the
angiotensin receptor blocker approved in US and Europe, drug reaches peak plasma concentration. Twenty-four
is now available in India. Multimodal action azilsartan hours after administration, azilsartan lowers the pressor
acts on the RAS system at AT1 receptor, thus selectively effect by approximately 60 percentage.
and competitively inhibiting angiotensin II and resulting In another study, azilsartan 40–80 mg were compared
into vasodilatation and sodium/fluid excretion and with valsartan 320 mg during 24 weeks of treatment. At
lowering BP. Azilsartan increases levels of the metabolite the end of the study, 24-h mean SBP was reduced by 14.9,
20 SECTION 1: Hypertension
15.3 and 11.3 mm Hg, respectively; p < 0.001 for both rationale behind use of renin-angiotensin system (RAS)
doses of azilsartan vs valsartan. blockers as antihypertensive therapy for protection
Azilsartan has also been compared in a clinical trial against hypertensive-based organ damage. However,
with olmesartan, one of the most potent available ARB RAS blockers have been perceived as unfavorable
until the launch of azilsartan. The study that included for the treatment of salt-sensitive hypertension. The
1,275 patients diagnosed of hypertension, with baseline antihypertensive effects of RAS blockers seem to be
24-h mean ambulatory systolic BP ≥ 130 and ≤ 170 mm attenuated under high salt loading in hypertensive
Hg (mean 146 mm Hg). Six weeks after treatment, as patients. Interestingly, RAS blockers have even been
anticipated, there wasa dose-dependent reduction in reported to enhance salt sensitivity. The analyses of renal
24-h mean SBP across all azilsartan groups. Azilsartan 80 tubular sodium transporters showed that azilsartan
mg provided superior reductions in 24-h mean SBP than reduced the expression of protein NHE3 (but not at the
olmesartan 40 mg (treatment difference -2.1 mm Hg; 95% transcriptional level) and did not alter protein expression
CI -4.0 to -0.1 mm Hg; p = 0.038).5 of the downstream transporters NKCC2, NCC, or ENaC.
Results of a pooled analysis of 3821 patients, derived Such, decreased NHE3 expression resulted in natriuresis.
from three different RCTs comparing the effects of These findings indicate that azilsartan (which strongly
azilsartan (40 and 80 mg), olmesartan (40 mg), valsartan blocks the effect of angiotensin II) reduces NHE3
(320 mg), and placebo on changes in ABPM and in-clinic expression and thereby, improves salt sensitivity.7
blood pressure (BP) among patients with hypertension
and prediabetes mellitus or T2DM suggested that AZILSARTAN: POTENTIAL EFFECT IN
azilsartan 80 mg/day lowers SBP by a significantly greater
CARDIORENAL PROTECTION
magnitude than olmesartan or valsartan at maximally
Data from seven randomized, double-blind, controlled
approved doses in patients with prediabetes mellitus and
trials indicate that azilsartan lowers BP in 3672 patients
T2DM.6
with mild, moderate or severe hypertension. Several
Preclinical studies are suggestive that treatment with
azilsartan completely antagonized the elevation of BP preclinical studies and in vitro experiments show that
induced due to ANG II, reduced the progression of cardiac azilsartan has shown beneficial effects on cellular
hypertrophy, attenuated kidney damage, and increased mechanisms of cardiovascular disease and possible
ANG (1–7) and EET/DHET ratio while diminishing 20- action on insulin sensitivity. In one of the preclinical
HETE levels. Increased ANG (1–7) and EETs levels point studies conducted on obese insulin-resistant mice fed a
towards novel therapeutic mechanisms contributing high fat diet, with left ventricular pressure overload after
towards antihypertensive and antihypertrophic actions aortic banding, the addition of azilsartan was associated
of azilsartan treatment and their relative role compared with a reduction in left ventricular wall thickness and
to AT1R blockade may depend on the underlying cardiac plasminogen activator inhibitor- 1 (PAI-1),
pathophysiology in each case of hypertension.7 as well as with an increase in cardiac output. After
Salt sensitivity was found in 51% of patients with myocardial infarction (MI), overexpression of PAI-1 in
hypertension and 26% of normotensive individuals. the heart may lead to negative left ventricular modelling
Such patients may have a greater tendency to manifest and heart failure. Inhibition of the AT1 receptor may
cardiovascular and renal events compared to non-salt- potentially blunt expression of the PAI-1 protein in the
sensitive patients, and present with a 3-fold higher wall of the aorta, subsequently reducing the threat of
incidence of cardiovascular events, again associated with atherosclerosis, a significant cause of morbidity and
increased mortality independent of blood pressure. The mortality globally.
CHAPTER 3: Azilsartan: A New Baby in Old Horizon 21
Guidelines Recommendations on TABLE 2: ACE- I and ARBs should not be used or used with caution
in certain circumstances
Management of Hypertension Secondary
ACE inhibitors (ACE- I) Angiotensin receptor
to Renal Impairment blockers (ARBs)
European Society of Cardiology (ESC) Hypertension To use with zz Women planning to zz Women planning to
Management Guidelines 2016 caution conceive conceive
zz Bilateral renal artery zz Bilateral Renal Artery
An angiotensin receptor blocker (ARB), where
stenosis Stenosis
tolerated, should be included as first-line therapy in zz Drugs which cause zz Drugs which cause
continued if:
CKD: Antihypertension treatment regimen should
—— GFR decline over 4 months is <30% from baseline
include an either ACE inhibitors (ACE-I) or
value (B);
angiontensin receptor blockers (ARBs)
—— Serum potassium is ≤5.5 mEq/L
In individual >18 years with CKD, initial (or add-on)
ACE- I and ARBs should not be used or used with
antihypertensive treatment should include an ACEI
caution in certain circumstances, as Table 2.
or ARB to improve kidney disease outcomes. This
may apply to all CKD patients with hypertension In accordance to US FDA approved prescribing
secondary to diabetic kidney disease (DKD) information, dose adjustment is not required in patients
with mild-to-severe renal impairment or end-stage
American Society of Hypertension/International renal disease (ESRD). A possible explanation for this
Society of Hypertension (ASH/ISH) is that azilsartan is metabolized into two primary
Hypertension and chronic kidney disease (CKD): First metabolites M-I and M-II, both M-I and M-II of which
Drug-ARB or ACE inhibitor. are pharmacological inactive. Following an oral dose of
14
C-labeled azilsartan, approximately 55% of radioactivity
Indian Guidelines of Hypertension could be traced in feces and approximately 42% in urine,
Reduction of proteinuria can be achieved by effective with approximately 15% of the dose excreted in urine in
blood pressure control specially with use of ACE azilsartan form. As per data available on Cmax and AUC
inhibitors and angiotensin II receptor blockers (ARBs). of azilsartan are not significantly affected by mild to
moderate renal impairment.
Recommendations from the Kidney Disease The exposure to candesartan is slightly increased
Outcomes Quality Initiative (KDOQI) Guidelines for with mild to moderate renal impairment and almost
Treatment of Hypertension Associated with Chronic doubles in patients with severe renal impairment
Kidney Disease and those individuals undergoing hemodialysis. C max
ACE inhibitors and ARBs can be used safely in most and AUC of Eprosartan increase by 30–50% and by
patients with CKD. 70–90% with moderate to severe renal impairment.
22 SECTION 1: Hypertension
Pharmacokinetics of irbesartan are unaffected in patients in these patients; where calcium channel blockers
with renal impairment or in patients on hemodialysis. (CCBs) are contraindicated due to their severe adverse
Irbesartan is not excreted by hemodialysis and no effects. Thus, switching to azilsartan might improve
dosage adjustment is required insuch patients. The the long-term prognosis of hemodialysis patients.
plasma concentrations and AUCs of losartan and Strong antihypertensive effects of azilsartan stems
EXP3174 are increased by 50–90% in patients with from a combination of ARB class-effect and stronger
mild or moderate renal insufficiency, and the renal suppression of the sympathetic nervous system. It was
clearance is reduced by 55–85% for both losartan and noted that, switching from olmesartan to azilsartan did
EXP3174 in such patients. The serum concentrations not modify serum sodium or serum potassium levels.
of olmesartan were prominently increased in patients There were no cardiovascular events during 9-month
with renal insufficiency, as compared to subjects with follow-up after switching to azilsartan.
normal renal function. Consistent with the virtual lack
of renal elimination of telmisartan, dose adjustment is SUMMARY OF THE UNIQUE FEATURES
not necessary in patients with reduced renal function. OF AZILSARTAN
Telmisartan by hemofiltration is not eliminated from Azilsartan produces greater affinity for AT1 receptor
blood. The exposure to valsartan (measured by AUC) blockade compared to several other angiotensin
apparently does not correlate to renal function in II receptor antagonists, including valsartan and
patients with different degrees of renal impairment. olmesartan
Consequently, no dose adjustment may be necessary in Azilsartan is known to demonstrate pleiotropic
patients with mild-to-moderate renal dysfunction.
cardioprotective effects, independent of its blood
The mortality rate for hemodialysis patients is 20%
pressure lowering effect.
during the first year of treatment and advances up to70% Pharmacokinetic profile permits for use as once-
post five years of treatment. Cardiovascular disease is
daily oral administration regime, making it a patient
high pervasive and a leading cause of morbidity and
compliant therapy.
mortality in hemodialysis patients, since hemodialysis
Efficacious in reducing 24-h mean systolic blood
patients possess several risk factors. It has been reported
pressure (SBP) compared to maximum approved
that treatment with antihypertensive drugs should be
dosages of olmesartan or valsartan
considered for patients on dialysis to reduce the very
Generally, well tolerated, most common adverse
high cardiovascular morbidity and mortality rate in
effects being headache and dizziness.
this population group. Measurement of blood pressure
is critical in hemodialysis patients, because disparate
REFERENCES
reading is obtained based on the timing, location,
1. Michel MC, et al. A systematic comparison of the properties
frequency, and technique of BP measurement. Azilsartan of clinically used Angiotensin II Type 1 receptor antagonists.
is a new ARB, and may help to reduce cardiac mortality Pharmacol Rev. 2013;65:809-48.
rates in hemodialysis patients. 2. Perry CM. Azilsartan Medoxomil. A Review of its Use in
Research indicates that switching from olmesartan to Hypertension. Clin Drug Investig. 2012;32(9):621-39.
azilsartan significantly decreased home-measured BP in 3. Miura S, et al. Unique binding behavior of the recently
approved angiotensin II receptor blocker azilsartan
hemodialysis patients with left ventricular hypertrophy
compared with that of candesartan. Hypertens Res.
(LVH). Switching did not alter serum potassium levels.
2013;36(2):134-9.
It is also reported that renin angiotensin blockade is not 4. Kurtz TW, et al. Differential pharmacology and benefit/risk
associated with hyperkalemia in patients on dialysis. of azilsartan compared to other sartans. Vascular Health
Azilsartan seemed to be useful for blood pressure control and Risk Management. 2012;8:133-43.
CHAPTER 3: Azilsartan: A New Baby in Old Horizon 23
5. Barrios V, et al. Azilsartan medoxomil in the treatment of 7. Hatanaka M, et al. Azilsartan Improves Salt Sensitivity
hypertension: the definitive angiotensin receptor blocker?. by Modulating the Proximal Tubular Na+–H+ Exchanger-3
Expert Opin. Pharmacother. 2013;14(16):2249-61. in Mice. PLoS ONE 2016;11(1):e0147786.doi:10.1371/
6. White WB, et al. Effects of azilsartan medoxomil compared journal. pone.0147786.
with olmesar tan and valsar tan on ambulator y and 8. Carroll MA, et al. Azilsartan Is Associated with Increased
clinic blood pressure in patients with type 2 diabetes Circulating Angiotensin-(1–7) Levels and Reduced
and prediabetes. Journal of Hypertension. 2016;34: Renovascular 20-HETE Levels. American Journal of
788-97. Hypertension. 2014;1-8. doi:10.1093/ajh/hpu201.
CHAPTER
4
Hypertension and Menopause
Anuj Maheshwari, Shipra Kunwar
Hypertension is the most common chronic disease activation of rennin–angiotensin (RA) pathway which
and the most important risk for cardiovascular disease. could be genetic in origin as rennin angiotensin gene
According to WHO report (2012) one in every three polymorphisms have been seen in women, or could be
adult above the age of 25 years in the world is suffering because of increase in plasma renin activity.
from hypertension. .With increasing age, there is an Postmenopausal women have a rise in endothelin
increase in blood pressure for both men as well as levels. The loss of sex hormones or a change in estrogen to
women. However, after menopause the increase in androgen ratio can be responsible for this rise. Although,
blood pressure is almost abrupt with premenopausal the activation of RA axis may also be responsible.
women having an incidence of hypertension of 1.5% as Whatever, the cause elevated endothelin levels do
compared to postmenopausal women having incidence contribute to oxidative stress (Fig. 1).
of 41%. In 1976, the Framingham investigators reported
a 2.6-fold higher incidence of cardiovascular events in
age-matched postmenopausal women compared with
premenopausal women.
Besides the increase in prevalence of hypertension
after menopause the pattern of hypertension is also
different in women with lesser fall of BP during night
hours leading to more target organ complications, also
the control of blood pressure may not be as effective
in females as compared to males even with the same
medication. This protective effect of sex hormones is not
clear completely, in fact it is multifactorial.
improves flow mediated dialation (FMD) only in those reduces bioavailability of nitric oxide, which is
women who do not have cardiovascular risk factors. responsible for salt sensitivity of systolic blood pressure
in otherwise healthy postmenopausal females who are
Arterial Stiffness not taking hormone replacement therapy. Estradiol
Though, few investigators did not find gender variation reduces salt sensitivity of BP in postmenopausal females.
in arterial wall properties with advancing age. In Low sodium diet has been found to benefit both in
females, it has been found coinciding with menopause. experimental as well as in real world too. Exercise
Postmenopausal women shows higher carotid-femoral also plays a positive role in reducing hypertension in
pulse wave velocity and larger common carotid artery association with low sodium diet.
diameters reflecting greater arterial stiffness which is self
explanatory of high rise of systolic pressure even after Genetic Factors
adjusting it for age, body mass index and smoking. Hypertension is a polygenetic disorder contributing
30–50% blood pressure variability among individuals.
Renin-angiotensin System Human hypertension has been studied for gender
Renin-angiotensin system (RAS) regulates blood specific associations with polymorphisms of component
pressure, fluid and electrolytes. Estradiol is conspicuous of RAS, aldosterone synthase and nitric oxide synthase.
of reducing activity of angiotensin 1-converting enzyme Menopause only provides a trigger in females having
(ACE) by AT1 receptor expression in vessels and kidney. higher probability of being hypertensive for genetic
Thus it gives cardiovascular protection by controlling reasons. Polymorphic genes regulating sodium
component of RAS. Role of RAS in hypertension of
absorption, like adducin-1 have been associated with
postmenopausal women is not very clear. Two years
blood pressure and hypertension. Gene environment
of estrogen therapy could not correlate blood pressure
interaction is shown in BMI and salt intake also. Gender
with plasma rennin activity in a placebo controlled
specific contribution of estrogen to hypertension is
study. Plasma rennin activity increased on oral but
genetic factor.
not on transdermal administration of estradiol. In fact,
Hereditary hypogonadotrophic ovarian failure
some studies has shown decreased activity also. Ovaries
is caused by inactivation of mutations occurring in
start producing prorenin in response to gonadotropin,
follicular stimulating hormone receptor (FSHR) gene
thus it regulates prorenin and rennin activity. Effect
which is also linked to essential hypertension in women.
of estrogen on prorenin and rennin seems complex
Gene-gender and gene-environment interactions have
and antihypertensive drugs which inhibit the RAS,
significant impact on hypertension in women where
complicate it further.
menopause is simply an environmental trigger.
Salt Sensitivity
Postmenopausal women are more salt sensitive. It is
HYPERTENSION: THE KEY RISK
caused by lack of vasodilation of the renal circulation FACTOR DURING MENOPAUSE
that occurs possibly due to less availability of nitric oxide Plenty of evidences are there, estrogen level before
(NO), more vasoconstrictor response to angiotensin menopause does not allow atherosclerosis to progress.
II or sometimes there may be diminution of l-arginine In this way, high estrogen level protects women from
conversion to nitric oxide in vascular endothelium hypertension and CV risks. Certain risk factors like
of kidney. It increases with age in both the genders. smoking, insulin resistance and diabetes withdraws this
Postmenopausal women are more salt sensitive than estrogen mediated cardiovascular protection in women.
premenopausal women. It is also seen in surgical Young women with estrogen deficiency have more
menopause. Presence of asymmetrical dimethyl-L- than seven fold higher risk of cardiovascular diseases
arginine with increased level of NO synthase antagonist due to development of coronary artery sclerosis. As
CHAPTER 4: Hypertension and Menopause 27
endogenous estrogen level declines with increasing achieve goal. Among diabetics only 21% achieved goal.
age especially after 40 years when reaching close to These results were due to inadequate treatment as most
menopause, they develop atherosclerosis with fibrous of the women were taking only one antihypertensive
cap formation. Carotid intima media thickness remains medication. Multidrug therapy may be necessary at
an important tool to diagnose subclinical atherosclerosis this age of women which should be added to life style
especially in women before menopause having multiple modifications like low sodium diet and exercise.
risk factors for coronary artery disease. After menopause,
atherosclerosis gets more extensive with inflammation CONCLUSION
and calcification of vessel wall. Cardiovascular events Hypertension in postmenopausal age group is significant
mostly occur in women after 63 years of age. In presence medical problem responsible for adverse cardiovascular
of advanced atherosclerotic disease, significantly outcomes. It is multifactorial. In spite of being good
decreased expression of estrogen receptor alters vascular compliance in women, level of hypertension control is
wall biology. Although estrogen dilates endothelium not better. There should be strategies to increase public
of vessel wall in healthy condition but its replacement awareness for hypertension and its adverse outcomes in
has serious side effects in diseased atherosclerotic postmenopausal women.
vascular wall. It activates inflammation and produces
vasoconstrictive factors, which makes atherosclerotic BIBLIOGRAPHY
plaque unstable. Early adverse CV events have been 1. Coylewright M, Reckelhoff JF, Ouyang P. Menopause and
observed after hormone therapy in randomized trials. hypertension an age-old debate. Hypertension. 2008;Part
II;952-9.
HOW SHOULD IT BE TREATED? 2. Hall JE, da Silva AA, do Carmo JM, Dubinion J, Hamza
S, Munusamy S, Smith G, Stec DE. Obesity-induced
Cardiovascular risk assessment should be first thing to hypertension: role of sympathetic nervous system, leptin,
do, while managing hypertension in postmenopausal and mela- nocortins. J Biol Chem. 2010;285(23):17271-6.
women. Most of the women develop hypertension in 3. h t t p : / / w w w . e u r o . w h o . i n t / e n / h e a l t h - t o p i c s /
their lifetime. Those who become hypertensive in their noncommunicable-diseases/diabetes/news/news/
early life, carry high cardiovascular adverse event risk. 2012/5/world-health-statistics-2012-report-increase-of-
In women, prevalence rises steeply after middle age. hypertension-and-diabetes accessed on 26/9/2017.
4. Kurtz EG, Ridker PM, Rose LM, Cook NR, Everett BM,
One third perimenopausal women free of cardiovascular
Buring JE, Rexrode KM. Oral postmenopausal hormone
disease develope hypertension in next ten years. The therapy, C-reactive protein, and cardiovascular outcomes.
50% of the women at high normal blood pressure Menopause. 2011;18:23-9.
become hypertensive in five years. Women with clear cut 5. Maheshwari A , Maheshwari B. Hyper tension and
hypertension at baseline have higher CV risks followed menopause. Hypertension J. 2017;3(1):23-6.
by women at high normal compared with normotensive. 6. Mass AHEM, Franke HR. Women’s health in menopause
with a focus on hypertension. Netherlands Heart Journal.
Sy s t o l i c hy p e r t e n s i o n i s p re d i c t o r o f a d v e r s e
2009;17(2):68-72.
cardiovascular events in those older than 50. Treatment 7. Rossi R, Nuzzo A, Origliani G, Modena MG. Prognostic role
of systolic hypertension avoids stroke, myocardial of flow-mediated dilation and cardiac risk factors in post-
infarction, CHF and death. Lifestyle modifications like menopausal women. J Am Coll Cardiol. 2008;51:997-1002.
low sodium diets decreases blood pressure. Strategies to 8. The 2012 Hormone Therapy Position Statement of The North
delay the development of hypertension in women can be American Menopause Society Menopause. 2012;19(3):257-
71. doi: 10.1097/gme.0b013e31824b970a
of larger public health benefit. Most of the women keep
9. Xing D, Nozell S, Chen YF, Hage F, Oparil S. Estrogen and
their blood pressure high despite treatment. Many of the
mechanisms of vascular protection. Arterioscler Thromb
women in postmenopausal age group are not recognized Vasc Biol. 2009;29(3):289-95.
and treated or treated inadequately. In a study, only 52% 10. Yanes LL, Reckelhoff JF. Postmenopausal hypertension
were found to receive medication but only 36% could Am J Hypertens. 2011;24(7):740-9.
CHAPTER
5
Renovascular Hypertension: Current Status
Puneet Rijhwani
Renovascular hypertension (RVHT) is a repercussion of the most common cause of RVHT in children. Specially
the unusual relation between anatomically axiomatic significant is a study from south Asia that reported 87%
arterial occlusive disease and increased blood pressure. of the patients of renovascular hypertension to be due to
arteritis.
PATHOGENESIS
A low perfusion pressure that is created by constriction Age-related Demographics
of arteries is the main indicator of pathogenesis and Patients less than 30 years or more than 50 years are more
is sensed by the juxtaglomerular cells, located on the disposed to the onset of RVHT. Systemic hypertension is
afferent arteriole wall which act as baroreceptors, less frequent in children than in adults, but nevertheless
resulting in renin secretion. The biochemistry involves the incidence of hypertension in this group is around
the conversion of angiotensinogen to angiotensin I which 1–5%. Approximately 5–25% of cases of secondary
is done by the secreted renin. Angiotensin I is converted hypertension in children is attributed to renovascular
to angiotensin II in the lungs, a process mediated by disease.
Angiotensin Converting Enzyme (ACE).
Angiotensin II causes constriction of both efferent Sex-related Demographics
and afferent arterioles, but because of the smaller basal Younger women and older men are more susceptible to
diameter of the efferent arteriole, the increase in efferent
RVHT. Atherosclerotic disease is the most common cause
resistance is more significant than afferent resistance
(Fig. 1). Angiotensin II–causes release of vasodilatory
nitric oxide and prostaglandins that further reduces
afferent vasoconstriction. Angiotensin II also reduces the
surface area available for filtration through constriction
of the glomerular mesangium.
RENOVASCULAR HYPERTENSION:
MAJOR CAUSES
Epidemiology
Role of Arteritis
A number of reports from Asia have zeroed down upon
arteritis, either Takayasu’s arteritis or aortoarteritis, as Fig. 1: Control of intrarenal hemodynamics and RAAS
CHAPTER 5: Renovascular Hypertension: Current Status 29
of RVHT in older people and it mainly affects the proximal failure having eGFR <30 mL/min/1.72 m 2. Another
one-third of the main renal artery. While younger women noninvasive alternative is Duplex ultrasonography but
develop RVHT mainly due to fibromuscular disease is technically complicated and relies on the skills of the
which affects the distal 2/3rd of the renal arteries and its operator.
branches. Duplex ultrasound is extensively available and
makes a sound assessment of both functional and
Clinical Presentation anatomical aspects of stenosed renal artery and is quite
Headache seems to be the most common symptom of accurate in diagnosis in the setting of renal failure when
RVHT. Others include changes in visual acuity, vomiting, other tests are contraindicated or inconclusive. The
altered mental status, seizures, coma, encephalopathy, conventional color Doppler echocardiography is outrun
hyperexcitability, hyperirritability. Some present with by Galactose-based echocardiography-enhanced duplex
congestive heart failure symptoms. Failure to thrive is ultrasound that produces accurate images of the renal
a common presentation in young children with RVHT. artery.
Oliguric renal failure is also seen in some patients. Whether gadolinium-enhanced magnetic reso
nance angiography may be used an alternative to
Clinical Clues conventional angiography or as screening test, remains
Patients having ≥2 of the below mentioned clinical clues, to be established. Apart from limited availability, the
indicating RVHT, need to be thoroughly investigated: drawbacks of this investigation include:
Patients aged >55 or <30 years with acute onset or Segmental and accessory renal arteries are not
ACE inhibitor or ARB associated increase in serum failure patients having eGFR <30 mL/min/1.72 m2
creatinine level ≥30% Costly.
Other atherosclerotic vascular disease, specifically in In the backdrop of a well documented and confirmed
smokers or having dyslipidemia anatomical stenosis, the following evidences might be
Hypertensive surges landing in recurrent pulmonary given for functionally significant stenosis
edema. >70% of the lumen area showing stenosis
DIAGNOSIS area
The appropriate test for diagnosing RVHT depends Lateralization of plasma renin activity in renal vein
majorly on the underlying clinical presentation (e.g. Doppler ultrasound indicating high arterial resistance
angiography. IVP*
Alternative imaging techniques are CT angiography Renal blood flow is impaired on captopril renogram*
and MR angiography; as these are less invasive and *contraindicated in patients having eGFR < 30 mL/
commonly available, disadvantage is lower sensitivity min/1.72 m2).
and specificity, especially in suspected fibromuscular
dysplasia with middle or distal renal artery involvement Treatment
in which they might be falsely negative. Also, the risk Preservation of renal function and achieving good BP
of gadolinium-induced dermatofibrosis renders MR control is the main purpose of treatment in patients
angiography contraindicated in patients with renal having renal artery stenosis (Table 1). Currently, there
30 SECTION 1: Hypertension
TABLE 1: Factors determining patient selection for revascu Points not Favoring Positive Response
larization
Post Revascularization
Atherosclerosis induced renal Aortic dissection
artery stenosis BP less than140/90 mm Hg on less than 3 anti
Fibromuscular disease Aortic endograft obstructing hypertensive drug regimen
zz Medial fibroplasia the renal artery Renal parameters are normal
zz Perimedial fibroplasia
zz Intimal fibroplasia
Unilateral contracted kidney (length <7.5 cm)
zz Medial hyperplasia
There is clinical evidence or history of cholesterol
Arterial embolus embolization
Other medical disorders: On Doppler ultrasonography renal resistive index is
zz Hypercoagulable state with
>80 mm Hg
renal infarction More than 1 gm/day proteinuria
zz Takayasu’s arteritis
zz Arterial dissection
medical management. Angiotensin converting enzyme
inhibitors, ARBs and Calcium channel blockers are
convincing in blood pressure control in unilateral RAS
is an ongoing debate regarding management of patients
and may result in reducing the speed of progression of
with renal artery stenosis, both in terms of methods used
disease (class I, level B).
for revascularization and whether it is actually beneficial
Published data from many clinical trials call for
practically. In cases where target blood pressure control
cannot be reached or there is evident deterioration of augmentation of antihypertensive therapy and checking
renal function, strong recommendation is in favor of additional risk factors (good glycemic control, smoking
revascularization. cessation, use of aspirin, statins, etc.).
The major threat of drugs used nowadays resides
Points Favoring Expected Positive in the deterioration of renal function, especially when
Response Post Revascularization using an ACE inhibitor or ARB, which are useful
Recurrent “flash” pulmonary edema antihypertensives in 86–92% patients of RVHT, usually
Resistant hypertension despite patient on three drug when combined with a calcium channel blocker and a
regimen diuretic. Angiotensin converting enzyme inhibitors and
Unexplained, progressive deterioration of renal ARBs are generally tolerated well, with only around 5%
parameters requiring the drug to be discontinued during the initial
Acute, reversible increase in serum creatinine if on 3 months. More than 30% decrease in eGFR (or >0.5
ACE inhibitor or ARB drugs mg/dL increase in S. creatinine) may be indicative of
Requirement of dialysis recently in a patient suspected considering renal revascularization.
to be having ischemic nephropathy Bilateral RAS or renal artery stenosis in a single
On Doppler ultrasonography renal resistive index is functional kidney is a contraindication for using ACEI or
<80 mm Hg ARB.
CHAPTER 5: Renovascular Hypertension: Current Status 31
There is evidence that diuretics of thiazide group between 10% and 30%, which varied as per the type of
and other hypertensives like hydralazine, beta-blockers stenosis as well as the time duration of follow-up.
are also effective in controlling BP in patients with renal As per the latest ESC guidelines for the treatment
artery stenosis. of peripheral artery disease, in patients considered for
angioplasty, it is recommended that stenting should
SURGICAL REVASCULARIZATION be done in ostial atherosclerotic RAS (Class I, LOE
As the number of angioplasty procedures is on the rise B). Angioplasty, preferably with stenting, may be
so surgical revascularization is rarely used nowadays. conducted in cases who are symptomatic and have >60%
For technical and anatomic reasons, bypass procedures stenosis of renal artery resulting from atherosclerosis;
from nonaortic donor regions (hepatic, mesenteric, endovascular therapy of RAS to be considered to be
celiac, or splenic artery) are commonly used now a appropriate in patients with poor renal function. Balloon
days as compared to the renal endarterectomy and the angioplasty along with or without stenting, may be
aortic-renal bypass. Surgical modality may be indicated considered in RAS patients with unexplained repeated
for patients going for repair of the aorta, patients with congestive heart failure or sudden pulmonary edema
complicated anatomy of the renal arteries, or after and preserved systolic left ventricular function.
unsuccessful endovascular procedure (class IIb, level C).
A meta analysis of forty seven retrospective or Summary of Current Thinking on
nonrandomized studies was done. It compared the
Renovascular Hypertension
results in patients treated surgically verses patients
Altogether it is apparent that advances in medical
treated by endovascular procedures. In terms of technical
therapy, vascular imaging and endovascular procedures
success rates the outcomes were same, had better long-
have change d the s cenar io of management of
term control of blood pressure and renal function,
renovascular hypertension. Many cases presenting
with a slightly high perioperative mortality in surgical
simply as new-onset hypertension with normal renal
revascularization group (mainly because of concomitant
function can be treated with existing antihypertensive
aortic surgery).
medication, usually including drugs that act upon the
ANGIOPLASTY renin-angiotensin system. Renovascular disease being
an important predictor of cardiovascular risk requires
The preferred treatment modality is renal percutaneous
transluminal angioplasty (RPTA) when the cause of intensive therapy to reduce this risk by including aspirin,
RVHT is fibromuscular dysplasia. The restenosis rate is statins, tobacco cessation, glycemic and weight control,
around 5–11% at the end of one year postprocedure. in addition to blood pressure control. For patients with
Treatment of atherosclerotic renal artery disease by complex disease, deteriorating renal function, or those
this procedure is controversial, as trials conducted have who fail to respond to antihypertensive medications,
not shown significant clinical benefits. further diagnostic workup with a commitment to
T h e o re t i c a l l y a n g i o p l a s t y p l u s s t e n t i n g i s restoring renal perfusion may be required.
advantageous, especially when done at sites having high
tendency for restenosis. Four years follow-up study, BIBLIOGRAPHY
which was the widely studied experience published was 1. Abela R, Ivanova S, Lidder S, et al. An analysis
comparing open surgical and endovascular treatment of
from Durros et al. Patients were treated with a particular,
atherosclerotic renal artery stenosis. Eur J Vasc Endovasc
early renal artery stent. These patients documented a Surg. 2009;38:666-75.
significant control in blood pressure, a slight decrease 2. Black HR, Elliot WJ. Hypertension. A Companion to
in antihypertensive drugs required for BP control, and Braunwald’s Heart Disease. Second Edition. Elsevier
the overall mortality rate was 26%. Rate of restenosis was Saunders. 2013;8:69-79.
32 SECTION 1: Hypertension
3. Durros G, Jaff M, Mathiak L, et al. Multicenter Palmaz stent 7. Rocha-Singh KJ, Eisenhauer AC, Textor SC, et al. American
renal artery stenosis revascularization registry report: Heart Association Atherosclerotic Peripheral Vascular
four-year follow–up of 1068 successful patients. Catheter Disease Symposium recommendations. Circulation
Cardiovasc Interv. 2002;55:182-8. 2008;118:2873-8.
4. Dworkin LD, Cooper CJ. Renal-Artery Stenosis. N Engl J Med. 8. Rosenthal J, Arlart I, Franz HE. Renovascular Hypertention.
2009;361:1972-8. In Rosenthal, Julian. Arterial Hypertension: Pathogenesis,
5. Gregory YH, John E. (2007-06-28). Comprehensive Diagnosis, and Therapy. Springer. 2012. pp. 201–202.
Hypertension. Elsevier Health Sciences. p. 101. ISBN ISBN 978-1-4612-5657-1.
9780323070676. 9. Safian RD, Textor SC. Renal artery stenosis. N Engl J Med
6. Hypertension Canada’s 2016 Canadian Hypertension 2001;344:431-42.
Education Program Guidelines for Blood Pressure 10. Stable patients with atherosclerotic renal artery stenosis
Measurement, Diagnosis, Assessment of Risk, should be treated first with medical management. Plouin
Prevention, and Treatment of Hypertension. Can J Cardiol. PF. Am J Kidney Dis 2003;42:851-7.
2016;32(5):569-88.
CHAPTER
6
Diuretics for Hypertension:
Review and Update
R Rajasekar
bioavalability—about 60–70% is absorbed and food cardiac preload and output. Long-term phase
intake hastens absorption. Some thiazides undergo is less reliably predicted. The continous
extensive metabolism and some remain unchanged antihypertensive of many thiazides is overall
and excreted almost intact in urine. reduction of systemic resistance. Though the
In HT patients 50% reduction of absorption is exact mechanism is less clear but CTD does not
observed so even after a year. It is not elusive about thiazide
CTD: 12.5 mg—prescribed in systolic hypertension exerting vasodilation or a reverse autoregulation
of SHEP study of elders. The dose can be increased property. Moreover, it is presumed. Thiazides
to 25 mg and is considered as good as alternative to may cause structural membrane changes and
CCB/ACE inhibitor in ALLHAT study But the risk of ion gradients. Another explanation is constant
diabetes and hypokalemia have to be checked. prescription of thiazides may keep a normal state
Bendroflurazide: It is also effective thiazide 24 hours of volume contraction, thus creating a downward
action-Dose—1.25 mg per day, and ameloride, transfer in vascular resistance.
potassium sparing diuretic is less effective. Diuretic tolerance: L ong and short-term
Indapamide: A modified thiazide. A lipid neutral adaptations are mainly due to have a protective
and standard thiagide. A vasodilating thiazide 2.5 effect on intravascular volume. Short-term
mg once daily. Now sustained release 1.5 mg is the tolerance is due to post-dosing of antinatruresis
standard dose. Potassium fall, blood glucose hikes initiated by reduction of extracellular fluid
and uric acid hikes are to be kept in mind. It induces volume. Renin angiotensin aldosterone and
regression LVH and is infact better than enalapril. sympathetic nervous system activation and
Loop diuretics for HT: suppression of secretion of atrial natriuretic
1. Frusemide is short acting and should not be peptide and renal prostaglandin are responsible
given and is not a fit routine antihypertensive for short-term tolerance. Dietary Sodium
drug, moreover, it has to be given twice a day. markedly influences post dose sodium retention.
Most thiazides have half life of 8–12 hours, so So dietary sodium restriction leads to negative
once daily dosing is possible. The thiazides CTD sodium balance and increases therapeutic
is long acting with half life of 50–60 hours due to response to thiazides. A continuous dietary
its extensive volume distribution. Almost 99% of sodium intake negativates this beneficial effect.
CTD is bound to erythrocyte cabonic anhydrase Long-term diuretic adaptation or breaking
and the drug has a strong inhibition action effect are due to return of sodium chloride to
than other thiazides. Thus, the marked binding electroneural level. A continous volume clearing
of chlorthalidone into erythrocyte carbonic seems to initiate prolonged activation of RAAS
anhydrase aptly by forming a tissue reservoir, resulting in circulating angiotensin 2 levels,
allowing constant CTD release back into plasma thereby promoting increased proximal sodium
thereby it exerts its effect beneficially. So this reabsorption, limiting final delivery of sodium
depot effect of CT has an advantage of once daily to distal region. The other volume independent
dosing. mechanism are uptitration of sodium
Pharmacodynamics: The hemodynamics of transporters downstream from primary region
thiazides are of two phases i.e. short- and long- of diuretic action and structural enlargement of
term phase. The first phase of reduction of blood distal Nephrons.
pressure is due to reduction of extracellular Tolerance is achieved by higher dosing or
fluid and plasma volume resulting in reduced combinations such as thiazide and loop diuretic
CHAPTER 6: Diuretics for Hypertension: Review and Update 35
to exert synergistic effect. But one has to be Excessive dietary sodium intake, real impairment,
careful of high doses and combinations to avoid food, NSAID may all cause resistance to natriuretic and
renal injury and electrolyte abnormalities. anti-HT action of diuretics.
Torsemide: It is tree of metabolic and lipid side
2.
effect but used in subdiuretic dose i.e. 2.5 mg or ABBREVIATIONS
even at a higher dose 5–10 mg being natriurectic DBP, Diastolic blood pressure
with risk of metabolic changes. SBP, Systolic blood pressure
ACEI, Angiotensin converting enzyme inhibitor
POTASSIUM-SPARING COMMON ARB, Angiotensin receptor blocker
COMBINATION DIURETICS BB, Beta-blocker
Though it is slightly costly, the diuretic induced CCB, Calcium channel blocker
hypokalemia and hypomagnesemia is prevented. DHP, Dihydro pyridine
By combination, risk of sudden cardiac death (SCD) CAD, Caronary artery disease
is reduced. Fixed dose combination of triamterene/ HT, Hypertension
ameloride with HCTZ is used. RAAS, Renin angiotensin aldosterone system
NSAID, Nonsteroidal anti inflammatory drugs
COMBINATION OF DIURETIC DM, Diabetes mellitus
WITH ANTI-HT DRUGS
Diuretic can be combined with all anti-HT (ACEs/ARBs/ BIBLIOGRAPHY
1. Ernst ME, Pharm D, Moser M. Use of diuretics in patients
beta-blockers) combination of ACE inhibitors, diuretics
with hypertension. N Engl J Med. 2009;361:2153-64.
can prevent hypokalemia. Combination of Indapamide 2. Kaplan NM. Kaplan’s Clinical Hypertension. (10th ed.).
with ACE inhibitors is ideal in elderly. Philadelphia, PA:Lippincott Williams & Wilkins. 2009.
3. Katritsis DG, Gersh BJ, Camm AJ. Clinical Cardiology
CONCLUSION Current Practice Guidelines (1st ed.). Oxford, UK: Oxford
Though metabolic side effects are like new onset of DM University Press. 2014.
4. Levine GN. Cardiology Secrets (4th ed.). Philadelphia,
especially at high doses. A low dose is ideal as an initial
United States: Elsevier-Health Sciences. 2013.
treatment especially in elders. It helps to reduce stroke/ 5. Opie L, Gersh B. Drugs for the Heart. (8th ed.). Philadelphia,
CAD in elderly thereby reducing mortality in mild-to- PA: Elsevier Saunders. 2013.
moderate HT.
CHAPTER
7
High Altitude Systemic Hypertension:
Unraveling the Mystery
VA Kothiwale, Deebanshu Gupta
net effect being either same or slight reduction in zz Exaggerated erytropoiesis causing increased red cell mass.
Contd...
38 SECTION 1: Hypertension
Contd...
Gaseous At HA, alveolar-arterial difference for oxygen is At HA, decreased driving pressure for oxygen from alveolar gas into
diffusion higher than would be predicted from measured arterial blood is insufficient to fully oxygenate blood as it passes
ventilation-perfusion inequality. through pulmonary capillary.
With more altitude-more sustained stay, exercise induced cardiac
output increases and blood spends less time at gas exchanging
surface (diffusion limitation).
Blood Initially at HA, hemoglobin concentration rises due As hemoglobin production-concentration rises, there is increased
to fall in plasma volume due to dehydration. Later, coagulability abd viscocity of blood and hence increased risk
hypoxia stimulates JGA of kidney for increased of stroke and venous thromboembolism. Neither aspirin nor
erythropoietin. So, hemoglobin production- venesection reduces incidence of venous arterial thrombosis.
concentration rises.
angiotensin system, elevated sympathetic activity and Association of HASH with deletion allele of angio
association of deletion allele of ACE gene leads to HASH. tensin-converting enzyme (ACE) gene
H A S H i s d e f i n e d a s p re s e n c e o f s u s t a i n e d
hypertension (>150/90 mm Hg, as per JNC criteria) in Role of Sympathetic Activation
low landers at HA (>2500 m). HASH can be categorized Role of ANS in controlling HR-CO is well established
as a type of secondary hypertension wherein prolonged Sensing of acute hypoxemia by peripheral-medullary
stay at high altitude acts as predisposing factor and chemoreceptors activates sympathetic nervous
thereby leads to long term morbidity, mortality caused system as reflected by increase in concentration of
by its effects on the human physiology. Exercise of any epinephrine- norepinephrine which leads to hypoxia
form or duration including daily activities at HA leads to induced tachycardia and hypertension.
further increase in systemic BP. Duplain et al, Rowell et al postulated that hypoxia
Prevalence of HASH is reported to be 28–62% in induced sympathetic activation is a defense mechanism
different studies. by which an increased cardiac output ensures proper
Interestingly, migratory population showed higher oxygen supply to critical organs.
prevalence compared to natives born there. Those exposed to chronic hypoxia also show
Fig. 2: After 9 weeks of stay at 5260 m, arterial blood pressure (BP) measurements and systemic and 2-leg vascular conductance (VC)
compared with readings taken after 6–9 months of returning to sea level
Source: Adapted from Calbet JAL. Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans.
The Journal of Physiology. 2003;551(Pt 1):379-86.
adrenaline spill over after a week which proved the have been reset at a higher set point as seen in sleep
above hypotheis (Fig. 2). apnea syndrome patients.
Calbert et al showed 3.8 fold increase in whole body At HA, 15–20% fall in blood volume in circulation
nor adrenaline release. Compared to sea level, this occurs which leads to fall in cardiac filling pressures
observed sympathetic over activity was accompanied by and consequently reduced stimulation of low
decreased systemic vascular conductance and increased pressure baroreceptors. This nullifies negative
systemic blood pressure as shown in the above graph. feedback and leads to more sympathetic activation.
This approves the hypotheis that SNS plays significant Other factors which increased SNS activity responsible
release in response to chronic hypoxemia, vascular —— Fall in production of nitric oxide (NO)
conductance decreased only by 1/3rd which was far —— Increasing Hb (enhanced erythropoiesis) causing
less than the quantum of NA spill over. This postulates more NO scavenging.
that some hypoxia induced vasodilatory mechanism So, chronic hypoxia causes increased systemic arterial
blunts the action of NA and vascular smooth muscle pressure and massive activation of the sympathetic
response to vasoconstrictors in chronic hypoxia. nervous system in healthy humans, despite improved
We can postulate that severely increased sympathetic arterial O2 content with acclimatization.
activity, resting BP in response to prolonged
hypoxia in healthy humans have definitive clinical Role of Increased Erythropoiesis
implications. Despite marked rise in blood pressure and Raised Hematocrit
at HA continued increase in noradrenaline spillover As discussed above, though sympathetic stimulation
occurred at HA and it should have blunted further seems to be the primary reason for pressor response to
sympathetic activation through stimulation of HA, other mechanisms may be involved, many of which
baroreceptors. This physiological phenomenon can were investigated in HIGHCARE-HIMALAYA study.
only be explained if we presume that baro receptors During high altitude permanence, hematocrit levels
40 SECTION 1: Hypertension
Also, frequency of the ACE D allele was higher in AGEING, HIGH ALTITUDE AND BLOOD
volunteers who developed systemic hypertension at PRESSURE-A COMPLEX RELATIONSHIP
higher altitude i.e. HASH.
Advancing age promote to development of hypertension
Thereby a positive correlation of ACE D allele (which
by stiffening of large vessels, enhanced atherosclerosis,
is responsible for elevated ACE activity) was found with
impairment of arterial baroreflex and renal dysfunction.
HASH.
Evidence is less clear on whether to what extent,
In earlier study by the same authors and others, no
combined effect of advancing age and chronic hypoxia
significant association between ACE D allele and HASH
on exposure to high altitude for prolonged periods
was observed in various Indian populations (Gorkha,
influences the blood pressure (Fig. 4).
Sikh, Assamese, Dogras, Jats, Kumaonis and Yadavas)
Nowadays a very significant elderly low lander
when studied at plains (Kumar et al. 2001).
population migrates to high altitude for prolonged
S o t h e i n t e ra c t i o n b e t w e e n t h e g e n e s a n d
the environment plays very significant role in the periods of stay.
development of systemic hypertension at high altitude.
Thus presence of ACE D allele as a genetic factor
BLOOD PRESSURE CHANGES WITH
not expressed fully in previous enviorment predisposes AGING
a population to have elevated blood pressure when Lewington et al. 2002 indicated that aging is associated
exposed to a new enviorment such as HIGH ALTITUDE. with progressive increase in BP levels.
Arterial system in youth is designed to receive spurts (PWVR) among dippers compared to higher ratios
of blood from LV to distribute this as steady flow through among nondippers.
peripheral capillaries. Factors of optical efficiency of Higher red cell distribution width (a phenomenon
vascular - ventricular interaction include: directly proportional to adverse cardiovascular
Greater distensibility of proximal than distal aorta outcomes) in nondippers compared to dippers.
Dispersion of peripheral reflecting sites Increased levels of asymmetric dimethyl arginine-
Location of heart in upper thorax (an indicator of oxidative stress) among non-
Inverse relationship between HR and body length. dippers compared to dippers.
As aorta ages it stiffens, aortic PWV (Pulse Wave Enhanced levels of mean platelet volume – an
Velocity) increases and tuning between LV and arterial indicator of platelet activation is higher among
tree is progressively lost. nondippers than dippers.
Exposure to high altitude is associated with
progressive reduction in central-peripheral pulse DIAGNOSIS OF HASH
pressure.
No set guidelines at present
Potential mechanisms of this include:
Diagnosis on the basis of JNC guidelines for
Reduction in stroke volume associated with hypoxia
diagnosing hypertension at sea level but the duration
triggered tachycardia
Increase in diastolic BP levels which is caused by
of stay at high altitude (>2500 m) should be for more
than 3 months in a person who was previously a low
an increase in vascular tone with increase in central
lander.
sympathetic stimulation of peripheral vasculature
Compared to conventional BP readings which
leading to increased PVR.
underestimate the BP effects of HA, ambulatory BP
HOW BP BEHAVES WITH AGING IN readings were found to be superior.
PEOPLE CHRONICALLY EXPOSED TO Absence of nocturnal dip in the BP due to increased
symphathetic activation attributed to exaggerated
HIGH ALTITUDE
reduction in SpO2 during sleep at high altitude is one
Course of vascular aging is different in subjects on
of the earliest markers of HASH.
exposure to chronic hypoxia at high altitude.
In various cross sectional studies when BP levels
were assessed as a function of age, highlanders exhibited
TREATMENT OF HASH
higher increase in BP levels with age as compared to low Being a new entity no set guidelines are available.
landers i.e. systolic BP of 0.75 vs 0.32 mm Hg/year and Based on the promising research following treatment
diastolic 0.32 vs 0.08 mm Hg. modalities are proposed.
TABLE 2: Role of carvedilol and nebivolol hemotocrit and hormonal realignments occuring in
Carvedilol Nebivolol subjects with conventional risk factors can predispose
Nonselective beta-adrenergic Competitive and selective beta1- them to HASH.
and alpha1-adrenergic receptor antagonist. The thin line dividing the rise in BP due to
blocking agent.
At high altitude carvedilol At high altitude nebivolol lost acclimatization and that due to pathologic process
fully maintains the BP- some of the antihypertensive causing morbidities needs to be defined.
lowering effect achieved at effect seen at sea level. De escalation to lower altitude can reverse the
sea level.
Does not have much effect Nightime BP reduction more than
pathology with re occurrence on re induction to high
on nocturnal dipping. that during day at high altitude. altitude.
Worse tolerability (quantified At HA, better exercise tolerability CCB, ACE inhibitors/ARB’s, Beta blockers alone or
by side effects score), and of a and performance.
in combination are effective drugs for treatment of
more pronounced reduction
in exercise capacity at HA. HASH in various studies but definitive guidelines
or evidence is still awaited in literature terming or
Administration of Telmisartan at high altitude was coining an ideal agent for treatment of HASH.
well tolerated with no negative impact on SpO2 and no
impact on exercise tolerance. BIBLIOGRAPHY
When we look at pressor response at HA if antihy- 1. Bilo, Grzegorz & Caldara, Gianluca & Styczkiewicz et al.
pertensives like RAS blocking drugs along with Effects of selective and nonselective beta-blockade on
24-h ambulatory blood pressure under hypobaric hypoxia at
calcium channel blocking agents are combined,
altitude. Journal of hypertension. 2010;29:380-7.
BP lowering effect was similar at HA as at sea level
2. Bilo, Grzegorz and Villafuerte, Francisco & Faini A, et
without much adverse effects and intolerance al. Ambulatory blood pressure in untreated and treated
although they were uable to abolish HA exposure hypertensive patients at high altitude: The high altitude
pressor response (Table 2). cardiovascular research-andes study. Hypertension.
Combined treatment with CCB (Nifedipine) and ARB 2015;65:1266-72.
(Telmisartan): 3. Calbet JAL. Chronic hypoxia increases blood pressure and
noradrenaline spillover in healthy humans. The Journal of
—— Effective and safe at HA with BP values that
Physiology. 2003;551(Pt 1):379-86.
remained lower compared to subjects receiving 4. Kumar R, Pasha MQ, Khan AP, Gupta V, Grover S, Norboo
placebo. T, et al. Association of high-altitude systemic hypertension
—— Subjects on above combination of drugs, showed with the deletion allele-of the angiotensin converting
higher values of SPO2 postulated to be nifedipine enzyme (ACE) gene. International journal of biometeorology.
induced vasodilatory effects on pulmonary 2003;48:10-4.
5. Louis Hofstetter, Urs Scherrer, Stefano F. Rimoldi. Going to
circulation with enhanced ventilation-perfusion
high altitude with heart disease. Cardiovascular Medicine.
ratio. 2017;20(04):87-95.
6. Norboo T, Stobdan T, Tsering N, Angchuk N, Tsering P,
CONCLUSION: CARRY HOME MESSAGES Ahmed I, et al. Prevalence of hypertension at high altitude:
HASH can be termed as a type of secondary hyper cross-sectional survey in Ladakh, Northern India 2007-
tension due to prolonged exposure to high altitude. 2011. BMJ Open 2015;5:e007026.
It can be considered as an extended by product of 7. Parati G, Ochoa JE, Torlasco C, Salvi P, Lombardi C, Bilo
G. Aging, high altitude, and blood pressure: a complex
physiologic continuum of acclimatization response
relationship. High Altitude Medicine & Biology. 2015;16:97-
to hypoxemic enviorment. 109.
Sympathetic stimulation, endothelial dysfunction, 8. Peter Bärtsch, Simon J, Gibbs R. Effect of altitude on the
role of D allele of ACE gene, role of increased heart and the lungs. Circulation. 2007;116;2191-202.
CHAPTER
8
Management of Isolated Systolic
Hypertension: Current Concepts
Girish Mathur, Shrikant Chaudhary
Over the last few years a paradigm shift has occurred TABLE 1: Blood pressure
about elevation of diastolic blood pressure to our Category Blood pressure (mm Hg)
current knowledge that an elevation of systolic or rather Systolic Diastolic
combination of higher systolic and lower diastolic Optimal <120 <80
pressure (i.e. widening of pulse pressure) are the major Normal <130 <85
determinants of cardiovascular risk. The “J” shape curve High normal 130–139 85–89
of hypertension causing complications suggest same ISH
trends. Nowadays systolic hypertension is considered Stage I 140–159 <90
important prognostic factor in elderly rather than only Stage II 160–179 <90
age related phenomenon as it was considered previously. Stage III >180 <90
Patients with isolated systolic hypertension (ISH)
are definitely at high risk for developing cerebral and Systolic hypertension can be divided into three
coronary artery diseases and CHF as well. subtypes:
Chicago Heart Association based on these researches 1. Isolated Systolic Hypertension in Young (ISHY):
found that adults with ISH are at high risk of dying from ISH in young adults (typically 15–25 years of age).
ISH, women are at more risk than men although ISH is 2. Systolic Diastolic Hypertension in Middle Age:
more prevalent in men. Typically occurs in 30–50 years of age and also have
Elevated systolic hypertension in young individual elevated diastolic BP.
was considered previously as “spurious” or “pseudo”, 3. Isolated Systolic Hypertension in Elderly: Occurs
due to white coat hypertension or other causes. Newer after the age of 55 years.
studies have shown that these patients are at increased
risk of cardiovascular complications and so they should PREVALENCE AND RISK FACTOR
be carefully investigated and early treatment is warranted According to National Health and Nutrition Examination
in them. Survey III, ISH is most prevalent type of hypertension
As per WHO and JNC8 guidelines ISH is now defined above the age of 60 years. There is high variable data
as BP >140/<90 (Table 1). available regarding prevalence of ISH in different studies
CHAPTER 8: Management of Isolated Systolic Hypertension: Current Concepts 45
ranging from 6% to 30%. Aging is the most important risk nocturia, leg cramps, epistaxis, palpitation are presenting
factor in old. In young, it’s prevalence is estimated much features. Headache, blurring of vision are present in both
less than elderly. Obesity, smoking, low education level, subtypes of ISH.
male sex, alcohol, Stress are major risk factors.
EVALUATION OF ISH
Etiology As otherwise also every effort should be made to
In elderly people age related atherosclerosis and find identifiable cause of secondary hypertension,
stiffening of major arteries are main cause of ISH. other cardiovascular risk factors, end organ damage,
In young, etiology is unknown, genetic factors known life style risk factors like sedentary life style,
may play a role. It has been recently suggested that obesity, smoking, excessive alcohol consumption, etc.
angiotensin gene expression may be altered in ISH. Thorough assessment of all peripheral pulses, both
Hyperthyroidism, hyperaldosteronism, renal disease, optic fundi, thyroid status, cardiac, pulmonary, renal
renal artery stenosis, drug induced (corticosteroids, and neurological findings are mist as base line clinical
NSAIDs) may be other causes. evaluation.
The desirable investigations are as under:
Pathophysiology Urine analysis–for proteinuria,
Atherosclerosis due to endothelial dysfunction together Complete blood count–for unexplained anemia,
with vascular remodelling and fibrosis decrease arterial Serum creatinine–for kidney function,
elasticity and increase arterial stiffness. Pulse wave Serum uric acid–for hyperuricemia,
velocity is faster through stiff vessel, so the usual Serum electrolytes–for Conn’s syndrome,
reflection of pressure wave back from periphery occurs in Blood sugar–for diabetes,
mid systole rather than diastole augmenting the already Lipid profile–for dyslipidemia,
elevated systolic pressure and removing a major support Thyroid function test–for hyperthyroidism,
for the diastolic pressure, probably that’s why there is A m b u l a t o r y B P m o n i t o r i n g – f o r w h i t e c o a t
isolated systolic hypertension in elderly.
hypertension,
The increased systolic pressure leads to ventricular ECG–for left ventricular hypertrophy,
remodelling, fibrosis and impaired diastolic relaxation
Chest X-ray–for cardiomegaly,
subsequently leading to left ventricular hypertrophy,
Echocardiography–for chamber enlargement,
heart failure, coronary artery disease and aortic
USG abdomen–for kidney size and corticomedullary
aneurysm.
differentiation,
In young, atherosclerosis is less likely, sympathetic
CT abdomen and chest–for pheochromocytoma,
nervous system involvement is more likely as young
Carotid color Doppler–for atherosclerosis,
patient are usually associated with increased cardiac
Renal Doppler–for renal arterial stenosis.
output and tachycardia. There is evidence of renin
angiotensin aldosterone pathway over activity in young
MANAGEMENT OF HYPERTENSION
patients with ISH.
JNC8 Recommendations
CLASSIFICATION OF ISH Recommendation 1
Clinical Presentation In the general population aged ≥60 years,
Most patients are asymptomatic. An obese, active Start pharmacologic treatment to lower blood
smoker person, highly anxious with complaints of effort pressure to a goal SBP <150 mm Hg and goal DBP <90
intolerance is the usual presentation in young. In elderly, mm Hg.
46 SECTION 1: Hypertension
Recommendation 4 Recommendation 9
In the population aged 18 years with CKD, If goal BP is not reached within a month of treatment.
Start pharmacologic treatment to lower BP at SBP Increase the dose of the initial drug or add a second
140 mm Hg or DBP 90 mm Hg, and drug from one of the classes in recommendation 6
Treat to goal SBP <140 mm Hg and goal DBP <90 mm (thiazide-type diuretic, CCB, ACEI, or ARB).
Hg. Physician should continue to assess and adjust
treatment until goal BP is reached.
Recommendation 5 If goal BP is not reached with two drugs, add and
In the population aged 18 years with diabetes, titrate a 3rd one.
Start pharmacologic treatment to lower BP at SBP
Do not use an ACEI and an ARB together in the same
140 mm Hg or DBP 90 mm Hg, and patient.
Treat to a goal SBP <140 mm Hg and goal DBP <90
If goal BP cannot be reached using only the drugs in
mm Hg recommendation 6, because of a contraindication or
the need to use more than 3 drugs to reach goal BP.
Recommendation 6
Antihypertensive drugs from other classes can be
In the general nonblack population, including those with
used.
diabetes,
Referral to a hypertension specialist may be indicated
Start antihypertensive treatment should include a
for patients.
thiazide-type diuretic, CCBs, ACE inhibitors, or ARBs.
In whom goal BP cannot be attained using the above
Recommendation 7 strategy.
In the general black population, including those with For the management of complicated patients.
diabetes,
Initial antihypertensive treatment should include a Treatment of ISH
thiazide-type diuretic or CCB. Treatment of ISH starts with lifestyle modification
followed by drug therapy.
Recommendation 8
In the population aged18 years with CKD, Nonpharmacological Treatment
Initial (or add-on) antihypertensive treatment should Weight reduction-keep body weight within normal
include an ACEI or ARB to improve kidney outcomes. BMI range.
CHAPTER 8: Management of Isolated Systolic Hypertension: Current Concepts 47
Salt restricted diet-moderate degree of daily salt should be useful in ISH. This is also shown in Systolic
intake should not be more then 2.4 gm or NaCl 6 gm/ Hypertension in Elderly Patients (SHEP) trial.
day which may lead to reduction in systolic BP by 2–8
mm Hg. Diuretics
Ad o p t i n g D A S H (d i e t a r y a p p ro a c h t o s t o p The current joint national committee guidelines
hypertension) meaning thereby the diet rich in fruits, recommend thiazide diuretics as initial therapy in most
vegetables, low saturated and total fat and high in patients with isolated systolic hypertension on the basis of
fiber content. their efficacy of reducing blood pressure, cardiovascular
Stopping tobacco by all means is must in managing complications and their low cost. These usually require
ISH. combination with other group antihypertensive drugs.
Moderation of alcohol consumption to not more than NSAIDs use may lead to reduced potency of thiazide
30 mL/day is effective in decreasing ISH upto 4 mm and lead to uncontrolled hypertension.
2011 British hypertension guidelines emphasize
Hg.
the use of thiazide like diuretics such as chlorthalidone
Physical exercise—Regular exercise like walking.
(12.5–25 mg once daily), in preference to conventional
Stress management—Stress management by yoga,
thiazide diuretics like hydrochlorthiazide, if there is high
pranayama and meditation may help in reducing
risk of heart failure. In presence of serum creatinine >2
stressful life.
mg/dL loop diuretics are of choice but metolazone also
Low caffeine—Caffeine is supposed to cause
act at low GFR.
temporary hypertension.
Elderly patients are prone to orthostatic hypotension,
Pharmacological Treatment dehydration, dyselectrolytemia and hypokelimia due to
Drug therapy recommendations: diuretics.
Lifestyle changes must always precede pharmaco
Calcium Channel Blockers
therapy as this may decrease the need for medication.
They can be labelled as ‘broad spectrum
The pharmacotherapy must be tailor made according
antihypertensives’ as they are effective as a single drug
to the patient’s cardiovascular profile and end organ
in almost 60% of patients in all demographic groups and
damage.
all grade of hypertension. Amlodipine is the only calcium
The general approach should be ‘start low – go slow’
channel blocker with established safety in patients with
to achieve the pharmacological effect.
severe heart failure.
To improve compliance long acting drugs should be
cardiovascular benefit over atenolol at the same level of study performed in Chinese ISH patients where active
BP control. treatment with nitrendipine significantly reduced the
following endpoint phenomenon:
b Blockers Total stroke—38%
reducing heart rate and cardiac output. Inhibit release of Cardiovascular mortality—39%
renin so effective in patients with elevated plasma renin Fatal and nonfatal cerebrovascular events—37%
activity such as young white patients. Bisoprolol and Intervention as a Goal in Hypertension Treatment
Nevibilol are beta blockers with less side effects and once (INSIGHT) Study which was performed in hypertensive
daily dose. patients with at least one additional risk factors such
Combination therapy: Most of the patients require as hyperlipidemia or diabetes mellitus. Though this
dual or even triple therapy to control ISH. The preferred study was not deliberately designed to investigate ISH
combinations are treatment, but it contained a subgroup of patients with
Diuretic and ACEI, defined ISH which were analyzed separately. Treatment
Diuretic and ARB, consisted of nifedipine (in the GITS form: Adalat-OROS)
Dihydropyridine CCB and ACEI, v/s hydrochlorothiazide. This subgroup was found to be
As per Avoiding Cardiovascular Events through more responsive than those with ‘ordinary’ hypertension
Combination Therapy in patients Living with Systolic to nifedipine–GITS. Interestingly, in these study patients
Hypertension (ACCOMPLISH) trial, the last combination with ISH whose DBP significantly decreased with
is more beneficial. increasing therapy were smokers with evidence of
Newer drugs: atherosclerosis.
Eplerenone: A newer aldosterone antagonist with very Both types of treatment (calcium antagonist v/s
low incidence of gynecomastia. diuretic) caused a significant and sustained reduction
Nitrates: Considered as potent drug by some experts in blood pressure (in particular SBP) and a significant
as new agent to treat ISH. reduction of the relevant endpoint parameters, such as
stroke and MI.
The ISH substudy of Losartan Intervention For
BENEFITS OF TREATMENT OF ISH
Endpoint reduction (LIFE) study compared Losartan
Multiple interventional trails like STOP-1 and STOP-
with atenolol and demonstrated that losartan reduced
2 clearly demonstrated the role of treating ISH in
the risk of stroke and CV death to greater degree than
preventing stroke and coronary artery disease.
atenolol.
Angiotensin II receptor antagonist telmisartan
INTERVENTIONAL TRIAL in isolated systolic hypertension (ARAMIS) studies
CONCERNING ISH demonstrated that Telmisartan (20–80 mg) produce
Systolic hypertension in the elderly (SHEP) showed significant reduction in SBP.
beneficial effect of treating elderly patients with Valsartan in isolated systolic hypertension (VALISH)
hypertension. showed a significant effect on ISH.
Systolic hypertension in Europe (SYST-EUR) showed
a significant reduction (by 42%) in incidence of stroke and SMALLER STUDIES ON ISH
vascular dementia (by 50%) by nitrendipine treatment. ACE inhibitors like Lisinopril, Enalpril, Periondopril are
Systolic hypertension in China (SYST-China) trial also suitable for blood pressure control in ISH patients
having the design quiet similar to that of the SYST-EUR and favorably influence cardiovascular risk factors.
CHAPTER 8: Management of Isolated Systolic Hypertension: Current Concepts 49
In 1578–1657 William Harvey described that blood Charles Friedberg’s in 1949 in his book “Diseases of
flows through the arteries i.e “Circulation of Blood” in Heart” stated that, people with mild benign hypertension
his book “D-e Motu Cordis”. Stephen Hales measured (blood pressure up to 210/100) need not be treated. Over
blood pressure for the first time in 1733. Fredrick next decade more evidence accumulated from various
Akbar Mohamed (1849–1884) reported for the first studies and Framingham heart study stated that benign
time that blood pressure can be elevated without hypertension can result in death and cardiovascular
kidney disease. Scipione Riva-Rocci 1896 invented the morbidity. The National Institutes of Health carried
cuff base sphygmomanometer which could help the out various studies on hypertensive populations and
clinician to measure blood pressure in his clinic. In determined that African Americans had a higher burden
1905, Nikolai Korotkoff introduced the korotkoff sounds of hypertension and its complications.
that are heard when the artery is auscultated with the
stethoscope during gradual deflation of the BP cuff of the MANAGEMENT OF HYPERTENSION
sphygmomanometer. Historically, hypertension was called ‘hard pulse disease’
In 1911, Eberhard Frank described term essential and reducing the quantity of blood by blood letting or
hypertension, when BP elevated without any cause. application of leeches was advocated by the emperor of
Physician from Mayo clinic in 1928 describe the term China, Cornelius as well as by scholars like Celsius, Galan
malignant hypertension when BP is very high, with and Hippocrates.
severe retinopathy and adequate renal function, which In the early and mid 20th century, different therapies
resulted in invariable death due to stroke, heart failure or were used for the treatment of hypertension, but very
renal failure in one year. few were effective. Strict sodium restriction (rice diet),
Frankling D Rooseveslt, the then President of America sympathectomy and pyrogen therapy were but some
was found to have blood pressure of 240/140, which was of the modalities used. In 1900, first chemical used
declared normal by his treating physician. The very next for treating hypertension was sodium thiocynate but
day, he succumbed to a stroke (hemorrhage)! was discarded due to its many side effects. In second
In 1931 John Hay, Professor of Medicine from Liver world war and post war hydralazine and reserpine were
pool University and in 1947 Paul Dudley White concluded reasonably effective in controlling the hypertension.
that hypertension is a compensatory mechanism and Major breakthrough was achieved in 1950 with
declared that it should not be tampered with. discovery of diuretics which was well tolerated and
CHAPTER 9: Blood Pressure Control with Changing Time 51
very effective. Chlorthiazide (Diuril) was derived from TABLE 1: Blood pressure goals for hypertension control, JNC 1 –
antibiotic sulphanilamide and available for clinical use JNC 7
from 1958. Report number Committee BP goal (mm Hg) Examples of
The first sponsored trial on hypertension was carried (Year of chair seminal studies/
publication) influential
out comparing hydrochlorothiazide + reserpine + reports
hydralazine verses placebo. This trial was stopped 1 (1977) Marvin DBP <90 8
early due to placebo group having significantly more Moser
complications of hypertension than the treatment group. 2 (1980) Iqbal Krishan zz DBP <90 9
In 1975, the Lashkar special public health award was zz DBP 90–100
for individuals
bestowed upon the team that developed Chlorthiazide.
with moderate
In 1972–1994 with therapy of hypertension there was or severe
significant reduction (50%) in stroke, ischemic heart hypertension
disease and heart failure. 3 (1984) Harriet DBP < 90 10–14
In 1960, British physician James W Black developed Dustan
beta-blockers which were used for angina for which 4 (1988) Aram BP <140/90 15–17
Chobanian
he received the Nobel Prize in 1988. Calcium channel
blockers were discovered next and found to be more 5 (1993) Ray Gifford BP < 140/90 18, 19
effective. In 1977 ACE (Captopril) and more recently ARB 6 (1997) Sheldon BP < 140/90 20–24
Shepsz and “Lower if
were added to the armamentarium. The modern era of tolerated”
treating hypertension was more effective and many trials 7 (2003) Aram zz P < 140/90
B 25, 26
were carried out in clinical practice. zz <130/80 in
Between 1977 and 2003, under the direction patients with
of National Institutes of Health, the Joint National JNC 1 based on limited Clinical Trail Data recommended that, all
Committee on Detection, Evaluation and Treatment persons with diastolic blood pressure more than 105 mm/Hg to be
of high blood pressure (JNC) issued 7 reports. The treated with anti hypertension Drug Therapy, while DBP 90/104 mm/
Hg recommended on individual basis with other risk factors.
JNC 8 guidelines were in process for several years and
the National Institute of Health subsequently made TABLE 2: JNC 2 classification of hypertension
the decision to withdraw from issuing guidelines. The
Classification Diastolic blood pressure (mm Hg)
responsibility for issuing the hypertension guidelines
Stratum 1 (mild) 90–104
was transferred to the American Heart Association (AHA)
Stratum 2 (moderate) 105–114
and American college of cardiology (ACC). Without
Stratum 3 (severe) > 115
the endorsement of AHA and NIH, JNC 8 committee
members issued guidelines for treating hypertension Step care approach. Thiazide diuretic and adding the other drugs, the
blood pressure should be controlled.
which is based on clinical trials carried out in the past.
The impact of guidelines the 1950 and 1996 age
JNC 1974 TO 2003 (1 TO 7) (TABLES 1 TO 6) adjusted mortality rates for stroke and CVS disease in
The JNC define hypertension and management based on USA decrease by 60–70% and the public awareness about
newer understanding pathophysiology of hypertension. the hypertension was increased.
The purpose of this review of JNC-1 to JNC-8 is keeping WHO/ISH also recommended a step-wise approach
track the changing recommendations for hypertension to drug therapy starting with diuretics, similar to the
management over time and to realise the dynamic nature JNC. However, subsequent WHO/ISH reports expanded
of the process of developing treatment guidelines. JNC, the recommendation for an starting drug therapy with
European and Canadian reports represent consensus any one of 5 different classes of anti hypertensive agents
document written by panel of experts.
52 SECTION 1: Hypertension
TABLE 3: JNC 3 and JNC 4 classification of hypertension TABLE 6: JNC 7 classification of hypertension
Classification BP range (mm Hg) Classification Systolic BP (mm Hg) Diastolic BP (mm Hg)
Diastolic Normal <120 AND < 80
Prehypertension 120–139 OR 80–89
Normal BP < 85
Stage 1 hypertension 140–159 OR 90–99
High normal BP 85–89
Stage 2 hypertension >160 OR >110
Mild hypertension 90–104
New clear and concise guidelines for clinician achieving goal blood
Moderate hypertension 105–114 pressure 140/90 mm/Hg and goal blood pressure 130/80 mm/Hg in
Severe hypertension >115 DM, CKD. Thiazide type diuretics recommended as first choice. Two
drugs required to achieve goal blood pressure or blood pressure 20/10
Systolic, when diastolic BP <90 mm/Hg above the goal.
Normal BP <140
Borderline isolated systolic hypertension 140–159 TABLE 7: NICE guidelines blood pressure
Isolated systolic hypertension >160 Step 1 A (for patients aged <55 years) or
C* (for patients aged _55 years and all black people of
Defining therapeutic goals on the basis of diastolic blood pressure. African or Caribbean descent)
Nonpharmacological treatment for DBP 90–94 mm/Hg should be
advised. Step 2 A + C*
Step 3 A+C+D
TABLE 4: JNC 5 classification of hypertension Step 4 Resistant hypertension A + C + D + further diuretic† (or
_ blocker or _ blocker if further diuretic treatment is not
Classification Systolic BP (mm Hg) Diastolic BP (mm Hg) tolerated or is contraindicated or ineffective) Consider
Normal <130 < 85 seeking specialist advice
High normal 130–139 86–89 Abbreviations: Key A, Angiotensin converting enzyme inhibitor or
angiotensin II receptor blocker; C, Calcium channel blocker;
Hypertension 90–104 D, Thiazide-like diuretic
Stage 1 (mild) 140–159 90–99 * Calcium channel blocker preferred, but consider thiazide-like
diuretics in people with oedema or high risk of heart failure
Stage 2 (moderate) 160–179 100–109
† Consider low dose spironolactone or higher doses of thiazide-like
Stage 3 (severe) 180–209 110–119 diuretic
Stage 4 (very severe) >210 >120 If blood pressure measured in the clinic is 140/90 mm Hg or higher:
zz Take a second measurement during the consultation
Advise drug therapy for SBP 140/149 and DBP 90/94 mm/Hg with life zz If the second measurement is substantially different from the first,
style modification and also had target organ damage. Diuretic beta take a third measurement
blocker may be used as first choice. The Goal BP 140/90 mm/Hg for zz Record the lower of the last two measurements as the clinic blood
TABLE 5: JNC 6 classification of hypertension (diuretics, ACE inhibitor, beta blockers, calcium-channel
blocker or alpha-blocker).
Classification Systolic BP (mm Hg) Diastolic BP (mm Hg)
Between 1950 and 1996 in the United States, the
Optimal <120 AND < 80
age-adjusted mortality rates for cardiovascular disease
Normal <130 AND < 85
and cerebrovascular accidents declined by 70% and
High normal 130–139 OR 86–89
60% respectively. These trends began about 1–2 decades
Hypertension
before the JNC 1. Between 1999 and 2009, the relative
Stage 1 140–159 OR 90–99
rates of death attributed to cardiovascular disease and
Stage 2 160 – 179 OR 100–109
cerebrovascular accidents declined by 33% and 37%
Stage 3 180–209 OR ≥110
respectively. This data represents the impact that the
Use risk stratification as part of treatment. High normal BP > 140/90
mm of Hg treatment should be initiated with beta blocker or diuretics.
guidelines have had on outcomes (Tables 7 and 8).
The compelling indication the specific drugs should be given e.g. These guidelines encorporate the atherosclerotic
Diabetes, CCF, systolic dysfunction, myocardial infarction and chronic cardiovascular risk calculator and reduce the cut off of
renal disease.
hypertension to 130 mm Hg and 80 mm Hg for systolic
CHAPTER 9: Blood Pressure Control with Changing Time 53
TABLE 8: The Indian guidelines blood pressure classification (Age 18 and above)
Category SBP (mm Hg) DBP (mm Hg)
Optimal < 120 AND < 80
Normal <130 AND < 85
High normal 130–139 85–89
Hypertension
Stage 1 140–159 90–99
Stage 2 160–179 100–109
Stage 3 >180 >110
Isolated systolic hypertension
Grade I 140–159 <90
Grade II >160 <90
TABLE 9: ACC/AHA guidelines for high blood pressure in adults: November 2017
BP category Systolic BP Diastolic BP Treatment or follow-up
Normal <120 mm Hg <80 mm Hg Evaluate yearly; encourage healthy lifestyle changes to maintain normal BP
Elevated 120–129 mm Hg <80 mm Hg Recommend healthy lifestyle changes and reassess in 3–6 months
Hypertension: Stage 1 130–139 mm Hg 80–89 mm Hg Assess the 10-year risk for heart disease and strok using the atherosclerotic
cardiovascular disease (ASCVD) risk calculator
zz If risk is less than 10%, start with healthy lifestyle recommendations and
Hypertension: Stage 2 >140 mm Hg >90 mm Hg Recommend healthy lifestyle changes and BP-lowering medication (2
medications of different classes); reassess in 1 month for effectiveness
zz If goal is met after 1 month, reassess in 3–6 months
and diastolic blood pressure respectively. The targets for opinions regarding hypertension management.
blood pressure control have also been reduced to 130 The goal would be resolution by an evidence based
mm Hg and 80 mm Hg for systolic and diastolic blood approach rather than by consensus statements. This
pressure respectively. This may represent the evolution would require collaboration with funding agencies.
of blood pressure management or may represent the The association of hypertension with other cardio
adhearance of evidence based approach to a fault. The vascular disease risk factors has been established
jury is still out on the practicality of these guidelines since decades. In a recent editorial, Peterson et al.
(Tables 7 and 8). suggested an integrated approach for prevention,
detection, evaluation and treatment of overall
Improving the Impact of Guidelines cardiovascular disease to have a greater impact than
(Table 9) discrete guidelines targeted for each individual risk
The following additional strategies could be considered to factor.
improve the impact of guidelines for hypertension: From a clinical and practical perspective, the primary
Research strategies might be recommended by hurdles to hypertension control may be related to the
guideline committes to resolve differences of inadequate implementation of recommendations by
54 SECTION 1: Hypertension
both health care providers and patients rather than recommendations by different groups highlights the
the guidelines themselves. The guidelines do not difficulty of translating science into policy especially while
devote attension to strategies for overcoming these remaining patient centric. Conflicting recommendations
barriers in implementation. Addressing these issues tend to confuse the health care providers and patients
will require collaboration with disciplines and patient alike with a potentially to challenge the credibility of all
groups that have historically never been involved in recommendations. This will remain a major challenge to
guideline formation. all professional groups in the time to come.
Finally, guidelines currently serve an important
educational function and should not be considered as BIBLIOGRAPHY
rigid rules for action. They serve the healthcare provider 1. Hypertension Detection and Follow-up Program Cooperative
Group. The effect of treatment on mortality in “mild”
to make informed clinical decisions and judgments
hypertension. N Engl J Med. 1983;307:976-80.
regarding the treatment of individual patients. 2. Joint National Committee on Detection, Evaluation,
and Treatment of High Blood Pressure. Report of the
CONCLUSION AND PERSPECTIVES Joint National Committee on Detection, Evaluation, and
In conclusion, guidelines are consensus statements Treatment of High Blood Pressure: a cooperative study.
JAMA. 1977;237:255-61.
developed by panels of experts in the field. Without a
3. Joint National Committee on Detection, Evaluation, and
doubt institution of guidelines for hypertension have Treatment of High Blood Pressure. The 1980 report of
contributed to improved blood pressure control and the Joint National Committee on Detection, Evaluation,
reduced death rates attributable to cardiovascular and Treatment of High Blood Pressure. Arch Intern Med.
diseases over the past few decades. As expected, 1980;140:1280-5.
guidelines change over time, based on new information 4. Joint National Committee on Detection, Evaluation, and
Treatment of High Blood Pressure. The 1984 report of
and research and also on the basis of development
the Joint National Committee on Detection, Evaluation,
and availability of effective antihypertensive agents. and Treatment of High Blood Pressure. Arch Intern Med.
Nevertheless, the rates of uncontrolled hypertension 1984;144:1045-57.
and cardiovascular diseases remain unacceptably high, 5. Joint National Committee on Detection, Evaluation, and
constituting the leading cause of mortality in the United Treatment of High Blood Pressure. The 1988 report of
the Joint National Committee on Detection, Evaluation,
States, accounting for approximately 34% of all deaths
and Treatment of High Blood Pressure. Arch Intern Med.
annually. 1988;148:1023-38.
The lengthy delay in producing a revision of 6. Joint National Committee on Detection, Evaluation, and
JNC 7 guidelines reflects a vulnerability of the guideline Treatment of High Blood Pressure. The fifth report of the
process. Compared to the NIH’s involvement in directing Joint National Committee on Detection, Evaluation, and
the JNC reports, European and Canadian guidelines Treatment of High Blood Pressure (JNC V). Arch Intern Med.
1993;153:154-83.
have been directed by professional societies rather
7. Peterson ED, Gaziano M, Greenland P. Recommendations
than by a funding agency. Europeans and Canadians for treating hypertension: What are the right goals and
approaches have, therefore been more pragmatic purposes? JAMA Published online Dec 18, 2013.
than the JNC reports in their approach, with a regular 8. Tanner L. Panel shifts blood pressure goal Milwaukee
frequency of reports and flexibility in changing earlier Journal Sentinel, Dec 19,2013;p3A.
9. WHO Expert Committee: Arterial hypertension. Technical
recommendations with emphasis on implementation
Report Series No. 628 Geneva. World Health Organization.
strategies. The recent decision by NHLBI to transfer the 1978.
responsibility for guideline development to the AHA 10. Working Group on Hypertension in the Elderly Statement on
and ACC is a reasonable step. The current variation in hypertension in the elderly. JAMA. 1986;256:70-4.
CHAPTER
10
Management of Hypertension in Diabetes
BB Thakur, Smita Thakur
TABLE 1: BP patterns based on office and out-of-office measure diuretics should be continued or not. Support stockings
ments may be helpful in orthostatic hypertensive patients.11
BP category Office/Clinic/ Home/Nonhealthcare/ Compared to patients without diabetes, hypertension
Healthcare setting Ambulatory BP monitoring
is characterized by an earlier onset of systolic
setting
hypertension and ISH is more prevalent at any age.12
Normotensive No hypertension No hypertension
The coexistence of hypertension and type 2 diabetes
Sustained Hypertension Hypertension
hypertension
is more common in women and the systolic BP is
higher in women compared to men.12 The clustering
Masked No hypertension Hypertension
hypertension of hypertension, glucose intolerance or frank type 2
Whitecoat Hypertension No hypertension diabetes, hyperlipidemia, central obesity and insulin
hypertension resistance has been documented in several populations
including Indians.13
glycemic control, and the presence of kidney disease
and other factors.4,5 The overall prevalence is estimated Hypertension in Diabetes: Complications
to be 1.5–3 times higher than that of no diabetic age- Extensive epidemiological evidences indicate that
matched groups. Regardless of age 80% of adults with diabetes mellitus along with dyslipidemia, obesity and
diabetes mellitus have hypertension.6 Before we come hypertension greatly increases the risk of development
to a definitive diagnosis of hypertension, we should and progression of atherosclerotic cardiovascular
consider and exclude masked hypertension, white-coat disease (ASCVD) resulting in a higher incidence of
hypertension and pseudo-hypertension (Table 1). coronary heart disease, heart failure, peripheral artery
Identification and exclusion of these conditions with disease, stroke, etc. with increased risk of morbidity
and mortality.14 Compared to the general population,
home blood pressure monitors helps in avoiding over-
people with diabetes face two to four fold increased
treatment of white-coat hypertension which is not at
risk of cardiovascular disease (CVD). 15 Concomitant
risk of elevated ASCVD and timely treatment of masked
hypertension triples the already high risk of coronary
hypertension to avoid complications. 7 Most of the
artery disease (CAD), doubles total mortality and stroke
evidences of benefits of management of hypertension
risk and may be responsible for up to 75% of all CVD
in diabetes are based on office measurement of blood
events.15 Similarly, hypertension significantly accelerates
pressure except for ACCORD trial.
the progression of diabetic nephropathy, retinopathy,
Orthostatic hypotension in type 2 diabetes is and neuropathy.16,17 Systolic blood pressure is a stronger
commonly found due to Diabetic autonomic neuropathy predictor than diastolic blood pressure for both CVD and
or volume depletion,8 and may be further exacerbated renal complications.
by antihypertensive medications. It’s a decrease in
systolic blood pressure of 20 mmHg or diastolic blood Hypertension in Diabetes: The Goal Blood
pressure of 10 mm Hg in comparison to the blood Pressure?
pressure in sitting or supine position 9 within 3 min How far the blood pressure should be lowered in
of standing and it increases the risk of mortality and people with diabetes? The primary goal of therapy
heart failure.10 It is important to assess for symptoms of of hypertension should be effective control of BP in
orthostatic hypotension to decide the blood pressure order to prevent, reverse or delay the progression of
goal and the most appropriate antihypertensive agent complications and thus reduce the overall risk of an
with its dose to minimize adverse effects of therapy. It individual without adversely affecting the quality of life.
also helps about the timing of antihypertensive drugs There is a continuous relationship between the level of
(to change to night dose) and whether a-blockers and blood pressure and the risk of complications. Starting at
CHAPTER 10: Management of Hypertension in Diabetes 57
115/75 mm Hg, CVD risk doubles with each increment only 28–36% of diabetic hypertensive patients have their
of 20/10 mm Hg throughout the blood pressure range. blood pressure control to target, primarily because of
There are robust data that supports that pharmacologic poor control of systolic blood pressure. Similar level of
treatment of blood pressure in patients with diabetes inadequate blood pressure control have been noted in
reduces the risks of ASCVD, heart failure, retinopathy type 1 diabetic population.37, 38 It’s a matter great concern
and albuminuria18-23 by decreasing both macrovascular that only around 4–10% of diabetic patients meet the
and microvascular complications. In the HOT study combined goals for blood pressure, LDL cholesterol and
Diabetic patients with the lowest target DBP had a glycated hemoglobin [HbA1c].
significantly lower risk of CAD. 24 The findings of The Disease, patient and clinician factors contribute
United Kingdom Prospective Diabetes Study (UKPDS) to poor blood pressure control in diabetics also. The
was also in conformity with HOT trial that a tight control isolated systolic blood pressure is more difficult to
of BP (average achieved: 144/82 mm Hg) in diabetic control. Clinician inertia—the failure to increase the
patients conferred a substantial reduction in the risk dose or number of medications for patients who do not
of CAD compared to a less tight control of BP (average achieve therapeutic goal is an important contributor to
achieved:25 154/87 mm Hg). poor control of blood pressure. Inadequate knowledge
Large benefits are seen when multiple risk factors of control of hypertension as the most cost-effective
are addressed simultaneously.20 Due to improvement intervention to prevent CVD may be another reason and
in control of blood pressure ASCVD morbidity and time pressure during short office visits with complicated
mortality have decreased substantially in people with patients with diabetes may also be a strong reason for
diabetes since 1990.26-28 Clinical trials using a variety of clinician inertia.
antihypertensive agents have demonstrated that even
modest reduction in blood pressure of just 9–11 mm Hypertension in Diabetes: Treatment
Hg systolic and 2–9 mm Hg diastolic decreases CVD Strategies
events by 34–69% and microvascular complications The basic paradigm for achieving blood pressure goal in
(retinopathy and nephropathy) by 26–46% within just people with diabetes has not changed appreciably from
2–5 years.29-32 that recommended by JNC 7. However, physicians should
The patients and clinicians should discuss and make adopt a more integrated, patient-centered management
a shared decision to determine individual blood pressure of hypertension especially in diabetics by treating the
targets with the understanding that the benefits and risks intricacies of each patient profile including their total
of intensive blood pressure targets are uncertain and CVD risk rather than focusing on the disease in isolation.
may vary across patients (Table 2). Although there are no well-controlled studies on lifestyle
changes in the treatment of hypertension in individuals
Goal: BP with diabetes, studies in nondiabetic individuals have
Hypertension with diabetes mellitus ≤130/80 mm Hg. shown antihypertensive effects similar to pharmacologic
Hypertension with diabetes mellitus and CKD: monotherapy by limiting salt intake to < 2.4 g/day,
≤130/80 mm Hg. reducing excess body weight through caloric restriction;
Hypertension and stable CVD or ≥10% 10-year adopting the Dietary Approaches to Stop Hypertension
ASCVD risk: ≤130/80 mm Hg. (DASH) eating plan, increasing consumption of fruits
and vegetables (8–10 servings per day), and low-fat
Hypertension in Diabetes: Status of dairy products (2–3 servings per day); avoiding excessive
Control alcohol consumption (no more than 2 servings per day
Over all control of vascular risk factors is inadequate in men and no more than 1 serving per day in women),
in people with diabetes. In community-based studies reducing sedentary time, increasing physical activities,
58 SECTION 1: Hypertension
TABLE 2: Randomized controlled trials of intensive vs. standard hypertension treatment strategies
ACCORD BP 4,733 participants with T2D Systolic blood pressure Systolic blood pressure zz No benefit in primary end point:
aged 40–79 years with prior target: <120 mm Hg target: 130–140 mm Hg composite of nonfatal MI, nonfatal
evidence of CVD or multiple Achieved (mean) Achieved (mean) stroke, and CVD death
cardiovascular risk factors systolic/ diastolic: systolic/ diastolic: zz Stroke risk reduced 41% with
Advance BP33 11,140 participants with T2D Intervention: a Control: placebo zz Intervention reduced risk of primary
aged 55 years and older with single-pill, fixed- Achieved (mean) composite end point of major
prior evidence of CVD or dose combination systolic/diastolic: macrovascular and microvascular
multiple cardiovascular risk of perindopril and 141.6/75.2 mm Hg events (9%), death from any cause
factors indapamide Achieved (14%), and death from CVD (18%)
(mean) systolic/ zz 6-year observational follow-up
HOT35 18,790 participants, including Diastolic blood Diastolic blood pressure zz In the overall trial, there was no
1,501 with diabetes pressure target: ≤ 90 mm Hg cardiovascular benefit with more
target: ≤ 80 mm Hg intensive targets
zz In the subpopulation with diabetes,
SPRINT36 9,361 participants without Systolic blood pressure Systolic blood pressure zz Intensive systolic blood pressure
diabetes target: <120 mm Hg target: < 140 mm Hg target lowered risk of the primary
Achieved (mean): Achieved (mean): 136.2 composite outcome 25% (MI, acute
121.4 mm Hg mm Hg coronary syndrome, stroke, heart
failure, and death due to CVD)
zz Intensive target reduced risk of
death 27%
zz Intensive therapy increased risks of
smoking cessation and engaging in yoga-meditation. (systolic blood pressure 130–139 mm Hg or diastolic
Management of obstructive sleep apnea in diabetes has blood pressure 80–89 mm Hg), hence all patients should
also been found to reduce blood pressure.39 Lifestyle be counseled regarding life style modifications (Tables 3
management not only lowers blood pressure but also and 4).
enhances the effectiveness of some antihypertensive
medications, positively affects glycemic and lipid control PHARMACOLOGIC TREATMENT
with positive effect on cardiovascular events and helps Over the past decade, the goals of treatment have
prevent or delay progression of Stage 1 hypertension gradually shifted from optimal lowering of blood pressure
CHAPTER 10: Management of Hypertension in Diabetes 59
↓ Sodium intake <1500 mg/day is optimal goal, but aim for at least 1000 mg/day reduction in most
adults
↑ Potassium intake 3500–5000 mg/day, preferably by consumption of a diet rich in potassium
Physical activity: Add aerobic exercises zz 90–150 min/week
zz 65–75% heart rate reserve
Physical activity: Isometric resistance training zz 4 × 2 min (hand grip), 1 minute of rest between exercises, 30–40% maximum
voluntary contraction, 3 sessions/week
zz 8–10/week
↓ Alcohol consumption For those who drink alcohol, the recommended daily consumption is no more than 2
drinks for men and 1 drink for women
*Type, dose, and expected impact on BP in adults with a normal BP and with hypertension
to patient’s overall well being, control of associated risk48 Class of Antihypertensive Medications
factors and protection from future target organ damage. Clinical trials involving large number of patients with both
Choice of an antihypertensive agent is influenced by diabetes and hypertension have demonstrated reduction
age, concomitant risk factors, presence of target organ in CVD events and microvascular complications with all
damage, other co-existing diseases, socioeconomic most all classes of drugs like diuretics. ACE inhibitors,
issues, and availability of the drug and past experience angiotensin receptor blockers (ARBs), dihydropyridine
of the physician. Due to a greater seasonal variation of (DHP) and nondihydropyridine (non DHP) calcium
temperatures in India, marginal alterations in dosages of channel blockers (CCBs), etc. β-blockers are preferred
drugs may be needed from time to time. in post infarct patients or in those with heart failure or
60 SECTION 1: Hypertension
unstable angina but not as a first line drug in hypertension RAS blocker (direct renin inhibitors) on interaction of
without cardiac problem. Quality of life factors like renin/prorenin with its receptor may be potentially
impotence with diuretics and masking of hypoglycemia useful in patients with diabetes mellitus as a second drug
with β-blockers might be an important factor to deicide or in combination with other drugs. DRI has been found
the therapy. to be cardio and reno protective in some of the trials.
In metabolic syndrome, lifestyle modification with Kidney function test along with assessment of serum
an emphasis on improving insulin sensitivity by means potassium levels is needed regularly if ACE inhibitors,
of dietary modification, weight reduction and exercise is ARBs or diuretics are being used.
the foundation of treatment. Given the modest efficacy In a large scale trial in hypertension with diabetes with
of lifestyle modifications and the importance of prompt single-pill combinations which assessed cardiovascular
blood pressure control, in diabetics with blood pressure and renal outcomes, the Avoiding Cardiovascular Events
≥130/80 antihypertensive drug treatment should be Through Combination Therapy in Patients Living With
initiated with a treatment goal of <130/80 mm Hg. Initial Systolic Hypertension (ACCOMPLISH), in patients with
first-line therapy for stage 1 hypertension includes high risk of cardiovascular events (60% with diabetes)
ACE inhibitors or ARB or CCBs. Two first-line drugs of demonstrated a decrease in morbidity and mortality with
different classes are recommended in patients with stage the ACE inhibitor benazepril plus the dihydropyridine
2 hypertension and those with average BP of 20/10 mm CCB amlodipine versus benazepril and the thiazide-
Hg above the BP target. Titration and/or addition of other like diuretic hydrochlorothiazide in spite of similar
blood pressure drug/drugs should be made at the earliest blood pressure reduction in both.53-55 The other studies
appropriate time to achieve blood pressure targets. like SHIELD and STITCH trials have also observed
In case if the target blood pressure is still not achieved, a better control and achievement of target BP with
a thiazide like diuretic should be added to those with an combination therapy in diabetic hypertensives. Fixed-
estimated glomerular filtration rate (GFR) ≥ 50 mL/min dose antihypertensive drug combination may improve
per 1.73 m2 and a loop diuretic for those with an estimated patient adherence as well as effectiveness in lowering
GFR < 50 mL/min per 1.73 m2. Outcome trials of people blood pressure. The results resembles the benefit that was
with type 1 and type 2 diabetes and established diabetic achieved with a similar ACE inhibitor/calcium antagonist
kidney disease (including urinary albumin excretion ≥ therapy in the ASCOT trial.56 In a recent trial in patients
300 mg/g creatinine) have demonstrated that an ACE with type 2 diabetes and microalbuminuria, Irbesartan
inhibitor or ARB at maximum doses slows the progression has been found to be renoprotective independent of
of kidney disease in comparison to placebo.49,50 Patients its blood pressure lowering effect. The use of both ACE
with any level of albumanria (urinary albumin excretion inhibitors and ARBs in combination is not recommended
≥ 30 mg/g creatinine)51 should be given an ACE inhibitor given the lack of added ASCVD benefit and increased
or ARB as primary antihypertensive agent. In patients rate of adverse events namely, hyperkalemia, syncope,
without albuminuria other antihypertensive agents and acute kidney injury.57
are similar to ACE inhibitors and ARBs.52 Most diabetic Because these patients are at such high cardiovascular
hypertensive patients require a combination of two to risk, they require an integrated intervention that also
three antihypertensive agents to lower blood pressure includes optimal achievement of goals for glycemic
to target and patients with concomitant chronic kidney control (glycated hemoglobin [HbA1 c] <7% and pre-
disease may even require more number of drugs. prandial capillary plasma glucose 70–130 mg/dL,
We may also like to add drugs such as aldosterone normal lipid levels, and inhibition of platelet aggregation
receptor blockers (particularly recommended in obese (therapy with low-dose aspirin 75–162 mg/day). All
diabetic patients and resistant hypertension), a different diabetes patients should be on a statin, with other drugs
sub class of CCBs or alpha-blockers. Addition of another added, if necessary, to bring the LDL to <70 mg/dL,
CHAPTER 10: Management of Hypertension in Diabetes 61
triglycerides <150 mg/dL, and high-density lipoprotein damage including cardiovascular and renal diseases a
cholesterol >40 mg/dL in men and >45 mg/dL in women. lower blood pressure targets (i.e. 140/90 mm Hg) may
We should ascertain that potassium level is <5 mEq/L, be advisable to avoid the progression of these diseases
with lifestyle modifications or adjustment of drug during pregnancy.
therapy, as it is found to decrease the cardiovascular risk. Methyldopa, labetalol, hydralazine and long-
acting nifedipine, clonidine, and prazosin are known
Bed Time Dose to be effective and safe antihypertensive drugs in
Evidence suggests an association between absence pregnancy. ACE inhibitors, ARBs, or spironolactone
of nocturnal blood pressure dipping and ASCVD is contraindicated in pregnancy, as they may cause
events. Significantly reduced cardiovascular events was fetal damage. Diuretic use during pregnancy has been
observed by shifting one antihypertensive medication to associated with restricted maternal plasma volume
bedtime.58,59 Its desirable to give at least one drug in the which might reduce uteroplacental perfusion66 however
evening to them who require multiple drugs. they may be used during late-stage pregnancy if needed
for volume control. Those patients with gestational
Monitoring hypertension who had preeclampsia should have their
Self-management is very important aspect of diabetes blood pressures observed for 72 h in the hospital and
care for both diabetes and hypertension and home blood for 7–10 days’ postpartum.63 Long-term follow-up is
pressure monitoring is essential and it’s as reliable as 24-h recommended for these women, as they have increased
ambulatory blood pressure monitoring and correlates lifetime cardiovascular risk.
better with ASCVD risk than office measurements. 60
Home blood pressures improves patient medication Hypertension in Diabetes: Resistant
adherence61 and cardiovascular risk reduction62 so the
Hypertension
updated guideline emphasizes patients to monitor their
Mineralocorticoid receptor antagonists (MRAs) are
own BP for hypertension diagnosis, treatment, and
effective for management of resistant hypertension in type
management.
2 diabetics and they may be added to the existing drugs
GESTATIONAL DIABETES like a renin-angiotensin system (RAS) inhibitor, diuretic,
and CCB. They reduce sympathetic nerve activity, reduce
The women with gestational hypertension of systolic
blood pressure, ≤ 160 mm Hg or diastolic blood pressure, albuminuria and have added cardiovascular benefits.67-69
≤ 105 mm Hg without the evidence of end-organ However, caution should be applied as they are known to
damage should not be treated with antihypertensive increase the risk of hyperkalemic episodes if added to an
medications, as there is no benefit vis a vis potential ACE inhibitor or ARB which can be managed with dietary
risks of therapy.63 There is no evidence to treat mild to potassium restriction, potassium-wasting diuretics, or
moderate preexisting hypertension in terms of reducing potassium binders.70
the risk of preeclampsia, preterm birth, fetal death, size
of infants in relation to gestational-age. 64 Low-dose Hypertension in Diabetes: Older Adults
aspirin is recommended to start at 12 weeks of gestation In older adults (Aged ≥ 65 years) diabetes and aging leads
for pregnant women at high risk of preeclampsia.65 Blood to arterial stiffness with increase in systolic and decrease
pressure between 120 and 160 mm Hg systolic and 80 in diastolic blood pressure. Systolic blood pressure
and 105 mm Hg diastolic is desirable for women who should be our main target of management in them which
need antihypertensive therapy. Lower blood pressure is difficult to achieve due to arterial stiffness and there
levels may cause impaired fetal growth. In pregnant are chances of iatrogenic complications like volume
women with hypertension and evidence of end-organ depletion, hypoglycemia and orthostatic hypotension.
62 SECTION 1: Hypertension
When considering pharmacological treatment in benefit by lowering blood pressure to target. There
older adults with diabetes we should be careful regarding is robust data that supports targeting blood pressure
drug selection, their doses and earliest sign of side effects reduction to at least 140/90 in most adults with diabetes.
as β-blockers may mask signs of hypoglycemia, drugs In selected patients on an individual basis with high
may increase orthostatic hypotension, and diuretics cardiovascular disease risk lower blood pressure targets
can enhance the volume depletion. Medicine-taking may be beneficial if they can be achieved without
behaviors may be affected in the older aged group due to undue burden and side effects. ACE inhibitors, ARBs,
mental status like cognitive dysfunction. dihydropyridine CCBs and thiazide-like diuretics have
The therapeutic strategy for those who are fit should shown to improve clinical outcomes and are preferred
be similar to that in younger individuals with a blood for blood pressure control. If the target blood pressure
pressure target of 130/80 mm Hg.71 We should initiate goal is not achieved with the initial dose of first-line
therapy with a single agent in the elderly, those with high drug, increases in doses or the addition of a second drug
CVD risk, or patients with a history of hypotension or from a different group are recommended. Regardless
drug-associated side effects. ACE inhibitors, angiotensin of the initial drug treatment In addition to lifestyle
receptor blockers (ARBs), thiazide-like diuretics, or modifications multiple drugs (many will require three
dihydropyridine calcium channel blockers are the drug or more) are often needed to attain blood pressure goal
of choice. Multiple-drug therapy is generally required to of ≤ 130/80 mm Hg. Achievement of the target blood
achieve blood pressure targets. We should be cautious pressure may be more important than the particular
when initiating antihypertensive pharmacotherapy drug regimen used. In patients with albuminuria an ACE
with 2 drugs in older patients because hypotension or inhibitor or ARB should be the initial antihypertensive
orthostatic hypotension may develop. Simultaneously therapy. In patients treated with an ACE inhibitor, ARB or
administering more than 1 renin-angiotensin system diuretic serum/estimated glomerular filtration rate and
blocker should be avoided. serum potassium levels should be monitored frequently.
In those with loss of autonomy and major functional Treatment decisions should, of course be, individualized
limitations, higher systolic blood pressure goals should on the basis of clinical characteristics of the patient
be considered and treatment should be modified in including comorbidities, expected benefit of reduction
the presence of low supine systolic blood pressure or in ASCVD, heart failure, retinopathy and progression of
presence of orthostatic hypotension. diabetic kidney disease and risk of adverse events as well
In older people with impaired vascular compliance as tolerability, personal preference and cost especially for
and pulse pressure of 60 mm Hg we should be careful in poor patients. Less expensive fixed-dose combinations
reducing the systolic pressure against the risk of lowering of many drugs are available with better compliance.
diastolic pressure below 65–70 mm Hg as lowering Effective behavioral and motivational strategies are
of diastolic pressure below 65–70 mm Hg in this age recommended to promote lifestyle modification along
increases the risk for coronary heart disease, mortality, with integrating home-based monitoring and telehealth
and other adverse cardiovascular outcomes. interventions. Outcome may improve with quality
improvement strategies at the health care system
CONCLUSION provider and patient level.
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66 SECTION 1: Hypertension
How many are really Diagnosed and Are they assessed for CHD risk factors?
—— This does not show daily variation/variation when over lifesyle modifications whereas more stress
the person is under physical stress/mental stress should be put on this.
—— Hence, before deciding complete treatment one —— Proper counseling needs to be given for lifestyle
—— This will show both the trough and crest in blood that lifestyle modifications are maintained.
pressure measurement and hence the physician
The many facets of HT therapy:
is more alert about maximum and minimum Centrally acting agonists
ranges, which makes it easy to prescribe an Diuretics
accurate drug (Fig. 2). Beta blockers
CCBs
Lifestyle Modification ACE inhibitors
Lifestyle modification is the sheet anchor in the ARBs
management hypertension.
This surely reduces the number of drugs used and Which Drug Should We Prescribe ?
their dosage in controlling HT. Choice must be tailored to individual patient
Any drug treatment has value only when coupled Should be rational and as per approved guidelines
with lifestyle modification. Only class1 evidence based medications to be used
Lifestyle modification: Suitable to patients’ purse
Weight reduction—5–20 mm/10 kg weight loss Can never be arbitrary
Adopt DASH eating plan—8–14 mm Hg
To consider HT is only in the ‘ARM’ and not in the Calcium Channel Blockers
body Action: Blocks calcium access to muscle cells. Examples
No concept of ‘pulse pressure’—Not seeing the whole of calcium channel blockers: Verapamil, Nifedipine,
Worry about side effects—Need to watch, not to worry Diltiazem
OK, some control is achieved—Why attain goal BP? Side effects
Not insisting on compliance with drugs and assess BP
ments Bradycardia
Pressure from patients—BP How much? May precipitate AV block
Concentrating on the pill and not on the ill—TLC Headache
Potassium supplement—KCL
cause psychological stress and hence cause increase
in hypertension.
Potassium‐sparing: Prevent hypokalemia
Mild HTN
ACE inhibitors
Angiotensin converting enzymes ending pril
Used in combination with other diuretics
Captopril
No supplement taken
Enalapril
Watch for hyperkalemia
Benzapril
Orthostatic hypotension
—— Peripheral vascular resistanse without
Dry mouth, irritation
cardiac output
<3.5)
Side effects
Disorientation
Headache
Dehydration
Orthostatic hypotension‐infrequent
Hypokalemia—Muscle pain and fatigue
Cough
Hyperuricemia—Inhibition of urate excretion
GI distress
Both cause pain, patient feels fatigued, not proper rest
and hence thiazide diuretics should be discontinued. Cough can cause a patient to stay awake in the night
Diuretics cause electrolyte imbalance which can can cause lack of sleep and hypertension.
cause disorientation which can cause missed doses of Hence, a patient receiving ACE inhibitors should be
antihypertensives which cause increase in hypertension. carefully monitored for these side effects.
70 SECTION 1: Hypertension
Bronchospasm, wheezing
Diabetic: Hypoglycemia
Headache
Direct Acting Vasodilators
Dizziness, tachycardia, fainting
Action: Direct arteriolar smooth muscle relaxation,
Weakness, lethargy
decreasing PVR
Uses: HTN, renal dx., toxemia of pregnancy
Interactions: Other antihypertensives (enhance
High Dose Statin Trials: IDEAL, 19 TNT, 20 PROVE IT with abnormal deposition of collagen, 26,27 leading to
TIMI-22,18 MIRCL9 have given good results. The benefit ventricular dysfunction after AMI. Ang-II stimulates
of statins starts early, in PROVE IT TIMI-22, Clinical fibroblasts to produce collagen and enhances chanses
benefits appeared in four weeks and MIRACL study after of fibrosis. So, there is evidences that Ang-II enhances
four months. High dose use of statin has been found atherosclerotic process. ACE inhibitors are beneficial for
to significantly reduce MI, unstable angina, CVA and CV health due to anti-inflammatory, plaque stabilizing,
chances of revascularization.21 anti-atherothrombotic and antiproliferative properties.
A recent meta-analysis involving 8 trials has shown a ACE inhibitors also reduce MMPs, hsCRP and platelet
statistically significant reduction of CV events when LDL aggregation.28 Meta-analysis of several trials have shown
level between 75 and 100 mg/dL was brought to less than reduced CV events on use of ACE inhibitors.29 The benefit
50 mg/dL.22 of HOPE and LIFE trials are well known. In PROGRESS
trial, risk reduction was 26% in CVD and 28% in stroke.30
CHOLESTEROL ABSORPTION INHIBITOR
Addition of Ezetimibe, when required, may be helpful in Anti-inflammatory Agents
further lipid lowering. Keeping in mind the immense role of inflammation
in causation of atherosclerosis, role of other anti-
Fibrates inflammatory agents such as methotrexate, colchicin,
Hypertriglyceridemia (↑ TG) appears to increase risk hydroxychloroquin, etanercep, toclizumab, cana
of CVD. There is some evidence that post prandial kinumab are being studied. Anti-inflammatory agent
increased level of TG may be a potent risk factor for canakinumab which is IL-1 beta inhibitor, has been
CVD and it may be an independent risk factor.23 A more recently evaluated in the CANTOS trial, 31 results of
recent and large meta-analysis involving 61 studies (N which came out in August 2017 only. This large trial
= 330566) has reported 22% increase in risk of CVD for included cases of previous MI with elevated hsCRP
every 88 mg/dL increase in TG.24 and were already on standard treatment including high
dose statin. Patients were given 150 mg canakinumab
PCSK-9 Inhibitors: Alirocumab, injection subcutaneous once in three month. Follow-up
Evolocumab period was four years. There was reduction in hs-CRP
Evolocumab subcutaneous monthly injection may be level by 37% and reduction in risk of major CV events by
used in extreme risk and still elevated LDL level despite 15% independent of lipid lowering. There was reduction
statins. It can be combined with statins. In the FOURIER in the incidence of lung cancer also. These findings are
trial25 on 27500 patients with baseline LDL level of 75 revolutionary.
mg/dL and already on statin treatment were given
evolocumab for 2.2 years. They showed 20% decrease CONCLUSION
in risk compared to placebo group. But this is expensive So,we have many weapons in our hand to check
and not cost effective. atherosclerosis. Life-style measures, control of risk
factors, lipid lowering drugs like statin (which have actions
ACE Inhibitors and ARB beyond lipid lowering including anti-inflammatory
Harmful effects of angiotensin-II (Ang-II) are well known. actions), PCSK-9 inhibitors which are more potent (but
It causes vasoconstriction, vascular inflammation, availability and cost are concerns) are well known. ACE
cardiac hypertrophy, activation of sympathetic inhibitors and ARB have already established their role
nervous system. Ang II has toxic effects on myocytes; in atherosclerosis. Anti-inflammatory agents such as
stimulates fibroblasts and causes muscle hypertrophy canakinumab has shown great promise. All methods are
78 SECTION 2: Cardiology
rewarding, but important factor is how intelligently, and The MIRACL study, a randomized controlled trial. JAMA.
optimally we utilize them. 2001;285 (13):1711-8.
10. Brugts JJ, Yetgin T, Hocks SE, et al. The benefits of statins in
Taming of atherosclerosis has become possible and
people without established cardiovascular disease but with
is bound to increase longevity of mankind; efforts must cardiovascular risk factors: Meta-analysis of randomized
go on. controlled trials. BMJ. 2009;338:b2376.
11. Taylor F, Ward K, Moore TH, et al. Statins for the primary
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Cardiol. 2007;100:1659-64. 19. Pedersen TR, Paergeman O, Kastelein JJ, et al. High dose
8. LIPID Study Group. Prevention of cardiovascular events atorvastatin vs usual dose simvastatin for secondary
and death with pravastatin in patients with coronary heart prevention after myocardial infarction. The IDIAL study: A
disease and a broad range of initial cholesterol level. The randomized controlled trial. JAMA. 2006;294(19):2437-45.
long term intervention with pravastatin in ischaemic heart 20. Larosa JC, Deedwania PC, Shepherd, et al. TNT investigators,
disease (LIPID) study group. N Engl J Med. 1998;339:1349- comparison of 80 versus 10 mg of atorvastatin on
57. occurrence of cardiovascular events after the first event
9. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Myocardial (from the treating to new targets [TNT] trial). Am J Cardiol
ischaemia reduction with aggressive cholesterol lowering 2010;105(3):283-7.
(MIRACL) study investigators. Effect of atrovastatin on early 21. Ridker PM, Danielson E, Fonseca FA, et al. Reduction of
recurrent ischaemic events in acute coronary syndrome: C-reactive protein and LDL cholesterol and cardiovascular
CHAPTER 12: Atherosclerosis: Can We Tame it? 79
event rates after initiation of rosuvastatin: A prospective 27. Weber KT, Brilla CG. Pathological hypertrophy and cardiac
study of JUPITER trial. Lancet. 2009;373:1175-82. interstitium, fibrosis and rennin-angiotensin-aldosterone
22. Boekholdt SM, Houingh GK, Mora S, et al. Very low levels system. Circulation. 1991;83:1849-65.
of atherogenic lipoproteins and the risk of cardiovascular 28. Scheiffer B, Bunte C, Witte J, et al. Comparative effects
events: A meta-analysis of statin trials. JACC. 2014;64:485- of AT-1 antagonism and angiotensin converting enzyme
94. inhibition upon markers of inflammation and platelet
23. Bansal S, Buring JE, Rifai N, et al. Fasting compared with aggregation in patients with coronary artery disease. JACC.
non fasting triglyceride and the risk of cardiovascular events 2004;44:362-8.
in women. JAMA. 2007;298:309-16. 29. Al-Mallah MH, Tleyjeh IM, AbdeL-Latif AA, et al. Angiotensin
24. Liu J, Zeng FF, Liu ZM, et al. Effects of blood triglycerides on converting enzyme inhibitors in coronary artery disease and
cardiovascular and all cause mortality: A systematic review preserved left ventricular systolic function: A systematic
and meta-analysis of 61 prospective studies. Lipid Health review and meta-analysis of randomized controlled trials.
Dis 2013;12:159. JACC. 2006; 47:1575-83.
25. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab 30. PROGRESS collaborative group. Randomised trial of
and clinical outcomes in patients with cardiovascular a perindropril based blood pressure lowering regimen
disease N Engl J Med. 2017. among 6105 individuals with previous stroke or transient
26. Lonn EM, Yusuf S, Jha P, et al. Emerging role of angiotensin- ischaemic attack. Lancet. 2001;358:1033-41.
converting enzyme inhibitors in cardiac and vascular 31. Ridker PM, et al. Anti-inflammatory therapy with canakinumab
protection. Ciruculation. 1994; 90:2056-69. for atherosclerotic disease. N Engl J Med. 2017.
CHAPTER
13
Cardiac Cachexia
AKP Singh
INTRODUCTION
Heart failure is currently appreciated as a systemic
and other multiorgan syndrome. The myocardium,
peripheral tissues and organs are affected by metabolic
failure, resulting in a global imbalance between catabolic
and anabolic signals, leading to tissue wasting and
ultimately to cachexia.
Cachexia is recognized today as severe complication
of CHF that worsens clinical symptoms and carries a
particulary Grave prognosis. Mortality in HF patients
with cachexia was as high as 50% at 18 months of follow-
up, compared with 17% in noncachectic patients.
evidence that PCI improves anginal status. The MASS angiographically significant with fractional flow reserve
II trial randomly assigned 611 patients with multivessel (FFR) measurement.12
disease, preserved left ventricular systolic function, and Patients who had at least one stenosis in a major
stable angina to CABG, PCI or optimal medical therapy.13 coronary artery having an FFR of 0.80 or less were
At one year, 88% of the patients in the CABG group, 79% randomly assigned to undergo FFR-guided PCI (stenoses
in the PCI group, and 46% in the medical therapy group with FFR ≤0.80 were to be treated with a drug-eluting
were angina free (p<0.0001). Furthermore, 10-year rates stent) along with best medical therapy or best medical
of freedom from angina were 64% with CABG, 59% with therapy alone. It was found that FFR guided PCI along
PCI, and 43% with medical therapy (P<0.001). with the best available medical therapy, as compared
with the best available medical therapy alone in patients
PATIENTS WITHOUT CLEAR with stable CAD and functionally significant stenoses
INDICATIONS FOR INTERVENTION decreased the need for urgent revascularization.
However in patients without ischemia, the best available
In some patients with stable CAD, the choice between
medical therapy appeared to have a favorable outcome.
revascularization and optimal medical therapy is not
Important limitations of FAME 2 include the absence
clear. The following factors need to be considered in this
of noninvasive documentation of ischemia prior to
patients.
diagnostic coronary angiography and the fact that it
was stopped early. Despite these limitations, FAME
Patient Preference
2 supports the use of PCI with stent in patients with
Patient preference becomes important for those
documented ischemia involving at least a moderate
who are not found to have anatomy that mandates
myocardial territory.
revascularization based upon a survival benefit. A
thorough discussion of the potential benefits and risks Reduced Left Ventricular Systolic Function
of revascularization should be explained to the patient.
Most of the patients enrolled in the randomized trials of
The discussion should emphasize both the benefits of
stable CAD had normal or near normal left ventricular
PCI (less angina and a lower likelihood of requiring an systolic function. Revascularization was found to
intervention in the first few years) and the drawbacks of improve symptoms as well as provide survival advantage
PCI, including the inherent risks of the procedure and in those subset of patients having a depressed left
the potential problems of long-term dual antiplatelet ventricular systolic function.
therapy. This discussion should take place before
diagnostic coronary angiography, since PCI is often REFERENCES
performed immediately after. The concept of the “heart 1. Alderman EL, Kip KE, Whitlow PL, et al. Native coronary
team” to fully discuss the risks and benefits of both PCI disease progression exceeds failed revascularization as
and CABG as well as OMT is encouraged.14,15 cause of angina after five years in the Bypass Angioplasty
Revascularization Investigation (BARI). J Am Coll Cardiol.
2004;44:766.
Severity of Coronary Artery Disease 2. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery
There is some evidence that in patients with more severe bypass graft surgery on survival: overview of 10-year results
CAD, but who do not meet criteria for CABG, outcomes from randomised trials by the Coronary Artery Bypass Graft
are better with PCI than optimal medical therapy. Surgery Trialists Collaboration. Lancet. 1994;344:563.
3. Myers WO, Schaff HV, Gersh BJ, et al. Improved survival
In the FAME 2 randomized trial, patients with stable
of surgically treated patients with triple vessel coronary
CAD who were being considered for PCI underwent artery disease and severe angina pectoris. A report from
diagnostic coronary angiography with subsequent the Coronary Artery Surgery Study (CASS) registry. J Thorac
evaluation of all stenoses that were thought to be Cardiovasc Surg. 1989;97:487.
CHAPTER 14: Is Intervention Still Relevant in Stable CAD? 85
4. Passamani E, Davis KB, Gillespie MJ, Killip T. A randomized 12. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow
trial of coronary artery bypass surgery. Survival of patients reserve-guided PCI versus medical therapy in stable
with a low ejection fraction. N Engl J Med. 1985;312:1665. coronary disease. N Engl J Med. 2012;367:991.
5. Katritsis DG, Ioannidis JP. Percutaneous coronar y 13. Hueb W, Soares PR, Gersh BJ, et al. The medicine,
intervention versus conservative therapy in nonacute angioplasty, or surgery study (MASS-II): a randomized,
coronary artery disease: a meta-analysis. Circulation. controlled clinical trial of three therapeutic strategies for
2005;111:2906-12. multivessel coronary artery disease: one-year results. J Am
6. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical Coll Cardiol. 2004;43:1743.
therapy with or without PCI for stable coronary disease. N 14. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/
Engl J Med. 2007;356:1503. ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and
7. Sedlis SP. Effect of PCI. N Engl J Med. 2015; 1937. management of patients with stable ischemic heart disease:
8. W i n d e c ke r S , S to r te c k y S , S te f a n i n i G G , e t a l . executive summary: a report of the American College of
Revascularisation versus medical treatment in patients Cardiology Foundation/American Heart Association task
with stable coronary artery disease: network meta-analysis. force on practice guidelines, and the American College
BMJ. 2014;348:g3859. of Physicians, American Association for Thoracic Surgery,
9. Stergiopoulos K, Brown DL. Initial coronary stent implantation Preventive Cardiovascular Nurses Association, Society for
with medical therapy vs medical therapy alone for stable Cardiovascular Angiography and Interventions, and Society
coronary artery disease: meta-analysis of randomized of Thoracic Surgeons. Circulation. 2012;126:3097.
controlled trials. Arch Intern Med. 2012;172:312. 15. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/
10. Bangalore S, Pursnani S, Kumar S, Bagos PG. Percutaneous ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis
coronary intervention versus optimal medical therapy and management of patients with stable ischemic heart
for prevention of spontaneous myocardial infarction in disease: a report of the American College of Cardiology
subjects with stable ischemic heart disease. Circulation. Foundation/American Hear t Association task force
2013;127:769. on practice guidelines, and the American College of
11. Shaw LJ, Berman DS, Maron DJ, et al. Optimal medical Physicians, American Association for Thoracic Surgery,
therapy with or without percutaneous coronary intervention Preventive Cardiovascular Nurses Association, Society for
to reduce ischemic burden: results from the Clinical Cardiovascular Angiography and Interventions, and Society
Outcomes Utilizing Revascularization and Aggressive Drug of Thoracic Surgeons. Circulation. 2012;126:e354.
Evaluation (COURAGE) trial nuclear substudy. Circulation.
2008;117:1283.
CHAPTER
15
Newer Oral Anticoagulants
in Clinical Practice
Anshul Kumar Jain
The term ‘newer oral anticoagulants’ (NOACs) refers to above VKAs in being safe, easy to use, not requiring any
a class of direct inhibitors of factor Xa or thrombin that blood tests and assured anticoagulant efficacy. Of course,
have been introduced recently in clinical practice. The the cost remains a major deterrent for wide scale use
major indications of use of the oral anticoagulants are of these drugs in India. One needs to exercise caution
in treatment and prevention of deep vein thrombosis for potential drug interactions and presence of renal
(DVT) and pulmonary embolism dysfunction while using them.
and stroke prevention for nonvalvular atrial The SAMe-TT2R2 scale identifies the patients that are
fibrillation (based on CHAD2DS2-VASc score) unlikely to respond well to VKAs (time in therapeutic
The term ‘nonvalvular’ excludes the patents with range less than 65%) and hence predicts preference for
atrial fibrillation who have either moderate to severe use of NOACs. This scale includes in Table 1.
mitral stenosis or a prosthetic valve. All cases with aortic The NOACs available for clinical use are summarized
stenosis, mitral regurgitation, postmitral repair, or in Table 2 with their basic pharmacology and dosing for
bioprosthetic valve (except first three months of surgery) various indications of oral anticoagulation.
are considered ‘non-valvular’.
Well-designed large trials have confirmed the efficacy TABLE 1: The SAMe-TT2R2
of using the NOACs in the above indications as compared zz Sex (female) 1
to the traditionally used Vitamin K antagonists (VKAs). zz Age<60 1 Total points 0–2 predicts
good response to VKA.
zz Medical history (at least 2 of 1
COMPARISON OF NOACs WITH VKA the following: hypertension,
diabetes, congestive heart
The VKAs are very effective oral anticoagulants which
failure, previous stroke,
have been used for the past several decades. They require pulmonary, hepatic or renal
the INR to be maintained within a predefined therapeutic disease)
range for which repeated blood tests are needed. Dietary zz Treatment-interacting drugs 1 2 or more favors use of
restrictions and drug interactions further complicate especially like amiodarone NOACs
zz Tobacco intake within 2 years 2
the use of these drugs. The most dreaded adverse effect
zz Race (non-caucasian) 2
includes intracranial bleeding, to which the Asian
Maximum score 8
population is very susceptible. The NOACs score well
CHAPTER 15: Newer Oral Anticoagulants in Clinical Practice 87
—— Dabigatran 150 mg twice a day (110 mg for GFR 30-50 mL/min) as per need. This therapy must be started after initial therapy with
parenteral anticoagulation.
—— Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg daily as per need.
—— Apixaban 10 mg twice a day for 7 days followed by 5 mg twice daily as per need. The dose for prevention of recurrent events is 2.5 mg
twice daily.
zz DVT prophylaxis after hip or knee replacement (dose to be started 24 hours after low risk surgery or 48–72 hours after high-risk surgery):
—— Dabigatran 220 mg (150 mg if GFR 30–50 mL/min) once daily for 2 weeks after TKR and 35 days after THR
—— Rivaroxaban 10 mg once daily for 2 weeks after TKR and 35 days after THR
—— Apixaban 2.5 mg once daily for 2 weeks after TKR and 35 days after THR.
The following points need to be stressed while using monitored at one month and then six monthly. In
the NOACs: case of pre-existing renal dysfunction, more frequent
tests may be ordered.
Patient Education Female patients must be warned about potential
Follow-up: The patients must be counselled about increase in menstrual flow with these drugs. Available
the need to use this class of drugs carefully. Routine data suggests a minimally increased menstrual
monitoring for any bleeding, renal impairment must bleeding with rivaroxaban specially. In case of
be done. Blood counts and renal function must be unusual bleed, the dose may be reduced, or the
88 SECTION 2: Cardiology
drug may be discontinued for a few days or changed elderly who may better tolerate/or not tolerate the
to apixaban, which is supposed to have a lesser anticoagulation.
incidence. (Female sex is an independent risk factor
for thrombotic episodes in the CHAD 2DS 2-VASc Extreme Weight
score but is not associated with overall higher rates of Obese patients have a higher risk of developing atrial
bleeding in response to NOAC administration). fibrillation (AF) (4% increase per unit increase in BMI).
Drug interactions: In our country, where a large There is no need to increase the dose of NOACs in obese
number of drugs are easily available without patients but there are some suggestions that these drugs
prescription, one must warn the patients about the should not be used in patients with BMI more than 40 kg/
use of NSAIDs, antibiotics, and antiplatelet agents. m2 or weight more than 120 kg because of limited data
Special note must be made of concomitant use of on drug usage in this subgroup and fear of suboptimal
macrolide group, antifungals and rifampicin used anticoagulation attained.
commonly in India that may inhibit or induce the The low weight on the other hand is a risk factor
drug metabolism. Similarly, antiarrhythmic drugs for excessive bleeding and the dosage of Apixaban and
like cordarone, verapamil, and diltiazem and anti- Edoxaban needs to be modified as per guidelines (Table 1).
epileptic drugs like carbamazepine also need careful
attention, if coadministered. Renal Failure
Missed dose: In case of missed dose of a drug with Table 2 summarizes the dosage of NOACs in patents with
twice a day dose, next dose may be taken upto 6 hours renal dysfunction.
before the next dose, else it has to be omitted. For
once a day dosing, the dose may be taken upto 12 Bleeding Complications/Antidote
hours after the scheduled time, else omitted. Though rare, bleeding by far is the most important
Double dose: In this case, omit the next dose after 12 adverse effect of these drugs. The effect of the drugs
hours and resume the routine next day. For once a vains off in 12–24 hours (may be delayed in presence of
day drugs, resume the schedule the next day. renal dysfunction). Other measures to contain bleeding
include:
Age/Fraility Maintenance of local hemostasis
3
The elderly patients more than 75 years of age are highly Replenish blood, and platelets (<60,000 cells/mm ),
score) and then start the drug. Utmost attention must be as a plasma expander, not as a reversal agent)
paid to “fraility index”: D e s m o p re s s i n ( i n ca s e o f c o a g u l o p at hy o r
‘Pre-fragile’ state is defined as the presence of 1–2 of may be used in cases of severe bleeding or conditions
above criterion and more than 3 is classified as ‘fragile’ mandating immediate reversal of anticoagulant
state. This scale helps in better characterization of those effect.
CHAPTER 15: Newer Oral Anticoagulants in Clinical Practice 89
TABLE 1: Variables used to calculate DAPT score when newer antiplatelets like prasugrel and ticagrelor
Variables Points were introduced.
Age >75 years –2 DAPT in ACS: The use of DAPT in patients with ACS was
Age 65–75 years –1 incorporated for the first time when CURE trial showed
Age <65 years 0 that addition of clopidogrel to aspirin versus placebo,
Current cigarette smoker 1 reduced MI, stroke and CV death by 20%. But there was
Diabetes mellitus 1 an increase in major bleeding observed. Further, PLATO
MI at presentation 1 and TRITON TIMI 38 trials showed that ticagrelor and
Stent diameter <3 mm 1 prasugrel were superior to clopidogrel respectively to
Prior PCI or prior MI 1 reduce ischemic events, in patients with ACS. Hence, all
Paclitaxel eluting stent 1 the present guidelines prefer prasugrel or ticagrelor over
CHF or LVEF <30% 2 clopidogrel for DAPT in patients with ACS.
Saphenous vein graft PCI 2
DAPT in stable CAD: The CREDO trial studied 2116
patients undergoing BMS PCI receiving 12 months
BLED, PARIS registry, and PRECISE-DAPT and DAPT
versus 28 days of DAPT. The incidence of ischemic
score. These scores have a moderate but not high level of
events was significantly lower at the ned of 1 year with
discrimination. The simplest and appropriate of them all
12 months of DAPT. With widespread use of DES, there
is the DAPT score (Table 1).
was an increase in the incidence of late stent thrombosis.
Results from the DAPT trial found that patients with
So after USFDA advisory in 2006, 12 months DAPT was
DAPT score >2, there was an 8.2 times greater reduction
recommended with all the generations of DES PCI by
in thrombotic events compared to increase in bleeding
AHA/ ACC.
in patients on prolonged DAPT. Likewise, there was
also increase in bleeding events, 2.4 times the absolute Shorter duration DAPT: Many trials examined safety and
reduction in thrombotic events. Patients on DAPT with efficacy of 6 months vs 12 months DAPT in stable CAD
DAPT score >2 should be treated with prolonged DAPT. after PCI with 2nd generation DES.
Higher the DAPT score (>2), higher is the benefit with
prolonged DAPT. DURATION OF DUAL ANTIPLATELET
THERAPY IN CASES OF STABLE
SHORT-TERM VERSUS LONG TERM CORONARY ARTERY DISEASE (CAD)
DAPT: THE EVIDENCE SO FAR AFTER PCI
In the debate of short term versus long term DAPT, it After PCI with bare metal stents (BMS): BMS is presently
is prudent to understand how the standard duration of limited to patients with bleeding tendency, high
DAPT of 12 months has evolved. Before 2000, clopidogrel likelihood of poor compliance to DAPT or planned
and ticlopidine were the only P2Y12 inhibitors available. elective surgical procedure. Atleast 1 month of DAPT
Ticlopidine use was phased out due to hematologic is recommended to prevent stent thrombosis (Class I)
complications. Till mid 2000, 28 days of DAPT was After PCI with first generation drug eluting stents (DES):
recommended as BMS was in use. Once DES were Earlier, it was thought that patients with first generation
introduced, concerns of late stent thrombosis and DES are at higher risk of acute stent thrombosis. So,
delayed endothelization needed to be addressed. So an 12 months of DAPT was recommended. However,
‘arbitrary cut off’ of 12 months duration of DAPT was 5 RCTs showed that incidence of stent thrombosis
recommended. The spectrum of DAPT became larger were comparable between shorter duration (3–6
92 SECTION 2: Cardiology
TABLE 2: Randomized controlled trials that examined <12 months vs >12 months DAPT
Trials DAPT duration ACS (%) 2nd gen DES Composite primary end point Rates of primary
(%) end point
ISAR-SAFE 6 vs 12 m 40 72 Death, MI, stroke, ST or TIMI major bleeding at 9 m 1.5% vs 1.6%
Italic 6 vs 24 m 24 100 Death, MI, TVR, stroke or TIMI major bleeding at 12 m 1.6% vs 1.5%
Optimise 3 vs 12 m 32 100 Death, MI, stroke or major bleeding at 12 m 6.0% vs 5.8%
Security 6 vs 12 m 38 100 Cardiac death, MI, stroke, ST, BARC 3 or 5 bleeding at 12 m 4.5% vs 3.7%
Prodigy 6 vs 24 m 75 50 Death, MI or stroke at 24 m 10% vs 10.1%
Reset 3 vs 12 m 55 82 Cardiac death, MI, ST, ischemia-driven TVR or bleeding at 12 m 4.7% vs 4.7%
Excellent 6 vs 12 m 51 75 Cardiac death, MI or ischemia-driven TVR at 12 m 4.8% vs 4.3%
months) DAPT and extended duration DAPT (12 DURATION OF DUAL ANTIPLATELET
months) (Table 2). So atleast 6 months of DAPT is THERAPY IN PATIENTS PRESENTING
recommended (Class I) WITH ACUTE CORONARY
After PCI with newer drug eluting stents (everolimus/
SYNDROME (ACS)
zotarolimus): Atleast 6 months of DAPT is recommended
(Class I) Patients of ACS Treated with
In all of the above three groups, DAPT can be extended Medical Therapy Alone
beyond the recommended duration if the patient has low Aspirin is recommended at a daily dose of 81 mg
bleeding risk (Class IIb).
(75–100 mg).
Among patients with stable CAD, clopidogrel is the P2Y12 inhibitor (clopidogrel or ticagrelor) should be
only P2Y12 inhibitor used.
continued for 12 months.
If the patient does not have overt bleeding or high risk
After DES PCI (any generation): of bleeding, DAPT can be continued over 12 months.
6 months
Ticagrelor is preferred over clopidogrel in cases
Duration of • If high bleeding risk after DES:
DAPT in SIHD 3 months presenting with NSTEACS.
• If old MI 1–3 years back: Continue
In SIHD, only DAPT, if low bleeding risk Patients of ACS Treated with Fibrinolysis
clopidogrel is After BMS PCI: 1 month
approved with aspirin If low bleeding risk: continue DAPT
Aspirin is recommended at a daily dose of 81 mg (75–100
>1 year after PCI mg). Clopidogrel is the P2Y12 inhibitor recommended
After CABG: Complete DAPT of and is given for atleast 14 days and ideally continued for
12 months
duration of 12 months.
DAPT can be continued beyond 12 months, if
High bleeding risk includes patients having overt patients tolerate well with no bleeding episodes and are
bleeding, or when they are at high risk of bleeding (e.g., at low bleeding risk.
oral anticoagulant therapy use, major intracranial or
vascular surgery) Patients of ACS Treated with PCI
Low bleeding risk denotes those patients who have After BMS or DES implantation, P2Y12 inhibitor should
not developed bleeding and DAPT score <2. be continued for a minimum duration of 12 months.
CHAPTER 16: Dual Antiplatelet Therapy: How Long? 93
Ticagrelor and prasugrel are preferred over clopidogrel clopidogrel. Likewise, in the PLATO trial, use of ticagrelor
for maintenance therapy. Prasugrel should be used only reduced cardiovascular mortality at 1 year compared to
in patients < 75 years, weighing > 60 kg and without clopidogrel.
history of stroke/TIA or bleeding tendency. CABG after PCI: Continue DAPT for duration of 12
In patients who are not at increased risk of bleeding, months (or as per recommended duration) after PCI
P2Y12 inhibitor can be continued beyond 12 months. If (Class I).
patients are at high risk of bleeding (oral anticoagulant CABG after ACS: Continue DAPT to complete the
Based on ACC/AHA focused update on DAPT, these —— Chronic phase: No need for clopidogrel loading.
practice guidelines would be useful in management of Start with 75 mg OD
these patients: —— To start 24 hours after last dose of prasugrel
TABLE 3: Laboratory tests for aspirin resistance TABLE 4: Aspirin challenge protocol for patients with aspirin
exacerbated respiratory disease (AERD)
Thromboxane production Thromboxane dependent
platelet function Time 0 Time 3 hours Time 6 hours
Serum thromboxane B2 PFA 100 (Most commonly used) Day 1 Placebo Placebo Placebo
Urine 11 deoxytromboxane B2 Optical aggregation (Gold Day 2 ASA 30 mg ASA 60 mg ASA 120 mg
standard) Day 3 ASA 150 mg ASA 325 mg ASA 650 mg
Impedence aggregation
Ultegra RPFA
TABLE 5: Wong et al. protocol
Type I resistance: Also called as pharmacokinetic Time (min) ASA (Dose in mg)
resistance. It is because of insufficient bioavailability 0 0.1
which can be due to missing compliance, inadequate 15 0.3
dosing, or protection of COX-1 against acetylation by 30 10
NSAIDs. 45 30
Type II resistance: Also known as pharmacodynamic 60 40
or true resistance. It is due to genetic changes in the 85 81
COX-1 protein, disabling acetylation by aspirin, or 110 162
acquired, transient overexpression of less aspirin- 135 325
sensitive COX isoforms.
Type III resistance: Least common mechanism. It
Types I, II, III are due to COX-1 inhibition. Type IV
occurs due to heightened stimulation of platelets by and Type V are immune mediated. Patients who have
aspirin sensitive mechanisms. Type II allergy cannot be desensitized. Since there is no
No treatment has been described for aspirin resistance fixed standard protocol for aspirin desensitization, there
till date. Higher dose of aspirin is not useful and has to be are no standard guidelines for the same.
avoided, as it increases the incidence of major bleeds.
Aspirin challenge protocol for patients with aspirin
induced cutaneous disease.
Aspirin Allergy
Studies have shown that low dose aspirin (75-100
The two common side effects of aspirin include aspirin
mg) to be beneficial in terms of lower bleeding and
exacerbated respiratory disease (10%) and aspirin
comparable ischemic protection compared to higher
induced urticaria (0.1%). Majority of the allergic
dose of aspirin (Table 5). Hence in patients on dual
reactions of aspirin are due to preferential activation
of leucotrienes and reduction of PGE2. Most cases of antiplatelet therapy, 81 mg aspirin (75–100 mg) is
aspirin allergy are able to safely undergo desensitization recommended and should be continued indefinitely.
except in cases of chronic idiopathic urticaria. Aspirin
should be indefinitely continued in all patients after
Clopidogrel Resistance
desensitization to prevent resensitization. Various types The 10–15% of patients exhibit resistance to clopidogrel.
are described below: Most common mechanisms include variations in
Type I: Rhinitis and Asthma due to NSAIDs concentrations of nitric oxide, ADP, etc. and genetic
Type II: Urticaria/Angioedema due to multiple polymorphisms in CYP3A4. Diagnosis is confirmed
NSAIDs in chronic idiopathic urticaria (CIU) by optical aggregation for ADP receptors. Treatment
Type III: Urticaria/Angioedema due to multiple options include increasing the maintenance dose of
NSAIDs clopidogrel to 300 mg OD, and replacing clopidogrel
Type IV: Urticaria/Angioedema due to single NSAID with prasugrel or ticagrelor. Routine genetic testing for
Type V: Anaphylaxis due to NSAIDs. clopidogrel resistance screening is not recommended.
96 SECTION 2: Cardiology
TABLE 6: Triple antiplatelet therapy: Practical guidelines weeks versus 6 months of DAPT. More than 600 patients
zz Individualize triple therapy by carefully assessing ischemic and who were on anticoagulation for atrial fibrillation, and
bleeding risks. now undergoing DES inplantation were randomized
zz Triple therapy duration should be appropriate: Too much or too to either 6 weeks or 6 months of triple therapy with
short duration should be avoided. aspirin, clopidogrel and warfarin, followed by dual
zz In selected patients, dual therapy (clopidogrel plus oral therapy with aspirin and warfarin thereafter. At 9 months,
anticoagulant) may be considered.
the incidences of definite stent thrombosis, bleeding
zz If warfarin is used, INR target to be lowered to 2.0–2.5. Low dose
aspirin (max. upto 100 mg) is preferred.
episodes, cerebrovascular accidents and mortality were
zz When either antiplatelet has to be chosen, clopidogrel is the
comparable between the two groups.
antiplatelet of choice. However, a large trial published recently, evaluated
zz In patients with previous GI bleed or for those at higher risk, PPIs more than 10,000 patients of atrial fibrillation undergoing
should be used. PCI and its long term results (6 year follow up) showed
zz BMS is preferred over DES so that minimum duration of DAPT that triple therapy did not decrease ischemic events.
can be restricted to 14 days in case of major bleeding. However, it increased the incidence of major bleeds and
hemorrhagic stroke.
Triple Therapy
Triple therapy refers to addition of an oral anticoagulant CONCLUSION
(VKA or NOAC) to DAPT in patients of AF undergoing Each patient needs an individualized approach based on
PCI. This therapy also seems to be a double edged sword, his risk factors for bleeding. Application of DAPT score in
as it could lead to life threatening bleeding (Table 6). routine outpatient department practice gives reasonable
Various modification have been tried, including VKA guidance on the duration of DAPT. Switch over of
plus P2Y12 inhibitor, continuing DAPT only or VKA plus antiplatelets and their dose adjustments during non
aspirin to reduce the bleeding risks. However, all these cardiac surgery should be meticulously planned. Newer
strategies resulted in increased ischemic events. guidelines regarding aspirin and clopidogrel resistance,
The ISAR-TRIPLE trial compared the incidence of and particularly aspirin desensitization are required. Its
thrombotic and bleeding events in patients receiving 6 apt to conclude with: Treat the patient, not the stent.
CHAPTER
17
Newer Biomarkers in Heart Failure
Saumitra Ray
advanced age, bacterial sepsis, renal failure, pneumonia, sensitive assays almost 2/3 rd cases are positive. In both
pulmonary hypertension, anemia and burn. Obesity at-risk normal populations and those with structural
may cause lower levels of NPs. Only BNP and not the heart disease, higher troponin levels are independently
NT pro-BNP is a substrate of neprilysin. So the new drug associated with known HF risk. The elevated troponin
for HF, angiotensin receptor neprilysisn inhibitor, ARNI, levels reflect chronic processes rather than acute
increases only the BNP level and not that of NT pro BNP. ischemia.
NP levels are used both in setting of chronic HF and
in acute set up of patients presenting with dyspnea. A OTHER BIOMARKERS
normal or mildly elevated NP in an acute setting keeps Many other biomarkers, are being studied to diagnose,
the HF diagnosis at the bottom of the list. prognosticate or guide therapies for HF. But none of these
In STOP-HF study, patients of stage A HF were has still been approved to be used outside experimental
subjected to BNP testing versus no BNP testing. settings.
Intervention group patients who had BNP more than These biomarkers may be classified as: (a) markers
50 pg/mL had echocardiography and were seen by of inflammation, e.g. CRP, TNF-alpha, IL-1,6,10,18,
cardiovascular specialist. This group had less er number lipoprotein associated phopholipase A2, adiponectin;
of composite end points. In another RCT, rapid up- (b) markers of oxidative stress, e.g. oxidized LDL,
titration of renin-angiotensin-aldosterone blocking myeloperoxidase; (c) markers of extracellular matrix
and beta adrenergic blocking showed reduction in remodeling, e.g. MMP, IL-6, galectin-3, myostatin; (d)
cardiovascular endpoints in diabetic patients with high neurohormones, e.g. noradrenalin, rennin, angiotensin
NT pro-BNP but without clinical heart disease. However, II, aldosterone, endothelin-1; (e) markers of myocyte
to develop a protocol for stage A HF patients is difficult. injury and apoptosis, e.g. troponi T and I, CPK-MB,
myosin light chain kinase-1; (f ) markers of myocyte
Prognostic Value of NP stress, e.g. NPs, sST2 and (g) markers of extracardiac
The ACC/AHA/HFSA 2017 update on HF guideline gives involvement, e.g. cystatin-C, NGAL, B2 microglobulin,
a class IA recommendation for measurement of BNP and tri-iodothyronine.
NT pro-BNP for assessing disease severity and outcome NGAL, neutrophil gelatinase-associated lipocalin
in chronic HF and for prognostication of hospitalised is produced by neutrophils and some epithelial cells
patients with acute HF. High initial value of NT pro BNP and increases in renal injury. Chronic HF patients have
indicates higher mortality and morbidity. higher levels in blood and urine. NGAL levels can predict
Predischarge NP levels can predict chance of early renal outcomes in HF patients.
re-hospitalization. But evidences are so far not strong Some other biomarkers such as soluble ST2 receptor
and ACC guideline recommends a class IIa indication and andgalectin-3 may be useful, particularly over and
for the predischarge NP level to establish a postdischarge above BNP levels. More trials are required in this field.
prognosis. Several biomarkers are awaiting validation with well-
defined outcome studies. At present, ACC gives a class
Cardiac Troponin IIb recommendation for such additional tests.
Cardiac troponin levels may increase in both chronic and
acute HF set ups indicating muscle injury. Troponins T
BIOMARKERS OF HFpEF
and I increase similarly in acute HF as in ACS. Raised Role of Natriuretic Peptides in HFpEF
values of either troponin T or I levels in acute HF indicate NPs may increase a little in symptomatic phases of
a poorer prognosis. HFpEF and normalize Natriuretic paptides (NPs) during
Troponins are found in blood in asymptomatic symptom-free periods. As myocardial stretch is not a
people of stage A and B of HF in 1 to 5 % cases. With high major feature of HFpEF, rise of NP is not significant.
CHAPTER 17: Newer Biomarkers in Heart Failure 99
Under specific circumstances, such as supraventricular The ALDO-HF trial with HFpEF, Galectin 3 predicted
tachycardia or fluid overload, levels of natriuretic peptides mortality and rehospitalization rates.
may become very high (as in HFrEF), but this is uncommon. In the RELAX trial of 216 stable outpatients with
Natriuretic peptides are measured as a screening test HFpEF (LVEF ≥ 50 %), Galectin 3 was associated with
in clinics for patients presenting with dyspnea. There renal dysfunction but not with congestion.
negative predictive value is very high.
Fig. 1: In addition to the ‘classic mechanisms’ (i.e. atherosclerotic disease and vasospastic disease) that lead to myocardial ischemia, coronary
microvascular dysfunction (CMD) has recently emerged as a ‘third’ potential mechanism of myocardial ischemia. As in the case of the other
two mechanisms, coronary microvascular dysfunction (alone or in combination with the other two) can lead to transient myocardial ischemia
as inpatients with coronary artery disease (CAD) or cardiomyopathy (CMP) or to severe acute ischemia as observed in Takotsubo syndrome.
Abbreviations: CFR, coronary flow reserve
Source: Adapted from Filippo Crea, et al. European Heart Journal. 2014;35:1101-11
High levels of C-reactive protein foundin patients CFR is reduced in aortic stenosis by multiple
with microvascular angina, having a role of inflammation mechanisms that include reduced diastolic filling time,
in the modulation of coronary microvascular responses. increased diastolic filling pressure and intramyocardial
CMD was prevalent in patients with systemic lupus pressure, leading to reduced subendocardial perfusion,
erythematosus and rheumatoid arthritis. Marked increased intramyocardial systolic pressure, and delayed
structural abnormalities ofthe small intramural myocardial relaxation after systole.17-19
coronary arteries, including medial hypertrophy, MVD presents in infiltrative cardiac diseases such
intimal hyperplasia, and decreased luminal size, are
as amyloidosis. The mechanism of MVD in these
considered themost relevant substrate producing CMD
diseases can be attributed to secondary changes,
and myocardial ischemiain HCM.15
including myocyte hypertrophy and fibrosis. Endothelial
Observations suggest that Takutsobu syndrome
dysfunction due to endothelial deposits and perivascular
is caused by intense microvascular constriction with
fibrosis leads to increased microvascular resistance.20, 21
subclinical CMD persisting over time, perhaps facilitated
by endothelial dysfunction.16 CMD may present with obstructive atherosclerotic
In myocarditis even there is no atherosclerosis, chest coronary arteries. Stable IHD patient may share common
pain may be caused by intense coronary vasoconstriction risk factors for microvascular dysfunction and these
due to myocarditis induced endothelial dysfunction may lead to presence of both micro and macrovascular
of the coronary microvasculature, together with direct disease. In ACS patient MVO is caused by the variable
infection of endothelial and/or vascular smooth muscle combination of four pathogenetic mechanisms: (i) distal
cells. atherothrombotic embolization; (ii) ischemic injury;
102 SECTION 2: Cardiology
avoid over diagnosis. There is need to develop a cheap, do not improve CFR and show inconsistent effects
effective, safe, and widely available noninvasive test for on symptoms, 42 while beta-blockers are effective for
detection of coronary microvascular dysfunction. improving chest pain symptoms.43 Ranolazine improves
both angina status and exercise stress test results in
TREATMENT OF CORONARY patients with MVA. In patients with abnormal cardiac
MICROVASCULAR DYSFUNCTION pain perception and normal coronary angiograms
In patients with MVA, a first important line of treatment imipramine improves symptoms; possibly through a
is represented by life style modification such as smoking visceral analgesic effect (Fig. 4). Finally, more demanding
cessation and weight-loss, which are known to improve forms of treatment are spinal cord stimulation 44 and
endothelial dysfunction and CMD. Perindopril and enhanced external counter pulsation.45 Cognitive behavioral
indapamide for 6 months can be prescribed in the therapy may be considered. Large-scale, practical, outcome
absence of myocardial diseases andobstructive coronary trials testing the efficacy of currently available traditional
artery disease. 39 Statins and angiotensin converting anti-atherothrombotic and anti-ischemic therapy, as
enzyme (ACE) inhibitors should bepresent as first line of well as novel therapies in this population, are warranted.
treatment in patients with MVA.40,41 Calcium antagonists Menopausal hormone therapy may improve emotional
CHAPTER 18: Coronary Microvascular Dysfunction: An Update 105
wellbeing in postmenopausal women with angina and also on symptoms in patients with refractory angina,
‘normal’ angiograms; yet, there is no symptom benefit for i.e. those who are judged not to be candidates for
this patients.46 revascularization procedures. Gene therapy initially
In HCM, alcohol septal ablation seems to improve appeared as the most valid approach to stimulate and
CFR and septalendocardial-to-epicardial MBF. 47,48 enhance microcirculation and collateral growth in
While verapamil, disopyramide, and ACE inhibitors refractory angina, but controlled randomized studies
fail to improve myocardial perfusion.49-52 In patients have on the whole been disappointing. Recently,
with dilated cardiomyopathy, beta-blockers,53,54 but not attempts to promote collateral have been based on the
calcium antagonists or ACE inhibitors55 seem to have intramyocardial administration of progenitor vascular
beneficial effects on CMD, likely as a result of improved cells but that need to be addressed in larger studies.
hemodynamics. Of note, favorable effects on CMD have In the setting of ACS two small randomized studies57,58
recently been reported by treatment with allopurinol.56 found a beneficial effect of manual thrombus aspiration
While CMD can be present and play an important vs. the standard procedure on surrogate endpoints of
role in the clinical presentation of acute myocarditis, myocardial reperfusion. Regarding pharmacological
no study has hitherto assessed the effects of any form therapy, intracoronary adenosine administration appears
of intervention on CMD in these patients. Drugs that to be the most promising approach. An attractive form of
increase diastolic time, like beta-blockers, might help treatment is ischemic conditioning, in particular, ischemic
in delaying the ominous onset. As an alternative to postconditioning59,60 and remote pre-conditioning61 have
beta-blockers, ivabradine, known to selectively reduce been found to improve MVO (Fig. 5).
heart rate but not blood pressure, might be of help in
this setting. Clinical outcome are lacking and should CONCLUSION
therefore be investigated in prospective randomized Patients with angina but no significant obstructive
trials. Therapeutic interventions able to promote epicardial coronary disease on standard coronary angio
collateral growth may have an impact on outcome and graphy are at increased risk of adverse cardiovascular
106 SECTION 2: Cardiology
Fig. 5: Diagnosis, prognostic value, and treatment of coronary microvascular dysfunction in different clinical settings
Abbreviations: ACH, acetylcholine test; AFD, Anderson-Fabry’s disease; AS, aortic stenosis; BG, blush grade; CABG, coronary aortic bypass
graft; CMD, coronary microvascular dysfunction; CMR, cardiac magnetic resonance; COCM, congestive cardiomyopathy; HCM, hypertrophic
cardiomyopathy; MVA, microvascular angina; MVO, microvascular obstruction; PET, positron emission tomography; pPCI, primary percutaneous
coronary intervention; PVB, Parvovirus B9; RF, risk factors; STR, ST segment resolution; Tn, troponin; TTDE, transthoracic Doppler
echocardiography. It is unknown the incremental prognostic value of coronary microvascular dysfunction in addition to that conveyed by risk
factors.
Source: Filippo Crea, et al. European Heart Journal. 2014;35:1101-11.
events compared with people without angina. CMD 3. Camici PG, Crea F. Coronary microvascular dysfunction.
is highly prevalent and clinicians need to be aware of N Engl J Med. 2007;356(8):830-40.
their clinical implication. Patients with CMD with and 4. Murthy VL, Naya M, Foster CR, et al. Improved cardiac
risk assessment with noninvasive measures of coronary
without epicardial CAD have been shown to have a poor
flow reserve. Circulation. 2011;124:2215-24. [PubMed:
prognosis including an increase in cardiac death, nonfatal 22007073]
MI, and hospitalizations. So, future effort is necessary 5. Pepine CJ, Anderson RD, Sharaf BL, et al. Coronary
to refine noninvasive methods for easy evaluation of microvascular reactivity to adenosine predicts adverse
microvascular and endothelial function. Now-a-days outcome in women evaluated for suspected ischemia:
PET, MRI or CT-perfusion, and contrast-enhanced Results from the national heart, lung and blood institute.
Doppler echocardiography offer significant promise to WISE (women’s ischemia syndrome evaluation) study. J Am
Coll Cardiol. 2010;55:2825-32. [PubMed: 20579539]
diagnose CMD. Identifying the mechanism underlying
6. Serruys PW, di Mario C, Piek J, et al. Prognostic value
the patient’s symptoms in important to provide a rational
of intracoronary flow velocity and diameter stenosis
treatment that aims at both improving the quality of life in assessing the short- and long-term outcomes of
and long term prognosis when feasible. Taken together, coronary balloon angioplasty: The DEBATE study (doppler
evidence gathered in recent years has shown that CMD is endpoints balloon angioplasty trial europe). Circulation.
a true clinical entity rather than a mystery or an academic 1997;96:3369-77. [PubMed: 9396429]
curiosity. 7. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes
DR, Lerman A. Long-term follow-up of patients with mild
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CHAPTER
19
How did Fractional Flow Reserve Change My
Clinical Decisions? Case-based Discussions
Nagendra Boopathy Senguttuvan
A B C
D
Figs 3A to D: Angiographically significant RCA (A), long segment, bifurcating lesion in LCx-OM (B) and calcified long
segment LAD (C) disease. The lower panel shows a FFR which is not significant (D)
to enable better stent deliverability and expansion) was All that is Seen by Dye is not True
done with 1.25 burr. Later circumflex-OM was stented A 50-year-old female who is a known insulin dependent
with good end results (Figs 4A to E). After one and half diabetes presented with NSTEMI acute heart failure with
year follow-up, she is doing fine without any coronary moderate LV dysfunction which globally reduced. She
events. Here FFR avoided an additional stent in RCA. also had LBBB which is old. After initial stabilization,
she underwent angiogram which showed critical RCA
DEFERRED PCI and LCx disease with borderline LM and LAD diseases.
A 45-year-old female a known diabetic presented Hence, she underwent FFR to LM and LAD. FFR to LM-
with exertional angina and dyspnea class 2. She was LAD was done which was 0.71. As she is IDDM patient
started on antianginals and became asymptomatic. She with TVD (Figs 6A and B), she was advised to have CABG.
underwent angiogram elsewhere. She was found to have She underwent the procedure and her LVEF was normal
eccentric proximal 70% LAD disease and was advised to after a month post-CABG. This case emphasizes the use
have PCI to proximal LAD. She approached us later. A of FFR when angiographic findings are ambiguous.
FFR guided PCI was suggested. FFR was found to be 0.81
(Not significant even after repeating the test for multiple ASSESSMENT OF SERIAL LESIONS
times) (Figs 5A and B). Hence PCI to FFR was deferred. FFR is very useful in patients who have serial lesions.
One and half years now, she is asymptomatic and is able After crossing the serial lesions, the wire was kept in the
to walk for 3 miles a day. But for FFR, she might have distal vessel and slowly pulled back with intravenous
received a stent which is not warranted. adenosine producing maximal hyperemia. Lesions with
CHAPTER 19: How did Fractional Flow Reserve Change My Clinical Decisions? Case-based Discussions 113
A B C
A B
Figs 5A and B: Eccentric proximal LAD disease (arrow)
A B
Figs 6A and B: Bordeline LM (Bold arrow in Figure A)
114 SECTION 2: Cardiology
Proximal Distal
Lesion A Lesion B
Proximal FFR FFR between Distal FFR
lesion A and B
FFR value 1 0.9 0.6
Mean pressure 85 76 52
Mean pressure drop 9 24
Fig. 7: Picture showing the presence of two tandem lesions. Here FFR pull back showed
significant pressure drop across the distal lesion. Hence it should be intervened first
and a repeat FFR should be done again to assess proximal lesion
A B
Figs 8A and B: Final FFR >0.8
maximal pressure drop will be identified and intervened of 0.78 with maximum drop in proximal lesions. Later
first and FFR should be repeated again SAS distal or proximal lesions were also stented with a final FFR >0.8
proximal lesion can affect the severity of the second (not suggestive of ischemia) (Figs 8A and B). In the
lesion (Fig. 7). A 59-year-old patient who is a known absence of FFR, an unwarranted intervention might have
diabetic, hypertensive with CAD underwent PCI to been done in diagonal while warranted interventions in
LAD/diagonal and OM in 2013. He presented to us in LAD might have been missed.
2016 with exertional angina and dyspnea. A TMT was
done which was showing evidence of stress induced
ischemia. Angiogram done revealed a tight ostial
CONCLUSION
diagonal disease and serial lesions in LAD (Fig. 7). FFR FFR is a useful tool in contemporary cardiology practice.
was done to diagonal which was 0.92 only and hence PCI It changes the management of clinical decision in both
to diagonal was deferred. A FFR to LAD was found to be stable CAD patients and patients with acute coronary
0.75 (suggestive of inducible ischemia) A slow pull back syndrome of a at least one-third of patients. In spite of
of FFR showed maximum pressure drop at the leval of such robust data, the use of FFR is less. Increasing the
lesion C and D. Hence PCI to mid and diatal LAD was utility of FFR based revascularization will definitely
done. Later FFR was repeated which again showed FFR improve the clinical outcomes of patients.
CHAPTER
20
Mega Trials in Cardiology
Sundeep Mishra
The trial was able to achieve the prerequired outcomes heart failure (CHF). The statin used was pravastatin
in nearly all patients in all the groups. Interestingly, 40 mg daily versus placebo. The trialists investigated
despite different thresholds for DBP control there was cardiovascular outcomes, the primary endpoint being a
no differences between the three groups with regards to composite of:
MACE (p = 0.50). Even secondary end-points; all stroke 1. CV mortality
(p = 0.74), all MI (p = 0.05), CV mortality (p = 0.49), and 2. Nonfatal MI. At the end of 5.0 years, patients on
total mortality (p = 0.32) were also not different. The pravastatin fared much better; lower rate of the
only group were there seemed to be benefit with tight primary endpoint (RR 24%). For secondary end-
control of DBP (≤80 mm Hg group) were diabetic patients points there was a lower nonfatal MI (RR 23%) but
where MACE rates seemed to be lower, RR 2.06, 95% CI there was no significant difference in CV mortality.
1.24–3.44, p = 0.005 as well as lower CV mortality, RR 3.0, Risk of revascularization (CABG/PCI ), another
p = 0.016 vis-à-vis those with a loose control (≤90 mm CVS event was also significantly lower in patients
Hg) group. Interestingly, it was notable that patients par taking pravastatin (RR 27%). There were a couple of
taking ASA fared better; fewer MACE - RR 0.85, p = 0.03 interesting points in the study:
and MI - HR 0.64, p = 0.002, however, the risk of bleeding Women experienced significantly larger magnitude of
in this group was higher; nonfatal major bleeding (RR reductions in the risk of coronary events as compared
1.8, p<0.001). Regarding other side effects, they were few; with men (p=0.05).
dizziness, headache, leg edema, flushing, and coughing Patients with higher baseline values of LDL (LDL
but overall all antihypertensives, in all the groups were >150 mg/dL) witnessed a larger benefit in terms of
well tolerated. risk reduction vis-a-vis to those with near normal
LDL between 125 mg/dL and 150 mg/dL at baseline
Take Home Message (35% vs. 26%, p=0.03).
Tight control of blood pressure is not required in
majority of patients. Take Home Message
Threshold of blood pressure control should be lower Statins are useful for secondary prevention of CAD
for diabetics. even in those without manifest dyslipidemia.
Overall, aspirin use in hypertensives is not required The benefit seems to depend on baseline LDL values,
(it does decrease cardiac events but this benefit is the higher starting values, the greater benefit.
over-ruled by increased bleeding risk. Women seem to benefit more with statin therapy.
was MACE and the patients were followed up for 5 from any cause (primary endpoint). The third arm
years.3 Patients with reduced left ventricular function was of placebo. Interestingly, there was no difference
(EF<40%) or with a history of CHF or those already in outcomes between amiodarone and placebo group
on a ACE-I therapy were excluded from HOPE study. (Mortality: placebo group - 29% versus miodarone
Patients received either ramipril (titrated to upto 10 mg group - 28%), but the outcomes were better in the
daily) or placebo. Investigators looked for a composite ICD group (Mortality: 22% versus 29% for placebo; p =
of MI, stroke, or CV death, as primary end-point. The 0.007), a risk reduction of 23%. Furthermore, the drug
ramipril arm demonstrated significantly reduced MACE amiodarone discontinuation rates were high (32% vs.
(compared to the placebo). Interestingly, the findings 22% of the placebo group), both mild; higher rates of
remained consistent in all sub-groups irrespective of sex, tremor (4%, p = 0.02) and serious; hypothyroidism
age, cardiac risk factors, presence of diabetes, evidence (6%, p < 0.001). Comparatively, only 5% of patients
of CV, baseline BP, or evidence of microalbuminuria. receiving ICDs experienced a significant complication,
However, the most common adverse effect of ramipril at least at the time of implantation (surgical correction,
was cough. hospitalization, new/unanticipated drug therapy),
although on follow-up 9% of patients developed such
Take Home Message complication. Thus, overall, while ICD implantation led
ACE-I are beneficial for secondary prevention of to a significant reduction in mortality, there was no such
CAD. advantage with amiodarone. Consequently, ICDs have
The benefit occurs irrespective of symptoms, now become the new gold-standard in patients with
hypertension, diabetes mellitus, presence of heart stable CHF and reduced LVEF.
failure or ejection fraction.
Take Home Message
ARRHYTHMIA In patients with stable CHF and reduced ejection
In the subspecialty of pacing and arrhythmia’s The fraction there is no benefit of amiodarone.
Sudden Cardiac Death in Heart Failure Trial (SCD- Amiodarone therapy is associated with both short
HeFT) remains a pathbreaking trial. Initially effective and long-term complications.
antiarrhythmics including drugs were considered ICD therapy is the gold-standard for preventing SCD
“gold standard.” Defibrillators were considered far too in these patients.
expensive reserved for really resistant cases. The SCD-
HeFT took a revolutionary approach for the time. They HEART FAILURE
evaluated effect of amiodarone vis-a-vis intracardiac Progression of heart failure is thought to be multifactorial
defibrillators (ICDs) while treating patients with mild- involving various pathophysiological systems, but perhaps
to-moderate heart failure.4 They included adults (age most important are neuroendocrine compensation of the
≥18 years) with significant symptoms (NYHA class II or body to decreased effective circulating volume leading to
III) with evidence of left ventricular dysfunction (LVEF the activation of the sympathetic and renin-angiotensin-
≤35%). Overall > 2500 patients were randomized and aldosterone system (RAAS). All this leads to myocardial
followed up for nearly 4 years (median of 45.5 months) remodeling and slow but progressive reduction in
and outcomes evaluated in all surviving patients One cardiac output. Most therapeutic agents target one or
arm composed of amiodarone loaded as per standard the other pathophysiological mechanisms. Aldosterone
protocol and then weight-adjusted maintenance dose blockade is relatively new therapeutic target and RALES
(a median dose of 300 mg daily). For the second arm, was the landmark RCT evaluating the role of aldosterone
a Medtronic single-chamber ICD was chosen and kept blockade in treating CHF.5 While RAAS and beta-blokade
on shock-only mode. The outcome measured was death remained cornerstone of mortality reduction while
118 SECTION 2: Cardiology
diuretics were useful for symptom reduction particularly Diabetes Study (UKPDS) undertook a number of trials
in volume overloaded states, aldosterone-inhibitors, like to enquire into exactly that: morbidity and mortality
spironolactone were considered minor players, more associated with DM. UKPDS series 33 and 34, was carried
like an add on to diuretic, on the background of ACE-I out in 23 participating centers and included patients
therapy. The hypothesis that aldosterone blockade with newly diagnosed T2DM, with broad range spectrum
would have additional role beyond the near optimal (aged 25–65 years). These patients were allocated in a
block RAAS with ACE-I/ARB seemed implausible. randomized controlled manner to different treatment
Furthermore, there was an additional risk of inducing groups versus conventional management (which involved
hyperkalemia with the use of aldosterone inhibitors. only lifestyle modifications) and were followed up for 10
However, there was some evidence that there could be years.6, 7 The UKPDS 33 demonstrated that while median
a escape from RAAS pathway even on optimal ACE- HbA1c levels were significantly lower in the treatment
inhibition or in other words ACE-I alone may not be groups: patients receiving sulfonylureas or insulin (7.0%
that effective in suppression of this pathway. With this compared to 7.9% for the control group, P<0.0001) and
in mind RALES trial sought to investigate whether the risk of microvascular complications (defined as
spironolactone would reduce mortality in patients with retinopathy, vitreous hemorrhage, neuropathy, and
advanced CHF, who were already on standard medical renal failure) was significantly reduced as well (a 25% risk
therapy. It was a multicentric (195 centers), multicountry reduction, 95% CI 0.60–0.93) but there was no significant
(15 countries) RCT enrolling 1,663 relatively sicker differences between pharmacologic therapy versus
patients, NYHA functional class III-IV, with markedly lifestyle modifications alone for the development of
reduced left ventricular function (LVEF <35%) on optimal macrovascular complications; CAD, peripheral vascular
medical therapy (as per that time); ACE-I, loop diuretic ± disease and cerebrovascular disease. Furthermore,
digoxin. On the top of that patients received either 25-50 in the treatment group, than was significantly higher
mg spironolactone once daily or the placebo. They had rates of hypoglycemic episodes than the control group
planned to follow-up the patients for 3 years but it had (P<0.0001). The other study, UKPDS 34, evaluated the
to be terminated at around 1 year because the benefits of impact of treating patients with T2DM with metformin.
spironolactone were so obvious. The study demonstrated They found that when compared to conventional therapy
not only a significant reduction in all-cause mortality (i.e. lifestyle changes alone), treatment with metformin
but death due to CHF, SCD and hospitalizations due was found to reduce diabetes-related death by 42% (95%
to CHF were also significantly reduced. Surprisingly, CI 0.37–0.91) and all-cause mortality by 36% (95% CI
the incidence of serious hyperkalemia was rare in both 0.45–0.91). Furthermore, metformin therapy was linked
groups. with fewer hypoglycemic episodes than treatment with
sulfonylureas or insulin. The UKPDS 38 took a different
Take Home Message route, they undertook to evaluate the effects of blood
Addition of aldosterone antagonists on the background pressure control in patients with newly diagnosed
of optimal medical therapy leads to improved oputcomes T2DM. It was a multicentric study (23 participating
in symptomatic patient. hospitals) of relatively long duration (10 years), with
very good follow-up program (Blood pressure was
DIABETES MELLITUS measured at clinic visits every 3–4 months). This trial
Diabetes mellitus (DM) is another important area for sought to compare outcomes of tight blood pressure
cardiologists. Many consider DM as CAD equivalent. control (<150/85 mm Hg) versus less tight control
Conventional wisdom would suggest that treating blood (<180/105 mm Hg). Patients received mandated blood
sugar effectively would decrease morbidity and mortality pressure agents; ACE-Is, beta-blockers to achieve these
associated with DM. The United Kingdom Prospective targets. The investigators found that unlike glycemic
CHAPTER 20: Mega Trials in Cardiology 119
control, a tight control of blood pressure (<150/85 mm aim was to prevent the development ESRD (need for
Hg) was associated with not only significantly fewer dialysis or renal transplantation), doubling of serum
microvascular complications but also macrovascular creatinine level, and death, taken as a composite primary
complications and even diabetes-related deaths when end-point. Other outcomes evaluated were morbidity
compared to control subjects with less tight blood and mortality from CV causes, progression of renal
pressure control (<180/105 mm Hg).8 The study revealed disease, and changes in the degree of proteinuria–all
that a tight control of BP led to a 32% reduction in the risk secondary end-points. Most patients received 100 mg of
of diabetes-related mortality compared to the less tight losartan (71%), while the rest received 50 mg of losartan
group (P=0.019). Diabetes-related mortality was defined in active group. It was found that treatment with losartan
as deaths resulting from myocardial infarction, sudden lead to 16% risk reduction in the composite primary
death, stroke, peripheral vascular disease, renal disease, endpoint (43.5% vs. 47.1%, p=0.02). Furthermore, the
hyperglycemia, or hypoglycemia. Furthermore, the risk risk of doubling serum creatinine was reduced by 25%
of macrovascular complications were 34% lower in the (21.6% vs. 26.0%, p=0.006) and end-stage renal disease by
tight control group (P=0.019). 28% (19.6% vs. 25.5%, p=0.002), all secondary end-points.
However, there was no significant difference in mortality
Take Home Message between the two groups (21.0% vs. 20.3%, p=0.88) as
In patients with diabetes mellitus a tight control also the secondary endpoint of morbidity and mortality
of blood sugar results in lower microvascular from CV causes. Patients in the losartan arm, however,
complications but has no effect on macrovascular did experience significant reductions in the amount of
complications or overall mortality. proteinuria (p<0.001).
There is a risk of episodes of hypoglycemia when In patients with T2DM, treatment wityh losartan
a tight control in blood sugars is achieved with leads to improvement in renal outcomes.
sulphonylureas or insulin.
Metformin therapy in T2DM was associated with CONCLUSION
reduction in total and diabetes related mortality. The HOT trial demonstrated that tight control of blood
Tight control of blood pressure was associated with pressure hypertensive patients but with no other
not only reduced macrovascular complications but comorbidities led to no benefit either in terms of MACE
also diabetes related mortality. or CV mortality—a DBP ≤90 mm Hg as good as that of
The RENAAL Trial aimed to investigate aspects of ≤85 mm Hg or ≤80 mm Hg. On the other hand, if patients
renal disease in diabetes mellitus. It was a prospective, had associated diabetes mellitus, targeting a DBP of
RCT enrolling >1,500 T2DM patients with usual age ≤80 mm Hg led to significant improvement in the risk
(31–70 years), and evidence of nephropathy (defined as of MACE and CV mortality (vis-à-vis a higher target
urinary protein ≥0.5 g/24 hours and serum creatinine of ≤90 mm Hg). Another important finding from this
between 115–254 μmol/L). type 1 diabetes, nondiabetic study was that along with antihypertensive treatment,
renal disease, or a history of CHF, recent MI, PCI, if a concurrent low-dose ASA was added, while it led
CABG or CVA were excluded from this study. The to significantly lower rates of MACE and MI but higher
study was carried out at 250 centers in 28 countries, rates of bleeding. Finally, antihypertensive therapy was
followed up for a mean period of 3.4 years.9 All patients generally well tolerated, with only some patients afflicted
received standard therapy, including conventional with dizziness, headache, leg edema, and coughing.
antihypertensive therapy (calcium-channel blockers, The UKPDS group of studies demonstrated that the
diuretics, alpha-blockers, and beta-blockers, but not use of pharmacologic agents like sulfonylureas, insulin,
ACE-I or ARBs) as mandated. In addition they were metformin and antihypertensives in patients with T2
randomized to receive either losartan or placebo. The DM. They found that while antidiabetic drugs such as
120 SECTION 2: Cardiology
insulin and sulfonylueas significantly reduced their risk ramipril, on cardiovascular events in high-risk patients. N
for developing microvascular complications, it was only Engl J Med. 2000;342(2000):145-53.
metformin that also reduced diabetes-related mortality, 4. Bardy, Gust H, et al. Amiodarone or an implantable
cardioverter–defibrillator for congestive heart failure. New
all-cause mortality, and had a lower risk of hypoglycemia.
England Journal of Medicine. 2005;352(3):225-37.
This study led to the establishment of metformin as the
5. Pitt, Bertram, et al. The effect of spironolactone on morbidity
first-line pharmacotherapy in managing T2DM. On the
and mortality in patients with severe heart failure. New
other hand, while antidiabetic pharmacotherapy was England Journal of Medicine. 1999;341(10):709-17.
ineffective in reducing macrovascular complications. 6. Turner RC, Holman RR, Cull CA, Stratton IM, Matthews DR, et
It was tight control of blood pressure control which led al. Intensive blood-glucose control with sulphonylureas or
to significant reductions in both microvascular and insulin compared with conventional treatment and risk
macrovascular complications, as well as diabetes-related of complications in patients with type 2 diabetes (UKPDS
mortality. These groups of studies have received most 33). Lancet. 1998;352(9131):837-53.
citations compared to any other cardiovascular mega trials. 7. Effect of intensive blood-glucose control with metformin on
complications in overweight patients with type 2 diabetes
(UKPDS 34). Lancet. 1998;352(9131):854-65.
REFERENCES
8. UK Prospective Diabetes Study Group. Tight blood pressure
1. Kjeldsen, Sverre E, et al. Hypertension Optimal Treatment
control and risk of macrovascular and microvascular
(HOT) Study. Hypertension. 1998;31(4):1014-20.
2. Sacks, Frank M, et al. The effect of pravastatin on coronary complications in type 2 diabetes: UKPDS 38. British
events after myocardial infarction in patients with average Medical Journal. 1998;317(7160):703.
cholesterol levels. New England Journal of Medicine. 9. Brenner, Barry M, et al. Effects of losartan on renal and
1996;335(14):1001-9. cardiovascular outcomes in patients with type 2 diabetes
3. Heart Outcomes Prevention Evaluation Study Investigators. and nephropathy. New England Journal of Medicine.
Effects of an angiotensin-converting–enzyme inhibitor, 2001;345(12):861-9.
CHAPTER
21
Rheumatic Valvular Heart Disease
RR Singh
Rheumatic heart disease, which is one of complication ASO titer, and CRP to check for the presence of strep
of rheumatic fever damages heart valves. Rheumatic antibodies and ECG. However, it is common, that signs
fever is a kind of inflammatory disease beginning of the streptococcal infection may be gone by the time
with Streptococcus haemolyticus of lance field group C patient is brought to the physician or cardiologist. In that
causing sore throat. It affects connective tissue of body case, the consultant will need to ask or remember whether
throughout, with special affection to the heart muscle the child or patient recently had a sore throat, joint pains
and valves, joints, skin and brain. As we know that or other symptoms of a streptococcal infection.
rheumatic fever affects human being irrespective of age. The clinician should do a physical examination and
Rheumatic fever is very common in children between check for signs of rheumatic fever, including flittering or
4 to 15 years age group. One has to treat streptococcal migrating joint pains and inflammation. The consultant
infection with antibiotics and that is best way to prevent should look for loud S1 and for abnormal rhythms
rheumatic fever and sore throat. or murmurs that may signify that the heart has been
strained.
SIGNS AND SYMPTOMS In addition to this, there are a few common tests,
Since the symptoms of rheumatic heart disease vary that may be used to check the heart and assess damage
till they cause damage to the heart muscle often is not including CBC, ESR, ASO titer, CRP, ECG, chest X-ray,
readily noticeable. When symptoms do appear, they may echocardiography and cardiac catheterization.
depend on the extent and location of the heart damage
patients may have migrating joint pain. TABLE 1: Jones criteria fo rheumatic fever
Infact, symptoms of rheumatic fever appear about
Major criteria Minor criteria
two weeks after the onset of an untreated strep throat
Pancarditis (pericarditis, endocarditis, Fever
infection. Apart from the sore throat caused by the strep myocarditis)
infection, children have a fever like symptoms joint
Polyarthritis Arthralgia
pains. Occasionally, the patient may be having shortness
Sydenham chorea Prolonged PR interval
of breath or dyspnea on exertion (Table 1).
Subcutaneous nodules Increased ESR or CRP*
The first step initially in diagnosing rheumatic heart
Erythema marginatum Leukocytosis
disease is establishing that child recently had a history of
*Erhtrocyte sedimentation rator or C-reactive protein
streptococcal infection. The consulting physician should **Two major or 1 major and 2 minor must be present to diagnoses
advice a throat culture, a blood test including CBC, ESR, rheumatic fever
122 SECTION 2: Cardiology
Physical Examination
An opening snap that is a high-pitch additional sound
may be heard after the A 2 (aortic) component of the
second heart sound (S2), which correlates to the forceful
opening of the mitral valve. The mitral valve opens when
the pressure in the left atrium is greater than the pressure
in the left ventricle. This happens in ventricular diastole
(after closure of the aortic valve), when the pressure in
the ventricle precipitously drops. In individuals with
Fig. 2: Rheumatic heart disease at autopsy had characteristic
findings, i.e. thickened mitral valve, thickened chordae tendinae, mitral stenosis, the pressure in the left atrium correlates
hypertrophied left ventricular myocardium with the severity of the mitral stenosis. As the severity
CHAPTER 21: Rheumatic Valvular Heart Disease 123
of the mitral stenosis increases, the pressure in the left Echocardiography (Fig. 2)
atrium increases, and the mitral valve opens earlier in Diagnosis of mitral stenosis is most easily made by
ventricular diastole. echocardiography, which shows left atrial enlargement,
A mid-diastolic rumbling murmur with presystolic thick and calcified mitral valve with narrow and “fish-
accentuation will be heard after the opening snap. The mouth”-opening orifice and signs of right ventricular
murmur is best heard at the apical region and is not failure in advanced disease. It can also show decreased
radiated. Since it is a low-pitch sound, it is heard best opening of the mitral valve leaflets, and increased blood
with the bell of the stethoscope. Its duration increases flow velocity during diastole. Doppler echocardiography
with worsening disease. Rolling the patient toward left is the gold standard in the evaluation of the severity of
as well as isometric exercise will accentuate the murmur. mitral stenosis (Table 2).
A thrill might be present when palpating at the apical
region of the precordium. Cardiac Chamber Catheterization
Advanced disease may present with signs of right- Another method of measuring the severity of mitral
sided heart failure such as parasternal heave, raised stenosis is the simultaneous left and right heart
jugular venous pressure, congested liver, ascites and/or chamber catheterization. The right heart catheterization
loud P2. (commonly known as Swan-Ganz catheterization) that
Almost all signs increase with exercise and pregnancy. gives cardiologist the clue of mean pulmonary capillary
Other peripheral signs include: wedge pressure, which is a reflection of the left atrial
Malar flush—due to back pressure and buildup of pressure.
carbon dioxide which is a natural vasodilator.
Atrial fibrillation—irregular pulse and loss of a-wave TABLE 2: Severity of mitral stenosis
in jugular venous pressure Degree of mitral stenosis Mean gradient Mitral valve area
Left parasternal heave—suggestive of right ventricular Progressive mitral stenosis <5 mm Hg >1.5 cm2
hypertrophy due to pulmonary hypertension Severe mitral stenosis 5–10 mm Hg 1.0–1.5 cm2
Tapping apex beat. Very severe mitral stenosis >10 mm Hg < 1.0 cm2
MEDICAL TREATMENT
Treatment of acute rheumatic fever includes antibiotics
to treat the streptococcal infection and supportive
treatment of symptoms. Usually, aspirin is given in large
doses until the joint inflammation subsides. Some times,
steroids are required. Once the acute disease phase
passes, patients need to take penicillin, or an equivalent
Fig. 3: Mitral valvuloplasty
antibiotic, till the age of 21 years to prevent recurrences.
This is a very important treatment because the risk of
Calcified valve and/or associated mitral regurgitation are
heart valve damage increases, if rheumatic fever recurs.
contraindications.
Any angina is treated with short-acting nitrovaso
Other serious complications with PBMV usually
dilators, beta-blockers and/or calcium-channel blockers.
relate to the technique of trans-septal puncture (TSP).
Any hypertension is treated aggressively, but caution Immediate results of PBMV are often quite gratifying.
must be taken in administering beta-blockers.
Heart failure is treated with digoxin, diuretics, nitro- BIBLIOGRAPHY
vasodilators and, if not contraindicated. One should be 1. Carapetis JR. Rheumatic heart disease in Asia. Circulation.
cautious inpatient administration of ACE inhibitors. 2008;118:2748-53.
2. Kaplan MH, Bolande R, Rakita L, Blair J. Presence of bound
SURGICAL TREATMENT immunoglobulins and complement in the myocardium in
acute rheumatic fever: association with cardiac failure. N
The indication for invasive treatment with either a mitral Engl J Med. 1964;271:637-45.
valve replacement or valvuloplasty is NYHA functional 3. Sanyal SK, Thapar MK, Ahmed SH, Hooja V, Tewari P. The
class III or IV symptoms. initial attack of acute rheumatic fever during childhood
in: North India; a prospective study of the clinical profile.
Mitral Valvuloplasty (Fig. 3) Circulation. 1974;49:7-12.
4. WHO Technical Report Series 923. Rheumatic fever
Mitral valvuloplasty which is a minimally invasive and rheumatic heart disease. Report of a WHO expert
common procedure to correct an uncomplicated mitral consultation, Geneva, Oct 29–Nov 1, 2001. World Health
stenosis by dilatation of the valve using a balloon. Organization, Geneva; 2004.
CHAPTER
22
Advances in Management of
Pulmonary Arterial Hypertension
Abhishek Gupta, S Ramakrishnan
Endothelin (ET-1) pathway: One of the potent vaso US-FDA approved for group 1 PAH in October 2013, it is
constrictors, ET-1, acts on 2 receptor subtypes (ETA not yet available in India.
and ETB). ETA and ETB receptors mediate smooth Riociguat should not be combined with PDE5
muscle constriction and proliferation, whereas ETB inhibitors. In 2015, riociguat was studied as a combination
also induces vasodilation mediated by the release therapy with sildenafil (PDE5 inhibitor) in PATENT PLUS
of NO and PGI2. Bosentan and ambrisentan are two study. 18 patients received sildenafil 20 mg thrice daily
widely available pulmonary vasodilators. In various with or without riociguat for 12 weeks. The study did not
BREATHE trials bosentan has shown efficacy in PAH demonstrate any significant clinical benefit and higher
patients, but transaminitis is a common side effect. rates of hypotension with combination therapy lead to
Ambrisentan is equally effective but is associated discontinuation over a period of 305 days.
with less liver injury. Routine liver function testing
is not needed with ambrisentan as compared to Macitentan
bosentan therapy. Most common side effect is Macitentan is a newer oral agent that has nonselective
peripheral edema. antagonist action on endothelin A/B (ETA/ETB)
Nitric oxide (NO) pathway: Endothelial dysfunction receptors. Macitentan is an endothelin antagonist
may be caused or aggravated by reduced NO that has high binding affinity to ETA and greater tissue
production and bioavailability. The nitric oxide penetration. Macitentan was evaluated in the SERAPHIN
pathway may be manipulated either by administration trial. Unlike most of the previous trials of PAH that had
of NO, phosphodiesterase-5 (PDE5) inhibitors or 6MWD as the primary end point, in this trial the primary
by the stimulation of soluble guanylate cyclase. end point was a composite of time to clinical worsening
Sildenafil and tadalafil are the commonly available (TTCW). ‘TTCW event defined as worsening PAH,
PDE-5 inhibitors. Sildenafil showed improvement in initiation of parenteral prostanoids, lung transplantation,
6 minute walk distance (6MWD) in the SUPER-1 trial. atrial septostomy, or death’. The trial included WHO FC
Later, Tadalafil, with a longer half-life, is shown to be II and III patients of group 1 PAH and 64% of patients
similarly efficacious in PHIRST-1 trial. were already on background therapy. Macitentan at 3
mg and 10 mg doses reduced time to clinical worsening
NEWLY APPROVED as compared to placebo. The trial was not powered to
MEDICATIONS FOR PAH show a difference in mortality, but there was significant
Riociguat improvement in functional class, exercise capacity
Another novel compound, riociguat, stimulates soluble and hemodynamics at 6 months. Macitentan was well
guanylate cyclase (sGC) and thereby modulates the nitric tolerated and did not result in more transaminitis or
oxide pathway. However, unlike PDE5 inhibitors riociguat edema. Headache, nasopharyngitis and anemia were the
does not alter the amount of NO. Riociguat increases the common side effects. Macitentan 10 mg was approved by
cGMP production by sensitizing sGC to endogenous NO US-FDA in 2013.
and directly stimulating sGC independently of NO.
PATENT 1 and 2 trials evaluated the safety and efficacy Oral Treprostinil
of riociguat in patients with group 1 PAH. Riociguat Treprostinil is a prostacycline analogue that can be
was found to be well tolerated; however syncope was given by subcutaneous or intravenous and inhaled
the most frequent side effect. There was significant formulations. Treprostinil diolamine is an oral form of
improvement in 6MWD, NT-pro BNP, functional class prostacycline analogue Treprostinil. Oral Treprostinil
and time to clinical worsening. These improvements has been studied in a series of FREEDOM studies. In
were maintained for up to 1 year. Although riociguat is the FREEDOM-M trial, Treprostinil showed significant
CHAPTER 22: Advances in Management of Pulmonary Arterial Hypertension 127
of Treprostinil and either ET receptor antagonist or Alternative diagnosis General measures and
PDE5 inhibitor was tested in the FREEDOM-C and C-2 excluded supportive therapy
Selexipag
Selexipag is potent pulmonary vasodilator acting as Class II: Start with Bosentan/Ambrisentan or Sildenafil/Tadalafil
a non-prostanoid prostacyclin receptor (IP receptor) (combination, if response is inadequate)
Class III/IV: Start with initial combination
agonist. It is known to significantly increase the cardiac
index and reduce PVR in a short term follow up phase
II study. In the GRIPHON study, selexipag was studied In inadequate response*, consider–
class III and IV PAH patients. Patients on pre-existing Balloon atrial septostomy/Pott’s shunt
therapy were also included, but patients already on
prostanoid therapy were excluded. The primary endpoint
Lung transplantation
of the study was a composite of all-cause mortality
and any PAH complication. The primary end point *Nonavailability of prostanoids and other newer agents in India is a major
handicap in the management of PAH patients with advanced disease.
occurred significantly less with selexipag. The effect was
irrespective of background therapy suggesting potential Fig. 1: Algorithm for the treatment of pulmonary hypertension in India
for combination therapy.
response). At a follow-up of 517 days, primary end point
COMBINATION THERAPY occurred in 18% and 31% respectively among patients
on combination therapy and on pooled monotherapy.
Initiating with Combination Therapy: Combination therapy resulted in greater improvements
AMBITION Trial in 6MWD (+49 minutes) as compared to monotherapy
PAH drugs were commonly used in sequence; that is start with ambrisentan (+27 minutes) or tadalafil (+22
with one group of agents, increase the dose and if nor minutes). However, combination therapy resulted in
response at a reasonable dose add another class. Since the more frequency of adverse effects in the form of edema
various pulmonary vasodilators have different modes of (45% versus 30%), headache (42% versus 34%), and
action, it is always thought that a simultaneous initiation anemia (15% versus 9%). Based on these results, recent
of different classes of agents may be more beneficial in guidelines do recommend upfront combination therapy
PAH. This question was addressed in the AMBITION trial. of tadalafil and ambrisentan as first line therapy in PAH
In this trial, eligible 500 treatment-naïve WHO class II patients (Group 1) presenting in FC II or III (Fig. 1). In
and III PAH patients were randomly assigned in a double India, considering the cost and side effects, we prefer to
blind randomized manner either to a monotherapy with still use sequential addition of agents in class II patients,
tadalafil/ambrisentan or a combination therapy with while a initial combination may be preferable in class III
tadalafil and ambrisentan. The primary end-point of state.
the trial was time to clinical failure (defined as all-cause Patients with PAH should be managed in a step-wise
mortality, hospitalization for worsening PAH, >15% therapy based on WHO FC and response to treatment
decline in 6WMD from baseline or unsatisfactory clinical (Fig. 1).
128 SECTION 2: Cardiology
TABLE 1: Adapted from modified Duke’s criteria for diagnosis of Cloxacillin/cefazolin administration may be associated
infective endocarditis with lower mortality rates as compared to other beta-
DEFINITE IE lactams. Antifungal agents include amphoterecin,
Pathological criteria echinocandin and voriconazole.
Culture or confirmatory histological evidence. Empirical therapy should be started promptly
Clinical criteria
after drawing three sets of blood cultures. For NVE
2 major criteria, 1 major criterion and 3 minor criteria, or 5 minor
criteria
(community acquired) ampicillin with cloaxacillin and
POSSIBLE IE gentamicin are recommended. For prosthetic valve
1 major criterion and 1 minor criterion, or 3 minor criteria cases, vancomicin, gentamicin and rifampicin may be
REJECTED started at appropriate dosage intravenously.
Confirmed alternative diagnosis It is reasonable suspect saureus, coagulase-negative
Early resolution of IE syndrome (≤ 4 days of antibiotics)
staphydococci, entrococci, fungi, gram negative bacill
Lack of pathological criteria at surgery criteria for IE not met
in intravenous drug users (IDUs). S. aureus may be the
MAJOR CLINICAL CRITERIA culprit with indwelling cardiac devices and catheters.
Blood culture and serology
Early (≤1 years prosthetic valve placement may be
Requires typical growth: at least 2 positive blood cultures samples
drawn > 12 hour apart or all 3 or a majority of ≥4 separate cultures
caused by coagulase negative staphytococcal or S. aureus
of blood (with first and last sample drawn at least 1 hour apart) infections. Fungi can also be the culprit along with
Single positive blood culture for Coxiella burnetii or antiphase 1 IgG other rare microbials in PVE. S. aureus in diabetes and
antibody titer ≥1:800 viridians group of streptococci postdental procedures are
Echocardiography commonly detected.
Evidence of oscillating intracardiac masses or vegetation, new
The duration of therapy varies from 2–6 weeks
valve regurgitation, annular abscess and prosthetic valve partial
dehiscence are major echocardiographic criteria. Transthoracic
depending on microorganism, native or prosthetic valve,
echocardiography (TTE) is initial choice for native valve drug combination used and location the vegetation.
endocarditis (NVE). Transesophageal echocardiography (TEE) is Treatment period is counted from the day blood culture
preferred, if IE if high suspicion TTE being negative, prosthetic valve becomes negative. An entire course of treatment is
patients with recent complications recommended if operative material is culture positive. It
MINOR CLINICAL CRITERIA imperative that on treatment, two sets of blood cultures
zz Heart condition predisposition, intravenous drug user be obtained every 24–48 hours till culture is negative.
zz Fever ≥38°C
Outpatient paraenteral antibiotic treatment after first
zz Vascular phenomena: Major arterial emboli, septic pulmonary
critical phase of 2 weeks is feasible.
infarcts, mycotic aneurysm, intracranial hemorrhage,
Suggested regimes based on common causative
conjunctival hemorrhages, and Janeway lesions
zz Immunological phenomena: Glomerulo nephritis, Osler nodes,
microorganisms are summarized in Table 2.
Roth spots, and rheumatoid factor
zz Culture positive but not as defined in major criteria. COMPLICATIONS
Heart Failure
and daptamycin are reasonable options. Bactericidal It is frequent and among the common indications for
drugs given together can act synergistically, e.g. certain surgery and usually due to severe or worsening aortic/
beta-lactams with aminoglycosides. mitral regurgitation.
Vanconycin as an alternative can be with poorer
outcomes. Rifampicin should be used only in PVE after Uncontrolled Infection
3–4 days of effective antibiotic therapy. Daptomycin It is among most dreaded complications leading to
and fusomycin are alternative agents for staphylococci surgery with high mortality rates. Persistent infection
and netilmicin for penicillin sensitive strepotococci. is defined as positive blood cultures after 7–10 days of
CHAPTER 23: Infective Endocarditis: An Update 131
stages of management. Early surgery when indicated this is in patients with implants and cardiac devices.
rehabilitation and prophylaxis must be considered. Urgent surgery is indicated in life-threatening situations
of hemodynamic compromise, uncontrolled infection
Endocarditis Team and embolic events. There is a need for creation of the
Multidisciplinary approach and referral centers are endocarditis team and referral IE centers.
desirable to tackle complicated and potentially lethal
endocarditis. BIBLIOGRAPHY
1. Ambrosioni J, Hernandez-Meneses M, Téllez A, Pericàs
PREVENTION J, Falces C, et al. The changing epidemiology of infective
endocarditis in the twenty-first century. Current Infect Dis
Universal prophylaxis is being discouraged due to global
Rep. 2017;19(21):1-10.
fear of antibiotic resistance. Recent studies have not 2. Baddour LM, Wilson WR, Bayer AS, Fowler Jr VG, Tleyjeh
shown negative impact of restrictive prophylaxis. IM, Rybak MJ, et al. Infective endocarditis in adults:
It is mandatory in prosthetic valve patients, implants, diagnosis, antimicrobial therapy, and management of
previous episodes of IE, congenital heart disease complications: a scientific statement for healthcare
cyanotic/repair with residual regurgitation/shunt. It professionals from the American Heart Association.
Circulation. 2015;132(15):1435-86.
is usually not recommended in native valve disease.
3. Bin Abdulhak AA, Baddour LM, Erwin PJ, Hoen B, Chu VH,
However, in rheumatic heart disease discretion is needed Mensah GA, et al. Global and regional burden of infective
for regurgitant lesions and aortic stenosis. endocarditis, 1990-2010: a systematic review of the
Low-grade bacteremia occurs during daily activities literature. Glob Heart. 2014;9(1):131-43.
like tooth brushing more frequently than with dental 4. Habib G, Lancellotti P, Antunes MJ, BongiorniMG, Casalta JP,
procedures which carry only a small risk. Judiciously Del ZF, et al. ESC guidelines for the management of infective
endocarditis: The task force for the management of infective
given 2 gm of amoxacillin (oral or IV) or Clindamycin
endocarditis of the European Society of Cardiology (ESC).
600 mg (if allergic to penicillin) 30–60 minutes before Endorsed by: European Association for Cardio-Thoracic
procedure is sufficient. In respiratory procedures Surgery (EACTS), the European Association of Nuclear
antistaphylococcal drugs and in major genitourinary/ Medicine (EANM). Eur Heart J. 2015;36(44):3075-128.
gastrointestinal procedures agents active against 5. Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG Jr, Ryan T,
enterococci should be included. Bashore T, Corey GR. Proposed modifications to the Duke
criteria for the diagnosis of infective endocarditis. Clin Infect
The consensus today is prevention by early diagnosis
Dis. 2000;30:633-8.
and treatment including surgery than prophylaxis. 6. National Institute for Health and Clinical Excellence (UK),
Centre for Clinical Practice at NICE (UK). Prophylaxis against
Infective Endocarditis Update: A Summary infective endocarditis. Antimicrobial Prophylaxis Against
Early diagnosis, early antibiotic therapy, and early Infective Endocarditis in Adults and Children Undergoing
surgery is crucial. No doubt, echocardiography is vital for Interventional Procedures. NICE Clinical Guidelines, No. 64.
In: 2008.
diagnosis, monitoring, treatment and follow up however
7. Pant S, Patel NJ, Deshmukh A, Golwala H, Patel N,
role of a multimodality imaging is emerging. Badheka A, et al. Trends in infective endocarditis incidence,
The indications for IE prophylaxis is shrinking and microbiology, and valve replacement in the United States
limited to high risk situations. Special concern regarding from 2000 to 2011. J Am Coll Cardiol. 2015;65(19):2070-6.
CHAPTER
24
Pregnancy and Heart Disease
Gurleen Wander, Gurpreet Singh Wander
Due to the vasodilatory effects of progesterone, nitric 3. Moderate-to-severe left ventricular outflow tract
oxide and prostaglandins the systemic vascular resistance obstruction (≥30 mm Hg).
and blood pressure decrease early in pregnancy, reaching 4. Left ventricular ejection fraction <0.30.
their lowest at 20–24 weeks causing hypotension which If a woman with one of these conditions falls pregnant,
is physiological at this gestation. Following this dip in early consultation with obstetrician and a cardiologist
blood pressure the systemic vascular resistance begins should take place in order to evaluate the patient’s risk
to rise and so does the blood pressure which reaches the and develop a care plan. Pregnancy with pulmonary
prepregnancy values by term. hypertension confers a very high risk for maternal
The maternal blood volume increases by 40–50% mortality. Termination is discussed in these conditions
above the nonpregnant level starting from 6 weeks to 8 for maternal concerns.
weeks of gestation and peaking at 32 weeks. Myocardial infarction, ischemic heart disease, and
Hence to summarize: There is an increase in plasma aortic dissection
volume by 50%, an increase in resting heart rate by Pregnancy itself increases the risk of acute myocardial
17% and an increase in cardiac output by 50% during infarction by three to four times, with the risk being
pregnancy. 30 times higher for women more than 40 years of age
compared to younger women (<20 years).
Normal Findings on Examination of the Other risk factors for ischemic heart disease include
Cardiovascular System in Pregnancy chronic hypertension, pre-eclampsia, diabetes, smoking,
These may include: obesity and hyperlipidemia.
Bounding/Collapsing pulse A high index of suspicion for myocardial infarction
Ejection systolic murmur in any pregnant woman presenting with chest pain is
Loud first heart sound essential for good management of these women. The
Third heart sound
differential diagnosis of aortic dissection should also be
Relative sinus tachycardia
kept in mind. All women with chest pain in pregnancy
Ectopic beats
should have an electrocardiogram analysed by a doctor
Peripheral edema
who is trained to pick up signs of cardiac ischaemia and
Normal ECG findings may include—Q–wave (small)
infarction. A thorough history taking and examination
and inverted T wave in lead III, ST segment depression including auscultation goes a long way in the correct
and T–wave inversion in inferior and lateral leads, left detection of the disease. In cases where the pain is
ward shift of the QRS axis. severe, patients should be referred for a CT scan or an
Cardiac disease is a leading cause of maternal death magnetic resonance imaging scan of the chest. A serum
in pregnancy in many developed and developing nations. troponin I measurement can also be useful.
One-third of these deaths are a result of myocardial Cardiac catheterization is permissible in pregnant
infarction/ischemic heart disease and a similar patients, with appropriate abdominal lead shielding for
number of late deaths are associated with peripartum the mother and fluoroscopy time should be kept minimal.
cardiomyopathy. Other significant contributors (5–10% Thrombolytic agents can be used, but the guidelines for
each) are rheumatic heart disease, congenital heart percutaneous coronary intervention should be followed.
disease and pulmonary hypertension.
It usually presents in late pregnancy or early postpartum Tachycardia is particularly a bad sign in patients with
period but can occur up to 6 months after delivery. MS. An echocardiogram is essential for the confirmation
Peripartum cardiomyopathy should be considered of the diagnosis and assessment of severity. Management
in any pregnant or postnatal woman who presents with: includes beta blockers, aggressive treatment of atrial
Increasing shortness of breath fibrillation, treatment and timely recognition of
Reduced exercise tolerance pulmonary edema. Balloon valvotomy and closed
Palpitations mitral valvotomy have very good results but are suited
Pulmonary and/or peripheral edema for noncalcified valves with minimal regurgitation. If
Symptoms relating to peripheral or cerebral emboli. women with severe MS attend prepregnancy they should
All such women should have an electrocardiogram, a be counselled regarding surgical options before planning
chest X-ray and an echocardiogram to evaluate the cause a pregnancy.
of the symptoms.
The management includes–delivery if antenatal. PROSTHETIC HEART VALVES
Thromboprophylaxis is essential. Anticoagulants are Anticoagulation for mechanical heart valves should be
necessary if there is severely impaired LV dysfunction, adjusted in pregnancy as warfarin must be discontinued
intra cardiac thrombus or arrhythmias. Conventional during the 1st trimester due to the risk of teratogenesis,
treatment of heart failure is given including diuretics, miscarriage, stillbirth and intracerebral bleeding.
vasodilators, cardio selective beta blockers (bisoprolol), Current guidelines support three approaches:
carvedilol, digoxin, ionotropes and ACE inhibitors 1. Low-molecular-weight (LMW) heparin administered
postdelivery. Approximately 50% patients make full subcutaneously twice daily throughout pregnancy
recovery. Mortality rate has reduced from 40% in the 2. Unfractionated heparin administered subcutaneously
older studies to 9–15% in more recent series. twice daily throughout pregnancy
3. Unfractionated or LMW heparin administered
RHEUMATIC HEART DISEASE subcutaneously twice daily until 13 weeks of
Mitral valve stenosis (MS) (the most common lesion and pregnancy followed by warfarin from weeks 13 to
the one that carries the highest risk) accounts for 90% of 35, followed by restarting unfractionated or LMW
rheumatic heart disease in pregnancy. If undiagnosed heparin subcutaneously twice daily until delivery.
MS can be dangerous in pregnancy. When LMWH is used, dose should be adjusted
according to anti factor Xa levels, maintaining 4-hour
Symptoms peak anti factor Xa levels at 0.8–1.2 U/mL. Low dose
May be asymptomatic aspirin (75 mg/day) should be added as adjuvant
Dyspnea, orthopnea, PND antithrombotic therapy.
Cough (pink frothy sputum or hemoptysis).
AORTIC DISSECTION
Signs Systolic hypertension is a key factor in most of the
Mitral facies deaths from aortic dissection. It is therefore essential
Tapping undisplaced apex beat to monitor blood pressure closely during pregnancy
Risk of atrial flutter/fibrillation and prompt antihypertensive therapy should be
Loud S1, loud pulmonary second sound (P2), opening given if the blood pressure becomes elevated. Aortic
snap. dissection (diagnosed by computed tomography scan,
Mid diastolic murmur, low pitched TOE or transthoracic echo, MRI scan) is the most
Sign of pulmonary edema common serious complication of Marfan syndrome. The
136 SECTION 2: Cardiology
management is surgical and includes cardiac surgery to change in murmur or any lung changes associated with
replace the aortic root. pulmonary edema should also be undertaken regularly.
Women with cyanotic heart disease should have their
CONGENITAL HEART DISEASE oxygen saturations checked periodically (each trimester
Eisenmenger syndrome is an absolute contraindication or more often if any signs of worsening clinical status).
for pregnancy since there is high maternal mortality of A further multidisciplinary meeting should take place
upto 30–40%. Mothers with cyanotic heart disease and at 32–34 weeks to determine a plan of management for
low flow physiology (Fallot Tetralogy) those survive to delivery. Key features of the plan include deciding who
this age can go through pregnancy. However, fetal loss is should be involved in supervising the labor, whether a
frequent. Also, abortions are common. cesarean section is needed, whether bearing down is safe
Among the acyanotic heart disease those with in the second stage and appropriate prophylaxis against
regurgitant lesions tolerate pregnancy fairly well. postpartum hemorrhage (routinely used oxytocin
Patients of pulmonary stenosis also can have problems regimes may not be safe; a low-dose syntocinon infusion
and preferably balloon pulmonary valvotomy should is probably the best option and prophylactic uterine
be done before pregnancy is planned since it is a simple compression sutures during cesarean sections can
procedure. be considered instead of oxytocin). The plan should
Among the left to right shunt ASDs and VSDs tolerate also include postpartum management, including
pregnancy fairly well. Patients of PDA also tolerate thromboprophylaxis if recommended and the length of
pregnancy although there is some risk of rupture or postnatal stay in hospital.
aneurysm.
Several recent studies have addressed congenital INTRAPARTUM
heart disease (CHD) in pregnancy. In general, regurgitant A general principle of intrapartum management is to
lesions are well tolerated, whereas obstructive lesions are minimize any cardiovascular stress during labor. The use
poorly tolerated. of early epidural anesthesia and assisted vaginal delivery
to cut short the second stage of labor are recommended
GENERAL PRINCIPLES OF depending upon the cardiac condition. Cesarean section
MANAGEMENT is usually recommended for obstetric indications.
Routine antibiotic prophylaxis for delivery (vaginal
Preconception or cesarean section) is not recommended by the
Girls with congenital heart disease should be referred 2008 American Heart Association/American Dental
to a joint cardiac/obstetric clinic for advice about Association guidelines.
contraception (and preconception counselling) once
older around puberty (12–15 years). Preconception CONCLUSION
counselling should also be offered to older women with Thus, pregnant women with heart disease need special
a new diagnosis. care and a team approach between obstetrician and
cardiologist. Frequent communication is important
Antepartum between the two teams. Labor and delivery are specially
A risk assessment of every woman with a heart murmur stressful for these patients and institutional protocols
or a history of cardiac defect should be carried out early with cooperation of family anesthetic, obstetrician and
in pregnancy in a joint clinic by a consultant obstetrician, cardiologist should be preferred.
cardiologist and anesthetist. Drugs that can be harmful to the mother and
Women should have their heart rate and BP measured are teratogenic, like ACE inhibitors and ARBs are
regularly in pregnancy. Auscultation to assess any contraindicated and should not be used. Exposure to
CHAPTER 24: Pregnancy and Heart Disease 137
case for screening and appropriate management. J Manag 24. Salvador DR, Rey NR, Ramos GC, Punzalan FE. Continuous
Care Pharm. 2007;13:S6-12. infusion versus bolus injection of loop diuretics in congestive
20. Shlipak MG, Mattes MD, Peralta CA. Update on cystatin heart failure. Cochrane Database Syst Rev. 2004;20:31-78.
25. Marenzi G, Lauri G, Grazi M, et al. Circulatory response
C: incorporation into clinical practice. Am J Kidney Dis.
to fluid overload removal by extracorporeal ultrafiltration
2013;62:595-603.
in refractory congestive heart failure. J Am Coll Cardio.
21. Knight EL, Verhave JC, Spiegelman D, et al. Factors 2001;38:963-8.
influencing serum cystatin C levels other than renal function 26. Fu P, Arcasoy MO. Erythropoietin protects cardiac myocytes
and the impact on renal function measurement. Kidney Int. against anthracycline-induced apoptosis. Biochem Biophys
2004;65:1416-21. Res Commun. 2007;354:372-8.
22. Devarajan P. Review: neutrophil gelatinase-associated 27. Jasuja D, Mor MK, Hartwig KC, Palevsky PM, Fine MJ, et al.
Provider knowledge of contrastinduced acute kidney injury.
lipocalin: a troponin-like biomarker for human acute kidney
Am J Med Sci. 2009;338:280-6.
injury. Nephrology (Carlton). 2010;15:419-28.
28. Manley HJ. Disease progression and the application of
23. Bonventre JV. Kidney injury molecule-1 (KIM-1): a urinary evidencebased treatment guidelines diagnose it early: a
biomarker and much more. Nephrol Dial Transplant. case for screening and appropriate management. J Manag
2009;24:3265-8. Care Pharm. 2007;13:S6-12.
CHAPTER
26
Heart Failure with Reduced
Ejection Fraction: Treatment Strategy
Amal Kumar Banerjee
or LAE) or LAE)
—— Diastolic dysfunction —— Diastolic dysfunction
Abbreviations: HF, heart failure; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction;
HFrEF, heart failure with reduced ejection fraction; LAE, left atrial enlargement; LVEF, left ventricular ejection fraction; LVH, left ventricular
hypertrophy
The Killip classification may be used to describe the features, particularly previous myocardial infarction,
severity of the patient’s condition in the acute setting greatly increase the likelihood of HF in a patient with
after myocardial infarction. appropriate symptoms and signs. Symptoms and
In clinical practice, a clear distinction between signs are important in monitoring a patient’s response
acquired and inherited cardiomyopathies remains to treatment and stability over time. Persistence of
challenging. In most patients with a definite clinical symptoms despite treatment usually indicates the need
diagnosis of HF, there is no confirmatory role for routine for additional therapy, and worsening of symptoms is
genetic testing, but genetic counselling is recommended a serious development (placing the patient at risk of
in patients with hypertrophic cardiomyopathy (HCM), urgent hospital admission and death) and merits prompt
idiopathic DCM or arrhythmogenic right ventricular medical attention.
cardiomyopathy (ARVC), since the outcomes of these
tests may have clinical implications. Investigations
The following diagnostic tests are recommended/should
DIAGNOSIS be considered for initial assessment of a patient with
newly diagnosed HF in order to evaluate the patient’s
Clinical suitability for particular therapies, to detect reversible/
Symptoms are often nonspecific and do not, therefore, treatable causes of HF and comorbidities interfering with
help discriminate between HF and other problem. HF.
Symptoms and signs of HF due to fluid retention may Hemoglobin and WBC, sodium, potassium, urea,
resolve quickly with diuretic therapy. Signs, such as creatinine (with estimated GFR), liver function tests
elevated jugular venous pressure and displacement of (bilirubin, AST, ALT, GGTP), glucose, HbA1c, TSH,
the apical impulse, may be more specific, but are harder ferritin, TSAT = TIBC should be done.
to detect and have poor reproducibility. Symptoms The plasma concentration of natriuretic peptides
and signs may be particularly difficult to identify and (NPs) can be used as an initial diagnostic test, especially
interpret in obese individuals, in the elderly and in in the nonacute setting when echocardiography is not
patients with chronic lung disease. Younger patients with immediately available. Elevated NPs help establish an
HF often have a different etiology, clinical presentation initial working diagnosis, identifying those who require
and outcome compared with older patients. A detailed further cardiac investigation; patients with values below
history should always be obtained. HF is unusual in the cutpoint for the exclusion of important cardiac
an individual with no relevant medical history (e.g. a dysfunction do not require echocardiography. Patients
potential cause of cardiac damage), whereas certain with normal plasma NP concentrations are unlikely
146 SECTION 2: Cardiology
to have HF. The upper limit of normal in the nonacute (COPD), pulmonary function testing with spirometry is
setting for B-type natriuretic peptide (BNP) is 35 pg/mL needed. The chest X-ray may, however, show pulmonary
and for N-terminal pro-BNP (NT-proBNP) it is 125 pg/ venous congestion or oedema in a patient with HF,
mL; in the acute setting, higher values should be used and is more helpful in the acute setting than in the
[BNP, 100 pg/mL, NT-proBNP, 300 pg/mL and mid- nonacute setting. It is important to note that significant
regional pro A-type natriuretic peptide (MR-proANP) 120 LV dysfunction may be present without cardiomegaly on
pmol/L]. the use of NPs is recommended for ruling-out the chest X-ray.
HF, but not to establish the diagnosis. Cardiac magnetic resonance (CMR) is acknowledged
Although there is extensive research on biomarkers as the gold standard for the measurements of volumes,
in HF (e.g. ST2, galectin 3, copeptin, adrenomedullin), mass and EF of both the left and right ventricles. It
there is no definite evidence to recommend them for is the best alternative cardiac imaging modality for
clinical practice. patients with nondiagnostic echocardiographic studies
An abnormal electrocardiogram (ECG) increases the (particularly for imaging of the right heart) and is the
likelihood of the diagnosis of HF, but has low specificity. method of choice in patients with complex congenital
Some abnormalities on the ECG provide information heart diseases. CMR is the preferred imaging method
on etiology (e.g. myocardial infarction), and findings to assess myocardial fibrosis using late gadolinium
on the ECG might provide indications for therapy (e.g. enhancement (LGE) along with T1 mapping and can
anticoagulation for AF, pacing for bradycardia, CRT if be useful for establishing HF etiology. CMR allows the
broadened QRS complex). HF is unlikely in patients characterization of myocardial tissue of myocarditis,
presenting with a completely normal ECG (sensitivity amyloidosis, sarcoidosis, Chagas disease, Fabry disease
89%). Therefore, the routine use of an ECG is mainly noncompaction cardiomyopathy and hemochromatosis.
recommended to rule out HF. Single-photon emission CT (SPECT) may be useful in
Echocardiography is the most useful, widely available assessing ischemia and myocardial viability.
test in patients with suspected HF to establish the Positron emission tomography (PET) (alone or with
diagnosis. It provides immediate information on CT) may be used to assess ischemia and viability.
chamber volumes, ventricular systolic and diastolic Coronary angiography is recommended in patients
function, wall thickness, valve function and pulmonary with HF who suffer from angina pectoris recalcitrant
hypertension. This information is crucial in establishing to medical therapy, provided the patient is otherwise
the diagnosis and in determining appropriate treatment suitable for coronary revascularization. Coronary
The information provided by careful clinical angiography is also recommended in patients with
evaluation and the above mentioned tests will permit a history of symptomatic ventricular arrhythmia or
an initial working diagnosis and treatment plan in most aborted cardiac arrest. Coronary angiography should be
patients. Other tests are generally required only if the considered in patients with HF and intermediate to high
diagnosis remains uncertain (e.g. if echocardiographic pretest probability of CAD and the presence of ischemia
images are suboptimal or an unusual cause of HF is in noninvasive stress tests in order to establish the
suspected). ischemic etiology and CAD severity.
A chest X-ray is of limited use in the diagnostic The main use of cardiac CT in patients with HF is as
work-up of patients with suspected HF. It is probably a noninvasive means to visualize the coronary anatomy
most useful in identifying an alternative, pulmonary in patients with HF with low intermediate pretest
explanation for a patient’s symptoms and signs, i.e. probability of CAD or those with equivocal noninvasive
pulmonary malignancy and interstitial pulmonary stress tests in order to exclude the diagnosis of CAD,
disease, although computed tomography (CT) of the in the absence of relative contraindications. However,
chest is currently the standard of care. For the diagnosis the test is only required when its results might affect a
of asthma or chronic obstructive pulmonary disease therapeutic decision.
CHAPTER 26: Heart Failure with Reduced Ejection Fraction: Treatment Strategy 147
Molecular genetic analysis in patients with should be cautiously initiated in hospital, once the
cardiomyopathies is recommended when the prevalence patient is stabilized.
of detectable mutations is sufficiently high and consistent Mineralocorticoid (MRA) (spironolactone and
to justify routine targeted genetic screening. eplerenone) block receptors that bind aldosterone
and, with different degrees of affinity, other steroid
PHARMACOLOGIC TREATMENT hormone (e.g. corticosteroids, androgens) receptors.
The goals of treatment in patients with HF are to improve Spironolactone or eplerenone are recommended in
their clinical status, functional capacity and quality of all symptomatic patients (despite treatment with an
life, prevent hospital admission and reduce mortality. It ACEI and a beta-blocker) with HFrEF and LVEF ≤35%,
is now recognized that preventing HF hospitalization and to reduce mortality and HF hospitalization.12,13 Caution
improving functional capacity are important benefits to should be exercised when MRAs are used in patients
be considered if a mortality excess is ruled out.5-7 with impaired renal function and in those with serum
Neurohormonal antagonists (ACEIs, MRAs and beta- potassium levels ≥5.0 mmol/L. Regular checks of serum
blockers) have been shown to improve survival in patients potassium levels and renal function should be performed
with HFrEF and are recommended for the treatment of according to clinical status.
every patient with HFrEF, unless contraindicated or not Ivabradine reduces the elevated heart rate often seen
tolerated. A new compound (LCZ696) that combines the in HFrEF and has also been shown to improve outcomes,
moieties of an ARB (valsartan) and a neprilysin (NEP) and should be considered when appropriate.
inhibitor (sacubitril) has recently been shown to be A combination of hydralazine and isosorbide dinitrate
superior to an ACEI (enalapril) in reducing the risk of may be considered in symptomatic patients with HFrEF
death and of hospitalization for HF in a single trial with who can tolerate neither ACEI nor ARB (or they are
strict inclusion/exclusion criteria.8 Sacubitril/valsartan is contraindicated) to reduce mortality.
therefore recommended to replace ACEIs in ambulatory Digoxin may be considered in patients in sinus
HFrEF patients who remain symptomatic despite rhythm with symptomatic HFrEF to reduce the risk of
optimal therapy and who fit these trial criteria. ARBs hospitalization (both all-cause and HF hospitalizations).
have not been consistently proven to reduce mortality in In patients with symptomatic HF and AF, digoxin
patients with HFrEF and their use should be restricted to may be useful to slow a rapid ventricular rate, but it is
patients intolerant of an ACEI or those who take an ACEI only recommended for the treatment of patients with
but are unable to tolerate an MRA. HFrEF and AF with rapid ventricular rate when other
ARBs are recommended only as an alternative in therapeutic options cannot be pursued.
patients intolerant of an ACEI. These medications should be used in conjunction
Beta-blockers reduce mortality and morbidity in with diuretics in patients with symptoms and/or signs
symptomatic patients with HFrEF, despite treatment of congestion. The use of diuretics should be modulated
with an ACEI and, in most cases, a diuretic,9,10 but have according to the patient’s clinical status.
not been tested in congested or decompensated patients.
There is consensus that beta-blockers and ACEIs are NONSURGICAL DEVICE TREATMENT4
complementary, and can be started together as soon as
Implantable Cardioverter-defibrillator
the diagnosis of HFrEF is made. There is no evidence
favouring the initiation of treatment with a beta-blocker Primary prevention: An ICD is recommended to reduce
before an ACEI has been started.11 Betablockers should the risk of sudden death and all-cause mortality in
be initiated in clinically stable patients at a low dose and patients with symptomatic HF (NYHA Class II–III), and
gradually up-titrated to the maximum tolerated dose. In an LVEF ≤35% despite ≥3 months of OMT, provided they
patients admitted due to acute HF (AHF) beta-blockers are expected to survive substantially longer than one year
148 SECTION 2: Cardiology
with good functional status, and they have: IHD (unless Patients with HFrEF who have received a conventional
they have had an MI in the prior 40 days), and DCM. pacemaker or an ICD and subsequently develop
worsening HF despite OMT and who have a high
Secondary prevention: An ICD is recommended to
proportion of RV pacing may be considered for
reduce the risk of sudden death and all-cause mortality
upgrade to CRT. This does not apply to patients with
in patients who have recovered from a ventricular
stable HF.
arrhythmia causing hemodynamic instability, and who
CRT is contraindicated in patients with a QRS
are expected to survive for >1 year with good functional
duration <130 msec.
status.
3. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update 10. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi
incorporated into the ACC/AHA 2005 guidelines for the P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz
diagnosis and management of heart failure in adults : a MK, DeMets DL. Effect of carvedilol on survival in severe
report of the American College of Cardiology Foundation/ chronic heart failure. N Engl J Med. 2001;344:1651-8.
American Heart Association Task Force on Practice 11. Willenheimer R, van Veldhuisen DJ, Silke B, Erdmann E,
Guidelines developed in collaboration with the International Follath F, Krum H, Ponikowski P, Skene A, van de Ven L,
Society for Heart and Lung Transplantation. Circulation. Verkenne P, Lechat P, CIBIS III Investigators. Effect on
2009;119(14):e391-e479. survival and hospitalization of initiating treatment for
4. Ponikowski P, Voors AA. Anker SD, Bueno H, Cleland JG, chronic heart failure with bisoprolol followed by enalapril,
Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and as compared with the opposite sequence: results of the
treatment of acute and chronic heart failure. The Task randomized. Cardiac Insufficiency Bisoprolol Study (CIBIS)
Force for the diagnosis and treatment of acute and chronic III. Circulation. 2005;112:2426-35.
heart failure of the European Society of Cardiology (ESC). 12. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez
Developed with the special contribution of the Heart Failure A, Palensky J, Wittes J. The effect of spironolactone on
Association (HFA) of the ESC. European Heart Journal. morbidity and mortality in patients with severe heart failure.
doi:10.1093/eurheartj/ehw128. N Engl J Med. 1999;341:709-17.
5. Stewart S, Jenkins A, Buchan S, McGuire A, Capewell 13. Zannad F, McMurray JJV, Krum H, Van Veldhuisen DJ,
S, McMurray JJJV. The current cost of heart failure to Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B. Eplerenone
the National Health Service in the UK. Eur J Heart Fail. in patients with systolic heart failure and mild symptoms. N
2002;4:361-71. Engl J Med. 2011;364:11–21.
6. Gheorghiade M, Shah AN, Vaduganathan M, Butler J, Bonow 14. Kadish A, Nademanee K, Volosin K, Krueger S, Neelagaru
RO, Rosano GMC, Taylor S, Kupfer S, Misselwitz F, Sharma S, Raval N, Obel O, Weiner S, Wish M, Carson P, Ellenbogen
A, Fonarow GC. Recognizing hospitalized heart failure as an K, Bourge R, Parides M, Chiacchierini RP, Goldsmith R,
entity and developing new therapies to improve outcomes: Goldstein S, Mika Y, Burkhoff D, Abraham WT. A randomized
academics’, clinicians’, industry’s, regulators’, and payers’ controlled trial evaluating the safety and efficacy of cardiac
perspectives. Heart Fail Clin. 2013;9:285-90, v–vi. contractility modulation in advanced heart failure. Am Heart
7. Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, J. 2011;161:329-37.e2
Vaduganathan M, Nodari S, Lam CSP, Sato N, Shah AN, 15. Borggrefe MM, Lawo T, Butter C, Schmidinger H, Lunati
Gheorghiade M. The global health and economic burden M, Pieske B, Misier AR, Curnis A, Bo¨cker D, Remppis A,
of hospitalizations for heart failure. J Am Coll Cardiol. Kautzner J, Stu¨hlinger M, Leclerq C, Ta´borsky´ M, Frigerio
2014;63:1123-33. M, Parides M, Burkhoff D, Hindricks G. Randomized,
8. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, double blind study of non-excitatory, cardiac contractility
Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg modulation electrical impulses for symptomatic heart
K, Zile MR. PARADIGM-HF Investigators and Committees. failure. Eur Heart J. 2008;29:1019-28.
Angiotensin-neprilysin inhibition versus enalapril in heart 16. Balion C, McKelvie R, Don-Wauchope AC, Santaguida PL,
failure. N Engl J Med. 2014;371:993-1004. Oremus M, Keshavarz H, Hill SA, Booth RA, Ali U, Brown
9. Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, JA, Bustamam A, Sohel N, Raina P. B-type natriuretic
Waagstein F, Kjekshus J, Wikstrand J, ElAllaf D, Vı´tovec J, peptide-guided therapy: a systematic review. Heart Fail Rev.
Aldershvile J, Halinen M, Dietz R, Neuhaus KL, Ja´nosi A, 2014;19:553-64.
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J, Rickenbacher P, Ball S, Gottlieb S, Deedwania P. MERIT- Pfisterer M, Eurlings LWM, Erntell H, Persson H, O’Connor
HF Study Group. Effects of controlled-release metoprolol on CM, Moertl D, Karlstrom P, Dahlstrom U, Gaggin HK, Januzzi
total mortality, hospitalizations, and wellbeing in patients JL, Berger R, Richards AM, Pinto YM, Nicholls MG. Effect of
with heart failure: the Metoprolol CR/XL Randomized B-type natriuretic peptide-guided treatment of chronic heart
Intervention Trial in congestive Heart Failure (MERIT-HF). failure on total mortality and hospitalization: an individual
JAMA. 2000;283:1295-302. patient meta-analysis. Eur Heart J. 2014;35:1559-67.
CHAPTER
27
Pulmonary Embolism: Focus on New Drugs
VK Katyal, Ashima Katyal, Naman Mukhi
INTRODUCTION PATHOPHYSIOLOGY
Venous thromboembolism (VTE) constitutes pulmonary Pathophysiologic cascade culminating in VTE includes
embolism (PE) and deep vein thrombosis (DVT). active inflammation, hypercoagulability and endothelial
It results in over one lac deaths annually in USA. insult. Venous thrombi form and flourish in an
While in-hospital mortality is 7% it rises to 30% if atmosphere of stasis, low oxygen pressure, oxidative
hemodynamic instability is associated. PE affects quality stress, enhanced expression of proinflammatory
of life and can cause major long-term complications markers and impaired endothelial cell mechanics.
which includes recurrent episode of VTE, chronic PE consequently, elicit a complex cardiopulmonary
thromboembolic pulmonary arterial hypertension response viz; heightened pulmonary vascular resistance,
(CTEPH) and chronic leg venous insufficiency. VTE neurohumoral activation, impaired gas exchange caused
although can affect any age, the incidence steadily by increased alveolar dead space and hypoxemia due
rises with age and recurrences despite anticoagulation to alveolar hypoventilation and right-to-left shunting
are common. VTE is usually outcome of interaction of blood. A sudden rise in pulmonary arterial pressure
between patients-related (permanent risk factors) and abruptly increases RV afterload with rise in RV wall
situation-related (temporary) risk factors. It’s considered tension resulting in RV dilatation (Fig. 1). Consequently,
“Provoked” if temporary or reversible risk factors viz; IVS shifts to left resulting in reduced LV filling causing
trauma, major surgery, immobilization, pregnancy, fall in systemic arterial pressure, impaired coronary
oral contraceptives or even hormone replenishment perfusion and myocardial ischemia. Elevated RV wall
therapy occur within preceding 6 weeks to 3 months. tension after massive VTE reduces right coronary
However, it is diagnosed “Unprovoked” in the absence flow, increases RV oxygen demand causing ischemia.
of such factors. Presence of risk factors influences the Perpetuation of this cycle results in RV infarction,
duration of anticoagulation. Advances in diagnostics, circulatory collapse, and death.
therapeutic modalities and preventive strategies added
with improved pathophysiologic understanding has CLINICAL PRESENTATIONS
resulted in improved outcome as there is now a focus on The symptoms and signs of PE are nonspecific. Dyspnea
newer modalities of treatment. is most prominent symptom and chest pain is unusual.
152 SECTION 2: Cardiology
Multidetector CT can identify upto 6 order branches of ovale and thrombus in RV or RA may be associated.
pulmonary artery and 3D images can be constructed. CT Other investigation like; lung scanning, venous
can also visualize 4-chambers of heart and pulmonary ultrasonography, MRI chest, pulmonary angiography are
artery and signs of RV dysfuction can be measured not routinely carried out in most patients of PE.
including
i. RV to LV diameter ratio (>0.9 suggest RV enlargement) MANAGEMENT OF ACUTE
ii. RV to LV volume ratio >1.2 abnormal PULMONARY EMBOLISM
iii. IVS bowing to left Risk stratification of acute PE is essential as it can have
iv. reflux of contrast into IVC. wide spectrum of presentations (Table 2). The patient
Echocardiography may be normal in upto 1/3rd of can be classified as high risk, intermediate (high or low )
patients. However, it is rapid, sensitive technique for RV and low risk PE based on clinical presentation and other
overload and dysfunction characterized by moderate to parameters as per risk score PESI as shown in pulmonary
severe RV hypokinesis with normal RV apex (McConell’s embolism severity index (PESI) identifies 11 clinical
sign), persistent PA hypertension, TR (>2.6 m/sec), parameters for risk stratification and 30 day mortality in
D-shaped LV and noncollapsing IVC, patent foramen class 5 is 10–24.5% (Table 3).
TABLE 2: Classification of patients with acute pulmonary embolism based on early mortality risk
Treatment of Acute Phase 0.36; 95% CI: 0.15–0.84) hemorrhage. As a result, NOACs
are recommended in the 2014 ESC guidelines as an
Anticoagulation
alternative to the standard heparin/VKA treatment.
Conventional anticoagulants: Early anticoagulation
All four NOACs mentioned earlier are now licensed for
is recommended in acute PE with aim to prevent
treatment of VTE in the United States and the European
death and recurrence. This consists of parenteral
Union.
anticoagulation with Unfractionated Heaprin, LMWH
The dosages of NOAC are: Dabigatran 150 mg bid
or Fondaparinaux for 5–10 days overlapping with oral
from D5, Rivoroxaban 15 mg bid (D1) and 20 mg od from
anticoagulants-vitamin K antagonists (warfarin or
D5, Edoxaban 60 mg od D5 and Apixaban 10 mg bid from
Acenocoumarin). Anticoagulants are continued for 3
D1–5, 5 mg bid thereafter (conventional anticoagulation
months in unprovoked VTE (extended usage if provoked
from D1–5). For long term use after VTE, all NOAC
or second episode) with INR goal of 2–3. Dose of UFH
are better for both all-cause mortality and recurrent
should be IV bolus of 80 units/kg followed by continuous
VTE than with placebo. For reversal of anticoagulation
infusion of 18 units/kg/hr. The aPTT should be targeted
in NOAC-Idarucizumab, an antibody fragment for
between 1.5 seconds and 2.5 seconds. LMWH is given
Dabigatran and Andexanet alfa, a modified recombinant
per kg dose as per agent used. While UFH heparin acts
human factor Xa molecule, for Adixaban have been
by binding to antithrombin, LMWH has anti-Xa activity.
developed.
Newer oral anticoagulants (NOAC): Two classes of NOAC have not been tested in pregnancy and chronic
oral direct anticoagulant agents are now available kidney disease with CrCl <30 mL/min. Certain specific
for use in clinical practice to overcome the limits situations use of anticoagulants have been defined as
of conventional anticoagulation. These agents are shown in Table 4.
synthetic, selective, and reversible inhibitors of factor
Xa (rivaroxaban, apixaban, and edoxaban) or thrombin Aspirin
(dabigatran). These act rapidly and have predictable Aspirin (100 mg/d) is indicated over no aspirin to prevent
anticoagulant effect permitting use in fixed dose without recurrent VTE if anticoagulants are stopped. However,
lab control. The short half-life of NOAC allows quick asprin is not as effective as standard anticoagulants.
reversal of anticoagulation in situations viz; needed Asprin shows a 32% reduction in recurrences of VTE and
for invasive procedures and bleeding complications. 34% reduction in risk of major vascular events.
Rivaroxaban and edoxaban offer the possibility of once-
daily administration. Reperfusion Therapies
Phase 3 trials investigating the new, nonvitamin Thrombolysis: Systemic pharmacological thrombo
K dependent oral anticoagulant agents apixaban lysis is indicates in patients with massive and high risk
(AMPLIFLY), dabigatran (RE-COVER, RE-COVER-II), PE with hypotension. Streptokinase (2.5 lacs loading
edoxaban (HOKUSAI), and rivaroxaban (EINSTEIN, over 30 min followed by 1 lac IU/hr over 12–24 hrs),
EINSTEIN PE) in the treatment of VTE have been urokinase (4400 IU/kg loading in 30 min, followed
completed and published. A meta-analysis 15 showed by 4400 IU/kg over 12–24 hrs) and rTPA 100 mg over
that these agents are noninferior to the standard heparin/ 2 hrs or 0.6 mg/kg over 15 mins are the agents used.
VKA regimen, in terms of prevention of VTE recurrence Thrombolysis results in reduction in RV pressure,
(relative risk [RR]: 0.90; 95% confidence interval [CI]: prevention of release of serotonin which exacerbate
0.77–1.06), and that they are probably safer in terms of PAH and dissolution of thrombus in pelvic or leg
major bleeding (RR: 0.61; 95% CI: 0.45–0.83), particularly veins. However for intermediate high risk patients,
intracranial (RR: 0.37; 95% CI:0.21–0.68) and fatal (RR: thrombolysis is controversial.
CHAPTER 27: Pulmonary Embolism: Focus on New Drugs 155
Catheter based reperfusion: 1% risk of intracranial months and platelet count <50000/uL. UFH, enoxaparin,
hemorrhage risk during thrombolysis has dampened asprin, warfarin, NOAC, fondaparinux (all in reduced
the enthusiasm of this therapy. Pharmacomechanical doses) and intermittent pneumatic compression of leg
catheter based directed reperfusion holds promise veins are all effective and can be given within 24 hours
with reduced dose of rtPA to 25 mg. Interventional of surgery.
techniques during this procedure includes mecha
nical fragmentation and aspiration of thrombus, BIBLIOGRAPHY
clot pulverization, rheolytic thrombectomy and 1. Agnelli G, Buller HR, Cohen A, et al. For the AMPLIFY
investigators. Oral apixaban for the treatment of acute
pigtail rotational catheter embolectomy. This may
venous thromboembolism. N Engl J Med. 2013;369:799-
be followed with balloon dilatation and stenting of 808.
pulmonary artery. 2. Becattini C, Agnelli G. Treatment of venous thromboembolism
Surgical embolectomy: Two indications are–Massive with new anticoagulant agents. J Am Coll Cardiol. 2016;67:
PE with hypotension, submassive PE with severe 1941-55.
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venous thromboembolism. N Engl J Med. 2010;363:2499-
thrombolysis or if thrombolysis failed. 510.
Inferior vena cava filters: AHA defines indication of 4. EINSTEIN–PE Investigators. Oral rivaroxaban for the
caval filters in treatment of symptomatic pulmonary embolism. N Engl J
i. contraindications to anticoagulation Med. 2012;366:1287-97.
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disease—A textbook of cardiovascular Medicine 10th
iii. very poor cardiopulmonary reserve.
edition Mann, Zipes, Libby, Bono weds volume-II, Elservier
Saunders. 2015. pp.1664-81.
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VTE once develops, is difficult to diagnose, potentially the treatment of symptomatic venous thromboembolism. N
lethal and expensive to treat and most preventable cause Engl J Med. 2013;369:1406-15.
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of death. Thus, VTE prophylaxis is essential and risk
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Score. Three risk factors have been defined where risk of Physicians Evidence- Based Clinical Practice Guidelines.
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156 SECTION 2: Cardiology
8. Konstantinides SV, Barco S, Lankeit M, Meyer G. 11. Schulman S, Kakkar AK, Goldhaber SZ, et al. for the
Management of pulmonary embolism-Present and future– RE-COVER II trial investigators. Treatment of acute venous
an Update. J Am Coll Cardiol. 2016;67:976-90. thromboembolism with dabigatran or warfarin and pooled
9. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC analysis. Circulation. 2014;129:764-72.
guidelines on the diagnosis and management of acute 12. Schulman S, Kearon C, Kakkar AK, et al. For the RE-
pulmonary embolism. Eur Heart J. 2014;35:3033-69. COVER study group. Dabigatran versus warfarin in the
10. Righini M, Roy PM, Meyer G, et al. The simplified pulmonary treatment of acute venous thromboembolism. N Engl J Med.
embolism severity index (PESI): validation of a clinical 2009;361:2342-52.
prognostic model for pulmonary embolism. J Thromb
Haemost. 2011;9:2115-7.
CHAPTER
28
Echocardiographic Navigation of AF from
Irregular Pulse to Slurring of the Speech:
Relevant at All Stages in India and the Real World
HK Chopra, Ravi R Kasliwal, Manish Bansal, Shraddha Ranjan
study risk score, was developed and validated which uses In this article, we try to do the same by reviewing the role
factors incorporated in the CHADS2 risk score, along of echocardiography in the evaluation and management
with renal dysfunction.7 of patients with AF.
Role of transesophageal echocardiographic (TEE)
evaluation in ruling out left atrial thrombi to allow for ECHOCARDIOGRAPHIC NAVIGATION IN
early cardioversion in new onset AF is undebatable and AF MANAGEMENT
has become a dictum in everyday cardiology practice.
But apart from that it is discouraging to see that in all
Left Atrial/Left Atrial Appendage Clot
these risk scores there has been no consideration of The primary indication for performing assessment
echocardiographic parameters which can be of immense of the LAA is to rule out the presence of a thrombus.
value in management of AF patients. The study Stroke The risk of systemic emboli, probably arising in the
Prevention in Atrial Fibrillation (SPAF) confirmed the LA cavity or LAA as a result of circulatory stasis, is an
usefulness of TEE for predicting thromboembolism. important consideration in AF. TEE is highly accurate
It showed that the rate of stroke was increased over for this purpose with some studies reporting sensitivity
threefold when TEE evidence of dense spontaneous echo and specificity of TEE to be as high as 100% and 99%
contrast (SEC) was present, increased by threefold for respectively 9 (Figs 1 to 3). Cardioversion carries an
reduced (<20 cm/second) left atrial appendage (LAA) intrinsic risk of stroke in nonanticoagulated patients
peak ejection flow velocity and for LAA thrombus, and (upto 7% of patients) which is reduced substantially by
increased fourfold by complex aortic plaque.8 the administration of anticoagulation.10,11 Patients who
In our country, though true prevalence is still have been in AF for longer than 48 hours should start OAC
unknown, it is a fact that AF may be a bigger problem at least 3 weeks before cardioversion and continue it for
than in the West considering the extra burden of valvular at least 4 weeks afterwards.2 However, when acute onset
AF due to Rheumatic Heart Disease (RHD) along with AF is encountered and early cardioversion is desired, TEE
the nonvalvular AF. In most of the patients, there is no can exclude the majority of left atrial thrombi, allowing
way to determine the actual time of commencement of immediate cardioversion. The advantages of TEE-guided
AF, medical attention is sought later and records are not early cardioversion with short term anticoagulation
meticulously maintained, making it all the more essential over the conventional strategy include the following:
for developing echocardiography as a modality which (1) On TEE, if no thrombus is seen the total duration of
can give us most of the answers with limited resources. anticoagulation can be reduced by weeks, potentially
A B
Figs 1A and B: Large left atrial appendage clot. (A) Two-dimensional image; (B) Three-dimensional image
CHAPTER 28: Echocardiographic Navigation of AF from Irregular Pulse to Slurring of the Speech 159
A B
Figs 2A and B: Small clot in one of the lobes of the left atrial appendage.
The clot is visualized only in one plane (A) but not in the orthogonal plane (B)
A B
Figs 4A and B: Measurement of left atrial volume by the biplane area-length method. Left atrial area and length are measured in both the
apical four and two-chamber views and used in the equation
A B
Figs 5A and B: Measurement of left atrial volume by the biplane Simpson’s method
Using the biplane area-length method, LA volume LAA are not included in the measurement. Irrespective
can be calculated as: of the method, the estimated LA volume should always
Left atrial volume= 8/3π (A1 × A2/L) be indexed to the body-surface area. The normal value of
indexed LA volume is ≤34 ml/m2.
A1 is the planimetric LA area in the four-chamber view The estimation of LA volume by the Simpson’s
A2 is the planimetric LA area in the two-chamber view method (Figs 5A and B) is based on the same principles
L is the length of the LA, measured as the perpendicular as for left ventricular volume estimation. LA endocardial
distance from the mid-point of mitral annular plane to border is trace in both the apical four-chamber and
the superior aspect of the left atrium (Figs 4A and B). the two-chamber views and the software inbuilt in the
The length is measured in both the four-chamber echocardiography machine automatically calculates the
and the two-chamber views and the shorter of the LA volume. While tracing the endocardial border, same
two is used in the equation. While doing planimetry precautions need to be exercised as described above for
foreshortening is avoided and pulmonary veins and the the area-length method.
CHAPTER 28: Echocardiographic Navigation of AF from Irregular Pulse to Slurring of the Speech 161
emptying phase is followed by a phase of diastasis in developing AF. It’s role in clinical decision making is
which the strain curve plateaus. With the onset of atrial discussed below:
contraction, marked by P-wave on the ECG, the left
atrium shortens again, resulting in second phase of Prediction of Atrial Fibrillation
strain reduction. The strain curve eventually reaches
LA strain if reduced predicts occurrence of AF in
the baseline by the onset of QRS. Since QRS is generally
numerous clinical settings. Few studies which were done
used as the reference point, most of the nomenclature
on patients undergoing coronary artery bypass surgery
for LA strain is based on this method only.32 The peak
or valve surgery showed that LA strain and strain rate
atrial longitudinal strain (PALS), measured at the
were significantly impaired in patients who developed
end of the ventricular systole represents the reservoir
postoperative AF and were independent predictors of
function of the LA; the reduction in strain from this peak
the development of AF in the overall cohort.38-40 LA strain
to the plateau phase indicates the conduit function;
can be helpful in predicting the risk of AF in nonsurgical
and the final phase of LA strain reduction during atrial
contraction (termed peak atrial contraction strain or patients also specially in rheumatic mitral stenosis.41,42
PACS) represents the booster function. PALS averaged
for all 12 segments (or all analyzed segments) is used Prediction of Stroke Risk
as global LA strain. Global PACS can also be calculated Stroke is the most feared but possibly preventable
in a similar manner. In addition, LA contraction strain complication of AF. LA strain can also be a useful
index can also be calculated as global PACS X 100/global parameter along with the validated risk scores when
PALS and represents the contribution of the LA active prevention of stroke is the matter on hand. Hsu et al.
contraction to the total LV filling. followed up 190 patients with persistent AF and found
LA strain is briefly reduced in patients with short- that baseline LA strain was found to be a predictor of
duration AF but gradually recovers with time,33,34 unless stroke event in these patients and had incremental value
there have been chronic structural changes in LA over CHA2DS2-VASc score.43 In another study with 286
myocardium. If AF persists, there is structural and consecutive patients of paroxysmal or persistent AF with
functional remodeling of left atrium characterized by or without acute embolism global LA strain was found to
increased fibrosis of LA myocardium. In such patients, be lower not only in patients with acute embolism, it had
LA strain is persistently reduced and is a determinant
an incremental value over the CHA2DS2-VASc score.44
of adverse clinical outcomes. Several studies have
Several other studies have demonstrated association
demonstrated close correlation between LA fibrosis and
between LA strain and the CHA 2DS 2-VASc score. 45,46
LA strain.35 In a study patients with persistent AF were
previous history of stroke47 and the future occurrence
found to have greater degree of fibrosis than those with
of stroke. 48 Moreover, impairment of LA strain has
paroxysmal AF. 36 Apart from AF, LA remodeling also
also been demonstrated in patients with stroke of
occurs whenever the left atrium is chronically exposed
undetermined etiology where it may indicate the
to elevated LV filling pressures and LA strain has been
possibility of undiagnosed paroxysmal AF.49
shown to be impaired, before other echocardiographic
manifestations of LA structural remodeling appear in
patients with hypertension, diabetes and heart failure Outcomes after Cardioversion
with preserved LV ejection fraction.37 In patients undergoing electrical cardioversion for
AF, reduced LA strain before the cardioversion or a
Role of LA Function Assessment in dampened increase in LA strain immediately after
Clinical Decision Making cardioversion has been shown to predict failure of
Abnormalities of LA strain have several important conversion and associated with lower probability of
clinical implications in patients with or, at risk of maintenance of sinus rhythm respectively.50
CHAPTER 28: Echocardiographic Navigation of AF from Irregular Pulse to Slurring of the Speech 163
Recurrence of Atrial Fibrillation after extending between the pulmonary artery above and the
Catheter Ablation LV. Internally LAA is trabeculated with the trabeculations,
Cather ablation of AF is an invasive procedure which known as pectinate muscles which run parallel to each
is associated with some risk of peri-procedural other, giving it a comb-like structure. In an autopsy study
complications and roughly 30–40% risk of AF recurrence of 500 normal human hearts, the LAA was bilobed in 54%
during follow-up.30,51 So, accurate selection of patients is and multilobed (>2 lobes) in 80% of hearts.62
crucial to optimize long-term clinical outcomes of this Although the LAA can be visualized on TTE also, in
procedure. Several studies have shown that LA strain most patients a detailed assessment is not possible due
can be a useful predictor of the recurrence of AF after to the posterior location of the LAA. Whereas, TEE, with
catheter ablation.30,52-54 Recently, a meta-analysis was the close proximity of the transducer to the LAA, allows
excellent imaging of the LAA and is therefore compulsory
performed of 8 studies evaluating role of LA strain for
for LAA assessment. On TEE, the LAA is best visualized in
prediction of AF recurrence after catheter ablation.55 A
the midesophageal two-chamber view (80–100°) and the
total of 686 patients were included in this analysis. LA
midesophageal aortic valve short-axis view (30–60°) and
strain was strongly associated with the recurrence of AF
are therefore the recommended views for this purpose.63
with a cut-off value of 22.8% (95% confidence interval
However, to exclude thrombus, it is essential to image
18.8–30%) yielding a sensitivity of 78% (95% confidence
the LAA from multiple imaging planes. This can be easily
interval 65–86%) and specificity of 75% (95% confidence
accomplished by first developing the midesophageal
interval 66–100%). LA strain have also been shown to
aortic valve short-axis view (30–60°) and then anteflexing
predict reverse LA remodeling after catheter ablation for
the transducer and rotating the multiplane angle from
AF.56
00 to 180°. This approach allows complete assessment
of LAA anatomy, its different lobes and the pectinate
Left Atrial Appendage Structure
muscles (Figs 7A and B). Sometimes it may be almost
and Function impossible to differentiate a thrombus from the pectinate
In conventional teaching, LAA was believed to be muscles or artefacts. The administration of ultrasound
a vestigial structure with no active role and hence contrast can be of great help in such situations.64-66 The
was not studied. However, with the advancements of recent availability of live-three dimensional TEE should
echocardiographic techniques, it has now become render imaging of the complex LAA anatomy much
apparent that the LAA is an actively contracting structure easier now.67
which plays an important role in cardiac hemodynamics. In addition to delineation of thrombus, TEE is also
More than that, dysfunction of LAA is the substrate helpful in detection of LAA SEC. SEC is a smoke-like
for thrombus formation which can lead to potentially swirling pattern seen on two-dimensional imaging
devastating embolic complications. 57-61 Therefore, a and is thought to reflect rouleaux formation resulting
comprehensive assessment of LAA structure and function from stasis of the blood. SEC has been shown to be
should be done to guide therapeutic decision-making the harbinger of thrombus formation and therefore, a
in a number of cardiac illnesses. Echocardiography, predictor of thromboembolic risk in many studies.68-70
particularly TEE, is currently the modality of choice for
evaluation of the LAA. It allows complete differentiation Assessment of LAA Function
of the LAA anatomy along with detailed assessment of its It has become obvious that an estimate of LAA function
function in most of the patients. can provide incremental information about the risk of
clot formation, embolic events, success of cardioversion,
Assessment of LAA Structure etc. Therefore, evaluation of the LAA function by doppler
The LAA is a small, pyramidal usually a multilobed measurement of LAA flow velocities is currently the
structure situated on the lateral aspect of the LA, preferred method of assessment of LAA function. 71
164 SECTION 2: Cardiology
A B
Figs 7A and B: Multilobed anatomy of the left atrial appendage. (A) Only one lobe (arrow) is visualized in this plane; (B) The complete extent of
the left atrial appendage is visualized in an orthogonal plane (open arrows mark the boundary of the appendage). Pectinate muscles are also
clearly visualized (arrow)
It is now often undertaken as part of the standard Assessment of LAA Structure and Function in
echocardiographic examination of the appendage. The Clinical Practice
LAA flow velocities by pulsed-wave Doppler can be Assessment of LAA anatomy and function plays an
obtained from any of the standard imaging planes on impor tant role in the diagnostic w ork-up and
TEE by keeping the pulsed-wave sample-volume in the management of many clinical conditions. It may be
proximal one-third segment (towards LA) of the LAA.71,72 a mandatory investigation prior to performance of
In patients with sinus rhythm, a typical quadriphasic intervention procedures such as BMV, or can be routinely
flow pattern (Figs 8A to C) can be seen consisting of sought when the cause of ischemic stroke is not apparent
Early diastolic emptying velocity followed by the most and a cardiac source needs to be ruled out. In addition
important phase of Late diastolic emptying velocity or to these well-known indications research has revealed
LAA contraction flow which results from active LAA newer indications for which LAA function assessment
scontraction and is thus a marker of LAA contractile may be warranted. The most practical indications are
function. It correlates with LAA ejection fraction, discussed here:
LA size and pressure and is a significant predictor of
thromboembolic risk.73 This is followed by a negative Presence of Thrombus or SEC
wave of LAA filling velocity and multiple low velocity Cardioembolic strokes account for ≥15% of all ischemic
systolic reflection waves. strokes79 among which LAA is the source of embolus in
In contrast to LAA flow velocity, which is an indirect majority of the cases. Approximately, 90% of intracardiac
measure of LAA function, measurement of tissue velocity thrombi in nonrheumatic AF and 60% in patients with
provides direct estimate of the LAA contractility. On rheumatic mitral valve disease form within the LAA.80
tissue velocity imaging, a similar wave pattern is seen as In patients with recent embolic event and AF, LAA
in the corresponding flow velocity. It was found to have thrombus is found in roughly 14% patients with short
good feasibility and correlated with the presence of LAA duration AF (started <3 days before) and in roughly 27%
SEC or thrombus, history of thromboembolic events patients with longer duration of AF.9 Therefore, imaging
and quantification of LAA contractile dysfunction in of the LAA to rule out thrombus or SEC is an important
mitral stenosis, hypertension or HCM even in absence indication of performing TEE in patients suspected to be
of AF.61,74-78
CHAPTER 28: Echocardiographic Navigation of AF from Irregular Pulse to Slurring of the Speech 165
100
cm/sec
Late diastolic emptying velocity
50
LAA filling
A B
having cardioembolic stroke. The presence of SEC alone in patients with LAA dysfunction (75% versus 58%).
may be enough to label it a cardioembolic stroke in this Furthermore, the risk of ischemic stroke in patients
context.69,70 with lower velocities was 2.6 times greater than in those
As discussed above, exclusion of LA/LAA thrombi is with higher velocities. Many other studies concluded
obligatory when planning intervention procedures such similar findings as well.58,59,81 The thromboembolic risk
as BMV, radiofrequency ablation of atrial arrhythmias is greater with AF than with flutter for same degree of
and also prior to cardioversion for AF of >48 hours LAA dysfunction.82,83 LAA dysfunction is severely marked
duration in patients who have not been on adequate
in patients with rheumatic mitral stenosis in AF, who
anticoagulation.
typically have very low or even absent LAA velocities.84
LAA dysfunction is a predictor of stroke risk in
Prediction of Thromboembolism
sinus rhythm also. A study published by Reddy et al
LAA dysfunction has been shown to be a strong predictor
of thrombus formation and the risk of embolic events, even reports the effect of BMV on LAA function in patients
if no clot is found at the time of initial examination.57-59,81 with symptomatic mitral stenosis in sinus rhythm.
In the SPAF III (Stroke Prevention in Atrial Fibrillation Significant improvement was seen in LAA flow and tissue
III) TEE substudy that included patients with AF, 17% velocities on TEE performed on 3rd day after BMV. The
patients with LAA contraction velocities < 20 cm/s had improvement in LAA function was accompanied by
thrombi as compared to 5% of the patients with higher complete disappearance or reduction of SEC in all the
velocities.57 The prevalence of SEC was also much higher patients who had SEC prior to the procedure.85
166 SECTION 2: Cardiology
Immediate and Short-term Outcome of 3. Mathur R, Pollara E, Hull S, Schofield P, Ashworth M, Robson
J. Ethnicity and stroke risk in patients with atrial fibrillation.
Cardioversion
Heart. 2013;99:1087-92.
As discussed with LA function, preserved LAA function 4. Va z i r i S M , L a r s o n M G , B e n j a m i n E J , L e v y D .
is associated with higher probability of conversion Echocardiographic predictors of nonrheumatic atrial
and subsequent maintenance in sinus rhythm. 86-90 A fibrillation. The Framingham Heart Study. Circulation.
multicenter study involving 408 patients undergoing 1994;89:724-30.
5. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused
cardioversion of AF showed that duration of AF <2
update of the ESC Guidelines for the management of
weeks, LA diameter <47 mm and mean LAA velocity >31 atrial fibrillation: an update of the 2010 ESC Guidelines
cm/s were the only independent predictors of success for the management of atrial fibrillation. Developed with
of cardioversion. 91 A temporary worsening of LAA the special contribution of the European Heart Rhythm
function, known as LAA stunning, can occur irrespective Association. European Heart Journal. 2012;33:2719-47.
6. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/
of the mode of cardioversion and is also seen after
HRS guideline for the management of patients with atrial
radiofrequency or surgical ablation of AF or flutter.92-96 fibrillation: a report of the American College of Cardiology/
Stunning is commonly associated with new or worsening American Heart Association Task Force on Practice
SEC and may thus predispose to thromboembolism.94,95,97 Guidelines and the Heart Rhythm Society. Journal of the
The time course of recovery of stunning varies but American College of Cardiology. 2014;64:e1-76.
7. Singer DE, Chang Y, Borowsky LH, et al. A new risk scheme
significant improvement in LAA function is known to
to predict ischemic stroke and other thromboembolism in
occur within 7–30 days after cardioversion.92,95,96
atrial fibrillation: the ATRIA study stroke risk score. Journal
of the American Heart Association. 2013;2:e000250.
CONCLUSION 8. Zabalgoitia M, Halperin JL, Pearce LA, Blackshear JL,
AF is a leading cause of morbidity and mortality worldwide, Asinger RW, Hart RG. Transesophageal echocardiographic
with increasing incidence as age advances. Management correlates of clinical risk of thromboembolism in nonvalvular
atrial fibrillation. Stroke Prevention in Atrial Fibrillation III
of AF remains complex with numerous uncertainties
Investigators. Journal of the American College of Cardiology.
existing about its pathophysiology, clinical outcomes 1998;31:1622-6.
and the impact of various therapeutic approaches 9. Manning WJ, Silverman DI, Gordon SP, Krumholz HM,
employed for its management. Echocardiography, is Douglas PS. Cardioversion from atrial fibrillation without
the most practical modality for the evaluation of LA prolonged anticoagulation with use of transesophageal
echocardiography to exclude the presence of atrial thrombi.
structure and function and provides critical diagnostic
N Engl J Med. 1993;328:750-5.
and prognostic information and thus help in timely 10. Airaksinen KE, Gronberg T, Nuotio I, et al. Thromboembolic
appropriate intervention to reduce the cardiac inflicted complications after cardioversion of acute atrial fibrillation:
morbidity and mortality. Therefore, Echocardiographic the FinCV (Finnish CardioVersion) study. Journal of the
navigation of AF is the cornerstone and relevant in all the American College of Cardiology. 2013;62:1187-92.
11. Hansen ML, Jepsen RM, Olesen JB, et al. Thromboembolic
stages from irregular pulse to slurring of the speech.
risk in 16 274 atrial fibrillation patients undergoing direct
current cardioversion with and without oral anticoagulant
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SECTION
3
Diabetes
ADA Standards of Care: An Update GLP-1 Analogs: Benefits Beyond Glycemic Control
Abhishek Pandey Rajeev Chawla, Shalini Jaggi
Can Medical Care Change the Natural History of Gliptins versus Sulfonylureas: Which is Better?
T2DM: Turning Fiction into Reality? V Palaniappen
Rajesh Rajput
Metformin—the Molecule of the Decade:
Are all Gliptins the Same: How to Decide Old is Gold
and Choose? Sanjay Dash
Harbir Kaur Rao, Rajinder Singh Gupta
A Decade of RCTs in Diabetes: Clinical Implications
Diabetes and Inflammation Suhas Erande
Jugal Kishor Sharma, Girish Khurana
Insulin Pumps in India
Pollution and Diabetes: Is there a Link? Narendra Pal Jain, Rishu Bhanot
Brij Mohan
Newer Insulins and Art of Insulin Therapy
Musculoskeletal Manifestations Mangesh Tiwaskar
of Diabetes Mellitus
Individualization of Diabetes Care
S Anita Nambiar, Divya G
KK Pareek, Girish Mathur
How to Hold the HOLD?
Diabetes and Immunity
NK Singh, Vaibhav Agnihotri, Richa Singh Agnihotri
Apurba Kumar Mukherjee, Indira Maisnam
Dyslipidemia Management: Newer Avenues
Novel Therapeutic Approaches to Preserve Beta
Nirupam Prakash
Cell Function in Diabetes Mellitus
Metformin versus Insulin in Treatment of Vijay Negalur
Gestational Diabetes Mellitus
Management of Diabetes in Resource
Sandeep Garg, Onkar Awadhiya, Sunita Aggarwal
Crunch Countries
Early Initiation of Insulin Therapy G Prakash
in Diabetes Mellitus
Exercise Prescription for Lifestyle Diseases:
Rajesh Kumar Jha, Sagar Dembla
A Cornerstone
Diabetic Complications in Indian Scenario: Anil Kumar Virmani
An Update
Nonhigh–Density Lipoprotein Cholesterol:
Sidhartha Das, Santosh Kumar Swain, Saroj Kumar Tripathy
Primary Target for Lipid Lowering
SN Narasingan
CHAPTER
29
ADA Standards of Care: An Update
Abhishek Pandey
care, general treatment goals, and tools to evaluate the quality ratings in the analysis
quality of care. B Supportive evidence from well-conducted cohort
studies
SECTION CHANGES zz Evidence from a well-conducted prospective cohort
study or registry
Section 1: Promoting Health and zz Evidence from a well-conducted meta-analysis of
resources and provide self-management support. more major or three or more minor methodological
flaws that could invalidate the results
Level of Description zz Evidence from observational studies with high
evidence
potential for bias (such as case series with
A Clear evidence from well-conducted, generalizable comparison with historical controls)
randomized controlled trials that are adequately zz Evidence from case series or case reports
powered, including
Conflicting evidence with the weight of evidence
zz Evidence from a well-conducted multicenter trial
emphasizing the importance of screening for prediabetes needed. A section was added describing the role of newly
using an assessment tool or informal assessment of available biosimilar insulins in diabetes care.
risk factors and performing a diagnostic test when Based on the results of two large clinical trials, a
appropriate. To reflect new evidence showing an recommendation was added to consider empagliflozin
association between B12 deficiency and long-term or liraglutide in patients with established cardiovascular
metformin use, a recommendation was added to disease to reduce the risk of mortality. The algorithm for
consider periodic measurement of B12 levels and the use of combination injectable therapy in patients
supplementation as needed. with type 2 diabetes has been changed to reflect studies
demonstrating the noninferiority of basal insulin
Section 6: Glycemic Targets plus glucagon like peptide 1 receptor agonist versus
Based on recommendations from the International basal insulin plus rapid-acting insulin versus two
Hypoglycemia Study Group, serious, clinically significant daily injections of premixed insulin, as well as studies
hypoglycemia is now defined as glucose, 54 mg/dL (3.0 demonstrating the noninferiority of multiple dose
mmol/L), while the glucose alert value is defined as 70 premixed insulin regimens versus basal-bolus therapy.
mg/dL (3.9 mmol/L).
PHARMACOLOGIC THERAPY FOR
Section 7: Obesity Management for the DIABETES
Treatment of Type 2 Diabetes
To be consistent with other ADA position statements and
Recommendations
to reinforce the role of surgery in the treatment of type 2 Most people with type 1 diabetes should be treated
diabetes, bariatric surgery is now referred to as metabolic with multiple daily injections of prandial inslulin and
surgery. basal insulin or continuous subcutaneous insulin
To reflect the results of an international workgroup infusion (A).
re p o r t e n d o r s e d by t h e A D A a n d ma ny o t h e r Most individuals with type 1 diabetes should use
organizations, recommendations regarding metabolic rapid-activing insulin analogs to reduce hypoglycemia
surgery have been substantially changed, including risk (A).
those related to BMI thresholds for surgical candidacy, Consider educating individuals with type 1 diabetes
mental health assessment, and appropriate surgical on matching prandial insulin doses to carbohydrate
venues. intake, premeal blood glucose levels, and anticipated
physical activity (E).
Section 8: Pharmacologic Approaches to Individuals with type 1 diabetes who have been
Glycemic Treatment successfully using continuous subcutanesou insulin
The title of this section was changed from “Approaches infusion should have continued access to this
to Glycemic Treatment” to “Pharmacologic Approaches therrapy after they turn 65 years of age (E).
to Glycemic Treatment” to reinforce that the section Metformin, if not contraindicated and if tolerated,
focuses on pharmacologic therapy alone. Lifestyle is the preferred initial pharmacolic agent fot the
management and obesity management are discussed in treatment of type 2 diabetes (A).
separate chapters. Long-term use of metformin may be associated with
To reflect new evidence showing an association biochemical vitamin B12 deficiency, and periodic
between B12 deficiency and long-term metformin use, measurement of vitamin B12 levels should be
a recommendation was added to consider periodic considered in metformin-treated patients, especially
measureme of B12 levels and supplementation as in those with anemia or peripheral neuropathy (B).
176 SECTION 3: Diabetes
Consider initiating insulin therapy (with or without can be achieved without undue treatment burden
additional agents) in patients with newly diagnosed (C).
type 2 diabetes who are symptomatic ad/or have A1C In pregnant patients with diabetes and chronic
≥10% (86 mmol/mol) and/or blood glucose levels hypertension, blood pressure targets of 120–160/80–
≥300 mg/dL (16.7 mmol/L) (E). 105 mm Hg are suggested in the interest of optimizing
If noninsulin monotherapy at maximum tolerated long-term maternal health and minimizing impaird
dose does not achieve or maintain the A1C target fetal growth (E).
after 3 months, add a second oral agent, a glucagon-
Treatment
like peptide 1 receptor agonist, or basal insulin (A).
Patients with confirmed office-based blood pressure
A patient-centered approach should be used to guide
>140/90 mm Hg should, in addition to lifestyle
the choice of pharmacologic agents. Consideration
therapy, have prompt initiation and timely titration
include efficacy, hypoglycemia risk, impact on
of pharmacologic therapy to achieve blood pressure
weight, potential side effects, cost, and patient
goals (A).
preferences (E).
Patients with confirmed office-based blood pressure
For patients with type 2 diabetes who are not
>160/100 mm Hg should in addition to lifestyle
achieving glycemic goals, insulin therapy should not
therapy, have prompt initiation and timely titration
be delayed (B).
of two drugs or a single pill combination of drugs
In patients with long-standing suboptimally
demonstrated to reduce cardiovascular events in
controlled type 2 diabetes and established athero
patients with diabetes (A).
sclerotic cardiovascular disease, empagliflozin
To better align with existing data, the hypertension
or liraglutide should be considered as they have
treatment recommendation for diabetes now suggests
been shown to reduce cardiovascular and all-cause
that, for patients without albuminuria, any of the four
mortality when added to standard care. Ongoing
classes of blood pressure medications (ACE inhibitors,
studies are investigating the cardiovascular benefits
angiotensin receptor blockers, thiazide-like diuretics,
of other agents in these drug classes (B).
or dihydropyridine calcium channel blockers) that have
Section 9: Cardiovascular Disease and shown beneficial cardiovascular outcomes may be used.
To optimize maternal health without risking fetal
Risk Management
harm, the recommendation for the treatment of pregnant
Recommendations patients with diabetes and chronic hypertension was
Screening and diagnosis changed to suggest a blood pressure target of 120–
Blood pressure should be measured at every routine
160/80–105 mm Hg. A section was added describing
visit. Patiens found to have elevated blood pressure the cardiovascular outcome trials that demonstrated
should have blood pressure confrmed on a separate benefits of empagliflozin and liraglutide in certain high-
day (B). risk patients with diabetes.
Goals
Most patients with diabetes and hypertension Section 10: Microvascular Complications
should be treated to a systolic blood pressure goal of and Foot Care
<140 mm Hg ana diastolic blood pressure goals of <90 A recommendation was added to highlight the
mm Hg. importance of provider communication regarding the
Lower systolic and diastolic blood pressure targets, increased risk of retinopathy in women with pre-existing
such as 130/80 mm Hg may be appropriate for type 1 or type 2 diabetes who are planning pregnancy
indivuals at high risk of cardiovascular disease, if they or who are pregnant. The section now includes specific
CHAPTER 29: ADA Standards of Care: An Update 177
recommendations for the treatment of neuropathic blocker is reasonable to assess the response to
pain. A new recommendation highlights the benefits of treatment and progression of diabetic kidney
specialized therapeutic footwear for patients at high risk diseases (E).
for foot problems. An ACE inhibitor or an angiotension receptor blocker
is not recommended for the primary prevention of
Recommendations diabetic kidney disease in patients with diabetes
Screening who have normal blood pressure, normal urinary
At least once a year, assess urinary albumin (e.g. spot albumin-to-creatinine ratio (<30 mg/g creatinine),
urinary albumin-to-creatinine ratio) and estimated and normal estimated glomerular filtration rate. (B)
glomerular filtration rate in patients with type 1 diabetes When estimated glomerular filtration rate is <60
with duration of ≥5 years, in all patiens with type 2 mL/min/1.73 m 2, evaluate and manage potential
diabetes, and in all patients with comorbid hypertension complications of chronic kidney disease (E).
(B). Patients should be referred for evaluation for renal
replacement treatment if they have an estimated
Treatment
Optimize glucose control to reduce the risk of slow
glomerular filtration rate <30 mL/min/1.73 m2 (A).
Promptly refer to a physician experienced in the care
the progression of diabetic kidney disease (A).
Optimize blood pressure control to reduce the risk of
of kidney disease for uncertainty about the etiology
of kidney disease, difficult management issues, and
slow the progression of diabetic kidney disease (A).
For people with nondialysis-dependent diabetic
rapidly progressing kidney disease (B).
kidney disease, dietary protein intake should be
Lipid Recommendations
approximately 0.8 g/kg body weight per day (the
recommended daily allowance). For patients on Age Risk factors Statin intensity*
dialysis, higher levels of dietary protein intake should <40 years None None
be considered (B). ASCVD risk factor(s)** Moderate or high
ASCVD High
I n n o n p re g a n t p a t i e n t s w i t h d i a b e t e s a n d
40–75 years None Moderate
hypertension, either an ACE inhibitor or an ASCVD risk factors High
angiotensin receptor blocker is recommended for ASCVD High
those with modestly elevated urinary albumin-to- ACS and LDL cholesterol ≥50 Moderate plus
mg/dL ezetimibe
creatinine ratio (30–299 mg/g creatinine) (B) and
(1.3 mmol/L) or in patients with
is strongly recommended for those with urinary a history of ASCVD who cannot
alubumin-to-creatinine ratio ≥300 mg/g creatinine tolerate high-dose statins
and/or estimated glomerular filtration rate <60 mL/ >75 years None Moderate
min/1.73 m2 (A). ASCVD risk factors Moderate or high
Periodically monitor serum creatinine and potassium
ASCVD High
ACS and LDL cholesterol ≥ Moderate plus
levels for the development of increased creatinine 50 mg/dL (1.3 mmol/L) or ezetimibe
or changes in potassium when ACE inhibitors, in patients with a history of
angiotensin receptor blockers, or diuretics are used ASCVD who cannot tolerate
high-dose statins
(E).
Continued monitrong of urinary albumin-to-
*In addition to lifestyle therapy.
**ASCVD risk factors include LDL cholesterol ≥100 mg/dL) (2.6
creatinine ratio in patients with albuminuria treated mmol/L), high blood pressure, smoking, chronic kidney disease,
with an ACE inhibitor or an angiotensin receptor albuminuria, and family history of premature ASCVD
178 SECTION 3: Diabetes
High-intensity statin therapy Moderate-intesity statin therapy atherosclerotic cardiovascular disease risk factors,
(lowers LDL cholesterol by ≥50%) (lowers LDL cholesterol by 30% clinical judgment is required (E).
– <50%)
Atorvastatin 40–80 mg Atorvastatin 10–20 mg Coronary Artery Disease
Rosuvastatin 20–80 mg Rosuvastatin 5–10 mg
Recommendations
Simvastatin 20–40 mg
Screening
Pravastatin 40–80 mg
In asymptomatic patients, routine screening for
Lovastatin 40 mg
coronary artery disease is not recommended as it
Fluvastatin XL 80 mg
does not improve outcomes as long as atherosclerotic
Pitavastatin 2–4 mg
cardiovascular disease risk factors are treated (A).
*Once-daily dosing, XL, extended release. Consider investigations for coronary artery disease
Dual antiplatelet therapy is reasonable for up to a disease, use aspirin and statin therapy (if not
year after an acute coronary syndrome and may have contraindicated) (A) and consider ACE inhibitor
benefits beyond this period (B). therapy (C) to reduce the risk of cardiovascular
Consider aspirin therapy (75–162 mg/day) as a events.
primary prevention strategy in those with type 1 or In patients with prior myocardial infarction,
type 2 diabetes who are at increased cardiovascular b-blockers should be continued for at least 2 years
risk. This includes most men and women with after the event (B).
diabetes aged ≥50 years who have at least one In patients with symptomatic heart failure,
additional major risk factor (family history of thiazolidinedione treatment should not be used (A).
premature atherosclerotic cardiovascular disease, In patients with type 2 diabetes with stable congestive
hypertension, smoking, or albuminuria) and are not heart failure, metformin may be used if estimated
at increased risk of bleeding (C). glomerular filtration remains >30 mL/min but should
Aspirin should not be recommended for be avoided in unstable or hospitalized patients with
atherosclerotic cardiovascular disease prevention congestive heart failure (B).
for adults with diabetes at low atherosclerotic
cardiovascular disease risk, such as in men or women Section 12: Children and Adolescents
with diabetes aged <50 years with no other major Additional recommendations highlight the importance
atherosclerotic cardiovascular disease risk factors, of assessment and referral for psychosocial issues in
as the potential adverse effects from bleeding likely youth. Due to the risk of malformations associated
offset the potential benefits (C). with unplanned pregnancies and poor metabolic
When considering aspirin therapy in patients control, a new recommendation was added encouraging
with diabetes <50 years of age with multiple other preconception counseling starting at puberty for all
CHAPTER 29: ADA Standards of Care: An Update 179
girls of childbearing potential. To address diagnostic Metformin and glyburide may be used, but both
challenges associated with the current obesity epidemic, cross the placenta to the fetus, with metformin likely
a discussion was added about distinguishing between crossing to a greater extent than glyburide. All oral
type 1 and type 2 diabetes in youth. agents lack long-term saftey data (A).
A section was added describing recent nonrando Metformin, when used to treat polycystic ovary
mized studies of metabolic surgery for the treatment of syndrome and induce ovulation, need not be
obese adolescents with type 2 diabetes. continued once pregnancy has been confirmed (A).
General principles for management of diabetes in
Section 13: Management of Diabetes in pregnancy
Pregnancy Potentially teratogenic medications (ACE inhibitors,
importance of glycemic control as close to normal as in normal pregnancy than in normal nonpregnant
is safely possible, ideally A1X <6.5% (48 mmol/mol), women. The A1C target in pregnancy is 6–6.5%
to reduce the risk of congenital anomalies (B). (42–48 mmol/mol); <6% (42 mmol/mol) may be
Women with preexisting type 1 or type 2 diabetes who
optimal if this can be achieved without significant
are planning pregnancy or who have become pregnant hypoglycemia, but the target may be relaxed to
<7% (53 mmol/mol) if necessary to prevent hypo-
should be counseled on the risk of development
glycemia (B).
and/or progression of diabetic retinopahty. Dilated
In pregnant patients with diabetes and chronic
eye examinations should occor before pregnancy
hypertension, blood pressure targets of 120–160/80–
or in the first trimester, and then patients should be
105 mm Hg are suggested in the interest of optimizing
monitored every trimester and for 1 year postpartum
long-term maternal health and minimizing impaired
as indicated by degree of retinopathy and as
fetal growth (E).
recommended by the eye care provider (B).
Insulin was emphasized as the treatment of choice in
Gestational diabetes mellitus pregnancy based on concerns about the concentration of
Lifestyle change is an essential component of metformin on the fetal side of the placenta and glyburide
management of gestational diabetes mellitus and levels in cord blood.
may suffice for the treatment for many women. Based on available data, preprandial self-monitoring
Medications should be added if needed to achieve of blood glucose was de-emphasized in the management
glycemic targets (A). of diabetes in pregnancy. In the interest of simplicity,
Insulin is the preferred medication for treating fasting and postprandial targets for pregnant women
hyperglycemia in gestational diabetes mellitus, as it with gestational diabetes mellitus and pre-existing
does not cross the placenta to a measurable extent. diabetes were unified.
180 SECTION 3: Diabetes
Section 14: Diabetes Care in the Hospital Basal insulin or a basal plus bolus correction insulin
This section was reorganized for clarity. A treatment regimen is the preferred treatment for noncritically
recommendation was updated to clarify that either basal ill patients with poor oral intake or those who are
insulin or basal plus bolus correctional insulin may be taking nothing by mouth. An insulin regimen with
used in the treatment of non-critically ill patients with basal, nutritional, and corrretion components is the
diabetes in a hospital setting, but not sliding scale alone. preferred treatment for noncritically ill hospitalized
The recommendations for insulin dosing for enteral/ patients with good nutritional intake (A).
parenteral feedings were expanded to provide greater Sole use of sliding scale insulin the inpatient hospital
detail on insulin type, timing, dosage, correctional, and setting is strongly discouraged (A).
nutritional considerations. A hypoglycemia management protocl should be
adopted and implemented by each hospital. A plan
Recommendations for preventing and treating hypoglycemia should be
Perform an A1C for all patients with diabetes or establised for each patient. Episodes of hypoglycemia
hyperglycemia admitted to the hospital if not in the hospital should be documented in the medical
performed in the prior 3 months (B). record and tracked (E).
Insulin therapy should be initiated for treatment The treatment regimen should be reviewed and
of persistent hyperglycemia starting at a threshold changed as necessary to prevent further hypoglycemia
≥180 mg/dL (10.0 mmol/L). Once insulin therapy is when a blood glucose value is <70 mg/dL (3.9
started, a target glucose range of 140–180 mg/dL (7.8– mmol/L) (C).
10.0 mmol/L) is recommended for the majority of There should be a structured discharge plan tailored
critically ill patients (A) and noncritically ill patients to the individual patient with diabetes (B).
(C).
More stringent goals, such as <140 mg/dL (<7.8 ACKNOWLEDGMENT
mmol/L), may be appropriate for selected patients, The author would like to acknowledge contributors and
as long as this can be achieved without significant editorial team of Diabetes Care, January 2017, Volume
hypoglcemia (C). 40, Supplement 1.
Intravenous insulin infusions should be administered
using validated written or computerized protocols BIBLIOGRAPHY
that allow for predefined adjustments in the insulin 1. http://care.diabetesjournals.org/content/diacare/
suppl/2016/12/15/40.Supplement_1.DC1/DC_40_S1_
infusion rate based on glycemic fluctuations and
final.pdf
insulin dose (E).
CHAPTER
30
Can Medical Care Change the Natural History
of T2DM: Turning Fiction into Reality?
Rajesh Rajput
adult population demonstrated high CV risk, owing to contribute to the development of heart-failure. 5 A
uncontrolled risk-factors. This observation provokes a few recently presented update from the CARDIA study
noteworthy aspects, and prompts realization of the tasks demonstrated that prediabetes of a longer duration is
at hand. Firstly, it compels an introspection regarding our associated with subclinical atherosclerosis, as well as
national framework for public-health research, which cardiac dysfunction. For every 10-years of prediabetes,
has been conspicuous by its inadequacies. Secondly, the risk for coronary artery calcification increased by
regarding the CV risk prevailing in the healthy Indian 21%, suggestive of increased atherosclerosis. Longer
adult population, this finding surfaces the big bottom of duration of prediabetes also demonstrated a significant
the iceberg. Prediabetes and overt diabetes are different deterioration in the functioning of the heart.6 While the
stages of the same pathological continuum. If we believe pathological development of CVD is well recognized in
that diabetes has already achieved a pandemic status in prediabetes, the incidence of CV events is less adequately
India, it is high time to revisit our notion, on the extent studied. A study done in older adults remarkably
to which this pandemic will grow. Being a household- suggested a liner relationship between the HbA1c levels,
level disease, the translation of prediabetes to overt and the risk of CV events.7 This means that the CV events
diabetes can affect a considerable fraction of our Indian increase proportionately to the HbA1c levels. A meta-
households in the ensuing years, resulting in reduced analysis of 53 prospective cohort studies, suggested
productivity, increased morbidity, early mortality, and that prediabetes was associated with increased risk of
worsened quality of life. CV disease and all-cause mortality. 8 The analysis of
PARADIGM-HF trial involving patients with heart-failure
Is There Increased CV Risk in Prediabetes and reduced ejection fraction, confirmed an increased
and Early Diabetes? incidence of heart-failure related events (including CV
While diabetes is well-recognized as a high CV risk death and hospitalizations for heart-failure), in patients
condition, the significance of increased CV risk in with prediabetes.9
prediabetes cannot be understated (Fig. 1). In fact, the All these findings clearly reflect an increased risk of
clinical phenotype of prediabetes is similar to that of CV disease, events, and overall mortality in patients with
overt diabetes; the CV risk factors manifest similarly prediabetes. Early intervention in prediabetes may help
in the patients of diabetes as well as prediabetes. The in preventing the progression of CV disease, apart from
vascular pathological mechanisms of dysglycemia the conversion to overt diabetes.
facilitate early development of atherosclerosis,
as well as heart-failure. Prediabetes also prompts When should be Intervene: The Golden
certain changes in the myocardial metabolism, which Years
Insulin sensitivity is known to reduce more than a decade
before the onset of diabetes. A steeper decline is observed
over 5 years, before the diagnosis of diabetes is made.
Insulin secretion is elevated, with a marked increase a
few years prior to diagnosis, followed by a steep decrease
until diagnosis.10 Weight loss is the primary approach to
reduce insulin resistance in prediabetes. However, it is
not possible to preserve the declining beta-cell function
only through weight management. It is now realized that
timing an intervention at the prediabetes stage, may
Fig. 1: Schematic representation of CVD risk also significantly alter the course of CV disease over the
modification in prediabetes years.15
CHAPTER 30: Can Medical Care Change the Natural History of T2DM: Turning Fiction into Reality? 183
Screening for Prediabetes: A Shot in the drugs like DPP-IV inhibitors, GLP-1 receptor agonists,
Dark? alpha glucosidase inhibitors, pioglitazone and SGLT-2
inhibitors are preferred for IGT. For patients having both
The importance of early intervention in prediabetes, for
IFG and IGT one can choose drugs with complimentary
preventing the development of diabetes as well as CV
mechanism of action with focus on weight neutrality
disease, is well recognized. However, the moot aspect is
or loss and risk of hypoglycemia. Because of risk of
about optimizing our efforts, in view of the prevention
hypoglycemia sulfonylurea, short acting insulin and
paradox. It is consistently demonstrated that the primary
premix insulins are not preferred options in these class
prevention is the most cost-effective method to reduce
of patients. Almost all classes of antidiabetic medicines
the incidence of diabetes and its complications. The
have been assessed in prediabetes, although none
guidelines recommend screening for adults with risk-
is specifically approved for this indication. A review
factors for prediabetes, including other major CV risk-
of trials suggested that in patients with prediabetes,
factors, family history of CVD or diabetes, polycystic
lifestyle interventions, as well as the use of metformin,
ovary syndrome, acanthosis nigricans, nonalcoholic fatty
significantly reduce the progression to diabetes by
liver disease, history of gestational diabetes, or other
around 1/3 rd, and 1/4 th respectively. 12 In this regard,
iatrogenic causes. ‘Opportunistic screening’ may be a
metformin may have a supplementary role to lifestyle
feasible approach for early identification of prediabetes.
modification in prediabetes. In a small study, glimepiride
If possible, all adults over 30 years of age should be
therapy was found to effectively reduce the progression of
screened for prediabetes, regardless of any other risk-
prediabetes to overt diabetes, in nonobese patients with
factor.
prediabetes.13 An early glycemic control in prediabetes,
maintained over a few years, may have a legacy effect
Therapy of Prediabetes and Early in delayed progression to diabetes, even years after the
Diabetes: Role of Antidiabetic Medicines therapy is stopped. This was observed in the DREAM
Lifestyle modification holds the pivotal role in the study of rosiglitazone.14 Thus it is pertinent to ensure
management of prediabetes. A good metabolic control is good glycemia control in patients with prediabetes, for
essential to delay the progression of prediabetes to overt improved outcomes in the long-term. The ORIGIN trial
diabetes. In overweight or obese patients of prediabetes, has shown that basal insulin analogue glargine can be
studies have demonstrated effectiveness of weight loss used effectively and safely in patients of prediabetes and
interventions, in preventing the development of overt early diabetes. The treatment with glargine decreased the
diabetes by over 50%. Studies have also demonstrated risk of progression from prediabetes to diabetes by about
benefits of lifestyle interventions that do not target 30% while in combined early diabetes and prediabetes
weight loss, in nonobese patients with insulin resistance. group the amount of insulin needed to maintain the
Simple interventions like patient-reminders on lifestyle target over five years was increased by a small amount
modification through regular text messages, have i.e. from 0.31 units/kg to 0.40 units/kg. Although trial was
demonstrated reduction in the development of diabetes not designed primarily for this purpose but these indirect
by up to a third.11 inferences suggest that early intervention is useful and
Presently, the choice of pharmacotherapy for basal insulin can be used if needed for this purpose.15
management of prediabetes and early diabetes is not Newer medicines may offer metabolic benefits
clearly established. One way to choose drug therapy beyond glycemia control, in patients with prediabetes
is to decide whether patient has IFG, IGT or both IFG and early diabetes with additional positive effects on risk
and IGT. Although majority of drugs have some effect of weight gain and risk of hypoglycemia. However, the
on both fasting and postprandial glucose excursion, evidence is limited on these aspects. VERIFY trial (Study
metformin and basal insulin are preferred for IFG while to compare combination regimen with vildagliptin
184 SECTION 3: Diabetes
6. Schöttker B, Rathmann W, Herder C, Thorand B, Wilsgaard 14. Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, et
T, et al. HbA1c levels in non-diabetic older adults – No al. Effect of rosiglitazone on the frequency of diabetes
J-shaped associations with primary cardiovascular events, in patients with impaired glucose tolerance or impaired
cardiovascular and all-cause mortality after adjustment for fasting glucose: a randomised controlled trial. Lancet.
confounders in a meta-analysis of individual participant 2006;368(9541):1096-105.
data from six cohort studies. BMC Medicine. 2016;14:26 15. Gerstein HC, Bosch J, Dagenais GR, et al. ORIGIN trial
DOI 10.1186/s12916-016-0570-1. investigators. Basal insulin and cardiovascular and other
7. Huang Y, Cai X, Mai W, Li M4, Hu Y. Association between outcomes in dysglycemia. N Engl J Med. 2012;367:319-28.
prediabetes and risk of cardiovascular disease and all 16. Novartis Pharmaceuticals. VERIFY: A study to compare
cause mortality: systematic review and meta-analysis. BMJ. combination regimen with vildagliptin and metformin versus
2016; 355:i5953. doi: 10.1136/bmj.i5953. metformin in treatment-naıve patients with type 2 diabetes
8. Kristensen SL, Preiss D, Jhund PS, Squire I, Cardoso JS, mellitus. In: ClinicalTrials.gov [Internet]. Available from
et al. Risk related to pre-diabetes mellitus and diabetes http://clinicaltrials.gov/show/NCT01528254.
mellitus in heart failure with reduced ejection fraction: 17. Abdul-Ghani M, DeFronzo RA. Is it time to change the type
Insights from prospective comparison of ARNI with ACEI to 2 diabetes treatment paradigm? Yes! GLP-1 RAs should
determine impact on global mortality and morbidity in heart replace metformin in the type 2 diabetes algorithm.
failure trial. Circ Heart Fail. 2016;9(1). pii: e002560. doi: Diabetes Care. 2017;40(8):1121-7.
10.1161/CIRCHEARTFAILURE.115.002560. 18. Rosenstock J, Seman LJ, Jelaska A, Hantel S, Pinnetti S, et
9. Tabák AG, Jokela M, Akbaraly TN, Brunner EJ, Kivimäki M, et al. Efficacy and safety of empagliflozin, a sodium glucose
al. Trajectories of glycaemia, insulin sensitivity, and insulin cotransporter 2 (SGLT2) inhibitor, as add-on to metformin
secretion before diagnosis of type 2 diabetes: an analysis in type 2 diabetes with mild hyperglycaemia. Diabetes Obes
from the Whitehall II study. Lancet. 2009;373(9682):2215- Metab. 2013;15(12):1154-60.
21. 19. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, et
10. Ferrannini E. Definition of intervention points in prediabetes. al. Pioglitazone after ischemic stroke or transient ischemic
Lancet Diabetes Endocrinol. 2014;2(8):667-75. attack. N Engl J Med. 2016;374(14):1321-31.
11. Hamman RF, Wing RR, Edelstein SL, Lachin JM, Bray GA, et 20. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik
al. Effect of weight loss with lifestyle intervention on risk of A, et al. Acarbose for prevention of type 2 diabetes
diabetes. Diabetes Care. 2006;29(9):2102-7. mellitus: the STOP-NIDDM randomised trial. Lancet.
12. Hostalek U, Gwilt M, Hildemann S. Therapeutic use of 2002;359(9323):2072-7.
metformin in prediabetes and diabetes prevention. Drugs. 21. Chaisson JL. Acarbose for the prevention of diabetes,
2015;75(10):1071-94. hypertension, and cardiovascular disease in subjects with
13. Kabadi UM. Comparative efficacy between glimepiride and impaired glucose tolerance: the Study to Prevent Non-
metformin in preventing progression of prediabetes to type Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) Trial.
2 diabetes. Journal of Diabetes Mellitus. 2013;3(3):129-33. Endocr Pract. 2006;12(Suppl 1):25-30.
CHAPTER
31
Are all Gliptins the Same:
How to Decide and Choose?
Harbir Kaur Rao, Rajinder Singh Gupta
tissues as well as liver. Incretin based treatment strategies in the hypothalamus. Increase in GLPI levels has an
have outsmarted all other antidiabetic options and any anorexigenic effect.
strategy which improves plasma incretin concentration
after carbohydrate meal also improves beta cell function. IDEAL ANTIHYPERGLYCEMIC DRUG
In 2009, in American Diabetic Association meet some The logic we draw from the above discussion is that any
new pathognomic factors have been proposed. agent that addresses the above factors e.g. improved beta
cell health (thiazolidine diones, GLP analogues, gliptins,
Lipotoxicity: Increasing resistance of the fat cells to the biguanides), suppression of glucagon production
antilipolytic effect of insulin results in higher levels of (incretin based drugs), decrease insulin resistance
free fatty acids (FFA). High fatty acid levels competitively (biguanides, TZD, incretin mimetics), decrease appetite
inhibit insulin mediated glucose metabolism, stimulate (GLPI analogues, biguanides), and suppress glucose
production of glucose in liver and reduces the insulin reabsorption in the kidneys (SGLT2 inhibitors) are
secretion rate resulting in impaired first and second useful in management of Type 2 DM. The most logical
phases of insulin release. combination out of these is incretin based agents with
metformin or thiazolidinediones.
Incretin: Incretins are hormones released from the gut in
response to oral carbohydrate meal and are responsible
DIPEPTIDYL PEPITIDASE-4 INHIBITORS
for efficient disposal of glucose. Two hormones identified
Since launch of first DPP4 inhibitor, Sitagliptin in 2006, a
are glucagon like peptide (GLPI) and gastric insulotropic
number of new agents have been approved (Vildagliptin,
peptide (GIP) and are responsible for 99% of incretin
Anagliptin, Linagliptin, Teneligliptin, Trelagliptin,
effect and amplification of this incretin effect is the basis etc). Now DPP4 inhibitors are an established class
of incretin based therapies. in management of Type 2 DM. They are reversible
Hyperglucagonemia: Alpha cells of pancreatic islets of competitive inhibitors of DPP4 and act at extracellular
Langerhans produce Glucagon which has an anti insulin level.
There are two groups of DPP4 inhibitors:
effect and increases blood sugar. GLPI in addition to
Peptidomimetics, that mimic the DPP4 molecule
increasing insulin secretion also suppresses glucagon
(vildagliptin, saxagliptin).
and hence reduces post prandial hyperglycemia.
Nonpeptidomimetics that do not mimic the DPP4
Kidneys: Glucose is filtered in the glomeruli of the kidneys. molecule (alogliptin, sitagliptin, linagliptin).
Out of this 90% is reabsorbed by the SGLT 2 (Sodium Nonpeptidomimetics interact with residues of DPP4
glucose like transporter type 2) transporter in the S1 substrate at the extra cellular site to form noncovalent
segment of proximal convulated tubule and remaining bond and results in immediate potent inhibition. In
10% is reabsorbed in S2 and S3 segment of proximal contrast peptidomimetics form a reversible covalent
tubule. Diabetic patients show increased glucose enzyme inhibitor complex. This complex binds to
reabsorption capacity resulting in hyperglycemia. the catalytic site of DPP4 substrate and dissociates
slowly resulting in DPP4 inhibition which is persistent
Brain: Brain has also been implicated in the pathogenesis and persists even after the inactivation of the drug.
of type 2 DM. These are wide spread receptors of This explains prolonged inhibition of DPP4 activity
GLPI throughout the brain and it is synthesized in the by Vidagliptin and Saxagliptin as compared to their
nucleus of the solitary tract. Potentiation of GLPI by short half lives. Various DPP4 inhibitors and their
any means will influence the satiety and feeding center pharmacological profile are mentioned in Table 1.
188 SECTION 3: Diabetes
carcinoma but hope they will stand the test of time and 6. Japanese Pharmaceuticals and Medical Devices Agency.
emerge as the only class of drugs that improves beta cell Teneligliptin; Review report. Available from URL: http://
www.pmda.go.jp/ les/000153594.pdf.
health and controls hyperglycemia.
7. Meier JJ, Nauck MA. Risk of pancreatitis in patients treated
with incretin-based therapies. Diabetologia 2014;57:
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CHAPTER
32
Diabetes and Inflammation
Jugal Kishor Sharma, Girish Khurana
receptor complex binds to the lipoprotein lipase gene fraction that includes preadipocytes, fibroblasts,
promoter, which enhances fatty-acid uptake. In addition, endothelial cells, histiocytes and macrophages.
stress can cause contraction of the splanchnic vessels of Preadipocytes can differentiate into macrophages
the gastrointestinal tract, resulting in gut ischemia, which though majority of them are transformed from monocytes
promotes the entry of LPS into the portal system, leading or bone marrow derived precursors. AT macrophage
to inflammatory cytokine production by Kupffer cells accumulation ranges from <10% in lean humans to
and, possibly, by hepatocytes and hepatic endothelial nearly 40% in the obese favouring a direct proportion to
cells as well. the magnitude of adiposity and suggest the inflammatory
process associated with an expanded fat mass may be
Genetic Predisposition involved in the development of insulin resistance and
G e n e t i c p re d i s p o s i t i o n t o c h ro n i c l o w - g r a d e type 2 diabetes.
inflammation through gene polymorphisms in PRRs
has shown to affect the innate immune response. The Cytokine and Macrophage Phenotypes
polymorphism Asp299Gly of the TLR4 gene is known to Inflammatory molecules like TNF-a, CRP, PAI-1, SAA
inversely affect innate immune function and atheroma MIF iNOS CSF-1 MCP-1, IL-6, resistin are increased
by attenuating receptor signaling, and is also associated in adiposity because of activation of innate immunity.
with a decreased risk of atherosclerosis. In addition, the AT macrophages either possess anti-inflammatory
polymorphism is associated with reduced plasma CRP phenotype M2 which secretes cytokines IL-10 or pro-
levels, and a decrease in the prevalence of angiographic inflammatory phenotype M1 which secretes IL-1. IL-6
coronary artery disease and diabetes. and TNF-a. A shift from type M2 to M1 is seen in diet
induced obesity whereas reverse is seen in bypass
Type-2 Diabetes and Innate Immune System surgery induced weight loss. Visceral fat secretes more
The metabolic syndrome and type 2 diabetes share IL-6 than subcutaneous fat and majority of it comes
many metabolic abnormalities of lipid profiles and through stromavascular fraction It contributes to 25–30%
elevated APP, which are also present in malignancy of total IL-6 in circulation.
and infection. Role of innate immune system in the The low-grade inflammation observed in obesity is
pathogenesis of type 2 diabetes was implicated when a linked with altered levels of several circulating factors,
graded increase in CRP, IL-6 and SAA levels serum sialic including CRP, TNF-a, IL-6 and other inflammation
acid concentrations was observed, with the lowest levels markers. Adipocytes share some properties with
seen in healthy individuals and the highest levels in type macrophages: both can activate complement, and
2 diabetic patients. produce inflammatory cytokines, fatty-acid-binding
proteins (FABPs) and many other factors. Also, adipocytes
Role of Obesity in Low Grade- store lipids and regulate metabolic homoeostasis
whereas, in proatherosclerotic conditions, macrophages
Inflammation, Insulin Resistance and
can also accumulate lipids to become foam cells.
Type-2 Diabetes
Adipose Tissue Composition Macrophage Infiltration in White Adipose Tissue
Adipose tissue (AT) is an established endocrine organ The increase in macrophage infiltration is significantly
that secretes numerous adipokines, cytokines and correlated with body mass index (BMI) and adipocyte
chemokines. Out of two types of AT identified—brown cell size. Subcutaneous adipocytes contain fewer
AT and white AT only the latter significantly persists macrophages than visceral fat. Mature adipocytes
throughout life in humans. White AT is heterogeneous, secrete Adipokine like adiponectin, leptin which
composed of mature adipocytes, and a stromavascular stimulate the diapedesis of blood monocytes for their
CHAPTER 32: Diabetes and Inflammation 193
differentiation into macrophages through a complex kinase which involve NFKB pathway, IKKf3, activating
phenomenon. Adiponectin displays anti- inflammatory protein-1 (AP-1), c-JunNH2-terminal kinase (JNK)
activity by inhibiting the production of TNF-a and IL-6 and protein kinase C-theta (PKC0) are also implicated.
by macrophages, and by binding LPS. Adiponectin also These pathways could interact with insulin signaling via
decreases hepatic gluconeogenesis and increases lipid serine/threonine inhibitory phosphorylation of IRS. The
oxidation in skeletal muscle. Circulating adiponectin proinflammatory NFKB pathway is clearly implicated
levels are decreased in patients with abdominal in insulin resistance, as selective inhibition of the
obesity, type 2 diabetes and/or coronary heart disease. NFKB function in liver and AT protects against insulin
Adiponectin may even play a protective role against resistance in nutritional and genetic animal models of
atherosclerosis and insulin resistance. obesity.
Leptin in addition to its role in food intake and energy Macrophage itself can lead to insulin resistance
expenditure also regulates immune process by its control in obese patients. Phosphorylation of the insulin
on TNF-a production and macrophage activation. receptor-f3 subunit (p-INSR-f3) is significantly reduced
Hyperleptinemia seen in obesity is associated with an in mononuclear cells (MNC) from obese subjects
increased inflammatory response. compared with those from normal controls. Ghanim et
Conversely, leptin can improve insulin sensitivity al. found that MNC are also characterized by increased
through AMP-activated protein kinase (AMPK) activation of the inflammatory pathway, including
activation. protein kinase C-f32 (PKC- f32), and suppression of
Other adipokines related to AT include visfatin, an cytokine-signalling-3mRNA (SOCS-3), which may
inflammatory adipokine that is highly expressed in contribute to alteration of insulin signal transduction
carotid plaques and associated with unstable lesions in and, thus, induce a state of insulin resistance in MNC.
patients with coronary heart disease, as well as vaspin
and omentin, which are prominently expressed in Endothelial Dysfunction,
visceral fat. Inflammation and Diabetes
Studies have shown that AT in obesity is hypoxic. Hyperglycemia is associated with an increase in cytokine
Obesity is associated with increased expression of production mediated by oxidative mechanisms. Thus,
hypoxia-inducible factor-1a (HIF-1a). In human the excess production of reactive oxygen species (ROS),
subcutaneous fat, the HIF-1a gene is down-regulated together with the interaction of advanced glycation
after bypass surgery. end-products (AGEs) with their receptors (RAGEs) on
Prolonged overnutrition and increased saturated endothelium, lead to cytokine production by endothelial
fatty-acid intake can increase nutritional endotoxaemia cells. Cytokine overproduction is also associated
and stimulate the TLR4–NFKB pathway in adipocytes as with endothelial dysfunction which involves reduced
discussed earlier. This mechanism might also be a causal vasodilation and prothrombic properties.
factor in the macrophage infiltration of AT in obesity. TNF-a can accelerate experimental atherosclerosis
through induction of VCAM-1, ICAM-1, MCP-1 and
Inflammatory Pathways to Insulin Resistance E-selectin in endothelial and vascular smooth muscle
TNF-a directly decreases insulin sensitivity while cell.
increasing lipolysis in adipocytes and play a major role A positive correlation between the acute-phase
in the pathophysiology of insulin resistance through response, endothelial dysfunction and insulin resistance
phosphorylation of the insulin receptor substrate-1 has been suggested. Serine phosphorylation of IRS-
(IRS-1) protein on serine residues. IL-1 and IL-6 are also 1, induced by cytokines, is one of the implicated
implicated in insulin resistance in type 2 diabetes, as mechanisms. It contributes to impairment of the
are other cytokines, such as IL-8 and IL-18. Few other normal insulin response and NO synthesis, and leads to
194 SECTION 3: Diabetes
reduced insulin-induced vasodilation. Increased plasma ATF6 on activation though its transit to Golgi
concentrations of soluble cell adhesion molecules have compartment leads to ERAD activation and chaperone
been reported in overweight and obese individuals, production.
suggesting that increased fat mass is associated with ER stress stimuli impair polypeptide folding, and try
early systemic endothelial activation. to preserve cell homoeostasis by adaptive increases in
chaperones and catalysts, within the ER lumen through
Role of Endoplasmic Reticulum unfolded protein response (UPR) sensor activation.
Stress in Type 2 Diabetes When this response cannot resolve ER stress, the cell
becomes subject to apoptosis using several pathways.
ER Stress and the Unfolded Protein Response
The endoplasmic reticutum (ER) is a membrane-bound ER Stress and UPR in Type-2 Diabetes
organelle that provides a unique environment for Presence of stressed ER in f3 cells and unfolded proteins
oxidative protein-folding in a correct manner to perform as proinsulin molecules suggest UPR activation as a key
specific functions and post-translational modification pathophysiological mechanism that might be involved in
of polypeptides such as disulphide bond formation. the initiation of diabetes. Proinsulin requires disulphide
Protein-folding in the ER needs molecular chaperones bond formation for its correct folding. Insulin resistance
such as binding immunoglobulin (Ig) protein (Bip) and is seen in XBP-1 deficiency whereas its overexpression
folding catalysts. in f3 cells show impair glucose-stimulated insulin
Three key factors act as sensors of unfolded protein secretion and increase f3-cell apoptosis. Deletion of the
accumulation in the ER: protein kinase (PKR)-like ER CHOP gene improves f3-cell function which makes it
kinase (PERK); inositol-requiring protein-1a (IRE-1a); responsible for protein-misfolding in the ER to oxidative
and activating transcription factor 6 (ATF6). These stress and apoptosis in f3 cells under conditions of
are collectively activated to maintain ER function by increased insulin demand.
degradation of misfolded proteins in case of heavy
translational load and preserve the cell against apoptosis. Fundamental Mechanism of β-Cell
The chaperone protein Bip is bound to the three ER Stress and Diabetes
sensory factors, which keeps them in an inactivated state. Various stimuli, including heat shock, energy deprivation,
However, when stress is present, Bip is released, leading hypoxia, metabolic dysfunction, drugs, increased levels
to activation of the three molecules PERK and IRE-1 and of circulating cytokines, FFA, nutrient excess cause ER
ATF6. stress and subsequent activation of the mammalian target
PERK when activated increases translation of ATF4 rapamycin (mTOR) pathway. Oxidative protein-folding in
mRNA through EIF-2a which is responsible for synthesis the ER can generate ROS which impede protein-folding
of ERAD machinery and enzymes that reduces oxidative through a complex mechanism and creates a vicious cycle
stress. ATF4 also induces transcription of the C/EBP of ER stress and oxidative stress. Periodic increases in
homologous protein (CHOP), which mediates apoptosis. proinsulin mRNA translation, induced by hyperglycaemia,
IRE-1 also activates genes encoding for ERAD can generate UPR activation in f3 cells.
machinery and chaperones through XBPI using a Obesity causes ER stress. which in turn, leads to
complex mechanism. It also has RNase activity, which suppression of insulin receptor signaling through
degrades mRNA to reduce the transcriptional load of hyperactivation of JNK and subsequent serine
newly synthesized proteins that require folding. IRE-1 phosphorylation of IRS-1.
can activate the NFKB pathway by interacting with JNK Thus, ER stress might be a common pathway that
and IKK which promotes apoptosis in response to ER induces both insulin resistance and f3-cell loss, thereby
stress. leading to type 2 diabetes.
CHAPTER 32: Diabetes and Inflammation 195
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CHAPTER
33
Pollution and Diabetes: Is there a Link?
Brij Mohan
The prevalence of Type 2 diabetes has increased know currently regarding pesticides and human diabetes
alarmingly over the last two decades. There is extensive may be the tip of an iceberg, in future a lot more to be
ongoing research to explore multiple possible defects discovered. Available evidences suggesting that use of
in causing Type 2 diabetes, predominantly centered on pesticides has increased fifty fold during last 50 years, it
lifestyle, genetics and pathophysiological pathways. We would not be unreasonable to speculate that pesticides
know obesity is considered to be main driver of pandemic are a ‘cog in the wheel’, contributing in some way to
of T2DM, a possible contribution of environmental possibly huge explosion in incidence of diabetes.
contaminants and pollutants has been suggested. There are different types of pesticides available but
Potential pollutants implicated in causation of diabetes most widely used include organophosphates [OP],
are: organochlorines [OC] and carbamates. Newer pesticides
Persistent organic pollutants like nicotinoid pesticides and insect growth regulators
Air pollutants are also available. OPs and OCs are known to act at
multiple pathways that also effect glucose homeostasis
PERSISTENT ORGANIC POLLUTANTS apart from neurotoxicity and cardiotoxicity. These
Persistent organic pollutants (POPs) are organic and chemicals might collectively contribute to possible
lipophilic compounds that are totally resistant to hyperglycemia. These pesticides have direct effects
environmental degradation. Because of this resistance to on glycogenesis, glycolysis, gluconeogenesis, insulin
degradation they persist in environment, bio accumulate expression, stress-induced activation of hypothalamic-
in human beings, animal tissue and bio magnify in food pituitary adrenal axis, autonomic nervous system,
chains. oxidative stress, inhibition of blood paraoxonase activity,
There is growing interest in contribution of pancreatic inflammation, adrenal gland stimulation
environmental contaminants, especially pesticides, further leading to hypersecretion of adrenaline and
in causation of diabetes and metabolic syndrome. alterations in metabolism of liver tryptophans.
Nowadays, we see significant number of cases of diabetes Dioxins and POPs are commonly known as endocrine
in farmers who do not have major contributing risk disruptors, they also effect mitochondria. The United
factors for diabetes. There are increasing number of Nations Environment Programme Governing Council
animal and human studies that show an association (GC) originally created a list of 12 POPs–known as
between pesticide exposure and diabetes. Whatever we “dirty dozen”. These were aldrin, chlordane, dichlorodi-
CHAPTER 33: Pollution and Diabetes: Is there a Link? 199
phenyltrichloroethane (DDT), dieldrin, endrin, Flow chart 1: Possible mechanisms–POP and Diabetes
heptachlor, hexachlorobenzene, mirex, polychlorinated
biphenyls (PCBs), polychlorinated dibenzo-p-dioxins
(PCDD or dioxins), polychlorinated dibenzofurans
(PCDF or furans) and toxaphene.
Pesticides represent an increasingly widespread
environmental exposure today and some of them (e.g.
organo-chlorine [OC]) have potential to accumulate in
human tissues either through direct exposure or through
the food chain. Different types of pesticides including OC
compounds have been directly associated with increased
evidence that exposure of pesticides increase the risk
T2D risk in a dose-response way as well as with diabetes
of T2DM. Larger prospective studies may show more
risk factors including adiposity, insulin resistance and
conservative risk effects; however, these also show that
dyslipidemia.
pesticides are harmful.
Common Persistent Organic Pollutants are: Epidemiological evidence is supported by various
Pesticides mechanistic studies, which suggest potential mechanisms
A l d r i n , He x a c h l o ro b e n ze n e, C h l o rd a n e, D D T, through which these compounds may increase diabetes
Dieldrin, Endrin, Heptachlor, Mirex, Toxaphene, risk (Flow chart 1). Underlying pathogenic mechanisms
Chlordecone, Lindane pentachlorobenzene, Alpha under this association need to be further assessed
-hexachlorocyclohexane, Beta-hexachlorocyclohexane. experimentally. There should be guidelines on use of
pesticides and risk of diabetes should be considered in
Industrial Chemicals order to reflect current evidence.
Hexachlorobenzene, Polychlorinated biphenyls
(PCBs), Hexabromobiphenyl, Hexabromodiphenyl Some Evidences
ether and Pentachlorobenzene, Heptabromodiphenyl In a study on impact of pesticide exposure on about
Ether, Perfluorooctanesulfonic acid, Perfluorooctane 2000 outdoor staff working as a part of insecticide
sulfonyl fluoride, Tetrabromodiphenyl ether and program in Australia. This group was compared with a
Pentabromodiphenyl ether. similar number of workers not exposed to insecticides.
Diabetes was more commonly reported by subjects using
By-products herbicides. In addition, standardized mortality ratio in
Hexachlorobenzene; polychlorinated dibenzo-p-dioxins such subjects with diabetes was much higher compared
polychlorinated dibenzofurans (PCDD/PCDF), and PCBs, with Australian general population.
pentachlorobenzene, alpha hexachlorocyclohexane and Lee et al. evaluated prospective associations of Type
beta-hexachlorocyclohexane. 2 diabetes with some organic pollutants among elderly.
Data are there from different sources quantifying Three OC pesticides were found to have significant odds
risk for diabetes for a wide range of pesticides. All types ratio for Type 2 diabetes. Authors concluded selected
of pesticides have been examined for their relation to persistent organic pollutants substantially increased the
diabetes. Exhaustive research strategy revealed that risk of future Type 2 diabetes in an elderly population.
mostly OC pesticides have been studied. Evidence on National Health and Nutrition Examination survey
several other types of pesticides are still limited and (NHANES), in a cross-sectional study of 749 subjects
should be further considered in future studies. The without diabetes aged 20 years, OC pesticides were most
findings from various analysis, yielded supportive strongly associated with HOMA-IR. Association between
200 SECTION 3: Diabetes
OC pesticides and HOMA-IR was further strengthened as association between air pollution exposure and diabetes
waist circumference increased. The authors concluded related traits and gestational diabetes cannot be presently
that OC pesticides and persistent organic pollutants drawn due to the limited data available. For short-term air
may interact with obesity, thereby increasing insulin pollution exposures, the results are more heterogeneous
resistance and further increased risk of Type 2 diabetes. and the evidence too weak to demonstrate a causal
Same authors also reported associations between relationship.
organochlorine pesticides and prevalence of metabolic Household indoor air pollution from solid fuels plays
syndrome. a major role in Asia, Latin America and Africa. Outdoor
air pollution from PM is of importance globally.
AIR POLLUTANTS SOURCES Recent studies have shown that there is some
Air pollution is a ubiquitous exposure effecting large evidence for an association between air pollution
proportion of global population. These compounds differ exposure and T2D. Several biological mechanisms have
in their dispersion, reactivity and toxicity. Air pollution in been proposed to explain such a link. PM exposure has
past has been linked to reduced life expectancy, mainly been associated with impaired endothelial function,
because of cardiovascular and respiratory diseases elevated systemic inflammation and oxidative stress,
such as coronary heart disease and lung cancer and endoplasmic reticulum stress, cardiac autonomic
obstructive lung disease. There is strong evidence that ner vous system dysfunction and mitochondrial
air pollution adversely influences many health indicators dysfunction. Further, epigenetic changes leading to
but links between air pollution and T2D development activation of key signaling pathways or changes in
have been only recently revealed. markers of coagulation, inflammation and endothelial
Air pollutants are emitted from many sources. These function, have been described following exposure to air
can be grouped as: pollutants.
conjunction with high-fat diet feeding, increased fasting, county level with PM2.5 (1% increase per 10 mg/m3);
postprandial glucose, insulin, and homeostasis model association persisted in counties with PM2.5 meeting
assessment-IR (HOMA-IR) measures. Changes in IR seen current annual standards (15 mg/m3).
with PM2.5 were incremental to that of high fat diet alone
Los Angeles: 3,992 women in the Black Women’s Health
over a period of 24 weeks. Mean concentration of PM2.5
Study: NO2 exposure by LUR and PM2.5 by local monitors;
was 60–65 mg/m3 (10-fold from ambient levels). Tumor
Results: NO2 exposure associated with 10-year incidence
necrosis factor (TNF)-a, interleukin-6 (IL-6), resistin,
of DM (adjusted HR 1.25; 95% CI 1.07–1.46); PM2.5 not
and leptin levels were all elevated following PM2.5
related
exposure in keeping with a proinflammatory insulin
An unanswered question exists regarding latent
resistant state. PM exposure also resulted in elevations
period of air pollution exposure. Does high air pollution
in prothrombotic adipokines such as plasminogen
exposure cause priming effects that manifest their
activator inhibitor 1 and increased circulating adhesion
risk even after a certain time of low exposure? Air
molecules such as intracellular adhesion molecule-1 and
pollution exposure sources are often located indoors.
E-selectin.
Household indoor air pollution concentrations often
In subsequent experiments, effect of PM2.5 exposure
exceed outdoor concentrations by a factor of two to
early in life with and without concomitant exposure to a
five and even occasionally up to a factor of 100. Air
high-fat diet was evaluated. C57BL/6 mice fed a normal
pollution concentrations in work environment are also
diet but exposed for 10 weeks exhibited metabolic
often higher than the mean concentration outdoors.
abnormalities including an increase in HOMA-IR and Air pollution concentrations indoors and in work
postprandial glucose that approached those seen environments have not yet been studied in relation to
with high-fat chow diet–fed mice exposed to filtered T2D. Another important gap is that role of potential
air. In another study, intratracheal exposure of PM2.5 environmental confounders, such as noise and reduced
potentiated IR at end of three weeks in high-fat fed male greenness, that are correlated with air pollution have not
rats. yet been extensively evaluated.
Taken together, these experiments do suggest Available evidences do support adverse effects
important interaction of PM2.5 exposure with high-fat of air pollution on diabetes. Its related high public
diet and they raise possibility that early life may represent health impact of an association justify need for further
a vulnerable period of enhanced susceptibility to PM2.5 investigations. More studies are needed to establish how
exposure effects. and to what extent air pollution control measures may
reduce global diabetes related burden of disease.
Human Studies
Ontario, Canada: 7,634 patients attending Individual BIBLIOGRAPHY
chronic exposure to two respiratory clinics NO2 (traffic- 1. Andersen ZJ, Raaschou-Nielsen O, Ketzel M, et al. Diabetes
related pollution) using LUR result : 1 ppb NO2 increased incidence and long-term exposure to air pollution: a cohort
the OR for DM prevalence (1.04; 95% CI 1.00–1.08) in study. Diabetes Care. 2012;35:92-8.
women; no significant association in men. 2. Beard J, Sladden T, Morgan G, Berry G, Brooks L, McMichael
A. Health impacts of pesticide exposure in a cohort of
Ruhr, Germany: 1776 nondiabetic women, PM10 (Mean: outdoor workers. Environ Health Perspect. 2003;111:724-
47; IQR 10 mg/m3) adjusted HR for developing DM over 30.
mean 16 years ranged from 1.15 to 1.42 per IQR increase 3. Brook RD, Jerrett M, Brook JR, Bard RL, Finkelstein MM. The
relationship
between diabetes mellitus and traffic-related
in PM10 or in relation to traffic exposures or NO2.
air pollution. J Occup Environ Med. 2008;50:32-8.
United States, wide ecological study. Cross-sectional 4. Coogan PF, White LF, Jerrett M, et al. Air pollution and
data of. 2,700 counties, multiple models of long-term incidence of hypertension and diabetes mellitus in black
PM2.5 exposure adjusted DM prevalence associated at women living in Los Angeles. Circulation. 2012;125:767-72.
202 SECTION 3: Diabetes
5. Lee DH, Lee IK, Jin SH, Steffes M, Jacobs DR Jr. Association National Health and Nutrition Examination Survey 1999–
between serum concentrations of persistent organic 2002. Diabetologia. 2007;50:1841-51.
pollutants and insulin resistance among nondiabetic adults: 7. Lee, et al. Diabetes Care. 2006.
results from the National Health and Nutrition Examination 8. Van Donkelaar A, et al. Use of satellite observations for long-
Survey 1999–2002 Diabetes Care. 2007;30:622-8. term exposure assessment of global concentrations of fine
6. Lee DH, Lee IK, Por ta M, Steffes M, Jacobs DR Jr. particulate matter. Environ Health Perspect. 2015;123:135-
Relationship between serum concentrations of persistent 43.
organic pollutants and the prevalence of metabolic 9. Wang, et al. Diabetes Care. 2008.
syndrome among non-diabetic adults: results from the
CHAPTER
34
Musculoskeletal Manifestations
of Diabetes Mellitus
S Anita Nambiar, Divya G
A B
Figs 1A and B: (A) Prayer sign in LJM; (B) Tabletop sign in LJM
Fig. 2: Radiograph of thoracolumbar spine showing hyperostosis Fig. 3: Trigger finger (Flexor tenosynovitis)
the treatment options. Surgery may be necessary, if there a development phase, a coalescence phase and a
is no improvement with conservative measures. remodeling phase. The off-loading of the affected joints
by total contact casts forms the mainstay of management
FLEXOR TENOSYNOVITIS of the disease.
Flexor tenosynovitis (FTS) or ‘Trigger Finger’ is due
to the proliferation of the fibrous tissue in the tendon DIABETIC AMYOTROPHY
sheath particularly over the pulleys (Fig. 3). The Diabetic amyotrophy is characterized by proximal lower
signs and symptoms include the locking in flexion or limb pain due to wasting and weakening of muscles.
extension with palpable or audible crepitus during Asymmetric loss of tendon jerks is typically observed. It
finger movements. The prevalence of FTS is around 11% occurs commonly in elderly males with type 2 diabetes
among and is linked to the duration of diabetes and not mellitus (T2DM) and weight loss. Management consists
age. Surgical decompression may be done in severely of stabilizing blood glucose levels and physiotherapy.
symptomatic cases.
OSTEOPOROSIS
NEUROARTHROPATHY A change in bone mineral density is seen in both T1DM
(CHARCOT’S JOINTS) and T2DM. In T1DM, the bone mineral density and bone
This condition results from impairment of joint sensa mass are reduced, though the mechanism is not clear
tions leading to progressive painless joint destruction and is detectable early in the disease. In T2DM, there
that can be established radiographically (Figs 4A and is increased incidence of fracture rates despite normal
B). Charcot’s joint are seen mostly in aged diabetics with bone mineral density due to increased bone porosity.
prolonged history of diabetic neuropathy. The weight
bearing joints are mostly affected, particularly, foot and DIABETIC MUSCLE INFARCTION
ankles. It occurs in chronic diabetics with uncontrolled blood
Patients remain unaware about the underlying sugar and microvascular complications. Patients present
changes in the foot structure due to poor sensation with acute pain and swelling of muscle which generally
and hence continue to mobilize. There are four stages subsides with conservative treatment. There is higher
of this condition: a prodromal inflammatory phase, risk of recurrence.
206 SECTION 3: Diabetes
A B
Figs 4A and B: Radiographs showing Charcot’s joint
HOLD refers to the ‘clustering’ of a number of metabolic prevalence increases with age. The increased prevalence
abnormalities namely Hypertension, Obesity, Lipid of metabolic syndrome in younger generation is very
abnormality and Diabetes. This is what has been viewed alarming. It implies to have a more prolonged exposure
as metabolic syndrome. Distinct clinical features and to atherosclerotic risk factors. HOLD prevalence is
metabolic predispositions are frequently noted in significantly more in among upper socioeconomic classes
people with abdominal adiposity, insulin resistance, compared to lower socioeconomic strata.
dyslipidemia, and hypertension. Current definitions
of metabolic syndrome differ and cardiovascular risk PECULIARITIES OF HOLD IN INDIA
appears to differ according to which component risk For any given BMI, Indians have more body fat in
factors present. comparison with whites and black Africans. It leads
There is greater cardiovascular risk with HOLD. It to higher levels of plasma non-esterified fatty acid
has been found that metabolic syndrome predisposes to and triglycerides and hyperinsulinemia. It has been
fivefold greater risk of developing diabetes in comparison found that 30–65% of adult urban Indians having either
with those without it. It also predisposes three times to
have a heart attack. Indians are highly Insulin resistant TABLE 1: Prevalence of metabolic syndrome in India
even with mild increase in (BMI) body mass index or
Author Percentage by NCEP- Year
abdominal adiposity. Interestingly compared with White ATP III
Caucasian neonates, Indians neonates have a higher Chow et al. 26.9% male, 2008
level of hyperinsulinemia as recorded at birth. [Atherosclerosis, 2007.] 18.4% female [Andhra
Pradesh rural areas]
PREVALENCE (TABLE 1) Deepa et al. 18.3% [Southern India] 2007
[Diabets Met Res Rev, 2007
The prevalence of HOLD is influenced by genetic
Swant et al. 19.52% [Mumbai] 2011
background, age, sex, unhealthy diet, levels of physical [Cholestero, 2011
activity, socioeconomic, environmental (obesogenic
Ramchandran et al. 41% [Urban Chennai] 2003
environment) and urbanization mainly. Different studies [Diabetes Res Clin Pract
from India show differences in prevalence of HOLD 2003;60:199–204]
components. Prevalence varies in different Indian studies Rajendra Pradeepa et al. 41.9% [South India]
in tune of urban (35%) and rural (19%). In both sexes, [JAPI, Vol.64(5) 2016]
208 SECTION 3: Diabetes
overweight or obese have a direct correlation with the can hold the HOLD by tackling multiple risk factors like
increasing prevalence of HOLD. behavior modification, dietary modifications, physical
activity enhancement, and by modifying smoking and
MECHANISTIC CHARACTERISTICS alcohol habits. Individual-based approach has been
High qualities studies have shown that nutrient found beneficial but to have a wider impact population-
overload and lack of physical exercise are responsible based community intervention is needed.
for insulin resistance and metabolic derangements.
Once hyperinsulinemia occurs it can induce elevation BEHAVIORAL MODIFICATION
of blood pressure by activation of sympathetic nervous Individual behavior modification must be directed
system and renin angiotensin aldosterone system. Thus towards bad-eating habits. It should be rewarded, if
volume expansion, endothelial dysfunction and renal children and younger adults especially correct their
dysfunction are consequential. habits. For older individual, more efforts are needed. We
Recently, it has been proposed that unexpected rise must try for sustainable goal-based lifestyle interventions.
of HOLD cannot be explained only by traditional risk
factors and role of persistent organic pollutants (POPs) is Dietary Modifications (Fig. 1)
now deciding core component of epidemic of HOLD in The most important interventions should target
India. Recent plethora of research provide evidence that reduction in high salt intake, and reduction in intake
exposure to POPs commonly present in food chains leads of saturated fat and refined carbohydrate. Reduction
to insulin resistance and associated metabolic disorders. in high intake of sweetened beverages is in priority
considering that Indian adolescents prefer nowadays
How to hold the HOLD (Flow chart 1) too much. We must impress younger generation to
It is important to quantify factors contributing to HOLD. revert back to our traditional diets. These days due to
Increasing awareness of cluster of risk factors and how to nutritional transition Indians are tuned to take higher
prevent them comprehensively should be emphasized saturated and Tran’s fat containing food stuffs. They take
in population-wide prevention strategies in Indians. We too much salted snacks and processed food in between
may range from 40% to 80% in high-risk individuals increase in LDL receptors but also with an increase
and subjects with CVD. Also great interpersonal in PCSK9 (proprotein convertase subtilisin kinase
variability in reduction of lipid parameters viz. 9) levels a serine protease which degrades LDL
LDL-C, non-HDL-C, and apo B has been reported receptors and negate its beneficial effect.
with a fixed statin dose. Newer approaches in management of Lipid disorders
Genetic lipid disorders may be refractory/less which focus on alternate pathways viz CETP activity,
responsive to effect of statins. In an observational correction of low and dysfunctional ApoA1 molecules
study of statin treated subjects with heterozygous (HDL) and elevated triglyceride levels to reduce risk of
familial Hypercholesterolemia, approx 21% subjects atherosclerosis and CVD are being discussed as under:
212 SECTION 3: Diabetes
GAUSS-2 N=307 low-dose statin ± LMT; Evo (140 mg Q2W, 420 mg −56.1% (P Q2W) vs −18.1(P)
Phase III QM) vs Placebo + EZE 12 wk −52.6% (P QM) vs −15.1 (P)
IVUS/Diabetic/CV risk reduction trials
GLAGOV (IVUS) N=968; On statins >4 wks with LDL >80 mg/dL or LDL –56.5 mg/dL LDL reduction (36.6 evo vs 93
60–80 with >1 major/3 minor CV RF, Epicardial stenosis placebo); percent atheroma vol ↓ 0.95% vs nil in
20–50%; Evo (420 mg QM) vs placebo; 78 wks placebo
ODYSSEY Diabetes N=413, T2DM with mixed dyslipidemia at high-risk of CVD; –32.5% Non-HDL-c vs Standard care.
Dyslipidemia Aliroc (75 mg/150 mg Q2W)vs standard therapy for 24 +
8 wks
FOURIER N=27564, ASCVD and LDL<70 mg/dL on maximal statin; –59% LDL(92 mg/dL–30 mg/dL); significant
Evo (140 mg Q2W, 420 mg QM) vs placebo; 48 wks reductionin primary end point (9.8% vs 11.3%)
FU median 2.2 yrs HR0.85; NNT 1 event of 67 treated for 2 yrs
account for observed side effects of diarrhea, nausea and No reduction in markers of atherosclerosis viz
abdominal pain. Similarly, inhibition of VLDL synthesis plaque burden (ILLUSTRATE) and CIMT thickness
in liver produces trapping of triglycerides in the liver (RADIANCE 1 and 2) observed with torcetrapib.
and accounts for dose dependent increase in hepatic Increase in CRP levels reported with use of Dalcetrapib
steatosis and elevation in liver enzymes. Lomitapide is in the dal–OUTCOMES trial and Evacetrapib in the
currently approved for use in subjects with homozygous ACCENTUATE trial.
familial hypercholesterolemia. CETP inhibition with Dalcetrapib, produced minimal
CETP INHIBITORS
Although epidemiological studies provide definite TABLE 3: REVEAL trial with anacetrapib
association of low levels of HDL with increased CV risk,
Trial Study characteristics Result
the same has not been reproduced with interventions
aimed at increasing HDL levels. The studies with CETP Define N=Anacetrapib (100 mg/d) vs + 138.1% HDL;
control + other LMT for 76 wk in +44.1 Apo A1;
inhibitors (Torcetrapib, Dalcetrapib and Evacetrapib)
pts with CHD/at risk (>20%) of CHD −39.8% LDL;
have not shown any positive benefits. The possible −31.7% non-HDL
reasons are as under: (Anacetrapib) +9.1
Off target hyperaldosteronism causing increase in (P)
systolic blood pressure (by mean 5.4 mm Hg) and Na+ Reveal N=30000; Anacetrapib (100 mg/d) 9% reduction in risk
retention induced by Torcetrapib, as being a possible vs control + Atorva 20-80 mg/d of major CV events
> 50 yrs subjects with high r/o (10.8% vs 11.8%)
cause of increase in CV (25%) and all cause mortality
CVD(prev h/o CVD/CVA) 4 yrs
(58%) in the ILLUMINATE trial.
CHAPTER 36: Dyslipidemia Management: Newer Avenues 215
The administration of AT04A vaccine reduced the total Bind to oxidized lipids
amount of cholesterol by 53%, atherosclerotic damage to Possess anti-inflammatory and antioxidant properties
blood vessels by 64%, and reduced by 21–28% biological Bind to lipid in the intestine and inhibit absorption
markers of blood vessel inflammation compared to The science of Apolipoprotein mimetics is still
unvaccinated mice. The induced antibodies were evolving with molecules like D4F, L4F and Apo A1 helix
functional over the whole study period with high 10 mimetics showing promising but mixed results of
concentrations maintained even at the end of the study. efficacy and yet not definite mode of action.
In contrast monoclonal antibodies (alirocumab and
evolocumab) show relatively short in vivo half-lives and Antisense Approach Against
therefore to produce long-term efficacy requires frequent Lipoprotein(a)
application and translate into high cost. IONIS APO(a) Rx and IONIS APO(a)LRx (ligand
conjugated) are two oligonucleotide molecule which
Apolipoprotein A1 (ApoA1) Mimetics inhibit Lp(a) synthesis. Oligonucleotide mediated
These class of drugs are designed to mimic the action inhibition of Lp(a) synthesis is shown to reduce their
of Apo A1 or HDL molecules to reverse the progression levels by 71–92%.
of atherosclerosis mainly through promoting reverse
cholesterol transport. The concept of use of ApoA1 arose, PCSK-9 Inhibition (Nonmonoclonal
when it was observed that individuals harbouring a Antibody)
variant of ApoA1 (Apo A1 Milano) had long lifespans and Small interfering RNA (siRNA) molecules have been
low atherosclerotic burden inspite of having low HDL targeted at mRNA of PCSK9 molecules, inducing RNA
levels. Since then trials with Apo A1 Milano have been induced silencing and degradation of PCSK9 mRNA
designed to study its role in prevention of CVD. Clinical and reducing its protein synthesis. Inclisiran a siRNA,
studies with infusion of Apo A1 Milano for 5 weeks administered as a single subcutaneous injection of
in patients with acute coronary syndrome has shown 300 mg in the phase 2 ORION trial produced 51%
regression in atheroma volumes by 4.2% as assessed on reduction in LDL levels over 6 months period.
intravascular ultrasound. In the AEGIS-1 trial, 4 weekly
infusions of CLS112 (a plasma derived Apolipoprotein Adenosine Triphosphate
A1 reconstituted and stabilised into disc shaped HDL) Citrate Lyase Inhibitor
when administered to subjects with acute MI showed Bempedoic acid is first in the class ATP citrate lyase
enhanced cholesterol efflux. inhibitor which inhibits cholesterol synthesis and
Following the success of apolipoprotein A1 infusion upregulates LDL-c receptors and LDL-c reuptake by
in regression of atherosclerosis, short synthetic hepatocytes. The ongoing Phase 3 CLEAR-Harmony
peptides with sequence homology to parts of natural and subsequent CLEAR outcomes trial will shed further
apolipoprotein have been designed retaining their in light on the efficacy and CV outcomes with the use of
vivo functional efficacy. These Apolipoprotein mimetic Bempedoic acid in subjects with increased CV risk.
216 SECTION 3: Diabetes
PPAR Agonists future for individuals with high CV risk, statin intolerance
Saroglitazaar a dual acting PPAR α and γ acting has shown and genetic dyslipidemia definitely seems hopeful.
efficacy in patients with diabetic dyslipidemia. However,
results of trials to prove its efficacy in reducing CV BIBLIOGRAPHY
outcomes are yet awaited. MBX-8025, a selective PPAR δ 1. Ahn CH, Choi SH. New drugs for treating dyslipidemia:
Beyond statins. Diabetes Metab J. 2015;39(2):87-94.
receptor agonist plays important role in regulating lipid
2. Bergheanu SC, Bodde MC, Jukema JW. Pathophysiology
storage and transport. Trials are underway to prove its
and treatment of atherosclerosis: Current view and future
role in management of dyslipidemia. perspective on lipoprotein modification treatment. Neth
Heart J. 2017;25:231-42.
Angiopoietin like 3 (ANGPLT-3) 3. Ito MK, Santos RD. PCSK9 inhibition with monoclonal
ANGPLT-3 protein is the main regulator of lipid antibodies: Modern management of hypercholesterolemia.
metabolism which acts by inhibiting lipoprotein lipase The Journal of Clinical Pharmacology. 2017;57(1):7-32.
activity. Subject with low ANGPLT-3 levels have low 4. Kosmas CE, De Jesus E, Rosario D, Vittorio TJ. CETP
Inhibition: Past failures and future hopes. Clinical Medicine
cholesterol and triglyceride levels. Antisense inhibitors
Insights: Cardiology. 2016:10:37-42.
of ANGPLT-3 protein have been shown to reduce TG 5. Update on the use of PCSK9 inhibitors in adults:
levels by 66% and total cholesterol by 36%. Recommendations from an Expert Panel of the National
With promising results coming in from newer Lipid Association. Journal of Clinical Lipidology. 201;11(4):
therapeutic approaches to control dyslipidemia, the 880-90.
CHAPTER
37
Metformin versus Insulin in Treatment
of Gestational Diabetes Mellitus
Sandeep Garg, Onkar Awadhiya, Sunita Aggarwal
American Diabetes Association (ADA) in the year 2017 hepatic glucose uptake, and decreased post-prandial
defines gestational diabetes mellitus (GDM) as diabetes insulin secretion. Women who have normal pancreatic
that is first diagnosed in the 2nd or 3rd trimester of function, have adequate insulin production for matching
pregnancy that is not clearly either pre-existing type 1 up with the insulin resistance during pregnancy and are
or type 2 diabetes. Females who have been diagnosed able to maintain glucose levels within normal levels,
with diabetes in the 1st trimester are said to have but women with GDM, cannot cope up with this stress
pre-existing pre-gestational diabetes (mainly type 2 and develop hyperglycemia which necessitates the
diabetes). Seshiah et al. reported in 2008 that GDM was treatment.
detected in 17.8% women in urban areas, 13.8% and 9.9%
in semiurban and rural areas in their study in which DIAGNOSIS OF GDM
prospective screening was done for GDM. The frequency There are two approaches to diagnose GDM and either of
of GDM is the highest in Indian women among all Asian two strategies can be used:
populations. 1. “One-step” 75-g OGTT.
2. “Two-step” approach with a 50-g screen followed by a
100-g OGTT.
MECHANISM OF DIABETES
IN PREGNANCY One-step Strategy
Increased insulin resistance lies at the core of GDM Screening for GDM is done in women who are not
pathogenesis. Insulin resistance increases during the diagnosed diabetic, at 24-28 weeks of pregnancy. Patient
2nd and initial part of 3rd trimesters and returns to the is advised fasting for minimum of 8 hours, after which 75
baseline level around the later part of the 3rd trimester. g OGTT (Oral Glucose Tolerance Test) is carried out and
There is a state of “facilitated insulin action” during 1st blood sugar is measured at 1 hour and 2 hour. Following
half of pregnancy and “diabetogenic stress” in the 2nd cut-off values have been set to diagnose GDM (Table 1):
half. This “Stress” is because of interplay of various factors Fasting plasma glucose: 92 mg/dL
such as high levels of counter-regulatory hormones (viz. 1 h plasma glucose: 180 mg/dL
progesterone, estriol and HCS) as well as decreased 2 h plasma glucose: 153 mg/dL
218 SECTION 3: Diabetes
TABLE 1: Cut-off values set to diagnose GDM Increased RBC turnover during pregnancy results
TIME Carpenter/Coustan NDDG criteria in decreased HbA 1c levels. The target level of A 1c in
criteria pregnancy is 6–6.5%. Keeping it 6% is optimal, if not
Fasting 95 mg/dL 105 mg/dL associated with significant hypoglycemia, but the target
may be relaxed to 7%, if required to avoid hypoglycemia.
1 hour 180 mg/dL 190 mg/dL
TABLE 2: Types of insulin used during pregnancy TABLE 3: The recommendations as per the latest evidence for the
use of metformin in GDM
Insulin Type Onset Peak Duration Dosing
name effect interval Institution Insulin OHAs
Aspart Rapid acting 15 min 60 min 2 hour At start of MOHFW 2014 RECOMMENDED NOT
each meal RECOMMENDED
Lispro Rapid acting 15 min 60 min 2 hour At start of DIPSI 2013 RECOMMENDED NOT
each meal RECOMMENDED
Regular Short acting 60 min 2–4 6 hour 60–90 CDA 2013 RECOMMENDED Metformin as
hour minutes alternative
before meal ACOG 2013 RECOMMENDED Equally effective as
first line therapy
NPH Intermediate 2 hour 4-6 8 hour Every 8 hour
acting hour ADA 2017 RECOMMENDED May be used
Insulin Long acting 2 hour - 12 hour Every 12 NICE 2015 RECOMMENDED Offer to those who
detemir hour deny insulin
gain. Insulin glargine, Glulusine and Degludec are not is mainly because of increased insulin resistance. The
recommended for use in GDM. recommendations as per the latest evidence for the use
of metformin in GDM is summarized in Table 3.
COMPARISON OF INSULIN VERSUS
METFORMIN IN GDM CONCLUSION
Insulin is the mainstay of pharmacologic therapy of Meta-analysis of various studies has now shown that
GDM. ADA, NICE and ACOG guidelines recommend metformin use and insulin therapy had comparable
to start insulin therapy, if MNT fails to achieve blood glycemic control profile. Metformin causes less neonatal
glucose targets in women with GDM. Amongst oral hypoglycemia, less weight gain in mothers as compared to
hypoglycemic agents only 2 drugs have been advocated in insulin and is more useful in PIH patients but associated
the management of GDM viz. Metformin and Glyburide with higher risk of prematurity. Glyburide causes more
(pregnancy category B drugs). There are some RCTs to macrosomia. ADA 2017 recommends that patients
support the efficacy and short-term safety of these drugs, who are being treated with OHAs should be counselled
but these are known to cross the placenta. There is lack of that metformin crosses the placenta. Although no fetal
data to support their long-term safety. Some studies have adverse effects have been demonstrated with metformin
shown that no significant difference is seen in controlling the long-term data regarding neurodevelopmental
high blood sugar in GDM with the use of metformin or outcomes are lacking. However, the guidelines from
insulin. MOHFW and Diabetes in Pregnancy Study Group in
Metformin also lowers the risk of pregnancy-induced India (DIPSI) does not recommends metformin use in
hypertension. When compared with insulin metformin GDM at present.
in a meta-analysis has shown to have lower average
2-hour postprandial glucose levels in the first week BIBLIOGRAPHY
after randomization as compared to insulin group, 1. Balsells M, Garcia-Patterson A, Sola I, Roque M, Gich I,
Corcoy R. Glibenclamide, metformin, and insulin for the
possibly because metformin reduces hyperglycaemia
treatment of gestational diabetes: a systematic review and
by suppression of glucose output from liver, increasing meta-analysis. BMJ. 2015;350:102.
insulin sensitivity and enhancing peripheral glucose 2. Diagnostic criteria and classification of hyperglycemia
uptake which is significant in GDM as this condition first detected in pregnancy: A World Health Organization
220 SECTION 3: Diabetes
Guideline. Diabetes Research and Clinical Practice. 4. Seshiah V, Banarjee S, Balaji V. Consensus Evidence-
2014;103(3):341-63. based Guidelines for Management of Gestational Diabetes
3. Jiang YF, Chen XY, Ding T, Wang XF, Zhu ZN, SuSW. Mellitus in India. J Assoc Physicians India. 2014;62(Suppl
Comparative efficacy and safety of OADs in management 7):55-62.
of GDM: network meta-analysis of randomized controlled 5. Standards of Medical Care in Diabetes 2017, ADA guidelines.
trials. J Clin Endocrinol Metab. 2015;100:2071-80. (Standards of Medical Care in Diabetes—2017. http://care.
diabetesjournals.org.
CHAPTER
38
Early Initiation of Insulin
Therapy in Diabetes Mellitus
Rajesh Kumar Jha, Sagar Dembla
Glargine is recombinant human insulin with acidic basal insulin with either GLP-1 Analog or short acting
solution leading to consistent depot formation with slow insulin for adequate control of HbA1c.
release. It showed predictable pharmacodynamics with a Multiple studies have shown injectable insulin with
smooth peak less 24 hours action. This resembles basal better achieved fasting and 2 hours postprandial glucose
insulin secretion of a healthy nondiabetic pancreas. compared oral agents in 2–3 months trials. Hanefeld et al.
Furthermore, it had no delirious effects like NPH. Various EARLY study showed significant reduction in HbA1c from
studies showed effective HbA 1c reduction and lower 8.7% to 7.4% after 24 weeks of insulin therapy. Patients
weight gain. also attained FBG levels and had better compliance
Detemir is modified analogue human insulin. compared to a maximum dose of oral agents. In a study
Addition of fatty acid leads to a longer duration of by S Jain showed baseline HbA1c reduction by 1.93% in
action. Detemir is pH neutral, thus enabling liquid form combined injectable therapy compared with 0.3% of
following injection, which differs from NPH and glargine. combined oral agents. Similarly Chen Hs in 2011 showed
In comparison to NPH, detemir is associated with fewer greater reduction of HbA1C from 11.3% baseline to 7.84%
complications like hypoglycemia and antigenicity. vs 11.9% baseline to 6.78% in oral agent vs basal insulin
Degludec is newest basal insulin introduced with respectively over 6 months. Moreover, early initiation
longest duration of action, i.e. more than 24 hours. of basal insulin showed better preservation of β-cell
Degludec is slowly and steadily absorbed, thus offers function and improved insulin sensitivity. Fonsea et al
simple titration with algorithm and shows more flexibility in 2008 observed similar benefits of early vs late use of
with the patient’s lifestyle. basal insulin. Similarly, hypoglycemia episodes were
lower with long acting basal insulin compared to oral
ROLE OF INSULIN IN TREATMENT OF hypoglycemic agent.
TYPE 2 DIABETES MELLITUS Weng J et al in 2008 showed that in vitro experimental
Insulin is the most potent glucose lower agent available hyperglycemia has toxic effects on pancreatic β-cell
at present. The initiation of insulin is feared by most function. With euglycemia these effects showed a
patients. Even physician delay its use, rather it should reversal in the form of improved β-cell function and
be a collaborated decision. The physician should insulin secretion. This concept was tested by Pennartz et
educate and motivate them. Various factors should be al in 2011 in new onset diabetes showed improved β-cell
taken into account like age, overall general health, cost, function with early initiation of glargine on a daily basis.
number of hypoglycemic episodes, macrovascular and Certain long-term studies have indicated the presence of
microvascular complications. metabolic memory in overt diabetes.
In ORIGIN (Outcome Reduction with an Initial
BENEFITS OF INSULIN THERAPY Glargine InterveNtion) results after a median follow-
IN DIABETES MELLITUS up of 6.2 years, concluded that all cause mortality or
Early Vs Late Use cardiovascular risk was similar in glargine group vs
ADA 2017 guidelines recommend that newly diagnosed standard care group. Hence, it disproved the belief of
diabetic with HbA1c less than 9% should initiate with increased cardiovascular risk with pre-diabetic or early
lifestyle modification and metformin monotherapy. type 2 diabetic with early insulin intervention.
Recommendations are made for HbA1c ≥ 9% to initiate
with dual therapy, i.e. metformin with either of BARRIERS TO BASAL INSULIN
sulfonylureas or DPP-4 inhibitors or SGLT-2 inhibitors IN TYPE 2 DIABETES MELLITUS
or GLP-1 analog or insulin. Whereas when HbA1c ≥ 10% Several surveys and studies were conducted to identify
or blood glucose ≥ 300 mg/dL or patient is symptomatic, barriers to diabetes care holistically, including insulin
recommended is combination injectable therapy with therapy, healthcare provider, doctor, patients and
CHAPTER 38: Early Initiation of Insulin Therapy in Diabetes Mellitus 223
their families. In second Diabetes Attitude, Wishes, or 10–20%. If target HbA 1c is not reached then either
and Needs (DAWN2) survey included over 15,000 the addition of a GLP-1 analog or rapid acting insulin
healthcare providers, patients and family members in should be added before largest meal. If still HbA1c is not
17 countries. The study concluded that nearly 2/3rd of controlled, then two or more boluses of rapid acting
the healthcare providing staffs need resources, training insulin with each meal or switch to pre-mixed insulin
and reimbursement to educate patients regarding self should be considered.
glucose monitoring and insulin therapy. Of 8596 patients
included in DAWN2 one-fourth reported suboptimal BIBLIOGRAPHY
self-monitoring. One-third reported worries about 1. Ghosal S, Batin M. The diabetes epidemic in India: where
hypoglycemia and one-fourth reported high disease we stand and future projections. Journal of the Indian
related stress. Family members reported high level of Medical Association. 2013;111(11):751-4.
frustration in not knowing how to help the individual 2. Gleason C, Gonzalez M, Harmon J, Robertson P. In
with diabetes; about one half were worried about various subjects determinants of glucose toxicity and its
reversibility in beta cell of the pancreatic islet, HIT-T15.
hypoglycemia and one half perceived as a financial
American Journal Physiology Endocrinology Metabolism
burden.
2000;279:E997-E1002.
In a 2013 study conducted by Sujeet Jha et al stated 3. Hanefeld M, Koehler C, Hoffmann C,Wilhelm K, Kamke
that most patients had psychological constraints to W: Effects of targeting fasting glucose level with long
insulin therapy, including fear of injection, social stigma, acting basal insulin glargine on glycaemic variability and
high gender based opposition by females, lack of home hypoglycemia risk with early diabetes: A randomized,
support and ineffective interpersonal interaction with controlled study. Diabetes Med. 2010;27:175-80.
healthcare providers. 4. Hu Y, Li L, Xu Y, Yu T, Tong G, Huang H, Bi Y, et al. Short-
term intensive therapy of insulin in newly diagnosed type 2
Similar results were published by Manjula GB in 2013
diabetes which partially restores both insulin sensitivity and
stating psychosocial and financial as major constrains
beta-cell function with long-term remission. Diabetes Care.
followed by fear of hypoglycemia and lack patient 2011;34(8):1848-53.
education. 5. International Diabetic Federation Atlas, 7th edition, South-
east regional data fact sheet, 2015.
HOW TO START INSULIN? 6. Larkin Mary E. Overcoming of psychological barriers to
Firstly, all patients should be well educated regarding insulin use in diabetes. US Endocrinology. 2008.pp.46-8.
their chronic condition, assessed for any complication 7. Lee P, Chang A, Blaum C, et al. Comparison of safety and
efficacy of long acting insulin glargine vs neutral protamine
and long term morbidity.
hagedorn insulin in older adult patients with type 2 diabetes
1. Newly diagnosed diabetes with HbA1c≥ 9% should be
mellitus: A pooled analysis. Journal American Geriatric
initiated on dual therapy, i.e. metformin with basal Society.2012;60(1):51-59.
insulin. 8. ORIGIN TRIAL investigators, Mellbin LG, Ryden L, Riddle MC,
2. In presence of cardiovascular complications basal et al. Does hypoglycemia increases the risk of cardiovascular
insulin should be preferred over oral agents. events? A definitive report from the ORIGIN trial. Eur Heart J.
3. Known diabetic patient on two or more oral agents 2013;34(40):3137-44.
with uncontrolled HbA1c. 9. Peyrot M, Burns KK, Davies M, Forbes A, Hermanns N,
Holt R, Kalra S, et al. Diabetes attitudes wishes and needs
Starting dose is usually 10U/day or 0.1–0.2 U/kg/day.
2(DAWN2): A multinational and multi-stakeholder study of
Titration of dose should be done twice weekly around
person centred care and psychosocial issues in diabetic
10–15% or 2–4 U to achieve target fasting blood glucose. patient. Diabetes Res Clinical Practical. 2013;99(2)174-84.
The patient should be advised to perform self blood 10. Plank J, Bodenlenz M, Sinner F,Magnes C, Gorzer E,
glucose monitoring. In case of hypoglycemia the cause Endahl LA, et al. Investigating the pharmacodynamics
should be addressed with a reduction of insulin by 4U and pharmacokinetic properties of the long-acting insulin
224 SECTION 3: Diabetes
analog i.e.detemir. A double-blind and randomized study. 13. Wangnoo SK, Maji D, Das AK, Rao PV, Moses A, Sethi B,
Diabetes Care. 2005;28(5):1107-12. et al. Barriers and solutions to diabetes management:
11. Porcellati F, Rossetti P, Busciantella NR,Marzotti S, Lucidi An Indian perspective. Indian Journal Endocrinology
P, Luzio S, Owens DR, et al. Comparisons of the long-acting Metabolism. 2013;17(4):594-601.
insulin analogs glargine vs detemirin type 1 diabetes in 14. Weng J, Li Y, Xu W, Shi L, Zhang Q, Zhu D, Hu Y et. al.Effect
pharmacokinetic and dynamics: Double-blind randomized of intensive insulin therapy on beta-cell function in newly
study. Diabetes Care. 2007;30(10):2447-52. diagnosed type 2 diabetes and effect on glycaemic control:
12. Ray KK, Seshasai SR, Sivakumaran R, Nethercott S, et. al. Randomised, multicentre parallel-group trial.Lancet.
A meta–analysis of RCT. Effects of intensive glucose control 2008;24;371(9626):1753-60.
on cardiovascular system outcomes and death in patient
with diabetes mellitus. Lancet. 2009;73(9677):1765-72.
CHAPTER
39
Diabetic Complications in
Indian Scenario: An Update
Sidhartha Das, Santosh Kumar Swain, Saroj Kumar Tripathy
zz Hearing loss
severe and with a higher complication rate than in with type 2 DM, particularly, those with the macrovascular
a nondiabetic. A diabetic subject may present as a disease was found in another recent study from New
case of myocardial infection (MI) or sudden cardiac Delhi. Persistent postprandial hypertriglyceridimia
death without any history of cardiac complaints. The may result in a proatherogenic environment leading to
CAD occurrence has a two to three decades earlier atherosclerosis (AS) and macrovascular disease (MVD)
presentation in diabetic patients as compared to their in T2 DM. 7
nondiabetic counterparts. Women diabetes patients are In the Chennai Urban Population Study (CPUS NO 5),
possibly more prone to develop CAD than men with the prevalence of CAD was 11% in the total population
diabetes.4 and the prevalence of CAD among diabetic subjects was
In Indians, the overall cardiovascular mortality is 21.4%, 14.9 % among impaired glucose tolerance (IGT)
predicted to have risen by 103% in men and 90% in and 9.1% among those with normal glucose tolerance
woman between 1985 and 2015. 1 A subject of great (NGT). The prevalence of CAD in Bikaner study was
concern is that 52% of the CAD death in India occurred in 25.8% and from North Delhi study was 7% in T2 DM
people aged below 70 years while the same was just 22% patients.8,9 A multicentric study conducted by Diabetes
in the developed countries.4 Another study from Eastern India (CINDI) had revealed that the prevalence of CAD
India in a tertiary care hospital revealed that the diabetics in newly diagnosed subjects with type 2 DM was 6%.10
with CAD had a higher prevalence of multivessel disease Incidence of cardiovascular disease among subjects with
along with more extensive involvement as compared to diabetes was 5–6 cases/1000 person years according to
nondiabetic cohort.5 an 11 year follow-up study from south India.11
The multifactorial pathogenesis of CAD in diabetes A North Delhi study regarding the prevalence of
is governed by various risk factors like traditional risk cardiovascular risk factor in the Type 2 DM without
factors viz. gender, increased total or LDL-c, decreased manifestation of overt CAD found that 28.9 % had silent
HDL-c, smoking and diabetes itself. Several novel CAD. This study observed, high LDL-c level and greater
risk factors proposed for CAD like apolipoproteins carotid intima–media thickness (CIMT) are particularly
A1 and B, microalbuminuria, plasminogen activator important parameters that can predict if a patient with
inhibitor–1 (PAI-1), prothrombin fragment 1 and 2, type 2 DM is at risk for silent ischemia.12
accelerated platelet activity and platelet aggregation, The prevalence of CAD amongst diabetics in India is
tissue plasminogen activator, fibrinogen, vascular and presented in Table 2.8-10
cellular adhesion molecules, lipoprotein (a) and insulin
resistance (IR). Cerebrovascular Disease
An urban South Indian study in patients of DM Diabetes is an independent risk factor for stroke. In
with CAD from India revealed a significant finding of patients with DM, there is recurrent stroke associated
increased platelet activation. Collagen induced GP IIb/ with higher mortality, with a female preponderance. The
IIIa binding was significantly higher among diabetic UKPDS study revealed 2.6% patients developed stroke on
subjects with CAD (p <0.05) and without CAD (P<0.05) a follow up of 7.9 years with the prevalence of recognized
and non diabetic subjects with CAD (P< 0.05) compared DM in patients with acute stroke approximating 8–20%
to nondiabetic subjects without CAD. Regression and unrecognized DM is estimated to the between 6 to
analysis showed collagen induced GP IIb/IIIa binding 42%.13 The prevalence of stroke is more than double in
to be significantly associated with CAD [odds ratio (OR) diabetic subjects compared to the general population.
: :1.029, P = 0.025] and diabetes (OR : 1.037, P = 0.007).6 The Indian studies conducted during 1970–80s revealed
A significant postprandial hypertriglyceridimia and incidence of stroke in diabetics varied from 0.5% to 9%.
significant delay in postprandial triglyceride clearance In 2011, our study from Cuttack showed the prevalence
following a standardized fat meal challenge in patients of DM was 38.75% among stroke patients. The same
228 SECTION 3: Diabetes
TABLE 2: Prevalence of CAD amongst diabetics in India8-10,67 TABLE 3: Intima media thickness (IMT) of common carotid artery
(CCA) distribution in relation to comorbidity among patients and
Author Year Place Prevalence
controls14
67
ICMR* 1985-90 Multicentric 8.1% Male
4.7% Female IMT in mm Cases Control p-value
V. Mohan (CUPS-5) 16
2001 Chennai 21.4 Overall mean IMT 0.88 ± 0.19 0.60 ± 0.09 (N 0.000
(Population- (N =80) = 40)
based) IMT in diabetes 0.90 ± 0.16 0.64 ± 0.11(N 0.013
Gupta PB 67
2001 Surat 19% (N = 31) = 14)
67
Gupta S 2001 Nagpur 33.5%-Male IMT in HTN 0.88 ± 0.16 0.65 ± 0.10 (N 0.006
21.5%-Female (N = 53) = 14)
PODIS** 61 2001 Multicentric 4.5% IMT in smokers 0.93 ± 0.20 0.63 ± 0.06 (N 0.000
67
Ramachandran et al 2002 Chennai 11.5% (N = 49) = 17)
Phatak S 55 2002 Ahmedabad 20.2%-Male IMT is a dependable marker of atherosclerosis.
26.1%-Female
J Ahmad et al 66 2007 Aligarh 37.7%
TABLE 4: Pulsatility Index (CCA) distribution in relation to co-
R Chawla 9 2012 New Delhi 7%
morbidities among patients and controls14
A Sosale et al 10 2014 Multicentric 6% (Newly
detected DM) PI in mm Pts. with ischemic stroke Control p-value
RP Agarwal et al 8
2014 Bikaner 25.8% Overall mean PI 1.71 ± 0.18 mm 1.53 ± 0.11 0.000
(N = 80) (N = 40)
*ICMR – Indian Council of Medical Research
PI in diabetes 1.76 ± 0.20 mm 1.49 ± 0.09 0.000
**PODIS – Prevalence of Diabetes in India Study
(N = 31) (N = 18)
PI in HTN 1.69 ± 0.18 mm 1.49 ± 0.09 0.000
study depicted the relationship of carotid plaque, (N = 53) (N = 18)
Intima Media Thickness (IMT), Resistivity index (RI), PI in smokers 1.82 ± 0.22 1.49 ± 0.09 0.000
Pulsatility index (PI) in Asian-Indian patients with (N = 49) (N =18)
acute ischemic stroke with and without type-2 DM.
Resistivity Index distribution in relation to co-morbidities among
These findings are elaborated in Tables 3 and 4.14 The patients and controls
mean CIMT of diabetic subjects was significantly higher
RI in mm Pts. with ischemic Control p-value
than nondiabetic counterparts as showed in the CUPS stroke
study. The prevalence of carotid atherosclerosis was Overall mean RI 0.76 ± 0.05 0.61 ± 0.06 0.000
20% in diabetic subjects as compared to 1% among (N = 80) (N = 40)
nondiabetics.15 In the same population, arterial stiffness RI in diabetes 0.76 ± 0.04 0.59 ± 0.06 0.000
was also greater and endothelial dysfunction was also (N = 31) (N = 18)
severe among diabetic subjects than non diabetic RI in HTN 0.76 ± 0.04 0.59 ± 0.06 0.000
counterparts in the CUPS Study.16 Another study from (N = 53) (N = 18)
South India Endocrine Centre documented 1.12% of RI in smokers 0.77 ± 0.04 0.59 ± 0.06 0.000
(N = 49) (N = 18)
diabetics had a diagnosis of cerebrovascular disease at
the time of presentation.17 Further, studies from India had
revealed that DM is a more common a cause for cerebral Peripheral Vascular Disease
infarction (22.1%) than cerebral haemorrhage (6.35%).18 D i ab e t e s p re s e nt i ng w i t h p e r i p h e ra l va s c u l a r
The data on stroke and CVD in India is inadequate. disease (PVD) is a major risk factor for lower limb
Incidence of DM amongst patients with CVD is amputation and also invariably associated symptomatic
presented in Table 5.19 cardiovascular disease and cerebrovascular disease.
CHAPTER 39: Diabetic Complications in Indian Scenario: An Update 229
TABLE 5: Incidence of DM amongst patients with cerebro- in type 2 diabetics in a study conducted in Bikaner
vascular disease (prior to the last decade of the past century)19 (Rajasthan) was 28% and North Delhi was 7.4%.8,9 The
Place/Country % most recent study from South India showed prevalence
Study from 11 Countries 2–28 rate 7.6% (Female 11.8%, Male 5.1%) and crude incidence
North Carolina, USA 13.9 17/1000 patient years with progression of PVD seen in
Michigan, USA 18.3 16.5% cases.23
Africa 4-8
Hong Kong 33.5 TYPE 2 DM AND METABOLIC SYNDROME
Das S, Cuttack 8.0 There is sparse data on the prevalence of metabolic
Mumbai 14.2 syndrome (MS) amongst Indian diabetic patients. Basing
Puducherry 32 on the NCEP ATP III guidelines a study conducted
Toole, Janway, Choi 28
on urban Indian diabetic population reported that
the prevalence of MS in 77.2% of patients which was
Even in patients with TIA or VBI, the incidence of DM was as high as 28
significantly higher in females (87.71%) as compared to
and 20% respectively.
males (19.33%) (p<0.0001). This study clearly depicts
It is an underdiagnosed and undertreated entity in that in the urban Indian diabetics MS is highly prevalent.
several countries including India. A fourfold increase So it should be identified by regular screening to avert or
in prevalence is seen in people with DM than in non- delay the progression to type 2 diabetes and its related
diabetics. PVD in T2 DM typically involves the arteries morbidity and mortality.24
below the knee such as anterior tibial, posterior tibial
and peroneal arteries showing arterial stenosis and MICROVASCULAR COMPLICATIONS
occlusion due to atherosclerotic changes in diabetic IN TYPE 2 DM
subjects. The increased prevalence of PVD in patients The microvascular complications of DM include
with diabetes is attributed to added risk factors like retinopathy, nephropathy and neuropathy. The
smoking, hypertension and hyperlipidemia. microvascular disease also can contribute to diabetic
An estimated 20% of symptomatic PVD patients had cardiomyopathy, exacerbation of limb ischemia
diabetes as revealed by the Framingham Heart Study. in diabetic foot. Hyperglycemia, hypertension and
The prevalence rate of PVD in Indian subjects is lower possibly lipid abnormalities provide a solid medium
than that in other ethnic groups. There is a striking for microangiopathy. Multiple pathogenic sequences
difference in the prevalence of CAD and PVD in India, may be triggered, viz advanced glycation end products
despite both being macrovascular disease. CAD occurs (AGE) formation, protein kinase C (PKC) activation
at a much younger age and at high rates while PVD and increased flux through the polyol (sorbitol) and
appears to show opposite trend, i.e. lower prevalence hexosamine pathways, all of which culminate in
and occurrence at older age groups. The different trend oxidative stress resulting in pathological vascular
of these two complications may be attributable to the remodeling, altered vascular tone, changes in the
differences in risk factors. basement membrane and permeability. The subsequent
In Asians, the prevalence of PVD ranges from 3% to 6%. pathogenic changes are peculiar to the concerned
The first population based study in South India (CUPS) target tissues. The mesangium shows an abnormal
reported that the prevalence of PVD was 6.3% among extracellular matrix (ECM) accumulation in diabetic
diabetics compared to 2.7% among nondiabetics.20 The nephropathy. Ischemia due to acellular capillaries
prevalence of PVD was 3.9% and 4% in another South coupled with neovascularization triggered by vascular
Indian clinic based study which included 18 patients endothelial growth factor (VEGF) results in diabetic
with gangrene.21, 22 The reported prevalence rate of PVD retinopathy (DR).25
230 SECTION 3: Diabetes
In New Delhi a recent study, done on the coagulation clinic-based studies to population-based studies. The
profile in diabetes and its possible association with population-based studies show that nearly 1 in every 5
diabetic microvascular complications revealed that diabetic individuals may have DR which is much lower
diabetic retinopathy was associated with decreased than that reported from west.
protein S and increas e d VWF levels. Diab etic The first population based study to document DR
nephropathy was associated with increased PAI-1 and in Indian population was the Chennai Urban Rural
VWF levels whereas diabetic neuropathy did not show Epidemiological Study (CURES), which revealed an
any significant relationship with any of the haemostatic overall prevalence 17.6% (among known diabetics 20.8%
variables. So, for the development of microvascular and 5.1% in newly detected diabetic subjects). Prevalence
complications of diabetes mellitus a hypercoagulable of DME in the total diabetic population was 5.0%. A 5
state as indicated by decreased fibrinolysis and increased year increase in duration of diabetes, increases the risk of
coagulability is responsible.26 DR by 1.89 times and for every 2% increase in HbA1c, the
It has been reported that some associations have also risk of DR increases by factor of 1.75 times was revealed
been noted between different diabetic microvascular by this study.27 A familial aggregation study documented
complications. The presence of diabetic retinopathy that familial clustering of DR was three times higher in
itself may reveal that the patients are at risk of diabetic siblings of type 2 diabetic subjects with DR compared
neuropathy and nephropathy. The CURE study identified to those without DR.29 A study carried out in rural Tamil
some common risk factors like age, glycosylated Nadu, The Chunampet Rural Diabetes Prevention Project
hemoglobin, duration of diabetes and serum triglycerides study (CRDPP Study) showed that the prevalence of DR
for these microvascular complications. The association also increases significantly with duration of diabetes. The
between retinopathy and nephropathy was stronger than prevalence of DR was seen in 6.6% even among diabetic
the association with neuropathy was also proved in the subjects with less than one year duration. According to a
CURE study.27 South India study conducted recently on prevalence and
risk factors for DR in Asian Indians with younger age of
DIABETIC RETINOPATHY onset revealed prevalence of DR in 52.7% in type 2 DM
A p o te nt ia l ly sight threaten i ng m i crova s cu la r patients. The age and gender adjusted prevalence of DR,
complication of diabetes is DR and is also an important DME, PDR in type 2 DM were 65.8%, 12.7% and 9.3%
preventable cause of blindness. DR is one of the respectively.28
hallmark of the disorder and considered as most specific The overall prevalence of DR in different parts of
complication of diabetes. Nonproliferative DR (NPDR) India as per different studies are presented in Tables 6
and proliferative DR (PDR) are the two major forms of and 7.8-10,30
opthalmological complications in T2 DM. The forms
which can lead to blindness are PDR and diabetic DIABETIC NEUROPATHY AND
macular edema (DME). The risk of DR is strongly DIABETIC FOOT
influenced by disease duration, glycemic status and Nearly 50% of all diabetic subjects are affected by diabetic
blood pressure control. The younger age of onset neuropathy (DN) and is considered to be the main cause
especially for type 2 DM may be an added risk for DR. A for morbidity. The severity and duration of hyperglycemia
patient with history of more than 15 years DM is affected governs the intensity and extent of diabetic neuropathy.
by DR in 60% and with a history of more than 25 years of Both type 1 and type 2 diabetes have an equal frequency
diabetes is affected to the tune of 90%.28 of affection. The prevalence of neuropathy varies from
In western population the prevalence of DR at 19% to 33% (clinic based studies) and 13–31% (population
diagnosis varies from 20% to 50% as compared to based studies).30 In an observational study at a tertiary care
5–7.3% in Indians. In India the prevalence varies from centre from Cuttack the clinical diabetic neuropathy were
CHAPTER 39: Diabetic Complications in Indian Scenario: An Update 231
TABLE 6: Prevalence of diabetic retinopathy in India (Clinic Based TABLE 8: Prevalence of Diabetic Neuropathy in India8-10,30
Studies)8-10,30
Author Year Type of City Prevalence
Author/Year Type of Study Place Prevalence (References) Study (%)
(References) (%) Ramachandran 1999 Clinic-based Chennai 27.5
Rema et al. 1996 63 Clinic-based Chennai 34.1 et al. 55
Ramachandran Clinic-based Chennai 23.7 Ashok et al. 56 2002 Clinic-based Chennai 19.1
et al. 1999 55 Chanda et al. 57 2006 Clinic-based Bengaluru 64.1
Pradeepa et al. Clinic-based South India 37.9 Pradeepa et al. 34
2011 Clinic-based Chennai 33.1
201134 9
Chawla et al. 2012 Clinic-based North Delhi 15.3
Chawla et al. 2012 9 Clinic-based North Delhi 21.2
Sosale et al. 10 2014 Clinic-based Multicentric 13.15 (Newly
Agarwal et al. 2014 62 Clinic-based Bikaner 32.5 detected DM)
Sosale et al. 2014 10 Clinic-based 14 centres 6.1 (Newly Agarwal RP 2014 Clinic-based Bikaner 26.8
detected DM) et al. 8
Pradeepa 2008 Population Chennai 13.1
TABLE 7: Prevalence of Diabetic Retinopathy in India (Population et al. 34 (CURES 55)
Based Studies)8-10,30 Vaz et al. 58 2011 Population Goa (Rural) 60
54
Author/Year Type of Place Prevalence Mohan et al. 2012 Population Chunampet 30.9
(References) Study (%) (CRDPP) (Tamil
Nadu)
Dandona et al. Population Hyderabad 22.4
199959
Though vasculopathy, infections and peripheral
Narendran et al. Population Palakkad 26.8
200260
neuropathy are traditionally blamed for diabetic foot
Rema et al. (CURES), Population Chennai 17.6
(DF), the common cause of diabetic foot problem in
200527 India is peripheral neuropathy. In India, 24% of hospital
Raman et al. 200964 Population Chennai 18 admission and 35% of total hospital days are due to
Vaz et al. 201158 Population Goa (Rural) 15.4 foot problems. Diabetic foot ulcers are common and
Mohan et al. 2012 Population Chunampet 18.2 estimated to affect 15% of all diabetic individuals during
(CRDPP)54 their lifetime. Diabetic foot ulcer precedes almost 85%
of amputations. According to a multicentric study from
in the following order of frequency: distal symmetrical India studying on pattern and cause of amputation
sensorimotor neuropathy, cranial mononeuropathy, in diabetic patients infection in 90% of cases results
mononeuropathy multiplex and autonomic neuropathy.31 in amputation in diabetic patients. The prevalence of
In the low body weight groups of type 2 DM the incidence neuropathy was 82% (high) and 35% had PVD in this
of peripheral neuropathy was common.32 study.35 The prevalence of neuropathy was 15% (n = 193)
A North-East Indian study on young diabetic patients and PVD was 3% (n = 64) in another multicentric study
documented peripheral neuropathy to be common in India. Infections were present in 7.6% (n = 100) of
(43.5%) in patients with fibrocalculous pancreatic patients. In the different centers of India, the infection
disease (FCPD).33 The CURES population based study rate varied from 6% to 11% in DF. Studies have revealed
reported the age-standardized prevalence of neuropathy that a minor or major amputation has to be performed in
to be 13.1% (Known diabetic (KD): 13.6% vs. 11.2% 3% of the patients.36
in Newly Detected DM (NDD), whereas the crude
prevalence rate was 26.1% (KD: 27.8%, NDD 19.5%).34 Diabetic Nephropathy
The prevalence rate of diabetic neuropathy in different The chronic kidney disease (CKD) which often goes
studies is presented in Table 8.8-10,30 unrecognized most of the times are closely related to
232 SECTION 3: Diabetes
hypertension and DM. An epidemiological study by risk for development of ESRD which suggest a genetic
Indian CKD Registry established under the aegis of component apart from environmental and host factors.
Indian Society of Nephrology (ISN) had made certain In our own study from Cuttack there was a
pertinent observations. CKD Registry has documented greater degree of IR and beta-cell dysfunction and
DM as the cause of CKD in 31.2% of patients. CKD also atherosclerosis in diabetics than non-diabetic CKD
leads to CVD as disease progress: in 0.7% in Stage 1 patients. 38 Another study from our institute revealed that
CKD to 48.5% in stageV CKD.37 The SEEK (Screening and proteinuria is common and more related to glycemic
Early Evaluation of kidney disease) study reported a high status. Improvement in proteinuria can be achieved
prevalence of CKD 17.4% (Urban 25.5 versus Rural 9.4%). with strict glycemic control. Microalbuminuria in type-
The main causes of CKD were DM and hypertension.38 2 DM was found to be a marker of generalized vascular
Nephropathy developed in 20.4% of subjects with type 2 endothelial dysfunction.38
DM over years. According to a recent study from Jhansi,
incidence of nephropathy in newly diagnosed type 2 DM OTHER COMPLICATIONS IN TYPE-2 DM
was 17.34% (52/300) and the most important associated There are several other complications which also occur
factor contributing to development of nephropathy was in long-standing type 2 DM patients besides the micro-
hypertension.39 and macrovascular complications. The spectrum of
The prevalence of nephropathy according to different chronic complications of DM are illustrated in Figure 2.
studies are: CURE study (microalbuminuria 26.9%, overt
proteinuria 2.2%), CRDPP study in Tamil Nadu 24.3%, Noncoronary Cardiac Complications
30.2% in Bikaner study (Rajasthan), microalbuminuria Diabetic cardiomyopathy and heart failure (HF),
in 41% patients in North Delhi study. 8,9,40 Various cardiovascular autonomic neuropathy (CAN) and
population-based studies has also observed familial sudden cardiac death (SCD) can occur in addition
clustering of nephropathy. In individuals with a family to CAD. Cardiomyopathy is seen in one third of the
history of ESRD, there was three to nine fold greater diabetic patients. Diastolic dysfunction usually precedes
systolic dysfunction. Early degenerative changes in and mortality in DM. Diabetes is an independent risk
the conducting system give rise to heart blocks. DM factor for tuberculosis (TB) and there is a three-fold
is an independent risk factor for Congestive Cardiac higher risk of developing TB. Worldwide data suggests
Failure (CCF) in the elderly and every 1% increase in the that diabetes is found in 15% of all tuberculosis and 21%
HbA1c increases the risk of CCF by 15%. Prevalence of of smear positive TB. 46 The prevalence of TB among
DM in people with CCF is estimated to be around 20% diabetic populations in India according to different
compared to 4–6% in control population. Poor glycemic studies are 14% (Bhutia 1975), 4.5% (Bhalkar 1975), 12%
control and longer duration of diabetes increases the risk (Nanda & Tripathy, 1968), 14% (Deshmukh et al, 1966),
of HF in diabetic subjects. In 50–70% of long-standing 5.9% (Patel JC, 1989), etc. A study revealed that in urban
diabetic subjects, there is coexistence of CAN in Indian areas increased prevalence of DM is associated with
studies.41 15.2% greater Smear-positive TB incidence compared
to rural areas. The study predicted that in India 18.4%
Hypertension (12.5–29.9%) of people with pulmonary TB (both smear-
Globally in 40–60% of patients with type 2 DM, positive and smear-negative) have diabetes and that in
hypertension coexists. The prevalence of hypertension the smear-positive group diabetes prevalence is 23.5%
in newly detected type 2 DM was 39% in the HDS- (12–44%).47 Another study revealed that 36% of cases
1 (Hypertension in Diabetes Study) report. Indian suffer from multidrug resistant TB (MDR-TB) amongst
studies showed that about half of the diabetic patients diabetics compared to 10% in nondiabetics (p<0.01) and
have coexisting hypertension. Recently, the cross- out of these 36% of MDR TB patients 23% never received
sectional study, Screening Indians Twin Epidemic (SITE) antitubercular drugs. Death from active TB accounted
conducted in 10 Indian states reported that DM and for 14% in the diabetic group and 1% of nondiabetic
hypertension coexist in 20.6% of patients.42 group. The incidence of extrapulmonary TB was 20%
in diabetic compared to 5% in the nondiabetic group.48
Chronic Liver Disease In a south Indian study conducted recently on diabetes
The etiology of chronic liver disease with and without prevalence among a cohort of TB cases registered under
DM studied by Amarpurkar et al. (2002) from India RNTCP revealed DM prevalence was 25.3% (95% CI 22.6
compared and found higher evidence of nonalcoholic – 28.5) and that of prediabetes was 24.5% (95% CI 20.4-
steatohepatitis (NASH), NASH with cirrhosis of liver 27.6).49 The most common infection seen in diabetes is
and cryptogenic cirrhosis in diabetic subjects than non urinary tract infection (UTI) and is also a common cause
diabetic counterparts. 43 In our study constituting 42 of hospital admission. Symptomatic UTI was reported
patients of NASH, it was observed that the development of to be 14% in mostly menopausal diabetic women in an
NASH was a decade earlier than the western population Indian series.50 In another study, the prevalence of UTI
was likely due to the early onset of Type 2 DM in our was found to be 9%. In a study from north India, mortality
population. About 19 (45.2%) out of 42 patients had related to UTI in diabetic patients was 2.4%.51 Klebsiella
DM 45 , which was very high as compared to study was the most common organism isolated in another
conducted prior by Bacon et al. and Amarpurkar, where Indian study in 11.6% of diabetic patients presenting
the incidence of DM was 21% and 22% respectively.43,44 with pneumonia.50 Mortality due to bronchopneumonia
IR and dyslipidemia rather than the glycemic status were in diabetes was 17.4% in an Indian study. The detail
determinant factors that had positive correlation with infections caused in a diabetic are represented in
the higher histopathological grades of NASH.45 Table 9.52
Infections CONCLUSION
There is an increased susceptibility for various acute In the post-insulin era due to decline of acute
and chronic infections leading to increased morbidity complications and infections in diabetes, the chronic
234 SECTION 3: Diabetes
TABLE 9: Infections in DM52 2. Powers AC. Harrison’s Principles of Internal Medicine, 19th
edn, 2015. pp. 2400-04.
Infections Risk (Proven association)
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Acute papillary necrosis 57 %
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Mucormycosis 42 %
6. Deepa R, Mohan V, Premanand C, Rajan VS, Karkuzhali K,
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CHAPTER
40
GLP-1 Analogs: Benefits
Beyond Glycemic Control
Rajeev Chawla, Shalini Jaggi
(albiglutide), or Fc fusion protein with immunoglobulin both as monotherapy and in combination with agents
G (dulaglutide), which increase their size and alters their such as metformin, sulfonylurea, and thiazolidinediones.
pharmacokinetic properties, efficacy as well as safety. It undergoes mainly renal elimination and does not seem
The prolonged half-life facilitates continuous stimulation to be significantly degraded in circulation. Exenatide
of the GLP-1 receptor and reduces fluctuations in peptide plasma concentrations increase in a dose-dependent
levels.14 Generallyliraglutide has demonstrable greater manner following subcutaneous injection.
efficacy than exenatide. On an average, liraglutide When used in above doses, exenatide monotherapy
reduces HbA1c by around 4 mmol/mol (0.33%) and leads to significant reduction in HbA1C. Significant
FPG about 1 mmol/L greater than exenatide.2,15-17 The reductions in HbA1C have been observed as monotherapy
other longer acting once-weekly formulations have as well as combination therapy of exenatide to a pre-
shown less potent reductions in HbA1c in comparison existing regimen of metformin, sulfonylurea, or both.
toliraglutide.2,16,18 Exenatide has demonstrated significant reduction in
HbA1C when used in combination with insulin glargine.
Liraglutide
Liraglutide is administered in daily doses of 1.2 or Extended Release Exenatide
1.8 mg subcutaneously. Its efficacy has been established The extended release formulation is prepared by
in the in LEAD (Liraglutide Effect and Action in Diabetes) incorporating the drug as extended-release microsphere
studies with more than 4400 patients. Liraglutide was formulation with D, L-lactide-co-glycolide polymer and
well tolerated, efficacious with average HbA1c reduction
sucrose in equal proportions. It is injected in doses of
of 1.5% and had a favorable weight profile with much
2 mg subcutaneously once a week irrespective of meals.
less hypoglycemia. Weight loss of about 2–4 kg were seen
The extended release preparation demonstrated a better
along with and slight improvements in systolic blood
improvement in glycemic control, similar reduction
pressure and β-cell function. Liraglutideis recommended
in body weight, and almost no increase in risk of
as monotherapy and in combination with glimepiride
hypoglycemia compared to the twice daily administered
and metformin.
exenatide preparation. The most common adverse
Liraglutide used alone or in combination therapy
event is mild-to-moderate nausea which generally
caused hypoglycemia in about 3–12% of the patients.
occurs at initiation of therapy and subsides eventually.
Most of these episodes were minor requiring no
There is no increase in hypoglycemia even when
assistance. However, the rate of hypoglycemia increased
taken with metformin due to the glucose-dependent
to 5–27% when it was combined with sulphonylureas.
Nausea occurred at initiation of liraglutide in 5–40% actions of exenatide. However, risk of hypoglycemia
patients but it gradually subsided within the first 4 weeks is slightly increased when used with a sulfonylurea.
of therapy. Although antibodies to liraglutide have been Rare occurrence of pancreatitis has been reported with
seen in few patients but there is no effect on its efficacy. exenatide use.
Exenatide Dulaglutide
Exenatide,a synthetic exendin-based GLP-1 analog has (Once Weekly; Sustained Release)
a 53% homology to native human GLP-1. It increases Dulaglutide is a long-acting GLP-1 analog that offers
glucose-stimulated insulin secretion, suppresses elevated convenient once weekly dosing. It demonstrated an
postprandial glucagon levels characteristic of T2DM, and HbA1c reduction of about 1.28–1.52% and weight loss of
slows gastric emptying. It is given subcutaneously in 1.40–2.51 kg in a randomized placebo-controlled double-
doses of 5–10 µg twice daily, within 60 minutes before blinded study involving 262 obese type 2 diabetics. The
meals and should not be taken after meals. It can be used commonly reported adverse events included upper
CHAPTER 40: GLP-1 Analogs: Benefits Beyond Glycemic Control 241
resonance imaging in rats have demonstrated that healthy low risk BMI of 18.5–24.9 kg/m2.31 A dramatic
these anorexigenic effects of GLP-1 may be regulated improvement in T2DM and related comorbidities is
by the paraventricular and arcuate nucleus area of documented with a weight loss of 5–10% from baseline.32
the hypothalamus and the brain stem. 30 Presence The global pandemic of obesity and its comorbidities
of GLP-1 receptors in several regions of the brain, poses a significant economic burden besides hampering
predominantly the hypothalamus and brain stem, the quality of life. The expenditure on overweight and
which are the core regulators of food intake and satiety, obesity is projected to comprise 16–18% of total health
has been demonstrated. GLP-1 crosses the blood brain care expenses in the US by 2030.33 Most obesity treatment
barrier to activate these receptors and inhibits food guidelines recommend pharmacotherapy in adults
intake by promoting satiety resulting in weight loss. with BMI of 30 kg/m 2 or higher or adults with a BMI
GLP-1 RAs also interact with the heart and blood of 27 kg/m2 or higher with at least one weight-related
vessels independent of their glycemic action, and may comorbid condition (hypertension, dyslipidemia, insulin
contribute to cardioprotection through various direct resistance, type 2 diabetes mellitus).34 Though bariatric
and indirect mechanisms. Preclinical studies with surgery has been recommended as a viable treatment
natural GLP-1 as well as GLP-1 RAs (liraglutide and option for morbid obesity, the search is ongoing forless
exenatide) showed their cardioprotective effects, while invasive options.33 Inspite of tremendous efforts, the
various clinical trials have documented their beneficial development of effective pharmacotherapeutic agents
effects in hypertension and dyslipidemia in patients for obesity has not been very promising35 though a few
with type 2 diabetes.29 Preclinical studies with liraglutide weight-management agents are currently available.32
showed reduced infarct size and improved survival post- The focus has now shifted to using GLP-1RAs as potential
myocardial infarction in rats as well as improved cardiac antiobesity agents. 33 The longer-acting GLP-1 RAs
function in mice fed on high-fat diet.29 Exenatide, when including exendin-4 derivatives and liraglutide, that
administered 1 hour after oral fat load, showed reduced are resistant to degradation by DPP-IV enzyme, may be
secretion of TAG and ApoB, suggesting that its effect promising anti-obesity agents.35 Remarkable weight loss
on postprandial lipid metabolism was independent of seen with liraglutide therapy prompted using a higher
delayed gastric emptying. These findings suggest a key dose formulation specifically for its anti-obesity use,
role of GLP-1 in control of chylomicron secretion which with Liraglutide 3 mg/day (trade name Saxenda) being
is unrelated to gastric emptying.29 approved by the US Food and Drug Administration for use
Hence the pleiotropic benefitsof GLP1 RAs may be as an anti-obesity drug for adults.33,34 Significant weight
seen in the cardiovascular system; on lipid metabolism; loss was demonstrated in overweight and obese patients
in neurological disorders; on blood pressure (especially with T2DM with subcutaneous liraglutide 3.0 mg daily
systolic) and on body weight. It is also important here over 56 weeks compared to placebo.32 Though bariatric
to point out that because of their widespread actions, surgery has proven clinical superiority than liraglutide
there is also a possibility of some non-beneficial adverse for both weight loss and improvement in metabolic
effects, such as those in the gastrointestinal system or an parameters, many individuals where surgery may not
increased heart rate with this class of agents. be preferred may rather benefit from with liraglutide.
Additional research is warranted for its potential use in
WEIGHT LOSS ASSOCIATED WITH THE combination with other weight loss treatments to further
USE OF GLP-1 RECEPTOR AGONISTS potentiate as well as sustain weight loss.33 Liraglutide
The risk of developing diabetes is directly associated with in clinical use demonstrated delayed gastric emptying
increase in body weight, being three timesat a body mass that may partially contribute to reduction in meal
index of 25.0–29.9kg/m 2, and increasing dramatically intake seen with this drug.26 A potential mechanism for
to 20-fold at a BMI of 35 kg/m2 and higher vis-a-vis a weight reduction may be through its effect on energy
CHAPTER 40: GLP-1 Analogs: Benefits Beyond Glycemic Control 243
expenditure primarily proposed to be due to GLP-1 not documented owing to potential species-specific
action on peripheral (vagal) and central pathways differences in GLP-1 receptor expression in thyroid
influencing food intake and metabolism byactivation of tissue.
hindbrain, hypothalamic nuclei as well as certain brain
Renal effects: There is limited data on GLP-1RA use
areas associated with motivation and reward processes33
in chronic kidney disease (CKD) patients. Exenatide
noninvasive pharmacological treatment
undergoes renal elimination and hence should be
avoided.44 Though liraglutide has no renal excretion,
SIDE EFFECTS AND ASSOCIATED RISKS
it should be used with caution till more safety data
OF GLP-1 RECEPTOR AGONISTS emerges.45 Similarly, data on lixisenatide, long-acting
Gastrointestinal effects: The most commonly associated exenatide and other once-weekly drugs are still very
side effects with GLP-1RAs are gastrointestinal such limited.40,45
as nausea, vomiting and diarrhea, attributable to their
mechanism of action. In extreme cases patients may Hypoglycemia: Hypoglycemia is not a major concern
discontinue treatment in distress. 36 GI disturbances with GLP-1 agonists per se. It only occurs generally
were seen in 10–42% of patients, with different doses when used in combination with insulin or sulfonyl ureas
used in different trials. Increased incidence was seen especially when their doses are not readjusted when
in high-dose regimens, though they tend to remit with starting a new agent.46,47 Therefore, it is recommended
time.37 These can be reduced by starting with lower doses to down-titrate the dose of these hypoglycemic therapies
initially and gradual uptitration of dose over the next few when adding a GLP-1 RA.47
weeks of treatment as tolerability improves with time.
CONCLUSION
Acute pancreatitis: GLP-1 RAs in diabetic patients have
The wide spread presence of GLP-1 receptors in the
been associated with a slightly increased risk of acute
body accounts for numerous favorable effects of these
pancreatitis38 with few cases reported in animals as well
novel incretin-based therapies on various organs as well
as humans treated with this class of drugs. So far, cases
as metabolic mechanisms apart from glycemic control.
have been reported with both exenatide and liraglutide
GLP-1 receptor agonists not only enhance endogenous
and none with lixisenatide as yet.39 Studies show an
insulin secretion and inhibit glucagon secretion in
average incidence of 1.6 cases of acute pancreatitis
response to meal ingestion but also suppress appetite
per 1000 patients/years of exposure with liraglutide.40
and food intake. Besides, they help in weight loss with
Current guidelines recommend use of GLP-1 RAs with
beneficial effects on metabolic regulation. These extra-
extreme caution in patients with history of pancreatic
glycemic benefits extend to the cardiovascular system,
pathology and suspending therapy if acute pancreatitis
lipid metabolism, neurological disorders, systolic
presents during drug use. All patients on these agents
blood pressure and body weight. GLP-1 receptors are
should be informed of this risk,which essentially seems
also found in the central nervous system, mainly in the
to be a class effect.41
nucleus tractus solitarius (NTS) in the caudal brainstem.
Medullary thyroid carcinoma: GLP-1 receptor expression GLP-1 expressing neurons in the NTS send projections
has been validated in thyroid tissue, especially the C to varied brain regions mainly in the hypothalamus
cells. 38,42 Preclinical animal studies with liraglutide and regulate feeding behavior and energy homeostasis.
showed an increase in C cell hyperplasia frequency Thus, GLP-1 receptor antagonists manifest wide spread
and thyroid cancer in mice and rats.43 GLP-1 receptor metabolic effects extending far beyond glycemic control,
stimulation induces calcitonin release in rodents but emerging as novel and preferred agents in current
the involvement of GLP-1 RAs in increasing incidence diabetes management algorithms. With new data
of medullary thyroid carcinoma in humans is yet pouring in on their further benefits on metabolism these
244 SECTION 3: Diabetes
are potential promising agents to be watched out for over Isolated Perfused Pancreas Study [Abstract]. Diabetologia.
the next few years with fast emerging extra-glycemic 2006;49:400-1.
11. Bush MA, Matthews JE, De Boever EH, Dobbins RL, Hodge
benefits and safety beyond glycemic control.
RJ, Walker SE, Holland MC, Gutierrez M, Stewart MW. Safety,
Tolerability, Pharmacodynamics and Pharmacokinetics of
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the American Diabetes Association and the European with Type 2 Diabetes Inadequately Controlled on Oral Drugs
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Herling AW. The GLP-1 Receptor Agonist AVE0010 Preserves 19. Seewoodhary J. Novel GLP-1 Mimetics in Diabetes:
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Pharmacodynamics of LY2189265, a Novel, Long-Acting Cardiovascular Risks Associated with Type 2 Diabetes.
Glucagon-Like Peptide-1 Analogue, in Patients with Type 2 Diabetes Research and Clinical Practice. 2013;100:1-10.
Diabetes. Diabetes, Obesity and Metabolism. 2011;13:426- 31. Deacon CF, Hughes TE, Holst JJ. Dipeptidyl Peptidase
33. IV Inhibition Potentiates the Insulinotropic Effect of
21. Thorkildsen C, Neve S, Larsen BD, Meier E, Petersen JS. Glucagon-Like Peptide 1 in the Anesthetized pig. Diabetes.
Glucagon-Like Peptide 1 Receptor Agonist ZP10A Increases 1998;47:764-9.
Insulin mRNA Expression and Prevents Diabetic Progression 32. Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A,
in db/db Mice. Journal of Pharmacology and Experimental Skjoth TV, Andreasen AH, Jensen CB, De Fronzo RA. Efficacy
Therapeutics. 2003;307:490-6. of Liraglutide for Weight Loss among Patients with Type 2
22. Werner U, Haschke G, Herling AW, Kramer W. Pharmacological Diabetes: The SCALE Diabetes Randomized Clinical Trial.
Profile of Lixisenatide: A New GLP-1 Receptor Agonist for JAMA. 2015;314:687-99.
the Treatment of Type 2 Diabetes. Regulatory Peptides. 33. Ladenheim EE. Liraglutide and Obesity: A Review of the
2010;164:58-64. Data So Far. Drug Design, Development and Therapy.
23. Bloom M, Bock J, Duttaroy A, Grzegorzewski K, Moore P, 2015;9:1867-75.
Ou YC, Wojcik S, Zhou X, Bell AC. Albugon Fusion Protein: A 34. Nuffer WA, Trujillo JM. Liraglutide: A New Option for the
Long-Acting Analog of GLP-1 That Provides Lasting Antidiabetic Treatment of Obesity. Pharmacotherapy. 2015;35:926-34.
Effect in Animals (Abstract). Diabetes. 2003;52:A112. 35. Kanoski SE, Rupprecht LE, Fortin SM, Jonghe BC, Hayes
24. Ou YC, Bloom M, Grzegorzewski KJ, Bock J, Duttaroy A, MR. The Role of Nausea in Food Intake and Body Weight
Moore P, Wojcik S, Zhou JX, Sung C, Bell AC. Pharmacokinetic Suppression by Peripheral GLP-1 Receptor Agonists,
and Pharmacodynamic Analysis of Albugon, a Long-Acting E xe n d i n - 4 a n d L i r a g l u t i d e . N e u ro p h a r m a c o l o g y.
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(Abstract). AAPS PharmSci. 2003;5:5263. 36. Tella SH, Rendell MS. Glucagon-Like Polypeptide Agonists
25. Rosenstock J, Reusch J, Bush M, Yang F, Stewart M. in Type 2 Diabetes Mellitus: Efficacy and Tolerability, a
Potential of Albiglutide, a Long-Acting GLP-1 Receptor Balance. Therapeutic Advances in Endocrinology and
Agonist, in Type 2 Diabetes: A Randomized Controlled Trial Metabolism. 2015;6:109-34.
Exploring Weekly, Biweekly, and Monthly Dosing. Diabetes 37. Sun F, Chai S, Yu K, Quan X, Yang Z, Wu S, Zhang Y, Ji L,
Care. 2009;32:1880-6. Wang J, Shi L. Gastrointestinal Adverse Events of Glucagon-
26. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Like Peptide-1 Receptor Agonists in Patients with Type 2
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of Clinical Endocrinologists’ Comprehensive Diabetes Diabetes Technology & Therapeutics. 2015;17:35-42.
Management Algorithm 2013 Consensus Statement— 38. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC.
Executive Summary. Endocrine Practice. 2013;19:536-57. Pancreatitis, Pancreatic, and Thyroid Cancer with Glucagon-
27. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini, Like Peptide-1-Based Therapies. Gastroenterology.
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Type 2 Diabetes: A Patient-Centered Approach. Position 39. Pappachan JM. Incretin-Based Therapies and Pancreatitis
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the European Association for the Study of Diabetes (EASD). 40. Scheen AJ. Pharmacokinetics and Clinical Use of Incretin-
Diabetologia. 2012;55:1577-96. Based Therapies in Patients with Chronic Kidney Disease
28. Zoungas S, Chalmers J, Ninomiya T, Li Q, Cooper ME, and Type 2 Diabetes. Clinical Pharmacokinetics. 2015;54:1-
Colagiuri S, et al. ADVANCE Collaborative Group. Association 21
of HbA1c Levels with Vascular Complications and Death 41. AACE 2015 Guidelines Type 2 Diabetes.
in Patients with Type 2 Diabetes: Evidence of Glycaemic 42. Gier B, Butler PC, Lai CK, Kirakossian D, DeNicola MM, Yeh
Thresholds. Diabetologia. 2012;55:636-43. MW. Glucagon Like Peptide-1 Receptor Expression in the
29. Seufert J, Gallwitz, B. The Extra Pancreatic Effects of Human Thyroid Gland. The Journal of Clinical Endocrinology
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246 SECTION 3: Diabetes
Cell Function after 3 Years in Metformin-Treated Patients 46. Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin
with Type 2 Diabetes. Diabetes Care. 2011;34;2041-7. P, Hale PM, Zdravkovic M, Blonde L. The LEAD-4 Study
44. Brunton S. GLP-1 Receptor Agonists vs. DPP-4 Inhibitors Investigators. Efficacy and Safety of the Human Glucagon-Like
for Type 2 Diabetes:Is One Approach More Successful or Peptide-1 Analog Liraglutide in Combination with Metformin
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Receptor Agonists Activate Rodent Thyroid C-Cells Causing Exenatide to a Thiazolidinedione in Suboptimally Controlled
Calcitonin Release and C-Cell Proliferation. Endocrinology. Type 2 Diabetes: A Randomized Trial. Annals of Internal
2010;151:1473-86. Medicine. 2007;146:477-85.
CHAPTER
41
Gliptins versus Sulfonylureas:
Which is Better?
V Palaniappen
Estimated number of people with diabetes worldwide A1c Goals for Glycemic Control
in 2015 was 415 millions, in 2040 it will be 642 millions. A1c ≤ 6.5%: For patients without concurrent serious
In South East Asia in 2015 Diabetes incidence was 78.3 illness and at low hypoglycemic control
millions, in 2040 it will be 140.2 millions. A1c > 6.5%: For patient with concurrent serious
A B
Figs 1A and B: The incretin effect. (A) Healthy controls; (B) Type 2 diabetes
Source: Adapted from Nauck M, et al. Diabetologia. 1986;29:46-52.
248 SECTION 3: Diabetes
i. Exenatide —— Vildagliptin
Fig. 4: Can DPP4 inhibitor prevent hypoglycemia? Fig. 5: DPP4-i: Consistently lesser hypoglycemia than SU
Source: Christensen MB, et al. J Clin Endocrinol Metabl. 2014;99(3):E418-26.
TABLE 1: Low free drug concentration and high selectivity favours avoidance of off target effects
Sitagliptin Vildagliptin Saxagliptin Linagliptin
IC50 for DPP4 19 62 50 1
DPP4 vs DPP8 >2600 < 100 < 100 40,000
DPP4 vs DPP9 >5550 < 100 < 100 > 10,000
DPP4 vs DPP2 >5550 >100,000 >50,000 >100,000
Highest selectivity for DPP4 vs DPP2/8/9
1. Trials listed in US prescribing information, except for vildagliptin, for which data from EU summary of product characteristics is shown.
2. 18 weeks’ treatment duration.
3. 24 weeks’ treatment duration.
4. Between group difference vs placebo.
2 year efficacy and safety of linagliptin compared with Linagliptin was associated with significantly fewer
glimipiride in patients with type 2 diabetes (Fig. 9): cardiovascular events (12 vs 26 patients; relative risk
Reductions in adjusted mean HbA
1c (baseline 7·69% 0·46, p=0·0213).
[SE 0·03] in both groups) were similar in the linagliptin
(−0·16% [SE 0·03]) and glimepiride groups (−0·36%
Conclusion
[0·03]); meeting the predefined non-inferiority
criterion of 0·35%. When metformin and lifestyle interventions fail
Fewer hypoglycemia (58 [7%] of 776 vs 280 [36%] to achieve glycemic control in a patient with type
p<0·0001) or severe hypoglycemia (1 [<1%] vs 12 [2%]) 2 diabetes, the optimum choice for an additional
with linagliptin compared with glimepiride. pharmacotherapy is unclear.
CHAPTER 41: Gliptins versus Sulfonylureas: Which is Better? 251
Fig. 9: Odds ratio of hypoglycemic events-safety margin Fig. 10: Liver disorder
Source: Adapted from Craddy P, Palin HJ, Johnson KI. Comparative
effectiveness of dipeptidylpeptidase-4 inhibitors in typ2 diabetes:
a systemic reviw and mixed treatment comparison. Diabetes Ther.
2014;5(1):1-41.
Fig. 14: Kidney disease end points in a pooled analysis of individual patient-level data from a large clinical trials program of dipeptidyl
peptidase 4 inhibitor linagliptin in type 2 diabetes
Source: Cooper ME, et al. Am J Kidney Dis. 2015
CHAPTER 41: Gliptins versus Sulfonylureas: Which is Better? 253
Fig. 15: Linagliptin had greater adherence to therapy compared to Fig. 16: Cardiovascular safety in gliptins
other diabetes medications
Source: Patorno E et al. Poster# 1707-P – Presented at the American
Diabetes Association 75th Scientific Sessions , Boston, MA, June 7,
2015
Methods
Pooled analysis of 19 trials (9459 subjects) of
linagliptin versus placebo/active treatment
Primary end point: composite of prospectively
comparator (glimepiride/voglibose/placebo)
To conclude DPP4i is the better choice on comparing
with SU in varies aspects & studies as discussed above.
For better glycemic target achievement which is better *Hypoglycemia: fingerstick blood glucose measurement £50 mg/dL
(2.75 mmol/L)
oral antihyperglycemic therapy (AHT)? Sulfonylurea is 1. Glucovance [package insert]. Princeton, NJ: Bristol-Myers Squibb Company;
2004. 2. UKPDS Group. Lancet1998; 352: 837–853. 3. Draeger KE, et al.
better: Horm Metab Res. 1996; 28: 419–425. 4. McGavin JK, et al. Drugs 2002;62;
1357–1364. 5. Metaglip [package insert]. Princeton, NJ: Bristol-Myers Squibb
Company; 2002
Best Responders to Sulphonylureas
Fig. 21: Hypoglycemia is common with SUs.
(Figs 21 to 24) Modern SUs have less hypoglycemic events
Duration of DM< 5 year (Sufficient reserve of Beta cell
TABLE 4: Sulphonylureas (SUs)
function) (Table 4)
CONS PROS
BMI<25 kg/m2
zz Hypoglycaemia zz Long track record
FPG 150–200 mg/dL
But not common zz Good evidence base
Insulin requirement <25 units/day zz Increase in beta-cell failure zz Safe
weight
CHAPTER 41: Gliptins versus Sulfonylureas: Which is Better? 255
Combination therapy was more efficient in reducing HbA1c than metformin or glimepiride monotherapy
Mean change in HbA1c at week 20 according to treatment
Fig. 30: Durability of glycemic response among second-line treatment options, as add-on to metformin therapy
258 SECTION 3: Diabetes
SUs versus DPP-4 Inhibitors as Add-on Agents with Myocardial Ischemic Preconditioning is NOT
Metformin Impaired by Modern SUs (Fig. 31)
DPP-4 inhibitors—Protects beta cell function similar Modern SUs do not inhibit the mitochondrial K ATP
to SUs channel opening in cardiac myocytes and thereby
SUs are more cost-effective. preserve myocardial ischemic preconditioning.
Is Weight Gain with SUs Correlated with Reduction Pleiotropic Benefits of Modern Sulfonylureas (Fig. 32)
in Glucotoxicity? (Figs 31 to 33) Antioxidative
Weight gain associated with SUs could be considered Angiogenesis
as in indicator for reduction in glucotoxicity Vascular health
Weight gain with SUs could be attributed to enhanced Ischemic preconditioning
utilization of ingested glucose and subsequent Insulin sensitisation
lowering in glycosuria Glucagon secretion
Weight gain is least with modern SU, glimepiride Insulin clearance.
when compared to other SUs.
targets with metformin monotherapy. (Grade A; with type 2 diabetes is limited. (Grade A; EL 4)
EL 1) —— There is insufficient evidence to recommend the
with dual combination therapy, owing to better metabolized in the liver (glipizide), should be
safety profile than older SUs. (Grade A, EL 1) the preferred SU in patients with moderate/
—— Fixed dose combinations (FDCs) containing severe renal impairment. In mild/moderate
SUs reduce cost, offer convenience and improve renal impairment, modern SUs may also be used,
patient adherence (Grade B; EL 1); hence FDCs preferably at lower doses. (Grade A; EL 3)
CHAPTER 41: Gliptins versus Sulfonylureas: Which is Better? 261
—— Reduction of SU dose and/or longer intervals ‘Increased risk of cardiovascular mortality’ is the
between dosing are recommended in patients warning sign commonly seen in the labeling
with mild/moderate hepatic impairment. (Grade information on all SUs, despite favorable outcomes
B;EL 4) in UKPDS
Sulfonylureas in combination and Ramadan: Potential pitfalls in designing and interpreting
—— Modern SUs may be used in combination with analyzes were noted by epidemiologists in SU and
other drugs during Ramadan, with appropriate other AHA-related observational studies
counseling and dose modification. (Grade A; EL 3)
—— Individuals on once daily SU should take their POINTS IN FAVOR OF SU
medication at Iftar (EVENING MEAL AT sunset Intensification of diabetes therapy is crucial
after breaking fasting). (Grade A; EL 3) Sulfonylureas are an important component in all T2
—— Individuals on twice daily SU may shift the DM patients
morning dose to Iftar and half of the evening dose Tolerability is good
to Suhur. (MEAL CONSUMED EARLY MORNING Lower costs
BEFORE FASTING). (Grade A; EL 4) Rapid efficacy
Well-established efficacy and safety profile
NEGATIVE IS NOT ABSOLUTELY Long tract record
NEGATIVE IN SU USAGE Consistant durability in efficacy
SU Combinations have a definite place
Association between SUs and
which decreases NPY (anorexigenic) and increases for any diabetes-related endpoint and a 25% risk
POMC (anorectic) expression. reduction for microvascular complications compared to
The mean weight loss is in the range of 1 to 5 kg, or a conventional therapy. A greater than expected benefit on
1% to 3% reduction from baseline. Weight loss is greatest macrovascular complications was seen for overweight
in the most obese patients and is durable for at least 10 patients on metformin; there were significant reductions
years in adherent patients from the DPPOS. Comparing in risk for all-cause mortality and stroke versus intensive
metformin with GLP-1 RA, it was shown that weight loss therapy with sulfonylureas or insulin.7 In a meta-analysis
at 52 weeks were similar in two groups ( -2.22 kg v/s -2.29 of 179 trials and 25 observational studies of head to head
kg, respectively)6 monotherapy or metformin based combinations on
cardiovascular mortality, it was found that metformin
CANCER BIOLOGY was associated with lower long-term CV mortality
Preclinical experiments have provided evidence that compared with sulfonylurea monotherapy.8
metformin can halt replication of cancer cell lines In two subsequent trials, HOME 9 and SPREAD-
(including breast, endometrium, ovarian, and prostate) DIMCAD,10 the risk reductions related to cardiovascular
in vitro. UKPDS has also shown metformin treatment endpoints were remarkably consistent at about 40%.
Reviewing 17 studies involving patients of DM with
reduced the risk of death from cancer by 29% relative to
CKD (eGFR <60 mL/mL/1.73m 2), CCF or CLD with
diet.
hepatic impairment , comparing treatment regimen
that includes metformin with those that did not include
PCOS
metformin, Crowley et al.11 found that metformin use
Insulin resistance leading to elevated free testosterone
was associated with lower all-cause mortality among
levels with resultant hyper androgenemia is one of
patients in each of the above noted three chronic
the key factors in pathogenesis of polycystic ovarian
conditions. Studies have shown that metformin is safe
syndrome (PCOS). Metformin reduce the insulin levels
in compensated cardiac failure and mild to moderate
by improving insulin sensitivity and thereby improve
kidney failure cases (eGFR >30 mL/mL/1.73 m2 ) as these
clinical manifestation of the disease.
individuals are not at significantly elevated risk for lactic
acidosis. As a result, many patients with comorbidities
Nonalcoholic Fatty Liver Disease can now safely take metformin.
In animal models, metformin has shown to improve fatty
liver, resolution of hepatomegaly and reversal of steatosis ADVERSE DRUG REACTIONS AND
in histology. However, human studies have shown CONTRAINDICATIONS
favorable results in weight and liver enzymes, but not in
The most common adverse effects of metformin are
histology. gastrointestinal disturbances in the form of recurrent
abdominal pain, loss of appetite, flatulence, and
Microvascular and Macrovascular diarrhea. These effects are usually transient and can be
Risk Reduction minimized by taking the drug with the meals and doing
The efficacy of metformin in improving glycemic gradual dose increments. 5% may not tolerate metformin
control and reducing microvascular complications of permanently. Upto 30% of metformin users have reduced
diabetes is similar to that of other oral hypoglycemic intestinal absorption of vitamin B12. Lactic acidosis, the
agents. Over a mean of 10 years of follow-up in UKPDS, dreaded complication of metformin may occur rarely
the improvement in the glycemic control with drug in presence of renal impairment, liver failure or hypoxic
therapy was associated with a 12% risk reduction conditions (MI, CCF, etc.).
CHAPTER 42: Metformin—the Molecule of the Decade: Old is Gold 265
Though there are fewer contraindications to or metformin. New England Journal of Medicine.
metformin now, a few still remain, including in acute 2002;346(6):393-403.
4. Perreault L, Pan Q, Mather KJ, et al. Effect of regression
medical illnesses like ARF, ALD, DKA, severe infection
from prediabetes to normal glucose regulation on long
and shock, decreased tissue perfusion, hemodynamic term reduction in diabetes risk: results from Diabetes
instability, advanced chronic liver disease, acute unstable Prevention Programme Outcomes Study. Lancet.
congestive heart failure and CKD with eGFR <30 mL/ 2012;379(9833):2243-51.
min/1.73 m2. 5. Wulffele MG, Kooy A, de Zeeuw D, Stehouwer CD, Gansevoort
RT. The effect of metformin on blood pressure, plasma
cholesterol and triglycerides in type 2 diabetes mellitus: a
Newer Antihyperglycemic Agents systematic review. J Int Med. 2004;256:1-14.
In the ever-expanding armamentaria of therapy for 6. Umpierrez G, ToféPovedano S, Pérez Manghi F, Shurzinske L,
T2DM newer agents are challenging the pole position of Pechtner V. Efficacy and safety of dulaglutide monotherapy
metformin as the first line of therapy. Two of the newly versus metformin in type diabetes in a randomized controlled
trial (AWARD-3). Diabetes Care. 2014;37(8):2168-76. Epub
introduced drugs, SGLT2I—empagliflozin and GLP-RA—
2014 May 19.
Liraglutide are now shown to have clear CV benefits and 7. UK Prospective Diabetes Study (UKPDS) Group. Effect
improved renal outcomes. Should they be able to replace of intensive blood glucose control with metformin on
metformin as the first line therapy? In the landmark complications in overweight patients with type 2 diabetes
trials EMPA-REG OUTCOME12 and LEADER13 showing (UKPDS 34). Lancet. 1998;352(9131):854-65.
8. Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-
robust cardiovascular benefits, it is to be noted that more
Cuervo C, Berger Z, Chu Y, et al. Diabetes Medications as
than 70% of the subjects already had metformin as the
Monotherapy or Metformin-Based Combination Therapy for
baseline drug. Type 2 Diabetes: A Systematic Review and Meta-analysis.
Ann Int Medicine. 2016;164(11):740-51. Epub 2016 April
CONCLUSION 19.
Metformin, with the possible exception of insulin has 9. Kooy A, de Jager J, Lehert P, et al. Long-term effects
of metformin on metabolism and microvascular and
unsurpassed efficacy in A1C reduction with added
macrovascular disease in patients with type 2 diabetes
advantages of least side effects, clear CV benefits along mellitus. Arch Intern Med. 2009;169:616-25.
with its low cost, catapulted the drug in less than a decade 10. Hong J, Zhang Y, Lai S, et al. SPREAD-DIMCAD Investigators.
to be the most commonly used oral antihyperglycemic Effects of metformin versus glipizide on cardiovascular
agent throughout the world. outcomes in patients with type 2 diabetes and coronary
artery disease. Diabetes Care. 2013;36:1304-11.
11. Crowley MJ, Diamantidis CJ, McDuffie JR, Cameron CB,
REFERENCES Stanifer JW, Mock CK, et al. Clinical outcomes of metformin
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insulin compared with conventional treatment and risk of Ann Intern Med. 2017;166:191-200.
complications in patients with type 2 diabetes (UKPDS 33). 12. Zinman B, Wanner C, Lachin JM, et al. EMPAREG OUTCOME
Lancet. 1998;352(9131):837-53. investigators. Empagliflozin, cardiovascular outcomes and
2. Silvio E Inzucchi. Is it time to change the type 2 diabetes mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-
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foundation therapy for type 2 diabetes. Diabetes Care 2017; 13. Marso SP, Daniels GH, Brown-Frandsen K, et al. LEADER
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CHAPTER
43
A Decade of RCTs in Diabetes:
Clinical Implications
Suhas Erande
Fig. 2: Primary major adverse cardiac event in cardiovascular Fig. 3: Cardiovascular death in cardiovascular outcome trials
outcome trials
centric (2011). Age, diabetes duration, life expectancy, 2015—empagliflozin reduces CV (38%) and all-
presence/absence of organ complications, patient’s cause mortality (32%) and HF by 35%, it also reduces
preparedness, family support were considered before microalbuminuria and renal end-points. Helps
opting for intensive (A1c<6.5 or 6%)/lenient (A1c~7.5 or weight and BP reduction and does not increase risk of
8%) approach. hypoglycemia. Small increase in risk of stroke noted
Later on, after 2008, came the era of CVOT in EMPAREG trial.8
(Cardiovascular Outcome Trials). The USFDA mandate 2016—liraglutide reduces CV composite end points
in 2008, asked the trialists to prove CV safety of diabetes by 13%-also helps wt and BP reduction—renal end-
medication before acquiring their license to market them points improved in LEADER trial.9 Stroke risk not
(This was preceded by the controversial meta-analysis increased. No risk of hypoglycemia. ADA guidelines
suggested earlier use of empagliflozin/liraglutide
on Rosiglitazone, which drew attention to harmful CV
(next add on to metformin) if high CV risk.
effects of this drug). Hence, CVOT studies became the
norm and various studies (essentially of newer drugs for
CENTRALITY OF RCTs IN
T2DM) followed.
These studies differ from the previous3-6 ones, in that
CLINICAL PRACTICE
If a clinician wants to know about a particular drug/
the focus is not on the approach conventional vs intensive
therapy/procedure/approach to treat a given patient,
with whatever established diabetes medication), but
he would be seeking details of the same. These details
to demonstrate CV safety of the new diabetes drug. CV
would be the efficacy, safety, the mechanism it works,
death, nonfatal MI or stroke (3 point MACE) and CV as
the limitations of its use, other drugs or therapies to treat
well as all-cause mortality were the primary end-points
the same patient and the relative/comparative merits/
in such studies (Figs 2 and 3).
demerits of it. Various tools are available to do the same.
All of these methodologies have their own strengths
IMPACT OF RECENT CVOT and limitations, but, to paraphrase Churchill on
IN DIABETES ON PRACTICE democracy, RCTs are far from perfect/infallible—the
2008—only metformin had proved CV safety (32% only good thing going with them is they are better
reduction in MI-UKPDS trial) than the other methods. In diabetes RCTs, patients
2013—saxagliptin may increase risk of hospitalization recruited follow treatment protocols and related
for HF (SAVOR TIMI 53 Study).7 periodic investigations rigorously-which may not
2014—sitagliptin neutral CV effects (TECOS Study). happen in real world practice. Hence, RWE (real world
268 SECTION 3: Diabetes
HAVE RCTs IN DIABETES HELPED It is worthy of note that McKinsey and Company
CLINICAL PRACTICE IN LAST DECADE? has observed that integrated diabetes care (patient
Indian diabetes practice has its own peculiar education and empowerment, care coordination,
challenges and demands which cannot be resolved by multidisciplinary team and individual care plans)
non-Indian solutions. We have started our approach is able to reduce (at least) HbA1c by 0.5% and also
in that direction. RSSDI guidelines of 2015 is an reduce hospitalizations. This analysis is based on
indicator. RCTs in diabetes in the last decade!11
We have started to address global risk and we are
trying not to be glucocentric in our thinking. We are REFERENCES
also trying to look at the early detection of diabetes 1. DCCT EDIC Study Research Group. NEJM. 2005;353:2643-
53.
and increasing mass awareness on diabetes.
2. UKPDS Group Lancet. 1998;252:837-53.
We are trying to assert intensive control approach
3. Holman RR, et al. NEJM. 2008;359:1577-89.
in newly detected diabetics, to reduce long-term 4. ADVANCE Collaborative Study Group. Lancet. 2007;370:829-
complications. We realize centrality of patient 40.
education and empowerment. 5. ACCORD NEJM. 2008;358:2545-59.
We have started looking for patient features so as 6. Duckwor th W, Abraira C, Monitz T, et al. For VADT
to select relevant diabetes medication (SES, age, investigators. Glucose control and vascular complications
in Veterans with type 2 diabetes NEJM. 2009;360:129-39.
BMI, WHR, other comorbidities, duration of DM,
7. Seirica BM, Bhatt DL, Braunwald E,Steg PG,Davidson J,
psychological preparedness, family support, etc.
Hirshberg B, et al. Saxagliptin and cardiovascular outcomes
Use and acceptance of glucometers and injectable in patients with type 2 diabetes. NEJM. 2013;369:1317-26.
therapies is increasing-though slowly. Use of social 8. Zinman B, Waner C, Lachin JM, Fitchett D, Hantel S, et al.
media, other gadgets to improve patient awareness- Empagliflozin, Cardiovascular outcomes and mortality in
education-compliance is increasing. type 2 diabetes NEJM. 2015;373:2117-28.
We are encouraged to be updated through CMEs 9. Marso SP, Daniels GM,Brown Frandsen,Kristiansen P,
and various academic activities happening around Mann JF, Nauck MA, et al. Liraglutide and cardiovascular
outcomes in type 2 diabetes. NEJM. 2016;375:311-22.
publication of diabetes RCTs.
10. Recent cardiovascular outcome trials of antidiabetic drugs:
In days to come, if we design a simple diabetes a comparative analysis. AK Singh, Ritu Singh (Eds). Indian
practice audit to have an introspection of impact of Journal of Endocrinology abd Metabolism. 2017;21:1.
RCTs and other knowledge syntheses on our own 11. The evidence for integrated care, Healthcare Practice,
practices, it can throw some light on this subject. 2015.
CHAPTER
44
Insulin Pumps in India
Narendra Pal Jain, Rishu Bhanot
The place of CSII or insulin pump therapy has been —— Pump (including controls, processing module,
respectively. Thus CSII or insulin pump mimics the subcutaneous
insertion (under the skin) and a
insulin provided by a normal functioning pancreas. tubing system to interface the insulin reservoir to
T2DM patients with advanced age are less likely to the cannula.
adapt to complex CSII technology than younger people
with T1DM. Initiation of CSII requires expenses born by
the user or insurance company.
These challenges can be
overcome (for people with T2DM) by effectively reducing
glucose levels, simple and cost effective insulin pumps/
CSII.
Continuous subcutaneous insulin infusion (CSII,
also known as insulin pump therapy) has become an
established and recognized treatment for type 1 diabetes
mellitus (T1DM) since 1970’s, especially in those who
have inadequate glycemic control on multiple insulin
injections. Despite the insulin pumps being in the
market for over 40 years, its use in type 2 diabetes has
been doubted. Fig. 1: Medtronic insulin pump
CHAPTER 44: Insulin Pumps in India 271
Low insulin depots allowing the reduction of glycemic despite of being on basal-bolus injections and full
variability adherence to treatment.
With the availability of new MDI regimens which Wide and abberant glycemic variations
use long acting insulin analogues have posed a fresh Frequent hypoglycemic episodes
challenge to the insulin pumps. So now the physicians “Dawn phenomenon” (early morning spike in blood
have to decide whether the patient will benefit with CSII glucose)
or MDI and make sure that proper patient selection is Pregnancy or planning for pregnancy
have shown the efficacy of CSII across all age groups. Which DM-2 patient is a good candidate for CSII?
The face of CSII is being changed by the availability of Patients with type 2 diabetes who:
continuous glucose sensors which allow for improved Patients who need the same multiple-daily injection
glucose control by decreasing glycemic variations and self-monitoring requirements as for type 1 diabetes
and manipulate insulin delivery to avoid incidence of and those who have evidence of beta-cell failure with low
asymptomatic hypoglycemia. C- peptide levels.
272 SECTION 3: Diabetes
control without heightened hypoglycemia or weight respectively. These are chiefly injected at mealtimes,
gain. In fact, the additional 0.5% decrease in HbA1c levels hence are also called “prandial” or “bolus” insulins.
seen in the combination group correlated with an 11.5% They reach their peak at 30–90 min and their duration
risk reduction for diabetes-related complications. At the of action is for 3–5 hours. They are also used in insulin
end of this study, nearly 53% patients on sulphonylurea pumps (subcutaneous insulin infusion systems or
therapy needed additional insulin to maintain glycemic SCII). Severe hypoglycemia is less frequent with these
control. formulations as compared to regular insulin.7,11,13,14
These viewpoints are reflected in the latest Short-acting insulin: Regular insulin is an example
American Diabetes Association (ADA) guidelines of short-acting insulin. Due to its delayed onset of
which recommend insulin therapy (in combination action, it must be injected 30–60 min before meals,
with or without other agents) in newly-diagnosed T2D which is inconvenient. Intravenous administration,
patients who are markedly symptomatic and/or present however, reduces its onset of action. It reaches its
with high blood glucose or A1C. Addition of insulin to peak in 2–4 hrs with a duration of action of 5–8
metformin as a second step of diabetes management is hrs.7,13,14
also recommended if HbA1c remains ≥9%.6 Intermediate-acting insulin: Represented by Neutral
Protamine Hagedorn (NPH) insulin which is regular
INSULINS AT A GLANCE insulin combined with protamine, to form a poorly
The three main components of insulin therapy are soluble complex. Its action kicks off in 1–3 hrs and
prandial (bolus) insulin, basal insulin and a correction- peaks at 8 hrs with duration of action being 12–16
dose or insulin supplement. Prandial insulin covers hrs. Lente insulin is synthesized by adding zinc with
postmeal requirement whereas the basal insulin takes regular insulin in an acetate buffer making it poorly
care of the constant levels of insulin present in blood. soluble compound. NPH and lente insulins are
The correction-dose or supplemental insulin rectifies commonly used as twice daily basal insulins. The
premeal or between-meal hyperglycemia, independent premixed formulations, e.g. insulin lispro protamine
from prandial insulin. 11 Refinement of the insulin and insulin aspart protamine (available as a part
manufacturing process and formulations have led to the of premixed solutions) have a similar time action
availability of several commercial preparations which profile as NPH, but has better prandial coverage and
vary in their pharmacokinetics and give the physician hypoglycaemia safely.7,13,14
and the patient a better chance to customize insulin Long-acting insulins: Ultralente is a very stable
therapy.12 insulin which is absorbed very slowly in its zinc
Insulin preparations are divided on the basis of their crystalline form. Insulin glargine is an analogue
onset of action into rapid, short, intermediate and long- with modifications made to make it more stable
acting types. The main types of insulin are: with increased solubility at an acidic pH of 4 and
Rapid-acting insulin: These are insulin analogs with reduced solubility at physiological pH. Subcutaneous
slightly modified amino acid sequences to prevent injection leads to the formation of a microprecipitate,
aggregation in solution. Their onset of action is resulting in slow dissolution from the injection site
very rapid (15 min) as they dissociate very quickly and consistent peakless delivery over 24 hrs. Detemir
into monomers in subcutaneous tissue. In case of is one more long-acting insulin which is acylated
insulin lispro, lysine at position 29 is switched with with fatty acid moiety at position 29 on lysine, which
proline at position 28, and insulin aspart has proline augments its albumin binding leading to gradual
at position 28 which is replaced with aspartic acid absorption from injection site. Its large size may also
while in insulin glulisine, aspart at B3 and lysine hamper trans-endothelial transport. These insulins
at B29 positions is replaced by lysine and Glucine have an onset of action of 1 hr with duration of acting
CHAPTER 45: Newer Insulins and Art of Insulin Therapy 275
lasting for 20–26 hrs. Insulin degludec is the newly associated comorbid conditions and available resources.
available novel long-acting basal insulin which The insulin therapy aims to achieve the glycemic targets
forms soluble multi-hexamer aggregates after being with minimal adverse effects especially hypoglycaemias.
injected subcutaneously leading to an ultralong Type 2 diabetics, in whom insulin therapy may
action profile of more than 24 hours. 7,13-15 prove beneficial, include those with symptomatic
Premixed insulin: Premixed analogues contain a hyperglycemia, failure of oral agents, pregnancy, acute
combination of a rapid-acting analog (for prandial medical or surgical emergency and in ICU/CCU. 6,16,17
coverage) and an intermediate or long-acting
analogue to cover basal needs. The advantages of Hospitalized Patients18
these analogs include absence of self-mixing and Based on available evidence, the American College of
reduction in the number of injections. It can be used Endocrinology (ACE) and the American Association of
to initiate insulin therapy, especially in Type 2 diabetic Clinical Endocrinologists (AACE) released a consensus
individuals with regular eating habits, in whom oral statement for the management of hyperglycemia in
agents have proved inadequate. Their onset of action the hospitalized patients. The key recommendations
varies depending upon the combination but their include:
duration of action is for 10–16 hrs.8,14
Critically Ill Patients
7
MODES OF INSULIN DELIVERY Insulin therapy must be inducted at blood glucose
The three main modes of insulin delivery include: >180 mg/dL
1. Syringe: Allows the patient to “freemix” insulin as per For most of the patients, maintain glucose levels at of
his/her needs. However, it includes a need for better 140–180 mg/dL once insulin therapy is initiated
doctor and patient education. Also, living daily life Prefer intravenous (IV) insulin infusions for achieving
with vials, syringes, etc. might become cumbersome. and maintaining glycemic goals
Insulin absorption might also change depending Validated protocols for Insulin infusion must be
upon the injection site. Insulin lispro and glargine followed with proven safety and efficacy, and with
are both clear solutions, so a great caution has to be minimal rates of hypoglycemia
exerted by the patients and they must be trained to Repeated monitoring of glucose is must to earn
read the labels very carefully before usage. optimal glucose control and to curtail incidence of
2. Pen: Convenient to carry, easy to use and distinguish hypoglycemia.
due to colour coding/size. The dose can be delivered
more accurately, and now 33 G needles are generally Noncritically Ill Patients
used for injections. It is however more expensive than For rest of the indoor patients on insulin, the
vialed insulins. preprandial glucose goal should be <140 mg/dL with
3. Pump: Involves fewer injections, removes site- random blood glucose level of <180 mg/dL. These
dependant absorption variability and ensures targets should be achieved safely.
physiological delivery with better control/lesser Tighter glucose control may be needed in steady
hypoglycaemia. Drawbacks include cost and the patients with previous tight glucose control.
special training needed to operate it along with Conversely, targets may be more flexible in mortally
likelihood of technical problems. ill patients or in patients with dismal brittleness.
Appropriate subcutaneous insulin injection, with
INITIATING INSULIN THERAPY prandial, basal, and correction boluses if needed,
Insulin treatment regimens depend upon the patient’s is the endorsed method for accomplishing and
location, educational status and willingness to learn, preserving glucose control.
276 SECTION 3: Diabetes
Sliding scale insulin as the solo regimen is neither 3. Insulin NPH twice a day or nocturnal and premeal
approved nor encouraged or advocated. regular human insulin 3 times per day (no missed
Antihyperglycemic agents other than insulin are not meals): Insulin NPH can be given before breakfast
preferred in most of the indoor patients and again at bedtime along with regular insulin
injection before all meals. Since regular insulin has
Type 1 Diabetes Patients 7,16,19 comparatively longer duration of action, its use at all
In T1D patients confined to critical care units, the mealtimes might make even once daily bedtime NPH
ideal therapeutic protocol includes initiation of an as a viable option for most patients.
IV insulin infusion (only regular human insulin to be
used) with repeated monitoring and titration of the Type 2 Diabetes Patients 6,7
insulin dose. Patients with new-onset type 1 diabetes Initial therapy of type 2 diabetes begins with lifestyle
respond favorably to a combination of background basal changes, then typically moves onto monotherapy with a
insulin and short-acting insulin taken before meals. The noninsulin agents. When switching from monotherapy
total daily insulin dosage in these adults and children to dual therapy, the 2015 ADA guidelines recommend
immediately postdiagnosis is normally 0.2–0.6 unit/ that basal insulin can be added for all patients in whom
kg/day. Initial basal insulin could be insulin glargine HbA1c is ≥9%, to achieve target levels more quickly. This
or degludec, although NPH insulin or insulin detemir combination results in similar control with less weight
may also be given twice a day. Overall, patients using gain, lower insulin doses and fewer hypoglycemic
insulin analogues (lispro, aspart, glargine) in regimens episodes than insulin alone or insulin used along
which mimic physiologic insulin release present with with sulfonylureas. Moreover, ADA recommends
fewer hypoglycemic episodes than patients using insulin initiation (with or without additional agents)
traditional insulins (regular and NPH). Prandial insulin even in newly detected T2D patients with remarkably
can be matched to carbohydrate intake/meal, premeal symptomatic and/or high blood glucose levels or A1C.
blood glucose and expected physical activity. One of Alternatively, if non-insulin therapy proves
the programs which helps in understanding this better inadequate, basal insulin can be added as the next step.
is Dose Adjustment For Normal Eating (DAFNE). This In patients who seem to require increasing doses of
program trains type 1 diabetic individuals to estimate the insulin due to poor control, thiazolidinediones (TZD)
carbohydrate in each meal and to inject the right dose of or sodium-glucose transporter 2 (SGLT2) inhibitors can
insulin.20 be added to enhance control. Conversely, combination
Three suggested options, in order of preference, for therapy, with basal and mealtime insulin, can be started
this patient category include: when glucose is ≥300 mg/dL and/or HbA1C is ≥10% or if
1. Glargine and premeal rapid-acting insulin: This is triple therapy inadequate to achieve targets.
one of physiological insulin regimens which offers Initiating insulin therapy in a stepwise, flexible
basal and prandial coverage over 24 hrs. Once-daily fashion by involving the patient in making dose
glargine given at bedtime with aspart/lispro/aspart adjustments based on self-monitored blood glucose
(in a 50:50 ratio) given at mealtimes allows patients levels might enhance patient compliance. Basal insulin
to skip meals or change mealtimes. Glargine achieves can be initiated at 10 U or 0.1–0.2 U/kg (based on blood
steady state in 2 hrs. This regimen is easier to use glucose levels). This can be used in combination with
since it has separate basal and prandial insulins. metformin and another non-insulin agent, if required.
2. Insulin NPH or detemir twice a day and premeal If fasting blood glucose reaches acceptable levels with
rapid-acting insulin: NPH or lente is given before this regimen but HbA1c levels remain elevated, a second
breakfast and at bedtime with lispro/aspart given injection can be added to provide prandial coverage.
before meals. This regimen is less flexible since NPH Prandial coverage can be achieved by adding a glucagon
can act as both a basal and a prandial insulin. like peptide (GLP-1) receptor agonist or prandial insulin.
CHAPTER 45: Newer Insulins and Art of Insulin Therapy 277
As a less flexible option, basal insulin can be replaced Usage of insulin supplements before or between
by premixed analogues (30/70 or 50/50 aspart mix, 25/75 meals should be done carefully since it might lead to
or 50/50 lispro mix). Yet another expensive option to the “insulin stacking.” To avoid this, supplements injected
“basal–bolus” therapy could be using a CSII or an insulin <3 hours after a previous insulin dose, can be given at
pump. half the dose. In physically active patients who exercise
Overall, a 50:50 ratio can be used to provide the 1-3 hours after meals, the dose of rapid-acting insulin
complete insulin dose required in a day i.e. 50% basal analogues may have to be reduced substantially to avoid
and 50% prandial, where the prandial can be split hypoglycaemia.22
equally between three meals. The approach to initiating/ “Adjustments” of insulin dosage are done on basis of
adjusting insulin treatment, suggested by the ADA a persistent change in blood glucose levels. In case of a
guidelines, is given in the Table 1. patient receiving bedtime NPH insulin and presenting
with frequent fasting hypoglycaemia, the adjustment
Fine-tuning Insulin Therapy 7,11 would be to decrease the bedtime insulin dose. Timely
Self-monitoring of blood glucose (SMBG) helps to and precise adjustments in the insulin regimen in
refine insulin therapy to ensure adequate control. accordance to the patients’ meal/activity levels are the
Supplemental insulins are fixed doses of rapid- or short- key to effective long-term glucose control.
acting insulin used to correct hyperglycemia. They are
typically injected with the usual prandial dose of insulin. OVERCOMING THE PSYCHOLOGICAL
A ballpark dose for patients with T1D is an additional 1U BARRIERS TO INSULIN THERAPY
per 50 mg/dL. For patients with T2D, 1U of supplemental Though the benefits of insulin therapy are well-studied,
insulin may be given per 30 mg/dL above the target many fears and misconceptions exist both in the minds of
glucose level. the patient and the physician making therapy initiation a
278 SECTION 3: Diabetes
challenge in type 2 diabetes patients. Some tactics which like hypoglycemia and weight gain might also worry
can be adopted by physicians to overcome their patients’ them. Each of these aspects can be dealt with separately.
fears include listening patiently, acknowledging their In many cases, asking the patient to interact with another
fears, probing gently to get to the root of the problem who is already on insulin therapy may do wonders for
and imparting adequate knowledge. The physicians their morale. It is also important for the physician to
are advised to decline use insulin therapy as a “threat”. constantly guide and monitor the patients to ensure
Some questions which might give some insight into the that the treatment regimen is being followed correctly.
patient’s fear include “What problems do you think will Please give positive feedback whenever necessary and
occur if you begin insulin therapy?” “What do you feel is if required enlist the help of family members or other
the most negative point about insulin?” Upon receiving caregivers to keep the patient motivated.9,23,24
answers to these questions, gently ascertain the real Some of main patient barriers to insulin therapy are
cause for concern by asking questions such as “Why do outlined in Table 2 along with possible solutions.
you feel like that?” or “Can you tell me more about that?” Physician-related inhibitions stem from a lack
Some of the patient fears stem from a dislike for of experience, an idea that it will be a burden to the
needles, social stigma, seeing insulin as a personal failure, patient, fear of inducing side-effects or inexperienced/
a last resort, a feeling that the regimen is complex and unwilling staff. However, delaying insulin therapy till it is
will interfere with their daily routine. Some other aspects “absolutely necessary” might result in the disease having
Insulin injections are painful (may zz Clarify that insulin needles are smaller and thinner and less painful
be based on antibiotic injections/ zz Give a dry injection to yourself in front of the patient or ask the patient to give themselves a
vaccinations) dry injection
zz Insulin pens can help overcome inhibitions
Fear of hypoglycemia zz Acknowledge their fear and assure them that you will help them and their family members/
caregivers to recognise, combat and devise ways to avoid hypoglycaemic episodes
zz Inform them and include long-acting insulins in their regimen where hypoglycemia is less of a
problem
Insulin causes weight gain zz Tailor regimens to limit weight gain. For example, use of newer analogs like glargine, detemir,
addition of metformin, glucagon like peptide 1 receptor agonists
zz Involve a nutritionist to identify strategies to combat weight gain
Source: Adapted from Funnell MM,23 Stotland NL,24 Alkhaifi M et al.25; Haslam D26
CHAPTER 45: Newer Insulins and Art of Insulin Therapy 279
progressed to an advanced stage where the patient might 5. American Diabetes Association. Implications of the United
be burdened by significant complications.25,27,28 kingdom prospective diabetes study. Diabetes Care.
2003;26(Suppl 1):S28-32.
6. American Diabetes Association. Approaches to glycemic
CONCLUSION treatment. Sec.7. In Standards of Medical Care in
More than 17% of the world’s diabetic population lives Diabetes-2015. Diabetes Care. 2015;38(Suppl 1):S41-8.
in India. 2 The discovery of insulin in 1921 and the 7. DeWitt DE, Hirsch IB. Outpatient insulin therapy in type
giant strides made in the development of commercial 1 and type 2 diabetes mellitus: scientific review. JAMA.
preparations of insulin and its analogs have helped 2003;289(17):2254-64.
in making control of blood glucose in diabetes a 8. Freeman JS. Insulin analog therapy: improving the match
with physiologic insulin secretion. J Am Osteopath Assoc.
manageable goal.12 Insulin therapy for type 1 diabetes
2009;109(1):26-36.
can be carefully calibrated in accordance to the meal
9. Marrero DG. Overcoming patient barriers to initiating insulin
patterns and physical activity of the patient to achieve therapy in type 2 diabetes mellitus. Clin Cornerstone. 2007;
optimal blood glucose levels. Though insulin was 8(2):33-43.
considered as “last resort” till not very long ago for type 10. Wright A, Burden AC, Paisey RB, Cull CA, Holman RR.
2 diabetes, ADA now recommends the use of insulin as UK Prospective Diabetes Study Group. Sulfonylurea
an adjunct to metformin when HbA1c remains ≥9% and inadequacy: efficacy of addition of insulin over 6 years in
also in selected newly diagnosed patients. Similarly, patients with type 2 diabetes in the UK Prospective Diabetes
Study (UKPDS 57). Diabetes Care. 2002;25(2):330-6.
combination insulin regimens are also being advocated
11. H i r s c h I B . I n s u l i n a n a l o g u e s . N E n g l J M e d .
for swift and accurate attainment of blood glucose 2005;13;352(2):174-83.
targets. 6 Though insulin therapy is a must in type 1 12. History of diabetes. American Diabetes Association ADA
diabetes and becomes essential during the course of [Internet] 2015 [cited 2015 July 16] Available from:
type 2 diabetes, misconceptions and fears regarding its http://www.diabetes.org/research-and-practice/student-
usage exist till date. Effective communication between resources/history-of-diabetes.html?referrer=https://www.
the physician and the patient can help overcome google.co.in/.
13. Herbst KL, Hirsch IB. Insulin strategies for primary care
barriers to insulin therapy. Self-monitoring of glucose
providers. Clin Diabetes. 2002;20:11-7.
levels, judicious use of the different types of insulin with 14. Insert C: Types of Insulin. The National Institute of Diabetes
meticulous refinement of insulin regimens as the disease and Digestive and Kidney Diseases. [Internet] [year
progresses will make management of T1D and T2D a unknown] [cited 2015 July 15] Available from: http://www.
much easier goal to attain for all patients of diabetes. niddk.nih.gov/health-information/health-topics/Diabetes/
diabetes-medicines/Pages/insert_C.aspx.
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1. Pozzilli P, Strollo P, Bonora E. One size does not fit all insulin: A novel basal insulin. Indian J Endocrinol Metab.
glycemic targets for type 2 diabetes. J Diabetes Invest. 2011;15 (Suppl 1):S12-6.
2014;5:134-41. 16. Mooradian AD, Bernbaum M, Albert SG. Narrative review:
2. IDF Diabetes Atlas 6 th Edition [Internet]. International a rational approach to starting insulin therapy. Ann Intern
Diabetes Association, 2014 [updated 2014;cited:2015;16]. Med. 2006;18;145(2):125-34.
Available from: http://www.idf.org/sites/default/files/ 17. American Diabetes Association. Glycemic targets. Sec. 6. In
Atlas-poster-2014_EN.pdf Standards of Medical Care in Diabetes-2015. Diabetes Care
3. Sorli C, Heile MK. Identifying and meeting the challenges 2015;38(Suppl.1):S33-S40.
of insulin therapy in type 2 diabetes. J Multidiscip Healthc. 18. Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D,
2014;7:267-82. Hellman R, Hirsch IB et al. American Association of Clinical
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19. Hirsch IB, Type 1 diabetes mellitus and the use of flexible 23. Funnell MM. Overcoming barriers to the initiation of insulin
insulin regimens. Am Fam Physician. 1999;15;60(8): therapy. Clin Diabetes. 2007;25(1):36-8.
2343-52, 2355-6. 24. Stotland NL. Overcoming psychological barriers in insulin
20. DAFNE. What is DAFNE? [Internet] 2015 [updated 2012 therapy. Insulin. 2006;1:38-45.
March 23; cited 2015 July 16] Available from: http://www. 25. Alkhaifi M, Alkhussaib G, Theodorson T, Ward MA, Al
dafne.uk.com/What_is_DAFNE_-I293.html. Mazrou’I A. Barriers in initiating insulin treatment in type 2
21. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini diabetes mellitus among physicians in Wilayat of Bowsher in
E, Nauck M, et al. Management of hyperglycemia in type 2 Oman. J Family Med Community Health. 2015;2(3):1034.
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and the European Association for the Study of Diabetes. 27. Maharaj S, Pirie F, Paruk I, Motala A. How to start and
Diabetes Care. 2015;38(1):140-9. optimise insulin therapy. Starting insulin therapy in type 2
22. Rabasa-Lhoret R, Bourque J, Ducros F, Chiasson JL. diabetes can be challenging. CME. 2010;28(10):458-64.
Guidelines for premeal insulin dose reduction for 28. Brod M, Alolga SL, Meneghini L. Barriers to initiating insulin
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2001;24(4):625-30.
CHAPTER
46
Individualization of Diabetes Care
KK Pareek, Girish Mathur
TREATMENT APPROACHES FOR T2 To achieve the target HbA1c level in patient with
DIABETES HbA1c > 8.0–8.5%, multiple anti-diabetes agents
There are two general treatment approaches for T2 DM. should be considered.
AACE guideline recommends multiple antidiabetes
1. Guideline approach: Antidiabetes agents such as
Metformin followed by Sulfonulurea addition with agents for newly diagnosed diabetic subjects with
subsequent (UPKDS) addition of insulin. This HbA1c >7.5%.
approach is known as treat to failure approach, and Treat to fail algorithm, the 2009 American Diabetes
has many challenges. Association/European Association of Study of Diabetes
2. Pathophysiology approach: Preferred combination (ADA/EASD) algorithm recommended metformin as
therapy according to defects in T2DM. The therapy initial therapy to achieve HbA1c <7–0%, followed by,
should consider patient’s overall health status sequential addition of SU, and if SU fails basal insulin
and co-morbid condition. This individualized should be added. The revised 2012 ADA/EASD algorithm
approach, which we refer to as the ABCD(E) of included newer antidiabetes agents such as GLP-1
diabetes treatment.
receptor agonists, DPP4i, and TZDs as potential choices
A - Age
if metformin fails (Fig. 1 and Table 1).
B - Body weight
The ADA/EASD 2012 does not consider initial
C - Complications (microvascular and macrovascular)
combination therapy in most newly diagnosed T2DM
D - Duration of diabetes
E - Life expectancy patients in achieving goal of HbA1c goal <6-0–6-5%.
F – Expense Diabetes care delivery should include strategies such
as shared-decision making motivational interviewing
Therapy in Newly Diagnosed T2DM techniques, shared medical appointments and
Patients multidisciplinary team collaboration which helps in
Goal is to achieve the targeted level of glycemic achieving glycemic targets and improving patients
control. HbA1c should be <60% in newly diagnosed quality of life.
diabetic patients without CVD. Long-term glycemic control:
Monotherapy will not reduce HbA1c <6.5–7.0%, hence Combination therapy is initiated with drugs targeting
Fig. 1: Non-insulin therapy for hyperglycemia in type 2 diabetes, treating defronzo’s octet match
patient characteristics to drug characteristics
The therapy should not only reduce HbA1c in long- Factors deciding treatment strategy:
term glycemic control but also reverse the pathogenic Patients attitude and efforts
defects. Hypoglycemia
Patient characteristic: Short duration of diabetes, long Metformin is first line agent for T2DM
expectancy and significant CVD Insulin therapy is considered in newly diagnosed
Less stringent A1C goals, i.e. <8% T2DM patient with markedly symptomatic and/or
Advanced microvascular or macrovascular compli elevated glucose levels and higher A1C.
cations In noninsulin monotherapy if the A1C target is not
Extensive comorbid conditions. achieved over 3–6 months, add a second oral agent, a
GLP-1 receptor agonist, or insulin
A patient-centered approach should be considered
Individualized Goal Based on
which include efficacy, cost, potential side effects,
Duration effects on weight, comorbidities, hypoglycemia risk,
Age expectancy and patient preferences
Co-morbid conditions DSME should focus on psychosocial problems, since
CVD/ microvascular complications emotional well-being is associated with positive
Unaware of hypoglycemia outcomes.
284 SECTION 3: Diabetes
Consider bariatric surgery for adults with BMI >35 IMPLEMENTATION STRATEGIES
kg/m2 Initial therapy
After surgery, life-long lifestyle support and medical Advancing to dual combination therapy
monitoring is necessary Advancing to triple combination therapy
Transitions to and titrations of insulin
PATIENT–CENTERED APPROACH
Antihyperglycemic Therapy OTHER CONSIDERATIONS (TABLE 2)
Glycemic targets Old age
—— HbA1C <7.2% (mean PG ~ 150–160 mg/dL [8*3– —— Decreased life expectancy
—— Postprandial PG <180 mg/dL (10.0 mmol/L) —— At risk for adverse events from polypharmacy
zz Disease duration
as GAD65Ab, IAAb, IA-2Ab, ZnT8Ab. There are also that are seen in diabetes mellitus. It is a known fact
candidate minor antigens like ICA12, VAMP2, NPY, etc. that low birth weight increases the risk of metabolic
The accelerating factor for β-cell loss are again infection, syndrome in the future. One of the mechanisms is
worsening insulin resistance such as puberty and weight heightened inflammation. Early life stress and low
gain. birth weight increases the stress response through the
activation of the hypothalamopituitary adrenal (HPA)
Type 2 Diabetes Mellitus axis causing hypercortisolemia resulting in an insulin
In recent decades, there has been prolific discussions resistant states. These early life changes are programmed
on the role of immune disturbances such as chronic in such a way that there is a chronic activation of the HPA
low-grade inflammation in type 2 diabetes mellitus axis in the life of the individual. Innate immunity aims to
causation and atherosclerotic cardiovascular diseases. restore homeostasis in the short-term conferring survival
The association of inflammation with carbohydrate advantage in the face of an environmental insult, but
metabolism can be traced back to historical reviews by in type 2 diabetes it is prolonged. Thus the adaptations
Shoelson et al. in the 19th century. They cited reports developed early in life becomes maladaptive. In the same
from over a century ago in which high-dose salicylates vein, there are suggestions that chronic psychological
decreased glycosuria in individuals classified as diabetic. stress is associated with risk of diabetes or worsening
The postulated mechanisms linking diabetes of diabetes outcomes in those already diagnosed. In
pathogenesis and immunological reactions are diverse. the Hoorn Study in the Netherlands, stressful life events
There are scientific reports suggesting that the innate in the previous 5 years predicted the development of
immunity is activated in type 2 diabetes resulting in the diabetes in people (aged 50–74 years) who did not have
release of inflammatory cytokines that worsen insulin diabetes mellitus.
resistance, promotes β-cell failure, alters T-cell mediated Cytokines such as TNF-α cause insulin resistance
immunity and even increases the risk for autoimmunity. by activation of the stress-induced kinase, c-Jun NH2-
The possible players in the predisposition to terminal kinase, serine phosphorylating signalling
enhanced innate immunity in type 2 diabetes are genetic proteins such as insulin receptor substrate-1 and 2 (IRS-1
and racial factors, nutrition, aging, chronic stress and and IRS-2). This inhibits insulin signalling and stimulates
early life programming. Polymorphisms in the TNF-α of expression of SOCS proteins which cause degradation
gene promoter, TNF-α receptor gene and IL-6 gene of IRS-1 and -2 by binding them. TNF-α, IL-1β, and IL-6
are variously associated with insulin sensitivity or downregulate PPAR-g expression. PPAR-g is involved in
resistance. Dietary factors have been postulated to be insulin sensitivity by promoting adipogenesis.
involved in type 2 diabetes causation via calorie excess, There are other smaller evidences that the adaptive
inflammation and alteration of the gut microbiota. immune response may also be impaired in type 2 diabetes.
High fat diet induces inflammation in the gut lining It was shown by Lindsay et al. elevated g-globulin, a non-
resulting in ‘leaky gut’ where bacterial products such specific marker of adaptive immunity increases the risk
as lipopolysaccharides (LPS) are easily absorbed and for type 2 diabetes mellitus development in American
transported in the circulation to organs including the Indians. The concept if type 2 diabetes is a slowly
adipose tissue. This induces inflammation in the adipose evolving autoimmune disease is a topic of significant
tissue resulting in the release of inflammatory cytokines debate. So far the existing signal is inadequate to
that cause insulin resistance. The alteration in the gut prove or disprove this idea. Obesity associated insulin
microbiota seen in obesity induced insulin resistance also resistance suggests the possibility of an activated innate
increases the efficiency of fat and LPS absorption further immune response mainly at central adipose tissue.
worsening insulin resistance. Aging is accompanied by Isolated T-and-B cells and/or antibodies from obese
an inflammatory cytokine profile mirroring the changes can transfer disease; and therapies targeting them have
288 SECTION 3: Diabetes
been shown to slow disease advancement. Also there response in bactericidal activity probably play an
has been demonstration of specific autoantibodies important role. These impairments can be worsened
linked to the insulin resistant or type 2 diabetes state like by hyperglycemia and acidosis. However, reversing
antibodies to Golgi SNAP receptor complex member 1 hyperglycemia and acidosis may not show immediate
(GOSR1) transcript variant 1, suggesting an autoimmune benefit, thereby suggesting that chronic processes such
pathophysiologic mechanism. GOSR1 transcript as accumulation of advanced glycation end products and
variant 1 is a protein involved in trafficking between other structural changes could contribute. Host factors
the endothelial reticulum and Golgi compartments. play an equally important role in the predisposition
Autoantibody against these proteins are seen in 30–70% to poor outcomes with infection in diabetes. These
of insulin-resistant individuals. include vascular insufficiency (microangiopathies
and macroangiopathies), peripheral neuropathy
DEFECTIVE IMMUNE RESPONSE (motor, sensory and autonomic) and skin and mucosal
IN DIABETES MELLITUS colonization with pathogens; among others. Infection
Immune function study in diabetes mellitus and obese and diabetes have a bidirectional relationship in that
humans and experimental animals have suggested that diabetes predisposes to increased risk of infections and
infection outcomes; and infection worsens diabetes
they are associated with impairments in host immune
status.
mechanisms. Patients with diabetes have been reported
to have a greater incidence of infections as well as
greater infection-related morbidity and mortality.
CONCLUSION
Understanding the association between diabetes and
Thus colonization by Staphylococcus aureus and
immunity is an important area for enhanced research;
Candida species; more severe infection with organisms
as immune disturbances have been suggested and
such as Klebsiella species; urinary tract infection and
shown to be involved both in the pathogenesis and
asymptomatic bacteriuria; risk of tuberculosis infection
complications of diabetes. Envisaging diabetes mellitus
and treatment failure; hepatitis C infection are increased
from an immunological perspective can help fill some
in diabetes mellitus. Infections such as rhinocerebral
of the lacunae we have in our understanding of diabetes
mucormycosis, malignant otitis externa, Fournier
and in the care of those who suffer from the disease.
gangrene and emphysematous cystitis, pyelonephritis
and cholecystitis occur almost entirely in diabetes.
BIBLIOGRAPHY
The infections in a diabetic patient are unique in that 1. Antonio Hernandez-Mijares, et al. Human Leukocyte/
they are recurrent, more severe, frequently require Endothelial Cell Interactions andMitochondrial Dysfunction
hospitalization, and also have higher mortality than in Type 2 Diabetic Patients and Their Association With Silent
controls. Myocardial Ischemia. Diabetes Care. 2013;36:1695-702.
Therefore on one hand there is heightened 2. Barbara Menart-Houtermans, et al. Leukocyte Profiles Differ
Between Type 1 and Type 2Diabetes and Are Associated
immunological response in diabetes resulting in its
With Metabolic Phenotypes: Results From the German
pathogenesis, on the other hand, impaired immune Diabetes Study (GDS). Diabetes Care. 2014;37:2326-33.
response seen in the condition is associated with DOI: 10.2337/dc14-0316.
increased risk of and worse outcomes with infections. 3. Clive S. Cockram, et al. Diabetes and Infections. In. Textbook of
Many aspects of neutrophil function are affected Diabetes. 4th edn. Oxford. Wiley-Blackwell. 2010. pp. 835-58.
4. John C Pickup. Inflammation and Activated Innate Immunity
in diabetes. Neutrophil function such as chemotaxis,
in the Pathogenesis of Type 2 Diabetes. Diabetes Care.
adherence to endothelium, phagocytosis, bactericidal 2004;27:813-23.
activity and opsonization are impaired in diabetes. The 5. Lício A Vellos, et al. Type 2 diabetes mellitus-an autoimmune
disturbance in the balance of oxidant and antioxidant disease? Nature Reviews Endocrinology. 2013;9:750-5.
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6. Marc Y Donath, Steven E Shoelson. Type 2 diabetes as 8. Paul A Davis, et al. Obesity and Immunity. In: Nutrition and
an inflammatory disease. Nature Reviews Immunology. Immunology. New York. Humana Press. 2000. pp. 295-301.
2011;11:98-107. 9. Sue Tsai, et al. Are Obesity-related Insulin Resistance
7. Marc Y Donath. Targeting inflammation in the treatment and Type 2 Diabetes Autoimmune Diseases? Diabetes
of type 2 diabetes: time to start. Nature Reviews Drug 2015;64:1886-97. DOI: 10.2337/db14-1488.
Discovery. 2014;13:465-76. 10. William T Cefalu. Inflammation, Insulin Resistance, and Type
2 Diabetes: Back to the Future? Diabetes. 2009;(58):306-7.
CHAPTER
48
Novel Therapeutic Approaches to
Preserve Beta Cell Function
in Diabetes Mellitus
Vijay Negalur
involve intra-islet inflammatory mediators mainly and function. It is still a matter of debate whether decline
cytokine interleukin [IL]-1β that trigger a common in beta cell mass or beta cell dysfunction is the major
pathway causing beta-cell apoptosis.9 underlying reason for beta cell failure.17 It is believed
In Asian Indians, this beta cell decline occurs more that considerable beta cell failure occurs at an early stage
rapidly. Staimez et al. used oral disposition index before diagnosis. Once beta cell failure is initiated, the
(DIO) to measure beta cell function and found a highly decline towards overt diabetes accelerates.18 In a study
significant difference between NGT and IFG or IGT by Butler AE et al., it was observed that obese individuals
even after adjustment for variables known to impact with IFG and T2D had 40% and 63% respectively
disease development. It was observed that Asian Indians lesser beta cell mass and volume when compared
with mild dysglycemia have marked reduction in beta- with non-diabetic individuals.19 Thus, owing to insulin
cell function which is independent of their age, family resistance and metabolic overload, the beta cells initially
history, adiposity or insulin sensitivity.10 try to compensate by increasing insulin secretion
T 1 D i s a n au t o i m mu n e d e s t r u c t i o n o n t h e but then eventually commence several pathological
pancreatic beta cells characterized by insulitis (beta-cell processes like glucotoxicity, lipotoxity and oxidative
inflammation) which leads to loss of most beta cells.11 It stress that synergistically achieve beta cell dysfunction
was common assumption in the past that 90% of beta cells and apoptosis.20
are destroyed from the time of clinical onset of disease
and as a rule less than 10% normal cells remained.12 THERAPEUTIC APPROACHES TO
However, there are accumulating data available to negate PRESERVE BETA CELL FUNCTION IN T1D
this assumption. In a recent study by Oram R et al., it was The ultimate aim in the course of T1D is to prevent
observed that, for more than 5 years, 73% of T1D patients autoimmunity or to prevent hyperglycemia in individuals
had detectable serum C-peptide 90 minutes post meal; whose beta cell destruction is already underway. This
indicating that majority of patients with T1D still retain a objective can be attained by preserving beta cell function.
some amount of functioning beta cells long after disease
onset.13 This amount of functional beta cells seem to Vitamin D Supplementation
correlate with the age of diagnosis of T1D. Massive beta Although numerous preclinical studies have shown
cell depletion at onset is only observed in children. A that Vitamin D supplementation has a beneficial effect
lesser decline in beta cells is observed when the age on insulin secretion and sensitivity, mixed results
of onset is above 15 years and this pattern remains have been observed in clinical trials. 21 Studies by
consistent through the subsequent years.14 The DiMelli Walter et al. on adult population and Bizzari et al. on
study by Thümer et al. also showed that a there exists adolescent population were unsuccessful in showing
a positive correlation between fasting C-peptide levels any beneficial effect of Vitamin D supplementation on
and age of onset of diabetes. Thus, it can be concluded beta cell function preservation.22,23 In a study by Gabbay
that more aggressive beta-cell destruction, and a higher et al., oral cholecalciferol 2000 IU/day for 18 months in
rate of metabolic decompensation is observed mainly in patients (6–16 years) with new onset T1D (<6 months)
younger patients.15 demonstrated slower decline of beta cell function after
T2D is a consequence of two main pathological vitamin D supplementation.24 One of the underlying
defects; impaired insulin activity caused by insulin mechanisms to preserve beta cells is by increasing the
resistance and dysfunction of pancreatic beta number of regulatory T cells (Tregs). Tregs are known
cells.16Although insulin resistance was assumed to be to secrete immune-modulatory cytokines and thus
the most important factor in T2D pathogenesis, recent suppress the process of autoimmune destruction of
evidences have highlighted that T2D mainly develops T1D.21In a recently published randomized controlled
due to deficiency and impairment in the beta cell mass trial, oral cholecalciferol 70 IU/kg/day for 12 months in
292 SECTION 3: Diabetes
patients (6–16 years) with new onset T1D (<3 months) improved stimulated C-peptide responses compared
was shown to lower the insulin needs and also improve with placebo group. This effect was strongest in patients
the suppressive capacity of the Tregs.25 that were randomized ≤6 weeks after diagnosis. 32
Although efficacious; it does not represent a cure for
Intensive Insulin Therapy patients. Thus, significant advances are required to halt
It has been observed that aggressive control on disease progression towards absolute insulin deficiency
glucose levels at the time of diagnosis preserves beta and reduce the dependence on exogenous insulin.31
cell function. 26 Shah et al. randomly assigned newly
diagnosed adolescents with T1D to receive conventional Anti-CD20
treatment or a glucose controlled insulin infusion Many diseases mediated by T-lymphocytes have a
system. After one year it was observed that, the mean B-lymphocyte constituent which plays a vital role as
plasma C peptide levels were significantly higher in the antigen presenting cells. Rituximab is an anti-CD20
insulin infusion system group than the control group.27 monoclonal that selectively depletes B-lymphocytes. A
Similar results were obtained in the DCCT study in phase II trial involving 87 patients with newly diagnosed
which T1D patients receiving intensive insulin therapy T1D, randomized to four weekly rituximab infusions
(IIT) had higher C-peptide levels and lower HbA1c levels or placebo showed that after one year, the rituximab
than patients receiving conventional therapy. Fewer group resulted in 20% elevation in C-peptide levels as
microvascular and macrovascular complications were compared with the placebo group. Significantly lower
observed in the IIT group compared to those receiving HbA1c levels were also observed in the rituximab group.
conventional therapy.28 Patients taking rituximab also required lesser insulin
to achieve better glycemic control.33 However, in a 30
Anti-CD3 month follow-up study, it was observed that C-peptide
Owing to the key role of T-cells in the pathogenesis of fall rate paralleled the fall observed in the control group.
T1D, T-cell directed therapies are extensively studied to This suggests that rituximab delayed that reduction
prevent or stop the progress of autoimmune processes in C-peptide levels but failed to alter the fundamental
involved in beta cell destruction. The anti-CD3 antibodies pathophysiology of the disease.34
treatment not only removes pathogenic T cells but can
also induce a state of operational tolerance by their CTLA-4
effects on regulatory T cells.29 Apart from the main antigen-driven signal, immune
Otelixizumab is one such anti-CD3 antibody that T-cells also require a costimulatory signal for complete
has shown been extensively studied. The phase I and activation. Abatacept is a CTLA-4-immunoglobulin
phase II trials showed positive safety and efficacy results fusion protein that modulates co stimulation and
for Otelixizumab, but the phase III trial results were prevents complete T-cell activation. A multicentric,
contradictory. Otelixizumab at high doses has shown randomized placebo controlled trial evaluated the
improvement in beta cell function but was accompanied efficacy of abatacept in recent onset T1D. Abatacept
with adverse effects. On the contrary, lower doses of the group had 59% higher levels of stimulated C-peptide
drug tested to avoid the associated adverse effects were than the placebo group; thus indicating that abatacept
not effective in beta cell preservation.30 slowed reduction in β-cell function over 2 years. HbA1c
Another anti-CD3 monoclonal antibody, Teplizumab, values were lower in the treatment group but insulin
has shown to preserve the C-peptide levels and reduce use was similar in both the groups.35 Similar results were
the need for exogenous insulin. 31 Results from the obtained post 1 year cessation of treatment implying that
Protégé Trial showed that after 2 years, patients who the effect of abatacept on beta cell function continued for
received a 14 day full dose of teplizumab significantly at least 1 year after cessation of therapy or 3 years from
CHAPTER 48: Novel Therapeutic Approaches to Preserve Beta Cell Function in Diabetes Mellitus 293
T1D diagnosis. However, as observed in anti-CD3 and 1RAs may have a role in increasing proliferation and
anti-CD20 antibodies, the rate of C-peptide fall in the differentiation of beta cell and in decreasing the rate
treatment group paralleled the decline in the placebo of beta cell apoptosis as an add-on to insulin therapy.
group after 9 months.36 However, long term randomized clinical trials are
required to further evaluate the application of GLP-1RAs
TUMOR NECROSIS FACTOR-α in TID.41
(TNF-α) AGONIST
Evidences from in vitro studies and animal models THERAPEUTIC APPROACHES TO
indicate that Tumor necrosis factor-α (TNF-α) play a PRESERVE BETA CELL FUNCTION IN T2D
role in the autoimmune process leading to pancreatic Declining beta cell function coupled with hyperglycemia
destruction. A pilot study was carried out to study the and insulin resistance characterizes T2D. However, early
efficacy and feasibility of etanercept therapy to extend metabolic control may help improve and preserve beta
endogenous insulin production in new onset pediatric cell function.
T1D patients. It was observed that, at week 24, etanercept
group had significantly lower HbA1c levels than the Early Short-term Intensive
placebo group. Etanercept group also had 39% higher Insulin Therapy
C-peptide levels. On the other hand, a 20% reduction The objective of providing early short-term intensive
in C-peptide levels was observed in the placebo group. insulin therapy (IIT) in T2D is to induce a state glycemic
Although the data suggests that etanercept preserves remission, wherein the patients maintain normal
beta cell function, larger studies may be required to glycemic levels without any antidiabetic drugs after
further assess the efficacy and safety.37 stopping IIT. Most studies involve a short term IIT for 2–5
weeks in newly diagnosed T2D patients. It was observed
Interleukin 2 that major proportion of newly diagnosed patients
Various immunological Interleukin 2 (IL-2) studies have achieved remission with this therapy.42
implied that deficiencies in receptor and its signaling A meta-analysis of 7 studies involving 899 patients
pathway deficiency may play an important role in T1D showed that post IIT, an increased beta-cell function and
pathogenesis.38 NOD mouse studies have also shown decreased insulin resistance was observed. Four of those
that combining IL-2 with sirolimus prevents and reverse studies showed that, after the glycemic remission rates
T1D by augmentation of IL-2 signaling.39 However, the were 66·2%, 58·9%, 46·3% and 42.1% after 3,6,12 and 24
results obtained in the phase I study that involved IL-2 months respectively. Thus, short term IIT can improve
and sirolimus were conflicting. It was observed that the insulin resistance as well as beta cell function (Fig. 2).43
IL-2-sirolimus combination demonstrated a decrease
in C-peptide levels for the first 3 months. Surprisingly, Dipeptidyl Peptidase-4 Inhibitors
the C-peptide levels eventually increased in almost all Dipeptidyl peptidase-4 inhibitors (DPP4i) are a
subjects indicating that decrease in C-peptide levels was promising therapeutic option for T2D. DPP4i prevent
only temporary.40 incretin hormone degradation (mainly GLP-1) which
results in reduced glucose and glucagon levels and
Glucagon-like Peptide-1 Receptor increased insulin levels.44 More and more evidences have
Agonist (GLP-1RA) now suggest that DPP4i may play a part in preservation of
Although approved for only T2D, glucagon like peptide-1 beta cell function.
receptor agonist (GLP-1RA) could have beneficial effects In a recent meta-analysis involving 52 clinical trials,
in both new onset and longstanding T1D patients. From it was observed that, DPP4i as a monotherapy and as an
various preclinical studies, it is observed that GLP- add-on therapy to other drugs had significantly improved
294 SECTION 3: Diabetes
observed with imeglimin may be due to improves β-cell delay disease progression. In this context, this review
function.55 tries to throw light on the various therapeutic approaches
aimed to preserve beta cell function in Type 1 diabetes
AS1842856 and Type 2 diabetes.
AS1842856 is a forkhead transcription factor forkhead A multimodality approach appears to be necessary
box O1 (Foxo1) inhibitor that has been orally effective to slow or arrest the progression of beta cell destruction
in diabetic db/db mice by causing a marked decrease in TID. Vitamin D supplementation has shown to slow
in fasting plasma glucose level. Foxo1 is essential in down the decline of beta cell function. However, early
mediating the effect of insulin on gluconeogenesis aggressive glucose control via IIT at the time of disease
in liver. It is suggested that suppressing the Foxo1 diagnosis has only resulted in temporary restoration
activity reduces hepatic gluconeogenesis and thus of endogenous insulin production. Several immune-
improves hepatic insulin action and peripheral glucose modulatory agents like otelixizumab, teplizumab,
metabolism.56 rituximab, abatacept, etanercept and IL-2 have also
been evaluated and have shown to slow down the rate
Anakinra of beta cell destruction. However, these effects waned
Anakinra is an interleukin-1b receptor antagonist that off over time and insulin secretion was parallel in both
has shown to improve glyemia and beta cell function. placebo-treated groups. Although a new therapy has
IL-B2 is a proinflammatory cytokine that is produced not been recognized that can be clinically applied for
as a result of hyperglycemia and it is implied that IL- T1D treatment, a lot of progress has been made towards
B2 inhibits beta cell function and promotes beta cell achieving the goal of beta cell preservation.
apoptosis. In a study by Larsen CM et al., it was observed In T2D, early IIT based therapy is one of the
that once daily anakinra significantly reduced HbA1c approached to cause temporary remission. This concept
values, increased C-peptide secretion and reduced the have yielded a new therapeutic strategy, wherein we first
proinsulin to insulin ratio.57 provide ‘induction’ therapy for early improvement in beta
cell function and then ‘maintenance’ therapy intended
Sinogliatin to preserve this beneficial beta-cell effect. Various oral
Sinogliatin or dorzagliatin is a novel fourth generation antidiabetic drugs like incretin based analogues, TZDs
glucokinase activator that has shown a potential role in and SGTL2i have shown to prevent or delay the onset of
the treatment of T2D. Glucokinase is a critical enzyme disease by preserving beta cell function. There are also
that involved in the regulation of both hepatic glucose newer molecules such as imeglimin, AS1842856, anakinra
production and insulin secretion. Thus, glucokinase and sinogliatin that have shown promise but large scale
is an attractive target T2D treatment. Preclinical study randomized trials are essential to confirm these claims.
by Wang P et al., suggested that sinogliatin displays its To conclude, the onset of both T1D and T2D involve
antidiabetic effects by improving glucokinase activity significant loss of functional β-cell mass. A better
and insulin resistance via liver and pancreas.58 Although understanding of β-cell mass and the various protective
mechanisms for improving β-cell function will help
Sinogliatin is currently in Phase III trial, the results of
develop newer therapeutic approaches that will be
the Phase 1 and II trials are unavailable in the public
helpful for modulating the natural progression of these
domain.59
diseases in the future.
DISCUSSION
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31. Vudattu N, Herold K. Treattment of new onset type 1 review and meta-analysis. Lancet Diabetes Endocrinol.
diabetes with teplizumab: successes and pitfalls in 2013;1(1):28-34.
development. Expert Opinion on Biological Therapy. 44. Gothwal S, Khosya S. DPP 4 (dipeptidylpeptidase-4)
2014;14(3):377-85. inhibitors: beyond glycemic control. Iosr Journal of
32. Hagopian W, Ferry R, Sherry N, Carlin D, Bonvini E, Johnson Pharmacy. 2013;3 (3):81-5.
S et al. Teplizumab preserves c-peptide in recent-onset Type 45. Lyu X, Zhu X, Zhao B, Du L, Chen D, Wang C et al.
1 diabetes: two-year results from the randomized, placebo- Effects of dipeptidyl peptidase-4 inhibitors on beta-cell
controlled protege trial. Diabetes. 2013;62(11):3901-8. function and insulin resistance in type 2 diabetes: meta-
33. Pescovitz M, Greenbaum C, Krause-Steinrauf H, Becker analysis of randomized controlled trials. Scientific Reports.
D, Gitelman S, Goland R, et al. Rituximab, B-lymphocyte 2017;7:44865.
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England Journal of Medicine. 2009;361(22):2143-52. peptide-1 receptor agonists on β-cell function in patients
34. Pescovitz M, Greenbaum C, Bundy B, Becker D, Gitelman with Type 2 diabetes. Journal of Diabetes & Metabolism.
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and β-cell function: two-year results. Diabetes Care. 47. Gupta D, Kono T, Evans-Molina C. The role of peroxisome
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35. Orban T, Bundy B, Becker D, DiMeglio L, Gitelman S, Goland and survival: therapeutic implications for the treatment of
R, et al. Co-stimulation modulation with abatacept in type 2 diabetes mellitus. Diabetes, Obesity and Metabolism.
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2011;378(9789):412-9. function in the management and prevention of Type 2
36. Orban T, Bundy B, Becker D, DiMeglio L, Gitelman S, Diabetes. Current Diabetes Reports. 2013;13(2):252-60.
Goland R, et al. Costimulation modulation with abatacept 49. Buchanan T, Xiang A, Peters R, Kjos S, Marroquin A,
in patients with recent-onset type 1 diabetes: Follow- Goico J. et al. Preservation of pancreatic-cell function and
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2013;37(4):1069-75. of insulin resistance in high-risk hispanic women. Diabetes.
37. Mastrandrea L, Yu J, Behrens T, Buchlis J, Albini C, Fourtner 2002;51(9):2796-803.
S et al. Etanercept treatment in children with new-onset 50. Xiang A, Peters R, Kjos S, Marroquin A, Goico J, Ochoa C,
Type 1 diabetes: Pilot randomized, placebo-controlled, et al. Effect of pioglitazone on pancreatic β-cell function
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38. Hulme M, Wasserfall C, Atkinson M, Brusko T. Central role for diabetes. Diabetes. 2006;55(2):517-22.
interleukin-2 in Type 1 diabetes. Diabetes. 2011;61(1):14- 51. DeFronzo R, Banerji M, Bray G, Buchanan T, Clement
22. S, Henry R, et al. Determinants of glucose tolerance in
39. Shapiro A, Suarez-Pinzon W, Power R, Rabinovitch impaired glucose tolerance at baseline in the Actos Now
A. Combination therapy with low dose sirolimus and for Prevention of Diabetes (ACT NOW) study. Diabetologia.
tacrolimus is synergistic in preventing spontaneous and 2009;53(3):435-45.
recurrent autoimmune diabetes in non-obese diabetic mice. 52. Singh H, Thangaraju P, Singh J, Kaushal S. Canagliflozin:
Diabetologia. 2002;45(2):224-30. A novel SGLT2 inhibitor for type 2 diabetes mellitus. North
40. Long S, Rieck M, Sanda S, Bollyky J, Samuels P, Goland R, American Journal of Medical Sciences. 2014;6(3):107.
et al. Rapamycin/IL-2 combination therapy in patients with 53. Polidori D, Mari A, Ferrannini E. Canagliflozin, a sodium
type 1 diabetes augments tregs yet transiently impairs-cell glucose co-transporter 2 inhibitor, improves model-based
function. Diabetes. 2012;61(9):2340-8. indices of beta cell function in patients with type 2 diabetes.
41. Popovic D, Stokic E, Popovic S. GLP-1 receptor agonists Diabetologia. 2014;57(5):891-901.
and Type 1 diabetes - where do we stand? Current 54. Merovci A, Mari A, Solis C, Xiong J, Daniele G, Chavez-
Pharmaceutical Design. 2015;21(36):5292-8. Velazquez A. et al. Dapagliflozin lowers plasma glucose
42. Retnakaran R. Emerging strategies for the preservation concentration and improves β-cell function. The Journal
of pancreatic beta-cell function in early Type 2 diabetes. of Clinical Endocrinology and Metabolism. 2015;100(5):
Clinical and Investigative Medicine. 2014;37(6):414. 1927-32.
298 SECTION 3: Diabetes
55. Pacini G, Mari A, Fouqueray P, Bolze S, Roden M. Imeglimin 2 diabetes mellitus. New England Journal of Medicine.
increases glucose-dependent insulin secretion and 2007;357(3):302-3.
improves β-cell function in patients with type 2 diabetes. 58. Wang P, Liu H, Chen L, Duan Y, Chen Q, Xi S. Effects of
Diabetes, Obesity and Metabolism. 2015;17(6):541-5. a novel glucokinase activator, hms5552, on glucose
56. Nagashima T, Shigematsu N, Maruki R, Urano Y, Tanaka metabolism in a rat model of Type 2 diabetes mellitus.
H, Shimaya A, et al. Discovery of Novel Forkhead Box Journal of Diabetes Research. 2017;2017:1-9.
O1 Inhibitors for Treating Type 2 Diabetes: Improvement 59. Long-term efficacy and safety of HMS5552 in T2D
of Fasting Glycemia in Diabetic db/db Mice. Molecular - Full Text View - ClinicalTrials.gov [Internet]. Clinical
Pharmacology. 2010;78(5):961-70. t r i a l s . g o v . 2 0 17 [ c i t e d 3 0 N o v e m b e r 2 0 17 ] .
57. Larsen CM1, Faulenbach M, Vaag A, Vølund A, Ehses JA, Available from: https://clinicaltrials.gov/ct2/show/
Seifert B, et al. Interleukin-1–receptor antagonist in type NCT03173391?term=HMS5552&phase=2&rank=1
CHAPTER
49
Management of Diabetes in
Resource Crunch Countries
G Prakash
issues and health economic factors, there is difficulty poor socioeconomic condition, the most common cause
in diagnosis of disease in developing world. Population of death in type 1 diabetes is lack of access to insulin.6
diagnosis is not practical across the entire rural areas Educating diabetic patient is the effective and integrated
particularly in India which represent a large population. part of diabetes therapy.
Involve health care providers in free medical camp both
in government and nongovernment sectors. Encourage PHARMACOLOGIC MANAGEMENT:
nondiabetic subjects to report for medical check-up and ORAL ANTIDIABETIC DRUGS
screening for Diabetes. Simple, noninvasive diabetes risk International guidelines recommend that the treatment
score is also available for identifying people with high of the diabetes should be individualized based on the
risk of diabetes. safety, efficacy, tolerability and economical condition
Indian Diabetes Risk Score (IDRS) is one among of patient. Currently, there are no ideal drug which can
the numerous risk scores and other low-cost tools for achieve required glycemic target. The ideal agent should
screening diabetes in the general population which has be inexpensive, effective, potent and safe.
been shown to be a cost-effective method of screening
for undiagnosed diabetes in the community.4 Metformin
American Diabetes Association also recommend Metformin is the first line therapy for treatment of
an assessment tool. ADA risk test for screening5 of type diabetes. Metformin is the oldest drug which provided
2 DM. Hence, it is reasonable to screen asymptomatic effective glycemic control and prevents further
individual for prediabetes or diabetes. cardiovascular and diabetes associated complications.
Has lower risk of hypoglycemic events. if there is no sustainable and affordable intervention in
Exhibit a higher exchange rate and lower binding Diabetes Management. The effective treatment should
affinity to beta cells. also consider political, cultural and social issues with
Secrete smaller amounts of insulin in fasting and the patient population. Diabetes is emerging as 21st
postprandial state. century challenge. This has to be fought with greater
understanding of the disease pathophysiology, proper
Pioglitazone diagnosis and easy access to available therapies.
The only other drug besides Metformin reduces insulin
resistance. It improves CV risk factors like ↑ HDL, ↓ TGL, REFERENCES
↓ inflammatory mediators beyond glycemic control. The 1. World Health Organization Care health indicators; the
increased incidence of bladder cancer with pioglitazone latest data from multiple WHO sources. United Republic of
in diabetic patients is still a debatable.12 Tanzania. Geneva, WHO 2006.
2. International Diabetes Federation IDF. Diabetes Atlas, 2015.
3. Paul Grant P. Management of Diabetes in resource poor
Insulin settings. Clinical Medicine. 2013;13(1):27-31.
Insulin is the mainstay for treatment of Type-1 DM, 4. Sharma KM, Ranjani H, Ngujen Ha, Shetty S, Dutta M, et al.
secondary drug failure in T2DM, acute metabolic Indian Diabetes Risk Score helps to distinguish Type-1 from
decompensation and diabetic pregnancies. The Non-Type 2DM Journal of Diabetes Science and Technology.
challenges in Type-1 DM are affordability, self- 2001;5:419-25.
5. American Diabetes Association. 2. Classification and
monitoring of blood glucose, storage of insulin and
Diagnosis of Diabetes. Diabetes Care. 2017;40(Suppl
cultural issues regarding self-injection. The need
1):S11-S24.
for consumables such as clean needles and insulin 6. Misra P, Upadhyay RP, Misra A, Anand KA. A review of the
syringes is a major problem. The barriers can be solved epidemiology of Diabetes in rural India. Diabetes Res Clin
by providing patient education utilizing health care Pract. 2011;92(3):303-11.
workers and educators. Landmark studies DCCT and 7. Abrahamson MJ. Should Sulfonylureas remain an
UKPDS done with conventional insulin alone highlights acceptable first line add on to Metformin therapy in patients
with Type 2 diabetes? Yes, they continue to serve as well!
the importance of glycemic control in prevention of
Diabetes Care. 2015;38:166-9.
complication. The government can provide insulin free 8. Prevention and Control of Non-Communicable Diseases:
of cost to poor needy patients who require insulin as Guidelines for Primary health Care in low resource settings
that is being followed by government of Tamil Nadu. WHO – 2012.
The government and various welfare organizations can 9. Ganji AS, Cukierman J, Gestein HC, Goldsmith CH, Clase
help in providing newer antidiabetic drugs like DPP4 CM. A systematic review and meta-analysis of hypoglycemia
inhibitors, SGLT-2 inhibitors and insulin analogs which and cardiovascular event: a comparison of glyburide with
other secretogogues and with Insulin. Diabetes Care.
had been highlighted for its cardio-vascular benefits
2009;30: 389-94.
besides glycemic control. 10. Lim PC, Chong CP. What next after Metformin? Focus on
therapy, Pharm Pract (Granada). 2015;13(3):606.
CONCLUSION 11. Van Dalem J, et al. Risk of hypoglycemia in users of
There is increasing prevalence of diabetes worldwide. Sulfonylureas compared with Metformin in relation to renal
Owing to the diverse factors in the resource crunch function and sulfonylurea metabolite group: Population
based cohort study. BMJ. 2016;354:3625.
countries, the disease management in challenging.
12. Balaji V, Seshiah V, Astalakshmi S, Ramanan SG,
Current research is focused on expensive new antidiabetic
Janar thinakani M. A retrospective study on finding
drugs which is unaffordable for majority of patients in correlation of pioglitazone and incidences of bladder
poor countries. The frequency of both microvascular cancer in Indian population. Indian J Endocrinol Metab.
and macrovascular complications will increase globally 2014;18(3):425-7.
CHAPTER
50
Exercise Prescription for Lifestyle
Diseases: A Cornerstone
Anil Kumar Virmani
after every thirty minutes of sedentary activity, they oxygen, improves cardiorespiratory fitness, increases the
should undertake atleast three minutes of some light threshold for lactic acid accumulation, and decreases
activity. The focus is to increase the physical activity blood pressure and body fat (Brisk walking, jogging,
during the office hours, traveling time, and also 15–20 minutes of continuous activity).
during the leisure time
Even, those who perform at least 150 minutes of Flexibility Exercise Like Yoga
moderate-intensity activity or 75 minutes of vigorous-
Recommendations for Asian Indians
intensity activity weekly during one or two sessions
Be active as far as possible and cut down on your
have 30% DECREASE in all-cause, CV and cancer
sedentary time, like reducing time to watch television,
mortality. They are also known as “weekend warriors”.
or working on computer, etc.
The health benefits of exercise are enormous, ranging
In presence of any cardiovascular disease or diabetes,
from low risk of noncommunicable diseases, colon and
always consult your doctor for medical advice
breast cancers, cognitive impairment, depression to
overall mortality, in both adolescents and adults. regarding type, duration and intensity of exercise.
Asian Indians require atleast one hour of exercise
Regular physical exercise releases a myokine
called Irisin, decreases visceral fat, increases cortisol daily, inclusive of all types of exercise, in comparison
and adrenaline and decreases expression of Toll-like to the ADA guidelines of 30 minutes.
Duration of exercise can be spread throughout the
receptors. These lead to a decrease in the proinflammatory
cytokines production and acute decrease in IL-6, leading day, with at least 10 minutes of exercise at one time.
Brisk walking is the best form of exercise, as it can be
to reduced systemic inflammation. Moreover, Irisin
promotes “browning” of mature adipocytes and scWAT done by everyone.
Physically intensive Yoga exercises should be
and increases cellular thermogenesis of adipocytes, but
inhibits adipogenesis and promotes osteogenesis during encouraged but more research is required in this
lineage-specific differentiation. area.
Exercise also increases noninsulin dependent It should be a structured, graded and individualized
glucose uptake of glucose called contraction-mediated exercise training depending on the needs of an individual.
uptake (CMGU), with the ultimate result that along with
Measures to increase physical activity:
insulin-signalling pathways, it leads to additive effects,
Reduce the screen/TV time to < 30 m/day
thus increasing glucose uptake by skeletal muscle. The
Take stairs instead of Lift/Escalator
types of exercise are:
Walk in the office for atleast 5 min every hour
Anaerobic exercise: In this, oxygen is not used for energy. Avoid prolonged sitting
It is a form of intense physical activity in which the Use cycle for nearby activities
body’s supply of oxygen to produce energy does not meet Park your car a distance from the shopping venue
flexibility. It can be: (a) Isometric–little or no movement No patient should leave a physician’s practice
(muscle tension; pushing against wall); (b) Isotonic– without: An assessment of current physical activity
repeated movements using weights (push-ups); (c) levels—and—a physical activity prescription and/or
Isokinetic–resistance is moved through entire range of referral to qualified resources for further counseling.
motion; (hydraulic).
Aerobic exercise: Continuous activity that uses oxygen. It Exercise is a Medicine
increases blood supply to muscles and ability to utilize Physicians should prescribe it, patients should take it!
304 SECTION 3: Diabetes
Plasma lipoproteins
Apo A-1
Apo B48 chylomicrons Apo B100 Apo B100 Apo B100 Apo B100 HDL
and remnants VLDL IDL LDL LP(a)
Non-HDL-C
accurate predictor of ASCVD risk as compared to to be the most common lipid abnormality in T2DM
LDL-C. Several large scale studies have indeed proven patients with CV events. Non-HDL-C was the most
this hypothesis 5-9 showing that non-HDL-C is a much common lipid abnormality among T2DM patients with
stronger predictor of all-cause and ASCVD mortality as CV events. Elevated non-HDL-C was 21.6% among
compared to LDL-C. For example, in the lipid Research patients who were on statin therapy with optimal LDL-C
Clinics Program, 4462 middle aged individuals who levels. Despite an optimal LDL-C level, 47% of the T2DM
were free from ASCVD were followed up for an average patients with CV events had elevated non-HDL-C.10
of 19 years.5 It was found that non-HDL-C was a much Non-HDL-C seems to predict ASCVD risk equally
stronger predictor of ASCVD outcomes as compared well regardless of TG levels. Though , EPICNORFOLK
to LDL-C (chi-square 24.3 for non-HDL-C and 5.0 for [European Prospective Investigation into Cancer and
LDL-C). A 30 mg/dL increase in non-HDL-C resulted in Nutrition–Norfolk] Study projected predictive accuracy
19% increase in mortality in men and 11% increase in of NON-HDL-c in patients with relatively low TG [200
women compared to 15 and 8% respectively for LDL-C, mg/dL], the SHEP [Systolic Hypertension in the Elderly
In other studies, non-HDL-C has been shown to correlate Program] study confirmed the same relationship in
well with subclinical atherosclerosis also, detected either patients with elevated TG levels [400 mg/dL]. Thus,
by imaging studies or assessed during autopsy. while the EPICNORFOLK (European Prospective
Non-HDL-C is particularly informative in diabetics Investigation into Cancer and nutrition–Norfolk)
who tend to higher TG levels, and thus have a greater study confirmed predictive accuracy of non-HDL-C in
difference between LDL-C and non-HDL-C. A post-hoc patient with relatively low TG (<200 mg/dL), the SHEP
analysis of 4 large prospective studies – The Framingham (Systolic Hypertension in the elderly Program) study11
Cohort Study, The Framingham off Spring study, The documented the same in those who had elevated TG
lipid research Clinics Program follow-up study and (>400 mg/dL). In contrast, in the SHEP study, LDL-C
Multiple Risk factor intervention trial—that included a lost its predictive value when TG levels exceeded
total of 19381 individuals showed that compared to non- 400 mg/dL.
diabetics, the diabetic subjects had significantly higher Non-HDL-C has also been compared with Apo B for
non-HDL-C levels. On multivariate analysis, ASCVD risk its ability to predict ASCVD risk, Since all atherogenic
in diabetics increased with elevation in non-HDL-C but lipoproteins, whether LDL, VLDL or Lp (a), contain one
not LDL-C. molecule of Apo B, Apo B is considered to be the most
Presence of elevated non-HDL among patients with accurate predictor of ASCVD risk. This was confirmed
T2DM with CV events despite of optimal LDL-C has by the INTERHEART study which showed that the ratio
been reported recently from South India. Conclusion of of Apo B to Apo A-I (the protein moiety present in HDL)
this research letter: Non-HDL in this study was found was the strongest determinant of MI risk in the studied
CHAPTER 51: Nonhigh–Density Lipoprotein Cholesterol: Primary Target for Lipid Lowering 307
Target level
Fig. 2: Meta-analysis of 8 trials: 4S, AFCAPS, LIPID, CARDS, TNT, IDEAL SPARCL, JUPITER
individuals.12 Since, non-HDL-C measures cholesterol analysis is strongly associated with increased risk of
component of all Apo B containing lipoprotein, it future CV events even if LDL is brought under control
correlate with the circulating level of Apo B. In the with statins. 100 mg/dL Non-HDL-C is associated with
Women Heart Study, the highest quintile on non-HDL-C increased risk of future CV events, even if LDL is under
had similar relative risk for major ASCVD events as control with statins.14
the highest quintile of Apo B. However, in the Health
Professionals follow-up study, non-HDL-C was found OTHER ADVANTAGES OF NON-HDL-C
to be an inferior predictor of CV events as compared to Apart from being a wholesome ASCVD risk marker, non-
Apo B.13 Nevertheless, it is important to that in both these HDL-C offers several other advantages that are relevant
studies, non-HDL-C was a better predictor of ASCVD risk to clinical practice:
than LDL-C. Estimation of non-HDL-C does not require any
Finally, there is robust evidence to show that non- additional testing. It can be easily calculated by
HDL-C is an accurate predictor of residual ASCVD risk subtracting HDL-C from total cholesterol.
in patients already on statin therapy. A meta-analysis of Unlike LDL-C, measurement of non-HDL-C does
62154 statin treated patient in 8 trials published between not need fasting blood sampling because both total
1994 and 2008 revealed that one standard deviation cholesterol and HDL-C are not acutely affected by
increase in LDL-C, Apo B and non-HDL-C increased feeding.
the risk of CV event by 13%, 14% and 16% respectively Since non-HDL-C includes both LDL-C and the
indicating that the strength of association with ASCVD TG rich non-LDL lipoproteins, using a non-HDL-C
was greater for non-HDL-C than for LDL-C or even based approach obviates the need to look at TG
Apo B. The results of this meta-analysis are depicted in levels separately. Furthermore, focusing on non-
Figure 2. People who had LDL levels < 100 mg/dL with HDL-C simplifies the management of LDL and other
Non-HDL level of ≥ 130 mg/dL had hazard ratio of 1.32 lipoproteins which are atherogenic. Furthermore,
indicating CV risk of 32% when compared to people as LDL-C is the major component of non-HDL-C,
who had uncontrolled LDL levels of > 100 mg/dL with focusing on non-HDL-C maintains focus on LDL-C
Non HDL level of ≤ 130 mg/dL who had hazard ratio of Non-HDL includes the risk created by small dense
1.02 indicating CV risk of 2%. Non-HDL-C in this meta- LDL-C which are more atherogenic than large
308 SECTION 3: Diabetes
buoyant LDL particles. When there is increase in TG HDL-C as the primary target for therapy.21 The primary
there is always an increase in small dense LDL-C. reason for this is that these guidelines have focused
The values of LDL which we normally get from on ASCVD-risk based approach rather than lipid-level
Labs do not provide information on small dense based approach for initiation and follow-up of statin
LDL-C. Elevated Non-HDL C is now considered as a therapy. Now 2016 ACC Expert consensus decision
surrogate for an elevated TG which indirectly covers pathway on the role of non-statin therapies for LDL-C
small dense LDL-C also covers, to some extent, the lowering management of ASCVD risk changed the
excess ASCVD risk imparted by the small dense form recommendations: Due to the frequency of elevated
of LDL, which is significantly more atherogenic than non-HDL-C despite near normal levels of LDL-C in
the normal large buoyant particles. Small dense LDL diabetics, non-HDL-C thresholds are included in
is the dominant form of LDL particles in patients high-risk patients. Ezetimibe is preferred as the initial
with elevated TG levels.15-17 Unfortunately, LDL-C non-statin therapy due to its tolerability, convenience,
levels do not provide any information about the LDL and single-tablet daily dose. Colesevelam has a modest
particle size but an elevated non-HDL-C, being a hypoglycemic effect that may be of benefit in some
surrogate for elevated TG, indirectly suggests greater diabetic patients with fasting triglycerides <300 mg/dL
proportion of the small dense variety of LDL particles. or in patients who are ezetimibe intolerant.22 2016 ESC/
EAS Guidelines for the management of dyslipidemias
What do the Guidelines Suggest? emphasized on non-HDL-C. The secondary targets
Based on the accumulated and emerging evidence, it is are 100,130 and 145 mg/dL for very high, high, and
being increasingly recognized by most experts worldwide moderate-risk subjects, respectively. If the goal is
that non-HDL-C would be a better target for lipid lowering not reached, statin combination with a cholesterol
therapy than LDL-C alone. Most of the current guidelines absorption inhibitor should be considered. If the goal
have incorporated this in their recommendations. The is not reached. Statin combination with a bile acid
JBS3 consensus recommendations for the prevention sequestrant may be considered.23
of ASCVD state that non-HDL-C should be used in
preference to LDL-C as the treatment goal for lipid What should be Recommended
lowering therapy.18 Following the same concept, the 2014 for Indians?
National Institute for Health and Clinical Excellence Several studies have shown that Indian have high
(NICE) lipid management guidelines recommend –“… prevalence of diabetes, obesity and metabolic syndrome,
before starting lipid modification therapy for the primary all of which are characterized by high TG levels,
prevention of ASCVD, take at least 1 lipid sample low HDL-C and higher prevalence of small dense
to measure a full lipid profile. This should include LDL particles, which is also known as atherogenic
measurement of total cholesterol, HDL-C, non-HDL-C dyslipidemia. High prevalence of elevated TG and low
and TG concentrations. A fasting sample in not needed”. HDL-C has been documented in various epidemiological
Similarly, the U.S National Lipid Association guidelines studies conducted in Indian subjects.24 For this reason, it
have also placed a greater emphasis on non-HDL-C than appears that non-HDL-C is likely to be an important
LDL-C.19 The International Atherosclerosis Society has target for the therapy for Indians. Furthermore, even
also recommended non-HDL-C alongside LDL-C as a though most of the trials have shown ASCVD risk
target for therapy.20 reduction mainly with statins, there is evidence from
However, the recently published ACC/AHA guidelines other studies that addition of a fibrate to statin therapy
for lipid management, in 2013, have not provided any leads to incremental ASCVD risk reduction in patients
specific recommendation about using LDL-C or non- with atherogenic dyslipidemia . Accordingly the lipid
CHAPTER 51: Nonhigh–Density Lipoprotein Cholesterol: Primary Target for Lipid Lowering 309
Association of India recommends non-HDL-C as a co- non-HDL after LDL goal will be appropriate approach in
primary target, as important as LDL-C, for lipid lowering managing lipids at this point of time.
therapy in indians. In all Individuals, the non-HDL-C
level should be kept within 30 mg/dL of LDL-C levels. REFERENCES
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The lipid association of India recommends non-
4. Libby P. The forgotten majority: Unfinished business
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practical tool for treatment decisions relating to lipid- lipoprotein cholesterol level as a predictor of cardiovascular
disease mortality . Arch Intern Med. 2001;161:1413-9.
lowering therapy since it does not require a fasting
6. Liu J, Sempos CT, Donahue RP, Dorn J, Trevisan M, Grundy
blood sample and takes care of both LDL-C and TG
SM. Non-high density lipoprotein and very low density
targets. lipoprotein cholesterol and their risk predictive valued in
In all individuals, the non-HDL-C levels should be
coronary heart disease. Am J Cardiol. 2006;98:1363-8.
kept within 30 mg/dL of LDL-C levels 7. Liu J, Sempos, Donahue RP, Dorn J, Trevisan M, Grundy
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or non-HDL-C
21.
Increasing the dosage of statins or switching to a
8. Bittner V, Hardison R, Kelsey SF, Weiner BH, Jacobs AK, sopko
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HDL cholesterol, apolipoproteins a-I and b100 standard
or a fibrate should be considered when above
lipid measures, lipid ratios, and crp as risk factors for
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CONCLUSION 10. Satyavani Kumpatla, Anju Soni, SN Narasingan, Vijay
Non-HDL should be considered as a primary target in Viswanathan. MV Hospital for Diabetes and Prof. M.
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LDL and hence, both are considered atherogenic
11. Frost PH, Davis BR,Burlando AJ, et al. Serum lipids and
lipoproteins. Moderate to high dose statins will help incidence of coronary heart disease Findings from the
to bring down non-HDL levels. Residual risk requires systolic hypertension in the elderly program [SHEP].
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310 SECTION 3: Diabetes
12. Yusuf S Hawken S, Ounpuu S, et al. Effect of potentially 20. An International Atherosclerosis society position
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14. Boekholdt SM, Arsenault BJ, Mora S, et al. Association of LDL report of the American College of Cardiology/American
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69. 2016;64(3):19-21.
SECTION
4
Endocrinology
Growth Hormone Replacement Therapy: Current Primary Hypoparathyroidism and its Management
Recommendations Ajay Aggarwal, Roopak Wadhwa
Minal Mohit
A New Look at Testosterone Therapy in Aging
Vitamin D Therapy: Hope or Hype Males
PK Sasidharan DC Sharma
Approach to a Patient with Short Stature Lipohypertrophy Secondary to Insulin Injection
Indira Maisnam Therapy
Sunil Gupta
Logical Approach to Thyroid Nodule
KJ Shetty, KN Manohar
CHAPTER
52
Growth Hormone Replacement Therapy:
Current Recommendations
Minal Mohit
ejection fraction, and abnormal left ventricular diastolic zz Decreased exercise capacity
zz Increased anxiety
METABOLIC COMPLICATIONS zz Lack of energy levels
Patients with GHD have elevated levels of total and low zz Social isolation
controls,29-32 COGHD results in reduced bone mass in GH is traditionally stopped. Retesting of the GH reserve
adult life33,34 and patients with AOGHD have an increased is appropriate to consider for most children once they
prevalence of fracture rates. GH replacement improves have attained final height. Re-evaluation of GH status at
radial BMD in 12 months and at trabecular sites in 18–24 final height is advised after GH has been discontinued
months, also reducing fracture risk.34-38 Measurement of for at least 1 month. ITT is recommended as a first-line
bone mineral content and BMD in GH-deficient patients stimulation test, many other stimulation tests have been
is therefore recommended before starting GH therapy. proposed as alternatives, including GHRH combined
Bone remodels slowly; therefore, the first DEXA scan with arginine (GHRH+ARG), glucagon, or ARG tests
after initiation of GH replacement should be conducted alone. A substantial proportion of children with isolated
about 2 years later, and could be repeated at 2- to 3-year idiopathic GHD recover normal GH reserve by the time
intervals thereafter. Long-term beneficial skeletal effects final height is attained.47,48 This is particularly likely in
of GH in combination with bisphosphonates or GH alone those previously diagnosed with partial GHD (i.e. peak
on BMD of up to 7 years’ duration have been shown in GH between 9 μg/L and 16.5 μg/L) on dynamic testing.
various studies.39,40 Patients with multiple pituitary hormone deficits, with
or without structural pituitary or peripituitary disease,49
QUALITY OF LIFE and/or previous cranial radiation therapy are more likely
Adults with COGHD and AOGHD experience to have ongoing GHD.48 However, there clearly exists a
diminished QOL in comparison with the normal group of patients with isolated GHD in childhood who
population.2 Reductions in physical and mental energy, subsequently satisfy the criteria for severe GHD when
dissatisfaction with body image, and poor memory retested as adults, and rarely, a group of children with
have been reported. 41,42 Previous studies using self- multiple pituitary hormone deficits who have normal
rating questionnaires such as the Hopkins Symptom GH reserve on retesting.50 On attainment of final height,
Check List, 45 the Nottingham Health Profile 43,44 the GH retesting is not necessary for individuals with a high
Psychological General Well-Being index43,44 and the QOL- likelihood of GHD such as severe GHD in childhood due
AGHDA (Assessment of Growth Hormone Deficiency in to a genetic cause, structural hypothalamic-pituitary
Adults)45,46 have shown improvements in QOL following disease, or central nervous system tumors, or as the
as early as 6 months of GH replacement. More recently, presence of at least 3 pituitary hormone deficiencies
a new QOL-specific questionnaire (QLS-H [Questions on or severe GHD and the receipt of high-dose cranial
Life Satisfaction-Hypopituitarism]) has been developed radiation therapy and serum IGF-I levels below the
for adults with GHD.42 Data derived from 576 patients given laboratory reference range (<2.5 percentile or <–2
with GHD enrolled in a phase 4 surveillance study of SDS in the absence of conditions that may lower serum
adults with GHD have shown that such patients have a IGF-1 levels). Radiologic evaluation of the hypothalamic-
baseline QLS Z-score significantly lower compared with pituitary region using magnetic resonance imaging
that of normal subjects. After 4 years of GH replacement, (MRI) showing ectopic posterior pituitary at the median
the QLS-H Z-score improved significantly.42 Therefore, eminence (rather than along the pituitary stalk), absence
the evaluation of QOL using self-rating questionnaires42-46 of a visible stalk, and diagnosed case of multiple pituitary
can become part of the clinical management of GH- hormone deficits (rather than isolated idiopathic GHD)
deficient patients, complementary to the measurement are all predictors of severe GHD on retesting.
of other surrogate biologic markers and other clinical
end points. DIAGNOSIS OF GHD IN ADULTS
The mainstay of a diagnosis of GHD in adults is the
TRANSITIONAL CARE OF GHD performance of a GH stimulation test. In the context of
The goal of GH treatment in childhood is primarily panhypopituitarism caused by organic destruction and
statural growth. When final adult height is achieved, associated with low serum IGF-I levels, no further testing
316 SECTION 4: Endocrinology
Flow chart 1: Treat if peak GH 11.0 µg/L in patients with BMI <25 kg/m2, peak GH 8.0 µg/L in patients with BMI 25 and <30 kg/m2 and
peak GH 4.0 µg/L in patients with BMI 30 kg/m2
is necessary. ITT is the gold standard GH stimulation TABLE 3: Factors that may affect GH dosing
test and the GHRH+ARG test is the alternative test of Increase GH dose Decrease GH dose
choice.51-53 Low serum IGF-I levels alone are not sufficient
Young patients regardless of Elderly patients
to make the diagnosis, since there are several reasons for onset type
decreased hepatic production of IGF-I other than GHD, Low serum IGF-I levels High serum IGF-I levels
and these include hepatic or renal failure, untreated
Addition of oral estrogen Discontinuation of oral estrogen
hypothyroidism and protein or calorie malnutrition.
Change from transdermal to Change from oral to transdermal
Flow chart 1 as a guideline for clinicians to diagnose
oral estrogen estrogen
GHD in adults.
To induce lipolysis Addition of testosterone
See Table 3.
equivalent clinical and biochemical response compared
Physiologic Factors with men. With decreasing GH secretion across the
During puberty and pregnancy higher GH dosing lifespan after puberty, clinical features and therapeutic
is required. 54,55 Pubertal girls require more GH than end-points differ with patient age. Sensitivity to side
pubertal boys.56,57 GH-deficient women require higher effects of exogenous GH is greater in elderly GH-deficient
GH doses during the initiation and maintenance phases patients; therefore, the starting dose, size of dose
specially in those with intact hypothalamic-pituitary- increments, and target serum IGF-I levels should all be
gonadal axis and in those on oral estrogens to achieve an reduced when GH replacement is considered.20, 21
CHAPTER 52: Growth Hormone Replacement Therapy: Current Recommendations 317
TABLE 4: AACE 2009 recommendations for GH replacement therapy in adults with GHD (Grade A; BEL 1)
Starting dose:
zz Age <30 years: 0.4–0.5 mg/day (may be higher for patients transitioning from pediatric treatment)
Use lower GH doses (0.1–0.2 mg/day) in all patients with diabetes or who are susceptible to glucose intolerance.
Dose titration: At 1- to 2-month intervals, increase dose in increments of 0.1–0.2 mg/day based on clinical response, serum IGF-I levels, side
effects, and individual considerations such as glucose intolerance. Longer time intervals and smaller dose increments may be necessary in
older patients.
Goal: Aim for serum IGF-I levels in the middle of the normal range appropriate for age and sex, unless side effects are significant. Consider a
trial of higher GH doses to determine whether this provides further benefit as long as the serum IGF-I levels remain within the normal range
and the patient does not experience side effects.
Monitoring: At 6-month intervals once maintenance doses are achieved. Monitoring should include clinical evaluation and assessment of side
effects, serum IGF-I, and fasting glucose levels. The lipid profile should be assessed annually, and QOL measurements may be done every 6 or
12 months. If the initial bone DEXA scan is abnormal, repeat evaluations at 2- to 3-year intervals are recommended. If pituitary microadenomas
or postsurgery residual pituitary tumor is still present, periodic MRIs should be undertaken. Patients on concurrent thyroid, glucocorticoid, and
gonadal hormone replacement may need dose adjustments after starting GH replacement therapy.
Special situations: It is important to retest patients transitioning from pediatric to adult care, especially those who had isolated GHD, and
consideration should be given to minimizing lengthy interruptions in their GH therapy.
Length of GH therapy: The appropriate length of GH therapy is unclear. If benefits are achieved, treatment should continue, but if no apparent
or objective benefits of treatment are achieved after at least 2 years, discontinuing GH therapy may be considered. If patients decide to
discontinue GH replacement therapy, a 6-month follow-up appointment should be offered, because a substantial number of patients may
wish to resume therapy, noting in retrospect that they did feel better on treatment.
318 SECTION 4: Endocrinology
Subcutaneous injections are usually administered in levels in the middle of the age- and sex-appropriate
the evening to mimic physiologic GH secretion.69 Once reference range quoted by the laboratory utilized (50th
maintenance doses are achieved, fasting glucose, IGF-I, percentile or 0 SDS). Ongoing monitoring of glucose
serum-free T4, and assessment of the hypothalamic- metabolism in the form of fasting blood glucose levels
pituitary-adrenal axis clinically or via early morning and hemoglobin A1c in patients receiving long-term GH
cortisol or cosyntropin stimulation test (in patients not replacement is highly recommended.
already taking glucocorticoid replacement), testosterone
and lipid levels, and overall clinical status should be Tumor Regrowth/Recurrence
assessed at 6- to 12-month intervals. If the initial bone The growth promoting effects of GH and IGF-I provide
DEXA scan is abnormal, repeat bone DEXA scans are a plausible theoretical basis by which GH treatment
recommended at 2- to 3-year intervals to assess the need could increase cancer risk and promote tumor regrowth/
for additional bone-treatment modalities. If patients recurrence. The published data so far, however, do not
taking replacement GH report significant QOL benefits suggest that GH therapy is associated with causing or
and/or there are objective improvements, such as in accelerating recurrences of pituitary-region tumors,
cardiovascular risk markers, BMD, body composition, although adult GH replacement is contraindicated in
or physical activity tolerance, then GH treatment active malignancy. The GH Research Society consensus
should be continued throughout life, like other pituitary statement advocates clinical screening for neoplasia in
replacement hormones, with the exception of estrogen, these patients to be based on current recommendations
which is stopped after the menopause. If there are for early detection and cancer prevention in the general
neither subjective nor objective benefits of treatment, population.52
some clinicians and patients might decide to consider
stopping GH treatment altogether. Cardiovascular Morbidity
Although it is well known that there is increased
SAFETY ISSUES WITH GH atherosclerosis and cardiovascular mortality in untreated
REPLACEMENT THERAPY GH deficient adults, there are scarce data regarding
cardiovascular morbidity in GHD per se. There are
Diabetes Mellitus many studies showing improvement in cardiovascular
There is no evidence to date that long-term GH risk markers with GH replacement. A meta-analysis of
replacement therapy increases the risk of diabetes 37 blinded, placebo-controlled GH replacement trials
mellitus in adults.70 The incidence of diabetes mellitus showed that overall beneficial effects are observed on
in GH-treated hypopituitary patients with normal BMI is lean and fat mass with no changes in weight, improved
same as that in the normal population. In normal subjects total and low density lipoprotein-cholesterol, and
as well as GH-deficient adults, not only obesity but also improved diastolic blood pressure, but with reduced
advanced age and decreased insulin sensitivity71 of other insulin sensitivity.71 Another meta-analysis of 16 trials
causes are risk factors for the development of diabetes (9 blinded, 7 open) showed positive effects on a number
mellitus. It is therefore important that hypopituitary of morphologic and functional cardiac parameters
patients with high risk of developing diabetes mellitus evaluated by echocardiography in GH-deficient adults
(obese patients or patients with previous history of on GH replacement therapy. 72 Therefore, annual
gestational diabetes) are given a very low dose of GH at measurements of BMI, waist circumference, waist-to-hip
initiation of therapy (i.e. 0.1–0.2 mg/day), and that the ratio and cardiovascular risk markers is recommended
dose of GH then is slowly increased based on the clinical in all patients, with the cardiovascular treatment targets
response, with less emphasis on achieving serum IGF-I being similar to the general population.
CHAPTER 52: Growth Hormone Replacement Therapy: Current Recommendations 319
Guidelines issued by AACE to summarize the current R7: In patients with hypothalamic GHD, e.g. idiopathic
knowledge regarding GH replacement therapy in GH- isolated GHD of childhood, the GHRH+ARG test may
deficient adults, to offer practical recommendations for be misleading; hence, an ITT or glucagon stimulation
clinicians, and to describe briefly the misuse of GH in test should be used (Grade A; BEL 1).
sports and aging. R8: Similar cut points for GH stimulation testing in
the transition patients coming off GH therapy are
SUMMARY OF RECOMMENDATIONS applicable as for adults (Grade B; BEL 2).
R1: GHD is a well-recognized clinical syndrome in R9: On restarting GH therapy, the starting dose of GH
adults that is associated with significant comorbidities in transition patients should be approximately 50%
if untreated (Grade A; BEL 1). of the dose between the pediatric doses required for
R2: GH should only be prescribed to patients growth and the adult dose (Grade C; BEL 3).
with clinical features suggestive of adult GHD and R10: Patients with irreversible hypothalamic-
biochemically proven evidence of adult GHD (Grade pituitary structural lesions and those with evidence
A; BEL 1). of panhypopituitarism (at least 3 pituitary hormone
R3: No data are available to suggest that GH has deficiencies) and serum IGF-I levels below the age-
beneficial effects in treating aging and age-related and sex appropriate reference range when off GH
conditions and the enhancement of sporting therapy are deemed to be GH deficient and do not
performance (Grade A; BEL 1). require further GH stimulation testing (Grade A;
R4: Patients with childhood-onset GHD (COGHD) BEL 1).
previously treated with GH replacement in childhood R11: The ITT remains the gold-standard test for
should be retested after final height is achieved diagnosing adult GHD. Acceptable alternative
and GH therapy discontinued for at least 1 month stimulation tests to diagnose adult GHD include the
ascertaining their GH status before considering GHRH+ARG test, the glucagon test, and, rarely, the
restarting GH therapy. Exceptions include those ARG test alone (Grade A; BEL 1).
with known mutations, those with embryopathic/ R12: Appropriate GH cut points based on body mass
c o ng e n i t a l d e f e c t s, t h o s e w i t h i r re v e r s i b l e index (BMI) should be used with the GHRH+ARG
hypothalamic-pituitary structural lesions, and those test, because BMI has a well-validated effect on GH
with evidence of panhypopituitarism (at least 3 responses to GHRH and ARG stimulation (Grade A;
pituitary hormone deficiencies) and serum IGF-I BEL 1).
levels below the age- and sex-appropriate reference R13: In patients where the ITT is not desirable
range off GH therapy (Grade A; BEL 1). and when recombinant GHRH is not available, the
R5: For childhood GH treatment of conditions other glucagon test is a reliable alternative, but not the
than GHD, such as Turner’s syndrome and idiopathic levodopa and clonidine tests (Grade C; BEL 3).
short stature, there is no proven benefit to continuing R14: Patients w ith hypothalamic GHD may
GH treatment in adulthood; hence, there is no demonstrate false-negative responses to the
indication to retest these patients when final height is GHRH+ARG test. If the peak GH level is above the
achieved (Grade B; BEL 2). cut point in such patients, then these patients should
R6: The preferred GH stimulation test to establish the be retested, if possible, with the ITT, glucagon test,
diagnosis of adult GHD in patients with COGHD is the or, rarely, the ARG test alone (using appropriate cut
insulin tolerance test (ITT). Acceptable alternative points) (Grade A; BEL 1).
stimulation tests include the GHRH+arginine (ARG) R15: Traumatic brain injury and aneurysmal
test, the glucagon test, and, rarely, the ARG test alone subarachnoid hemorrhage are now recognized
(Grade A; BEL 1). conditions causing GHD. However, in patients with
CHAPTER 52: Growth Hormone Replacement Therapy: Current Recommendations 321
these conditions, GHD may be transient; therefore, R24: After initiating GH therapy, physicians should
it is recommended GH stimulation testing to be follow up on patients at 1- to 2-month intervals, and
performed at least 12 months after the event (Grade the GH dosage should be increased in steps of 0.1–0.2
B; BEL 2). mg/day based on clinical response, serum IGF-I
R16: Dosing of GH replacement therapy in all patients levels, side effects, and individual considerations.
should be individualized (Grade A; BEL 1). Longer time intervals and smaller dose increments
R17: As GH-deficient women with an intact may be needed for older patients (Grade A; BEL 1).
hypothalamic- pituitary-gonadal axis and women R25: When maintenance doses are achieved, serum
on oral estrogens are generally more GH resistant IGF-I, fasting glucose levels, hemoglobin A1c, BMI,
than men, these patients will require higher initiation waist circumference, waist-to-hip ratio, serum-free
and maintenance doses of GH than their male T4, and assessment of the hypothalamic-pituitary-
counterparts to achieve an equivalent clinical and adrenal axis clinically or via early morning cortisol
biochemical response (Grade B; BEL 2). or cosyntropin stimulation test (in patients not
R18: There are insufficient data regarding its safety to on glucocorticoid replacement), testosterone and
make recommendations about the use of GH during fasting lipid panel, and overall clinical status should
pregnancy (Grade D).
be performed at 6- to 12-month intervals (Grade B;
R19: The sensitivity to side effects of exogenous GH
BEL 2).
is greater in elderly GH-deficient patients; therefore, R26: Adults with GHD have an increased risk of
the starting dose, size of dose adjustments, and target
cardiovascular morbidity and mortality; therefore,
serum IGF-I levels should be reduced when GH
cardiovascular parameters to consider monitoring
replacement is considered (Grade B; BEL 2).
during follow-up include fasting lipid profile,
R20: For patients with compliance issues, clinicians
systolic and diastolic blood pressure, heart rate, and
may consider administering GH injections on
electrocardiogram results, while more expensive
alternate days or three times per week using the same
and complex examinations such as echocardiogram
total weekly dosage (Grade C; BEL 3).
and carotid echo-Doppler examinations should
R21: There is no evidence that one GH product
be performed only if clinically indicated (Grade C;
is more advantageous over the other, apart from
BEL 3).
differences in pen devices, dose increments and
decrements, and whether or not the product requires
R27: Adults with GHD have an increased risk of
refrigeration; therefore, we do not recommend the developing osteopenia and osteoporosis; therefore,
use of one commercial GH preparation over another we recommend measurement of bone mineral
(Grade D; BEL 4). content and bone mineral density (BMD) in GH-
R22: GH dosing regimens should be individualized deficient patients before starting GH therapy. If
independent of body weight, starting with a low dose, the initial bone dual energy X-ray absorptiometry
and then gradually increasing this to the minimal (DEXA) scan is abnormal, repeat bone DEXA
dose that normalizes serum IGF-I levels without scans are recommended at 2- to 3-year intervals
causing unacceptable side effects (Grade A; BEL 1). to assess the need for additional bone-treatment
R23: Initiating and maintaining GH therapy using modalities.
low GH dosages (0.1–0.2 mg/day) may be more R28: In GH-deficient adults on GH replacement
appropriate in GH-deficient patients with concurrent therapy with pituitary microadenomas or postsurgery
diabetes, obesity, and in those with previous residual pituitary tumor, periodic magnetic resonance
gestational and family history of diabetes so as not to imaging should be undertaken to assess the size of
aggravate blood glucose levels (Grade A; BEL 1). the tumor (Grade C; BEL 3).
322 SECTION 4: Endocrinology
R29: Adults with GHD have diminished quality continued long-term surveillance of patients with
of life (QOL); therefore, we recommend a specific pituitary-region tumors regardless of whether or not
questionnaire be administered to adults with GHD these patients are treated with GH therapy (Grade D;
before they begin GH treatment; subsequently, these BEL 4).
adults should be evaluated annually to determine
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324 SECTION 4: Endocrinology
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calcium homeostasis, and bone metabolism in adults hormone (GH) deficiency in young adults who received GH
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1996;81:3352-9. 50. Shalet SM, Toogood A, Rahim A, Brennan BM. The diagnosis
39. Biermasz NR, Hamdy NA, Pereira AM, Romijn JA, Roelfsema of growth hormone deficiency in children and adults. Endocr
F. Long-term skeletal effects of recombinant human Rev. 1998;19:203-23.
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40. Drake WM, Rodriguez-Arnao J, Weaver JU, et al. The Hormone Research Society (GHRS) Workshop on Adult
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growth hormone replacement on bone metabolism and 1998;83:379-81.
bone mineral density in hypopituitary adults: a 5-year study. 52. Ho KK. Consensus guidelines for the diagnosis and
Clin Endocrinol (Oxf). 2001;54:525-32. treatment of adults with GH deficiency II: a statement of
41. Badia X, Lucas A, Sanmarti A, Roset M, Ulied A. One year the GH Research Society in association with the European
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42. Rosilio M, Blum WF, Edwards DJ, et al. Long-term Society, and Endocrine Society of Australia. Eur J Endocrinol.
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with growth hormone (GH) deficiency: response to treatment 54. Martha PM Jr, Gorman KM, Blizzard RM, Rogol AD, Veldhuis
with recombinant human GH in a placebo controlled JD. Endogenous growth hormone secretion and clearance
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F. An amplitude-specific divergence in the pulsatile
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gender difference in mean GH concentrations in men cardiac abnormalities associated with adult onset GH
and premenopausal women. J Clin Endocrinol Metab. deficiency (GHD). J Endocrinol Invest. 2003;26:420-8.
1996;81:2460-7. 69. Ho KY, Evans WS, Blizzard RM, et al. Effects of sex and age
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2002;87:2042-5. BA, Johannsson G. Growth hormone treatment reduces
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CHAPTER
53
Vitamin D Therapy: Hope or Hype
PK Sasidharan
Subsequently, similar finding was noticed in a few more low cut of value of <200 IU/day). If we had kept 400 IU per
patients with active tuberculosis. It appeared thus that day as the cut for normal dietary intake the percentage
vitamin D deficiency was probably linked to the cause would have been much higher. Among the cases there
of tuberculosis as it was already known to be associated was one patient with tuberculous arthritis of the ankle
with malnutrition.1 In 1999 a controlled study was done joint, who looked perfectly normal but for the arthritis,
to look for the association between tuberculosis, Vitamin had the lowest level of vitamin D (less than 1 ng/mL).14
D and nutrition.1 Because of the firm belief that vitamin D This patient did not have symptoms of hypocalcemia
deficiency did not exist in India, there was a discouraging and the serum calcium and phosphorus and alkaline
attitude from all the quarters and hence the study got phosphatase values did not suggest deficiency (Table 1,
delayed till 1999. The study enrolled 35 new cases of patient no. 13). It was also observed that the mean levels
pulmonary and extrapulmonary tuberculosis, before of calcium, phosphorus and alkaline phosphatase were
starting anti-tuberculous treatment and comparison in the normal range in the study subjects1.
was done with 16 age and sex matched healthy controls.
Their clinical features, details regarding intake vitamin Review of the Landmark Study
D containing foods, details of sunlight exposure, serum We had a relook at the original study after the consensus
25 hydroxy vitamin D levels and other biochemical regarding normal levels of vitamin D became available.
characteristics were compared with the controls. 1 It is now well accepted that 20–100 ng/mL is the normal
Those who were otherwise likely to develop vitamin D range and less than 20 ng/mL indicates deficiency.9,11
deficiency due to causes other than sunlight exposure and On application of these values to the original data we
dietary inadequacy were excluded. Sunlight exposure observed that all the study subjects with tuberculosis had
was estimated based on the number of hours they spent vitamin D deficiency and there was only one case with
outdoors in daylight. An exposure more than ten hours even 30 ng/mL. Just three cases out of 35 had vitamin
a week was considered adequate.1 Besides these, the D level above 20 ng/mL and the mean value of 10.7/
necessary investigations for diagnosing tuberculosis, mL got in the study subjects suggested gross deficiency
calcium, phosphorus, alkaline phosphatase, renal and in patients with tuberculosis.9,11 It was observed that
liver function tests and were done.1 there was significant deficiency even among the healthy
25 hydroxy vitamin D3 in the cases ranged from controls, 10 of them out of 16 had vitamin level below
1 ng/mL to 30 ng/mL and the mean value was 10.7 20 ng/mL (Table 2). Only two out 16 healthy controls had
ng/mL. Vitamin D levels in the controls ranged from a value of more than 25 ng/mL, and above 30 ng/mL only
9–58 ng/mL with mean of 19.4 ng/mL, the difference in just one subject. In spite of the small sample size the
being statistically significant (p<0.005). The study was land mark study itself had thrown light on the existence
completed in 2000, but there was no consensus then on of widespread deficiency and its probable causes in the
the normal levels of Vitamin D. The lowest value of vitamin population of Kerala and thus the whole of India.
D obtained in the healthy control group (9 ng/mL) was
arbitrarily taken as normal. There were 16 cases out of REASONS FOR WIDESPREAD
35 who had values below 9 ng/mL. The 72% of the cases DEFICIENCY OF VITAMIN D
had adequate exposure to sunlight. The serum levels The primary reasons for the widespread deficiency
of Vitamin D between those who got adequate sunlight of vitamin D in India are lack of balanced diet,
exposure and those who did not get was not significantly hyperpigmentation of the skin and partly reduced
different, and we concluded that inadequate sunlight sunlight exposure. On closer observation of the problem,
exposure was not the cause of vitamin D deficiency in it becomes clearer that it is due to combination of several
the study subjects. But it was observed that the dietary other problems as well and is indeed a complex issue,
intake was inadequate in 54% of the cases (even with a interlinked to diet and lifestyle habits. The research tools
328 SECTION 4: Endocrinology
that we employ now are not enough to find out root environment of people who get diseases and of those
causes of such problems; but the root causes can always who remain healthy without any diseases even after
be traced by close observations of the diet, lifestyle and eighty or ninety years.
CHAPTER 53: Vitamin D Therapy: Hope or Hype 329
What is Good Lifestyle and What is from taking dietary items, which contain Vitamin D.
Wrong with Lifestyle? In Kerala for example, several people avoid pulses
Good lifestyle include several habits like regular intake believing that it produces gas or dyspepsia, even as
of a balanced diet, drinking adequate water, ensuring the diet does not contain adequate nonvegetarian
safety of food and water, cleaning teeth in morning items as a source of protein. The gas or dyspepsia
and before bedtime, washing hands before eating or is due to disordered motility of the gastrointestinal
after visiting toilet. People with good lifestyle also avoid tract due to reduced fiber in the diet resulting
smoking, alcohol, overeating, fried food, fast food and from decreased intake of vegetables and fruits.
all the junk foods. Good lifestyle also involves doing Urgent attention from all quarters, to empower the
some kind of physical exercise regularly, avoiding undue society for regular consumption of balanced diet is
mental stress or of managing stress through relaxation absolutely essential to solve the problem of Vitamin D
techniques. Adopting the right posture while working, deficiency and for fighting all diseases, because “food
sitting, travelling or while using computers, and even is the primary medicine”.
the practice of good waste disposal habits all are good Second larger issue behind Vitamin D deficiency is
lifestyle habits. Thus it becomes obvious that absence defective 25 hydroxylation of dietary or cutaneously
of good lifestyle practices lead to weight gain or obesity, synthesised Vitamin D, due to clinical and subclinical
hypertension, diabetes, fatty liver, heart attacks, strokes liver diseases. The incidence and prevalence of liver
and cancers. All abnormal lifestyle practices can be diseases is steadily increasing every year due to
traced to unchecked and unhealthy promotion of changed lifestyle habits. Overeating and development
consumerism and lack of social empowerment. The of fatty liver is the most common reason for liver
observations on the causes of vitamin D deficiency in disease now. The growing acceptance of alcohol and
relation to lifestyle are given below. the increased consumption of it is another cause
Lack of regular consumption of balanced diet is for liver disease. Besides these two often there is
the most common cause of Vitamin D deficiency. exposure to other hepatotoxic substances through
Majority do not even have the chance to get a diet and as medicines and health preparations
balanced diet even by accident due to the lack of (including indigenous medicine) is common among
social empowerment. Balanced diet should contain all groups including the poorer ones. Almost all of
one source of calories (e.g. any one cereal in the these coexist often in most individuals and cause
Indian diet-no cereal is superior in that), adequate clinical and subclinical liver dysfunction.
protein (any one of the pulses/curd/fish/egg or meat) Another important cause for the deficiency is
vegetables-preferably raw or steamed only and never defective metabolism of vitamin D in the kidneys (the
overcooked-and fresh whole seasonal fruits and 1-hydroxylation). Kidney diseases are increasing due
adequate safe drinking water. Therefore, vegetarians to increasing prevalence of diabetes, hypertension
should always eat a combination of “anyone cereal and due to toxins in diet and environment, high
+ any one of the pulses + vegetables + fruits” in the protein diet in the affluent, nephrotoxic drugs
right proportions every time we eat (nonvegetarians like NSAID as over the counter medications and
should take egg, fish or meat instead of the pulses). If the reduced water intake. Toxins in the diet and
we are using roots and tubers as a source of calories, as environment that are potentially damaging to the
in a western diet, the source of protein should always kidneys could be cadmium, mercury, lead, copper
be nonvegetarian or at least curd should be used as a from electronic equipment or from some indigenous
source of protein. Lack of awareness about balanced preparations. Adequate water (approximately two
diet, some beliefs and wrong concepts about diet liters per day) is absolutely essential to prevent renal
and lack of social empowerment prevent people damage from hyperuricemia, high blood pressure
330 SECTION 4: Endocrinology
and urinary tract infections. In controlling high sample of the people of Kerala and could indicate
blood pressure salt restriction alone is stressed often similar situation in the rest of the country. The author’s
ignoring the role of adequate water intake, which has observation spanning three decades is that vitamin D
several other benefits as well. Hypomagnesemia as a deficiency is only an indicator sign of malnutrition or
result of clinical and subclinical renal damage, also it shows only the tip of the iceberg of malnutrition and
indirectly contributes to vitamin D deficiency. wrong lifestyle habits in a society. It is malnutrition
Hypomagnesemia is an important reason for Vitamin which initiates or perpetuates diseases like Tuberculosis
D deficiency. The 1-hydroxylation of vitamin D in the and even progression HIV infection to AIDS, since proper
kidneys is parathyroid hormone (PTH) dependent nutrition and Vitamin D has decisive role in maintaining
and PTH secretion in turn is magnesium dependent. cell mediated immunity. 1-5 The most common cause
Hypomagnesemia is primarily due to poor intake of for low CD4 count is malnutrition. Thus Vitamin
vegetables and fruits, besides the renal and GI losses. D deficiency is only an indicator of the subclinical
Sometimes there is poor absorption of magnesium and clinical malnutrition, which is widely prevalent.
from the intestine due to parasites and infections like Malnutrition is the most important cause for the higher
tuberculosis of intestine. Thus an individual could prevalence of HIV and tuberculosis in India, Africa and
have multiple reasons for hypomagnesemia, which other developing countries. It is a common observation
is always subclinical and is often overlooked. Thus that those with advanced AIDS have severe malnutrition
magnesium deficiency, due to multiple causes, would as well, and it could be a cause rather than the effect.
lead to reduced parathyroid hormone (PTH) secretion Besides, there are several examples of persons living
and the consequent reduction of 1-hydroxylation of with HIV for long periods if they follow a healthy diet and
vitamin D in the kidneys is an important and is an lifestyle. What is common to the people affected severely
unrecognized cause of Vitamin D deficiency.7,12,13 by tuberculosis and AIDS anywhere is malnutrition. The
Decreased sunlight exposure—Even if there is enough results of the study supported the already known link
sunlight in India, the habit of exposing our body to between tuberculosis and malnutrition. Randomized
sunlight, even by accident, is becoming very rare due controlled studies are not effective or feasible for
to changed lifestyle and lack of empowerment. The establishing the link between all aspects of nutrition,
preference for indoor jobs alone and not doing any lifestyle and diseases. The observations also suggest that
outdoor activities or outdoor exercise is a lifestyle tuberculosis and other infections control or all disease-
disorder resulting in reduced cutaneous biosynthesis control programmes, to succeed, need to incorporate
of vitamin D. dietary intervention and education and empowerment
The increasing use of obstructive clothing due to of the people for regular intake of balanced diet and
imitation of the western culture or for religious exercise in sunlight. This observation is particularly
reasons could be contributing to reduced sunlight relevant since, even relatively affluent section of society
exposure. do not really know of or consume a balanced diet but
Even if we expose our skin to sunlight, the increased they consume all kinds of fast foods, junk foods and
melanin content in the skin of our people, could be many of them are exposed to overeating, sedentary
interfering with ultraviolet light mediated vitamin D habits, alcohol and tobacco smoking and develop organ
synthesis.7,11 damages, which lead to defective vitamin D metabolism.
The very same people are confining to indoor activities
Social Relevance of the Landmark Study or do white-collar jobs only with hardly any sunlight
The landmark study itself had suggested that vitamin D exposure.
deficiency is very common in the subjects, including the It is also interesting to note the recently recognized
apparently healthy controls, who were representative role of Vitamin D in decreasing the risk of many chronic
CHAPTER 53: Vitamin D Therapy: Hope or Hype 331
illnesses, including common cancers, autoimmune etc. and people should be made aware of and empowered
diseases, other infectious diseases, hypertension, to make use of all these. If exercise is done in natural
diabetes and cardiovascular diseases all indicating setting we would get enough sunlight as well or else sun
the role of balanced diet and avoiding overeating in exposure by plan should be included in good lifestyle
controlling all these diseases. 8,9,11-13,16 It is reported habit. In short, all our people should be empowered to
that raising the serum 25(OH)D level to 40–60 ng/mL take a balanced diet in moderation and to do regular
would prevent breast, prostate and colorectal cancers. exercise in the open as a part of their lifestyle to solve the
There are no risks from intake of 1000–2000 IU per day problem of Vitamin D deficiency in the society rather
of vitamin D 3. 9-11 Vitamin D deficiency is also found than just focusing only on Vitamin D therapy.
to be associated with low HDL, high triglyceride and
high total cholesterol.15 Thus, it is obvious that etiology REFERENCES
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habits rather than on Vitamin D therapy alone, which is actions. Annual Review of Nutrition. 1984. pp. 493-520.
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be regulated and the maximum dose to be used as
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1000 IU per day indefinitely in those who have deficiency disease; Harrison’s Principles of Internal Medicine. McGraw
rather than giving massive doses intermittently. It is Hill, 17th edn. 2008;2:346.
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All sections of people should get balanced diet and
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like oil or wheat-flour also may be tried till such time hyperparathyroidism in the elderly: Consequences for bone
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CHAPTER
54
Approach to a Patient with Short Stature
Indira Maisnam
Adolescence phase (onset to completion of puberty): is a cause of short adult height. These children have early
Growth spurt starts at 10 years in girls and 12 years in height acceleration and epiphyseal fusion (Table 1).
boys. Growth rate is around 8–14 cm/year. In assessing a child presenting with short stature, the
following need to be answered. They are:
DIAGNOSTIC APPROACH TO A CHILD how short is the child?
zz Cardiac disease
zz Immunologic diseases
subtracting 6.5 cm for girls. Projected height (PH) for a electrolytes, creatinine, bicarbonate, calcium, phosphate,
child >2 years is determined by extrapolating the child’s alkaline phosphatase and albumin.
growth along the current channel to the 18- to 20-year Karyotype is done in all girls with short stature.
mark. If bone age is advanced or delayed the PH should Thyroid function tests are done in most cases of short
be plotted based on the bone age. stature. Children with features of GHD should be
Bone age is determined from X-rays of the left screened for IGF1 and IGFBP-3. If screening suggests
hand and wrist. It is calculated by comparing with the GHD, then stimulation tests are done to confirm.
Greulich and Pyle Atlas and the Tanner-Whitehouse Exogenous steroid is an important cause of Cushing’s
(TW2) method. Delayed or advanced bone age is syndrome. Suppressed 8am cortisol with physical
defined as a bone age 2 SD ≤ or ≥ the mean, respectively. features of Cushing’s establishes the diagnosis of
This translates to a difference between bone age and exogenous Cushing’s. Tests for endogenous Cushing’s
chronological age of approximately 12 months between include overnight dexamethasone suppression test,
2 and 4 years, 18 months between 4 and 12 years, and 24 24-hour urinary free cortisol, low dose dexamethasone
months after 12 years. suppression test and midnight salivary (or serum)
Growth parameters are described as follows : cortisol. Further testing and imaging is directed by the
chronologic age → calendar age; bone age → age for biochemical results of the initial tests.
which bone maturation is average, and height age → age Tests to detect systemic illness are done based on
at which height is average. history and clinical examination. Skeletal survey are
The disturbances of linear growth can be categorized helpful in skeletal dysplasias.
broadly into three growth patterns: intrinsic shortness,
delayed growth and attenuated growth (Table 2). CONCLUSION
Intrinsic short stature is intrinsically determined like A detailed history and clinical examination along with a
familial and genetic factors; and skeletal dysplasias. In systematic approach helps establish the cause of short
delayed growth there is slow growth and delayed puberty stature in most cases. Physiological variants like FSS
but normal final height. CDGP is an important cause. and CDGP are the most common causes. A scientific
Attenuated growth is a more severe form of delayed approach is cost-beneficial by helping identify children
growth. Growth velocity is low; bone age and height age needing further evaluation and treatment, and avoiding
are low; and are lesser than chronologic age. Endocrine extensive evaluation in children who have physiological
causes, chronic illnesses and malnutrition are the causes. variants. Timely diagnosis and treatment is important
The algorithm guides the extent of testing (Flow because most endocrine causes of short stature and many
chart 1). Tests include complete blood count and secondary causes respond satisfactorily to treatment
erythrocyte sedimentation rate, C-reactive protein, when proper treatment is instituted at the right time.
336 SECTION 4: Endocrinology
Abbreviations: HV, Height velocity; PH, projected height; TH, Target height; BA, Bone age; GDPP, gonadotropin-dependent precocious puberty
BIBLIOGRAPHY 3. http://www.uptodate.com/contents/diagnostic-approach-
1. Cooke DW, et al. Normal and aberrant growth. Shlomo to-children-and-adolescents-with-short-stature. Accessed
Melmed, Kenneth Ed. S. Polonsky, P. Reed Larsen, Henry M. on 18th August 2017.
Kronenberg. In. Williams Textbook of Endocrinology. 12th 4. Hussain K, et al. Applied physiology: Understanding growth.
Edition. Philadelphia. WB Saunders. 2011;935-1053. Current Paediatrics. 2006;16:430-3.
2. Cuttler L, et al. Somatic growth and maturation. JL Jameson, 5. Oostdijk W, et al. Diagnostic approach in children with short
LJ De Groot (Eds). In: Endocrinology adult and paediatric, stature. Horm Res. 2009;72:206-17.
7th Edition. Philadelphia: Elsevier Saunders. 2016;382-
417.
CHAPTER
55
Logical Approach to Thyroid Nodule
KJ Shetty, KN Manohar
more than 4 cm
zz
MANAGEMENT
Based on the above inputs—clinical, laboratory, USG,
roadly speaking, the chances of malignancy
B
scintiscan and FNAC, decision-making regarding
depending on the gross features of nodule are3
management has to be undertaken (Flow charts 1A
—— Solid lesions about 20% risk of being malignant
and B). If there is a definite evidence of thyrotoxicosis
—— Cystic lesions measuring less than one centimeter
low TSH with high T3/T4 and a hot nodule on scintiscan
the risk is 0.1% and if the lesion is more than then the patient is started on antithyroid drug (ATD),
4 centimeter the risk is about 2% consisting of tab carbimazole (CMZ) or methimazole or
—— With mixed lesions the malignancy risk is about
propylthyouracil along with tab propranolol 60–80 mg/
7% day and reassessed once in 8–12 weeks both clinically
Isotope scan: Radio-nucleotide scan with either and hormonally, with the dosage of ATDs readjusted
iodine [I131/125] or 99m Technetium (cheaper and accordingly. ATD is continued for 12–18 months unless
lesser in vivo retention) will reveal increased uptake there is drug hypersensitivity or toxicity (agranulocytosis
by the nodule (Hot nodule), diminished or no uptake hepatitis) and then stopped keeping a watch for relapse
(Cold nodule) or similar uptake as the rest of the either clinical or hormonal.6 If there is a relapse, ATD is
gland (Warm). Probability of malignancy is 10–15% restarted till toxicity is controlled and definitive therapy
on cold nodules, while in case of the ‘hot’ nodule it is with either I-131 ablation or partial thyroidectomy (only
about 1–4%, and 5% in ‘warm’ nodules. if there are pressure symptoms) is offered. Patient has
FNAC: FNAC is considered as the gold standard in to be followed up and put on thyroxin supplements for
the evaluation of thyroid nodule4 and is indicated in hypothyroidism and continued for life.
CHAPTER 55: Logical Approach to Thyroid Nodule 339
B
340 SECTION 4: Endocrinology
On the other hand, if the patient is euthyroid or The full work up of thyroid nodule besides a Physician
hypothyroid and the nodule is reported as malignant, or an Endocrinologist, involves the Radiologist, the
total thyroidectomy with block dissection of lymph Nuclear Medicine Specialist and most importantly a
nodes is the usual treatment. The follow up, will involve a Cytopathologist. Fine needle aspiration and the expert
watch for recurrence – a six monthly TBG estimation with opinion on the aspirate has become an essential requisite.
a careful clinical evaluation. Thyroxin replacement in a We do not have many centers with cytopathology but
high dose is obligatory with due considerations about a good histopathologist with practice and experience
radiotherapy. should be able to help.
The third scenario is a hypothyroid or euthyroid The stepwise approach in this write up is evidence
patient with a nodule reported as suspicious either in based and practiced in most large centers all over the
USG or scintiscan and FNAC yield no definite diagnosis. world. It will be possible to practice in any setting, if one
Surgical excision with the assistance of frozen section has the aptitude and initiative to organize teamwork.
facility should be the choice – rather than repeat FNAC.7
The repeat FNAC may not be acceptable to the patient REFERENCES
1. Accuracy of thyroid nodule ultrasound to predict thyroid
and also in the absence of cytopathologist we may not
cancer—Systematic review and metanalysis. JCEM. 2014;
get a definitive diagnosis. Our protocol involves a frozen 99(4):1253-63.
section biopsy. In this procedure, patient is prepared 2. Cibas ES, Ali ZS, The Bethesda System for reporting Thyroid
as for any thyroid surgery in consultation with the cytopathology: Thyroid 2009;19:1151-65. (PubMed)
histopathologist. After an incision along the crease of 3. Garg S, et al. To establish Bethesda system for diagnosis
of thyroid nodules on the basis of FNAC with histologic
the neck, lobectomy with the nodule is done and sent to
correlation. J Clin Diagnosis Res. 2015;EC. 17-21. (PMC
the laboratory–the histopathology report will usually be Free article in Pub Med).
available within few minutes. Depending upon this the 4. Hegedus L. Thyroid ultrasound and features and risk of
surgeon will proceed either to do a total thyroidectomy or carcinoma. Thyroid 2015. Endocrinology and Metabolism
carry out only lobectomy.8-10 This process has helped us Clin North Am. 2015;30:339-60, viii–x.
5. Shrikant J, et al. Thyroid nodule—update on diagnosis and
to reduce unnecessary morbidity of total thyroidectomy
management. Clinical Diabetes and Endocrinology. 2016;
in some centers (including the one in which the authors 2:17.
are associated with). 6. Likay K. The evaluation of thyroid nodules. Thyroid disorders
Despite all measures about 5% of nodules may and therapy. 2015;4:2.
remain nondiagnostic and after careful consideration, a 7. Regi S, Bajaj S. ITS clinical manual of thyroid disorders. Find
needle aspiration cytology, Elsevier. First edition. Jayakumar
surgical option should be considered.
RV (Ed). 2012;161:171-82.
8. Kannan S, et al. Improving Bethesda reporting in thyroid
CONCLUSION cytology: A team effort goes a long way and still Miles to
In the present scenario, in our practice we need to go… Indian Journal of Endocrinology and Metabolism.
develop a systematic approach to evaluate a thyroid 2017;2:277-81.
9. Unnikrishnan AG. Nontoxic thyroid goiters. Indian Thyroid
nodule. These patients are seen by or referred to different
Society - Clinical manual of thyroid disorder edition Ed.
specialists Surgical, ENT, Oncologist and at times the 2012.
Gynecologist or Obstetrician—if diagnosed initially for a 10. Yoon YH, et al. Diagnostic accuracy of US guided fine needle
gynecological problem or during pregnancy.9,10 aspiration biopsy. Thyroid. 2011. pp. 993-1000.
CHAPTER
56
Primary Hypoparathyroidism
and its Management
Ajay Aggarwal, Roopak Wadhwa
Parathyroid hormone (PTH) deficiency, a key hormone of primary hypoparathyroidism in India, given the total
essential for calcium homeostasis, causes primary population of 1.3 billion. Clark BL et al reported the
hypoparathyroidism. It is an uncommon disorder, prevalence rate of 37 and 22 per 100,000 personyears in
characterized by low serum calcium, high phosphorus US and Denmark respectively. Another study from US
and low or low-normal PTH. It can be divided into, reported 74% hypoparathyroid patients to be in the age
primary hypoparathyroidism due to intrinsic defects group of 45 years or more and occurrence of 75% cases
within parathyroid glands, primarily due to genetic in females. Cipriani et al in an Italian study reported
causes, and secondary or acquired forms due to hospitalizations rate of 72.2% and 27.8% among women
etiologies affecting parathyroid function. The diagnosis and men respectively due to hypoparathyroidism.
is easy once serum calcium, phosphorus and PTH levels
are known, but determining the cause of nonsurgical PATHOPHYSIOLOGY
hypoparathyroidism may be challenging. The extracellular fluid (ECF) concentration of ionized
Pseudohypoparathyroidism (PHP), even less common calcium remains nearly constant. Its maintenance in
disease, is characterized by low serum calcium, high both intra- and ECF is highly regulated and modulates
phosphorus but high PTH level due to PTH resistance. the functions of bone, renal tubular cells, adhesion
Autoimmunity, which affects either the parathyroid molecules, clotting factors, excitable tissues, etc. A
glands alone or multiple endocrine glands, is the most G-protein coupled receptor, extracellular calcium-
common cause in adults. Primary hypoparathyroidism sensing receptor (CSR), has been isolated from
may also be caused by rare genetic disorders, due to gene parathyroid, kidney and brain cells. Mutations in this
mutations involving the development of the parathyroid receptor may lead to disturbance in serum calcium
glands and synthesis or secretion of PTH. status. The secretion of PTH is regulated by this receptor
in parathyroid cells. Activating mutations of this receptor
EPIDEMIOLOGY causes hypocalcemia, due inhibition of PTH exocytosis,
KVS Hari Kumar et al estimated burden of parathyroid the intracellular mechanism(s) of which remains
disorders in India. They reported incidence rate unknown.
of primary hypoparathyroidism as 2.6 per 100,000 Normally, exocytosis of PTH occurs when there
personyears thereby giving a prevalence rate of 15.6 per is fall in ECF ionized calcium, which restores normal
100,000 population and approximately 200,000 patients range of ECF ionized calcium, by its effects on the
342 SECTION 4: Endocrinology
kidneys and skeleton. PTH causes bone resorption and dental abnormalities, brittle nails, dry, rough skin, raised
releases ionized calcium into the ECF by activating intracranial pressure with papilloedema, and hyper-
osteoclasts. The proximal tubular reabsorption of reflexia are other important signs.
phosphate from the lumen is also inhibited by PTH. So, The etiologies like DiGeorge’s syndrome (recurrent
in hypoparathyroidism, the phosphate concentration infections, congenital heart disease, micrognathia,
in plasma is elevated and in conditions of primary PTH speech delay, cleft palate and ear abnormalities),
excess, hypophosphatemia occurs. Familial APS-I (mucocutaneous candidiasis, adrenal
PTH retains calcium by its effect on the distal renal failure, vitiligo and dental enamel hypoplasia) may cause
tubules. This effect in hypoparathyroidism leads to other symptoms and signs.
calcium wastage through kidneys, which increases
the urinary calcium excretion and decreases the ECF INVESTIGATIONS
ionized calcium. PTH, by stimulating renal 1-alpha- S e r u m ca lc iu m, ph o sphate, P T H a n d alkalin e
hydroxylase, also plays important role in the synthesis of phosphatase levels are the blood tests required for
1,25-dihydroxy vitamin D. It allows better dietary calcium diagnosis. The results suggestive of hypoparathyroidism
absorption. Thus, both 1,25-dihydroxy vitamin D and include low serum calcium, high phosphate, low PTH
PTH contribute to a rise in the ECF ionized calcium. and normal alkaline phosphatase. Serum magnesium
The P TH deficienc y negatively affects bone may be low, CKD also needs to be excluded. The
resorption, phosphaturic effect, renal distal tubular measurement of vitamin 25(OH)D3 and its active
calcium reabsorption, and 1,25-dihydroxy vitamin D metabolite (1,25(OH)2D3) helps to rule out vitamin D
mediated dietary calcium absorption, thereby causing deficiency as a cause of hypocalcemia. 25(OH)D3 levels
hypocalcemia. are normal in hypoparathyroidism, but 1,25(OH)2D3 is
low due to PTH deficiency.
SIGNS AND SYMPTOMS The thyroid and adrenal insufficiency should
The patients present with the symptoms of hypocalcemia. ruled out, if autoimmune process is suspected. The
This may ranges from just an asymptomatic laboratory measurement of serum TSH, T4, thyroid autoantibodies,
finding to severe metabolic disturbance. Symptoms ACTH and adrenal antibodies helps. Ultrasound
include muscle pains, bone pains, abdominal pain, abdomen may detect renal calculi and brain MRI scan
paresthesia of the face, fingers, facial twitching, may reveal basal ganglia calcification, suggestive of long-
carpopedal spasm, stridor and convulsions. The other standing disease.
symptoms include syncope, emotional lability, anxiety,
depression, confusion, memory impairment, lethargy, TREATMENT
headaches, dry hair, skin and painful menstruation. Past Careful evaluation and consideration of the treatment
history of neck surgery, family history of hypoparathyroid options other than calcium supplementation are required
disorders are important points to be included in the to treat hypoparathyroidism. A diet rich in calcium and
history. vitamin D should be emphasized. Severe hypocalcemia
Clinical signs include Chvostek’s sign which detects with symptoms, such as tetany needs urgent IV calcium
latent tetany. It involves contraction of the facial muscles infusion.
caused by tapping of the facial nerve at the angle of the jaw. The primar y goals of management includes
The positive response in 25% of the normal population symptoms control, to maintain serum calcium in the
makes this sign nonspecific. Another important sign is low-normal range (8–8.5 mg/dL) and serum phosphorus
Trousseau’s sign which involves induction of carpopedal within normal range with calcium and vitamin D
spasm by occluding arterial circulation of the forearm supplementation. It helps to prevent hypercalciuria, renal
for three minutes using a blood pressure cuff. Cataracts, stones or calcium phosphate deposition in soft tissues.
CHAPTER 56: Primary Hypoparathyroidism and its Management 343
Vitamin D analogs such as calcitriol or alfacalcidol are to calcium and vitamin D, Natpara (rhPTH[1-84]), a
helpful. Calcitriol 0.5 μg or alfacalcidol 1 μg daily are usual parathyroid hormone is indicated.
starting doses. Dose is titrated every 4–7 days to achieve a The active ingredient in Natpara is produced by
low-normal serum calcium level. Calcitriol is preferred as recombinant DNA technology using a modified strain
it is more potent, has rapid onset of action and short half- of E.coli. Parathyroid hormone has 84 amino acids and
life. The patients with gain-of-function mutations of the a molecular weight of 9425 daltons. It raises plasma
calcium-sensing receptors when on vitamin D treatment calcium levels by increasing intestinal absorption and
may suffer from hypercalciuria, nephrocalcinosis, and renal reabsorption of calcium and increasing bone-
renal impairment. The asymptomatic patients can turnover rates to release calcium from bone. It may
simply be followed. Thiazide diuretics increase distal increase the risk of osteosarcoma. It is initiated at
renal tubular calcium reabsorption, thereby decreasing 50 mg daily as subcutaneous injection. The dose may be
urinary calcium excretion. Diuretics in combination with increased every four weeks in 25 mg increments up to a
low-salt, low-phosphate diet and phosphate binders are maximum dose of 100 µg daily.
beneficial. Serum calcium, phosphorus, and creatinine
should be measured at regular intervals initially for dose CONCLUSION
adjustments and then periodically once the therapy The management of primary hypoparathyroidism
protocol has stabilized. requires to diagnose the etiology of hypocalcemia,
Unfortunately, due to the limitations of therapy followed by supplementation with calcium and vitamin
patients with hypoparathyroidism may have poor quality D. Further enhancement of treatment by introducing
of life. The property to correct hypercalciuria and reduce thiazide diuretics and other options can help to treat
the risk of nephrocalcinosis, nephrolithiasis, and renal hypocalcemia and prevent symptoms. The results with
insufficiency makes replacement therapy with PTH, a current treatment are suboptimal and are associated
viable option. It reduces the wide fluctuation in serum with increased risk of wide fluctuations in serum
calcium and also helps to decrease the large doses of calcium, hypercalciuria, renal impairment. The patient
calcium and vitamin D required to maintain serum should be treated aggressively and monitored regularly,
calcium in normal range. To control hypocalcemia after evaluation and determination of the etiology of
in patients with hypoparathyroidism, as an adjunct hypocalcemia.
CHAPTER
57
A New Look at Testosterone
Therapy in Aging Males
DC Sharma
As the age advances the concentration of serum There have been three large longitudinal studies also
testosterone and to a greater extent free testosterone showing a decline in serum testosterone with aging.2
decline in men, this decrease is also described as Around 20, 30, and 50% men in their 60s, 70s, and 80s
andropause or “late onset hypogonadism”. Unlike respectively had total serum testosterone levels in
menopause in women where there is a complete serum hypogonadal range.3
estrogen deficiency the decrease in serum testosterone is Serum sex hormone binding globulin(SHBG)
modest and the possible clinical effects thereof have not increase with age resulting in a decrease in serum free
been well understood. testosterone levels by 2.8% per year.
Several physical and phenotypical changes in The sperm production does not appear to change
body function in aging men are similar to the clinical significantly with age. However, there is a small decline
picture seen in hypogonadism suggesting that these in the size of testes with age. There is a small increase in
changes could be because of testosterone deficiency. the level of gonadotropins, follicle stimulating hormone
However, whether these changes could be reversed with (FSH) rises more than luteinizing hormone (LH), but
testosterone supplementation and the long term safety of the change is not so large as one would expect from
testosterone at this age are not clearly answered. the decrease in testosterone, suggesting a role of both
primary and secondary hypogonadism contributing to a
CHANGES IN REPRODUCTIVE fall in serum testosterone.4
HORMONES WITH AGE
Several cross sectional and longitudinal studies have EFFECTS OF DECREASE IN
shown a decrease in serum testosterone concentration, TESTOSTERONE
an increase in sex hormone binding globulin (SHBG), Several changes taking place in parallel with a decrease
and a decrease in free testosterone with aging. in serum testosterone are observed suggesting a possible
The European Male Aging Study (EMAS), the largest causal relationship of these changes to falling levels of
cross sectional study to date, showed a decline of serum serum testosterone.
total testosterone concentration by 0.4 percent a year and The sexual symptoms (poor morning erection,
so a large number of older men have testosterone level decrease in libido, and erectile dysfunction) are
sufficiently low to be considered hypogonadal in young significantly correlated with a decline in serum
men.1 testosterone with aging.
CHAPTER 57: A New Look at Testosterone Therapy in Aging Males 345
With the advancing age, there is a decrease in testosterone treatment was not associated with increased
bone mineral density (BMD) and risk of bone fracture. risks of clinical cardiac events or prostate cancer, these
However, the risk of nonvertebral fracture increases in data suggested requirement of more scientific evidences
those who have low serum concentration of bioavailable to clarify these observations.8
estradiol, or free testosterone and high sex hormone
binding globulin (SHBG) concentration. SUGGESTED APPROACH
There is decline in muscle mass and increase in fat If men presents with suggestive symptoms of testosterone
mass with increasing age. In hypogonadal males, these deficiency such as decreased libido, energy, or mood, or
changes are reversed with testosterone replacement. osteoporosis or anemia, measure serum total testosterone
Some studies have shown improvement in several in the morning. If it is below 300 ng/dL, measure it twice
group of muscles with testosterone therapy in hypo since testosterone concentration fluctuate.
gonadal males but the effect in elderly males with Free testosterone should be measured only in obese
low testosterone have not been consistent. Similarly subjects.
inconsistent improvement in mood and cognitive function If the total serum testosterone is found to be less than
have been reported with testosterone replacement in 200 ng/dL, evaluate for known causes of hypogonadism.
elderly patients with low serum testosterone. Testosterone Consider treatment only in those who have been
treatment improves hemoglobin level in this population. documented to have consistently low testosterone in the
morning sample and after having a clear discussion and
Does a State of Hypogonadism explanation to the patients of potential benefits and risk
in Older Men Exist? of the therapy.
The studies have shown that a small population of elderly If the decision is made to treat an older men with
men shows clinical manifestations of hypogonadism, like testosterone, the target serum concentration should be
symptoms of sexual dysfunction, low muscle mass, bone lower than that for younger men, for example 300 to 400
density, energy, anemia, and impaired glucose tolerance. ng/dL, rather than 500 to 600 ng/dL, to minimize the
These features are more frequent in those with lower potential risk of testosterone dependent diseases.9
serum testosterone.5-7 Before initiating treatment a thorough evaluation
be done to rule out testosterone dependent conditions
Status of Testosterone Administration like sleep apnea, abnormally low HDL, marked benign
Although clinical observations suggest a relation prostate hyperplasia and prostate cancer. A digital rectal
of declining testosterone with age and its adverse examination should be performed and serum prostate
consequences, the effect of testosterone replacement in specific antigen (PSA) be ensured. If a nodule is detected
older men with low serum testosterone and hypogonadal or serum PSA is found to be raised, appropriate urology
symptoms has been unclear. evaluation should be undertaken periodic monitoring
A recent multicenter testosterone trial enrolling 790 like blood counts, lipid profile, digital rectal examination
men who were given testosterone gel therapy over one and serum PSA be carried out.
year confirmed that testosterone treatment of older men
with unequivocally low testosterone levels is efficacious SUMMARY
in improving sexual function, walking, mood, depressive Serum testosterone concentration decline with
symptoms, anemia, and bone density, all to a modest increasing age and free testosterone concentrations
degree. Testosterone treatment, however, did not fall even more. This decline might have adverse
improve vitality or cognition and was associated with consequences on energy, sexual function, muscle
an increase in coronary artery plaque volume. Although mass and strength, erythropoiesis, and bone.
346 SECTION 4: Endocrinology
INTRODUCTION using insulin for more than six months as 77.4% and 36%
Insulin is the only treatment for people with type 1 respectively.
diabetes and most of the person with type 2 diabetes
sooner or later in their life needs insulin therapy for DEFINITION OF LIPOHYPERTROPHY
control of hyperglycemia. Weight gain and hypoglycemia Lipohypertrophy is a thickened ‘rubbery’ tissue
are two commonly discussed complications of insulin. swelling which is usually firm but may sometimes
Insulin injection therapy is also associated with few of the present as a soft lesion, and thus it may easily be missed
common but less addressed skin related complications, during a standard clinical medical examination2.
such as lipoatrophy, lipohypertrophy, insulin edema
or allergy. Lipohypertrophy (LH) is the one of the most CAUSES OF LIPOHYPERTROPHY
common cutaneous complication amongst them which The exact etiology of LH is not known. Studies have
is characterized by a tumor-like swelling of fatty tissue at observed several local factors, which may play an
the subcutaneous area in insulin injection sites.1 important role in causation of LH. Insulin molecule has a
strong growth-promoting properties and repeated trauma
PREVALENCE due to poor injection practices, such as infrequent/
The reported prevalence of LH in patients receiving missed injection site rotation, repeated injections at the
insulin injections varies widely in published studies, same site and/or frequent reuse of needle. As LH areas
possibly due to the lack of a well-structured diagnostic are relatively painless, patients tend to inject at the same
flow-chart. Fujikura J et al1 reported LH prevalence as site repeatedly rather than moving to a new injection site
29% in people with type 1 diabetes, while Vardar and which may be little painful. Other possible risk factors
Kizilci2 found it to be 48.8% in 215 Turkish patients who in type1 DM is longer duration of insulin therapy, and
had been using insulin for at least 2 years. Similarly, high number of insulin injections per day. The risk of
Seyoum and Abdulkadir 3 found 31% of 100 insulin LH significant increases if the needle is being used for
injectors in Ethiopia to have LH, while Hauner et al4 more than five times. Development of insulin antibodies
reported that 28.7% of 233 German T1D patients had the is also suggested as a possible underlying mechanism.
condition. The prevalence of LH was found to be 76.4% in LH is thought to be the direct anabolic effect of insulin
T1DM as noted by M. Blanco.5 Indian study6 has shown on local skin leading to fat and protein synthesis.
the prevalence of LH amongst type 1diabetics and T2 DM However, a large body of evidence also lends support
348 SECTION 4: Endocrinology
to a significant association between LH and many other increases. This imposes an extra economic burden of
factors, including female sex, low socioeconomic level, the disease for both patients and the healthcare system.
high body mass index, as well as long-standing disease Therefore, it is crucial to identify LH so as to educate
and/or insulin treatment.7 patients on good insulin injection habits. Hence, the
diagnosis of LH at all insulin injection sites should be
DIAGNOSIS implemented.7
Clinical Findings Blanco et al 5 in their study on 430 subjects those
Lipohypertrophy usually present as soft dermal nodules were injecting insulin. They filled a detail questionnaire
like lipomas or fibrocollagenous scar in subcutaneous regarding their insulin injection technique. The study
tissue and can vary in size from golf balls to an orange. was to assess the frequency of lipohypertrophy (LH) and
If large areas are involved, then the appearance can be its relationship to site rotation, needle reuse, glucose
unsightly. Initial skin changes can be subtle and manifest variability, hypoglycemia and use of insulin. 64.4% of
only as thickening of skin. This can be easily missed by studied subjects (Both T1DM and T2DM) had LH. He
visual inspection and so areas should be palpated. It is showed a strong relationship between the presence of LH
recommended that, in order to feel subtle skin thickening, and nonrotation of sites. More so, he demonstrated that
the hand should be stroked firmly in a sweeping motion correct rotation technique have the strongest protective
rather than using traditional techniques of light and deep value against LH. Of the patients who correctly rotated
palpation. LH is most commonly seen on either side of sites, only 5% had LH while, of the patients with LH, 98%
the umbilicus and mid thigh as these are commonly used either did not rotate sites or rotated incorrectly. Also,
sites for injection and are easily reached and convenient 39.1% of patients with LH had unexplained hypoglycemia
for patients. and 49.1% had glycemic variability compared with only
5.9% and 6.5%, respectively, in those without LH. The
CLINICAL CONSEQUENCES OF LH risk increased significantly when needles were used
LIPOHYPERTROPHY > 5 times. Total daily insulin doses for patients with and
A missed diagnosis of LH may have major clinical without LH averaged 56 and 41 IU/day, respectively.
consequences. In ultrasound examination, these lesions appeared as
homogeneous hyperechogenic densities filling part or
Glycemic Oscillations all of the SC tissue at injection sites, and could clearly be
The injection of insulin into LH may cause wide glycemic distinguished from adjacent normal subcutaneous tissue.
variability, including inappropriately high glucose levels Correct injection site rotation appears to be the critical
and a high rate of unexplained hypoglycemic episodes. in preventing LH and associated glycemic variability,
Thus patient may require large frequent changes in unexplained hypoglycemia, insulin consumption and
insulin doses. Proper insulin injection techniques the costs (Tables 1 and 2).5
related education programs aimed specifically for people
with LH have proven to be effective and have shown Bruising
significant reduction in glucose oscillations.7 Bruising is another complication of insulin injection-
Most studies suggest that insulin absorption at areas related skin lesions at the injection site. Bruising disturbs
affected by LH may be both delayed and erratic, leading to diabetic patients due to the resulting blemishes, for which
increase in doses of insulin and deteriorating metabolic there are as yet no solutions. Unfortunately, injection-
control. This causes undesirable glucose fluctuations related problems negatively affect the overall compliance
causing serious hypoglycemic episodes. Similarly, of diabetic patients for insulin therapy. It is important
whenever patients suddenly switch from affected to note that injection site-related adverse events, such
injection sites to normal ones, risk of hypoglycemia as pain, redness, bruising, and bleeding, are significant
CHAPTER 58: Lipohypertrophy Secondary to Insulin Injection Therapy 349
TABLE 1: Data for patient according to diabetes (DM) type and presence of lipohypertrophy (LH)5
Total T1D T2D LH present LH absent
Patient (n) 430 177 253 277 153
Gender (M/F) 221/202 89/86 132/116 142/130 79/72
Age (years, mean ±SD ) 49 ± 22.8 41 ± 23.2 55 ± 20.7 47 ± 23.8 54 ± 20.1
Since DM diagnosis (years, range) 6–15 6–15 6–15 6–15 6–15
(% in range) (43.7) (39.0) (47.0) (41.2) (48.4)
Insulin treatment (years, range) 1–5 6–13 1-5 6–13 1–5
(% in range) (44.2) (37.3) (54.9) (35.0) (64.1)
Frequent unexplained HG (n) 117 71 46 108 9
(%) (27) (40) (18) (39) (6)
Glycemic variability (n) 146 89 57 136 10
(%) (34) (50) (23) (49) (7)
TABLE 2: Data for diabetes patient according to injection site rotation and needle reuse5
Total Site rotation Needle reuse
None or Claimed and Never reuse Reuse at least
incorrect correct once
Patient (n) 430 288 100 190 240
Gender (M/F) 221/202 141/142 56/43 102/87 119/115
Age (years, mean ± SD ) 49 ± 22.8 47 ± 23.7 50 ± 21.5 47 ± 24.2 50 ± 21.6
Since DM diagnosis (years, range) 6–15 6–15 6–15 6–15 6–15
(% in range) (43.7) (44.1) (48.0) (46.8) (41.3)
Insulin treatment (years, range) 1–5 6–13 1–5 1–5 1–5
Reuse needle (at least once. n) 240 172 33 190 240
(%) (56) (60) (33) (0) (100)
Rotation claimed (n) 287 145 100 143 144
(%) (67) (50) (100) (75) (60)
Rotation correct (n) 106 6 100 69 37
(%) (25) (2) (100) (36) (15)
Rotation claimed and correct (n) 100 288 100 67 33
(%) (23) (0) (100) (35) (14)
Rotation correct and no reuse (n) 69 2 67 69 37
(%) (16) (1) (67) (100) (0)
Presence of lipohypertrophy (n) 277 264 5 109 168
(%) (64) (92) (5) (57) (70)
Skin cleansed with antiseptic (n) 69 50 12 30 39
(%) (16) (17) (12) (16) (16)
Frequent unexplained HG (n) 117 104 5 37 80
(%) (27) (36) (5) (19) (33)
Glycaemic variability (n) 146 134 7 55 91
(%) (34) (47) (7) (29) (38)
350 SECTION 4: Endocrinology
barriers to patient adherence to treatment regimens injection technique (IT). The nurse then examined the
involving multiple daily injections. Surprisingly, in few patient’s injection sites for the presence of LH, followed
of the studies one-half of the patients reported that by an individualized training session in which sub-
injection-related problems are due to their healthcare optimal IT practices highlighted in the questionnaire
providers who were unable to resolve the associated were addressed. All patients were taught to rotate sites
pain and bruising.7 Thus, it is important that physicians correctly to avoid LH and were begun on 4 mm pen
and/or healthcare providers should have sufficient needles to avoid intramuscular (IM) injections. They
experience, training and should possess sufficient
were instructed not to reuse needles. The purpose of the
knowledge to provide assistance to all patients taking
study was to assess whether proper injection technique
insulin therapy.7
(IT) is associated with improved glucose control over a
Glucose Control three-month period. Nearly 49% of patients were found
During the visit of insulin-injecting patients in clinician’s to have LH at study entry. After three months, patients
chamber, most of the discussions goes for blood glucose had mean reductions in HbA1c of -0.58% (0.50–0.66%,
control and dose adjustments, while very little time is 95% CI), in fasting blood glucose of -14 mg/dL (10.2–17.8
spent on improving Injection Technique (IT). However, mg/dL, 95% CI) and in total daily insulin dose of -2.0
IT may in certain cases be just as important to diabetes IU (1.4–2.5 IU, 95% CI) all with p < 0.05. 7 Follow-up
management as the type of insulin or dosage used.8 questionnaires showed that significant numbers of
In a cross-sectional study, conducted on 174 patients patients acknowledged the implication of IT and were
with T1DM (aged 13–18 years) taking multiple daily executing the injection technique more correctly.
insulin injections for a minimum duration of 1 year, it was Most of them found the 4 mm needle more convenient
shown that nearly 46% of patients were found to reuse
and comfortable. The study concluded that targeted
needles, while 42.5% failed to rotate the injection site and
individualized training in IT is associated with improved
23% revealed unexplained hypoglycemic events. 47%
glycemic control, better satisfaction with therapy,
of patients showed grade 1 LH, followed by 33.7% with
improved and simpler injection practices and possibly
grade 2 and 19.3% with grade 3 LH. A higher frequency of
lower consumption of insulin after a 3-month period.8
LH was observed in the thigh region (n = 28, 33.7%) than
in the arm (n = 23, 27.7%). People with uncontrolled DM
had a greater likelihood of having LH (59.5%) than those
with controlled diabetes (20.8%). Significant differences
in LH were observed based on needle length, needle
reuse, and rotation of the injection sites.9
EVERY HEAD HAS ITS OWN HEADACHE overuse headache). So we would deal with these
An old Arabian proverb sums it all. Headache is one of the problems one by one.
Challenges in the headache:
common complaints in the primary outpatient setting
—— First severe headache
and if not correctly diagnosed and treated, may indeed
—— Chronic daily headache/Medication overuse
become a headache for the physicians. Newer insights
into the pathophysiology and treatment necessitate the headache
—— Headache in pregnancy
physician to be aware of the different types of headaches
—— Headache in elderly
so that a proper treatment protocol is initiated. One
—— Headache with comorbidities
needs to understand that cure rate for headache is not
—— Status migranosus
100% and a large number of patients have psychiatric
—— Menstrual migraine
comorbidity.
To make it easier to manage the headache patients,
ICHD came up with a classification system to bring FIRST SEVERE HEADACHE
uniformity in coding and choice of treatment plan. Although majority of patients coming to outpatient
However, the diagnostic criteria might be useful for setting would have a prior headache history but with
research purpose but would pose a challenge in the ease of availability of medical facilities, patients present
outpatient practice. Even the ICHD beta version early to the medical facility even when they have their
specialists do not expect the general practitioners to first headache. The purpose of the evaluation is to
remember it by heart but to use it as a guiding tool. Since correctly diagnose the type of headache
a large number of headaches would be treated initially to screen for potential secondary causes
by a general physician and not a headache specialist, to look for red flag signs
this article would focus on the main challenges faced The history and examination is of paramount
by a physician in the outpatient or emergency setting. importance in leading to a correct diagnosis in majority
Such problems if not treated appropriately in the nascent of patients. First ever headache in general requires
stage would lead to bigger therapeutic dilemmas later investigations to rule out secondary causes. However, the
on (especially chronic daily headache and medication cost and constraints of availability may limit investigating
356 SECTION 5: Neurology
all the patients. However, there are certain subsets of need to be taken into confidence and psychiatric
patients when investigations need to be emphasized. comorbidities need to be looked into. Patient should
These groups are have a sleep hygiene improvement, detoxification
first or worst headache of life (withdrawl of offending overuse drug), a proper diet plan
progressively worsening headache and prevention of dietary and environmental triggers.
age more than 50 years The patient needs to understand that there might be
atypical history for a primary headache worsening of the headache severity and frequency
headache getting worsened with cough, sneezing, initially but withdrawl of overuse drugs would pay
valsalva maneuvers dividends in the long run. Regular exercises (especially
s p e c i a l m e d i c a l c o n d i t i o n s ( p a t i e n t o n low load cervical exercises) and acupuncture may
anticoagulation, contraceptives, recent head trauma) also help in the treatment program. Biofeedback and
thunderclap headache (headache reaching peak relaxation techniques would help in improvement in
within one minute) quality of life indices. Certain prophylactic drugs such as
autonomic symptoms (all autonomic cephalalgias gabapentine, divalproex and Topiramate have efficacy in
need exclusion of a secondary cause) reducing the headache frequency. Beta blockers efficacy
associated signs (fever, neck stiffness, autonomic is uncertain. Botulinum toxin and use of occipital nerve
symptoms, unilateral Horner’s) stimulation have shown promising results. Recently, a
short neck (for craniovertebral junctional anomalies, portable external trigeminal nerve stimulator (CEFALY)
Arnold Chiari malformation) has shown good results in chronic migraine.
Asymmetric pulses
antiemetics (prochlorperazine, metoclopramide), low Rule out secondary or complicating factors (fever,
dose corticosteroids and NSAIDs. Only prophylactic neck stiffness)
agents which may be used are low dose propranolol and Since sleep disruption and dehydration frequently
probably gabapentine. perpetuate the headache, hydration and sleep aids
may help. Intravenous antiemetics and sumatriptan
HEADACHE IN ELDERLY may help if not already given. The analgesic abuse
In elderly, one needs to understand that the pattern of requires detoxification process by withdrawl and
headache might be different and that the secondary substitution with alternate drug; and/or initiation of
causes are to be particularly looked for. Also, certain appropriate prophylactic therapy
headache types are unique to elderly (e.g. temporal If patient continues to have headache, intravenous
arteritis, hypnic headache, TIAs masquerading as aura valproate or a short term course of steroids
or headache). Also, comorbid illnesses and change (prednisolone or dexamethasone) may help.
in the hepatic function may require a modification of
the dosages of drugs. Migraine in elderly may appear
MENSTRUAL MIGRAINE
with visual or sensory symptoms without headache Large numbers of women report an association between
(migraine accompaniments). Tension type headache is migraine and menstrual periods. Menstrual migraine
could be pure menstrual migraine (that occurring only
more frequently seen than in younger age group. Hypnic
during menstruation, i.e. 1+/–2 days of menstruation, and
headaches occur only in elderly and awaken patients
at no other times of cycle. The first day of menstruation
from sleep. Medication used for comorbid illnesses
is day 1 and the preceding day is –1. By definition, no
(like nitroglycerine for CAD) should be screened as
day zero exists) or menstrually related migraine in which
a cause of headache. One needs to rule out cardiac
attack occurs on days 1+/-2 of menstruation in at least 2
cephalalgias, subdural hematomas, TIAs, etc. in elderly
out of three menstrual cycles and additionally at other
with a thorough history taking and clinical examination
times of cycle. Majority of women have menstrually
(especially focal signs, temporal artery tenderness,
related migraine than pure menstrual migraine. Acute
papillary asymmetry, etc.). Poor cognitive capacity
treatment stays the same. There is an additional
may pose hindrance to accuracy of history. Hence, one
option of perimenstrual prophylaxis depending on the
should have a low threshold for investigations. Certain severity of migraine and regularity of cycles. Options
medications may not be used in elderly (e.g. triptans, include perimenstrual NSAIDs, e.g. naproxen 550 mg/
dihydroergotamines, amitryptiline). One should try to day, estradiol supplementation during luteal phase,
minimize the use of drugs for above mentioned reasons perimenstrual triptan prophylaxis and continuous
and ensure lifestyle modification and adjustment of 84/168 days of contraceptive prophylaxis for women
other drugs to an optimal level. requiring contraception. Important point to consider is
that combined hormonal contraceptive should not be
STATUS MIGRANOSUS given to women with migraine with aura due to risk of
A migraine attack lasting longer than 72 hours, regardless stroke.
of treatment, is labeled as status migranosus. It may
occur in both types of migraine (i.e. with and without HEADACHE WITH COMORBIDITIES
aura). Possible mechanism could be an inflammation of It is not unusual to have patient with migraine who
the intracranial blood vessels. For an effective treatment has other illnesses. One needs to take advantage of the
Underlying triggers or perpetuating factors should be therapeutics of the antimigraine prophylaxis to choose
looked for (sleep disruption, dehydration, overuse of the drug. Below is the table showing the choice of drugs
analgesics, anxiety) for migraine in the presence of comorbid illnesses.
358 SECTION 5: Neurology
their course and present as single cranial neuropathy of foramina of exit of various cranial nerves.
or multiple cranial neuropathies. The complete work Features favoring INTRINSIC lesion (within the
up to reach a conclusion while dealing with cranial brainstem)
neuropathiesis a difficult task and a real challenge for Symmetric or asymmetrical
the treating physician. Correct localization is the initial Simultaneous involvement of multiple cranial nerves
step in the diagnosis. Multiple cranial nerves get involved Early involvement of motor neuronal and long
multiple cranial neuropathies.1 side and sensory motor involvement on opposite side
Horner’s syndrome, internuclear ophthalmoplegia
Local spread from nasopharyngeal tumor, chordoma, common cause of cavernous sinus syndrome are
sarcoma tumors. These may be metastatic disease, a result of
Trauma, carotid artery dissection, jugular vein local tumor extension (nasopharyngeal carcinoma,
thrombosis pituitary adenoma or craniopharyngioma) or a primary
Paget disease, basilar invagination, Arnold-chiari and tumor (meningioma, lymphoma). The other causes are
bony disorders sarcoidosis, Wegener’s granulomatosis, or polyarteritis
Perineural invasion of spindle cell, basal cell, parotid nodosa. Painful ophthalmoplegia is the most common
and squamous cell cancer clinical feature of Tolosa-Hunt syndrome which is an
Granulomas and infectious diseases (sarcoid, idiopathic inflammatory granulomatous disease and
Wegener granulomatosis, Lyme disease, CMV) the most common cause of cavernous sinus syndrome
(Table 1). Spontaneous remission occurs in up to a third
Herpes zoster and other viral and postinfectious
of patients. The good response to steroids is one of the
inflammatory lesions
diagnostic clues.
Mixed connective tissue disease
An anterior cavernous sinus syndrome causes
Tolosa-Hunt-like syndrome, Melkersson Rosenthal
involvement of III, IV and VI cranial nerves along with
syndrome
involvement of ophthalmic division of Vth cranial nerve.
The III, IV, VI cranial nerve involvement with proptosis
Localizing the Site of Lesion suggest superior orbital fissure syndrome. Orbital apex
As the cavernous sinus lies within a dural envelope that syndrome involves optic nerve and III, IV, V and VIth
funnels the upper cranial nerves to the orbit, even a cranial nerves. Middle and posterior cavernous sinus
small lesion can produce multiple cranial neuropathy.3 syndromes are considered if V2 and V3 are involved
Common causes of cavernous sinus involvement can simultaneously. All three divisions of trigeminal nerve
be divided into vascular, neoplastic, inflammatory, and are likely to be affected in parasellar lesions. Involvement
miscellaneous disorders. Cavernous sinus thrombosis of VII and VIII along with or without VI suggests a
usually results from paranasal sinus infections, orbital cerebellopontine angle lesion. Unilateral caudal cranial
cellulitis, or a facial infection. Staphylococcus is the nerve involvement suggests a jugular foramen syndrome
most common causative organism. In diabetics, of the affected side and diseases of intracranial and
mucormycosis is of particular concern. The most extracranial structures of the base of the skull.
Chest X-ray
Blood Imaging of chest, abdominal or pelvis
Complete blood count and differential Biopsy of lymph node or tissue
Biochemistry panel Meningeal biopsy
Erthrocyte sedimentation rate
C-reative protein CONCLUSION
Antinuclear antibody An accurate diagnosis of multiple cranial palsy
Extractable nuclear antibody poses a clinical challenge to the physician. Rare
Antineutrophilic cytoplasmic antibodies diagnoses such as leptomeningeal carcinomatosis
Rheumatoid factor and neurolymphomatosis must be considered in
Angiotensin converting enzyme undiagnosed cases. If nonspecific inflammation is
Lyme antibody suspected, a brief course of steroids may be effective.
FTA Other treatment is generally directed at the cause. Patient
HIV must be followed up with repeated neuroimaging if there
Cryptococcal antigen is no remission.
362 SECTION 5: Neurology
Nocturia
Bladder diary
Diminished bladder
Polyuria
capacity
Global polyuria
Nocturnal polyuria
(24 hr vol > 40 mL/kg)
symptoms (urinary frequency, urgency), and urinary medications allow for an increase in the bladder
incontinence. capacity and may reduce nocturia by both
Physical examination : Orthostatic vital signs, decreasing urge-associated voids and increasing
cardiovascular and pulmonary examination, rectal bladder capacity. Agents differ in efficacy, side
examination, focused neurourologic examination effects, costs, and impact on comorbid conditions
(anal wink, perineal sensations). that may improve or be exacerbated by the drug.
Anticholinergics with antimuscarinic effects are
TREATMENT frequently prescribed for nocturia.
Initial treatment includes adjustment of fluid intake, —— Antidiuretic therapies–Desmopressin : The
Patient can present with nausea, vomiting, and the patients do not show positive aquaporin 4 antibody.
hiccup. They are considered to be seronegative NMOSD in
Narcolepsy can be important clinical features in some appropriate clinical background.
cases.
Aquaporin 4 antibody which is an autoantibody Pathogenesis
(NMO IgG) is an important marker of NMO and its AQP4-IgGs play an important role in pathogenesis.
spectrum. This can be demonstrated in blood and These IgGs bind to aquaporin 4. This binding results in
CSF in majority of cases. down-regulation of surface aquaporin-4 (AQP4) and
A section of people suffering for disease show CSF changes water homoeostasis in the CNS. It also activates
cells >50/µL (neutrophils) classical complement system leading to membrane
MRI brain is also important because it can show damage. There is increased BBB permeability and
signal changes in areas other than MS. infiltration of leukocytes, particularly eosinophils and
neutrophils that can be found in the CSF during acute
Diagnosis attacks. Interleukin 6 (IL-6) dependent plasmablasts
Because of the various clinical manifestations and may play a role in pathogenesis of NMO. It has been seen
course of the disease, there were constant change in that plasmablast population expands during relapse of
diagnostic criteria. However in 2006 Dean Wingerchuk, NMO. IL-6 also increases the survival of plasmablasts
had proposed certain criteria which have been well and their AQP4 antibody secretion. The combination
accepted by various authorities. In clinical practice, if of complement-mediated injury and leukocytosis
we find visual loss due to optic neuritis and features leads to the death of astrocytes, oligodendrocytes. The
suggestive of myelitis on clinical examination along with complement membrane attack complex causes changes
brain and spinal cord MRI findings (Figs 1 and 2) as in blood vessels, including their irregular thickening and
already described and a positive aquaporin 4 antibody hyalinization.
in CSF and blood, we can make presumptive diagnosis
of NMO. It is better to have two criteria from laboratory Treatment
backup namely MRI finding and positive aquaporin O nce the diagnosis of NMO/NMO SD is made,
4 antibody along with visual and spinal problem in management of acute exacerbation and prevention of
clinical background. It is also been noted that some of relapse is of paramount importance.
Fig. 1: Case 1: MRI brain and spinal cord in two of our cases
CHAPTER 62: Neuromyelitis Optica: A Physician’s Perspective 369
Fig. 2: Case 2: MRI brain and spinal cord in two of our cases
TABLE 4: Patients at increased risk for seizure recurrence after TABLE 5: Differential diagnosis of a single seizure
first seizure
zz Syncope (including breath holding and pallid syncope)
Prior brain lesion or insult (most powerful predictor)
zz Transient ischemic attacks
Persistence of epileptiform EEG abnormality
zz Metabolic encephalopathy (including hypoglycemia or
Significant brain imaging abnormality electrolyte disturbance)
Note: The latter two risk factors increased the risk of seizure recurrence zz Cardiac arrhythmias
to 60% or more.
zz Pseudoseizures
sleep deprived EEG will detect epileptiform (spike) seizures. The decision to provide anticonvulsant
discharges. Sleep deprived EEG may be carried out in treatment after first seizure should be individualized.
any routine EEG laboratory. Antiepileptic drug choice: The chosen antiepileptic
8. Kho LK, Lawn ND, Dunne JW, Linto J. First seizure American Epilepsy Society. Neurology. 2007;69(21):1996-
presentation: do multiple seizures within 24 hours predict 2007.
recurrence? Neurology. 2006;67(6):1047-9. 10. Shinnar S, Berg AT, O’Dell C, et al. Predictors of multiple
9. Krumholz A, Wiebe S, Gronseth G, et al. Practice parameter: seizures in a chohort of children prospectively followed
evaluating an apparent unprovoked first seizure in adults from the time of their first unprovoked seizure. Ann Neurol.
(an evidence-based review): report of the Quality Standards 2000;48(2):140-7.
Subcommitte of the American Academy of Neurology and the
CHAPTER
64
An Overview and Practical Clinical Hints in
the Diagnosis of Temporal Lobe Epilepsy
Venkataraman Nagrajan
areas, Cingulate gyrus, amygdale, hippocampal gyrus experienced (Jamais-vu) if visual, (Jamais-Entandu).
and selected thalamic nuclei. An analysis of autonomic A condition called panoromic vision, which is a rapid
substrata of CPS offers an explanation, for the multiple recollection of episodes from the past experiences
clinical manifestation and electroclinical correlates of can occur.4 Affective symptoms composes features of
this disorder. fear, pleasure, displeasure, depression, rage, anger,
irritability, elation, and erotism. In some cases, there
CLINICAL FEATURES may severe autonomic symptoms such as papillary
The main features of CPS is impairment of consciousness, dilatation, pallor, flushing, piloerection, palpitation
which may or may not be preceded with symptoms. and systolic hypertension.5
(Motor, sensory, autonomic and psychic). There may Certain symptoms less commonly, occurs, with
be total absence of any other signs or symptoms during feeling of exhilaration, elation, serenity, satisfaction
the impaired conscious state, or automatisms may be and pleasure (Ecstatic seizures, Dostoyevesky
present. epilepsy).6,7
Such exhilaratory feelings may be sexual. This
INTERNATIONAL CLASSIFICATION OF sexual pleasure during an aura may consists of
THE CPS3 either sexual arousal or orgasm.8 Visual perceptions
CPS with simple partial onset with impairment of like polyoptic illusions, mono ocular diplopia,
consciousness only macropsia, micropsia, or distortion of distance.
CPS with simple partial onset followed by impaired Auditory perceptions distortions of sound like micro
consciousness and automatisms and macroacusia. Depersonalization, a feeling that
CPS with impairment of consciousness at the onset, the persons is outside the body may occur. Altered
and getting continued with motor seizures perception of size and weight of a limb is observed.
CPS with impairment of consciousness at the onset Structured hallucinations are perceptions without
with automatisms. corresponding external stimuli, affecting the
somatosensory, visual, auditory, olfactory and
SEIZURE PHENOMENA gustatory senses.2
Impairment of consciousness: The patient may look
vacant or frightened. Occasionally able to recall Automatism
vague sensations, and also do not realize anything Various type automatism which is a phenomenon
more has occurred. that includes, alimentar y-chewing movements,
Simple partial onset of seizures: May be with motor borborygmus, Mimetic—facial grimaces, fear expression,
signs with somato sensory or special sensory bewilderment, vacant tranquil look, laughing (Gelastic
symptoms, autonomic symptoms Automatisms seizures), or crying (Lacrimonic seizures), lip smacking,
alone. chewing, and kissing gestures.
Simple partial onset with psychic symptoms: Due to Gestural—purposeful or nonpurposeful hand
discharges occurring in focal areas of temporal limbic movements, sexual gestures such as masturbating
structures, they may be dysphasic symptoms, in the activity, pelvic thrust ing (Foci arising and reflecting in
form of ongoing speech arrest, vocalization, palilalia, the frontal area of the brain9
Dysmensic symptoms: Distortion of memory, temporal Ambulator y—Wandering or running (cursive
disorientation a state of dreamy state, a flash back, a seizures) are dangerous forms of seizures, as the patient
sensation of previously occurred experience, (Deja- has no awareness of what is happening, wherein the
vu phenomenon – visual, auditory (Deja-entendu). patient may unknowingly traverse a traffic, or fall in a
It can also a sensation which the patient has not well or ditch and injure himself.
378 SECTION 5: Neurology
A B
Figs 1A and B: Irregular fibrosis of hippocampus3
Verbal phenomenon—shrill cries, humming, short staring present, speech during the attack is absent.
phraces, explecities or swearing repeated in automatic Absent postictal confusion. Also characterized by the
fashion. classical EEG findings–3 Hz spike and wave, more
provoked by hyperventilation.
EEG PHENOMENON IN TLE OR CPS Migraine, syncope, onset usually adult, occurs in
Most of interictal EEG are normal. Scalp surface EEG, erect posture, flaccid muscle tone, pale skin, cold
positive in 10% of cases. Special procedures of EEG, like and clamy, EEG may not show seizure findings. May
sphenoidal EEG, hyperventilation EEG, sleep EEG, sleep be positive ECG changes. Clinically plantar is flexor,
deprivation EEG, enhances; the yield to positivity. The bladder incontinence is rare.
positivity of EEG shows spikes, and spike wave over the Hysterical (pseudo seizures): Motivationally
site of focus, and become some time generalized, when determined episodic behavior-tongue biting,
simple partial seizures becoming generalized. Focal incontinence may absent or rare. Self injury rare.
slowing and low voltage complexes are also observed. Often identifiable secondary gains. Normal ictal and
interictal EEG.
IMAGING STUDIES CT VS MRI TIA: Usually conscious patient, focal symptoms and
The hallmark of temporal lobe epilepsy could be signs. Focal deficit lasting and recovering with in
mesial temporal sclerosis on MR imaging is an atrophic 24 hours. Absent aura, and no significant abnormal
hippocampus associated with hyperintense signal EEG findings relevant to CPS. Mostly associated with
on long-repetition-time sequences confined to the cardiovascular findings. These features are absent in
hippocampus. Amidst CT and MRI, MRI would be CPS.
superior investigation. SPECT, PET, spectral analysis of Affective psychosis : Ideational disturbances,
MRI, may be contributory (Figs 1A and B).10,11 hallucina-tions, inappropriate affects which do occur
during CPS, which develop suddenly but do; not
DIFFERENTIAL DIAGNOSIS continue for ever, as they are in affective psychosis.
Absence seizures: Usually childhood, no aura, usually Other miscellaneous conditions do mimic CPS and
upto 10–15 seconds, alertness is out of contact, they are hypoglycemia, drugs in take, alcohol intake,
automatism—lip licking (Cf. lip smacking in TLE), may mimic, and they are appropriately ruled out.
CHAPTER 64: An Overview and Practical Clinical Hints in the Diagnosis of Temporal Lobe Epilepsy 379
consequences (after time point t2), including neuronal —— Remote (e.g. posttraumatic, poststroke, etc.)
CHAPTER 65: Changing Scenario in Management of Status Epilepticus 381
status
Elderly (≥60 years)
—— Focal
seizures (Jacksonian)
epilepticus that continues or recurs 24 h or more after the
—— Epilepsia partialis continua onset of anesthetic therapy, including those cases where
(EPC) status epilepticus recurs on the reduction or withdrawal
—— Adversive status
—— Focal inhibitory SE
of anesthesia. This has high mortality and morbidity
rates. This term was first used in the London-Innsbruck
zz Tonic status
Colloquium on status epilepticus held in Oxford in 2011.
zz Hyperkinetic SE
temperature between 32 and 35 °C. Endovascular cooling infection, thrombosis, disseminated intravascular
is the currently preferred method in adults. Hypothermia coagulation and cardiac arrhythmias.
benefits through reduction of brain metabolism and
ATP consumption and prevention of mitochondrial Magnesium and Pyridoxine Infusions
dysfunction and oxidative stress. It decreases the Both the drugs carry little risk and are easy to administer.
permeability of the blood-brain barrier and limits pro- Magnesium may be infused at 2–6 gm/hour to obtain
inflammatory reactions. The complications include acid– a serum level of 3.5 mmol/L. This may be continued
base and electrolyte disturbances, coagulation disorders, if effective and stopped if ineffective. In children,
384 SECTION 5: Neurology
very resistant cases where first and second line therapies 2. Dubey D, Kalita J, Misra UK. Status epilepticus: Refractory
fail. They include and super-refractory. Neurol India. 2017;65:S12-7.
Electroconvulsive therapy
3. Ferlisi M, Shorvon S. The outcome of therapies in refractory
and super‑refractory convulsive status epilepticus and
Cerebrospinal fluid drainage
recommendations for therapy. Brain. 2012;135(Pt 8):
Vagal nerve stimulation
2314‑28.
Deep brain stimulation 4. Gaspard N, Foreman BP, Alvarez V, Cabrera Kang C,
Repetitive transcranial magnetic stimulation. Probasco JC, Jongeling AC, et al. New-onset refractory
status epilepticus: etiology, clinical features, and outcome.
Neurology. 2015;85:1604-13.
CONCLUSION
5. Khoujah D, Abraham MK. Status epilepticus: What’s New?
Status epilepticus is one of the most happening subjects Emerg Med Clin North Am. 2016;34(4):759-76.
in the field of neurology with rapidly changing concepts 6. Lionel KR, Hrishi AP. Seizures—just the tip of the iceberg:
in its diagnosis and treatment. The mystery is not Critical care management of super-refractory status
yet unraveled and more developments are expected epilepticus. Indian J Crit Care Med. 2016;20:587-92.
7. Rossetti AO, Lowenstein DH. Management of refractory
in the coming years. The most recent development
status epilepticus in adults: Still more questions than
has been the identification of super-refractory status
answers. Lancet Neurol. 2011;10:922‑30.
epilepticus. The neuronal antibody mediated disorders 8. Shorvon S, Ferlisi M. The treatment of super‑refractory
are increasingly recognized to present as super-refractory status epilepticus: A critical review of available therapies
SE. Immunotherapy is thus being recognized as a form of and a clinical treatment protocol. Brain. 2011;134(Pt
therapy in SE in addition to antiepileptic drugs and has to 10):2802‑18.
9. Trinka E, Cock H, Hesdorffer D, et al. A definition and
be initiated without delay especially in situations where
classification of status epilepticus—Report of the ILAE Task
the etiology remains uncertain despite all investigations. Force on Classification of Status Epilepticus. Epilepsia.
2015;56:1515-23.
BIBLIOGRAPHY 10. Zaccara G, Giannasi G, Oggioni R, Rosati E, Tramacere L,
1. Betjemann JP. Current trends in treatment of status Palumbo P. Convulsive status epilepticus study group of
epilepticus and refractory status epilepticus. Semin Neurol. the uslcentro Toscana, Italy. Challenges in the treatment of
2015;35(6):621-8. convulsive status epilepticus. Seizure. 2017;47:17-24.
CHAPTER
66
Present Status of Thrombolysis in Acute
Ischemic Stroke: Indian Scenario
V Shankar
This was comparable to the data in the European Safe affinity to PAI-1 and a 4-fold prolonged plasma half-life.
Implementation of Thrombolysis in Stroke-monitoring It is administered as a single bolus. It is less expensive
study and pooled results from randomized controlled than alteplase.
trials. An Indian trial in 92 patients with 0.2 mg/kg of
Age <60 years, admission glucose level <8 mmol/L, tenecteplase found an improvement =/>4 points on
NIHSS score of 10 +/– 6 were associated with major the NIHSS scale in 24 hours in 58% and =/>8 point
neurological improvement at 24 hours and this was an improvement in 22% of patients. The mRS score of 0–1
independent predictor of good outcome at 12 months. was seen in 70% of patients at 90 days. The intracerebral
Cardioembolic strokes and small vessel occlusions hemorrhage rate was 1.19% and the mortality at 90 days
benefit from thrombolysis. Advanced age and more was 5.49%.
severe strokes as assessed by NIHSS scores were
independent predictors of poor outcome. TELESTROKE
Telestroke is useful to reach out to patients in remote
THROMBOLYSIS DOSAGE locations. A telestroke management program has
The dose of tPA used in several Indian studies is the been developed in the state of Himachal Pradesh in
standard dose of 0.9 mg/kg. However, some centers have collaboration with AIIMS. The eighteen primary stroke
used dose ranges of 0.6–0.9 mg/kg, or a fixed dose of 50 centers have been set up in state hospitals with CT scan
mg in the 3–4.5 hour time window. The proportion of
facilities. One hundred and twenty doctors have been
patients with mRS 0–2 at 3 months was about 50% with
trained and patients have been managed successfully.
intracerebral hemorrhage rate of 0–1.7%.
This program can be replicated in other states. The
The need for a properly randomized dose optimization
Telemedicine network of ISRO links 78 remote health
study was highlighted in a study where 46 patients
centres to 22 speciality hospitals in major cities. A hub
received 0.6–0.7, 0.7–0.8, and 0.8–0.9 mg/kg. Clinical
and spoke model can work well wherein specialists at the
improvement was noted in 75%, 85.7% and 66.7% of
hub can interact with physicians in the spoke hospitals
patients in the three different groups.
and guide thrombolysis. Simpler alternatives like
smartphones, online data transfer, apps like whatsapp
SONOTHROMBOLYSIS
can also be used to guide thrombolysis.
Intravenous tPA was combined with transcranial low-
frequency ultrasound waves targeted on the occluded
arterial segment in 18 patients with large artery acute
COMPLICATIONS AND OTHER
ischemic stroke. Immediate dramatic improvement in OBSERVATIONS
NIHSS scores was seen in 30% and within next 24 hours Hemorrhage, anaphylaxis or arterial occlusions are
in 50%. At 6 months, 63% achieved mRS 0–2. 11% of known complications of IV tPA. Two cases of acute
the patients died. Symptomatic ich occurred in 5.5%. myocardial infarction following IV tPA have been
Authors concluded that sonothrombolysis was a safe way documented.
to augment effect of tPA and flow through the occluded Recurrent cardioembolic stroke in the initially
artery could be monitored in real time. unaffected side during thrombolysis for an acute
ischemic stroke has been reported.
TENECTEPLASE IV thrmbolysis has been used in stroke which was
Tenecteplase is a glycoprotein which has a similar later found to be due to right ventricular myxoma with
structure as alteplase with modification at three sites. PFO. It has also been used in a case of left atrial myxoma.
It has certain pharmacological advantages namely a 15 There is also a report of the use of IV thrombolysis
fold higher fibrin specificity, a 80-fold reduced binding beyond guidelines in a patient with a recurrent acute
388 SECTION 5: Neurology
ischemic stroke who had suffered a posterior circulation An Indian study of 45 patients who had
stroke 5 days earlier. contraindications to iv tpa or failed iv tPA and underwent
endovascular therapy found that 51% achieved a mRS of
INTRAARTERIAL tPA 0 and 64% a mRS of <2 at 3 months follow up. There was 1
Intraarterial tPA has been administered between 4.5 and procedural complication and mortality of 18%.
6.5 hours to acute ischemic stroke patients and mRS sores
</=2 at 90 days were achieved in 7 out of 10 patients. CONCLUSION
Since recanalization rates with IV tPA are low in Time is brain. We have to increase awareness of stroke
large artery occlusions, intraarterial tPA was used in symptoms and the need to reach hospital in time among
17 patients with MCA, carotid T and basilar occlusions the general public. Training programs for doctors,
presenting within 0.5–6 hours after onset. The eight development of national guidelines by the Indian Stroke
patients had a mRS score</= 2 at 3 months and there Association, development of primary and comprehensive
were 3 deaths in the series. stroke centres and the National Program on Prevention
Intraarterial tenecteplase has been used in a case of and Control of Cardiovascular Disease, Diabetes and
M1 MCA occlusion on the third postoperative day after Stroke can contribute to improving thrombolysis in
closed mitral commissurotomy with dramatic recovery. acute ischemic stroke to the required level in the overall
With the recent beneficial experience in using scheme of stroke management.
endovascular therapy with stent retrievers, the newer
American Stroke Association guidelines recommend BIBLIOGRAPHY
e n d ova s c u l a r m e c ha n i ca l t h ro mb e c t o my ove r 1. Bhatia R. A continuing journey. The fight against stroke in
intraarterial thrombolysis as first line therapy and India. World Neurology. 2014;29(6):1.
2. Boddu DB, Srinivasarao Bandaru VC, Reddy PG,
comment that initial intra arterial thrombolysis no
Madhusudan M, Rukmini MK, et al. Predictors of major
longer reflects current practice. neurological improvement after intravenous thrombolysis
in acute ischemic stroke: a hospital-based study from south
THROMBOLYSIS AND ENDOVASCULAR India. Neurol India. 2010;58(3):403-6.
THERAPY 3. Huded V, Nair RR, de Souza R, Vyas DD. Endovascular
treatment of acute ischemic stroke: an Indian experience
Thrombolysis for acute ischemic stroke is not an end in
from a tertiary care center. Neurol India. 2014;62(3):276-9.
itself. In a comprehensive stroke centre any patient who 4. Khurana D, Das B, Kumar A, Kumar SA, Khandelwal N, Lal V,
is eligible for tPA in the time window should receive tPA Prabhakar S. Temporal trends in intravenous thrombolysis
as early as possible. Noninvasive intracranial vascular in acute ischemic stroke: Experience from a tertiary care
imaging like CT angiography should then be obtained center in India. J Stroke Cerebrovasc Dis. 2017;26(6):1266-
as quickly as possible. If there is a proximal large vessel 73.
5. Pandian JD, Sudhan P. Stroke epidemiology and stroke care
occlusion, patients >18 years of age with prestroke mRS
services in India. Journal of Stroke. 2013;15(3):128-34.
0–1, ASPECTS score >/=6 and NIHSS score >/=6, should 6. Rha JH, Shrivastava VP, Wang Y, Lee KE, Ahmed N,
receive endovascular therapy with a stent retriever if Bluhmki E, Hermansson K, Wahlgren N. SITS investigators
groin puncture can be achieved <6 hours from onset. thrombolysis for acute ischaemic stroke with alteplase in an
Endovascular therapy should be considered in patients Asian population: results of the multicenter, multinational
with contraindications to IV tPA and those outside Safe Implementation of thrombolysis in stroke-Non-
European Union World (SITS-NEW). Int J Stroke. 2014;9
the IV tPA time window of 4.5 hours. Ideally patients
(Suppl A100):93-101.
treated with IV tPA in primary stroke centers should be 7. Sharma S, Padma MV, Bhardwaj A, Sharma A, Sawal N,
transported as early as possible to comprehensive stroke Thakur S. Telestroke in resource-poor developing country
centers for possible endovascular therapy if required. model. Neurol India. 2016;64(5):934-40.
CHAPTER
67
Immunomodulation in
Neurological Disorders
Man Mohan Mehndiratta, Ashish Duggal
Drugs that bind to Inhibition gene transcription of cytokines (e.g. IL-2) Multiple sclerosis
immunophilins in T lymphocytes (blocking their proliferation), Chronic inflammatory demyelinating
(Immunophillics) inhibition of cytokines of T lymphocytes Polyradiculoneuropathy
Cyclosporine A, Inflammatory myopathies
Tacrolimus Myasthenia gravis
Lambert-Eaton myasthenic syndrome
Fig. 1: T2W MRI showing white matter hyperintensities perpendicular to the lateral ventricles typical of MS
months indicates secondary progression and should the effectiveness of steroids. Overall 15% of patients may
not be treated with acute medication. Steroids hasten not have any effect and one–third of patients may report
recovery from relapse but do not have any effect on worsening of symptoms with steroids.2 ACTH in a dose
overall function. Beneficial effect starts between 7 days of 40 units of ACTH gel IM 2 times a day for 7 days, then
and 10 days after a 5-day course of steroids and it is 20 units 2 times a day for 4 days, and 20 units once a day
prudent to wait for at least 2 weeks before deciding on for 3 days is also approved for use in MS relapse. Being
392 SECTION 5: Neurology
more expensive and less readily available, it is used as a There are 2 approaches to using DMTs in MS:
second line agent in patients who had no or a suboptimal escalation and induction (Fig. 3). Escalation therapy
response to steroids, or had intolerable side effects to consists of an early start with first line DMDs (beta
steroids. Plasma exchange is also approved as 2nd line interferon, glatiramer acetate, teriflunomide, dimethyl
treatment for acute MS relapse and about 93% of patients fumarate) and if DMDs are ineffective or partially
showed marked improvement and 46% recovered to effective, switching to second line drugs (mitoxantrone,
baseline EDSS after a course of PE. The protocol is to give natalizumab, fingolimod, alemtuzumab).4-6 Induction
1.1 plasma volume units at each exchange every alternate therapy on the other hand consists of the early use
day. Initially 4 exchanges are given and any meaningful of highly active immunosuppressants followed by
improvement should occur by the fourth exchange, so long-term maintenance treatment, generally with
any noticeable improvement should prompt a full seven- immunomodulatory agents. Induction therapy is
session course. Tumefactive or fulminant MS relapses primarily meant for use in patients with aggressive MS i.e.
may be treated with PE, cyclophosphamide with steroids, 2 or more severe attacks with incomplete recovery that
Alemtuzumab and Natalizumab, although there are no affect more than 1 functional systems, MRI shows more
established protocols. 3 IV immunoglobulin (IVIG) is than 2 Gadolinium enhancing lesions or there are more
commonly used in neurologic practice, but its usefulness than 2 spinal cord lesions. Cladribine, cyclophosphamide
in MS is speculative with mixed results. and Stem cell transplant are 3rd line agents that are used
in aggressive MS patients with poor response to 1st or 2nd
DISEASE-MODIFYING line drugs. Medication can be stopped if patients develop
IMMUNOTHERAPY FOR MS secondary progression with EDSS >7 and do not suffer
From the first disease-modifying therapy (DMT), any relapses for at least 2 years.
interferon (IFN) b-1b (Betaseron) that was approved
in 1993, today we have more than 13 DMTs which Neuromyelitis Optica Spectrum
can be used by oral or parenteral route. DMTs can be Disorders
classified as Drugs of moderate efficacy (average relapse Neuromyelitis optica spectrum disorders (NMOSD) is
reduction in 30–50% range) that include the interferons an autoimmune disorder, mediated in most cases by
and oral agents and Drugs of high efficacy (average antibodies to the aquaporin-4 (AQP4) water channel.
relapse reduction substantially more than 50%) which Clinically, NMOSD is characterized by recurrent
include agents such as Alemtuzumab, Natalizumab optic neuritis (ON), relapsing longitudinally extensive
and Mitoxantrone (Table 2). In spite of such many transverse myelitis (LETM), area postrema syndrome,
drugs, there is a consensus that none of the currently acute brainstem syndrome, symptomatic narcolepsy or
available disease-modifying therapies significantly acute diencephalic clinical syndrome and symptomatic
modifies progressively increasing disability that is cerebral syndrome. NMSOD may be associated with
unrelated to relapses (progressive nonrelapsing MS). several other autoimmune disorders. In contrast to MS,
Currently all patients who are diagnosed to have RRMS ON in NMOSD is more often bilateral and severe with
by the MAGNIMS 2016 criteria should be offered DMTs. incomplete recovery, myelitis presents as a complete
Patients who had been diagnosed as RRMS but are not spinal cord syndrome with a lesion involving >3 vertebral
on any DMT and had not have relapses in 2 or more years segments and cerebral lesions may resemble ADEM.
and do not have new MRI lesion activity may be observed Intravenous methylprednisolone (IVMP) and plasma
by serial imaging and close follow-up. Patients with exchange comprise the standard treatments for acute
CIS should be offered consider interferon or glatiramer disease exacerbations in NMO. In contrast to MS, in NMO
acetate if there are more than 2 brain or spinal cord spectrum disorders IV methylprednisolone should be
lesions consistent with MS within 6 months of the event. followed by a prolonged prednisone taper, usually in the
CHAPTER 67: Immunomodulation in Neurological Disorders 393
range of 2–6 months because all patients with NMOSD receive prolonged immunosuppression because relapses
will require prolonged immunosuppression. The length in NMOSD can be seriously disabling. Azathioprine,
of taper will depend on the choice of immunosuppressive mycophenolate and Rituximab are the usual first line
agent, being longer in patients started on azathioprine agents used for attack prevention in NMOSD (Table 3).
and shorter in those initiated on Rituximab. If the It is important to note that Interferons, Natalizumab and
symptoms do not clearly improve with IVMP, plasma Fingolimod which are used in MS may be detrimental in
exchange is administered daily or every other day for up NMOSD.7
to five treatments. PLEX should be strongly considered in
situations where corticosteroids fail to stabilize worsening MYELIN OLIGODENDROCYTE
deficits, especially in cases of ascending cervical myelitis GLYCOPROTEIN (MOG) ASSOCIATED
because of the risk of neurogenic respiratory failure and DEMYELINATION
in patients who had previously been successfully treated MOG antibodies are predominately found in children
with PLEX. PLEX may prove to be beneficial in 50–60% with CNS demyelinating diseases, but have also been
of steroid refractory patients. In contrast to MS, PLEX described in adults with ADEM, in anti-AQP4 antibody–
should be used early in course of disease, with some negative NMOSD cases, optic neuritis, transverse
clinicians using combination of IVMP and PLEX. IVIG myelitis, recurrent optic neuritis and in patients with
and cyclophosphamide have also been used in acute antiNMDA receptor encephalitis with demyelination.
relapses of NMOSD. As mentioned earlier all patients MOG-IgG-associated myelitis has been reported
with NMOSD (AQP4 positive or AQP4 negative) should to be relapsing, although relapses appear to be less
CHAPTER 67: Immunomodulation in Neurological Disorders 395
TABLE 3: Prophylactic agents used in NMOSD as altered consciousness (lethargy, stupor, coma) and/
Agent Dose Mechanism or altered behavior (irritability or confusion) is one of
the major ADEM defining symptoms as proposed by
Prednisolone 2–20 mg daily Multiple
the international pediatric MS study group (IPMSSG).
Rituximab 1 g at day 1 and day AntiCD 20 antibody
14, repeat every 6
In the absence of encephalopathy, a diagnosis of CIS is
months (optional: entertained. Multiphasic ADEM (MDEM) is defined as
monitoring of CD19 two episodes consistent with ADEM separated by three
counts) months but not followed by any further events. The
Cyclophosphamide 7–25 mg/kg IV Inhibits mitosis term recurrent ADEM is now no longer used and third
monthly for 6 months
ADEM-like event is no longer consistent with MDEM,
Especially in cases
with concomitant but indicates a chronic relapsing demyelinating disorder,
SLE/SS often leading to a diagnosis of ADEM followed by optic
Azathioprine 2.5–3.0 mg/kg daily Blocks synthesis neuritis (ADEM-ON), NMOSD, MOG–IgG associated
of adenine and demyelinating disease or possibly MS. An initial episode
guanine of ADEM needs to be differentiated from ADEM because
Mycophenolate 750–3000 mg daily Inhibits inosine the long-term treatment is different (Table 4). Treatment
monophosphate of ADEM is high-dose intravenous methylprednisolone
dehydrogenase,
primarily the type II 10–30 mg/kg/day up to maximum dose of 1 g/day OD
isoform found in T for 3–5 days followed by oral taper for 4–6 weeks. An
cells and B cells increased risk of relapse has been reported with steroid
Mitoxantrone Initiation with 12 mg/ Intercalates DNA, taper of 3 weeks or less. IVIG and PLEX are 2 nd line
m2 monthly for 3–6 inhibits mitosis therapies but early use of these modalities alone or
months, maintenance
either one in combination with corticosteroids might
with 6–12 mg/m²
every 3 months; be beneficial in patients at risk of complications from
maximum cumulative cerebral edema and raised intracranial pressure.8
dose of 120 mg/m2
Methotrexate 7.5–25 mg once Folic acid antagonist Autoimmune Mediated Encephalopathy
weekly
Autoimmune mediated encephalopathy (AME)
represents a complex category of disease with diverse
frequent than with AQP4-IgG seropositive NMOSD. So, immunologic associations, clinical manifestations, and
treatment with prednisolone to prevent relapse might therapeutic outcomes that is caused by inflammation
be necessary for 6–12 months but the role of long term of the CNS that is initially incited by the interaction of
immunosuppressive treatment is still not clear though autoantibodies in the CSF or serum with specific neuronal
it might be justified in individual patients if there are antigens or sometimes non–neural specific antigens. A
further relapses. classification of AME is given in Figure 5. Neural specific
antigens can be either–intracellular proteins or neuronal
ACUTE DISSEMINATED cell surface or synaptic proteins (Table 5). Patients
ENCEPHALOMYELITIS with AME may present with limbic encephalitis (triad
Acute disseminated encephalomyelitis (ADEM) is a of anterograde amnesia, seizures, psychiatric illness),
postinfectious autoimmune demyelinating condition diencephalic encephalitis (somnolence, narcolepsy,
which produces inflammatory demyelination in the brain hyperthermia, hypothalamic-pituitary dysfunction,
and spinal cord (Fig. 4). ADEM has a polysymptomatic, weight gain or sexual dysfunction), brainstem
multifocal neurological presentation that rapidly progress encephalitis (cranial neuropathy, ophthalmoparesis,
to maximal deficit in 2–5 days. Encephalopathy, defined opsoclonus, parkinsonism, dysarthria or dysphagia) or
396 SECTION 5: Neurology
Fig. 4: T2 weighted hyperintensities in white matter of parieto-occipital lobe and thalamus in a 28-year-old male who developed polyfocal
neurological deficit following a febrile illness suggestive of ADEM
encephalomyelitis (additional myelopathy, spasms). those who cannot tolerate corticosteroids) and plasma
In addition, there may be peripheral nervous system exchange (generally reserved for critically ill patients).
involvement in the form of sensory neuronopathy In severe cases, combination of IVIG and IVMP has also
or peripheral nerve hyperexcitability. In general, been tried. The response to immunotherapy is variable
considering the high incidence of tumors, a thorough and significant predictors for improvement include:
screening for any neoplasm should be made and treated subacute onset, fluctuating course, shorter delay to
appropriately. All cases with a diagnosis of AME should treatment, presence of non-neural specific and cell
receive a trial of immunotherapy which also serves surface antibodies. Following the acute course–high
as a diagnostic test in seronegative cases. The acute dose oral steroids, or weekly IVMP or monthly IVIG
therapeutic phase consists of a trial of high dose pulse can be given for at least 6 weeks if there is a response
iv corticosteroids, IVIG (particularly in diabetics and to steroids. Steroids or IVIG can gradually be tapered
CHAPTER 67: Immunomodulation in Neurological Disorders 397
TABLE 4: ADEM vs MS
MS ADEM
Age of presentation Young adults - onset of MS has been Children: Children less than 10 years of age are more likely to have
reported at 1 year of age ADEM than MS at the time of an initial demyelinating event
Lesion distribution Bilateral and not completely Bilateral and more symmetric than MS
symmetric
Enhancement Variable between lesions Frequently simultaneous in all lesions or none enhancement
Optic neuritis Present and usually unilateral Present and bilateral more frequently than in MS: Neuromyelitis optica
(NMO) is well recognized as a cause of a bilateral ON and may be an
alternative diagnosis in many cohorts, possibly limiting the usability of
bilateral ON as distinctive factor
Spinal cord lesions More common in the cervical spine Usually thoracic spinal cord
Minimal cord selling and contrast Cord swelling is common and variable contrast enhancement
enhancement is also less common
T2 lesion is peripheral, ovoid and T2 lesion is multifocal, flame shaped and can be large (>1/2 of spinal
paracentral (< ½ of spinal cord) cord)
TABLE 5: Intracellular vs synaptic antigens mediating AME IV) followed by maintenance therapy with methotrexate
Intracellular, onconeuronal Cell surface or synaptic receptor (MT X), azathioprine (AZ A), or less frequently,
antigen mycophenolate mofetil (MMF). It is recommended to
Affect older individuals Affects younger individuals and initiate high dose steroid therapy when the diagnosis is
children
suspected and if possible only start cyclophosphamide
Usually paraneoplastic May or may not be associated when there is diagnostic confirmation by angiography
with cancer
or histology. Cyclophosphamide can be given in daily
Damage is mediated by T-cell Appear to be antibody
mechanisms mediated oral dose or monthly pulses. Subsequently after 6
Examples: Hu, CRMP5, Ri, Yo, Examples: NMDAR, AMPAR,
months, consideration of a low-risk immunosuppressant
Ma2 GABA(B)R, LGI1, Caspr2, GlyR such as Azathioprine (1–2 mg/kg daily), methotrexate
Largely resistant to treatment Often responsive to (20–25 mg/week), or mycophenolate mofetil (1–2
(although stabilization or immunomodulatory therapies g daily) for maintenance of remission is advised.
improvement may occur)
Tumor necrosis factor α (TNFα) blockers such as
Infrequent relapses (usually Varies with antigen (10–25%
Infliximab can successfully treat patients with primary
monophasic and irreversible) may relapse)
CNS vasculitis that is resistant to glucocorticoids and
immunosuppressants.
after 4–6 months under cover of a steroid sparing agent
such as azathioprine, mycophenolate, methotrexate or
DISEASE AFFECTING THE PERIPHERAL
rituximab. In case, there is no response to 1st line therapy
NERVOUS SYSTEM
within 10 days second line therapy with Rituximab or
cyclophosphamide should be initiated in antibody Acute Inflammatory Demyelinating
positive cases (Fig. 6). In antibody negative cases, a brain Polyradiculoneuropathy
biopsy may be considered if the response is inadequate. Acute inflammatory demyelinating polyradiculo
Periodic attempts to withdraw immunosuppression neuropathy (AIDP) is an immunological disorder with
should be made every 2–3 years since some patients may an acute, often fulminant evolution characterized by
experience spontaneous remissions while others may a syndrome of rapidly progressive flaccid paralysis,
require lifelong therapy. Hashimoto Encephalopathy areflexia and albumin cytological dissociation in the
(now known as Steroid responsive autoimmune CSF (Fig. 7). Immunotherapy with PLEX or IVIG is
encephalitis with autoimmune thyroiditis) is managed considered as the mainstay of treatment and should be
in a similar way. started as soon as possible. The north American trial and
French Plasmapheresis Group trial have demonstrated
PRIMARY ANGIITIS OF CNS that PLEX halves the need for ventilation, hastens
CNS vasculitis can be secondary to systemic vasculitis or recovery and improves outcome at 1 year if administered
isolated to the CNS [Primary Angiitis of CNS (PACNS)]. within 4 weeks of onset. A Cochrane review confirmed
In contrast to common belief PACNS does not present as the value of plasma exchange over supportive therapy
recurrent strokes, instead the common presentations are: in hastening the recovery from GBS when started within
acute or subacute encephalopathy, relapsing remitting 30 days after disease onset. It is indicated in moderate-
neurologic deficits or symptoms suggestive of rapidly severe cases who are unable to walk without support
progressive space-occupying lesion with headache and >10M, with a significant decrease in VC or oropharyngeal
focal neurologic deficits. CSF is usually abnormal and paralysis (Table 6). The benefit is more when IVIG
angiography may reveal beading in small arteries, but is started within 2 weeks of onset and the strength of
meningeal biopsy is usually needed for confirmation. recommendation is weaker for use of IVIG beyond 4
PACNS is treated with a combination of corticosteroids weeks. In ambulatory patients, benefit of IVIG is not
(initially high dose IVMP) with cyclophosphamide (Class clear, but because there is no way to distinguish mild
CHAPTER 67: Immunomodulation in Neurological Disorders 399
Fig. 7: Showing makedly prolonged distal latencies, reduced nerve conduction velocity and nonrecordable sensory nerve action potential
in right median nerve of acute onset with two weeks duration of proximal weekness in all four limbs suggestive of acute inflammatory
demyelinating polyneuropathy—Guillain Barré syndrome
cases from progressive cases, ambulatory patients are The mean time to improvement of one clinical
also treated with IVIG, particularly if neurological deficits grade in the various controlled, randomized PLEX and
are progressing. IVIG studies ranged from 6 days to 27 days. With both
400 SECTION 5: Neurology
TABLE 6: Plasma exchange and IVIG in AIDP four trials of oral corticosteroids oral corticosteroids may
Plasma exchange slow recovery, while IV steroids showed a nonsignificant
Indications trend towards more benefit as compared to placebo. The
zz Non-ambulatory patients: 4–5 PE (2–2.5L each time) within 4
combination of IVIG with methylprednisolone failed to
weeks of onset (Level A Class II evidence)
zz Ambulatory patients: 2 PE within 2 weeks of onset (Level B,
find significant long-term advantage over IVIG alone in
limited Class II) one trial.
zz Dose: 200–250 ML/KG (alternate day PE is better than daily PE)
zz Bleeding
is more resistant to treatment (responds only to PE,
Depletion of plasma components minimally to IVIG). According to EFNS guidelines, a
zz Loss of clotting factors, globulins
trial of steroids should be considered in all patients
zz Loss of protein bound drugs
with CIDP and significant disability. Clinical experience
IVIG
suggests that steroids are more likely to induce remission
Indications
zz Non-ambulatory patients: 2 g/kg over 5 days within 2 weeks of as compared to other modalities, but the response is
onset (Level A, Class II) usually slower, with first signs of improvement usually
zz 2 g/kg over 5 days within 2–4 weeks of onset (Level B, Class II)
seen by 4 weeks, but occasionally it may take up to 5
zz Ambulatory patients: No indication but may be used in patients
who are progressing and present within 2 weeks of onset of months.12,13 Besides oral steroids, weekly doses of IVMP
illness and oral dexamethasone has also been used. Once a
Complications response is observed which usually takes 1–3 months,
zz Headache including aseptic meningitis
slow steroid tapering is started and most patients require
zz Deep venous thrombosis
zz Myocardial Infarction
low dose steroids for 1–2 years. In case of relapse or
zz Oligaemic renal failure unwanted adverse effects, immunotherapy with steroid
zz Anaphylaxis—especially in IgA deficiency
sparing agents may be added. The overall benefit with
IVIG is like that of steroids or PLEX, but the response
PLEX and IVIG, one or more episodes of deterioration is usually faster seen within 7–10 days, with maximum
following the initial improvement or stabilization after benefit in 2–3 weeks. The response is short lived and
treatment, described as “treatment-related fluctuations repeat courses are required after 4–6 weeks. Benefit
(TRIF)” may be encountered in as many as 6–16% of may not however be apparent after the first course of
patients. In patients who suffer such relapses or TRIFs, IVIG treatment, and some experts advocate repeating
additional courses of PE or IVIG are indicated.9-11 infusion of IVIG (1 g/kg) three weeks after the initial
There is, however, no evidence that PE beyond 250 treatment before determining efficacy. Subsequent
mL/kg or IVIG greater than 2 g/kg are of any added infusions are given at 3–8 week interval depending on
benefit in patients with AIDP, who have stable deficits clinical evaluation. Once maximum benefit is reached,
that are not improving as quickly as the patient and their same dose is continued for 6 months and then frequency
physician would like. The role of steroids is unclear as the of injections is gradually decreased. Notably in the
CHAPTER 67: Immunomodulation in Neurological Disorders 401
Fig. 8: Nerve conduction study of median nerve in a patient with CIDP shows increased distal latency and
conduction block with temporal dispersion
2. Timing and duration of symptoms-vertigo lasting for the specified duration helps narrow the diagnosis
zz Seconds to minutes: Benign paroxysmal positional vertigo, vertebrobasilar transient ischemic attack, perilymphatic fistula
3. Trigger factors
zz Vertigo that occurs when the patient is rolling over in bed or following sudden turning of head suggests benign paroxysmal positional
vertigo
zz Dizziness that occurs following getting up and not in supine position favors hemodynamic mechanisms
zz Vertigo triggered by loud sound suggests tulip phenomenon seen in superior semicircular canal dehiscence
4. Associated symptoms
zz Associated symptoms of cranial nerve dysfunction favours central vertigo
5. Past history
zz History of migraine suggests migraine associated vestibulopathy
zz History of trauma may suggest post traumatic vertigo or may precede BPPV, vertebral artery dissection
zz History of diabetes mellitus, systemic hypertension and other vascular risk factors favor central cause of vertigo
zz History of drug intake that are known to produce dizziness may suggest drug induced etiology
TABLE 2: General examination and tests of vestibular function Stroke in posterior inferior cerebellar artery—
General examination Bilateral symmetric reduction in VOR gain
zz Anemia Stroke in anterior inferior cerebellar involvement—
zz Nystagmus
Bilateral asymmetric reduction in VOR gain with
zz Otological examination
—— Dynamic visual acuity saccadic and smooth pursuit eye movements in vertical
zz Vestibulospinal assessment and horizontal gaze. The characteristics of the nystagmus
—— Finger nose coordination for past pointing—Finger under
that helps differentiate central from peripheral disorders
shoots on the side of lesion and overshoot is evident on the
are summarized in Table 3.
contralateral side
—— Fukuda Unterberger test
zz Assessment of nystagmus
vertigo includes:
zz Assessment of skew deviation Triage-Triaging a patient with red flag signs that
Fig. 1: TiTrATE approach to patients presenting with episodic and acute vestibular syndrome
Abbreviations: BPPV, benign paroxysmal positional vertigo; CPPV, central paroxysmal positional vertigo;
HINTS, head impulse test, nystagmus, test for skew
Trigger-Trigger denotes the activity and the circum Chronic persistent with obligate triggers
stances under which vertigo develops and targeted Chronic persistent without obligate triggers
examination to identify the possible etiology The targeted examination and the possible etiologies
Based on the above attributes the vertiginous patient of the acute presentation is depicted in Figure 1.
may fall into one of the following categories:
Episodic spontaneous
Peripheral Causes of Vertigo
Episodic triggered Benign Paroxysmal Positional Vertigo (BPPV)
Acute vestibular syndrome - spontaneous It is the leading cause of episodic vertigo characterized
Acute vestibular syndrome - triggered by vertigo that lasts from seconds to minutes provoked
CHAPTER 68: Vertigo: Clinical Approach and Management 407
by changes in head position and rolling in bed. It results TABLE 4: Disease specific treatment in vertigo
from dislodgement of calcium carbonate crystals from Etiology Treatment
the otoconia that then traverses the semicircular canal.
Benign paroxysmal zz Posterior canal: Epley maneuver,
These crystals inappropriately stimulate the cupola of
positional vertigo Semont maneuver
the semicircular canals. The posterior semicircular canal zz Horizontal canal: Log roll exercise,
onset and last for few hours and may last upto days. In canal. When the intracranial pressure increases during
labyrinthitis, there is an accompanying hearing loss. sneezing, coughing and during valsalva maneuver, it
In herpes zoster oticus, patient may have ear pain in causes the pressure to be transmitted through the defect
association with vesicles in the external ear. resulting in episodes of vertigo associated with nausea
Examination reveals hypofunction of the involved and vomiting. Tulio phenomenon, vertigo induced by
vestibular apparatus evidenced by impaired head loud sounds occurs in patients with superior semicircular
impulse test and caloric test. Primary position nystagmus canal dehiscence. Vestibulo-ocular reflex evoked by click
may be evident with fast component opposite to in cervical vestibular evoked myogenic potential has
the side of lesion, does not change direction and it large amplitude with decreased threshold in patients
increases with an attempted gaze towards the side of with tulio phenomenon. HRCT of the temporal bone is
fast component (Alexander’s law). The intensity of the useful in detecting the defect.
nystagmus gradually decreases with time due to central
compensatory measures. Nevertheless, head impulse Central Causes of Vertigo
test is abnormal and can be used to demonstrate the It is essential to differentiate central causes of vertigo from
vestibular hypofunction. The nystagmus is absent when other benign causes. The symptoms are less disabling
the vestibular neuritis affects the inferior vestibular as compared to peripheral vestibular involvement.
nerve. Recurrence of vestibular neuritis is rare and hence However, the signs are more prominent and frequently
when present alternate diagnosis of episodic vertigo the patient is unable to walk unaided. Vertigo and
such as Meniere disease should be considered. Caloric imbalance may result due to involvement of central
testing may indicate the laterality of the vestibular vestibular pathway, ascending projections, thalamus
hypofunction. As it mimics acute stroke, neuroimaging is and cortex. The central vestibular pathway is depicted in
required in elderly patients with vascular risk factors and Figure 2. The central causes of vertigo may result from:
in those with atypical features. Disease is self limiting
and treatment required corticosteroids and vestibular Structural Causes
sedatives in the short term. Acylovir or valacyclovir Vertebrobasilar stroke/Transient ischemic attack
should be added in herpes zoster oticus. Demyelination
Tumor (Medulloblastoma, vestibular schwannoma)
Ménière’s Disease Craniovertebral junction lesions
It is characterized by endolymphatic hydrops owing to
vascular, genetic and immunologic factors. Patients are Nonstructural
usually affected in the ages between 40–60 years of age Vestibular migraine
with men and women affected equally. It is characterized Episodic ataxia syndromes
by episodes of vertigo, hearing loss and fullness of the Drugs and toxins
ear. Sudden falls without loss of consciousness may also
occur (Tumarkin otolithic crisis). Each episode of vertigo Structural Causes
may last from 20 minutes upto 12 hours. Audiometric and Vertebro basilar stroke/transient ischemic attack
vestibular assessment are nonspecific. Neuroimaging is (TIA): Stroke or TIA resulting from involvement of
required to rule out central causes of vertigo in patient the vertebrobasilar system that supplies the central
presenting with acute vestibular syndrome. vestibular connections causes imbalance. The symptoms
lasts for less than 24 hours in transient ischemic attack
Superior Semicircular Canal Dehiscence with a median duration of 8 minutes. The involvement
Superior semicircular canal dehiscence results from of the vestibular nucleus and cerebellum may result in
thinning of the superior wall of the superior semicircular sustained rotational vertigo. However, involvement of
CHAPTER 68: Vertigo: Clinical Approach and Management 409
higher ascending projections, thalamus and cortex may favor the attribution of vertigo to multiple sclerosis as
result in transient rotational vertigo. The presence of they do not occur in peripheral etiology: gaze evoked
accompanying clinical findings such as diplopia, facial nystagmus, upbeat nystagmus, pendular nystagmus,
palsy, nystagmus, visual field defects may help delineate periodic alternating nystagmus, see-saw nystagmus,
the vascular territory. The brainstem involvement may parinaud syndrome and internuclear ophthalmoplegia.
result from vascular compromise of posterior inferior Malignancy: Medulloblastoma is the most common
cerebellar artery, anterior inferior cerebellar artery, infratentorial tumor in children. The involvement of
superior cerebellar artery, paramedian penetrating the cerebellum and vestibulocerebellar fibers causes
arteries and short circumflex arteries arising from unsteadiness along with features of raised intracranial
basilar artery and top of basilar artery. The wide spread pressure including headache and vomiting. Vermian
vascular etiology for the occurrence of vertigo suggest the involvement produces truncal and gait ataxia whereas
extensive and intricate vestibular and cerebellar network the hemispheric involvement produces incoordination
that pans across the brainstem. In the absence of vascular of limbs.
involvement in neuroimaging, the following needs to be Vestibular schwannoma is the most common
considered: cardiac and paradoxical thromboemboli, cerebellopontine angle tumor. It presents with
hypercoagulable and hyperviscosity syndromes, basilar unsteadiness, vertigo, hearing loss, facial palsy and
migraine and disorders of mitochondria. trigeminal sensory involvement. When the patient
Demyelination: Demyelination disorder exemplified by presents acutely, intratumoral hemorrhage should be
the multiple sclerosis may present with vertigo due to considered. Neuroimaging reveals T1 hypointense to
isotense lesion in the cerebellopotine angle with T2
demyelination involving the brainstem. However, vertigo
mixed hyperintensity and intense contrast enhancement.
in a multiple sclerosis patient is not always demyelination
and can be due to benign paroxysmal positional vertigo Craniovertebral junction lesions: It includes Chiari
or migraine. The presence of the following features may malformation, atlantoaxial subluxation and basilar
410 SECTION 5: Neurology
invagination. Vertigo occurs due to involvement streptomycin and tobramycin, the drugs and toxins
of the vestibular pathways in the medulla and that cause postural and gait instability by affecting the
vestibulocerebellum. cerebellar fibers include antiepileptic drugs (phenytoin,
The clinical manifestation of the imbalance and carbamazepine), chemotherapeutic drugs (cytarabine,
associated symptoms may depend on the site of 5 fluorouracil, vincristine) and toxins (alcohol, carbon
involvement by the structural lesion (Fig. 2). tetrachloride, toluene).
Acute upper gastrointestinal (UGI) bleeding is a common Causes of UGI bleed common Less common
medical emergency worldwide. It accounts for about Peptic ulcer (Duodenal/Gastric) Esophagitis
50–60% of all patients hospitalized for GI bleeding. The Variceal bleed (Esophageal/Gastric) Dieulafoy’s lesion
annual rate of hospitalization for UGI bleed has been Erosions Vascular ectasias
Mallory Weiss tear Portal congestive
estimated at 30–100 patients per 100,000 population.
gastropathy
It has a significant morbidity and mortality. Mortality
Gastric antral vascular ectasia
rates from UGI hemorrhage have remained fairly stable (GAVE)
at 3.5–7% over the past 20-30 years. The likely reason for UGI tumors
this is an increasing proportion of elderly patients with
comorbidities who have a higher mortality. Various causes of acute UGI bleed are shown in
Table 1.
ETIOLOGY
Peptic ulcer disease is the most common cause of acute RISK FACTORS
UGI bleed, accounting for about 50% of cases. Bleeding Independent risk factors for ulcer hemorrhage are
from duodenal ulcer is commoner than gastric ulcer (i) older age, (ii) use of aspirin or nonsteroidal anti-
bleed. Ulcer bleed stops spontaneously in 70-80% cases. inflammatory drugs (NSAIDs), and (iii) patients with
Mortality in such patients are negligible. In the group of history of previous peptic ulcer. In patients taking aspirin
patients, where bleeding recurs or persists the mortality is or NSAIDs the risk of bleeding is higher during initial
high at 25–30% especially in those with severe comorbid period of treatment and is dose dependant. COX 2
conditions. inhibitors have relatively lower risk compared to COX 1
Variceal bleed is another common cause of UGI inhibitors. Concomitant use of aspirin, NSAIDs, steroids,
bleed. In India, variceal bleed is common in some anticoagulants or dual antiplatelet therapy and advanced
regions whereas ulcer disease is commoner in other age may increase the risk of ulcer bleeding. H-Pylori
regions. Variceal bleed occurs in patients with liver infection is associated with recurrent peptic ulcer but is
cirrhosis and portal hypertension. Esophageal varices not an independent risk factor for ulcer bleed. However,
occurs in about 30–40% patients with cirrhosis and 60% H. Pylori eradication reduces the risk of ulcer bleed in
of patients with cirrhosis and ascites. aspirin users with a prior ulcer bleed.
416 SECTION 6: Gastroenterology/Hepatology
Upto 25% of cirrhosis patients with new varices will a brief history and physical examination should be done
experience bleeding within 2 years. The most important concurrently.
risk factors for variceal bleed include (i) pressure within An early decision must be made whether ICU or ward
the varix, (ii) variceal size, (iii) tension on the variceal care is indicated depending on severity of bleed and
wall and (iv) severity of the liver disease. The risk of hemodynamic stability. All patients with severe bleed
bleeding by 2 years is 7% patients in small varices as should be considered for ICU admission.
compared to 30% in those with large varices. Airway protection is critical during severe UGI
bleed, especially for those with altered sensorium or
CLINICAL PRESENTATION respiratory complications which have a significantly
Patients with UGI bleeding present with hematemesis, higher mortality. Endotracheal intubation should be
melena, or both. Hematochezia may be the only considered for prevention of aspiration in patients
presentation in 5–15% patients with UGI bleed. Painless with continuing hematemesis, altered mental status,
(silent) bleeding ulcers may often be the presenting altered respiratory status, or with severe neuromuscular
feature in elderly patients, inpatients or those on NSAIDs disorders. An adequate intravenous (IV) access, should
or aspirin. Patients with age >60 years, inpatient bleed be established with wide bore cannula and appropriate
and presence of comorbidities especially cardiovascular, fluid and blood products are infused. Blood–products
respiratory, hepatic, or malignant disease have a higher should be given with the aim of keeping hemoglobin
mortality. Several scoring systems are used to stratify above 7–8 g/dL, platelet count above 50,000/mm,
patients of ulcer bleed into high or low risk. Rockall and INR below 1.5. Fresh frozen plasma should be
and Glasgow Blatchford scoring (GBS) systems have given in cirrhotic patients, if fibrinogen level <1 g/L
been commonly used. Recently a modified GBS system or prothrombin time >1.5 times normal. Prothrombin
has been used as a better predictor of outcome in UGI complex concentrate should be considered in patients
bleed. In patients with variceal bleed the mortality is taking warfarin and actively bleeding.
best predicted by severity of liver disease score such Recent data suggests that a restrictive transfusion
as assessed by Child’s Pugh score or MELD score. strategy (packed red blood cells transfusion given
Patients with advanced liver disease (Childs-C or MELD only at hemoglobin level <7 g/dL, with a target of
>18), bleeding at time of endoscopy, severe anemia, 7–9 g/dL). However, this strategy needs to be modified
hypotension, failure to control bleeding, presence of in hypotensive patients with severe bleed or those with
renal dysfunction or requirement of >4 units of blood are associated cardiovascular disease. Over transfusion
some of the predictors of outcome from variceal bleed. should be avoided especially in patients with variceal
bleed since it may lead to rebound increase in portal
MANAGEMENT pressure.
The steps of management are: Nasogastric tube (NG) should be placed in patients
Resuscitation with severe bleed, hemodynamically unstable, altered
Assessment/stabilization sensorium or those where the site of bleed is unclear. NG
Medical therapy tube provides help in assessment of blood loss in patients
Definitive therapy (Endoscopy/Surgery/Inter with severe bleed and may also help to clear the stomach
ventional radiology) with gastric lavage prior to endoscopy. There is no value
Prevention of re-bleed of cold saline lavage and water may be used. Large
Initial management at first encounter with a patient volume lavage should be avoided since it may increase
with UGI bleed is resuscitation and stabilization with the risk of aspiration. The use of IV prokinetics such as
correction of fluid losses and restoring hemodynamic metoclopramide or erythromycin prior to endoscopy
stability. An evaluation of the severity of the bleed, and remains debatable.
CHAPTER 69: Acute Upper Gastrointestinal Bleeding 417
MEDICAL THERAPY should be considered for patients with shock and signs of
The aim of medical management is to reduce morbidity, ongoing bleed where hemodynamic stability is difficult
mortality, risk of re-bleeding, transfusion requirements, to achieve or when prior endoscopy has not localized the
duration of hospitalization, and need for endoscopic source. For all other patients, early endoscopy within 24
intervention or surgery. Gastric acidity adversely hours (preferably within 8–12 hours) should be the rule.
influences clot formation with maximal clot lysis at Endoscopy is diagnostic in almost 95% of patients
pH 2. Increasing intragastric pH to >6 improves the with severe UGI bleed and helps to stratify patients into
coagulation process and helps reduce bleeding. PPIs are high and low risk groups. Endoscopically demonstrated
most effective acid inhibitors and provide sustained high stigmata of recent hemorrhage (SRH) on ulcers identify
intragastric pH. Early institution of IV PPI reduces severity high risk ulcers from low risk of re-bleed. Endoscopic
of ulcer bleed, reduces the rate of re-bleeding, but does hemostasis for high risk ulcers reduces re-bleeding rates,
not decrease mortality. Re-bleeding is most common duration of hospitalization, need for the transfusion, and
during the first 72 hours, PPIs such as pantoprazole, need for surgery although its effects on mortality remains
esomeprazole should be given as a bolus of 80 mg IV, uncertain. At endoscopy, ulcers are graded as per Forrest
followed by an 8 mg/hr infusion for 3 days. There is no classification which grades the ulcer into those with high
clear benefit of one PPI over the other and in clinical versus low risk of rebleeding and mortality (Table 2).
practice any one may be used in the standard doses. Approximately 20–25% of patients with severe ulcer
In high-risk bleeding ulcer patients, endoscopic bleeding requiring ICU admission have a nonbleeding
therapy + PPI is superior to PPI infusion alone in visible vessel. Approximately 50% of these patients re-
preventing recurrent bleed. Patients with low-risk bleed during hospitalization when treated medically,
endoscopic findings (such as clean ulcer base or flat and 40% with severe bleed, not treated with endoscopic
spots) should be treated with oral PPI once daily. More hemostasis, require ulcer surgery. Only about 15% of
recent trials have suggested that: high-dose oral PPI is ulcer have active arterial type bleeding at endoscopy and
just as effective as an IV infusion after endoscopy therapy. is a challenge for endoscopic hemostasis with significant
In patients of variceal bleed, restrictive strategy of failure and recurrence of bleed.
transfusing PRBCs only when the Hb level is less than There are a number of endoscopic modalities for
7 g/dL has been shown to be associated with better treatment of ulcer bleed (Table 3). Combination of
survival in patients with cirrhosis. Antibiotics should two modalities has been found to be more effective in
be given to all patients to prevent bacteremia and achieving hemostasis compared to one modality. The
spontaneous bacterial peritonitis. Endoscopic therapy most common method used is injection of adrenaline
along with early pharmacologic therapy is better than
TABLE 2: Risk stratification of Forrest classification
pharmacologic treatment alone. Vasoactive agents are
associated with improved hemostasis and a shorter Forrest classification Rebleeding Mortality
rate rate
hospitalization period. Terlipressin, somatostatin and
Active bleed
octreotide are the options for pharmacologic therapy
Ia. Spurting bleed 55–100% 11%
but only terlipressin has survival benefit. Pharmacologic
Ib. Oozing bleed
treatment should be continued for 3–5 days to prevent
early re-bleeding. Recent bleed
IIa. Nonbleeding visible vessel (NBVV) 40–50% 11%
and treatment of UGI bleed because of high diagnostic IIc. Flat spot 10% 3%
accuracy and low complications. Emergency endoscopy II1. Clean base 5% 2%
418 SECTION 6: Gastroenterology/Hepatology
TABLE 3: Endoscopic modalities of treatment of ulcer bleed option and hemoclipping is likely to be more beneficial
zz Injection since it causes no significance tissue injury. Surgery in
—— Adrenaline such patients carries a higher morbidity and mortality.
—— Tissue glues
Variceal bleeding cannot be controlled in 10–15% of
—— Clotting factors
—— Nano powder
patients despite endoscopic therapy. When two attempts
zz Thermal at endoscopic treatment fail to control variceal bleed,
—— Heater probe alternative intervention such as transjugular intrahepatic
—— Bipolar probe
portosystemic shunt (TIPS) should be done. This group of
—— Nd: YAG laser
Arterial embolization has been compared to surgery in gastrointestinal risks. In high risk cardiovascular patients
patients with failed endoscopic hemostasis and shown with recent coronary stenting, aspirin may be continued
to decrease the risk for subsequent surgery and reduce after endoscopic hemostasis.
complications without increasing the mortality rate. Re-bleeding after variceal bleed occurs in about 80%
cases within two years. Thus all variceal bleed patients
PREVENTION OF RE-BLEED should receive secondary prophylaxis with repeated
After endoscopic hemostasis of ulcer bleed, treatment sessions of EVL at 3–4 weeks interval till obliteration of
with PPIs is recommended for 6–8 weeks. Long term varices. Usually 2–4 endoscopic sessions are required.
acid reduction treatment is required for patients on Concomitant use of oral nonselective beta blockers such
continuing aspirin, NSAID or warfarin therapy. H. pylori as propranolol, nadolol or carvedilol is recommended to
positive patients should receive antibiotic therapy. reduce portal pressure.
The management of patients with ulcer bleed while An algorithm for management of UGI bleed has been
receiving antiplatelet therapy such as aspirin, clopidogrel shows in Flow chart 1.
or other anticoagulant is controversial. Although early
reintroduction of low dose aspirin after hemostasis BIBLIOGRAPHY
has a higher risk of recurrent bleed but this strategy 1. Bambha K, Kim WR, Pedersen R, et al. Predictors of early
decreases all-cause mortality rates due to reduction re-bleeding and mortality after acute variceal haemorrhage
in patients with cirrhosis. Gut. 2008;57:814-20.
in cardiovascular and cerebrovascular complications.
2. Barkun AN, Bardou M, et al. International Consensus.
Therefore, patients requiring secondary cardiovascular Recommendations on the management of patients with
prophylaxis should restart aspirin treatment within non-variceal gastrointestinal bleeding. Ann Intern Med.
7 days or as soon as cardiovascular risk outweigh 2010;152: 101-13.
420 SECTION 6: Gastroenterology/Hepatology
3. de Francis R, Baveno VI faculty. Expanding consensus in Society of Gastrointestinal Endoscopy (ESGE) guideline;
portal hypertension: report of the Baveno VI consensus Endoscopy-2015.
workshop: Stratifying risk and individualising care for portal 7. Mehta D, Non-variceal upper gastrointestinal bleed, API
hypertension. J Hepatol. 2015;63:743-52. Medicine Update, 2013.
4. Garcia-Tsao G, Abraldes JG, Berzigotti A, et al. Portal 8. Sachar H, Vaidya K, et al. Intermittent vs continuous proton
hypertensive bleeding in cirrhosis: Risk stratification, pump inhibitor therapy for high-risk bleeding ulcers: a
diagnosis and management: 2016 practice guidance by systematic review and meta-analysis, JAMA Intern Med.
the American Association for the study of liver disease. 2014; 174:1755-62.
Hepatology. 2017;65:310-35. 9. Singh SP, Panigrahi MK. Spectrum of upper gastrointestinal
5. Garcia-Tsao G, Bosch J. Varices and variceal hemorrhage in haemorrhage in coastal odisha, tropical gastroenterology,
cirrhosis: a new view of an old problem. Clin Gastroenterol 2013.
Hepatol. 2015;13:2109-17. 10. Villanueva C, Colomo A, et al. Transfusion strategies for
6. Gralnek lan M, et al. Diagnosis and management of non- acute upper gastrointestinal bleeding. N Engl J Med. 2013.
variceal upper gastrointestinal hemorrhage: European
CHAPTER
70
Acute Pancreatitis
G Loganathan, L Santhosh Vivekanadan
Fig. 1: The classification and mortality against the severity of acute pancreatitis
A B
C D
Figs 2A to D: Specific etiology of acute pancreatitis. (A) MRCP image showing calculi in the CBD (white arrow). (B) MRCP image showing
pancreas divisum. Pancreatic duct is seen draining into the minor papilla (white arrow) while the CBD is seen draining into the major papilla
(white asterisk). (C) CECT image showing traumatic disruption of the pancreatic duct (white arrow) communicating with a small anteriror
peripancreatic collection (white asterisks). Dilated distal pancreatic duct in the tail. (D) CECT image showing diffusely enlarged, sausage-
shaped pancreas in a known patient of autoimmune pancreatitits
Disease Classification and and readily available, Bedside Index of Severity in Acute
Assessment of Severity Pancreatitis (BISAP) score,17 Harmless Acute Pancreatitis
The severity of acute pancreatitis is classified as mild Score18 (HAPS) with advantage of use within 30 minutes
(absence of local and systemic complications), moderate of admission with high specificity and predictability in
(presence of local or systemic complications or transient identifying patients who will not progress into severe
organ failure for < than 48 hours) and severe (persistent acute pancreatitis (Table 2) and organ failure based
organ failure for > 48 hours). Many scores are available scores like Goris multiple organ failure score,19 Bernard
but none is perfect. Ranson and Glasgow take 48 hours score, 20 sequential organ failure assessment (SOFA)
to complete,12-14 APACHE is a physiological score and is score,21 the logistic organ dysfunction score22 and the
cumbersome to use, systemic inflammatory response Marshal organ dysfunction score23 are used. This author
syndrome score (SIRS),15,16 is inexpensive, easy to use believes in use of CRP >150 at 48 hours24 and persistent
CHAPTER 70: Acute Pancreatitis 425
American College of Gastroenterology (ACG) – ACG guidelines recommend the following clinical findings associated with a severe course for
initial risk assessment.33
Patient characteristics Laboratory findings
Age > 55 years Blood Urea Nitrogen (BUN >20 MG/dL
Obesity (Body Mass Index > 30 Kg/m2) Rising BUN
Altered mental status Hematocrit > 44%
Comorbid disease Rising hematocrit
Elevated creatinine
Systemic inflammatory response Radiological findings
syndrome
As given in 3.1 under SIRS Pleural effusion
Pulmonary infiltrate
Multiple or extensive extra pancreatic
collections
The presence of organ failure and/or pancreatic necrosis defines severe acute pancreatitis.
Contd...
426 SECTION 6: Gastroenterology/Hepatology
Contd...
of intra vascular volume depletion and cardiopulmonary In moderate-to-severe acute pancrreatitis, oral
reserve that is available to handle the fluid.31 feeding can be withheld for 2–3 days and started
Antibiotics as Prophylaxis and Treatment thereafter once the bowel movement is set in and free
Meta-analysis have shown no benefit of prophylactic from ileus. Simple tube feeding has replaced feeding
antibiotics and is not recommended for any type of acute through complex deeply placed intestinal tubes. Tube
pancreatitis unless infection is confirmed.32,33 feeding is required only if oral feed is not tolerated for 2
days beyond 72 hours.37,38 No significant advantage was
Nutrition
seen between nasojejunal and nasogastric tube feeding,
Mild acute pancreatitis in the absence of ileus can be
use of elemental, semielemental vs polymeric diet. Total
placed on oral nutrition from the day of admission
and should not evoke pain.34 A low fat diet soon after parenteral nutrition which is expensive, riskier and no
admission in the absence of severe pain, nausea, more effective than enteral nutrition should be reserved
vomiting and ileus can be started and is safe, associated only for those intolerant to enteral feeds or in unmet
with shorter hospital stay than clear liquids with slow nutritional goal status though in reality, it is more often
advancement to solid food.35,36 used.1,9,39,40
428 SECTION 6: Gastroenterology/Hepatology
The use of endoscopic ultrasound (EUS) for detcction treatment and usually resolve. They form a wall and
of stones in common bile duct is emerging. An ERC evolve into pseudocyst with clear fluid over 4 weeks.
with EUS is most effective and EUS first strategy helps These pseudocysts need intervention, if they become
in establishing indication for ERC. EUS first startegy in symptomatic with infection, bleed within the cyst
a meta-nalysis was showed that it is promising and 71% or increase in size of the cyst resulting in pressure
ERC procedures can be avoided without a negative effect symptoms.
on the clinical course of acute pancreatitis. 42 Further, Acute necrotic collection (ANC) contains debris and is
EUS first startegy is less costly than ERC as observed by a mix of solid and semisolid tissue. Over 4 weeks with
decision tree analysis of cost-effectiveness.43 the formation of capsule, this becomes a walled-off
A B
C D
Figs 5A to D: CECT images showing severity of acute pancreatitis. (A) Diffusely enlarged pancreas with peripancreatic oedema (asterisks)
and perirenal edema (white arrows). (B) Diffusely enlarged pancreas with peripancreatic fluid collection posterior to the distal body and tail.
(C) Small area of no parenchymal contrast enhancement in the tail suggestive of necrosis (<30% volume). (D) Large area of no parenchymal
contrast enhancement suggesting necrosis in the neck, body and tail (white arows) with associated splenic vein thrombosis (white asterisks)
430 SECTION 6: Gastroenterology/Hepatology
A B
C D
Figs 6A to D: Severity of acute pancreatitis. CECT images showing complications of acute pancreatis. (A) Peripancreatic abscess with air
pockets (white asterisks). (B) Peripancreatic fluid collections, thrombosis of the retropancreatic splenic vein (white arrows) and the splenoportal
confluence (white asterisk). (C) Pancreatitis with ascites (white asterisks). (D) Pancreatic pseudocyst with capsule (arrows)
A B
C D
Figs 7A to D: Pancreatic ductal disruption, collection and bridging of disruption with stent. The USG (A) showing disruption in the course of
PD in the body region with collection and (B) showing upstream track of collection. ERCP (C) showing PD disruption in the tail region and (D)
showing a pancreatic stent across the PD disruption. A and B are from one patient and C and D are from another patient.
Abbreviations: USG, Ultrasound; PD, Pancreatic duct; ERCP, Endoscopic retrogarde cholangio pancreaticogram
better outcomes with good results. PFC and ANC take baskets under direct vision and may require multiple
3–5 days to form and CECT done after 5–7 days would sessions in a few cases. The most common complications
identify these lesions. For pseudocyst and WON a are bleeding, perforation and infection. Use of carbon
repeat imaging using USG/CT/EUS will facilitate dioxide would minimize air embolism. Use of wide lumen
identification and guide in choice of the intervention. metal stents, fully covered self-expandable metal stents,
It is pertinent to postpone intervention till a wall lumen opposing metal stents that allow endoscope
is well formed usually within four weeks for better to pass into the cavity helps in better debriement and
drainage. has more success rate. Transpapillary drainage is done
Observations show that most of the acute PFC resolve in communicating small collections. Laparoscopic
while less than 15% form pseudocyst while more than necrosectomy using a retrogastric transmesocolic or
1/3rd of ANC evolved into WON and in that 55% required retroperitoneal approach to the lesser sac is the presently
intervention. used technique.46 Videoscopic–assisted retroperitoneal
debridement (VARD) is an alternate method.
Indications
Nageshwar Reddy et al.,47 Boumitri C et al,48 and Hon
A sterile ANC with presence of symptoms (abdominal
Chi Yep et al.49 have vividly described the interventions
pain or mechanical obstruction—gastric outlet
with images and results and recommend management
obstruction or biliary obstruction). Delay intervention
by multi-disciplinary team.
for 4 weeks or longer, if possible to 6 weeks.
The other complications observed are splenic artery
Infected pancreatic fluid collection needs endoscopic
aneurysm, splenic and portal venous thrombosis, gastric
drainage over percutaneous drain since a fistula can
stress ulceration, gastroparesis and ileus, obstructive
be avoided and over surgical drainage since it is more
symptoms due to compression of duodenum, bile duct
morbid and mortal.
by edematous and inflammed pancreas, abdominal
Asymptomatic WON or sterile ANC do not require
compartment syndrome, pancreaticopleural fistula.
intervention regardless of size since they resolve over
Symptom may enlarge to vomiting, vomiting blood,
time.
jaundice, breathlessness and needs cause directed
Procedure: Percutaneous/Endoscopic/Surgical approach.
Intervention is primarily drainage and can be done
radiologically, endoscopically and surgically. Drainage PREVENTION
of necrotic debris improves over all health, prevents The National Confidential Enquiry into Patient Outcome
organ failure. The requisites are presence of wall with and Death (NCEPOD) 26 observed that in 50% with
thickness of 4 mm, absence of demonstrable collaterals acute pancreatitis, the care needs to be improved,
in the planned region of entry and close approximation efforts to prevent recurrent episodes of pancreatitis
with neighboring organ for endoscopic cystogastro/ due to alcohol and gallstone need improvement by
cystoduodenostomy. Percutaneous drainage under 21%, better antibiotic use (unnecessary use in 20%),
USG/CT guidance avoiding hollow/solid viscous inadequate nutrition management in 15%, omission of
penetration. Endoscopic ultrasound-guided transmural use of early warning scores in 31%.26 Thus prevention
drainage (EUS-TD) is the preferred intervention in can be achieved in alcohol consumers by conjoint
nonbulging lesion within 1.5 cm from the gastric counseling, recurrence of acute biliary pancaretitis
wall and are more precise. The technique of Direct can be achieved by cholecystectomy in the same
Endoscopic Necrosectomy (DEN) involves dilatation of admission, hypertriglyceridemia induced pancreatitis by
the cystogastric tract with balloon, advancement of the optimal drugs, drug indueced pancreatitis by avoidance,
endoscope into the cavity of WON, normal saline lavage obstrucive causes by elimination or providing adequate
of the cavity, removal of necrotic debris using snares or drainage.
CHAPTER 70: Acute Pancreatitis 433
17. Wu BU, Johannes RS, Sun X, et al. The early prediction of saline in patients with acute pancreatitis. Clin Gastroenterol
mortality in acute pancreatitis: a large population-based Hepatol. 2011;9:710-7.
study. Gut. 2008;57(12):1698-703. 31. Campion W, Forsmark CE, Vege SS, and Wilcox C. Acute
18. Lankisch PG, Weber-Dany B, Hebel K, Maisonneuve P, pancreatitis. N Eng J Med. 2016;375:1972-81.
Lowenfels AB. The harmless acute pancreatitis score: a 32. Villataro E, Mulla M, Larvin M. Antibiotic therapy for
clinical algorithm for rapid initial stratification of nonsevere prophylaxis against infection of pancreatic necrosis
disease. Clin Gastroenterol Hepatol. 2009;7(6):702-5; quiz in acute pancreatitis. Cochrane Database Syst Reev.
607. PMID: 19245846. 2010;5:CD002941.
19. Goris RJ, te Boekhorst TP, Nuytinck JK, Gimbrère JS. Multiple- 33. Tenner S, Baillie J, Dewitt J, et al. American College
organ failure. Generalized autodestructive inflammation? of Gastroenterology Guideline: Management of acute
Arch Surg. 1985;120:1109. pancreatic. Am J Gastroenterol. 2013;108:1400-15.
20. Bernard GR, Doig G, Hudson L, et al. Quantification of organ 34. Eckerwall GE, Tingstedt BB, Bergenzaun PE, Andersson
failure for clinical trials and clinical practice. Am J Respir Crit RG. Immediate oral feeding in patients with mild acute
Care Med. 1995;151:A323. pancreatitis is safe and may accelerate recovery – a
21. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis- randomized clinical study. Clin Nutr. 2007;26:758-63.
related Organ Failure Assessment) score to describe 35. Jacobson BC, Vander Vliet MB, Hughes MD, et al. A
organ dysfunction/failure. On behalf of the Working Group prospective, randomized trial of clear liquids versus low fat
on Sepsis-Related Problems of the European Society of solid diet as the initial meal in mild acute pancreatitis. Clin
Intensive Care Medicine. Intensive Care Med. 1996;22:707.
Gastroenterol Hepatol. 2007;5:946-51.
22. Le Gall JR, Klar J, Lemeshow S, et al. The logistic organ
36. Teich N, Ashdassi A, Fischer J, et al. Optimal timing of
dysfunction system. A new way to assess organ dysfunction
oral refeeding in mild acute pancreatitis: results of open
in the intensive care unit. ICU Scoring Group. JAMA.
randomized multicentre trial. Pancreas. 2010;39:1088-92.
1996;276:802.
37. Bakker OJ, Van Brunschot S, Van Santvoort HC, et al.
23. Marshall JC, Cook DJ, Christou NV, et al. Multiple organ
Early versus on-demand nasoenteric feeding in acute
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38. Stimac D, Poropat G, Hauser G, et al. Early nasojejunal
24. Corfield AP, Cooper MJ, Williamson RC, et al. Prediction of
tube feeding versus nil-by-mouth in acute pancreatitis: a
severity in acute pancreatitis: prospective comparison of
randomized clinical trial. Pancreatology. 2016;16:523-8.
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39. Al-Omran M, Albalawi ZH, Tashkandi MF, Al-Ansary LA.
25. Mortele KJ, et al. A modified CT severity index for evaluating
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26. O’Reilly D A, McPherson S.J, Sinclair M T, et al. Lessons 40. Yi F, Ge L, Zhao J, et al. Meta-analysis: total parenteral
from a national audit of acute pancreatitis: A summary of nutrition versus total enteral nutrition in predicted severe
the NCEPOD report ‘Treat the Cause’. Pancreatology. 2017. acute pancreatitis. Intern Med. 2012;51:523-30.
pp.329-33. 41. Schapers NJ, Bakker OJ, Besselink MG et al. Early biliary
27. Mao EQ, Tang YQ, Fei J, et al. Fluid therapy for severe acute decompression versus conservative treatment in acute
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28. Mao EQ, Tang YQ, Peng YB, et al. Rapid haemodilution is 42. Liu CL, Fan ST, Lo CM, et al. Comparison of early
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pancreatitis: recent advances through randomised trials. 43. De Lisis S, Leandro G, Buscarini E, et al. Endoscopic
Gut. 2017 Aug 24. pii: gutjnl-2016-313595. doi: 10.1136/ ultrasonography versus endoscopic retrograde cholangio
gutjnl-2016-313595. [Epub ahead of print] Review. Dutch pancreaticography in acute biliary pancreatitis: a systemic
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2017;21:23(15):2660-72. Oxford 1998. p.489.
CHAPTER
71
The Gut Microbiota: A Forgotten Organ
Balvir Singh, Ram Prakash Pandey, Mridul Chaturvedi, TP Singh, Ashish Gautam
INTRODUCTION
Gut microbiota (gut flora) is the complex group of
microorganisms that lives in the human gastrointestinal
tract and health is usually due to intestinal microbiota.
Microbiota of one person can be different than others
in species and relative amount. Chiefly the gut flora are
strict anaerobes.
It is proved that alteration and diversification of gut
flora in intestine leads to various diseases such as allergies,
obesity and diabetes, dyslipidemia, cancer and intestinal
Fig. 1: Kinds of cells in the human body
inflammatory diseases and pseudomembranous colitis,
etc.1 More than 10 times the number of cells in our body
The gut microbiome is 150 times larger than the
COMPOSITION OF GUT MICROBIOTA human genome
On human body total human cells are approx one quarter Most heavily colonized organ: GIT
and rest are bacterial, fungal and protozoal (Fig. 1). Colon alone: > 70% microbes
Hu m a n g u t m i c ro b i o t a m a i n l y c o n s i s t s o f
phyla Firmicutes, Bacteroidetes, Proteobacteria, EMERGENCE OF MICROBIOTA
Verrucomicrobia, Actinobacteria, Cyanobacteria and After the delivery of baby gut seems to be sterile, but it
Synergistes. Out of these Firmicutes and Bacteroidetes has been observed that fetal colonization of microbiota
consists of 65% and 35% respectively.2 may occur in the newborn babies also. The microbial
strains present in upper gastrointestinal tract resembles
HUMANS AS MICROBIAL DEPOTS (FIG. 2) to mothers fecal microbiota.3
The microbial populations that reside in and on the The babies born by caesarean section are typically
host cells are commonly referred to as “microbiota”.2,4 having microflora like Staphylococcus, Corynebacterium
Gut microbiota is approx. 200 trillion cells and Propionibacterium species.5
More than thousand diverse specieces of gut micro All infants are initially colonised by large number of
biota Escherichia coli and Streptococci. During the first week
CHAPTER 71: The Gut Microbiota: A Forgotten Organ 437
Fig. 2: Microbiota diversity and its number increases as we procede downwards in GIT
of life, bacterial succession of strict anaerobic species mediators and helps ATP generation in liver), succinic
mainly Bifidobacterium, Bacteroides, Clostridium, and acid (anti-inflammatory).10
Ruminococcus.6 Breastfed babies become dominated by The gut microbiota also having favorable impact on
bifidobacterial (B.breve, B.bifidum, B.infantis), possibly lipid metabolism as well as in suppressing the inhibition
due to the contents of bifidobacterial growth factors of lipoprotein activity in adipocytes.13
in breast milk, 7 while formula-fed infants intestinal Anaerobic metabolism of peptides and proteins
microbiota is more diverse and have high numbers (putrefaction) by the microflora also produces short
of Enterobacteriaceae, Enterococci, Bifidobacterial, chain fatty acids but at the same time it generates a
Bacteroides and Clostridia (Fig. 3).8 series of potentially toxic substances also like ammonia,
amines, phenols, thiols and indols.11,12
GUT MICROBIOTA AS AN ORGAN Metabolically gut microbiota synthesizes the vitamin
There is a symbiotic relationship with the intestinal K and various components of B-complex.13 Bacteroides
mucosa and as an organ it imparts substantial metabolic, also synthesize conjugated linoleic acid (CLA), which
gut protective, immunological and trophic actions in is thought to be antidiabetic, antiatherogenic, anti
normal healthy individuals.9 obesogenic, hypolipidemic and immunomodulatory
properties.14 Gut microbiota have role in xenobiotic and
drug metabolism.15
Metabolic Functions
Undigested oligosaccharides and carbohydrates get
fermented to short chain fatty acids (SCFA), like acetic Prevention of Infection
acid (used by muscles), butyric acid (absorption of In vitro, bacteria compete for attachment sites in the
fluids and stimulation of proliferation in normal cells, brush border of intestinal epithelial cells, 16 bacteria
inhibits cell proliferation in neoplastic cell lines), compete for nutrient availability in ecological niches
propionic acid (decreases production of inflammatory and maintain their collective habitat by administering
438 SECTION 6: Gastroenterology/Hepatology
Fig. 3: Human microbiome over time: response to environmental conditions and life stages
and consuming all resources. They have influence on In irritable bowel syndrome–ratio of Firmicutes
mucosal barrier by mucus production and by epithelial to Bacteroidetes increased along with increased
growth. Finally, bacteria can also inhibit the growth of Clostridium and decreased Bifidobacterium,
their competitors by producing antimicrobial substances Bacteroidetes.18
called bacteriocins.17 Inflammatory bowel disease-increased number of
Enterobacteriaceae, Escherichia coli and decreased
Gut Microbiota as an Immunomodulator Firmicutes, Bacteroidetes.19
The innate and adaptive immune systems also have been Colorectal cancer—increased Fusobacterium species,
modulated by gut microbiota. Gut associated lymphoid E.coli.20
tissues (GALT), effector and regulatory T cells, B cells Obesity—increased Firmicutes to Bacteroidetes
take keen role and participation in immunomodulation ratio, increased Actinobacteria and decreased
of immune system (Fig. 4).17 Bifidobacterium.21
Type 2 diabetes mellitus–increased opportunistic
LINK BETWEEN GUT FLORA pathogens (Clostridium spp., E. coli), Bacteroidetes
AND DISEASES spp. and decreased Butyrate producing organisms,
Microbial composition usually changes with age, Firmicutes.22
inflammation, use of antibiotics, use of probiotics and Parkinson disease—increased number of Entero
prebiotics, diet, weight loss, pregnancy, drugs (like bacteriaceae and decrease number of Provotellaceae.23
steroids, NSAID), stress, radiation, alcohol, pollution Hepatic encephalopathy—increased Entero
(Fig. 5). bacteriaceae, Streptococcaceae and decreased Lachno
Changes in gut microbiota is linked to various diseases spiraceae, Ruminococcus and Clostridium.24
like irritable bowel syndrome (IBS), inflammatory bowel
disease (IBD), Type 2 diabetes mellitus, obesity, hepatic FUTURE HOPES FOR VARIOUS DISEASES
encephalopathy, dyslipidemia, Parkinson disease, Probiotics are live microorganisms, sufficient amount
allergies and colonic cancer. of which reach the intestine in an active state, thus
CHAPTER 71: The Gut Microbiota: A Forgotten Organ 439
Fig. 5: Various factors influencing the density, diversity, and gut microbiota activity
440 SECTION 6: Gastroenterology/Hepatology
positive health effects. They mostly include lactic 5. Maria DB, Martin B, Ruth L, Rob K. Development of
acid-producing bacteria and yeasts that reach the the human gastrointestinal microbiota and Insights
from high throughout sequencing. Gastroenterology.
gut unaltered, without providing damage to the host.
2010;140(6):1713-9.
Lactobacillus and Bifidobacterium produce harmful 6. Favier CF, Vaughan EE, De Vos WM, Akkermans ADL. Molecular
substances for Gram-positive and Gram-negative monitoring of succession of bacterial communities in
bacteria, and they compete with pathogens for cell human neonates. Applied and environmental microbiology.
adhesion. Probiotics has been observed for enhancing 2002; 68(1):219-26.
the immune system and favorable effect on lipid 7. Coppa Giovanni V, Bruni Stefano, Morelli Lorenzo, Soldi
Sara, Gabrielli Orazio.The first prebiotics in humans. Journal
profile, control of infections particularly decreases
of clinical gastroenterology. 2004;38(6 suppl):S80-3.
diarrheal incidences and act like antibiotics, suppress 8. Harmsen Hermie JM, Wildeboer-Veloo Alida CM, Raangs
tumors and prevent against various cancers like colon Gerwin C, Wagendorp Arjen A, Klijin Nicolette, Bindels
and bladder.25 Jacques G, Welling Gjalt W. Anaiysis of intestinal flora
Prebiotics are defined as “a selectively fermented development in breast-fed and formula-fed infants by using
ingredient that allows specific changes, both in the molecular identification and detection methods. Journal of
pediatric gastroenterology and nutrition. 2000;30(1):61-7.
composition and/or activity in the gastrointestinal
9. Sonneberg JL, XU J, Leip DD, Chen CH, Westover BP,
microflora that confers benefits upon host well-being Weatherford J, Buhler JD, Gordon JI. Glycan foraging in
and health”.26 vivo by an intestine-adapted bacterial symbiont. Science.
Fecal microbiota transplantation (FMT): Transfer 2005;307:1955-9.
of gut microbiota from a healthy volunteer donor to 10. Macfarlane S, Macfarlane GT. Regulation of short-chain
the recipient. Usually it is being done as retention fatty acid production. Proc Nutr Soc. 2003;62:67-72.
11. Macfarlane GT, Cummings JH, Allison C. Protein
enema, nasogastric tube, nasoduodenal tube or
degradation by human intestinal bacteria. J Gen Microbiol.
through colonoscope. Besides this capsules having 1986;132:1647-56.
freezed-dried material is also may be given orally 12. Smith EA, Macfarlane GT. Enumeration of human colonic
to re-establish the microbial population in the bacteria producing phenolic and indolic compounds:
gut of recipient. First documented in humans in effects of pH, carbohydrates availability and retention time
1958. Currently, it is very useful in the treatment of on dissimilatort aromatic amino acid metabolism. J App
Bacteriol. 1996;81:288-300.
pseudomembranous colitis caused by Clostridium
13. Baddini Feitoza A, Fernandes Pereira A, Ferreira da Costa N,
difficile infection. The future indications are ulcerative Goncalves Ribeiro B. Conjugated linoleic acid (CLA): effect
colitis, Crohn’s disease, Irritable bowel syndrome, modulation of body composition and lipid profile. Nutr Hosp.
Obesity, Diabetes mellitus, metabolic syndrome and 2009;24:422-8.
multiple sclerosis.27 14. Clayton TA, Baker D, Lindon JC, Everett JR, Nicholson JK.
Pharmacometabolomic identification of a significant host-
microbiome metabolic interaction affecting human drug
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CHAPTER
72
Nonalcoholic Fatty Liver Disease:
Is it Really Benign?
AK Chauhan
altered gut microbiota may play a role in promoting the greater risk of HCC compared with patients without
progression of NAFLD, thereby increasing the risk of diabetes.
HCC.
PATHOPHYSIOLOGIC LINK OF
ROLE OF METABOLIC RISK FACTORS METABOLIC RISK FACTORS WITH HCC
IN DISEASE PROGRESSION A chronic inflammatory condition is seen in patients
Central obesity and diabetes are by themselves risk with the metabolic syndrome such as those with obesity,
factors for hepatocellular carcinoma. Patients with diabetes. The same factors are believed to trigger
diabetes are known to be associated with a 2–4 fold progressive disease in those with NAFLD (Box 1).
444 SECTION 6: Gastroenterology/Hepatology
BOX 1: Pathophysiologic mechanisms leading to progression TABLE 2: Single nucleotide polymorphisms associated with
increased hepatic fat content and elevated plasma liver enzyme
zz Insulin resistance and hyperinsulinemia
levels.
zz Oxidative stress
Single nucleotide polymorphism Attributed role
zz Hepatic stellate cells activation
PNPLA3 rs738409 C > G It is associated with the risk of
zz Cytokine/adipocytokine signaling pathways polymorphism progression to cirrhosis
zz Genetic and environmental factors
PNPLA3 I148M polymorphism Favors NAFLD progression and
liver fibrosis
BOX 2: Oxidative stress and its impact on hepatic cells Increased risk of HCC in severely
obese individuals
zz Apoptosis
zz Necrosis
NAFLD. Genome studies have shown single nucleotide
zz Inflammation
polymorphisms which are clearly associated with
zz Hepatic stellate cell activation
increased hepatic fat content and elevated plasma liver
zz Fibrogenesis
enzyme levels (Table 2).
zz Proinflammatory cytokine expression
zz Cell proliferation
EXTRAHEPATIC COMPLICATIONS
OF NAFLD
Insulin resistance: Insulin resistance and the compen NAFLD and CV Risk
satory hyperinsulinemia is believed to play a key role in Population based studies appear to indicate, that the
the pathogenesis of NAFLD-related HCC. The insulin- patient of NAFLD, is at a higher risk of CVD and related
like growth factor (IGF) axis, and the upregulation of morbidity and mortality with worse outcomes compared to
IGFs and IRS-1 production, have been shown to be that of progressive liver disease. NAFLD is an independent
contributing factors of HCC pathogenesis. contributor to the development of atherosclerosis and
Oxidative stress (and hepatic stellate activation): other cardiac alterations, leading to CVD. This is not
Oxidative stress and release of reactive oxygen species surprising, as both CVD and NAFLD appear to be linked
(ROS), at the hepatic mitochondrial, peroxisomal, and to with respect to the basic pathophysiology of insulin
microsomal levels can lead to significant hepatocellular resistance, oxidative stress, abnormal adipocytokine
injury which may trigger progression to HCC (Box 2). profile, endothelial dysfunction, lipid abnormalities, and
High concentrations of ROS at the damage site, can lead activation of inflammatory cascade. Based on strength of
to DNA alteration which in turn can result in genomic evidence, it has been suggested that the management of
instability and mutations in proto-oncogenes and tumor NAFLD and CVD must be integrated towards a common
suppressor genes, resulting in neoplastic transformation. approach of dealing with the underlying pathology.
NAFLD and Colorectal Cancers insulin resistance and hyperinsulinemia, oxidative stress,
NAFLD and colorectal cancer (CRC) have common hepatic stellate cell activation, cytokine/adipocytokine
risk factors which trigger disease progression. As with signaling pathways, and genetic and environmental
NAFLD, high levels of insulin and insulin-like growth factors. NAFLD in subjects with risk factors, also leads
factors may promote the development of CRC through to extra-hepatic complications with worsening or pre-
their proliferative and antiapoptotic effects. Decreased existing CVD and CKD. More recent data appears to link
levels of adiponectin lead to increased insulin levels it with colorectal cancer as well.
and insulin growth factor-1 (IGF-1) leading to cell
proliferation, apoptosis, and increased production of BIBLIOGRAPHY
vascular endothelial growth factor, all of which increased 1. Kalra S, Vithalani M, Gulati G, Kulkarni CM, Kadam Y,
Pallivathukkal J, et al. Study of prevalence of nonalcoholic
risk of NAFLD progression as much as raise the risk
fatty liver disease (NAFLD) in type 2 diabetes patients in
of CRC. A better understanding of the benefit of early
India (SPRINT). J Assoc Physicians India. 2013;61(7):448-
screening of CRC in NAFLD patients, may impact of 53.
treatment of NAFLD in the modulation of the risk of 2. LaBrecque DR, Abbas Z, Anania F, Ferenci P, Khan AG,
colorectal cancer. Goh KL, et al. World Gastroenterology organisation global
guidelines: Nonalcoholic fatty liver disease and nonalcoholic
CONCLUSION steatohepatitis. J Clin Gastroenterol. 2014;48(6):467-73.
3. Liu H, Lu HY. Nonalcoholic fatty liver disease and
Nonalcoholic liver disease may present as simple
c a rd i ov a s c u l a r d i s e a s e . Wo r l d J G a s t ro e n te ro l .
steatosis, or may occur as nonalcoholic steatohepatitis 2014;20(26):8407-15.
with or without cirrhosis development. NAFLD appears 4. Marcuccilli M, Chonchol M. NAFLD and chronic kidney
to be pathophysiologically linked to the metabolic disease. Int J Mol Sci. 2016;17(4):562.
syndrome—with obesity, T2DM and dyslipidemia 5. Muhidin SO, Magan AA, Osman KA, Syed S, Ahmed MH. The
raising the risk of development of NAFLD. Among relationship between nonalcoholic fatty liver disease and
colorectal cancer: the future challenges and outcomes of
the components of metabolic syndrome, obesity and
the metabolic syndrome. J Obes. 2012;2012:637538.
diabetes have been strongly linked to hepatocellular
6. Streba LA, Vere CC, Rogoveanu I, Streba CT. Nonalcoholic
carcinoma (HCC). Pathophysiologic mechanisms fatty liver disease, metabolic risk factors, and hepatocellular
that lead to NAFLD development and its progression carcinoma: an open question. World J Gastroenterol. 2015;
to nonalcoholic steatohepatitis and cirrhosis include 21(14):4103-10.
CHAPTER
73
Glucose Metabolism Disorders
in Chronic Liver Disease
Aparna Agrawal, Prashasti Gupta
of disorders of liver are associated with pancreatic in 14% to 71%) by various researchers. Prevalence of IR
disease like hemochromatosis and alcoholic liver disease varies from 34% to 69%. Prevalence of NAFLD in type 2
(ALD) which may also contribute to hyperglycemia. diabetes was found to vary from 10% to 87%. The wide
variation in prevalence is because of the differences
MECHANISM OF LD IN DM in the demographic profile, the underlying LD of the
Mechanisms of diabetes contributing to liver damage patients studied (which varies from chronic hepatitis to
include (i) adipokine mediated increased oxidative end-stage liver disease enrolled for liver transplantation)
stress and aberrant inflammatory response in diabetes and LD of varied etiologies.
damaging the hepatoc ytes, (ii) insulin causing
overexpression of connective tissue growth factor [which CORRELATION OF GMD WITH
is known to induce several extracellular matrix (ECM) ETIOLOGY AND SEVERITY OF CLD
components especially in association with steatosis and AND RISK FACTORS OF DM
inflammation] in hepatic stellate cells (HSC) leading to GMD in CLD occurs independent of the established
fibrogenic response, and (iii) hyperglycemia causing risk factors for DM as most studies have refuted the role
activation of hepatic stellate cells through increased of traditional risk factors of DM like age more than 45
expression of the receptor for advanced glycation end- years, female gender, positive family history of DM and
product (RAGE) modulated by the transforming growth high BMI in causing GMD in CLD patients, though, few
factor β-1. Ligand activation of RAGE leads to formation have implicated older age as a risk factor. Obesity as a
of reactive oxygen species, which also contributes to the part of metabolic syndrome has been linked to NAFLD.
deposition of ECM in the liver. Likewise in studies trying to correlate the severity of
Progression from adipose tissue IR to NAFLD and liver disease with occurrence of GMD, majority showed
NASH has been explained as a four step process: (i) IR increased prevalence of IR, pre-diabetes and diabetes
provides a ‘lipotoxic environment’ that ensures a high with increasing severity of liver disease as per the CTP
free fatty acid flux and compensatory hyperinsulinemia score and also the liver fibrosis stage. IR and GMD have
which stimulates increased hepatic triglyceride synthesis, been found to be more prevalent in decompensated
(ii) development of hepatic steatosis and of a lipid pool cirrhosis as compared to compensated cirrhosis, which
from where lipid derived toxic metabolites may activate is higher than in patients with chronic hepatitis. Also,
inflammatory pathways, (iii) failure of liver to adapt to as per literature certain etiologies of liver cirrhosis like,
long-standing triglyceride accumulation brings about chronic hepatitis C, NAFLD, autoimmune liver disease,
chronic necrosis and inflammation, and (iv) chronic alcoholic liver disease and hemochromatosis may be
activation of HSC causing the final fibrosis. more commonly associated with GMD in most studies.
Hepatic steatosis is a feature of CHC, ALD and NAFLD Chronic hepatitis B on the other hand has not been
also and it further aggravates IR and type 2 DM, resulting found to have a higher prevalence of GMD.
in a vicious cycle.
As liver is a major storage organ for glycogen, in CLINICAL PRESENTATION
conditions where glycogen breakdown is impaired like OF GMD IN CLD
severe acute liver disease and advanced liver cirrhosis, Unlike the usual clinical presentation of type 2 DM, GMD
hypoglycemia can occur. in CLD are frequently asymptomatic. The classical triad
of weight loss, polydipsia and polyuria, other symptoms
BURDEN OF GMD AND due to recurrent styes, slow or non-healing ulcers,
IR IN CLD AND OF LD IN DM recurrent vaginitis, oral thrush and microangiopathic
Prevalence of GMD in patients with liver cirrhosis has target organ damage, i.e. nephropathy, retinopathy and
been found to be varying from 33% to 96% (overt DM neuropathy are rarely if at all seen. Macroangiopathy is
448 SECTION 6: Gastroenterology/Hepatology
also less common except in patients with NAFLD and Medical Nutrition Therapy
chronic hepatitis C (CHC). It may be due to the protective and Lifestyle Modification
effects of low serum levels of lipids, Lp(a),decreased
These are the same as for diabetes in general except that
coagulation function and thrombocytopenia associated
sufficient daily intake of calories and proteins (not >20%
with cirrhosis.
of energy intake) is required as most CLD patients are
malnourished. Alcohol consumption must be stopped.
IMPLICATIONS OF GMD ON Active exercise is difficult in patients with active LD and
COMPLICATIONS OF CLD in patients with gross edema and ascites.
CLD with GMD are associated with increased morbidity
and mortality as compared to those with CLD alone. This
Pharmacotherapy
is a consequence of increase in complications related
Most oral antidiabetic (OAD) agents can be given in child
more to the underlying hepatic disease like bacterial
A CLD. Altered drug metabolism is primarily a concern
infections, spontaneous bacterial peritonitis, refractory
in patients with advanced LD. Also, CLD can sometimes
ascites, gastrointestinal bleed, hepatic encephalopathy
alter renal function, hence altering metabolism not
and hepatorenal syndrome and less so due to general
only of drugs metabolized in the liver but also those
or complications related to diabetes except for slightly
eliminated by the kidneys. Acarbose, incretin based
increased cardiovascular and cerebrovascular diseases
therapies and short-acting insulin analogues are the
in patients with NAFLD and CHC. Increased risk of
safest in Child B and C CLD.
hepatocellular carcinoma has been reported in patients
If blood sugars are not controlled with MNT and
of CLD with GMD. In patients with CHC, IR and GMD
LSM, start with OADs and rapidly advance to short acting
aggravate the course of hepatic inflammation with
prandial insulin if: blood sugar is still not controlled,
earlier and more severe fibrosis and a lower spontaneous
transaminases are >2 × ULN, or decompensation of
viral remission in response to antiviral therapy. GMD is
cirrhosis occurs. Watch for hypoglycemia.
associated with a longer hospital stay, shorter 30 days
A detailed description of management of DM in CLD
survival and increased 90 days rebleed and mortality
is not possible and only the special features of each class
following portal hypertensive variceal bleed.
of OADs are being mentioned here:
DIAGNOSIS AND MONITORING
The criteria for diagnosis of pre-DM and DM associated Metformin
with LD is the same as in the general population. However, Insulin sensitizing agent metformin is the oral agent
HbA1c may be falsely low in patients with cirrhosis, hence of choice except in patients with advanced LD, those
it is unreliable for diagnosis or monitoring. In patients with GFR <30 mL/min and in alcoholics because of the
with decompensated LD, monitoring must be done using risk of lactic acidosis. Additionally metformin has been
SMBG and fructosamine assay. If this is not available, found to decrease the risk of hepatic encephalopathy,
then for long term control we can use HbA1c but the target hepatocellular carcinoma and liver related deaths.
HbA1c should be 7.5–8.0% in CLD patients.
Sulfonylureas
TREATMENT OF GMD IN CLD Avoid insulin secretagogues – sulfonylureas in advanced
Optimization of blood glucose level is required not only LD because of increased risk of hypoglycemia and
to avoid late complications of DM but also for cirrhosis hepatotoxicity (reported with some). In mild CLD,
associated complications and outcomes following short-acting sulfonylurea can be used with a watch on
antiviral therapy. hypoglycemia.
CHAPTER 73: Glucose Metabolism Disorders in Chronic Liver Disease 449
Guidelines (Consensus) development. J Endocrinol Diabetes 8. Leclercq IA, Da Silva Morais A, Schroyen B, Van Hul N,
Obes. 2015;3(3):1073-81. Geerts A. Insulin resistance in hepatocytes and sinusoidal
5. Johnson DG, Alberti KG, Faber OK, Binder C. Hyperinsulinism liver cells: Mechanisms and consequences. J hepatol
o f h e p a t i c c i r rh o s i s : d i m i n i s h e d d e g r a d a t i o n o r 2007;41(1):142-56.
hypersecretion? Lancet. 1977;1(8001):10-3. 9. Paradis V, Perlemuter G, Bonvoust F, Dargere D, Parfait
6. Kawaguchi T, Taniguchi E, Itou M, Sakata M, Sumie S, Sata B, Vidaud M, et al. High glucose and hyperinsulinemia
M. Insulin resistance and chronic liver disease. World J stimulate connective tissue growth factor expression: a
Hepatol. 2011;3(5):99-107. potential mechanism involved in progression to fibrosis
7. Khan R, Foster GR, Chowdhury TA. Managing diabetes in non-alcoholic steatohepatitis. Hepatol. 2001;34(4 Pt
in patients with chronic liver disease. Postgrad Med. 1):738-44.
2012;124(4):130-37.
CHAPTER
74
Hepatorenal Syndrome:
Clinical Considerations
Tanuja Pravin Manohar
ascites and finally to HRS. HRS is on the extreme thereby augmenting renal vasoconstriction and causing
spectrum of hemodynamic changes which accompany decline in GFR. Loss of renal auto-regulation also
cirrhosis with portal hypertension. Systemic and contributes in causation of renal dysfunction. All these
splanchnic vasodilation together with severe renal factors contribute in developing renal dysfunction, i.e.
arterial vasoconstriction is the pathognomic feature of HRS.
HRS. Splanchnic vasodilation occurs because of actions
of various vasodilators like nitric acid produced by PRECIPITATING FACTORS
hepatocytes and stellate cells. Mesenteric angiogenesis (FLOW CHART 1)
driven by platelet-derived growth factor (PDGF) and Following factors are known to precipitate HRS:
vascular endothelial growth factor (VEGF) is also found to Gastrointestinal bleeding
circulation and splanchnic vasodilation. Splanchnic Aggressive diuretic use causing renal fluid losses
vasodilation produces a reduction in mean arterial Large volume paracentesis without volume expansion
pressure (MAP) as well as effective arterial blood volume Spontaneous bacterial peritonitis
responses. These compensatory mechanisms include Use of nephrotoxic drugs such as NSAIDs or amino
fluid balance is critical in managing patients of renal free liver dialysis or albumin dialysis. It helps to remove
dysfunction in cirrhotic patients. The treatment of HRS albumin-bound substances accumulating in liver failure.
aims at plasma volume expansion and increase in renal
perfusion pressure. vasopressor therapy with albumin is Liver Transplant
mainstay of treatment in HRS. Liver transplant (LT) is the only definitive treatment for
Type 1 and 2 HRS as in majority of times HRS is either
Albumin with Vasoconstrictors recurrent or irreversible. Rest of the treatments act only
Terlipressin with albumin: Terlipressin with albumin as a bridge till LT is done. In order to improve graft
is the therapeutic combination of choice for type survival after LT, it is very important to reverse HRS with
1 HRS. Patient is given albumin infusion 20-40 g/
pharmacological treatment or RRT. If renal functions
day. Terlipressin is started with 0.5 mg 6 hourly as
remain deranged >4 weeks prior to LT, consideration
IV boluses. Serum creatinine is measured after 3
should be given to simultaneous liver and kidney
days. If reduction in serum creatinine is < 25% from
transplant.
baseline, the dose of terlipressin is doubled. Dose
can be titrated up to 12 mg/day. This treatment
is continued for 14 days. Almost 50% of patients
SUMMARY
show reversal of HRS type 1. As per recent research, Hepatorenal syndrome (RS) is a dreaded complication of
continuous infusion of terlipressin 2 mg/day is liver cirrhosis with significant morbidity and mortality.
equally effective and have comparatively less side With revised diagnostic criteria, HRS can be diagnosed
effects. Terlipressin is contraindicated in patients at an early stage and associated with early institution
having ischemic heart disease, peripheral vascular of pharmacotherapy. Emphasis should always be given
disease and cerebrovascular disease. This therapy to prevent and treat precipitating factors aggressively.
can be beneficial in 60–70% of patients with type 2 Pharmacotherapy has only a limited role in the
HRS. management of HRS as it usually recurs even when
Midodrine with octreotide (with albumin): Midodrine reverted with the medical management. Liver transplant
is given orally 5–10 mg, three times/day and titrated is the only definitive modality of treatment. If renal
up to 12.5 mg three times/day. Octreotide is started dysfunction remains >4 weeks prior to LT combined
with 100 μg thrice a day subcutaneously and can be liver-kidney transplant may be considered for better
increased up to 200 μg thrice a day. results.
Noradrenaline with albumin: Noradrenaline infusion
0.5–3 mg/hour as continuous IV infusion along with BIBLIOGRAPHY
albumin can also be used effectively especially in 1. Acevedo JG, Cramp ME. Hepatorenal syndrome: Update on
critically ill patients. diagnosis and therapy. World J Hepatol. 2017;9(6):293-9.
2. Bucsics T, Krones E. Renal dysfunction in cirrhosis: acute
Renal Replacement Therapy kidney injury and the hepatorenal syndrome. Gastro
Patients who fail to respond to medical line of treatment enterology Report. 2017;5(2):127-37.
should be started on renal replacement therapy 3. European Association for the Study of the Liver. EASL
clinical practice guidelines on the management of ascites,
(RRT). RRT is usually kept reserved for patients awaiting
spontaneous bacterial peritonitis, and hepatorenal
liver transplantation.
syndrome in cirrhosis. J Hepatol. 2010;53:397-417.
4. Fukazawa K, Lee HT. Updates on Hepato-renal syndrome.
Liver Replacement Therapy J Anesth Clin Res. 2013;4:352.
Molecular adsorbent recirculating system (MARS) is the 5. Ge PS, Runyon BA. The changing role of beta-blocker therapy
modality used with mixed results. It represents a cell- in patients with cirrhosis. J Hepatol. 2014;60(3):643-53.
CHAPTER 74: Hepatorenal Syndrome: Clinical Considerations 455
6. Lei L, Li L, Zhang H. Advances in the Diagnosis and 9. Mattos AZD, Mattos AAD, Mendez-Sannchez N. Hepatorenal
Treatment of Acute Kidney Injury in Cirrhosis Patients. syndrome: Current concepts related to diagnosis and
Biomed Res Int. 2017;2017:8523649. management. Annals of Hepatology. 2016;15(4):474-81.
7. Low G, Alexander GJM, Lomas DJ. Hepatorenal syndrome: 10. Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis,
Aetiology, diagnosis, and treatment. Gastroenterol Res prevention and treatment of hepatorenal syndrome in
Pract. 2015;2015:207012. cirrhosis. Gut. 2007;56:1310-8.
8. Mathur P, Nabi BN. Hepatorenal syndrome-current concepts
in pathophysiology. Gastroenterol Hepatol Open Access.
2017;7(1): 00225.
CHAPTER
75
Cirrhosis of Liver: Beyond
Beta-blockers and Diuretics
Anup K Das
Ascites Low Sodium Diet Low Na+ diet, diuretics, large volume paracentesis, 50% at 2 years 75% at 1 year (in
TIPPS, surgical shunts Refractory ascites)
Hepatic encephalopathy Treating precipitants (Infection, bleeding, electrolyte 42% at 1 year 23% at 3 years
imbalance, sedatives, high proteins) lactulose, (After hospitalization)
rifaximin, metronidazole
SECTION 6: Gastroenterology/Hepatology
Contd...
Associated issues Learning points Remarks
Nutritional Multifactorial—decreased or unbalanced food intake, malabsorption, Early dietician review needed. BMI and skin-fold thickness
Sarcopenia is predominant—due metabolic, inappropriate fasting/restricted diet and intestinal bacterial inaccurate for nutritional assesment. Subjective global
to reduced energy intake, reduced overgrowth. Exocrine pancreatic deficiency common. Multidisciplinary assessment is helpful. Hand grip test predicts outcome
substrate for muscle production, BCCA intervention — Energy 30-35 kcal/kg/day ( Protein 1-1.5 g/kg/day, Glucose (correlates with MELD). DEXA scan of abdominal muscles
oxidation, myostatin expression and 5-6 g/kg/day, 25-30% of total calories as medium chain triglycerides.). Enteral gold standard.
pro-inflammatory cytokines. Predictive of feeding preferred> Continuous/cyclical naso-gastric/jejunal feeds in sick Low serum retinol may predispose to HCC in alcoholic
survival. patients> Parenteral feeds where enteral feeding is impossible (end stage cirrhosis. But Vit A supplementation above 100,000 units/
Micronutrient deficiency is common and liver disease). Gastrostomy contraindicated in gastric varices. day must be avoided.
SECTION 6: Gastroenterology/Hepatology
End-of-Life care Teminal illness where Terminal decompensation and ACLF common presentations. Earlier Integrated palliative and supportive care needed
no cure is possible. Clear guidelines identification of cases surviving in near future difficult but Supportive and with symptom contro, improving quality of lifel plus
unavailable. It is important to identify the Palliative Care Indicators Tool (SPICT) may be useful psychological, social, spiritual and practical symptom.
needs of the patient and family.
Preventive aspect a) P
rimary prevention: To prevent cirrhosis, b) Secondary prevention: To detect To screen high-risk populations HBV/HCV +ves,
Epidemiologically, 10% of general cirrhosis at earliest stage, c) Tertiary prevention: To anticipate and detect Alcohol/iv drug abusers, unsafe sex, obesity, NAFLD,
population is expected to develop complications, d) Primordial prevention: Eliminating risk factors of cirrhosis Diabetes mellitus, Family members of Wilson, disease,
cirrhosis and 67% of cirrhosis are detected to develop, i.e. alcohol-related/NASH: related cirrhosis hemochromatosis, AIH, HBV and treat the underlying
accidentally. disease. Educating adolescent children about lifestyle,
sanitation. Non-availability of alcohol is a primordial
prevention
CHAPTER 75: Cirrhosis of Liver: Beyond Beta-blockers and Diuretics 461
use is associated with worse outcomes compared In a cirrhotic liver, vascular distortion can not be
with those not receiving beta blockers. In those with reversed unlike the fibrosis part. Hepatic fibrosis is a
bacterascites (bacteria present in the ascitic fluid, but dynamic process where hepatic stellate cells (HSC),
PMN <250 cells/mm3) antibiotics are given. Renal failure, Kupffer cells and recruited mononuclear cells are the
a major cause of death, develops in 30–40%. The risk key players. In early, compensated stages, it may regress.
decreases with IV albumin (1.5 g/kg body weight within Oxidative stress (ROS) accelerates the process and may
six hours of diagnosis and 1.0 g/kg body weight on day be induced by rennin angiotensin pathway of HSC,
three). along with other mediators such as TGF-β, nitric oxide
Acute-on-chronic liver failure (ACLF) is a syndrome and inflammatory cytokines (Table 2). Vasoconstrictor
in cirrhosis characterized by acute decompensation, angitensin II is produced leading to inflammation, tissue
organ failure, (s), and high short-term mortality. It may repair and fibrosis. Degree of fibrosis varies according to
develop at any phase during the clinical course of the the duration, composition, spatial distribution and scar
disease. According to the number of organ failures, cellularity. Increased septal thickness and micronodules,
ACLF is graded into three stages: ACLF-1 = renal failure which are proportional to ECM crosslinking, predicts
or single nonrenal organ failure if associated with renal poor outcomes. In addition to targeting the etiology
dysfunction and/or cerebral dysfunction; ACLF-2 = two of cirrhosis, anti-fibrotic agents are being developed
organ failures; and ACLF-3 = three to six organ failures, to downregulate HSC activation, angiotensin receptor
with increasing 28-day mortality rate (from 23 to 74%). antagonists and other mediators of fibrogenesis in the
ACLF patients show marked systemic inflammation future.
(ie, increased plasma cytokines levels) and immune
dysfunction. Alcohol, sepsis and HBV are common CONCLUSION
triggers for ACLF, but in 20%–45% of cases, the trigger There are many treatment related, multisystem,
remains unknown. Liver transplant is the definitive complex issues particularly in decompensated cirrhosis.
treatment. Prevention at different levels is important as is anticipating
In adults liver injury stimulates bone-marrow the complications and their fall out. Importantly, the fact
derived stem cells for hepatocyte regeneration. Stem cell that liver transplant is the only curative, but expensive
transfusion is being tried in cirrhosis and hepatocellular treatment option, will add to the burden of end-of-life
failure. Granulocyte Colony Stimulating factors [(G-CSF terminal care in our setting.
(5 mg/kg daily SC for 6–12 days)] have been tried in ACLF.
It may promote hepatocyte repair by facilitating migration BIBLIOGRAPHY
of bone marrow-derived progenitor cells and stem cells, 1. Gourdas Choudhury (Ed) Cirrhosis. 1st edn. Reed Elsevier
especially CD34+ cells. Increased hepatocyte growth India Ltd. 2015:51-55.
factor, induction of hepatic progenitor cell proliferation 2. Greenslade L. End-of-Life-Care for Patient with Liver
Disease. In: Tim Cross (Ed). Liver Disease in Clinical Practice
and improvement of hepatic microenvironment are
Switzerland: Springer International Publishing. 2017;355-
other reported effects of G-CSF. Improved neutrophil 67.
count and neutrophil function may contribute to some 3. Jung YK, Yim HJ. Reversal of liver cirrhosis: current evidence
reversal of immune dysfunction commonly observed in and expectations. Korean J Intern Med. 2017;32: 213-28.
ACLF. Upto 44% reduction in short term (60–90 days) 4. Kathleen Yan, Sc.B, Guadalupe Garcia-Tsao, Novel
mortality, improvement in liver function, increased Prevention Strategies for Bacterial Infections in Cirrhosis.
Expert Opin Pharmacother. 2016;17(5):689-701.
WBC count and CD34+ count (peripheral and hepatic)
5. King A, Barton D, Beard H A, Than N, Moore J, et al. REpeated
have been reported in Asian ACLF patients. It may be an AutoLogous Infusions of STem cells In Cirrhosis (REALISTIC):
alternative in ACLF when liver transplant is unavailable a multicentre, phase II, open-label, randomised controlled
or contraindicated, but needs further studies. trial of repeated autologous infusions of granulocyte
462 SECTION 6: Gastroenterology/Hepatology
colony-stimulating factor (GCSF) mobilised CD133+ bone 8. Tandon P, Jame s MT, Abraldes JG, Karvellas CJ, et al
marrow stem cells in patients with cirrhosis. A study Relevance of New Definitions to Incidence and Prognosis of
protocol for a randomised controlled trial. BMJ Open. Acute Kidney Injury in Hospitalized Patients with Cirrhosis:
2015;5(3):e007700. A retrospective population-based cohort study PLoS One.
6. Kirnake V, Arora A, Gupta V, Sharma P, Singla V, et al 2016;11(8):0160394.
Hemodynamic response to carvedilol is maintained for long 9. Tripath D, Peter C. Hayes Beta-blockers in portal hyper
periods and leads to better clinical outcome in cirrhosis: A tension: new developments and controversies Liver Inter
prospective study. J clin Exp hepatol. 2016;6:175-85. national. 2014;4;655-66.
7. Shah SC, Shah PS, Shah KP (Eds). Preventive Measures 10. Wang SZ, Ding HG. New therapeutic paradigm and concepts
for Cirrhosis of Liver and its Progression. 1st edn Jaypee for patients with cirrhotic refractory ascites. Sugg Zhonghua
Brothers Medical Publishers. 2016. pp. 1-23. Gan Zang Bing Za Zhi. 2017;25:249-53.
CHAPTER
76
Hepatitis B: Are We Moving
Ahead Towards Cure?
Anil C Anand
liver necroinflammation in liver +/- fibrosis) many one can achieve higher rates of HBeAg seroconversion
patients may lose HBeAg and develop anti-HBe (i.e. and HBsAg loss. However, the efficacy of interferons is
seroconversion) and is followed by significant HBV-DNA only modest, and treatment has several adverse effects.
inhibition. After this phase patients may enter phase 3. Adverse effects and the fact that it involves prolonged
Phase 3: HBeAg-negative chronic HBV infection : injections limit its tolerability and acceptability.
(Antibodies to HBeAg appear, HBV-DNA levels are low Nucleoside analogues are given orally, have minimal
or undetectable and ALT is normal; there is minimal liver adverse effects and are required to be given for an
necro-inflammation and fibrosis in liver), these patients indefinite duration. They effective suppress the viral
may loose HBsAg spontaneously in 1to 3% of cases per replication but do not cure the patient.
year folllowed by appearance of anti-HBs. Serum HBsAg
levels in this phase are typically low (<1,000 IU/mL). What is Cure in HBV Infection?
Initially HBeAg seroconversion was considered as a
Phase 4: HBeAg-negative chronic hepatitis B: (Detectable
desirable endpoint of treatment, however, subsequently
antibodies to HBeAg, moderately high HBV-DNA and
discovery of latent HBV infection and cccDNA changed
elevated ALT; as well as necroinflammation biopsy
that. Today we are satisfied with loss of HBsAg as
present in liver) a majority these patients have HBV
acceptable endpoint, but if it will signify cure and
mutations in the precore and/or the core promoter
elimination of cccDNA is not clear. The available
regions and will rarely develop spontaneous disease
antivirals can suppress HBV replication as long as they
remission.
are given but are unable clear HBsAg consistently, hence
Phase 5: HBsAg-negative phase: (Patients are HBsAg need to be given indefinitely. Available drugs are not very
negative, antibodies to HBcAg positive, HBV-DNA effective against cccDNA, the ‘seemingly indestructible
undetectable or very low and normal ALT; minimal or no “mini-chromosome” of the hepatitis B virus in nuclear
liver necroinflammation in liver), this is apparent cure and episomal location’. This mini-chromosome continues
but occult infection (cccDNA) is persisting in the liver. to produce virus progeny in infected host liver cells, even
Such patients will remain at risk of developing HCC. If in people being treated. If cure is desired, we would
these patients are immunosuppressed for some reason, have to find ways to destroy or silence cccDNA and also
HBV reactivation can occur in these patients. provide long-term immunity. It is possible that any single
drug may not be able to achieve that end. Scientists are
MANAGEMENT OF CHRONIC HBV hopeful that another big leap in the search for a cure of
INFECTION AND INNOVATIVE HBV is possible if new complementary drugs against
APPROACHES fresh targets are identified. 18
Available Treatments
The currently available treatments include immunomo-
NEWER DRUGS AND INNOVATIVE
dulatory therapies (including conventional IFN-α, Peg- APPROACHES
IFN-α and thymosin α), and nucleoside/nucleotide Once it is understood as to how HBV interacts with host
analogues (NA). The latter include nucleoside analogues liver cells, we can evolve methods to interfere at various
(lamivudine (L AM), entecavir, telbivudine and stages of life cycle of HBV. Several new drugs are being
emtricitabine) and nucleotide analogues (adefovir, developed with exactly same thought to attempt a cure of
tenofovir). Tenofovir and Entecavir are the preferred NA HBV. A summary of these drugs is given below.19-21
because they have highest barrier to drug resistance.
These two drugs are currently the first-line treatment. Drugs Targeting Viral Replication Cycle
Advantage of pegylated interferon is that it has a finite Entry inhibitors: This group of drugs block the entry of
duration of treatment, there is no drug resistance and hepatitis B into liver cells. It is achieved through binding
466 SECTION 6: Gastroenterology/Hepatology
to a specific viral protein called ‘pre-1’ and/or a specific RO 7020322 (RG7834) is currently in phase I clinical
liver cell protein working as receptor for HBV. An example trials
is myrcludex B (undergoing phase II clinical trials) which
Antisense molecules: These drugs bind to the viral mRNA.
targets sodium taurocholate cotransporting polypeptide
This action interferes with its transcription to viral
to inhibit entry of HBV into hepatocyte.
protein.
siRNA: SiRNA or “silencing” RNA, are nucleotide drugs IONIS-HBVRx (GSK 3228836), is currently in phase I
trials. development
INO-1800 is currently in phase I development
HBV-DNA polymerase inhibitors: Like existing drugs,
HB-110, DV-601, TG1050 and Hep-T-cell are currently
they inhibit DNA polymerase. Tenofovir alafenamide
(already marketed), besifovir and other modified in phase I development
TomegaVax HBV is in preclinical trials
tenofovir pro-drugs. Its advantage is that it can penetrate
into liver cells more easily. CMX 157 is currently in phase Innate and adaptive immune defense pathways: As has
II clinical trials. been outlines above, innate immune system plays a
HBsAg inhibitors: These drugs interfere with the crucial role in elimination of several viruses. Several
transcription of hepatitis B surface antigen (HBsAg). This new approaches are being explored to stimulate innate
protein is essential for virus to enter the liver cell and also immune system so as to overcome the stealth and
exit the liver cell. Examples of these drugs are: cunning of HBV.
Rep 2139 is currently in phase II clinical trials GS 9620 is a TLR-7 agonist currently undergoing
Pegylated interferon lambda stimulates cell mediated appears highly probable that a combination with drugs
immune responses and is undergoing Phase II that enhance immune responses against HBV will do the
clinical trials trick and achieve ultimate goal of a ‘definitive cure’ from
STING agonists produce type-1 Interferon dominant chronic HBV infection.
cytokine responses and are undergoing preclinical
studies REFERENCES
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development viruses: A Global overview. Clin Liver Dis. 2010;14:1-21.
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PD-1/PD-L1 inhibitors have been developed with
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CHAPTER
77
HIV/Hepatitis Coinfections
PK Agrawal
The majority (85%) living with HIV who become advertently with change in HIV therapy for virologic
infected with HCV have chronic hepatitis C an infection failure, hence consider maintaining HIV therapy with
that will stay with them for life unless they are successfully activity against HBV when changing ART.
treated. Hepatitis C can cause mild to moderate liver
scarring (fibrosis) or serious liver scarring (cirrhosis). HIV HIV-HCV Coinfection
increases the risk for and can speed up the development HCV–RNA persistence impairs response to ART and
of liver damage from hepatitis C. People with fewer than enhances renal, bone and CNS comorbidities in HIV.
200 CD4 cells are more likely to have liver damage from HIV accelerates progression of HCV disease. Sustained
hepatitis C. viral response (SVR) is associated with a decrease in liver
Effect of HCV coinfection on HIV progression is related, AIDS related and nonliver related and non-AIDS
unknown. There could be accelerated clinical progression related mortality in HIV/HCV.
of HIV-1. There may be impaired CD4 cell recovery ART should be initiated for most HIV/HCV coinfected
and faster HIV disease progression in HCV coinfected patients regardless of CD4 cell count. In HIV treatment
patients despite ART therapy. There could be no impact patients with CD4 >500 cells/mm3, ART may be deferred
on CD4 count, viral load, HIV progression or survival. until HCV treatment is completed. In patients with CD4
<200 cells/mm3, ART should be initiated immediately,
TREATMENT HCV therapy delayed until HIV treatment is stable.
HIV-HBV Coinfection Decision when to initiate HCV treatment is case by
For the treatment of HIV –HBV coinfection, agents case. Initiating HIV treatment first can increase CD4
selected should be active against both viruses if either counts, may improve response to HCV therapy. Initiating
HIV or both HIV/HBV infections meet the criteria for HCV treatment first (in those with high CD4 counts and
therapy. low viral load) can simplify treatment and improve ART
First goal of the clinician is to select the patient tolerability.
whether to treat for HIV alone, for HBV alone or for both PEG-IFN treatment should be deferred in HIV/HCV
the viruses. For patients having HIV or HIV with HBV the co-infected patients with liver decompensation. These
treatment endpoints remains the same although loss of patients could be considered for liver transplantation.
HBeAg or HBsAg as well seroconversion to anti-HBeAg PEG-IFN plus Ribavarin therapy can be considered in
and anti-HBs is not common. The treatment must patients with compensated cirrhosis (Child-Pugh class
include agents active against both viruses in HIV-HBV A). The treatment in coinfected patients should be
coinfection. Not doing so will lead to emergence of HIV continued for 48 weeks regardless of HCV genotype.
strains that are resistance to NRTI (nucleoside reverse Avoid didanosine, stavudine and zidovudine in
transcriptase inhibitor). The recommendations from combination with ribavarin therapy. Antiretroviral
the recent USA and Europe guidelines advocate the use agents may cause drug induced liver injury (nevirapine),
of two anti-HBV drugs as part of HAART in HBV - HIV caution should be taken.
coinfection. The aim of this combination therapy is to Various newer directly acting anti HCV drugs
decrease the development of resistance even though very are available like sofosbuvir, simeprevir, daclatasvir,
little data exists on either mono or coinfected patients ledipasvir, velpatasvir, they are efficacious but caution
with such therapy. should be taken considering these drugs because of
The preferred treatment for dual HBV/HIV co- various interaction with antiretroviral drugs. Combination
infection is the combination of tenefovir and lamivudine of daclatasvir with sofosbuvir is recommended for HCV
(emtricitabine). Rebound hepatitis may be associated genotype 2 and 3 And combination of ledipasvir with
with removal of hepatitis B therapy it could occur in sofosbuvir is recommended for HCV genotype 4, 5 or 6.
CHAPTER 77: HIV/Hepatitis Coinfections 471
VACCINATION CONCLUSION
Vaccination against hepatitis A and B should be given The liver is frequently affected in patients with HIV. HIV/
to all HIV patients who are not immune. Response viral hepatitis shows more rapid liver fibrosis progression.
to vaccination is poor in HIV patients especially in With improved control of HIV disease with HAART, liver
those with lower CD4 counts. These individuals poorly disease has emerged as one of the leading causes of
maintain the antibody titres after vaccination. May death in patients with HIV. The complexities of HBV/
consider increase dose (double the dose ) of HBV vaccine HCV-HIV coinfection highlight the importance of close
for adequate response. Patient with higher CD4 counts working relationships between hepatologists, infectious
and undetectable plasma HIV-RNA may give improved disesase specialists and primary care providers in order
response on doubling the HBV vaccine dose. to optimize patient outcomes.
CHAPTER
78
Fecal Microbiota Transplantation:
Current Indications and Methods
L Ilavarasi, SS Lakshmanan
TABLE 1: Minimum general steps to follow for the preparation of fresh and frozen fecal material
Fresh fecal material
zz Fresh stool should be used within 6 hours after defecation
zz To protect anaerobic bacteria, the storage and preparation should be as brief as possible
zz Until further processing, the stool sample can be stored at ambient temperature (20–30°)
zz Fecal material should be suspended in saline using a blender or manual effort and sieved in order to avoid the clogging of infusion
zz The final suspension should be clearly labelled and traceable, and stored at –80°C
zz On the day of fecal infusion, fecal suspension should be thawed in a warm (37°C) water bath and infused within 6 hours from thawing
zz After thawing, saline solution can be added to obtain a desired suspension volume
treatment for CDI, with promising results. In 2014, a IRRITABLE BOWEL SYNDROME
meta-analysis of clinical studies showed that FMT was Overall, subjects with IBS-D had significantly higher
effective in 87% of diarrhea cases (a total of 536 patients) levels of Enterobacteriaceae and significantly lower
caused by Clostridium difficile, with primary resistance levels of Faecalibacterium prausnitzii compared with
to prior therapy with metronidazole and vancomycin. the healthy control subjects, suggesting an imbalance
Long-term follow-up study of 77 patients who had of protective and potentially harmful bacteria. Chassard
undergone FMT for recurrent CDI (follow-up period of and colleagues noted that in individuals with IBS-C,
17 months) reported a primary cure rate of 91%, with the number of Enterobacteriaceae was increased 10-
all late recurrences of CDI (in 15 of 77 patients, 19%) fold compared with healthy control subjects.11 Long-
occurring in the setting of antimicrobial therapy for an term follow-up study of 45 patients with IBS-C were
infection unrelated to C difficile.8 administered a liquid culture containing 20 species of
nonpathogenic enteric aerobes and anaerobes through
INFLAMMATORY BOWEL DISEASE colonoscopy. Thirty of the patients were followed during
a period of 9–19 months. Improvements, including
Dysbiosis more frequent defecation and an absence of bloating
It is a shift in the composition of the microbiota, with and abdominal pain, were reported in 60% of patients.
reduced diversity of luminal microbiota which happens Evidence for FMT in IBS is limited. Need more studies.
in patients with IBD. There is a decrease in Firmicutes
and Bacteroidetes and a concomitant increase in FMT IN OBESITY/INSULIN RESISTANCE
mucosal-adherent bacteria such as Proteobacteria.9 AND DIABETES
Firmicutes are major producers of short-chain fatty Studies in mice and humans have shown a relative
acids such as butyrate, a substrate with immunoregulatory abundance of Firmicutes with a corresponding decrease
properties. of Bacteroidetes in obese subjects. In 2004, investigators
Fecal microbiota transplantation [FMT] has been found that the alteration of microbiota in mice leads to
investigated as a potential treatment for inflammatory increased body fat in the recipient mice.13 More studies in
bowel disease [IBD]. Many trials conducted. A systematic humans are needed, results suggest that alterations of the
review found 9 articles, representing 26 patients (18 microbiota have potential for treating insulin resistance
ulcerative colitis, 6 Crohn’s disease, and 2 indeterminate)
FMT IN NEUROLOGICAL DISEASES (FIG. 3)
who had received FMT for management of IBD. Out of
The close association between the digestive system
26, 17 completed study. Following FMT, 13 of 17 patients
and the brain has been recognized for many centuries.
(76%) were able to discontinue all IBD medications
Disruption in the this axis has been implicated in
within 6 weeks, and at 4 months, all had symptom
altered stress response and overall behavior, and the
reduction or resolution.10
significant role of microbiota in homeostasis of this
A systematic review was conducted until January neural network has been an active area of research.12
2017. It was concluded that FMT appears effective in UC This may contribute role of FMT in many neurological
remission induction, but long-term durability and safety diseases like parkinsons, depression, anxiety and
remain unclear. Additional well-designed controlled demyelination disorders.
studies of FMT in IBD are needed, especially in CD and
pouchitis. Less response seen in Crohns Disease. Not CURRENT AND FUTURE DIRECTIONS
all studies of FMT for the treatment of IBD, have had This consensus indicates that the only clinical
positive outcomes. indication with sufficient evidence of benefit from
476 SECTION 6: Gastroenterology/Hepatology
the implementation of FMT in clinical practice is 3. Salzman NH, Underwood MA, Bevins CL. Paneth cells,
CDI. The consensus panel strongly recommends the defensins, and the commensal microbiota: a hypothesis on
intimate interplay at the intestinal mucosa. Semin Immunol.
implementation of FMT centers for the treatment of CDI
2007;19(2):70-83.
in adults.14 Moreover, there is no strong evidence-based 4. Zhang F, Luo W, Shi Y, Fan Z, Ji G. Should we standardize
recommendation for the use of FMT in other clinical the 1,700-year-old fecal microbiota transplantation? Am J
conditions, although interesting findings come from the Gastroenterol. 2012;107(11):1755.
application of FMT for the treatment of UC, MS, IBS and 5. Schwan A, Sjolin S, Trottestam U, Aronsson B. Relapsing
more recently, graft-versus-host disease. Indeed, future Clostridium difficile enterocolitis cured by rectal infusion of
homologous faeces. Lancet. 1983;2(8354):845
therapy may include artificial FMT capsules with defined
6. Kelly CR, de Leon L, Jasutkar N, et al. Fecal microbiota
bacterial payloads that target a specific disease state. transplantation for relapsing Clostridium difficile infection in
26 patients: methodology and results. J Clin Gastroenterol.
REFERENCES 2012;46(2):145-9.
1. Brandt LJ. American Journal of Gastroenterology Lecture: 7. Hamilton MJ, Weingarden AR, Sadowsky MJ, et al.
Intestinal microbiota and the role of fecal microbiota Standardized frozen preparation for transplantation of
transplant (FMT) in treatment of C. difficile infection. Am J fecal microbiota for recurrent Clostridium difficile infection.
Gastroenterol. 2013;108(2):177-85. Gastroenterology. 2010;142:490-6.
2. Hooper LV. Do symbiotic bacteria subvert host immunity? 8. Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term
Nat Rev Microbiol. 2009;7(5):367-74. follow-up of colonoscopic fecal microbiota transplant for
CHAPTER 78: Fecal Microbiota Transplantation: Current Indications and Methods 477
recurrent Clostridium difficile infection. Am J Gastroenterol. 12. Mayer EA. Gut feelings: the emerging biology of gut-brain
2012;107(7):1079-87. communication. Nat Rev Neurosci. 2011;12(8):453-66.
9. Sartor RB. Microbial influences in inflammatory bowel 13. Backhed F, Ding H, Wang T, et al. The gut microbiota as an
diseases. Gastroenterology. 2008;134(2):577-94. environmental factor that regulates fat storage. Proc Natl
10. Allegretti JR, Hamilton MJ. Restoring the gut microbiome Acad Sci USA. 2004;101(44):15718-23.
for the treatment of inflammatory bowel diseases. World J 14. Drekonja D, Reich J, Gezahegn S, et al. Fecal microbiota
Gastroenterol. 2014;20(13):3468-74. transplantation for Clostridium difficile infection: a
11. Chassard C, Dapoigny M, Scott KP, et al. Functional systematic review. Ann Intern Med. 2015;162:630-8.
dysbiosis within the gut microbiota of patients with
constipated-irritable bowel syndrome. Aliment Pharmacol
Ther. 2012;35(7):828-38.
SECTION
7
Respiratory System
Clinical Approach to a Patient of Dyspnea ARDS: Recognition and Management
Alok Gupta, Rajat Gupta Niteen D Karnik, Priya Bhate
Syndrome Z Clinical Approach to Solitary Pulmonary Nodule
Devendra Prasad Singh BNBM Prasad
Asthma COPD Overlap Syndrome Challenges in the Management of CAP
Kashinath Padhiary Prashant Prakash, Akhilesh Kumar Singh
Global Warming and its Health Impact Air Pollution and its Health Impact
PS Shankar Vishal Chopra, Prabhleen Kaur, Siddharth Chopra
CHAPTER
79
Clinical Approach to a Patient of Dyspnea
Alok Gupta, Rajat Gupta
aspect of dyspnea. According to data from Institute for sensed by central and peripheral chemoreceptors
Health Metrics and Evaluation (IHME), India (2015), respectively.
among the 10 top causes of mortality in India, ischemic Work effort : Stimulated by respiratory motor
heart disease, COPD, cerebrovascular disease, lower command-sensed by chest wall receptors, muscle
482 SECTION 7: Respiratory System
EF and lower normal stroke volume. Later on due to and pulmonary thromboembolic disease. These
progressive limitation of cardiac output, lactic acidosis conditions cause increase in pulmonary artery pressure
develops and further stimulation of metaboreceptors and which leads to pulmonary receptor stimulation, resulting
chemoreceptors contribute in development of dyspnea. dyspnea manifests as hyperventilation, tachypnea,
Various etiological factors include: tuberculosis, trauma, tachycardia and hypoxemia. Various predisposing risk
malignancy, radiation, connective tissue disorders, etc. factors associated with pulmonary embolism are deep
(Fig. 2). venous thrombosis (DVT) of lower limbs, recent surgery,
obesity, prolonged immobilization, genetic factors, etc.
Diseases of the Pulmonary Vasculature According to WHO, pulmonary hypertension is divided
Ventilation as well as perfusion of pulmonary system both into five categories: PAH, PH due to left heart disease, PH
are important aspects in maintaining the integrated circuit due to chronic lung disease, PH associated with chronic
of breathing. When there is a deficit in the given standards, thromboembolic disease, and a group of various diseases
shown by V/Q mismatch, it leads to the subjective as well that only rarely cause PH, e.g. sarcoidosis, sickle cell
as objective experience of dyspnea. Certain pathologic disease, schistosomiasis, etc. PAH itself is an important
conditions related to pulmonary vasculature are like entity in causation of dyspnea irrespective of varied
primary pulmonary hypertension, pulmonary vasculitis etiology.
484 SECTION 7: Respiratory System
Diseases Related to the Airways the alveolar-capillary gas exchange interface which may
Airway patency and dynamic conduit are essential lead to hypoxemia. During investigative analysis, PFT of
requirements to complete a respiratory cycle constituting these group of patients reveal reduction in vital capacity
active inspiration followed by passive expiration. There (VC) and total lung capacity (TLC), a high normal
are multiple conditions characterized by expiratory Tiffeneau index, and decreased CO diffusion. In patients
airflow obstruction due to chronic inflammation, called over age 65 years, dyspnea is one of the main symptoms
as obstructive lung diseases (Asthma and COPD), of pneumonia suggestive of infective pathology. Among
associated with dynamic hyperinflation of lungs and immunocompromised patients, however, especially
the chest wall with altered dynamic airway functions those who are HIV-positive, increasing shortness of
and reduced tidal volume. Asthma and COPD, both are breath is often the sole presenting symptom of pulmonary
the conditions of ventilation perfusion (V/Q) mismatch infection. Diffuse pulmonary fibrosis from any cause
(initially hypoxia followed by hypercapnia) which usually presents with the gradual onset of dyspnea. Other
worsens later and progress into Type II respiratory signs of diseases causing pulmonary fibrosis, such as
failure. sarcoidosis, scleroderma, and asbestosis, may be present
Diseases of the upper airways involves ears, nose, or it may be idiopathic (Fig. 3).
and throat can also cause dyspnea. In disturbances of
the upper airways, the main symptom associated with Other Diseases
dyspnea is stridor, a high pitched breath sound resulting Mild to moderate anemia is associated with exertional
from turbulence in airflow manifest as inspiratory dyspnea, however there is not any sharp cut-off value of Hb
stridor in supraglottic airway compromise, expiratory in below which anemic patients show symptoms of dyspnea
bronchopulmonary airway compromise, and biphasic and it varies with every other individual. The mechanism
stridor in airway compromise at or just below the glottis. of obesity related breathlessnss is probably due to high
cardiac output condition and reduced compliance of
Diseases Related to the Chest Wall the chest wall causing impairment of ventilatory pump
As we all know respiration is a synchronous effort of function. Cardiovascular deconditioning (poor fitness)
active and passive process. Chest wall abnormality is an is recognized by the early development of anaerobic
important issue regarding the case of dyspnea. There are metabolism followed by generation of lactic acidosis in
some conditions causing stiffening of chest wall such as muscles and stimulation of chemo- and metaboreceptors
kyphoscoliosis and some causing weakness of ventilatory with a very low threshold of exertion.
muscles such as myasthenia gravis or the Guillain-Barré Neuromuscular diseases that can cause dyspnea by
syndrome are associated with increased respiratory ventilatory muscle weakness and resultant increased
efforts. Large pleural effusion when associated with efforts include muscle diseases such as myasthenia,
atelectasis causes dyspnea by stimulation of pulmonary muscular dystrophies, motor neuron diseases such as
receptors and increased work of breathing. amyotrophic lateral sclerosis, and neuropathies such as
Guillain-Barré syndrome.
Diseases Related to the Lung Parenchyma Various psychological and social factors also play an
Interstitial lung diseases are a group of diseases related important role in perception of breathlessness which
to lung parenchyma, originating from infections, chronic causes a large proportion of patients presenting with
inflammatory conditions, occupational exposures, or dyspnea in the hospital settings. There are various groups
autoimmune disorders characterized by decreased of mental illnesses like anxiety disorders, somatization
compliance of lung parenchyma due to increased stiffness disorders, panic disorders or “functional complaints”
and increased work of breathing. In addition, there is which are included in the assessment of dyspnea, it
V/Q mismatch and the thickening and/or destruction of should be kept as diagnosis of exclusion before that
486 SECTION 7: Respiratory System
Figure 3 contd...
CHAPTER 79: Clinical Approach to a Patient of Dyspnea 487
Figure 3 contd...
an extensive somatic work-up to rule out any other That’s why assessment and measurement of severity of
pathological disease has to be performed. Improvement dyspnea in a well planned approach remains a crucial
of dyspnea with distraction or physical exercise may be a part in evaluation and management of the symptom as
clue towards this type of causes (Fig. 4). it is well established that qualitative aspect of difficult
breathing varies with a very wide range among patients.
ASSESSMENT OF DYSPNEA Following questionnaires in conjunction with clinical
Dyspnea is a complex and synthetic sensation that arises methods provide baseline information in assessment of
from multiple sources of signalling of various receptors individuals’ status regarding their illness perception and
rather than from a single neural receptor or mechanism. also set a benchmark to assess course of disease, whether
488 SECTION 7: Respiratory System
Fig. 4: Algorithm of differential diagnosis of dyspnea which are related neither of respiratory nor to cardiovascular system
Abbreviations: PFT, pulmonary fuction testing; ERV, expiratory reserve volume; FRC, fuctional residual capacity; MTx, methotrexate
CHAPTER 79: Clinical Approach to a Patient of Dyspnea 489
the condition is improving or deteriorating, so helpful in —— associated with emotional stress, anxiety, panic
timely intervention in form of management of diseases. condition
Modifie d Me dical Res earch Council (MRC ) Pathogenesis
Visual analogue dyspnea scale (VADS) —— diseases involving mixed cardiac and pulmonary
(wheezes, rhonchi, prolonged expiratory phase, and erythrocyte sedimentation rate, basic metabolic panel,
diminished breath sounds are clues to disorders of the electrocardiography, chest radiography and spirometry.
airways; decreased breath sounds in pleural effusion, If still the diagnosis remains in doubt after these tests,
pneumothorax, etc.; rales suggest interstitial edema or further advanced investigations and other causes like
fibrosis, end inspiratory coarse squeaks in interstitial anxiety related hyperventilation, neuromuscular disease
lung diseases; pleural rub often indicates a pleural or deconditioning should be considered.
effusion; whispering pectoriloquy in lung parenchyma
consolidation, succussion splash in hydropneumothprax, Chest Radiography
etc.). Evidence of conditions related to stasis of blood Chest radiography is important tool in evaluating
flow e.g. deep venous thrombosis may indicate the patients presenting with complain of dyspnea of
presence of pulmonary thromboembolism. suspected pulmonary origin irrespective of other
The cardiac examination include careful inspection physical examination findings. However, it must be kept
and palpation of precordium, apical impulse and beat, in mind that negative chest radiography does not rule
any thrill/heave, signs of elevated right heart pressures out infiltrative lung disease. Chest radiography is also
(jugular venous distention, edema, tender congestive helpful in diagnosing the patients of heart failure in acute
hepatomegaly, accentuated pulmonic component to (prominence of bronchovascular markings) as well as in
the second heart sound); pulmonary hyperexpansion chronic setting (cardiomegaly) and evidence of specific
e.g. emphysema, obesity, or cardiac tamponade are chamber enlargement in valvular heart disease.
the conditions of decreased heart sounds. An S3 or S4 Some findings in chest radiograph may be deceptive,
heart sound may indicate decreased left ventricular specially in pulmonary embolism, which are helpful in
compliance, while murmurs may suggestive of valvular recognition of disease. Skiagram signs in pulmonary
pathology or any septal defect. embolism are following:
On abdominal examination of patient, the paradoxical Fleischner sign: Enlarged pulmonary artery
movement of the abdomen should be noted: inward Hampton hump: Peripheral wedge of airspace
motion in inspiration is a sign of diaphragmatic weakness opacity and implies lung infarction
while pulmonary edema is suspected when there is Westermark sign: Regional oligemia (highest positive
underlying heart disease, electrolyte abnormalities, measurement of lung volumes must be done to confirm
or various systemic disease all possibilities should the diagnosis. To differentiate between intra- or extra-
be considered. A history and ECG suggestive of atrial thoracic obstruction, and fixed or variable obstructive
fibrillation increases the likely diagnosis of congestive disorders, flow-volume loop curves studies must be
heart failure. Prior infarction may be found in patients considered.
with ischemic cardiomyopathy. Other conditions like
obesity, hypothyroidism, COPD, pericardial effusion, Blood and Serum Tests
infiltrative heart disease, etc. show features of low In a patient complaining of shortness of breath, initial
precordial QRS voltages in ECG. Cor pulmonale is defined laboratory testing include a complete blood count,
as an alteration in the structure and function of the right ESR and basic metabolic panel. Anemia may cause
ventricle of the heart caused by a primary disorder of the dyspnoea which is typically aggravated on exertion and
lung, pulmonary vasculature and thoracic cage. It can associated with generalized fatigue, while polycythemia
be suspected by peaked P waves (p-pulmonale >0.25 may indicate chronic hypoxia as seen in COPD patients.
mV) in electrocardiograph, which is helpful for early Abnormalities in white blood cell differentials like
intervention. leukocytosis or neutropenia, may suggest underlying
immune processes or infectious pathology.
Pulse Oximetry and ABG Analysis Brain natriuretic peptide (BNP) is a cardiac
Pulse oximetry is a rapid and effective screening tool neurohormone secreted by myocardium of ventricular
in emergency department for patients presenting with wall in response to tension. In assessment of dyspnea,
unpleasant breathing efforts to detect hypoxia, with plasma N-terminal proBNP concentrations are increased
the advantage of lower cost, easy to use technique, in left ventricular hypertrophy, dilatation, systolic as
non-invasiveness, immediate results and continuous well as diastolic dysfunction, although it has no role in
assessment as compared with ABG sampling. Pulse pulmonary dysfunction. Because of its correlation with
oximetry has become an important tool in the hands of NYHA class, it is a valuable tool in the early diagnosis and
physician. Low SpO2 in a febrile patient may indicate strategic management of patients with heart failure thus
an early ventilatory therapy specially in the settings of reducing mortality. A BNP level more than 100 pg/mL is
conditions like viral pneumonia. taken as the cut-off value as significant for heart failure.
An arterial blood gas (ABG) analysis is a very specific If the clinical analysis suggestive of an acute coronary
and descriptive tool helpful in the initial assessment by syndrome as the cause of dyspnea, serial determination
defining the cause of dyspnea respiratory or metabolic, of cardiac biomarkers viz. troponin (troponin I or
pH of blood acidosis or alkalosis, types of respiratory troponin T) can be used with a high degree of certainty to
failure hypoxic or hypercarbic, etc. In a chronic smoker rule out acute myocardial ischemia (positive predictive
patient with acute dyspnea it is used to detect elevated value 75–80%).
carboxyhemoglobin levels. D-dimer, a marker of fibrin degradation, persist for
about 7–12 days and indicative of recent or ongoing
Spirometry fibrinolysis, has an important role in assessing severity
In evaluation of dyspnea, spirometry should be included of pulmonary embolism and also helpful in defining the
as an early investigation which is performed to diagnose risk of recurrence of thromboembolic disease. However,
airflow obstruction. Obstructive airway disease, such a negative test can help in excluding pulmonary embolus
as COPD, asthma, or chronic bronchitis is indicated condition.
by reading of reduced forced expiratory volume in one
second (FEV1) or FEV1/forced vital capacity (FVC) ratio; ADVANCED STUDIES
while reduced FVC and normal or increased FEV 1/ Additional advanced testing depends on the suspected
FVC ratio is suggestive of restrictive lung disease, but cause of dyspnea includes pulmonary function tests,
492 SECTION 7: Respiratory System
echocardiography, imaging studies like computed appropriate and widely used imaging study is high-
tomography (CT), MRI, ventilation/perfusion scanning, resolution chest CT. HRCT chest generates extremely high
stress testing, direct visualization by bronchoscopy and definition images at multiple section levels of airways,
right or left cardiac catheterization, depending upon lung alveoli, interstitium and pulmonary vasculature
indication. which aids a milestone in diagnostic approach of
dyspnea.
Comprehensive Pulmonary Function Tests CT contrast angiography is an investigation of
In addition to spirometry, pulmonary function tests choice for the diagnosis of pulmonary embolism either
include a wide group of measurements like blood gas acute or chronic. Also it is very helpful in diagnosing
evaluation, lung volume measurement (i.e. RV, FRC various inflammatory disorders or malignancies,
and TLC) and carbon monoxide diffusion in the lung mediastinal disease, interstitial lung disease, or occult
(DLCO). Total lung capacity, which is the max amount emphysema. Cardiac CT is helpful in differentiation of
of air that can fill in the lungs is reduced in patients transmural and subendocardial infarction. Coronary
with restrictive parenchymal disease, but is normal or calcium (Agatston score minimal 0–10, mild 10–100,
increased in air trapping conditions e.g. obstructive lung moderate 100–400 or severe >400) can be determined
disorders like COPD with air trapping. In patients with with the help of cardiac CT scan which is an important
normal spirometry and lung volumes measurement tool to detect coronary artery calcification.
but a reduced DLCO, the possibilities include anemia, Cardiac MRI using gadolinium based contrast agent
early interstitial lung disease, and pulmonary vascular is an important noninvasive tool for the assessment of
disease for which further evaluation should be done. cardiac function and morphology. It is the best current
Neuromuscular causes of dyspnea have a characteristic method to detect size and assess the transmural extent
finding of reduction in maximal inspiratory and of myocardial scar and determine myocardial viability.
expiratory pressures. It is helpful to separate ischemic from nonischemic
cardiomyopathy, diagnosis and follow-up of patients
Echocardiography with congenital heart disease and valvular disease,
Echocardiography is an important and convenient pericardial disease and cardiac tumors.
diagnostic test in assessment of cardiovascular status of Technitium scan, positron emission tomography
patients. With the help of this diagnostic modality, we (PET), single photon emission computed tomography
can identify impaired systolic and/or diastolic function, (SPECT) are the various radionuclide perfusion imaging
ejection fraction, right ventricular and pulmonary studies which rely on sarcolemmal integrity and
artery pressures, wall thickness and compliance, and intact energy production via effective mitochondrial
valvular anomalies. Transthoracic echocardiography function. It is useful to differentiate hibernating viable
is routinely done in established centers in patients myocardium, stunned viable myocardium and scar.
whenever dyspnoea of cardiac origin is suspected. Radiopharmaceuticals used in SPECT study are
Transesophageal echocardiography has higher sensitivity technitium-99m sestamibi, tetrofosmin, thallium 201,
and specificity as compared to previous and used in iodine 123 metaiodobenzylguanidine (MIBG). In PET
special circumstances e.g. aortic dissection, acute study, perfusion tracers used are ammonia (N 13 ),
endocarditis, thromboembolic conditions, valvular heart rubidium (Rb 82 ), etc., while metabolic tracers are
disease, etc. fluorodeoxy-glucose18 (physical half- life 110 min), C11
acetate, C11 palmitate.
Computed Tomography/
Magnetic Resonance Imaging Ventilation/Perfusion Scanning
In dyspnea of uncertain diagnosis and if there is suspicion A ventilation/perfusion (V/Q) scan is a nuclear medicine
of diffuse or localized pulmonary disease, the most scan that uses radioactive material to examine airflow
CHAPTER 79: Clinical Approach to a Patient of Dyspnea 493
(ventilation) and blood flow (perfusion) in the lungs. of ischemic coronary artery disease inspite of medical
Ventilation/perfusion scanning, because of its high therapy. Gallium scanning may be used to identify
sensitivity, should be done to exclude thromboembolic inflammatory, infectious or neoplastic processes.
cause of pulmonary hypertension. A rare patient in whom exact cause of dyspnea remain
Initial ventilation phase of the test, inhalation of unidentified, specialized procedures such as a lung
gaseous radionuclide ( aerosol xenon or technetium biopsy, myocardial biopsy, genetic evaluation may be
DTPA) is followed by the perfusion phase of the test required.
(injection of radioactive isotope technetium macro
aggregated albumin (Tc99m-MAA) intravenously), later MANAGEMENT
on involves consecutive image capturing by gamma The first and most important goal in management
camera. A localized area of decreased uptake, indicative of dyspnea is to correct or lessen the intensity of the
of decreased perfusion with normal ventilation images underlying disease which is, responsible for the symptom
(mismatched defect) suggests a pulmonary embolus or that may help to improve the patients’ quality of life.
blood clot in the lungs. The V/Q scan may be used in some Supplemental O2 should be administered if the patient’s
circumstances as in renal failure, where radiocontrast saturation falls to the significant and worrisome levels
would be inappropriate. It is also an important lung at any stage of physical activity. Various therapeutic
performance quantification tool pre- and post-lung interventions are used to treat dyspnea depending
lobectomy surgery. upon their pathophysiologic mechanisms e.g. exercise
training, O2 supplementation, pharmacologic therapy,
Stress Testing nutrition, inspiratory muscle training, positioning, cold
Cardiovascular stress testing with the virtue of its air application on the face, chest wall vibration, ventilator
capability to determine ventilatory gas exchange and support, continuous positive pressure support, surgical
metabolic oxygen demands like Treadmill testing, stress volume reduction, desensitization, education, cognitive
echocardiography (exercise or dobutamine induced), behavioral approach, etc. Specific management in
dobutamine stress MRI, stress perfusion imaging a dyspneic patient depends upon rapid work-up for
(Technitium scan, Thallium scintigraphy, SPECT, PET cardiopulmonary and other causes, so that definitive
scan) may identify the likelihood of coronary ischemia. It therapy may be instituted early. Yoga and graded exercise
is also a very important tool to assess myocardial viability can now be included as an adjunct to conventional
in pre as well as post-PTCA and post-CABG patients therapy for pulmonary rehabilitation programs for
because of its noninvasiveness. COPD patients as recent studies suggest that it helps by
reducing dyspnea, fatigue and pulse rate, and improving
Invasive Testing functional performance and peripheral capillary SpO2.
Bronchoscopy, together with bronchio-alveolar lavage
or biopsy, is now a routinely available tool to identify CONCLUSION
malignancy, interstitial lung diseases, sarcoidosis, Dyspnea is the highly unpleasant experience of
to confirm typical or atypical infectious processes breathlessness experienced by patients due to varied
like fungal infections, etc. Diagnosis of pulmonary pathologies, such as respiratory, cardiovascular, both
arterial hypertension is established with the help of cardiorespiratory, metabolic and neuromuscular
right heart catheterization, which is a definitive tool diseases, mechanical causes, and panic disorder.
to test the vasoreactivity of the pulmonary circulation Because of the highly subjective nature of complaint,
and assess the hemodynamic impairment severity. the clinician confronts the main difficulty, whose
Coronary angiography may be needed for diagnostic task is to determine the diagnosis by ruling out other
and therapeutic intervention in symptomatic patients possible differentials, judge the severity of the underlying
494 SECTION 7: Respiratory System
condition and start an appropriate and rational treatment 5. Fedullo A, Sinburne A, McGuire-Dunn C. Complaints of
for the benefit of patients’ life as soon as possible. breathlessness in the emergency department. NY State J
Med. 1986;86:4-6.
Treatment of the primary cause of dyspnea is essential,
6. Gillespie D, Staats B. Unexplained dyspnea. Mayo Clinic
but despite optimum treatment, patients often continue Proceedings. 1994;69(7):657-63.
to suffer from dyspnea and the associated decrease in 7. L i g h e z a n , D a n i e l F, et a l . Ac u te d y s p n e a : Fro m
quality of life. To improve and optimally target, the best pathophysiology, evaluation to diagnosis. TMJ. 2006;56:n.
possible approach of managing a patient of dyspnea and 8. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J,
better understanding of the underlying mechanisms is Loscalzo J. eds. Harrison’s Principles of Internal Medicine,
19th Edition. New York, NY: McGraw-Hill; 2016.
necessary because “one size does not fit all”.
9. Michelson E, Hollrah S. Evaluation of the patient with
shortness of breath: an evidence based approach. Emerg
BIBLIOGRAPHY Med Clin North Am. 1999;17:221-37.
1. Boyars MC, Karnath BM, Mercado AC. Acute dyspnea: A sign 10. Nishino T. “Dyspnoea: Underlying mechanisms and
of underlying disease. Hosp Phys. 2004;7:23-7. treatment”. BJA. 2011;106(4):463-74.
2. Burki N, Lee LY. Mechanisms of dyspnea. Chest. 2010;138: 11. Parshall MB, Schwartzstein RM, Adams L, et al. An official
1196-201. American Thoracic Society statement: update on the
3. Cinarka, Halit. An evaluation of chronic dyspnea in a mechanisms, assessment, and management of dyspnea.
chest disease clinic. Journal of Pulmonary & Respiratory Am J Respir Crit Care Med. 2012;185:435-52.
Medicine. 2014;4(2):n. 12. Wahls Steven A. Causes and evaluation of chronic
4. Dyspnea. Mechanisms, assessment, and management: dyspnea. Am Fam Physician. 2012;86(2):n.
a consensus statement. American Thoracic Society. Am J
Respir Crit Care Med. 1999;159(1):321-40.
CHAPTER
80
Syndrome Z
Devendra Prasad Singh
have OSA. Sleep apnea is very commonly coupled with activation and inhibition of vagal tone leading to
496 SECTION 7: Respiratory System
OSA correlates with an increased burden of systemic Diagnosis: The gold standard—overnight polysomno
inflammation and higher concentration of hsCRP, IL- gram.
1, IL-8, IL-6, TNF-alfa and ICAM. Sleep apnea severity index is apnea hypopnea index
(AHI).
Cardiovascular Diseases are Associated AHI is the number of apnea and hypopnea per hour
with Higher Incidence of OSA of sleep. Mild OSA–AHI of 5–14 events/h moderate
Epidemiological studies show that OSA is found in OSA–AHI of 5–29 events/h and severe OSA: AHI of
7–10% of general population while 30–83% patients of ≥30 events/h.
hypertension, 30–58% of coronary artery disease and Cardiovascular consequences of Syndrome Z
43–91% of cases of strokes are associated with obstructive
sleep apnea. Therefore OSA should be screened in such OSAs AND HYPERTENSION
patients by sleep studies. Patients of OSA are more prone to develop hypertension.
Wisconsin Sleep Cohort study, the sleep heart health study
DIAGNOSIS OF SYNDROME Z and the nurses health study confirm dose dependent
There are five components of Syndrome Z: OSA, central relationship between severity of sleep apnea and risk of
obesity, hypertension, dyslipidemia and Type-2 diabetes hypertension. OSA occupies the top position in the list
mellitus. of secondary causes of hypertension in JNC-VII. OSA
1. OSA: Diagnosis by characteristic clinical features and is also a very common cause of resistant hypertension.
sleep study. If a patient requires 3 or more antihypertensive drugs
2. Central obesity: Defined by waste circumference with screening for OSA is mandatory. ABPM rules out
ethnic specific values i.e. for south Asians or Indians: diagnosis of spurious hypertension like white-coat and
≥90 cm for males and ≥80 cm for females. also is a method of choice for detecting true resistant
3. Hy p e r t e n s i o n : B e s t m e t h o d i s a m b u l a t o r y hypertension.
BP monitoring (ABPM) which displays not only
“nondipping” pattern but also detects true resistant OSA and Cardiovascular Disease
hypertension. There are robust bodies of evidence to confirm that there
4. Dyslipidemia: By laboratory diagnosis—Serum are more incidences of fatal and nonfatal MI in patients
triglyceride >150 mg/dL and HDL <40 mg/dL in male of OSA. OSA is also associated with higher mortality
and <50 mg/dL in female. and cardiovascular events and it is well correlated with
5. T2DM: By fasting blood sugar >100 mg/dL. severity of OSA i.e. AHI. Prognosis of congestive heart
failure also increases when associated with OSA. There
OSA: CLINICAL FEATURES is more incidence of stroke in severe OSA. Therefore
Nocturnal symptoms: Snoring is the most frequent association of OSA with metabolic syndrome makes
symptom of OSA, witnessed apnea. Syndrome Z more deadly and more fatal.
Daytime symptoms : During daytime patients
Treatment of OSA: The main objectives of treatment
complain of fatigue, morning headache, decreased
of OSA is to reduce the cardiovascular morbidity and
vigilance, excessive daytime sleepiness (EDS) and
mortality and correct the metabolic abnormalities.
forgetfulness. EDS is assessed by Epworth Sleepiness
OSA is treated by life style modification, continuous
Scale (ESS).
positive airway pressure (CPAP), oral appliances and
Physical examination : Reveals obesity, neck
surgery.
circumference >17 cm in male and >15 cm in
female, retrognathia or micrognathia and class III/IV Continuous Positive airway pressure (CPAP): CPAP is the
Mallampati score. standard and effective therapy of OSA. The device uses
498 SECTION 7: Respiratory System
3. Foster GD, Sankers MH, Miliman R, Zammit G, Borradaile 6. Reid PT, Innes JA. The sleep-disordered breathing.
KF, et al. Obstructive sleep apnea among obese patients Davidson’s Principles & Practice of Medicine, 22nd Edition,
with type 2 diabetes. Diabetes Care. 2009;32:1017-9. Churchill Livingstone, Elsever. 2014. pp. 725-7.
4. Macy Mei-sze Lui, Jamie Chung-mei MM Lam, et al. 7. Wellman A, Redline S. Harrison’s Principles of Internal
C-reactive protein is associated with obstructive sleep apnea Medicine. 19th Edition, McGraw Hill Education. 2015;1723-7.
independent of visceral obesity. Chest. 2009;135:950-6. 8. Wilkos I, McNamara SG, Collins, Fl. et al. “Syndrome Z”: the
5. Paul E. Peppard, is obstructive sleep apnea a risk factor for interaction of sleep apnea, vascular risk factor and heart
hypertension—Differences between the Wisconsin sleep disease. Thorax. 1998;53(Suppl):525-8.
cohort and the sleep heart health study. J Clin Sleep Med. 9. Young T, Finn L, Preppard PE, Szklo-Coxe, M, Austin D, et al.
2009;5(5):404-5. Sleep disordered breathing and morality; eighteen-year follow-
up the Wisconsin sleep cohort, Sleep. 2008;31:1071-8.
CHAPTER
81
Asthma COPD Overlap Syndrome
Kashinath Padhiary
and >50% in patients over 80 years. ACOS accounts for CLINICAL FEATURES
15–25% of cases of COPD.5 Pooled prevalence of ACOS in Often it starts as breathlessness and wheezing and later
COPD population has been found out to be 27% and 28% on they develop cough and sputum production. Chest
in population and hospital-based studies respectively.4 tightness at late night or early morning is also complained
by some. Like bronchial asthma or chronic bronchitis
PATHOGENESIS episodic increase in symptoms are observed. The
Eosinophilic inflammation is mainly seen in asthma. frequency of acute exacerbations is more in ACOS than
Asthmatics who becomes smokers develop neutrophilic in COPD patients. Very quickly their respiratory function
inflammation of the small airways, such inflammation gets compromised forcing them for hospitalisation.
are resistant to bronchodilator inhalation. Long-standing Examination shows lengthening of expiratory time,
nonsmoker asthmatics also develop remodeling of the diffuse ronchi (wheezing), diffuse crackles. Evidence
small airways causing partial response to bronchodilator, of temporary air trapping can also be observed during
a feature of ACOS. About 16% of asthmatics develop acute exacerbations. Peripheral eosinophilia and
overlap syndrome after 20 years of follow-up. sputum eosinophilia can be detected as evidence of
bronchial hyper-responsiveness.
CONTRIBUTING FACTORS Like asthma or COPD, there will be no much changes in
Age: Very rare below 40 years of age and above 85 X-ray chest. However, alteration of pulmonary functions
years of age. In certain studies, it is found that the can be noticed. FEV1, FEV1/FVC and PEFR are reduced.
incidence of ACOS is about 1.6% in the age group of In acute conditions, oxygen saturation may be reduced
20–44 years of age, 4.5% in the age group of 60–85 (clinical evidence is cyanosis). Some reversibility of the
years of age. airway obstruction can be demonstrated. Reversibility
Sex: Women are at a greater risk of suffering from is not as complete as in asthma. 68% had exertional
ACOS. dyspnea (COPD feature), 63% about had paroxysmal
Smoking status: Smokers and ex-smokers are at dyspnea with wheezing (asthma feature), 72% had
greater risk. Both active and passive smoking increase chronic productive cough (COPD feature).
the chances of developing ACOS. However, vehicular
smoke is not associated with higher risk of developing DIAGNOSIS
ACOS, though it contributes to develop COPD. Symptoms of airway obstruction and non-reversible
Pre-existing respiratory illness: It is not yet certain that airway inflammation in middle-aged individuals are the
in ACOS the two entities just exist together or itself hallmark of ACOS. Though objective evidence of both
is an independent entity. But it is postulated that in can be established but it is not feasible to use them in
some cases it starts as asthma and the COPD part gets daily practice. Different biomarkers have been utilised
added to it later on, particularly if these people start to detect ACOS.6 These are-Surfactant protein-A (SP-A),
smoking. Long duration of asthma also predisposes soluble receptor for advanced glycation end products
to develop ACOS. (sRAGE), myeloperoxidase (MPO) and neutrophil
Higher frequency of ACOS was observed in patients gelatinase-associated lipocalin (NGAL). Out of them, the
having history of pulmonary tuberculosis and first two are derived from pneumocyte and the latter two
bronchiectasis. from neutrophil. Only NGAL assessment has been useful
Many comorbid factors have been tried to be co- to detect ACOS. Researchers have tried to find objective
related to ACOS. Only hypertension, obesity, diabetes evidence for ACOS by measuring fractional exhaled nitric
and metabolic syndrome had some correlation. oxide (FENO) and blood level of IgE. FENO is considered
Features of allergic rhinitis were more common in as a biomarker of asthma like airway inflammation, and
asthma than ACOS (59% vs 53%). elevated IgE indicates presence of atopic factors. Usually,
502 SECTION 7: Respiratory System
the cut off value of FENO is taken as >35 ppb. And that of acute exacerbations and hospitalizations. They have
IgE is 173 IU/mL. Presence of these factors also indicates a worse quality of life in comparison to either asthma
that these patients will be benefited by ICS. Taking 35 or COPD alone. 9 Acute exacerbations are 2–3 times
ppb as the cut-off value the incidence of ACOS in COPD more frequent than COPD cases. Exacerbations
patients is 16.3%. GINA and GOLD both have approved increase the morbidity, mortality and hospital stay
use of these two biomarkers to detect ACOS patients. and compromises the quality of life. However, 6 MWD
Different researchers have given different guidelines (6 minutes walking distance) was not significantly
for diagnosis. A Spanish study 7 gave two major and different in any of the three group. Frequency of hospital
two minor criteria. The major criteria are positive admission, ICU admission, and attendance of emergency
bronchodilator test and sputum eosinophilia. Minor ward were higher than COPD cases.10 ACOS patients
criteria are high IgE level in serum and moderately required higher costs (5 times more) of treatment in
positive bronchodilator test (FEV1 >12% and FEV1 >200 comparison to asthma. Health-related quality of life was
mL increase after inhalation of bronchodilator). These lower than both COPD and asthma.
criteria have not been accepted widely.
Some important factors for diagnosis are: TREATMENT
—— Major: Age >40, raised IgE, smoking history, Inhalational corticosteroids (ICS) are essential for the
post-bronchodilator FEV1<80%, FEV1/FVC<70% treatment of these cases. In addition to that LABA are
—— Minor: > or = 15% rise or . >or = 12% and or = 200 useful. Long-acting muscarinic antagonists (LAMA)
mL increase following bronchodilator inhalation. such as tiotropium bromide are also useful. Leukotreine
Increase in peak expiratory flow rate by 20% or more. receptor antagonist, oral corticosteroids and SABA
Presence of bronchial hyper-responsiveness can be are also beneficial in some cases. Even theophylline
delineated. As challenges to different agents can lead derivatives can also be used. Briefly, it can be told that
to very severe attacks of bronchospasm, these are rarely treatment is combination of COPD and asthma.
practiced. However histamine, mannitol, hypertonic
saline, adenosine and methacholine can be used to REFERENCES
detect bronchial hyper-responsiveness (BHR). 1. Zeki AA, Schivo M, Chan A, et al. The asthma-COPD overlap
syndrome: A common clinical problem in elderly. J Allergy
BODE index (Body mass index, airflow obstruction,
(Cairo). 2011;2011:861-926.
dyspnoea, exercise capacity) has also been utilized to 2. Asthma, COPD and Asthma: COPD Overlap syndrome
diagnose these ailments. BODE index was higher in (ACOS) Global initiative for Asthma (GINA) 2014. http://
ACOS group than COPD group. www.ginasthma.org/.
Spirometry, eosinophil count and total IgE have 3. de Marco R, Pesce G, Marcon A, et al. The coexistence
of asthma and chronic obstructive pulmonary disease:
been utilized to help the diagnosis. ACOS group had
Prevalance and risk factors in young, middle-aged and
less eosinophil count and higher IgE value compared to
elderly people from the general population. PLos One
asthma group. 2013;8:e62985 (PubMed).
High-resolution CT can be utilized to find out the 4. Alshabanat A, Zafari Z, Albanyan O, et al. Asthma and
ACOS patients from COPD patients.8 COPD overlap syndrome (ACOS): A systematic review and
meta-analysis. https://doi.org/journal.pone.0136065
5. Skold CM. Remodelling in asthma and COPD—differences
PROGNOSIS
and similarities. Clin Respir J. 2010;(Suppl 1):20-7.
People above 85 years of age rarely show ACOS though 6. Iwamoto H, Gao J, Koskela J, et al. Differences in plasma
COPD is common. This means the overall outcome and sputum biomarkers between COPD and COPD-asthma
of ACOS is worse than COPD. They get more frequent overlap. Eur Respi J. 2014;43:421-9. (Pubmed)
CHAPTER 81: Asthma COPD Overlap Syndrome 503
7. Soler–Cataluna JJ, Cosio B, Izquierdo JL, et al. Consensus 9. Kauppi P, Kupiainen H, Lindqvist A, et al. Overlap syndrome
document on the overlap phenotype COPD-asthma in COPD. of asthma and COPD predicts low quality of life. J Asthma.
Arch Bronchopnemol. 2012;48:331-7. 2011;48(3):279-85.
8. Hardin M, Silverman EK, Barr RG, Hansel NN, Schroeder JD, 10. Menezes AM, Montes de Oca M, Perez-padilla R, et al.
Make BJ, et al. The clinical features of the overlap between Increased risk of exacerbation and hospitalisation in
COPD and asthma. Respir Res. 2011;12:127. subjects with an overlap phenotype: COPD Asthma. Chest.
2014;145(2):297-304.
CHAPTER
82
Global Warming and its Health Impact
PS Shankar
Combustion of fossil fuels, including coal, petroleum ailment and injuries. It is associated with an increased
products and natural gas has resulted in global warming financial loss.4
at an alarmingly increasing speed. There is emission of
green house gases, airborne particulate matter, nitrogen SURFACE TEMPERATURE
oxide, and sulphur dioxide into the atmosphere. During the past hundred years from 1906 to 2005, average
surface temperature of the globe has risen by 0.75 degree
HEALTH IMPACT Celsius. During the corresponding period the global sea
Global warming has posed a public health challenge level has risen on an average by approximately 2 mm
due to its impact on health of the people. 1 Montreal per year. The green house effect is predominantly due to
Protocol of 1987 gave new directions in safeguarding the high concentration of carbon dioxide (CO2). The level of
planet by phasing out chlorofluorocarbons (CFCs) and CO2 has risen from 280 to 360 parts per million (ppm).
related compounds which were causing depletion of the This is evident since the industrial revolution, and it
ultraviolet (UV) rays-absorbing ozone.2 has occurred predominantly due to the burning of fossil
There is deforestation and burning of fossil fuels due to fuels. The climate is changing at a faster rate in the recent
human activities. They are bringing about a change in the years than in any period during the last millennium.5
concentration of atmospheric constituents or properties The United Nations Inter-governmental Panel
of the earth’s surface that facilitate absorption or scatter on Climate Change (IPCC) of the United Nations
of radiant energy. 3 The result is markedly increased Environmental Program (UNEP) and the World
production of anthropogenic green house gases such as Meteorological Organization (WMO) visualized that if
carbon dioxide, methane and nitrous oxide. In addition current trends continue, sea level will rise between 18
there is emission of noxious particles and pollutant gases and 59 cm and global temperature between 1.8°C and
such as sulphur dioxide, carbon monoxide and nitrous 4.0°C by the end of this century. The concentration of
oxide. Warm air and raised atmospheric temperatures carbon dioxide is likely to increase from 540 ppm to
cause rapid water evaporation of surface water, increased 970 ppm by 2100 if there is an unhindered use of fossil
humidity and greater amount of precipitation, resulting fuel. Decreasing snow cover, melting of polar icecaps,
in heat waves, hurricanes, floods and droughts and their receding glaciers, and raising temperature of sea water
attendant physical effects.3 They affect the health of the have already caused detectable rise in the sea level. All
people and there is an increase in the number of patients these events have serious consequences on the health
getting admitted to the hospital for treatment of their of people living in coastal regions. It brings the areas of
CHAPTER 82: Global Warming and its Health Impact 505
towns and cities under water, makes the sewage systems affect food production. Its consequences are mostly
inoperable, salinates the rice fields, and affects hygiene indirect leading to poor nutritional status, starvation
and health in the region. and undernourishment. Water is scarce and very little
Any small alteration in global temperatures can is left over for washing. The hygiene is poor. There is an
bring about relatively large changes in the frequency of increased incidence of diarrheal diseases, micronutrient
extreme temperatures. High temperatures are associated deficiencies, scabies, conjunctivitis and trachoma,
with increased deaths of elderly and persons with pre- undernourishment, and increased susceptibility to
existing diseases. Heat waves causing higher average infection. Fungal growth is facilitated by an increase in
ambient air temperatures not only increase mortality soil temperature. Dry conditions are associated with wild
from cardiovascular, cerebrovascular and respiratory fires and smoke. Rising sea levels inundate low-lying
diseases, but also cause air pollution. areas leading to environmental exodus and salinate the
Extremes of temperature cause physical injury. There land.
is poor nutritional status and an increased incidence of
respiratory and diarrheal diseases due to overcrowding, OZONE
disruption of water supplies and choked sewage system. There is an increase in ground level ozone formed
There is an increased chance of occurrence of floods chemically from temperature dependent precursor
due to an increased evaporation of ocean water. It leads pollutants (nitrogen oxide, volatile organic compounds
to occurrence of floods, which is associated with an from power plant emission and automobile exhaust,
increased number of injuries and drowning. This is felt in presence of light and higher temperature. Ozone
immediately in the community. As days pass, there is decreases pulmonary function, irritates conjunctiva
an acute shortage of clean drinking water. There is an and mucosa of the upper respiratory passages, induces
increased chance of contamination of water leading to asthma and pulmonary edema.7 Rise in the local air
spread of diseases such as cholera and hepatitis A and pollution and warm weather conditions act as risk
hepatitis E. Ultimately the increased salination leads factors for an increased incidence of chronic obstructive
to the destruction of the crop lands leading to marked pulmonary disease (COPD).
reduction in the output of agricultural products. It causes Experimental studies have shown that a higher
under-nutrition and malnutrition in the community. concentration or carbon dioxide leads to an increased
production of pollens and ragweed (Ambrosia
EL NINO artemisifolia).
The El Nino event causes shift of warm equatorial water When the level of CO2 doubles from 300 to 600 ppm,
from the Western to Eastern Pacific ocean. This occurs there is likelihood of a four-fold increase in the level of
periodically every 3–7 years leading to extremely dry this highly allergic pollen.8 Global warming increases
conditions, droughts and devastating fires in many the concentration of radon in the lower layers of the
regions of the World and torrential rains and flooding atmosphere.9 Being a source of alpha radiation radon
in other regions.6 There is an increased incidence of is likely to increase the development of bronchogenic
communicable diseases such as cholera and hepatitis carcinoma.
A due to drinking of contaminated water, leptospirosis
due to contact with contaminated water from excreta DISEASES
of rodents, respiratory infections from overcrowding of The ecology of many arthropod vectors responsible
flood survivors or from overgrowth of molds in flooded for transmission of diseases to human beings has
houses.3 changed due to global warming. There is emergence
Global climate change brings about changes in or resurgence of different types of infectious diseases.
hydrologic cycle (floods and droughts). Droughts Among them diseases that are indirectly transmitted
506 SECTION 7: Respiratory System
stand distinctly apart. They require either a vehicle for Heavy rainfall can increase risk of water-borne disease
transfer from host-to-host (e.g. water- and food-borne outbreaks. Fecal contamination of drinking water leads
diseases) or an intermediate host or vector as part of to cholera epidemics. There is contamination of drinking
their life cycle. Arthropod vectors such as mosquitoes, water due to discharge of the excess waste water directly
flies, ticks or fleas play an important role in spread of into surface water bodies. It results in infections with
many diseases. The insects being cold-blooded, any Escherichia coli and Campylobacter jejuni.11 There can
slight change in temperature can bring about significant be occurrence of contamination of drinking water by a
biologic effect on transmission of diseases. Warmer protozoan, Cryptosporidium parvum, and it may lead to
climate is associated with overproduction of mosquito, an increased morbidity and mortality.12 This is especially
sandfly and tick vectors, their biting and transmission noted in developed countries. There is an increased risk
of diseases such as malaria, dengue, leishmaniasis, Rift of cholera outbreaks in the land in the vicinity of the
Valley fever causing hemorrhagic fever syndrome and great lakes of Africa.13 N meningitides, the pathogen of
tick-borne Lyme disease.10 Hot summer months facilitate Meningococcal meningitis is carried by dust particles,
the spread of West Nile virus through bites of mosquitoes and it occurs during dry seasons. There is lengthening
across Western hemisphere. Unsafe domestic water of dry periods due to El Nino effect. It is associated
storage practices in unusually warm and dry conditions with a wider spread of pathogens in African countries.
facilitate viral infection such as chikungunya in the Aedes
Their epidemics are striking once in 5–10 years.14 Winter
mosquitoes.
temperatures in Lima, Peru are increased due to El Nino
Anopheles mosquitoes do not have any control over
event. The temperatures are increased by more than 5 °C
their temperature regulation system. A rise in humidity
above normal. It is noted that there is increased number
or ambient temperature is associated with a sustained
of admissions in the hospital for childhood diarrhea by
influence on their activity, dispersal and spread. Malaria
8% for every degree centigrade rise in air temperatures
which has a great potential to spread in the tropical
above normal.15
zones, will increase its area of activity to larger areas due
to climate change. Among tropical diseases, Malaria is
FUTURE
an extremely climate-sensitive disease. Dengue fever
Human population is threatened with health hazards in
is spread by the bites of mosquito, Aedes aegypti. The
the coming years due to climate change. This is due to
mosquito has widened its geographical boundaries in
tropical regions. Aedes is strongly influenced by climate disruption of water and food supplies. In addition, there is
changes that include variability in temperature, moisture an increased spread of vector-borne diseases. There is an
and solar radiation. Any small rise in temperature urgent need for reduction of greenhouse gas emissions.
facilitates viral introduction into a susceptible community, It is only possible by reducing combustion of fossil fuels,
in turn causing an increased chance of an epidemic. and development of renewal energy technology. There is
The ambient temperature influences the spread and need to establish stations equipped with remote sensing
activities of the sandflies, vectors of leishmaniasis. Heavy (RS) and geographic information systems (GIS) to
rainfall is associated with an explosion of the mouse monitor sea-level rise and extreme weather conditions.
population which may increase the chances of outbreak In addition public health education programs are to
of Hantavirus pulmonary syndrome (HPS). Extreme be held regularly. Ongoing preventive measures, and
flooding with an increased population of rodents can control measures for vector borne diseases have to be
lead to outbreak of leptospirosis. continued. Every attempt has to be made to improve the
Successful stabilization of carbon dioxide emissions, nutritional status of the population.4
vector-control program, relocation of human population Changes in climate and ecology affect health status of
and vaccination are to be undertaken to control such the population. Instead of concentrating the fight against
diseases. a single agent of the disease, the preventive measures
CHAPTER 82: Global Warming and its Health Impact 507
should be of broad range affecting the environment from production of common ragweed as a test case. World
different angles.16 Resource Review. 2000;12:449-57.
9. Cuculeanu V, Iorgulescu D. Climate change impact on
the radon activity in the atmosphere. Romanian Jour
REFERENCES Metereology. 1994;1:55-8.
1. Patz JA, Eingelberg D, Last J. The effects of changing weather 10. Yoganathan D, Ram WN. Medical aspects of global warming.
on public health. Ann Rev Public Health. 2000;21:271-397. Am J Ind Med. 2001;40:199-210.
2. Staropoli JE. The public health implication of global 11. Hrideu SE, Payment P, Huck PM, et al. A fatal water-borne
warming. JAMA. 2002;287:2282. disease epidemic in Walkerton, Ontario, comparison with
3. Patz JA, Kaliq M. Global climate change and health in other water-borne outbreaks in the developed world. Water
challenges for future practitioners. JAMA. 2002;287: Sci Technol. 2003;47:7-14.
2283-4. 12. MacKenzie WR, Hoxie NU, Proctor ME, et al. A massive
4. Gross J. The severe impact of climate change on developing outbreak in Milwaukee of Cryptosporidium infection
countries. Med Glob Surviv. 2002;7:96-100. transmitted through the public water supply. N Engl J Med.
5. IPCC, Climate change 2007, impacts, adaptation and 1994;33:161-7.
vulnerability: contribution of working group II to the fourth 13. WHO Cholera in 1997. Weekly Epidemiological Record.
assessment report of the IPCC. Cambridge (UK), Cambridge 1998;73:201-8.
University Press, 2007. 14. Hart CA, Cuesvas LE. Meningococcal disease in Africa Ann
6. Patz J. Public risk assessment linked to climatic and Trop Med Parasitol. 1997;91:777-85.
ecological change. Human and Ecological assessment. 15. Checkley W, Epstein LD, Gilman RH, et al. Effect of El
2001;7:1317-27. Nino and ambient temperature on hospital admissions
7. McConnell R, Bechane K, Gilliand F, et al. Asthma in for diarrheal diseases in Peruvian children. Lancet.
exercising children exposure to ozone: a cohort study. 2000;355:442-50.
Lancet. 2002;359:386-91. 16. Patz JA, Uejio CK, Gibbs HK. Disease emergence from
8. Ziska LH, Caulfield FA. The potential influence of rising global climate and land use change. Med Clin N Am.
atmospheric carbon dioxide (CO2) on public health: pollen 2008;92:1473-91.
CHAPTER
83
ARDS: Recognition and Management
Niteen D Karnik, Priya Bhate
INTRODUCTION of 200 and 300. SpO2 is not always concordant with PaO2
Acute respiratory distress syndrome (ARDS) was first (e.g. having SpO2 of 100% on FiO2 of 1.0 would be severe
recognized in 1967. Mortality increases with severity and ARDS using S/F ratio regardless of PaO2). Extravascular
ranges from 26% to 58%. Prompt diagnosis and optimal lung water (EVLW) measured using transpulmonary
treatment of ARDS is life-saving. Diagnosis is made thermodilution techniques may help to diagnose ARDS.
when all four criteria of the Berlin definition (Table 1) Increased EVLW is associated with higher mortality in
are met. The 2012 Berlin definition is compared to the ARDS. However EVLW is expensive, invasive and not
1994 American-European consensus criteria (AECC) easily available.
definition in Table 1. Conditions that mimic ARDS (Table 3) should be
excluded.
RECOGNITION CPE is the chief differential for ARDS (Table 4).
ARDS should be suspected in a patient with new onset However, cardiac dysfunction and ARDS may coexist.
respiratory distress or within one week of a known
clinical insult (Table 2). Recognizing high risk patients MANAGEMENT
and intervening with a conservative fluid strategy or The management of ARDS involves the following aspects:
Treatment of underlying medical and surgical
lung-protective ventilation may decrease risk of ARDS.
Lung Injury Prediction Score (LIPS), biomarkers (Plasma disorders (e.g. tropical infections, sepsis, aspiration,
angiopoietin-2, IL-6, TNF α) or genetic markers (e.g. ACE trauma, etc.)
gene polymorphism) may aid recognition. Supportive treatment of the critically ill patient (e.g.
and arterial blood gas analysis (ABG) are mandatory Numerous interventions (Table 5) have been studied
investigations. Echocardiography is needed to exclude but only some are recommended (Table 6) in ARDS.
hydrostatic edema.
When ABG is unavailable/difficult, the ratio of Low Tidal Volume Ventilation
oxyhemoglobin saturation using pulse-oximetry (SpO2) Conventional MV leads to cyclic overdistension causing
to FiO2 (S/F ratio) may be used instead of PaO2/FiO2 (P/F ventilator induced lung injury (VILI). Inflammatory
ratio). S/F ratios of 235 and 315 correlate with P/F ratios mediators released due to VILI can extend the
CHAPTER 83: ARDS: Recognition and Management 509
zz Cardiomegaly
30 cm H2O vs recruitment maneuvers (RM), higher PEEP and Pplat< 40 cm H2O: found improved
oxygenation, decreased need for rescue therapy, no mortality benefit. (2008)
zz Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress
syndrome (EXPRESS) trial compared lower PEEP vs higher PEEP-found more ventilator free days (VFD)
and more organ failure-free days with higher PEEP, no difference in mortality. (2008)
zz Meta-analysis by Briel et al compiled data from the above 3 trials (2299 patients): improved survival
investigators: improved survival of 71% with ECMO for influenza A (H1N1) ARDS. (2009)
Prone positioning zz Meta-analysis by Gattinoni et al: prone positioning reduced mortality in severe ARDS by ~10% but
can cause complications. (2010)
zz Prone positioning in severe acute respiratory distress syndrome (PROSEVA) study: early prone-
Abbreviations: ATS, American Thoracic Society; ESICM, European Society of Intensive Care Medicine; SCCM, Society of Critical Care Medicine;
KSCCM, Korean Society of Critical Care Medicine; KATRD, Korean Academy of Tuberculosis and Lung Diseases
a
Strong (1) and Weak (2) recommendations based on high (A), moderate (B) and low (C) quality of evidence.
inflammatory response of ARDS. Low tidal volume —— Plateau pressures (Pplat): ≤ 30 cm H2O
ventilation (LTVV) can reduce VILI. Procedure for If Pplat> 30 cm H O: decrease VT by 1 mL/kg
2
administering LTVV (based on ARDS net protocol): (minimum = 4 mL/kg).
Calculate PBW (predicted body weight) If Pplat< 25 cm H O and VT< 6 mL/kg, increase
2
Males = 50 + 2.3 [height (inches)-60] VT by 1 mL/kg until Pplat> 25 cm H2O or VT
Females = 45.5 + 2.3 [height (inches)-60] = 6 mL/kg.
Set initial tidal volume (VT) = 8 mL/kg PBW, initial
If Pplat< 30 and breath stacking occurs: may
Higher PEEP CO 2 at lower blood flow rates than that required for
Higher PEEP improves recruitment, reduces lung stress, oxygenation, enabling ultra-lung protective ventilation
and prevents atelectrauma. Potential risks include (VT=4 mL/kg). The possible benefit of this strategy needs
injury like pneumothorax and pneumomediastinum evaluation.
from end-inspiratory alveolar overdistention, increased
intrapulmonary shunt, increased dead space, and higher CONCLUSION
pulmonary vascular resistance. Higher PEEP can be The last decade has seen emergence and recognition
administered using various strategies. In EXPRESS study, of ARDS as a major cause of morbidity and mortality
PEEP was kept as high as possible so that Pplat remained in ICUs worldwide. Innovate strategies have evolved
28–30 cm H2O. In ALVEOLI study, it was based on the to improve the survival of ARDS patients and decrease
Table 7. their length of stay on ventilator and in ICUs. The use
of ECMO to improve the survival of tropical infections
Recruitment Maneuvers related ARDS in the developing world could be a major
future challenge.
Recruitment maneuvers (RMs) are transient elevations
in applied airway pressures to open/recruit collapsed
BIBLIOGRAPHY
alveoli. RMs cause short-term physiological benefits
1. Aokage T, Palmér K, Ichiba S, Takeda S. Extracorporeal
(reduced intrapulmonar y shunt and increased membrane oxygenation for acute respiratory distress
pulmonary compliance). Complications include syndrome. J Intensive Care. 2015;3:17.
hemodynamic compromise and barotrauma. 2. Boyle AJ, Mac Sweeney R, McAuley DF. Pharmacological
treatments in ARDS; a state-of-the-art update. BMC Med.
Extracorporeal Membrane Oxygenation 2013;11:166.
3. Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter
Extracorporeal membrane oxygenation (ECMO) is SD, et al. Higher vs lower positive end-expiratory pressure
indicated in severe ARDS for refractory hypoxemia or in patients with acute lung injury and acute respiratory
severe respiratory acidosis despite optimal conventional distress syndrome: systematic review and meta-analysis.
measures. ECMO oxygenates blood and removes carbon JAMA. 2010;303:865-73.
dioxide (CO 2 ) using an extracorporeal membrane 4. Cho YJ, Moon JY, Shin ES, Kim JH, Jung H, Park SY, et al.
Clinical practice guideline of acute respiratory distress
oxygenator that consists of a blood chamber and a gas
syndrome. Korean J Crit Care Med. 2016;31:76-100.
chamber separated by a semipermeable membrane. Gas 5. Davies A, Jones D, Bailey M, et al. Extracorporeal membrane
exchange occurs as venous blood and sweep gas pass oxygenation for 2009 influenza A(H1N1) acute respiratory
along either side of the membrane. Oxygenated blood distress syndrome. JAMA. 2009;302:1888-95.
is returned to a vein (veno-venous ECMO) or an artery 6. Fan E, Del Sorbo L, Goligher EC, et al. An official American
Thoracic Society/European Society of Intensive Care
(veno-arterial ECMO).
Medicine/Society of Critical Care Medicine Clinical Practice
Lower VT and airway pressures than current standard- Guideline: Mechanical ventilation in adult patients with
of-care may reduce VILI. Reduction of VT is limited acute respiratory distress syndrome. Am J Respir Crit Care
by hypercapneic respiratory acidosis. ECMO removes Med. 2017;195:1253-63.
CHAPTER 83: ARDS: Recognition and Management 513
7. Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency 10. Koh Y. Update in acute respiratory distress syndrome. J
oscillation in early acute respiratory distress syndrome. N Intensive Care. 2014,2:2.
Engl J Med. 2013;368:795-805. 11. Matthay MA, Ware LB, Zimmerman GA. The acute respiratory
8. Ferguson ND, Fan E, Camporota L, Antonelli M, Anzueto A, distress syndrome. The Journal of Clinical Investigation.
Beale R, et al. The Berlin definition of ARDS: an expanded 2012;122(8):2731-40.
rationale, justification, and supplementary material. 12. The ARDS Definition Task Force Acute respiratory distress
Intensive Care Med. 2012;38:1573-82. syndrome: the Berlin definition. JAMA. 2012;307(23):2526-
9. Guérin C, Reignier J, Richard JC, et al. PROSEVA Study 33.
Group. Prone positioning in severe acute respiratory 13. Thompson BT, Chambers RC, Liu KD. Acute respiratory
distress syndrome. N Engl J Med. 2013;368:2159-68. distress syndrome. N Engl J Med. 2017;377:562-72.
CHAPTER
84
Clinical Approach to Solitary
Pulmonary Nodule
BNBM Prasad
TABLE 1: Causes of SPN etiology differs in various studies depending upon the
zz Developmental type of population studied. High incidences have been
—— Bronchial cyst
reported among patients who underwent low dose
—— Bronchial atresia with mucoid impaction
—— Sequestration
CT scan for cancer screening with prevalence of SPN
zz Vascular
ranging from 12% to 51%. 8, 9 Similarly surgical studies
—— AV malformation have observed high incidences of malignancy because
—— Hematoma
surgical approach was mandated by high clinical
—— Pulmonary infarction
—— Round pneumonia
examination are initial steps that offer significant clues to
—— Dicrofilariasis a diagnosis. Most of the SPN discovered during routine
—— Echinococcal cyst
chest radiography remain asymptomatic at the time of
Inflammatory (noninfection) detection. Young individuals under the age of 30 years,
—— Rheumatoid nodule
—— Paraffinoma
otherwise asymptomatic and nonsmokers are unlikely
—— Sarcoidosis to have malignancy. Most of the benign SPNs upto
—— Wegener’s granulomatosis
90%, are granulomatous in origin and may manifest
Tumor with constitutional or systemic symptoms. History
Malignant
—— Metastasis-breast, colon, kidney, head and neck, etc. of travel to endemic areas, low grade fever, human
—— Primary lung cancer immunodeficiency virus (HIV) infection, hemoptysis,
—— Carcinoid
—— Pulmonary lymphoma
and chest pain may be present. Tuberculosis is common
—— Pulmonary sarcoma in many parts of the world including India and forms
—— Plasmocytoma
an important differential diagnosis. Every effort should
Benign
—— Hamartoma
be made to rule out tuberculosis before labeling SPN
—— Chondroma as malignant. Rarely tuberculosis and malignancy
—— Teratoma
may coexist especially in high risk groups. History of
—— Lipoma
with the age and majority of cases detected are between the borders of the nodule and study the relationship
4 th and 6 th decades of life. Bronchogenic carcinoma of the nodule with adjacent structures such as vessels
is the most common cause of malignant SPN. Other and the pleura. 12 While studying the SPN in various
malignant conditions though rare include carcinoid CT sections, attention should be given to size, shape,
tumor, sarcoma, solitary metastasis and lymphoma. location and margins of the lesion. Careful examinations
Recent or past history of malignancy of head and neck of CT sections for the presence or absence of associated
should be obtained since it helps to differentiate whether findings such as calcification, ground glass attenuation,
the SPN is secondary to metastasis or due to primary satellite lesions, focal pleural thickening, feeding blood
lung cancer. History of smoking, exposures to radiation vessels, parenchymal infiltrates, and lymphadenopathy
and mineral dusts such as silica, asbestos, arsenic, (that are otherwise missed in the chest X-ray) are
cadmium and chromium are associated with increased essential for determining the nature of the lesion. CT
risks of lung cancer. scan is highly useful in making specific diagnosis in
Thorough general physical and systemic examinations, several conditions such as rounded atelectasis, a mucous
specifically looking for evidence of developmental plug, AV malformation or bronchial cyst.13,14 By careful
anomalies, systemic infections, inflammations and analysis of following features it is possible to differentiate
malignancy are to be carried out in every case. Clinical whether the SPN is benign or malignant.
evaluation should also specifically look for SPN mimics
such as a skin nodule, nipple shadow and monitor leads. Size: Small lesions, lymphadenopathy, chest infiltrates
Inflammatory conditions such as collagen vascular and focal pleural thickening can be detected easily by
disease, Wegener’s granulomatosis and sarcoidosis high resolution mutidetector-row CT scanners that use
are extremely rare to present as SPN but should always 16–128 detector channels to obtain thin sections ranging
be kept in mind. Presence of systemic findings such from 0.6 mm to 2 mm. Benign SPNs are generally smaller
as subcutaneous nodule, eye and musculoskeletal in size, often subcentrimetric. Malignant SPNs are
involvements aid diagnosis in such conditions. usually larger in size with high probability of malignancy
when the size is more than 2.3 cm in diameter.
Chest radiology: Chest X-ray generally is able to identify
nodules when they are about 0.8–1 cm in diameter. 7 Margin: Benign lesions have smooth margins and
Some nodules may be missed in PA view and therefore are round in shape. Lobulated margin is a feature
lateral view is always recommended while screening of hamartoma but can be seen in carcinoids and
for pulmonary nodules. Careful evaluation of apex, adenocarcinoma.15 Rarely malignant lesion can have a
diaphragmatic area, behind the heart and behind ribs smooth margin especially in those solitary metastasis
should be done since small nodules in these locations from breast, colorectal region and kidney. Malignant
may be missed. Efforts should be made to locate the nodules have irregular spiculated margins otherwise
nodule (pulmonary or outside lung) and ascertain that known as ‘corona radiata’ (Fig. 1).12
detected opacity fulfills all criteria’s of SPN. Normal Distribution: Benign SPNs can be present in any part
anatomic structures such as nipple shadows should of the lung either right or left. Bronchial cyst that is
be distinguished from SPN by using nipple markers. easily detected by CT scan are close to tracheobronchial
Previous X-ray if available should be obtained and tree often abutting these structures, with CT scan
reviewed along with the current one for assessing the density as that of water. Presence of air-fluid level
stability of the nodule.
heralds communication with the airway and secondary
CT scan of the chest: CT scan is the corner stone for infection. SPN due to sequestration of the lung is more
diagnosis as it helps to define and characterize a common in posterior basal segment of the left lung.
pulmonary nodule.7 By employing thin-section high- Malignant lesions have a predilection for distribution in
resolution CT imaging it is possible to clearly define upper lobe of right lung since most of the carcinogens
CHAPTER 84: Clinical Approach to Solitary Pulmonary Nodule 517
Fig. 2: CT images of a well-circumscribed SPN in left upper lobe having a spec of calcification
suggestive of benign nature of the lesion
assess the growth pattern by three dimensional volume TABLE 2: Schedule of follow-up CT imaging in solid SPN
analysis of the tumor. Three dimensional volume Size No risk factor for cancer Risk factor cancer
analysis is time consuming and labor intensive.6 Serial ≤4 mm No follow-up CT after 12 months, no
CT scans are required to be done over a period of time further imaging if nodule
for assessing the growth pattern of the SPN. Studies shows no change
have shown that volumetric CT scan of the nodule >4–6 mm CT in 12 months CT at 6–12 months
No change then no Repeat CT at 18–24
repeated after 30 says or even earlier after the initial additional follow-up months if nodule shows no
study can detect any change in the volume of a 5 mm change
nodule.2,25-27 It may be noted that in the natural evolution >6–8 mm CT 6–12 months CT 3–6 months
of the cancer, a single cancer cell to begin with multiplies Repeat at 18–24 months Repeat CT at 9–12 months
if there is no change and 24 months if
relentlessly to become about 1 billion cells after 30
nodule shows no change
doublings when the tumor attains 1 cm diameter. Further,
>8 mm CT 3–6 months CT at 3 months
it takes another 10 doublings for the tumor to attain a Repeat CT at 9–12 Repeat CT at 6, 12 and 24
diameter of 10 cm, when patient has usually died.29 For months and 18–24 months if nodule shows no
the tumor to double its volume there is an increase in the months if nodule shows change
no change
diameter of the nodule by 26%. Most of malignant SPNs
have a doubling time ranging from 20 days to 300 days.5,6
Among lung tumors doubling time varies depending on TABLE 3: Schedule of follow-up CT imaging in nonsolid SPN
histology. It has been observed that squamous and large Pure ground-glass nodule Part-solid, part ground-glass
cell tumors have an average doubling time of 60–80 days nodule
while adenocarcinomas have a doubling time of about Nodule size ≤5 mm; no follow- Nodule ≤8 mm: CT imaging at 3,
up needed 12 and 24 months with annual
120 days. Small cell carcinoma of the lung has a faster
CT for 1–3 years thereafter
growth rate with a doubling time that is even less than
Nodule size >5 mm: CT at 3 Nodule >8 mm: CT imaging at
30 days in some cases.28 Benign nodules have a doubling months and if no change then 3 months followed by PET and/
time that is generally either below 20 days or more than follow-up annually for 3–5 years or biopsy if nodule persists
400 days. SPN due to acute infection or inflammation
exhibits rapid growth with a doubling time of less than years is recommended for the evidence of malignancy
20 days. Slow growth is observed in chronic granulomas when the lesion is partly solid or ground glass in
and hamartoma. It has been observed that SPNs which appearance.6, 30, 31 Based on expert consensus guidelines,
remain stationary for about 2 years are mostly benign.5, 6 the schedule for conducting follow-up CT imaging in
Follow-up imaging: There is always a debate how long solid and nonsolid nodules are shown in Tables 2 and 3
respectively.6
and how frequently SPN has to be followed up by serial
chest CT imaging. It is recommended to follow up SPN by Positron emission tomography (PET): PET imaging
serial low dose HRCT with thin sections.6 If facility exists of SPN is used for precise localization of SPN and
much more sensitive volumetric CT is recommended for determining whether the nodule is benign or
for facilitating growth detection. Frequency of follow malignant by measuring uptake of positron-emitting
up by CT imaging depends on the size and density of radioisotope-18 fluorodeoxy-D-glucose (FDG). The
the nodule and probability for lung cancer. Generally uptake of FDG depends on metabolic activity of SPN.
small nodules less than 4 mm with no lung cancer Majority of malignant tumors are FDG avid denoting
risks do not require follow up. Solid lesions that remain their high metabolic activity with FDG uptake of 2.5 SUV
stable on CT scan without any significant increase (standard uptake value) or more. Though a threshold
in size for two years is benign warranting no further level of 2.5 SUV is used to differentiate a benign lesion
follow up. However longer follow up for another 1–3 from malignancy, it is the degree of FDG uptake by the
520 SECTION 7: Respiratory System
nodule that determines malignant nature of the nodule. stains or molecular analyses, especially in malignant
It has been observed that greater FDG uptake by the nodules where it may be impossible for pathologists
tumor (compared to mediastinal blood pool) is more to distinguish primary from metastatic carcinoma of
strongly associated with malignancy. 6,32,33 However, nonpulmonary origin such as colon, breast, etc. by
lower FDG uptake can be seen in lesions that are less conventional histological methods.
than 8 mm in size and in certain malignancies such as
Transthoracic needle aspiration/CT guided needle biopsy:
lepidic predominant adenocarcinoma (bronchoalveolar
CT guided transthoracic needle aspiration (CT FNA) is a
cell carcinoma), minimally invasive adenocarcinoma/ useful technique even when the lesion is small and less
c a rc i n o m a i n s i t u , c a rc i n o i d s a n d m u c i n o u s than 2 cm in diameter. High diagnostic yield is expected
adenocarcinomas.34, 35 On the contrary higher SUV for when SPN is peripheral in location (outer third of the
FDG are seen in various granulomatous conditions lung). CT FNA has very high sensitivity of 90%, when
like tuberculosis, mycoses, sarcoidosis, rheumatoid employed for sampling peripherally located nodule with
arthritis and atypical mycobacterial infections, besides a diameter of 1.5 cm or more.5, 39 Major complications of
uncontrolled hyperglycemia.36-38 transthoracic FNA include pneumothorax, air embolism
Tissue diagnosis: Various diagnostic options including and hemorrahage. Risk of pneumothorax can be high
fiberoptic bronchoscopy, percutaneous CT-guided up to 35% with 10–15% requiring tube thoracostomy
biopsy, and surgical resection are available. These or catheter drainage. 40 Presence of emphysema and
procedures are limited by complications and difficulty bullous disease makes this procedure highly risky. It is to
in obtaining adequate tissue when the lesion is small. be avoided in those who have poor respiratory reserve,
Choosing a particular option of diagnosis depends on bleeding diathesis and severe pulmonary hypertension.
the location and size of SPN as well as availability of Bronchoscopy: Specimens for cytological and histological
resources and cost, benefits and risks associated with studies can be obtained by fiberoptic bronchoscopic
such a procedure. They should be employed in patients techniques-bronchial lavage, bronchial brushing,
with a high risk for malignancy. While deciding whether bronchial biopsy and transbronchial lung biopsy.
to biopsy the lesion or not, it is extremely important Bronchoscopy enables multiple sampling from the
to decide whether the result of the biopsy is going to suspicious area without an appreciable increase in the
drastically change the management. For example, risk for pneumothorax or major bleeding. Diagnostic
when SPN is detected in a known case of malignancy, yield by bronchial lavage, brushing and biopsy is variable
likelihood of metastasis is very high and decision to depending upon the location and size of the nodule.41
biopsy is to be taken only when primary lung tumor is Diagnostic yield is high when there are bronchial
strongly suspected or some other alternative diagnosis mucosal abnormalities or a bronchoscopically visible
other than metastasis like tuberculosis is a strong nodule. Proximal/centrally located SPN of more than 2
possibility. CT findings strongly favoring malignancy cm in diameter and a CT finding of positive bronchus sign
such as irregular margins, eccentric cavitation, solid (a bronchus visible on CT that is leading to or contained
indeterminate nodule, and nodule having varied density within the nodule) are associated with diagnostic yields
(part solid and part ground glass density) with evidence ranging from 60% to 90%. 42 In peripherally located
of growth on serial imaging, obviously warrant an SPN, bronchoscopic yield proportionately decreases
early tissue diagnosis so also in patients having high as the distance between the nodule and main stem
risks for malignancy such as heavy smoking, history bronchi increases. Diagnostic yield by combining
of occupational exposures and older age. Whatever bronchoscopic techniques of brushing, lavage and
option the clinician may chose, it is imperative to obtain transbronchial biopsy is 34% and 63% in lesions that
sufficient tissue that is required for gross and microscopic are less than 2 cm in diameter and more than 2 cm in
examination as well as for special immunochemical diameter respectively.39,43 Ultrathin bronchoscopes can
CHAPTER 84: Clinical Approach to Solitary Pulmonary Nodule 521
be used to sample distal lesions. Further, diagnostic consequences of therapy–surgical or nonsurgical on the
yield can be enhanced by fluoroscopy, electromagnetic outcome. If the probability for cancer is close to 0, then
navigation (using three-dimensional CT reconstruction observation with serial CT scan is good enough. On the
combined with electromagnetic navigation of an other hand, if the probability of cancer is close to 1, going
extended working channel) and radial endobronchial for surgical excision after staging work up is the best
ultrasound (EBUS). In systematic review of results of option in an otherwise surgically fit candidate. Those
these advanced techniques, the reported diagnostic yield SPN that comes under intermediate probability of cancer
varied from 67% to 73%-electromagnetic navigation 67%, risk require careful evaluation by various nonsurgical
radial EBUS 71%, ultrathin bronchoscopy 70%, guide methods before considering surgery as a diagnostic or
sheath techniques 73%, and virtual bronchoscopy 72%.41 a therapeutic measure. Risk assessment is an important
These sophisticated techniques requiring high degree step for appropriate management of a SPN.5, 6 SPN with
of expertise are costly, time consuming and limited to high risks of malignancy includes a diameter of 2.3 cm
few select centers. However, they enable sampling of or more with spiculated margin or corona radiata (on
even a small nodule (as small as 7 mm) with a very high imaging) in current smokers (>20 cigarettes per day)
diagnostic yield of 80% or more. who are more than 60 years old with previous history
Surgical biospsy: Surgical biopsy employs conventional of cancer. Low probability of malignant SPN includes a
thoracotomy or Video-Assisted Thoracic Surgery (VATS) smooth well defined nodule with a diameter less than 1.5
for obtaining tissue for diagnosis and for carrying out cm in individuals who are under 45 years of age and are
surgical resection. VATS is preferred over conventional nonsmokers. Moderately increased risk for malignancy
thoracotomy as it has low morbidity and mortality with is observed in SPNs that are between 1.5 cm and 2.2 cm
a short hospital stay.44 Surgical resection remains the in diameter with scalloped edge (on imaging) in smokers
“gold standard” since this procedure offers adequate (up to 20 cigarettes per day/former smokers within last 7
tissue and definitive therapy for patients with malignant years) who are aged between 45 years and 59 years.
SPN including solitary metastasis from solid tumors.45 Specific therapy is to be instituted once diagnosis is
Diagnostic yield is much higher compared to other established. Surgery can be considered in malignant SPN
methods with sensitivity close to 100%. Lesions can either primary or due to metastasis after assessing the
be missed if they are tiny and difficult to palpate. risk benefit ratio and lobectomy with systematic lymph
Surgical biopsy enables adequate tissue sampling for node sampling remains the procedure of choice.46 Role of
various studies including frozen section examination wedge or segmental resections in the management of lung
before proceeding for lobectomy or wedge resection. cancer remains controversial. Thermal ablation using
Complications of surgery occur due to both general radiofrequency energy is a minimally invasive procedure
anesthesia and lung resection. Common complications that can be usefully employed to treat a malignant SPN
associated with pulmonary resection are persistent due to primary or metastasis in cases where surgery is
air leak and infection. Risk factors for surgery include contraindicated.47 Surgery is also warranted in certain
severe underlying co-morbidities such as uncontrolled complicated and symptomatic benign conditions such as
hypertension, severe heart disease, bleeding diathesis cyst, sequestration and hamartoma.
and poor lung reserve with projected post operative Finally the decision for definitive surgery either
FEV1<40% and VO 2 max <15 Ml/kg/min. Surgical VATS or conventional thoracotomy depends on many
mortality and morbidity and for pulmonary resection is factors including cost, risks, availability of expertise,
around 2% and 10% respectively. patient preferences and absence or presence of severe
comorbidities.48 Systematic approach to management of
MANAGEMENT a SPN taking into consideration cancer risks (probability
Management strategy of SPN revolves on the probability of cancer), consequences of surgery-benefit and harm
of the lesion of being malignant or nonmalignant and and existing comorbidities is outlined below:
522 SECTION 7: Respiratory System
If SPN has benign calcification pattern or 2 years in such cases. No further follow up is recommended
of radiographic stability, then no further testing is when the nodule is small and remains static for 2 years.
recommended except in stable GGO where further In those cases with imaging evidence of malignancy
1–3 years follow up is recommended. including significant changes in growth pattern, surgical
If SPN is unstable and negative for benign pattern of resection is the best option, provided surgical risk is low.
calcification, then assess probability of cancer and In remaining cases with high probability of cancer and
surgical risks (lobectomy). If probability of cancer is high surgical risk, alternative therapeutic options such as
high and lobectomy risk is minimal, then surgery is limited resection, radiofrequency ablation, stereotactic
the best option. If lobectomy risk is high but is feasible, surgery and active observation are considered.
then lobectomy is recommended. If the probability of
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CHAPTER
85
Challenges in the Management of CAP
Prashant Prakash, Akhilesh Kumar Singh
INTRODUCTION > 37.7°C, chills, and rigors, and/or severe malaise); and
A number of international guidelines for community (c) new focal chest signs on examination (bronchial
acquired pneuomonia (CAP) are available which include breath sounds and/or crackles); with (d) no other
the Infectious Disease Society of America (IDSA), explanation for the illness.2
American Thoracic Society (ATS), British Thoracic When a chest radiograph is available, CAP is defined
Society (BTS), and European Respiratory Society (ERS) as: symptoms and signs as above with new radiographic
guidelines. In this context a need for Indian Guidelines shadowing for which there is no other explanation (not
on Management of Pneumonia seem to be the need of due to pulmonary edema or infarction).2 Radiographic
the hour. shadowing may be seen in the form of a lobar or patchy
The process of Indian/National pneumonia consolidation, loss of a normal diaphragmatic, cardiac or
guidelines development was undertaken as a joint mediastinal silhouette, interstitial infiltrates, or bilateral
exercise by the Department of Pulmonary Medicine, perihilar opacities, with no other obvious cause.
Postgraduate Institute of Medical Education and
Research, Chandigarh, with sponsorship from two
EPIDEMIOLOGY AND ETIOLOGY
National Pulmonary Associations (Indian Chest Society Epidemiology of CAP in India
and National College of Chest Physicians) and this was Around 20% of the mortality due to infectious diseases in
published in 2012.1 In this chapter, we will be reviewing India is caused by lower respiratory tract infections. The
the challenges in the management of CAP with emphasis mortality in India has been variably reported between
on International Guidelines and with special reference to 3.3% and 11% in other studies.1
Indian/National guidelines.
Etiology of CAP Worldwide
DEFINITION OF CAP A microbiological diagn osis could be made in only
CAP can be defined both on clinical and radiographic 40–71% of cases of CAP. 1 A list of etiological agents
findings. In the absence of chest radiograph, CAP is responsible for CAP has been outlined in Table 1.3
defined as: (a) symptoms of an acute lower respiratory
tract illness (cough with or without expectoration, DIAGNOSIS OF CAP
shortness of breath, pleuritic chest pain) for less than 1 The algorithmic approach to diagnosis and management
week; and (b) at least one systemic feature (temperature of CAP is outlined in Figure 1.1
526 SECTION 7: Respiratory System
A chest radiograph is the cornerstone for the diagnosis patients with CAP.
of CAP. 1 Importantly, resolution of chest radiograph
findings may lag behind clinical cure during follow- Sputum Gram Stain and Cultures
up, and upto 50% of patients may not show complete The yield of sputum cultures varies from 34% to 86%.
CHAPTER 85: Challenges in the Management of CAP 527
Recommendations (as per National Pneumonia Pneumococcal Antigen and PCR Detection
Guidelines)1 Pneumococcal antigen can be detected in the urine using
An initial sputum Gram stain and culture (or an
proprietary rapid immunochromatographic membrane
invasive respiratory sample as appropriate) should be tests. Pneumococcal PCR has a poor sensitivity.
obtained in all hospitalized patients with CAP.
Sputum quality should be ensured for interpreting Recommendations (as per National Pneumonia
Gram stain results. Guidelines)1
Sputum for acid-fast bacilli (AFB) should be obtained Pneumococcal antigen detection test is not required
as per RNTCP guidelines for nonresponders. routinely for the management of CAP.
528 SECTION 7: Respiratory System
Respiratory rate Low blood pressure Multilobar CXR Multilobar CXR ventilation
≥30/min (diastolic blood pressure involvement involvement —— Septic shock with the need
Low blood ≤60 mm Hg or systolic Low albumin (<3.5 g/dL) Respiratory rate (≥25/min) for vasopressors
pressure (diastolic blood pressure ≤90 mm Respiratory rate (≥25/min) Tachycardia (≥125/min) zz Minor criteria
≤60 mm Hg or Age ≥65 years Confusion Poor oxygenation (PaO2 ≥30 breaths/min
systolic blood Poor oxygenation (PaO2 <70 mm Hg; SpO2 <93%) —— PaO /FiO ratio ≤250
2 2
pressure ≤90 mm <70 mm Hg; SpO2 <93%) —— Multilobar infiltrates
Hg) Low pH (<7.35) —— Confusion/disorientation
Age ≥65 years —— Uremia (BUN level
≥20 mg/dL)
—— Leukopenia (WBC count
<4000 cells/mm3)
—— Thrombocytopenia (platelet
temperature <36°C)
Recommendations (as per National Pneumonia TABLE 3: Indications for empiric combination therapy in CAP7
Guidelines)1 Presence of comorbid medical conditions
Risk stratification should be performed in two steps
Chronic heart, lung, liver, or renal disease
(Fig. 1) based upon the need for hospital admission
Diabetes mellitus
followed by assessment of the site of admission
(nonICU vs. ICU). Accordingly, patients can be Alcoholism
levofloxacin 750 mg daily) may be used if tuberculosis Piperacillin- 4.5 g four times a day (IV)
tazobactam
is not a diagnostic consideration at admission.
Imipenem 0.5–1 g three to four times a day (IV)
Patients should also undergo sputum testing for acid-
Meropenem 1 g thrice daily (IV)
fast bacilli simultaneously if fluoroquinolones are
being used in place of β-lactams.
Route of administration (oral or parenteral) should
Diagnostic/therapeutic interventions should be
be decided based upon the clinical condition of done for complications, e.g. thoracentesis, chest tube
the patient and the treating physician’s judgment drainage, etc. as required.
If a patient does not respond to treatment within 48–
regarding tolerance and efficacy of the chosen
antibiotics. 72 h, he/she should be evaluated for the cause of non-
response, including development of complications,
Antimicrobial Therapy in Inpatients, ICU presence of atypical pathogens, drug resistance, etc.
Recommendations (as per National Pneumonia The doses of antimicrobial drugs used in various
Guidelines)1 settings of CAP are outlined in Table 4.1
The recommended regimen is a β-lactam (cefotaxime,
testing for acid-fast bacilli simultaneously if clinical improvement in moderate to severe CAP.
fluoroquinolones are being used. Patients can be considered for discharge if
Antimicrobial therapy should be changed according they start accepting orally, are afebrile, and are
to the specific pathogen(s) isolated. hemodynamically stable for a period of at least 48 h.
CHAPTER 85: Challenges in the Management of CAP 531
or linezolid
BTS guidelines Amoxicillin 500–1000 mg thrice a day zz If oral therapy possible: Co-amoxiclav plus clarithromycin (plus
(October 2009)2 or clarithromycin/erythromycin or Amoxicillin plus levofloxacin if legionella is suspected)
doxycycline clarithromycin or or
Doxycycline or Levofloxacin Cefuroxime/cefotaxime/ceftriaxone
or Moxifloxacin plus clarithromycin (plus levofloxacin if
zz If oral therapy not legionella is suspected)
possible: IV amoxicillin or
or benzylpenicillin plus Benzylpenicillin plus levofloxacin/
clarithromycin or IV ciprofloxacin
levofloxacin
Outpatients should be treated for 5 days and in There is no role of other adjunctive therapies
patients for 7 days. (anticoagul ants, immunoglobulin, granulocyte
Antibiotics may be continued beyond this period in colony-stimulating factor, statins, probiotics, chest
patients with bacteremic pneumococcal pneumonia, physiotherapy, antiplatelet drugs, over-the-counter
Staphylococcus aureus pneumonia, and CAP cough medications, β2 agonists, inhaled nitric oxide,
caused by Legionella pneumoniae and nonlactose- and angiotensin-converting enzyme inhibitors) in
fermenting Gram-negative bacilli. Antibiotics may the routine management of CAP.
also be continued beyond the specified period in CAP-ARDS and CAP leading to sepsis and septic
those with meningitis or endocarditis complicating shock should be managed according to the standard
pneumonia, infections with enteric Gram-negative management protocols for these conditions.
bacilli, lung abscess, empyema, and if the initial Noninvasive ventilation may be used in patients with
therapy was not active against the identified pathogen. CAP and acute respiratory failure.
TABLE 6: High-risk groups in whom vaccination is recommended7 is not recommended. Pneumococcal vaccine may
Pneumococcal disease be considered for prevention of CAP in special
zz Chronic cardiovascular, pulmonary, renal, or liver disease
zz Diabetes mellitus
populations who are at high risk for invasive pneumo
zz Cerebrospinal fluid leaks coccal disease (Table 6).7
zz Alcoholism
Influenza vaccination should be considered in adults
zz Asplenia
zz Hemoglobinopathies
REFERENCES
zz Immunocompromising conditions/medications
TYPES OF POLLUTANTS 1 mm. The size of the particles determines the site in
1. Gaseous pollutants are produced mainly due to the respiratory tract in which they will deposit. Coarse
combustion of fossil fuels contribute to a great particles deposit mainly in the upper respiratory tract
extent in composition variations of the atmosphere. while fine and ultra fine particles are able to reach
Nitrogen oxides are emitted as NO which reacts with till lung alveoli. The major components of PM are
ozone or radicals in the atmosphere forming NO2. metals, organic compounds, material of biologic
Ozone is formed by a series of reactions involving NO2 origin, ions, reactive gases, and the particle carbon
and volatile organic compounds, a process initiated core in varying composition. There is strong evidence
by sunlight. CO, on the other hand, is a product to support that ultra fine and fine particles are more
of incomplete combustion and its major source is hazardous than coarse particles, in terms of mortality
road transport. SO2 results from the combustion of and cardiovascular and respiratory effects.
sulphur-containing fossil fuels like coal and heavy
oils and the smelting of sulphur containing ores, EFFECTS OF AIR POLLUTION ON
volcanoes and oceans are its major natural sources. DIFFERENT ORGANS
Volatile organic compounds (VOCs) includes
Respiratory System
chemical species of organic nature such as benzene.
Many studies have described the effects of short term
They fuel combustion and especially combustion
exposure to higher concentration and long term exposure
processes for energy production and its major
to lower concentration of air pollutants on respiratory
sources are road transport.
system and airways. Nasal congestion, throat irritation,
2. Persistent organic pollutants are toxic group of
bronchoconstriction and dyspnea are known to occur
chemicals which persist in the environment for long
after exposure to especially to higher levels of SO2, NO2
periods of time, and as they move through the food
chain their effects are magnified, a process known as and heavy metals. Particulate matter has shown to
biomagnification. They include pesticides, dioxins, increase the lung inflammation which deteriorates the
furans and PCBs. Dioxins are produced during disease. Respiratory infections both bacterial and viral
incomplete combustion and whenever materials are shown to increase. Patients having asthma or COPD
containing chlorine (plastics) are burned. deteriorate in lung functions during increased pollution.
3. Heavy metals include lead, mercury, cadmium, silver Long term exposure to heavy metals is also known to
nickel, vanadium, chromium and manganese, are cause lung cancer.
natural components of the earth’s crust. They cannot
be degraded or destroyed, and can be transported by Cardiovascular System
air, and can enter water and human food supply. They Systemic inflammatory changes are known to occur
tend to bio-accumulate in the human body which in patients people exposed to increased particulate
means an increase in the concentration of a chemical matter. Lung inflammation can lead to changes in blood
in a biological organism over time, compared to the coagulation which can lead to clotting in coronary vessels
chemical’s concentration in the environment. causing angina and myocardial infarction. Increased
4. Particulate matter major sources are factories, carbon monoxide concentration binds to hemoglobin
power plants, refuse incinerators, motor vehicles, reducing the transfer of oxygen to all organs leading to
construction activity, fires, and natural windblown impaired concentration, slow reflexes and confusion.
dust, etc. Different categories of particles are defined Heavy metals cause tachycardia, increased blood
based on the particle size: Ultrafine particles, smaller pressure and anemia. The mortality due to ischemic
than 0.1 mm in aerodynamic diameter, fine particles, heart disease is shown to increase due to exposure to
smaller than 1 mm, and coarse particles, larger than organic pollutant.
CHAPTER 86: Air Pollution and its Health Impact 535
Contd...
by the same virus, and institution of antiretroviral therapy and effective therapeutic measures for certain cancers.
in AIDS has led to regression of regression of Kaposi’s Further research on pathogenesis and advanced
sarcoma caused by KSHV (a herpes virus). Subtractive molecular detection methods is need of the hour.
methods have been used to demonstrate causality.
Duncan et al. had applied computational subtraction to BIBLIOGRAPHY
search for virus genomes in colorectal cancer. Another 1. Dalton-Griffin L, Kellam P. Infectious causes of cancer and
method known as digital transcript subtraction (DTS) their detection. Journal of Biology. 2009;8(7):67.
2. IARC. Monographs on the evaluation of carcinogenic risks to
uses advanced sequencing methods to identify RNA and
humans, Lyon, France: IARC. 2017.pp.1-119
DNA virus transcripts. However, these methods need to
3. Khurana S, Dubey ML, Malla N. Association of parasitic
be employed in carefully selected tumors to get results. infections and cancers. Indian J Med Microbiol. 2005;23
Bradford Hill’s causation criteria are now considered the (2):74-9.
tool to infer causality of virus and cancer relationship. 4. Liao JB. Viruses and human cancer. The Yale Journal of
These rules along with detection of pathogenic genomes, Biology and Medicine. 2006;79(3-4):115-22.
can help linking an infectious agent with cancers. 5. Mager D. Bacteria and cancer: cause, coincidence or cure?
A review. J Transl Med. 2006;4:14.
6. Moore PS, Chang Y. Common commensal cancer viruses.
CONCLUSION PLoS Pathog. 2017;13(1):e1006078.
The discovery of infectious agents as a cause of cancers 7. Morales-Sánchez A, Fuentes-Pananá EM. Human viruses
has driven our attention towards preventive (vaccines) and cancer. viruses. 2014;6(10):4047-79.
CHAPTER
88
Transfusion Transmitted Infection
Apu Adhikary, Tuhin Santra
test which detects both p24 antigen and antibody to HIV MALARIA
(window period 15–18 days). MP-NAT is not a mandatory Malaria is the first reported transfusion transmitted
screening test but still used in some centers in India. infection. It is endemic in India. It is detected by thick
Improvements in donor testing, donor education and and thin peripheral blood smear examination and rapid
questioning processes have led to the selection of a detection tests based on the detection of malaria parasite
blood donor population with an incidence of new HIV antigen in blood. In India, strategies adopted to prevent
infections that is 10-fold lower than that of the general transfusion transmitted malaria are:
population. Deferral of donors with fever (presumably malaria) in
OTHER INFECTIOUS AGENTS blood transfusion from a negatively screened donor but
Various parasites- babesiosis and Chagas disease can have now become positive for an infection
be transmitted by blood transfusion. Tests for some
pathogens are available, such as Trypanosomacruzi, REFERENCES
but not universally required. Prion disease like variant 1. Chandra T, Rizvi N F, Agarwal D. Decreasing Prevalence
Creutzfeldt-Jakob disease (vCJD) can be transmitted of Transfusion Transmitted Infection in Indian Scenario.
Scientific World Journal. 2014;2014:1-4.
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2. Nandi S, Maity S, Bhunia SC, Saha MK. Comparative
PATHOGEN INACTIVATION assessment of commercial ELISA kits for detection of HIV in
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TECHNOLOGY
3. Petersen LR, Satten GA, Dodd R, et al. Duration of time
The concept of pathogen inactivation in blood
from onset of human immunodeficiency virus type 1
components is to eliminate the risk of known and infectiousness to development of detectable antibody.
unknown pathogens without/minimally interfering The HIV Seroconversion Study Group. Transfusion.
the function the blood components. In India where 1994;34(4):283-9.
infections are rampant this method is desirable. Current 4. Dodd RY. Germs, gels, and genomes: a personal recollection
methods employed are use of methylene blue, solvent of 30 years in blood safety testing. In: Stramer SL, ed. Blood
detergent (SD) plasma and exposure of ultraviolet A safety in the new millennium. Bethesda, MD: American
(UV-A) radiation. Association of Blood Banks; 2001. pp. 97-122.
5. Koff RS. Natural history of acute hepatitis B in adults re
DONOR SCREENING QUESTIONNAIRE examined. Gastroenterology. 1987;92(6):2035-7.
Common questions need to be asked for donor screening. 6. Bobde V, Parate S, Kumbhalkar D. Seroprevalence of viral
Whether currently taking any antibiotic, aspirin or transfusion transmitted infections among blood donors at a
other medication. government hospital blood bank in central India. The Health
Pregnancy within past 6 weeks or current pregnancy. Agenda. 2015;3(1):15-18.
Vaccination in the past 8 week. 7. Offergeld R, Faensen D, Ritter S, Hamouda O. Human
Blood component donation in the past 8 weeks.
immunodeficiency virus, hepatitis C and hepatitis B
A sexual contact with a person who has HIV/AIDS,
infections among blood donors in Germany 2000–2002:
risk of virus transmission and the impact of nucleic acid
gonorrhea, syphilis, hepatitis, hemophilia or has used
amplification testing. Euro Surveill. 2005;10(2):8-11.
clotting factor concentrates, IV drug abuser in the
8. Schreiber GB, Busch MP, Kleinman SH, et al. The risk of
past 1 year.
transfusion-transmitted viral infections. The Retrovirus
An accidental needle-stick or tattoo in last 1 year.
Epidemiology Donor Study. N Engl J Med. 1996;334(26):
Organ, tissue, or bone marrow transplantation in last
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1 year. 9. Dodd RY, Notari EP, Stramer SL. Current prevalence and
Any history of lockup, jail, juvenile detention or
incidence of infectious disease markers and estimated
prison for more than 72 hours. window-period risk in American Red Cross blood donor
population. Transfusion. 2002;42(8):975-9.
Donor Deferral Lists 10. Kuehnert MJ, Roth VR, Haley NR, et al. Transfusion-
A list of deferred donor should be kept in blood bank to transmitted bacterial infection in the United States, 1998
make sure not to collect from risky donor. through 2000. Transfusion. 2001;41(12):1493-9.
11. Kleinman SH, Kamel HT, Harpool DR, et al. Two-year
Lookback experience with aerobic culturing of apheresis and whole
It is a programme which helps in identification and blood-derived platelets. Transfusion. 2006;46(10):
notification of recipients who had previously received 1787-94.
CHAPTER
89
Arboviral Infections: Is Effective
Vaccination a Possible Solution?
Ashok Kumar, Shubha Laxmi Margekar, Venugopal Margekar
offspring and is important for survival if no vertebrate disease. Arboviral infections, with an estimated high
host is available. As there is low virus concentration and fatality rate of 17 million deaths per year worldwide are
brief duration of viremia in human blood, human behave of major public health concern. The most overpopulated
as dead end hosts. But in diseases like yellow fever and and economically backward countries in Southeast Asia
dengue, humans act as reservoirs of the virus because of are the highly affected areas. In India, the rural, tribal and
high-level viremia. urban slum areas are more prone to develop vector borne
Infection by arboviruses usually does not result disease and are considered as high risk groups. Dengue
in disease neither in the arthropod vector nor in the is considered as the most important human arboviral
vertebrate animal (natural host). Disease (yellow fever) infection and is the leading cause of hospitalization
occurs primarily when the virus infects dead-end hosts, and death among children in the Southeast Asia region.
i.e. human, but it causes harmless infection among the Japanese encephalitis is the leading cause of encephalitis
jungle monkeys in South America. epidemics worldwide, mainly in Korea, China, India, and
Indonesia. More than 3 billion people residing in Asia
CLINICAL FINDINGS AND are at risk, and approximately 30,000–50,000 cases are
EPIDEMIOLOGY reported annually. Chikungunya, a dengue-like disease,
The diseases range in severity from mild to rapidly fatal. started causing epidemics in India and Southeast Asia
The clinical picture is divided into following categories: since 1950s and now it is widely spread in other countries
(1) encephalitis; (2) hemorrhagic fever; or (3) fever with also.
myalgias, arthralgias, and nonhemorrhagic rash. The
pathogenesis involves cytocidal effect of the virus, and a VACCINATION
prominent immunopathologic component. Immunity is Emerging Aedes mosquito-borne viral diseases are
usually lifelong after recovery from the disease. Primarily, public health challenge. Vaccines are essential to limit
arboviral diseases occur in the tropics but are also found disease burden as mosquito control programs are not
in temperate zones (United States, Alaska and Siberia). effective for outbreak containment. Along with yellow
At the interface between human communities and jungle fever vaccines, dengue vaccine is also available, while
or forest areas they tend to cause sudden outbreaks of research has started on vaccines against Zika. Several
CHAPTER 89: Arboviral Infections: Is Effective Vaccination a Possible Solution? 549
vaccine candidates against chikungunya are undergoing may be quarantined for up to 6 days, refused entry,
preclinical studies, and few of them have been tested in or vaccinated on site, if they arrive without proof of
Phase II trials. vaccination. Travelers who are not vaccinated because of
contraindication to YF vaccine or other medical grounds
YELLOW FEVER VACCINE and who cannot avoid travel to a country requiring
Vaccination is an important measure for preventing YF vaccination should request a waiver from a physician
and is available for >60 years. Prompt recognition and before embarking on travel.
control of outbreaks through vaccination is important
to prevent epidemics in high risk areas. Vaccination JAPANESE ENCEPHALITIS
coverage must reach at least 60–80% of the at-risk Japanese encephalitis (JE) is the common cause of viral
population to prevent outbreaks. Two 17D substrain encephalitis in many Asian countries. The infection
vaccines namely 17DD and 17D-204 are manufactured. is caused by the JE virus (a flaviviruses) and it exists
The 17DD YF vaccine is manufactured and used in Brazil in a transmission cycle between mosquitoes, pigs
and also in South American countries. The 17D-204 YF and/or water birds (enzootic cycle). Infected mosquito
vaccine is a freeze-dried, live attenuated, highly effective bite transmits infection to human and is common in rural
vaccine. It is available in single- or multi-dose vials and and periurban region. According to recent literature,
should be stored at 2–8 °C. It should be used within 1 about 30% of cases of Japanese encephalitis result in
hour of reconstitution with normal saline. Dose is 0.5 mL permanent neuropsychiatric sequelae. Transmission is
to be given subcutaneously. People at continued risk of observed throughout the year in tropical climate region
exposure to YF virus require revaccination in every 10 but is endemic with seasonal distribution in temperate
years. The YF vaccine is safe and affordable, providing climate areas of Asia, South and South-East Asia.
effective immunity within one week for 95% of vaccines. Currently, JE is considered hyperendemic in parts of
A single dose provides protection for more than 30 years India and Nepal, where authorities have responded with
and probably lifelong. Serious side effects are extremely immunization campaigns.
rare. The risk related to vaccinations is much less than
death from YF. Japanese Encephalitis Vaccination
JE immunization is recommended by WHO in all regions
Contraindication of YF Vaccine where the disease is identified as public health problem,
Children aged <9 months for routine immunization and for people traveling to endemic regions. Several
(or <6 months during an epidemic) vaccines are available but its use has been limited due
Pregnant women—except during a YF outbreak when to its price, cumbersome immunization schedules, and
the risk of infection is high lack of recognition of the burden of disease. Surveillance
People with severe allergies to egg protein of disease and availability of new vaccines helped in
People with severe immunodeficiency due to control of Japanese encephalitis. Global Alliance for
symptomatic HIV or other causes, or in the presence Vaccines and Immunization (GAVI) has committed to
of a thymus disorder. support JE vaccination in eligible countries once a WHO-
prequalified vaccine is available.
International Certificate of YF Vaccination
Travelers must have a certificate of YF vaccination for Licensed Vaccines
entry to certain countries especially to Africa or Latin The mouse-brain derived inactivated vaccines are
America from Asia, under the International Health p ro d u c e d by s e v e ra l m a n u f a c t u re r s. P r i m a r y
Regulations (IHR) of WHO to prevent importation immunization requires 3 dose of vaccine and boosters.
and indigenous transmission of YFV. Such travellers Vaccines are relatively expensive. Vero-derived
550 SECTION 8: Infections
Beijing 1 inactivated vaccine is produced by Japanese particularly with wild type infection. Primary infection
manufacturers for pediatric use and a similar product is with one type of strain provides lifelong immunity to
registered in China as well. Another cell-culture derived that strain and around two years cross protection from
inactivated JE vaccine (attenuated SA 14-14-2 strain) other strains. It has been seen that there is occurrence of
is developed by an Austrian biotech company and is severe dengue in individuals if secondary infection with
available as a traveler’s vaccine. Indian manufacturer other strain occur in them after cross protection due to
has also developed similar product and has received primary infection wanes. The mechanism for this effect
marketing authorization. Research is ongoing on is believed due to antibody-dependent enhancement
pediatric indication. of infection along with other causes. It has been found
A live attenuated vaccine using the SA 14-14-2 strain that symptomatic dengue due to third or fourth infection
manufactured by a Chinese company is the most widely is rare following secondary infection and presumably
used JE vaccine in endemic countries. It is grown on due to reinforcement of nontype specific by secondary
primary hamster kidney cells and only 1–2 doses of infection which provides additional cross protection
vaccine is required to confer long-lasting immunity, also against remaining serotype and this phenomenon
the vaccine is made available at a highly competitive is known as multitypic immunity. This multitypic
price to low-income countries. Another live attenuated, phenomenon has been in consideration for development
chimeric vaccine which uses yellow fever vaccine as of new and effective vaccine against dengue infection.
vector and is combined with E protein encoding gene
from the SA 14-14-2 virus and is grown on Vero cells, has Current Status of Dengue Vaccine
obtained marketing authorization in some JE endemic Currently Dengvaxia® (CYDTDV) is the only licensed
countries. It is given as single dose vaccine, and booster vaccine for dengue infection developed by Sanofi
dose requirement is still to be determined. Pasteur in 2015 in Mexico. The vaccine is a three dose
live recombinant tetravalent dengue vaccine licensed to
Pipeline Vaccines use in individuals of 9–45 years of age who are residing
Various candidate Japanese encephalitis vaccines in endemic areas and administered 0, 6 and 12 month
are under development. These consist of adjuvanted schedule. It has been observed that efficacy of vaccine
inactivated vaccines, candidates using different virus is higher against serotype 3 and 4 than serotype 1 and 2.
strains, and other genetically engineered constructs. Also in the individuals who were already been exposed
to dengue, the vaccine efficacy as higher than infection
DENGUE VACCINE naïve individuals.
Dengue virus belongs to family Flaviridae, genus
Flavivirus, which is single stranded RNA virus, having Status of Vaccine R and D Activities
four serotypes (DENV1–DENV4). Genetic variations in Clinical Pipeline
these serotypes lead to variable pattern of disease and There are two tetravalent live recombinant vaccines
its severity due to variation in virulence, fitness and TV003/TV005 and DENVax are moving towards phase
transmission. Incidence of dengue has been increased 3 clinical trials. The response of these vaccines are
to 30 folds over the period of five decades.4 Diagnosis of encouraging and elicited seroconversion rate are over
dengue can be made by clinical features along with either 90% by one dose of TV005.
isolation of virus, viral serology (MAC-ELISA, IgG ELISA,
NS1 ELISA, and PRNT), or by molecular methods (RT- Preclinical Pipeline
PCR) which is gold standard. There are various approaches in developing effective
Postinfection immunity in individuals recovered vaccine in preclinical pipeline that includes conventional
from dengue infection is not very well understood and novel technological approaches. The various target
CHAPTER 89: Arboviral Infections: Is Effective Vaccination a Possible Solution? 551
for dengue vaccine development includes, recombinant live vectored, chimeric, virus like particle [VLP], subunit
subunit vaccines, DNA vaccines, VLP vaccines, virus- protein, DNA) are currently in preclinical and clinical
vectored vaccines, purified inactivated virus vaccines, development.
live attenuated virus vaccines, heterologous prime-boost
approaches, and simultaneous administration with two KYASANUR FOREST DISEASE
technologically different vaccine candidates. The KFD virus (KFDV) belongs to genus Flavivirus and
For reaching WHO goal of decreasing dengue of family Flaviviridae. Concomitant illness in monkeys
morbidity by at least 25% and mortality by at least 50% by (Semnopithecus entellus and Macacaradiata) and in
2020, a safe, efficacious and cost effective vaccine is the humans leads to discovery of this virus in 1957. This virus
need of time to control of disease. genome is single-stranded, positive sense RNA, spherical
in shape and about 45 nm in diameter. Initially disease
CHIKUNGUNYA VACCINE was seen in some area of Karnataka district Shimoga in
Chikungunya fever, caused by chikungunya virus Sagar, Shikaripur and Sorabtaluks, later on other districts
(CHIKV), is an acute febrile illness characterized by also become endemic like Chikmagalur, Dakshina
high grade fever with severe, debilitating polyarthralgia Kannada, Udipi and Uttar Kanada. Indian council of
and rashes. Disease can progress to chronic stage Medical Research states the annual incidence rate of
in which joint pain can be there for more than three 40–1000 KFD cases with mortality rate of 4–15% in them.
years postinfection in around to third if cases. Disease
occurs across all age groups with similar frequencies Mode of Transmission
and is associated with fever and severe myalgia (90% of Wild monkeys Semnopithecus entellus and Macaca
patients), polyarthralgia and polyarthritis (95%), and radiate gets infected by KFDV through the bites of
rash (50%). The virus belongs to family togaviridae and infected H. spinigera ticks leading to severe febrile illness
its genome is enveloped, positive-sense single stranded in monkeys. After death of infected monkeys, the ticks
RNA. Over the past decade CHIKV has emerged as a shed from their body that help in further spread of the
major cause of vector-borne disease with transmission virus. Humans come in the cycle when bitten by infected
reported in more than 100 countries and territories unfed nymph. No human to human transmission is
worldwide. The estimated case fatality is very low known. But the personnel working on the virus and
(0.1–5%) compared to some other arboviral diseases. Till handling the infected monkeys can develop disease and
date, vector control has been the primary response to around 100 cases were noted.
chikungunya outbreaks but effectiveness has not been
extensively evaluated and may face challenges due to Clinical Features
insecticide resistance in Aedes spp. vectors. Symptoms of KFDV infection in humans are similar
to other viral hemorrhagic illness. There is high grade
Status of Chikungunya Vaccine fever with chills, frontal headaches, photophobia, severe
There are no licensed vaccines for chikungunya. body aches sometimes associated with gastrointestinal
Throughout world there are four lineage of chikungunya symptoms like, nausea, vomiting, and loose motion. An
virus are found, the East, Central, and Southern African important diagnostic sign in some patients is appearance
(ECSA) lineage, the West African lineage, the Asian of papulovesicular lesions on the soft palate. Patients
lineage, and the Indian Ocean lineage (IOL). As all may develop bleeding manifestations in the form of
chikungunya virus lineage appears to single serotype, epistaxis, hemoptysis, malena or bleeding from.
therefore a single vaccine can be expected to protect
all virus strains. The chikungunya vaccine pipeline Vaccination
appears robust. More than 15 vaccine candidates based National Institute of Virology at Pune, India developed
on a range of platforms (inactivated, live attenuated, vaccine against KFDV and is available since 1966.
552 SECTION 8: Infections
The vaccine is formalin inactivated and is prepared supported its use, although the drug is not approved by
by growing the virus in chick embryo-fibroblast cells FDA to be use in CCHF cases.
by using modern cell culture techniques. In India,
the vaccine is used nowadays in the endemic regions CONCLUSION
and annually over 50 thousand vaccine doses being There is no doubt that arboviral infections are becoming
administered. Large numbers of new KFDV cases still the dangerous threat to human life in terms of morbidity
occurs from Karnataka questioning the efficacy of the and mortality. Although there are several vaccine
existing vaccine. Therefore, there is need of KFD virus against flaviviruses (i.e. against yellow fever, Japanese
identification and development of highly efficacious encephalitis, TBE and Dengue virus), there are no
vaccine against the KFDV to prevent the epidemics in vaccine available against Zika virus and no vaccines
India. against an important Alphavirus such as chikungunya.
The present licensed dengue vaccine has low pooled
CRIMEAN CONGO HEMORRHAGIC efficacy and very limited data available of its use.
FEVER VIRUS Even after so much technical advancement, there
Crimean Congo hemorrhagic fever virus (CCHFV) appears to be delay in development of effective vaccine.
belongs to family Bunyaviridae, genus Nairovirus Development of vaccine requires huge investments and
containing three negative sensess RNA segment. Its financial resources. A global commitment is needed;
wide geographical distribution, mode of transmission, public/private partnership is essential to develop
severity of the disease, and high mortality rate in humans, vaccine candidates and make them available.
together with therapeutic difficulties and lack of an FDA-
approved vaccine, make CCHFV a significant threat to BIBLIOGRAPHY
public health. Disease is spread in humans by the bite of 1. Broor S, Devi LS. Arboviral infections in India. Indian Journal
of Health Sciences and Care. 2015;2(3):192-202.
ticks, by contact with infected patient during acute phase
2. Dash AP, Bhatia R, Sunyoto T, Mourya DT. Emerging and re-
or bycontact with body fluid secretions, blood or tissues emerging arboviral diseases in Southeast Asia. Journal of
from viremic livestock. There were two major outbreak Vector Borne Diseases. 2013;50(2):77.
of CCHF in India. In 2011 and 2013, few districts and 3. Mourya DT, Yadav PD, Patil DY. Highly infectious tick-borne
viral diseases: Kyasanur forest disease and Crimean–
villages were affected and there were sporadic cases in Congo haemorrhagic fever in India. 2014.
between 2011 and 2012. 4. Smalley C, Erasmus JH, Chesson CB, Beasley DW. Status
The only available vaccine is an inactivated virus of research and development of vaccines for chikungunya.
Vaccine. 2016;34(26):2976-81.
produced on suckling mouse brain (inactivated by
5. Vannice KS, Durbin A, Hombach J. Status of vaccine
chloroform, heated at 58 °C, and adsorbed on aluminum research and development of vaccines for dengue. Vaccine.
hydroxide). This vaccine is currently used in Bulgaria 2016;34(26):2934-8.
and originated from the USSR in 1970. Recently, it has 6. Wallace D, Canouet V, Garbes P, Wartel TA. Challenges
in the clinical development of a dengue vaccine. Current
been found that even after 4 doses of this vaccine the Opinion in Virology. 2013;3(3):352-6.
protective antibody titers are low. Therefore there is great 7. Wilder-Smith A, Gubler DJ, Weaver SC, Monath TP, Heymann
need to find effective vaccine for this deadly disease. DL, Scott TW. Epidemic arboviral diseases: priorities for
research and public health. The Lancet infectious diseases.
At present, there is no safe and effective, commercially
2017;17(3):e101-e6.
available vaccine against CCHFV. There is some role 8. World Health Organization. Dengue vaccine: WHO position
of antiviral drug Ribavirin and Indian CCHFV cases paper—July 2016. WklyEpidemiol Rec. 2016;30:349-64.
CHAPTER
90
MDR-TB and XDR-TB: What are the Options?
Bidita Khandelwal
TABLE 1: Acute encephalitis syndrome northern districts of West Bengal particularly Darjeeling,
Japanese Non-JE—viral Non-JE—nonviral Jalpaiguri and Cooch Behar districts since 2011. After
encephalitis the mass vaccination campaign conducted in late 2013,
Single stranded Enterovirus—Polio Parasitic there were significant decrease incidence of JE cases with
RNA virus of (Malaria)
increase of nonJE AES.
Flaviviridae Non-polio
family (Vector is Japanese encephalitis: Till date Japanese encephalitis
Coxsackie Echo Others
Culex mosquito)
A/B is the leading cause of AES all over India, both in
Chandipura virus Protozoal pediatric and adult population. Japanese encephalitis
(Amoebic)
(JE) is a mosquito borne zoonotic viral disease caused
West Nile virus Spirochetal
by arbovirus (flavi virus). The virus is divided into four
(Syphilis)
genotypes (I, II, III and IV). Genotype III is mostly found
Herpes Scrub typhus
pan India whereas genotype I is found in UP and West
Varicella Trypanosomiasis
Bengal. Genotype II and IV rarely found in India. The JE
Dengue Acute TBM virus is mainly isolated in ardied birds (e.g. cattle egrets,
Toxoplasmosis Bacterial pond herons, etc.) and they are called as natural reservoir,
Tick borne encephalitis Fungal whereas when the virus multiply in body of some animal
(Cryptococcal) particularly Pigs which are called amplifying host.
Venejuelian encephalitis Toxin
Dawson Chemicals Transmission
9 and 10-not found in India Unknown cause The infection is transmitted through the bite of an
infected culicine mosquito. Most important vector
species in India is Culex vishnui group consisting of
be regular reporting of cases and thus establish the
C.tritaeniorhynchus, C. vishnui and C.pseudovishnui.
laboratory based sentinel surveillance in 15 endemic
Culex mosquitoes generally breed in water bodies with
states in India. The system starts reporting separately
luxurious vegetation like irrigated rice fields, shallow
AES and JE cases.
Figure 1 represents the number of AES and JE ditches and pools. Culex mosquitoes are zoophilic, feed
positive cases in India since 2008 collected, collated and primarily on animal and wild birds. In monsoon and
analyzed through this established routine surveillance postmonsoon period, when the vector density is high,
system between 2008 to 2013. It is observed that there is the epidemic of JE usually occur. Female mosquitoes get
a gap between the total AES and JE positive cases over infected after feeding on a viaemic host and can transmit
the years; the percentage of JE cases as proportion of the virus to other hosts after an extrensic incubation
total AES varied from 8.93% to 14.72%. This represents period of 9 – 12 days. The mosquitoes remain infected
that AES is not synonymous with JE, rather in contrast for life. The average life period of a mosquito is about
to earlier belief, AES is a spectrum of diseases with 21 days. Culex mosquito can fly for long distances (1–3
equal contribution of JE and non-JE etiology. Moreover km or even more). The transmission cycle is maintained
after starting the widespread JE vaccination it has been in animals and birds. Infection in man is incidental
observed a paradigm shift of AES from JE to non-JE and occur by bite of infected mosquito when man stays
infections. From the surveillance data it has also been close to the animal reservoir (amplifying host). Man to
observed that more than 90% of the total AES cases have man transmission has not been documented. So man is
been reported from 5 endemic states in the country the dead end of the transmission cycle. The incubation
viz., Assam, Bihar, Uttar Pradesh, Tamil Nadu, and West period in man, following mosquito bite varies from
Bengal. JE cases are increasingly being reported from 5 days to 15 days.
558 SECTION 8: Infections
Fig. 1: State-wise mean AES incidence in India (Collected from NVBDCP website)
like ocular palsies, piramidal and extrapyramidal signs HSV encephalitis, although other herpes viruses (e.g.
in the form of hemiplegia, quadriplegia, dystonia, VZV, EBV, human herpes virus 6) can also produce
choreoathetosis and coarse tremors. same clinical picture.
Involvement of the thalamus or basal ganglia is very
Differentiation of Japanese Encephalitis much suggestive of arboviral diseases like JE. Others
and Non-JE, AES may be encephalitis due to respiratory viral infection
During epidemic all cases of acute fever with altered and Creutzfeldt-Jakob disease.
sensorium persisting for more than two hours with The presence of hydrocephalus may suggest nonviral
a focal seizure or paralysis of any part of body, is etiologies, such as bacteria (Tuberculosis), fungal, or
suggestive of encephalitis. Presence of rash with fever parasitic agents.
CHAPTER 91: Acute Encephalitis: Indian Scenario 559
A B
Figs 2A and B: MRI image of temporal lobe enhancement. (A) In herpes simplex encephalitis;
(B) T2W and flair MRI image in Japanese B encephalitis patient
TABLE 2: Location of abnormal signal of demyelination in MRI viral encephalitis are increased white blood cell count
scan suggesting specific etiologies (usually less than 250/mm3), the differential showing
Disease Japanese Non-JE AES a predominance of lymphocytes (early infection may
encephalitis reveal a predominance of neutrophils), elevated protein
Relation to onset of About 6 weeks after Starts within 3 days concentration (usually less than 150 mg/dL) and normal
rains onset of rain after onset of rain
glucose concentration. Presence of red blood cells in CSF
Pain abdomen No 50%
(in a nontraumatic tap); is suggestive of HSV-1 infection
Diarrhea No 50%
or other necrotizing encephalitis. Specific diagnostic
CSF examination Lymphocytic Normal except in
tests for etiologic diagnosis include polymerase chain
finding pleocytosis increased ICT
reaction (PCR) tests for viruses, culture for bacteria, fungi
CT scan of brain Hypodense in Middle cerebral
thalamus artery infarction and mycobacteria and serology for the arboviruses.
MRI brain Hyperintensity in Middle cerebral
thalamus artery infarction Serology
The detection of virus specific IgM antibody (MAC
CT scan of brain is only useful to rule out space- Elisa) can provide definitive diagnosis rapidly on
occupying lesion or brain abscess. a single specimen of CSF. This class of antibody is
present in body fluids only for 1–3 months and thus
Electroencephalography presence of IgM antibody in body fluid denote acute JE
Electroencephalography usually shows abnormal spicks encephalitis. Viruses for which detection of virus-specific
in acute encephalitis. Spicks in the temporal lobe region IgM antibodies are available include JEV, dengue,
is suggestive of HSV encephalitis. chikungunya, West Nile, measles, rubella, and mumps.
abnormal in the presence of inflammatory disease of the is 200 mg/kg/day-12 g/day IV Q6h in adult) must be
CNS. The CSF pressure should be usually high in case given, which can be stopped when investigation does
of encephalitis. Other common CSF abnormalities in not reveal bacterial meningitis.
560 SECTION 8: Infections
Even though epidemiological data on herpes simplex TABLE 3: Therapeutics agents commonly used in encephalitis
encephalitis from India is lacking, the consensus Indication Typical dosing/administration*
recommendation of the expert group is that acyclovir Cerebral edema Mannitol 0.25 – 1 g/kg bolus every 4–6 hours
(Dose is 10 mg/kg IV Q8h) must be started in all Hypertonic saline
cases of sporadic viral encephalitis, keeping in mind Active brain herniation, 23% daline (30 mL
bolus via central venous access)
that HSE is a treatable disease. Acyclovir should be
Maintenance, 2–3% saline (250–500 mL
stopped if an alternative diagnosis has been made boluses or continuous venous infusion; 3%
like CSF serology positive for ZE, or HSV PCR in the saline via central venous access)
CSF is negative. Seizures status
epilepticus
Increased intracranial pressure: Symptoms and signs
First line, initial Lorazepam 0.1 mg/kg IV up to 4 mg per dose
of increased intracranial pressure include headache,
dosing Midazolam 0.25 mg/kg IM up to 10 mg
vomiting, and a decreased level of consciousness. The maximum
following steps are used in the management of raised Diazepam 0.15 mg/kg IV up to 10 mg
intracranial pressure. The patient should undergo Second line, Fosphenytoin 20 mg PE/kg IV
intubation if the GCS is less than 8, or if there is evidence initial dosing Levetiracetam 1,000–3,000 mg IV
Valproate sodium, 20–40 mg/kg IV
of uncal or cerebellar herniation, or if the patient has
Third line, Propofol 1–2 mg/kg
irregular respirations and inability to maintain airway. If loading dose Phenobarbital 20 mg/kg IV
there are signs of impending herniation, then the patient Pentobarbital 5–15 mg/kg IV
should be hyperventilated to a target PaCO 2 of 30– Herpes simplex Acyclovir, 10 mg/kg IV q8 hours × 14-21 days
35 mm Hg. encephalitis
control groups. Studies are ongoing to investigate other Reduction in man-vector contact; and
JE Vaccination in India the presence of other agents calls for designing and
Two types of JE vaccines are available in India: implementing novel preventive strategies that would
1. Inactivated vaccine derived from vero cell prepared focus on containment of water-borne enteroviruses and
from an Indian strain of Japanese encephalitis virus vectors for Chandipura virus. This will need a multisector
(JENVAC). This vaccine is very safe and effective for approach involving health, water resources, sanitation
all known strains of Japanese encephalitis. Two doses and rural development departments. Recently, the
of this vaccine given 1 month apart will have sero thought process on such an approach has been initiated.
conversion of around 98% in population of more than In addition, we also need to move from JE surveillance
1 year and up to 55 years of age. to surveillance for the entire spectrum of AES, so that
2. The recently introduced Chinese live attenuated evidence based public health actions can be planned
SA-14-14-2 JE vaccine now available in the routine and carried out.
i m mu n i z at i o n i n c h i l d re n u n d e r Un i ve r s a l
Immunization Program in the 181 endemic districts BIBLIOGRAPHY
of India since 2011. In 3rd July 2014, the Government 1. Gore MM. Acute encephalitic syndrome in India: Complexity
of the problem. J Commun Dis. 2014;46(1):35-49.
of India had announced the introduction of single
2. Guideline of clinical management of acute encephalitic
dose of JE vaccine for adults in endemic districts. syndrome including japanese encephalitis. Directoraye
In the state of Assam, West Bengal and Uttar Pradesh of National Vector Borne Disease Control Programme
NVBDCP has identified 20 hyperendemic districts for Government of India, August 2009.
introduction of adult JE vaccination (>15–65 years). 3. Joshi R, Kalantri SP, Reingold A , Colford JM. Jr.
Till now, eight districts have been covered by the adult Changing landscape of acute encephalitis syndrome in
India: A systematic review. Natl Med J India. 2012;25:212-
vaccination programme.
20.
4. Operational Guideline: National Programme for Prevention
Recent Trends of AES in India and Control of Japanese Encephalitis/Acute Encephalitis
In recent years, investigations into large outbreaks Syndrome; Ministry of Health and Family Welfare, Govt of
of AES have been negative for JEV (or a flavi virus). India; 2014.
Instead outbreaks were found to be due to a rhabdo- 5. Ravi V, Mani R, Govekar S, Desai A, Lakshman L, Ravikumar
BV. Aetiology and laboratory diagnosis of acute encephalitis
virus (Chandipura virus), or water-borne entero viruses.
syndrome with special reference to India. J Commun Dis.
Factor might account for entero viruses replacing JEV 2014;46(1):12-23.
as the major cause of AES is JE vaccination campaigns, 6. Sen PK, Dhariwal AC, Jaiswal RK, Shiv Lal, Raina VK, Rastogi
launched in endemic districts, may have brought A. Epidemiology of acute encephalitis syndrome in India:
about this shift. The introduction of JE vaccination in Changing Paradigm and Implication for Control. J Commun
endemic regions reduced the overall incidence of AES. Dis. 2014;46(1):4-11.
7. Suri V, Narang U, Bhalla A. Viral encephalitis in India:
The emergence of non-JEV etiologies in outbreaks
Management Update: Update on Tropical Fever.
and surveillance studies directly impacts preventive 8. Vashishtha VM, Ramachandran VG. Vaccination Policy for
measures for AES. While vector control programs Japanes Encephalitis in India: Tread with Caution : Indian
and JEV vaccination remain important strategies, Pediatrics; 2015. p. 52.
CHAPTER
92
Tropical Fever: A Case-based Approach
Manoranjan Behera, Sidhartha Das, Jayant Kumar Panda
infection. Like proper history, a quick, judicious clinical TABLE 1: Differential diagnosis of physical findings for some
examination is also equally important in arriving at a tropical infections
provisional diagnosis. Localizing clinical feature like Physical finding Differential diagnosis
headache, seizure, altered sensorium; arthralgia and Lymphadenopathy HIV, rickettsioses, brucellosis, leishmaniasis,
myalgia; photophobia, conjunctivitis; skin rashes, infectious mononucleosis, tuberculosis,
bleeding, localized dermal lesions; lymphadenopathy, toxoplasmosis, melioidosis, lymphatic
filariasis
hepatosplenomegaly; jaundice, and anemia are
Hepatomegaly Malaria, typhoid, viral hepatitis, leptospirosis,
important in making a probable diagnosis (Tables 1
leishmaniasis, schistosomiasis, liver abscess
and 2). The geographic and travel history (inside (amoebic or pyogenic) dengue
the country and abroad, both recent and past) are of
Splenomegaly Malaria, typhoid, typhus, leishmaniasis,
immence importance. Information regarding areas with trypanosomiasis, brucellosis, acute or chronic
recent outbreaks (e.g. HINI/H5NI influenza, dengue) can schistosomiasis, tuberculosis, toxoplasmosis
be of immence help in diagnosing the clinical entity. The Jaundice Viral hepatitis, malaria, leptospirosis, dengue,
onset of illness in relation to known incubation periods scrub typhus
and time of possible exposure can be of great help to
establish or exclude various infectious diseases. Wheezing Löffler’s syndrome, tropical pulmonary
eosinophilia
Since the clinical features of many infections may
overlap with one another and with severe bacterial
sepsis, and sometimes presence of coinfections,
practically it may be very difficult to arrive at a diagnosis TABLE 2: Skin lesions associated with tropical infections
at the time of presentation. Hence, a practical approach Skin lesion Differential diagnosis
is to group these constellations of symptoms and signs
Maculopapular Arbo-viruses, acute HIV, rickettsiae, secondary
in a syndromic fashion so as to enable the physician to rash syphilis, typhus, typhoid, rubeola, rubella,
reach at a probable diagnosis and start emperic therapy disseminated gonococcal or meningococcal
at the earliest. Though it is known that a syndromic infections
approach may not be able to cover atypical or unusual Petechiae/ Rickettsioses, meningococcemia, viral
presentations of common tropical illnesses, yet it can be ecchymoses hemorrhagic fevers, dengue, leptospirosis,
septicemia and disseminated intravascular
of immence value in guiding the physicians for initiating
coagulopathy
therapy in critically ill patients during emergency
Eschars Tick bite fever, scrub typhus, anthrax
hours. The tropical infections may have the following
“syndromic approach”. Nodules Onchocerciasis, leprosy, atypical mycobacteria,
erysipeloid, erythema nodosum
Acute Febrile Encephalopathy/Acute Fig. 1: A case of Falciparum malaria with severe anemia and icterus
Encephalitic Syndrome
hepatosplenomegaly may be present. The features of
Acute febrile illness with altered sensorium, the common
severe malaria may be cerebral malaria, severe anemia,
differential diagnoses are:
Encephalitis: Herpes simplex virus, Japanese B,
hypoglycemia, metabolic acidosis, acute kidney injury,
ARDS, shock (algid malaria), DIC, hemoglobinuria,
enterovirus and other viruses.
Meningitis: S. pneumoniae, N. meningitides, H.
hyperparasitemia (>5%) alone or in combination
(Fig. 1). Diagnosis is established by either microscopy
influenzae, enteroviruses.
Others: Cerebral malaria, typhoid encephalopathy,
(Thick smear: parasite detection; thin smear: species
identification), quantitative buffy coat test (QBC) or rapid
scrub typhus.
diagnostic tests (RDTs): histidine rich protein, lactate
Fever with Multiorgan Dysfunction dehydrogenase antigen based immunochromatography.
Possibility of malaria is excluded if two RDTs reports are
The common causes are Falciparum malaria, lepto
negative. Treatment should be antimalarials as per latest
spirosis, scrub typhus, bacterial sepsis, dengue, hanta
WHO recommendations.
virus infection, hepatitis A or E with fulminant hepatic
failure and hepato-renal syndrome, hemophagocytosis
and macrophage activation syndrome.
Dengue Fever
Dengue fever is clinically characterized by an acute
As many infections can have overlapping presen
febrile illness of 2–7 days duration with two or more
tations and there can be coinfections, it is essential
of the following manifestations: headache, retro-
that a physician should be well aware of the common
etiological agents and their epidemiology in the defined orbital pain, myalgia, arthralgia, rash, and hemorrhagic
geographic region to be able to make a provisional manifestations without evidences of capillary leak
diagnosis and initiate treatment. (Fig. 2).
Dengue hemorrhagic fever (DHF): A case with clinical
SPECIFIC INFECTIONS criteria of DF plus hemorrhagic tendencies evidenced
The salient features of common tropical infections are by one or more of the following (positive torniquet test,
discussed below. bleeding from skin, mucosal or gastrointestinal tract)
plus thrombocytopenia (<100,000 platelets/cmm) plus
Malaria Fever evidence of plasma leaking due to increased vascular
Clinically character ized by paroxysm of fever, permeability, manifested by one or more of the following
shaking chills and sweats, occurring every 48 or 72 (a rise in hematocrit for age and sex >20% from baseline,
hours, depending on species. Pallor, icterus and pleural effusion, ascites, hypoalbuminemia).
CHAPTER 92: Tropical Fever: A Case-based Approach 565
Fig. 2: Dengue fever with flushed face and suffused conjunctiva Fig. 3: Toxic face of enteric fever
Dengue shock syndrome (DSS): All the above criteria constipation, hepatosplenomegaly, encephalopathy
for DHF with evidence of circulatory failure manifested (2nd week), intestinal bleeding, perforation, multiorgan
by rapid and weak pulse, narrow pulse pressure (<20 dysfunction syndrome (MODS) (3rd week) (Fig. 3).
mm Hg), hypotension, cold and clammy skin and For confirmation of diagnosis, blood culture is the gold
restlessness. standard method during 1st week of fever, positive in
40-80% of patients; bone marrow culture is one of the
Expanded dengue syndrome (EDS): Unusual or atypical
most sensitive method (sensitivity 80–95%), may remain
manifestations of organ dysfunction; encephalitis,
positive after several days of antibiotic treatment or
myocarditis, hepatitis, renal failure, ARDS or associated
regardless duration of illness; widal test is nonspecific.
with various coinfections (e.g. malaria, leptospira), RDT: Typhoid test is also very useful, sensitivity 95–97%,
or associated with comorbidities. For confirmation of specificity >89%. Treatment : Ceftriaxone IV 50–75
dengue infection National Vector Borne Diseases Control mg/kg/day for 10–14 days. Can use azithromycin and
Programme (NVBDCP) recommends use of ELISA-based ciprofloxacin or ofloxacin alternatively.
antigen detection test (NS1) for diagnosing the case from
the first day onwards (usually up to day 5) and antibody Scrub Typhus
dection test IGM capture ELISA (MAC-ELISA) for Clinically characterized by fever, headache, myalgia,
diagnosis the cases after the fifth day of onset of illness. breathing difficulty, jaundice, vomiting, cough, delusion,
DF can be managed symptomatically. As DHF is a maculopapular rash and eschar (Fig. 4). Most important
volume depleted state due to capillary leak, isotonic complicatoins are pneumonia with ARDS, hepatitis,
fluid infusion just sufficient to maintain effective aseptic meningitis, myocarditis, ARF, and DIC. Diagnosis
circulation during the period of plasma leakage guided is established by indirect fluorescent antibody detection
by serial hemotocrit measurements is the cornerstone of test which is the ‘gold stanard’ and specific. Weil-Felix
management. Blood transfusion or platelet transfusion test is of poor sensitivity and specificity, ELISA based
can be done as per WHO/NVBDCP guidelines. detection of IgG and 1gM antibodies are sensitive
and specific in >90% cases. Doxycyline is the drug of
Enteric Fever choice for management. Azithromycin or Rifampicin or
Clinically characterized by fever, headache, relative chloramphenicol can be used as alternatives in children
bradycardia (1st week), abdominal pain, diarrhea or and pregnant women.
566 SECTION 8: Infections
Fig. 4: Eschar and maculopapular rash Fig. 5: Icterus and subconjunctival hemorrhage of a case of
of a case of Scrub typhus leptospirosis
Emperical use of antimalarials should be discouraged scrub typhus, enteric fever and acute pyogenic meningitis.
as indiscriminate use may potentiate drug resistance. However, if the patient fails to respond to empirical
With the changing pattern of tropical infections, it therapy in ensuing 48 hours, then the patient should
is preferable and safe to use ceftriaxone along with be reviewed for alternative diagnosis, complication and
doxycycline in most cases as they tend to cover management. Table 3 and Flow chart 1 describes the
most common treatable infectins and the results are management protocol for tropical fevers.
encouraging. This combination covers leptospirosis,
Flow chart 1: An algorithmic approach for the diagnosis and management of critical tropical infections
3. Hai Err, Viroj Wiwanitkit. “Syndromic approach” to diagnosis M Chugh TD, Rungta N. Tropical Fevers: Management
and treatment of critical tropical infections. Indian J Crit guidelines. Indian J Crit Care Med. 2014;18(2):62-9
Care Med. 2014;18(7):479. (Reproduced with Permission)
4. John TJ, Dandona L, Sharma VP, Kakkar M. Continuing 6. WHO, India. National Guidelines for Clinical Management
challenge of infectious diseases in India. Lancet. 2011; of Dengue Fever, National Vector Borne Disease Control
377:252-69. Programme; 2015.
5. Singhi S, Chaudhari D, Varghese GM, Bhalla A, Karthi N,
Kalantri S, Peter JV, Mishra R, Bhagchandani R, Munjal
CHAPTER
93
Vivax Malaria: No Longer Benign!
K Nagesh
INTRODUCTION EPIDEMIOLOGY
Historically, malaria is as old as the mankind itself. King In the 21st century, malaria still continues as the greatest
Alexander in 323 BC developed fever during a war, which killer in the tropical countries including India. It ranks
increased day by day and finally he drifted into coma one among the ten leading killer diseases in the world.
and died. This 33-years-old warrior, who had conquered Half of the world’s population across hundred countries
almost all the known world, at the height of his power are still living under the dark shadow of malaria (Fig. 1).
died of a disease called ‘Malaria’. In the ancient wars, About 300–500 million cases are being reported every
malaria has killed more people than the actual weapons; year across the globe, killing around one million people
but for malaria, the results of many wars, the destiny of per year.
many kings and the geographical boundaries would have In India, malaria is prevalent all over except Jammu
been different. and Kashmir (Fig. 2). 77% of the burden of malaria in
South East Asia is from India, 40% of the global Malaria Plasmodium ovale
death outside Africa is in India. Plasmodium malariae
It is very unfortunate that, though malaria is pre Plasmodium knowlesi
ventable and potentially curable; in the battle between Plasmodium vivax and Plasmodium falciform are the
malaria and mankind, malaria still has the upper hand two dominant species in India. Plasmodium knowlesi is
(Fig. 3).1 not reported in our country.
Fig. 3: Global mortality due to malaria for the last three decades1
contributed by Vivax malaria. Compared to Plasmodium TABLE 1: Comparison of organ involvement (Severe P. vivax vs P.
falciparum, Plasmodium vivax has got slightly longer falciparum malaria)5
incubation period (12 days to several months), similar Organ system Vivax malaria Falciparum malaria
N=488 N=233
erythrocytic cycle (42–48 hrs) and produces fewer
Thrombocytopenia 435 (89.13%) 178 (79.82%)
merozoites per schizont. As Plasmodium vivax require
Hepatic 95 (9.46%) 81 (36.32%)
duffy antigen to invade host erythrocytes, it is less
Renal 156 (31.96%) 123 (55.15%)
common in sub Saharan Africa. Recently, this has been
Cerebral 40 (8.19%) 32 (14.35%)
challenged by the observation that Plasmodium vivax
Lungs 8 (1.63%) 5 (2.24%)
transmission in a population found to be duffy antigen
Deaths 44 36
negative,3 however further studies are needed in this
% Deaths 9.01% 16.14%
regard. Plasmodium vivax has apparent preference for
invading young red cells in contrast to falciparum, which
vivax malaria has started showing its malignant face.
invades broader range of erythrocyte ages. A proportion
The severe complications with organ involvements like
of sporozoites persistently remains in the hepatocytes
ARDS, acute renal failure, hepatitis, coma, severe anemia,
as hypnozoites, which can cause relapse of infections in
thrombocytopenia, DIC have been reported in vivax
few weeks to many years. This ability to relapse renders
malaria from all across the endemic countries including
Plasmodium vivax resilient to eradicate from human
India” (Table 1).2,4-7,15
host.
In asia, Plasmodium vivax is emerging as a dominant
species, with chloroquine resistance starting to spread,
MALIGNANT BEHAVIOR OF makes it an important health issue. Severe fatal drug
PLASMODIUM VIVAX resistant severe vivax malaria challenges our perception
For centuries, Vivax malaria was called as ‘benign of vivax malaria as a benign disease. It has been neglected
tertian malaria’, it was believed as, it does not cause under the shadow of Plasmodium falciparum by the
organ involvement, no mortality, can be managed on researchers, policy makers and the funding bodies.
outpatient basis with oral medication. “Of late this benign Although the emphasis on Plasmodium falciparum is
CHAPTER 93: Vivax Malaria: No Longer Benign! 573
appropriate the burden of vivax malaria should not be polyarthralgia, dry cough, acute abdomen, psychosis,
under appreciated.2 frequent urination, ataxia, acute GE, jaundice, coma, etc.
Plasmodium vivax has started punching above its weight. Malaria can mimic anything and everything, physicians
practicing in endemic areas should develop a high degree
PATHOPHYSIOLOGY of suspicion.
The exact pathogenesis of this malignant behavior
of Plasmodium vivax remains unclear and poorly CLINICAL CLASSIFICATIONS
understood, because of paucity of researches in this field, Uncomplicated malaria
however the possible postulations are: Severe malaria
Although cytoadherence and sequestration is known Uncomplicated malaria is one where the patient does
to be the main mechanism for severe falciparum not exhibit any organ involvement, generally does not
malaria, the same is not a feature in Plasmodium carry any mortality. The term complicated malaria has
vivax. Recently, this paradigm has been challenged been given up and has been replaced by the term “severe
suggesting that Plasmodium vivax infected red cells malaria”.
can also sequestrate in organs such as lung.8
Few studies have clearly demonstrated that severe Severe Malaria
Vivax malaria is strongly associated with potent Patient who is found positive for malaria parasite
proinflammatory response and ‘cytokine storm’. and if has any one of the feature listed in Table 2, is
Interferon gamma (IFN) is also implicated in disease supposed to be suffering from severe malaria.
severity. Conversely plasma interleukin-10 (IL-10), Severe malaria is a medical emergency.
a cytokine that down regulates inflammation, was If untreated/missed, carries mortality near to 100%.
lower with increased disease severity.9 All deaths in malaria are due to severe malaria.
The direct lytic effect, immunological reaction, splenic Urgency and aggressiveness is the key to success.
sequestration and oxidative stress are some of the IV antimalarial should be used in preference.
suggested mechanism for severe thrombocytopenia
in Vivax malaria.10 Lab Diagnosis
Altered rheological properties of parasitized red Parasitological confirmation is mandatory before starting
cells and vascular endothelial changes contribute antimalarial treatment.12
to the microvascular obstruction. New evidence Microscopy
and generalized ischemic hypoxia may enhance Quantitative buffy coat (QBC)
Bone marrow studies ACT should be given for at least three days.
Polymerase chain reaction (PCR) Primaquine: single dose of 0.75 mg/kg body weight
Microscopy with thin and thick smear is still the on day 2, 13 and 0.25 mg/kg body weight in low
gold standard for the parasitological confirmation of transmission area.12
malaria. One can identify the species and also quantify
the paracytemia. The disadvantages are it is time Second Line Treatment
consuming, needs skilled personnel. A negative smear Alternative ACT
does not rule out malaria in a strongly suspected case, or
repeated smear examination may be needed. Rapid Oral Artesunate + Doxycycline/Clindamycin for
diagnostic tests (RDT) are simple, easy to perform, yields 7 days
quick and reliable results, has been fully approved by or
WHO for the confirmation of malaria. The disadvantages Oral Quinine + Doxycycline/Clindamycin for 7 days
of RDT are, one cannot quantify and may remain positive
Oral Artesunate monotherapy has been banned in India.
for several weeks after the acute infection, hence should
not be used to detect recrudescence. The QBC is almost
Management of Severe Malaria12,13
equalent to a good thick and thin smear examination.
IV artesunate 2.4 mg/kg, 0 hr, 12th hr and 24th hr,
Bone marrow studies are not routinely recommended
then once daily.
except in a desperate situation to prove the diagnosis
IV quinine may be used if only IV artesunate is not
in a rare case. PCR tests should be reserved for research
available in the dose of 20 mg/kg stat and then 10 mg/
purposes considering its cost and nonavailability in
kg every 8th hrly, (IV infusion in dextrose over 4 hrs).
peripheral centers.
Artimether 3.2 mg/kg IM on admission then 1.6 mg/kg
IM OD.
MANAGEMENT
Alpha-beta artether 150 mg IM, OD for three days.
Treatment of uncomplicated P. vivax malaria:12
IV antimalarial should be given for a minimum of
Chloroquine 25 mg base/kg body weight divided over
24 hrs, thereafter ACT may be started
three days.
Supportive measures like antipyretics, anti
Primaquine 0.25 mg/kg once daily for 14 days.
convulsants, good oral and intravenous hydration,
Chloroquine resistant vivax should be treated with
should be taken care. Artificial ventilation, blood
Artemisinin based combination therapy (except AS
transfusion and dialysis may be considered if
+SP) + Primaquine.
indicated.
Primaquine is contraindicated in pregnancy, infancy,
mothers breast feeding infants less than six months of Revised dose recommendation for parenteral Artesunate in
age and in patients with G6PD deficiency. young children:12
Children weighing <20 kg should receive a higher dose of
Treatment of uncomplicated PF malaria: Artesunate (3 mg/kg bw per dose) than larger children and adults
ACT is the treatment of choice (Table 3) (2.4 mg/kg bw per dose) to ensure equivalent exposure to the drug.
Liquid Culture
At present liquid cultures are regarded as the “Gold
Standard” for detection of mycobacterial susceptibility
Fig. 1: BACTEC MGIT 960 system (BD, USA)
to anti-tubercular drugs. The significant advantages of
liquid medium are:
—— MB Redox (biotest diagnostics, USA)
The sensitivity for the growth of M. tuberculosis has
Semiautomated system
seen a significant increase (up to 20%), and
—— BACTEC 460TB (BD, USA)
A significant reduction in detection time (10–14
Fully automated systems
days compared with up to 4 weeks). The drawback
—— BACTEC 9000 MB (BD, USA)
is a higher rate of contamination of liquid medium.
—— BACTEC MGIT 960 (BD, USA) (Fig. 1)
For primary isolation of mycobacteria, WHO has
—— ESP culture system II (Trek Diagnostics, USA)
recommended the use of traditional solid media
—— MB/BacT ALERT 3D system (BioMerieux, NC)
along with liquid media.
Liquid medium most frequently used is Middlebrook
RAPID DETECTION OF DRUG
7H9 broth. It is supplemented with 10% OADC (oleic
acid, albumin, dextrose, and catalase) and, to prevail
RESISTANCE: IN-HOUSE METHODS
over contamination with other microorganisms, PANTA Advantages of these in-house methods are rapid
(an antibiotic mixture of polymyxin, amphotericin detection of drug-resistance under low-income settings.
B, nalidixic acid, trimethoprim, and azlocillin) is Some of these methods are as shown below:
Microscopic observation of drug susceptibility
added. Mycobacteria Growth Indicator Tube (MGIT) is
considered as the best tool with regard to sensitivity, (MODS)
Thin layer agar (TLA)
while LJ solid medium sets the current standard for
Colorimetric redox indicator (CRI) methods
specificity. Liquid media may provide positive results
Nitrate reductase assay (NRA)
in about half of time that is required for those in case of
solid media. All types of clinical specimens, pulmonary
as well as extra-pulmonary (except blood and urine), Microscopic Observation Drug
can be processed for primary isolation in the MGIT tube Susceptibility (MODS) Assay
using conventional methods. At present, a number of The microscopic observation drug susceptibility (MODS)
commercially available elaborate culture systems are in assay is a low-tech as well as a low-cost tool for detection
existence: of tuberculosis and drug resistance tuberculosis. The
Simple system underlying principles being:
—— MGIT (BD diagnostic systems, USA) The growth of M. tuberculosis (MTB) is faster in liquid
M. tuberculosis growth in liquid media is characterized propensity to reduce nitrate to nitrite which is detected
by microscopic appearances of cording, strings or by adding a specific reagent like Griess reagent.
tangles making them to be noticed much earlier than These low cost in-house methods have almost
waiting for the macroscopic appearance of colonies comparable precision to commercial liquid culture
on solid media. systems. These methods can be implemented in high-
It is possible to integrate the antitubercular drugs burden, low-income settings as an intermediate solution
like isoniazid and rifampicin into the MODS assay to significantly reduce the cost of overall national
to have a concurrent confirmation of drug resistance programs. There drawbacks include the requirement
tuberculosis directly. of extensive operator training, standardization and
MODS culture offers faster and more sensitive results quality assurance before implementation. WHO
than existing gold-standard methods. It provides side- has recommended MODS as an interim solution for
by-side detection of drug resistance tuberculosis and developing countries with low incomes that are waiting
being a low cost in-house tool may become feasible in for the regular implementation of liquid culture methods
a resource-limited settings. The disadvantages of the in their respective National Tuberculosis Control
MODS include Programmes.
1. requirement of an inverted microscope, which is
costly and not routinely available in laboratories,
DIAGNOSIS OF TB BASED
2. microscopically, differentiation between micro ON DNA TOOLS
colonies of Mycobacterium tuberculosis and those of For over two decades, numerous tools have been
rapidly growing mycobacteria may be difficult, and develop e d and des cr ib e d for the dete ction of
3. the assay requires daily examination, is time- M. tuberculosis using technology of polymerase chain
reaction (PCR) assay. The principle is to amplify a DNA
consuming, and carries a risk of laboratory trans
fragment specific for M. tuberculosis using appropriate
mission.
oligonucleotide primers that vary from tool to other tool.
One method incorporates polymerase chain reaction
COLORIMETRIC REDOX
(PCR) and restriction enzyme analysis (PRA) of the gene
INDICATOR METHODS
coding for the heat shock protein hsp65.
The method employs a preincubation of M. tuberculosis
Other method uses the amplification of the 16S
containing clinical specimen for several days in vitro rRNA gene specific for M. tuberculosis. This can be done
added with different antitubercular drugs and in different either by an in house methods or using a commercially
drug concentrations. This is followed by culture in a available kit : the MicroSeq 500 16S ribosomal DNA
liquid media to which added a colored indicator (Alamar (rDNA) bacterial sequencing kit (Applied Biosystems,
blue and Resazurin) in a microtiter plate. Colorimetric Foster City, Calif.).
redox indicator (CRI) methods are characterized by A commercially available method named as
the reduction of this colored indicator. Mycobacterial AccuProbe (Gen- Probe Inc.) uses a chemiluminescent
resistance to antitubercular drugs lead to a change in label that hybridizes to the ribosomal RNA of the targeted
color of the indicator. The change of color is proportional mycobacteria in clinical specimen. The results of the test
to the number of viable mycobacteria in the medium. are read using a luminometer and rapid diagnosis can be
achieved. Separate tools for the identification of various
Nitrate Reductase Assay mycobacteria species are available.
Nitrate reductase assay (NRA) requires culture of clinical
specimen containing mycobacteria over a solid media Nucleic Acid Amplification Tests
(conventional Lowenstein-Jensen medium) into which The nucleic acid amplification (NAA) tests are noteworthy
potassium nitrate has been added. M. tuberculosis has due to rapidity to provide the results within 6 hours.
CHAPTER 94: Newer Modalities in Diagnosis of Tuberculosis 579
A comparison with smear microscopy highlights the contamination and no requirement for biosafety facilities.
importance of NAA tests in term of having (1) better Diagnostic accuracy of this technique in term of sensitivity,
positive predictive value (over 95%) in settings in which specificity, positive predictive value and negative
non-tuberculous mycobacteria are common, and (2) predicted value for diagnosis of pulmonary tuberculosis
ability to detect M. tuberculosis in 50–80% of smear- were 79.5%, 100%, 100% and 94%, respectively and those
negative, culture-positive clinical specimens. for the detection of rifampicin resistance were 57.1%,
NAA tests are superior to culture methods in term 100%, 100% and 94.9%, respectively. The WHO has
of detecting M. tuberculosis weeks earlier than culture
endorsed the use of nucleic acid amplification tests in
in up to 90% of patients suspected with pulmonary
resource-limited settings since 2008.
tuberculosis in whom TB is ultimately confirmed by
culture. Still, a recent meta analysis considering accuracy
Loop-mediated Isothermal Amplification
of commercially available NAA tests in over 125 studies
noted an unacceptably high degree of variability in Test (LAMP)
accuracy across the studies. The meta-analysis noted The method is commercially made available by Eiken
a need for improvement in diagnostic accuracy of Chemical Co., Japan. This technology amplifies target
NAA tests. This was assessed that presently available DNA under isothermal conditions (at 65°C) and is
commercial NAA tests cannot replace “Gold Standard” intended to detect mycobacterial DNA visually in less
culture and microscopy for diagnosing pulmonary TB. than two hours. The step to denature double stranded into
Current US recommendation is “NAA testing should be a single stranded form is not required. Amplification and
performed on at least one respiratory specimen from detection of the DNA takes place in the same microfuge
each patient suspected with pulmonary TB for whom a tube (Fig. 3). WHO is conducting independent studies to
diagnosis of TB is being considered but has not yet been assess the feasibility and cost-effectiveness of the assay
established, and for whom the test result would alter case and whether it can replace sputum smear microscopy.
management or TB control activities.”
Various NAA tests commercially available are: Line Probe Assays
Amplified Mycobacterium tuberculosis Direct Test
The individual anti-tubercular drug resistance in M.
(MTD, Gen-Probe, San Diego, California)
Amplicor Mycobacterium tuberculosis Test (Amplicor,
tuberculosis is often characterized by mutations in well
described genes. The extensive knowledge regarding
Roche Diagnostics, Basel, Switzerland)
GeneXpert (Xpert MTB/RIF)
genes associated with drug resistance enabled the
Loop-Mediated Isothermal Amplification Test
development of line probe assays, which allow for the
(LAMP) (Eiken Chemical Co., Japan) simultaneous detection of multiple resistances rapidly
within 24–48 hours. Line probe assays have proven
GeneXpert (Xpert MTB/RIF) efficacy in detecting drug resistance tuberculosis in
This is a commercially available cartridge-based system a variety of geographical settings. It is observed to be
to detect M. tuberculosis as well as rifampicin resistance cost-effective when compared with mycobacterial
in a clinical specimen in flat 2 hours. The fully automated culture followed by DST. Two of the commercial systems
system purifies, concentrate, detect and identify available for the rapid identification are:
targeted nucleic acid sequences and do not require any 1. INNO-LiPA MYCOBACTERIA v2 (Innogenetics NV,
preprocessing of clinical samples. It utilizes real-time Ghent, Belgium),
PCR (rt-PCR) technology. 2. GenoType mycobacterium CM/AS tests (Hain
The test is module based and machines with 1, 4, Lifesciences, Nehren, Germany).
16 and 48 modules are available, with each module The WHO has recommended LiPA for the rapid
independently processing one cartridge at a time; diagnosis of MDR-TB in high TB-burden, low-income
(Fig. 2). The system is fully closed so there is no risk of settings.
580 SECTION 8: Infections
Fig. 2: GeneXpert MTB/RIF four module system. Placing of GeneXpert cartridge is shown here; and GeneXpert MTB/RIF cartridge
filtrate protein, CFP-10. These antigens are are unique to and IgM against M. tuberculosis antigens in serum. They
M. tuberculosis. Two commercially available IGRAs include: have been in use in some parts of the world in past mainly
1. Quantiferon TB Gold tests, Cellestis, Victoria, due to commercial interests. Recent meta-analyses and
Australia systematic reviews after extensive deliberations over the
2. T-SPOT TB, Oxford Immunotec, Abington, UK. subject concluded against serological tests for providing
Superior efficacy of IGRA tests over the TSTs for the inconsistent results due to issues of cross reactivity with
detection of tubercular infection has been described by other mycobacterial antigens and poor sensitivity.
various past studies. IGRAs is not intended to distinguish The WHO recommends against their use for the
between latent infection and active tubercular disease diagnosis of pulmonary as well as extrapulmonary
and should not be used as a biomarker for the diagnosis
tuberculosis and Government of India, through a Gazette
of active TB. This is particularly so in high tubercular
notification, has banned them as diagnostic tests for
infection prevalence regions like India and isolated
tuberculosis disease.
positive IGRA without any clinical and other laboratory
findings cannot be a basis to diagnose active tuberculosis
CONCLUSION
warranting the start of antitubercular drugs.
The diagnostic modalities presently available for clinical
SEROLOGICAL DIAGNOSIS OF TB management of tuberculosis diagnosis and identification
There have been numerous studies in past aimed at of drug resistance tuberculosis are concisely summarized
detection of antibodies like immunoglobulins IgG, IgA in Table 1.
Stage of Remission
This initial stage is followed by a period of remission with
clinical improvement and most patients recover fully.
Fig. 1: Aedes aegypti
Stage of Intoxication
The virus can be transmitted from monkey to human or
The symptoms may recur after 24–48 hours in 15 to 20%
from human to human via mosquitoes bite in this cycle.
of patients and progress to intoxication stage which is
Urban characterized by high fever, relative bradycardia (Paget
In this cycle, transmission of the virus occurs between a sign), hypotension, hemorrhagic manifestations (nasal,
viremic humans infected in the jungle or savannah and oral, gastrointestinal), severe hepatic dysfunction
urban mosquitoes, primarily Aedes aegypti (Fig. 1). and jaundice (hence it is called “yellow fever”), renal
People cannot spread yellow fever among themselves failure, cardiovascular dysfunction, delirium and central
through casual contact, although the infection can be nervous system dysfunction which may progress to
transmitted directly into the blood through contaminated coma, and shock. Antibodies may be detected during
needles. this stage and viremia has usually resolved in this stage.
There may be 20–60% case fatility range in patients with
PATHOGENESIS severe disease as the treatment is supportive, because no
The viruses replicate in the lymph nodes and antiviral therapies are currently available.
infect dendritic cells after the bite of an infected mosquito.
They reach the liver and infect hepatocytes via Kupffer LABORATORY FINDING
cells, which leads to eosinophilic degradation of cells There may be leukopenia but it may not be present at the
and cytokines are released. Councilman bodies appear onset. Proteinuria as high as 5–6 g/L with kidney disease
in the cytoplasm of hepatocytes after apoptosis. is present, sometimes, and usually disappears completely
with recovery. Bilirubin can be remarkably abnormal
CLINICAL PRESENTATION with the levels of liver enzymes (AST usually doubling
The clinical manifestations may be difficult to recognize those of ALT). Prothrombin time may be elevated as well.
in early stage by most physicians who have never seen Serologic diagnosis is made by using capture ELISA to
a case of yellow fever. Yellow fever is suspected on the measure IgM during the acute and convalescent phases.
basis of clinical presentation and, a definitive diagnosis is Viral culture is used in epidemic settings. Rapid test
confirmed later which requires specialized laboratories. involving PCR and monoclonal antibody assays against
circulating viral antigens are available in specialized
Clinical Illness Manifests in Three Stages laboratories. The plaque reduction neutralization assay
Stage of Infection is the most frequently used test. IgM antibodies are
The incubation period is 3–6 days during which patients shown to persist in up to 73% of recipients 3–4 years after
present with a nonspecific febrile illness that is difficult vaccination.
CHAPTER 95: Resurgence of Yellow Fever: A Great Challenge 585
Hyperferritinemia (Secondary failure. Mainly hepatocytes and Kupffer cells are affected
Hemophagocytic-Lymphohistiocytosis by the virus.
It is a life-threatening condition, it may be seen in primary Heparin sulphate, an acidic glucosaminglycan found
and secondary infection of dengue—it can present as in liver itself, is central to intrusion of the virus in liver cells.
following signs and symptoms: persistent fever, rash, When hepatocytes are infected by DENV hepatocellular
hepatitis, liver failure, seizures, altered sensorium. It apoptosis sets in. This can manifest as liver enzymes
is a dreadful complication and usually unrecognized elevation or fulminant hepatic failure. Management,
condition of dengue fever. just like any other hepatitis case, is primarily supportive.
Prognosis is usually good. However, one must be careful
Diagnostics Guidelines for HLH-2004 regarding the drugs being used in treatment as many
HLH can be diagnosed, if one of either of two criteria (see drugs can worsen the liver damage.
below) is fulfilled.
1. Molecular diagnosis confirmatory of HLH.
2. Diagnostic criteria for HLH fullfilled (5 out of 8 BIBLIOGRAPHY
criteria below) 1. Bhatt S, Gething PW, Brady OJ, et al. The globaldistribution
A. Initial diagnostic criteria: and burden of dengue. Nature. 2013;496(7446):504-7.
Clinical criteria: Fever, splenomegaly 2. Brady OJ, Gething PW, Bhatt S, et al. Refining the global
Laboratory criteria: Cytopenias (affecting ≥ 2 of 3 spatial limits of dengue virus transmission by evidence-
based consensus,” PLoS Neglected Tropical Diseases.
lineages in the peripheral blood)
2012;6(8):Article ID e1760.
Histopathologic criteria: Hemophagocytosis in
3. Chen R, Vasilakis N. Dengue-Quo Tu et Quo Vadis?” Viruses.
bone marrow or spleen or lymph nodes.
2011;3(9):1562-608.
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B. New diagnostic criteria low or absent NK-cell and current status, Novartis Foundation Symposium.
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Dengue viral infections. Postgraduate Medical Journal.
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before initiation of corticosteroids. Early recognition virus and prospects for a vaccine. Annual Review of
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7. Sanofi Pasteur Media Release, http://www.sanofipasteur.
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com/en/articles/First-Vaccinations-against-Dengue-Mark-
severe form dengue infection. The role of steroids, IVIG
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8. Stanaway JD, Shepard DS, Undurraga EA, et al. The global
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HEPATIC COMPLICATIONS 9. World Health Organization, Dengue: Guidelines for
Hepatic involvement can range from asymptomatic Diagnosis, Treatment, Prevention and Control, WHO, Geneva,
elevation of hepatic transaminases to fulminant hepatic Switzerland; 2009.
CHAPTER
97
Scrub Typhus: Need for Alert
Raman Sharma, Sunil Mahavar, Mayank Gupta
Fig. 1: A tough black scab surrounded by elevated red areola neither Fig. 2: A tough black healing scab mimicking a cigarette burn mark
painful nor pruritic
590 SECTION 8: Infections
TABLE 1: Scrub typhus: Prevalence of signs and symptoms As these laboratory findings are relatively nonspecific,
Varghese, et al Sharma R, et al to confirm the presence of O. tsutsugamushi infection
Year of study 2005–2010 2012–2013 four methods can be used more definitively: serology,
Number of cases 623 125 biopsy, culture, and polymerase chain reaction. Serology
Location South India North India is the most used diagnostic tool. Immunofluorescence
Population Local residents Local residents and immunoperoxidase studies are the most reliable.
Signs and symptoms (%) The Weil-Felix test detects cross-reacting antibodies
Fever 100 100
to Proteus mirabilis OX-K and is still used because of
Headache 46 81.6
its low cost but it lacks sensitivity and specificity and
Cough and dyspnea 38 58.4
should be replaced by IFA or ELISA. Polymerase chain
reaction assay carried out on blood, eschar material,
Myalgias — 48
or lymph node samples are useful. Histopathology of
Nausea/vomiting 54 46.5
eschar or generalized rash reveals intense vasculitis with
Altered sensorium 26 20.8
perivascular collection of lymphocytes and macrophages.
Adenopathy — 29
Hepatosplenomegaly — 59.4
DIFFERENTIAL DIAGNOSIS
Eschar 43.5 17.6
The differential diagnosis includes fever of unknown
MODS (Multiorgan Dysfunction) 34 28.86
origin, enteric fever, dengue, dengue hemorrhagic
Case-fatality rate % 9 10.4
fever, malaria, other rickettsioses, tularemia, anthrax,
leptospirosis and infectious mononucleosis.
Varghese et al in South India studied 623 cases of
scrub, in which MODS occurred in (34%) and the overall TREATMENT
case fatality rate was 9%. Sharma R, et al. in North India Owing to the potential for severe complications, diagnosis
studied 125 cases with MODS occurring in 28.86% and a and decision to initiate early treatment should be based
mortality rate of 10.4%. (Table 1) on clinical suspicion or confirmation by serological
Paradoxically, scrub infection has been reported testing.
to lead to a diminution of viral load in human The recommended treatment regimen for scrub
immunodeficiency virus (HIV)-1–infected patients and typhus is doxyc ycline (4 mg/kg/day PO or IV divided
to help restore the immune status of infected patients. every 12 hours, 100 mg BD; maximum 200 mg/day for
7 days).
DIAGNOSIS Alternative regimens include tetracycline (25–50 mg/
As with all rickettsial diseases, no laboratory test is kg/day PO divided every 6 hours, 500 mg QID; maximum
diagnostically reliable in the early phases of scrub 2 g/day) or chloramphenicol (50–100 mg/kg/day divided
typhus. The disease is usually recognized when clinicians every 6 hr IV or PO, 500 mg QID; maximum 4 g/24 hr) or
correlate the presence of compatible clinical signs, Azithromycin (500 mg OD for 7 days).
symptoms, and laboratory features, with epidemiologic Azithromycin is also the drug of choice in pregnancy
clues. and children.
Patients with scrub typhus may develop the following Cases resistant to doxycycline have been reported,
laboratory abnormalities: and rifampin (600–900 mg orally daily) is a reasonable
The lymphocyte count is decreased and the T4 : T8 alternative often in combination with doxycycline in
ratio is diminished; lymphocytosis can also occur; such cases.
Liver enzyme levels, serum bilirubin and creatinine are Quinolones are not effective and should be avoided.
increased in 60% of cases and thrombocytopenia may be Duration of treatment should be at least 5–7 days or
present which is sufficient to cause bleeding. until the patient has been afebrile for ≥ 3 days to avoid
CHAPTER 97: Scrub Typhus: Need for Alert 591
relapse. Scrub typhus is so responsive to treatment that leads to a lot of confusion. Clin Infect Dis. 2007;44:391-
if patient does not become afebrile within 48 hours, 401.
2. Chapter 221, Scrub Typhus (Orientiatsutsugamushi)
diagnosis of Scrub typhus is unlikely or presence of other
by Megan E. Reller and J. Stephen. Textbook of Nelson
concomitant infection should be thought of. Pediatrics, 19th edn.
After apparent recovery, relapses frequently occur 3. Mandell, Douglas andBennette’s PPID, 8th edn. 2015.
and may also follow short treatment courses. Relapse is 4. Parola P, Watt G, Brouqui P. Orientia tsutsugamushi (scrub
usually less severe than the first attack. typhus). In: Yu VL, Weber R, Raoult D (Eds). Antimicrobial
Therapy and Vaccine, 2nd edn. New York: Apple Trees
Productions; 2002:883-7.
PREVENTION
5. Phimda K, Hoontrakul S, Suttinont C, et al. Doxycycline
Prevention is based on avoidance of the chiggers that versus azithromycin for treatment of leptospirosis and scrub
transmit O. tsutsugamushi. Protective clothing is the next typhus. Antimicrob Agents Chemother. 2007;51:3259-63.
most useful mode of prevention. No vaccine is available 6. Phongmany S, Rolain JM, Phetsouvanh R, et al. Rickettsial
till date. infections and fever, Vientiane, Laos. Emerg Infect Dis.
2006;12:256-62.
Mite control: The use of insect repellants and miticides 7. Scrub typhus: Clinical features and diagnosis- UptoDate
such as N,N-diethyl-3-methylbenzamide (DEET) are 2017; www.uptodate.com.
highly effective when applied to both clothing and 8. Sharma R, Krishana VP, et al. Analysis of Two Outbreaks of
Scrub Typhus in Rajasthan: A Clinico-epidemiological Study.
skin. Permethrin and benzyl benzoate are also useful
J Assoc Physician India. 2014;62:24-29.
agents when applied to clothing and bedding. 9. Varghese GM, Trowbridge P, Janardhanan J, et al. Clinical
profile and improving mortality trend of scrub typhus in
BIBLIOGRAPHY South India. Int J Infect Dis. 2014;23:39-43.
1. Blacksell SD, Bryant NJ, Paris DH, et al. Scrub typhus 10. Watt G, Kantipong P, de Souza M, et al. HIV-1 suppression
serologic testing with the indirect immunofluorescence during acute scrub-typhus infection, Lancet. 2000;356:
method as a diagnostic gold standard: a lack of consensus 475-9.
CHAPTER
98
Pyrexia of Unknown Origin:
Current Concept
SV Ramana Murty, Chakravarthy DJK
wars. Of these by far the greatest and the most terrible is Neutropenic zz Temperature > 38.3°C
fever”. —Sir William Osler (1849–1919). zz Neutrophil count less than or equal to 500/mm3
zz Evaluation of at least 3 days
cytomegalo virus infection, Epstein-Barr virus, disease, injected illicit drug use predisposing to
histoplasmosis, candidasis, trypanisomiasis. hepatitis B and C, HIV and infective endocarditis
Occupational histor y with exposure to birds
Physical Examination
Look carefully
For skin rash, conjunctival petechiae, clubbing and
osteomyelitis (Fig. 1)
Migratory asymmetric arthritis: Cardiovascular
In general noninvasive investigations should be done early in the disease. It is specific and reliable but false
first before resorting to invasive investigations such as positive results may occur.
biopsy, endoscopy and others.
Gene Xpert MTB/RIF
Urinary A cartridge based nucleic acid amplification test automated
Mid stream urine is to be collected for microscopy and diagnostic test that can identify Mycobacterium
culture. tuberculosis DNA and resistance to rifampicin by nucleic
acid amplification test (NAAT).
Hematological
A complete blood count and ESR in all cases. (ESR Imaging Studies
above 80 mm/1st hour is seen in TB, malignancy, X-ray: When pneumonia and TB, paranasal sinuses,
connective tissue diseases and temporal arteritis) bones and joints and others. Suspected, chest for lung
A peripheral smear for abnormal cells, malaria abscess (Fig. 4)
parasite and atypical lymphocytes. Skeletal survey in suspected cases of multiple
myeloma.
Microbiological
Ultrasound to detect organomegaly, free fluid in
Blood culture in all fevers persisting for more than a
pleural, peritoneal or pericardial sac, may detect
week. repeated blood cultures may have to be done to
abnormalities hepatic tumor or abscess, biliary
isolate the organism, e.g. infective endocarditis.
system disease, retroperitoneal lymphadenitis, or TO
Blood Biochemistry mass
Rise in serum uric acid level in malignancies like Echocardiography: To detect intracardiac vegetations,
lymphomas. atrial myxoma, the most valuable tool to confirm or
Rise in serum alkaline phosphatase indicates liver rule out infective endocarditis.
cell involvement. CT scan brain for lesions like cerebral abscess (Fig. 5)
and liver (Fig. 6)
Polymerase Chain Reaction (PCR) Gallium 67scan to detect infection/malignancy
PCR is very valuable in detecting the nuclear or Indium labeled leukocytes to detect occult septic
cytoplasmic components of infecting organisms focus
Fig.6: CT scan liver abscess Fig. 7: MRI of brain T2 weighted tuberculous granuloma of brain
Fig. 8: MRI of TB spine D1 tuberculous granuloma of brain Fig. 9: MRI T1w and T2w images showing TB spine a female patient
from Orthopedic department.
(Fig. 10) FDG-PET scan to detect malignancy and Malarial antigen (malaria)
Transthoracic/transesophageal echocardiography to
Diseases of connective tissue and vasculitis when
detect bacterial endocarditis suspected
Venous Doppler study to detect venous thrombosis. Rheumatoid factor, ANA profile, ANCA
CHAPTER 98: Pyrexia of Unknown Origin: Current Concept 597
Management
Principles
Unless the patient is acutely ill, no specific therapy is
started
Because nonspecific therapy is ineffective and mostly
delays the diagnostic process
An exception is neutropenic FUO for which delay
could lead to severe complications
Hence after blood samples for cultures are taken,
Fig. 10: MR spectroscopy tuberculous granuloma of brain aggressively treated with higher antibiotics in addition
to granulocyte colony stimulating factor.
Gastrointestinal Endoscopy Note:
May suggest inflammatory bowel disease, tuberculous Many undiagnosed cases of PUO may spontaneously
Muscle biopsy: In cases of suspected polymyositis and Drug related fever: Eosinophilia and rash in only 1/5th
Dermatomyositis muscle biopsy will clinch the diagnosis of the patients, fever usually begins in 1–3 weeks after
starting the drug and, remits 2–3 days after the drug is
Bone Marrow Aspiration and Biopsy withdrawn, virtually all drug classes can cause fever.
Useful in case of hematological disorders such as However betalactum antibiotics, quinidine, anti-
leukemias, myeloma. neoplastic drugs, neuroleptics are more prone.
598 SECTION 8: Infections
Flow chart 1: Clinical approach to PUO nulomas in one or more organ systems, irreversible
fibrosis and honeycombing of lungs with mediastinal
lymphadenopathy, musculoskeletal system involvement
and hepatosplenomegaly.
Lymphoma: Occurs at any age but common at 60s
multicentric in origin and spreads rapidly to non
contiguous areas discrete, painless, firm, lymph nodal
enlargement is the most.
Common presentation Waldeyer’s ring and epitroclear
lymph nodes are frequently involved, bone marrow
involvement is common and early; and can produce
cytopenias.
Osteomyelitis: Osteomyelitis usually causes localized
swelling, pain and tenderness which are deep seated,
treated with systemic higher antibiotics, surgical
debridement.
BIBLIOGRAPHY 6. Mueller PS, Terrell CL, Gertz MA. Fever of unknown origin
1. Cunha BA, Lortholary O, Cunha CB. Fever of unknown origin: caused by multiple myeloma: a report of 9 cases. Arch
a clinical approach. Am J Med. 2015;128:1138. intern Med. 2002;162:1305.
2. Dejaco C, Duftner C, Buttgereit F, Matteson EL, Dasgupta 7. Petersdorf RG, Beeson PB. Fever of unexplained origin:
B. The spectrum of giant cell arteritis and polymyalgia report on 100 cases. Medicine (Baltimore). 1961;40:1-30.
rheumatica: revisiting the concept of the disease. 8. Wongsrichanalai C, Barcus MJ, Muth S, Sutamihardja A,
Rheumatology (Oxford). 2016;(1) [MEDLINE]. Wernsdorfer WH. A review of malaria diagnostic tools:
3. Durack DT, Street AC. Fever of unknown origin- reexamined microscopy and rapid diagnostic test (RDT). Am J Trop Med
and redefined .Curr Clin Trop Infect Dis. 1991;11:35-51. Hyg. 2007;77(6 Suppl):119-27 [MEDLINE].
4. Grace E Max, Edward D Chan. Tuberculosis Research and 9. Zinzani PL, Gandolfi L, Broccoli A, et al. Midtreatment
Treatment. Volume 2011 (2011), Article ID 798764, 9 18F-fluorodeoxyglucose positron-emission tomography in
pages http//dx doi org/10. 1155/2011/798764. aggressive non-Hodgkin lymphoma. Cancer. 2011;1:117(5):
5. Horowitz HW. Fever of unknown origin or fever of too many 1010-8 [MEDLINE].
origins ? N Engl J Med. 2013;366:197.
CHAPTER
99
Approach to a Patient of Meningitis
Sanjiv Maheshwari, Vijay Prakash Hawa
classical clinical features as fever, headache, projectile Fulminant meningococcal septicemia can cause
vomiting and nuchal rigidity may not be present in all cases Waterhouse-Friderichsen syndrome (hemorrhage within
but almost all patients (~95%) with bacterial meningitis adrenal glands) characterized by sudden onset high
present with at least two of these four features (Flow chart 1). grade fever, large petechial hemorrhage, cardiovascular
Altered sensorium and photophobia are also common. collapse and DIC.
Seizure can also occur as a part of initial presentation Along with the above symptoms other symptoms of
or during course of disease in 20–40% of cases. It may be predisposing conditions like discharge from ear (otitis),
focal or generalized.
chronic headache (sinusitis), cough (pneumonia),
Focal neurological deficit can be found in 33% of
weight loss, fatigue, recurrent infection (immuno-
cases.
compromised state) can also be found.
In meningococcemia rash may be present which
begin as diffuse enythematous, maculopapular rash
resembling viral exanthems. They rapidly become EXAMINATION
petechial. They are found on trunk, lower extremities, Initially all the efforts should be directed to differentiate if
mucus membrane, conjunctiva and occasionally palm the infection is predominantly in the subarachmoid space
and soles. (meningitis) or it is generalized or focal involvement of
602 SECTION 8: Infections
brain tissue in the cerebral hemispheres, cerebellum or bradycardia, chaotic respiration, etc.) may be present in
brainstem. patient of meningitis with varying degree and percentage.
Evidence of meningeal irritation is usually present as
evidence by a stiff neck, Kernig’s sign, Brudzinski’s sign, INVESTIGATION
etc. Nuchal rigidity caused by meningitis resists passive Whenever bacterial meningitis is suspected lumbar
flexion but can be rotated easily from side to side while in puncture should always be performed as soon as possible
cervical spine disease resistance present in all direction for CSF examination. Neuroimaging (CT and/or MRI
of neck movement. Neck stiffness disappears during head) is indicated prior to lumbar puncture if patients
coma. In elderly, patients neck stiffness may be difficult has focal neurological deficit, seizures, papilloedema,
to evaluate because of osteoarthritis in neck or stiffness coma or is in an immunocompromised state.
of neck muscles secondary to based ganglia disorders. It
is falsely positive in subarachnoid hemorrhage, tetanus, CSF EXAMINATION
strychnine poisoning, cervical spondylosis and hysteria.
Findings on CSF examination suggest the cause of
Kernig’s sign can be elicited in supine patient when
meningitis even before the results of culture are available
the thigh is flexed on abdomen with the knee flexed
(Table 1).
and attempt to passively extend the knee cause pain in
Initial CSF pressure is usually found elevated (>180
presence of meningeal irritation.
mm H2O in 90% patients).
Brudzinski’s sign is again elicited in supine patient
Examining the gram stained smear of the sediment
and considered positive when passive flexion of the neck
of CSF reveals the etiologic agent in 60–80% cases of
causes spontaneous flexion of the hips and knees.
bacterial meningitis. Aerobic culture of antibiotic naïve
Although a lot is said about these tests on physical
examinations, the sensitivity and specificity of Kernig’s CSF shall reveal the etiologic agent in 80–90% cases
and Brudzinski’s sign are approximately 30% or lower. of bacterial meningitis. Broad range PCR on CSF may
Both of them may be absent or reduced in very young be a better option in diagnosing bacterial meningitis
or elderly patients, immunocompromised persons, or in patients in whom antimicrobial therapy was begun
patients with a severely depressed mental status. before lumbar puncture or when culture are negative and
Physical findings suggesting multiple cranial nerve a bacterial origin is still suspected.
involvement (third, fourth, sixth, or seventh nerves), focal For diagnosing CNS viral infections, amplification of
neurological signs (visual field defects, gaze preference, viral specific DNA or RNA from CSF by PCR amplification
dysphasia, hemiparesis, etc.), signs of increased CSF is the most important method now a day. Suspicion of
pressure (obtund consciousness, papilloedema, sixth intraventricular rupture of a cerebral abscess should
and third nerve dysfunction, abnormal reflexes, Cushing always be kept if one finds extremely high cell counts
response of decerebrate prostuning, hypertension, (>50,000/µL).
Bacterial species like Borrelia burgdorferi, Trepo When bacterial meningitis is suspected blood culture
nema palladium, Leptospira sp., Francisella sp., should be immediately obtained.
Brucells sp., mostly do have lymphocytic pleocytosis. Serum procalcitonin level is mostly increased in
Polymorphonuclear leukocytosis may predominate bacterial meningitis.
in the first 48 hours of illness with infections due to
Mycobacterium tuberculosis, or in echovirus 9, West Nile NEUROIMAGING
virus, eastern equine encephalitis virus or mumps. PMN Although not always required but whenever indicated,
pleocytosis with low glucose may also be a feature of MRI is preferred over CT scan because of its superiority
CMV infection in immunocompromised patients. in demonstrating areas of cerebral edema and ischemia.
A large number of test measuring level of various CSF Diffuse meningeal enhancement is often seen after
proteins, enzymes and mediators including C-reactive the administration of gadolinium in patients with
protein, lactic acid, lactate dehydrogenase, neopterin, meningitis, but it is not diagnostic because it can occur in
quinolinate, Il-lβ, Il-6, soluble Il-2 receptor, β 2 – any CNS disease associated with increased blood brain
microglobulin and TNF have been proposed as potential barrier permeability.
discriminators between viral and bacterial meningitis
but due to unproved sensitivity and specificity they are TREATMENT
not routinely used for clinical diagnostic purposes. Maintaining the vital parameters of the patient is
Extreme elevation of CSF protein (>1000 mg/dL) may
always the first and foremost aim.
indicate CSF flow obstruction (Froyn’s syndrome).
Diagnose and treat the cause of meningitis. If any
Traumatic lumbar puncture will have rise in both
delay in lumbar puncture, empirical antibiotic
protein and cells and should be corrected:
therapy should be started after taking sample for
CSF protein level is corrected by subtracting 1 mg/dL
blood culture.
for every 1000 red blood cells.
Provide adequate supportive measures.
Corrected WBC in CSF
exhibit any signs of infection whereas temporary carriers presence of leukoc ytes, er ythroc ytes in ur ine,
may suffer from disease. Leptospira shed in urine of albuminuria, increases in blood urea and creatinine can
carrier animals remain in the environment and probably be observed.
multiply. Biofilm formation by Leptospira alone or in In more severe form with liver and kidney involvement
combination with other bacteria may aid in its survival is known as Weil’s disease. Hepatic features marked by
in the environment as well as in renal colonization of mild-to-severe Jaundice, tender hepatomegaly and may
reservoir and carrier animals. progress to hepatic encephalopathy. Renal involvement
Direct transmission from animals to humans is may manifest as acute tubular necrosis (ATN), interstitial
common in occupational groups that handle animals necrosis and renal failure. RBC casts are common in
and animal tissues such as butchers, veterinarians, cattle urine microscopy.
and pig farmers and rodent control workers, whereas Renal dysfunction worsens during 1st to 2nd week
and complete recovery may occur by 4th week in
indirect transmission is common in workers exposed to
cases with appropriate renal support. Pulmonary
wet environment such as rice farmers, sewage workers,
involvement includes cough, respiratory distress with
minors or in subjects engaged in water-related sports.
signs of crepitation in basal regions spreading upwards.
The most common portal of entry is through intact
Radiological signs of basal and mid zone opacity may
skin or mucous membrane of potential hosts where
accompany. Hemorrhagic pneumonitis, interstitial,
penetration is aided by the rotational movement of
intra-alveolar hemorrhages are commonly observed in
bacteria. After entry, Leptospira spreads by hematogenous very severe cases. Cardiovascular system may present
dissemination and initiate infection. Vascular endothelial with shock, and arrhythmias. Central nervous system
damage is the primary lesion in leptospirosis, caused abnormalities commonly present with features of
either by direct physical injury, by bacteria or as a result meningitis, irritability and restlessness that may lead
of some immune mechanism. to seizures, encephalitis and focal neurological deficits
macular, maculopapular erythematous skin irruptions
CLINICAL PRESENTATION are commonly observed in face, trunk and extremities.
While asymptomatic infections go unnoticed, the Pregnancy with leptospirosis accompany bad prognosis.
symptomatic cases may present with mild form of The death due to leptospirosis occurs in large
disease that lasts for 5 to 7 days is called anicteric phase proportion of cases presenting with alveolar hemorrhage
of leptospirosis. This phase corresponds to phase of and renal complication. The case fatality varies between
leptospirosis. It presents with sudden onset of remittent 0–15%.
fever, chills, severe myalgia, intense headache and Laboratory results show, elevated total WBC and
bilateral conjunctival suffusion. This may accompany neutrophilia, high ESR, thrombocytopenia increased
asymptomatic urinary abnormalities in the form of BUN and marked increase in serum creatinine
mild proteinuria with few casts and cells in urine, and phosphokinase. These clinical features needs to be
chest manifestation such as cough and chest pain. differentiated from other diseases such as falciparum
Hemorrhagic features are not common in this stage. malaria, dengue, scrub typhus, typhoid, viral hepatitis,
The clinical features either decrease or disappear in acute encephalitis syndrome and pylonephritis.
two to three days and then may reappear or progress in
few cases to severe leptospirosis. DIAGNOSIS
The icteric phase represents severe form of disease, Laboratory based diagnosis includes conventional
where leptospires transfer from blood vessels to the methods such as dark-field microscopy, immuno
organs. Here patients present with fever, myalgia, fluorescence, culture, histopathological staining
headache, conjunctival suffusion, acute renal failure assay and molecular methods such as PCR, real-
manifesting as oliguria/anuria, nausea, vomiting, time quantitative PCR, loop-mediated isothermal
diarrhea, abdominal pain, and hypotension. During this amplification that assist in early diagnosis and are
phase, laboratory features of eleveted aminotransferases, more specific. Serological tests such as microscopic
606 SECTION 8: Infections
agglutination test (MAT), ELISA and other serological test irregular pulse, alternative consciousness should be
such as indirect hemagglutination (IHA), microcapsule immediately shifted to higher centers. Elevations of serum
agglutination test and lateral flow assays aid in diagnosis potassium and serum phosphorus are common, and if
after one week of onset of disease, when antibodies are potassium and phosphorus level gets too high special
formed ELISA and MAT are used to confirm the diagnosis. measures should be taken. Corticosteroid administration
Single MAT titer more than or equal to 1:400 has been in gradual doses (prednisolone) during 7–10 days in case
considered as a test to consider probable diagnosis since of severe hemorrhagic may be considered.
it can persist for a long time. IgM ELISA and other rapid Chemoprophylaxis may be used in deserving
tests are simple sensitive and specific tests for diagnosis. subjects at high risk with doxycycline 200 mg, once a
MAT is the gold standard test for detection of serovar/ week. Control measures such as rodent control, health
serogroup specific antibodies. Culture and isolation, education, personal protection and animal vaccination
MAT test are said to be gold standard. While PCR and may be undertaken as protection measures.
immune-chromatography tests are sensitive and used
to help early diagnosis. MAT and ELISA (four-fold rise BIBLIOGRAPHY
of antibody titer in convalescent samples compared to 1. Himani D, Suman MK, Mane BG. Epidemiology of
initial titer) shows result after a week of disease onset. leptospirosis: an Indian perspective. J Foodborne Zoonotic
Dis. 2013;1:6-13.
2. Oliveiraa MAA, Leal EA, Correia MA, Filho JCS, Dias RS,
TREATMENT AND PREVENTION
Serufo JS. Human leptospirosis: occurrence of serovars of
Treatment with effective antibiotics should be initiated as Leptospira spp. in the state of Minas Gerais, Brazil, from
soon as the diagnosis of leptospirosis is made, preferably 2008 to 2012. Brazilian J Microbiol. 2017;48:483-8.
before the 5th day after onset of disease. Clinicians 3. Programme for Prevention and Control of Leptospirosis.
should never wait for results of laboratory test before National Guidelines; Diagnosis, case management
starting treatment with antibiotics because serological prevention and control of leptospirosis. National Centre for
test do not become positive until about a week after the Disease Control (Directorate General of Health Services);
2015.
onset of disease (5th–7th day of onset). Leptospira are
4. Sethi S, Sharma N, Kakkar N, Taneja J, Chatterjee SS,
susceptible to most of the antibiotics such as penicillin,
Banga SS, Sharma M. Increasing Trends of Leptospirosis in
doxycycline, cephalosporins, tetracyclines, macrolides Northern India: A Clinico-Epidemiological Study. PLo S Negl
and fluoroquinolones. Antibiotic therapy should start Trop Dis. 2010;4:e579.
very early after onset of disease to prevent progression. 5. Shivakumar S. Indian Guidelines for the Diagnosis and
The drug of choice for outpatient treatment is Management of Human Leptospirosis. Infectious Dis. 2013.
doxycycline 100 mg twice daily for seven days and that 6. Shivakumar S. Leptospirosis: Current Scenario in India.
for inpatient (severe cases) treatment is crystalline Medicine Update. 2008;18.
7. Suppiah J, Chan SY, Ng MW, Khaw YS, Ching SM, et
penicillin 20 lakhs IU, IV six hourly should be initiated
al. Clinical predictors of dengue fever coinfected with
early. Pregnant and lactating mothers should be given
leptospirosis among patients admitted for dengue fever: a
ampicillin 500 mg every six hourly. Cases sensitive pilot study. J Biomed Sci. 2017;24:40.
to penicillin be given ceftriaxone or cefotaxime 1 gm 8. V i j a y a c h a r i P, S u g u n a n A P, S h a r m a S , R o y S ,
intravenously six hourly for seven days. Natarajaseenivasan K, Sehgal SC. Leptospirosis in the
In disease progression affecting multiple organs Andaman Islands, India. Trans R Soc Trop Med Hyg. 2008;
such as kidney, lungs, liver, CNS and CVS the patients 102:117-22.
may require dialysis, assisted ventilation, and case 9. Vijayachari P, Sugunan AP, Shriram AN. Leptospirosis:
an emerging global public health problem. J Biosci.
management does not differ then that of non-leptospirosis
2008;33:557-69.
causes. All suspected leptospirosis cases, whether
10. Vijayachari P, Sugunan AP, Singh SS, Mathur PP.
positive or negative with immunodiagnostic test having Leptospirosis among the self-supporting convicts of
features of organ dysfunction such as hypotension, Andaman Island during the 1920s: the first report on
oliguria (<400 mL/day), jaundice serum billirubin >3.0 pulmonary haemorrhage in leptospirosis? Indian J Med Res.
mg % hemoptysis or breathlessness, bleeding tendency, 2015;142:11-22.
CHAPTER
101
Kala-azar Elimination in India
Shyam Sundar
suggest that apart from humans animals could act as Control of Vector
reservoir. The infectiousness of these animals to sand fly Effective vector control management strategy is
vector if confirmed, will pose a major hindrance in path cornerstone in VL elimination programme. Although
of VL elimination. effective insecticides, indoor residual spraying is effective,
Treatment of Post-kala-azar Dermal the use of this procedure to decrease VL transmission
remains controversial. This might not affect outdoor
Leishmaniasis
sandfly populations, which may be an important aspect
Post-kala-azar dermal leishmaniasis (PKDL) is cha
of VL transmission as most of people from endemic
racterized by macular, popular and nodular lesions or
areas in Bihar sleep outside their houses. In a cluster
a mixture of these. It is mainly seen in Sudan and India,
randomised trial in India and Nepal medicated nets did
in 50% and 5–10% of VL treated cases, respectively.
Infectivity of these lesions especially nodular variety to reduce indoor sandfly density by 25%, although no effect
sand fly has been found. So how much infectivity and was seen on disease transmission.
from which type of lesion need to be found out. It further
complicates the vision of VL elimination. Uninterrupted Supply of Drugs
As the patients coming from endemic area cannot afford
HIV-VL Coinfection treatment antileishmanial drugs are provided free of
HIV changes the nature of the human VL infection, charge so that a full course of treatment is completed.
the response to treatment, and the epidemiology. Therefore, a strong commitment from government is
The HIV/VL coinfected patients have a high parasite essential for continuos supply of drugs. Single dose
burden and a weak immune response, respond poorly LAmB is excellent option as it does not require admission
to treatment, and have a high relapse rate. Therefore, however requirement of cold chain and cost remains a
they are the ideal candidates to harbor and spread drug constraint for its wide availability.
resistant parasites. With the growing burden of HIV
in India, HIV/VL coinfection could become a major CONCLUSION
problem. In India about 5.6% of over 2000 adult patients For making a sustained and successful VL elimination
with visceral leishmaniasis in Bihar, India, were found to of VL we need a better understanding of transmission,
be coinfected with HIV. optimal use of existing resources, and development of
Treatment of VL new, more effective tools to interrupt the progression of
After a landmark study on treatment of VL by miltefosine, the disease, and proper treatment of PKDL cases which
it was adopted as first line treatment of VL in Indian act as reservoir of infection. Role of domestic animals
subcontinent. Being an oral drug, it became the backbone through xenodiagnosis studies are also required. More
of VL elimination programme started by India, Nepal sensitive, cheap, and easily available rapid diagnostic
and Bangladesh. Unfortunately, the relapse rates with and epidemiological tools to monitor L. donovani
miltefosine doubled when studied after decade of its infection needs to be explored. Various methods of
use. Relapse rates of up to 20% were reported in Nepal in diagnostics like DNA-based diagnostic tests, portable
2013. Single dose liposomal amphoterecin B (LAmB) also and field-friendly molecular testing kits that could
recommended as first line treatment after revolutionary identify all Leishmania species at low densities and
trial on LAmB on Indian VL patients. Its use it however whole blood interferon gamma release assay tools
limited by cost and need of cold chain. Other effective still warrants further validation. Single-dose drug
combination therapy of paramomycin and miltefosine regimens offer great opportunities for better control
is used when there is difficulty in maintain cold chain. but mechanisms of drug action and resistance need
However the assumption of having an oral effective drug to be explored further for designing better and more
for elimination no more exist. effective drug regimens. Apart from this, targeted vector
CHAPTER 101: Kala-azar Elimination in India 609
control-related research should be intensified, including 3. Singh OP, Hasker E, Boelaert M, Sundar S. Elimination of
the identification of new insecticides to combat the visceral leishmaniasis on the Indian subcontinent. Lancet
Infect Dis. 2016;16(12).
resistance of available insecticides. Despite the various
4. Singh OP, Singh B, Chakravarty J, Sundar S. Current
challenges and obstacles the commitment towards challenges in treatment options for visceral leishmaniasis
VL elimination by Governments of India, Nepal and in India: a public health perspective. Infectious Diseases of
Bangladesh is tremendous which has lead to decrease in Poverty. 2016;5(1):2016.
incidence of new cases and hopefully soon will achieve 5. Sundar S, Singh A, Singh OP. Strategies to overcome
antileishmanial drugs unresponsiveness. Journal of Tropical
the target of VL elimination.
Medicine, vol. 2014, Article ID 646932.
6. WHO-SEARS. Health Ministers commit to eliminate kala-
BIBLIOGRAPHY azar [press release]. Dhaka: World Health Organization
1. Bhattacharya SK, Sur D, Sinha PK, Karbwang J. Elimination Regional Office for southeast Asia; 2014.
of leishmaniasis (kala-azar) from the Indian subcontinent 7. WHO. Kala-azar elimination programme: Report of a
is technically feasible & operationally achievable. Indian J WHO consultation of partners. Geneva: World Health
Med Res. 2006;123:195-6. Organization; 2015.
2. NVBDCP. National Road map for kala-azar elimination. New 8. WHO. Regional strategic framework for elimination of kala-
Delhi, India: Directorate of National Vector Borne Disease azar from the South-East Asia Region (2005–2015). New
Control Programme; 2014. Delhi: World Health Organization; 2012.
CHAPTER
102
Sickle Cell Crisis: How to go Forward?
Srikant Kumar Dhar
Sickle cell disease (SCD) is an autosomal recessive waiting for investigations. Different type of crisis with
disorder of the b-globin gene in which hemoglobin S which SCD presents are vaso-occlusive, hemolytic,
polymerizes in erythrocytes in deoxygenated conditions aplastic, sequestration and acute chest syndrome (ACS)
causing occlusion of small blood vessels. Pain is the out of them ACS is most fatal.
hallmark of presentation in patients presenting as
painful vaso-occlusive crisis. HOW TO MANAGE?
Initial medical assessment does not need to be
HOW TO DIAGNOSE? exhaustive but should focus on detection of the medical
The diagnosis of a pain crisis is only on clinical diagnosis complications requiring specific therapy such as
where no laboratory test can be of assistance for infection, dehydration, acute chest syndrome (fever,
diagnosis. History taking of a suspected case of a sickle tachypnea, chest pain, hypoxia, other chest signs),
cell pain crisis is most useful tool. Past history of sickle severe anemia, splenic enlargement, abdominal crisis,
cell hemoglobinopathy, no of hospitalization, drugs, cholecystitis, neurological events (cerebral infarct,
infection, blood transfusions, joint involvements that cerebral hemorrhage, transient ischaemic attack,
provide clue to diagnosis and further management. seizure) and priapism. During sickle cell crisis, when
Careful physical examinations helps to know cause of the severity of the episode is assessable, self-treatment
crisis. Adjuvant investigations such as CBC (complete at home with bed rest, oral analgesia, and hydration
blood count) and peripheral smear showing hemolytic is possible. Individuals with SCD often present to the
picture, reticulocytosis, target cells, polychromasia, hospital after self-treatment is ineffective or fails. Clinical
Howell Jolly bodies, and specific hematological tests, presentation is usually the pain of which may appear
e.g. sickling test, Hb electrophoresis, HPLC (high anywhere in your body and in more than one body sites,
performance liquid chromatography) as well as tests such e.g. arms and legs, abdomen, chest, hands and feet (more
as, LFT (liver function test) LDH (lactate dehydrogenase), typical in young children), lower back. Adult present with
RFT (renal function test), ABG (arterial blood gas), serum large joint pain, e.g. knee, hip, ankle, elbow, etc. Or rarely
iron profile, CRP (C-reactive protein), D-dimer, urine may present with breathlessness, headache, priaprism,
analysis will yield for definite diagnosis. Radiological or stroke.
Investigations such as chest X-ray, USG abdomen, CT Treatment strategies should include goals to manage
brain and thorax, guide for management. However, sickle of vaso-occlusive crisis, pain syndromes, hemolytic
cell crisis warrants immediate management without anemia, treatment and prevention of infections and
CHAPTER 102: Sickle Cell Crisis: How to go Forward? 611
complications and the various organ damage syndromes as paracetamol, ibuprofen and diclofenac should be
associated with the disease. Therapy should also take prescribed if there are no contraindications. Ketorolac is
care for prevention of stroke as well as detection and also a preferred agent which can be given both IM or IV
treatment of pulmonary hypertension. but it should not be given more than 5 days. Aspirin to
be avoided. Codeine containing analgesics or Tramadol
PRINCIPLES OF MANAGEMENT may be used for mild-to-moderate pain and which are
Effective analgesia should be given within 30 minutes of useful for weaning patients off the stronger opiates. PCA
the patient presenting to hospital. Adequate hydration (patient control analgesia) can be considered, if break-
(60 mL/kg/24 hrs) to be maintained taking care of through pain is occurring. Pethidine should be avoided.
anemia, cardiac status and fluid overload. Oxygenation
plays a vital role in management. Prophylactic or FLUID REPLACEMENT
therapeutic antimicrobials to prefer, if fever, to be chosen Increased plasma osmolarity from a reduced plasma
according to site of infection. Incentive spirometry is volume can worsen a vaso-occlusive crisis by causing
reserved for acute chest syndrome in recovery. Re- intracellular dehydration, hemoglobin polymerization
assessment and titration of analgesia have been done for and further sickling. During dehydration, the affinity of
maintenance and non responders. hemoglobin S for oxygen is increased so aggravates crisis.
Nitrous oxide (50%) and oxygen (50%) (Entonox, If tolerated, oral rehydration should be used in patients
Equanox) can be used in the ambulance and for the first with milder vaso-occlusive crises, patient should take
30–60 min in hospital not beyond. 60 mL/kg/day. The parenteral route of rehydration
The aim of treatment is to break the vicious cycle of is indicated in patients with severe pain, vomiting or
sickling, hypoxia and acidosis leading to more sickling all volume depletion.
of them exacerbated by dehydration.
TREATMENT OF ACUTE
ANALGESIA CHEST SYNDROME
Pain is the most common mode of presentation and Defined clinically as an acute pulmonary illness along
management of pain is mainstay of crisis treatment.
with body pain and chest discomfort characterized by a
Opiate analgesia is usually drug of choice for painful
new radiographic pulmonary infiltrate, fever, hypoxemia,
crises and should be administered within 30 minutes
of presentation to hospital aiming to achieve effective chest pain, cough and wheezing which is leading
analgesia by 60 minutes. A pain chart should be cause of mortality. Special investigations may yield
commenced for all patients as drug response varies in clue to diagnosis, e.g. ABG analysis, chest X‐ray, blood
different individuals. cultures, sputum cultures, respiratory atypical serology
Morphine is the opiate of choice for the management (Chlamydia, Legionella, Mycoplasma), complete blood
of sickle cell crisis wherever available. Morphine 5 mg count and reticulocyte count, renal and liver function
intravenously should be given initially as loading dose. tests.
This can be diluted in normal saline to give a 1 mg/mL
solution which can be given over the next 10 minutes. For Initial Management
effective analgesia, initial dose can be repeated after one
Intravenous fluids with close monitoring of fluid
hour. Closely monitor for hypoxia every 30 minutes until
balance is mainstay of treatment, oxygen therapy to
pain settled and then every 2 hours. If respiratory rate
<10/second stop opiates, with further drop to < 6 give 100 increase oxygen saturations >95% monitoring pO2 on
ug naloxone intravenous repeated every 2 minutes when air, pulse, respiratory rate, arterial blood gases and
required. Hb. Antibiotics given preferably IV co‐amoxiclav (plus
In Indian conditions where morphine is not easily clarithromycin 500 mg bd, if atypical pneumonia
available NSAIDs can be useful adjunctive therapy such suspected), bronchodilators preferred, if there is
612 SECTION 8: Infections
evidence of wheeze or reversible airways disease, or blood and exchange transfusion .Corporeal aspiration,
a history of asthma. Additional supportive and pain and phenylephrine injection to induce smooth muscle
management (analgesia as per painful crisis) to continue. contraction to be instituted initially and shunt surgery to
Consider positive pressure ventilation for patients with be performed if conservative therapy fails.
poor respiratory effort or reduced ventilation however
Incentive spirometry (10 deep breaths 1–2 hourly) when Stroke
awake and stable. Frusemide 0. 5–1 mg/kg if signs of fluid Stroke is a manifestation of cerebral sickling. Patient
overload to introduce. Prophylatic low molecular weight may manifest with neurodeficit or convulsion. Mainstay
heparin may be instituted. Transfusion has major role, if of management is exchange transfusion along with
the patient’s hemoglobin has fallen to <6. 0 g/dL, initial usual treatment for stroke. Other agents such as anti-
transfusion to be given. Simple transfusion is given for inflammatory agents, hydroxyurea also play important
moderately severe illness, but do not transfuse acutely to role in therapy. For secondary prevention in stroke
patient with Hb%>10g/dL, or take the hematocrit above suggest that lifelong blood transfusions may be necessary,
30%. Other useful method is exchange blood transfusion as there is a high risk of recurrence relatively soon after
with an aim to bring HbS <30%. With no improvement transfusion cessation.
and further detoriation consider noninvasive ventilation,
or subsequent invasive ventilation (CPAP). Review Role of Hydroxyurea
analgesia protocol, if needed. Hydroxyurea is a novel agent with robust clinical evidence
to be used for SCD. It causes fetal hemoglobin induction
Sequestration Crisis through soluble guanylyl cyclase activation and altered
It is characterized by sudden massive pooling of red erythroid kinetics. It lowers neutrophil and reticulocyte
cells in spleen, liver resulting in pain, hypoxemia, counts from ribonucleotide reductase inhibition and
hypovolemic shock and cardiovascular collapse. Main
marrow cytotoxicity, decreased adhesiveness circulating
treatment is packed cell or exchange transfusion along
neutrophils and reticulocytes. It also reduces hemolysis
with usual management.
through improved erythrocyte hydration, macrocytosis,
and reduced intracellular sickling; and causes NO
Hyperhemolytic Crisis
release leading to local vasodilatation and improved
Described as episodes of accelerated hemolysis
vascular response. indications of hydroxyurea are acute
characterized by decreased blood Hb, increasing
chest syndrome, Painful dactilitis (mostly children), low
reticulocytes and other markers of hemolysis, it occurs
HbF, elevated TLC, LDH, chronic hypoxemia. Patient
in resolving phase of vasocclusive crises. DHTR (delayed
instituted with hydroxyurea to be monitored CBC weekly-
hypersensitive transfusion reaction) may occur in
for first 4 weeks, fortnightly for next 8 weeks, monthly
multiply transfused, alloimmunized patients producing
thereafter, if counts stable followed by 3 monthly unine,
accelerated hemolysis. Concurrent G6PD deficiency is
LFTs, urate, LDH and HBF% with regular review. Dose of
other factor to be ruled out.
hydroxyurea to start initially at 15–20 mg/kg/day orally,
Aplastic Crisis if there is a good clinical response continue on this dose.
Whenever any disruption in rapid production of red cells If clinical response is suboptimal, check adherence,
in SCD as in parvo virus B 19 infection it leads to aplastic then increase by 2.5–5 mg/kg/day every 8 weeks until
crisis. Treatment is conservative with blood transfusions. limited by toxicity. If there is a significant rise in Hb (>11
g/dL in HbSS) stop the hydroxycarbamide and consider
Priapism venesection. Common toxicities are bone marrow
Painful persistent penile erection for hours may be suppression and cytopenias, hyperpigmentation of nails
benefited by hydration, hyperbaric oxygen, analgesia, and skin, Nausea and vomiting, diarrhea, skin rash and
CHAPTER 102: Sickle Cell Crisis: How to go Forward? 613
uncommon toxicities are alopecia, teratogenicity, and more DHTR characterized by fever pain and signs
leg ulcer. of hemolysis occurring few days to 2 weeks after a
transfusion. Iron overload is factor to be observed.
Role of Transfusions
There are two types of transfusions: RECOMMENDATIONS FOR
1. Episodic simple transfusion VACCINATION
2. Exchange transfusion In adults, the pneumovax should be re-administered
every 5 years. Other vaccines recommended are Hib,
Episodic Simple Transfusion hepatitis B, and annual influenza vaccination.
It is considered in sequestration crisis, aplastic crisis,
hyperhemolysis, when Hb less than 5 g%, or more CONCLUSION
than 20% decline in Hb% from baseline. And in acute Sickle cell disease is a chronic, debilitating disorder
complications of pregnancy. with diverse symptoms that make disease treatment
challenging. Pain is the most common mode of
Exchange Transfusion presentations to hospital. Gene therapy and bone-
It is administered in ACS, priaprism, prevention of stroke, marrow transplant remains definite treatment of SCD,
preoperative, leg ulcers refractory to conservative therapy, however patients attending to emergency department
critically ill patients. Exchange transfusion is a potentially with different crisis needs aggressive but watchful
life-saving procedure that allows correction of anemia treatment.
without increasing blood viscosity and may improve
tissue oxygenation while reducing microvascular BIBLIOGRAPHY
sickling. The aim of exchange transfusion is to lower the 1. Byrne J. Sickle Cell Disease, Guideline for the Management,
HbS level to 30% or less while keeping the hemoglobin Author Dr Jennifer Byrne.
close to 10 g/dL. It has advantage of decreased iron 2. Guidelines for the management of the acute painful
overload. crisis in sickle cell disease. Rees, et al. British Journal of
Transfusion may lead to complication such as TRBC Haematology. 2003;120:744-52.
3. Nice guideline CG143 Sickle cell acute painful episode;
alloimmunization (19–30% with <15 units transfusion)
June 2012.
due to extensive antigenic phenotyping. It may cause 4. The management of Sickle Cell Disease, NIH Publication
hemolytic reactions and decreases RBC survival of 2/2117N22?NIH Publication No. 02-2117IH Publication
infused RBCs, further warranting transfusion. Further No. 02-2117.
CHAPTER
103
Do Not Rash When
Fever Coincides with Rash
Sriprasad Mohanty
Bullae >5 mm in diameter, containing fluid are more intensely erythematous and pruritic. There is
Pustules Lesions containing purulent exudates history of new drug intake and absence of prostration.
Purpura Bleeding into skin. <3 mm is petechiae>3 mm is Rashes may persist up to 2 weeks after the offending drug
echymosis. Papable purpura is due to vasculitis. is discontinued.
Ulcer Defect in the skin surface Rickettsial illness presents with centrally distributed
Escher Necrotic lesion covered with a black crust maculopapular eruptions. Epidemic typhus is usually
seen in a setting of war or natural disaster when the
Most of the febrile rashes are centrally distributed people are exposed to body lice. In scrub typhus, there is
maculopapular eruptions. However, some can have eschar at the site of mite bite.
other patterns. Examples are as given here: Rash of measles stats at the hairline 2–3 days after
Centrally located maculopapular eruptions: Measles,
onset fever. Then they spread downwards sparing palms
rubella, drug reaction, acute meningococcemia, and soles. The rash begins as discrete erythematous
infectious mononucleosis, primary HIV infection, lesion; but become confluent later. Koplik’s spots
rickettsial infection, leptospirosis, dengue fever are white or bluish lesions of 1–2 mm size with an
erythema marginatum, still’s disease. erythematous halo on the buccal mucosa. They are seen
Peripheral eruptions: Chikungunya, hand-foot-mouth
within first 2 days of illness and are pathognomonic.
disease, secondary syphilis, bacterial endocarditis, Rubella rash also starts from hairline and spreads
erythema multiforme. downwards. But unlike measles, they tend to clear from
Confluent desquamatic erythema: Scarlet fever,
the originally affected areas as they spread down. It may
kawasaki disease, streptococcal toxic shock syndrome, be pruritic. Postauricular and suboccipital adenopathy is
staphylococcal toxic shock syndrome, Stevens- common as is arthritis.
Johnson syndrome, toxic epidermal necrolysis Leptospirosis presents with centrally distributed
(TEN), drug reaction with eosinophilia and systemic ma cu la p o pu la r e r u p t i o n w i t h su b c o n ju c t i va l
symptoms (DRESS). hemorrhage. Patients may have renal, hepatic disfunction
Vesiculobullous or pustular eruptions: Hand-foot- or aseptic meningitis; persons exposed to animal urine
mouth syndrome, staphylococcal scalded skin usually suffer from this Weil’s disease.
syndrome, TEN, DRESS, vericella, variola, herpes,
eyethema gangrenosum. VIRAL HEMORRHAGIC FEVERS
Urticaria-like eruptions: Vasculitis, serum sickness,
Viral hemorrhagic fever is an acute systemic febrile
drugs, connective tissue disorder. syndrome caused by over 30 viruses. Microvascular
Nodular eruptions: Fungal infection, erythema instability with capillary leak and impaired hemostasis
nodosum, sweet syndrome. are the pathogenic hallmarks. The viruses that cause
Purpuric eruption: Arbo-virus infections including hemorrhagic fever are zoonotic. Consequently, the
dengue, meningococcal infection, DIC, hemolytic endemic areas of the various viral HF are limited to
uremic syndrome, thrombotic thrombocytopenia distribution of their mammalian reservoirs and/or
purpura, cutaneous small vessel vasculitis. arthropod vectors. Ebola is a nightmare, especially for
Eruptions with ulcers and/or escher: Scrub typhus, health workers. Hantavirous has spread worldwide. It
rickettsial-spotted fevers, erythema gangrenous, can present as hemorrhagic fever with renal syndrome
anthrax, tularemia. or hantavirous pulmonary syndromes. The first case of
Since, the patient has to take medicines, drug rash Crimean-Congo hemorrhagic fever of India was detected
poses a common and difficult differential diagnosis. Drug in Sanand, Gujurat in January, 2011. Kyasanur forest
reaction can manifest in many forms but exanthematous disease is endemic in Karnataka. However, the most
drug induced eruptions are most common and they important causes of febrile rash in India are dengue and
resemble viral exanthems. However, the former ones chikungunya at present. Both are transmitted by the
616 SECTION 8: Infections
same vector (Aedes aegypti), both are seen at the same Symptoms Chikungunya Dengue
season and both have joint pain as a major complain Thrombocytopenia Infrequent Common
in addition to fever and rash. But in Dengue mortality Hematocrit Normal High
is high which is not so in chikungunya. In the later, the
morbidity may be prolonged. Following few points are In dengue NSAIDs should not be used. Whereas
useful in differentiating them. they can be useful to control the severe pain seen in
chikungunya. But unlike NS1Ag for dengue, we do not
Symptoms Chikungunya Dengue
have antigenic marker for chikungunya. We have to wait
Abdominal pain 31.6% 50%
for 5–7 days till IgM antibody appears or depend upon
Conjuctival injection 55.6% 32.8%
RT-PCR for laboratory diagnosis.
Maculopapular rash 59.6% 12.1%
Myalgia/Arthralgia 40% 12% BIBLIOGRAPHY
Coma 0 3% 1. Harrison’s Principle of Internal Medicine, 19th edition;
Fever onset Acute Gradual 2015.
Duration 2–4 days 5–7 days 2. Manson’s tropical Disease, 23rd edition; 2014.
3. National guideline for clinical management of chikungunya;
Hypovolumic shock Rare Common
Directorate of National Vector Borne Disease Control
Leukopenia Common Infrequent
Programme, Govt. of India; 2016.
CHAPTER
104
Disseminated Intravascular Coagulation:
Management Updates
Puneet Saxena, Aradhna Sharma, Madhulata Agarwal, Sher Singh Dariya, Hitesh Sharma
2. Amplification and sustained generation of thrombin bleeding is the most common manifestation of acute
due to inhibition of anticoagulant pathway and DIC, most common whereas chronic thromboembolic
activation of coagulant pathways complications are the most common manifestation of
3. Propagation of fibrin deposition and thrombus chronic DIC; as thrombin generation and procoagulant
formation due to inhibition of fibrinolytics. factor production go hand inhand.
can occur, if it involves GIT, lungs or CNS zz Nonbacterial thrombotic endocarditis (Libman-Sacks endocarditis,
D-dimer/Fibrin degradation products: Evidence TABLE 3: ISTH-SSC diagnostic scoring system for DIC
of plasmin-mediated biodegradation of fibrin and Risk assessment: Is there an underlying disorder associated with
fibrinogen, elevated in patients with DIC overt DIC
zz If “Yes” proceed
Activated partial thromboplastin time (aPTT):
zz If “No” , do not use this algorithm
Measure of intrinsic andcommon coagulation
pathways, prolonged in 50–60% of patients with DIC. Order global coagulation tests: PT, platelet count, fibrinogen, fibrin
related marker
Imaging and other studies: Depending on underlying
Score the test results
disorder and areas of thrombosis and hemorrhage. 9 9 9
zz Platelet count (>100 × 10 /L = 0, <100 × 10 /L = 1, <50 × 10 /L =
positive. Levels of V, VIII, X, XIII are decreased. zz Fibrinogen level (>1 g/L = 0, <1 g/L = 1)
are frequently decreased in DIC and have prognostic zz <5 suggestive for non-overt DIC: repeat next 1–2 days
also patients with HIT do not have global coagulation receive coagulation factor replacement. Options
abnormalities. include fresh frozen plasma(FFP; contains 0.7-1
HELLP syndrome; occurs 28 weeks after gestation, in U/mL of factors II, V, VII, VIII, IX, X, XI, XII and
cases with severe pregnancy induced hypertension. 2.5 mg/mL of fibrinogen), Plasma frozen within
Presents with elevated liver enzymes, low platelet, 24 hrs of phlebotomy (PF24) and Cryoprecipitate
hemolysis and normal FDP and negative D-dimer (Fibrinogen 150 mg/bag, Factor VIII 80–120 units/
and Coombs’ positive. bag and factor XIII and vWF). FFP is the first agent
of choice for coagulation factor replacement and
TREATMENT cryoprecipitate and fibrinogen concentrates are
Cornerstone of treatment is to treat the underlying cause second-line alternatives. Rapid infusion of platelets,
to stop the excess generation of thrombin by removing FFP, cryoprecipitate and fibrinogen concentrate can
the inciting injury.1,2 For example, in Abruptio placentae, lead to hypotension.
placenta has to be delivered, snake bite, administer Treatment of chronic DIC: Dominant thrombotic
snake anti-venom and sepsis initiate antibiotics. signs—In chronic DIC of malignancy with venous
Supportive measures: Mechanical ventilation to maintain or arterial thromboembolism or Purpura fulminans
airway and respiration. Restoration of physiological with acral ischemia; heparin in therapeutic doses
coagulation pathways:1,2 By suppressing coagulation and shall be considered. In cases with increased risk
facilitating anticoagulation using agents such as Heparin. of bleeding use continuous infusion of UFH at 4–5
U/kg/hour with aPTT being in range of 1.5–2.5
Hemodynamic support or replacement therapy:1,2 Only
times control. Direct thrombin inhibitors that do
in cases of ongoing hemorrhage or at risk of bleeding
not require antithrombin (AT-III) for there action
as assessed by DIC diagnostic scoring system, about to
are better than heparin which requires AT for its
undergo invasive procedures or deficient in coagulation
action which is reduced in DIC. But use of direct
factors or platelets.
In case of acute hemolytic transfusion reaction
thrombin inhibitors is not yet recommended due to
lack of RCT’s demonstrating there benefits in DIC.
aggressively hydrate the patient.
In case of massive blood loss RBCs need to be
Drotrecogin alpha (recombinant human activated
Protein C) used in the past for treatment of sepsis, has
transfused urgently.
Treatment of acute DIC: Low risk of bleeding: Treat the
been withdrawn in 2011 due to lack of efficiency in
clinical trials (PROWESS-SHOCKTrial).4
underlying cause. Patients who are not at increased
Underlying hyperfibrinolysis: Administration of
risk of bleeding and have platelet counts well above
antifibrinolytics5 such as tranexemic acid or Epsilon
>20 × 109/L there is no need of prophylactic platelet
amino caproic acid are to be used with extreme
administration.
caution as they inhibit fibrinolysis. Used occasionally
High risk of bleeding: Patients with platelet count
in case of severe refractory bleeding resistant to
<20 × 10/L, or having ongoing hemorrhage or at
conventional therapy (Grade C, Level IV). Similarly
increased risk of bleeding or those about to undergo
Prothrombin complex concentrates (PCC) are also
invasive procedures and platelet count < 50 × 109/L
avoided for the same reason.
should be given platelet transfusion. Give two units of
RDP/10 kg body weight or one single donor apheresis Emerging therapies: Antithrombin III; 6 Is an anti-
unit daily. One unit of RDP (contains 5.5 × 10 10 inflammatory and anticoagulant molecule which is
platelets) increases platelet count by 5,000–10,000/L decreased in DIC. Goal is to achieve 125–150% of normal
and one SDP (contains 3 × 1011 platelets) = 6 units of levels of AT III. However it is efficacy is not yet confirmed
RDP. and use not recommended at present.
Patients with severe bleeding and prolonged PT Inhibitor of tissue factor pathway (Tifacogin); 7
and aPTT as well as fibrinogen levels <1 g/L should complexes with TF, FVIIa and FXa; tested in phase III
CHAPTER 104: Disseminated Intravascular Coagulation: Management Updates 621
trial in severe sepsis revealed no benefit on mortality and 2. Levi M, De Jong E, van dear Poll T. New treatment strategies
increased the risk of bleeding. for disseminated intravascular coagulation based on
current understanding of the Pathophysiology. Ann Med.
Recombinant human soluble thrombomodulin
2004;36:41-9.
(ART-123);8 has anticoagulant and anti-inflammatory 3. Taylor FB Jr, Toh CH, Hoots WK, et al. Scientific Subcommittee
properties and is showing efficacy in Sepsis with DIC in on Disseminated Intravascular Coagulation (DIC) of the
phase IIb trial. Recombinant F VIIa (rFVIIa);9 new agent International Society of Thrombosis and Haemostasis
for severe refractory hemorrhage in DIC. Recombinant (ISTH). Towards definition, clinical and laboratory criteria,
and a scoring system for disseminated intravascular
Hirudin (r-hirudin); Direct thrombin inhibitor and
coagulation. Thromb Haemost. 2001;86:1327-30.
Recombinant Nematode Anticoagulant c2 (NaPc2); 10 4. Lowes R. Sepsis Drug Xigris Pulled from worldwide
Discrete inhibitor of complex between TF/FVIIa and market. Medscape Medical News. Available at http://www.
Fxa has been tested in animal models in DIC and proven medscape.com/viewarticle/752169. Accessed: 14,2014.
effective. 5. Avvisati G, ten Cate JW, Buller HR, et al. Tranexemic acid
for control of hemorrhage in acute promyelocytic leukemia.
Recombinant IL-10; anti-inflammatory cytokine,
Lancet. 1989;2:122-4.
modulates coagulation and abrogates endotoxin- 6. Warren BL, Eid A, Singer P, et al. Caring for the critically
induced effects on coagulation. ill patient. High-dose Antithrombin III in severe sepsis: a
Similarly, protease inhibitors of thrombin and randomized controlled trial. JAMA. 2001;286:1869-78.
plasmin such as Gabexate mesylate and C1- Inhibitors 7. Abraham E, Reinhart K, Demeyer I, et al. Efficacy and safety
of Tifacogin (recombinant tissue factor pathway inhibitor)
all proved of no efficacy in management of DIC.
in severe sepsis: a randomized controlled trial. JAMA.
2003;290:238-47.
Prognosis:1,2 DIC does not resolve as soon as inciting
8. Vincent JL, Ramesh MK, Ernest D, et al. A randomized,
injury is removed, as resolution requires synthesis of double-blind, placebo- controlled, Phase IIb study to
coagulation factors, clearance of anticoagulant factors evaluate the safety and efficacy of recombinant human
and fibrin degradation products from circulation soluble thrombomodulin, ART-123, in patients with sepsis
which can take several days. Mortality rate ranges from and suspected disseminated intravascular coagulation. Crit
Care Med. 2013;41:2069-79.
40–80% in patients with severe sepsis, trauma or burns
9. Franchini M, Manzato F, Salvagno GL, et al. Potential role
and depends on degree of coagulation impairment and of recombinant activated factor VII for the treatment of
treatability of the underlying condition. severe bleeding associated with disseminated intravascular
coagulation: a systematic review. Blood Coagul Fibrinolysis.
2007;18:589-93.
REFERENCES 10. Moons AH, Peters RJ, Cate H, et al. Recombinant nematode
1. Franchini M, Lippi G, Manzato F. Recent acquisitions in the anticoagulant protein c2, a novel inhibitor of tissue factor-
Pathophysiology, diagnosis and treatment of Disseminated factor VIIa activity, abrogates endotoxin-induced coagulation
intravascular coagulation. J Thromb; 2006. p. 4. in chimpanzees. Thromb Haemost.2002;88:627-31.
CHAPTER
105
Adult Immunization:
Current Scenario in India
Prasanta Kumar Bhattacharya, Subrahmanya Murti V
Achieving resistance to infection is immunization. This with increased life expectancy, the chance of adults
is can most commonly achieved artificially by vaccines, developing communicable disease has increased.
which are biologic agents that stimulate one’s adaptive Adults with immunosuppression, those with chronic
immunity. It has been shown that immunization has diseases of the liver, lung and kidneys, vulnerable
led the control and elimination of various diseases of groups such as healthcare workers are more prone to
infectious etiology, many of which are life threatening. It develop many infectious diseases which are basically
has also been estimated that successful vaccination can preventable by vaccination, thereby reducing morbidity
prevent 2 to 3 million deaths annually. Vaccination is and mortality significantly in these groups of people.
cost effective, does not require any lifestyle modification Additionally, diseases that are common in childhood
and can be effectively delivered to vulnerable and hard when manifested in adulthood tend to be more severe
to reach populations through appropriate outreach with worse outcomes, which also depend on the prior
activities; a clear example is the ‘Pulse Polio programme’, immunization status in childhood. 1 Further, adult
which led to the WHO declaring India ‘Polio free’ on 27th immunization coverage in India is negligible, with no
March 2014. national governmental policy guideline in existence.
Immunization in the pediatric group has been a Even in the USA, where the Centre for Disease Control
major thrust area for all national and international (CDC) releases a yearly guideline, adult vaccination
agencies for a long time. The National Immunization data for 2015 revealed that only about one third of adults
Schedule of India, supported by the Indian Association were adequately vaccinated.2,3 The latest CDC guidelines
of Pediatrics (IAP) has been a success in our country, have been brought out in 2017. The Indian guidelines
with the latest ongoing programs being the ‘Mission for immunization in adults have been published in 2009
Indradhanush’—seven colors of the rainbow to represent under the initiatives of the API and have been updated
seven diseases such as tuberculosis, hepatitis B, polio, in 2014.4,5 Table 1 summarizes the indications and dose
tetanus, diphtheria, whooping cough and measles which schedule of different of different vaccines which are
can be prevented by immunization through vaccines. recommended in adults in our country.
This programs covers all pregnant women and children
aged less than two years. HEPATITIS B VACCINE
However, adult immunization has never been The vaccine that is recommended for all adults in India
included so far in any national programs of the country. is the recombinant Hepatitis B vaccine. 4 Patients at
In the current era of globalization and urbanization, high risk for infection include Intravenous (IV) drug
CHAPTER 105: Adult Immunization: Current Scenario in India 623
TABLE 1: Indications and dose schedule of different vaccines recommended for use in India in adults
Vaccine Indication Schedule
Hepatitis B All adults 20 μg (1 mL) IM at 0,1 and 6 months. For patients
with CKD and immunosuppression, 40 μg (2 mL)
IM at 0, 1, 2, and 6 months. Routine boosters only,
if high chance of reinfection, e.g. CKD on dialysis
DPT/DT/TdaP/Td All adults 0.5 mL intramuscular (IM) dose, booster once
every 10 years till age 65
MMR May be given in HIV if CD4 count >200 cells/µL 2 doses 0.5 mL SC 28 days apart
HPV Female: 13–26 Years 0.5 mL IM at 0, 1 and 6 months
Male: 13–21 Years, may also be given in 22 to 26 years
Other vaccines indicated in specific groups
Hepatitis A (Havrix/vaqta) High-risk individuals only - IV drug users, haemophilias Vaqta IM 1 mL—2 doses at 0 and at 6–18 months
and as post-exposure prophylaxis. Infection with other of first dose
hepatitis viruses, awaiting/received liver transplant, food Havrix IM 1 mL—2 doses at 0 and at 6–12 months
handlers and CKD of first dose
Varicella vaccine Adults without prior varicella infection/immunization, HIV 2 SC doses (0.5 mL) given 4 to 8 weeks apart
with CD4 count >200 cells/µL, outbreak control and for
post exposure prophylaxis within 3 to 5 days of exposure
to varicella rash
Zoster vaccine Age >60 years, chronic illness including HIV with CD4 single 0.65 mL dose SC
count >200 cells/µL
Pneumococcal vaccine PPSV23 in adults between 19 to 64 years with COPD, CLD, Both 0.5 mL IM/SC
(PPSV23 and PCV13) diabetics and in smokers. All adults >65 years: single dose Single dose of PCV13 2 weeks prior to elective
PCV13 followed by PPSV23 after 1 year. splenectomy
People >19 years with immunocompromise, CSF leak,
asplenia: PCV13 followed by a dose of PPSV23 after 8
weeks with PPSV23 booster after 5 years
Meningococcal vaccine Health care workers, close contacts of cases, Both 0.5 mL SC single dose. 2 doses at 2 months
(MPSV4 and 2, MCV4) immunocompromised, asplenia, outbreaks, travellers apart for asplenia
to epidemic areas and crowded fairs/festivals and Haj For travel, single dose bivalent polysaccharide
piligrims 10–14 days before travel
Haemophilus inflenzae type High risk only—asplenia, immunosuppression including Single 0.5 ml dose IM
b Vaccine HIV and transplant recepients
Influenza Vaccine (TIV/LAIV) Adults >50 years, diabetes, COPD, CKD, healthcare TIV single IM 0.5 mL dose
personnel and immunosuppressed. LAIV nasal spray
Not recommended in India
users, healthcare workers, people living with HIV/ four doses are given, the second, third and fourth doses
AIDS, diseases requiring multiple blood transfusions, being administered at one, two and six months form the
patients of chronic liver and kidney disease and those first injection and the dose per injection is doubled to
with other sexually transmitted diseases or high-risk 40 μg (2 mL). Routine boosters are not recommended
behavior. It is contraindicated only if there is known except in patients with repeated risk of reinfection
yeast hypersensitivity. It is given as three doses of like CKD patients on maintenance haemodialysis.6-9 A
intramuscular injections, the second and third doses combination vaccine with hepatitis A is also available
being administered at one and six months from the first with the same dosing schedule.
dose. The standard regimen consists of three doses of Appropriate protection levels are said to be achieved
20 μg (1 mL) each, but in patients with chronic kidney when Anti-HBs levels are above10 mIU/mL. If the Anti-
disease (CKD) and those with immunosuppression, HBs levels, after a full schedule of vaccination with
624 SECTION 8: Infections
20 μg/1 mL vaccine are suboptimal in persons with a booster of Td irrespective of previous immunization
normal immunity, then three more doses, given status. Contraindications for use of this vaccine include
atleast one month apart is recommended and anti- a history of anaphylaxis and any acute neurological
HBs levels should be retested atleast one month after conditions. The conventional vaccines for diphtheria,
the last dose. If the anti-HBs level is stall less than pertussis and tetanus used in pediatric immunization
10mIU/mL, then another three doses with double the are whole cell (wp) and diphtheria toxoid (DT) vaccines
strength of the vaccine, i.e. 40 μg is to be repeated, respectively. These are not used in adults because of
the second and third doses being administered one higher risk of neurological complications.10,11
and six months, respectively after the first dose. Post- Post-exposure prophylaxis: For minor/unconta
exposure prophylaxis can be provided with hepatitis-B minated wounds, one dose of tetanus toxoid (TT) should
immunoglobulin, which should be administered as early be given, if the last dose of TT was taken more than 10
years ago. However, for major/contaminated wounds, a
as possible, within 72 hours of exposure, to be followed
dose of TT should be given, if last dose of TT was given
by a full course of vaccination.
more than 5 years ago.
HEPATITIS A VACCINE In pregnant women, if Td has been received in the
past 10 years, a single booster immediately after delivery
In India, inactivated Hepatitis A vaccine (Havrix and
must be given. During pregnancy, plain TT is preferred
Vaqta) is available. A combination vaccine with Hepatitis
over Td. If more than 10 years have passed since the last
B (twinrix) is also available. As per the Indian guidelines,
dose of TT/Td, a single dose of TT vaccine must be given
universal immunization is not recommended in India
in the second or third trimester. If previous immunization
by the API expert panel.4 The vaccine is only indicated
is incomplete or status unknown, then a full course of
in high-risk individuals live IV drug users, hemophiliacs
3 doses of TT must be given in the second or third trimester
and as post exposure prophylaxis. Hepatitis A is known
with a gap of at least 3 weeks between each dose.
to be more severe if it occurs as a coinfection with other
hepatitis viruses or in case of chronic liver disease, hence MEASLES, MUMPS AND
it is mandatory in such patients,especially in post liver RUBELLA VACCINE
transplant cases or those awaiting a liver transplant.8It is It is available as an attenuated vaccine. The usual
also essential for food handlers. However, caution is to be adult dose comprises of 2 doses of 0.5 mL vaccine
exercised for its use in pregnancy. The standard schedule given subcutaneously 28 days apart. It is not required
comprises 2 intramuscular doses: the first dose followed in those who have already been vaccinated with
6-18 months later by a second dose. MMR in childhood. Despite being a live attenuated
vaccine, it can still be given in HIV-infected persons,
DIPHTHERIA, PERTUSSIS AND
if CD4 count is above 200 cells/µL. 3 The vaccine is
TETANUS VACCINES
contraindicated in individuals with earlier history of
The available vaccines in adults are the acellular
hypersensitivity to gelatin or neomycin, pregnancy,
pertussis (ap), tetanus toxoid (TT), reduced diphtheria
Severe immunodeficiency and fever. Precautions for use
with tetanus toxoid combination (Td) and combination
include a recent history of antibody containing blood
of acellular pertussis, reduced diphtheria and tetanus
product transfusion and conception must be avoided for
toxoid (Tdap). These are indicated in all adults who did
at least 3 months after vaccination.
not have any prior immunization. A single dose of Tdap
is recommended for all adults up to the age of 65 years.
All adults must receive a booster dose of Td once every VARICELLA AND ZOSTER (SHINGLES)
10 years till the age of 65 years. Adults in close contacts VACCINES
with infants, particularly those suffering from diphtheria Both are live-attenuated vaccines (Oka strain). The
or tetanus must be vaccinated with Td, if not done in difference between the two vaccines is that the zoster
the past 2 years. Health-care professionals must receive vaccine has 18 times the viral content of the varicella
CHAPTER 105: Adult Immunization: Current Scenario in India 625
vaccine. The zoster vaccine has been demonstrated to immunocompromised, or are having cerebrospinal leak,
reduce the incidence of herpes zoster and post-herpetic cochlear implants or anatomical/functional asplenia
neuralgia and by 51% and 66% respectively.5 should receive a single dose of PCV13 followed by a
Varicella vaccine is indicated in all adults without a single dose of PPSV23 after at least 8 weeks.
prior varicella infection. It is strongly indicated in patients In patients planned for elective splenectomy, a single
with high-risk including in HIV patients with CD4 count dose of PCV13 must be given 2 weeks before the surgery,
>200 cells/µL.3 The vaccine is also recommended for followed by a booster dose of PPSV23 after 5 years.3
postexposure prophylaxis in case of adults with no prior
history of infection or immunization. In such a case, a MENINGOCOCCAL VACCINE
single dose of vaccine must be given within 3 to 5 days
It is available as polysaccharide and conjugate
of exposure to patients with varicella.5 Varicella vaccine
vaccines. Polysaccharide vaccine may be quadrivalent,
is administered as 2 doses (0.5 mL) subcutaneously
containing four antigens—A, C, Y, and W135 (MPSV4)
4 to 8 weeks apart. It is contraindicated in pregnancy,
or bivalent with A and C antigens. MPSV4 has no effect
severe immunodeficiency, history of allergy to gelatine
on nasopharyngeal carriage. The conjugate vaccine
or neomycin, or if the patient has received blood
is quadrivalent (MCV4), and is more immunogenic
transfusion within the past 5 months.
Zoster vaccine is recommended in elderly people with immune protection starting 28 days following
above the age of 60 years and persons with any chronic immunization. It is not recommended for use above
illness including HIV infection with CD4 count of more the age of 55 years. MCV4 reduces mucosal carriage in
than 200 cells/µL.3 Zoster vaccine is given as a single the nasopharynx and promotes herd immunity.None of
subcutaneous injection of 0.65 mL. It is contraindicated these vaccines protect against group B meningococci. 14
in pregnancy, severe immunodeficiency and age Meningococcal vaccine is recommended for
below 60 years. The use of Zoster vaccine has not been health care and laboratory workers, contacts of cases,
recommended in India due to lack of strong evidence in people living in crowded spaces such as jail inmates,
this regard.5 immunocompromised persons and persons with
anatomical or functional asplenia. Patients with
PNEUMOCOCCAL VACCINE deficiency of late complements, e.g. C8, C9 are prone
Two types of pneumococcal vaccine are available. The to meningococcal infections and should therefore be
first is a polysaccharide vaccine containing 23 serotypes
vaccinated.
(PPSV23), which is associated with a lesser immune
During outbreaks of meningococcal meningitis,
response and lack of mucosal protection. The other form
or as pre-exposure prophylaxis in people travelling to
is a conjugate vaccine containing polysaccharide capsules
epidemic areas (e.g “meningitis belt” of central Africa),
from 13 serotypes (PCV13) bound to diphtheria toxoid.
or for people visiting crowded fairs or festivals, a single
The latter is more immunogenic and provides lifelong
dose of bivalent polysaccharide vaccine should be
immunity along with mucosal protection. 12,13 Both
vaccines can be given intramuscularly or subcutaneously given 10–14 days before the planned visit. As per Indian
at a dose of 0.5 mL. national policy, a single dose of MPSV4 vaccine is given
As per the CDC guidelines, adults above 65 years to all Haj pilgrims. Both vaccines are given as a 0.5 mL
of age with normal immune status should receive a subcutaneous single dose injection. For people with
single dose of PCV13 followed at least one year later functional or anatomical asplenia 2 doses of MCV4
by a single dose of PPSV23.3 For adults below 65 years, must be given 2 months apart. These vaccines are
those who are smokers or are suffering from chronic contraindicated only if there is a history of allergic to
diseases of the liver, heart or lungs should receive latex. MCV4 is to be used with caution if there is a history
a single dose of PPSV23. 3Adults of all ages, who are of GBS.
626 SECTION 8: Infections
administered as a single 0.5 mL IM/SC dose with booster communicable diseases and improve the general
given every 3 yearly. Vi CPS is contraindicated below the well-being and productivity of the most economically
age of 2 years. significant component of the population—the Adults.
disease among infants and children—Use of 13-valent and guidance for use: Advisory Committee on Immunization
p n eumococ c a l c on j uga te va c c i ne and 23-val en t Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep.
pneumococcal polysaccharide vaccine. Recommendations 2010;59:273.
of the Advisory Committee on Immunization Practices (ACIP) 15. Dengue vaccine: WHO position paper—July 2016; Weekly
MMWR Recomm Rep. 2010;59:1-18. Epidemiological. Record, No 30, 2016;91:349-64.
13. Ku m a r D , We l s h B , S i e g a l D , C h e n M H , H u m a r 16. Malaria vaccine: WHO position paper—January 2016.
A. Immunogenicity of pneumococcal vaccine in renal Weekly Epidemiological Record. 2016;91(4):33-52.
transplant recipients: Three-year follow-up of a randomized 17. Hepatitis E vaccine: WHO position paper – January 2016.
trial. Am J Transplant. 2007;7:633-8. Weekly epidemiological record. No. 18, 2015;90:185-200.
14. Centers for Disease Control and Prevention (CDC). 18. WHO–HIV/AIDS Vaccine resource. www.who.int/hiv/topics/
Licensure of a meningococcal conjugate vaccine (Menveo) vaccines/Vaccines/en/.
CHAPTER
106
H1N1 Influenza: 9 Years’ Journey in Gujarat
Asha N Shah
Swine influenza is a disease affecting pigs and it is caused PB1, polymerase PA, followed by hemagglutinin, nuclear
by virus. There are regular outbreaks of swine influenza protein, neuraminidase and then matrix proteins and
among pigs. H1N1 swine flu is a strain of the flu virus non-structural proteins.
that jumped from pigs to humans in 2009 and was then
transmitted from human to human. WHO declared Antigenic Shift/Drift
on June 2009 that H1N1 2009 influenza pandemic had The virus undergoes mutation that can take place within
attained level 6 criteria and it was the first flu pandemic the genome (Antigenic drift)/or re-assortment among
the genetic materials of subtypes (antigenic Shift)
in 41 years.1 This H1N1 flu virus spread to every continent
resulting in a new virus.
except Antarctica involving almost 200 countries though
Antigenic drift is responsible for new seasonal strains
disease was not severe. Actually term “swine flu” has
that make necessary surveillance to detect these strains
recently been used incorrectly to refer to the seasonal
and to prepare new seasonal influenza vaccine.
influenza A (H1N1) pdm09 virus, which infects humans.
Antigenic shift may result in a new virus easily
A new swine flu virus was detected in some areas of
transmissible from man to man for which the population
world in 2011 which was named influenza A (H3N2)v. It
has no immunity: Results in Pandemics
infected few people (mainly children). As per CDC, more
Researchers from the MIT (Massachusetts Institute
people were infected in the 2012-2013 flu season but
of Technology) detected the mutation—named K166Q in
at present, not many people are infected with H3N2v.1 Indian samples and they observed that it affects middle-
Another virus which was H3N2 (but not with “v” ) which aged people as it lowers these people’s immunity to
was different then H3N2v was also detected and it also circulating influenza strains but as per NIV Pune, there is
caused flu. So it can be said that, all influenza A strains slight antigenic drift.
have a structure similar to the H1N1 virus (Fig. 1). Influenza viruses basically are from the family of
Orthomyxoviridae viruses. They are divided into three
HISTORY OF REASSORTMENT EVENTS main types—A, B and C.2
IN THE EVOLUTION OF THE 2009 Influenza A is the most virulent group, causes
INFLUENZA A (H1N1) VIRUS pandemics, epidemics, seasonal outbreaks and sporadic
There are eight segments within each virus code. The cases. It has following surface antigens:
following are the proteins of the influenza A virus (which Hemagglutinin (H or HA)
may be associated with or without headache, bodyache, People aged 65 years or more;
vomiting and diarrhea. They do not need Oseltamivir Patients who are having heart disease, lung diseases,
and they should be given symptomatic treatment. All chronic kidney diseases, liver disease, any blood
patients should be observed for their progress and they disorders, diabetes, patients having neurological
have to be reassessed at 24 to 48 hours. They should be disorders, patients suffering from cancer or patients
advised to be confined to home. having HIV/AIDS;
They do not require testing for H1N1. Patients who are on long-term steroids.
CHAPTER 106: H1N1 Influenza: 9 Years’ Journey in Gujarat 631
Tests for H1N1 are not required for the Category-B1 Children with ILI (influenza like illness) with severe
and Category B2. disease as manifested by the red flag signs (high and
Category-B patients should have home isolation. persistent fever, somnolence, inability to feed well,
The other change from 2009 guidelines is that seizures).
all these patients, Broad-spectrum antibiotics for Deterioration of any underlying chronic medical
transmission. Incubation period is average 1-2 days . The patients also require hematological, biochemical,
People are contagious 1 day prior to symptoms and as radiological and microbiological tests.
long as they have symptoms. Children, especially infants,
may remain contagious for two weeks or longer. Collection of Specimen
Antibodies appear 7 days after an attack; reach Nasopharyngeal swab, throat swab, nasal swab and
maximum Level in 2 weeks; drops to pre-infection tracheal aspirate for intubated patients.
level in 8-12 months. German researchers observed
and calculated that when around 33% of a population Treatment
becomes immune to the virus, herd-immunity would Isolation ward with dedicated team, early implementation
develop and transmission would stop. This may have of infection control Prompt treatment to prevent severe
happened in 2010. But people with no immunity are illness and death. Early identification and follow-up of
born everyday and people with old age may lose their persons at risk.
immunity to a particular strain every few years. Another Oseltamivir for weight <15 kg 30 mg BD for 5 days
factor is the phenomenon of antigenic drift. along with supportive therapy is given.
Zanamavir: Treatment of 7 year and older patients 10
CYTOKINE STORM IN YOUNG mg (2puffs). BID 5 days, IV Zanamavir and IV Paramavir
It is the systemic expression of a healthy and vigorous is an option in western countries for severe cases.
immune system resulting in the release of more than Cases in Gujarat (mostly category C cases as testing
150 inflammatory mediators. Both pro-and anti- was done in only C category as per GOI guidelines).
inflammatory cytokines are elevated in serum with lethal As can be seen from Table 1, 2009 pandemic cases
interplay of these cytokines referred to as a “Cytokine started in July but peaked in December 2009 and January
Storm”. The primary contributors are TNF-a and IL-6. 2010. This pattern was consistent with increase cases
The end result of cytokine storm is MODS (multiple in rainy seasons and persisting in winter. Because of
organ dysfunction syndrome) acquiring herd immunity, there were hardly any cases in
Diagnosis is by RT-PCR, virus isolation in culture or 4 2011 and 2012.Interestingly the pattern changed in 2013
fold rise in virus specific neutralizing antibodies (ELISA). and maximum cases occurred in February and March
and in 2015, there was a heavy outbreak reaching all time spike in 2015 in the same way it happened in 2013
high cases in February and March. in US and Mexico epidemics. So it is probable that
It can be clearly seen that the number H1N1 cases middle-aged people who were affected in 2015 were
record 2 spikes every year. In the 2009-10, 2014-15 more vulnerable to the mutated strain of H1N1, and
and 2016-17 seasons, the largest spike was seen from cytokine storm which probably affected younger
January to April (Fig. 4). population in 2009 was less observed.
Whereas in 2010-11 months of July–September In recent years, the agewise mortality has seen a
recorded most number of cases and same trend is significant change with emergence of probable
being observed this year. K166Q strain or antigenic drift. In 2009, CFR in
We published original article in JAPI for 2009-2010 6-15 and >46 years age group was 13.6% and 7.4%
pandemic cases.4 A total of 965 (64.9%) cases were respectively (Fig. 5). Whereas in 2017 the >46 years
seen amongst the young age group of 13 to 45 years.5 age group registered a CFR of 16.6%.
We also observed that case fatality in nonpregnant RECOMMENDED NORTHERN HEMISPHERE
women was 25.9% while in pregnant women it was VACCINE (2017–18) INFLUE N Z A TRIVAL E N T
53.3%. VACCINE:
Surprisingly, mortality in 2015 outbreak was high Contains:
in age group of >45 years. In 2016 also CFR was high —— An A/Michigan/45/2015 (H1N1) Pdm09-like
in the same age group (19%) and same trend is also virus,
seen in 2017 (Tables 2 and 3). Proving that this is —— An A/Hong Kong/4801/2014 (H3N2)-like virus,
TABLE 2: Age-and sexwise H1N1 Report, 2017 (1st January to 31 TABLE 3: Age-and sexwise H1N1 Report, 2016 (1st January to 8
December 2016) August 2017)
Male Female Male Female
Age Positive Death CFR% Positive Death CFR% Age Positive Death CFR% Positive Death CFR%
0 to 5 20 3 15.0 7 0.0 0 to 5 44 3 6.8 29 4 13.8
6 to 15 5 1 20.0 5 1 20.0 6 to 15 23 0 0.0 13 4 30.8
16 to 30 15 1 6.7 37 6 16.2 16 to 30 51 4 7.8 72 8 11.1
31 to 45 57 5 8.8 69 10 14.5 31 to 45 163 17 10.4 159 20 12.6
46 and 97 9 9.3 99 19 19.2 46 and 255 32 12.5 225 44 19.6
above above
Total 194 19 9.8 217 36 16.6 Total 536 56 10.4 498 80 16.1
BACKGROUND the largest and most complex Ebola outbreak since the
In August 1976, a 44-year-old headmaster named virus was first discovered in 1976. There were more cases
Mabalo Lokela arrived back in the town of Yambuku and deaths in this outbreak than in all others combined.
in the Democratic Republic of the Congo, after two It also spread between countries, starting in Guinea then
weeks spent touring with a local mission. A few days moving across land borders to Sierra Leone and Liberia.
after his return, he checked into the local hospital with The virus causing the 2014–2016 West African outbreak
nosebleeds, dysentery, and a fever. The doctors treated belonged to the Zaire ebola virus species (Table 1).
him for malaria, but to no avail. Lokela got worse. In
early September, two weeks after his first symptoms, he TRANSMISSION
died. And meanwhile, other people who had come into Natural reservoir host of Ebola viruses has not yet
contact with him started getting sick. been identified. Fruit bats are believed to be carriers of
Over the next three months, 318 people became disease and are able to spread the disease without being
infected, and 280 of them died. That outbreak, and affected by it. Scientists believe that the first patient in
another that took place simultaneously in South Sudan, an outbreak becomes infected through contact with an
alerted the world to the existence of a lethal new disease, infected animal, such as a fruit bat or primate (apes and
which eventually took the name of the waterway on monkeys), and it is called a spillover event. Ebola then
which Yambuku is situated—the Ebola river. spreads through human-to-human transmission via:
Ebola virus disease (EVD), which was previously 1. Direct contact (through broken skin or mucous
known as Ebola hemorrhagic fever, is a rare and membranes) with the blood, secretions, organs or
deadly disease. It is caused by infection with one of other bodily fluids of infected people.
the Ebola virus species. The virus family Filoviridae 2. Surfaces and materials (e.g. syringes, needles,
includes three genera: Cuevavirus, Marburgvirus, and bedding, clothing) contaminated with these fluids.
Ebolavirus. Within the genus Ebolavirus, five species 3. Possibly from contact with semen from a man who
have been identified: Zaire (now known as Ebola virus), has recovered from Ebola (e.g. by having oral, vaginal,
Bundibugyo, Sudan, Taï Forest and Reston. Apart or anal sex).
from reston virus, which causes disease in nonhuman Only a few species of mammals (e.g. humans, bats,
primates, the rest four viruses are known to cause disease monkeys, and apes) have shown the ability to become
in humans. The 2014–2016 outbreak in West Africa was infected with and spread Ebola virus. In Africa, Ebola
CHAPTER 107: Ebola 637
Contd...
may also spread as a result of handling bush meat (wild People remain infectious as long as their blood or
animals hunted for food) and contact with infected bats. bodily secretions contains the virus.
Ebola virus has been found in the semen of some
men who have recovered from Ebola. However, it is CLINICAL SYMPTOMS
not known if Ebola can be spread through sex or other The incubation period is about 2–21 days. Humans
contact with vaginal fluids from a woman who has had are not infectious until they develop symptoms, which
Ebola. Viral load decreases, in the semen over time and includes sudden onset of fever fatigue, muscle pain,
eventually disappears. The time it takes for Ebola virus to headache and sore throat. This is followed by vomiting,
leave the semen is different for each man. Contact with diarrhea, rash, symptoms of impaired kidney and liver
semen from a man who has had Ebola should be avoided function. Internal and external bleeding (e.g. oozing from
or barrier contraceptive should be used, until semen is the gums, hematemesis, melena, petechiae, purpura,
negative for virus on two ocassions. ecchymosis or hematomas), may be seen in many cases.
Burial ceremonies that involve direct contact with the Death is due to low blood pressure caused by fluid
body of the deceased also contributes significantly in the loss. Bleeding from any site worsens the prognosis.
transmission of Ebola. In 2014–16 outbreak about 60% Survivors may have muscular and joint pains, liver
cases were caused by observing such rituals. inflammation, lethargy, fatigue, decreased appetite and
Health-care workers have frequently been infected difficulty in regaining pre-illness weight.
while treating patients with suspected or confirmed In some people who have recovered from EVD, the
EVD. Exposure to Ebola can occur in health care virus is seen to persist in immune privileged sites. These
settings where hospital staff are not wearing appropriate sites include testicles, the central nervous system and the
personal protective equipment and infection control eye. The virus also persists in placenta, amniotic fluid
precautions are not strictly followed. Infected needles and fetus of infected pregnant women. The virus may
and syringes should be properly cleaned and disposed, persist in breast milk of infected women.
virus transmission can continue and amplify if adequate Viral persistence studies indicate that in a small
sterilization of the instruments is not done. percentage of survivors, some body fluids may test
CHAPTER 107: Ebola 639
Later in disease course or zz IgM and IgG antibodies (NAT) for routine diagnostic management.
after recovery
Rapid antigen detection tests for use in remote
Retrospectively in deceased zz Immunohistochemistry testing
patients zz RT-PCR
settings where NATs are not readily available. These
zz Virus isolation by cell culture tests are recommended for screening purposes as
part of surveillance activities, however reactive tests
positive on reverse transcriptase polymerase chain should be confirmed with NATs.
reaction (RT-PCR) for Ebola virus for longer than 9
months. Symptomatic illness in someone who has TREATMENT AND VACCINES
recovered from EVD due to increased replication of At present no FDA-approved vaccine or medicine (e.g.
the virus in a specific site is a rare event, but has been antiviral drug) is available for Ebola. Good supportive
documented. care and patient’s immune response play a significant
role in recovery.
DIAGNOSIS The following basic interventions, when used early,
can significantly improve the chances of survival:
Suspecting Ebola in a person, initially is difficult because
Providing adequate oral hydration or intravenous
the early symptoms, such as fever, are nonspecific
fluids and electrolytes.
to Ebola infection and are also seen in patients with
Maintaining oxygen status and blood pressure.
more common diseases like meningitis, malaria and
Treating other infections if they occur.
typhoid fever. However, person should be isolated and
In a trial led by WHO, in Guinea, an experimental
public health authorities notified if they have the early
Ebola vaccine proved highly protective against the virus.
symptoms of Ebola and have had contact with
the trial involved 11,841 people the vaccine, called rVSV-
Blood or body fluids from a person sick with or who
ZEBOV, was studied during 2015. Among the 5837 people
has died from Ebola who received the vaccine, no Ebola cases were recorded
Infected fruit bats and primates (apes and monkeys)
10 days or more after vaccination. In comparison, there
Objects that have been contaminated with the blood
were 23 cases 10 days or more after vaccination among
or body fluids of a person sick with or who has died those who did not receive the vaccine.
from Ebola
Semen from a man who has recovered from Ebola
LESSONS LEARNT
Ebola virus is detected in blood only after onset of EVD has got high mortality rate. Killing between
symptoms. It may take up to three days after symptoms 25–90% of these infected by it, with an average of
start for the virus to reach detectable levels (Table 2). about 50%. However, when proper and advanced
For diagnosis the preferred specimens include: medical support was available to the patients, the
Whole blood collected in ethylenediaminetetraacetic mortality figures dropped very significantly. The last
acid (EDTA) from live patients exhibiting symptoms. and biggest outbreak was extremely challenging as
640 SECTION 8: Infections
it involved urban and densely populated areas. In screening helped to identify those at risk for Ebola
contrast to predominantly rural and remote area and prevent disease transmission to other countries
outbreaks in past even after providing some medical More than 339,000 people were screened before
care the mortality was about 40%. leaving Guinea, Liberia and Sierra Leone. Enhanced
Now, there are many EVD survivors and many entry screening was also implemented globally.
are experiencing the sequelae of the disease. Adequate hydration/IV fluids/electrolytes/blood
As ebola virus can persist for several months in transfusion and use of life support system can bring
immunologically privileged sites like testis, eyes, down the mortality rates significantly.
CNS. This persistence of virus is responsible for many Control of outbreaks requires coordinated medical
smaller outbreaks so more caution and appropriate services, alongside a certain level of community
infection control practices should be adhered til engagement. There should be rapid detection of
ebola virus testing is negative on two occasions. cases of disease, contact tracing of those who have
Cost of Ebola epidemic to the resource poor African come into contact with infected individuals, quick
countries is enormous. Besides the devastating health access to laboratory services, proper health care for
effects, the Ebola epidemic also had a pronounced those who are infected, and proper disposal of the
socio-economic impact in Guinea, Liberia, and Sierra dead through cremation or burial.
Leone. Lower investment and a substantial loss in The potential for widespread infections in countries
private sector growth were also a result of the disease. with medical systems capable of observing correct
Health-care workers caring for patients with Ebola medical isolation procedures is considered low.
were among those at highest risk for contracting the Usually when someone has symptoms of the disease,
disease. Guinea, Liberia, and Sierra Leone, reported they are unable to travel without assistance. Human-
a total of 881 confirmed health worker infection to-human transmission of Ebola virus through
along with 513 reported deaths from the start of the air has not been reported to occur during
the outbreak to November 2015. Liberia lost 8% of EVD outbreaks. The apparent lack of airborne
its doctors, nurses, and midwives to Ebola; Sierra transmission among humans is believed to be due
Leone and Guinea lost 7% and 1% of their healthcare to low levels of the virus in the lungs and other parts
workers, respectively. of the respiratory system of primates, insufficient to
Nearly 20% of all Ebola cases occurred in children cause new infections.
under 15-years-old. In June 2014, all schools in People who care for those infected with Ebola
Guinea, Liberia, and Sierra Leone closed because should wear protective clothing including masks,
of the epidemic. By the time the schools reopened gloves, gowns and goggles. Centers for Disease
in 2015, due to school closures, students had lost Control (CDC) recommends that the protective
approximately 1,848 hours of education, ranging gear should leave no skin exposed. These measures
from around 33 weeks in Guinea to 39 weeks in are also recommended for those who may handle
Sierra Leone. A gap in vaccination schedules was objects contaminated by an infected person’s body
also seen as routine immunizations decreased by fluids. In 2014, the CDC recommended that medical
30% as the funding and logistics previously dedicated personnel receive training on the proper suit-up and
to vaccination campaigns were redirected to fight removal of personal protective equipment (PPE). In
the epidemic or were postponed to avoid public addition, a designated person, appropriately trained
gatherings. More than 17,300 children have been in biosafety, should be watching each step of these
orphaned because of Ebola. procedures to ensure they are done correctly. The
Travelers leaving West Africa were screened at infected person should be in barrier-isolation from
airports to prevent Ebola from crossing borders. Exit other people. All equipment, medical waste, patient
CHAPTER 107: Ebola 641
waste and surfaces that may have come into contact TABLE 3: Details of various outbreaks post West Africa 2014
with body fluids need to be disinfected. outbreak
Eb o l a v i r u s e s ca n b e e l i m i nat e d w i t h h e at Country Time Cases Contacts
(heating for 30–60 minutes at 60 °C or boiling Liberia March 2015 1 192
for 5 minutes). To disinfect surfaces, some lipid Liberia June 2015 7 126
solvents such as some alcohol-based products, Sierra Leone August 2015 6 840
detergents, sodium hypochlorite (bleach) or calcium Sierra Leone Sept 2015 1 780
hypochloride (bleaching powder), and other Liberia Nov 2015 3 165
suitable disinfectants may be used at appropriate Sierra Leone Jan 2016 2 >150
concentrations. Guinea and Liberia March 2016 13 >1200
Bushmeat, an important source of protein in the
diet of some Africans, should be handled and but it is difficult to predict whether these antibodies
prepared prepared and thoroughly cooked before will protect from reinfections, or infection with
consumption. another Ebola species. Further studies with these
When a person with Ebola disease dies, direct contact survivors are warranted to answer these questions.
with the body should be avoided. Certain burial
r i t u a l s, w h i c h m a y h av e i n c l u d e d m a k i n g BIBLIOGRAPHY
various direct contacts with a dead body, require 1. Bausch DG, Towner JS, Dowell SF, Kaducu F, Lukwiya M,
Sanchez A, Nichol ST, Ksiazek TG, Rollin PE. Assessment of
reformulation such that they consistently maintain a
the risk of Ebola virus transmission from bodily fluids and
proper protective barrier between the dead body and fomites. J Infect Dis. 2007;196(Suppl 2):S142-7.
the living. 2. CDC. 2016. 2014 Ebola Outbreak in West Africa – Case
The World Health Organization (WHO) is responsible Counts. January 20. Accessed January 22, 2016. https://
for determining when a country will be declared www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/
case-counts.html.
free of Ebola virus transmission. Public health
3. CDC. 2016. Outbreaks Chronology: Ebola Virus Disease.
authorities in these countries should maintain active January 20. Accessed January 22, 2016. https://www.cdc.
surveillance for new cases of Ebola and identify, gov/vhf/ebola/outbreaks/history/chronology.html.
locate, and monitor any potential contacts. 4. Ebola virus disease Fact sheet No. 103. World Health
WHO now declares a country free of Ebola virus Organization. September 2014.
transmission after 42 days since last Ebola patient 5. Evansa DK, Goldstein M, Popova A. 2015. “Health-
care worker mor tality and the legacy of the Ebola
(two incubation periods).
epidemic.” The Lancet Global Health 3 (8): e439–e440.
Seven documented clusters as shown below Accessed December 22, 2015. doi:10.1016/S2214-
have occurred following control of the epidemic 109X(15)000650. http://www.sciencedirect.com/science/
(Table 3). Recent outbreaks appear to be related to article/pii/S2214109X15000650.
viral persistence in survivors. Rapid and coordinated 6. Qureshi AI, Chughtai M, Loua TO, Pe Kolie J, Camara
HF, Ishfaq MF, N’Dour CT, Beavogui K. Study of Ebola
efforts controlled all 7 flare-ups.
Virus Disease Survivors in Guinea. Clin Infect Dis.
In 2017, Anne Rimoin and her team tracked down 2015;61(7):1035-42.
14 survivors of the 1976 Ebola epidemic. Rimoin’s 7. Ruzek, edited bySingh SK, Daniel. Viral hemorrhagic fevers.
team showed that the immunity against Ebola virus Boca Raton: CRC Press, Taylor & Francis Group. 2014.
extended for decades. All of the 14 people they p. 444.
8. UNDP. 2014. “Assessing the socio-economic impacts of
studied still carried antibodies that recognize at
Ebola Virus Disease in Guinea, Liberia and Sierra Leone:
least one of the Ebola virus’s proteins, and four had The Road to Recovery.” Accessed December 22, 2015.
antibodies that could completely neutralize the virus. 9. World Health Organization. 2015. Ebola Situation Report –
Ebola infections can lead to long-lasting antibodies, 4 November 2015.
SECTION
9
Human Immunodeficiency Virus
90-90-90 Strategy in HIV Epidemic Neurological Manifestations of HIV
R Sajith Kumar Dipanjan Bandyopadhyay, Amit Adhikary
ART in HIV Infection: State-of-the-Art Cardiopulmonary Manifestations of HIV
BB Rewari, Manish Bamrotiya, Suman Singh Alaka K Deshpande
Opportunistic Infections in HIV: Changing Scenario Immune Reconstitution Inflammatory Syndrome
Amar R Pazare Vinay Rampal
CHAPTER
108
90-90-90 Strategy in HIV Epidemic
R Sajith Kumar
It is certain that HIV treatment is a critical tool services for people who inject drugs, and programming
towards ending the AIDS epidemic, but it is not the only focused prevention for other key populations. To put
one. While taking action to maximize the prevention in place an all inclusive response to end the epidemic,
by way of HIV treatment, urgent efforts are needed concerted efforts will be needed to eliminate stigma,
on similar grounds to scale up other core prevention discrimination and social exclusion based on sero status.
strategies, including total elimination of mother-to- AIDS will disappear, perhaps only with uninterrupted
child transmission, condom programming, pre/post- delivery of lifelong antiretroviral drugs for of millions
exposure antiretroviral prophylaxis, voluntary medical of people. This in turn is possible only with strong,
male circumcision in priority countries, harm reduction flexible health and community systems, protection of
CHAPTER 108: 90-90-90 Strategy in HIV Epidemic 647
Fig. 3: Status of India in the 90-90-90 target (Adopted from NACO materials)
Note: Diagnosed, PLHIV ever registered–(PLHIV dies + PLHIV Permanent LFU)
Source: Monthly progress Report (Aug 2017)
human rights, and self-financing that is able to support Brief July 2017 also states that ART initiation should be
treatment programmes across the world and throughout offered the same day to people who are ready to start.
the lifespan of people living with HIV. Just as prophylaxis
for Pneumocystis carinii pneumonia served in the early HIV Treatment Averts AIDS-related Deaths
years of AIDS as a life-saving bridge to the antiretroviral The initial worry about shortened survival for HIV
treatment era for millions of people living with HIV, the infection is also gradually waning off. In the pretreatment
world needs to improvise the existing tools aimed at era, someone who acquired HIV infection could expect
extending lives towards a day when a cure or simpler to live only between 2 and 12.5 years. But today a
treatment options will become standard. young person becoming infected can expect to live for
25–50 years with the use of uninterrupted therapy. The
difference in survival between people with HIV infection
HIV Treatment Prevents HIV-related in developed countries and low income countries
Illness is also decreasing, as the cost of therapy is coming
As years passed by, the threshold for starting ART in HIV down. A major contributor for this development is the
infected people kept on changing. The initial cut off value pharmaceutical industry in India that made generic
of 200 CD4+ cells per cmm quickly got replaced with, 350 drugs at costs far below their multinational counterparts.
and later 500 CD4+ cells per cmm. In the last ten years, Thus more and more people could afford ART.
many studies have shown the definite benefit of starting
ART at higher levels, and as of now all agencies across HIV Treatment Prevents New HIV
the globe have accepted the ‘Treat All’ policy, which Infections
implicates initiation of ART in all patients, irrespective of Ever since the epidemic started, there has been lot of
CD4+ cell count. Many HIV related and non HIV related focus on preventive strategies. Many interventions
causes of morbidity and mortality can be efficiently have been instituted. But HIV treatment by itself has
prevented by this strategy. The Treat All policy also been shown to be the most effective of all. It is common
ensures definite treatment initiation. The WHO Policy knowledge that if the number of replicating or active
648 SECTION 9: Human Immunodeficiency Virus
that interfere with free testing and treatment efforts for treatment protocols. This considerable loss to follow
certain key populations are to be amended to achieve the up, underscores the need for efficient interventions to
90-90-90 target. enable retention in therapeutic services. In collaboration
A global consultation convened by UNAIDS on the with partners, WHO has identified key research and
adolescent treatment challenges found that adolescents development priorities, including the development of
living with HIV confront innumerable obstacles to age-appropriate fixed dose combinations for children
meaningful treatment access and thereby ensuring and prioritized development of fixed dose combinations
favorable health outcomes. Some of these challenges that include especially promising new antiretroviral
are well known and include stigma, discrimination drugs, such as dolutegravir or TAF.
and problematic laws and policies, including parental At a societal level–whether broadly defined for high-
consent laws. Many of them limit young people’s ability prevalence countries, or at a population level for key
to access HIV testing and other health care services on populations–knowledge of HIV status has often yet to be
their own. Like adults and younger children, adolescents established as a fundamental social norm. While working
often struggle with health care linkage and retention, to leverage every available strategy–community-centered
with particular challenges experienced as adolescents testing campaigns, full implementation of provider-
transition from paediatric to adult services. Many young initiated HIV counseling and testing, social marketing,
people often have poor access to sex education and selftesting and the like–specific efforts are needed to
limited exposure regarding their sexual and reproductive elements of the 90-90-90 target, a rights-based educate
health and rights. Many adolescents living with HIV communities regarding the HIV testing approach that
struggle with disclosure of their HIV status, in part rejects coercion and stigmatization is imperative.
because they are frequently left on their own to navigate Augmented release of funds are required to end the
the complexities of living with HIV as a young person. AIDS epidemic by 2030, but the resources needed for
Without HIV treatment, half of children living with such rapid scale-up towards the 90-90-90 target are not
HIV will die by age two. Even with continued progress in so unmanageable. It has been estimated that to reach the
prevention of mother-to-child transmission, WHO and ambitious 90-90-90 target, HIV treatment, including drug
UNICEF project that 1.9 million children will require HIV expenses, service delivery, community mobilization to
treatment in 2020. For children born to women living ensure access to testing and retention in treatment, and
with HIV who are not effectively linked to diagnostic preART costs, will require an enormous total of USD 14
services through systems to prevent mother-to-child billion by 2016. In 2016–2020, funding will need to ramp
transmission, HIV testing is not routinely offered in up incrementally each year, reaching USD18 billion
child-focused programmes. This failure represents a by 2020. From peak spending in 2020, it is definite that
major missed opportunity, as there is often very high treatment costs will come down through 2030, when the
prevalence among children with needs addressed by same will total USD16.9 billion
other service systems. Children today suffer from the
reality that after detection of HIV infection, treatment ENDING THE AIDS EPIDEMIC
options available are limited. Most of the antiretroviral The tools and strategies that exist now are sufficient in
medicines approved for use in adults are not approved themselves to see the end of the AIDS epidemic by 2030.
for use in children. The few medicines available for use in However, achieving these requires unprecedented action
very young children tend to be unpalatable and require now to scale up early antiretroviral therapy, as delay
regimens than are more complicated than those for adults. will merely allow the epidemic to continue to outpace
There is an urgent need for pediatric-specific fixed-dose the response. Inspired by what has been achieved to
combinations that reduce medication burdens and help date and undaunted by the challenges ahead, the entire
improve treatment adherence. Children are frequently global community should resolve not to allow this
lost to follow up even after getting enrolled into HIV historic opportunity to pass by.
CHAPTER 108: 90-90-90 Strategy in HIV Epidemic 651
FOR HIV INFECTION Clinical goals Increased survival and improvement in quality
of life
There has been a rapid decline in HIV related mortality
and morbidity with the wider availability of affordable, Virological goals Greatest possible sustained reduction in viral
load
more efficacious and less toxic antiretroviral (ARV)
drugs over last two decades. Antiretroviral therapy Immunological Immune reconstitution, that is both
goals quantitative and qualitative
(ART) consists of use of combination of at least three
antiretroviral drugs from different classes to inhibit the Therapeutic Rational sequencing of drugs in a manner that
goals achieves clinical, virological and immunological
replication of HIV and reduce viremia to undetectable goals while maintaining future treatment
levels. Durable suppression of viral replication leads options, limiting drug toxicity and facilitating
to a restoration of immune response reflected by adherence
an increase in CD4 count leading to slowing of the Preventive goals Reduction of HIV transmission by suppression
disease progression, reduced frequency of opportunistic of viral load
Infections, improvement in the quality of life and
increased longevity. Successes achieved by antiretroviral cells and fluids (e.g. brain, liver and lymphoid tissue)
therapy (ART) have now transformed the perception despite prolonged suppression of plasma viremia to
about HIV infection from being a ‘virtual death sentence’ <50 copies/mL by ART. The primary goals of ART are
to a ‘chronic manageable illness’. ART was earlier known maximal and durable reduction of plasma viral levels and
as Highly Active ART (HAART) and as combination restoration of immunological functions. The reduction
ART (cART). in viral load also leads to reduced transmissibility and
reduction in new infections. The defined goals of ART are
GOALS OF ANTIRETROVIRAL depicted in Table 1.
THERAPY Due to continued viral suppression, the destruction
ART cannot cure HIV infection as the currently of CD4 lymphocyte cells is reduced and over time there
available ARV drugs cannot eradicate the virus from is an increase in CD4 count, which is accompanied
the human body. This is because a pool of latently by partial restoration of pathogen-specific immune
infected CD4 cells is established during the earliest stages function. This leads to a reduction in opportunistic
of acute HIV infection and persists within the organs/ infections, reduced morbidity and mortality.
CHAPTER 109: ART in HIV Infection: State-of-the-Art 653
Darunavir (DRV) 600 mg twice a day (when used Hepatotoxicity, skin rash (10%), diarrhea, nausea, headache, hyperlipidaemia,
with Ritonavir 100 mg twice daily) serum transaminase elevation, hyperglycemia
Ritonavir (RTV) 100 mg Twice daily (used only to Common-gastrointestinal (diarrhea, nausea, vomiting, abdominal pain (upper
boost another PI) and lower)), rarely neurological disturbances (including paraesthesia)
Integrase inhibitors
Raltegravir (RAL) 400 mg twice daily Rhabdomyolysis, myopathy, myalgia, diarrhea, fever, rash, Stevens-Johnson
syndrome, toxic epidermal necrolysis, hepatitis and hepatic failure
insomnia
Dolutagrevir (DTG) 50 mg once daily Insomnia and headache; Dolutagrevir can cause serious, life-threatening side
effects. These include hypersensitivity (allergic) reactions and liver problems.
To be used with caution in people with a history of hepatitis B virus (HBV) or
hepatitis C virus (HCV) infection or deranged LFT
to assess baseline status, treatment of pre-existing informed decision and preparedness to initiate
CHAPTER 109: ART in HIV Infection: State-of-the-Art 655
ART on the benefits of treatment, understanding of comprehensive prepared ness counseling for the patient.
lifelong medication, adherence issues and positive In general, the clinical management of an HIV infected
prevention patient revolves around optimizing the treatment
All patients with CD4 less than 350 cells/cmm need to regimen, reducing drug toxicity, reducing the pill burden
be put on co-trimoxazole preventive therapy (CPT). and increasing adherence to the treatment.
All patients need to be screened for TB, using the
4-symptom tool (current cough, fever, night sweats When to Start ART in Adults
and weight loss) and those who do not have TB need and Adolescents?
to be started on isoniazid preventive therapy (IPT) in The guidelines on When to start ART have been evolving
addition to ART. over the years towards earlier initiation of ART; CD4
ART should not be started in the presence of an active
count off point moving for ART initiation from less than
OI: In general, OIs should be treated or stabilized 200 cells/cmm in 2004 to less than 350 cells/cmm in 2010
before commencing ART. Mycobacterium avium and then to less than 500 cells/cmm in 2013. The current
complex (MAC ) and progressive multifocal recommendation is to TREAT ALL, regardless of clinical
leukoencephalopathy (PML) are exceptions, in which stage or CD4 count. These changes have been based on
commencing ART may be the preferred treatment, evidence from various randomized clinical trials (RCT)
especially when specific MAC therapy is not available. and large observational cohorts which have revealed that
Some conditions which may regress following the with the earlier ART initiation, there was a significant
commencement of ART include candidiasis and delay in progression to AIDS and reduction in incidence
cryptosporidiosis. For those with HIV TB coinfection, of TB. These studies are summarized in Figure 1.
start antitubercular treatment first and start ART as
soon as possible after 2 weeks of ATT but definitely zz As per DHHS, WHO 2016 and NACO 2017 Guidelines
before 2 months. For those with CD4 less than zz All HIV positive persons (adults. adolescents, children, pregnant
50/cmm, start ART and ATT simultaneously. women, those with coinfections like TB, hepatitis, etc.) are eligible
Once the evaluation of patient is completed, the for ART initiation regardless of CD4 count, viral load or WHO
clinical staging
following guidelines for ART need to be followed after a
Ensuring good adherence to the treatment is imperative recommended that all PLHIV with HIV-1 infection be
for the success of treatment as well as for the prevention of initiated on a regimen consisting of
drug resistance. To achieve this, counseling must start from
TENOFOVIR (TDF 300 mg) + LAMIVUDINE (3TC 300 mg)
the first contact of the patient with the clinical team and
+ EFAVIRENZ (EFV 600 mg) (TLE) as Fixed Dose
should include preparing the patient for treatment and
Combination (FDC) in a single pill once a day.
providing psychosocial support through an identified
caregiver/guardian/treatment buddy and through support This regimen has the advantage of harmonization of
networks. All patients should undergo at least two counseling treatment for all adults, adolescents, pregnant women
sessions (preparedness counseling) before the initiation and those with HIV-TB and HIV hepatitis coinfections. It
of ART. The period of waiting for investigations and their is the simplest, most potent and least toxic regimen that
results should be utilized for counselling, cotrimoxazole offers the advantage of a decentralized service delivery
prophylaxis and isoniazid preventive therapy (in eligible and monitoring. It also simplifies the supply chain and
patients) and treatment preparation. minimizes the monitoring requirements.
In cases where the preferred first line ARV regimen of
What to Start: Antiretroviral Therapy TDF+3TC+EEV cannot be used, the alternative regimen
Regimens of AZT+3TC+EFV, TDF+3TC+NVP, ABC+3TC+EFV or
Fixed-dose combinations (FDCs) of ARVs are preferred ABC+3TC+NVP can be used.
because they are easy to prescribe and easy for patients to
take, which facilitates improved and desirable treatment Note: The patients with HIV-2 and both HIV-1 and HIV-2
adherence. This is essential for PLHIV as treatment co-infections need to be initiated on a PI containing
is life-long and we need to minimize the chances of regimen, as NNRTIs (EFV/NVP) are not active against
developing drug resistant mutants in their body and the HIV-2 virus. For patients with HIV-2 infection, the
resultant treatment failure. preferred first line ART regimen shall be Tenofovir
(300 mg) plus Lamivudine (300 mg) plus Lopinavir/
RECOMMENDED CHOICE OF Ritonavir (800/200 mg)
FIRST LINE REGIMEN A summary of different ARV regimens with specific
The basic principle for first line ART for treatment naïve indications are given below in Table 4.
adult and adolescent patients is to use a triple drug
combination from two different classes of ARVs. The MONITORING OF PATIENTS ON ART
first line ART essentially comprises of a NRTI backbone, Follow-up and monitoring is essential in patients
preferably nonthymidine (Tenofovir plus Lamivudine) initiated on ART to track clinical progress, monitor
and one NNRTI, preferably EFV. Based on evidence wellbeing and to identify adverse drug reactions and
supporting better efficacy and fewer side effects, it is now toxicities.
Nevirapine containing ART ALT Yes Yes Yes Yes Yes Yes Yes
(SGPT)
Efavirenz containing ART Lipid profile Yes Yes Yes Yes Yes Yes Yes
Atazanavir containing ART LFT Yes Yes Yes Yes Yes Yes Yes
Lipid profile
Lopinavir containing ART Lipid profile and Yes Yes Yes Yes Yes Yes Yes
Blood sugar
ART monitoring includes clinical monitoring and inter-current illnesses and drug-drug interactions and
laboratory monitoring. Clinical monitoring includes other metabolic abnormalities. The summary of the
monitoring of ART adherence as well. The client should laboratory monitoring recommended under the program
be monitored every month for clinical progress, for the is presented in the Table 5. Additional laboratory tests
side effects of the ARV/s and for the treatment adherence. outside this schedule may be performed as clinically
The various monitoring indicators are listed below: indicated.
Clinical monitoring
zz Proximal myopathy
TREATMENT FAILURE: WHEN TO guidelines and should be started as soon as the patient
CHANGE AND WHAT TO CHANGE is stabilised on ATT. In HIV-infected patients with TB
The adherence to ART is one of the most crucial who are not currently on ART, and who are provided
determinants of success of ART on long term basis. The Rifampicin-based anti-TB treatment, initiate ART directly
adherence of 95% or more is crucial for patients to achieve with EFV. No lead in dose is required for EFV. Nevirapine
desirable suppression of viral replication. However even or PIs should not be administered along with Rifampicin
with good adherence levels, resistance occurs to ARV because of the enzyme inducing effect of Rifampicin
drugs over a period of time due to viral mutation and which renders NVP levels sub-therapeutic. EFV blood
this requires change of ARV drugs. The virological failure levels are also decreased in presence of Rifampicin,
appears first followed by immunological failure which but remain at therapeutic levels. It is recommended to
finally leads to clinical failure. It is desirable to switch use the standard dose of EFV (usually 600 mg/day) in
the entire regimen from first to second line as soon as patients receiving EFV and Rifampicin or use Rifabutin
virological failure is detected. Table 7 depicts the criteria if patient is on LPV/r based ART. Details on initiation
for suspecting and confirming treatment failure. guidelines have already been discussed.
The second line regimen for patients failing on first
line ART is AZT + 3TC + ATV/r for those on TDF in first CONCLUSION
line regimen (and TDF+3TC+ATV/r for those on AZT or Antiretroviral therapy is quite effective in suppressing
d4T based regimen in first line). viral replication, delaying the progression of disease
and has changed the management of HIV disease
HIV/Tuberculosis Coinfection dramatically. Millions of lives and millions of new
Initiation of treatment for active TB should always be on infections have been saved due to ART. Present day ART
priority followed by initiation of ARV therapy as per the with initiation with single pill FDC regardless of CD4
CHAPTER 109: ART in HIV Infection: State-of-the-Art 659
TABLE 7: Defining antiretroviral failure. WHO definitions of clinical, immunological and virological failure for the decision to switch ART
regimens
Failure Definition Comments
Clinical failure Adults and adolescents New or recurrent clinical event The condition must be differentiated from immune
indicating severe immunodeficiency (WHO clinical stage 4 reconstitution inflammatory syndrome occurring after
condition)a after 6 months of effective treatment initiating ART
For adults, certain WHO clinical stage 3 conditions
(pulmonary TB and severe bacterial infections) may also
indicate treatment failure
Immunological failure Adults and adolescents CD4 count at or below 250 cells/ Without concomitant or recent infection to cause a
mm3 following clinical failureb or persistent CD4 levels transient decline in the CD4 cell count
below 100 cells/mm3 Current WHO clinical and immunological criteria
have low sensitivity and positive predictive value for
identifying individuals with virological failure
Virological failure Viral load above 1000 copies/mL based on two consecutive An individual must be taking ART for at least 6 months
viral load measurements in 3 months, with adherence before it can be determined that a regimen has failed
support following the first viral load test
a & b
Previous guidelines defined immunological failure based on a fall from baseline, which is no longer applicable in the context of CD4-
independent treatment initiation. The option of CD4 cell count at or below 250 cells/mm3 following clinical failure is based on an analysis of
data from Uganda and Zimbabwe
against Toxoplasma and anti-retroviral therapy decreases population) possibly due to increased number of HIV
the risk of toxoplasmosis. cases. While in hospital base study shows incidence
Ver y few adults and children (10–20%) are of 1.09 cases/1,000 admissions in 2009. Patch in the
symptomatic for toxoplasmosis, but it is life-threatening mouth, trachea or esophagus are of three main types
for HIV/AIDS patients. Toxoplasmic encephalitis is like pseudomembranous, erythematous (atrophic) and
the most common manifestation of toxoplasmosis in hyperplastic. It presents as painless lesion or burning
HIV/AIDS patients. Clinical findings include altered sensation in mouth or bad taste due to the presence of
mental state, seizures, hemiparesis, cranial nerve palsies, the membranes. Sometimes there may be dysphagia due
movement disorders, neuropsychiatric manifestations. oropharynx or esophageal candidiasis. The trachea and
Most aids patients with cerebral toxoplasmosis the larynx may also be involved may cause hoarseness of
respond to pyrimethamine and sulphadiazine therapy the voice. Treatment with fluanazole for 10–15 days cures
but relapses are very common once therapy is stopped. the candidiasis. And there is no need for prophylaxis.
Hence maintenance therapy is advised reduced dose.
Cytomegalovirus
Cryptococcosis Fifty to eighty percent of the adult population is infected
One million cases of cryptococcal meningoencephalitis by cytomegalovirus (CMV) but disease is found in
and 600,000 deaths occurs each year globally and most immuno-compromized patients. CMV infection was the
of them are HIV/AIDS patients with CD4 is less than most common OI in AIDS patients (25–40%) with a CD4
100 cells/mL. With an introduction of ART incidence less than 50/mL.
of cryptococcal meningoencephalitis has declined Incidence of CMV retinitis decreased by 55–83% with
considerably. To diagnose cryptococcal infection, serum introduction of ART. Common presentation of CMV is
and CSF cryptococcal antigen (CrAg) and CSF culture is the chorioretinitis, (80–90%) which may start unilaterally
the ideal test. and then progresses bilaterally. Decreased visual acuity
Cryptococcal meningoencephalitis is the most or/and visual field loss are the common symptoms of this
common presentation and manifest with fever, headache, disease and blindness may occur if left untreated.
vomiting, stiff neck, photophobia, altered mental status. CMV colitis may occur in 5–10% of HIV/AIDS patients
Cryptococcal pulmonary disease may be with CD4 less than 50 cells/mL and presents as diarrhea,
asymptomatic or present with acute respiratory distress weight loss, abdominal pain, anorexia, and fever.
syndrome. Rarely, it may manifest as a mass that may Submucosal ulceration and hemorrhages and may be
compress superior vena cava. Fever, malaise, cough, seen on endoscopy and vasculitis and CMV inclusions
pleuritic pain, and hemoptysis are the manifestation body may be seen on biopsy. Patients may sometimes
of pulmonary cryptocosis. There may be cavity, hilar suffer from esophagitis and presents with dysphagia.
lymphadenopathy, and pulmonary fibrosis on X-ray Rarely these patients present with radiculopathy,
chest. transverse mylitis, encephalitis or pneumonia.
Myocarditis, chorioretinitis, hepatitis, peritonitis, These patients may be treated with ganciclovir and
renal abscess, prostatitis, myositis, adrenal involvement foscarnet
may be the other presentation of cryptococal infection.
Treatment includes amphotericin B with or without Tuberculosis
fluconazole or flucytosine for 2 weeks. Tuberculosis (TB) and HIV are closely associated and
incidence of TB has increased with a advent of HIV
Candidiasis infection. TB is the most common OI and main cause of
Incidence of candidiasis in population study have death in HIV/AIDS patients. 30% world’s population is
increased in Europe and USA in 1990s (7.28/100,000 infected with Mycobacterium tuberculosis (WHO) and
662 SECTION 9: Human Immunodeficiency Virus
900000 new cases of active TB occurs every year. HIV and and HIV negative patients when CD4 is more than
TB coinfection present in 50–80% sub-Saharan African 350 cells/mL. However, when CD4 drops below 350,
patients while 8.6% in the United States patients. presentation becomes atypical (extrapulmonary and
As per HPTN 052 study, initiation of early ART (CD4 disseminated disease).
more than 350 cells mL) was associated with a 47%
reduction in the risk of active TB versus ART started Mycobacterium Avium Complex
when CD4 below 250 cells/mL. Incidence of multidrug-
Mycobacterium avium complex (MAC) usually occurs
resistant TB (MDRTB) is fluctuates in the USA (0.4% in
in immunocompromised patients like AIDS, leukemia
1980, 3.5% in 199, 1% in 1997, 1.3% in 2010). MDRTB
and patients receiving chemotherapy, steroids. MAC
and XDRTB are a increasing problem in developing
is primarily a pulmonary pathogen but it may present
countries.
TB may occur early as well as any stage of HIV disease. with osteomyelitis; synovitis; and lymphadenitis.
Incidence of TB increases as CD4 decreases. Risk of TB Common environmental sources of MAC are aerosolized
remains high in HIV/AIDS patients with normalization water, house dust, birds, farm animals, etc. Treatment
of CD4 count even after ART, compare to the general includes macrolides (clarithromycin or azithromycin),
population. The presentation of TB also depends on ethambutol, rifampin or rifabutin or streptomycin or
CD4 counts. Presentation of TB is similar in HIV positive amikacin for at least 12 months.
CHAPTER
111
Neurological Manifestations of HIV
Dipanjan Bandyopadhyay, Amit Adhikary
mg/kg PO QID; or
zz Ampho B deoxycholate (ABDC) 0.7–1.0 mg/kg IV/d plus
25 mg/kg PO QID; or
zz LAB 3–4 mg/kg IV daily plus fluconazole 800 mg PO or IV daily or
threatening mass effects and medications to control or zz ABDC 0.7–1.0 mg/kg IV daily alone; or
with fever and headache (65–90%), neck stiffness (30%), Consolidation Therapy (For At Least 8 Weeks, Followed by
altered sensorium (20%) and seizure/focal deficit Maintenance Therapy)
zz Begin after >2 weeks of successful induction therapy
(<10%). The diagnosis is based on elevated opening
Preferred Regimen:
pressure of CSF with lymphocytic pleocytosis, CSF India zz Fluconazole 400 mg PO or IV OD
PROGRESSIVE MULTIFOCAL
LEUKOENCEPHALOPATHY
Progressive multifocal leukoencephalopathy (PML) is
an OI of the CNS, caused by the polyoma virus JC virus
(JCV) and characterized by focal demyelination. PML
manifests as insidious and progressive focal neurological
deficits. Any region of the CNS can be involved, but
favored areas include the occipital lobes (hemianopsia),
frontal and parietal lobes (aphasia, hemiparesis, and
hemisensory deficits), cerebellar peduncles and deep
white matter (dysmetria and ataxia) (Fig. 2). MRI shows
distinct white matter lesions which are hyperintense on
T2 - weighted and fluid attenuated inversion recovery
(FLAIR) sequences and hypointense on T1- weighted Fig 2: PML in a PLHIV with CD4 36
sequences. In contrast to cerebral toxoplasmosis and
primary CNS lymphoma, no mass effect or displacement NEUROLOGICAL DISEASE ARISING
is seen in PML. FROM ART
Stavudine, didanosine and zalcitabine all cause
HIV ASSOCIATED MALIGNANCIES peripheral neuropathy. Somnolence, insomnia, vivid
AFFECTING THE CNS dreams and depression are caused by Efavirenz, while
Primary CNS Lymphoma depression and suicidal ideation are related to Rilpivirine.
Primary CNS lymphoma (PCNSL) without extra-cranial Insomnia, depression and suicidality have been reported
involvement occurs in <5% of AIDS patients. These with the integrase strand transfer inhibitors (INSTI),
tumors are usually aggressive, high-grade, diffuse B-cell albeit rarely. However, it must be emphasized that
neoplasms, which consist of either large immunoblastic immune reconstitution arising with effective ART may
or small non-cleaved cells. Symptoms evolve slowly and lead to a wide spectrum of OI affecting the nervous
include headaches, confusion, lethargy, focal signs and system, with TBM, CM and TE, being the most common
seizures. The CD4 is usually <50 cells/µL. CSF changes in India.
are non-specific with pleocytosis and hypoglycorrhachia,
but CSF, EBV, DNA positivity is almost diagnostic. BIBLIOGRAPHY
Periventricular solitary mass lesions are seen on MR. 1. Manji H, Miller R. The Neurology of HIV infection. J Neurol
Elevated choline and lipid/lactate peaks combined with Neurosurg Psychiatry. 2004;75:i29-i35.
2. Satishchandra P, Mathew T. Neurological manifestations
high Cho/Cr ratios is seen on MRS. NAA peak is reduced.
associated with HIV infection: Indian Perspective. In: Rao
Cho/NAA and lactate/Cr ratios are also increased when
MS, Ed. Medicine Update 2010. Mumbai: Ass Phy India.
compared to normal gray matter, thus differentiating 2010;760-5.
from CNS toxoplasmosis. Treatment consists of whole 3. Tan IL, Smith BR, Geldern GV, Mateen FJ, McArthur JC.
brain irradiation, steroids to reduce edema and mass HIV-associated opportunistic infections of the CNS. Lancet
effect, and HAART. Neurol. 2012;11:605-17.
CHAPTER
112
Cardiopulmonary Manifestations of HIV
Alaka K Deshpande
The first case reports of a new disease entity appeared in —— Dilated cardiomyopathy
June 1981 which was later called as acquired immuno- —— Isolated left or right ventricular dysfunction
deficiency syndrome caused by human immuno Endocardial involvement:
deficiency virus (HIV) infection. —— Non-bacterial thrombotic (marantic) endo
Kaposi sarcoma of heart at autopsy. Since then several neoformans and Aspergillus Fumigates
reports recognized cardiac involvement in HIV infection. Pulmonary hypertension:
The Veterans affairs study is the largest study of CVS —— HIV-related pulmonary hypertension (HRPH)
complications related to HIV/HAART which did not Cardiac malignancies—Kaposi’s sarcoma (KS)
reveal significant increase in CVS disease compared to Malignant lymphomas
age adjusted, non-infected US population. As against, Cardiac arrhythmias
the French hospital data base study and Data Collection Vascular lesions:
on adverse effects of anti-HIV drugs (DAD) showed —— Coronary artery disease
Cardiac involvement in HIV disease may be classified Inflammatory vascular diseases—PAN, Kawasaki,
as follows: Takayasu’s arteritis.
Pericardial disease
after HAART, however, treatment defaulters can present most sensitive technique. Speckled appearance and
with any of the osteogenesis imperfectas. heterogenicity of myocardium indicates infiltration of
lymphoma.
Myocardial Disease
Myocarditis due to various causes is common. HIV Arrhythmias
directly or by autoimmunity, other viral infections, Various rhythm disturbances due to myocarditis,
bacterial causes, toxoplasmosis result into myocarditis. electrolyte disturbances, autonomic dysfunctions have
Dilated cardiomyopathy (DCM) is common due to been documented.
multiple factors. HIV per se has been incriminated. Other
factors include OIs, nutritional deficiencies, metabolic CARDIOTOXIC DRUGS
abnormalities, autonomic dysfunctions. Pathogenesis is Amphotericin DCM, HTN, bradyarrhythmix
complex and is related to cytokine imbalance. Foscarnet Cardiomyopathy
DCM in HIV disease has a poor prognosis with Gancyclovir VT
median survival of about 101 days in presence of poor Doxorubicin DCM
cardiac parameters. Erythropoietin HTN
Interferon Arrhythmia, MI, DCM, AV blocks,
Endocardial Disease sudden death
Pre-HAART era reported 3–5% of AIDS patients with HAART CHD, PVD, DCM
marantic endocarditis with systemic embolization. Pentamidine, Septran QT prolongation, Torsade de
Infective endocarditis of various etiologies is common Pointes
frequently associated with IVDUs.
HIV-related pulmonary hypertension is being CORONARY ARTERY DISEASE
increasingly recognized as cardiovascular complication H I V- i n f e c t e d i n d i v i d u a l s h a v e l o w l e v e l s o f
related to lung infections, LV dysfunction and venous HDL cholesterol while LDL levels are raised. This
thromboembolism. derangement is further contributed by therapy with
HIV-related primary pulmonary hypertension is protease inhibitors. Various studies have shown that 74%
thousand times more common in HIV/AIDS compared HIV cases receiving protease inhibitors as therapy have
to general population. It is common in younger age lipid abnormalities which may precede lipodystrophy.
group, without much disability, however, mortality at the Endothelial dysfunction is reported in HIV disease due
end of one year is reported to be more than 50%. to increased susceptibility to cytomegalovirus infection
or may be by HIV per se.
Malignancies Patients may remain asymptomatic or may have
HAART has increased survival time with increased serious complications with fatal results. Baseline
longevity, which is associated with rise in the malignant investigations should include cardiac evaluation by
disorders related to chronic HIV infection. Although echocardiography. HIV patients may present with acute
Kaposi’s sarcoma is commonly seen in other countries. coronary syndromes or other vascular complications at
It is a rarity in India. The various lymphoid malignancies younger age.
are increasing. B-cell lymphomas and NHL involving Management of these conditions is same as in non-
heart have been reported. The cardiac involvement in HIV cases.
lymphoma may present with congestive heart failure, A wide variety of inflammatory vascular diseases
superior vena cava syndrome, complete heart block have been reported in HIV-infected individuals, such
due to lymphomatous infiltration, pericardial effusion as polyarteritis nodosa, Henoch-Schönlein purpura,
and cardiac tamponade. Echocardiography is the Takayasu’s arteritis and a Kawasaki-like syndrome.
CHAPTER 112: Cardiopulmonary Manifestations of HIV 669
With more effective and safer antiretroviral drugs, the In addition, immune status needs to be assessed by
longevity is increasing as a result of which one is likely to CD4 estimation.
see more cardiac events due to OIs, immunosuppression,
drug therapies of HIV as well as OIs . BACTERIAL INFECTIONS
Post-cARV the OIs are declining and bacterial
PULMONARY MANIFESTATIONS pneumonias are occurring more frequently.
The first report in MMWR in June 1981 was of patient Strept. pneumoniae, H. influenzae, Klebsiella,
with Pneumocystis carinii pneumonia in young patients
Pseudomonas aeruginosa and Staph. aureus are
with evidence of deficiency of cell-mediated immunity.
common pathogens. Fever, cough, shortness of breath
The experience of managing OIs in HIV disease led
are presenting features.
to chemoprophylaxis studies. The guidelines directed
In 2012, the Advisory Committee on Immunization of
use of daily one tablet of TMP-SMX as chemoprophylaxis
CDC and updated DHHS Guidelines recommend that all
against PCP when CD4 declined to less than 200. This
strategy resulted in dramatic decrease in cases of PCP. HIV-infected patients aged 19 years or greater, regardless
The advent of cARV further controlled the disease of CD4 counts, receive pneumococcal vaccination.
process by acting on the virus, which improved the Individuals who are pneumococcal vaccine-naïve
immune status of the patient increasing his CD4 cell should first receive one dose of pneumococcal conjugate
count. Most of the OIs decreased with rising CD4 counts. vaccine PCV 13. It should be followed by one dose of 23
However newer challenges appeared. valent polysaccharide pneumococcal vaccine 23 PPV in
P o s t-A RT e ra, t h e s p e c t r u m o f p u l m o n a r y patients with CD4 counts ≥200 cells/μL at least 8 weeks
manifestations of HIV/AIDS changed in the developed after receiving PCV13. For patients with CD4 counts
world. PCP declined but bacterial pneumonias are <200 cells/μL, 23 PPV could be offered 8 weeks after
dominating. In other countries with paucity of health receiving PCV13, or deferred until the CD4 counts
care resources, illiteracy and poverty still reigning increase to >200 cells/μL with cART
supreme; various OIs affect the lungs, tuberculosis cARV and pneumococcal vaccine together have
dominating the clinical picture. The OIs are caused by decreased the risk of bacterial pneumonias, however,
various pathogens including bacteria, viruses, fungi, and there is no unequivocal evidence to suggest its efficacy
parasites. In addition to OIs the lungs are involved in in prevention of pneumonias caused by nonvaccine
various malignancies like NHL, lung cancers (smoking serotypes.
being additional risk factor) and Kaposi’s sarcoma.
Mycobacterial infections are the most common OIs
The main obstacle in diagnosis of these conditions
in developing world including India. The presentation
is lack of rapid diagnostics and need of extensive
depends on the immune status of the patient. At higher
investigations. The investigations include:
CD4 counts >350, the tubercular manifestations are
Sputum smear
Appropriate culture/PCR
similar to non-HIV cases. Upper lobe infiltrations,
Chest radiography
cavitations are common. With declining CD4 counts the
HRCT
extra-pulmonary tuberculosis as well as disseminated
Bronchoscopy
TB is seen more frequently. Despite adequate anti-TB
BAL treatment the relapse rates are 9 to 10 folds higher in
CT-guided biopsy presence of HIV infection compared to non-HIV cases.
Thoracoscopy The incidence of MDR and XDR-TB is increasing in HIV
Open biopsy cases similar to non-HIV patients. South Africa reports
S. LDH alarmingly high prevalence of MDR (39%) and XDR-TB
Arterial blood gases (6%) in HIV patients.
670 SECTION 9: Human Immunodeficiency Virus
The present strategy of treating all HIV-infected cases Epstein-Barr virus may cause lymphoproliferative
with cARV irrespective of the CD4 counts is expected to disease of the lung, which manifests as multiple nodules
successfully control the various OIs including TB. of peribronchovascular or subpleural distribution.
Parasitic infections are rare and they occur in
Non-tubercular Mycobacteria patients with advanced HIV disease. The most common
Atypical mycobacterial infections are seen with an parasitic infections include pulmonary toxoplasmosis,
increased frequency in AIDS patients. The most common strongyloidosis, Cryptosporidium and Microsporidia.
atypical mycobacterial infection is with M. avium or M.
intracellulare species the Mycobacterium avium complex FUNGAL INFECTIONS
(MAC). It has been suggested that prior infection with Pneumocystis carinii pneumonia was an AIDS-defining
M. tuberculosis decreases the risk of MAC infection. The illness in the early part of epidemic. With effective
most common presentation is disseminated disease chemoprophylaxis and with the advent of cARV the
with fever weight loss and night sweats. At least 85% of prevalence has drastically reduced. Earlier it was thought
patients with MAC infection are mycobacteremic, and to be a parasite but now it has been shown to be an
large numbers of organisms can often be demonstrated atypical fungus—Pneumocytis jirovecii.
on bone marrow biopsy. The chest X-ray reveals Clinically, patient presents with fever, non-productive
lower lobe infiltrates, miliary shadows,mediastinal cough, rapidly increasing dyspnea, and hypoxemia.
lymphadenopathy. Therapy consists of macrolides, Bilateral crackles are noted. Plain radiographs may be
usually clarithromycin with ethambutol. Rifabutin is normal in 10% of cases but HRCT may reveal ground-
used. cARV has changed the scenario. glass infiltrate, perihilar reticular opacities. Cystic
lesions are seen in few patients particularly those
Nocardiosis receiving prophylaxis with aerosolized pentamidine and
The etiological agent is Nocardia asteroides, currently trimethroprim-sulfamethoxazole. It is the most common
considered as a bacterium (formerly thought to be a reason for hospitalization of AIDS patient to ICU.
fungus). Infection appears with low CD4 counts < 200 Other fungal infections include aspergillosis,
cell/mm 3. Cough is prominent and produces small histoplasmosis, and pulmonary cryptococcosis.
amounts of thick, purulent sputum that is not malodorous.
Fever anorexia weight loss are common; Remissions MALIGNANT NEOPLASMS
and exacerbations over several weeks are frequent. Kaposi sarcoma is the most common AIDS-associated
Roentgenographic findings include pneumonia, nodular malignancy. It is affecting almost exclusively adult
densities. Culture isolates the organism. Patients are homosexual or bisexual men and their partners, with
treated with minocycline, linezolid, imipenam, amikacin. a male/female ratio of 50 to 1. The course is variable—
Long-term use of TMP-SMX is also recommended. slowly progressive or aggressive. It is a rarity in this
Viral infections are rare and are associated with country.
marked immunosuppression. Of the 8 types of human Malignant lymphomas, both Hodgkin’s and non-
herpes viruses, 6 are associated with substantial morbidity Hodgkin’s lymphomas are seen more frequently in India
in patients with AIDS. They include cytomegalovirus, particularly after universal access to ART which has
herpes simplex virus type 1 and type 2, varicella zoster resulted in the increased survival.
virus, Epstein-Barr virus and human herpes virus Carcinoma of the lung is also reported frequently.
type 8. Pulmonary infection by any of these viruses Non-infectious, non-neoplastic lesions such as
may manifest as diffuse interstitial pneumonitis, while lymphocytic interstitial pneumonitis in children,
herpes simplex virus may also produce focal necrotizing bronchiolitis obliterans, nonspecific interstitial
tracheobronchitis. Cytomegalovirus causes pneumonitis. pneumonitis are other reported lesions.
CHAPTER
113
Immune Reconstitution
Inflammatory Syndrome
Vinay Rampal
has evidence of HIV viral RNA suppression”. Though TABLE 1: Infectious and noninfectious causes of IRIS in HIV-
no specific risk factors have been described till date, infected patients 6-17
however some of the following risk factors are supposed Infectious etiologies Noninfectious etiologies
to have a positive relation with the development of zz Mycobacteria zz Rheumatoid arthritis
IRIS.3,10 zz Mycobacterium tuberculosis zz Systemic lupus
zz Mycobacterium avium erythematosus (SLE)
complex zz Graves disease
CLINICAL FACTORS ASSOCIATED WITH zz Cytomegalovirus zz Autoimmune thyroid disease
zz Hepatitis C virus
Shorter interval between OI therapy initiation and
zz Progressive multifocal
ART initiation2,10 leukoencephalitis
Similarly, a classification has been proposed: zz Parvovirus B19
process was diagnosed prior to the initiation of infection and other parasitic
infections
HAART zz Molluscum contagiosum and
or quantitative viral load at ART initiation or their rate treatment for OI and starting ART, a rapid fall in HIV-1
of change during HAART between IRIS and non-IRIS RNA after ART, and being ART-naïve at the time of OI
patients, while other studies demonstrate only trends diagnosis. Other significant predictors have also included
or no significant difference between IRIS and non-IRIS younger age, a lower baseline CD4 cell percentage, a
patients. An alternative immunological mechanism lower CD4 cell count at ART initiation, and a lower CD4
may involve qualitative changes in lymphocyte function to CD8 cell ratio at baseline. Future epidemiologic and
or lymphocyte phenotypic expression. For instance, genetic studies conducted within diverse cohorts will
following ART an increase in memory CD4 cell types be important in determining the importance of host
is observed possibly as a result of redistribution from susceptibility and underlying opportunistic infections on
peripheral lymphoid tissue. This CD4 phenotype is the risk of developing IRIS.
primed to recognize previous antigenic stimuli, and thus
Manifestations: Although commonly the patients present
may be responsible for manifestations of IRIS seen soon
with severe prostration, with onset of high grade fever,
after ART initiation. After this redistribution, naïve T cells
fresh lymphadenopathy, severe dehydration with
increase and are thought to be responsible for the later
leukocytosis and altered renal and liver functions but the
quantitative increase in CD4 cell counts.12
disease specific manifestation are:
The third purported pathogenic mechanism for
IRIS involves host genetic susceptibility to an exuberant
MYCOBACTERIUM TUBERCULOSIS IRIS
immune response to the infectious or noninfectious
Mycobacterium tuberculosis (TB) is among the most
antigenic stimulus upon immune restoration. Although
frequently reported pathogens associated with IRIS,
evidence is limited, carriage of specific 1-ILA alleles
presenting with fever, lymphadenopathy and worsening
suggest associations with the development of IRIS and
respiratory symptoms. Pulmonary disorders, such as new
specific pathogens. Increased levels of interleukin-6 (lL-6)
pulmonaiy infiltrates, mediastinal lymphadenopathy,
in IRIS patients may explain this exuberant response to
and pleural effusions are also common. Extrapulmonary
mycobacterial antigens in subjects with clinical IRIS.
presentations are also possible, including disseminated
Such genetic predispositions may partially explain why
tuberculosis with associated acute renal failure, systemic
manifestations of IRIS differ in patients with similar
inflammatory responses (SIRS), and intracranial
antigenic burden and immunological responses to ART.13
tuberculomas, persistent fever, weight loss, and
Epidemiology of IRIS: Large retrospective studies have worsening respiratory symptoms. Abdominal TB-IRIS
been carried out on IRIS in John Hopkins (1996– can present with nonspecific abdominal pain and
2006) 6 Houston (1997–2000) 10 AND North Carolina obstructive jaundice.
and Johansberg, South Africa.3 The authors studied the In most studies, TB-IRIS occurs within two months
phenomenon prospectively in 450 patients over a period of ART initiation, the median onset of IRIS was 12–15
of 5 years (2004–2009).14 In a large retrospective analysis days (range 2–114 days), with only four of these cases
examining all forms of IRIS 25% of patients exhibited occurring more than four weeks after the initiation of
one or more disease episodes after initiation of ART. antiretroviral therapy. These studies suggest the onset
Other cohort analyses examining all manifestations of mycobacterial-associated IRIS is relatively soon after
of IRIS estimate that 17–23% of patients initiating ART initiation of ART, and clinicians should maintain a high
will develop the syndrome. Another large retrospective level of vigilance during this period.7-10
study reported 32% of patients with M. tuberculosis, M. Paradoxical CNS TB reactions are well described
avium complex, or Cryptococcus neoformans coinfection in HIV negative patients, and include expanding
developed IRIS after initiating ART. 3-10 Risk factors intracranial tuberculomas, tuberculous meningitis, and
identified for the development of IRIS in one cohort spinal cord lesions (vide supra).4,5 TB-associated CNS
included male sex, a shorter interval between initiating IRIS has also been reported in HIV-positive patients.
674 SECTION 9: Human Immunodeficiency Virus
thought to be due to the presence of residual CMV weeks), and no cases occurred before 4 weeks of therapy.
antigens or proteins which serve as the antigenic Both studies identified significant increases in CD8
stimulus for the syndrome. Clinical manifestations T cells as a risk factor for developing dermatomal zoster.20
include vision impairment and floaters17,18
Male gender, use of ART, higher CD4 cell counts, Clinical Features and Treatment
and involvement of the posterior retinal pole are factors Although complications such as encephalitis, myelitis,
associated with a reduced risk of developing IRU, cranial and peripheral nerve palsies, and acute retinal
whereas prior use of intravitreous injections of cidofovir, necrosis can occur in immune compromised HIV
large retinal lesions, and adequate immune recovery on patients, the vast majority of patients exhibit typical or
ART were associated with increased risk. atypical dermatomal involvement without dissemination
or systemic symptoms.
Clinical Features and Treatment A randomized, controlled trial demonstrated
The diagnosis of ocular manifestations of IRIS requires oral acyclovir with corticosteroids to be effective for
a high level of suspicion. In addition to signs of retinitis, dermatomal zoster in HIV-infected patients, facilitating
inflammatory symptoms include vitritis, papillitis, and healing and shortening the time of zoster-associated
macular edema, resulting in symptoms of loss of visual pain. Its use in cases of varicella zoster IRIS appears to
acuity and floaters in affected eyes. Treatment of IRIS be of clinical benefit. The combination of corticosteroids
associated CMV retinitis and IRV may involve antiCMV and acyciovir decreased healing times, improved acute
therapy with gancyclovir or valgancyclovir. However, pain, and quality of life, but did not affect the incidence or
the occurrence of IRU in patients receiving anti-CMV duration of postherpetic neuralgia.20,21 The incidence of
therapy draws its use into question. The use of systemic postherpetic neuralgia in immune competent individuals
corticosteroids has been successful, and IRV may require does not differ significantly from HIV-infected patients,
periocular corticosteroid injections. Due to its significant but increases with increasing patient age. Successful
morbidity and varying temporal presentations, clinicians symptomatic management involving opioids, tricyclic
should maintain a high level of vigilance for ocular antidepressants, gabapentin, and topical lidocaine
manifestations of CMV-associated IRIS.19 patches individually or in combination has been shown
to be beneficial and should be attempted in HIV patients
VARICELLA ZOSTER VIRUS with post-herpetic neuralgia as a complication of herpes
INFECTION IRIS zoster IRIS.
Although multidermatome zoster, once, one of the
hallmarks of AIDS, with the introduction of protease CRYPTOCOCCUS NEOFORMANS
inhibitors, increasing rates of herpes zoster were noted INFECTION IRIS
in HIVinfected patients. Two studies comparing ART and Accurate incidence of C. neoformans-associated IRIS
nonART patients reported increased incident cases of is unknown. It is infrequently reported in overall IRIS
zoster and rates estimated at 6.2–9.0 cases per 100 person cohorts, but in study of authors it constituted the 2nd most
years, three to five times higher than rates observed in common cause of IRIS.14 The majority of cryptococcal
the pre-HAART era. While another study reported no IRIS cases represent reactivation of previously treated
difference in overall incidence between HAART eras cases, suggesting either an immunological reaction
(3.2 cases per 100 person-years), the use of HAART was to incompletely treated disease or an inflammatory
associated with risk of zoster, which is reflected in large reaction to residual antigens. Although reports of
observational IRIS cohorts, where dermatomal varicella cryptococcal lymphadenitis and mediastinitis have
zoster comprises 9–40% of IRIS cases. Mean onset of been reported, most cryptococcal IRIS cases present as
disease from ART initiation was 5 weeks (range 1–17 meningitis. 80% of the cases result as a reactivation of
676 SECTION 9: Human Immunodeficiency Virus
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William & Wilkins. DU, Torriani FJ, Garcia CR, Freeman WR. Intraocular viral
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10
SECTION
like in early period of paracetamol overdose poisoning, TABLE 1: Indications for ICU admission
or the symptoms may be masked by other coexisting zz Respiratory depression or distress
conditions, like myocardial ischemia in patients with zz Need for emergency intubation
carbon monoxide poisoning. zz Seizures
The patient stabilization should take precedence zz Cardiac arrhythmias
over the detailed physical examination. Once stability zz Prolonged QRS of more than 0.12 ms
is achieved, a more comprehensive physical and zz Second or third degree atrioventricular block
systemic examination must be performed. In most of the zz Systolic BP less than 80 mm Hg
poisoning patients, alert/verbal/painful/unresponsive zz Glasgow coma scale score less than 12
scale (AVPU) may be used as a simple and rapid method zz Need for renal replacement therapy or extra-corporeal removal
of assessing consciousness. of toxins
zz Worsening metabolic acidosis
LABORATORY INVESTIGATIONS zz Pulmonary edema secondary to poisoning, including inhalation
Complete blood count, serum electrolytes, renal function injury
tests, random blood glucose, liver function test, arterial zz Tricyclic or phenothiazine with cardiologic or neurological
blood gases, chest X-ray and electrocardiograph should manifestations
be done in all patients. A pregnancy test must be zz Need for pralidoxime in patients with organophosphate toxicity
performed in all female patients of child-bearing age. zz Need for antivenom administration
The anion gap, serum osmolality, and osmolal gap zz Need for continuous infusion of naloxone
should be measured in each patient.
Specific investigations may have to be done to TABLE 2: Indications of extracorporeal toxin removal
confirm the cause of poisoning. For example, serum Hemodialysis Hemoperfusion Plasma ECMO
cholinesterase levels for organophosphorus poisoning, pheresis
serum drug levels (for digoxin, paracetamol, etc.), and Methanol Theophylline Tricyclic anti Amiodarone
oxygen saturation gap (SaO 2–SpO 2) must be done in depressants
patients with suspected carbon monoxide, cyanide, Ethylene Phenobarbital Thyroxine Beta-blocker
methemoglobinemia, and hydrogen sulfide poisoning. glycol
ICU admission may be indicated in certain patients Boric acid Phenytoin Heavy metals Calcium channel
blockers
(Table 1).
Salicylates Carbamazepine Theophylline Opioids
Lithium Paraquat Organophosphorous
DECONTAMINATION
Glutethimide Paraquat
In patients with suspected or confirmed dermal
Tricyclic
exposures, the clothing should be immediately removed
antidepressants
and the skin should be properly washed with a mild soap
and water. Eyes should be irrigated in ocular exposure to
acids or alkalis. cyanide. Also, it may not be useful if the patient presents
Gastric lavage is only of benefit in the hyperacute late, after more than 4–6 hours of ingestion.
phase of poisoning (<1 h). In addition, airway must
be secured before attempting lavage. Administer ENHANCED ELIMINATION
50-g charcoal as soon as possible and another 50 g Alkalinization of urine may be tried to improve excretion
every 4 h thereafter while indication persists. Certain of certain drugs like phenobarbital, salicylates, and
contraindications to charcoal administration exists chlorpropamide. In addition, dialysis and charcoal
which include poisoning with elemental metals like iron h e m o p e r f u s i o n s h o u l d a l s o b e c o n s i d e re d i n
and lithium, pesticides, strong acids and alkalis, and severe poisoning if the toxin is dializable (Table 2).
CHAPTER 114: Critical Care Toxicology: Update 2018 683
Plasmapheresis may also been be useful for removal of may be required as per the suspected poisoning. In
certain poisons (Table 2). Other newer modalities like addition to the general supportive measures, measures
extra corporeal membrane oxygenation (ECMO) has also to reduce absorption and enhance elimination, should
been tried in patients with acute poisoning (Table 2). be instituted immediately to improve outcomes.
Antidotes, if available, should be used early in the course.
BIBLIOGRAPHY
1. American College of Medical Toxicology. ACMT position
Intravenous Fat Emulsion
statement: interim guidance for the use of lipid resuscitation
Recently, there has been an increased interest in the use of therapy. J Med Toxicol. 2011;7:81-2.
intravenous fat emulsion (IFE) therapy in the management 2. Boyle JS, Bechtel LK, Holstege CP. Management of the
of several poisoning. It is recommended in patients critically poisoned patient. Scand J Trauma Resusc Emerg
with severe local anesthetic overdose (bupivacaine, Med. 2009;17:29.
3. Brooks DE, Levine M, O’Connor AD, French RN, Curry
mepivacaine, ropivacaine, levobupivacaine, prilocaine,
SC. Toxicology in the ICU: Part 2: specific toxins. Chest.
lignocaine, lidocaine) and is also been increasingly used 2011;140(4): 1072-85.
in several other poisoning, like beta-blockers, calcium 4. Ghannoum M, Roberts DM, Hoffman RS, Ouellet G, Roy
channel blockers, and tricyclic antidepressants, with L, Decker BS, Bouchard J. A stepwise approach for the
varied results. Even though its exact mechanism of action management of poisoning with extracorporeal treatments.
Semin Dial. 2014;27:362-70.
is unknown, it is postulated to mediate antidote activity
5. Lam SH, Majlesi N, Vilke GM. Use of intravenous fat
or act by compartmentalization of the offending drug emulsion in the emergency department for the critically ill
into a lipid phase, thereby removing it from its target poisoned patient. J Emerg Med. 2016;51(2):203-14.
receptors. The current recommended dosing states 6. Levine M, Brooks DE, Truitt CA, Wolk BJ, Boyer EW, Ruha AM.
administration of a bolus of 1.5 mL/kg, followed by an Toxicology in the ICU: Part 1: general overview and approach
intravenous infusion at the rate of 0.25 mL/kg/min. to treatment. Chest. 2011;140(3):795-806.
7. Levine M, Ruha AM, Graeme K, Brooks DE, Canning J, Curry
SC. Toxicology in the ICU: part 3: natural toxins. Chest.
CONCLUSION 2011;140(5): 1357-70.
A high index of suspicion is required for diagnosing 8. Ouellet G, Bouchard J, Ghannoum M, Decker BS. Available
extracorporeal treatments for poisoning: overview and
acute intoxication. The initial resuscitation is based on
limitations. Semin Dial. 2014;27(4):342-9.
the “ABCDE” approach. Obtaining a detailed history is 9. Singh O, Nasa P. General poisoning management. ICU
vital in diagnosing the cause of poisoning and in addition protocols: A stepwise approach. 1st edb. Chawla R, Todi, S
to the routine investigations, special investigations (Eds). Springer. 2012;68:547-52.
CHAPTER
115
Hypoglycemia in ICU
Sundaram Arulrhaj, Aarathy Kannan, Manikandan R, Vinodh Kumar A
TABLE 1: Signs and symptoms of hypoglycemia TABLE 2: Risk factors for hypoglycemia
Early adrenergic symptoms Neuroglycopenic signs Common risk factors Less common risk factors
zz Pallor zz Confusion zz Mismatch of insulin zz Endocrine deficiencies
zz Diaphoresis zz Slurred speech timing, amount, or type for (cortisol, growth hormone, or
carbohydrate intake both), nonbeta cell tumors
zz Tachycardia zz Irrational or uncontrolled behavior
zz Oral secretagogues without zz Ingestion of large amounts of
zz Shakiness zz Extreme fatigue
appropriate carbohydrate alcohol or salicylates
zz Hunger zz Disorientation intake
zz Anxiety zz Loss of consciousness zz History of severe zz Sudden reduction of
zz Irritability zz Seizures hypoglycemia corticosteroid dose
zz Headache zz Pupillary sluggishness zz General anesthesia or zz Emesis
zz Dizziness zz Decreased response to noxious sedation that places patient
stimuli in an altered conscious
zz Reduction of oral intake zz Reduction of rate of IV
dextrose
In case of prolonged hypoglycemia, when brain zz New NPO status zz Unexpected interruption of
glucose dependence combined with low glucose stores enteral feedings or parenteral
nutrition
causes CNS dysfunction which leads to occurance of
neuroglycopenic signs and symptoms. zz Unexpected transport after zz Drug dispensing error insulin
injection of rapid- or fast-
acting
Neuroglycopenic Signs and Symptoms zz Critical illnesses (hepatic,
Headache, impaired concentration, disorientation, cardiac, and renal failure;
confusion, irritability, slurring of speech, lethargy, sepsis; and severe trauma)
altered behavior may mimic like dementia. In some
cases, patients may show focal seizures, choreoathetosis, thrombosis. Deep coma, shallow breathing, papillary
hemiplegia and patchy involvement of cerebellar dilatation, hypotonia and bradycardia occur when blood
and brainstem area, which mimic like basilar artery glucose is – 10 mg/dL, which signify the medullary phase.
CHAPTER 115: Hypoglycemia in ICU 687
Clinical Mimics
Adrenal crisis
Alcoholism
Addison disease
Anxiety disorders
Cardiogenic shock
Hypopituitarism (Panhypopituitarism)
Insulinoma
Fig. 3: Consequences of hypoglycemia
Pseudohypoglycemia
occasional mortality, with recurrent hypoglycemia being Older age Long duration of diabetes
the most common complication. This places high risk Impaired hypoglycemia awareness Nil per oral without change in
treatment
patients at more severe hypoglycemia risk with a dose-
Severe illness disease, Food malabsorption e.g.
dependent response, with high mortality proportionally gastroenteritis celiac
with the frequency and severity of hypoglycemia (Fig. 3
Septic shock Drug dispensing error
and Tables 3 and 4).
Mechanical ventilation Drugs
Hypoglycemia affect cognitive function in adults, but
Renal failure Beta blockers
the effects are more significant in children under the age
Hepatic dysfunction Quinine
of 5 years. In a 18 year follow-up of the Diabetes Control
Malignancy Sulphonylureas
and Complications Trial (DCCT) showed transient
Severe trauma Salicylates
cognitive dysfunction but similar performances on
Sulfonamides trimethoprim
cognitive tests between patients with a known history
and without a history of severe hypoglycemia, reassuring
that there is no permanent brain damage (Fig. 4). TABLE 4: Frequent asymptomatic hypoglycemia and increased
Mostly in children, a number of case reports, have risk of arrhythmias in patients with type 2 diabetes
fatal hypoglycemia have been attributed to ventricular Bradycardia 8.42 1.40; 51.0 0.02
arrhythmias, termed as ‘dead in bed syndrome’. Atrial ectopic 3.98 1.10; 14.40 0.04
Only NICE-SUGAR, a large multicenter trial, reported VPB 3.06 2.11; 4.44 <0.01
an overall increase in mortality with intensive insulin Complex VPB 0.79 0.22; 2.86 0.72
therapy. Also, in a retrospective analysis of diabetic Hypoglycemia may increase the risk of arrhythmias in patients with
type 2 diabetes and high cardiovascular risk
patients admitted to the general wards a correlation
of hypoglycemia with increased mortality was found,
but this association has been found true even at one multicenter randomized-controlled trials (VISEP and
year postdischarge, implying that hypoglycemia was a Glucontrol) had to be terminated early owing to high
“marker of disease burden” rather than a direct cause rates of severe hypoglycemia, but there was no evidence
of mortality. While others failed to show any significant of increased mortality.
association, several studies demonstrated a decrease A post hoc analysis of the NICE-SUGAR trial revealed
in mortality with intensive insulin control, and two the increased levels of hazard ratios after adjustment for
688 SECTION 10: Intensive Care Unit
TABLE 5: Risk factor for mortality in the ICU TABLE 6: Types of hypoglycemia in critical care
Condition Severe hypoglycemia Mortality Spontaneous hypoglycemia Iatrogenic hypoglycemia
Diabetes 3.07* 0.97
Septic shock 2.03* 1.33 Occurs in sick hospitalized zz Originates from treatment
Creatinine >3 mg/dL 1.10 1.30* patients with organ failure, zz Aggressive glycemic therapy
Mechanical ventilation 2.11* 2.43* malnutrition, or those taking (usually insulin)
predisposing medications zz Also include drug-to-drug
Tight glycemia control 1.59 0.67*
interactions
APACHE II score 1.07 1.14*
zz Patients who develop organ
Age 1.01 1.03*
failure while already taking
Severe hypoglycemia — 2.28*
(≤40 mg/dL antidiabetic agents
Fig. 6: Hypoglycemia increase mortality by 2-fold in patients with acute myocardial infarction not receiving insulin
Sympathetic nervous system activation The following are the myocardial effects of hypo
glycemia:
ECG Changes in Hypoglycemia —— Ejection fraction is increased
Diastolic BP is decreased
Myocardial effects are mediated by insulin and Increase in central aortic pressure
TABLE 7: Intensive glycemic control studies showing rates of hypoglycemia and mortality
Study (Reference) Characteristics Definition of hypoglycemia Rate of Mortality impact
N (% diabetes) hypoglycemia
Surgical ICU (30) Glucose goal Glucose 5% vs 0.78% ↓
N = 1,548 (13%) 80–110 mg/dL vs usual care (≤215 mg/dL) <40 mg/dL arterial blood 43% ICU p = 0.01
34% Hospital p = 0.01
Medical ICU (38) Glucose goal Glucose 18.7% vs 3.1% ↓
N = 1,200 (16.9%) 80–110 mg/dL vs usual care (≤200 mg/dL) <40 mg/dL arterial blood 9.5% p = 0.009 (overall)
↑
(In first 3 days)
Pediatric ICU (39) Normoglycemia vs conventional therapy Glucose 24.9% vs 1.4% ↓
N = 700 (0.9%) (≤214 mg/dL) <40 mg/dL (or <30 mg/dL for 3% p = 0.038
neonates) arterial blood
VISEP (41) Glucose goal Glucose <40 mg/dL (method 17% vs 4.1% ↔
N = 537 (30.4%) 80–110 mg/dL vs conventional not documented) Study terminated early
(≤200 mg/dL)
Glucontrol (42) Glucose goal Glucose 8.7% vs 2.7% ↔
N = 1,101 (18.8%) 80–110 mg/dL vs conventional <40 mg/dL (method variable) Study terminated early
(140–180 mg/dL)
Nice-sugar (40) Glucose goal Glucose 6.8% vs 0.5% ↑
N = 6,104 (20%) 81–108 mg/dL vs conventional <40 mg/dL (method of testing 2.6% p = 0.-2
(≤180 mg/dL) variable) At day 90
↔
At day 28
Digami (43) Intravenous insulin and glocose for 24 Glucose 15% vs 0% ↓
N = 620 (100%) hours followed by basal-bolus insulin vs <54 mg/dL (method not 28% p = 0.011
standard therapy reported) At 5 years
Digami 2 (44%) Two arms with intravenous insulin Glucose 12.7% in ↔
N = 1,253 (100%) and glucose for 24 hours (one more <54 mg/dL (method not intensive Between the 3 arms
aggressive) followed by basal-bolus reported) therapy vs 9.6%
insulin vs standard therapy vs 1.0%
Treatment (Fig. 7 and Table 8) Interrupt insulin pump infusion till blood glucose
If patient who is on subcutaneous insulin pump becomes become >60 mg/dL. If unable to interrupt infusion
hypoglycemic, then: pump infusion and patient shows alteration in level
CHAPTER 115: Hypoglycemia in ICU 691
TABLE 8: Treatment
BG less than 70 mg/dL and patient unconscious or uncooperative or NPO
Immediate action/treatment Repeat Follow-up
*Staff to remain with patient Repeat BG and retreat q15 min If patient NOT NPO or when able to swallow, feed
DO NOT WAIT FOR LAB CONFIRMATION until BG >70 mg/dL without patient carbohydrate to avoid recurrent hypoglycemia.
OF BG BEFORE TREATING symptoms or BG >80 mg/dL. zz If more than 1 hour until next meal/snack, also give
zz If IV access: Give 50 mL (25 gm) D50 IVP over Glucagon should only be 15 grams of carbohydrate*:
2–5 minutes repeated x 1 —— 3 graham crackers OR
zz If no IV access AND glucose <60 mg/dL: Give Add order to check BG once —— 6 saltine crackers OR
STAT. Patient must be turned on their side zz If more than 2 hours until next meal/snack.
Recheck BG in 1 hour.
zz IF NO IV ACCESS: Obtain MD orders for IV fluids with
Contd...
BG 60–100 mg/dL and patient symptomatic and is conscious, cooperative and able to swallow
Give 15 gm carbohydrate: Repeat BG and retreat q15 min zz If more than 1 hour until next meal/snack, also give
zz 4 oz juice or regular pop OR until BG >100 OR symptoms 15 gm of carbohydrate*:
zz 3 glucose tablets OR resolved *3 graham crackers OR
zz 1 TBSP jelly or sugar OR Add order to check BG once *6 saltine crackers OR
zz 1 tube Dextrose gel
every 2 hours *8 oz skim milk
zz If more than 2 hours until next meal/snack. Also add
protein:
*½ sandwich OR
*3 graham crackers with one TBSP peanut butter
Notify treating person ASAP and certainly PRIOR to
administering the next insulin or oral diabetes agent for
medication and glucose monitoring orders
BG 60–70 mg/dL and patient has no symptoms of hypoglycemia and can take orally
No treatment required if the patient is going to Repeat BG and retreat q15 min zz If more than 1 hour until next meal/snack, also give
take meal with in 30 min until BG >100 OR symptoms 15 gms of carbohydrate*:
If meal takes more than 30 min, give 15 gm resolved *3 graham crackers OR
carbohydrate: Add order to check BG once *6 saltine crackers OR
zz 4 oz juice or regular pop OR every 2 hours *8 oz skim milk
zz 1 TBSP jelly or sugar OR zz If more than 2 hours until next meal/snack. Also add
Ask patient to take 120 mL of juice with 2 table spoon —— Parenteral nutrition
thickener in case of level one pured diet. —— Patient transportation and other handoffs
Ask patient to take only glucose gel if he/she is taking —— Hypoglycemia—BG <70 mg/dL
or insulin, wrong dosages administered; correct timing advantage of increasing dosing flexibility when caloric
of the drugs, especially insulin; and also the presence intake is erratic.
of comorbidities, such as pituitary insufficiency, renal
insufficiency, adrenal insufficiency, and which increases Monitoring of Glucose Levels
the risk for hypoglycemia. Self-management by diabetic Bedside capillary blood glucose monitoring must be
patients who are well controlled as outpatients and who performed for at least four times daily (i.e. and before
possess the ability of managing the insulin regimen in the meals and at bedtime for patients who are taking food).
hospital, like those who wear an insulin pumps or those An early morning glucose check at 3:00 am can also be
who use multiple daily injections of glargine, aspart or used in patients with fasting hyperglycemia. An increased
lispro, can be a means to decrease hypoglycemia. glucose level at that time will indicate insufficient
nighttime dose of insulin, but a low glucose level at that
Prescheduled Insulin Therapy time will indicate an early peak in the evening insulin or
Even though endocrinologists used to warn against its insufficient food intake at night time.
use for decades, the regular and rapidly acting analog
Medical Nutritional Therapy
insulin sliding scale, without basal insulin replacement
It is very important to have a consistent carbohydrate
is a common method to control hyperglycemia in the
diet to appropriately match the insulin dosage or the
hospital. Because of concern for hypoglycemia, usually
secretagogue activity to food for optimum glucose level
no basal insulin is given and prandial insulin will be
control and prevent hypoglycemia. All the three meals
given only if the premeal blood glucose level is elevated.
should therefore follow a consistent carbohydrate
If insulin is not given before a meal, the blood glucose
approach and that will emphasize the importance of a
level will rise substantially and it will remain elevated
mixed meal.
even at the time of the next meal. Then, if a large dose
of regular or aspart or lispro insulin is given, which Applying the Systems
could cause hypoglycemia, especially if administered at The recent ADA technical review have discussed the
nighttime without a meal. use of protocols for scheduled and corrected dose
insulin, which might reduce the reliance on sliding
Inpatient Use of Oral Hypoglycemic Agents scale management for maintaining the glycemic control
Oral drugs should not be used by ill patients who are in the hospital. A team or multidisciplinary approach
not able to maintain adequate caloric intake or who will be necessary to establish hospital pathways and to
are on NPO status. Because Secretagogues can cause implement intravenous insulin infusions for the majority
hypoglycemia as side effects, alpha glucosidase inhibitors of patients who are having prolonged NPO status outside
will be ineffective without carbohydrate intake and the critical care units.
metformin will increase the risk in renal compromised
or in heart failure patients. Thiazolidinediones must be Practice Points
discontinued Class III or Class IV heart disease patients, The relationship between mortality and glycemic
although the side effects of TZDs may last several weeks. control demonstrates a U- shaped or J–shaped curve
A common mistake in such population of patients with increased risk of death at both ends.
is the discontinuation of oral drugs in the absence of Spontaneous hypoglycemia is associated with
other alternative methods for diabetes control. These more mortality when compared to iatrogenic
patients should recieve a subcutaneous or IV insulin hypoglycemia. It may imply that hypoglycemia may
regimen during hospitalization. Glycemic control with not be a true cause of mortality rather it may be a
insulin in these circumstances is safer and has the added biomarker for poor prognosis.
694 SECTION 10: Intensive Care Unit
Current guidelines suggest to maintain blood glucose The occurrence of hypoglycemia in critically ill
values in the range of 140–180 mg/dL (7.8–10 mmol/L) patients, weather spontaneous or due to insulin infusion
for most patients. Glucose levels <100 mg/dL (5.6 is associated with poor prognosis and higher mortality.
mmol/L) should be avoided, and treatment needs to This is especially high in cases of severe hypoglycemia.
be revised when levels are < 70 mg/dL (3.9 mmol/L) Increased incidence of severe hypoglycemia is
Particularly in critically ill and elderly patients associated with intensive insulin therapy in order to
hypoglycemia unawareness is common as often they achieve normoglycemia. Due to the dreadful effects of
have low glucose values without any symptoms. Due hypoglycemia and its consequences, hypoglycemia is
to this, it is better to treat patients with glucose levels
the limiting factor for tightly controlling sugar levels in
<70 mg/dL with or without hypoglycemic symptoms.
critically ill.
In healthy and stable patients intensive glycemic
control may be appropriate where as for elderly and
critically ill patients less intensive control seems BIBLIOGRAPHY
appropriate. 1. Bates DW. Unexpected hypoglycemia in a critically ill
Risk factors for hypoglycemia include aggressive patient. Annals of Internal Medicine. 2002:137(N 2);110-7.
glycemic control, recent hospitalization, older 2. Egi M, Bellomo R, Stachowski E, et al. Hypoglycemia
age, terminal illness, renal failure, mechanical and outcome in critically Ill patients. Mayo Clin Proc.
2010;85(3):217-24.
ventilation, shock, malignancy, other comorbidities,
3. Hulkower RD, Pollack RM, Zonszein J. Understanding
hy p o a l b u m i n e m i a a n d p re v i o u s h i s t o r y o f
hypoglycemia in hospitalized patients. Diabetes Manag
hypoglycemia.
(Lond). 2014;4(2):165-76.
4. Hypoglycemia and risk of death in critically Ill patients.
CONCLUSION The NICE-SUGAR Study Investigators. N Engl J Med.
In critically ill patients diagnosing hypoglycemia is a 2012;367:1108-18.
challenge. Beside we cannot rely upon glucose analyzer 5. Lacherade JC, Jacqueminet S, Preiser JC. An overview of
at low ranges of glucose, and neurological signs related to hypoglycemia in the critically IllJ Diabetes Sci Technol. 2009;
hypoglycemia may be masked. 3(6):1242-9.
CHAPTER
116
Biomarkers in Sepsis
Virendra Kumar Goyal, Mohit Goyal
TABLE 2: Diagnostic criteria for SIRS TABLE 3: Characteristics of a “perfect” biomarker for sepsis
zz Temperature dysregulation: > zz Tachycardia: heart rate >90 zz High sensitivity and specificity
38ºC or <36ºC bpm zz Appearance or surge in its levels should precede the clinical
zz Tachypnea: respiratory rate zz TLC i.e. white blood cells signs and symptoms
> 20/min, or pCO2 < 32 mm dysregulation: > 12000/mm3 zz Should be easily detectable (in terms of equipment required)
Hg or the patient requires or < 4000/mm3 or > 10% and affordable
mechanical ventilation bands
zz Should be biologically plausible
SIRS is diagnosed when >2 of these criteria are met.
TABLE 4: Examples of biomarkers in sepsis therapy and most estimation assays are cost effective as
zz Acute phase protein zz Coagulation well. It has a short half-life of 19 hours.
—— CRP —— Activated partial thromboplastin
—— Procalcitonin
—— Pentraxin 3 (PTX3)
time (aPTT) waveform analysis
—— Protein C receptor
Procalcitonin
—— Lipopolysaccharide —— Thrombomodulin Procalcitonin (PCT) is a precursor of the peptide
binding protein calcitonin. It is almost universally expressed as part of
(LBP) the inflammatory response to a various insults discussed
zz Cytokines and zz Endothelial damage earlier in the chapter. Although studies investigating
chemokines —— Heparin binding protein
—— Syndecan -1 and -2
regard to diagnosing bacteremia in particular, PCT have
shown excellent diagnostic ability; so, PCT is superior to
zz Cell surface markers zz Vasodilation
—— Soluble CD14 —— Copeptin (AVP precursor) CRP in diagnosing systemic infections. Judicious use of
(presepsin) PCT can help optimize the duration of antibiotic therapy
—— Neutrophil CD64
and help find the earliest time for discontinuation of the
index (CD64in)
—— mHLA-DR
same.
(monocyte HLA-DR
levels) Triggering Receptor Expressed on
—— CD-163
Myeloid Cells 1
zz Receptor markers zz Cell damage
—— VEGF —— MicroRNA
Triggering receptor expressed on myeloid (TREM)
—— Soluble VEGF- —— Microparticles belong to the superfamily of immunoglobulins by
receptor 1 (sFLT) zz Cell repair
structure and are cell-surface receptors by function.
—— Soluble urokinase —— Procollagen III amino
plasminogen propeptide
TREM-1 is expressed mainly on macrophages and
activator (suPAR) neutrophils, and has been identified as an amplifier of
—— sTREM-1 the immune response that strongly enhances leukocyte
—— RAGE (soluble
activation in the presence of microbial products. Levels
receptor for
advanced glycation of TREM-1 at the cell surface are up-regulated in the
end products) presence of bacteria or fungi; however, nonmicrobial
stimuli (e.g. urate crystals) have also been shown to
The list of proposed sepsis biomarkers is rather long enhance the expression of TREM-1.
(more than 170). Some examples are listed in Table 4. A In addition to the membrane-bound form, a soluble
few of them are discussed below. TREM-1 variant (sTREM-1) has been detected in several
body fluids. Findings suggest that proteolysis of the
C-REACTIVE PROTEIN membrane-anchored TREM-1 is the source of sTREM-1.
C-reactive protein (CRP) is an acute-phase protein Elevated sTREM-1 is found in fluids from patients
synthesized in hepatocytes and alveolar macrophages. with microbial infections, as well in patients with
IL-6 and some other cytokines trigger the production of noninfectious conditions, such as inflammatory bowel
C-reactive protein. Interestingly, this protein has pro- as disease and chronic obstructive pulmonary disease, and
well as anti-inflammatory effects. Serum CRP enthuses in patients undergoing cardiac surgery.
all clinicians and intensivists as its levels in the blood The latter results suggest that sTREM-1 can be
rise rather sharply, it goes down rapidly after response to released by a broad spectrum of inflammatory stimuli.
698 SECTION 10: Intensive Care Unit
The first promising result of the use of sTREM-1 in of the innate immune system and guide management
plasma to diagnose sepsis in ICU patients indicated decisions in a patient with sepsis.
that sTREM-1 might be that perfect diagnostic sepsis
biomarker. BIOMARKER COMBINATIONS
Diagnostic accuracy of sTREM-1 has been most Sepsis can have varied etiology, may be caused by
extensively investigated is pneumonia and sepsis. innumerable pathogens, can have varied pathogenic
The measurement of sTREM-1 in BAL fluid might mechanisms and can involve any organ or major organ
be practicable in an ICU setting, particularly bacterial system; thus no single marker is expected to have very
infections. high sensitivity and specificity for its detection.
Therefore, as we discussed earlier, the search for a
Cytokines single “master key” might be futile but an appropriate,
After the initial host-microbial pathogen interaction, research backed combination of markers could improve
there is activation of all humoral and cellular factions diagnosis, prognosis and treatment efficacy. The right
of the innate immune response. For a comprehensive combination of biomarkers could be the right crack of
response humoral as well as cellular components have the cryptic “sepsis code”.
A combination of the three best-performing markers
roles.
i.e. CRP, PCT and neutrophil count is frequently used
The good age old proinflammatory cytokines
in practice and the ideal as of today would be to use the
produced by mononuclear cells hold ground when
six markers as discussed in the ROC curve. Future bears
it comes to detecting sepsis as well. These include
the possibility of multimarker panels that will add to the
interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α,
diagnostic accuracy and risk assessment in sepsis.
and other uncommonly used ones like IL-12, IL-15 and
macrophage migration inhibitory factor (MIF). CONCLUSION
The rise in levels of the proinflammatory molecules
Accurate and timely diagnosis of infection and
is only a part of the developing immunological response.
monitoring of response are the most important for
Anti-inflammatory modulators, such as IL-1 receptor improvement of patient outcome. For the same there is
antagonist, IL-10 and soluble TNF-α receptors I and need for a biomarker for sepsis that is reliable, can be
II also play important roles. Severe sepsis is more of quickly estimated and is cost effective.
a dysregulation of the immune system rather than a Current evidence suggests that CRP still remains
black and white rise in “pro-” or “anti-” inflammatory an important sensitive marker of inflammation and
substances. infection, and when combined with PCT, the specificity
Being central is the process of sepsis, cytokines are also increases significantly.
important sepsis biomarkers. Single measurement
of most cytokines has proven to be insufficient for STATEMENT OF UNMET NEED
distinguishing between infected and noninfected STREM-1 is the best among the studied markers and still
patients. Studies have suggested an encouraging role is only as accurate as the toss of a coin. Studies into the
IL-6 as a biomarker especially in neonates. An ROC-AUC mechanism of the innate immune response to infections
of 0.75 has been reported for distinguishing SIRS from have laid down the possibilities for various biomarkers.
sepsis. More such in-depth studies are needed to find such
Based on the present knowledge of biomarkers in markers and then their role in diagnosis and predicting
sepsis while levels of single cytokines may not have great prognosis shall need to be validated with further studies.
value but real-time monitoring of multiple cytokines and A perfect biomarker has an AUC of 1, whereas a non-
receptors may help determine the level of dysregulation discriminating marker has an area of 0.5.
CHAPTER 116: Biomarkers in Sepsis 699
antibiotics within 3 hours of Emergency Department identify the causative organisms and make de-escalation
(ED) triage or within 1 hour of recognition of severe possible. In a review of 493 studies it was observed that
sepsis/septic shock did not result in any mortality that there was lack of sufficient evidence to conclude
benefit. While exact time beyond which initiation of if de-escalation was safe and effective in adult patients
antibiotic will prove detrimental is not known, it is with sepsis.
unlikely that administration of first dose of antibiotic will
have major impact on patient’s outcome without other Duration of Therapy and Dosing
supportive therapies. Hence appropriate cultures should There is a risk of relapse of infection with inadequate
be sent prior to antibiotic dose and supportive therapies eradication due to shorter course of therapy. At the same
initiated simultaneously. time prolonged course of antibiotics is associated with
increased chances of toxicity, higher cost and selection
Selection of Appropriate Antibiotic: of multidrug resistant (MDR) pathogens. Decision about
Monotherapy vs Combination Therapy duration of antibiotics should be individualized based on
severity of illness, presence of persistent septic focus, site
Though there is mortality benefit in administration of
of infection and presence of MDR pathogens. Infections
appropriate and adequate antibiotic initially in patients
due to Staphylococcus aureus and Pseudomonas
with sepsis, combination therapy as initial empiric
aeruginosa are often associated with treatment failure
choice has remained controversial. While there are
early relapse, metastatic complications and may warrant
advantages like-broader coverage and antibacterial
longer duration of treatment (14–21 days) against usual
synergy, potential disadvantages are super-infection,
guidelines of 7–10 days. In addition to clinical response,
increased chances of resistance and toxicity in addition
biomarkers like procalcitonin (PCT) can assist in
to increased cost. Combination therapy does increase the
determining duration of antibiotic therapy. PRORATA
likelihood of appropriate therapy more so in presence of
trial, which was a large trial done in 621 ICU patients
multidrug resistant (MDR) pathogens. Gram-negative
with severe sepsis and septic shock, measurement of
coverage typically involves a beta-lactam antibiotic in
PCT concentrations helped in shortening duration of
combination with fluoroquinolone or aminoglycoside.
antibiotic therapy without causing harm.
Quinolones have more lung penetration and less renal
Hydrophilic antibiotics like beta-lactam, glyco
toxicity as compared to aminoglycosides, but evidence peptides, lipopeptides and aminoglycosides are
demonstrates trend towards increased survival with distributed in extra-cellular space and have renal
aminoglycoside-containing regimens. However routine clearance. These drugs usually need a loading dose
use of combination therapy for treatment of Gram- and dose adjustment in setting of hypoalbuminemia
negative infections is not recommended. Combination (higher dose required), renal failure (lower dose) and
therapy should be reserved for patients with very severe dialysis. Lipophilic antibiotics like fluoroquinolones,
illness, septic shock, having risk factor for resistant macrolides, tetracyclines, lincosamides and glycylcyclins
infection, nosocomial infections, neutropenia, severe have intracellular penetration and hepatic clearance.
respiratory infection and sepsis due to unknown source. They do not need loading dose and dose adjustment
is needed in setting of severe hepatic failure only. Also
De-escalation with certain drugs having time-dependent killing (beta-
While one is justified in starting combination in certain lactam and glycopeptides) continuous intravenous
situations, every effort must be made to change to infusions are more effective as they achieve higher
narrow spectrum antibiotic coverage once culture blood concentrations exceeding minimum inhibitory
reports are available, as a part of “antibiotic stewardship” concentration (MIC) of pathogen by prolong infusion.
program and optimize the use of antibiotics. However, in For patients with ventilator associated pneumonia (VAP)
practice only in 20–30% cases subsequent culture reports aerosolized delivery of antibiotics through nebulizer
702 SECTION 10: Intensive Care Unit
can achieve higher MIC of drug at lesser risk of systemic infection. Potential for infection with resistant organism
toxicity and resistance. But size of droplet generated for is judged by patient’s risk factors like comorbid illness
delivery should be ideally between 1 µm and 3 µm as (DM/CKD/HIV/immune-suppressive therapy), prior
larger droplets are trapped in circuit and smaller one antibiotic exposure, hospitalization and presence of
are expelled during expiration. However meta-analysis indwelling devices. However diagnosis can only be
of use of colistimethate sodium this used as adjunct confirmed by isolating causative organism from blood
in treatment of VAP have revealed conflicting results or appropriate fluid by culture. This takes several days
with more clinical and microbiological response but no for results and also if patient is already on antibiotics
mortality benefit. chances of positivity of culture report are bleak. There
are more rapid methods like – polymerase chain reaction
Selection of Regimen for Empirical (PCR) and mass spectrometry to identify causative
Antibiotic Therapy organisms. But, these are not routinely available and
Antibiotics remain the standard therapy for patients with when available are expensive. Gram stains and data from
sepsis since long. MONARCS trial, done in 2004, on over local hospital infection control committee often help in
2500 patients of sepsis demonstrated significant decrease choosing the correct empirical regimen. Hence, most
in crude mortality in patients receiving adequate of the times physicians have to administer antibiotics
antibiotic therapy. Selection of regimen should begin empirically, while awaiting laboratory confirmation.
with detailed clinical assessment to identify the site Table 2 gives the recommendation for selection of
of infection. Routine laboratory investigations and empirical regimen to cover most likely pathogens,
imaging are usually sufficient to identify source of according to probable site of infection. But therapy
TABLE 2: Regimen for empirical selection of antibiotics in severe sepsis and septic shock
Suspected source of infection Special situation Antimicrobials of choice
Urinary tract infection No risk for MDR pathogen Ceftriaxone 1
Or
Levofloxacin
Risk for MDR pathogen Cefaperazone and sulbactam
Prior history/ antibiotics Or
Indwelling catheter/stent Piperacillin tazobactum
+/ – Amikacin/ Gentamycin
Postoperative setting/Nosocomial +Vancomycin
Community acquired pneumonia No risk of Pseudomonas Ceftriaxone
Plus azithromycin or levofloxacin
Risk for Pseudomonas Cefepime
structural lung disease, steroid Or
therapy, malnutrition Piperacilllin tazobactum
Plus
Azithromycin
+/-
Aminoglycoside/tobramycin
Intra-abdominal sepsis Piperacillin tazobactum
Or
Cefepime
+Metronidazole
+/ – Aminoglycoside
Contd...
CHAPTER 117: Early and Empiric Antibiotics in Sepsis: Current Controversy 703
Contd...
should be individualized considering above factors. with severe sepsis and septic shock. Toxin-neutralizing
Invasive fungal infections are considered as possibility antibodies for Clostridium, fecal flora reconstitution by
in neutropenic patients, major abdominal surgery, fecal transplant, monoclonal antibodies for Pseudomonas
patients on parenteral nutrition, transplant recipients and Staph. aureus are some emerging adjuvant therapies.
and on chemotherapy. Once empirical therapy is Targeting bacterial pore-forming toxins (PFT) with
initiated, response is assessed periodically by clinical liposomes to reduce their virulence is one innovative
and laboratory parameters. Whenever possible after therapy under investigation.
stabilizing patient, source control should be achieved
like drainage of abscess, debridement and removal SUMMARY
of infected device. De-escalation to narrow spectrum In spite of standard recommendations and availability
antibiotics is recommended once culture reports are of guidelines for early and empiric antibiotic therapy
available. in sepsis, there are controversy at each step—regarding
In absence of clinical response, patient should diagnosis, timing, selection of antibiotic, mode of
be reassessed for alternative diagnosis as several administration, dose and duration of antibiotic. As sepsis
noninfective conditions mimic sepsis. In addition to is a complex pathophysiological syndrome, multiple
delayed initiation of antibiotics, persistent septic focus, interventions are needed to have favorable outcome in
uncontrolled DM, antimicrobial resistance and super
these patients. Physicians must follow the prevailing
added fungal infection are common causes for failure of
recommendations as most are based on good evidence
response to therapy. One must also consider that target
but treatment has to be individualized depending on
site penetration of antibiotics is hampered in patients of
severity of illness, patient’s comorbid conditions and
shock due to microvascular hypoperfusion.
prevailing degree of antimicrobial resistance.
FUTURE THERAPY
BIBLIOGRAPHY
With limited number of new antibiotics in pipeline 1. Liang, Stephen Y, Kumar A. Empiric antimicrobial
and presence of multiple factors resulting in failure of therapy in severe sepsis and septic shock: optimizing
antibiotic therapy, there is a need to focus on therapies pathogen clearance. Curr Infect Dis Rep. 2015;17(7):493.
other than antibiotics to reduce mortality in patients doi:10.1007/s11908-015-0493-6
704 SECTION 10: Intensive Care Unit
2. MacArthur RD, Miller M, Albertson T, Panacek E, Johnson 5. Venkatesh, Srinivas & Chauhan, Lakhbir & Gadpayle,
D, Teoh L, Barchuk W. Adequacy of early empiric antibiotic Adesh & S. Jain, T & Wattal, Chand & Aneja, Satinder &
treatment and survival in severe sepsis: Experience Ghafur, Abdul & Puri, Manju & Sinha, Ajit & Singh, Varinder
from the MONARCS Trial, Clinical Infectious Diseases. & Baveja, Usha & Dutta, Renu & Gaind, Rajni & Sardana,
2004;38(2):284-8.
Raman & Manchanda, Vikas & Kotwani, Anita & Hans,
3. Michael B, et al. The early antibiotic therapy in septic
Charoo & Chandelia, Sudha& Jain, Piyush & Jain, Sarika.
patients-milestone or sticking point? Critical Care. 2014;
(2016). National Treatment Guidelines for Antimicrobial Use
18:671.
4. Sterling SA, Miller WR, Pryor J, Puskarich MA, Jones AE. The in Infectious Diseases.
impact of timing of antibiotics on outcomes in severe sepsis 6. Vincent JL, Bassetti M, François B, Karam G, Chastre J,
and septic shock: A systematic review and meta-analysis. Torres A, et al. Advances in antibiotic therapy in the critically
critical care medicine. 2015;43(9):1907-15. ill. Crit Care. 2016;133:10.1186/s13054-016-1285-6.
CHAPTER
118
Arterial Blood Gas Analysis: Simple
Steps for Understanding
Ravindra Kumar Das
considered accurate. For all clinical purpose Van Slyke Gas Analysis
Equation according to the Zander is the best choice for Purpose of gas analysis should be to establish the relation
derivation of BE and can be obtained with high accuracy. between PaO2 and SpO2, severity of hypoxemia (mild,
The equation involves pH, PaCo2, cHb and SpO2. From moderate and severe), cause of hypoxemia (decreased
the BE thus obtained, measured HCO 3- is derived as FiO2, ventilation defect, Ventilation–Perfusion mismatch,
follows: shunt and diffusion defect across the alveolar wall),
Derived BE = Measured HCO3- - Normal value of type of respiratory failure (Type 1 and type 2 respiratory
HCO3- failure) and to know arterial oxygen content (CaO2).
= Measured HCO3- -24 For gas analysis we proceed in the following steps:
So, Measured HCO3- = BE +24.
Step 1: We look for SpO 2 (oxygen saturation). SpO 2
Derived HCO3- is achieved by clinically applicable
reflects how much of the oxygen carrying capacity by
Handerson Equation and from total CO2 on electrolyte
hemoglobin is utilized.
panel.
In my other observation 18% of ABG were found Step 2: We look for PaO 2 (partial pressure of oxygen
inaccurate with this method while they were found in arterial blood). It is an indicator of adequacy of
accurate by the second method. oxygenation of blood by the lung.
Step 2: pH and H+ relation (Table 1) also satisfies the Step 3: The relation between PaO2 and SpO2. It is decided
accuracy of ABG. In the patient whose ABG sample is by Figure 1 and Table 2.
inaccurate by the above method, the relation between H+ For ready reference of relation between PaO 2 and
and pH is decided. If they match, in that condition also SpO2 we can take help of the Table 2.
the ABG is accurate. Step 4: We calculate PAO 2 (alveolar oxygen content).
H+ can be derived either by the Handersan equation PAO2 is a derived value and is calculated as:
H = 24 × PaCO2/HCO3-
+
or by H+ = 83- two digits of pH after decimal if the pH PAO2 = FiO2 (PB-PH2O) – PaCO2/R
falls in range of 7.10–7.60. = 150 – 1.25 × PaCO2
Where FiO2 (oxygen fraction in inspired air) = 0.21. PB
(barometric pressure) = 760 mm of Hg at sea level, PH2O
TABLE 1: Relation between pH value and corresponding H +
concentration (water vapor pressure) = 47 mm of Hg. PaCO2 (partial
pressure of carbon dioxide). R (respiratory quotient)
pH [H+] mmol/L pH [H+] mmol/L
6.70 200 7.40 40
=0.8.
6.75 178 7.45 35 Normal value of PAO2 is 96–98 mm of Hg.
6.80 158 7.50 32 Step 5: P(A-a) O2 gradient (mm of Hg) = PAO2-PaO2. Other
6.85 141 7.55 28 simple way to decide the value is age/4+4. Normally, it is
6.90 126 7.60 25 <15 mm of Hg. It may be as high as 30 mm of Hg in elderly.
6.95 112 7.65 22
If this value is increased it indicates parenchymal lung
7.00 100 7.70 20
disease. The value of P(A-a) gradient in type 2 respiratory
7.05 89 7.75 18
failure helps to determine whether the patient has
7.10 79 7.80 16
associated lung disease or just reduced respiratory effort.
7.15 71 7.85 14
7.20 63 7.90 13 Step 6: We look for PaCO2 (partial pressure of carbon
7.25 56 7.95 11 dioxide). PaCO 2 is an indicator of the efficacy of
7.30 50 8.0 10 ventilation. Normal value is 36–45 mm of Hg. But for the
7.35 45 purpose of ABG analysis, it is taken as 40 mm of Hg. More
CHAPTER 118: Arterial Blood Gas Analysis: Simple Steps for Understanding 707
TABLE 2: Relation between PaO2 and SpO2 In an adult of 72 kg the normal value of CaO2 is 200 mL
PaO2 Corresponding SpO2 Interpretation O2/L of blood. O2 dissolved in plasma = 3 mL/L of blood
(mm of Hg) (%) When the cardiac output is low, we should calculate
80–100 95–100 Normal oxygen delivery (DO2).
60–80 90–94 Mild hypoxemia
DO2 = Cardiac output (CO) × arterial oxygen content
40–60 75–89 Moderate hypoxemia
(CaO2) and then evaluate tissue diffusion.
<40 <75 Severe hypoxemia
Electrolyte Analysis
than 49 mm of Hg is considered as due to hypoventilation
Purpose of electrolyte analysis is to provide the complete
and not due to compensatory effect.
picture of acid-base derangement. Sometimes, it adds
Step 7: Type of respiratory failure is decided. It is defined
key insight in difficult diagnosis. It helps in management.
as Type1 respiratory failure- when there is moderate
Some calculated parameters help in modern way of acid-
hypoxemia (PaO 2 <60 mm of Hg) in the absence of
base analysis.
hypercapnea and Type 2 respiratory failure when there is
Modern blood gas analyzers offer the option of
hypercapnea (PaCo2 > 49 mm of Hg). Type 2 respiratory
measuring electrolytes using part of the ABG sample.
failure may be associated with hypoxemia.
In general, sodium largely reflects reciprocal change
Step 8: Causes of hypoxemia is determined from the in body water content, chloride generally change in
value of PaCo2, P(A-a)O2 and the knowledge of response parallel with plasma Na+. Chloride is low in metabolic
to supplemental O2 by the Flow chart 1. alkalosis and high in some form of metabolic acidosis.
Step 9: We calculate P/F i.e. PaO2/FiO2. It is known as Potassium may reflect potassium shift in and out of
hypoxemia index. It is the measure of gas exchange. P/F cells related to H+ ion. Each decrease in blood pH of
<300, indicates the development of acute lung injury 0.10, the plasma potassium should rise by 0.6 mmol/L.
(ALI). In the absence of pneumonia and heart failure, This relation is not invariable. Other than the pH, low
progressive diffuse pulmonary infiltration in X-ray chest level of potassium generally means excessive losses
and P/F <200, suggest the acute respiratory distress (gastrointestinal or renal). High level usually means renal
syndrome (ARDS). dysfunction. In critically ill patient free calcium should
Step 10: Calculate the arterial oxygen content (CaO2), be assessed with acid-base disturbances.
particularly when there is anaemia and/or hypoxemia. Step 1: We calculate osmolality.
CaO2 = Hb(gm/L) ×1.34×SpO2/100+0.003×PaO2 Osmolality =
708 SECTION 10: Intensive Care Unit
Step 6: Chloride level. Normal value of chloride 98–107 When delta gap is added with measured HCO3–, the
mmol/L. sum value should satisfy the normal range of HCO3– i.e.
Its value is low in metabolic alkalosis. It is high in 22–26 mmol/L. If this value is greater than 26 mmol/L it
some form of metabolic acidosis. Value of chloride indicates the additional presence of metabolic alkalosis
generally changes in parallel with plasma Na+. and reduction to less than 22 indicates nonanion gap
metabolic acidosis.
Step 7: Anion Gap (AG). AG is calculated as
AG = [(Na+)+(K+)] – [(Cl–) + (HCO3–)] mmol/L. Step 9: Gap-gap ratio.
+ Gap-gap ratio is calculated in high AG acidosis
Concentration of K must be taken in AG calculation
by anion gap excess (Measured AG-12)/HCO 3– deficit
in the critically ill patients. Normal value of AG is 12 ± 4
(24-measured HCO3–).
(i.e. 8–16) mmol/L. For all purpose of measurement of
If the ratio is <1 means coexistence of non AG
delta gap and gap-gap ratio we consider normal anion
metabolic acidosis or treatment with N/S.
gap as 12 mmol/L.
If the ratio is >1 means coexistence of metabolic
AG increases most often due to increase of
alkalosis or when NaHCO3 is added.
unmeasured anions and less commonly due to decrease
in unmeasured cations. Major unmeasured cations Step 10: Base excess (BE).
are calcium, magnesium and gamma globulin. Major Base excess is defined as the fully ionized acid which
unmeasured anions are negatively charged plasma could be required to return the patient blood pH 7.4
proteins (albumin), sulphate, phosphate, lactate when CO2 has been adjusted to 40 mm of Hg.
and other organic anions. Albumin is the principal BE is determined by Van Slyke equation according to
unmeasured anion and principal determinant of the Zander is
the anion gap. Decreased AG is usually caused by BE = (1 – 0.014.cHb) . [(1.45.cHb + 7.7)
hypoalbuminemia and severe hemodilution. Since the (pH-7.4) – 24.8 + CHCO3–].
hypoalbuminemia is present in as much as 90% of the It is calculated by machine.
ICU patients, the following formula for the “Corrected Otherwise, BE = HCO3– (measured)-24 (Normal value
AG” (AGc) has been proposed to include the contribution of HCO3–).
of albumin. Normally, BE is zero. Positive value indicates
AGc = AG + 2.5 [4.5 – (albumin in gm/dL)] metabolic alkalosis and negative value indicates
metabolic acidosis. BE of ± 5 mmol/L or greater requires
AG should always be calculated for two reasons.
explanation. BE is true reflection of nonrespiratory
1. AG is useful to decide the cause of metabolic acidosis.
component of AB balance.
2. AG ≥20 mmol/L supports a primary metabolic acid–
base disturbance regardless of the pH or serum HCO3–.
Cause of metabolic acidosis has been grouped as
Acid Base Analysis
If a patient has PaCo2 36–45 mm of Hg, HCO3– 22–26
high, normal and low anion gap metabolic acidosis.
mmol/L, pH 7.36–7.44, BE < ± 5 mmol/L and AG <20 then
In a patient all three can be present simultaneously
there is no acid base disorder and thus no need of further
and there can be simultaneous presence of metabolic
analysis for acid base.
alkalosis. To segregate these four, we take the help of
The purpose of acid-base analysis is to identify
Delta Gap, ∆Gap + HCO3–, Gap-Gap ratio and BE of the
the primary disorder, evaluate the compensatory
patient.
response and to decide the disorder as simple or mixed.
Step 8: Delta gap. If mixed, decide the respiratory acidosis or alkalosis
Delta Gap = Patient’s AG – Normal value of AG with metabolic alkalosis and/or metabolic acidosis. If
= Patient’s AG – 12. metabolic acidosis, decide high, non or low anion gap.
710 SECTION 10: Intensive Care Unit
Use the “gaps” to evaluate high anion gap metabolic Step 6: Compensatory change of acid-base disturbance is
acidosis for associated nonanion gap metabolic acidosis predicted as indicated in Table 3.
and/or metabolic alkalosis. To conclude we proceed The plasma HCO3– concentration rarely exceeds 45
systematically in the following steps. mmol/L as a result of compensation for respiratory
acidosis. Plasma HCO3– concentration rarely falls below
Step 1: We look for pH and H+ simultaneously and decide
12–15 mmol/L as a result of compensatory respiratory
academia/alkalemia. H+ is derived as stated in accuracy
alkalosis.
of ABG. Normal value of pH as 7.4 and H+ as 40 mmol/L
for all calculation of ABG. A normal pH can be normal, Step 7: In high anion gap metabolic acidosis and/or
compensated or mixed defect. mixed disorder, we take help of Delta Gap + HCO3– and
Gap–Gap ratio to know about associated nonanion gap
Step 2: See HCO 3–. Its normal value is 24 mmol/L for
metabolic acidosis and/or metabolic alkalosis. In mixed
analysis of ABG. It is >24 mmol/L in metabolic alkalosis.
disorder, respiratory acidosis and respiratory alkalosis do
It is <24 mmol/L in metabolic acidosis.
not coexist.
Step 3: See the direction of movement of H+ and HCO3–. If
Step 8: We thus decide the acid-base disturbance and try
they move in the opposite direction–primary metabolic
to search the cause of it in the particular patient.
cause. If they move in the same direction–primary
respiratory cause.
Complete Diagnosis of ABG
Step 4: See PaCO2. This part includes diagnosis of gas analysis, electrolyte
Step 5: See the direction of movement of PaCO2 and analysis and acid-base analysis together. Then etiology
HCO3–. If they move in the same direction–simple cause. is searched and corelated with provisional diagnosis
If they move in the opposite direction–mixed disorder. If and history of the patient. Management is planned
one value is normal–simple cause. accordingly. In critically ill patients, it is also an important
Other ways to know about mixed disorder are: monitor.
–
Know the expected value of PaCO or HCO
2 3 from
Table 3. If expected value and actual value match– CASE HISTORY/
mixed disorder unlikely. If expected and actual value PROVISIONAL DIAGNOSIS
differ–mixed disorder likely. For easy understanding of the method I have taken ABG
In respiratory cause if BE >±5 it is mixed disorder. of five patients admitted in emergency department.
In respiratory cause with AG>20 is also mixed Those are:
disorder.
Predicted compensation
Case 1 Was not taking insulin from last 5 days. Parameters were
A 17 yrs/HM presented in ED with the c/o altered pulse 120/minute, BP 100/60 mm of Hg, RR 32/m SpO2 94%,
sensorium on 19.06.17 and had history of type 1 DM. febrile, diagnosed clinically as a case of diabetic ketoacidosis.
Accuracy of ABG
– –
BE Measured HCO 3 Derived HCO 3 Difference Accurate/not accurate pH H+ Matched/not matched
–16.7 7.3 7.7 -0.4 Accurate 7.286 51.8 Matched
Gas analysis
SpO2% PaO2 PAO2 P(A-a)O2 mm PaCo2 P/F CaO2 Conclusion Provisional clinical
mm Hg mm Hg Hg mm Hg mm Hg mL/L of blood diagnosis
97.1 110.6 128.4 17.8 16.6 526.7 140.50 Hyperventilation Diabetic ketoacidosis
Electrolyte analysis
+ + ++ –
Na K Ca Cl Osmality Hct(%)/ Volume AG AGc D Gap Gap/Gap D Gap + HCO3– BE Conclusion
mmol/L mol/L mmol/L mmol/L mOsm/kg Hb(g/ L mmol/L mmol/L mmol/L ratio mmol/L mmol/L
dL)
131.8 1.31 0.484 109.7 263.6 37/10.8 5.41 15.6 - 3.6 3.6/16.7 11.1 –16.7 Hypokalemia
<1 Hypocalcemia
Low osmalality
Normal anion
metabolic acidosis
Case 2 year Ganja smoking for 15 yrs, and was working as a cook
A 50 yrs/HM admitted in ED on 02.07.17 with c/o for 10 yrs, diagnosed as a case of pneumonia. Parameters
Breathlessness for 7 days and Fever for 10 days. Had past were Pulse 110/m, BP 110/70 mm of Hg, RR 38/m, SpO2
history of alcohol intake for 10 yrs, Toddy drinking for 1 70%, temp febrile ECG-P-Pulmonale.
Accuracy of ABG
– –
BE Measured HCO 3 Derived HCO 3 Difference Accurate/not accurate pH H+ Matched/not matched
8.6 32.6 35.9 –3.3 Accurate 7.360 43.7 Matched
712 SECTION 10: Intensive Care Unit
Gas analysis
SpO2% PaO2 PAO2 P(A-a)O2 PaCo2 P/F CaO2 Conclusion Provisional clinical
mm Hg mm Hg mm Hg mm Hg mm Hg mL/L of blood diagnosis
90 60 72.3 12.3 65 285.7 130.25 Type 2 RF with hypoxemia Pneumonia
due to hypoventilation
and ALI
Electrolyte analysis
+ + ++ –
Na K Ca Cl Osmality Hct(%)/ Volume AG AGc D Gap Gap/gap D GAP + HCO3– BE Conclusion
mmol/L mmol/L mmol/L mmol/L mOsm/kg Hb(g/dL) L mol/L mmol/L mmol/L ratio mmol/L mmol/L
112.8 3.62 0.199 80 228.2 49.3/10.8 4.05 0.4 — –11.6 24.3 8.6 Hyponatrimia
Hypocalcemia
Low osmalality
Hypovolemia
Accuracy of ABG
BE Measured HCO3– Derived HCO3– Difference Accurate/not accurate pH H+ Matched/not matched
1.8 25.8 22 3.8 Accurate 7.60 25.1 Matched
Gas analysis
SpO2% PaO2 PAO2 P(A-a)O2 PaCo2 P/F CaO2 Conclusion Provisional clinical
mm Hg mm Hg mm Hg mm Hg mm Hg mL/L of blood diagnosis
99.4 134.2 134.2 0 23 639 159.8 Unnecessary use of O2 CKD
Electrolyte analysis
+ + ++ –
Na K Ca Cl Osmality Hct (%)/ Volume AG AGc D Gap Gap/gap DGap + HCO3– BE Conclusion
mmol/L mmol/L mmol/L mmol/L mOsm/kg Hb (g/dL) L mmol/L mmol/L mmol/L ratio mmol/L mmol/L
121.9 3.92 0.567 96.1 245.3 42.2/12 4.74 7.7 — 4.3 — 26.3 1.8 Hyponatremia
Hypocalcemia
Low osmalality
Metabolic alklosis
CHAPTER 118: Arterial Blood Gas Analysis: Simple Steps for Understanding 713
Accuracy of ABG
– –
BE Measured HCO 3 Derived HCO 3 Difference Accurate/not accurate pH H+ Matched/not matched
-04 23.6 21.9 1.7 Accurate 7.436 32.6 Matched
Gas analysis
SpO2% PaO2 PAO2 P(A-a)O2 mm PaCo2 P/F CaO2 Conclusion Provisional clinical
mm Hg mm Hg Hg mm Hg mm Hg mL/L of blood diagnosis
99 123.1 123.1 0 29.6 586.4 183.0 mmol/L Unnecessary use of O2 COPD
Electrolyte analysis
+ + ++ –
Na K Ca Cl Osmality Hct(%)/ Volume AG AGc D Gap Gap/ D Gap + BE Conclusion
mmol/L mmol/L mmol/L mmol/L mOsm/kg Hb(g/dL) L mmol/L mmol/L mmol/L Gap Ratio HCO3– mmol/L
mmol/L
130.7 2.8% 0.546 106.6 261.5 43.3/13 4.6 5 – –7 –7/2.1<1 14.9 –0.4 Hypocalcemia
Hyponatremia
Metabolic Acidosis
Case 5 edema+, absent breath sound in the base, doll’s head sign
A 58 yrs male presented in ED in unconscious state for 1 present diagnosed as a case of hepatic encephalopathy
day, distension of abdomen 1 month, B/L pedal edema with volume overload. Pulse-100/m BP-110/m RR-24/m
20 days. Past history of T2 DM/CLD, O/E jvp+, Ascites+, temp-980 F, SpO2 90%.
714 SECTION 10: Intensive Care Unit
Accuracy of ABG
– –
BE Measured HCO 3 Derived HCO 3 Difference Accurate/not accurate pH H+ Matched/not matched
-13 11 10.9 0.1 Accurate 7.457 35 Matched
Gas analysis
SpO2% PaO2 PAO2 P(A-a)O2 PaCo2 P/F CaO2 Conclusion Provisional clinical
mm Hg mm Hg mm Hg mm Hg mm Hg mL/L of blood diagnosis
88.1 66.1 128.5 62.4 15.7 314.9 6.6 Type 1 RF with shunt/ Hepatic
alveolar filling defect encephalopathy
Electrolyte analysis
+ + ++ –
Na K Ca Cl Osmality Hct(%)/ Volume AG AGc D Gap Gap/ D Gap+ BE Conclusion
mmol/L mmol/L mmol/L mmol/L mOsm/kg Hb(g/dL) L mmol/L mmol/L mmol/L Gap ratio HCO3– mmol/L
mmol/L
119.1 5.30 0.599 97.2 240 23.2/5.6 - 16.3 20.05 8.05 8.05/ 18.95 -13 Hyponatremia
13.1<1 Hypocalcemia
Hyperkalemia
Low osmalality
High AG and
Normal AG
Metabolic acidosis
BIBLIOGRAPHY 6. Marino PL, Marino’s The ICU Book, 4th edition, Wolters
1. Brenner and Rector. The Kidney 9th edition, Elsevier Kluwer Health, 2014. pp. 587-98.
Saunders. 2012. pp. 604-37. 7. Rao SM, Nagendranath V. Arterial blood gas monitoring,
2. Coombs M. Making sense of arterial blood gases. Nursing Indian J Anaeth. 2002;46(4):289-97.
Times. 2001;97(27):36. 8. Sood P, Paul G, Puri S. Interpretation of arterial blood gas.
3. Dubin A, Menises MM, Masevicius FD, et al. Comparison Indian Journal of Critical Care Medicine. 2010;14(2):57-64.
of three different methods of evaluation of metabolic acid- 9. Thomas D, DuBose, Jr. Harrison’s Principles of Internal
base disorders. Crit Care Med. 2007;35:1264. Medicine, 19th edition, McGraw Hill Education. 2015. pp.
4. Electrolyte analysis using ABG samples, 2007, Uploaded 315-24.
online in http://www.r tmagazine.com/2007/02/ 10. Wiliams AJ. ABC of oxygen: Assessing and interpreting
electrolyte-analysis-using-abg-samples/. arterial blood gasses and acid-base balance. BMJ. 1998;
5. Field MJ, Burnett L, Sullivan DR, Stewart P. Davidson’s 317:1213-6 Periodical.
Principles and Practice of Medicine, 21st Edition, Churchill
Livingstone Elsevier. 2010. pp. 442-6.
CHAPTER
119
Superbugs in ICU and the Need
for Antibiotic Stewardship
Pankaj Kumar
the bacterial cell. Alternately, efflux pumps could Some Important Nosocomial
be activated and cause efflux of antibiotic from Pathogens Seen in ICU
the bacterial cell. These mechanisms can cause
There are several organisms which are extremely difficult
resistance to fluoroquinolones, macrolides, and
to treat due to their resistance profiles and are the new
aminoglycosides.
superbugs in intensive care unit. These include ESKAPE
Production of biofilms: These are collection of one or
pathogens namely Enterococcus faecium, Staphylococcus
more species of bacteria enmeshed in extracellular
aureus, Klebsiella pneumonia, Acinetobacter Baumaanii,
matrix. All foreign bodies whether endotracheal
Pseudomonas aeruginosa, and Enterobacter species,
tubes or catheters could acquire a biofilm. Antibiotics
which account for majority of the nosocomial infections
may not be able to penetrate biofilms. So eventhough
and consequent increased morbidity and mortality of
bacteria may be sensitive to antibiotics, the immune
hospitalized patients.
cells and antibiotics are unable to penetrate deeper
In India, Gram-negative organisms are responsible
and hence cannot kill them.
for majority of the nososcomial infections. They possess
Large inoculums: Antibiotics may be rendered
multiple mechanisms for antibiotic resistance. E. coli
ineffective, if large number of bacteria infect a
and Klebsiella are most common and produce ESBL.
patient. They may produce increased quantity of
Porin channel loss and multidrug efflux pumps may also
hydrolyzing enzymes.
be present. Klebsiella is further equipped with Plasmid-
Genetic Transmission of Bacterial Resistance mediated carbapenemases such as KPC and NDM
The resistance could develop as a result of mutations make Klebsiella resistant. Acinetobacter Baumaanii,
( vertical transmission dependent) or may be due to Pseudomonas aeruginosa, and Enterobacter species too
mobile genetic elements (horizontal transmission). are less amenable to antibiotics because of thick cell wall.
These may then be passed on to bacteria of same species The resistance is further compounded, if plasmids too
as well as other species. Plasmids are one of the most are acquired.
important causes of development of antibiotic resistance. Polymyxins are being used again due to emergence
These are extrachromosomal genetic materials, capable of resistance but Serratia, Proteus and Providencia are
of multiplying in bacterial cytoplasm independent of inherently resistant to these. Tigecycline has no activity
bacterial DNA. Their resistance genes (r-genes) are against Pseudomonas, Proteus and Providencia. It is
easily exchanged or transferred between plasmids and bacteriostatic and not much effective in bloodstream and
chromosomes. Integrons are bigger DNA sequences urinary infections.
which are packed with gene cassettes. Each cassette Gram-positive organisms are more permeable
then has small recognition site with a r-gene attached to antibiotics. However, Enterococcus is inherently
to it. These integrons are distributed in environment resistant to certain antibiotics such as penicillin and
and are not mobile, but crucial for transfer of r-genes. aminoglycosides. Enterococcus faecium is also emerging
Transposons are DNA sequences which are associated as resistant organism because of resistance to BL
with the genome of a bacterial cell and are also called antibiotics and vancomycin due to B-lactamases and Van
as “jumping genes”. Plasmids can integrate a transposon A mutations especially in bloodstream infections and
and pass it on to other plasmids or to the chromosome of endocarditis. A virulent organism, Staphylococcus aureus
the bacteria. causes necrotizing infections. Methicillin-resistant
Genetic material could be transferred between Staphylococcus aureus (MRSA) is one of the most
bacteria by either conjugation, transduction or dangerous organisms associated with resistant infections
transformation. and have been reported from community as well.
718 SECTION 10: Intensive Care Unit
Antibiotic Resistance Threat in India Using alternates to antibiotics: Though several alternatives
Several factors have contributed to widespread resistance are being explored, none have reached the stage of being
in India: marketed and accepted as standard therapy. Inhibitors
Excessive indiscriminate use of antibiotics: Antibiotics
of quorum sensing, antibodies, phage therapy, Lysins,
are increasingly being prescribed over the counter agents to target type IIa topoisomerases, antimicrobial
and used for even viral or non infective conditions. peptides or lipopeptides, efflux pump inhibitors are
Prolonged duration of intake, sometimes in being evaluated for possible future use.
suboptimal dosage or usage as part of multiple
antibiotic regime has further compounded the
Antimicrobial Stewardship Program
problem. A robust antimicrobial stewardship program must
Quality of antibiotic: With no quality checks in place,
be in place in every hospital to ensure judicial use
the spurious drugs are also available. of antibiotics. It should include timely and optimal
Indiscriminate use in agriculture, poultry and
selection of antibiotic with optimal dose and duration for
meat industry too has lead to antibiotic resistance the best clinical outcome for the treatment or prevention
developing in mass population. of infection with minimum possible toxicity to the patient
and minimum impact on resistance and other ecological
How to Tackle this Problem? adverse effects. Centres for Disease Control has defined
the core elements of an antimicrobial stewardship
There is an urgent need to control this looming threat
program as follows:
about antibiotics and it needs commitment from all
quarters of society. Clinicians, microbiologists, hospital Committed leadership: Dedicating necessary human,
administrators, pharmacologists, drug manufacturers, financial, information technology resources.
policy makers, government and drug controllers need to
Accountability: Appointing a single leader ( ideally a
come together to overcome this menace.
physician) responsible for program outcomes.
Judicial use of antibiotics: In view of absence of new
Drug expertise: Appointing a single pharmacist leader
antibiotics and molecules, there is no way except
responsible to improve antibiotic use.
to prolong life of current antibiotics. Guidelines for
antibiotic use need to be strictly adhered to for achieving Action: systemic evaluation of ongoing treatment need,
this goal. Right patient, right drug, right dose for correct after a set period of initial treatment.
duration and appropriate e-escalation are few cardinal Tracking: Monitoring antibiotic prescribing and
principles. resistance patterns.
incidence among diabetic patients undergoing The surgical trauma leads to higher production of
cardiac or noncardiac surgery. Patients having cardiac stress hormones, the amount of which parallels the
and/or kidney disease are at greater risk of fluid severity of operation or any postsurgery complications.
overload. Presence of autonomic neuropathy causes It also inhibits anabolic hormone especially insulin.
higher risk of postoperative postural hypotension, In patients without DM this can cause transient
cardiac arrhythmia and delayed gastric emptying. hyperglycemia, but in the diabetic patients, insulin
Postural hypotension may precipitate AKI in those production is already marginalized so the metabolic
with kidney disease. Neuropathy affects nearly changes causes marked catabolic state requiring careful
30–50% of people placing them at increased risk attention. Many of the anesthetic drugs also have
of heel ulceration and delayed wound healing, variable effect on glycemic control so needs proper
specially if PVD is also present. Current evidence consideration.
suggests that many a times high risk patients are
not identified before surgery with a failure to ensure PRINCIPLES AND TARGET OF
proper perioperative interventions.
PERIOPERATIVE MANAGEMENT
Increased perioperative infection: Hyperglycemia
To optimize the diabetic management especially
impairs leukocytic activity including impaired
targeting HbA1c <8.5% (69 mmol/mol) prior to
chemotaxis and phagocytic function thereby
surgery and identification with optimization of
increasing infection which accounts for 65% of
comorbidities. So postpone elective surgery if
postoperative complications and nearly 25% of
possible when glycemic control is poor (HbA1c
perioperative deaths in patients with diabetes
mellitus. >8.5%).
Er ro r s i n i n su l i n p re s c r i p t i o n a n d c o mpl e x
To maintain electrolyte level within normal range and
polypharmacy: Patients having diabetes many optimize intraoperative kidney and cardiovascular
a times require or are already on multiple drug function, to use appropriate anesthetic agent, IV
regimens with high probability for mistakes. Many a fluids, analgesics and minimally invasive techniques
times drugs are omitted in error or judicially stopped to lessen postsurgery pain and gut dysfunction
and never started, sometimes drugs are continued thereby facilitating early return to normal diet.
inappropriately. Insulin being one of the top listed Plan for rapid mobilization and discharge with early
high alert medicine needs proper and careful use, it return to usual diabetic management and normal
could be life saver but with probability of becoming activities.
life threatening if proper care not taken. To maintain CBG target of 6–10 mmol/L (upto
Absence of institutional guidelines for perioperative 12 mmol/L acceptable), presently lower limit of
care of diabetes and untrained staff in this regard. 8 mmol/L is considered better during perioperative
period.
METABOLIC RESPONSE TO SURGERY Hypoglycemia (<6 mmol/L) must be avoided,
AND ANESTHESIA AND THE EFFECT patient must be made sensitive of the hypoglycemic
OF DIABETES symptoms.
Surgery frequently requires starvation period and
also causes trauma to the system. Starvation leads to PREOPERATIVE MEASURES
a catabolic state which can be managed in diabetics Patient should ideally be optimized at the primary
by insulin and glucose infusion -180 g/day, however level and then should be sent to surgery outdoor with
if starvation period is short e.g. only one meal missed, important data like type and duration of diabetes,
patient can be managed without insulin infusion. comorbidities and complications present with their
722 SECTION 10: Intensive Care Unit
present status, treatment patient is taking and his BMI, needs longer starvation period, emergency operation or
blood pressure, current blood glucose and HBA1c level. when glycemic level is keeping outside the target range.
Once surgery is decided, arrangement for preoperative Patient with diabetes should be prioritized on the
assessments needs to be made soon possible to optimize surgery list and be kept 1st in the morning so as to cause
the patient. Patient should be admitted on the day of least disturbance to the normal dietary routine
operation Diabetes specific preadmission needs to be
avoided.
INTRAOPERATIVE MANAGEMENT
Preoperative assessment aims for current blood The day case surgery and patient with diabetes on
only dietary therapy could be managed by proper
glucose parameters with HbA1c, blood urea and serum
manipulation of the patients normal medication and the
electrolytes and ECG for all patients with diabetes
diet.
and specific investigation as required for present and/
Use of variable rate intravenous insulin infusion
or expected comorbidities beside general routine
(VRIII) are preferred-in those who needs longer period of
investigation. If HbA1c >8.5% and/or comorbidities are
starvation; patients having type 1 diabetes and have not
found not to be optimized, elective surgery if feasible
received background insulin; those with poorly managed
should be delayed.
DM (HbA1c >8.5%) and nearly all patients with diabetes
Planning admission—It is advised to ensure norm-
requiring emergency surgery. Its use however needs
oglycemia (CBG: 6–10 mmol/L) before admission and
experienced staff (Table 3).
the patient is also asked for adjustment of existing therapy
Conventional glucose-insulin-potassium (GIK)
during perioperative period as per the requirement that infusion may be used in these situation. This provides
is whether patient is fit for day case surgery needing a safe substrate with coadministered insulin and is well
short starvation period or needs IV glucose/insulin supported by evidence.
consideration. (Tables 1 and 2).
Patient fit for day case surgery are those who requires MEASURES DURING SURGERY
short starvation period (less than 12 hrs) missing only Before induction of anaesthesia, CBG (capillary blood
one meal and is well controlled (HbA1c <8.5%). Patients glucose) should be checked and there after regularly-
needs inpatient surgery who are not well controlled, hourly or more frequently-during the procedure. If CBG
Daily 3, 4 or 5 doses Usual dose Basal bolus regimen: zz Give usual morning
continued zz Leave morning and lunch time dose dose
zz Cut the basal by 20% if taken in the morning zz Drop the lunch dose
CHAPTER 120: Perioperative Management in Diabetes 723
Sulphonylureas Leave morning dose Leave both morning zz Stop all the drugs except
and evening dose GLP1 once VRII commenced
Metformin Usual dose continued If taken once or twice daily – take as normal
zz Do not restart until patients
(If eGFR >60/mL/min/1.73 m2) If taken thrice daily, omit lunch time dose begins eating and drinking
normally
Pioglitazone Usual schedule maintained
DPP4 inhibitor Usual schedule maintained
GLP1 analogue Usual schedule maintained
SGLT-2 inhibitor Drop on the day of surgery
In accordance with recent guidelines
exceeds 12 mmol/L and is not on insulin, DKA should But then if someone with type 1 diabetes is on insulin
be looked for and managed as medical emergency if infusion, it must not be stopped unless subcutaneous
present. Otherwise increased blood glucose should be insulin has been given. Management of hyperglycemia
lowered by giving additional subcutaneous insulin or in a patients with type 1 diabetes-SC rapid acting insulin
by using a VRIII if two subcutaneous (SC) insulin fails analogue up to a maximum of 6 IU should be given,
to work or by changing the rate of VRIII if already in assuming that 3 mmol/L of CBG will drop with 1 IU. A
use. However, VRIII should not be used unnecessarily. second dose should be planned only after 2 hrs.
724 SECTION 10: Intensive Care Unit
Hospital acquired infections (HAI) or nosocomial Pneumonia must meet one of the criteria (only in patients >12
months of age)
infections are defined as infections which are not present
zz Rales or dullness to percussion on chest examination and one of
at the time of hospital admission and develop after 48
the following:
hours of admission or even after discharge from hospital. —— new onset of purulent sputum or change in character of
Catheter associated urinary tract infection (CAUTI) transtracheal aspirate, bronchial brushing or biopsy;
—— isolation of virus or detection of viral antigen in respiratory
Catheter related blood stream infection (CRBSI)
secretions;
Nosocomial surgical site and soft tissue infection
—— diagnostic single antibody titer (IgM) or four-fold increase in
inflammation of the lung parenchyma due to infectious unit (ICU) (ICU HAP).
726 SECTION 10: Intensive Care Unit
If HAP occurs in initial 96 h of hospital admission it TABLE 2: Treatment for ventilator associated pneumonia (VAP)
is called ‘early-onset’ and termed ‘late-onset’ if it occurs Gram-positive Gram-negative Gram-negative
after 96 h of hospital admission. antibiotics with antibiotics with antibiotics with
Ventilator associated pneumonia (VAP) is a type MRSA activity antipseudomonal antipseudomonal
activity: β-lactam– activity: Non-β-lactam–
of HAP, diagnosed in patients who are on mechanical based agents based agents
ventilation at the time of infection. About 86% of all
Vancomycin 15 Piperacillin– Fluoroquinolones
ICU HAP are ventilator associated pneumonia. The mg/kg IV q8–12h tazobactam 4.5 g Ciprofloxacin 400 mg
American Thoracic Society criteria for the diagnosis of IV q6h IV q8h
VAP are pneumonia in a patient mechanically ventilated Levofloxacin 750 mg
IV q24h
for greater than 48 h with at least two of the following
OR OR OR
criteria:
Fever Linezolid 600 mg Cefepime 2 g IV q8h Aminoglycosides
IV q12h Ceftazidime 2 g IV zz Amikacin 15–20 mg/
Leukocytosis or leukopenia
q8h kg IV q24h
Purulent tracheal secretions. zz Gentamicin 5–7 mg/
DIAGNOSIS Aztreonam 2 g IV
q8h
Bi o ma rk e r s s u c h a s s e r u m p ro c a l c i t o n i n a n d
bronchoalveolar fluid level of soluble triggering receptor
expressed on myeloid cells (STREM-1) have been found studies as MDR or late onset pathogens are also present
to be useful in diagnosing nosocomial pneumonias. in the culture of early onset group of HAP/VAP.
However, the recent IDSA guidelines for treatment of
VAP recommend use of clinical criteria alone rather than TREATMENT
biomarker (serum PCT or STREM-1) plus clinical criteria Treatment of HAP/VAP should be based on the common
for decision on initiation of antibiotics. organisms isolated and the resistance pattern observed
in the ICU and wards at the individual hospital and
CAUSATIVE ORGANISMS local antibiogram and antibiotic guidelines should be
Methicillin-sensitive Staphylococcus aureus (MSSA), S. generated.
pneumoniae, and Haemophilus spp. as early-onset Emperical treatment of clinical suspected VAP/HAP
pathogens and P. aeruginosa, MRSA (methicillin- should include coverage for S. aureus (MRSA is quite
resistant Staphylococcus aureus), Enterobacter spp., prevalent), Pseudomonas aeruginosa, and other gram
Acinetobacter spp., and S. maltophilia as late-onset negative bacilli (Table 2).
pathogens. It is recommended to use two antipseudomonal
But this distinction of early onset and late onset HAP antibiotics from different classes for treatment of
on the basis of microbes has been challenged in recent suspected VAP/HAP in high risk patients for MDR such
CHAPTER 121: Hospital Acquired Infections 727
as patients on prior antibiotics, septic shock, ARDS, >4 catheterization and it depends on the indication for
days of hospitalization or on dialysis. catheterization such as:
Empirical therapy in nonventilated HAP patients 1. Surgery, 2. Urine output measurement, 3. Urine
without high risk factors includes vancomycin (or retention and 4. Urinary incontinence.
linezolid) plus any one of piperacillin-tazobactem/ Most bacteriuria in short-term catheterization is
fluroquinolones/carbapenems/ceftazidime or cefepime. of single organism most commonly Escherichia coli.
In case of high risk of mortality or MDR pathogens Others include Pseudomonas aeruginosa, Klebsiella
aminoglycosides should be added to above regimen. pneumoniae, Proteus mirabilis, Staphylo co ccus
epidermidis, enterococci, and Candida species.
PREVENTIVE MEASURES Long-term catheterization is associated with
General aseptic techniques polymicrobial bacteriuria with common uropathogens
Application of general infection control measures such as E. coli, Klebsiella and others organisms like
Judicious antibiotic use Providencia stuartii.
Semirecumbent patient positioning
Oral endotracheal tube
DIAGNOSIS
Oral gastric tube CAUTI in patients with indwelling urethral, suprapubic,
Aseptic tracheal suctioning-closed circuit suctioning or intermittent catheterization is defined by the presence
Avoiding unplanned extubation of symptoms or signs compatible with UTI with no other
identified source of infection along with >10 3 colony
Less frequent ventilator tube changing.
forming units (cfu)/mL of 1 bacterial species in a single
catheter urine specimen or in a midstream voided urine
NOSOCOMIAL URINARY TRACT
specimen from a patient whose urethral, suprapubic, or
INFECTIONS
condom catheter has been removed within the previous
The most common hospital acquired infection is
48 h.
nosocomial urinary tract infection (UTI) and is generally C A-ASB (Catheter associated-asymptomatic
associated with urinary tract catheterization. bacteuria) is defined by the presence of >105 cfu/mL of 1
bacterial species in a single catheter urine specimen in a
Pathogenesis patient without symptoms compatible with UTI.
Insertion of a catheter may carry urethral organisms Signs and symptoms suggestive of CAUTI include
into the bladder. fever (it may be new onset or worsening of pre-existing
The drainage tube of the urine collecting bag may be
fever), chills and rigors, altered sensorium, generalized
contaminated with bacteria that can ascend the bag weakness; flank pain; tenderness over renal angle;
and catheter. hematuria; pelvic discomfort. In patients where catheters
Even in a closed system, the bacteria can enter the
have been removed, symptoms include dysuria, frequent
bladder directly through the space present between urination and suprapubic pain or tenderness.
the external catheter and the mucosal wall of urethra In the catheterized patient, pyuria is not diagnostic of
and this is the most common route for bacterial entry. CAUTI and the presence or degree of pyuria should not
A biofilm is formed over the drainage bags, catheter be used to differentiate CA-ASB from CAUTI.
and even uroepithelium which provide a favorable
microenvironment for growth of bacteria. TREATMENT
The most important risk factor for the development Unnecessary catheterization should be avoided.
of catheter-associated bacteriuria is the duration of All efforts should be made to reduce inappropriate
728 SECTION 10: Intensive Care Unit
urinary catheter insertion and minimize the duration of A short term catheter (<14 days) is commonly
catheterization. colonized along the external surface of catheter from a
Screening and treatment for CA-ASB is not re skin microbe, therefore, the roll-plate culture method
commended in general, except in pregnant women and is highly sensitive. Whereas in long-term catheters
patients who undergo urologic procedures. (>14 days) the bloodstream infection occurs due to the
Treatment for CAUTI is with broad spectrum intraluminal spread of microbes from the catheter hub.
antibiotics such as piperacillin-tazobactam with or A definitive diagnosis of CRBSI is made when there
without aminoglycosides or as per the culture reports is a positive percutaneous blood culture along with
and resistance pattern. Seven days of antibiotic treatment concordant microbial growth from the tip of catheter or
is recommended for patients who shows good response catheter-drawn blood cultures.
to antibiotics, and in others treatment should continue
for 10–14 days. TREATMENT
The empirical treatment is with vancomycin (linezolid
CATHETER RELATED BLOOD STREAM in proven cases but not suspects) and coverage for
INFECTION gram negative bacilli with either of a fourth-generation
The use of intravascular devices and catheters have cephalosporin, carbapenem, or β-lactam/β-lactamase
increased considerably over recent times for therapeutic combination, with or without an aminoglycoside.
and monitoring patients such as peripheral arterial line, In patients with neutropenia or severe sepsis CRBSI
central venous catheters, pulmonary arterial catheters. should be empirically treated with combination antibiotic
The risk of bloodstream infections due to catheters covering gram negative bacilli such as Pseudomonas
depends on the type of intravascular device, the site of aeruginosa.
insertion, intended use for the catheter, the duration, on In certain high risk patients, suspected to have
how frequently the catheter is accessed, the preventive candidemia, antifungal such as echinocandin or
measures followed and the patients characteristics. The flucanazole should be added empirically. These includes
most infections occurs either from the site of catheter patients on total parenteral nutrition, hematologic
insertion or hub of catheter, or both. malignancy, on broad-spectrum antibiotics for long
I n n o n c u f f e d p e rc u t a n e o u s c a t h e t e r s, t h e duration, recipients of bone marrow or solid-organ
commonly associated microbes are: coagulase-negative transplant, femoral catheterization, or colonization of
staphylococci, S. aureus, Candida species, and enteric Candida species at multiple sites.
gram-negative bacilli. Removal of long term catheters should be considered
For surgically implanted catheters and peripherally in patients with CRBSI associated with : severe
inserted CVCs, they are coagulase-negative staphylococci,
sepsis; endocarditis; suppurative thrombophlebitis;
enteric gram-negative bacilli, S. aureus, and P. aeruginosa.
bloodstream infection persisting even after >72 h of
culture sensitive antimicrobial therapy; or infections
DIAGNOSIS
with S. aureus, P. aeruginosa, fungi, or mycobacteria.
Fever is a common presentation. Patient should be
Short-term catheters should be removed in patients
examined for any signs of local inflammation or pus
discharge around the catheter insertion site. with infections due to gram-negative bacilli, S. aureus,
The suspicion for catheter related blood stream enterococci, fungi, or mycobacteria.
infection (CRBSI) is high if no other source of infection
is identified, and the blood cultures are positive for NOSOCOMIAL SURGICAL SITE AND
organisms commonly associated with CRBSI, as SOFT TISSUE INFECTION
mentioned above. If within 24 hrs of catheter removal, SSI can be superficial involving only skin and
the symptoms improve, it is suggestive of CRBSI. subcutaneous tissue, or deep SSIs involving fascia and
CHAPTER 121: Hospital Acquired Infections 729
to coma in which the patient can be aroused by RAS and cerebral cortex.
vigorous stimuli.
Akinetic mutism: Represents fully awake patient ASSESSMENT OF COMA
capable of thinking but has no motor functions or Assessment comprises of detailed history, general
speech. This is due lesions in the medial thalamic physical examination and neurological assessment.
nuclei, frontal lobes or massive hydrocephalus.
Abulia: Is similar to akinetic mutism but a milder HISTORY
form in which patient has decreased ability to The course of events and progress of neurological
initiate activity. The lesion is in frontal lobe and its lesion in time and space.
connections. History of preceding symptoms of fever, raised
Catatonia: Is a disorder seen in psychotic and intracranial tension, seizures.
schizophrenic patients. The patient looks like akinetic Medication and drug abuse.
mutism but evidence of focal neurological damage in Associated co-morbid illness.
the form of extensor plantar, hypertonia is absent.
The locked-in state: There is no speech or motor GENERAL PHYSICAL EXAMINATION
activity of the limbs. The only movement is lid Fever: Suggestive of anticholinergic overdose, heat
elevation and vertical eye movements. This is as a stroke, bacterial/viral meningitis, sepsis, neuroleptic
result of hemorrhage in ventral pontine region. malignant syndrome.
734 SECTION 11: Toxicology
—— Concussion
—— Viral encephalitis
upper or lower limb is suggestive of hemiplegia.
—— Miscellaneous: Fat/cholesterol embolism, carcinomatous Occasional twitching movements of the limb may be
meningitis, etc. suggestive of underlying seizure activity. Myoclonic
zz Causes with abnormal imaging with or without CSF abnormality jerking is seen commonly in patients with anoxic/
—— Cerebrovascular accident
—— Brain abscess
ischemic encephalopathy and other toxic or metabolic
—— Intracranial space occupying lesion with surrounding edema disorders.
—— Massive bilateral cerebral injury Abnormal posturing as:
—— Metabolic causes as described above associated with
—— Decorticate posture: In which the patient lies with
previously coexisting focal brain damage
—— Miscellaneous: Sagittal sinus thrombosis, viral encephalitis, flexion at elbows and wrist with supination of the
vasculitis, thrombotic thrombocytopenic purpura, etc. arm suggestive of bilateral midbrain lesion
—— Decerebrate posture: Characterized by extension
Hypothermia: Toxicity of barbiturate/sedative/ of the elbows and wrist with pronation either
phenothia-zine, peripheral circulatory failure, spontaneously or on noxious stimuli indicating
hypothyroidism. Hypothermia itself causes coma damage to the motor tracts in the mid brain or
when the temperature is <31°C caudal diencephalon.
Tachypnea: Seen in systemic acidosis, sepsis and
brain stem lesions. Level of Arousal
Hypertension : Hypertensive encephalopathy, The Glasgow Coma Scale (GCS) (Table 2) was initially
intracranial bleed, head injury devised for patients with head injury but it is now used as
Hypotension: Seen in acute coronary syndrome, bedside tool to assess the level of consciousness in all the
sepsis, myxoedema coma, Addisonian crisis, cases of coma irrespective of cause.
barbiturate poisoning, and alcohol intoxication. The GCS has certain limitations:
Cutaneous petechiae: As in bleeding diathesis leading —— Mild impairment of consciousness may not be
tumor, inflammatory processes, cerebral abscess and dolls eye movement, GCS less than 5 are poor prognostic
diffuse axonal injury. indicators.
EEG: Useful in nonconvulsive seizures, herpes virus
encephalitis, prion (Creutzfeldt-Jakob) disease and to BIBLIOGRAPHY
assess severity of metabolic encephalopathy. 1. Di Perri, Thibaut A, et al. Measuring consciousness in coma
and related states. World J Radiol. 2014;6:589-97.
CSF in the diagnosis of meningitis and encephalitis.
2. Huff JS, Stevens RD, et al. Emergency neurological life
Toxicological analysis in cases of poisoning and when support: approach to the patient with coma. Neurocrit Care.
diagnosis is obscure. 2012;17(Suppl 1):S54-9.
3. Kasper DL, Hauser SL, Jameson JL, et al. Harrison’s
PROGNOSIS Principles of Internal Medicine. 19th edition, McGraw-Hill.
This depends on the cause and severity of coma. Comas 2015. pp. 1171-7.
due to metabolic causes are usually reversible unless 4. Oliveira deAmorim RL, Nagumo MM, et al. Current clinical
approach to patients with disorders of consciousness. Rev
associated with hypoxic brain damage. A significant
Assoc Med Bras. 2016;62(4):377-84.
degree of recovery occurs after 48 hours of coma. In
5. Plum F, Posner JB, Saper CB, Schiff ND. Plum and Posner’s
coma due to structural lesions, nature of the lesion Diagnosis of stupor and coma, fourth edition, Oxford. 2007.
and rapidity with which it is corrected are important pp. 309-27.
determinants of prognosis. Absence of pupillary reflex, 6. Young GB. Coma. Ann NY Acad Sci. 2009;1157:32-47.
CHAPTER
123
Common Poisoning and Management
Saurabh Srivastava
and myocarditis can also occur. ST-T wave changes, monitoring to manage shock. Refractory hypotension
ventricular arrhythmias and conduction blocks can may require low-dose dopamine (4–6 Hg/kg/min)
occur in case of severe myocardial injury and steroids. Sodium bicarbonate is given to correct
metabolic acidosis.
Respiratory: Cough, dyspnea, cyanosis and pulmonary
edema are common presenting complaints, however ORGANOPHOSPHATE POISONING
in severe cases patient can have respiratory failure and
Organophosphates (OP) are commonly used
ARDS.
as insecticides (agricultural domestic and industrial),
Neurological: Consciousness is maintained till the late medications, and nerve gas. OPs are one of the most
stage, but headache, altered sensorium, convulsion and common causes of poisoning worldwide, as suicidal
coma can also occur. poison. Intentional or unintentional contamination of
food sources is the common cause of organophosphate
Other features: Patients can have severe metabolic
exposure. Commonly used compounds are malathion,
acidosis, disseminated intravascular coagulation,
parathion, etc. Absorption of poison is possible by all
intravascular hemolysis and acute adrenocortical
routes—respiratory, eyes, skin and gastrointestinal.
insufficiency.
Carbamates include carbaryl, carbofuran and propoxur,
etc.
Diagnosis
The diagnosis is based on history, clinical features, and
MECHANISM OF TOXICITY
foul garlic smell; however gastric aspirate or breath, silver
Acetylcholinesterase (AChE) enzyme is inhibited by
nitrate impregnated paper test is done, for confirming
organophosphates. AChE hydrolyzes acetylcholine,
the diagnosis.
leading to excess of acetylcholine at sympathetic and
parasympathetic synaptic junctions. Excess acetylcholine
Management
at synaptic junction, results in initial stimulation of
The deleterious effects of poison are due to phosphine, so
neurotransmission followed by paralysis.
the management is directed to sustain life till phosphine
is excreted. CLINICAL FEATURES
In early presentation, gastric lavage is done to Clinical presentation of organophosphate poisoning can
reduce absorption of phosphine, using potassium be divided into three broad categories:
permanganate in 1:10000 dilutions. Activated charcoal
is also useful. Phosphine excretion is through breath 1. Muscarinic Effects
and urine so adequate ventilation and renal perfusion is Cardiovascular: Hypotension, Bradycardia
maintained. Respiratory: Rhinorrhea, bronchorrhea, broncho
There is no antidote to reduce the deleterious effects spasm, respiratory distress
of phosphine on various organs. Magnesium sulphate Gastrointestinal: Nausea, vomiting, abdominal pain,
has been used to reduce these effects, but with variable diarrhea and increased salivary secretions (Hyper
results. One gram of magnesium sulphate is given salivation)
intravenously, followed by 1 g every hour for the next Ocular: Miosis and blurred vision.
two hours, thereafter 1.0–1.5 g is given every 4–6 hourly Glands: Diaphoresis and increased lacrimation
for around 3–5 days. Other regimen is 1 gm of MgSO4/ Genitourinary: Incontinence.
intravenously followed by 1 gm every 4–6 hours, with
magnesium levels within safe limits (3–3.6 mEq.). 2. Nicotinic Effects
Two-three litres of saline is infused over the first Common nicotinic effects include weakness, muscle
3–6 hours, preferably under central venous pressure fasciculations, cramps and diaphragmatic failure.
CHAPTER 123: Common Poisoning and Management 739
INTRODUCTION
India is a country known to the western population as
a country of snake charmers and snakes over centuries,
despite generation after generations some families in our
country who play with snakes (snake charmers) we fail to
protect the community from snake bite which requires
at least education of the common people, how to protect
themselves from snake bite as well as what to do after the
bite has occurred.
The estimated death in India is an underestimate
because of lack of proper registration of snake bite. The
real number of death in our country probably much
higher. The persons or population at risk of snake bite in
Fig. 1: Complicated and uncomplicated snake bite cases. Complicated
our country is around 50 million people which may occur
cases are more who comes late and reaches about 100% who comes
any time in the life (Fig. 1). 3 days after
The infrastructure of the medical profession in India
is maldistributed in such a manner to protect this poor to establish a single protocol for both first-aid and
rural population against the snake bite. Scientifically and treatment which contained evidence based procedures
ethically we, the doctors cannot treat the patients of snake and was relevant to the Indian context. In July 2006, a
bite properly. Moreover, ignorance of the people around National Snake Bite Conference was convened, including
the snake bite victims, the misbelieves about snake Indian and International experts. Moreover publications
bite and ignorance of the medical profession also play issued by the WHO Regional Office for South-East Asia,
a large part to care this patients in a proper way. There written and edited by David A Warrell in the year 2015
are large number of conflicting protocols for dealing and enduring efforts of the scientist and doctors working
with first aid and treatment. In 2004, WHO established a indifferent regions of India is the back bone of these
snake bite Treatment Group, whose role was to develop update. We have treated about 10000 cases of snake
recommendations to reduce mortality according to bite patients in Medical College Hospitals, Kolkata,
international norms. A primary recommendation was Tarakeswer Rural Hospitals and Seba Nursing Home,
CHAPTER 124: Management of Snake Bite in India 743
Tarakeswar, Hooghly, West Bengal, SRI Hospitals, Betai, GH = Get to Hospital immediately. Traditional
Nadia, West Bengal since 1987. remedies have NO PROVEN benefit in treating snake
Early treatment definitely reduces complications that bite.
can be proved by a study done in South India presented T = Tell the Doctor of any systemic symptoms that
application of a pressure-pad over the bite wound, Increased risk of necrosis with 4/5 of the medically
immobilization of the bitten limb and transport of the significant snakes of India. (Fairly, 1929) (Pugh et al,
patient to a place where they can receive medical care 1987) OA/Auell, 1995)
without delay. Increased risk of massive neurotoxic blockade when
The first aid being currently recommended is based tourniquet is released (Watt, 1988).
around the mnemonic. Risk of embolism if used in viper bites. Procoagulant
“CARRY NO R.I.G.H.T.” It consists of the following: enzymes will cause clotting in distal blood. In addition,
CARRY = Do not allow victim to walk even for a short the effect of the venom in causing vasodilatation
distance; just carry him in any form, specially when bite presents the danger of massive hypotension and
is at leg. neuroparalysis when the tourniquet is released.
No-Tourniquate They do not work! (Tun Pe 1987) (Khin-Ohn Lwin
from nonvenomous species. Only 50% of bites by encourages them to delay their journey to hospital.
venomous species actually envenomate the patient Diagnosis of the species of snake responsible for
I = Immobilize in the same way as a fractured limb. the bite is important for optimal clinical management.
Use bandages or cloth to hold the splints, not to block This may be achieved through expert identification
the blood supply or apply pressure. Do not apply any of the dead snake or a (mobile-phone) image of it, or
compression in the form of tight ligatures, they do not by inference from the resulting “clinical syndrome”
work and can be dangerous! of envenoming. It is recommended that syndromic
744 SECTION 11: Toxicology
approaches and algorithms for diagnosing the species chance to move away. If collecting grass that has
responsible for snake bites be developed in different previously been cut and placed in a pile, disturb the
parts of India. grass with the stick before picking the grass up.
Keep checking the ground ahead when cutting crops
SNAKE BITE PREVENTION AND like Millet, which are often harvested at head height
OCCUPATIONAL RISK and concentration is fixed away from the ground.
The normal perception is that rural agricultural workers Pay close attention to the leaves and sticks on the
are most at risk and the bites occur first thing in the ground when wood collecting.
morning and last thing at night. However, this is of very Keep animal feed and rubbish away from your house.
little practical use to rural workers in preventing snake They attract rats and snakes will follow.
bite since it ignores the fact that often snake bites cluster Try to avoid sleeping on the ground.
around certain biomechanical activities, in certain Keep plants away from your doors and windows.
geographic areas, at certain times of the day. Snakes like cover and plants help them climb up and
Grass-cutting remains a major situational source of into windows.
bites.
In rubber and coconut plantations clearing the DIAGNOSIS PHASE
base of the tree to place manure causes significant Symptoms (Figs 2 to 11)
numbers of bites.
General
Harvesting high growing crops like Millet which
There are a great many myths surrounding snake
require attention focused away from the ground.
Rubber tapping in the early hours 03:00–06:00.
symptoms. Table 1 below summarizes the evidence-
Vegetable harvesting/fruit picking.
based situation. Hemostatic abnormalities are prima
facie evidence of a Viper bite. Cobras and Kraits do not
Tea and coffee plantation workers face the risk of
cause generally hemostatic disturbances.
terrestrial vipers when picking or tending bushes.
Saw Scaled Vipers do not cause renal failure whereas
Clearing weeds exposes workers to the same danger
Russell’s Viper and Hump-nosed Pitviper do.
as their grass-cutting colleagues.
Russell’s Viper can also manifest neurotoxic
Walking at night without a torch barefooted or
symptoms in a wide area of India. But in our study none
wearing sandals accounts for a significant number of
of the Russell’s Viper bite presented with neurotoxic
bites.
feature.
Bathing in ponds, streams and rivers, in the evening.
A B
Fig. 2A and B: Two types of krait. (A) Narrow band throughout the body. Very dangerous, No ASV available, Can kill a person silently;
(B) Wide band starts from the nake sparing the tail, less toxic to humen
Fig. 3: Daboia Russelii (Russel Viper), most important hematotoxic Fig. 4: Nonpoisonus snake, mixes with the green leaves (Laudaga)
snake in India, but ASV is available in India
Fig. 5: Very beautiful to see, known in the mythology for killing Fig. 6: Type krait. Usually very timid but dangerous if bite named
lakhinder the husband of Behula named Kalnagini, very little toxic Sankhamuthi. Maintain the environment and ecology by eating
to human snakes
746 SECTION 11: Toxicology
Fig. 7: Narrow band throughout the body. Very dangerous, no ASV Fig. 8: King Kobra (Naja naja) very lethal snake, neurotoxic, can kill
available, can kill a person silently an elephant within seconds
Fig. 9: Naja kautia, neurotoxic, ASV available in India Fig. 10: Naja kautia, neurotoxic, ASV available in India
Low back pain, indicative of a early renal failure the length of time it can take for symptoms to manifest.
or retroperitoneal bleeding, although this must be Often this can take between 6 hours and 12 hours. Late
carefully investigated as many rural workers involved onset envenoming is a well documented occurrence (Ho
in picking activities complain of back pain generally. et al, 1986) (Warren et al. 1977) (Reitz,1989).
The skin and mucous membranes may show evidence This is also particularly pertinent at the start of the
of petechiae, purpura ecchymosis. rainy season when snares generally give birth to their
The passing of reddish or dark-brown urine or young. Juvenile snakes, 8–10 inches long, tend to bite the
declining or no urine output. victim lower down on the foot in the hard tissue area, and
Lateralizing neurological symptoms and asymmetri thus any signs of envenomation can take much longer to
cal pupils may be indicative of intracranial bleeding.
appear.
Muscle pain indicating rhabdomyolysis.
Parotid sw elling, conjunctival e dema, sub-
DIAGNOSIS PHASE: INVESTIGATIONS
conjunctival hemorrhage.
20 Minute Whole Blood Clotting Test
General Signs and Symptoms of Elapid (20 WBCT)
Envenomation Considered the most reliable test of coagulation and
Swelling and local pain (Cobra), may be asymptomatic should be carried out at the bedside by treating physician.
in case of Krait (Figs 2A and B) patient often could It can also be carried out in the most basic settings. It is
not recognize the bite significantly superior to the ‘capillary tube’ method
Local necrosis and/or blistering (Cobra). of establishing clotting capability and is the preferred
Descending paralysis, initially of muscles innervated
method of choice in snake bite.
by the cranial nerves, commencing with ptosis,
A few mililiter of fresh venous blood is placed in
diplopia, or ophthalmoplegia. (The patient complains
a new, clean and dry, glass vessel and left at ambient
of difficulty in focusing and the eyelids feel heavy.
temperature for 20 minutes. The vessel ideally should be
There may be some involvement of the senses of taste
a small glass test tube. The use of plastic bottles, tubes or
and smell but these need further research).
syringes will give false, readings and should not be used.
Paralysis of jaw and tongue may lead to upper airway
obstruction and aspiration of pooled secretions The glass vessel should be left undisturbed for 20
because of the patient’s inability to swallow numbness minutes and then gently tilted, not shaken. If the blood is
around the lips and mouth, progressing to pooling of still liquid then the patient has incoagulable blood. The
secretions, bulbar paralysis and respiratory failure. must not be washed with detergent as this will inhibit
Hypoxia due to inadequate ventilation can cause the contact element of the clotting mechanism. The test
cyanosis, altered sensoriun and coma. This is a life should be carried out every. 30 minutes from admission
threatening situation and needs urgent intervention. for three hours and then hourly after that. If incoagulable
Paradoxical respiration, as a result of the intercostal blood is discovered, the 6 hourly cycle is then be adopted
muscles becoming paralyzed is a frequent sign. to test for the requirement for repeat doses of ASV.
Stomach pain which may suggest submucosal
hemorrhages in the stomach (Kularatne 2002) (Krait). MANAGEMENT OF SNAKE BITE
Krait bites often present in the early morning with IN GENERAL
paralysis that can be mistaken for a stroke (Figs 2A
and B). Pain
Snake bite can often cause severe pain at the bite site; this
LATE-ONSET ENVENOMING can be treated with pain killers such as paracetamol.
The patient should be kept under close observation for at Aspirin should not be used due to its adverse impact on
feat 24 hours. Many species, particularly the Krait and the coagulation. Do not use nonsteroidal anti-inflammatory
Hump-nosed pitviper (Joseph et al, 2006) are known for drugs (NSAIDs) as they can cause bleeding. This can
748 SECTION 11: Toxicology
be particularly dangerous in a patient already having may be questionable. These species should be detected
coagulopathy. first and special measures to be taken for these bites.
If available, mild opiates such as Tramadol, 50 mg can
be used orally for relief of severe pain. In cases of severe ASV ADMINISTRATION CRITERIA
pain at a tertiary center, Tramadol can be given IV. ASV (hyperimmune immunoglobulin), a lifesaving,
WHO-recognized, essential medicine, is the only effective
HANDLING TOURNIQUETS antidote for envenoming. However, they are scarce, costly
Care must be taken when removing tight tourniquets commodity and should only be administered when there
which most of the time used. Sudden removal can lead are definite signs of envenomation. Unbound, free
to a massive surge of venom leading to neurological flowing venom, can only be neutralized when it is in
paralysis, hypotension due to vasodilatation, etc. the bloodstream or tissue fluid. In addition, antisnake
Before removal of the tourniquet, test for the presence venom carries risks of anaphylactic reactions and should
of a pulse distal to the tourniquet. If the pulse is not therefore be used unnecessarily. The doctor should
absent ensure a doctor is present before removal. be prepared for such reactions. It is recommended that
Be prepared to handle the complications such as antivenom should be used in all patients with signs
sudden respiratory distress or hypotension. If the of systemic and/or severe local envenoming in whom
tourniquet has occluded the distal pulse, then a blood the benefits of treatment are judged to exceed the risks
pressure cuff can be applied to reduce the pressure of antivenom reactions. It should not be used in the
slowly. absence of evidence of envenoming
ONLY if a patient develops one or more of the
Antisnake Venom (Figs 3 to 6) following signs/symptoms will ASV be administered.
After assessing patient whenever decision is taken for
giving antisnake venom (ASV), start ASV whatever Systemic Envenoming
dose is available in hand, do not wait for full dose to be Evidence of coagulopathy: Primarily detected
available. by 20WBCT or visible spontaneous systemic
In India polyvalent ASV is only available, it is effective bleeding, gums, etc. Further laboratory tests for
against all the four common species; Russell’s viper thrombocytopenia, fibrinogen abnormalities, PCV,
(Fig. 3) (Daboia russelii), Common Cobra (Raja naja) peripheral, smear, etc. provide confirmation, but
(Fig. 8), Common Krait (Bungarus caeruleus) and Saw 20WBCT is paramount importance.
Scaled viper (Echis carinatus). There are no currently Evidence of neurotoxicity: Ptosis, external ophthal-
available monovalent ASVs primarily because there are moplegia, muscle paralysis, inability to lift the head,
no objective means of identifying the snake species, in etc.
the absence of the dead snake. And unavailability of The above two methods of establishing systemic
ELISA method to detect species specific envenomation envenomation are the primary determinants. They
for these reason it would be impossible for the physician are simple to carry out, involving bedside tests
to determine which type of monovalent ASV to employ in or identification of visible neurological signs and
treating the patient. symptoms. In the Indian context and in the vast
There are known species such as the hump-nosed majority of cases, one of these two categories will be
pitviper (Hypnale hypnale) where polyvalent ASV is the sole determinant of whether ASV is administered
known to be ineffective. In addition, there are regionally to a patient.
specific species such as Sochurek’s Saw Scaled Viper Cardiovascular abnormalities: Hypotension, shock,
(Echis carinatus sochureki) in Rajasthan, and Kalach in cardiac arrhythmia, abnormal ECG.
West Bengal where the effectiveness of polyvalent ASV Persistent and severe vomiting or abdominal pain.
CHAPTER 124: Management of Snake Bite in India 749
of snake bite during pregnancy. There have been cases when hypotension is corrected can be given to avoid
CHAPTER 124: Management of Snake Bite in India 751
adrenalin induced arrhythmia which is common in Length of time upward gaze can be maintained
elderly. FEV 1 or FVC (If available)
If after 10–15 minutes the patient’s condition has not Water column measurement. (Length of water
improved or is worsening. column that can be held with blowing through tubes).
A second dose of 0.5 mg of adrenalin 1:1000 IV is For example, if single breath count or inter incisor
given. This can be repeated for a third and final distance is selected the breath count or distance between
occasion but in the vast majority of reactions, 2 doses the upper and lower incisors, and more objective
of adrenaline will be sufficient. waterlevel measurement that much patient can blow
If there is hypotension or hemodynamic instability, are measured and recorded. Every 10 minutes the
IV fluids should be given. measurement is repeated. The average blood plasma
Once the patient has recovered, the ASV can be time for neostigmine is 20 minutes, so by T+ 30 minutes
restarted slowly for 10–15 minutes, keeping the patient any improvement should be visible by an improvement
under close observation. Then the normal drip rate in the measure.
should be resumed.
Adrenaline should be given iv in case of anaphylactic RECOVERY PHASE
reaction, because If an adequate dose of appropriate antivenom has been
1. Faster action administered, the following responses may be seen:
2. Predictable availability Spontaneous systemic bleeding such as gum bleeding
3. Intramascular hematoma in patient with coagulo usually stops within 15–30 minutes.
pathy can be avoided. Blood coagulability is usually restored in 6 hours.
Late Serum sickness reactions can be easily treated Principal test is 20WBCT.
with an oral steroid such as prednisolone, adults 5 mg 6 Postsynaptic neurotoxic envenoming such as the
hourly, pediatric dose 0.7 mg/kg/day. Oral antihistaminic Cobra may begin to improve as early as 30 minutes
provide additional symptomatic relief. after antivenom, but can take several hours.
Presynaptic neurotoxic envenoming such as the
effective for post synaptic neurotoxins such as those of within a few hours and the urine returns to its normal
the Cobra (Watt et al, 1986). color.
In the case of neurotoxic envenomation where In patients who were in shock, blood pressure may
in the event of continued coagulation defect and in that what should the clinician do after say, 30 vials have been
case ASV to be given over 1 hour CT tests and repeat administered and the coagulation abnormality persists?
doses of ASV should continue on a 6 hourly pattern until It has been established that envenomation by the
coagulation is restored or unless a species is identified as Hump-nosed Pitviper (Hypnale hypnale) does not
one against which polyvalent ASV is not effective. respond to normal ASV. This may be a cause as, in the
The repeat dose should be 5–10 vials of ASV i.e. half case of Hypnale, coagulopathy can continue for upto
to one full dose of the original amount. The most logical 3 weeks.
approach is to administer the same dose again, as was
administered initially. Some Indian doctors however, Surgical Intervention
argue that since the amount of unbound venom is Whilst there is undoubtedly a place for a surgical
declining, due to its continued binding to tissue, and due debridement of necrotic tissue, the use of fasciotomy is
to the wish to conserve scarce supplies of ASV, there may highly questionable. The appearance of (Joseph, 2003):
be a case for administering a smaller second dose. In the Pain on passive stretching
absence of good trial evidence to determine the objective Pain out of proportion
adopted. Pallor
Parasthesia
When coagulation has been restored no further ASV With significant swelling in the limb, can lead to the
should be administered, unless a proven recurrence of a conclusion that the intracompartmental pressure is
coagulation abnormality is established. If patient comes above 40 mm of mercury and thus requires a fasciotomy.
with features of coagulopathy ASV to be administered Fasciotomy is required if the intracompartmental
(10 vials). There is no need to give prophylactic ASV pressure is sufficiently high to cause blood vessels
to prevent recurrence (Srimannarayana et al, 2004). to collapse and lead to ischemia. Nowadays, we are
Recurrence has been a mainly US phenomenon, due to using multiple puncture technique using large bore
the short half-life of Crofab ASV. needle. Fasciotomy does not remove or reduce any
Indian ASV is a F(ab)2, product and has a half- envenomation. It is recommended that fasciotomy
life of over 90 hours and therefore is not required in a should never be carried out in snake bite patients unless
prophylactic dose to prevent re-envenomation. But if
or until hemostatic abnormalities have been corrected,
the patient comes even after few days reinstitute ASV
clinical features of an intracompartmental syndrome are
therapy, because sometime absorption of snake venom
present and a consistently raised intracompartmental
depot under skin is erratic. If there is no improvement
pressure has been confirmed by direct measurement.
from the beginning of the whole blood clotting time,
T h e re i s l i t t l e o b j e c t i v e e v i d e n c e t h a t t h e
rather it goes on increasing then we are dealing with
intracompartmental pressure due to snake bite in India,
the snake bites which are not amenable to our usual
ever reaches the prescribed limit for a fasciotomy. Very
polyvalent ASV.
limited trial data has tended to confirm this.
What is important is that the intracompartmental
ANTIHEMOSTATIC MAXIMUM ASV
pressure should be measured objectively using saline
DOSAGE GUIDANCE manometers or newer specialised equipment such as
Repeat Dose: Hematotoxic the Stryker Intracompartmental Pressure Monitoring
The normal guidelines are to administer ASV every 6 Equipment.Visual impression is a highly unreliable guide
hours until coagulation has been restored. However, to estimating intracompartmental pressure.
CHAPTER 124: Management of Snake Bite in India 753
The limb can be raised in the initial stages to see if Mechanical ventilation to be avoided as far as possible, as
swelling is reduced. However, this is controversial as because most of the death in ventilated snake bite patient
there is no trial evidence to support its effectiveness. is ventilator associated pneumonia. Early initiation and
early weaning from ventilator is the strategy, noninvasive
Renal Failure in Snake Bite ventilator with a patent upper air way is better option.
The acute renal failure which occurs due to snake bite
are multifactorial 1) Severe and persistent hypotension Heparin and Botropase
leading to acute tubular necrosis, 2) Hb and other No role
cellular parts of RBC and others (myoglobin and
rhabdomylysis) 3 part of DIC 4) vasculitis 5) acute Snake Bite Management in Primary/Community/
diffuse intersticial nephritis) extra capillary proliferative Dispensary Health Care Centers
glomerulonephritis. A key objective of this protocol is to enable doctors
Most of the patients of acute tubular necrosis in Primary Care Institutions to treat snake bite with
recovers by few weeks, with the help of occational need confidence. Evidence suggests that even when equipped
of hemodialysis, but who develops cortical necrosis with antisnake venom, primary care doctors lack the
confidence to treat snake bite due to the absence of
requires reanal replacement therapy on along term
a protocol tailored to their needs and outlining how
basis. It is the hyoperkalemia rather than elevated urea,
they should proceed within their context and setting
creatinine requires dialysis. The hyperkalemia of snake
(Simpson, 2007).
bite AKI is a hypermetabolic hyperkalemia, which may
kill the patient within few minutes and calcium gluconate
Patient Arrival and Assessment
and glucose insulin is mostly ineffective.
Patient should be placed under observation for 24
Early urgent adequate treatment with ASV can
hours.
reverse the whole process of deterioration of renal
The snake, if brought, should be carefully examined
function which is far from our expectation in our country.
and compared to the snake identification material.
Renal failure is a common complication of Russell’s Pain management should be considered.
Viper and Hump-nosed Pit viper bites (Tin-Nu-Swe et 20WBCT in clean, new, dry, glass test tubes should be
a1,1993) Joseph et al, 2006). The contributory factors are carried out every 30 minutes for the first 3 hours and
intravascular hemolysis, DIC, direct nephrotoxicity and then hourly after that. Attention should be paid for
hypotension (Chugh et a1, 1975) and rhabdomyolysis. any visible neurological symptoms.
Renal damage can develop very early in cases of 20 WBCT must be done in glass tube never in plastic
Russell’s Viper bite and even when the patient arrives tube, should be done at bed side, sample must not be
at hospital soon after the bite, the damage may already sent to laboratory.
have been done. Studies have shown that even when ASV Severe, current, local swelling should be identified.
is administered within 1–2 hours after the bite, it was If no symptoms develop after 24 hours the patient can
incapable of preventing ARF (Myint-Iewin et al, 1985). be discharged with a TT.
Today, in the 21st century, we still do not have proper TABLE 1: Classes of stem cells1,2
treatments for many diseases like Parkinsons, Alzheimers, Stem cells classes Features
multiple sclerosis, cardiomyopathies, etc. Some light of Totipotent cells Only zygote can form an entire organism
hope for the treatment of these incurable diseases are: Pluripotent cells It can differentiate into any tissue type except
the stem cells. The stem cell therapies even at the initial placental tissue e.g. embryonic stem (ES) cells
stages have an extraordinary potential to revolutionize Multipotent cells Can form many cell lineages but not all e.g.
the medical care.1 hematopoeitic stem (HS) cells
Oligopotent cells They are more restricted in forming the cell
(progenitor or lineages e.g. neural stem cells
STEM CELL precursor cells)
A cell can be called a stem cell if it fulfils two requirements:
unique ability to produce same daughter cells i.e. self-
(allogeneic stem cells). HSCT is the gold standard as all
renewal and to differentiate into specialized cell types
other stem cell transplantation therapies are measured
(Tables 1 and 2).2
against it.3
TABLE 2: Types of stem cells with their source1,2 Engraftment phase: Several weeks; management of
Types of stem cells Source GVHD and prevention of viral infections like CMV are
Embryonic stem Blastocysts or immune-surgically isolated the biggest challenges in this phase. For engraftment, a
cells inner cell mass from blastocysts dose of 1 × 108 marrow mononuclear cells per kilogram
Hematopoietic They are CD34+ cells. in autologous and 2 × 108 marrow mononuclear cells per
stem cells Plerixafor (chemokine receptor 4 (CXCR4)
kilogram in allogenic marrow transplants is required.
inhibitor) is used in conjunction with G-CSF
to mobilize HS cells to peripheral blood for Postengraftment period: Months to years.
collection
Induced Formed from the conversion of terminally
pluripotent stem differentiated cells into ES-like cells by over
HSCT-Peripheral Blood Stem Cell
cells (iPSC) expressing four transcription factors. It is associated with rapid engraftment, decreased
Advantage–genetically identical to those of leukemia relapse rates because of higher GVL effect,
the patient and have less ethical constraints as
ESCs. Disadvantage–more prone to mutations
better overall survival, but increased chronic GVHD.
Umbilical cord Contains two classes of stem cells; HSC and
blood stem cells MSC. Volume of cord blood obtained is less Uses of Stem Cell Therapy
and therefore, these cells are sufficient to
transplant an individual of <40 kg only IHD and cardiomyocyte regeneration: For successful
Mesenchymal Bone marrow, muscle, peripheral blood and myocardial repair, stem cell therapy are delivered either
stem cells (MSC) umbilical cord blood systemically or locally so that functional cardiomyocytes
Adipose stem cells Fat that couple mechanically and electrically with the
recipient myocardium are produced after survival,
Autologous HSCT engraftment and differentiation.4
Advantage: Immunosuppression is not needed. Diabetes: ES and iPS cells can be differentiated into
Disadvantage: not used for correction of immuno- insulin producing cells but these cells have a low content
deficiencies. of insulin and a high rate of apoptosis.5 Clinical trials are
going on in both type 1 and type 2 diabetes.
Allogeneic HSCT Neurological diseases:
Spinal cord injury (SCI): Both ES cells and MSCs can
The most important factor in this type of transplantation
is the degree of HLA match between the donor and the facilitate remyelination of nerve cells. It was the first
recipient because the risk of graft versus host disease disorder targeted for the clinical use of ES cells.6
Stroke, Parkinson’s disease, Huntington’s chorea,
(GVHD) is less in matched transplants. Because of the
graft-versus-leukemia (GVL) effect, lower relapse rate Amyotrophic lateral sclerosis, Alzheimer’s disease,
are associated with allogeneic transplants than are multiple sclerosis and muscular dystrophies.
autologous transplants. Hence, more the GVHD, more Liver: The available evidence suggests that transplanted
the GVL effect and lower the relapse rate. HSCs and MSCs can generate hepatocyte-like cells in the
liver only at a very low frequency, but there are beneficial
5 Phases of HSCT consequences presumably related to indirect paracrine
Conditioning: 7–10 days to deliver chemotherapy, effects.
radiation, or both.
Tissue repair: Regenerative responses by migrating
Stem cell infusion. into a tissue and differentiating into specific cell types
Neutropenic phase: 2–4 weeks; supportive care and are observed with the help of stem cells. So stem cell
empirical antibiotic therapy are needed for this phase as therapies to promote replacement of cells in damaged
immune system is affected in this phase. organs are being evaluated.
CHAPTER 125: Stem Cell Therapy in Various Diseases: Dawn of a New Era 761
India (DGI), they can be used only in “clinical trials. The transplantation: Clinical and ethical considerations. Stem
only approved therapy is use of HS cells for treating blood Cells International. 2017;7:2017.
4. Zhan-quan L, Ming Z, Yuan-zhe J, Wei-wei Z, Ying L, Li-jie
disorders. India is a hub for medical tourism for people
C, et al. The clinical study of autologous peripheral blood
worldwide because treatment here costs only 25 % of
stem cell transplantation by intracoronory infusion in
what it costs in Western countries with no waiting period. patients with acute myocardial infarction (AMI). Int J Cardiol.
The top picks are: 2007;115(1):52-6.
Life cell (Chennai and Gurugram) 5. Bhansali A, Asokumar P, Walia R, Bhansali S, Gupta V, Jain
Baby cell (Lonavala, Mumbai) A, et al. Efficacy and safety of autologous bone marrow-
Cord life (Kolkata)
derived stem cell transplantation in patients with type 2
diabetes mellitus: a randomized placebo-controlled study.
Cell transplantation. 2014;15:23(9):1075-85.
SUMMARY 6. Dai G, Liu X, Zhang Z, Yang Z, Dai Y, Xu R. Transplantation
Stem cells show great promise for regenerative of autologous bone marrow mesenchymal stem cells in
medicine. the treatment of complete and chronic cervical spinal cord
Ethical concerns need to be taken into account. injury. Brain research. 2013;1533:73-9.
Proper guidelines are needed to ensure appropriate 7. Barmania F, Pepper MS. CC chemokine receptor type five
(CCR5): An emerging target for the control of HIV infection.
conduct of the research.
Appl Transl Genom. 2013;2:3-16.
Much research needed before definitive therapies are 8. Leventhal A, Chen G, Negro A, Boehm M. The benefits and
realized. risks of stem cell technology. Oral Dis. 2012;18(3):217-22.
9. Al Jefri AH, Abujazar H, Al-Ahmari A, Al Rawas A, Al
REFERENCES Zahrani Z, Alhejazi A, et al. Veno-occlusive disease/
1. Buzhor E, Leshansky L, Blumenthal J, Barash H, Warshawsky sinusoidal obstruction syndrome after haematopoietic
D, Mazor Y, et al. Cell-based therapy approaches: the stem cell transplantation: Middle East/North Africa regional
hope for incurable diseases. Regenerative medicine. consensus on prevention, diagnosis and management.
2014;9(5):649-72. Bone marrow transplantation. Bone Marrow Transplant.
2. Mahla RS. Stem cells applications in regenerative medicine 2017;52(4):588-91.
and disease therapeutics. International Journal of Cell 10. Dubovsky JA, Flynn R, Du J, Harrington BK, Zhong Y,
Biology. 2016;19:2016. Kaffenberger B, et al. Ibrutinib treatment ameliorates
3. Riezzo I, Pascale N, La Russa R, Liso A, Salerno M, Turillazzi murine chronic graft-versus-host disease. J Clin Invest.
E. Donor selection for allogenic hemopoietic stem cell 2014;124(11):4867-76.
CHAPTER
126
Basics of Hematopoietic Stem Cell
Transplant: Autologous and Allogeneic
Punit L Jain
—— Amyloidosis
hematopoietic stem cells (HSCs), or of a matched
HLA identical stem cell donor. These infused HSCs zz Non-Hodgkins lymphoma:
—— Peripheral T-cell lymphomas
are multipotent and carry the ability to self-renew and
—— Relapsed B-cell lymphomas
differentiate into multilineage hematopoietic elements
zz Relapsed/Refractory Hodgkins lymphoma
(HE), giving rise to a new donor derived HS in the recipient.
Dr E Donnall Thomas, a 1990 Nobel laureate conducted zz Solid tumors:
—— Germ cell tumors
the first such successful allogeneic HSCT in a patient —— Neuroblastomas
with a refractory leukemia. Since then, more than a —— Medulloblastomas
zz Malignant disorders
Autologous HSCT —— Acute myeloid leukemia (AML)
Indications —— Acute lymphoblastic leukemia (ALL)
Common indications have been listed in Table 1.
zz Inherited metabolic disorders
Steps:
—— Osteopetrosis
—— Stem cell mobilization : An HSCT recipient
( au t o l o g o u s a n d a l l o g e n e i c) u n d e rg o e s —— Adrenoleukodystrophy
764 SECTION 12: Hematology/Oncology
HSC mobilization and a special catheter for its —— Reduced toxicity myeloablative conditioning
collection. (RTC): RTC involves chemotherapeutic drugs
—— BM: This collection is an intraoperative procedure,
with similar potency and reduced toxicity as a
requiring general anesthesia, and thus a higher standard MAC regimens. Common regimens
morbidity for the donor. It does not require are intravenous fludarabine and busulfan/
any special catheter or any cytokine support.
treosulphan.
Other features include a longer neutropenia and
Po s t- t ra n s p l a n t i m m u n o s u p p re ss i o n ( P T I ) :
delayed engraftment, due to the lower number of
T cells in BM. Cyclosporine and methotrexate are the most
—— Cord blood: This is a painless collection as it is commonly used drugs as PTI. More recently, post-
collected from the umbilical cord, causing no transplant cyclophosphamide is being commonly
morbidity to the donor. Engraftment and immune used, especially in haploidentical transplants.
reconstitution is slower due to a lower amount Supportive care: Allogeneic HSCT have a longer
of SC dose in each collection. The incidence of duration of neutropenia, requiring extensive
GVHD is lower due to the increased tolerance of support and care till engraftment as well as immune
the HLA disparity in recipient with CB. recovery is complete. Strict isolation and use of HEPA
Choosing the right conditioning regimen: (high efficiency particulate air) filters offers better
These include: protection from infections in the peritransplant
—— Myeloablative conditioning (MAC): MAC involves
period.
doses of chemotherapy that cause an irreversible Engraftment and chimerism: Once the HSCT recipient
and fatal pancytopenia, unless accompanied achieves engraftment, chimerism analysis helps
by SC rescue. Common regimens include detect the percentage of donor-derived cells in the
cyclophosphamide/total body irradiation (Cy/ recipient. This is done through PCR amplification
TBI) and cyclophosphamide/busulfan (Bu/ of highly repetitive short tandem repeat (STR)
Cy). High MAC dose attempts to eradicate the sequences, followed by capillary electrophoresis.
defective or tumor cells and thus can be very Fluorescent in situ hybridization (FISH) studies
toxic. These are reserved for younger patients (< can also help in assessing the chimerism, if donor-
45 years). recipient are of separate gender. An incomplete
—— Reduced intensity conditioning (RIC): RIC
chimerism would necessitate immunomodulation or
involves chemotherapy with at least 30% reduced and use of donor lymphocyte infusion (DLI).
doses in the alkylating agents or TBI, but still Complications in an allogeneic HSCTL:
requires a SC rescue. Common regimens are —— Early complications: Nausea, vomiting, painful
does not actually need a SC rescue. A common GVHD: This is due to an interplay between
—— Steroid purpura
Color may change over time from purple to brown to —— Abnormal platelet function in renal and hepatic
orange/green. disorders
—— Thrombocytosis in myeloproliferative disorders
Extravasation of red cells depend upon integrity of blood —— Ehler Danlos syndrome
—— DIC
—— Thrombotic Thrombocytopenic purpura
—— Monoclonal cryoglobulinemia
—— Warfarin necrosis
—— Embolic–Cholesterol, Fat, Tumor emboli, Emboli
from Atrial myxoma
—— Henoch–Schönlein purpura
—— Urticarial vasculitis
—— Polyarteritis nodosa
Any bleeding or thrombotic disorder history/family both legs, buttocks and lower abdomen (Figs 2 and 3).
history must be taken. Certain drugs may interfere Respiratory system and CVS exam: Within normal
A B
Figs 2A and B: Palpable purpura in legs and lower abdomen
IVIG has been the drug of second choice for many Leukocytoclastic Vasculitis
years. For cutaneous predominant leukocytoclastic Vasculitis
Rituximab is a third line therapy. (LCV), colchicine or dapsone is used.
Platelet transfusion may be required to control For systemic involvement, corticosteroids, immuno-
clinically significant bleeding. suppressive drugs (e.g. Cyclophosphamide) and
If >6 months medical management fails to bring Rituximab can be used.
platelet count >30,000/mL, splenectomy may be
considered. Henoch–Schönlein Purpura
For pain management, NSAIDs or Paracetamol may
TTP be used, but with caution in patients with renal
The treatment of choice is plasma exchange with fresh failure. Corticosteroids with or without azathioprine,
frozen plasma.5 cyclophosphamide and high dose IVIG have been used.6
CHAPTER 127: Clinical Approach to Patient with Purpuric Spot 771
CONCLUSION REFERENCES
Purpura denotes red or purple lesion on the skin or 1. Schneiderman PI. The vascular purpuras. In: Ernest Beutler,
mucous membrane resulting from leakage of RBC’s Marshall A. Lichtman. Williams Hematology. 6th Edition.
New York: McGRAW Hill. 2001. pp. 1603-13.
from the blood vessels. Purpura can be classified as
2. Korman NJ. Macular, papular, vesiculobullous and pustular
palpable or nonpalpable. Purpuras usually do not diseases. In: Lee Goldman, Andrew I. Schafer. Goldman-Cecil
blanch on pressure, even if they do, a nonblanching Medicine. 25th Edition. New York: Elsevier. 2016;2:2673-5.
component will always remain. Thrombocytopenia, 3. Leung AKC, Chan KW. Evaluating the child with purpura.
hypercoagulable or hypocoagulable states, endothelial American Family Physician. 2001;1:64(3):419-29. Available
dysfunction and extravascular factor may contribute to from: http://www.aafp.org/afp/2001/0801/p419.html
4. Sandler SG, Tutuncuoglu SO. Immune thrombocytopenic
the development of purpuras. Various life-threatening
purpura–current management practices. Expert Opin
conditions like meningococcemia may present with Pharmacother. 2004;5(12):2515-27. Available from:
petechiae or purpura. The presence of purpura in https://www.ncbi.nlm.nih.gov/pubmed/15571469
a patient with sepsis should raise concern for DIC. 5. Scully M, Hunt BJ, Benhamin S, Liesner R, Rose P, Peyvandi
Palpable purpuras result from underlying vascular F, et al. Guidelines on the diagnosis and management of
inflammation (vasculitis). Palpable purpura is a classic thrombotic thrombocytopenic purpura and other thrombotic
microangiopathies. Br J Haematol. 2012;158(3):323-35.
clinical presentation of leukocytoclastic vasculitis. An
6. Faedda R, Pirisi M, Satta A, Bosincu L, Bar toli E.
early recognition by meticulous clinical assessment with Regression of Henoch-Schölein disease with intensive
supporting laboratory investigation is most necessary. immunosuppressive treatment. Clin Pharmacol treatment.
Prompt treatment approach depending upon the cause Clin Pharmacol Ther. 1996;60(5):576-81. Available from:
is most rewarding. https://www.ncbi.nlm.nih.gov/pubmed/8941031.
CHAPTER
128
Thrombocytosis: Clinical Approach
Sudhir Mehta, Laxmi Kant Goyal, Shaurya Mehta, Gunja Jain
*Adapted with modification from Jonathan S Bleeker and William J Hogan et al.1
Abbreviations: CML, chronic myeloid leukemia; PMF, primary myelofibrosis; ET, essential thrombocytosis; MPN, myeloproloferative neoplasms
Source: Adapted with modification from Jonathan S Bleeker and William J Hogan et al. 1
Thrombocytosis can also occur as a rebound effect The myelodysplastic disorders related w ith
following drug or alcohol associated thrombocytopenia.9 thrombocytosis are the 5q-syndrome and refractory
If thrombocytosis occurs in iron deficiency state, one anemia with ring sideroblasts (RARS).
should suspect overt/occult blood loss. In CML, dysregulated clonal expansion of all cells
However, presence of a cause for reactive thrombo lines along the granulocytic maturation pathway occurs
cytosis does not exclude a concomitant clonal process with characteristic “Philadelphia chromosome” and
in case of persistent thrombocytosis as both may coexist. resultant BCR-ABL fusion protein. About half of the cases
of CML have thrombocytosis (Flow chart 1).10
JAK2V617F is an acquired point mutation, found in
Clonal Thrombocytosis
PV (95%), ET (40–60%) and PMF.1,11
Myeloproliferative neoplasms (MPNs) are characterized Other mutations in the JAK2 gene are also detected in
by a clonal expansion of particular lineage of mature PV in absence of V617F mutation.1 Mutations in the MPL
and/or maturing myeloid cells that arise from a common gene are found in PMF (5–7%), ET (1–4%) and not in PV.12
hematopoietic stem cell. The most common causes of MPL mutations are also found with JAK2V617F.12
clonal thrombocytosis are essential thrombocythemia TET2 mutations are found in myeloid disorders,
(ET), chronic myeloid leukemia (CML), polycythemia including PhMPNs (13%) and are more common in
vera (PV) and primary myelofibrosis (PMF). geriatric patients.1
CHAPTER 128: Thrombocytosis: Clinical Approach 775
PV is diagnosed on the basis of increased red cell In ET, recurrent spontaneous abortion and fetal
mass, low/normal serum erythropoietin and a clonal growth retardation occurs in 50% cases and are caused
marker (i.e. JAK2 mutation). 1 Thrombocytosis (50%) by multiple placental infarctions due to platelet
can be the only hematologic finding in PV, as the thrombosis.1,13
expected erythrocytosis can be concealed due to volume Though uncommon, bleeding can occur in clonal
expansion or with concomitant iron deficiency.1 thrombocytosis and is attributed to platelet function
PMF is diagnosed in view of peculiar bone marrow abnormalities along with acquired von Willebrand’s
findings including reticulin fibrosis along with syndrome resulting from increased absorption of large
megakaryocytic proliferation. Thrombocytosis (30%) is vWF multimers by the elevated circulating platelets.1
also found but the grading of thrombocytosis decreases
with disease progresses and mostly thrombocytopenia DIFFERENTIAL DIAGNOSIS
occurs due to splenomegaly.1 Clinical history and physical examination are important
Diagnosis of ET is essentially a diagnosis of exclusion. in differentiating reactive and clonal thrombocytosis.
The presence of an infective or inflammatory condition,
CLINICAL FEATURES hemolysis, blood loss or recent surgery or trauma points
Thromb o c ytosis is ass o ciate d w ith vas omotor to a reactive thrombocytosis. Conversely, vasomotor
s y m p t o m s ( h e a d a c h e, v i s u a l s y m p t o m s, l i g ht
symptoms, pruritus, splenomegaly and acral erythema
headedness, atypical chest pain, acral dysesthesia,
favor clonal thrombocytosis. Spurious thrombocytosis
erythromelalgia), bleeding (“platelet type” bleeding
can be excluded with the help of peripheral blood film
involving spontaneous hemorrhage at superficial sites
and manual platelet counting.
i.e. the skin or mucous membranes) or thrombotic
Rais e d er ythro c yte s e dimentation rate and
complications. 13 These symptoms does not correlate
C-reactive protein (acute phase reactant) favor reactive
with degree of thrombocytosis and are common in clonal
thrombocytosis.1,13 Giant megakaryocytes are feature of
thrombocytosis.1,13 The qualitatively normal interaction
MPN and hyposplenism.
between platelets and vessel wall may be the reason of
In peripheral blood film, leukocytosis with toxic
absence of these symptoms in reactive thrombocytosis.13
granules and Döhle bodies are seen in infection and
The major causes of morbidity and mortality in MPNs
chronic neutrophilic leukemia, 14 and hypochromia
are bleeding and thrombosis.13
with microcytosis suggests iron deficiency, Howell Jolly
Digital microvascular ischemia with palpable
peripheral pulses is characteristic of ET.13 Erythromelalgia bodies suggests hyposplenism and macrocytosis with
is also common in ET, characterized by intense burning dysplastic forms/platelet debris (platelet drifts) suggests
and/or throbbing pain with a patchy distribution in clonal neoplasm.13 A leukoerythroblastic blood film and
hands and feet with warmth, duskiness and mottled teardrop poikilocytes suggests primary myelofibrosis.
erythema of the involved areas.13 Thrombocytosis with a dimorphic blood film and
Neurologic complications are due to cerebrovascular Pappenheimer bodies is typical of refractory anemia with
ischemia (platelet-mediated) and present with ring sideroblasts and thrombocytosis.1,13
nonspecific symptoms such as chronic headache or Bone marrow aspiration-biopsy, cytogenetic and
dizziness or focal neurologic signs.13 molecular analysis are used when clinical features and
Venous thrombosis is more common in MPNs than blood smear remain inconclusive.
arterial thrombosis and may manifest as deep vein On bone marrow aspiration biopsy, large hyper
thrombosis, pulmonary embolism, intra-abdominal lobulated megakaryocytes are found in ET, normal in
thrombotic complications such as hepatic-vein reactive thrombocytosis, pleomorphic in PV, pleomorphic
thrombosis (Budd–Chiari syndrome) and portal-vein with dysplastic changes in PMF and smaller size in CML.
thrombosis.13 Reticulin fibrosis is characteristic of PMF.
776 SECTION 12: Hematology/Oncology
On molecular analysis, BCR-ABL is found in CML, side effects which include fluid retention, palpitation,
JAK2 mutation in PV (almost 100%) and mutation of JAK2 arrhythmias, heart failure, and headache. So caution
(almost 50%) or MPL in ET or PMF. is required in aged patients or heart disease. The side
In the 5q-syndrome, macroc ytic anemia, effects of anagrelide decrease over time, but progressive
thrombocytosis and hypolobulated megakaryocytes are anemia develops in many patients.13
found. Interferon alfa is an effective, nonmutagenic agent
and is drug of choice in pregnancy as hydroxyurea is
TREATMENT teratogenic and anagrelide crosses the placenta.1,13
Secondary/reactive thrombocytosis is a self limited Hematopoietic stem cell transplantation can be
process and thrombocytosis reverts to normal when considered for selected young patients with advanced
the underlying cause resolves. In persistent reactive complicated clonal thrombocytosis.
thrombocytosis, occult cancer should be looked into and Aspirin is highly effective for vasomotor symptoms
a thorough search should be conducted. and as an adjunctive drug in ET if patient have recurrent
In clonal thrombocytosis, specific platelet lowering thrombotic complications, digital or cerebrovascular
therapy is required because these patients are at high risk ischemia. In PV, low-dose aspirin (100 mg per day) can
for thrombosis/bleeding. The risk of arterial thrombosis prevent thrombotic complications without increase in
the risk of major bleed.13
is more in ET than PV.15 The high risk patients include
PV patient requires therapeutic phlebotomy for
those with history of thrombosis or bleeding, leukocytosis
maintaining a hematocrit below 45% in men and below
(9.4 × 109/L), associated cardiovascular risk factors, or
42% in women.1 Hydroxyurea is needed in addition to
above 60-year-old.1,16
phlebotomy in high risk patients. Low dose aspirin is
Patients with ET with active cerebrovascular/digital
used in all cases of PV to reduce thrombosis. Interferon
ischemia should be treated urgently and aggressively
alfa is therapy of choice in pregnancy. JAK2 inhibitor
with platelet-lowering agents.
(Ruxolitinib) is used when hydroxyurea is ineffective/
Plateletpheresis is reserved for acute cerebrovascular
intolerant.1,13
complications, digital ischemia or active bleeding when
rapid depletion in the platelet count and symptomatic
Carry Home Message
relief are required.1
Reactive/secondary thrombocytosis is more common
Platelet reducing (cytoreductive) therapy is required
than clonal thrombocytosis.
in clonal thrombocytosis. Agents commonly used are Reactive thromboc ytosis resolves when the
hydroxyurea, anagrelide and interferon alfa.
underlying cause is identified and treated.
Hydroxyurea, a nonalkylating agent, is the platelet- The clonal thrombocytosis are associated with
lowering agent of choice because of its ease of use. It is thrombotic and bleeding complications.
given in dosage of 500 mg–2 gm/day and the common These patients require prophylactic platelet-
side effects include hyperpigmentation, rash, cytopenias cytoreductive therapy along with aspirin.
and skin ulceration. The only concern is its leukemogenic
potential, especially after prolonged use, in combination REFERENCES
with other drugs, or in cases of ET with 17p-deletion.13 1. Bleeker JS, Hogan WJ. Thrombocytosis: Diagnostic
Anagrelide is the alternative first-line platelet lowering evaluation, thrombotic risk stratification, and risk-based
therapy in patient of clonal thrombocytosis. Anagrelide is management strategies. Thrombosis. 2011;16:536062.
Article ID 2011;doi:10.1155/2011/536062.
nonleukemogenic and is drug of choice in young patients
2. Kaushansky K. Regulation of megakaryopoiesis. In:
of ET as they need therapy for platelet-count over long Loscalzo J, Schafer AI, eds. Thrombosis and hemorrhage.
period of time. However, it is intolerant in about 30 % 3rd ed. Philadelphia: Lippincott Williams and Wilkins. 2003.
patients due to its vasodilatory and positive inotropic pp. 120-39.
CHAPTER 128: Thrombocytosis: Clinical Approach 777
3. Hitchcock IS, Kaushansky K. Thrombopoietin from 10. Savage DG, Szydlo RM, Goldman JM. Clinical features at
beginning to end. Br J Haematol. 2014;165:259-68. diagnosis in 430 patients with chronic myeloid leukaemia
4. Wolber EM, Fandrey J, Frackowski U, Jelkmann W. Hepatic seen at a referral centre over a 16-year period. British
thrombopoietin mRNA is increased in acute inflammation. Journal of Haematolog. 1997;969(1):111-6.
Thromb Haemost. 2001;86:1421-4. 11. Kralovics R, Passamonti, Buser AS, et al. A gain-offunction
5. Kaser A, Brandacher G, Steurer W, et al. Interleukin-6 mutation of JAK2 in myeloproliferative disorders. NEJM.
stimulates thrombopoiesis through thrombopoietin: role in 2005;352(17):1779-90.
inflammatory thrombocytosis. Blood. 2001;98:2720-5. 12. Beer PA, Campbell PJ, Scott LM, et al. MPL mutations in
6. Teofili L, Pierconti F, Di Febo A, et al. The expression pattern
myeloproliferative disorders: analysis of the PT-1 cohort.
of cmpl in megakaryocytes correlates with thrombotic risk in
Blood. 2008;112(1):141-9.
essential thrombocythemia. Blood. 2002;100:714-7.
13. Schafer AI. Thrombocytosis. N Engl J Med. 2004;350:1211-
7. Axelrad AA, Eskinazi D, Correa PN, Amato D. Hypersensitivity
19.
of circulating progenitor cells to megakaryocyte growth
14. Bain BJ, Ahmad S. Chronic neutrophilic leukaemia and
and development factor (PEG-rHu MGDF) in essential
thrombocythemia. Blood. 2000;96:3310-21. plasma cell-related neutrophilic leukaemoid reactions. Br J
8. Tefferi A, Ho TC, Ahmann GJ, Katzmann JA, Greipp PR. Haematol. 2015;171(3):400-10.
Plasma interleukin-6 and C-reactive protein levels in 15. Marchioli R, Finazzi G, Landolfi R, et al. Vascular and
reactive versus clonal thrombocytosis. American Journal of neoplastic risk in a large cohort of patients with polycythemia
Medicine. 1994;97(4):374-7. vera. Journal of Clinical Oncology. 2005;23(10):2224-32.
9. Haselager EM, Vreeken J. Rebound thrombocytosis after 16. Carobbio A, Antonioli E, Guglielmelli P, et al. Leukocytosis and
alcohol abuse: a possible factor in the pathogenesis of risk stratification assessment in essential thrombocythemia.
thromboembolic disease. Lancet. 1977;1:774. Journal of Clinical Oncology. 2008;26:2732-6.
CHAPTER
129
Macrophage Activation Syndrome
Tarun Kumar Dutta, Tony Kadavanu, Arunkumar Ramachandrappa
Flow chart 1: Pathogenetics of MAS. Genetic mutations lead to a sequence of events that ultimately lead to cytokine storm and MAS
Raised liver enzymes: Aspartate aminotransferase the presence of hypofibrinogenemia and liver
[AST] and lactate dehydrogenase [LDH]. dysfunction.
Ominous trends: A falling ESR with either an increasing
Hypertriglyceridemia C-reactive protein or a rising serum follistatin-like
Markers of coagulopathy such as elevated D-dimers protein 1 have been found to be associated with bad
and hypofibrinogenemia prognosis.
Elevated markers of inflammation e.g. C-reactive Hemophagocytosis: Hemophagocytosis in bone
protein, soluble IL-2 receptor alpha chain [sCD25] marrow though helpful to confirm the diagnosis of
Paradoxical ESR : Er ythrocyte sedimentation HLH, is often absent, especially in the early stages.
rate (ESR), the common marker of nonspecific One study found hemophagocytosis in only 60.7%
inflammation, may be relatively low because of of patients with MAS in their initial bone marrow
CHAPTER 129: Macrophage Activation Syndrome 781
examination. Serial bone marrow biopsies may be Currently, only specialized immunology or research
required to demonstrate hemophagocytosis in the laboratories can measure NK cell function and soluble
negative cases. However, this is not essential for a interleukin 2 receptor α chain (sIL-2Ra, CD25) which
diagnosis of MAS to be made. are required by the HLH 2004 criteria.
A critically ill child with coagulopathy should not
DIAGNOSTIC CRITERIA be made to undergo bone marrow biopsy just to detect
Since MAS is considered clinically similar to HLH, hemophagocytosis.
some recommend the use of the HLH-2004 (Table 3) The above tests, thus, may not be available in time
diagnostic guidelines, which were developed mainly to which can cause a delay in initiation of appropriate
diagnose homozygous genetic disorders leading to fHLH. treatment which may be detrimental to the patient.
Consensus-derived classification criteria for MAS in
Limitations of 2004 HLH Criteria sJIA have recently been published to help distinguish
active sJIA from MAS (Table 3). The platelet count and
Absolute drop: Owing to the inflammatory nature of sJIA,
fibrinogen levels do overlap with the normal range.
it would be more useful to consider a relative drop in
However, it is these levels when present in a child with
white blood cell count, platelets or fibrinogen instead of
significant systemic inflammation that should raise
the absolute decrease which is required by the HLH-2004
suspicion of MAS.
criteria to make an early diagnosis.
Ferritin levels: The diagnosis of HLH requires a ferritin FURTHER APPROACH
level of above 500 ng/mL. This low threshold may not Once diagnosed, the underlying cause should be looked
discriminate MAS from a flare of sJIA since many patients into by searching for genetic mutations using flow
with active sJIA, have ferritin levels above that level even cytometry. Specific mutations should then be confirmed
in the absence of MAS. In the acute phase of MAS, ferritin using molecular genetic analysis. Viruses such as EBV,
levels may have values >5000 ng/mL. CMV, adenovirus, parvovirus B19, human herpes virus
6, HSV, human herpes virus 6 and varicella zoster virus
TABLE 3: MAS diagnostic criteria should be screened using PCR . If a bone marrow biopsy
is performed, a sample should also be sent for PCR
Revised 2004 diagnostic criteria 2016 criteria of MAS in sJIA
for HLH
looking for leishmania infection.
Either: A febrile patient or suspected
zz Molecular genetic sJIA with: DIFFERENTIAL DIAGNOSIS
confirmation zz Ferritin >684 µg/L and
Several conditions can closely mimic MAS (Table 4).
or zz Any two of the following:
zz Either of:
which requires increased awareness of the condition
—— Fasting triglycerides ≥265 amongst the medical community, followed by prompt
mg/dL treatment.
or
—— Fibrinogen ≤1.5 g/L
Steroids: High-dose intravenous (IV) methylprednisolone
zz Ferritin ≥500 µg/L
zz Tissue hemophagocytosis (30 mg/kg, maximum 1000 mg, daily for 3 d) followed by
zz Decreased NK cell function oral prednisolone 2–3 mg/kg/d in divided doses are
zz sIL–2R ≥ 2400 U/mL
usually part of the initial treatment regimen.
782 SECTION 12: Hematology/Oncology
Cyclosporin: Cyclosporin (2–7 mg/kg/d IV) is often used MAS occuring in patients while taking these drugs have
as a second line agent in steroid ineffective cases. Several also emerged.
case series have found it to be effective under these
Anakinra: It is a recombinant, nonglycosylated form of
circumstances.
human IL-1Ra. It blocks the biologic activity of both IL-
IVIg: Intravenous immunoglobulin (IVIg, 2 g/kg in a 1α and IL-1β by competitively inhibiting their binding
single dose) can be considered, when it is difficult to to IL-1R. It is now widely used for the treatment of sJIA
exclude sepsis. and, occasionally, MAS. The consensus is that anakinra,
particularly at higher doses, might be effective at least in
Etoposide: Etoposide may be considered as part of the
some patients with sJIA-associated MAS.
HLH-2004 treatment protocol. It is metabolized by
the liver and excreted by the kidneys. Severe MAS can Rituximab: A monoclonal antibody against CD20,
impair both these organs thus leading to toxicity. It can rituximab has been found to be effective in cases of MAS
have side effects such as bone marrow suppression and caused by Ebstein Barr virus.
overwhelming sepsis which may be reduced by using
Tocilizumab: It is a monoclonal antibody against the
lower doses of etoposide.
IL-6 receptor. It has been found to be effective in the
ATG: Patients with MAS who have renal or hepatic treatment of sJIA in several trials.
involvement, antithymocyte globulin (ATG) can be used
Future therapies: The targets in pathways that trigger the
as an alternative to etoposide. Generally it is tolerated
cytokine storm (Flow chart 1) are INF ϒ and IL-18 and
well, however it is known to cause infusion reactions
trials of drugs which block them are ongoing.
especially in the context of hematopoietic stem cell
transplantation.
CONCLUSION
MAS is a potentially life threatening complication
BIOLOGICALS
of rheumatologic conditions in children. Important
In the past decade, biologic agents have been given to
clinical features include fever, lymphadenopathy,
treat steroid- and cyclosporin-refractory MAS.
h epato spleno me ga ly, c yto p e nias a nd extreme
Tumor necrosis factor inhibitors: These drugs have shown hyperferritinemia. It is crucial to recognize and treat
efficacy in some cases. Unfortunately some reports of it early. Consensus criteria for diagnosis of MAS in
CHAPTER 129: Macrophage Activation Syndrome 783
the context of sJIA will help with this process. Initial BIBLIOGRAPHY
treatment revolves around supportive care and high- 1. Bracaglia C, Prencipe G, Benedetti FD. Macrophage
dose corticosteroids with addition of cyclosporin activation syndrome. Pediatric Rheumatology. 2017;15:5
for unresponsive cases. Etoposide or ATG have also 2. Cron RQ, Davi S, Minoia F, Ravelli A. Clinical features and
correct diagnosis of macrophage activation syndrome.
been used, in refractory cases. Anakinra however is
Expert Rev Clin Immunol. 2015;11:1043-53.
increasingly being reported as the next step after steroids
3. Sen ES, Steward CG, Ramanan AV. Diagnosing haemo
and cyclosporin. phagocytic syndrome. Arch Dis Child. 2017;102:279-84.
CHAPTER
130
Hemotransfusion Therapy: Boon or Bane?
Anil Kumar Gupta
level, however with increased demand, extraction of Additional dosage may be required, if prothrombin time
oxygen can go upto 50%. No more oxygen is extracted is > 1.5 times of normal or INR is > 2.0. Factor VII, VIII, IX
with further increased demand, and compensatory have their half life < 24–48 hrs, thus necessitate daily FFP
hemodynamics sets in patients including trachycardia transfusion till coagulation return normal.
(>100/min), tachypnea (>30/min ), dizziness, weakness, FFP should not be used as volume expanders due to
angina and decreased mental response. RBCs are risk of TTI, allergic reaction and TRALI. FFP should be
contraindicated for treatment of nutritional anemia ABO compatible and Rh-typing is not required.
(iron, folic acid, vitamin B12 deficiency); not to be given as
tonic to enhance the general well being, promote wound HEMOTHERAPY, INHERENT RISKS
healing or infection;2 due to inherent risk of TTI. One unit Hemothearpy although saves lives but not without risks
of RBCs should raise a Hb. By 1–1.5 g/dL in an adult, but and complications. Each component of hemotransfusion
increment appears more rapidly than the whole blood. is a potential source of inherent risks, thus required
a judicious management of hemotherapy. Various
Platelets concerns are:
Platelets are frequently used in thrombocytopenia,
due to increased destruction (e.g. DIC) or decreased Risks with RBCs
thrombopoiesis (e.g. chemotherapy). Platelets are Hemolytic transfusion reactions (HTR): HTR are mostly
prepared from a unit of blood is called random donor due to ABO incompatible RBCs or plasma. They can
platelets (RDP), while from apheresis machine is called be of immediate HTR or delayed HTR usually 3–7 days
single donor platelets (SDP). after transfusion. Immediate HTR shows fever, chills,
A unit of RDP should raise platelets by 5–10000/ chest pain, back pain, hypotension, abdominal pain and
µL; and SDP should raise by 20–60000/µL in an adult hemoglobinuria, shock, anemia, oliguria, DIC. Delayed
from initial count.Platelets increment may be less with HTR, are less severe,occur when a sensitized patient
splenomegaly, high fever, septicemia, DIC, hemorrahge (either through pregnancy or previous hemotransfusion)
and platelet antibodies. Platelets count done between 10 receives incompatible RBCs. Patients show slow fall of
min and 60 min of transfusion, are less likely affected by Hb, fatigue, and jaundice often go unnoticed.3
above variables. If HTR occurs, transfusion should be stopped, vitals,
Platelets of same ABO group as that of patients renal output maintained through infusion and vasoctive
is selected for transfusion. ABO incompatible plate drugs should be given.
lets may be given in emergency but show lesser
increment after transfusion. Rh immunoglobulins are Risks with Leukocytes
given prophylactically with transfusion of platelets Febrile nonhemolytic transfusion recation (FNHTR):
contaminated with Rh positive RBCs in women of Hemotransfusion may initiate a severe febrile
reproductive age group. A vial of Rh immunoglobulin reaction, due to leukocytes present in the blood.
containing 300 µg is sufficient for 3 SDP or 30 RDP.2 Leukodepleted reduced products minimize this
FNHTR.
Fresh Frozen Plasma Transfusion-related acute lung injury (TRALI): TRALI
Plasma is separated from RBCs and frozen within 6 hours is now the most frequent cause of reaction with high
of collection; is fresh frozen plasma (FFP), contains all fatality due to leukocyte antibody in donor plasma.
coagulation factors, used to treat multiple or single factor Antibodies directed against leukocytes are formed
deficiency to stop or prevent bleeding. in donor plasma as a result of the sensitization with
Dose of FFP is 10–15 mL/kg of body weight; usually past pregnancies or hemotransfusion. Patients have
4–6 units of FFP are required to correct coagulopathy. dyspnea, hypotension, fever and rigors soon after the
786 SECTION 12: Hematology/Oncology
reaction followed by pulmonary edema and hypoxia. induced) reaction. Patient may be over-transfused
The administration of oxygen with respiratory resulting in hypervolemia, develops dyspnea,
support, is vital in the acute stage of TRALI. cyanosis, cough, frothy blood-tinged sputum. It may
Transfusion-associated graft versus host disease be fatal, if not treated promptly; transfusion should be
(TvGVHD): TA-GVHD occurs when transfusion stopped and administer diuretics.
is from first or second degree donors in a poorly
developed or immunocompromised patients, e.g. Bacterial Contamination Risk
lymphoma,bone marrow suppression, fetus with Bacterial contamination of blood may follow rapid
intrauterine transfusion, newborn with exchange onset and death. Bacteria can get entry in a blood from
transfusion. T-lymphocytes present in transfused the skin during phlebotomy. Platelets rather than RBCs
blood, engraft in the recipient, proliferate at the are more prone for bacterial contamination due to its
cost of native cell population and is invariably storage temperature of 22–24°C. patients may have chills,
fatal. TA-GVHD occurs 1–6 weeks after transfusion. headache, vomiting, muscular pain, diarrhea, high fever,
Patients may have diarrhea, abdominal pain, nausea hypotension and shock within 30 min. The transfusion
and vomiting, jaundice and skin rash. No definite should be stopped, infuse broad spectrum antibiotics
treatment is available, therefore prevention is the and maintain vitals.
only way. Leukoreduced components reduces
occurence but not eliminated totally. Irradiating Transfusion-transmitted Infections
blood components is ideal to prevent TA-GVHD In India, all blood donations are subjected for mandatory
tests for HIV, HBV, HCV, syphilis and malaria that make
Risks with Plasma hemotherapy safe.
Allergic reactions: Most commonly noted reaction in Hepatitis: Strengthening of surrogate markers in the
wards; is due to sensitization with plasma proteins wake of the AIDS epidemic and screening for HCV,
and occurs in about 1% of transfusion. It is mediated incidence for hepatitis has come down (i).
through IgE; antigen antibody complex is attached on H I V : I n c i d e n c e d e c r e a s e d m a r k e d l y f o r
mast cell, histamine is released, produces vascular HIV transmission after screening for HIV. HIV
dilatation and increased vascular permeability. is still possible from a donation during window
Reaction occurs within 30 minutes of transfusion phase,although newer generation kit, incorporation
and cause urticaria, pruritis, hives and weals. Fever is of p24 antigen and NAT testing has reduced the risk
usually not present. Edema of the face, lips or mouth considerably
results in respiratory distress. Treatment is to stop Syphilis: Treponema pallidum, causative agent of
transfusion immediately and administer a suitable syphilis, cannot survive at 4°C if blood is stored 48–72
antihistaminic. hrs, thus incidence of transmission is nil.
Anaphylactic reactions: Antibodies to IgA appear to Malaria: Malaria can be acquired by receiving blood
be a cause, developed in patients sensitized through from asymptomatic donor, and is the most common
past pregnancies or hemotransfusion. They are of complication of hemotransfusion. Plasmodium can
immediate hypersensitivity type, vary from mild survive at storage temperature of 4°C for a week.
urticaria to severe anaphylactic shock, can be fatal, Incorporation of sensitive tests with higher sensitivity
if immediate intervention is not done. Transfusion for malaria has reduced the transmission.
should be stopped immediately; and adrenalin Emergent infections: Dengue fever virus, West Nile
administered. Corticosteroid may also be helpful. virus (WNV), Trypanosoma cruzi (Chaga’s disease),
TACO: Transfusion-associated circulatory overload Babesia sp (babesiosis), human herpes virus-8 (KS
(TACO) is an example of iatrogenic (physician- virus), variant Creutzfeld-Jakob disease (vCJD), ZIKA
CHAPTER 130: Hemotransfusion Therapy: Boon or Bane? 787
Cryptococcus: Cryptococcal meningitis is the most and IgM)4 – Immunoglobulin levels may be normal
common presenting opportunistic infection in most or slightly low. Lymphocyte proliferation Assays-
series published.5 Involvement of bone (osteomyelitis), proliferation may be depressed or normal.
Measurement of serum specific antibodies to
skin, and musculoskeletal systems, and may occur before
disseminated infections. vaccines 4- Results are usually normal if the only
detectable defect is CD4 lymphopenia.
Human papilloma virus: Persistent genital infection with
HIV-1, HIV-2, tuberculosis, hepatitis B and C, and
HPV is a common infection in patients. Types 2, 3, and 18
several other viruses-EBV, CMV, HHV-6, RSV, HTLV-
cause various clinical manifestations, including chronic
1 and 2, need to be excluded which can also cause
pruritic papules, skin warts, anogenital dysplasia, and
lymphopenia sometimes transient.
Bowen’s disease.
Other possible tests—These might help depending on
Mycobacterial infections: Patients with ICL may suffer historical/epidemiological clues:
from mycobacterial infections, including tuberculosis Peripheral blood mononuclear cells (PBMCs)
the disease is challenging. Under such circumstances, include blood cultures, serum cryptococcal antigen,
the diagnosis of ICL cannot technically be made until the galactomannan testing for Aspergillus, and image
tuberculosis infection has been treated; at which point, guided biopsies depending on clinical scenarios.
lymphocytopenia should be reassessed. Serologic assays for measles virus and human
Varicella-zoster virus: Varicella-zoster virus, some papilloma virus (HPV).
times affecting multiple dermatomes simultaneously can
be seen. DIAGNOSIS
Candida: Chronic mucocutaneous candidiasis is also Idiopathic CD4 lymphocytopenia (ICL) is a diagnosis
seen in almost 8% of total infections.5 of exclusion. CD4+ T cell counts below 300 cells/mm3
Children may rarely present with recurrent bacterial or less than 20% of total lymphocytes on at least two
infections. separate analyses. The testing should be atleast one to
Pneumocystisjiroveci, Aspergillosis, EBV, CMV, Toxo three months (usually six weeks) apart. Immunological
plasmosis, Histoplasmosis, JC virus, Nocardia and many abnormalities or predisposing infections that cause
other unusual pathogens are known to occur with ICL. lymphopenia should be absent.
790 SECTION 12: Hematology/Oncology
TABLE 1: Regional guidelines on HCC surveillance These differences in diagnostic criteria are
Society Region Target groups Test Interval attributable to regional variations in HCC prevalence
KLCSG-NCC Asia Cirrhosis/HBV/HCV US+AFP N/A as well as management options. Western guidelines
APASL Asia Cirrhosis/HBV/HCV US+AFP 6 Mo
are optimized for maximum specificity (not sensitivity)
to dovetail with policy regarding liver transplantation
JSH Asia Cirrhosis/HBV/HCV US+AFP+ 3–12 Mo
DCP+ADP-L3 allocation. Other imaging options include: Contrast-
EASL Europe Cirrhosis/HBV US 6 Mo enhanced ultrasonography (CEUS) and/or tissue-
Carriers/HCV F3 specific MRI contrast media, proposed by certain
AASLD USA Cirrhosis/HBV US 6 Mo societies such as Asia Pacific Association for the Study
Carriers of Liver (APASL) and JSH, as well as rising AFP proposed
Abbreviations: KLCSG-NCC, Korean Liver Cancer Study Group – National by the 2014 Korean Liver Cancer Study Group–National
Cancer Center; JSH, Japanese Society of Hepatology; APASL, Asia Pacific
Cancer Center (KLCSG-NCC) guidelines
Association for the Study of Liver; EASL, European Association for the Study
of Liver; AASLD, American Association for the Study of Liver Diseases.
TISSUE DIAGNOSIS
can provide additional detection only in 6–8% of cases HCC is the only major cancer which does not require
not visualized by US. This has led to certain Western a mass biopsy. Liver biopsy is recommended only if
guidelines dispensing with the recommendation for imaging does not demonstrate characteristic features of
AFP, citing a lack of cost effectiveness. In contrast, Asian HCC as described above.
guidelines recommend US and AFP in combination.
Furthermore, a recent Japanese Society of Hepatology STAGING
(JSH) guideline advocates the combined use of tumor Staging of HCC is crucial for defining treatment strategy.
markers (AFP >200 ng/mL), AFP-L3 (lens culinaris
The Barcelona-Clinic Liver Cancer (BCLC) staging
agglutinin) >15%), or descarboxyprothrombin (DCP)
system is widely utilized in the West to guide decision
>40 mU/mL) for the diagnosis of HCC. The comparative
making regarding treatment and prognosis. This system
efficacy of these differing strategies in HCC surveillance
not only incorporates tumor burden and extension,
is unclear, and will depend on geographic and clinical
but also hepatic functional reserve and performance
variables.
status. These factors have been shown in cohort studies
Table 1 summarizes the guidelines proposed by
and randomized controlled trials to have prognostic
major international societies.
significance. However, the BCLC system has several
drawbacks and some Asian societies such as the KLCSG-
DIAGNOSIS NCC have chosen to adopt the modified International
Noninvasive Diagnosis Union for Cancer Control (UICC) to stage HCC. It is
HCC diagnosis is based on characteristic imaging important to note that a global consensus on the ideal
patterns noted on four-phase multidetector computed staging system is lacking.
tomography (MDCT) or contrast-enhanced dynamic
MRI. These diagnostic criteria include arterial phase TREATMENT
hypervascularity and venous or delayed phase washout. Approach to HCC management shows a geographic
Western guidelines utilize these criteria to allow variation. Although BCLC staging has been adopted in
noninvasive diagnosis only for nodules >1 cm in cirrhosis most Western centers to determine treatment options,
whereas Asian guidelines allow imaging diagnosis of its basic principles are the source of controversy for
subcentimeter nodules based on typical appearance of many Asia-Pacific experts. Asian guidelines recommend
HCC in those who have either cirrhosis or chronic liver locoregional therapy and surgical resection for more
diseases. advanced tumors than do BCLC guidelines.
CHAPTER 132: Hepatocellular Carcinoma: Surveillance, Diagnosis and Management 793
Flow chart 1 illustrates an algorithmic approach to to intrahepatic tumor burden upto 3 lesions, as long as
HCC management based on APASL guidelines. there is no macrovascular invasion and liver function is
well preserved. LR has been found to be most beneficial
SURGICAL THERAPIES FOR HCC for single tumors in patients without cirrhosis, conferring
postresection 5-year survival rates of 41–74%. For
Liver Resection (LR) vs Liver cirrhotics with local lesions and good liver function
Transplantation (LT) (Child-Pugh A), the choice of a resection versus LT is a
The decision regarding surgical treatment for HCC subject of discussion. Western guidelines recommend LT
depends on tumor burden and nature of underlying as the first approach since recurrence occurs following
liver disease. In general, LR is the first line therapy for resection in a significant number of cases (approximately
those with limited tumour burden and no cirrhosis. LT 50% and 70% at 3 and 5 years respectively). Organ
is reserved for those with decompensated cirrhosis and/ allocation policies in the West prioritize tumours which
or multiple lesions. In the West, resection is limited to satisfy Milan criteria (solitary tumor <5 cm or up to 3
those with solitary tumor and no portal hypertension. In tumors ≤3 cm each without evidence of vascular invasion
contrast, Asian guidelines expand resection indications or extrahepatic spread).
794 SECTION 12: Hematology/Oncology
CLASSIFICATION zz Polycythemia
—— Relative polycythemia (isolated decrease in plasma volume)
In polycythemia, there is an increased concentration —— Absolute polycythemia (increase in RCM)
—— Idiopathic erythrocytosis
an increase in the number of red blood cells and the
hematocrit (PCV) (Table 1). zz Absolute polycythemia
—— Primary e.g. polycythemia vera
delivery to the kidney as in vascular occlusion. zz B and C are called primary familial polycythemia
lating the Epo production. This happens in polycythemia —— Right to left cardiac shunts
—— Sleep apnea
vera an Epo independent erythrocytosis resulting in low
—— Massive obesity
serum concentrations. In Epo dependent erythropoiesis —— High altitude
(e.g. hypoxia or Epo producing tumors) which is found —— Red cell defects (e.g. congenital methemoglobinemia, carbon
—— Hepatocellular carcinoma
—— Cerebellar hemangioblastoma
MAJOR CAUSES OF POLYCYTHEMIA —— Pheochromocytoma
(Table 2). There is a subset of patients with polycythemia stenosis, distal tubular acidosis
zz Following renal transplantation
(idiopathic polycythemia) who cannot be categorized
zz Miscellaneous causes
into primary or secondary and they should have a regular
—— Use of androgen or anabolic steroids
follow up for a long period of time to understand the —— Diuretics by reducing plasma volume
nature and progression of the disease. —— Blood doping in athletes (autologous blood transfusion)
—— Self-injection of Epo
—— Poems syndrome
INITIAL EVALUATION OF PATIENTS —— Idiopathic polycythemia (failure to categorize patients)
WITH POLYCYTHEMIA
History and physical examination Medications and lifestyle (androgens, anabolic
Complete blood count (CBC) with differential count steroids, self-injection of Epo, etc.)
and the red cell indices History of smoking and possibly diet with high iron
Ultrasound of the abdomen. Increase in the blood viscosity account for most
of the symptoms of polycythemia. They include chest
History and abdominal pain, fatigue, headache, myalgia and
Some of the following points in the history may be helpful: weakness, blurred vision or transient loss of vision,
History of respiratory or cardiac illness and details paresthesia and slow mentation. Polycythemia vera
of previously diagnosed respiratory and cardiac may have specific symptoms like pruritis after a bath,
diseases, history of renal transplantation, prior stroke erythromelalgia symptoms of gout, arterial or venous
or venous thrombosis thrombosis, hemorrhage and early satiety due to
Family history of polycythemia splenomegaly.
CHAPTER 133: Approach to a Patient with Polycythemia 797
values more than 5% strongly suggest polycythemia Bone marrow aspiration and biopsy is usually not
secondary CO excess. necessary for most of the patients during the workup of
When hypoxia is suspected, screening with pulse PV but may be useful if a PV related complication like
oximetry should be done. If this is not available, myelofibrosis, myelodysplasia or myeloid leukemia is
arterial oxygen saturation (ABG) should be measured suspected.
during rest, after mild exertion on during sleep.
DIAGNOSIS OF POLYCYTHEMIA VERA
Direct measurement of arterial hemoglobin oxygen
Polycythemia vera is one of the four classic
saturation should be investigation when the cause
myeloproliferative neoplasms (MPN). The other three
polycythemia is not clear and especially when
are essential thrombocythemia, primary myelofibrosis
arterial oxygen tension (pO2) is normal. A low arterial
and chronic myeloid leukemia.
hemoglobin saturation in the presence of normal
The 2016 WHO criteria for diagnosing PV are:
arterial oxygen saturation is a pointer for the presence
of high concentrations of carboxyhemoglobin or
methemoglobin. This can be confirmed by co-
Major Criteria
oximetry. A family history of polycythemia suggests
Increased hemoglobin HGB level (more than 16.5
the presence of high oxygen affinity hemoglobin. This gm/dL in males or more than 16 gm/dL in females),
is confirmed by showing a left shifted hemoglobin hematocrit HCT (more than 49% in males and more
oxygen dissociation curve. than 48% in females) or other tests of increased
blood volume. Hypercellularity for age with trilineage
Blood volume studies if available should be ordered to growth (panmyelosis) on bone marrow biopsy. Biopsy
determine if the polycythemia is due to an elevation should show prominent erythroid, granulocytic and
in the red cell mass (RCM), a reduction in plasma megakaryocytic proliferation with pleomorphic
volume or both. But this investigation is not readily mature megakaryocytes.
available. However, a venous HCT significantly more Exon 14 JAK2 V617F or JAK2 exon 12 mutation
than 56 to 60% in men and 50–55% in women is
(Figs 1 and 2).
almost always associated with an absolute increase
in RCM.
Minor Criterion
In all other situations, one should proceed for the test Serum Epo level below the reference range for normal PV
which will measure the serum erythropoietin (Epo) is diagnosed if all three major criteria are present. It may
concentration. In India, this is an important test for be diagnosed also if first two major criteria together with
economic reasons and a low serum erythropoietin the minor criterion are present. If there is a persistent
(Epo) level in patients with polycythemia can be absolute erythrocytosis (hemoglobin more than 18.5 gm/
taken as a strong specific evidence for polycythemia dL or hematocrit more than 55.5% in men, hemoglobin
vera (PV). It may be seen in other rare situations more than 16.5 gm/dL or hematocrit more than 49.5%
also e.g. congenital erythrocytosis. Polycythemia in women) bone marrow biopsy is not necessary for
associated with increased serum Epo is unlikely diagnosis provided that the third major criterion and the
to be PV and secondary polycythemia should be minor criterion are present.
considered as the working diagnosis.
JAK2 mutation testing is essential if the diagnosis of TREATMENT OF POLYCYTHEMIA VERA
PV is being considered as virtually all patients will For patients below 60 years of age and without any
have a mutation in either 12 or 14th exon of this gene. history of prior thrombosis, phlebotomy (350–500
But in India we do not see this and some patients with mL) once or twice weekly to keep the HCT below
a clinical diagnosis of PV do not have JAK2 mutation. 45% is the treatment of choice. If there were no
CHAPTER 133: Approach to a Patient with Polycythemia 799
Fig. 2: Excess JAK2 signaling due to JAK2 mutation and increased proliferation of RBC
800 SECTION 12: Hematology/Oncology
contraindications, all the patients with PV should be 55–60% may result in relief of the symptoms. If the
given aspirin in a dose of 75 mg per day. levels are reduced less than that 55% they are likely
For patients at higher risk of thrombosis (above 60 to exacerbate symptoms of the underlying hypoxic
years of age and prior thrombosis) treatment with condition.
phlebotomy and aspirin should be supplemented
with the use of a myelosuppressive agent. The best SUMMARY
recommended is hydroxy urea in the doses of 15–20 Polycythemia refers to a laboratory finding of increase in
milligrams per kilogram per day. Dose adjustments the concentration of hemoglobin in the peripheral blood
should be made only once a week since the effect of this along with an increase in the number of red cells and
drug is seen only by 3–5 days. Iron supplementation the hematocrit PCV. It is divided into absolute (increase
should not be given as this drug acts by creating an in the red cell mass RCM) and relative (an isolated
iron deficiency state. It is reasonable to use interferon decrease in the plasma volume). Absolute polycythemia
alpha 2a, another cyto reducing agent, in intractable is further divided into primary (no detectable causes)
pruritis, in high risk women of childbearing potential and secondary (secondary to many diseases). Secondary
including pregnancy and in patients refractory to all polycythemia is much more common. The classical
other medications. Supportive treatment includes example of absolute polycythemia is polycythemia vera
allopurinol for symptomatic hyperuricemia and (PV) which is one of the four classic myeloproliferative
second line drugs like busulfan in hydroxy urea neoplasms (MPN). Common examples of secondary
resistant cases. The new drug ruxolitinib (JAK2 polycythemia are chronic lung diseases, left to right cardiac
inhibitor) should be used only in patients having shunts, AV fistula, erythropoietin producing tumors,
post PV myelofibrosis with hydroxy urea refractory living in high altitude and chronic carbon monoxide
symptomatic splenomegaly or severe constitutional poisoning including smoking. The various causes of
symptoms. secondary polycythemia and primary polycythemia are
differentiated by a careful history, physical examination
MANAGEMENT OF SECONDARY and laboratory investigations. Serum erythropoietin
POLYCYTHEMIA levels are increased in secondary polycythemia. A
The most important aspect of the management will low serum erythropoietin is characteristic of PV. JAK 2
be treatment or removal of the underlying cause e.g. mutation is virtually found in all cases of PV. Revised
surgical removal of an Epo secreting tumor, means of 2016 WHO classification criteria help us to diagnose
stopping carbon monoxide exposure, surgical closure PV. Treatment of PV consists of careful combination of
of large arteriovenous shunt, stopping drugs like phlebotomy, aspirin, cytoreducing drugs and newer
testosterone or anabolic steroids. drugs targeting JAK2 mutation. Secondary polycythemia
Limited phlebotomy—When there are symptoms is treated by removing/ treating the causes and by limited
and increased blood volume and viscosity limited phlebotomy. Newer drugs targeting JAK2 mutations are
phlebotomy is appropriate e.g. patients with expected in the future.
secondary polycythemia due to various conditions
of hypoxia have increased blood volume and/or BIBLIOGRAPHY
viscosity. This may produce symptoms like fatigue, 1. The 2016 revision to the World Health Organization
classification of myeloid neoplasms and acute leukemia.
headache, blurred vision, transient loss of vision,
2. Uptodate: Sections on approach to polycythemia and
paresthesia and slow mentation. These symptoms polycythemia.
occur when the HCT rises to 65%. Careful phlebotomy 3. Wintrobe’s clinical hematology: Chapters on Erythrocytosis
to reduce their HCT into the range of approximately and polycythemia vera.
CHAPTER
134
Immunotherapy: A New Weapon
in Cancer Treatment
Vineet Talwar, Venkata Pradeep Babu K
Some of the pathogenic viruses such as herpes ADOPTIVE CELL THERAPY (ACT)
simplex virus and vaccinia virus are genetically Tumors create immunosuppressive environmental by
engineered to become nonpathogenic. Currently, the secreting cytokines which recruits T regulatory cells (T
most advanced oncolytic virus agent approved by FDA regs) and Myeloid Derived Suppressor Cells (MDSCs) in
is Talimogene laherparepvec (T-VEC), for the treatment its own microenvironment. The Adoptive T cell transfer
of advanced melanoma. T-VEC is first and only approved technique attempts to reverse the functional impairment
oncolytic virus till now in oncology, indicated for the local of tumor specific T cells that reside within the tumor
treatment of unresectable cutaneous, subcutaneous, often referred to as Tumor Infiltrating Lymphocytes
and nodal lesions in patients with melanoma recurrent (TILs). These T cells are isolated from peripheral blood,
after initial surgery. It is however contraindicated in draining lymph nodes or resected tumor tissue, and
immunocompromised patients and in pregnancy. grown and cultured ex vivo, replicated in sufficiently
large numbers and then reinfused along with cytokine
cocktail.
VACCINES IN IMMUNOTHERAPY
Improvement in genetic engineering techniques has
Vaccination against the cancer neoantigens is one of the
explored two strategies to broaden the use of TILs. The
earliest attempts for the immunotherapy in oncology,
first strategy is engineered expression of alpha and beta
with the basic understanding that all of us harbor CD8+
chains of T cell receptor with antigen specificity. This
and CD4+ T cells capable of recognizing tumor antigens. is accessible to any patient whose tumor expresses the
The main difference between prophylactic and tumor HLA peptide complex and expresses the target antigen
vaccines is that, active immunity is required for the former, that can be recognized by TCR. The second strategy is
whereas the tumor vaccines requires the breakage of development of Chimeric antigen receptors (CARs),
immune tolerance induced by tumor. For this to happen, which virtually can recognize any specific antigen that
Dendritic cells must be targeted with high quantities of is expressed on cell surface, omitting the need for MHC
antigens, expanded, activated with appropriate agents. expression and antigen processing in the target tumor
The most crucial step in the development of successful cell. These strategies are being actively evaluated in B cell
cancer vaccine is identification of antigens specific to malignancies, melanoma, synovial sarcoma and several
tumors and exposing them at a specific peptide length to other cancers.
Dendritic cells for stimulation.
Sipuleucel-T, a dendritic cell vaccine, cultured with IMMUNE CHECK POINT BLOCKADE
a fusion protein consisting of prostatic acid phosphatase The multitude of somatic gene mutations confers
potential antigenicity to human cancers, but this immune
linked to the dendritic cell growth and differentiation
response is inhibited by cell mediated and cytokine
factor GM-CSF (granulocyte macrophage colony-
mediated responses by tumor as already described in
stimulating factor), showed approximately 4-month
previous session. One of the very important mechanism
improvement in median survival, which led to US-FDA
is induction of tolerance among tumor specific T cells by
approval in 2010 for the treatment of asymptomatic or
expression of inhibitory ligands that binds the inhibitory
minimally symptomatic metastatic castrate resistant receptors that are naturally present over T cells. Some
(hormone refractory) prostate cancer. Despite this of the inhibitory ligands are CTLA-4, PDL-1, BTLA,
increase in survival, Sipuleucel-T have failed to show VISTA and LAG-3. This inhibition of T cells also occurs
meaningful decreases in tumor volumes in randomized naturally to control total amount of immune response
clinical trials. Moreover, this therapy is available in only and it is referred to as checkpoint. The most exciting part
few centers across the globe, as it is a very cumbersome of immunotherapy was ensued with the success of this
technique. checkpoint inhibitors causing “Checkpoint blockade”
CHAPTER 134: Immunotherapy: A New Weapon in Cancer Treatment 803
to trigger antitumor immune response and it strikes Currently, immunotherapy directed at PD1, PD-L1
in a new era in the treatment approach to advanced and CTLA-4 has shown activity in several immunogenic
cancers. Because this is the most important part of the cancers such as melanoma, lung cancer, head and
immunotherapy let us discuss these mechanisms and neck cancer, renal cell carcinoma and bladder cancer
drugs more clearly. which are shown in Table 1. Several trials targeting
As a part of normal physiological response, when new pathways like IDO (Indoleamine Dioxygenase) are
tumor sheds antigens or expresses on the cell surface, underway.
these are recognized, digested into smaller epitopes and So, to summarize the treatment modalities in
presented by antigen presenting cells to CD4 and CD8 oncology has taken enormous shift with time, where
cells. For this process to occur and immune response to once it was entirely dependent on surgical modality, then
develop, two positive signals are required through two radiotherapy followed by chemotherapy and finally now
receptors on T cell. The first interaction is between T in an exciting era of immunotherapy. These tailor-made
cell receptor and MHC on APC. The second interaction immunotherapies are associated with less morbidities,
is between CD28 on T cell and either activating ligans acts in more specific manner as described above. In
B7 on APC or inactivating ligand which can be either cancer underneath, what might seem like overwhelming
CTLA-4 or PDL-1 which leads to abortion of immune diversity is a deep genetic unity and this immunotherapy
response. This inhibitory response is used to prevent tries to exploit that concept. As old proverb runs, there
autoimmune response in lymphoid organs. The same are mountains beyond mountains, we have hope beyond
inhibitory ligands may also be expressed by several what at present is possible, that is to convert cancer into a
tumors escaping from the natural immune response. chronic disease like diabetes and hypertension.
The most common and well-studied inhibitory pathway
in tumors is programmed death receptor and ligand BIBLIOGRAPHY
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and combination immunotherapy. Nat Rev Clin Oncol. PD-1/PD-L1 pathway and amp; Translational Blockade of
2016;13(6):394. Immune Checkpoints. Int J Mol Sci. 2016;17(7):18.
5. Kohrt HE, Tumeh PC, Benson D, Bhardwaj N, Brody J, 9. Moon YW, Hajjar J, Hwu P, Naing A. Targeting the indoleamine
Formenti S, et al. Cancer Immunotherapy Trials Network 2,3-dioxygenase pathway in cancer. J Immunother Cancer.
(CITN). Immunodynamics: a cancer immunotherapy trials 2015;15:3-51.
network review of immune monitoring in immuno-oncology 10. Ott PA, Hodi FS, Kaufman HL, Wigginton JM, Wolchok JD.
clinical trials. J Immunother Cancer. 2016;15:4-15. Combination immunotherapy: a road map. J Immunotherapy
6. Kourie HR, Awada G, Awada A. The second wave of immune Cancer. 2017;21:5-16.
checkpoint inhibitor tsunami: advance, challenges and
perspectives. Immunotherapy. 2017;9(8):647-57.
CHAPTER
135
Metronomic Chemotherapy in
Metastatic Malignancies: A New Concept
Ankur Bahl
leukocytes. Because of their relative genetic stability, in adult patients. Patil et al. from India demonstrated
endothelial cells are inherently less susceptible to the clinical benefit rate of 66.67% with an estimated
development of drug resistance than are tumor cells. Even median progression free survival of 5.2 months by
when maximally tolerated doses of chemotherapy drugs using metronomic chemotherapy for palliation in
are no longer effective, significant inhibition of tumor advanced oral cancer.9
growth and sparing of normal tissue can sometimes be
achieved by simply changing to a metronomic dosing TOXICITY OF METRONOMIC
regimen. CHEMOTHERAPY
Cyclo-oxygenase 2 (COX 2) inhibitors also show Metronomic chemotherapy appears to be safe and
antitumor activity, caused partly by inhibition of convenient based on various clinical trials done in adult
angiogenesis. These compounds, being orally active, are as well as pediatric patients. Metronomic chemotherapy
suitable for long-term administration and cause only also may be a cost effective/cost-saving treatment option
moderate side-effects. Preliminary preclinical studies as demonstrated in various trials. High-grade toxic
have shown that the antitumor activity of some cytotoxic effects are rare. The most common toxic effects noted
agents is potentiated when combined with COX2 in trials so far includes grade 1 nausea and/or vomiting,
inhibitors. Celecoxib (COX-2 inhibitor) treatment of cells grade 1 and 2 anemia, neutropenia, leukopenia and
in culture has been shown to result in cell cycle arrest.7 lymphopenia as well as low-grade fatigue. However, data
Thalidomide, an immunomodulator is known to have are still limited and definitive conclusions cannot be
powerful antiangiogenic activity. It has well established drawn regarding the tolerance of these combinations.
anticancer activity against multiple myeloma and Overall, metronomic chemotherapy is associated with
Kaposi sarcoma and various other tumors. Thalidomide minimal toxicity and can provide significant clinical
increases the degradation of the mRNA of a number of benefit and improve the quality of life of patients with
peptide-signaling molecules such as fibroblast growth advanced and/or relapsed cancer.10
factor and tumor necrosis factor-alpha (TNF-α).8 The
suppression of TNF-α in cancer patients may be of CONCLUSION AND
particular palliative benefit since high levels of TNF-α FUTURE DIRECTIONS
have previously been linked to cachexia and tumor- Future preclinical and clinical studies will need to define
related malaise. the best agents for use according to tumor type, the
number of agents to be incorporated, the doses of each
METRONOMIC CHEMOTHERAPY IN agent to be used alone or in combination, and the timing
ADULT CANCERS of drug administration. Generally, this type of therapy is
Till date majority of clinical trials investigating continued till progression of the disease. By combining
metronomic chemotherapy in adults have been done well-known drugs “of the past” with an innovative
in patients with breast carcinoma . Many investigators treatment schedule, these metronomic chemotherapy
have used various metronomic chemotherapy regimen regimen appears to be well tolerated and associated with
for patients with advanced and recurrent ovarian possible cancer stabilization for few months.
carcinoma, advanced multiple myeloma, hormone
resistant prostate cancer, nonhodgkin lymphoma and REFERENCES
others. These regimens showed only modest response 1. Shimizu K, Oku N. Cancer anti-angiogenic therapy. Biol
rate to metronomic chemotherapy and overall clinical Pharm Bull. 2004;27:599-605.
2. Fidler IJ, Ellis LM. Chemotherapeutic drugs: more really is
benefit. There has been no other randomized clinical not better. Nat Med. 2000;6:500-2.
study comparing metronomic chemotherapy with 3. Folkman J. Tumor angiogenesis: therapeutic implications. N
conventional chemotherapy in progressive malignancies Engl J Med. 1971;285:1182-6.
808 SECTION 12: Hematology/Oncology
4. Gasparini G. The rationale and future potential of 8. Yoneda T, Alsina MA, Chavez JB, Bonewald L, Nishimura
angiogenesis inhibitors in neoplasia. Drugs. 1999;58:17- R, Mundy GR. Evidence that tumour necrosis factor plays
38. a pathogenetic role in the paraneoplastic syndromes of
5. Kosmaczewska A, Ciszak L, Potoczek S, Frydecka I. The cachexia, hypercalcaemia, and leukocytosis in a human
significance of Treg cells in defective tumor immunity. Arch tumour in nude mice. J Clin Invest. 1991;87(3):977-85.
Immunol Ther Exp. (Warsz). 2008;56:181-91. 9. Patil V, Noronha V, D’cruz AK, Banavali SD, Prabhash K.
6. Browder T, Butterfield CE, Kräling BM, Shi B, Marshall Metronomic chemotherapy in advanced oral cancers. J
B, O’Reilly MS, Folkman J. Antiangiogenic scheduling of Cancer Res Ther. 2012;8(Suppl):S106-10.
chemotherapy improves efficacy against experimental drug 10. Rome A, André N, Scavarda D, Gentet JC, De Paula
resistant cancer. Cancer Res. 2000;60:1878-86. AM, Padovani L, Pasquier E. Metronomic chemo
7. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. therapyinduced bilateral subdural hematoma in a child
Cyclooxygenase regulates angiogenesis induced by colon with meningeal carcinomatosis. Pediatr. Blood Cancer.
cancer cells. Cell. 1998;93:705-16. 2009;53:246-7.
13
SECTION
Rheumatology
Asymptomatic Hyperuricemia: What to Do? Clinical Approach to a Patient with Vasculitis
Arup Kumar Kundu, Shyamashis Das N Subramanian
Polyarteritis Nodosa: An Enigma Osteoporosis Screening, Prevention, and
Ghan Shyam Pangtey, Paramjeet Singh Treatment
Tanu Shweta Pandey
Chikungunya Arthritis
Harpreet Singh, Neeraj Kumar
CHAPTER
136
Asymptomatic Hyperuricemia: What to Do?
Arup Kumar Kundu, Shyamashis Das
TABLE 1: Causes of hyperuricemia formation, chronic and acute urate nephropathy, and
(A) Urate underexcretion (>90%): uric acid nephrolithiasis. It has been demonstrated in
zz Primary hyperuricemia (genetic polymorphism of urate longitudinal studies that there are increased risk of gouty
transporters: SLC2A9, SLC22A12, ABCG2) arthritis and nephrolithiasis with increasing degrees of
zz Secondary hyperuricemia hyperuricemia and hyperuricosuria. Studies showed that
—— Chronic renal failure (clinical gout rare)
the incidence of gout increases with increasing blood
—— Inhibition of urate secretion (ketoacidosis, lactic acidosis)
level and duration of hyperuricemia both; one of such
—— Pre-eclampsia
studies showed the annual incidence of gout was only
—— Drugs (thiazide and loop diuretics, low-dose aspirin,
cyclosporine, ethambutol, pyrazinamide, angiotensin 0.1% in people with serum uric acid levels lower than
converting enzyme inhibitors, non-losartan angiotensin II 7.0 mg/dL, rising to 0.5% in people with uric acid levels
receptor blocker)
from 7.0 to 8.9 mg/dL, and to 4.9% with uric acid levels
—— Lead nephropathy (saturnine gout)
higher than 9.0 mg/dL ; in this study, the sum total
—— Others—hypertension, primary hyperparathyroidism,
ethanol intake incidence of gout was 22% after five years, when the uric
(B) Urate overproduction (approximately, 10%): acid level in serum is ≥ 9 mg/dL. In another study, the
zz Primary hyperuricemia incidence of gout was 12% where patients with serum
—— Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) urate levels between 7 and 7.9 mg/dL were followed
deficiency for 14 years. The initial episode of gout usually occurs
—— Phosphoribosyl-pyrophosphate (PRPP) synthetase after nearly two decades of AH. Studies have shown
overactivity
that increased levels of GM-CSF, IL-8 and TNF-α in AH
—— Glucose-6-phosphatase deficiency with glycogen storage
disease could be a predictor of gouty arthritis. In patients with
zz Secondary hyperuricemia AH, likelihood of progression to gout increases with
—— High nucleotide turnover (severe psoriasis, myeloproliferative increased amounts of alcohol intake, excessive meat/
and lymphoproliferative diseases, hemolytic disorders, seafood ingestion, hypertension, obesity and use of
malignancy, etc.)
certain drugs like thiazide or loop diuretics, etc.
—— Excessive dietary purine or fructose intake
Increased urinary uric acid excretion is associated
—— Ethanol intake
with elevated risk of urate (not calcium oxalate) stone
—— Vigorous exercise
formation. Uric acid stones account for 5 to 10% of all
(C) Combined:
zz Ethanol intake
renal stones. An epidemiologic study showed that the
zz Tissue hypoperfusion annual incidence of nephrolithiasis was 0.3% in patients
with AH and 0.9% in those who are suffering from gout.
Hyperuricemia occurs due to deranged uric acid Acute uric acid nephropathy occurs after a sudden
rise in uric acid production and hyperuricemia,
metabolism, such as, increased production, decreased
commonly seen in tumor lysis syndrome in patients
excretion, or both (Table 1). Prevalence wise, most
with lymphoproliferative or myeloproliferative disorders
patients with gout are underexcreters. Patients with
after initiation of chemotherapy. This reversible and
gout excrete about 40% less uric acid, due to decreased
potentially preventable cause of acute renal failure is
proximal tubular secretion, than healthy individuals for
due to deposition of uric acid in the renal tubules and
any given level of serum uric acid concentration.
collecting ducts resulting in obstruction of urinary
flow. In contrast to tumor lysis or related syndrome,
CLINICAL CONSEQUENCES OF where urate overproduction is the main pathology,
PERSISTENT HYPERURICEMIA hyperuricemia in chronic kidney disease occurs due to
This can be broadly classified as urate crystal deposition impaired capacity of kidney to excrete urate.
disorders and noncr ystal deposition disorders. Non-crystal deposition disorders, e.g. systemic
Deposition of MSU crystals causes gouty arthritis, tophus hypert ension, chronic renal insufficiency, coronary
CHAPTER 136: Asymptomatic Hyperuricemia: What to Do? 813
artery diseases, metabolic syndrome, diabetes mellitus or hyperechoic cloudy areas. Crystal deposition in joints
and insulin resistance have all been associated with has been observed in a considerable number of persons
hyperuricemia. But, it has not been definitely established with traditionally defined AH, especially of long duration.
as a causal factor in any of these disorders. However, further studies are required to say that AH with
MSU crystal deposits predict an earlier onset and/or
EVALUATION OF PATIENTS WITH worsened outcomes of clinical gout.
ASYMPTOMATIC HYPERURICEMIA
Elevated urate levels should be confirmed by repeating Are There Any Beneficial Effects
the test after at least one week interval. In case of of Hyperuricemia?
confirmed AH, it needs to identify the following: It has been observed that antioxidant effects of
Patients at particularly high risk for gouty arthritis, hyperuricemia lessen oxidative damage in DNA .
tophi, or urolithiasis and who warrant urate lowering Neurological disorders like Parkinson’s disease, multiple
therapy (ULT) by allopurinol, febuxostat, probenecid sclerosis, Huntington’s chorea and Alzheimer’s disease
or uricase. may be related to low uric acid level in serum. On the
Hyperuricemia-inducing drugs or toxins that can be other way round, increased serum uric acid is associated
removed or replaced for normalization of serum uric with greater intelligence, achievement-oriented behavior
acid level. and good school performance.
Individuals whose hyperuricemia is a sign of another
medical management, when ULT is indicated. For ULT, similar to keep the serum uric acid level below 6 mg/dL
the clinical consequences from hyperuricemia should (360 micromol/L) to prevent the consequences, if there
be weighed against the potential benefits and risks of is any.
lifelong pharmacotherapy.
There is paucity of evidences regarding the outcomes
BIBLIOGRAPHY
of patients with clinically AH but MSU crystal deposition
1. Das S, Ghosh A, Ghosh P, et al. Sensitivity and specificity of
demonstrated by imaging; therefore, ULT is yet not
ultrasonographic features of gout in intercritical and chronic
recommended in such condition. Similarly, urate-
phase. Int J Rheum Dis. 2017;20(7):887-93.
lowering pharmacotherapy for prophylaxis against
2. Kundu AK. Hyperuricemia revisited. In: Das AK, Ed.
nephrolithiasis is not justified in most individual in AH.
Puducherry: Indian College of Physicians. Postgraduate
Due to lack of definite evidence, ULT is not indicated Medicine. 2009; XXIII:257-63.
if hyperuricemia is associated with different non- 3. Neogi T. Clinical practice. Gout. NEJM. 2011;364:443-52.
crystal deposition disorders like systemic hypertension, 4. Poon SH, Hall HA, Zimmermann B. Approach to the
cardiovascular disease, metabolic syndrome, etc. treatment of hyperuricemia. Medicine and Health, Rhode
As is the case with nontophaceous gout, the aim of Island. 2009;92(11):359-62.
ULT in persons with sustained but AH (if indicated) is 5. Richette P, Bardin T Gout. Lancet. 2010;375:318-28.
CHAPTER
137
Polyarteritis Nodosa: An Enigma
Ghan Shyam Pangtey, Paramjeet Singh
CASE VIGNETTE
A 19-year-old young boy presented with a ten months
history of intermittent fever, colicky abdominal pain.
He also gave history of Raynaud’s phenomenon,
subcutaneous nodules over forehead and recently
diagnosed hypertension. There was no history of
oral ulcers, alopecia, malar rash, skin tightening or
arthritis. Neither there was any history of blood in
stool or urine. On examination, he had multiple small
1 cm2 subcutaneous nodules on his forehead, which
were painless, soft to firm in consistency and with
overlying skin normal. He was febrile to touch; his
pulse rate was 102 beats per minute, blood pressure
150/100 mm Hg in right arm, supine position. Rest of the Fig. 1: Digital subtraction angiography (DSA) of right kidney showing
multiple pseudoaneurysms (arrows)
systemic examination: chest, CVS and CNS was within
normal limits. On laboratory evaluation, he had mild
of medium-sized arteries, the findings were consistent
hypochromic microcytic (HCMC) anemia, neutrophilic
with a diagnosis of classical-PAN. The patient was
leukocytosis and raised erythrocyte sedimentation rate
started on oral prednisolone 1 mg/kg/day, resulting in
(100 mm Hg/1st hr). His renal function was normal but
immediate feeling of well-being and resolution of fever.
liver function and liver function was normal. Blood test
for HBsAg and anti-HCV were negative. Antineutrophil The skin nodules and abdominal pain also resolve in
cytoplasmic autoantibody (ANCA) was also found to few days. His hypertension was persistent for which he
be negative by indirect immunofluorescence method. was prescribed oral enalapril 5 mg once a day. He was
Conventional digital subtraction angiography (DSA) discharged after 10 days of treatment with prednisolone.
revealed multiple micro-aneurysmal dilatation up Considering his young age the decision to start on
to 1 cm involving the parenchymal branches of the cyclophosphamide was withheld and prednisolone was
hepatic artery, splenic artery, renal artery (Fig. 1), and tapered after 6 weeks of treatment. He was prescribed
splanchnic vessels (Fig. 2). Biopsy of the subcutaneous azathioprine as steroid sparing agent and planned to
nodule over forehead revealed necrotizing inflammation continue the same for at least 3 years.
816 SECTION 13: Rheumatology
Fig. 2: Angiography of abdominal aorta and its branching showing Fig. 3: Non-healing ulcer over leg in a patient of polyarteritis nodosa
renal micro-aneurysms (white arrows) and splanchnic vessel
aneurysm (white arrow head)
its multi-system involvement and vide spectrum of renal biopsy which were done in the past are rarely
manifestation, the diagnosis of PAN is still an enigma to done in present time considering poor yield and other
the internists as well as rheumatologists. easily accesible tissue availabilty. Renal histology in
classic PAN is of ischemia secondary to renal stenosis,
EPIDEMIOLOGY aneurysm leading to parenchymal infarct. Imaging by
The prevalence of PAN can range from 2 to 33 per million MRI or CT scan and electrophysiological study may help
population. The annual incidence in three regions of in localization of tisse for biopsy as sometime PAN may
Europe was estimated to be 4.4 to 9.7 per million by ACR have patchy tissue involvement.
criteria versus 0–0.9 per million by CHCC definition.
The large variation in estimates may be explained by CLINICAL FEATURES
differences in diagnostic criteria but regional variations Clinically, the PAN can have very varied and weird
may also be there. It can develop at all ages including presentations. PAN can affect virtually any organ like
elderly and children but most cases are between 40 and kidneys, skin, joints, muscles, nerves and gastrointestinal
60 years old, with slight male predominance ratio 1.5:1. tract usually in some combination but the lungs are
Most cases of PAN are idiopathic. It can be associated usually spared. The patient may first visit a dermatologist
with chronic hepatitis B infection (HBV) and also with for skin lesions or to a physician with difficult to diagnose
HIV, parvovirus B19 and HCV infection. Hepatitis B PUO, can land up with neurologist with wrist drop,
infection related PAN usually presents as acute disease foot drop or other neurological deficits, can present to
occurring within 6 months of an HBV infection. As per a surgeon with acute abdomen, to a cardiologist with
WHO report, India have moderate-high prevalence of refractory hypertension or CHF, to an ophthalmologist
HCV and HBV infection, yet we do not see proportionate with acute visual loss and to a nephrologist with acute
cases of PAN for reasons unknown. This may be due kidney injury (AKI). At times, the diagnosis may not
to lack of knowledge of PAN among treating clinicians, be made in first visit or first admission even at the
lack of diagnostic facilities, our genetic constitution apex institutes especially when the patient is in early
or lack of systemic recording of cases. Worldwide stage of disease evolution. It can be a nightmare for the
marked reduction in hepatitis B viral infection has been clinicians when the patient present with acute crisis,
associated with a parallel reduction in prevalence of PAN. such as bleeding GIT or major vessel bleed. The clinical
In addition to infectious causes, PAN also has association manifestations tend to be more severe in case of HBV-
with hematological diseases and malignancies like hairy related PAN.
cell leukemia. In most of the patients of PAN some form of
Classic PAN characteristically involves medium-sized constitutional symptoms are always present, in some
muscular arteries with a tendency to involve branch series it has been reported in upto 90% of cases. The
point of arteries and it is a panarteritis, involving all layers symptoms may includes fever, myalgia, arthralgia,
of the vessel wall. It spares large arteries such as aorta fatigue and weight loss. There can be combination
and its major branches, small vessels lacking muscular of constitutional features with ischemic symptoms.
coat, arterioles, capillaries and venules. Segmental Skin manifestations can occur in 25–60% of patients in
involvement of vessel wall followed by healing leads the form of ulcerations, infarctions, livedo reticularis,
to aneurysm formation and endothelial proliferation subcutaneous nodules. The nodules can ulcerate and
leads to stenosis of the artery resulting in ischemia of the patients can present with non-healing ulcers. Arthralgia
involved organ. or arthritis can be there in around 60% of patients.
Primary vasculitis disgnosis is primarily based on Arthritis is usually asymmetrical, non-deforming. In the
histopathology finding. The various tissues used for very early stage of the disease the patients can have non
biopsies for diagnosis of PAN are muscle biopsy, nerve specific arthralgias. Myositis, myalgias and claudications
biopsy and deep skin biopsy. Testicular biopsy and can be present. Peripheral neuropathy have been found
818 SECTION 13: Rheumatology
in up to 85% of patients with PAN. The onset is very acute conventional angiography. Although microaneuryms
and its more common in lower limbs than upper limbs are not pathognomonic, they are commonly present in
and more common in HBV-related PAN. Inflammation of > 60% patients of PAN. The most frequently involved
vasa nervosum can cause mononeuritis which clinically vessels are renal and splachnic vessels branches: hepatic
manifests as wrist drop or foot drop. CNS involvement and mesenteric arteries. The typical angiographic
although less common can include headache, seizures, appearance includes the long segments of smooth
cranial nerve dysfunction and stroke. arterial stenosis with alternating areas of normal or
Renal manifestations are characterized by vascular dilated artery, smooth-tapered occlusions without
nephropathy without glomerulonephritis. Renal infarcts significant atherosclerosis. The dilated segments
can cause renal failure. The patients can have hyper including aneurysms strongly suggests PAN.
tension and proteinuria. Hypertension develops in In some cases, tissue diagnosis can be established by
20–50% of cases and is particularly associated with taking biopsy from potential sites such as skin nodule
HBV related PAN. The patients can have acute severe and involved muscles in patients with myalgias with
postprandial abdominal pain due to mesenteric ischemia or without mononeuritis multiplex. Nerve biopsy from
mimicking acute abdomen though tenderness is not there. involved nerve or sural nerve can be performed when
Some patients presents with acute GI bleeding, diarrhea the patient has distal mononeuritis multiplex. Renal
or pancreatitis. GI involvement can occur in around biopsy is not recommended for PAN as it does not cause
70% of cases and is more common with HBV related glomerulonephritis and involves renal arteries only. One
PAN. Coronary arteritis can lead to acute myocardial of the characteristic feature of PAN on histology is the
infarction but is generally silent. Cardiomegaly is seen coexistence of necrotising vasculitis and a healed lesion
in around 20% of patients. Endocarditis is usually not or normal arteries.
observed in patients with PAN. The cardiac MRI has been
found to be useful in evaluation of coronary arteritis an to PROGNOSIS
assess the extent of myocardium involvement. Orchitis is PAN is classically considered to be a monophasic disease
one of the most characteristic feature of classic PAN but that do not tend to recur once remission is achieved
has been reported in only approximately 20% of patients. with disease modifying antirheumatic drugs (DMARDs)
Lungs are surprisingly spared in PAN for reasons but in our experience this does not holds true. We have
unknown. seen cases of PAN in remission presenting with upper
GI bleed, sudden onset visual loss, recurrent seizures
LABORATORY EVALUATION and non healing wounds or ulcers indicating recurrence.
AND IMAGING These patients have poor prognosis and high mortality
As with other systemic inflammatory illnesses, the rates.
markers of inflammation are raised as reflected by French Vasculitis Study Group (FVSG) developed
raised erythrocyte sedimentation rate (ESR) and CRP Five-Factor Score (FFS) for systemic necrotizing vascu
levels, thrombocytosis and hypoalbuminuria. The litis, which is commonly used for evaluation of prognosis
antineutrophil cytoplasmic antibody (ANCA) is ussually at the time of diagnosis. The prognostic Five Factor Score
negative in classic PAN. Rheumatoid factor when (FFS) includes 5 parameters that are predictors of poorer
present is frequently associated with cryogloblinemia. outcome and mortality. These include proteinuria
Compliment levels (C3 and C4) may be reduced in HBV greater than 1 gm/day, creatinine level (>1.58 mg/dL),
related PAN. cardiac involvement, gastrointestinal involvement and
Conventional angiography is the gold standard CNS manifestations. A FFS of greater than 2 is associated
test for detecting microaneurysms. Digital subtraction with greatly increased mortality although with early
angiography (DSA), CT angiography (CTA) and magnetic diagnosis and appropiate DMARDs use especially
resonance imaging (MRA) can be newer alternatives to corticosteroids and cyclophosphamide, the 5 year
CHAPTER 137: Polyarteritis Nodosa: An Enigma 819
mortality has signifcantly decreased in past few decades. evidence of effectiveness has been coroborated from
The patients with FFS score of one or < 1 can be treated primary systemic vascultis treatment in the past due
with systemic steroid without cyclophosphamide. to rarity of PAN as well as previous clssification (ACR)
clubbing together MPA into classical PAN.
MANAGEMENT Patients with severe disease and FFS score of ≥2
Mortality of untreated PAN is very high and previous should be traeted with cyclophosphamide oral or
studies have documented mortality in first year to be intrvenous. In few studies of systemic vascultis, it
as high as up to 73%. The mainstay of treatment of has been found that intravenous cyclophosphaide is
polyarteritis nodosa (PAN) is by immunosuppression equally effective to oral cyclophosphamide and has
similar to other systemic vasculitis except for patients better toxicity profile. There are various protocol for
with active HBV or HCV infection–related PAN in which cyclophosphamide infusion for PAN and other sytemic
case instead of immunosuppression first control of vasculitis. In one of the commonly used regimen (NIH),
active viral disease is priority and in many cases the intravenous cyclophosphamide is given at dose of
manifestations of PAN may also improve with antiviral 15 mg/Kg every month for 4–6 months as Induction
therapy. Recent development of potent HCV and HBV therapy and this is usually followed by azathioprine,
viral therapy has markedly decreased the incidence MMF, methotrexate or rituximab for next 2–3 years as
of this post-viral PAN to less the five percent of overall maintenance therapy. According to European Vascultis
prevalence. Society (EUVAS) protocol cyclophosphamide infusion is
The treatment of HBV-related PAN is different from given 2 weekly for 3 doses, then 3 weekly for 3–4 months
classic PAN without HBV infection as with institution of to a maximum of 6 more doses for a total of 6 months and
immunosuppression there may be remission of active the total duration depends on response.
vasculitis but it may lead to increased viral replication Rituximab an CD-20 inhibitor has been found to be
leading to hepatic decompensation and death. A short equally effective as compared to IV cyclophosphamide
course of 2–3 weeks of aggressive immunosuppression in induction of remission in patients of ANCA associated
with systemic steroid should be followed by series of vascultis (RAVE trial, RITUXVAS trial). Although classic
plasma exchanges and concomitant antiviral therapy. PAN is ANCA-negative vascultis but still it has been
found to be effective in PAN. Multiple reports has been
Non-HBV Related PAN published in various journals. Rituximab is given at a
Once the diagnosis of non-HBV related PAN is confirmed dose of 375 mg/m2 every week for 4 weeks for induction
my clinicoradiologic and histologic evaluation, they therapy and can be followed by 6 monthly infusion for
should be aggressively treated with immunosuppressive maintenance therapy. It is costly drug as compared to
agents. Acute vasculitis with imminent threat to vital cyclophosphamide with advantage of lesser adverse
organ or life, needs emergency treatment with any of effects, especially cytopenia and ovarian failure in
the one or more of the immunomodulating therapy, females.
which can be life saving: Pulse methylprednisolone, Patients with PAN disease FFS score of < 2 can be
plasmapheresis, intravenous immunoglobulin (IVIG), managed with induction of disease with sytemic steroid
surgery/interventional vascular procedure (vascular with or without oral methotrexate or mycophenolate
embolization, etc.) for acute bleed from microaneurysm, mofetil (MMF) and maintence therapy with azathioprine
and/or renal replacement therapy in case of acute or MMF.
kidney injury. The treatement of non-HBV related
classical PAN is with cytotoxic and immunosuppressive HBV-related PAN
drugs (cyclophosphamide, methotrexate, azathioprine, HBV-related PAN is treated differently compared to
mycophenoalate mofetil (MMF), tacrolimus, cyclosporin) the other primary systemic vasculitis. The underlying
and anti-B cell therapy (Rituximab) but most of the pathogenesis of HBV-related PAN is deposition of
820 SECTION 13: Rheumatology
immune complexes over medium and small arteries The characteristic histopathology finding is of focal
secondary to ongoing viral replication. The treatment and segmental transmural necrotising inflammation
of HBV related PAN should be initiated with high dose with fibrinoid necrosis in medium-sized vessels.
systemic steroid for 2–3 weeks to stabilize the patient and Diagnosis of PAN requires strong clinical suspicion
reduce end organ damage secondary to active vascultis. and confirmation by tissue histology or radiologic
The patients who are very sick can also be treated with imaging of micro-aneurysm or stenosis of medium
methyl prednisolone pulse (500–1000 mg/day) for 3–5 and small arteries.
days depending on patient condition. Treatment for non-HBV-related PAN is based on
Once patient is stabilized the plasma exchanges immunosuppression with corticosteroids and
(PE) should be started for physically removing immune cyclophosphamide depending upon Five-Factor
complexes from the circulation. The schedule for PE Score (FFS) for systemic necrotizing vasculitis
developed by French Vasculitis Study Group (FVSG)
depends upon local protocol and availability. In usual
Treatment for HBV-related PAN utilizes a short
setting, for initial three weeks 4 sessions of PE should
course of high-dose corticosteroids, followed by
be done per week, this is followed by 3 sessions per
a combination of antiviral therapy and plasma
weeks for next 3 weeks. The inter session periods is
exchange.
subsequently increased. The ideal endpoint of PE is HBV
PAN is considered to be monophasic disease but
PCR negativity or development of HBsAg or antiHBe
it may have chronic as well as relapsing remitting
antibodies. Antiviral drug against HBV should be
course similar to other primary systemic vasculitis.
started concomitant to PE sessions to reduce viral load
and immune complexes, leading to seroconversion.
BIBLIOGRAPHY
Oral lamivudine 100 mg once a day is the preferred 1. Chatur vedi V, Thabah M. Polyar teritis nodosa. In:
anti-HBV antiviral agent and has shown successful Narsimulu G, Ravindran V. Monograph on vasculitis. Indian
seroconversion. This treatment regimen is based on College of Physicians; 2015. pp. 69-75.
expert advice, as due to the rarity of disease there 2. Das CJ, Pangtey GS. Images in clinical medicine. Arterial
microaneurysms in polyarteritis nodosa. N Engl J Med.
is marked paucity of evidence. Patient whose HBV
2006;355(24):2574.
infections fail to seroconvert or PAN relapses should 3. Guillevin L. Polyarteritis nodosa. In: Sharma A (Ed). Textbook
take expert hepatologist advice for alternative antiviral of systemic vasculitis. The Health Sciences Publisher; 2015.
therapy. Interferon-alpha, adefovir dipivoxil, entecavir, pp. 277-88.
telbivudine and tenofovir are the newer HBV antiviral 4. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross
WL et al. 2012 Revised International Chapel Hill Consensus
agents, which can be used in case of relapse or failure.
Conference Nomenclature of Vasculitides. Arthitis Rheum.
2013;65:1-11.
SUMMARY 5. Luqmani R, Ponte C. ANCA-associated vasculitides and
PAN is a rare form of systemic vasculitis that affects polyarteritis nodosa. In: Bijlsma JWJ, Hachulla E. Textbook on
only medium or small size arteries without involving Rheumatic Diseases, 2nd edition. EULAR; 2015. pp. 717-53.
6. Ntatsaki E, Watts R, Scott DGI. Polyarteritis nodosa and
arterioles, capillaries, venules.
cogan syndrome. In: Hochberg MC (Ed). Rheumatology, 6th
The ANCA test is usually negative in PAN but its edition Elsevier mosby; 2015. pp. 1290-99.
negativity is not absolute and mutually exclusive. 7. Pangtey GS, Jain P. Vasculitis-related Interstitial Lung
Hepatitis B virus (HBV)-related PAN has become very Diseases: Clinical Diagnostic and Management Issues.
rare since the introduction of effective immunization In: Bhalla AS, Jana M (Eds). Clinical Radiological Series:
Imaging of Interstitial Lung Diseases. 2017; Jaypee Brothers
program against the virus.
Medical Publishers, Delhi. pp. 121-31.
Angiography typically demonstrates <1 cm2 micro 8. Polyarteritis nodosa – Management – Approach – Best
aneurysms and focal narrowing in medium-sized Practice – English best practice.bmj.com/best-practice/
blood vessels. monograph/351/treatment/step-by-step.html
CHAPTER
138
Chikungunya Arthritis
Harpreet Singh, Neeraj Kumar
Mosquito transmitted chikungunya virus (CHIKV) It is characterized by severe joint pain associated
is common in tropical area. Familarization about with inflammation and tissue destruction and release of
chikungunya by public and doctors in India has been inflammatory cytokines such as IL-1b, IL-6, and TNF-α.
quite evident for last 3–4 years due to its assumed Also the IFN produced by infected fibroblast produce
epidemic proportion in several parts of the country.1 high level of prostaglandin, however exact mechanism
The disease gets its name chikungunya which means responsible for chronic or relapsing form of joint disease
‘bent up’—a posture the patient assumes due to severity are yet not fully understood. It is not entirely clear
of pain in disease. It causes an acute febrile illness with whether joint damage is caused by direct viral effect or by
polyarthralgias which are often severe and debilitating. viral activation of the immune system and its associated
After its discovery in 1952 in Tanzania, few sporadic inflammatory reaction.3 It has been suggested that joint
outbreaks were described in Africa and Asia. In 2005, the pain is immune mediated although regular presence of
virus underwent a mutation that enabled transmission autoantibodies has not been shown.4 Ever since the La
through Aedes albopticus, a widely distributed mosquito, Reunion outbreak, the chronic joint disease associated
has lead to numerous CHIKV epidemics reported in with CHIKV have been reported frequently although
Africa, South-east Asia, the Indian Ocean islands, and prior joint abnormalities have not been excluded. Also,
Europe and thus posing a global public health problem. it is likely that the development of joint disease like
CHIKV spreads through resident dendritic cells osteoarthritis and rheumatoid arthritis later on may
(DCs), including Langerhans cells to target organs, not be related to prior CHIKV infection. Ambiguities
such as muscles, liver, kidney, heart, and brain. regarding CHIKV associated joint disease may be due
Nonhematopoietic fibroblast cells have been reported to non-availability of exactly replicating animal models
to be susceptible to in vitro CHIKV replication and to be which could have helped to know the potential reason
the main cell type infected in target tissues (muscle, joint,
and skin) in mice, and as well as in humans (Table 1).2 TABLE 1: Organ tissue and there respective target cells
Fever experienced by all CHIKV patients is associated Organ tissue Target cells
to the synthesis of cytokines such as interleukin (IL- involved
1b, IL-6) and tumor necrosis factor-α (TNF-α), which Lymphoid tissue Stromal cells, macrophage and dendritic cells
patients closely resembles the symptoms induced by Muscle Satellite cells and fibroblasts
for progressive irreversible joint damage that is reported TABLE 2: Articular manifestation of chikungunya virus
after acute CHIKV infection.3, 4 The association of chronic Acute manifestation
joint pain in CHIKV infection is yet not clear. Many of the Polyarthralgia zz Fingers, wrists, knee, ankle, toes are
chronic patients do not respond well to usual analgesics most frequently involved
zz Symmetric pattern is common
suggesting that pain may not only be nociceptive but also
neuropathic. Myalgia Very common
After the fever subsides, patient generally develops Myalgia Very common
include patients age older than 45 years and presence evidence of similar illness in the family, age of onset,
of underlying osteoarthritis. Patients with two or more absence of serological (RA/anti-CCP), radiological
comorbid condition are likely to experience long lasting changes like erosions, (marginal) and histopathological
musculoskeletal symptoms after CHIKV.10 evidence. Additionaly seronegative spondyloarthritis
Inflammatory marker such as ESR and CRP are (psoriatic arthritis and ankylosing spondylitis have been
frequently elevated in patient with musculoskeletal reported after CHIKV infection particularly in those
symptoms in acute stage. During the acute phase who are HLA B27 positive.12 There is paucity of studies
elevated liver enzyme especially transaminitis and regarding the clinical progression of CHIKV infected
muscle enzymes (creatine phosphokinase, lactate patients having already a preexisting autoimmune
dehydrogenase) have been documented in 50% of rheumatological disease.13
p at i e nt s, o f t e n a c c o m p a n i e d w i t h c y t o p e n i a s The Centres for Disease Control and Prevention
(thrombocytopenia/leukopenia).11 Laboratory results recommends supportive treatment that includes rest,
are normal during chronic stage. Radiolgraphic studies adequate hydration with fluids and acetaminophen
are typically normal or show mild swelling consistent and nonsteroidal anti-inflammatory drugs (NSAIDs) for
with joint pain. Ultrasonography may show evidence fever and joint pain. The role of corticosteroids has been
of tenosynovitis/enthesopathy. MRI finding were studied. Simon et al observed dramatic improvement
joint effusion, bony erosion, marrow edema, synovial of acute and chronic rheumatic symptoms in CHIKV
thickening, tendinitis and tenosynovitis.4,5 infected travelers treated with corticosteroids.14 These
So, the diagnosis of CHIKV infection is based data suggest that a low-dose corticosteroid treatment
on clinical features (fever and arthralgia/arthritis), can be beneficial in relieving the acute rheumatic
epidemiologic factors (residence or return from endemic symptoms of CHIKV infection and in improving quality
area with in 15 days of onset of symptoms) and laboratory of life. However, a prolonged course (1–2 months) with
findings (definitive diagnosis of CHIKV infection is slow tapering may be required to prevent rebound
made by) detection of viral RNA in serum by reverse symptoms.15 Indian study has shown that the persistent
transcription polymerase chain reaction (RT-PCR) arthragia in CHIKV patients mimicking rheumatoid
during first 7 days of infection or detection of IgM and/or arthritis in 70.58 %.5 Therefore DMARD can be effective.
IgG antibodies by ELISA after first 5 days of illness. Combination may help in reducing the dosage of the
Parvovirus B19 may also mimick of CHIKV infection individual drugs which may help in better toleration of
as it causes fever with symmetrical polyarthritis in DMARDS.6,16 Combination of DMARDS or corticosteroids
adults though has seasonal pattern or their is history of with hydroxychloroquine has been successful in treating
exposure to an infected individuals. Moreover patients chronic rheumatic manifestations.17 Early results with
with persistent arthralgias, and particularly those with DMARDS like sulfasalazine and methotrexate are
arthritis, should be followed closely and examined emerging.16 Methotrexate and sulfasalazine combination
for other serious causes of chronic arthritis including was found effective for chronic CHIKV arthritis. TNF
rheumatoid arthritis, systemic lupus erythematosus, blockers were successfully in 6 patients with RA
spondyloartritis and vasculitis. Surprising, a few were diagnosed post-CHIKV infection who failed methotrexate
positive for rheumatoid factor or anti-citrullinated therapy.8 It is not clear when it is appropriate to start
protein antibodies. 5 In a Manimunda’s study it was DMARD therapy for CHIKV induced arthritis. However,
confirmed that the levels of RF/anti CCP were not immunosuppressive agents should be reserved for the
elevated in contrast to what is seen in traditional chronic stages of CHIKV infection.
RA.5 In the same study one-third of patients who had The initiative to stimulate protective immunity as
joint pain met ACR criteria to classify them with RA. a strategy for preventing CHIKV infection in humans
Some of differentiating feature between RA and post- began in the early 1970s. A new formulation using virus-
chikungunya chronic arthritis could be nature of onset, like particles has been shown to induce neutralizing
824 SECTION 13: Rheumatology
antibodies in macaques but all are in early phases of trial 9. Win MK, Chow A, Dimatatac F, Go CJ, Leo YS. Chikungunya
to be used in humans.18 fever in Singapore: acute clinical and laboratory features,
and factors associated with persistent arthralgia. J Clin
Clearly, a virus capable of infecting an estimated
Virol. 2010;49: 111-4.
7.5 million people over a 5-year period, resulting in 10. Gérardin P, Fianu A, Michault A, et al. Predictors of
chronic arthralgia in ~30% of these individuals, deserves Chikungunya rheumatism: a prognostic survey ancillary to
more attention. Private and public funding organizations the TELECHIK cohort study. Arthritis Res Ther. 2013;15:R9-
have helped to raise awareness for global health issues 12.
11. Borgherini G, Poubeau P, Staikowsky F, et al. Outbreak
such as HIV infection, malaria and tuberculosis, but this
of chikungunya on Réunion Island: early clinical and
unfortunately represents only a proverbial ‘small bite’ out laboratory features in 157 adult patients. Clin Infect Dis.
of a major problem re-emergent viruses such as CHIKV. 2007;44:1401-77.
12. Malvy D, Ezzedine K, Mamani-Matsuda M, et al. Destructive
REFERENCES arthritis in a patient with chikungunya virus infection
1. Staples JE, Breiman RF, Powers AM. Chikungunya fever: an with persistent specific IgM antibodies. BMC Infect Dis.
epidemiological review of a re-emerging infectious disease. 2009;9:200.
13. Vaughan JH. Viruses and autoimmune disease. J Rheumatol
Clin Infect Dis. 2009;49:942-8.
1996;23:1831-3.
2. Sourisseau M, et al. Characterization of re-emerging
14. Simon F, Parola P, Grandadam M, et al. Chikungunya
chikungunya virus. PLoS Pathog. 2007;3:e89.
infection: an emerging rheumatism among travelers
3. Gardner J, Anraku I, Le TT, Larcher T, Major L, Roques P, et
returned from Indian Ocean islands. Report of 47 cases.
al. Schroder WA, Higgs S, Suhrbier A. Chikungunya virus
Medicine (Baltimore). 2007;86:123-37.
arthritis in adult wild-type mice. J Virol. 2010;84:8021-32.
15. Padmakumar B, Jayan JB, Menon RMR, Krishnankutty
4. Chopra A, Anuradha V, Lagoo-Joshi V, Kunjir V, Salvi S,
B, Payippallil R, Nisha RS. Comparative evaluation of
Saluja M. Chikungunya virus aches and pains: an emerging
four therapeutic regimes in chikungunya arthritis: a
challenge. Arthritis Rheum. 2008;58:2921-2. prospective randomized parallel-group study. Indian Journal
5. Manimunda SP, Vijayachari P, Uppoor R. Clinical progression of Rheumatology. 2009;4;94-101.
of chikungunya fever during acute and chronic arthritic 16. Pandya S. Methotrexate and hydroxychloroquine
stages and the changes in joint morphology as revealed by combination therapy in chronic chikungunya arthritis: a 16
imaging. Trans R Soc Trop Med Hyg. 2010;104:392-9. week study. Indian Journal of Rheumatology. 2008;3:93-97.
6. Ganu MA, Ganu AS. Post-chikungunya chronic arthritis-our 17. Chopra A, Saluja M, Venugopalan A. Effectiveness of
experience with DMARDs over two year follow-up. J Assoc chloroquine and inflammatory cytokine response in
Physicians India. 2011;59:83-86. patients with early persistent musculoskeletal pain and
7. Narsimulu G, Parbhu GD. N Post-chikungunya chronic arthritis following chikungunya virus infection. Arthritis
arthritis . J Assoc Physicians India. 2011;59:81. Rheumatol. 2014;66:319-26.
8. Bouquillard E, Combe B. A report of 21 cases of rheumatoid 18. Akahata, W. A virus-like particle vaccine for epidemic
arthritis following Chikungunya fever. A mean follow-up of chikungunya virus protects nonhuman primates against
two years. Ann Rheum Dis. 2009;68:1505-6. infection. Nature Med. 2010;16:334-8.
CHAPTER
139
Clinical Approach to a Patient with Vasculitis
N Subramanian
TABLE 1: Frequency distribution of vasculitic disorders in India Nodular lesions may occur in small vessel vasculitis
(N=1064)*
and livedo reticularis in medium vessel vasculitis. Most
Disease No. Percentage
common type of vasculitis of all times although less
Aortoarteritis 215 20.20 reported.
Giant cell arteritis 35 3.36
Polyarteritis nodosa (PAN) 94 8.83
Small vessel ANCA vasculitis: Common features include
Cutaneous PAN 13 1.22
recurrent sinusitis, cough and breathlessness, rash
Wegener’s granulomatosis 147 13.81
and hematuria apart from systemic features and also
myocardial infarction in eosinophilic granulomatosis.
Microscopic polyangiitis 42 3.94
Churg-Strauss syndrome 19 1.78
Medium Vessel Vasculitis
Henoch-Schönlein purpura 232 21.80
Patients may present with abdominal pain, bloody
Small vessel vasculitis 61 5.73
diarrhea, rash and chest pain, testicular pain, myalgia
Behçet’s disease 145 13.62
and weakness, mononeuritis multiplex.
Kawasaki disease 05 0.46
Undiagnosed 50 4.69 Large Vessel Vasculitis
Others** 6 0.56
Patients come to the consultation with headache, visual
*Based on data from Bangalore, Baroda, Chandigarh, Chennai, Delhi,
loss, absent upper limb pulses and syncope. Stroke
Hyderabad, Kolkata, Lucknow and Mumbai.
**Cogan, Bazins, CNS vasculitis and cerebral bleed in a young patient should raise the
Reproduced from VR Joshi, JAPI 2006. concern about vascultis. Takayasu arteritis may manifest
with absent pulse, claudication pain, and sometimes
Cutaneous Vasculitis gangrene. Giant cell arteritis most commonly presents
Palpable purpuric rash 1 to 3 mm size is the most with headache in temporal region, jaw claudication and
common manifestation and may coalesce and ulcerate. headache.
CHAPTER 139: Clinical Approach to a Patient with Vasculitis 827
Drugs that can cause vasculitis are innumerable but A proof of concept study identified a potential new
common ones include NSAIDs, allopurinol, betalactam use of optical coherence tomography (OCT) to image the
antibiotics, diuretics, diltiazem, ACE inhibitors, and temporal artery but warrants further investigation in the
cocaine. field of large vessel vasculitis.
Infections often coexist with vasculitis like hepatitis
B and C, human immunodeficiency virus, infective MANAGEMENT
endocarditis, and tuberculosis are important secondary Various guidelines have been proposed in the
causes of vasculitis. management of vasculitis. As there is variability of clinical
practice here, most patients are managed following
INVESTIGATIONS the extrapolation of western guidelines. Principles
Vasculitis presents several diagnostic challenges. of management include correct diagnosis, induction
Patients could present with spectrum of clinical of remission and maintenance regimen followed by
manifestations from isolated skin vasculitis to management of flares and comorbidities.
multisystem disease.
Drugs used for acute vasculitis: Prednisolone (oral/
Several medical diagnosis could mimic the pre
intravenous), cyclophosphamide in organ threatening
sentation of vasculitis.
disease—(renal, gut and cerebral) and tocilizumab
Vasculitis could occur as a primary disease itself.
(interleukin–6 blockers) in Takayasu vasculitis resistant
There are five important clinical questions to ask
to cyclophosphamide.
when faced with a patient with possible vasculitis
Rituximab has been proven to be effective in ANCA
(Suresh et al. Postgrad Med Journal 2006).
vasculitis both in remission induction and maintenance
1. Is this a condition that could mimic the presentation
regimen. Despite the increasing use of RTX as an
of vasculitis?
induction agent in AAVs, we still have few data on patients
2. Is there a secondary underlying cause?
with severe renal disease.
3. What is the extent of vasculitis?
Plasma exchange should be considered for patients
4. How do I confirm the diagnosis of vasculitis?
with AAV and serum creatinine of > 5.0 mg/dL in the
5. What specific type of vasculitis is this?
setting of new or relapsing disease. PEX can also be used
G eneral evaluation : Neutrophilia, eosinophilia, for the treatment of severe diffuse alveolar hemorrhage.
thrombocytosis, raised ESR and CRP. Cyclophosphamide has been used for many decades
for life threatening systemic vasculitis as rescue therapy
Immunology
ANCA levels–C ANCA (PR3) specific for granulo
for steroid sparing immune modulation. Van Daalen
et al. assessed the malignancy risk in patients with AAVs
matosis with polyangitis (GPA),
P A N C A ( M P O ) s p e c i f i c f o r e o s i n o p h i l i c
treated with RTX compared to the general public and
granulomatosis with polyangitis (EGPA). Clinical
value of serial measurements of ANCA titers during TABLE 2: Disease specific organ based imaging
the follow-up of AAV patients is still debatable. ANA Diseases Commonest vessels Imaging
and RF are mostly negative, but false positive can Takayasu arteritis Carotid and aortic CT angiography
occur. arch (Fig. 2)
Giant cell arteritis Temporal artery MR angiography
Specific Tests (Table 2) ANCA vasculitis Pulmonary and renal CT thorax (Fig. 3)
Tissue biopsy (skin biopsy, nasal mucosal biopsy, biopsy Polyarteritis Celiac vessels CT angio-abdomen
from lung, renal biopsy and sometimes brain biopsy) nodosa
showing necrotic tissue and granulomatous neutrophilic Retinal vasculitis Retinal vessels CT angio-brain and
infiltration. eyes
828 SECTION 13: Rheumatology
Fig. 2: CT angiography showing left subclavian stenosis Fig. 3: CT thorax showing nodules and infiltrates due to pulmonary
hemorrhage in a patient with GPA
to CYC-treated patients and it was lower in RTX-treated Infection may be masking the acute presentation as
patients than in those treated with CYC. with any autoimmune diseases.
Tocilizumab has been effective in Takayasu’s ANCA remains an important tool in diagnosing small
arteritis both in severe disease and also in systemic vessel vasculitis.
vasculitis. Mepolizumab, an IL-5 antagonist, has shown Aggressive early induction therapy and sustained
encouraging results in preliminary studies (82–84) and is maintenance of remission is the key.
currently under investigation in patients with relapsing
and refractory EGPA. CONCLUSION
Vasculitis may be an enigma in emergency setting.
Maintenance drugs: Methotrexate, azathioprine and
Systemic vasculitis is a multisystem disease with
mycophenolate have been proven to be effective in
significant mortality and appropriate management with
disease maintenance regimen and they need to be
the help of specialists would improve the outcome in the
monitored regularly.
long-term.
Recent Indian studies report that relapse occurred in
14/54 (26%) patients after a mean duration of 21 months.
Patients with primary systemic vasculitis should continue
BIBLIOGRAPHY
1. Bambery P, Sakhuja V, Bhusnurmath SR, Jindal SK,
maintenance therapy for 24 months after achieving
Deodhar SD, Chugh KS. Wegener’s granulomatosis: clinical
successful disease remission. Patients who remain ANCA experience with eighteen cases. J Assoc Physicians India.
positive should continue immunosuppression for up to 1992;40:597-600.
5 years. 2. Charles P, Neel A, Tieulie N, Hot A, Pugnet G, Decaux O, et
al. Rituximab for induction and maintenance treatment of
PRACTICAL POINTS ANCA-associated vasculitides: a multicentre retrospective
study on 80 patients. Rheumatology (Oxford, England)
Patient who present with unexplained fever, rash, 2014;53:532-9.
tiredness, leg edema and any systemic organ signs like 3. Jennette JC, et al. Revised International Chapel Hill Consensus
breathlessness, hematoproteinuria, epistaxis should Conference Nomenclature of Vasculitides. Arthritis &
raise the suspicion of vasculitis. Drugs and infections are Rheumatism. 2012;65:1-11, doi: 10.1002/37715.
common causes to exclude before concluding as primary 4. Joshi VR, G Mittal. Vasculitis–Indian perspective. J Assoc
Physicians India. 2006;54(Suppl):12-14.
systemic vasculitis.
CHAPTER 139: Clinical Approach to a Patient with Vasculitis 829
5. Mohammad AJ, Hot A, Arndt F, et al. Rituximab for the 7. Suresh E. Diagnostic approach to patients with suspected
treatment of eosinophilic granulomatosis with polyangiitis vasculitis. Postgrad Med J. 2006;82:483-8. doi: 10.1136/
(Churg-Strauss). Ann Rheum Dis. 2016;75:396-401. pgmj.2005.042648.
6. Nagaraj S, Joshi P, Sharma V, et al. Anca-associated 8. Yates M, et al. Ann Rheum Dis. 2016;75:1583-94.
vasculitis: A retrospective study from western India. Annals doi:10.1136/annrheumdis-2016-209133.
of the Rheumatic Diseases. 2013;71:232.
CHAPTER
140
Osteoporosis Screening,
Prevention, and Treatment
Tanu Shweta Pandey
Osteoporosis is a crippling metabolic bone disorder Mortality higher in men because they are less likely to
characterized by compromised bone strength and receive treatment due to under diagnosis.
skeletal fragility predisposing a person to an increased Osteoporosis has two defining characteristics: (a)
risk of pathological fracture due to low bone mass. It is low bone mass with bone loss but normal mineralization
one of the leading causes of morbidity and mortality and (b) microarchitectural disruption which causes
in elderly men and women. A woman’s chances of fewer, thinner bony spicules resulting in structural
suffering from osteoporosis related fracture is greater weakness. This provides less support and leads to
than the risk of cervical, uterine and breast cancer pathological fractures. There are three types of bone cells
combined. The lifetime risk for women is 40% and for that have different functionalities. Osteoblasts cause
men is 13%. Fractures of the hip and vertebrae are the bone formation. Osteoclasts are responsible for bone
resorption. Osteocytes provide structure and support.
most common and associated with increased mortality
The basic mechanism of osteoporosis is that there is
of 20%. A pathological fracture is defined as one that
more bone resorption as compared to bone formation.
occurs with minimal trauma like a fall from less than
Both processes occur in osteoporosis. “High turnover”
the height of the person. These fractures in osteoporosis
osteoporosis has predominantly increased resorption.
are associated with increased morbidity and mortality
“Low turnover” osteoporosis has predominantly
including poor quality of life, chronic pain, disability, loss
decreased formation. Both can occur in the course of the
of independence, and death. disease.
It is a major public health threat for men and women
above 50 years of age. Globally millions of people have OSTEOPENIA
osteoporosis. In the US alone 12 million men and women Osteopenia is a condition that precedes osteoporosis.
were estimated to have osteoporosis in the year 2012. There is low bone density without having bone loss.
Fifty percent of postmenopausal women are anticipated In the US, almost 35 million people have osteopenia.
to have an osteoporosis-related fracture during their There are many secondary causes of osteopenia
lifetime. In the latest statistics, 25% of women and 5% besides osteoporosis, including hyperparathyroidism,
of men above the age of 65 have osteoporosis. In India, prolonged steroid therapy, chemotherapy or radiation,
a conservative estimate is that 46 million women have osteomalacia, malnutritional states, lack of sunlight, and
osteoporosis–about 20% of all women above age 50. multiple myeloma.
CHAPTER 140: Osteoporosis Screening, Prevention, and Treatment 831
Role of Estrogen for measuring bone mass and measures bone mineral
Estrogen inhibits bone resorption and promotes the density in the lumbar spine and hip. It is a reliable,
deposition of bone matrix by causing calcium and safe, cost-effective, widely available, noninvasive way to
phosphate retention. Postmenopausal women have assess the risk of fractures in postmenopausal women.
low estrogen level and increased bone resorption and Measurement of osteoporosis is done using the T-score.
bone loss. Evidence that women above the age of 70 who It is the number of standard deviations of the bone-
continue to produce small amounts of estradiol have mineral-density measurement above or below the
lower risk of fractures than those who do not. young-normal mean bone density as per WHO.
Normal range is more that -1 standard deviation
Vertebral fractures are the most common type of
T-score of -2.5 SD or below is osteoporosis
pathological fractures in osteoporosis. There are three
T-score of -1.0 to -2.5 SD is osteopenia
types-wedge, compression, and biconcave (or codfish
Severe osteoporosis is a T-score of -2.5 Sd or less with
(or fish)) fractures. Dowager’s hump occurs in elderly
women due to progressive kyphosis resulting from a pathological fracture
multiple compression fractures of the vertebrae. Each At the spine, a T-score of -1 represents about 10% bone
High alcohol intake > 2 drinks per day (1–2 drinks —— At age 65 is 20%
risk is equal to or greater than that of a 65-year-old white Are there Any Labs Needed?
woman with no additional risk factors. Current evidence Serum calcium, phosphate, and a metabolic panel
is insufficient to assess the balance of benefits and harms TSH
of screening for osteoporosis in men. The National 25-hydroxyvitamin D
Osteoporosis Foundation recommends screening in all Biochemical markers of bone turnover like
men above 70 years of age. procollagen not indicated
Bone biopsy rarely indicated:
How to Calculate Risk —— Unusual skeletal lesions
calculated by using the FRAX tool. It is a questionnaire —— Young patients with severe osteoporosis and no
available online that collect data of an individual and obvious secondary cause
calculates their risk. According to FRAX, a 65-year-old
white woman with no other risk factors has a 10-year Treatment of Osteoporosis
fracture risk of 9.3%. The goal of treatment is to reduce mortality and
morbidity from pathological fractures which decreases
Why is Screening Important? cost of medical care. Overall, less than 20% patients with
Scientific evidence shows that the rate of fractures is pathological fractures get treatment for osteoporosis.
high in women >65 with osteoporosis. Clinical trials Treatment is three pronged and includes lifestyle
show decrease in fracture incidence with treatment of modifications, pharmacologic therapy, and treatment
osteoporosis. Screening and treatment cause reduction of pathological fractures. Lifestyle modifications include
in morbidity and mortality as well as cost of healthcare. smoking cessation, regular weight-bearing exercise,
no more than two alcoholic drinks a day, and calcium
(1200–1500 mg daily) and vitamin D (400–800 units
Absolute Indications for Screening
daily) supplementation. Prior to starting pharmacologic
Pathological fracture
treatment serum vitamin D level should be normalized.
Loss of height >2 cm
Pharmacologic treatment includes:
Drugs like long-term steroids–prednisone >5 mg
Antiresorptive therapy: Reduces bone turnover by
daily for >6 months
decreasing bone resorption
Secondary causes: —— Bisphosphonates
—— Hyperparathyroidism
—— Selective estrogen receptor modulators (SERMs)
—— Hyperthyroidism
—— Estrogens
—— Cushing’s syndrome
—— Calcitonin
—— Hypogonadism
Anabolic therapy: Rebuilds skeletal losses by sti
Due to side effects and long-term therapy compliance is and cardiac events and it is to be used if other therapies
suboptimal. Esophagitis is common and it must be taken are contraindicated or not tolerated.
on empty stomach in the morning and stay upright for
30–60 mins. Rarely osteonecrosis of the jaw can occur Calcitonin
and good dental hygiene is important. Daily, weekly, This works by inhibiting osteoclast activity and thus
monthly and yearly regimens are available as below: reducing vertebral fracture incidence. Only used
Alendronate (Fosamax) - 5–20 mg/day or 35–70 mg/ for pain from spine fractures and not used routinely
wk for osteoporosis treatment. Available as nasal or
Risedronate (Actonel) - 5 mg/day or 35 mg/wk subcutaneous 200 IU.
Ibandronate (Boniva) - 150 mg/month
Currently, following are taken absolute contraindications Patient has no obvious risk for premature death due
Pre-existing conditions do not deteriorate following thallium imaging, stress echocardiography or coronary
transplantation angiography according to local practices and protocol.
Minimal surgery related complications. Patient with a abnormal cardiac test should be further
investigated and treated preferably before RT is done.
Age Other issues, which are important from a point of view
At any age transplantation can be done, however co- of cardiovascular risks, are:
Routine examination of the iliac vessels is not
morbidity related to age can be a limiting factor. There
is disparity between the supply of donor organs and necessary. If there is a history of claudication or
need for RT in India. Therefore, patient >65 years are when physical examination reveals signs of arterial
discouraged to get cadaver renal transplant. insufficiency, non-invasive vascular studies can help
to select patients in whom angiography is indicated.
Preferably should have Matching Blood In patients with a history of transient ischemic
Should have Acceptable Viral Status Recipient is evaluated to assess that recipient should not
All prospective transplant recipients should be tested have pre-existing antibodies which can reject new kidney
pre-existing viral infections including: and for long-term graft outcome, there should be better
CMV
HLA matching between recipient and donor.
HLA matching for A, B and DR antigen
Epstein-Barr virus (EBV)
Panel reactive antibodies (PRA)
HBV
Cross match test with various methods
HCV
—— CDC (complement dependent cytotoxicity)
Varicella Zoster virus (VZV)
—— Flow crossmatch
Human immunodeficiency virus (HIV).
—— Crossmatch based on luminex platform
Immunization should be given to all hepatitis B (if not
already immunized) and VZV antibody negative patients
Should be Economically Viable
before transplantation. Patients otherwise suitable for
renal transplantation with evidence of chronic hepatitis B
for Transplant Expanses
and/or C or HIV infection should be managed according Transplant is a costly treatment and everybody will not be
to their own merit. It is recommended that the potential able to afford it. In addition to initial cost of surgery, there
RT recipient should have molecular tests, fibroscan is life-long cost of maintenance immunosuppression
(MIS) as well as lifelong cost of investigation and follow-
with or without liver biopsy to assess liver damage and
up. Major cost on follow-up is of MIS medication and
consideration of treatment before transplantation.
it varies depending upon the type of MIS used. On an
EBV negative recipients of an EBV positive donor has a
average, long-term cost is Rs. 12000-15000/ per month.
seven-fold increased risk of post-RT lymphoproliferative
disorder (PTLD). Recipient CMV status at transplantation
DONOR EVALUATION
will be useful to guide antiviral prophylactic strategies.
Renal transplant donors are of following broad category:
The advent of highly active antiviral therapy for HIV has
changed the prognosis of HIV, and recent experience
Living Donor
suggests similar graft and patient survival rates between
Living near relatives
HIV-positive and negative renal transplant recipients.
Living other than near relative
Should have Acceptable Lower Urinary
Deceased Donor (Cadaver Donor)
Tract According to Transplant Human Organ Act (THOA),
Ureter of donor kidney is anastomosed with the recipient near relation includes parents, grandparents, children,
bladder. So, recipient lower urinary tract should be grandchildren, sibling and spouse. Any relation other
normal. It is mostly assessed by than these are included as “other than near relative” and
X-ray [kidney, ureter and bladder (KUB)]
they have to go through a process of clearance from the
Ultrasound abdomen
authorization committee, which include government
Micturating cystourethrogram (MCU)
and non-government members.
Any abnormality should be managed before RT on its In this document, I will restrict to primarily living
own merit. donor evaluation. Donor evaluation should be keeping
following principles in mind:
Should be Immunologically Should be an adult with donation being voluntary
Recipient get a kidney from other person and being Donor should not have any transmissible infection/
Donor should have two normal and equally assess these infections, following tests are usually done
functioning kidneys in prospective donor:
Donor should have acceptable anatomy of vessels HBsAg
HIV
Donor should be an adult, > 18 years old. There is no These infections if found, need to be treated and
clear cut upper age limit of the donor. It is renal function donor needs to be declared free from infection before he/
of donor rather than chronological age which is more she can donate the organ. In case of CMV positive donor,
important. Donor with age of 70–75 years have also been depending upon recipient status, CMV prophylaxis is
taken who otherwise are normal in term of renal function used.
and other systemic function.
Donation should be voluntary. There should not Donor should have Two Normal and
be any pressure on the donor. Therefore, a psychiatry Equally Functioning Kidneys
evaluation of all potential donor for RT is must. Donor As donor is giving one kidney to recipient, he/she must
must be able to understand the issues and risk involved have two normal and equally functioning kidneys, so
in the process of donation and should be able to make an that one good functioning kidney goes into recipient and
informed decision. equally good functioning kidney is left in donor so as to
keep donor life free from risk in future while donating
There should not be a Major Systemic one kidney. For assessing this, following tests are done:
Illness Routine complete urine examination
Living donor should not have any major systemic illness, Urine protein/creatinine ratio
which can put him at extra-risk of general anesthesia, to 24 hour urine test for protein
he should not have any illness which later affect the US abdomen
remaining single kidney to extra-risk for deterioration Glomerular filtration rate and percentage distribution
after donation of one kidney. For evaluation of systemic of GFR in both kidneys.
illness following tests are done: In above investigations, there should not be any
Complete hemogram evidence of kidney disease. In Indian context, a GFR of
Complete biochemistry 70 mL is acceptable for donation of kidney. Of the 70 mL,
Blood sugar, HbA1c, (GTT if required) nearly 50% each should be distributed in both kidneys.
X-ray chest If there is difference in GFR of two kidneys, better is left
EKG (Echocardiography in selected cases) in the donor and marginal kidney is transplanted in the
Gynecologic evaluation in female donor recipient.
Donor should not have any Transmissible Donor should have Acceptable
Infection/Disease Anatomy of Vessels and Ureter
Donor should not have any infection or disease, which Donor renal artery and veins are anastomosed into
can be transmitted through donation of organ. There are recipient’s pelvic vessels and ureter is anastomosed into
some infections, which can be transmitted from donor recipient bladder. For evaluating donor renal vessels
to recipient through the process of organ donation. To and drainage system, currently CT-angiography is being
CHAPTER 141: Recipient and Donor Selection for Renal Transplantation in India: Current Status 841
Simple cyst
cyclophosphamide, mycophenolate mofetil (MMF) and Steroid dependent NS Two consecutive relapses while
(SDNS) receiving prednisolone on tapering
calcineurin inhibitors (CNI). The various terminologies (post initial response), or within 15
used for disease characterization and response to days of its discontinuation
treatment are given in Table 1. Steroid resistant NS Lack of remission despite 16 weeks of
In the last few years, rituximab (RTX) has been used (SRNS) therapy with daily prednisolone (1mg/
kg/d)
to treat several of the glomerular diseases. Rituximab
CNI dependent NS Remission of SDNS is achieved during
is a monoclonal antibody of mixed nature (human
treatment with CNIs (tacrolimus or
and murine). It binds specifically to the CD20 receptor cyclosporin)
present on both the mature and pre B cells. However, this CNI resistant NS No response to therapy CNI therapy for
receptor is absent on plasma cells. Binding of RTX to the 3–6 months
receptor leads to depletion of B lymphocytes through
three mechanisms namely antibody-dependent cellular available evidence are from retrospective observational
cytotoxicity, complement-dependent cytotoxicity, and studies, but lately some of the data are from high quality
induction of apoptosis. Rituximab is FDA approved in controlled trials at least in some specific glomerular
nonhodgkins lymphoma, chronic lymphatic leukemia, diseases. Dosing regimens used in clinical studies
vasculitis and rheumatoid arthritis. Now, it has been (weekly 375 mg/m2 for four weeks or fortnightly 1 gm two
proposed as a promising option for glomerular diseases. doses) found no difference in efficacy or adverse effects.
This article gives a brief review on the efficacy and safety It is prudent to dose according to CD-19 levels after the
of rituximab in glomerular diseases. Much of the earlier first dose to cut down exposure and costs.
CHAPTER 142: Rituximab: Panacea of Glomerular Diseases 843
with co-trimoxazole is recommended. Data from SLE follow-up. J Am Soc Nephrol. 2016;28. doi: 10.1681/
patients show increased herpes zoster reactivation. ASN.2016040449.
3. Geetha D, Specks U, Stone JH, et al. Rituximab versus
Other rare but notable side effects being progressive
cyclophosphamide for ANCA-associated vasculitis. N Engl J
multifocal leukoencephalopathy and RTX- associated Med. 2010;363:221-32.
lung injury. 4. Hassan RI, Gaffo AL. Rituximab in ANCA-associated
vasculitis. Curr Rheumatol Rep. 2017;19:6.
5. Jayne D, Rasmussen N, Andrassy K, et al. A randomized
CONCLUSION trial of maintenance therapy for vasculitis associated with
Rituximab induces and maintains remission in steroid- antineutrophil cytoplasmic autoantibodies. N Engl J Med.
dependent nephrotic syndrome. This helps in reducing 2003;349:36-44.
the total dosage of steroids and discontinuation 6. Jones RB, Cohen Tervaert JW, Hauser T, et al. Rituximab
of CNIs. However, in steroid-resistant NS patients, versus cyclophosphamide in ANCA-associated renal
vasculitis. N Engl J Med. 2010;363:211-20.
who also fail CNI therapy, response to rituximab is
7. Mallat SG, Itani HS, Abou-Mrad RM, et al. Rituximab use
less promising. Rituximab may be useful in cases of in adult primary glomerulopathy: Therapeutics and Clinical
resistant lupus nephritis. The role of rituximab in AAV Risk Management. 2016;12:1317-27.
(induction, maintenance) has been established. Its role 8. Rovin BH, Furie R, Latinis K, et al. Efficacy and safety
in membrano-proliferative glomerulonephritis and IgAN of rituximab in patients with active proliferative lupus
needs to be clarified in further studies. nephritis: The Lupus Nephritis Assessment with Rituximab
study. Arthritis Rheum 2012;64:1215-26.
9. Segarra Medrano A, Romero Jaller K. The current evidence
BIBLIOGRAPHY supporting rituximab treatment in primary glomerular
1. Cravedi P. Rituximab in Membranous Nephropathy: Not All diseases causing nephrotic syndrome:. Critical review OA
Studies Are Created Equal. nephron Clinical practice 2016; Nephrology. 2013;1(1):1-11.
135:46-50. 10. Sinha A, Bagga A. Rituximab therapy in nephrotic syndrome:
2. Dahan K, Debiec H, Plaisier E, et al. Rituximab for severe Implications for patient management. Nat Rev Nephrol.
membranous nephropathy: A 6-month trial with extended 2013;9:154-69.
CHAPTER
143
ABO-Incompatible Kidney Transplantation
Dinesh Khullar, Sagar Gupta
ABO ANTIGENS AND BLOOD GROUPS in peritubular capillaries. By end of second post-
The discovery of ABO system for blood grouping is operative week, accommodation is established and
credited to the Austrian scientist Karl Landsteiner. It exposure to anti-A/B antibodies even at higher titres
is based on the expression of genetically determined causes no harm.
A, B and H blood group antigens. These antigens are
expressed on the surface of a variety of different cell TECHNIQUES OF DESENSITIZATION
types like red blood cells, endothelial cells and kidney Reduction of pretransplant anti-A/B antibody titres
parenchymal cells including the endothelial cells, tubuli below a permissive threshold is the major principle
and glomeruli. Blood group AB individuals are universal of desensitization. Titer thresholds at which one
recipients as they express A and B antigens with no can anticipate damage to the allograft from anti-
A/B antibodies are not clearly established. There is
significant anti-A or anti-B antibodies. People with blood
considerable variation in desensitization protocols
group A have anti-B antibodies while people with blood
across different transplant centers. The goal is to remove
group B have anti-a antibodies. O is the universal donor
as much antibodies as possible and bring anti-A/B
as they do not express the A or B antigens. The Rh factor
IgG antibody titers below 1:8, preferably less than 1:4.
status (positive or negative) is generally not taken into
Desensitization protocols are based on a multi-pronged
clinical consideration in KT because of its insignificant
approach targeting different pathways of the immune
expression on renal parenchymal cells.
system.
Antibody removal to reduce anti-A/B antibody
PATHOGENESIS
levels to empirically defined target titers is done
The presence of preformed iso-hemagglutinins
by pretransplantation apheresis, double-filtration
(antibodies with the intrinsic ability to agglutinate
plasmapheresis or membrane filtration. Number
erythrocytes) that react to non-self ABO antigens is
of sessions needed depends on various factors like
the critical immunological barrier to ABOi KT. This
starting titer values, goal titers, dose of plasmapheresis
natural immunity emerges in early infancy (3–6 month
prescribed, patient weight, hematocrit, etc. A caveat of
of age). It increases in strength until the age of 10–12 plasmapheresis is the elimination of essential plasma
years and then persists throughout life. Natural anti-A/B components, such as albumin and coagulation factors,
antibodies consist of IgM, IgG and IgA classes, with a which limits the volumes of plasma that can be processed
predominance of IgG1 and IgG2 subclasses. Anti-A/B and frequently necessitates plasma substitution.
IgG is generally thought to be complement fixing and In countries like USA where FDA (Food and Drug
of primary pathogenic importance. If recipients are Administration) has not approved immunoadsorption
not appropriately desensitized, preformed anti-A/B techniques, plasmapheresis is the only available method
antibodies activate the complement system and cause for antibody depletion.
severe antibody mediated rejection. In the worst cases, Many desensitization protocols in Europe incorporate
hyperacute rejection leading to immediate renal allograft the technique of immunoadsorption (IA). Single use,
loss occurs. low-molecular weight carbohydrate columns with
immobilized blood-group A or B antigens linked to a
ACCOMMODATION sepharose matrix are used. When patient’s plasma is run
One of the key phenomenon playing a critical role in against them, these columns specifically deplete anti-A or
the success of ABOi-KT is accommodation. Controlled anti-B antibodies. IA columns are routinely used in India.
exposure of antigens in the kidney allograft to anti-A/B In certain patients with very high anti-A/B antibody
antibodies in the early post-operative period results in a titers, we use both IA columns and plasmapheresis to
phenotype exhibiting accommodation. The histological achieve goal reduction in anti-A/B antibody levels. Serial
manifestation of this on kidney biopsy is C4d deposition anti-A/B antibody monitoring is performed before and
848 SECTION 14: Nephrology
during desensitization to guide the intensity of recipient might contain substantial levels of anti-A/B blood group
preconditioning. antibodies which can have a potentially deleterious
Intravenous immunoglobulins (IVIgs) can also be effect. Hence, PRBC transfusions need to be of the
used to modulate the recipient’s immune system and recipient blood type and fresh frozen plasma of AB or
prevent anti-A/B antibody rebound in the early post- donor blood group.
operative period. IVIg may also help to decrease the rates Higher rates of infectious complications like
of infections by substituting immunoglobulins removed pneumonia, wound infection, urinary tract infection and
during plasmapheresis. pyelonephritis have been reported in various studies.
Depletion of B lymphocytes was previously achieved Cytomegalovirus (CMV), herpes simplex and BK viremia
by splenectomy. Considering the risks associated infections are also slightly more common. This can be
with a major surgical procedure and increased rates attributed to the more intensive immunosuppression
of infectious complications, splenectomy gradually used in ABOi-KT. Although speculated to be higher,
gave way to the use of anti-CD20 antibody Rituximab. actual rates of malignancies reported are comparable to
It is administered 2–4 weeks in advance of transplant ABO compatible transplants.
surgery. The dose of Rituximab used was higher in
the past, ranging from 500 mg to 1 gm. Lower doses of CONCLUSION
200 mg are increasingly being studied and are found Owing to the development of effective strategies for
to have non-inferior outcomes. We utilize a single low recipient desensitization, ABOi transplantation has
dose of 200 mg or 100 mg of Rituximab at our transplant become a routinely accepted treatment option with
center (administered 2 weeks preoperatively) and have favorable outcomes. By this approach, about 30% of
observed similar graft outcomes with lesser infections living donors who were rejected in the past due to ABO
complications. incompatibility can now donate their kidneys thereby
Interaction of anti-A/B antibodies with the allograft significantly expanding the living donor pool. Allograft
endothelium results in activation of the complement survival and patient survival rates are comparable to
cascade. Patients are started on a CNI (calceneurin ABO compatible transplantations.
inhibitor like tacrolimus or cyclosporine) and an anti-
metabolite (more commonly mycophenolate than BIBLIOGRAPHY
azathioprine) 7–14 days in advance of the procedure to 1. Christian Morath, Martin Zeier, Bernd Döhler, Gerhard Opelz,
Caner Süsal. ABO-incompatible Kidney Transplantation; Front.
minimize this. Immunol. 8:234
Induction immunosuppressive therapy comprises 2. Gabriel M. Danovitch. Handbook of Kidney Transplantation; 6th
of high dose intravenous corticosteroids and a T-cell edition; Wolters Kluwers; 2017.
depleting agent like anti-thymocyte globulin (ATG) or 3. Georg A. Böhmig, Andreas M. Farkas, Farsad Eskandary,
Thomas Wekerle. Strategies to overcome the ABO barrier in
rarely alemtuzumab. IL-2 receptor blocker antibody
kidney transplantation, Nature Reviews Nephrology. 2015;11:
Basiliximab (Simulect) may also be used. 732-47.
4. Gerold Thölking, Raphael Koch, Hermann Pavenstädt,
COMPLICATIONS Katharina Schuette-Nuetgen, Veit Busch, Heiner Wolters, et al.
Antigen-specific versus non-antigen-specific immunoadsorption
There is increased risk of bleeding complications,
in ABO-incompatible renal transplantation; PLoS ONE 10(6):
particularly in patients who underwent splenectomy e0131465. doi:10.1371/journal.pone.0131465.
in the past. Removal of coagulation factors during 5. Juhan Lee, Jae Geun Lee, Sinyoung Kim, Seung Hwan Song,
plasmapheresis or membrane filtration is a major Beom Seok Kim, Hyun Ok Kim, et al. The effect of rituximab
contributing factor in the current era. An important dose on infectious complications in ABO-incompatible kidney
transplantation; Nephrol Dial Transplant. 2016;31:1013-21.
consideration for the perioperative blood product
6. Milljae Shin, Sung-Joo Kim. ABO Incompatible Kidney
transfusions is that various blood products, such as Transplantation—Current Status and Uncertainties. Journal of
plasma preparations or platelet and RBC concentrates Transplantation; Volume. 2011; Article ID 970421.
CHAPTER
144
Prevention and Management of
Diabetic Kidney Disease
Pritam Gupta, Rajesh Aggarwal, Blessy Sehgal
Diabetes mellitus (DM) is an increasing global public 25 years versus the historical prevalence of 40%. In
health problem. It is the leading cause of CKD and ESRD Asia, higher mortality from DM is more prominent in
in the world accounting for more than 40% ESRD patients. patients age 50–60 years which translates to a reduction
According to the International Diabetes Federation, the in life expectancy of more than a decade. About 50%
number of people with Diabetes worldwide is projected of the ESRD patients have DM. Among this group of
to increase from 382 million in 2013 to 592 million by ESRD with DM, only 60% have diabetic nephropathy
2035, i.e. 10% of whole world population. The rise of DM i.e. normal sized kidneys, proteinuria >1 g with or
and metabolic syndrome is very dramatic in India and without retinopathy, 13% have ischemic nephropathy
because of this India has the dubious distinction of being (i.e. smaller kidney size and modest or no proteinuria).
labeled as “Diabetes capital of the world”. Apart from overt 27% have primary renal disease, i.e. IgA nephropathy,
DM in Indian elderly a phenomenon seen worldwide, membranous, FSGS, analgesic nephropathy, chronic
the concern in India is increasing overt DM, prediabetes interstitial nephritis, SLE, Multiple myeloma, etc.
and obesity in the young. Indian because of genetics
and lifestyle are not only more prone to develop DM but SPECTRUM OF RENAL INVOLVEMENT
also diabetic nephropathy (DN) which progresses faster. IN DIABETES MELLITUS (TYPE 2)
Indian diabetics have higher waist circumference despite Only 60% of Diabetic Kidney Disease (DKD) due to
lower BMI have pronounced insulin resistance, lower
Type 2 DM have retinopathy where as 95% patients of
adiponectin and higher inflammatory markers which
DKD due to Type I DM have retinopathy
leads to more DM and DN. Crux of the problem is lifestyle
causing visceral obesity which in turn causes increased
Only 30–40% of type I and type 2 diabetic develop
insulin resistance and metabolic syndrome. 30–40% of nephropathy.
DM develop diabetic nephropathy (DN). It is 40% more
in Asian Diabetics as compared to Caucasians. Since RISK FACTORS FOR THE DEVELOPMENT
the increased longevity of diabetic patients worldwide OF DIABETIC NEPHROPATHY
due to decreased cardiovascular mortality nowadays
Albuminuria/Proteinuria
prevalence of DN is increasing and more diabetics are
developing ESRD. In western world, prevalence of ESRD
(Microalbuminuria and Macroalbuminuria)
due to DM has stabilized because of good glycemic Proteinuria is a powerful predictor of CVS events, of
control (HbA 1C<7%), blood pressure, weight control, progressive loss of GFR and all cause mortality (20–
lifestyle changes. Studies suggest in Type I DM, good 200 times) as compared to DM without proteinuria
glycemic control of 7%, only 9% will develop ESRD after (Tables 1 to 3).
850 SECTION 14: Nephrology
zz Microalbuminuria 30–299 mg/24 hrs 2% 2.8% in urban citizens with diabetes in “Chennai
zz Macroalbuminuria >300 mg/24 hrs 3.5% 2.3% urban rural epidemiology” study and overt
zz Raised creatinine 19.2% nephropathy is 2.2%.
CHAPTER 144: Prevention and Management of Diabetic Kidney Disease 851
patient can either revert back to normoalbuminuria —— Mesangial expansion and nodules
In accord, advance studies, intensive glycemic decreasing progression of renal failure and it is not
control in T2 DM did not decrease CVS events but it just control of blood pressure.
increased risk of hypoglycemia. No role in primary prevention, i.e. in normotensive
Evidence of benefit from HbA 1C is better for normoalbuminuric.
microvascular end point than macrovascular end ACE/ARB inhibitors are first line antihypertensive
point. agents for control of proteinuric diabetic patients
with or without hypertension.
WHAT IS OPTIMAL TARGET HBA1C? For antiproteinuric effect of ACE/ARB inhibitors we
It should be individualized.
can give higher dose of ACE/ARB inhibitors even if
Recently diagnosed diabetic with no complication
BP is controlled.
strict glycemic control HbA1C <7%, no weight gain and
Unfortunately, monotherapy is usually insufficient to
avoid hypoglycemia.
achieve target blood pressure.
Patients with long standing diabetes and known
CVS/CKD stage IV–V > 7%–< 8%.
Escape or nonresponsive to conventional doses of
RAS blocked.
BLOOD PRESSURE CONTROL Add hydrochlorothalidone
In type I DM, microalbuminuria precedes hyper Decrease salt intake to 4–5 gms/day to get ARB/ACE
tension. inhibitor effect. Check 24 hours urinary sodium to
In type 2 DM, hypertension precedes onset of DM confirm salt intake.
in at least 40% type 2 DM. Hypertensive are 25 times Dose escalation of ACE/ARB
more prone to get DM. Aldosterone escape phenomenon after 6–9 months
Control of blood pressure is single most important of ARB/ACE inhibitors therapy. Aldosterone more
factor to decrease the progression of overt diabetic than before starting ARB. So add spirinolactone. Keep
nephropathy and to decrease cardiovascular watch on potassium.
morbidity and mortality. If still BP is not controlled add nondihydropyridine
Higher BP is associated with increasing albuminuria
calcium channel blocker, i.e. diltiazem.
with more rapid progression and cardiovascular
events and retinopathy.
Other Drugs
JNC VIII and DOQI has recommended a target of
BP of 140/90 mm Hg for all diabetic patients with Aliskiren (Antirenin drug): It decreases proteinuria
nephropathy. BP less than this is associated with but with ARB/ACE inhibitors, it increases nonfatal
more CVS problems. strokes, hypotension, hyperkalemia and renal
24 hrs BP measurement is more useful as high complications so trial was stopped prematurely.
night time BP in type I DM preceded the onset of ARB + ACE inhibitors: This combination is not been
microalbuminuria. used any more as it causes more hyperkalemia
doubling AKI events.
BLOCKADE OF RENIN More renal function decline in some patients and
ANGIOTENSIN SYSTEM possible increase in mortality.
In diabetes, RAS is activated. Several other agents like allopurinol, pentoxyphylline,
Blockade RAS with ACE or ARB reduces proteinuria, doxycycline, paricalcital has been investigated for
progression of renal failure and controls blood delaying progress in DN and have not been found to be
pressure. ARB and ACE inhibitors have class effect in very useful.
CHAPTER 144: Prevention and Management of Diabetic Kidney Disease 853
may be up to 5–6 mg/day in hemodialysis patients. In formulations are equally effective and have similar side
patients with renal anemia, iron absorption capacity is effect profile.
lower particularly due to systemic inflammation and up IV iron preparations include iron dextran, iron
regulated hepcidin which decrease iron absorption from sucrose, iron gluconate and newer preparations like ferric
the gut and enhance iron sequestration in macrophage. carboxymaltose, ferumoxytol, and iron isomaltoside
Because of these factors, oral iron is less effective as 1000. Stability of preparation decides the maximum dose
compared to parenteral iron. However, because of low which can be administered in single dose as 1000 mg
cost and patient convenience a trial of oral iron therapy of iron sucrose may be given in single dose compared
is justified in CKD non dialysis patients for 1–3 months. to iron gluconate which can be given maximum upto
Intravenous (IV) iron should be started if response to oral 125 mg in single dose. Ferric carboxymaltose and iron
therapy is insufficient. IV route of iron administration is isomaltoside may be given up to 1000 mg in single
preferred in CKD 5D and this is supported by evidence administration whereas usual dose of ferumoxytol is
from various RCTs. Intravenous iron administration has 510 mg. There is risk of hypersensitivity reactions with all
shown a greater improvement in Hb level, a lower ESA the IV preparations.
dose or both.
Untreated or inadequately treated iron deficiency ERYTHROPOIESIS STIMULATING
is one of the important causes of hyporesponsiveness AGENTS (ESAs)
to Erythropoiesis Stimulating Agents (ESAs). Iron ESA therapy is an option if there is suboptimal response
status tests should be performed to assess the level of to iron or serum ferritin is ≥100 µg/mL in the absence
iron in tissue stores or the adequacy of iron supply for of inflammation. The KDIGO guidelines recommend
erythropoiesis. Iron status assessment is most commonly use of ESAs in CKD 5D patients when the hemoglobin
done by serum ferritin which indicates storage iron status is between 9.0–10.0 g/dL to prevent the Hb level falling
and by transferrin saturation (TSAT) which measures the below 9 g/dL with the general consideration that ESAs
availability of iron to support erythropoiesis. Percentage are not to be used at Hb level more than 11.5 g/dL. ESA
of hypochromic red cell (PHRC), soluble transferrin therapy should be deferred in CKD patients with Hb
receptors, zinc protoporphyrin and reticulocyte Hb >10 g/dL, however in patients with Hb ≤10 g/dL, therapy
content (CHr) are the other important tests for assessing must be individualized based on fall of Hb, symptoms
iron status. Serum ferritin level <30 ng/mL indicates attributable to anemia, prior response to iron therapy, the
severe iron deficiency. risk associated with blood transfusion and ESA therapy.
The recent KDIGO guidelines suggest a trial of iron Recombinant human erythropoietin (rHuEPO) has
when transferrin saturation (TSAT) is ≤30% and ferritin been a major advancement in treatment of anemia
level is ≤ 500 ng/mL in CKD patients with anaemia who in CKD patients. Before initiation of ESA therapy
are not taking iron supplement and ESA therapy. It is also all correctable causes (including iron deficiency
recommended in patients on ESA therapy in whom an and inflammatory states) should be treated. First
increase in Hb concentration or a decrease in ESA dose generation ESAs include epoetin-alfa and epoetin beta,
is required. Routine use of iron is not advised in patients which have short half-life (6–8 hours after intravenous
with ferritin level >500 ng/mL and TSAT >30% because of administration) and need to administer two to three
risk of iron toxicity. times per week. Darbepoetin alfa is a second generation,
200 mg elemental iron must be provided by oral long acting ESA and it is a supersialylated analogue
iron preparation for effective erythropoiesis. Among all of EPO. Darbepoetin has approximately three times
available oral preparations, commonly used preparation longer half-life than epoetin alfa after intravenous
is ferrous sulphate because of its easy availability and administration. Pegylated derivative of epoetin beta
cheaper cost. Various studies have shown that all iron known as continuous erythropoietin receptor activator
856 SECTION 14: Nephrology
Previous studies have suggested a positive effect of multimodality approach is required including treatment
androgen on renal anemia. The mechanism of action of multiple factors to achieve target Hb. Recognition of
of androgens on erythropoiesis is still not completely various causes by detailed history, clinical examination
understood and proposed mechanisms of action of and investigations contributes to more logical treatment
these drugs include increased erythropoietin production and better survival and quality of life in these patients.
from renal or nonrenal sites, increased sensitivity of
erythroid progenitors to the effects of erythropoietin and BIBLIOGRAPHY
increased red blood cell survival. However, because of 1. Agarwal R. Iron deficiency anemia in chronic kidney disease:
various side effects like acne, virilization, priapism, risk Uncertainties and cautions. Hemodialysis Int. 2017;21:78-
82.
for peliosis hepatis, liver dysfunction and hepatocellular
2. Appel GB, Radhakrishnan J, Agati VD. Secondary glomerular
carcinoma regular use of androgens have lost favor.
disease. In: Skorecki K, Chertow GM, Mardsen PA, Yu ASL,
Although deficiencies of vitamin B 12 and folate are Taal MW, eds. Brenner and Rector′s The Kidney, 10th edn.
important causes of anemia but rarely associated with Elsevier Health-US; 2015.pp.1091-160.
ESAs hyporesponsiveness. There is no concrete evidence 3. BonominiM, Vecchio LD, Sirolli V, Locatelli F. New treatment
to suggest that in the absence of documented deficiency approaches for the anaemia of CKD. Am J Kidney Dis.
2016;67(1):133-42.
of these vitamins they are useful adjuvants in patients on
4. Elliott J, Mishler D, Agarwal R. Hyporesponsiveness to
ESAs therapy. The KDIGO guidelines do not recommend
erythropoietin: Causes and management. Adv Chronic
use of androgen, folic acid, vitamin C, vitamin D, vitamin Kidney Dis. 2009;16:94-100.
E, pentoxifylline and L-carnitine as an adjuvant to ESAs 5. Hsu CY, McCulloch CE, Curhan GC. Epidemiology of
in treatment of anemia of CKD. anaemia associated with chronic renal insufficiency among
adults in the United States: Results from the Third National
OPTION IN FUTURE Health and Nutrition Examination Survey. J Am Soc Nephrol.
2002;13: 504-10.
Continuous research in field of CKD with anemia is
6. Hung SC, Tarng DC. ESA and iron therapy in chronic kidney
going on to develop new molecules with improved disease: a balance between patient safety and haemoglobin
characteristics and/or easier manufacturing processes target. Kidney Int. 2014;86(4):676-8.
than those currently available. All these are currently 7. Jodie L, Babitt, Lin HY. Mechanisms of anaemia in CKD. J
being tested in Phase I to III clinical trials. The Hypoxia Am Soc Nephrol. 2012;23(10):1631-4.
Inducible Factor (HIF) stabilizers (Roxadustat, 8. Kidney Disease: Improving Global Outcomes (KDIGO)
anaemia work group. KDIGO clinical practice guideline
Molidustat) inhibit degradation of HIFα and cause an
for anaemia in chronic kidney disease. Kidney Int.
increase in endogenous EPO production. Activin traps 2012;2(Suppl):279-335.
(Sotatercept, Luspatercept) act by trapping circulating 9. Locatelli F, Bárány P, Covic A, De Francisco A, Del Vecchio
activin and other members of the TGFβ superfamily L, Goldsmith D, et al. Kidney disease: Improving global
which are involved in regulation of erythropoiesis either outcomes guidelines on anaemia management in chronic
by directly affecting erythroid progenitor or precursor kidney disease: a European renal best practice position
statement. Nephrol Dial Transplant. 2013;28(6):1346-59.
cells or by altering the behavior of bone marrow accessory
10. Macdougall IC, Eckardt KU. Anaemia in chronic kidney
cells. EPO mimetic peptides are synthetic cyclic peptides disease. In: Feehally J, Floege J, Johnson RJ, eds.
capable of stimulating the EPO receptor. Others include Comprehensive clinical nephrology. 5th edn. Philadelphia:
EPO fusion protiens, antibody agonist to EPO receptor, Mosby Elsevier 2015.pp.967-74.
EPO gene therapy. 11. Parfrey PS. Critical appraisal of randomized controlled trials
of anemia correction in patients with renal failure. Curr Opin
Nephrol Hypertens. 2011;20:177-81
CONCLUSION
12. Rozen-Zvi B, Gafter-Gvili A, Paul M, Leibovic L, Shpilberg O,
Correction of anemia leads to significant improvement Gafter U. Intravenous versus oral iron supplementation for
in physical and mental wellbeing and better quality the treatment of anaemia in CKD: Systematic review and
of life in CKD patients. In majority of CKD patient’s meta-analysis. Am J Kidney Dis. 2008;52:897-906.
SECTION
15
Geriatrics and Genetic
Geriatric Teaching Indian Relevance Management of Gender Dysphoric Persons, Sex
OP Sharma Change Surgeries and Our (Indian) Experience
Richie Gupta, Rajat Gupta
Therapeutic Uses of Human Endothelial
Progenitor Cells Anemia in Elderly: Experience at a Large
Ananda Bagchi, Aradhya Sekhar Bagchi Tertiary Center
PS Ghalaut, Ragini Ghalaut
CHAPTER
146
Geriatric Teaching Indian Relevance
OP Sharma
AGEING
Ageing is progressive, generalized impairment of
function resulting in loss of adaptive response to stress
and in increasing risk of age related diseases. This is a
physiological phenomenon. The WHO report on ageing,
which predicted that by the year 2000, 61% of elderly
population will be in developing countries (Figs 1 and
2). Further the declaration in the UN Assembly on 01st
October 1998 by Secretary General Dr. Koffi Annan that
1999 will be International Year of Older Persons.
The world over the governments started focusing on
the welfare of older persons and no wonder health was
among one of the measures to be taken. Fig. 1: WHO report on ageing
In elderly whatever may happen, the clinical Hypotension, Diabetic Neuropathy, and Hypoglycemia
presentation is in the form of Acute Confusion, and Poor Vision.
Depression, Incontinence, Heart Failure, Fall and
Fainting. NEED V/S AVAILABILITY
There are certain organs which are commonly Currently, the estimated number of senior citizens
affected and they are called weak links. These includes is 112 Million and we have only handful of trained
Brain, Lower Urinary Tract, CVS and Musculoskeletal Geriatricians in the country. As such whatever the
System. number of Geriatricians, they are all located in metros,
In elderly one organ is affected but the other organ hence the elderly in rural and semiurban are totally
may show symptoms. For example, an elderly suffering deprived of trained medical as well as paramedical
from Pneumonia, like adults may not have Fever, Cough, personal. As the number of elderly grows every year, the
Septicemia but on the contrary, may present with existing gap will continue to widen.
confusion, fall and incontinence. Similarly, an elderly
suffering from hyperthyroidism may not show tremors, NEED BASED SOLUTIONS
weight loss, increased appetite but may present with
With five teaching medical institutions producing eight
heart failure.
Geriatricians every year, we will never be able to meet
An elderly sometimes with mild changes; the
the demand of Geriatricians in the country. It is therefore
symptoms may be disproportionately more i.e. mild
good to take a practical approach and divide our
increase in serum calcium due to hyperparathyroidism
requirements as immediate need and future planning.
may present with cognitive impairment. An elderly
with slight enlargement of prostate may present with
Immediate Need
retention of urine. An elderly with slight ischemia with
As on now we have 112 million senior citizens, whom we
preexisting diastolic relaxation abnormality may present
can divide in two categories. First category are those with
with cardiac failure.
minor problems and usually in the age group of 60–75
In elderly certain things may not be significant i.e.
years. They mostly consult family physicians. Second
few ventricular premature contractions, bacteriuria,
category are the people with complicated medical
impaired GTT (Specially if fasting normal PP high), while
problems or above the age of 75 years. They approach
for many things one has to be more vigilant like anemia,
incontinence and confusion. physicians or respective specialists. The second category
It is usual in adults to explain the symptoms with a has to mostly visit institutions and occupy majority of
single disease while in elderly every sign/symptom may beds in hospitals. For the first category the updating to
have different explanation i.e. in a young patient having family physicians will greatly help them serving elderly
Fever, Anemia, Retinal Embolism and a Heart Murmur (Fig. 3). This updating may be done in routine ways as
– one thinks of Infective Endocarditis on the contrary in well as need based in cases of emergency.
elderly the fever may be Viral in origin, Anemia may be The updating of family physicians may be done by
due to Aspirin Induced Blood Loss, Retinal Embolism establishing four centers in the four corners of country
may be due to Cholesterol Embolus and Heart Murmur and starting telemedicine which provide help and also by
may be due to a Calcified Valve. printing small booklets, doing CME’s and an electronic
In elderly one symptom like confusion may occur due newsletter.
to Mild Dementia, Deafness, Poor Vision, and Electrolyte For emergency situations like poisoning, adverse
Imbalance and Heart Failure. Similarly, one symptom drug reactions, sudden outbreak of diseases, etc., the
like falls may occur because of many reasons like same telemedicine centers may provide help or SMS in
Transient Ischemic Attacks, Drugs induced Orthostatic regional languages may be sent to practitioners.
864 SECTION 15: Geriatrics and Genetic
using the inhibitor of DNA binding I (ID-I). This allows Peripheral arterial obstructive disease.
preventing apoptosis. 13 Physical activity positively EPCs to common CV disorders like CAD, AMI and heart
influences both peripheral and bone-marrow EPC failure (HF).
counts. Low concentrations of circulating EPCs have shown
Hypercholesterolemia negatively influences both EPC to be the independent predictors of atherosclerotic
count and its function, indeed EPC levels have an inverse CV disease progression. Endothelial integrity has an
relationship with TC and LDL-C levels. 14 Increased excellent balance between endothelial damage and
oxidative stress linked with dyslipidemia may partly be repair. Atherosclerotic risk factors are linked with
involved in the impaired regulation of EPC maturation, reduced counts and activity of circulating EPCs, it is
mobilization and survival; of note, circulating EPCs are possible that advancement of atherosclerosis is driven by
too sensitive to oxidized LDL, thus causing premature an impairment of EPC repairing capacity. Additionally,
apoptosis. Also LDL-C levels have an inverse relation disease process that hamper the endothelium per se
with EPC migratory capacity. Elevated LDL-C and also lead to endothelial tissue detachment, causing elevated
oxidized LDL concentrations impair EPC migration, via concentrations of circulating endothelial cells (CEC)
VEGF mediated pathway, and blocks VEFG-included in the blood. An inverse association has been found
EPC migration by inhibiting NO production.15 between EPCs and CECs 19 as high number of CEC
Systolic blood pressure has a negative association on have been seen in patients with CAD whereas decline
the concentration of circulating EPCs, but the clonogenic in the count of circulating EPCs has been linked with
potential is retained by the arterial hypertension. CAD20 especially multivessel CAD. In contrast, Guven
et al demonstrated that the count of EPCs was elevated
Angiotensin II speeds up the onset of EPC senescence,
in patients with significant CAD especially in those
resulting in impaired proliferation of EPCs; that may
who require coronary intervention, and EPC counts
be inhibited by angiotensin II type 1 receptor blocker
corresponded to the maximum severity of angiographic
like valsartan. Ramipril also revamps proliferation and
stenosis. Quantification of EPCs is of predictive value for
migration of EPCs, and also, in vitro, vasculogenesis in
CV consequences in patients with stable CAD. There is a
CAD patients. These observations were finalized in the
link between baseline values of EPCs and crucial adverse
Endothelial Progenitor Cells in Coronary Artery Disease
cardiac events. This relationship was independent of
(EPCAD) Study,16 demonstrating that ACEI treatment
CAD severity, CV risk factors and pharmacological
was linked with enhanced counts and also improved
therapies known to impact CV results. Also, EPC count
clonogenic potential of circulating EPCs, as compared
and activity is closely linked with coronary endothelial
to patients who were not consuming angiotension-
function. Multivariate analysis exhibited that the count
converting enzyme inhibitor drugs.17
of EPCs forecasted severe endothelial impairment
Although techniques linking CV risk factors and independently of classical CV risk factors.
impaired EPC mobilization and function are not well Acute coronary syndrome (ACS) is linked with
understood, the studies strongly indicate that oxidative elevated levels of inflammatory and hematopoitic
stress and chronic inflammation may play a censorious cytokines, which mobilizes EPCs from the bone-marrow
role, in spite of substantial resistance of endothelial and this mobilization is not affected by the type of
progenitors to the oxidative burden.18 revascularization whether primary angioplasty or
thrombolytic therapy.21 However, ischemia may be a
EPC AND ATHEROSCLEROTIC primary factor for EPC mobilization, given a significant
CARDIOVASCULAR DISEASE increase in the EPC counts in patients with unstable
Physiological and conventional risk factors for angina, an inflammatory state shown by increased CRP
atherosclerosis are related to the variations in the counts levels, is also involved in modulating adhesive properties
and function of EPCs and may be the bridge, associating of EPCs in ACS.
868 SECTION 15: Geriatrics and Genetic
EPCs are notably upregulated in heart failure effect on the echocardiographic parameters of diastolic
(NYHA Class I-II) but their mobilization is depressed function in patients after AMI.26
in patients with advanced heart failure (NYHA class III- It is crucial to note that, in all these trials the
IV) irrespective of origin of the disease.22 Reduction in reproducibility of the reinfusion therapy and the safety
EPCs has been associated with elevated levels of TNF-α have been under lined.
indicating endothelial precursors as victims of excessive
inflammation seen in heart failure. EFFECT OF CARDIAC DRUGS ON EPCs
Restenosis after coronary artery stenting remains a
Statins
notable problem in the clinical practice of interventional
The consequence of statins on EPCs are too complex. It
cardiology. Here EPCs are singly responsible for stent
is related to an increase in the count of circulating EPCs
restenosis, because of a strong correlation between
in CAD patients. While short term treatment with statins
circulating CD34+ cells and late luminal loss after
have shown to increase both EPC count and activity,
coronary angiography. 23 The activity of EPCs in
long term treatment with statins may have effects to be
postarterial injury recovery/impairment is complex.
contradictory. Indeed, statins have a biphasic effect on
Inoue et al, have confirmed an elavation in EPC counts
EPC numbers. Statins aid to mobilize early EPCs which
following bare metal stent implantation in CAD patients
is very crucial in acute ischemic conditions such as AMI,
and the extent of EPC elevation in counts correlated with
but long term positive effects of statins is partly explained
risk of stent restenosis. In contrast, DESs (e.g. sirolimus
by expansion of ECFC which is believed to be the true
drug eluting stents) are able to prevent procedure related
EPC responsible for the vasculogenesis.
EPC mobilization.
been examined in several studies done under the on EPCs demonstrating that the inhibitory effects of
HEALING (Healthy Endothelial Accelerated Lining hyperglycemia on EPC can be reversed by the NO
Inhibits Neointimal Growth) programme, the results are donors, but not by other antioxidants.
encouraging. First in man and HEALING II study have So, the conclusion is adverse metabolic stress factors
shown efficacy and safety of ECS (EPC Coated Stent) in diabetes are linked with decreased EPC counts and
and a favorable clinical result after 1 year. In addition, angiogenicity and this dysfunction of EPC contributes to
untimely stoppage of dual antiplatelet therapy may be the pathogenesis of vascular complications of diabetes.
possible in reducing their inherent risk. Administration of PPAR-gamma agonists has been
linked with elevated EPC counts and improvement of
Uses of EPCs in Cerebrovascular Disease their activity. Han et al, showed PPAR–gamma agonists
The number of EPCs was significantly lower in patients regulate CFU-EC, thus promoting vasculogenesis, 32
with cerebrovascular disease (Acute or Chronic). In there are also provasculogenic effects of PPAR-gamma
patients with history of cerebral ischemic episodes,28 agonists on ECFCs. The hormone estrogen augments
Taguchi et al, found no relation between the degree of the creation and survival of EPCs, thereby elevating
cerebrovascular atherosclerosis and EPCs conversely, the circulating levels of EPCs. 33 Moreover, estrogens
after an acute cerebral infarction, the EPCs were not only enhance EPC count, but also are capable of
increasing moderately, coming back to baseline levels effectively reaching to sites of vascular lesions. Estradiol
after nearly a month. 29 Impaired EPC levels during may enhance EPC mobilization through NO-mediated
acute phase were linked with absence of crucial adverse pathways.
clinical results. It has been demonstrated that patients
with reduced EPC number have a decreased capacity ROLE OF EPCs IN TUMOR GROWTH
for angiogenesis, repair of the endothelial damage and EPCs are important in growth of tumor and are critical
development of the collateral vessels. Similarly, other for angiogenesis and metastasis. Ablation of EPCs in
studies have reported a better prognosis linked to the the bone marrow lead to a significant decline in tumor
elevated EPC number during an ischemic event. growth so EPCs has become a novel therapeutic target.
Lately, it has been found that miRNAs modulate
USES OF EPCs IN DIABETES MELLITUS EPC biology and tumor angiogenesis.34 This research
Type 1 diabetes mellitus is associated with reduced by Plummer et al, found that, in particular targeting of
vascular repair, as indicated by impaired wound healing the miRNAs, miR-10b and miR-196b led to significant
and reduced collateral formation in ischemia. Recently deficiency in angiogenesis mediated tumor growth by
EPCs have been identified as important regulators of reducing the mobilization of EPCs to the tumor. These
these processes because EPCs are dysfunctional in finding indicate that directly targeting these miRNAs
diabetics and their numbers in type I DM patients are in EPC may bring about a novel strategy for inhibiting
44% lower as compared to age and sex matched control tumor angiogenesis.
subjects, this reduction was inversely related to levels of
HbA1C.30 ROLE EPCs IN ENDOMETRIOSIS
Hyperglycemia significantly decreases the production In endometriosis, about 37% of microvascular
of eNOS by EPCs with a corresponding reduction in endothelium of ectopic endometrial tissue emerges from
NO bioavailability. The effects of hyperglycemia could the endothelial progenitor cells.35
be made unsatisfactory by the coincubation of EPCs
with the NO donor like sodium nitroprusside or P38 USES OF EPCs IN WOUND HEALING
mitogen-activated protein kinase inhibitor, and declined The responsibility of EPCs in wound healing remains
by eNOs inhibitor.31 In contrast, other antioxidants like uncertain. Blood vessels have been shown infiltrating
Vit C, N-acetylaysteine, etc. have no significant effect ischemic tissue by mechanically forced entrance of
870 SECTION 15: Geriatrics and Genetic
existing capillaries into the avascular compartment, to identify CV disease and to forecast better/worse CV
and mainly instead of through sprouting angiogenesis.36 sequelae, thus proposing their evolution as a rational
These observations refute sprouting angiogenesis marker in various defined clinical scenarios. There are
driven by the EPCs. By and large with the incapacity many promising clinical studies to suggest EPCs as a
to find bone-marrow derived endothelium in the new novel therapy for CV disease. A broad consensus seems
vasculature, there is now small material support for to be needed for defining EPC, as well as the other cell
postnatal vasculogenesis. Instead, angiogenesis is types co-operating in vivo with EPCs and operating
possibly driven by the process of physical force. as the support cells. Recent clinical studies should be
The practicality of EPC implantation has been shown referred to the definition of standardized methods for
by genetic retardation of glycogen synthase kinase - 3β the identification and application of EPCs as diagnostic,
signalling in human EPCs that was linked with significant prognostic and therapeutic indices in clinical practice.
improvement of their angiogenic possessions in an
animal model of ischemia. In addition, the angiogenic ABBREVIATIONS
prospective of EPCs can be revamped by nongenetic ex AMI: Acute myocardial Infarction
vivo stimulus (e.g. by exposure to hypoxia). However, BM: Bone marrow
clinical application of these approaches needs further EPC: Endothelial progenitor cell
exploration. ECFC: Endothelial colony forming cell
CFU–EC: Colony forming unit – endothelial cell
USES OF EPCs IN PERIPHERAL CV: Cardiovascular
ARTERIAL OBSTRUCTIVE DISEASE ECS: EPC capture stent
The gold standard treatment of peripheral arterial NO: Nitric oxide
obstructive disease is surgical or endovascular revascu VEGF: Vascular endothelial growth factor
larization. However, one third of these patients are not
suitable for invasive interventions. Recent studies have REFERENCES
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It is logical that EPCs are involved in vascular 6. Lyden D, Hattori K, Dias S, et al. Impaired recruitment
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After endothelial damage, a mechanism of repair
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9. Fadini GP, Agostini C, Sar tore S, et al. Endothelial 17.
progenitor cells in the natural history of atherosclerosis. 25. Assmus B, Erbs S, et al. Intracoronary infusion of bone
Atherosclerosis. 2007;194(1):46-54. marrow derived mononuclear cells abrogates adverse left
10. Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial ventricular remodelling post AMI-insights form the reinfusion
progenitor cells, vascular function and cardiovascular risk. of enriched progenitor cells and infarct remodelling in AMI
N Engl J Med. 2003;348:593-600. (REPAIR-AMI) trial. European Journal of Heart Failure. 2009;
11. Kondo J, Hayashi M, Jakeshita K, et al. Smoking cessation 11(10):973-9.
rapidly increases circulating progenitor cells in peripheral 26. Meyer GP, Wollert KC, et al. Intracoronary bone marrow cell
blood in chronic smokers. Arterioscler Thromb Vasc Biol. transfer after AMI-5 year follow up from the randomized
2004;24:1442-7. – controlled BOOST TRIAL. European Heart Journal.
12. Wang XX, Zhu JN, Chen JZ. Effects of nicotine on the number 2009;(24):2978-84.
and activity of circulating endothelial progenitor cells. J Clin 27. Inoue T, Masataka S, Fakuda D, et al. Mobilization of CD34+
Pharmacol. 2004;44:881-9. bone marrow derived cells after coronary stent implantation:
13. Rehman J, Karlsson G, Panchal VR, et al. Exeercise acutely impact on restenosis. Circulation. 2007;115:553-61.
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Cardiol. 2004;43:2314-8. 29. Yip HK, Chang LT, et al. Level and value of circulating
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2001;103:2102-7. late endothelial progenitor cells by modifying nitric-oxide
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2005;353:999-1007. 32. Werner C, Kamani CH, Laufs U, et al. The perioxisome
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Drug Ther. 2004;18:203-9. Diabetes. 2007;56:2609-15.
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correlate with risk factors for coronary artery disease. Circ factor inhibitor of DNA binding I to selectively target
Res. 2001;89:1-7. endothelial progenitor cells offers novel strategies to inhibit
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23. Kipshidze N, Dangas G, Leon MB, et al. Role of endothelium exercise on endothelial progenitor cells in patients with
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CHAPTER
148
Management of Gender Dysphoric
Persons, Sex Change Surgeries and
Our (Indian) Experience
Richie Gupta, Rajat Gupta
Unlike the earlier rigid views in respect to sex and gender, ie presence of genital organs, while conversely, gender
the modern society and medicine recognizes that there reflects the role, that this person’s brain wishes to play
are many shades of gray to a person’s sexuality. The in society, i.e. masculine or feminine. Generally, the
phenomenon is well known to Indian mythology in ‘sex’ of a person is in alignment with ‘gender’.1 However,
the form of Ardhanarishwara, considered the supreme in certain individuals, this is not so. As a result, these
form of God, King Ila during Ramayana period and, individuals are at conflict with society and their own
Shikhandinini during the Mahabharata period. Arjuna, bodies, and experience a discomfort, known as ‘Gender
one of the greatest warriors of his time, spent a year in Dysphoria’. Some Gender Dysphoric (GD) persons
trans-sexed condition.1 The phenomenon is visible to experience a severe form of discomfort, leading to
most of us, as we travel and come across transgenders depression, attempts to suicide and an existential
in the streets and during course of our work. It also crisis. They feel trapped in their physical body, and
gets highlighted by media, when celebrities like Bruce need to change it, to bring it into alignment with their
Jenner transitions to Caitlyn Jenner. What caused an gender identity. This subset of individuals is known
Olympic Gold Medal winning decathlete, an event which as trans-sexuals.1 This group of individuals, otherwise
determines the champion of champions amongst men, genotypically and phenotypically normal men and
and the father of famous Kadarshian/Jenner sisters, to women are the candidates for surgical and hormonal
opt, to become a woman? change of ‘sex’.
Recent data suggests that nearly 0.6% of US The trans-sexuals, who transition form man to
population (1.4 million people) may be transgenders.2,3 woman are known as transwomen (MTF) and, the
‘Transgenders’ is a diverse and broad group of individuals, reverse as transmen (FTM). The incidence varies from
who transcend the norms for gender role, as defined 1:19000 to 1:45000 for transwomen, and 1:30400 to
culturally, by a society. This umbrella term includes 1:200000 for transmen, as per the meta-analysis by De
genderqueer individuals such as pangender, bigender, Cuypere (2007).5 The MTF incidence is thus 3–5 times
agender and gender fluid individuals. It also includes that of FTM. This may also be since boys behaving like
the individuals, who identify with a third gender, as well girls may be more noticeable and less acceptable in
as the ‘trans-sexuals’.4 To understand the trans-sexual society, and hence report to the medical profession
phenomenon, we need to understand the difference earlier and more often. In authors gender identity
between sex and gender. An individual’s sexual identity clinic (GIC) however, the number of FTMs are 5 times
is the one, that is assigned at birth based on phenotype those of MTFs. This may be a case of selection bias,
CHAPTER 148: Management of Gender Dysphoric Persons, Sex Change Surgeries and Our (Indian) Experience 873
since the authors center is well known worldwide, for psychiatric disorders, which can sometimes mimic the
performance of phalloplasties, an FTM operation, which condition, and treats the underlying conditions such as
is performed in very few centers, compared to MTF depression. The criteria for diagnosis of trans-sexualism
procedures. The trans-sexual etiology is multifactorial. are:1
Sexually dimorphic hypothalamic nuclei, such as BSTc, A sense of discomfort and inappropriateness about
of brain, during the first period of testosterone surge at and not limited to period of stress.
12 weeks gestation.11,12 An abs ence of physical inters ex or g enetic
which are at variance from one’s assigned sex at birth, The psychiatrist assesses the impact on patient,
is a common and culturally diverse phenomenon of any stigmas attached to the condition and, the
and should not be viewed with skepticism.5 Yet, these available surrounding support structure. In addition,
individuals, continue to face ridicule and sarcasm, not the psychiatrist helps the patient through his transition
only from public, but from medical profession as well. by encouraging role playing, and involving people at
It is not as if, a man decides to become a woman, or vice patient’s workplace/ educational environment. The
versa, on the spur of a moment. As the field of psychiatry psychiatrist also counsels the patient regarding means
advanced rapidly, from the last years of 19th century, so of gender expression and treatment options in the
did the understanding of transgenders and transsexuals. form of hormone therapy and surgery. A vital part of
Works of Sigmund Freud, Magnus Hirschfeld, Arthur the long-term diagnostic therapy is the so called real-
Koestler, Harry Benjamin, Stoller and Norman Frisk life experience, in which the patient lives as a member
led to an organized and structured diagnosis and of the desired sexual role continually and in all social
treatment of trans-sexuals. In 1979, Harry Benjamin spheres to accumulate the necessary experience. At the
International Gender Dysphoria Association (HBIGDA), end of assessment and psychotherapy, the psychiatrist
was founded and published the first version of Standards issues a certificate incorporating the patient’s diagnosis,
of Care (SOCs). HBIGDA is now known as WPATH, resolution of all psychiatric issues to his satisfaction and
and has published the seventh SOCs for treatment of patient’s mental fitness for consenting and undergoing
transsexuals, transgenders and gender nonspecified further treatment in the form of hormone therapy
individuals in 2011. The management of trans-sexuals is and surgery. In general, opinion of one psychiatrist is
largely based on the 7th SOCs, as published by WPATH, required for instituting hormone therapy, or performing
but as specified by WPATH itself, the treatment needs to breast surgery. Two different psychiatry opinions
be modified by local sociocultural situations, in view of are required before performing any genital surgery.5
regional variations and diversities. Authors prefer to take both psychiatry opinions prior to
The trans-sexuals are best treated at Gender Identity initiating hormonal and surgical treatment. Of these, one
Clinics (GICs), where the various specialists required to psychiatrist belongs to the author’s GIC and the other,
treat them are available and can provide a comprehensive preferably from a different institution.
and seamless management. The specialties of Hormone therapy is the second pillar, on which
psychiatry, plastic surgery and endocrinology provide treatment of trans-sexuals is based. Initially there was
the three pillars, on which, the treatment is largely based. some ambiguity regarding the age at which hormone
Psychiatrist diagnoses the condition, rules out severe therapy should be started in these individuals. For a
874 SECTION 15: Geriatrics and Genetic
few years, in countries such as Netherlands, hormone the breast dimensions achieved on hormone therapy.
therapy was started before the onset of puberty. This Similarly, many MTF transsexuals opt for facial and
approach had clear advantages in view of the fact, that the body hair removal measures such as lasers, especially if
puberty was totally suppressed, and the phenotype of GD hormone therapy has been delayed.
individual (in terms of body dimensions) developed in The cross-sex hormone therapy is now without risks.
the direction of his/her perceived gender. However, later Feminizing hormone therapy may result in increased
it was found that in 80–95% of children, the GD abated risk of venous thromboembolic disease, hypertension,
spontaneously, leading to a considerable incidence of Type 2 diabetes and hypertriglyceridemia. Masculinizing
regret.5,13 The works of Dr Cohen-Kettenis have shed hormone therapy may result in increased risk of
considerable insight into the timing of hormone therapy cardiovascular diseases, hypertension, Type 2 diabetes,
for GD individuals (transsexuals). hyperlipidemia, acne, polycythemia, androgenetic
In cases of clear cut GD, GnRH may be started in the alopecia, etc.5 Hence, the cross-sex hormone therapy
age range of 12–16 years, with parental consent. This has is started only after proper patient evaluation, consent,
the effect of delaying/freezing the puberty, and gives the understanding implications of long term therapy and
individual, the necessary time to explore with the mental ongoing and periodic examination and lab investigations,
health professional, his/her wish for sexual reassignment, under the guidance of an endocrinologist.
as well as to spend this period productively, in the Sex reassignment surgery (SRS) is the third and final
company of peers, without the obvious disadvantages of pillar of treatment of GD individuals. This surgery is also
GD and associated depression and social phobias. The called Gender Affirmation Surgery (GAS), as, ‘Gender’
effects of GnRH analogues are reversible and stopping being hardwired into brain, cannot be changed, and can
these will allow puberty to progress. Cross-sex hormones only be affirmed by bringing the patient’s phenotype,
are not indicated at this stage. The cross-sex hormone into alignment.
treatment is started after Tanner stages 2–3 of puberty, at SRS for MTF transsexuals include vaginoplasty, penec
age 16–18 years or later, with parental consent.14,15 tomy, orchidectomy, clitoroplasty, labiaplasty, breast
Hormone therapy, though not necessary for life, augmentation, facial feminizing surgery, feminizing
helps in transitioning of the individual in his/her new laryngoplasty (voice change and laryngeal shaving), and
sexual role and alleviates GD. Masculinizing hormones ancillary procedures such as rhinoplasty, abdominoplasty,
given to FTM trans-sexual will result in facial and hair transplants to correct hairline and androgenetic
increased body hair growth, redistribution of body alopecia, laser removal of facial and body hair, etc. For
fat to masculine, cessation of menses and clitoral FTM transsexuals, surgical procedures may include
enlargement in 3–6 months. It will also cause scalp hair phalloplasty (penile reconstruction), urethroplasty,
loss with more masculine hairline, increased muscle scrotoplasty, testicular and penile implants, hysterectomy,
mass and strength and deepened voice in 6–12 months. bilateral salpingo-oophorectomy, vaginectomy, bilateral
Feminizing hormones given to MTF trans-sexuals breast reduction and ancillary procedures such as
will cause softening of skin, redistribution of body fat lipoplasty, abdominoplasty, chest wall contouring,
to feminine, breast growth, decreased muscle mass, rhinoplasty, masculinizing laryngoplasty, etc.
stopping of progression of male pattern baldness and Not all the procedures that are listed above are
decreased testicular volume in 3–6 months. There is also necessary. Psychiatric, endocrine and plastic surgical
thinning and slowed growth of facial and body hair in interventions (the three pillars, or triad) are carried
6–12 months.5 Breast growth may continue usually up out on an, as needed basis, only to alleviate the gender
to 18 months, and does not increase in size after that. dysphoria suffered by the patient, unless legally
Around 25–50% of MTF trans-sexuals opt for breast necessary in that country, for change of sex in patient’s
augmentation and the remaining are satisfied with legal and official documents. Some sporting events
CHAPTER 148: Management of Gender Dysphoric Persons, Sex Change Surgeries and Our (Indian) Experience 875
INTRODUCTION
Anemia in elderly is not due to old age but due to
some disease which need to be investigated. The
common cause of anemia in elderly are chronic kidney
disease (CKD), anemia due to iron efficiency (IDA),
anemia of chronic disease (ACD) or anemia of chronic
inflammation, and malignancies rather than IDA which
is commonly seen in 30% of population in the world
(WHO).1 Etiological spectrum of anemia in elderly at
PGIMS Rohtak, Haryana 2015–16 is shown in Figure 1.
In a n o t h e r stu dy , t h e e t i o l o g i ca l sp e c t r u m Fig. 1: Etiological spectrum of anemia at
PGIMS Rohtak, Haryana, India
of Pancytopenia at PGIMS Rohtak, Haryana shows
Megaloblastic anemia is most commonly seen (39%)
followed by aplastic anemia (29%) and aleukemic TABLE 1: Etiological spectrum of pancytopenia at PGIMS Rohtak,
leukemia (15%) (Table 1). Haryana, India
S. no. Diagnosis Female Male Total
CLASSIFICATION OF ANEMIA N (%) N (%) (%)
Anemia can be classified on the basis of: 1 Megaloblastic anemia 21 (53.8) 18 (46.2) 39
Etiology of anemia
2 Aplastic anemia 11 (37.9) 18 (62.1) 29
Red cell morphology (Table 2) 3 Aleukemic leukemia 5 (33.3) 10 (66.7) 15
4 Lymphoma 0 (0.0) 4 (100) 4
Based on Etiology 5 Multiple myeloma 2 (50.0) 2 (50.0) 4
6 MDS 1 (50.0) 1 (50.0) 2
Anemia Due to Blood Loss
7 Myelofibrosis 2 (100) 0 (0.0) 2
It may be due to acute blood loss or chronic blood
8 Infection 0 (0.0) 2 (100) 2
loss. Acute loss may be external (e.g. as after trauma or
9 Hyperplenism 0 (0.0) 2 (100) 2
obstetric hemorrhage) and or internal (e.g. as bleeding
10 SLE 1 (100) 0 (0.0) 1
from GI tract, rupture of spleen, ruptured ectopic
Total 43 57 100
pregnancy, subarachnoid hemorrhage). Chronic blood
CHAPTER 149: Anemia in Elderly: Experience at a Large Tertiary Center 877
TABLE 2: Based on morphology anemia can be normocytic, TABLE: 3 Etiology of iron deficiency anemia
microcytic and macrocytic
Increased demand Increased iron loss Decreased iron intake
Type MCV and MCHC Conditions for iron or absorption
Normocytic (MCV-76-96fl, Acute blood loss, liver zz Rapid growth zz Chronic blood zz Inadequate diet
Normochromic MCHC-30-35g/dL) disease, endocrinopathy, in infancy or loss, menses
anemia of infections, etc. adolescence
Macrocytic (MCV->96, MCHC- Vitamin B12 and folic acid zz Pregnancy zz Acute blood loss, zz Malabsorption from
30-35g/dL) deficiency, etc.
blood donation disease (sprue,
Microcytic (MCV-<76fl, MCHC- Iron deficiency anemia, crohn’s disease,
30g/dL) thalassemia, sideroblastic, postgastrectomy)
pyridoxine deficiency, etc.
zz Erythropoietin zz Phlebotomy as zz Acute or chronic
therapy treatment for inflammation
loss could be due to worm infestation, menses, repeated polycythemia
blood donation, repeated phlebotomy as treatment of
polycythemia vera, etc.
TABLE 4: Etiology of vitamin B12 deficiency anemia
Hemolytic Anemia Due to Destruction of RBCs Nutritional Malabsorbtion Gastric causes Intestinal
Hemolytic anemia may be due to the destruction Pure Pernicious Congenital Intestinal
o f R e d Bl o o d C e l l s d u e t o h e re d i t a r y d e f e c t s vegetarian anemia intrinsic factor stagnant loop
deficiency, syndrome: jejunal
(hemoglobinopathies, enzymopathies, membrane- partial or total diverticulosis,
c ytoskeletal defects, familial hemolytic uremic gastrectomy ileocolic fistula.
syndrome) or acquired defects (Paroxysmal nocturnal Tropical sprue,
transcobalamin
hemoglobinuria, toxic agents, drugs, infections or
II deficiency, ileal
autoimmune diseases, etc.) resection and
crohn’s disease,
Impaired RBC Production fish tapeworm
Defective proliferation and differentiation of stem cells: It
may be seen in aplastic anemia, chronic renal failure,
TABLE 5: Etiology of causes of folic acid deficiency anemia
endocrinopathy (defective production of hormones
of pituitary, thyroid, suprarenal glands and testis). Dietary Malabsorbtion Drugs
Defective proliferation and maturation of differentia- Infancy, poverty, Tropical sprue, Anticonvulsants,
tion of the blasts : It may be due to defective DNA decreased gluten induced antitubercular
synthesis (Vit B12, folic acid deficiency), defective intake, chronic enteropathy, diabetic drugs tetracycline,
alcoholism enteropathy nitrofurantoin
hemoglobin synthesis (Haem–iron deficiency and,
pyridoxine deficiency and Globin-thalessemia
and hemoglobinopathies), sideroblastic anemia,
TABLE 6: Causes of aplastic/hypoplastic anemia
anemia of chronic disease (infections, inflammation,
Acquired causes Inherited causes
neoplasms) and myelophthisis anemia due to
Radiation Fanconi anemia, dyskeratosis
infiltration of bone marrow.2
zz
deficiency anemia, (2) Vit B12 deficiency, (3) Folic acid zz Pregnancy
zz Paroxysmal nocturnal
deficiency (Tables 3 to 5)
Hemoglobinuria
Aplastic/hypoplastic anemia zz Drugs
It is of two types i.e. due to acquired causes or inherited zz Idiopathic
A B
C D
Figs 2A to D: Koilonychia (spoon shaped nails), fissured tongue, angular stomatitis and frequent ulcerations
TABLE 7: Various cells with different etiology Evaluation of Iron Deficiency Anemia
Type of cells Possible diagnosis Typical findings include MCV <76 fl, MCHC <30 gm/
Sickled cells Sickle cell anemia dL, MCH <25 pg. Serum ferritin is low with a level of
Spherocytes Hereditary spherocytosis <12 ng/mL. Serum iron is decreased. Total iron-binding
Elliptocytes Hereditary elliptocytosis capacity is increased. Transferrin saturation is at low
Schistocytes Microangiopathic hemolytic anemia level of <15%. Hepcidin level are low. Fecal occult blood
Heinz bodies G6PD deficiency
test, urine analysis for blood/hemosiderin, colonoscopy,
upper GI endoscopy, small bowel endoscopy, antitissue
Target cells Liver diseases and HbSc diseases
transglutaminase antibodies are reliable investigations.4-6
Parasites Malaria
Reticulocyte count is increased. Serum haptoglobin level adequate, up to 300 mg elemental iron/day can be
is reduced. Serum homocystiene level increased (n-5- given depending on patients requirement. Oral iron
15). Serum MMA level is increased to 1–20 (n-<0.04). supplements are available as: Iron sulphate 325 mg (65
mg of elemental iron), Iron gluconate 324 mg (30 mg
Evaluation in Hemolytic Anemia
of elemental iron), Iron fumarate 324 mg (106 mg of
Typical finding shows that indirect bilirubin is increased.
elemental iron). The total amount of iron needed can
PBF may show abnormalities in shape of red blood
be calculated by using formula: body wt. (kgs) × 2.3 ×
cells. Absolute reticulocyte count is increased. Serum
(15- patients Hb) + 500 or 1000 for reduced iron stores.
haptoglobin is decreased. Direct and indirect Coombs
Roughly elemental iron total dose in mg is 1500 mg if Hb
tests may be positive urine hemosiderin, LDH is markedly
is less than 9 gm%.5
raised. Osmotic fragility, bleeding and coagulation
profile may show abnormaility.7-10
Parental Iron Preparations
Investigations in Anemia of These are Iron dextran, Ferumoxytol (Feraheme) which
Chronic Disease/Inflammation deliver 510 mg of iron per injection, Sodium ferric
Investigations included are ESR, Mauntox test, Chest gluconate (Ferrlecit) which delivers 125 mg of iron per
X-ray, CRP, RA factor. AntiCCP, ANA, antihistone, injection, Iron sucrose (venofer) delivering 200 mg of
DS-DNA, Hepcidine, serum EPO level, TSH, serum iron and Ferric carboxymaltose (Injectafer) delivering
creatinine and estimated glomerular filtration rate. 750 mg of iron per injection.6
Some other important investigations required are serum
protein electrophoresis, especially if total globulins are Treatment of Megaloblastic Anemia
elevated, blood culture, Widal, Mantoux test and Hepatic Megabloblastic anemia is managed using oral and iv B12
transaminases. and folic acid therapy to correct deficit and replace body
stores. The two preparation of B12 available are hydroxy
Evaluation of Hematological Malignancy
and cyanocobalamin. Cyanocobalamin 100–1000
Investigations included are peripheral blood film, CD
µg must be given daily for 2 weeks then weekly until
panel, bone marrow aspiration, lymph node biopsy and
hematocrit values are normal then monthly for life. Folic
serum electrophoresis.
acid 3–5 mg should be given orally.
Unexplained Anemia
It’s a serious disorder (5–15%), mostly normocytic. This Treatment of Hemolytic Anemia
anemia is generally mild Hb (9–12 g/dL), normocytic, Incriminating drug/toxin should be eliminated. Treatment
include corticosteroids (IHA), splenectomy (hereditary
and hypoproliferative [low reticulocyte count]. To be
spherocytosis), immunoglobulins, transfusion therapy,
differentiated from ACD by CRP and IL-6 levels. It may
plasmapheresis in TTP, eculizumab (anti CD 5 in PNH, regular
mimic occult MDS, when MCV >100, TLC <3000/cumm,
folic acid supplementation (1 mg/dL) in those patients.
Plt <1.5 lakh. Investigations such as serum ferritin,
methylmalonic acid, soluble transferrin receptor are Treatment of Anemia of Chronic
normal.
Kidney Disease
This includes erythropoietin stimulating agents Epoietin –
MANAGEMENT OF ANEMIA IN ELDERLY
alpha (eposis) and Darbopoietin–alpha (Arnasp,
A Management of Iron Deficiency Anemia Cresp). The adverse effect of these can be hypertension,
Oral Therapy Treatment of Iron Deficiency thrombosis and potential of increase in malignancy.
Iron deficiency is managed using oral and IV iron Erythropoietin is indicated when hemoglobin is < 10 g/dL.
preparations. In asymptomatic patients oral iron is Iron to be given according to serum ferritin level.
CHAPTER 149: Anemia in Elderly: Experience at a Large Tertiary Center 881
Treatment of Anemia of Chronic Disease and other indices. In the management of anemia in
Treatment of anemia due to hematopoietic malignancy elderly it is important to manage the cause along with the
will require treatment of the primary disease. In ACI/ replacement of deficiency of iron or vitamins.
ACD, Erythropoietin can be given at the dose of is 50–150
U/kg three times a week S/C. REFERENCES
1. Jatav RK. Prevalence of anemia in adult patients: a hospital
based study in South India. Int J Adv Med. 2014;1:9-12.
Treatment of Unexplained Anemia 2. Verma P, Singh S. Prevalence of anemia in adults: A hospital
In anemia of unknown cause symptomatic treatment based study of North India. Int J Biol Med Res. 2012;3:2422-8.
including blood transfusion will be required till the cause 3. Chib R. Statistics on prevalence of anemia in adults: A
community based study in Jammu City. Indian J App Res.
of anemia will be found.
2014;4:2249-555.
4. Kim ki Soon, et al. The prevalence of anemia and iron depletion
INDICATIONS OF BLOOD TRANSFUSION in the population aged 10 years and older. Korean J Hematocol.
Blood transfusion is required if Hb is less than 7 g/ 2011;46:196-9.
5. Denny SD, Kuchibhatla MN, Cohen HJ. Impact of anemia
dL in asymptomatic patients. If hemoglobin is less on mortality, cognition, and function in community-dwelling
than 10 g/dL transfusion is needed in patients for elderly. Am J Med. 2006;119:327.
a predetermined therapeutic programme such as 6. Normal erythropoiesis. In: Hematology in Clinical Practice,
Hillman RS, Ault KA (Eds), McGraw-Hill, New York 2001. p. 3.
bone marrow suppression i.e. PNH, aplastic anemia.
7. Hillman RS, Ault KA, eds. Clinical approach to anemia. In:
Symptomatic anemia resulting in–Tachycardia, mental Hematology in clinical Practice. McGraw-Hill, New York.
states changes, and angina/ECG changes of ischemia, 2011. pp. 29-42.
SOB, light headedness and dizziness on mild exertion are 8. Prakash KG, Devendrappa, Madhukumar KR, Priyashri MH,
Avinash BH. Clinical profile of anemia in elderly: A cross
other indications for blood transfusion.
sectional from a tertiary care center. Sch J App Med Sci.
2015;3(3C):1266-70.
SUMMARY 9. Chavhan B Nilesh, Natu A Sanjay. A study of clinical profile and
Anemia is the most common (30%) clinical condition etiology of severe anemia in children aged 6 months to 5 years.
Global J Research Anal. 2016;5(6):2277-8160.
seen in general medical practice. While investigating
10. SR Pasricha, J Black, S Muthayya, et al. Determinanats of
one should try to interpret simple investigations like anemia among young children in rural India. Pediatrics.
complete blood count with peripheral blood picture 2010;126(1):140-9.
SECTION
16
Social Issues
Medical Ethics Cooking Oils: Which to Use?
Hem Shanker Sharma Sonia Arora, Vitull K Gupta, Meghna Gupta
Soul and Spiritual Health IT Solution in Regulation of Medical Education and
SP Yoganna Medical Practice
Ajay Kumar
CHAPTER
150
Medical Ethics
Hem Shanker Sharma
of nonmalificence tells the doctors not to inflict harm to Controversy arises when one seeks second opinion.
his patient when he knows that there is no indication to Is it breach of confidentiality when one share every
do so. details of the patient to some other doctor who is not
There are some important ethical points which are the part of the team? This is said that even though
of utmost importance and needs to be applied in day-to- one seeks second advise, care should be taken before
day practice: disclosing all the information to the colleagues.
Ethics around informed consent: This is false but Confidentiality: Doctor has no legal obligations to
common belief in India that doctors need not take inform the police except some limited statutory
consent from its patients for everything because of the exceptions. This, however, is ethical to give
diffusely scattered illiteracy and notion that patient information about patients, concealing of which
would not be able to understand the sophistications might cause injury to others. It all comes down to a
and intricacies associated with the medical diagnosis balancing act between nature of confidential matter
and treatment on account of being illiterate. and importance of public interest.
In contrast, every human has equal right to know Family: Female seeking contraception without the
what is being done to his or her own body. prior consent from his partner, the doctor is bound
In Indian context, the doctors are given paternal by his duty of confidentiality to her for concealing the
importance in such a way that “whatever the doctor
information. In fact, the partner or husband has no
does is best for the patient” but now more and
right about the child in the uterus.
more GOOGLE educated patients are seeking
The primary aim of doctor should be to convince
logical reasoning behind each and every medical
the patient that this should be a joint decision.
intervention given to the them.
Public interest: Medical records can be disclosed in
Disclosure: In US and Canada, the courts have obliged
courts if it is necessary. The confidentiality is always
the doctors to disclose all the relevant information
in conflict with public interest. If the beam slings
regarding the procedure and let the patients choose
towards the importance of disclosure, then it must be
his or her own fate. In clinical scenario, this is at
undertaken in place of confidentiality.
times not possible to shower upon the patient all the
Patients autonomy: Right to autonomy is sometimes
minute details of all the tricks and traps applied by the
overridden by interest of masses. The respect of
doctors to catch and kill the disease, hence a pathway
in between is to be chosen in away that patient are autonomy is, however, the cornerstone of doctor-
told whatever they are interested in knowing. patient relationship. Even touching the patient
Disclosing the ultimate grief: Both Charaka and
without consent is an assault even, if this was in
Susrata believed that patient should be carefully told greatest good for patient.
Dignity: The human rights are based on human of
about the incurable disease, in any case, it should
never be told bluntly. human rights takes this very well in account. This
There are arguments for and against the same. It is encircles the controversial matter of Euthanasia
quite logical that a person if told about their untreatable failing which may prevent patient dignity this
diagnosis it would cause severe depression and stress. foundation was laid after the World War II, the
This is against ethical conscience. The argument in preamble and universal declaration from Dying with
support of the disclosure is that patient has the right Dignity.
to think and decide about his own life and choose his Although none of the ancient literature support
own path to life and exercise his autonomy. euthanasia but there are supporters of the fact that
Sharing information with healthcare team: Medical treatment should be abandoned in terminally ill.
profession is not a game of one man army it is But before that treatment should be given to
rather a team play which involves doctors, nurses. decrease the sufferings when recovery is not possible.
CHAPTER 150: Medical Ethics 887
The word ‘spiritual’ is formed by combination of two energy got imprignated into the exploded particles of
words, ‘spirit’ which means ‘soul’ and the word ‘ritual’ the primary matter. Each such particle later evolved in
meaning religious practices, ultimately meaning, the it’s own gynecological pathway till today and resulted in
religious practices that keeps the soul healthy. The soul the creation of different components of present universe.
means energy. Spirituality includes science about energy Life came into existence at one point of time of evolution
and philosophy about spiritual lifestyle, thus spiritual process, after the formation of all the necessary required
health is a combination of science and philosophy. infrastructure for the survival of living beings. Human
Spiritual health is concerned with the health of soul being made appearance at one point of time in the
which is an atom of transcendental energy present in the evolution process of life. It is not known as to whether
human being, which has connection with the universe. male and female appeared separately since the beginning
There are many misnomers about spirituality. It is or later get differentiated from bisexual human.
misunderstood by many people as superstitious beliefs, Since all the components of the universe including
which is not true. On other hand, it is superconscious the man have come from the same primary source of
facts of universal truths. To understand spiritual health primary matter and energy, each component of the
the knowledge about origin and evolution of universe, universe is connected with each other including the man.
human development and his connection with the This integration may be visible or invisible, perceivable
universe is essential. or imperceivable by normal senses. Spirituality involves
the knowledge of knowing the process of origin of
ORIGIN AND EVOLUTION OF universe and all connections of man with the universe.
UNIVERSE—MATTER AND ENERGY The available scientific evidences establishes that the
THEORY (BIG BANG THEORY) creation evolution and happenings in the universe and
The exact time and mode of origin of the universe is man are preprogrammed.
not know till today. It is said that about 14 billion years
ago universe came into existence. Matter and energy NATURAL PRINCIPLES OF UNIVERSE
collusion hit theory is accepted to be the mode of origin The universe has evolved it’s own natural principles
of universe, as on today. The primary matter hit the to maintain it’s preprogrammed processes, so that
primary energy resulting in explosion of the primary “universally integrated natural chains are regulated and
matter into various pieces, during the process primary maintained constantly. If they are distributed, it results in
CHAPTER 151: Soul and Spiritual Health 889
imbalances of nature and human functions. The nature the source of energy and matter of the body is ultimately
finds its own methods to reset even the disturbed chain from the universe, which have come from sun and
so as to continue its preprogrammed evolution. These food, etc., human being is a form or manifestation of
natural principles of universe are called ‘universal truths’ universal energy. Like this every component of universe
of the nature, which are not completely understood is a manifestation of supreme universal energy and
even by modern science. Birth, growth, development, hence are connected with each other.
changes, transformation (death) and rebirth are the
ultimate universal truths of creation. Nothing can HUMAN BEING IS THE MINIATURE
either be created or destroyed but something can be OF THE UNIVERSE
transformed from one form to other. Each component When human being appeared in the universe during
of the universe continuously undergoes recycling in its evolution is still not known. However, it is estimated
the universe by a process of transformation. So also by podology and fossils survey that about 20 crores
human being. The future evolution of the universe is not years ago the human race might have appeared and
known to the modern science. But the available spiritual has evolved to the present status of modern man. The
knowledge reveals that human being is the ultimate age of the present modern man is estimated to be about
most evolved component of the universe and there is no 10 to 15 thousand years. The human being is the most
further evolution in man with reference to the physical evolved component in the universe and hence has all the
body. It is said that there is further evolution to individual foot prints and mirror images of all the components of
mind, where in it can acquire supernatural power which the universe from which he has evolved and vice-versa.
is capable of understanding the preprogrammed natural For example, the replica of technologies of IT and BT
principles of the universe. Some of the natural principles may be noticed in the functions of nervous system and
of nature and human being are perceivable even to immune system. For discovery of them the functions of
normal senses. Whereas others are perceivable only to the human body itself were the source of inspiration. The
superconscious mind, which is not present in ordinary events that are noticed in the universe can be noticed in
human beings. the human body either directly or indirectly through an
analogous event. Hence, human being is the miniature
HUMAN IS A MANIFESTATION of the universe. Hence, the entire universe could be
OF UNIVERSAL ENERGY understood by understanding human and vice-versa.
The matter and energy present in human being is the
contribution of the universe. The bioelectrical energy HUMAN BEING IS HOLISTIC
(action potential) which is the prime energy source in the Mind is the most evolved component in the human
human body is converted into different types energy, in being and also in the universe. It has influence on each
different parts of the body so as to carry out the work and cell of the human body and the universe. Since man has
functions of the concerned system. In cardiovascular, evolved from the universe, he has symbiotic biological
respiratory and musculoskeletal system bioelectrical relationship with each component of the universe, which
energy is converted into kinetic energy to move the heart, may be visible or invisible, perceivable or imperceivable
blood, air and joints respectively. In reproductive system, by normal senses. Man is connected through waves
it is converted into reproductive energy to reproduce. with the universe. Hence, universe influences the health
The capacity to do a work undertaken is energy. The status of the human and vice-versa. The slogan of the
capacity of an individual to do the work depends upon WHO that “Think Globally, Act Locally” is based on this
the capacity of the individual mind and hence there scientific fact. Since man is connected with the universe
shall be mental energy with reference to mind. Since and he has to be viewed holistically.
890 SECTION 16: Social Issues
What is Human Being? observations even with reference to evolution of man will
Human being is defined as a spiritual being composed of establish this fact. The structural components of modern
soul (energy), body and mind having constant regulation man especially the mind, the brain and others organs of
by the universe. The human life starts with combination the body have also evolved systematically to the present
of soul, body and mind and exists till they are intact. state of progression from primitive state only, without
Life ends when disintegration of these components any retrospective regression.
occurs. Hence, ‘Human life may be defined as a constant The matter and energy of the human is cycled
integrated state of body, mind, soul and universe’. The continuously between birth, life span, death and
life exists for a fixed duration, i.e. life span, which is also rebirth in the universe. In the same way, all other
predetermined. The life style followed during the life components of the universe also undergo continuous
transformations. The minute zygote is transformed into
influences the life span. The human life exists in human
preprogrammed mega fetus through preprogrammed
life cycle which is composed of Birth–life – Life span,
stages of development by the nutrients supplied to it
Death and Rebirth.
from the universe in the womb. Soon after birth, the
child again passes through the preprogrammed stages
What is Birth?
of infancy, childhood, adolescence, adulthood, old age
The sperm and ovum which are also produced by the
and death. The specific physical, mental and emotional
products of universe gives raise to zygote which develops
changes that appears during each of these stages are also
into fetus by the food supplied by the universe. Hence,
predetermined.
birth is a transformation of universal products of sperm,
The physical growth of different organs of the body
ovum, food into a form of fetus.
also occurs over a definite specified period. For example,
though the sexual organs are present since birth in the
What is Death?
body, they mature and start functioning only at puberty.
Death results due to loss of integration between body,
Even during puberty though millions of ovum are present
soul, mind and universe. After death, these separated
in the ovaries, only one ovum matures and get ovulates
components joins the universe and forms the raw
during one menstrual cycle from each ovary alternatively.
materials for the rebirth of something else. This is the In the digestive system, as soon as the food enters one
concept behind rebirth. Hence, there is no destruction part of the intestine, the next distal part gets ready to
or loss of anything in death. It is only transformation receive the food, by automatically relaxing and proximal
from one form to other. Hence, death is defined as a state part contracts pushing the contents forward producing
of separation of soul, body and mind from the human peristalsis. Even the secretion of digestive juices and the
being. It is a type of transformation in the universe. Birth, activation of the proenzymes also occur systematically
life, death and rebirth are the different forms or state of and automatically in a sequential manner. As soon as
matter and energy. glucose enters the Cryb’s cycle the further activation
of inactive enzymes is automatic till the final product
PREPROGRAMMED EVOLUTION citric acid is formed. Like this preprogrammed biological
AND HUMAN BODY FUNCTIONS reactions can be observed in several physiological
Though, both progressive and destructive events have reactions of the body. All these facts establishes that
constantly occurred in the process of evolution of the even the physiological functions of the human body
universe, it is worth observing that the progressive is predetermined. The circadian biorhythms, diurnal
events have always superseded the destructive events. and geographical variations of body functions, further
Otherwise, the universe would not have progressed to establishes that body physiology is preprogrammed. Like
the present state of progression, since its origin. The this plenty of examples can be adduced to establish that
CHAPTER 151: Soul and Spiritual Health 891
body functions and all the happenings in the universe are Internal and External Happiness
preprogrammed. Happiness is a state of ease felt by the mind. Source
Each cell is programmed for its duration of survival of happiness may be internal or external. Internal
which is called “apoptosis”. When the modern medical happiness comes from within and is genetic. It is not
knowledge has accepted the concept of apoptosis, the influenced by external environmental factors. The mind
concept of predetermined birth and death advocated is in a constant state of happiness in the womb and also
by spiritual knowledge has to be believed, as the soon after birth. The child becomes discomfortable and
body is made of millions of cells, whose life span is
unhappy only when it’s natural instincts like hunger,
preprogammed.
defaecation and micturation etc. are not satisfied and
expresses the discomfort by way of crying, otherwise the
Purpose of Human Life is to be Happy child will be always in a state of happiness expressing
The purpose of universal creation and the human
lough. This state of mind is called “innocent mind” as it
life is mysterious and both have not been completely
has no external influence.
understood by modern science till today. It is a well-
established natural principle that nothing happens in
Conditioning of Mind
the universe without a reason and purpose. Each human
As the child grows the external environmental factors
soul while it is in the body shall be happy and when it is
influences the mind and precondition the mind on
not in the body i.e., when it is in the universe, it shall be a
various issues. Depending upon the environmental
part of universal energy, is the universal truth.
influence the child starts developing it’s own sense
The purpose of human life can be understood
of discrimination, priorities, likes and dislikes and
by observing the effects of physiological acts of the
accordingly the innocent mind gets attached to external
body itself. All the physiological acts of body gives
sources of happiness and gets preconditioned to them.
sense of happiness (ease). The physiological acts like
eating, defaecation, micturation, sexual activities, and The inborn internal happiness thus gets surrounded by
sleep etc., produce sense of comfort and happiness external happiness and becomes pushed into the deeper
and any disturbances in them results in discomfort layer of mind over a period of time. The happiness
and unhappiness. Man does all the activities in life induced by external factors is external happiness.
to get happiness. The state of happiness produces The external happiness inducing factors are multiple,
positive biological effects on the body functions and variable and not constant.
causes physiological balance between sympathetic and Thought generation in the mind is the route
parasympathetic nervous system, resulting in positive cause of all actions which ultimately determines the
state of health. On the other hand, state of unhappiness happiness and unhappiness. Fulfillment of desires
and discomfort produces negative effects on the health by produce happiness, whereas unfulfilled desires produce
increasing the sympathetic nervous activity. Happy state unhappiness. Thought generation is under the influence
of mind influences psycho-neuro-endocrino-cellular of environment. Desires cannot be constant. After the
axis positively so as to regulate the normal physiological fulfillment of one desire the mind aspires for another
functions positively. Endorphins are released during desire, like this the mind gets entangled in a visceous
happiness which helps to maintain normal homeostasis. cycle of happiness and unhappiness. The preconditioned
Whereas Adranaline, Noradranaline and Cortisol adult mind for external happiness starts hunting for
increase during unhappiness disturbing the homeostasis. happiness one after the other and hence constant
All these establishes that the purpose of human life is to happiness becomes impossible. The mind which gets
be happy. attached to external happiness is called ‘ignorant mind’.
892 SECTION 16: Social Issues
The ignorant mind is unhappy most of the time and is the well coordinated so as to achieve the state of normal
route cause of genesis of ill health. homeostasis. The mind influences each cell of the body
The mind can be spiritually trained in such way that through “psycho-neuro-endocrino-cellular axis” and
it will not get influenced by external source of happiness maintains normal homeostasis. Mind is influenced by
thereby allowing the inborn internal happiness to external environmental factors through hypothalamus.
blossom, so that mind always generates such thoughts Mind receives kinesthetic, other subconscious and
which results in constant happiness. An adult mind conscious sensations through afferent nervous system
which has been preconditioned for external happiness and send efferents to regulate the body functions.
can be spiritually trained to decondition it from the Mind is very much vibrant and it always swings
influence of external happiness. When it happens between calmness and tremulousness (unease). The
automatically internal happiness blossoms gradually to mind is genetically predetermined to develop both
the superficial plane, which is a constant happiness. This positive and negative emotions like love, courage,
state of mind is called “enlightened mind”. Enlightened patience, happiness, lough, desires, sense of universality,
mind also acquire superconscious power. etc. (positive emotions) and hatredness, fear, anger,
unhappiness, weep, etc., (negative emotions). Though
Unscientific Mind in a Scientific Body both positive and negative emotions are acquired
The structure and functions of the body are universally genetically, positive feelings dominates over negative
same in all the individuals. Scientific facts are universally feelings genetically, since birth. But the external
true. Hence body is scientific. Whereas same thing is environment plays an important role in further culturing
not true with the mind. The character and behavior of these emotions in a child after birth. Thus mind may be
the mind varies from individual to individual and in preconditioned more for either the positive or negative
the same individual from time to time. The influence of emotions by the environment. Positive emotions give
environment on mind is more sensitive than the body. raise to happiness, whereas negative emotions give raise
Mind is always engaged in one thought or the other to unhappiness. Depending upon emotions, thoughts
and is always vibrant. For the same stimulus, the mind are generated in the mind. State of positive emotions give
reacts differently in different individuals and in the same raise to genesis of universal thoughts, whereas negative
individual differently under different circumstances. emotions result otherwise. Thoughts also influences
Nothing can be universally generalized with reference to emotions. Hence, emotions and thoughts generation are
mind unlike that of body. Hence, there is an unscientific interrelated.
mind in a scientific body. This paradoxical combination Mind always exists in thoughts, even in sleep as
is the route cause of many problems of the human being. dreams. Thoughts result in actions (Karma) which inturn
Spiritual religious practices converts the unscientific mind influence the happiness and unhappiness. Emotions,
to a scientific mind and brings coordination between thoughts, actions, unhappiness and happiness areinter-
the body, mind and soul and helps the mind to acquire related.
superconscious power, by which it can understand the Thoughtless and positive thought mind is peaceful
ultimate universal truths which are not perceived by the and happy. It is impossible for a common man’s mind
ordinary senses of the mind. to be thoughtless. The mind has to trained in such a way
that either it is thoughtless or generates only positive
Spiritual Culturing of Mind thoughts, the execution of which keeps it happy without
Human mind is the most evolved component in producing unhappiness. Positive thoughts intiate the
the human being and in the universe. Mind is an human to take up only such actions which strengthen
instrument through which the milieu interior and the universal truths. The process of training the mind
exterior are regulated and body, soul and universe are to develop positive thoughts and ultimately making
CHAPTER 151: Soul and Spiritual Health 893
the mind thoughtless and peaceful is called “spiritual connection of man with the universe. It explains both the
culturing of the mind”. vertical and horizontal aspects of universe. The modern
science explains in depth about a particular component
Spiritual Knowledge of the universe (vertical) not giving much importance
Truths about the creation and happenings in the to its other horizontal connections, whereas spiritual
universes is knowledge. False things cannot be knowledge. knowledge is both horizontal and vertical. Hence,
The spiritual knowledge comprises perceivable and spiritual knowledge is holistic.
imperceivable universal truths by normal senses about
the creation and the man. It specifically contains truths Philosophy of Spirituality
about birth, life and death and truths which are beyond Man being the most evolved component of universe,
birth, death and life which are not perceivable by he is entrusted with the responsibility of protecting
ordinary mind. Some of them are appreciable even by and promoting the natural principles of universe by
a common man and some are appreciable only by the the creator. Hence, his thoughts and actions are to
superconscious mind. be generated accordingly. Actions which are against
Spiritual knowledge can be broadly classified as the natural principles of nature not only disturbs the
worldly and transcendental spiritual knowledge. Worldly preprogrammed process of the nature but also disturb
spiritual knowledge contains the truths of life and the human homeostasis, making his life miserable.
universe which can be appreciated by normal special Philosophical aspects of spirituality involves culturing
senses, following of which will keep the man happy in the mind spiritually, so as to make it to generate, positive
the wordly business. Transcendental spiritual knowledge thoughts and acquired superconscious power.
contain the ultimate truths of the creation which can Spiritual knowledge also deals with the purpose
only be appreciated by super conscious mind, not by of life, priorities, desires, likes, dislikes and lifestyle
ordinary special senses. It contain the knowledge about measures which assists the universal principles of
transcendental power and the union of the soul with that nature. The lifestyle measures which protects and
super power to attain eternal happiness. Individuals who promote the natural principles of creation are religious
acquire spiritual energy will be able to appreciate the practices or (Dharma). Since each component of the
transcendental energy. universe has come from the same source of primary
There are two schools of thoughts regarding the origin matter and energy and all are interconnected, any
of spiritual knowledge. One school of thought is said that measure undertaken by the human should not destroy
Rishis, the ancient spiritual scientists by their constant the predetermined natural bondage that exists between
spiritual effort were able to acquire superconscious each component of the universe. On the other hand, it
power to their mind which was able to know the entire shall further protentiate such bondages. The religious
science of creation and the same was propogated by practices preaching love, equality, nonviolence, peace,
them to others by oral tradition. Later Vyasa Maharishi etc., that are practiced by human beings since his
the ancient spiritual scientist reduced this knowledge to appearances in the universe came to be practiced on
writing in the form of Vedas. Vedas are the first ancient this principle. That is how the ‘Dharma’ (Religion) came
literature known to man in the World. The other school into existence. Valmiki wrote “Ramayana” epic and
of thought is that, the creator who created the universe Vyasa wrote “Mahabharatha” incorporating all aspects
himself explained about all the aspects of creation at of Vedas and preaching spirituality through practical
the first instance itself when the creation was done. The lifestyle stories. These two epics and Bhagavath Githa are
spiritual knowledge explains, the processes of creation the treasuries of spiritual knowledge, preaching natural
and the interlinks between the different components of principles of creation to the mankind through practical
the creation. It explains the universal truths regarding stories and examples. Later many saints, preachers,
894 SECTION 16: Social Issues
writers, poets, like Buddha, Patanjali, Christ, Mohammad Effects of Spiritual Energy
Paigambar, Einstein, Worldsworth, Shakespear, etc., The effects of spiritual energy are variable depending
around the world preached the spiritual knowledge in upon the quantity of energy acquired. The effects
their own ways in different languages and forms. are only perceivable cannot be demonstrated in the
The knowledge regarding, the source of energy laboratory. Can happiness, unhappiness, hunger, etc.,
in the human being, its evolution, functions and its be demonstrated by any evidence in the laboratory ?. No,
connections with the universe constitute the science of they have to be experienced like this effects of spirituality
spiritual health. Whereas the lifestyle practices which has to be felt by the body and mind. The effects can be
strengthens the bondage of this energy with the different summarized as below.
components of universe constitute the philosophical It calms down the mind and cultures the mind
appreciate the super natural power and its influence energy by constant mild to moderate spiritual practice
in the body. There are many such people (Yogis) who is quiet sufficient to regulate psycho-neuro-endocrino-
have acquired this power. cellular axis, so as to maintain normal homeostasis.
Alternative pathways: There are alternative metabolic The ancient spiritual literature has described spiritual
and other physiological pathways in the human body energy centers located in the midline of the body
which are in primitive state since birth, but they do probably in the spinal cord. The lowest center called
not work normally. Example – Anaerobic pathways ‘Muladara’ situated in the perineum (coccygeal segment)
of respiration, alternative speech ways (lip reading), and highest center ‘Sahasarara’ situated in the vertex
alternative energy pathway like utilization of solar (Brain), the other 5 centers are situated in between them,
energy, for body energy, appreciation of waves in the in the pubis, umbalicus, epigastrium, root of the neck
environment, etc. The spiritual energy makes these and globella respectively from below upwards. Body
alternative pathways to evolve, so that they come acquires different types of feelings and activities when
to the superficial plane and works. There are many the energy flows up from the bottom center muladara
living examples even to day wherein Rishis in the to the top center sahasrara through other centers.
Himalayas live without food and water for many years Ascend of spiritual energy depends upon the quantity of
by using the solar energy. spiritual energy acquired. There are channels in the body
(Kundalis) through which this energy flows energizing
Spiritual Energy Centers the body.
Spiritual energy centers have been identified by ancient
spiritual scientists (Table 1). These centers have been SOUL (ATMA)
named to explain different types of feelings, produced Soul means energy. Atma is a Sanskrit word which also
due to different planes of spiritual energy acquired. At means energy. Human soul has different dimensions,
the height of acquisition of spiritual energy, the mind both scientific and philosophical. Soul being a
acquires superconscious power. Everyone may not attain component of universal energy has universality and
such high degree of spiritual energy in the process. It universal connections and appreciation of it will produce
needs constant and vigorous spiritual practice to acquire universal feelings, which constitute philosophical
such supreme state, which may take one’s entire life dimension. Hence, Soul can be defined as.
span. But acquisition of even little to moderate spiritual Part of universal energy in the human being
and
TABLE 1: Site and effects of spiritual energy centers Sense of universal awareness and oneness
for vitality and life. The soul that comes out of the body an inborn component of universal awareness in him/her
during death is again used for birth of other components which has to be allowed to blossom in life. Hence each
of the universe which is called “rebirth”. Hence the individual feels that he/she belongs to universe and all
concept that soul has no death and has rebirth is are one. This feeling constitute the philosophical aspect
scientific in this way. of Atma. Once the feeling of universality appears, the
mind acquires all positive feeling like love, happiness,
What is Soul? coordination and concern to universe, etc., which are
Soul has scientific and philosophical components. Soul philosophical aspects of spirituality. Once the positive
means energy. Energy is defined as the capacity to do emotions appears negative emotions automatically
work. The energy that does the work in the human body disappears producing the state of ease.
is bioelectricity produced inside the cell by electrolytes,
sodium and potassium. It is the bioelectrical energy Personal Identity
in the cells which is ultimately responsible for all the Though all the human beings are the products of
activities of the cell and ultimately the human body. Loss the same universe, each individual differs in his or
of the electrical activity of the cell is the most important her identity. Even the twins differs. The Iris, thumb
abnormality noticed in individual cell death and in the and palmar impressions and palmar arch of each
death of the human being. Cardiac arrest will stop the individual are different and are taken for identification
circulation and will halt the supply of oxygen and other of individuals. This fact throw a strong evidence that
nutrients necessary to synthesize the bioelectricity in each individual has his or her own identity by his own
the entire body cells, resulting in abrupt cessation of Atma component, which has its own identity and historic
production of bioelectricity resulting in the death of evolution pathway.
the physical body. This energy is synthesized from the
components of the universe and hence the energy in the Religions (Dharma)
human body is a component of universal energy. Hence, Religions are the human life style practices evolved by
soul is defined as a component of universal energy in the human beings based on basic spiritual knowledge so
human body. The resting action potential that is present as to protect and promote the universal truths of the
inside the cells of the body, at the time of death comes Universe. Religious practices affects life styles and mental
out of cell and merges in the universe, as energy cannot health thereby influencing health. During the vedic
be destroyed. It is this energy which may be defined as period, there was only vedic religion. But later as many
soul. Like this, every component of universe has its own people understood the vedic knowledge they started
soul. interpreting it in their own ways which gave birth to
The bio energy present in the body comes out and many religious preachers and thus many religions came
joins the universal energy and the body matter also joins to be practiced.
the universe in different forms soon after death. These, “Hinduism” is the oldest religion known to man. Later
forms the raw materials for the birth of another life or “Christianity” established by Christ and Islam established
matter in the universe, which is defined as rebirth. These by Mohammad Paigambar are popular religions in
changes goes on continuously in the universe in a cyclical the world today. The religious preachers made further
manner from one form to other in all the components of branches in these basic three religions giving birth to
the universe, both in living or nonliving things. much more sub-religions. In the process, some of the
preachers misunderstood and misinterpreted the real
Universal Awareness and Oneness spirit of vedic spiritual knowledge and introduced their
Since human being is a product of universe and he/she own views and polluted the basic vedic religion and
is connected with each components universe, there is introduced the life style practices which are against the
CHAPTER 151: Soul and Spiritual Health 897
natural principles of universe. These practices even first instance which is called “Self Union” and later it
contain the practices, which destroys the basic natural brings the union of onself with the universe which is
principles of nature thus giving birth to Adharma. called “Universal Union”. These unions already exists as
Adharma preaches things which are against the natural man is connected with the universe. But yoga brings the
principles of creations. There is no universality in awareness of these unions and further strengthens them.
Adharma, whereas there is universality in Dharma.
Dharmic life styles brings coordination between body, Components of Yoga
mind, soul and universe and brings happiness whereas The great ancient spiritual scientist Patanjali about five
Adharmic life styles disturbs the coordination of the thousand years ago described and documented the Yogic
body, mind, soul and universe resulting in spiritual ill practices. There are four major components in yogic
health and unhappiness. practice. Though each one of them will produce desired
effects, all of them if followed in combination constantly,
WAYS OF ACQUIRING will produce optimum effects. The components are
SPIRITUAL ENERGY Jnana Yoga
Karma Yoga
The different ways of acquiring spiritual energy are:
Genetic Bhakti Yoga
God and Godman These are called External Yoga as they involve
external components
Genetic and Age Niyama – (Do’s)
The spiritual energy comes from genes itself but it will Yama – (Do not Do’s)
be at lower plane. The spiritual life style practices further Asanas – (Postures)
enhances this energy. As the age advances the energy —— Internal Yoga
gradually increases naturally. This can be appreciated by These are called Internal Yoga as they involve
the observations of appearance of spiritual feelings in old inversion of mind into the body and soul.
age naturally in all individuals even without any routine Pranayama (Breathing exercises)
spiritual practices. Yogic and other religious life practices Pratyahara (Deconcentration of mind)
natural predetermined chains of connections with the Meditation practices train the mind to be less vibrant,
human beings. Karma yoga also precondition the mind nonvibrant, peaceful and culture the mind spiritually. It
for generation of spiritual thoughts which intiates the initiates generation of spiritual thoughts in the mind and
mind to do such Karmas which strengthens the natural keeps the mind stress free. It makes the mind to acquire
bondages in the universe. ‘Bhakti Yoga’ contains the such power to deal stressful situations without much or
materials, the practice of which not only will calm down no damage to the body. It also helps the mind to acquire
the mind but also remove arrogancy and anger thereby supernatural power of understanding the imperceivable
helps to imbibe the qualities of superego, i.e. feelings of universal truths which are beyond birth, death and life.
reasoning, sacrifice and cooperation etc. It helps to acquire a personality of enjoying each present
‘Raja Yoga’ deals with the practices which train movement of life without the influence of past and future.
the mind to coordinate the body, mind, soul and ‘Samadhi’ is a state of self and universal union, i.e.
transcendental energy and makes the mind to acquire merging of the human being with that of the universe and
supernatural power. It contains eight components, hence transcedental energy. The mind becomes completely
it is also called ‘Asthanga (eight) Yoga’. Niyama deals with thoughtless in this state. It is the ultimate state attained
the simple principles of life that are to be followed in by all the spiritual practices. When this happens one
routine day to day life. Most of them are also advocated feels that he is a part of the universe and is inseparable
by modern Medical Science. It contains mostly food and from the universe. In this state, the mind acquires the
personal habits. ‘Yama’ deals with the practices that are capacity of understanding all the happenings of the
not to be practiced in life as they injure health and brings universe, past, present and future. There are plenty of
unhappiness. Most of them are also with reference to examples in the history, who have achieved the state of
actions, food and habits. Samadhi. Christ, Mohammad Paigambar, Ramakrishna
‘Pratyahara’ deals with practices of deconcentration Paramahansa are few among them.
of mind. It trains the mind to deconcentrate it from The basic principles of all the religions i.e., Hinduism,
sources of external happiness and makes it to concentrate Christianity and Islam, etc. can be traced to different
on inner happiness. ‘Asanas’ are particular postures in components of yoga which is the most ancient spiritual
which one can be very much comfortable for long time so practice in the world. The spiritual practices makes the
as to do meditation. It contains different types of ‘Asanas’ positive feelings to supercede the negative feelings, so
in which the particular part of the body or organ can that there is always genesis of constant state of happiness.
be stimulated to be healthy. There are about more than
8,000 described Asanas. GOD AND GOD MEN
‘Pranayama’ is a process of controlling the mind and What is God?, Who is God?, Where is he?, whether
enhancing the spiritual energy through breath. There God is there or not, whether he is a creation of man or
is inverse physiological relationship between mind creator of the universe, is God only a belief or is he really
and respiration. Whenever there is increased mental or there, whether he has form or forms or formless, is it the
physical stress the rate of respiration increases and depth supreme transcedental energy, can it be seen or felt are
of respiration decreases. Whereas whenever the body certain questions surrounding the God.
and mind are peaceful, the rate of respiration decrease Belief in God is the prime requisite of spirituality.
and depth becomes shallow, thus ventilating the lungs “God can be traced to transcedental energy which is
better. Pranayama contains practices which harmonizes the creator and regulator of the universe”. Marching of
the mind, soul and body through respiration. Respiratory evolution of the universe including the man since its
movements are supposed to be the reflection of kinetic origin only towards progression till today establishes
energy of the body. Pranayama regulates the body energy the fact that origin of universe and its evolution is
through the respiratory kinetic energy and vice-versa. preprogrammed with a creator and regulator. The
CHAPTER 151: Soul and Spiritual Health 899
whole universe is made up of matter and energy. The It regulates the body, mind, soul and universe so that
components of the universe are different manifestations all of them are well coordinated and constant state of
of prime matter and energy, which gave birth to ease is maintained.
the present universe. The prime energy from which It regulates psycho-neuro-endocrino-cellular axis
different components of the universe have evolved is so that natural biorhythms are maintained so as to
regulating them, towards preprogrammed evolution. maintain constant homeostasis.
This transcedental, regulating energy, has been named It triggers the anabolic metabolism and regulates the
as ‘God’ in spirituality. Since each component of the catabolism so that the body is energized.
universe, is a manifestation of God, i.e. the transcedental Mental health is regulated so that mind becomes
energy of God can be felt in each component of the less vibrant and peaceful. Mind acquires a
universe. Hence, each component of the universe is also supernatural power of understanding the invisible
viewed as God. This gave way for worshipping rivers, and imperceivable universal truths which are not
animals, earth, sun, eclipses as God. This give birth to perceivable by ordinary mind. Mind gets cultured
different names and forms of Gods. Since God is in the spiritually and it acquires quality of nonattachment
form of energy it has to be felt by experience and by its to external happiness, so that internal happiness
effects. blossoms, which comes to the surface so that constant
The preachers of spirituality who either acquired ease is attained.
spiritual energy and/or felt the God later became Psycho-neuro-endo-immuno-cellular axis is
God men. People started understanding spirituality strengthened so that the body develops natural
and experience of God through these God men. Thus immunity to combact the diseases by natural
different God men came into existence. To draw the immunological process at the preliminary stages of
visual attention of the common man for the purpose the disease itself.
concentration and preaching the spirituality idols of God Maintains harmoneous balance between sympathetic
men were made. This has given birth to idol worships, and parasympathetic nervous system so that the
which is also a type of meditation and form of Bhakti adverse effects of catecholamines are prevented.
Yoga. The life stories of these God men, who practiced The body acquires the strength to deal both physical
spirituality came to be written and thus sacred religious and mental stressful situations without injury or
books, like, Mahabharata, Bible, Kuran, etc., came into much injuries to the body.
existence. It regulates the predetermined physiological
functions, so that they are not altred to lead on to
WHAT IS SPIRITUAL HEALTH? pathophysiological state.
“The spiritual health can be defined as the ultimate state It creates universal feeling and belongingness of one.
of constant ease (happiness) that is produced due to the
integrated effect of physical, mental and social health DIAGNOSTIC APPROACH
ultimately leading on to union with the transcedental The diagnosis of spiritual health is both subjective and
energy. The spiritual life style practices bring such objective and is very complex unlike physical, social and
integration between different aspects of health”. The mental health. However, the following informations will
spiritual life style involves both philosophical and help broadly to assess the status of spiritual health of an
scientific aspects. individual.
man thinks that the purpose of life is to be constantly and other biorhythms normal vital signs, happy
happy. charmful face, normal biorhythms, good physical
The reaction to stressful situations whether the and social health indicates normal spiritual health.
individual reacts aggressively or peacefully to stressful Alteration indicates ill health. Bradycardia, slow and
situations, etc. Spiritually healthy individuals reacts shallow respiration are features of good spiritual
calmly and peacefully to stressful situations. health.
The attitudes of the individual to other human beings Assessment of mental health: Good mental health is
and the universe, as to whether he has sense of love, an evidence of good spiritual health.
cooperation and sense of oneness and universality, Endocrinal assessment: Normal endocrinal functions
etc. Spiritual individual will have positive outlook to are evidence of good spiritual health.
these feelings. Biochemical parameters: Normal blood biochemical
Whether the spiritual practices are practised since parameters are evidences of good spiritual health.
childhood or later. Individuals practicing spirituality
since childhood will have better spiritual health.
CHAPTER
152
Cooking Oils: Which to Use?
Sonia Arora, Vitull K Gupta, Meghna Gupta
During the past decades, the world, particularly the supplies more than double the calories as compared to
developing countries like India have witnessed rapid carbohydrate or protein making it an important dietary
changes in diets and lifestyles. General improvement component with concentrated source of energy. Fat
in the standard of living has been accompanied by intake gives taste to diet, is metabolically important
unhealthy dietary patterns and insufficient physical constituent of the body, helps absorption of fat soluble
activity resulting in increased prevalence of lifestyle and vitamins A, D, E, and subcutaneous fat helps insulates
diet-related chronic diseases worldwide. World Health the body.
Organization states that by 2020 the place of largest
causes of death and disability will be occupied by CVDs COMPOSITION OF FATS
and prevalence of obesity, T2DM and hypertension Fats or lipids consist of fatty acids which are of two types:
which are considered to be chronic diseases related to 1. Saturated fatty acids (SFAs): SFAs are saturated with
the diet and lifestyle is also increasing. hydrogen atoms as carbon atoms have no double
bonds in the fatty acid chain comprising of lauric
INTRODUCTION acid, palmitic acid and stearic acid which provide
Diet includes foods and nutrients which provide energy stability to saturated fats and are usually solid at
and are essential for normal metabolism, physiologic room temperature because single bonds between
and biochemical processes, growth and physical well- the carbon atoms are more stable than double
being. Diet essentially comprises of macronutrients bonds. Fat intake increase total cholesterol (TC) and
like proteins, carbohydrates, fats and micronutrients LDL cholesterol which is an important risk factor
like vitamins and minerals which are required in for CVDs, certain cancer and also impairs insulin
small quantities. Triglycerides are components of sensitivity. SFAs is present in milk products (cream,
fat comprising of esters of alcohol glycerol and fatty ghee, butter, khoya, paneer), animal tallow, palm oil,
acid chains. Generally, the words “lipids”, “oils” and coconut oil, etc.
“fats” are used interchangeably. Fats that are liquid at 2. Unsaturated fatty acids (USFAs): USFAs comprises
room temperature are called “oils” and generally have of monounsaturated fatty acids (MUFA) and
unsaturated or short fatty acid chains. Word “fats” polyunsaturated fatty acids (PUFA). MUFA contain
broadly means solid fats at room temperature and one double bonds and PUFA contain more than one
word “lipids” include all oils and fats in general. Fat double bonds within the fatty acid chain.
902 SECTION 16: Social Issues
MUFAs: Lipid peroxidation occurs to a lesser degree and N-3 are converted into biological active components
in MUFA as compared to PUFA as MUFA contain one by competing for the common enzymes so when one
double bond only, e.g. oleic acid, erucic acid. Studies component is consumed more than the other, it leads to
have shown decrease in total mortality and CHD imbalance in the metabolism of N-6 and N-3 gradually
deaths with increased intake of MUFA. It is suggested affecting several metabolic processes. Recommendations
that MUFAs are useful because it helps decrease free suggest that adequate intake of N-6 and N-3 depends on
cholesterol by promoting cholesterol esterification in several factors like age, gender and life style, etc. and
liver, promote receptor mediated LDL uptake, lower LDL several organizations have recommended different ratios
and increase HDL. Recent evidence stress on exploring like N-6:N-3 of 4:1 (Institute of Medicine), 5:4 (World
the role of ratio of SFA, PUFA and MUFA in diet and Health Organization) and several suggest that ratio near
intake of individual fat components as they influence 1:1 may be considered as optimal ratio. Several foods
LDL/HDL ratio and lipoprotein metabolism. Dietary are good sources of both N-6 and N-3 and ratio may be
sources of MUFA include almonds, peanuts, fruits like different like N-6: N-3 ratio is 4:1 in walnuts, 1689:1 in
olives and avocados, olive oil, rice bran oil, groundnut almonds. In green-leafy vegetables, the ratio is less than
oil, canola oil and mustard oil. 1. So to improve the ratio several food combinations are
PUFAs: Contain two or more double bond, e.g. linoleic suggested to get the ration of at least 10 to 1.
acid, linolenic acid, arachidonic acid, eicosapentaenoic
acid (EPA), docosahexaenoic acid (DHA). PUFA intake TRANS FATTY ACIDS (TFAs) OR
decreases LDL and increases insulin sensitivity. Dietary PARTIALLY HYDROGENATED
sources include invisible fats present in pulses and FATTY ACIDS
cereals, sunflower oil, corn oil, safflower oil. Incomplete hydrogenation of vegetable oils results in
formation of Trans fats (TFs) and complete hydrogenation
Omega-3 and omega-6 fatty acids: Omega-3 (alpha-
linolenic acid) and omega-6 (linoleic acid) fatty acids results in formation of SFs. TFs may confer texture to food
are unsaturated “essential fatty acids” (EFAs) because and structural stability. Lamb and beef contain small
human metabolism cannot create them. quantity of natural trans fatty acids (TFAs). A review
suggested that even low consumption of 1–3% of total
Omega-6 fatty acids (linoleic acid N-6): At N-6 position, calorie intake of TF leads to increased risk of CAD and TFs
there is double bond between carbon-carbon atoms and are more dangerous to cardiovascular health than any
more number of double bonds make omega-6 fatty acids other macronutrient even on a per-calorie basis because
more prone to lipid per oxidation. Studies have shown it can lead to increase in LDL, triglycerides, lipoprotein
beneficial effects with lower incidence of T2DM and (a) and decrease in HDL adversely affecting metabolism
substantial reduction in risk of CHD. But, the beneficial of EFA and prostaglandins promoting thrombogenesis
effect of omega-3 is reduced by intake of more quantity of and insulin resistance. Sources of TFs include Dalda and
omega-6. Dietary sources include invisible fat in cereals Vanaspati ghee, margarines, baked foods, readymade
and pulses, margarine, safflower oil, corn oil, sunflower mithais and processed foods and ready to eat snacks.
oil, kardi oil, etc.
Cholesterol: Cholesterol, an essential component of
Omega-3 fatty acids (alpha-linolenic acid N-3): Omega-3 animal life is found in animal fats including dairy
consists of double bond at N-3 carbon atom and is
products and non-vegetarian foods. Chemically
precursors to anti-inflammatory products in the body.
cholesterol is a waxy sterol of fat. Very small amount of
Dietary sources include legumes, green-leafy vegetables,
cholesterol is present in plants so generally plant oils
citrus fruits and nuts and fish especially fatty fish.
are devoid of cholesterol. It is thought that absorption of
Omega 6 (N-6) to omega 3 (N-3) ratio: Balanced ratio of cholesterol from intestine is decreased by phytosterols, a
N-6 and N-3 is important for efficient body functions. N-6 plant product because both phytosterols and cholesterol
CHAPTER 152: Cooking Oils: Which to Use? 903
compete with each other for absorption in intestine. It is high smoke point are useful, fat composition of various
recommended to restrict the cholesterol consumption to oils, ratio between SFA, MUFA and PUFA or the shelf life
less than 200 mg by decreasing animal fat consumption. of oil or other specific qualities or flavor determine the
Adverse effects of increased consumption of cholesterol preference for use of that oil.
are because it increases total cholesterol and LDL but
Mustard oil: Mustard oil is economical, vegetarian oil
the adverse effects are relatively less as compared to
with characteristic pungent aroma and hot nutty taste,
increased consumption of SFAs and TFAs. Cholesterol
popularly used in East and North India containing 70%
broadly is of two types, low density lipoprotein (LDL)
MUFA (42% erucic and 12% oleic acid), 22% PUFA (10%
and high density lipoprotein (HDL). LDL is considered
N-3 and 12% N-6) and SFA is 8%. Evidence suggest that
as “bad cholesterol” responsible for atherosclerosis and
mustard oil which was previously thought to be harmful
CAD where as HDL is “good cholesterol” help prevent
because of high erucic acid content, is now considered
and retard progression of atherosclerosis.
as one of the best as it has near ideal N-6:N-3 ratio of 6:5
Cold pressed oils: Cold pressed oils are called when and contain low SFAs and high MUFAs and PUFAs along
ancient methods of hydraulic press is used to produce with high amount of antioxidants. Cold pressing adds to
oils and oils such produced are in natural state retaining the nutritional value of this oil. Studies indicate a dose
natural odor, taste, color, flavor and nutrition. dependent benefit of intake of vegetables/use of mustard
Refined oils: Refined oil are produced using mechanical oil on IHD risk.
and chemical extraction methods from seeds and Rapeseed oil (canola oil): It is produced from plant
vegetable products and these methods affect taste, belonging to Brassica family which is related to mustard
destroy antioxidants, generate free radicals and are more plant. It has high MUFA and low SFA contents with
susceptible to turn rancid but refined oils are relatively favorable omega-3 levels and is also known as “Canola
pure. oil” after the term ‘Canadian oil’.
Unrefined oils: Oils which are extracted from seeds or Olive oil: As the name indicates olive oil is extracted from
other vegetable material by exerting continuous pressure
olives and considered to be the best oil as it has 75%
at high temperature of 200–250°C are called unrefined
MUFA and numerous useful antioxidants (hydroxytyrol).
oils and these are different from ‘cold pressed’ oils called
High levels of MUFA and antioxidants (oleuropein or
‘expeller pressed’ oils. Unrefined oils retain antioxidants,
tyrosol) are present in extra-virgin or virgin olive oil which
other nutrients, flavor so these oils are considered better
is produced by minimum processing and intake of MUFA
and recommended for use.
is known to decrease LDL and increase HDL which exerts
antiinflammatory, antithrombotic, antihypertensive and
WHAT ARE COOKING OILS?
vasodilatory effect. Evidence suggests that antioxidants
Fatty acids triesters with glycerol which are in liquid
(oleuropein or tyrosol) have beneficial effect against
form at room temperature are the class of lipids known
some cancers, increases arterial elasticity, decreases risk
as oils and are generally found in both plants and
of stroke and IHD. Big disadvantage is its unfavorable
animals. Triglycerides that are solid or semisolid at
N-6:N-3 ratio.
room temperature are classified as fats and occur
predominantly in animals. Any material which has an Soya bean oil: Soya bean oil is one of the most commonly
oily or greasy feel and cannot be mixed with water is used cooking oils which is rich in PUFA and contains 51%
called “oil”. linoleic acid, 23% oleic acid and 7–10% alphalinolenic
acid (unsaturated fatty acids) and 10% palmitic acid and
Which Oils to Use? 4% stearic acid (SFAs). Soya bean oil should be used fresh
Out of numerous available oils, which oil to use depends because it tends to turn rancid earlier. It is suggested that
on the purpose of their use like for deep frying, oils with to achieve the combination of high PUFA and MUFA
904 SECTION 16: Social Issues
contents by combining the oils rich in MUFA or PUFA because its consumption may decrease total cholesterol,
like olive oil, mustard oil or groundnut oil to achieve LDL as well as HDL cholesterol. Other disadvantage is
optimum health benefits. that PUFA may turn rancid or toxic on exposure to high
temperatures.
Rice bran oil (RBO): RBO is produced from rice husk
and germ and contain 47% MUFA, 33% PUFA and 20% Palm oil: Fruits of palm are used to extract palm oil
SFA making it oil with most favorable constituents rich which is economical and has high smoke point making
in phytosterols, gamma-oryzanol and vitamin E. Its mild it favorable for frying. Cardiac benefits of palm oil are
flavor and high smoke point (254°C) makes it useful for controversial as it may contain 48% SFAs and unfavorable
deep frying. Only disadvantage is unfavorable N-6/N-3 N-6:N-3 ratio of 20:1. Red palm variety of palm oil is rich
ratio of 23:1. in carotenes like coenzyme Q10, glycolipids tocotrienols,
Sunflower oil: Sunflower oil is a good cooking medium tocopherols and phytosterols.
with clean taste and has high PUFA, low SAFs and low Coconut oil: Coconut oil is a plant fat extracted for
TFs with high contents of waxes, carotenoids, lecithin coconut fruit and contains high levels of SFAs (90%) very
and tocopherols. Sunflower oil has high levels of N-6 and little PUFA, MUFA, no cholesterol, vitamin E, vitamin
unfavorable N-6/N-3 ratio of 120:1. Moreover evidence of K and minerals such as iron. Coconut oil is primary oil
health benefits of high N-6 intake is limited. used by tropical people and its SFAs consist of lauric
Cotton seed oil: Cotton seed oil is economical, stable acid which differs from SFAs of animal origin. Lauric
for frying, has long shelf life because of natural rancid acid is responsible for increasing HDL levels and thereby
free property and contain 18% MUFA, 52% PUFA with increases total cholesterol.
naturally occurring SFAs (myristic, palmitic, stearic Butter: Butter is from animal source with high contents
acids) thereby called as “naturally hydrogenated” oil. of cholesterol and SFAs. Butter can increase total, LDL
It’s very high SFA and very low MUFA contents make and HDL cholesterol and its low smoke point makes is
its health benefits controversial. Moreover because of unfavorable for deep frying.
excessive use of agrichemicals, cotton seeds and so
cotton seed oil tends to contain high levels of pesticides, Ghee: Ghee is made by clarifying butter which has high
which may cause adverse health effects. It is commonly smoke point making it favorable for frying.
used in various types of processed and snack foods. Vanaspati ghee: Vanaspati ghee is made by hydrogenation
Corn oil: Germ of corn is used to extract corn oil (maize of refined vegetable oil. Hydrogenation increases TFAs,
oil) which contains 55% PUFA, 30% MUFA and 15% SFA. makes it less likely to turn rancid, more stable, increases
It is cheap and because of high smoke point useful for shelf life, but it does not contain bioactive compounds,
frying purposes. Its increased level of N-6 as compared natural vitamins or antioxidants and because of low
to N-3 may cause or predispose to some disease and smoke point it is not favored for deep frying. It is
depression. considered to be responsible for development of IHD
because of its adverse lipid profile.
Ground nut oil: Ground nut oil has a pleasant taste, high
smoke point and contains 56% MUFA (oleic acid), 26% CHOOSING THE RIGHT OIL
PUFA (linoleic acid) and 8% SFA (palmitic acid) which
Properties of cooking oil like fatty, acid contents,
makes it cardiac friendly oils because it rich in MUFA and
micronutrients, shelf life, smoke point, etc. are helpful
a balanced oil.
in selection of right cooking oil. Among the available
Safflower oil: Safflower oil has high smoke point favorable cooking oils, none of it fulfills the recommended profile
for frying and contains low SFAs (6%), low MUFA (13%) because if oil has high MUFA which is desirable, it may
and high PUFA (76%). It is not considered healthy oil not have desired N-6:N-3 ratio or appropriate ratio of
CHAPTER 152: Cooking Oils: Which to Use? 905
MUFA, PUFA or SFAs. So, it is recommended to rotate the various lipid contents, it is desirable to blend or rotate
oils like mustard oil, groundnut oil, canola oil, rice bran different cooking oils with favorable lipid contents and
oil, etc. to achieve the desired lipid contents. limit the use of visible fat content for achieving desired
favorable cardiovascular and overall health benefits.
WHY BLENDS ARE NEEDED?
Evidence suggest that cardiovascular health is greatly BIBLIOGRAPHY
influenced by dietary fat profile and type of fat affects the 1. Bester D, Esterhuyse, Truster EJ, van Rooyen J.
lipid profile of the individual increasing or decreasing Cardiovascular effects of edible oils: a comparison between
the CVD risk. Total cholesterol and LDL cholesterol are four popular edible oils. Nutr Res Rev. 2010;23:334-48.
2. Bockisch M. Fats and Oils Handbook. Champaign, IL: AOCS
increased with increased intake of SFs. Intake of TFAs
Press; 1998. pp. 95-6.
increase LDL cholesterol and decrease HDL cholesterol. 3. Cicero AF, Gaddi A. Rice bran oil and gamma-oryzanol in the
Intake of PUFA greatly reduces the CVD risk as compared treatment of hyperlipoproteinemias and other conditions.
to MUFA. CVD protection is imparted by both N-6 and N-3 Physiother Res. 2001;15:277-86.
by various mechanisms like vasodilation, antiarrhythmic 4. Connor WE. Alpha-linolenic acid in health and disease. Am J
effect, anti-inflammatory effects, improves endothelial Clin Nutr. 1999;69(5):827-8.
function, decreased platelet aggregation and reduces 5. Harris WS. Fish oils and plasma lipid and lipoprotein
metabolism in humans: a critical review. J Lipid Res.
collagen deposition. Evidence suggests that different lipid
1989;30(6):785-807.
components have different favorable and adverse health 6. Hill EG, Johnson SB, Lawson LD, et al. Perturbation of the
effects. No cooking oil can fulfill the recommended ratio metabolism of essential fatty acids by dietary partially
of different lipid components for favorable health and hydrogenated vegetable oil. Proc Natl Acad Sci USA.
CVD effects, necessitating the need to blend cooking oils 1982;79(4): 953-7.
to achieve desired lipid contents for health benefits. 7. Howell WH, McNamara DJ, Tosca MA, et al. Plasma lipid and
lipoprotein responses to dietary fat and cholesterol: a meta-
analysis. Am J Clin Nutr. 1997;65(6):1747-64.
CONCLUSION
8. Joshi S, Joshi SR. Medicine Update 2013: Chapter 140.
In this present era of consumerism, people are exposed www.apiindia.org/medicine_update_2013/chap140.pdf.
to different type of cooking oils glorified with tall 9. Kris-Etherton P, Daniels SR, Eckel RH, et al. Summary
health claims and benefits, advertizing various cooking of the scientific conference on dietary fatty acids and
oils with attractive slogans, highlighting presence or cardiovascular health: conference summary from the
absence of different lipid contents to influence people’s nutrition committee of the American Heart Association.
choice of cooking oils. This chapter discusses various Circulation. 2001;103(7):1034-9.
10. Marina AM, Che Man YB, Amin I. Virgin coconut oil: emerging
lipid contents, their harms and health benefits, desired
functional food oil. Trends in Food Science & Technology.
composition of different lipid contents and composition 2009;20(10):481-7.
of different cooking oils in an attempt to demystifying the 11. Martin G, et al. Health effects of oxidized heated oils.
fancy statements for all the people. Out of the discussed Foodservice Research International. 2001;13:41-55.
edible oils, none of the oils fulfill the recommended 12. Mishra S, Manchanda SC. Cooking oils for heart health. J.
criteria of lipid contents but two oils rapeseed and Preventive Cardiology. 2012;1(3):122-31.
mustard oil which have high PUFA and MUFA, low SFA 13. Rastogi T, et al. Diet and risk of ischemic heart disease in
India. Am J Clin Nutr. 2004;79(4):582-92.
content and highest N-3/N-6 ratio seems to be imparting
14. Tarrago-Trani MT, et al. New and existing oils and fats used
most health and CVD benefits. Evidence suggests use of
in products with reduced trans-fatty acid content. J Am Diet
ghee and butter as a cooking oil should be limited and Assoc. 2006;106(6):867-80.
use of reheated fats and oils should be avoided. Since 15. Turner R, et al. Antioxidant and anti-atherogenic activities of
none of the available cooking oils fulfill the criteria of olive oil phenolics. Int J Vitam Nutr Res. 2005;75(1):61-70.
CHAPTER
153
IT Solution in Regulation of Medical
Education and Medical Practice
Ajay Kumar
IT has percolated into the human life globally through of Clinical Establishments, approval system for medical
different modalities. It has a major role to play in modern colleges. The admission to medical and dental colleges
day activities. To think life without IT solutions is like of the country has been made online. Other activities
boat without a rudder. Like rudder of the boat, IT helps like National Organ and Tissue Transplant Organization
to navigate life in an intended direction. Delivery of (NOTTO), Central Drug Standard Control Organisation
healthcare to the people of today cannot be imagined (CDSCO) have their separate web portals.
without the help of IT solutions. E-governance provides The healthcare providers in public and private
the ground for IT driven healthcare. India stands at sector and also the health insurance companies are
54th position in e-governance. With the vision and transforming the activities through IT solutions for better
mission of our beloved Prime Minister Shri Narendra patient care. There is also fast growing sector of tele-
Modi e-governance is growing leaps and bounds in our health, mobile health and wireless health to benefit the
country. rural masses which constitutes 75% of the population
E-health has been launched by Govt of India which of the country. Smart hospital are the future of the
has got multiple components. Ministry of Health and country which is about transforming health towards
Family Welfare has taken initiative to streamline the decentralized and connected care.
medical education. It has amended the MCI regulation With a wide geographical economical, social and
early this year to make it compulsory for all medical cultural diversity and excessive population burden where
colleges of the country to monitor the faculty attendance few island of prosperity is draining the resources of vast
and live streaming of teaching activities. MCI, through sea of poverty, it is mammoth task to provide healthcare
its Digital Mission Mode Project (DMMP) has been to the last door step of the country.
actively pursuing the IT based activities including With a positive mindset of the government and
OFAMOS (Online faculty attendance monitoring system) enlightened minds supported by electronic solutions
for medical colleges and generation of UPRN for every we are inching forward to improve the healthcare in our
practioners of the country registered with Medical country across the board. I conclude with a famous poem
Council of India. Live streaming of the teaching activities of Robert Frost.
in medical colleges is underway which will be monitored “The woods are lovely, dark and deep,
by MCI. But I have promises to keep,
Through e-governance portal the Ministry of Health And miles to go before I sleep,
and Family Welfare has started many activities. Registry And miles to go before I sleep.”
SECTION
17
Miscellaneous
Changing Trends in Medicine: Past, Present and An Approach to Recurrent Falls in the Elderly
Future S Ramnathan Iyer, Revati R Iyer
Pritam Gupta, Ghan Shyam Pangtey, Sujata Mangla
Ultrasonography in Critically Ill Patients
Isoniazid Preventive Therapy: Operational Sameer Gulati, Bhupendra Gupta
Guidelines
Imaging Parameters in Pulmonary
Mohanjeet Kaur, Ashish Chawla
Thromboembolism
Hypnotherapy in Medical Disorders Priya Jagia, Niraj Nirmal Pandey
Rajeev Mohan Kaushik
CHAPTER
154
Changing Trends in Medicine:
Past, Present and Future
Pritam Gupta, Ghan Shyam Pangtey, Sujata Mangla
of several earlier works and was written c. 1600 BC. various ailments later formed large part of Ayurveda.
It is an ancient textbook on surgery from Egypt and It means “complete knowledge for long life” is another
describes detailed examination, diagnosis, treatment medical system of India. Charaka and Sushruta are the
and prognosis of various diseases known during that two famous divisions of Ayurveda and its date backs
time. to around 600 BC. According to the compendium
of Charaka, the Charakasamhitā, which dealt with
Ancient Greek Civilization: is known for having good
medical-nonsurgical part of Ayurveda, according to it
medical knowledge and therefore also considered
the health and disease are not predetermined and life
to be the stepping-stone for modern medicine. The
may be prolonged by human effort. The compendium of
most famous Greek physician Hippocrates is well
Suśruta, the Suśrutasamhitā, which dealt with surgical
known to everyone. The Hippocratic oath was first
part of medicine, described detailed surgical procedure
written in 5 th Century BC in Greece and even today
of various forms of surgery, which included rhinoplasty,
every physicians swear upon it on entry into medical
ear lobes repair, perineal lithotomy, cataract surgery, and
profession. Hippocrates stressed that doctors should
several other excisions, and other surgical procedures.
carefully observe the patients symptoms and take note
Both these ancient Indian compendia include details of
of them. Although, on one hand most Greeks believed
the examination, diagnosis, treatment, and prognosis of
in their god of healing called Asclepius. The sacrifices
numerous ailments.
or offerings were gifted to the god by the diseased and
In western world from ancient times up to Renaissance
people even used to sleep overnight in the temple with
period of 14 th century the knowledge of living world
the belief that, god would visit them overnight in their
changed very little and any distinction between animate
sleep (i.e. dreams) and this will heal them. At the same
and inanimate objects was blurred and speculations
time, few Greek doctors developed a rational theory
about living being were based of old prevailing ideas of
of disease and sought their cures. However, one did
the society.
not replace the other. The cult of Asclepius and Greek
Advances in science and philosophy throughout
medicine existed side by side.
the 16 th and 17 th centuries in Europe led to equally
Medical schools were formed in Greece and in
momentous changes in medical sciences. Belgian
Greek colonies around the Mediterranean. A number of
anatomist Andreas Vesalius also known as founder
Greeks speculated that the human body was made up
of modern anatomy, swept away the centuries of
of elements; if they were properly balanced the person
misconceptions about the human body structure
will be healthy. However, if they became unbalanced
and function. He published the first illustrated book
the person will fall ill. Similarly, Aristotle (384–322 BC)
of human anatomy “de humani corporis fabrica” in
brought the idea that the human body was made up of
16th century. The work of Isaac Newton, and Robert
four humors. They were phlegm, blood, yellow bile and
Boyle disposed of the basic Aristotelian elements of
black bile. If a person had too much of one humor they
earth, air, fire, and water; Robert Hooke invented the
fell ill. For instance, if a person had a fever he must have
first medical microscope, which showed the world
too much blood. The treatment was to cut the patient
microscopic organisms, which were invisible till then.
and let him bleed. The ancient Greek people also knew
In 1628, William Harvey described the circulation of the
that diet, exercise and cleanliness are important part of
blood, a discovery that, because it was based on careful
health.
experiments and measurement, signaled the beginnings
Ancient India: The Atharvaveda, a sacred text of Hinduism of modern scientific medicine.
is one of the first Indian textbooks dealing with medicine. After steady progress during the 18th century, the
The Atharvaveda contained herbal prescription for biological and medical sciences began to advance at
various ailments. The use of herbal medicines to treat a remarkable rate during the 19th century, which saw
CHAPTER 154: Changing Trends in Medicine: Past, Present and Future 911
the genuine beginnings of modern scientific medicine. Clinical Epidemiology and Public Health
Charles Darwin’s “theory of evolution” changed the Modern epidemiology came into existence during the
whole course of biological thinking, and this was followed later part of 20th century, when increasingly sophisticated
by Gregor Mendel’s ground breaking fundamental laws of statistical methods were first applied to the study of
inheritance, which are the root to modern genetics. Louis noninfectious disease to analyze the patterns and
Pasteur and Robert Koch founded modern microbiology. associations of diseases in large populations. The
Koch’s postulated the causal relationship between emergence of clinical epidemiology marked one of the
microbes and disease production thus giving rise to most important successes of the medical sciences in the
modern microbiology. These advances in the biological 20th century.
sciences were accompanied by practical developments The epidemiologic information about the frequency
at the bedside, including the invention of the stethoscope and distribution of noncommunicable disease (NCD)
by Lennec and sphygmomanometer by SS Karl Ritter von cancer, diabetes, stroke heart attack, etc. and in particular,
Basch in 1881. The first use of X-rays, the development the speed with which their frequency increased in
of anesthesia, the early development of the use of association with environmental change, provided
statistics for analyzing data obtained in medical practice excellent evidence that many of them have a major
occurred in the 19th century. All these were the major environmental component. The first major success of
advancement in medicine, which played pivotal role in clinical epidemiology was the demonstration of the
shaping modern medicine. relationship between cigarette smoking and lung cancer
Significant advances in public health occurred on by Austin Bradford Hill and Richard Doll in the United
both sides of the Atlantic. After the cholera epidemics Kingdom. This work was later replicated in many studies.
World Health Organization estimation suggest that
of the mid 19th century led to significant advancement
upto 8.8% of deaths (4.9 million) and 4.1% of disability-
in public health on both sides of Atlantic, public
adjusted life years (59.1 million) are secondary to
health boards were established in many European and
tobacco use.
American cities. The Public Health Act, passed in the
The other major development that arose from
United Kingdom in 1848, provided for the improvement
the application of statistics to medical research was
of streets, construction of drains and sewers, collection
the development of the randomized controlled trial.
of refuse, and procurement of clean domestic water
Ronald Fisher first set out the principles of numerically
supplies. Equally important, the first attempts were made
based experimental design in the year 1920s. Evidence
to record basic health statistics.
based medicine (EBM) is another valuable addition
in the way medical professional think on the basis of
MEDICINE IN THE 20TH CENTURY judicious, conscientious use of best available evidence
There was rapid gain in life expectancy during 20 th before making decisions about the care of individual
century largely due improvement in public health patients. The EBM comes from previous experience,
and lesser due to progress in medicine. The slow trials and research and this has lead to development of
development in medical sciences was most likely due good clinical practice in medical profession. It integrates
to burden of two world wars. The position changed clinical experience and patient values with best available
dramatically after World War II, a time that many still research information, particularly implementation, or to
believe was the period of major achievement in the say getting research into practice.
biomedical sciences for improving the health of society.
Some major developments and the effect they have had Control of Infectious Diseases
on medical practice in both developed and developing The control of communicable infections has been
countries will be highlighted in this section. another major achievement in the medical science
912 SECTION 17: Miscellaneous
of 20th centur y. The contribution of improved and more vengeance. The ‘Edinburgh method’ of
environmental conditions and betterment of public combined anti tubercular therapy was first developed
health had significant role in controlling these infection. by Sir John Crofton and his team in the 1950s. This has
The development of successful immunization against been recognized as the single-most important treatment
childhood infections, discovery and treatment of newer of tuberculosis (TB) and was adopted worldwide. This
pathogens with antibiotic chemotherapy were vital in significantly reduced death rates from TB and is one of
achieving the reduction in mortality and morbidity due the major finding of the century.
to communicable diseases. Currently, 29 vaccine (live In summary, although the 20 th century witnessed
or killed) against common communicable diseases remarkable advances in the management of
has been licensed for use worldwide; these are based communicable disease by developing newer antibiotics,
on bacterial polysaccharides, bacterial toxoids or viral the current position is uncertain due to development
particle based. The best example of the vaccination of resistance. The emergence of new infectious agents,
success is the eradication of smallpox from the world as evidenced by the severe acute respiratory syndrome
since year 1977. (SARS) epidemic and recent Ebola virus infection in
The World Health Organization’s (WHO) launched Africa is a reminder of the constant danger posed by
Expanded Program on Immunization (EPI) in year the appearance of novel organisms. More than 30 new
1974, which was introduced in India after four years in infective agents have been identified worldwide since
1978. In 1985, the EPI program was renamed by Indian 1970.
Government as Universal Immunization program (UIP)
and under the program vaccination of pregnant woman Management of Noncommunicable
with tetanus toxoid vaccine was also added, while Diseases
typhoid vaccination was removed. The various vaccines The second half of the 20 th century has resulted in
given under UPI schedules are Bacillus Calmete-Guerin significant improvement in knowing the pathophysiology
(BCG), oral Polio vaccine, DPT vaccine and measles. and management of NCD especially cardiac disease,
Recently Haemophilus Influenzae type b, Hepatitis B cancer and gastroenterology. This phase of medical
vaccine, and rotavirus vaccine has also been added to sciences also evidenced significant advancement
the UPI vaccination program, which is better known as secondary to developments in the pharmaceutical
“Mission Indradhanush”. industry, and had led to a situation in which few
The discovery of penicillin and sulphonamide noncommunicable disease (NCD) exist for which there
antibiotic around World War II remarkably changed is no treatment.
the scenario of infectious disease. The effectiveness of Cardiovascular advances: Cardiovascular system (CVS)
these antibiotics is still considered one of the greatest received major technological advances in 20th century,
achievements for the medical science. This was followed which has led to better appreciation of cardiac physiology
by further progress and discovery of other antimicrobial and pathology of CVS. Electrocardiography, left and right
agents, which were found to be effective against bacteria, heart catheterization, development of echocardiography
fungi, viruses, protozoa, and helminths. In spite of and recent development of radiologic and nuclear
more than half century of successful use of antibiotics imaging (Cardiac CT, Cardiac MRI and radioisotope
we are now on the verge of losing these potent tools to scanning of heart). Development and effectiveness
fight microbes due to irrational antibiotics use as well of various CVS drugs (beta blockers, ACE inhibitors,
as development of smart pathogens that can escape diuretics and anticoagulants, etc.) has also played
these drugs by developing antibiotics resistance. These major role in reducing cardiac mortality and improving
antibiotics resistant microbes can become multi drug patient’s quality of life in 20th century. Cardiothoracic
resistance (MDR) pathogen leading to higher virulence surgery (on and off pump), coronary bypass surgery,
CHAPTER 154: Changing Trends in Medicine: Past, Present and Future 913
balloon angioplasty are the additional achievements MEDICAL SCIENCE AND TECHNOLOGY
of cardiology. Development of implantable cardiac IN 21ST CENTURY
defibrillator and pacemaker has also saved many Newer technological advances in medical field have
cardiac patients from end stage heart failure and markedly improved the diagnosis and management of
sudden arrhythmias. Recent successful Heart and Lung many diseases. Considering rapid growth in technology
transplantation has given more hope to these heart in last two decades, the expectation is very high that
failure patients. many more disease and condition can be cured or
Cancer: Oncology is another medical branch after controlled. The sections that follow briefly outline some
cardiology, which has seen significant improvement in examples of the new technologies that should help
achieve these aims.
patient’s diagnosis, with development of sophisticated
diagnostic technology. Management has also with
Genomics, Proteomics, and Cell Biology
improved secondary to better advanced localized
In the last couple of decades, there have been some major
radiotherapy machines and the use of powerful
development in the field of molecular and cell biology.
anticancer drugs. This approach has led to remarkable
The human genome project was partially completed
improvements in the outlook for particular cancers,
in 2001 but till date not much have been achieved with
including childhood leukemia, some forms of lymphoma,
it. As we know that the majority of common diseases
testicular tumors, and tumors of the breast.
clearly do not result from the dysfunction of a single
Gastroenterology: Development of flexible endoscopy gene, most diseases can ultimately be defined at the
and proton pump inhibitor therapy markedly improved biochemical level. The human genome project also
the natural history and management of acid peptic encompasses many infectious agents, animals that
disease. Further improvement in endoscopic techniques are valuable laboratory models of human diseases,
leading to further diagnostic and therapeutic utility disease vector and wide variety of plants. The study of
revolutionized gastrointestinal field and improved human genome will require identification and analysis
patient’s experience and safety as well as physicians of function of up to 25000 gene (proteonomics) and the
satisfaction. mechanisms whereby genes are maintained in active
or inactive states during development (methylomics). It
High Technology Cost and Its Economic will also involve the exploration of the roles of the family
of regulatory ribonucleic acid (RNA) molecules. All this
Consequences
information will have to be integrated by developments
The health care expenditure has increased exponentially
in information technology and systems biology. These
with development of sophisticated modern medical
tasks are time consuming and may take many decades to
practices. The problem has become so severe that it’s fully elucidate human genome.
becoming difficult for even industrialized countries to The first application of DNA technology in clinical
bear the cost of it, while for developing countries like practice is being done by using candidate gene approach
India; it is becoming impossible to control. The cost or using DNA markers of monogenic diseases. This
escalation of medical healthcare may be due to higher information is being used in clinical practice for carrier
cost of newer technology as well as other reasons such as detection, for prenatal diagnosis, and for defining
overpopulation, greater public awareness and consumer of the mechanisms of phenotypic variability. It has
demand for medical care, and greater ability to control been particularly successful in the case of the most
most chronic illnesses. This will need further research common monogenic diseases, the inherited disorders
and improvisation in health care delivery system to make of hemoglobin synthesis, which affect hundreds of
it cost effective so that it can reach poorest of poor. thousands of children in developing countries.
914 SECTION 17: Miscellaneous
In developing countries, rapid diagnostic kit are person’s genetic profile for metabolism of common
being made using DNA technology. These methods use drugs can be worked out. This will lead to individualized
PCR technique to identify pathogenic organism antigen drug treatment and care; this may be become part of
or DNA in blood or tissue. These approaches are being physicians toolkit in coming years.
further refined for identifying organisms that exhibit
drug resistance and also for subtyping many classes Stem Cell and Organ Therapy
of bacteria and viruses. The Cartridge Based Nucleic Organ transplant surgeries have its limitations in organ
Acid Amplification Test (CB NAAT)/ Gene expert test availability, expensive surgeries and follow up costs;
for diagnosis of rifampicin resistance in Mycobacterium the successful stem cell therapy can overcome these
tuberculosis (MTB) is classic example of this techniques limitations by readily supplying the cells to replace the
use in clinical practice, which has drastically improved tissues. The pluripotent stem cells can be obtained
diagnosis of MDR/rifampicin resistance in MTB. from various tissues; early embryos, placenta, bone
Although much remains to be learned about the cost- marrow, etc. Therapeutic cloning is an area of research
effectiveness of these approaches compared with more in cellular biology that is raising great expectations and
conventional diagnostic procedures. Another example of bitter controversies too. Bone marrow transplantation
this type of technology being used is in identification of has been successfully done in wide range of blood
new organisms like coronavirus, which was responsible
diseases. The technique of somatic cell nuclear transfer
for SARS outbreak in 2002. The remarkable speed with
involves adult cell nuclei transfer into egg without
which a new corona virus and its different subtypes were
nucleus leading to development of embryo, which can
identified was amazing and helped a lot in managing and
be used for regenerative therapy for particular donor
tracking the SARS infection.
cells. This, follows similar lines to those that would be
Genomics is likely to play an increasingly important
required for human reproductive cloning, therefore
role in the control and management of cancer. It is now
raising number of controversies. If society is able to
well established that malignant transformation of cell
overcome the various terms of ethical issues, this field
populations usually results from acquired mutations
holds considerable promise for correction of a number of
in two main classes of genes oncogenes or tumor
different intractable human diseases.
suppresser gene. Chronic myeloid leukemia (CML) due to
Philadelphia chromosome resulting from translocation
between chromosomes 9 and 22: t(9:22)(q34:q11) is
Immunotherapy for Cancer
classical example of genetics being successfully used CAR T cells immunotherapy for leukemia: Chemeric
in cancer diagnosis and management. The disease antigen receptor T cell therapy has been the most
can be treated with Tyrosine kinase inhibitor, whose recently approved treatment of refractory and relapsed
transcription results from this translocation. acute lymphoblastic leukemia (ALL). It’s a form of
Array technology, which examines the pattern of emerging immunotherapy approach also known as
expression of many different genes at the same time, is adoptive cell transfer. In this technique, the patients
already providing valuable prognostic data for cancers of own immune cells (T cells in this case) are collected
the breast, blood, and lymphatic system. This technology and modified in vitro so that they recognize the cancer
will become an integral part of diagnostic pathology cells receptors and kill the cancer cells once they are
in the future, and genomic approaches to the early reintroduced back into the body. Many more CAR T
diagnosis of cancer. based drugs are in pipeline for various indications from
Pharmacogenomics is another potential develop leukemia, lymphoma to solid tumor as well. The only
ment from the genomics revolution. Each individual has major problem at present with the drug is exorbitant
considerable variability in the metabolism of drugs. In pricing. The FDA approved Novartis drug Kymriah with
future, clinical medicine can reach a stage where every price of $475,000 for relapsed ALL.
CHAPTER 154: Changing Trends in Medicine: Past, Present and Future 915
Information Technology 2.5 billion people and projected food requirement will be
The explosion in information technology has important more then double. Considering there is regular decline
implications for all forms of biomedical research, clinical in annual rate of cereal production in world and 20–40%
practice, and teaching. Genomic public database of potential production is lost to pathogens in developed
biomedical research has been kept securely in triplicate and developing countries, respectively. Considering the
in the following places in three different continents upcoming shortage of food in future the GM plants have
(Europe-European Bioinformatics Institute, United considerable potential for improving food shortage in
the world. The main aim of GM crop is to enhance the
States-GenBank and Japan-DNA Data Bank of Japan).
nutritional value of crops and make them resistance to
Twenty first century also brought the emergence
pathogens so that crop loss is minimal. Concerns are
of Electronic publishing of high-quality journals and
also expressed about the safety of GM crops, and a great
related projects and international biomedical website,
deal more research is required in this field. The results
which helped in linking scientists in industrial countries
of biosafety trials in Europe raise some issues about the
with developing countries. The increasing availability of
effects of GM on biodiversity.
telemedicine education packages will help disseminate
Researchers are also trying to produce GM plants,
good practices in resource limited setting (rural and
which can be used for controlling disease. The GM plants
developing countries).
can be modified to produce molecules that are toxic to
disease carrying vectors or they may also be modified
Minimally Invasive Surgery to make edible vaccine. These edible vaccines will be
Minimally invasive surgery (MIS) has been a game cheaper then conventional vaccines and will also have
changer in medical-surgical field in 21st century. It has the advantage of easy transportation, as they can be
changed the hospital admission and discharge practice freeze dried and shipped anywhere in the world. Edible
of inpatient care by reducing the number of days of Hepatitis B vaccine is being made in transgenic plant for
stay of post surgical patients leading to significant cost oral immunization.
reductions and reduced morbidity. The advances in
endoscopic imaging and instruments have also made Newer Technologies and Developing
many open procedures as day care procedures, which Countries
can be done endoscopically. The following procedures: The scientific technology has given the hope of
the gall bladder surgery, treatment of adhesions, removal improvement in medical healthcare by leaps and bounds
of fibroids, nephrectomy, and many minor pediatric but there is also major apprehension about it, especially
urological procedures are being done routinely as MIS. considering the poor economic, social and health care
infrastructure state in developing countries. According to
Robot in Medicine WHO, it may be too early to consider that the full benefits
Robot’s use in surgeries like Heart, Cancer, Prostate, of genomics and related technology will be available
Kidney and Brain is very common which minimizes the to developing countries of Asia and Africa, instead the
complications, blood loss and helps in early mobility. industrialized-developed countries will only exploit the
Intravascular injections of chemotherapy for targeting most pressing and potentially exciting developments
inoperable cancers are also being done by robots. from the new scientific technologies.
Liquid biopsies for circulating tumor DNA: the NCD taking over communicable diseases. The future
technological advancement in genetics can detect appears bright with significant contribution coming
early cancers by analyzing blood samples for cell free from developments in science and technology. The
circulating tumor DNA (ctDNA). This test is called liquid average life expectancy has increased in most countries.
biopsies and studies to formalize this test by detecting But with these developments, some different form of
ctDNA are in early phase of clinical trials. Experts believe problems has arisen: urbanization, increasing geriatric
it’s only a matter of time before diagnosing and treating populations and spiraling healthcare cost. Another
cancer become a routine like a annual medical checkup. major issue is regarding disparity in distribution and
availability of medical technology research. There is
Genome editing or CRISPR-Cas9: Clustered Regularly
very wide gap in world research funding with majority
Interspaced Short Palindromic Repeats and CRISPR-
of disability and premature mortality occurring in poor
associated protein 9 is adapted from naturally occurring
developing country while the research area and topics
genome editing bacteria. These gene-editing technologies
are severely tilted towards industrialized countries of
allow genetic material to be added, removed, or altered
Western countries. This bias needs against developing
at particular locations in the genome. The CRISPR-Cas9
countries needs to be corrected before we work towards
system has generated a lot of excitement in the scientific
universal healthcare coverage for all.
community because it is faster, cheaper, more accurate
Although with advancement of technology, medical
and efficient than other methods.
fraternity has got extra edge in overall patient care,
CRISPR-Cas9 was adapted from a naturally occurring
making appropriate diagnosis and treatment; but this
genome editing system inside bacteria. The Cas-9,
technological dependence has also led to deterioration
endonuclease of bacteria breaks DNA of invading viruses
of practice of clinical medicine. We have lost the art of
and uses them to create CRISPR arrays. The CRISPR
proper history taking, doing relevant examination and
arrays allow the bacteria to “remember” the viruses
the art healing touch as we are more and more relying
(or closely related ones). If the viruses attack again, the
on laboratory and radiologic test reports. We have
bacteria produces RNA segment from the CRISPR arrays
developed some so advanced technological centers
to target the viruses’ DNA and disables the virus.
where there is no patient-physician interaction, instead
only machine-patient interaction, with these centers we
SUMMARY
also lost the opportunity to show empathy with patient
The exponential development in the medical science
and their care givers.
and technology has markedly improved medical
We have to take middle path where we should
healthcare and reduced the suffering of human mankind.
keep the art of clinical medicine, healing touch and
Disease treatment, methods, dental procedures and
soothing empathetic words intact and combine it with
scriptures have been found since ancient civilizations
newer technological advances, and then only we can
of Egypt, Babylon, China and India; but the foundation
progress as a true healer. We will have to make our
of modern medicine was laid down after renaissance
medical practice more patient oriented and empower
period in Europe (14th Century) with development of
our patients in decision-making. This middle path will
important scientific theories and scientific methods.
also keep check on spiraling cost of medical care that is
The medical healthcare showed rapid growth and
going out of reach of general population and bring more
developed into modern medicine in 19 th–20th century
patient’s satisfaction.
with maximum pace of growth seen after World War
II. Significant advances were reported in specialty
BIBLIOGRAPHY
of cardiology, oncology, gastroenterology and renal 1. Alber ti G. Noncommunicable diseases: Tomorrow’s
medicine. India as well as many developing countries Pandemics. Bulletin of the World Health Organization.
is in epidemiologic transition phase with burden of 2001;79(10):907.
CHAPTER 154: Changing Trends in Medicine: Past, Present and Future 917
2. Bumol TF, Watanabe AM. Genetic information, genomic 5. Weatherall D, Greenwood B, Chee HL. Science and Technology
technologies, and the future of drug discovery. Journal of for Disease Control: Past, Present, and Future. In: Jamison
the American Medical Association. 2001;285(5):551-5. DT, Breman JG, Measham AR, et al., editors. Disease Control
3. Cooter R, Pickstone J. Medicine in the Twentieth Century. Priorities in Developing Countries. 2nd edn. Washington (DC):
Amsterdam: Harwood acdemics. 2000. The International Bank for Reconstruction and Development/
4. https://ghr.nlm.nih.gov/primer/genomicresearch/genome The World Bank; 2006. Chapter 5. Available from: https://
editing. www.ncbi.nlm.nih.gov/books/NBK11740/Co-published by
Oxford University Press, New York.
CHAPTER
155
Isoniazid Preventive Therapy:
Operational Guidelines
Mohanjeet Kaur, Ashish Chawla
Tuberculosis is a highly infectious disease with TB burden Number (lakhs) Rate per 100,000
significant mortality. It is estimated that every year about India Global India Global
2 million people develop TB in India. WHO had declared Incidence 28.4 104 217 142
tuberculosis as a Global Emergency in 1993. Table 1 and Mortality 4.8 14 32 19
2 shows epidemiology of TB in India and its comparison
globally.
TABLE 2: MDR-TB burden
TB AND HIV MDR-TB burden India Global
The estimated annual incidence of HIV–TB co-infected % of new cases with MDR/RR 2.5 3.9
patient in India is 1,10,000. As per notification under % of previously Rx cases with 16 21
RNTCP, it has been found that due to HIV and TB MDR/RR
coinfection, the death rate is as high as 15% in India. Incidence of MDR/RR 1.3 lac (79000 5.8 lacs
among notified)
HIV-TB COLLABORATIVE ACTIVITIES 9.9/lac 7.9/lac
The National AIDS Control Programme (NACP) and Notified in RNTCP 28876 1.32 lacs
RNTCP have undertaken joint collaborative efforts in Put on Rx 26966 1.25 lacs
this direction. A National framework was developed Abbreviations: MDR, Multidrug Resistance; RR, Rifampicin resistance
in 2008 and 2009 which was later updated in 2013. It
incorporated the National AIDS control organization
All HIV patients should be screened with 4-symptoms
(NACO) and central TB division (CTD) to initiate an (4s) algorithm for TB (Figs 2 and 3).
integrated TB and HIV services. The emphasis is laid on Availability of car tr idge based nucleic acid
preventive measures to ensure a reduction in incidence amplification Test (CBNAAT) for all PLHIV to detect
as well as mortality (Fig. 1). TB at the earliest stage. This detects rifampicin
resistance as well.
SINGLE WINDOW SERVICES Dispensing of daily ATT.
In order to deliver seamless services for early diagnosis, Dispensing of INH for prophylaxis in PLHIV.
treatment and prevention of tuberculosis; single window Dispensing co-trimoxazole (CTM).
approach has been adopted by the government of India. Educational activities regarding AIC.
CHAPTER 155: Isoniazid Preventive Therapy: Operational Guidelines 919
IPT in Children
As per standard 16 of TB care in India following groups of
children require IPT:
Any child below 6 years of age who is in close contact
If a patient while on IPT develops active TB, he should EVALUATION OF THE PATIENTS
get drug sensitivity test followed by appropriate (BEFORE STARTING IPT)
treatment. Following things should be ruled out:
If a person develops TB after completing IPT, he Active and chronic hepatitis
for TB in the past, should receive INH for 6 months symptoms of numbness and burning sensation.
(secondary prophylaxis). It should be given in PLHIV
irrespective of their degree of immune status. REGIMEN PLAN FOR IPT
In an HIV patient who has just completed ATT; INH The regimen plan and dosing charts are given below
should be given for another 6 months. (Tables 3 and 4)
includes the medial temporal lobe, part of the medial The worst hypnotic subjects usually have very short
prefrontal cortex, the posterior cingulate cortex, the attention spans, tend to focus on past and future rather
adjacent ventral precuneus and inferior parietal cortex, than present, are overly critical, use logic instead of
is considered to generate spontaneous thoughts and to emotions, have lower IQ’s and have great difficulty in
be essential for creativity. letting themselves go. Senility, brain damage, mental
retardation, inability to understand the language of the
PHYSIOLOGICAL EFFECTS OF HYPNOSIS hypnotherapist and overall cynical attitudes also inhibit
Hypnosis is a natural body-and-mind phenomenon. the induction of hypnotic trance.
A constellation of physiological changes is produced
during hypnosis, in addition to shifts in perception. Levels of Hypnosis
Generally, there is an increase in the production of alpha For simplicity, it is possible to divide hypnotic
rhythms. This EEG pattern is similar to that of relaxation. susceptibility into five stages. Stages three, four and five
In addition, there occurs an increase in basal skin are clinically relevant.
resistance, decrease in respiration, basal metabolism, 1. Insusceptible
cardiac output and an increase in body temperature. So it 2. Hypnoidal-precursor to hypnotic state, no symptoms
resembles relaxation physiologically while cognitively, it 3. Light stage
looks more like dreaming. Neurophysiologic studies have 4. Medium stage
shown that despite similarities, hypnosis is more than 5. Deep stage
and different from simple imagination, relaxation, sleep It is important to keep in mind that hypnosis is like
and the placebo response. any other therapeutic modality: it is of major benefit to
some patients with some problems, and it is helpful with
FACTORS AFFECTING many other patients, but it can fail, just like any other
THERAPEUTIC RESPONSE clinical method.
trance is achieved by a subject without another person’s TABLE 1: Common examples of medical disorders or conditions
help, this is called self-hypnosis. There is no difference where hypnotherapy is useful
between the hypnotic states of heterohypnosis and self- zz Cardiovascular disorders
—— Hypertension
hypnosis, and their effect is the same. —— Coronary artery disease
—— Raynaud’s disease
may be able to self-induce a hypnotic trance without
zz Neurological disorders
needing someone else to do it. Therefore, good subjects —— Cerebrovascular disease
should always be taught self-hypnosis and to give —— Migraine
—— Tension headache
themselves helpful suggestions.
—— Parkinsonism
—— Tremors
APPLICATIONS OF HYPNOTHERAPY —— Tics
—— Writer’s cramps
—— Blepharospasm
Stress is a vital factor in many diseases and hypnosis —— Tinnitus
zz Gastrointestinal disorders
Hypnotherapy can be expected to help in two ways: as
—— Peptic ulcer
a prophylactic agent and in the cushioning of shock. —— Irritable bowel syndrome
—— Crohn’s disease
the threshold for fear, shock and stress. It can produce
—— Hyperemesis gravidarum
a rapid insight for the patient. Moreover, by its power —— Chemotherapy-induced nausea and vomiting
—— Bronchial asthma
and soma and might increase an individual’s capacity
—— Hay fever
to withstand any further emotional difficulty. It can —— Vasomotor rhinitis
—— Obesity
of actual organic disease.
zz Musculoskeletal disorders
The best technique to use in many of the cases is —— Rheumatoid arthritis
—— Fibromyalgia
method of recall is allowed but often a state of peace
zz Genitourinary disorders
and relaxation followed by a few minutes suggestion —— Renal failure
at the end of session may be found the most beneficial —— Psychogenic retention of urine
—— Incontinence
technique of all.
—— Eneuresis
—— Impotence
Direct Symptom Removal —— Frigidity
zz Bleeding disorders
Hypnotherapy can be used for direct symptom removal.
—— Hemophilia
It can be used to alleviate acute or chronic pain in
zz Dermatologic disorders
conditions like cancer, tension headache, migraine, —— Eczema
—— Neurodermatitis
A mechanism for analgesic hypnosis has been
—— Psoriasis
demonstrated in a PET study revealing significant —— Pruritus
—— Psychogenic purpura
cingulate cortex consistent with the encoding of perceived
CHAPTER 156: Hypnotherapy in Medical Disorders 925
unpleasantness, whereas the primary somatosensory which assesses not only the somatic part of an illness,
cortex activation was unaltered. A National Institute but also the underlying psychological factors adversely
of Health panel found strong evidence for the use of affecting the individual. Hypnotherapy in combination
hypnosis in alleviating pain associated with cancer. with medicine may be effective in this connection.
Hypnosis is useful for sleep management in patients with
disturbed sleep particularly those with cancer. BIBLIOGRAPHY
1. Ezra Y, Gotkine M, Goldman S, Adahan HM, Ben-Hur
As a Modifier of Allergic Response T. Hypnotic relaxation vs amitriptyline for tension-type
headache: let the patient choose. Headache. 2012;52:785-
The hypnotic state is capable of a bridging function 91.
in the supposed dualism between mind and body. 2. Faymonville ME, Boly M, Laureys S. Functional neuroanatomy
Many studies have shown a link between the use of of the hypnotic state. J Physiol Paris. 2006;99:463-9.
hypnosis and a changed response to an allergic stimulus 3. Gay MC. Effectiveness of hypnosis in reducing mild
or to a lessened bronchial hyper-reactivity. There is essential hypertension: a one-year follow-up. Int J Clin Exp
Hypn. 2007;55:67-83.
some evidence for an influence on the neurovascular
4. Häuser W, Hagl M, Schmierer A, Hansen E. The efficacy,
component of the allergic response. safety and applications of medical hypnosis. Dtsch Arztebl
Int. 2016;113:289-96.
HYPNOANALYSIS 5. Iserson KV. An hypnotic suggestion: review of hypnosis for
clinical emergency care. J Emerg Med. 2014;46:588-96.
In many cases, hypnoanalysis can detect the actual cause
6. Peters SL, Muir JG, Gibson PR. Review article: gut-directed
of the disease lying at the subconscious level and can be
hypnotherapy in the management of irritable bowel
used as psychocathartic i.e. abreaction instrument. The syndrome and inflammatory bowel disease. Aliment
process of hypnosis allows a repressed incident to come Pharmacol Ther. 2015;4:1104-15.
to consciousness and to be abreacted with subsequent 7. Samim A, Nugent L, Mehta PK, Shufelt C, Bairey Merz
relief of the symptom. CN. Treatment of angina and microvascular coronary
dysfunction. Curr Treat Options Cardiovasc Med.
Contraindications to hypnosis are psychosis,
2010;12:355-64.
constitutional predisposition to severe psychoneurotic 8. Wortzel J, Spiegel D. Hypnosis in cancer care. Am J Clin
reactions or antisocial behavior. Hypn. 2017;60:4-17.
9. Xu Y, Cardeña E. Hypnosis as an adjunct therapy in the
PROSPECTS management of diabetes. Int J Clin Exp Hypn. 2008;56:
63-72.
In all branches of medicine today, one can witness a
10. Zech N, Hansen E, Bernardy K, Häuser W. Efficacy,
revival of interest in psychogenic elements as causative acceptability and safety of guided imagery/hypnosis in
or aggravating factors of a disease. Much can be fibromyalgia - A systematic review and meta-analysis of
accomplished for a patient by an all-embracing approach randomized controlled trials. Eur J Pain. 2017;21:217-27.
CHAPTER
157
An Approach to Recurrent Falls in the Elderly
S Ramnathan Iyer, Revati R Iyer
TABLE 1: Important signs (all signs arising from pleural line) in lung ultrasonography
1 Pleural line Horizontal hyperechoic line sliding half a centimeter under the ribs.
2 Bat sign Acoustic shadows of two ribs and the sliding pleural line in between resemble a flying bat.
3 Merlin space An area in between the acoustic shadows of two adjacent ribs.
4 A line Horizontal repetition artefacts of the pleural line.
5 Lung sliding To and fro movement at the pleural line.
6 Lung pulse Heart beats are identified at the pleural line because of a non inflating lung. This discriminates
pneumonia and atelectasis.
7 B line An artifact, due to coexistence of elements with a major acoustic impedance gradient such as fluid and
air, with 7 features - hydroaeric comet tail artifact, emerging from the pleural line, hyperechoic, well
defined, spreading up indefinitely, erasing A lines and moves together with lung sliding.
8 Seashore sign (M mode) A stratified pattern above and a sandy pattern under the pleural line.
9 Stratosphere sign (M mode) A stratified pattern under and over the pleural line indicating pneumothorax.
10 Lung point At a precise location, in patients with A’ profile, lung signs such as transient B lines and lung sliding
suddenly appear with respiration. This location is called as lung point, which is pathognomonic of
pneumothorax.
11 Dynamic air bronchogram Inspiratory centrifugal movement of hyperechoic air in branching echogenic structures of the
consolidated lung, which is seen in alveolar consolidation.
over the anterior chest, upper hand touching the clavicle. posterior axillary line corresponds to the PLAPS point.
The upper and lower BLUE points will correspond Such a three point assessment may cut down the
to a place which lies at the center of the upper and duration of examination to three minutes. The distinct
lower hand respectively. A position at the junction of a sonographic lung patterns have been enumerated in
horizontal line through the lower BLUE point and the Table 2.
CHAPTER 158: Ultrasonography in Critically Ill Patients 931
PROCEDURE: FOCUSSED if RV:LV is 0.6-1.0 and critical if this ratio is more than 1.
ECHOCARDIOGRAPHY The interventricular septum is shifted towards the left in
The purpose of goal directed echocardiography is presence of RV overload (e.g. acute pulmonary embolism,
to immediately identify life threatening causes of acute respiratory distress syndrome, or ventilation with
hemodynamic failure, to categorize shock in order to high pressures). Due to the right ventricular overload, the
plan initial management strategy and to identify any left ventricle changes it’s normal circular shape to a “D”
other coexisting diagnosis. shape on left parasternal short axis view.
The focussed echocardiography may be utilized by
the intensivist for the following purposes (Table 3): Diagnosis of Pulmonary Embolism
Right ventricular dilatation and dysfunction in presence
Assessment of Right and of a positive CUS for LEDVT is highly suggestive of
Left Ventricular Function pulmonary embolism. The pattern of RV dysfunction
“Eyeball” estimates of the LV function, as assessed by involving mid septum with apical sparing is quite distinct
skilled examiner, is similar to calculated ejection fraction. for acute pulmonary embolism.
Frequent echocardiographic evaluations may be done to
monitor the efficacy of therapeutic interventions. The Diagnosis of Pericardial Effusion
right ventricular (RV) function may also be assessed Pericardial effusion is revealed as an echo free space
visually. The RV dilatation is assessed by calculating around the heart. The collapse of the right atrium (RA)
RV:LV ratio. The ratio is considered normal when it along with RV in the diastole suggests the occurrence
is <0.6 (moderate dilatation = ratio 0.6-1.0; critical of cardiac tamponade. A hemodynamically significant
dilatation = ratio >1). Dilatation is considered moderate pericardial effusion is identified if RA collapse
persists beyond one third of the RR interval. The real may help in determining the appropriateness of a fluid
time echocardiography may also help in draining a challenge.
hemodynamically significant pericardial effusion.
PROCEDURE: SCREENING
Assessment of Hypovolemia ABDOMINAL ULTRASONOGRAPHY
Assessment of hypovolemia and volume responsiveness A screening abdominal USG may be done by the
is achieved by determining the size of inferior vena intensivists to identify intra abdominal fluid and
cava (IVC) and it’s respiratory variedness. An increased examination of the aorta in a hypotensive patient.
IVC diameter (≥2 cm), in a patient with spontaneous Examination of aorta in its complete path, with special
respiration, is suggestive of raised pressures of the attention to aorta below renal arteries, is crucial to
right heart. Variability of IVC diameter (≥12%) with eliminate possibility of an aneurysm. It is scanned right
respiration is a predictor of improvement in cardiac through the epigastrium to the division of the iliac
output after volume expansion. Besides, hypovolemia arteries. The transducer is oriented transversely, directing
is also recognized by identification of “kissing sign” on towards the posteriorly placed aorta. Abdominal aorta is
the PLAX view (systolic effacement of the LV cavity at the placed left to the inferior vena cava just anterior to the
level of papillary muscle). vertebral body. Evaluation should be done in short axis
plane in order to determine the maximum diameter
Echocardiographic Assessment During of aorta (distance between outer wall to outer wall).
Cardiopulmonary Resuscitation An abdominal aortic aneurysm (AAA) is diagnosed if
Focussed echocardiography may help to determine vessel diameter exceeds 3 cm. Presence of echogenic
the reversible causes of arrest and to observe activity thrombus or an intimal flap with differential doppler flow
of the heart during cardiopulmonary resuscitation in suggestive of aortic dissection should also be ruled out.
presence of absent pulse. This modality can pick up A longitudinal assessment of the aorta will complete the
causes such as pneumothorax, hypovolemia, aortic examination.
dissection, cardiac tamponade, PE and coronary artery US evaluation is not a good modality to rule out
disease. Identification of the correct cause may help in aortic dissection. Still it has been utilized to diagnose
determining the best intervention to save a patient. The aortic dissection in certain settings. Screening for
USG evaluation is carried out through the subcostal aortic dissection should include transthoracic
window during brief periods of pulse checks during the echocardiography to look for signs of dilatation of aortic
cardiopulmonary resuscitation. root, aortic regurgitation, pericardial effusion and/or
aortic intimal flap.
Assessment of a Hypotensive Patient
A systematic USG approach can help the intensivist ULTRASONOGRAPHY IN TRAUMA
in determining the cause of hemodynamic instability. The focussed assessment with sonography in trauma
Echocardiographic assessment can help in ruling out (FAST) examination has substituted peritoneal lavage in
systolic dysfunction of LV, massive PE, hypovolemia recognition of the origin of intra abdominal hemorrhage.
and cardiac tamponade. An enlarged RA and RV may be An initial negative FAST may be repeated in appropriate
indicative of acute PE. As discussed previously, “kissing clinical settings. A positive examination in presence
sign” on PLAX view may be observed in hypovolemia. of hemorrhagic shock may call for urgent operative
The IVC diameter and its variation with respiration management. The extended FAST (eFAST) evaluation,
must be determined to assess volume status. Finally, in the setting of thoracic trauma, is done to incorporate
the presence or absence of B profile on lung ultrasound ultrasonographic examination of anterior chest, lateral
934 SECTION 17: Miscellaneous
chest and the heart through the subcostal view. Such BIBLIOGRAPHY
an examination may pick up pericardial tamponade, 1. Bouhemad B, Zhang M, Lu Q, et al. Clinical review: Bedside
pneumothorax and/or hemothorax. Hence, the “point of lung ultrasound in critical care practice. Crit Care. 2007;
11(1):205.
care” US is considered to be a best imaging method for 2. Chacko J, Brar G. Bedside ultrasonography: Applications in
emergent assessment of thoracic and abdominal trauma. critical care: Part I. Indian journal of critical care medicine:
peer-reviewed, official publication of Indian Society of
ADVANTAGES AND LIMITATIONS Critical Care Medicine. 2014;18(5):301.
3. Di Bello C, Koenig S. Diagnosis of deep venous thrombosis by
Critical care sonography has found widespread critical care physicians using compression ultrasonography.
acceptance because of certain advantages. It is a bedside Open Crit Care Med J. 2010;3:43-7.
modality which may be done rapidly to help in making 4. Ha YR, Toh HC. Clinically integrated multiorgan point of care
ultrasound for undifferentiated respiratory difficulty, chest
a diagnosis or to follow up patients after therapeutic pain, or shock: a critical analytic review. J intensive Care.
interventions. The patients do not need to be transferred 2016;4:54.
out of the ICU for the procedure and there is no exposure 5. Karim A, Arora VK. Applications of ultrasonography in
respiratory intensive care. Indian J Chest Dis Allied Sci.
to ionizing radiation. Significantly, the inter and intra
2014;56(1):27-31.
observer variability is small (<5%). 6. Kilker BA, Holst JM, Hoffmann B. Bedside ocular ultrasound
The goal directed USG also has its limitations. It is in the emergency department. European Journal of
limited in scope and requires formal training to acquire Emergency Medicine. 2014;21(4):246-53.
7. Lichtenstein DA, Meziere GA. Relevance of lung ultrasound
necessary knowledge and skills in image acquisition in the diagnosis of acute respiratory failure: the BLUE
and image interpretation. Fortunately, the time required protocol. Chest. 2008;134(1):117-25.
to achieve these skills is short except those needed to 8. Lichtenstein DA, Mezière GA. The BLUE-points: three
standardized points used in the BLUE-protocol for ultrasound
identify pneumothorax. It may be difficult to conduct an
assessment of the lung in acute respiratory failure. Crit
USG evaluation in obese patients and in patients with Ultrasound J. 2011;3:109-10.
large thoracic dressings and subcutaneous emphysema. 9. Lichtenstein DA. BLUE-protocol and FALLS-protocol: two
To conclude, point of care US should complement applications of lung ultrasound in the critically ill. Chest.
2015;147(6):1659-70.
clinical examination of the critically ill patients. It may 10. Lichtenstein DA. Lung ultrasound in the critically ill. Ann
be utilized to make swift diagnosis of life threatening Intensive Care. 2014;4(1):1.
emergencies so that appropriate interventions may be 11. Seif D, Perera P, Mailhot T, et al. Bedside ultrasound in
resuscitation and the rapid ultrasound in shock protocol.
carried out immediately to save lives. More and more
Crit Care Res Pract. 2012;2012:503254.
intensivists should undergo training to utilize US to its 12. Whitson MR, Mayo PH. Ultrasonography in the emergency
maximum potential. department. Critical Care. 2016;20(1):227.
CHAPTER
159
Imaging Parameters in Pulmonary
Thromboembolism
Priya Jagia, Niraj Nirmal Pandey
DIAGNOSIS OF PULMONARY
EMBOLISM AND DEEP VENOUS varies with different pretest clinical probabilities of PE,
the patient’s clinical condition, availability and cost of
THROMBOSIS
the particular modality, inherent risks accompanying
A diagnosis of PE cannot be reliably excluded nor
exposure to iodinated contrast medium and ionizing
confirmed solely on the basis of clinical examination,
radiation.
symptomatology and use of routine laboratory tests.
However, combining these variables can be used
IMAGING MODALITIES
to determine the clinical probability of PE. Recent
guidelines advocate the clinical probability assessment Chest Radiograph
of PE before deciding upon the diagnostic modality to be Chest radiograph depicts abnormalities in most cases
used. of pulmonary embolism but the findings are most
Estimation of plasma d-dimer levels has been shown often non-specific. The classic radiographic findings
to have a high negative predictive value (NPV) and a low of pulmonary infarction include a Hampton’s hump
positive predictive value (PPV) for the diagnosis of PE. (a wedge-shaped, pleural-based triangular opacity) or
Hence, it is the diagnostic test of choice in patients with a the Westermark sign (focal oligemia). Although these
low to moderate pretest probability of PE. findings are highly suggestive of pulmonary embolism,
Various radiologic tests are utilized in the diagnostic they are not frequently observed. Other findings include
algorithm of PE and DVT and they are listed in Table 1. a prominent central pulmonary artery, presence of right
The diagnostic modality adopted in a particular scenario sided chamber enlargement and pulmonary edema.
936 SECTION 17: Miscellaneous
A normal chest radiograph in a patient presenting TABLE 2: Diagnostic criterion employed in CT angiography for the
with severe dyspnea and hypoxemia, in the absence of any diagnosis of acute and chronic PE
evidence of bronchospasm or a cardiac shunt, strongly Acute PE
suggests the presence of pulmonary embolism. Occluded artery due to a large filling defect with the diameter of
the involved artery seen to be larger than the adjacent uninvolved
vessel
Ventilation-Perfusion Scintigraphy
Partial intraluminal filling defect outlined by contrast (Figs 1 and 2)
or SPECT
Peripheral filling defect within the lumen forming an acute angle
Before the advent of CT pulmonary angiography, with the vessel wall (Figs 1A and 2)
V/Q scan or SPECT showing ventilation/perfusion Other nonspecific findings which may be observed include:
mismatch were the main diagnostic modalities used. zz Peripheral wedge shaped infarcts in the lungs
DVT, owing to its high sensitivity (>90%) and specificity Contrast opacified vessels showing webs or membranes within
(Fig. 3D)
(about 95%) for proximal DVT.
Eccentric vessel wall thickening with calcification
CT venography may be done along with pulmonary CT
Abnormal vessel tapering and “cutoffs” (Fig. 3C)
angiography using a single intravenous contrast injection
In chronic thromboembolic pulmonary hypertension (CTEPH):
but it only marginally enhances the DVT detection rate zz Dilated central pulmonary arteries, often larger in diameter than
while significant increasing the amount of ionizing the aorta, with or without calcified walls
zz RV hypertrophy along with right atrial enlargement
radiation and hence is not routinely recommended.
zz Presence of bronchial or systemic collaterals
CT Pulmonary Angiography
With the advent of multidetector computed tomography
ECG gated CT angiography: Obtaining retrospective
(MDCT) scanners, CT angiography has become the
ECG gated scans produces less motion artefacts and also
modality of choice for imaging the pulmonary vessels
enables functional assessment of right ventricle (RV).
for suspected embolism owing to its high spatial and
The latter helps to prognosticate patients as presence of
temporal resolution. It has been accepted as the standard
RV dysfunction is associated with worse prognosis.
diagnostic test in patients with a high pretest probability
of PE, and also in patients having low to moderate pretest Triple rule out CT: It is a tailored ECG-gated examination
probability but with concurrent positive d-dimer test. planned to enable simultaneous assessment of the
The findings seen on CT angiography for the diagnosis coronaries and the aorta along with the pulmonary
of acute as well as chronic PE are listed in Table 2. vasculature and adjacent intrathoracic structures, in
MDCT angiography has a high sensitivity (83%), a patient presenting with atypical acute chest pain.
specificity (96%), PPV (86%) and NPV (95%) for diagnosis Although it is an attractive option for evaluation and
of PE. The positive predictive value however varies triaging of patients with chest pain in the emergency
according to the location of the embolus with values of department, its use is associated with increased radiation
97%, 68% and 25% when PE is in main or lobar artery, exposure and hence is recommended in selected cases
segmental and sub-segmental arteries respectively. only.
CHAPTER 159: Imaging Parameters in Pulmonary Thromboembolism 937
A B
Figs 1A and B: Acute pulmonary embolism. CT Pulmonary angiogram (A) axial and (B) coronal images demonstrates a partial filling defect
(*) within the left descending pulmonary artery surrounded by contrast material suggestive of an acute thrombus. Axial images (A) also show
presence of thrombus (*) within the right descending pulmonary artery (RDPA) forming acute angles with the vessel wall
A B
C D
Figs 3A to D: Chronic pulmonary embolism. Oblique coronal CT pulmonary angiogram image (A) shows presence of peripheral filling defect
(indicated by arrows) in the left pulmonary artery (LPA) forming obtuse angle with the vessel wall, suggestive of chronic thrombus. Coronal
image (B) shows extension of the chronic thrombus (*) into the left descending pulmonary artery (LDPA). Maximum intensity projection images
(C) show presence of abnormal tapering of the upper lobe branches. Coronal CT pulmonary angiogram images (D) of another patient shows
presence of web (indicated by thick arrow) within the left descending pulmonary artery (LDPA)
ancillary findings used to diagnose RV dysfunction are TABLE 3: Various measurements made on pulmonary CT
enumerated in Table 3. Volumetric assessment of the RV angiography and ancillary findings used to diagnose RV
dysfunction
along with calculation of LV and RV ejection fractions is
possible on ECG-gated CT angiography. RV size to left ventricle (LV) size ratio in short axis view more than 1
(Fig. 4A)
Thrombus burden scores can be used to assess
the severity of PE. These include angiographic scores Ratio of diameters of the main pulmonary artery diameter to that
of aorta greater than 1
adapted for CT such as Miller and Walsh scores along
Presence of a dilated IVC with or without reflux of contrast into the
with dedicated CT scores such as the Qanadli and
IVC
Mastora scores. However, it has been shown that central
Leftward bowing or S-shaped configuration of the interventricular
location of the embolus is more important in predicting
septum (Fig. 4B)
short term mortality in patients with PE rather than the
total percentage of pulmonary obstruction.
CHAPTER 159: Imaging Parameters in Pulmonary Thromboembolism 939
A B
Figs 4A and B: (A) CT scan reveals that the right ventricle (RV) (short axis diameter) is wider than that of the left ventricle (LV) with mild leftward
bowing of the interventricular septum (*), indicating presence of right ventricular strain. (B) Axial CT images (lung window) shows mosaic
attenuation in both lungs in the presence of chronic thrombus in both right and left interlobar arteries
Flow chart 1: Proposed diagnostic algorithm in a patient with suspected pulmonary embolism
4. Qanadli SD, El Hajjam M, Vieillard-Baron A, Joseph T, 7. Stein PD, Fowler SE, Goodman LR, Gottschalk A, Hales CA,
Mesurolle B, Oliva VL, et al. New CT index to quantify Hull RD, et al. Multidetector computed tomography for acute
arterial obstruction in pulmonary embolism: comparison pulmonary embolism. N Engl J Med. 2006;354(22):2317-27.
with angiographic index and echocardiography. Am J 8. Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè
Roentgenol. 2001;176(6):1415-20. N, Pruszczyk P, et al. Guidelines on the diagnosis and
management of acute pulmonary embolism: the Task Force
5. Sadigh G, Kelly AM, Cronin P. Challenges, controversies,
for the Diagnosis and Management of Acute Pulmonary
and hot topics in pulmonary embolism imaging. Am J
Embolism of the European Society of Cardiology (ESC). Eur
Roentgenol. 2011;196(3):497-515. Heart J. 2008;29:2276-315.
6. Sostman HD, Stein PD, Gottschalk A, Matta F, Hull R, 9. Wittram C, Maher MM, Yoo AJ, Kalra MK, Shepard JA, McLoud
Goodman L. Acute pulmonary embolism: sensitivity and TC. CT angiography of pulmonary embolism: diagnostic
specificity of ventilation-perfusion scintigraphy in PIOPED II criteria and causes of misdiagnosis. Radiographics. 2004;
study. Radiology. 2008;246(3):941-6. 24(5):1219-38.
INDEX
Note: Page numbers followed by f or t represent figures or tables respectively.
walled-off necrosis (WON), 428, etiology, 415, 415t newer vaccines, 627
430, 431–432 incidence rates, 415 dengue, 627
mortality against, 422t management, 416, 419f hepatitis E, 627
overview, 421 medical therapy, 417 HIV/AIDS, 627
prevention, 432 prevention of re-bleed, 419, 419f malaria, 627
scoring systems, 424–426, 425t–426t risk factors, 415–416 pneumococcal vaccine, 625
severity assessment, 424–426, stigmata of recent hemorrhage typhoid vaccine, 626–627
425t–426t (SRH), 417 varicella and zoster (shingles)
Acute peripheral vestibulopathy, 404 surgical treatment, 418 vaccines, 624–625
Acute pulmonary embolism (PE), Adaptive immune system, HBV yellow fever vaccine, 626
153–155, 153t infection and, 466–467 Adult-onset GHD (AOGHD), 313.
Acute renal failure, infective ADEM. See Acute disseminated See also Growth Hormone
endocarditis, 131 encephalomyelitis (ADEM) Deficiency (GHD)
Acute renocardiac syndrome, 138–139, Adenosine triphosphate citrate lyase AECC. See American-European
141 inhibitor, 215 consensus criteria (AECC)
Acute respiratory distress syndrome Adhesive capsulitis of the shoulder AED. See Antiepileptic drug (AED)
(ARDS), 508–512 (ACS), 204 Aedes albopticus, 586, 821
Berlin definition vs. AECC Adipocytokine signaling pathways,
definition, 508, 509t Aerobic exercise, 303
NAFLD-related HCC risk and,
defined, 508, 509t AES. See Acute encephalitis syndrome
444
(AES)
diagnosis, 508, 509t Adipose tissue (AT)
Affective psychosis, seizure, 378
fever with, 564 composition, 192
Age/ageing, 861–862, 861f. See also
management, 508, 510t, 511–512, macrophage infiltration in white,
Geriatrics
511t 192–193
ACOS incidence and, 501
extracorporeal membrane Adjunctive therapies, in CAP, 531
oxygenation (ECMO), blood pressure changes with, 41–42
Adolescents
512 high altitude and, 41
ambulatory blood pressure
higher PEEP, 512, 512t monitoring in, 13 ‘newer oral anticoagulants’
low tidal volume ventilation, (NOACs), 88
growth phase, 334
508, 511 status epilepticus (SE), 381
Adoptive cell therapy (ACT), 802
prone positioning, 511 Age-related demographics, 28
A-DROP, 528
recruitment maneuvers, 512 AIDP. See Acute inflammatory
Adult immunization, 622–627. See also
mimics, 509t demyelinating
Vaccines/vaccination
recognition, 508, 509t polyradiculoneuropathy
cholera vaccine, 626
risk factors, 509t Air pollutants, sources, 200–201
diphtheria, pertussis and tetanus
vs. CPE, 509t Air pollution, 533–535
vaccines, 624
Acute rheumatic fever diabetes and, 200–201, 200f
Hemophilus influenzae vaccine,
medical treatment, 124 626 effects on different organs
mitral valvuloplasty, 124, 124f hepatitis A vaccine, 624 cardiovascular system, 534
surgical treatment, 124 hepatitis B vaccine, 622–624 gastrointestinal system, 535
Acute symptomatic seizure, 372 HPV vaccine, 626 nervous system, 535
Acute tubular necrosis (ATN), 453 indications and dose schedule, 622, pregnancy and, 535
Acute upper gastrointestinal (UGI) 623t psychiatry, 535
bleeding, 415–419 influenza vaccine, 626 respiratory system, 534
angiographic therapy, 418–419 Japanese encephalitis vaccine, 626 urinary system, 535
clinical presentation, 416 measles, mumps and rubella global effects, 533
endoscopic therapy, 417–418, 417t, vaccine, 624 health effects, mechanisms, 533
418t meningococcal vaccine, 625 pollutants types, 534
Index 943
Benign paroxysmal positional vertigo Bisphosphonates, for osteoporosis, Body weight, metformin and, 263–264
(BPPV), 406–407 832–833 Bone age, 335
Benign prostatic hyperplasia (BPH), Bladder relaxant therapies, nocturia, Bone marrow
nocturia, 366 365 biopsy, 879
Benzodiazepines poisoning, 740–741 Bleeding examination, 878
Berlin definition, of ARDS, 508, 509t re-bleeding, 417, 419 BOOST Trial, 868
vs. AECC definition, 508, 509t UGI (See Acute upper Brain, DM and, 187
Bernard score, 424 gastrointestinal (UGI)
Brain natriuretic peptide (BNP), 491
Beta adrenergic blocking agents, 70 bleeding)
Brainstem lesions
alpha-1 adrenergic blockers, 70 Blood, multiple cranial nerve palsy, 361
multiple cranial nerve palsy
centrally acting alpha-2 agonists, 70 Blood cultures, CAP investigations and,
526 causes of, 359–360
side effects, 70 diagnosis, 361
Blood pressure (BP)
Beta blockers, high altitude systemic intermediate syndrome, 361
hypertension, 42 ageing and, 41
investigations in, 361
Bethesda System of reporting thyroid ambulatory measurements vs.
home measurements, 9 sites of lesion, 360–361, 360t
cytology (TBSRTC), 338
azilsartan and, 19–20 British Thoracic Society (BTS), 525
Bhakti Yoga, 898
behaving with aging in people guidelines, 530, 531t
Bifidobacterium, 437, 440
chronically exposed to high Bronchoscopy, 597
Biofilms, production of, 717
altitude, 42 of SPN, 520–521
Biomarkers
changing with aging, 41–42 Bronchus sign, SPN, 517
ACOS assessment and, 501
control of, 852 Bruising, lipohypertrophy (LH), 348,
of AKI, 141 350
conclusion and perspectives, 54
in CAP, 528 Butter, 904
improving the impact of
in cardiorenal syndrome (CRS), guidelines, 53–54, 53t Butyric acid, 437
140–141, 140t
JNC 1974 to 2003 (1 to 7), 51–54, By-products, 199
in heart failure, 97–99 51t–53t
cardiac troponin, 98 management of hypertension,
diagnosis, 97–98 50–51 C
HFpEF, 98–99 hypertension in diabetes, 56–57 CABG. See Coronary artery bypass
overview, 97 night-time, 8, 8t grafting (CABG)
prognostic value of NP, 98 in OSA, 498 CAD. See Coronary artery disease
in HRS, 453 variability, 6–7, 6f (CAD)
in sepsis, 695–698 Blood pressure instruments, 70–71 Calcineurin inhibitors (CNIs), 843
applications, 695, 695t benefits of automated, 71 Calcitonin, and osteoporosis, 833
combinations, 698 blood pressure monitoring, 71 Calcium channel blockers, 69
C-reactive protein (CRP), features, 71 ACE inhibitors, 69
697–698 pressure and target organ damage, action, 69
diagnostic criteria, 695–696, 696t 71 isolated systolic hypertension (ISH),
examples, 697t time of measurement, 71 47
ROC curves, 696, 696f Blood tests side effects, 69
Biopsy of donor for FMT, 474 Calcium scoring, 75
liquid, 916 in dyspnea, 491 Calcium-sensing receptor (CSR), 341
for polyarteritis nodosa, 818 Blood transfusion, 881 Canaglifozin, 853
Birth, 890 B-lymphocytes, 292 Cancer biology, 264
BISAP score. See Bedside Index of BODE index (Body mass index, airflow Cancer(s), 913
Severity in Acute Pancreatitis obstruction, dyspnea, immunotherapy for, 914
(BISAP) score exercise capacity), 502 infection associated, 539–542
Index 947
agents, 540, 541t Cardiac troponin, 98, 140 Carpal tunnel syndrome (CTS), 204–
chlonorchis, 540 Cardiogenic pulmonary edema (CPE), 205
detection and proving 508 Cartridge Based Nucleic Acid
association of agents, vs. ARDS, 509t Amplification Test (CB NAAT),
540, 541t–542t, 542 Cardiology, mega trials in, 115–120 914
Epstein Barr virus, 540 Cardiopulmonary manifestations, of Carvedilol, 456
HBV, 540 HIV/AIDS, 667–670 Catabolic activation, 80
HCV, 540 bacterial infections, 669–670 Cathelicidins, 472
Helicobacter pylori, 540 cardiotoxic drugs, 668 Catheter based reperfusion, 155
human papilloma virus, 540 coronary artery disease, 668–669 Catheter related blood stream infection
human T-lymphotropic virus fungal infections, 670 (CRBSI)-, 728
type 1, 540 malignant neoplasms, 670 Cavernous sinus syndrome, 360
IARC classification, 539–540, pericardial disease, 667–668 Cavernous sinus thrombosis, 360
540t pulmonary manifestations, 669 Cavitation, SPN, 518
incidence, 539 Cardio-renal protection, 20–22 CCHFV. See Crimean-Congo
Kaposi Sarcoma-Associated Cardiorenal syndrome (CRS) hemorrhagic fever virus
Herpes Virus, 540 biomarkers in, 140–141, 140t (CCHFV)
opisthorchis, 540 defined, 138 CD34 antibody coated stents, 868–869
pathogenesis, 539 management, 141–142 Cell biology, 913–914
Schistosoma Hematobium, 540 neurohormonal activation, 139 Centilator associated pneumonia
metronomic chemotherapy other factors, 140 (VAP), 726, 726t
(See Metronomic oxidative stress, 139–140 Centrally acting alpha-2 agonists, 70
chemotherapy) pathophysiology, 139–140, 140f Central obesity, 497
Cancer viruses, 539. See also specific renal biomarkers, 140–141, 140t Cerebrospinal fluid (CSF)
entries type CRS (secondary cardiorenal examination in meningitis, 602–603,
Candidiasis, 661 syndrome), 139 602t
CAP. See Community acquired type I (acute cardiorenal multiple cranial nerve palsy, 361
pneuomonia (CAP) syndrome), 138 study, AES and, 559
Capsid inhibitors, HBV infection and, type II (chronic cardiorenal Cerebrovascular disease, 227–228
466 syndrome), 138 EPCs in, 869
Carbohydrate metabolism, liver role type III (acute renocardiac CETP inhibitors, 214–216
in, 446 syndrome), 138–139
Chandipura virus (CHPV), 556
Cardiac biomarkers, 140, 140t, 152 type IV (chronic renocardiac
Chang sign, 490
syndrome), 139
Cardiac cachexia CHD. See Congenital heart disease
Cardiotoxic drugs, 668
anabolic failure, 80 (CHD)
Cardiovascular diseases (CVD)
catabolic activation, 80 Chest computed tomography, 152–153
dyspnea due to, 482–483, 484f
insulin resistance, 80–81 Chest radiography
NAFLD and, 444
overview, 80 of CAP, 526
OSA and, 497–498
pathophysiology, 80 in dyspnea, 490
Cardiovascular system (CVS), 912–913
skeletal muscle, 81 for pulmonary embolism, 935–936
air pollution effects on, 534
Cardiac chamber catheterization, 123 Chest radiology, SPN diagnosis, 516
GHD, 314, 318
Cardiac CT, 75 Chest wall-related diseases, dyspnea
high altitude systemic hypertension
Cardiac ICU and, 36 and, 485, 486f–487f
hypoglycemia in, 688–689 Cardioversion, immediate and short- Chikungunya fever, 551
Cardiac MRI (CMRI), 76 term outcome of, 166 vaccine for, 551
Cardiac resynchronization therapy Carotid intima-media thickness Chikungunya virus (CHIKV), 551,
(CRT), 148 (CIMT), 75–77 821–824
948 Medicine Update 2018
in outpatient setting, 529, 529t Computed tomography (CT) risk factors and pathophysiology,
treatment protocol for, 530–531 CAP diagnosis, 526 100–102, 101f
biomarkers in, 528 in dyspnea, 492 treatment of, 104, 105f
chest radiography, 526 of SPN, 518, 518f Corrosive poisoning, 739–740
clinical features, 526 chest, 516 Corticosteroids, 823
CT of, 526 Congenital heart disease (CHD), 136 Cotton seed oil, 904
defined, 525 antepartum, 136 Covalently closed circular DNA
diagnosis, 525–526, 527f (cccDNA), 464
aortic dissection, 135–136
COX 1 inhibitors, 415
epidemiology, 525 general principles of management,
136 COX 2 inhibitors, 415
etiology, 525, 526t
intrapartum, 136 CPAP therapy, in OSA, 498
general investigations, 528
guidelines, 525 peripartum cardiomyopathy, CPE. See Cardiogenic pulmonary
134–135 edema (CPE)
HRCT findings, 526
preconception, 136 Craniovertebral junction lesions,
immunization in, 531–532, 532t vertigo, 409–410
microbiological investigations prosthetic heart valves, 135
CRB-65, 528, 529t
blood cultures, 526 rheumatic heart disease, 135
CRC. See Colorectal cancer (CRC)
Legionella antigen detection, signs, 135
C-reactive protein (CRP), 528, 697–698
528 symptoms, 135
Creatinine, 141
other pathogens, 528 signs, 135
Crimean Congo hemorrhagic fever
sputum gram stain and cultures, symptoms, 135
virus (CCHFV), 552
526–528 Conjugated linoleic acid (CLA), 437
CRISPR-Cas9, 916
pathogens associated with, 526t Consciousness, 894
Critical care toxicology, 681–683
risk stratification in, 528–529, 529t Continuous positive airway pressure
decontamination, 682
Community-based interventions, (CPAP), 497–498
enhanced elimination, 682–683,
209–210, 209t Conventional anticoagulants, 154
682t
Comorbid illnesses, headache, 357– Cooking oils, 903–904 initial resuscitation and
358, 358t Corn oil, 904 management, 681–682
Comorbidities, heart failure and, 149 Corona radiata, 516, 517f laboratory investigations, 682, 682t
Complex partial seizure (CPS), 376. See Coronary artery bypass grafting Cryptococcosis, 661
also Seizures (CABG), 82 Cryptococcus neoformans infection
automatism, 377–378 duration of DAPT in patients IRIS, 675–676
classifciation of, 377 undergoing, 93 CT. See Computed tomography (CT)
CT vs. MRI, 378, 378f Coronary artery disease (CAD) CT contrast angiography, 492
diagnosis, 378 diabetes mellitus (DM) in India, CT coronary angiography, 76
EEG phenomenon, 378 226–227
ctDNA. See Circulating tumor DNA
etiology, 376 HIV/AIDS and, 668–669 (ctDNA)
features of, 377 secondary prevention of, 116 CT guided needle biopsy, of SPN, 520
management, 379 severity of, 84 CTLA-4-immunoglobulin fusion
pathology, 376 Coronary microvascular dysfunction proteins, 292–293
pathophysiology, 376 (CMD) C-type lectins, 472
prognosis, 379 clinical profile, 102–104 Culture-based methods, TB diagnosis
Comprehensive pulmonary function invasive methods, 103–104 conventional solid media, 576–577
tests, in dyspnea, 492 noninvasive method, 103 liquid culture, 577
Compression ultrasonography (CUS), diagnosis, 102, 102f CURB-65, 528, 529t
931 diagnostic algorithm, 104f CUS. See Compression ultrasonography
for DVT, 936 overview, 100 (CUS)
950 Medicine Update 2018
Cutaneous vasculitis, 826 expanded dengue syndrome (EDS), fundamental mechanism of b-Cell
CVD. See Cardiovascular diseases 565 ER stress and, 194
(CVD) hepatic complications, 587 gestational, 61–62
CV events, prediction of, 8–9 hyperferritinemia (secondary GHD, 318
Cyanobacteria, 436 hemophagocytic- hypertension, 233
Cyclophosphamaide, NMO, 369 lymphohistiocytosis), 587 ideal antihyperglycemic drug, 187
Cyclophosphamide, 827 overview, 586 importance of glycemic control in
Cystatin C (CysC), 453 unusal complications, 586 curbing burden of, 247–251
Cytokine and macrophage phenotypes, usual complications, 586 incidence of DM amongst patients
192 vaccine for, 550–551, 627 with cerebro-vascular
Cytokines clinical pipeline, 550 disease, 229t
as biomarkers in sepsis, 698 current status of, 550 in India, 225–226
NAFLD-related HCC risk and, 444 preclinical pipeline, 550–551 infections, 233
Cytokine Storm, 632–634 Dengue hemorrhagic fever (DHF), 564, inflammation and, 193–194
Cytomegalovirus, 545, 661 586 intraoperative management, 722,
Cytomegalovirus infection IRIS, 674– Dengue shock syndrome (DSS), 565, 723t
675 586 LD in
Dengvaxia®, 550 mechanism of, 447
Depression, 472 prevalence of, 447
D postmenopausal hypertension, 25 long-term complications of, 226f
Daclatasvir, 470 Desensitization, and ABO- macrovascular complications,
Daytime symptoms, of OSA, 497 incompatible KT, 847–848 226–229
D-dimer, 491 DEXA scan-dual energy X-ray management, 300
Death, 890 absorptiometry, 831, 832 measures during surgery, 722–724
Deep vein thrombosis (DVT), 151, 483 Diabetes mellitus (DM), 118–119, 446, metabolic syndrome (MS) and, 229
compression ultrasonography for, 472, 849 metformin, 186, 263
931, 936 air pollution and, 200–201, 200f microvascular complications in
CT venography for, 936 cerebrovascular disease, 227–228 type 2 DM, 229–230
diagnosis of, 935, 935t chronic complications in, 226t mortality rate, 850t
Default mode network (DMN), 922–923 chronic liver disease, 233 noncoronary cardiac complications,
Defective immune response in diabetes complications in, 226, 226t 232–233
mellitus, 288 coronary artery disease, 226–227 other complications in type-2 DM,
Defensins, 472 defective immune response in, 288 232–233
Deferred PCI, 112, 113f diabetic neuropathy and diabetic overview, 225
Delamanid, for M/XDR-TB, 554 foot, 230–232, 231t pancreatic beta cell mass function
Delta hepatitis (HDV), 469 diabetic retinopathy, 230 in, 290–291, 290f
Demographics dipeptidyl pepitidase-4 inhibitors, pathogenesis of, 186–187
age-related, 28 187, 188t brain, 187
sex-related, 28–29 early initiation of insulin therapy in, hyperglucagonemia, 187
Demyelination, vertigo, 409 221–223 incretins, 187
Dengue fever (DF), 550, 564–565, 565f education, 300 insulin resistance, 186
complications, 586 efficacy, 188–189 kidneys, 187
dengue hemorrhagic fever (DHF), in elderly recommendation, 259– lipotoxicity, 187
564 261 progressive beta cell loss,
dengue shock syndrome (DSS), 565 endothelial dysfunction and, 186–187
diagnostics guidelines for HLH- 193–194 perioperative management in,
2004, 587 FMT in, 475 720–724
Index 951
factors causing adverse good tissue distribution of, 249t tolerance, 34–35
outcome, 720–721 hypoglycemia and, 249f torsemide, 35
metabolic response to surgery low free drug concentration and types of, 33–35
and anesthesia, 721 high selectivity favours bendroflurazide, 34
preoperative measures, 721–722, avoidance, 249t CTD, 34
722t–723t Diphtheria vaccine, 624 HCTZ, 33–34
principles and target of, 721 Direct acting vasodilators, 70 indapamide, 34
risk of poor diabetic control, 720 Direct Endoscopic Necrosectomy loop diuretics for HT, 34
peripheral vascular disease, 228– (DEN), 432
DKD. See Diabetic kidney disease
229 Direct sputum smear microscopic (DKD)
pharmacologic therapy for, 175–180 examination, TB, 576
DM. See Diabetes mellitus (DM)
postoperative managemant, 724 Disease-modifying antirheumatic
drugs (DMARDS), 823 DMARDS. See Disease-modifying
prevalence of CAD amongst
antirheumatic drugs
diabetics in India, 228t Disease-modifying therapy (DMT),
(DMARDS)
renal involvement in, 849 392, 393t, 394, 394f
DMN. See Default mode network
risk factors for, 447 Diseases
(DMN)
safety, 189 due to global warming, 505–506
DMT. See Disease-modifying therapy
spectrum of chronic complications gut microbiota and (DMT)
in, 232f future perspectives, 438, 440 DN. See Diabetic nephropathy (DN)
sulfonylureas (SU), 186 relationship between, 438, 439f, DNA (deoxyribonucleic acid), 913–914
uses of EPCs in, 869 472, 473f
circulating tumor, 916
Diabetic amyotrophy, 205 Disseminated intravascular
DNA tools, TB diagnosis, 578–580
Diabetic foot, 230–232, 231t coagulation (DIC), 617–621
GeneXpert (Xpert MTB/RIF), 579
Diabetic kidney disease (DKD), 849– diagnosis, 618–619, 619t
line probe assays, 579
853 differential diagnosis, 619–620
loop-mediated isothermal
biochemical markers, 851 etiology, 617, 617t
amplification test (LAMP),
screening for, 851 ISTH-SSC diagnostic scoring system 579, 580f
treatment of, 851–852 for, 619, 619t
nucleic acid amplification (NAA)
Diabetic muscle infarction, 205 pathogenesis, 617–618, 618f tests, 578–579
Diabetic nephropathy (DN), 849 treatment, 620–621 Donor screening questionnaire, 546
dyslipidemia in, 853 Diuretics, 69 Donor selection
predictors, 850t bendroflurazide, 34 fecal microbiota transplantation,
risk factors for development, 849– combination of diuretic with anti- 472, 474t
850, 850t HT drugs, 35 blood screening, 474
Type I, 851 CTD, 34 history obtained from donor,
diuretic tolerance, 34–35 474
Diabetic neuropathy, 230–232, 231t
effect of low dose diuretic, 33 stool evaluvation, 474
Diabetic retinopathy, 230
HCTZ, 33–34 stool preparation (European
Diagnostic errors, 3–4
indapamide, 34 Consensus 2017), 474
DIC. See Disseminated intravascular
isolated systolic hypertension (ISH), Dorzagliatin, 295
coagulation (DIC)
47 Dosing, GHD, 316t
Diet, 901
loop diuretics for HT, 34 compliance, 317
Digital transcript subtraction (DTS),
542 pharmacodynamics, 34 medications, 317
Dipeptidyl peptidase-4 inhibitors potassium-sparing, 69 obesity and glucose, 317
(DPP4), 293–294 common combination, 35 physiologic factors, 316
comparable efficacy in individual side effects, 69 strategy, 317–318, 317t
trials, 250f thiazides, 69 Doubling time (dt), 518
952 Medicine Update 2018
DPP-4 inhibitors, 449 triple therapy, 96, 96t chest wall-related diseases and, 485,
Drug related fever, 597 variables used to calculate score, 486f–487f
Drugs and toxins, vertigo, 410 91t classification, 482, 483t
Drugs/drug therapy. See also Medical Dulaglutide, 240–241 comprehensive pulmonary function
therapy Dupuytren’s contracture/disease, 204 tests , 492
atherosclerosis, 76–77 Dysbiosis, 446, 475 computed tomography, 492
doses, in CAP, 530t Dyslipidemia, 495 conditions related to, 483t
indirect-acting, HBV infection adenosine triphosphate citrate lyase defined, 481
host-acting pathway, 466 inhibitor, 215 differential diagnosis, 488f
innate and adaptive immune angiopoietin like 3 (ANGPLT-3), 216 diseases of pulmonary vasculature
defense pathways, antisense approach against and, 483
466–467 lipoprotein (a), 215 echocardiography, 492
therapeutic vaccines, 466 antisense oligonucleotide against electrocardiography, 490–491
seizure, 379 apolipoprotein B (Apo B), heart failure and, 482
targeting viral replication cycle, in 214 history taking, 489
HBV infection apolipoprotein A1 (ApoA1) imaging, 492–493
antisense molecules, 466 mimetics, 215
interstitial lung diseases and, 485
capsid inhibitors, 466 approaches for PCSK9 inhibition,
invasive testing , 493
212
entry inhibitors, 465–466 laboratory studies, 490–491
CETP inhibitors, 214–216
HBsAg inhibitors, 466 left heart-related diseases and, 482
in diabetic nephropathy, 853
HBV cccDNA inhibitors, 466 lung parenchyma-related diseases
diagnosis, 497
HBV-DNA polymerase and, 485
inhibitors, 466 microsomal triglyceride transport
magnetic resonance imaging, 492
protein (MTP) inhibitor,
siRNA, 466 213–214, 213t management, 493
Dual antiplatelet therapy (DAPT) overview, 211 mechanism, 481–482, 482f
in ACS, 91 In patients with ASCVD air hunger, 481
aspirin allergy, 95, 95t (atherosclerotic chest tightness, 482
aspirin resistance, 94–95, 95t cardiovascular disease), dyspnea relief, 482
clopidogrel resistance, 95 212–213 work effort, 481–482
debate about, 90 PCSK-9 inhibition (nonmonoclonal neuromuscular diseases and, 485
duration in patients undergoing antibody), 215 other diseases, 485, 487
CABG, 93 PPAR agonists, 216 overview, 481
duration of dual antiplatelet therapy proprotein convertase subtilisin/ pericardium-related diseases and,
in cases of stable CAD after PCI, kexin type 9 (PCSK9) 482–483, 484f
91–92 inhibitors, 212
physical examination, 489–490
in patients with ACS, 92–93 therapies of the future, 215
psychological factors, 485, 487
elective noncardiac surgery in Dyspnea, 481–493
pulse oximetry, 491
patients treated with DAPT ABG analysis, 491
social factors, 485, 487
and PCI, 93–94 advanced studies , 491–493
spirometry, 491
overview, 90 airways-related diseases and, 485
stress testing , 493
risk stratification, 90–91 anemia and, 485
ventilation/perfusion scanning,
shorter duration, 91 assessment of, 487, 489 492–493
short-term vs. long term, 91 blood and serum tests , 491
special circumstances, 94–96 cardiovascular diseases and, 482–
in stable CAD, 91 483, 484f E
switch over between antiplatelets, causes of, 482–487 EARA. See Endothelin A receptor
94 chest radiography , 490 antagonists (EARA)
Index 953
EUS. See Endoscopic ultrasound (EUS) causes of, 926–927 Feeding vessel sign, SPN, 517
EVD. See Ebola virus disease (EVD) clinical examination, 927 Fever of Unknown Origin (FUO). See
Evidence based medicine (EBM), 911 prevention of, 927–928 Pyrexia of Unknown Origin
recurrent, 926 (PUO)
EVL. See Endoscopic variceal ligation
Fever(s)
(EVL) Family history of short stature (FSS),
334 with acute respiratory distress
Evolocumab, 77
syndrome, 564
Exenatide, 240 Family history of slow growth (CDGP),
with multiorgan dysfunction, 564
Exercise 334, 335
skin lesions associated with, 563t
aerobic, 303 Fats
undifferentiated, 563
anaerobic, 303 composition of, 901–902
Fever with rash, 563, 614–616
flexibility, 303 meaning of, 901
diagnosis, 614–615
gestational diabetes mellitus (GDM) Fatty acids
overview, 614
and, 218 MUFA, 902 viral hemorrhagic fevers, 615–616
as a medicine, 303 omega-3, 902 Fibrates, 77
Expanded dengue syndrome (EDS), omega-6, 902 Fibrinolysis, 92
565 PUFA, 902 Fine needle aspiration cytology
Expanded Program on Immunization saturated, 901 (FNAC), thyroid nodule, 338,
(EPI), 912 trans, 902–903 340
Extensively drug resistant TB (XDR- unsaturated, 901 Firmicutes, 436, 475
TB), 553–555 Febrile-infection related epilepsy 5-alpha reductase inhibitors, nocturia,
anti-TB drugs for, 553 syndrome (FIRES), 381 365
bedaquiline for, 554 Fleischner sign, 490
Fecal enemas, 474
defined, 553 Flexibility exercise, 303
Fecal microbiota transplantation
(FMT), 440, 472–476 Flexor tenosynovitis (FTS) or ‘Trigger
delamanid for, 554
Finger,’ 205, 205f
epidemiology, 553 administration routes, 474
Fluid replacement, SCD and, 611
high dose isoniazid for, 555 Clostridium difficle infection,
Fluid resuscitation, acute pancreatitis,
management, 553 474–475
426
newer drugs options, 554 colonoscopy guided, 474
FMT. See Fecal microbiota
overview, 553 current and future directions, transplantation (FMT)
regimes, 554, 554t 475–476 Focal segmental glomerulosclerosis
shorter duration therapy option, in diabetes, 475 (FSGS), 843
555 donor blood screening, 474 Focussed echocardiography, 932–933,
surgical options, 555 donor selection, 472, 474t 932t
treatment duration, 555 donor stool preparation (European Follow-up imaging, of SPN, 519, 519t
Consensus 2017), 474 Forrest classification,. ulcers, 417, 417t
Extracellular fluid (ECF), 341–342
dysbiosis, 475 4-phenyl butyric acid (PBA), 195
Extracellular matrix (ECM), 447
fecal enemas, 474 Fractional flow reserve (FFR)
Extracorporeal membrane oxygenation
history obtained from donor, 474 assessment of serial lesions, 112–
(ECMO), 512, 683
in inflammatory bowel disease, 475 114, 113f–114f
Extrinsic lesion, 359
characteristics of, 110–111
in irritable bowel syndrome, 475
clinical decisions and, 110–111
in neurological diseases, 475, 476f
F in obesity/insulin resistance, 475
deferred PCI, 112, 113f
defined, 110
Factitious fever, 598 pre- and post-FMT changes, 476f
functional PCI, 111–112, 112f
Faecalibacterium prausnitzii, 475 stool evaluvation, 474 identifying culprit vessel and
Falls, 926–928 techniques, 472, 473f doing appropriate
age related changes and, 926 upper GI endoscopy guidance, 474 revascularization, 111
Index 955
Health care expenditure, 913 Heart failure with reduced ejection siRNA, 466
Health impact, of global warming, 504. fraction (HFrEF), 482 epidemiology in India, 463–464
See also Global warming Heart transplantation, 149 HIV-HBV coinfection, 470
Heart failure (HF), 97–99, 117–118 Heavy metals, air pollution due to, 534 immunopathogenesis, 464
arrhythmias and conductance Helicobacter pylori, 540 incidence, 463
disturbances, 149 Hematochezia, 416 indirect-acting drugs
biomarkers in, 97–99 Hematology/oncology, 757–808 host-acting pathway, 46
biomarkers of HFpEF, 98–99 Hematopoietic stem cell innate and adaptive immune
cardiac troponin, 98 transplantation (HSCT), 759– defense pathways,
classification, 144–145, 145t 761, 763–766 466–467
comorbidities, 149 allogeneic, 760, 764–766 therapeutic vaccines, 466
and comorbidities, 149 autologous, 760, 763–764 management of, 465
definition of, 145t indications, 759 natural history of infection, 464–465
diagnosis, 97–98, 145–147 5 phases of, 760 HBeAg-negative chronic HBV
clinical, 145 principles, 763–766, 763t infection (phase 3), 465
investigations, 145–147 sources, 759 HBeAg-negative chronic
dyspnea and, 482 Hemolysis, 878 hepatitis B (phase 4),
Hemolytic anemia, 877 465
EPCs and, 868
treatment of, 880 HBeAg-positive chronic HBV
heart transplantation, 149
Hemopoietic Stem Cells (HSC), 865 infection (phase 1), 464
Infective endocarditis (IE), 130
Hemotransfusion therapy, 784–787 HBeAg-positive chronic hepatitis
mechanical circulatory support B (phase 2), 464–465
(MCS) systems, 148–149 Henoch–Schönlein purpura, 768–769
HBsAg-negative phase (phase
monitoring, 149 Hepatic complications, of dengue fever,
5), 465
587
nonsurgical device treatment, pathogenesis, 469–470
147–148 Hepatic encephalopathy, 457
gut microbiota in, 438 and polyarteritis nodosa, 817,
cardiac resynchronization 819–820
therapy (CRT), 148 Hepatic steatosis, 447
prevalence of, 463
implantable cardioverter- Hepatic stellate activation, 444, 444b
treatments, 465, 470
defibrillator, 147–148 Hepatic stellate cells (HSC), 447
Hepatitis C virus (HCV), 469, 540, 544
implantable electrical devices, Hepatitis A vaccine, 624
148 HIV-HCV coinfection, 470
Hepatitis A virus, 544
overview, 97 pathogenesis, 470
Hepatitis B surface antigen (HBsAg),
pathophysiology of, 80f 463, 464 and polyarteritis nodosa, 817
pharmacologic treatment, 147 Hepatitis B vaccine, 622–624 Hepatitis E vaccine, 627
prognostic value of NP, 98 Hepatitis B virus (HBV), 463–467, 469, Hepatitis E virus, 544
role of natriuretic peptides in 540, 544 Hepatocellular carcinoma (HCC),
diagnosis of, 97–98 cure in, 465 791–794
urinary volume, 363–364 described, 464 NAFLD and, 442
Heart failure with mid-range ejection drugs targeting viral replication Hepatorenal syndrome (HRS), 451–454,
fraction (HFmrEF), 482 cycle 457
Heart failure with preserved ejection antisense molecules, 466 biomarkers in, 453
fraction (HFpEF), 482 capsid inhibitors, 466 classification, 451
in acute setting, 99 entry inhibitors, 465–466 defined, 451
galectin 3 and ST 2, 99 HBsAg inhibitors, 466 diagnosis, 453
natriuretic peptides (NP) in, 98–99 HBV cccDNA inhibitors, 466 diagnostic criteria, 453
prognostic value of plasma HBV-DNA polymerase epidemiology, 451
biomarkers in, 99 inhibitors, 466 overview, 451
958 Medicine Update 2018
pathophysiology, 451–452 High density lipoprotein (HDL), 903 opportunistic infections (OI)
precipitating factors, 452, 452f Higher PEEP, ARDS and, 512, 512t affecting CNS, 664–665,
preventive measures, 453 Highly active antiretroviral therapy 665f, 666t
treatment, 453–454 (HAART), 469, 671 peripheral neuropathy, 664
albumin with vasoconstrictors, High resolution computed tomography primary CNS lymphoma, 666,
454 (HRCT) imaging, 514, 519 666f
liver replacement therapy, 454 CAP diagnosis, 526 progressive multifocal
leukoencephalopathy
liver transplant, 454 History taking, dyspnea assessment,
(PML), 666
renal replacement therapy, 454 489
opportunistic infections in, 660–662
High altitude (HA) HIV/AIDS, 464, 469, 543–544, 643–677
candidiasis, 661
BP behaving with aging in people antiretroviral therapy (ART), 652–
658 cryptococcosis, 661
chronically exposed to, 42
antiretroviral drug toxicity, 657, cytomegalovirus, 661
defined, 36
658t Mycobacterium avium complex
High altitude systemic hypertension
considerations before initiation (MAC), 662
(HASH)
ageing, high altitude and blood of, 654–656, 655f Pneumocystis carinii
pressure, 41 first line regimen selection, 656, pneumonia (PCP), 660
ageing and, 41 656t TB, 661–662
blood pressure changes with aging, goals, 652, 652t toxoplasmosis, 660–661
41–42 integrase inhibitors, 653, 654t 90-90-90 strategy in HIV epidemic,
BP behaving with aging in people 645–650, 646f, 647f
non-nucleoside reverse
chronically exposed to high transcriptase inhibitors, vaccine, 627
altitude, 42 653 HIV Associated Neurocognitive
carry home messages, 43 nucleoside/nucleotide reverse Disorder (HAND), 663, 664t
with deletion allele of ACE gene, transcriptase inhibitors, HIV-HBV coinfection, 470
40–41 653 HIV-HCV coinfection, 470
diagnosis of, 42 patient monitoring, 656–657, HIV/hepatitis co-infections, 469–471
effects of high altitude on 657t epidemiology, 469
cardiovascular system, 36 principles, 653, 653t incidence rates, 469
endothelin 1 level, 40–41 protease inhibitors, 653 overview, 469
association of HASH with regimens, 656 pathogenesis, 469–470
deletion allele of ACE treatment failure, 658 treatment
gene, 40–41 cardiopulmonary manifestations of, HIV-HBV coinfection, 470
importance of recognizing, 42 667–670 HIV-HCV coinfection, 470
need for definition of HASH -and its bacterial infections, 669–670 vaccination, 471
prevalence, 36–38
cardiotoxic drugs, 668 HIV/TB co-infection, 658, 918, 919f
overview, 36
coronary artery disease, 668–669 HIV-VL coinfection, 608
pathophysiology of, 38–40
fungal infections, 670 HLH-2004, diagnostics guidelines for,
endothelial dysfunction, role
malignant neoplasms, 670 587
of, 40
pericardial disease, 667–668 H1N1 influenza, 629–634
increased erythropoiesis and
raised hematocrit, role pulmonary manifestations, 669 antigenic shift/drift, 629–630, 630f
of, 39–40 neurological manifestations of, Cytokine Storm, 632–634
sympathetic activation, role of, 663–666 government of India guidelines
38–39 acute seroconversion illness, 663 category A, 630
treatment of, 42–43 ART and, 666 category B1, 630
antihypertensives, 42–43 direct viral invasion, 663 category B2, 630–631
beta blockers, 42 myelopathy due to, 663–664 category C, 631–632
Index 959
kala-azar elimination in, 607–608 Epstein Barr Virus, 540 clinical benefits based on
asymptomatic carrier, 607–608 HBV, 540 inflammatory theory,
HIV-VL coinfection, 608 HCV, 540 195
treatment of post-kala-azar Helicobacter pylori, 540 clinical implications of
dermal leishmaniasis, inflammation in type-2
human papilloma virus, 540
608 diabetes, 195
human T-lymphotropic virus
uninterrupted supply of drugs, drugs related to the
type 1, 540
608 endoplasmic reticulum
IARC classification, 539–540, stress theory, 195
vector control, 608 540t
VL, treatment of, 608 genetic predisposition, 192
incidence, 539
malaria prevalence, 570–571, 571f innate immune system
Kaposi Sarcoma-Associated activation, 191
metabolic syndrome in, 207t Herpes Virus, 540
insulin, 195
peculiarities of HOLD in, 207–208 opisthorchis, 540
link between, 191–194
PUO in, 592–593, 593t pathogenesis, 539
scope of stem cell therapy in, overview, 191
Schistosoma Hematobium, 540 stress and, 191–192
761–762
diabetes mellitus (DM) in India, 233 Toll-like Receptors (TLRs) and,
snake bite management, 742–754
infective endocarditis (IE), 130–131 191
Indian Guidelines of Hypertension, 21
prevention of, gut microbiota and, type-2 diabetes and innate
Indirect-acting drugs, HBV infection
437–438 immune system, 192
host-acting pathway, 46
uncontrolled, 130–131 endothelial dysfunction and,
innate and adaptive immune
Infectious diseases, control of, 911–912 193–194
defense pathways, 466–467
Infectious Disease Society of America Inflammatory bowel disease (IBD), 472
therapeutic vaccines, 466
(IDSA), 525 dysbiosis, 475
Individualization of diabetes care
Infective endocarditis (IE) FMT in, 475
antihyperglycemic therapy, 284
acute renal failure, 131 gut microbiota in, 438
implementation strategies, 284
antimicrobial therapy, 129–130, Inflammatory pathways to insulin
individualized goals, 283–284
130t resistance, 193
key points, 285
changing epidemiological profile, Inflammatory response inhibitor, 853
other considerations, 284–285
129 Inflammatory theory, clinical benefits
patient-centered approach, 284
common pathogens and based on, 195
therapeutic patient education, 285 antimicrobial therapy in, Influenza vaccine, 626
therapy in newly diagnosed T2DM 131t
patients, 281–283, 282f, Inhalational corticosteroids (ICS), 502
complications, 130–131
282t In-hospital prophylaxis, 155
diagnostic issues, 129
treatment approaches for T2 Initial resuscitation and management,
echocardiography, 129, 130t 681–682
diabetes, 281–284
embolic events, 131 Innate immune system
Industrial chemicals, 199
Infants heart failure, 130 activation, 191
growth phase, 333 indications for surgery, 131–132 HBV infection and, 466–467
gut microbiota, 436–437 endocarditis team, 132 Innocent mind, 891
Infection(s), 537–641. See also Co- follow-up after antimicrobial Inpatients, antimicrobial therapy for
infections; specific entries therapy, 131–132 CAP in
associated cancer, 539–542 pathological criteria and blood ICU, 530, 530t
agents, 540, 541t culture, 129 nonICU, 530
chlonorchis, 540 prevention, 132 Institute for Health Metrics and
detection and proving uncontrolled infection, 130–131 Evaluation (IHME), 481
association of agents, Inflammation Insulin injection technique,
540, 541t–542t, 542 diabetes and, 193–194 lipohypertrophy, 350, 350f
962 Medicine Update 2018
Insulin pump Integrase inhibitors, for HIV infections, Interleukin 2 (IL-2), 293
components of, 270 653, 654t Interleukin (IL)-6, 444
current scenario of, 272 Integrons, 717 Intermediate-acting insulin, 274
in India, 270–272 Intensive care unit (ICU), 679–679 Intermediate (savannah) cycle, of
indications for, 271 antibiotic resistance in yellow fever virus, 583–584
medtronic, 270f defined, 716 Intermediate syndrome, 361
superiority of, 271 judicial use of antibiotics and, Internal pancreatic fistulas (IPF),
718 430–431
types, 271
mechanisms, 716–717 International Agency for Research on
Insulin resistance (IR), 80–81
newer interventions, 718 Cancer (IARC), 539
in CLD
threat in India, 718 classification of infection associated
mechanism of, 446–447
critical care toxicology, 681–683 cancers, 539–540, 540t
prevalence of, 447
decontamination, 682 International Club of Ascites (ICA), 453
DM and, 186
enhanced elimination, 682–683, International League Against Epilepsy
FMT in, 475 682t (ILAE), 380
inflammatory pathways to, 193 initial resuscitation and Interstitial lung diseases, 485
NAFLD-related HCC risk and, 444 management, 681–682 Intraarterial tPA, 388
obesity and, 192–193 laboratory investigations, 682, Intracranial pressure, increased, 560
OSA and, 495, 498 682t Intrauterine growth phase, 333
Insulins, 301 hypoglycemia in, 684–694 Intravascular ultrasound (IVUS), 76
gestational diabetes mellitus acute coronary syndrome, 689– Intravenous fat emulsion (IFE) therapy,
(GDM), 219 694, 689t, 690t 683
inflammation and, 195 brain and, 688f Intravenous immunoglobulins (IVIgs),
intermediate-acting insulin, 274 in cardiac ICU, 688–689 848
long-acting insulins, 274–275 classification, 684 Intravenous steroids, NMO, 369
premixed insulin, 275 clinical mimics, 687 Intrinsic lesion, 359
rapid-acting insulin, 274 complications and Intrinsic short stature, 335
short-acting insulin, 274 consequences, 687–688,
Invasive testing , in dyspnea, 493
687f, 687t
Insulin therapy, 221–223 IPT. See Isoniazid preventive therapy
defined, 684
barriers to basal insulin in type 2 (IPT)
ECG changes, 689
diabetes mellitus, 222–223 IR. See Insulin resistance (IR)
hemodynamic changes, 689
basal insulin, 221–222 IRIS. See Immune reconstitution
induced mortality, 688, 689t,
benefits of, 222 inflammatory syndrome (IRIS)
690t
early vs late use, 222 Iron deficiency anemia
management challenges, 688,
fine-tuning, 277 689t evaluation of, 879
GMD in CLD, 449 myocardial effects, 689 management of, 880
hospitalized patients, 275–276 neuroglycopenic signs and oral therapy treatment of, 880
initiating, 275–277 symptoms, 686 Iron therapy, 854–855, 854t
need for, 273–274 overview, 684 Irritable bowel syndrome (IBS), 472
overcoming the psychological pathogenesis, 684–689, 685f FMT in, 475
barriers to, 277–279, 278t prevalence of, 685, 686f gut microbiota in, 438
overview, 221 reason for death and, 688 Isolated systolic hypertension (ISH)
role of insulin in treatment of type 2 recognition of, 685–686, 686t angiotensin converting enzyme
diabetes mellitus, 222 nosocomial pathogens seen in, 717 inhibitors, 47
starting insulin, 223 Intensive insulin therapy (IIT), 292, 293 angiotensin 2 receptor blockers,
type 1 diabetes patients, 276 Interferon gamma (IFN-γ) release 47–48
type 2 diabetes patients, 276–277 assays, 580–581 antihypertensives, useful in, 47–48
Index 963
GMD in CLD and, 448 Long-acting insulins, 274–275 global scenario, 570, 570f
OSA and Long-acting muscarinic antagonists history, 570
antiplatelets and statins therapy, (LAMA), 502 Indian scenario, 570–571, 571f
498 Loop diuretics for HT, 34 lab diagnosis, 573–574
behavioral methods, 498 Loop-mediated isothermal malignant behavior of Plasmodium
blood pressure, 498 amplification test (LAMP), vivax, 572–573, 572t
insulin resistance, 498 579, 580f
management, 574, 574t
Likert scale, 489 Low density lipoprotein (LDL), 903
parasite, 571
Limited joint mobility, 203–204 Low grade-inflammation, obesity and,
pathophysiology, 573
Linagliptin, 187, 188t, 189, 189t 192–193
second line treatment, 574
albuminuria lowering associated Low tidal volume ventilation (LTVV),
508, 510t, 511 severe malaria, 573, 573t
with, 252f
Low volume ascites, 457 treatment in pregnancy, 574–575
CV risk inot increased with, 253f
Low-volume voids, nocturia, 364 vaccine, 627
CV safety meta-analysis, 254f
Vivax malaria, 571–572
Line probe assays, 579 LT. See Liver transplantation (LT)
Malignancy, vertigo, 409
Lipase, 423 Lung Injury Prediction Score (LIPS),
508 Malignant neoplasms, HIV/AIDS and,
Lipid metabolism, gut microbiota and, 670
437 Lung mass, 514. See also Solitary
pulmonary nodule (SPN) Malnutrition, vitamin D deficiency, 330
Lipid profile, metformin, 263
Lung parenchyma-related diseases, Mannitol, 560
Lipohypertrophy (LH)
dyspnea and, 485 Mantoux test, 580
bruising, 348, 350
Lung transplantation, 128 Marshal organ dysfunction score, 424
causes of, 347–348
Lung ultrasonography, 929–930, 930t MAS. See Macrophage activation
definition of, 347
Lupus nephritis (LN), 844 syndrome (MAS)
diagnosis, 348
Lymphoma, 598 Masked hypertension, 8
glucose control, 350
MCD. See Minimal change disease
glycemic oscillations, 348, 349t (MCD)
management, 350–351 M MDR-TB. See Multidrug-resistant
prevalence of, 347 tuberculosis (MDR–TB)
Macitentan, pulmonary arterial
Lipotoxicity, DM and, 187 hypertension (PAH), 126 Mean arterial pressure (MAP), 452
Liquid biopsies, 916 Macroalbuminuria, 849–850 Mean corpuscular volume (MCV),
Liquid culture, TB diagnosis and, 577 Macroangiopathy, 447–448 NMO, 369
Liraglutide, 240 Macrophage activation syndrome Measles, mumps and rubella vaccine,
Liver, role in carbohydrate metabolism, (MAS), 778–782 624
446 Macrophage infiltration in white Mechanical circulatory support (MCS)
Liver disease (LD), 446 adipose tissue, 192–193 systems, 148–149
in DM Magnesium and pyridoxine infusions, Medical ethics, 885–887
mechanism of, 447 super-refractory status governing bodies and rules, 887
prevalence of, 447 epilepticus, 383–384 important points, 886–887
glucose metabolism in, 446 Magnetic resonance imaging (MRI), theories of, 885–887 (See also
in T2DM, 251 492 specific theories)
Liver replacement therapy, for HRS Malaria fever, 544, 564, 564f Medical management, RVHT, 30–31
treatment, 454 clinical classifications, 573–574 Medical nutrition therapy
Liver transplantation (LT), 451 clinical features, 573 gestational diabetes mellitus
for HRS treatment, 454 clinical malaria, 575 (GDM), 218
Lixisenatide, 241 epidemiology, 570–571 for GMD in CLD, 448
LN. See Lupus nephritis (LN) global mortality, 572f Medical research pyramid, 268f
Index 965
Microbiology laboratory, 718 MOG. See Myelin oligodendrocyte investigations in, 361
Microbiota, gut. See Gut microbiota glycoprotein sites of lesion, 360–361, 360t
(gut flora) Molecular adsorbent recirculating Multiple sclerosis (MS), 389, 472
Microscopic observation drug system (MARS), 454
ADEM vs., 397t
susceptibility (MODS) assay, Monosodium urate (MSU) crystals, 811
577–578 disease-modifying immunotherapy
deposition of, 813
for, 392, 393t, 394, 394f
Microscopic polyangiitis (MPA), 816 Monounsaturated fatty acids (MUFA),
Microsomal triglyceride transport 901, 902 relapses
protein (MTP) inhibitor, 213– Montreal Protocol of 1987, 504 immunotherapy for, 389, 391–
214, 213t 392, 391f
Moral objectivism, 885
Microvascular and macrovascularrisk Multiple seizure, 371. See also Seizure
Moral pluralism, 885
reduction, 264 Musculoskeletal manifestationsof
Moral relativism, 885
Midodrine, with octreotide, 454 diabetes mellitus
Morphine, 611
Mind adhesive capsulitis of the shoulder
MPA. See Microscopic polyangiitis
conditioning of, 891–892 (ACS), 204
(MPA)
innocent, 891 carpal tunnel syndrome (CTS),
MRI. See Magnetic resonance imaging
spiritual culturing of, 892–893 204–205
(MRI)
unscientific, 892 diabetic amyotrophy, 205
MS. See Multiple sclerosis (MS)
Minimal change disease (MCD), 843 diabetic muscle infarction, 205
MSU crystals. See Monosodium urate
Minimally invasive surgery (MIS), 915 Flexor tenosynovitis (FTS) or
(MSU) crystals
Ministry of New and Renewable Energy ‘Trigger Finger,’ 205, 205f
MUFA. See Monounsaturated fatty
(MNRE), 535
acids (MUFA) hyperostosis, 204
Ministry of Petroleum and Natural Gas
Multidrug resistant (MDR) pathogens, limited joint mobility, 203–204
(MoPNG), 535
701 neuroarthropathy (charcot’s joints),
MIS. See Minimally invasive surgery
Multidrug-resistant tuberculosis 205, 206f
(MIS)
(MDR–TB), 553–555
Mitoxantrone, NMO, 369 osteoporosis, 205
anti-TB drugs for, 553
Mitral stenosis, 122 overview, 203
bedaquiline for, 554
with close-upon mitral valve, 122– reflex sympathetic dystrophy (RSD),
defined, 553
124, 122f 206
pathophysiology, 122 delamanid for, 554
Rosenbloom syndrome (RS),
physical examination, 122–123 epidemiology, 553
203–204
signs and symptoms, 122 high dose isoniazid for, 555
Mustard oil, 903
severity of, 123f, 123t management, 553
Myasthenia gravis (MG), 402, 402t
Mitral valvuloplasty, 124, 124f newer drugs options, 554
Mycobacterium avium complex
MMN. See Multifocal motor overview, 553
(MAC), 662
neuropathy regimes, 554, 554t
Mycobacterium tuberculosis (TB) IRIS,
Modafinil, 498 shorter duration therapy option,
673–674
Model for end-stage liver disease 555
surgical options, 555 Mycophenolate, 828
(MELD) score, 456
treatment duration, 555 Mycophenolate mofetil, NMO, 369
Moderate volume ascites, 457
Modes of insulin delivery Multifocal motor neuropathy (MMN), Mycoplasma, 528
pen, 274 401–402, 401f Myelin oligodendrocyte glycoprotein
pump, 274 Multiorgan dysfunction, fever with, 564 (MOG), 394–395
syringe, 274 Multiple cranial nerve palsy, 359 Myeloperoxidase (MPO), 501
Modified Borg dyspnea scale, 489 causes of, 359–360 Myocardium-related diseases, dyspnea
Modified Medical Research Council diagnosis, 361 and, 482
(MMRC) scale, 489 intermediate syndrome, 361 Myrcludex B, 466
Index 967
prevalence of, 447 NSSB. See Non-selective beta-blockers behavioral methods, 498
progression of, 442–443, 443f, 443t (NSSB) blood pressure, 498
risk factors, 442–443, 443f, 443t Nucleic acid amplification (NAA) tests, insulin resistance, 498
type 2 diabetes mellitus and, 442 578–579
with metabolic syndrome X (See
Nonalcoholic steatohepatitis (NASH), Nucleoside/nucleotide reverse Syndrome Z)
442 transcriptase inhibitors
nocturnal symptoms, 497
Noncommunicable diseases, for HIV infections, 653
obesity and, 495
management of, 912–913 Nucleoside reverse transcriptase
occurrences, 495
Noncoronary cardiac complications inhibitor (NRTI), 470
physical examination, 497
in diabetes mellitus (DM), 232–233 Nutrition
treatment, 497–498
Non-high-density lipoprotein acute pancreatitis, 427
type 2 diabetes mellitus and, 498
cholesterol (non-HDL-C), GMD in CLD, 448
305–309 vascular effects of, 496, 496f
Nutritional anemia, 877, 877t, 878, 879f
advantages of, 307–309 Octreotide, 417
as an indicator of ASCVD risk, midodrine with, 454
305–307 O Oils, 901
Non-nucleoside reverse transcriptase Obesity, 472, 495 blending, 905
inhibitors ambulatory blood pressure cold pressed, 903
for HIV infections, 653 monitoring in, 13 cooking, 903–904
Nonosmotic release of antidiuretic central, 497 refined, 903
hormone (AVP/ADH), 452 diagnosis, 497 selection of, 904–905
Nonpalpable purpura, 767–768 FMT in, 475 unrefined, 903
Nonpeptidomimetics, 187 gut microbiota in, 438
Older adults
Non-selective beta-blockers (NSSB), insulin resistance and, 192–193
ambulatory blood pressure
456 low grade-inflammation and,
monitoring in, 13–15
Nonspecific bacterial infections at 192–193
gestational diabetes, 61–62
different sites, 593 NAFLD and, 447
hypertension in diabetes, 61–62
Nonsteroidal anti-inflammatory drugs nocturia, 364
(NSAIDs), 419, 823 OSA and, 495 Olive oil, 903
risk of UGI bleeding and, 415 postmenopausal hypertension, 25 Omega-3 fatty acids (alpha-linolenic
acid N-3), 902
Nonstructural, vertigo, 408, 410 related breathlessnss, 485
type-2 diabetes and, 192–193 Omega-6 fatty acids (linoleic acid N-6),
Nonsurgical device treatment, 147–148
902
cardiac resynchronization therapy Obstructive sleep apnea (OSA)
Oncolytic viruses, in immunotherapy,
(CRT), 148 apnea hypopnea index (AHI), 497
801–802
implantable cardioverter- cardiovascular diseases and,
defibrillator, 147–148 497–498 ONSD. See Optic nerve sheath
diameter (ONSD)
implantable electrical devices, 148 characteristics, 495–497
clinical features, 497 Opisthorchis, 540
Noradrenaline, with albumin, 454
CPAP therapy, 497–498 Optical coherence tomography (OCT),
Normal growth. See Growth (short
76
stature) daytime symptoms, 497
defined, 495 Optic nerve sheath diameter (ONSD),
Nosocomial pathogens, in ICU, 717
931
Nosocomial pneumonia, 725–726, 725t diagnosis, 497
Oral antidiabetic drugs, 300–301, 448
Nosocomial surgical site and soft tissue drug therapy of, 498
infection, 728–729 hypertension and, 495, 497–498 insulin, 301
Nosocomial urinary tract infection insulin resistance and, 495 Metformin, 300
(UTI), 727 lifestyle modifications pioglitazone, 301
NRTI. See Nucleoside reverse antiplatelets and statins therapy, sulfonylurea, 300–301
transcriptase inhibitor (NRTI) 498 Organophosphate poisoning, 738–739
Index 969
preoperative measures, 721–722, Platelet-derived growth factor (PDGF), laboratory investigations, 797
722t–723t 452 mechanisms, 795–796
principles and target of, 721 Pneumococcal antigen detection, physical examination, 797
risk of poor diabetic control, 720 527–528 relative, 795
Peripartum cardiomyopathy, 134–135 Pneumococcal conjugate vaccine secondary, 800
Peripheral arterial obstructive disease, (PCV), 532
systemic examination, 797
870 Pneumococcal vaccine, 625
Polycythemia vera, 798–800
Peripheral vascular disease, 228–229 Pneumocystis carinii pneumonia Polymerase chain reaction (PCR) assay,
Persistent organic pollutants (POP), (PCP), 660
578
198–200, 199f Pneumonia severity index (PSI), 528 Polyunsaturated fatty acids (PUFA),
by-products, 199 Poisoning 901, 902
HOLD, 209–210, 209t aluminium phosphide poisoning Polyvalent polysaccharide vaccine
industrial chemicals, 199 (celphos poisoning), 737 (PPV), 531–532
pesticides, 199 anticoagulants, 740 Positron emission tomography (PET),
some evidences, 199–200 benzodiazepines, 740–741 492, 922
Pertussis vaccine, 624 clinical features, 737–738 of SPN, 519–520
Pesticides, 199 corrosive poisoning, 739–740 Post-kala-azar dermal leishmaniasis
PET. See Positron emission tomography kerosene oil, 740 (PKDL), treatment of, 608
(PET) mechanism of toxicity, 737 Postmenopausal hypertension
Pharmacodynamics, 34 organophosphate poisoning, arterial stiffness, 26
Pharmacogenomics, 914 738–739 depression and anxiety, 25
Pharmacological interventions rodenticides, 740 endothelial dysfunction, 25–26
gestational diabetes mellitus zinc phosphide, 740 genetic factors, 26
(GDM), 218–219, 219t Pollution and diabetes obesity and fat distribution, 25
HOLD, 210 air pollutants sources, 200–201 preventable, 25
Pharmacologic therapy. See Medical human studies, 201 renin-angiotensin system (RAS), 26
therapy persistent organic pollutants salt sensitivity, 26
Physical activity (POPs), 198–200, 199f sympathetic overactivity, 25
and EPC, 866–867 Polyarteritis nodosa (PAN), 815–820, treatment of, 27
HOLD, 209 816f Postnatal growth, 333
nocturia, 366 case study, 815–816, 815f, 816f Postoperative managemant, in
Physical examination classification of, 816 diabetes, 724
in dyspnea, 489–490 clinical features, 817–818 Potassium-sparing common
obstructive sleep apnea, 497 definition of, 816 combination diuretics, 35
Pioglitazone, 301, 449 epidemiology, 817 Pott’s shunt, 128
Pipeline vaccines, Japanese laboratory evaluation, 818 PPAR agonists, 216
encephalitis, 550 management of, 819–820 Pranayama, 898
Plaque morphology, 76 prevalence of, 817 Pratyahara, 898
Plasma exchanges (PE), 820, 827 prognosis, 818–819 Prebiotics, 440
NMO, 369 Polycystic ovarian syndrome (PCOS), defined, 440
Plasmids, 717 264 Prediabetes
Plasmodium falciparum, 572–573 Polycythemia antidiabetic medicines, 183–184
uncomplicated, 575 absolute, 795 increased CV risk in, 182
Plasmodium vivax, 571 causes, 796, 796t Indian epidemiology, 181–182
malignant behavior of, 572–573, combined, 795 screening for, 183
572f, 572t idiopathic, 795 therapy of, 183–184
uncomplicated, 574–575 initial evaluation, 796 when should be intervene, 182
Index 971
Pulmonary functional status and sarcoidosis, 598 RAS. See Renin angiotensin system
dyspnea questionnaire vasculitis, 597 (RAS)
(PFSDQ), 489 infections, 593 Rash. See Fever with rash
Pulmonary function tests malignancies, 593 Reactive oxygen species (ROS), 444
comprehensive, in dyspnea, 492 management, 597 Re-bleeding
Pulmonary hypertension, 483 miscellaneous, 593–596, 594f–596f after endoscopy therapy, 419
categories, 483 nonspecific bacterial infections at prevention in UGI bleeding, 419,
Pulmonary thromboembolic disease, different sites, 593 419f
483 serological tests, 596 in UGI bleeding, 417
Pulmonary vasculature diseases, systemic autoimmune disorders, Receiver-operator characteristic (ROC)
dyspnea and, 483 593 curves, 696, 696f
Pulmonary vasculitis, 483 systemic lupus erythematosus, 598 Receptor for advanced glycation
Pulse oximetry, in dyspnea, 491 temporal/giant cell arteritis, 597 endproduct (RAGE), 447
PUO. See Pyrexia of Unknown Origin uncommon manifestations, 598 Recombinant human erythropoietin
(PUO) (rHuEPO), 855
vasculitis, 593
Purpura Recruitment maneuvers (RMs), 512
case studies, 768 Recurrent bacterial meningitis, 600
defined, 767 Q Recurrent falls (RF), 926
Henoch–Schönlein purpura, Quality of life, GHD, 315 Red Blood Cells
768–769 hemolytic anemia due to, 877
management, 769–770 impaired production, 877, 877t
nonpalpable, causes of, 767–768
R Reduced left ventricular systolic
palpable, causes of, 768 Radiological scoring systems, 426 function, 84
pathophysiology, 767 Radon, 505 Refined oils, 903
purpuric spots, 768 Raja Yoga, 898 Reflex sympathetic dystrophy (RSD),
Rajiv Gandhi Grameen Vidyutikaran 206
Purpura fulminans, 769
Yojana, 535 Refractory status epilepticus, 381
Pyretics, 821
Raloxifene, 833 Relapses, multiple sclerosis, 389, 391–
Pyrexia of Unknown Origin (PUO),
Ramadan, 261 392, 391f. See also Multiple
592–598
Randomized controlled clinical trials sclerosis
bronchoscopy and bronchoalveolar
(RCTs) Relaxed-circular (rc) DNA, 464
lavage, 597
centrality of, 267–268 Relief of angina, 83–84
classification, 592t
DCCT/EDIC, 266 Religions, human beings and, 896–897
defined, 592
in diabetes helped clinical practice Remote symptomatic seizure, 372
epidemiology, 592, 593t
in last decade, 269 Remote Village Electrification
Indian perspective, 592–593
factors which influence physician Programme, 535
etiology, 593
practice, 268 Renal biomarkers, 140–141, 140t
etymology, 592
impact of recent Cvot in diabetes on Renal failure, 87t, 88
factors defining, 598 practice, 267 Renal percutaneous transluminal
gastrointestinal endoscopy, 597 importance of clinical practice angioplasty (RPTA), 31
history, 592 guidelines, 268 Renal replacement therapy (RRT), for
important conditions in medical research pyramid, 268f HRS treatment, 454
drug related fever, 597 prelude, 266 Renal transplant (RT), 837
factitious fever, 598 tighter glucose control, 266–267 advantages of, 837
fungal infections, 597 UKPDS, 266 contraindications of, 837
lymphoma, 598 Rapeseed oil, 903 donor evaluation, 839–841
osteomyelitis, 598 Rapid-acting insulin, 274 recipient evaluation, 837–839
Index 973
Renin angiotensin aldosterone system other routine techniques, 124 Saturated fatty acids (SFAs), 901
(RAAS), 452 medical treatment, 124 Saxagliptin, 187, 188, 188t, 189t
Renin-angiotensin system (RAS), 852 mitral stenosis, 122–124, 122f SBP. See Spontaneous bacterial
postmenopausal hypertension, 26 pathophysiology, 122 peritonitis (SBP)
Renovascular hypertension (RVHT) physical examination, 122–123 SCD. See Sickle cell disease (SCD)
angioplasty, 31 signs and symptoms, 122 SCFA. See Short chain fatty acids
causes of, 28–29 mitral valvuloplasty, 124, 124f (SCFA)
age-related demographics, 28 signs and symptoms, 121, 121t, 135 Schistosoma Hematobium, 540
clinical clues, 29 surgical treatment, 124 Scoring systems. See also specific
clinical presentation, 29 symptoms, 135 entries
epidemiology, 28 Rheumatic valvular heart disease. See acute pancreatitis, 424–426,
sex-related demographics, 28–29 Rheumatic heart disease 425t–426t
diagnosis, 29–30 rHuEPO. See Recombinant human Scrub typhus, 565, 566f, 588–591
medical management, 30–31 erythropoietin (rHuEPO) clinical manifestations, 589–590,
Ribavarin therapy, HIV/HCV co- 589f, 590t
pathogenesis, 28
infection, 470 diagnosis, 590
points favoring expected
positive response post Rice bran oil (RBO), 904 differential diagnosis, 590
revascularization, 30 Rifampicin resistant TB (RR-TB), 553 epidemiology, 588
points not favoring positive Rifaximin, 457 etiology, 588
response post Right ventricular (RV) function incidence, 588
revascularization, 30 focussed echocardiography for, 932 overview, 588
summary of current thinking on, 31 Riociguat, 126 prevention, 591
surgical revascularization, 31 Risedronate, 833 transmission, 588
treatment of, 29–30 Risk stratification, in CAP, 528–529, 529t treatment, 590–591
REPAIR-AMI Trial, 868 Rituximab (RTX), 292, 369, 827, 842 Secondary cardiorenal syndrome, 139,
Reperfusion therapies, 154–155 142
adverse effects of, 844–845
catheter based reperfusion, 155 Secondary prevention of CAD, 116
and lupus nephritis, 844
surgical embolectomy, 155 and membranous nephropathy, 843 Seizures, 371, 601. See also Complex
thrombolysis, 154–155 partial seizure (CPS)
Robot, in medicine, 915
Resistant hypertension, 61 AED, 371, 372
Rockall and Glasgow Blatchford scoring
gestational diabetes, 61 (GBS) systems, 416 approach to, 373–374
Resistin, 444 Rodenticides, poisoning, 740 diagnosis of, 373t
Respiratory system, 479–535 Rosenbloom syndrome (RS), 203–204 management, 374
air pollution effects on, 534 multiple, 371
RRT. See Renal replacement therapy
Restrictive transfusion strategy, UGI (RRT) phenomena, 377–378
bleed and, 416 RT. See Renal transplant (RT) provoked vs. unprovoked, 372t
Resuscitation, UGI bleed and, 416 Rule of halves, 67–70 recurrence, 372–373, 373t
Revascularization strategy, 110–111 Ruminococcus, 437 types of, 372
Reverse halo sign, SPN, 517 Selexipag, 127
Revised Atlanta Classification (2012), Sepsis
423, 429t S biomarkers in, 695–698
RF. See Recurrent falls (RF) Safflower oil, 904 applications, 695, 695t
Rheumatic heart disease, 135 Salt sensitivity, postmenopausal combinations, 698
echocardiography, 123, 123f hypertension, 26 C-reactive protein (CRP),
cardiac chamber Samadhi, 898 697–698
catheterization, 123 Sarcoidosis, 598 diagnostic criteria, 695–696, 696t
974 Medicine Update 2018
chest radiology, 516 SPN. See Solitary pulmonary nodule Section 12: Children and
clinical evaluation, 515–516 (SPN) Adolescents, 178–179
contrast enhancement, 518 Spontaneous bacterial peritonitis Section 13: Management of
CT scan of chest, 516 (SBP), 451, 457, 458t, 461 Diabetes in Pregnancy, 179
Sputum Gram stain and cultures, CAP Section 14: Diabetes Care in the
density, 517
investigation and, 526–528 Hospital, 180
distribution, 516–517
SRS. See Sex reassignment surgery Staphylococcus, 360
follow-up imaging, 519, 519t (SRS) Staphylococcus aureus, 129
growth pattern, 518–519 Stable coronary artery disease (CAD) Statins/statins therapy, 76–77, 76t, 868
margin, 516, 517f duration of dual antiplatelet therapy in OSA, 498
PET imaging, 519–520 after PCI, 91–92
Status epilepticus (SE), 380
size, 516 improvement in survival with PCI,
age, 381
surgical biospsy, 521 83
EEG correlates, 381
tissue diagnosis, 520 indications for PCI, 83
management of, 82 etiology, 380–381
transthoracic needle aspiration/
overview, 82 FIRES, 381
CT guided needle
biopsy, 520 patient preference, 84 NORSE, 381
doubling time (dt), 518 patients without clear indications refractory, 381
feeding vessel sign, 517 for intervention, 84 semiology, 380, 381t
halo sign, 517 reduced left ventricular systolic super-refractory (See Super-
function, 84 refractory status
malignant conditions, 515–516
relief of angina, 83–84 epilepticus)
management, 521–522
severity of coronary artery disease, Status migranosus, headache, 357
overview, 514
84 Steatohepatitis, 442
prevalence, 515
Standards of Care (ADA), 173–180 Steeple sign (wine bottle sign), 490
reverse halo sign, 517
Section 1: Promoting Health Stem cells, 914
satellite lesions, 517 andReducing Disparities in classes, 759
Soluble receptor for advanced glycation Populations, 173 defined, 759
end products (sRAGE), 501 Section 2: Classification and transplantation methods, 759
Solute diuresis, urinary volume, 363 Diagnosis of Diabetes, 174
Stem cell therapy, 128, 759–762. See
Somatostatin, 417 Section 3: Comprehensive Medical
also Hematopoietic stem cell
Sonothrombolysis, 387 Evaluation and Assessment
transplantation (HSCT)
Soul, 895–897 of Comorbidities, 174
ethical issues, 761
Section 4: Lifestyle Management,
defined, 896 important trials in, 761
174
part of universal energy, 895–896 recent advances, 761
Section 5: Prevention or Delay of
Soya bean oil, 903–904 Type 2 Diabetes, 174–175 risks, 761
Spiritual energy, 894 Section 6: Glycemic Targets, 175 scope in India, 761–762
centers, 895, 895t Section 7: Obesity Management for uses of, 760–761
effects of, 894–895 the Treatment of Type 2 Stigmata of recent hemorrhage (SRH),
ways of acquiring, 897–898 Diabetes, 175 417
Spiritual health, 888 Section 8: Pharmacologic Stool evaluvation, for FMT, 474
defined, 899 Approaches to Glycemic Stool preparation, for FMT, 474
Treatment, 175
diagnosis of, 899–900 Stress
Section 9: Cardiovascular Disease
effect of, 899 diabetes and, 191–192
and Risk Management, 176
Spirituality, 893–894 Section 10: Microvascular inflammation and, 191–192
Spiritual knowledge, 893 Complications and Foot Stress testing , in dyspnea, 493
Spirometry, in dyspnea, 491 Care, 176–178 Stroke risk, prediction of, 162
976 Medicine Update 2018
Tourniquets use, 743 sylvatic (jungle) cycle, 583 culture-based methods for
Toxicology, 731–755 urban cycle, 584, 584f diagnosis
Toxoplasmosis, 660–661 Transposons, 717 conventional solid media,
Trans fatty acids (TFAs), 902–903 Trans-sexuals, 872, 873 576–577
Transfusion transmitted bacterial liquid culture, 577
Transthoracic needle aspiration, of
infection (TTBI), 545 SPN, 520 described, 576
Transfusion transmitted infections Transwomen (MTF), 872–873 direct sputum smear microscopic
(TTI), 543–546 examination, 576
Trauma, ultrasonography in, 933–934
arboviruses, 545 DNA tools, diagnosis based on,
Treatment protocol, for antimicrobial
bacteria, 543 578–580
therapy in CAP, 530–531
bacterial infections, 545 GeneXpert (Xpert MTB/RIF),
Trelagliptin, 188t, 189t
579
cytomegalovirus, 545 Treprostinil, 126–127 line probe assays, 579
donor screening questionnaire, 546 Treprostinil diolamine, 126–127 loop-mediated isothermal
Epstein–Barr Virus, 545 Triage-Titrate approach, 405–406, 406f amplification test
hepatitis A virus, 544 Triggering receptor expressed on (LAMP), 579, 580f
hepatitis B virus, 544 myeloid (TREM), 697–698 nucleic acid amplification
hepatitis C virus, 544 Triglycerides, 901, 903 (NAA) tests, 578–579
hepatitis E virus, 544 Triple therapy, 96, 96t epidemiology of, 918t
human immunodeficiency virus, Tropical fevers, 562–568 extensively drug resistant (See
543–544 acute febrile encephalopathy/acute Extensively drug resistant
human T-lymphotropic virus I and encephalitic syndrome, 564 TB (XDR-TB))
II, 544–545 latent tuberculous infection
with acute respiratory distress
malaria, 544 syndrome, 564 diagnosis
other agents, 546 clinical approach to, 562–563, 563t interferon gamma (IFN-γ)
Parvovirus B19, 545 release assays, 580–581
defined, 562
pathogen inactivation technology, serological diagnosis, 581
dengue fever, 564–565, 565f
546 tuberculin skin test, 580
enteric fever, 565, 565f
prion disease, 543 and meningitis, 600
investigation strategy, 566
protozoa, 543 multidrug-resistant [See Multidrug-
leptospirosis, 566, 566f
syphilis, 544 resistant tuberculosis
malaria fever, 564, 564f (MDR–TB)]
virus, 543
with multiorgan dysfunction, 564 newer modalities in diagnosis of,
West Nile Virus, 545
overview, 562 576–581
Transgenders, 872
with rash/thrombocytopenia, 563 nitrate reductase assay (NRA), 578
Transient ischemic attack (TIA), 378,
408–409 scrub typhus, 565, 566f rapid detection of drug resistance
Transjugular intrahepatic skin lesions associated with, 563t MODS Assay, 577–578
portosystemic shunt (TIPS), treatment strategy, 566–567, Tumor, role of EPCs in growth of, 869
418 567f–568f Tumor necrosis factor (TNF)-α, 444
Transmen (FTM), 872–873 undifferentiated fever, 563 25 hydroxy vitamin D3, 327, 328t. See
Transmission Trypsinogen, 423 also Vitamin D deficiency
AES, 557 TTI. See Transfusion transmitted 20 minute whole blood clotting test (20
arboviruses, 547–548, 548f infections (TTI) WBCT), 747
horizontal, 717 Tuberculin skin test (TST), 580 Type 1 diabetes mellitus
scrub typhus, 588 Tuberculosis (TB), 553, 661–662, 918 immunity, 286–287
of yellow fever virus, 583–584 annual incidence of, 918 staging of, 174
intermediate (savannah) cycle, colorimetric redox indicator Type 2 diabetes mellitus (T2DM)
583–584 methods, 578 barriers to basal insulin in, 222–223
978 Medicine Update 2018
Venous thromboembolism (VTE), 151 TTIs of, 543 World Meteorological Organization
Ventilation/perfusion (V/Q) scan, in Visceral leishmaniasis (VL), 607 (WMO), 504
dyspnea, 492–493 HIV-VL coinfection, 608 World Professional Association for
Ventilation-perfusion scintigraphy, for treatment of, 608 Transgender Health (WPATH),
pulmonary embolism, 936 Visual analogue dyspnea scale (VADS), 873
Ventilator induced lung injury (VILI), 489 WPATH. See World Professional
508, 511 Vital capacity (VC), 485 Association for Transgender
Verrucomicrobia, 436 Vitamin D, 326 Health (WPATH)
Vertebral fractures, 831 deficiency, 326–327, 331
Vertebro basilar stroke/transient
ischemic attack (TIA), 408–409
relation to lifestyle, 329–330 X
social relevance, 330–331
Vertigo, 404 XDR-TB. See Extensively drug resistant
supplementation, 291–292
approach to, 404, 405t, 406t TB (XDR-TB)
Vitamin K antagonists (VKAs)
BPPV, 406–407
‘newer oral anticoagulants’
classification of, 404 (NOACs) vs., 86–89 Y
Ménière’s disease, 408 Vivax malaria, 571–572 Yellow fever (YF)
nonstructural, 408, 410 Volatile organic compounds (VOCs),
clinical presentation, 584
peripheral vs. central vestibular 534
disorders, 404–405, 406t described, 583
structural causes, 408–410 differential diagnosis, 585
superior semicircular canal
W laboratory finding, 584
dehiscence, 408 Walled-off necrosis (WON), 428, 430 pathogenesis, 584
treatment of, 407t, 410–411 management of, 431–432 prognosis, 585
Triage-Titrate approach, 405–406, Wegener’s granulomatosis, 825 resurgence of, 583–585
406f Weight, ‘newer oral anticoagulants’ treatment and prevention, 585
vestibular neuritis, 407–408 (NOACs), 88
Yellow fever vaccine, 549, 626
Vestibular disorders Weight loss, GLP-1 receptor agonists
and, 242–243 contraindication of, 549
peripheral vs. central vestibular international certificate of, 549
disorders, 404–405 Westermark sign, 490
West Nile Virus (WNV), 545 Yellow fever virus
Vestibular migraine, vertigo, 410
White-coat HTN, 7–8 transmission of, 583–584
Vestibular neuritis, 407–408
WHO. See World Health Organization intermediate (savannah) cycle,
Vestibular rehabilitation therapy,
(WHO) 583–584
vertigo, 411
Wisconsin Sleep Cohort Study, 495, 497 sylvatic (jungle) cycle, 583
Vestibular schwannoma, vertigo, 409
Women urban cycle, 584, 584f
Video-assisted retroperitoneal
GHD (See also Growth Hormone Yoga, 303, 897
debridement (VARD), 431, 432
Deficiency (GHD))
Video-Assisted Thoracic Surgery components of, 897–898
oral estrogen, 317
(VATS), 521
puberty and pregnancy, 316
Vildagliptin, 187, 188, 188t, 189t
Village Energy Security Programme,
World Health Organization (WHO), Z
463, 481, 483, 585
535 Zanamavir, 632
case definition of AES, 556
Viral hemorrhagic fevers, 615–616 Expanded Program on Zinc phosphide, poisoning, 740
Virtue ethics, 885 Immunization, 912 Zoledronate, 833
Virus(es). See also specific names report on air pollution, 533 Z-score, 831