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Editor-in-Chief: Lawrence F. Nazarian, Rochester, NY Associate Editors: Tina L. Cheng, Baltimore, MD Joseph A. Zenel, Sioux Falls, SD Editor, In Brief: Henry M. Adam, Bronx, NY Consulting Editor, In Brief: Janet Serwint, Baltimore, MD Editor, Index of Suspicion:

Deepak M. Kamat, Detroit, MI Consulting Editor Online and Multimedia Projects: Laura Ibsen, Portland, OR Editor Emeritus and Founding Editor:

Robert J. Haggerty, Canandaigua, NY Managing Editor: Luann Zanzola Medical Copy Editor: Deborah K. Kuhlman Editorial Assistants: Sydney Sutherland, Kathleen Bernard

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(ISSN 0191-9601) is owned and controlled by the American Academy of Pediatrics. It is published monthly by the American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007-1098 Statements and opinions expressed in Pediatrics in Review are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees. Recommendations included in this publication do not indicate an exclusive course of treatment or serve as a standard of medical care. Subscription price for 2010 for print and online/online only: AAP Fellow $172/ $131; AAP Candidate Fellow $161/$120; Nonmember $215/$167; Allied Health or Resident $160/$108. Institutions call for pricing (866-843-2271). For overseas delivery, add $95. Current single issue price is $10 domestic, $12 international. Replacement issues must be claimed within 6 months from the date of issue and are limited to three per calendar year. Periodicals postage paid at ARLINGTON HEIGHTS, ILLINOIS and at additional mailing offices. © AMERICAN ACADEMY OF PEDIATRICS, 2011. All rights reserved. Printed in USA. No part may be duplicated or reproduced without permission of the American Academy of Pediatrics. POSTMASTER: Send address changes to PEDIATRICS IN REVIEW , American Academy of Pediatrics Customer Service Center, 141 Northwest Point Blvd., Elk Grove Village, IL 60007-1098.

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Richard Antaya, MD, FAAP, disclosed that he participates in Astellas Pharma, US,

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Jacob Hen, Bridgeport, CT Hal B. Jenson, Springfield, MA Donald Lewis, Norfolk, VA Gregory Liptak, Syracuse, NY Susan Massengill, Charlotte, NC Jennifer Miller, Gainesville, FL Blaise Nemeth, Madison, WI Renata Sanders, Baltimore, MD Thomas L. Sato, Milwaukee, WI Sarah E. Shea, Halifax, Nova Scotia Andrew Sirotnak, Denver, CO Nancy D. Spector, Philadelphia, PA

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Cover: The artwork on the cover of this month’s issue is by one of the winners of our 2009 Cover Art Contest, 9-year-old Grace A of Williamsville, NY. Grace’s pediatrician is Bohdan Dejneka, MD.

Answer Key: 1. C; 2. E; 3. A; 4. E; 5. A; 6. D; 7. E; 8. B; 9. B; 10. C

contents Pediatrics in Review Vol.32 No.1 January 2011 Commentary 3 The Pediatrician as Teacher Lawrence
contents
Pediatrics
in Review
Vol.32 No.1 January 2011
Commentary
3
The Pediatrician as Teacher
Lawrence F. Nazarian
Articles
5
Infants of Drug-dependent Mothers
Lauren M. Jansson, Martha L. Velez
14
Inflammatory Bowel Disease
Sarah R. Glick, Ryan S. Carvalho
27
Visual Diagnosis: Perceived Fevers and
Back Pain in a 1-week-old Infant
Delia L. Gold
31
Focus on Diagnosis: A Primer on D-dimer
Cristyn N. Camet, Donald L. Yee
Pediatrics in the Community:
34
The Haiti Earthquake
Sachin D. Shah, C. Andrew Aligne
Index of Suspicion
35
Case 1: Recurrent Oral Ulcers in an Adolescent
Case 2: Visual Impairment in an Autistic Child
Case 3: Fever and Hepatosplenomegaly in an Infant
Case 1: Benjamin Bruins, Howard F. Fine, L. Nandini Moorthy
Case 2: Ayesha Jain, Ashok K. Jain, Thomas W. Milligan
Case 3: Rinku Patel
In Brief
41
Thrombotic Disorders
Michael Roth, Deepa Manwani
Internet-Only Articles
Abstracts appear on page 26.
Ethics for the Pediatrician:
e1
Physician Interaction With the
Pharmaceutical Industry
Mark X. Cicero, Michael B. Curi, Mark Mercurio
e4
Delayed Tooth Emergence
Jeffrey M. Karp
CME Statements:
The American Academy of Pediatrics (AAP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to
provide continuing medical education for physicians.
The AAP designates this journal-based CME activity for a maximum of 36 AMA PRA Category 1 Credits TM . Physicians should claim only
the credit commensurate with the extent of their participation in the activity.
This activity is acceptable for a maximum of 36 AAP credits. These credits can be applied toward the AAP CME/CPD* Award available
to Fellows and Candidate Members of the AAP.
The American Academy of Physician Assistants accepts AMA PRA Category 1 Credits TM from organizations accredited by the ACCME.
This program is approved for 36 NAPNAP CE contact hours; pharmacology (Rx) contact hours to be determined per the National
Association of Pediatric Nurse Practitioners (NAPNAP) Continuing Education Guidelines.
*Continuing Professional Development
How to complete this activity
Pediatrics in Review can be accessed and reviewed in print or online at http://pedsinreview.aappublications.org. Learners can claim credit
monthly online or submit their scannable answer sheet for credit upon completion of the 12-month activity. A CME scannable answer sheet
for recording your quiz answers can be found bound in the January 2011 issue. The deadline for submitting the 2011 answer sheet for this
activity is December 31, 2013. Credit will be recorded in the year in which it is submitted. It is estimated that it will take approximately
3 hours to complete each issue. This activity is not considered to have been completed until the learner documents participation in that
activity to the provider via online submission of answers or submission of the answer sheet. Course evaluations will be requested online and
in print.
The Pediatrician as Teacher Lawrence F. Nazarian Pediatr. Rev. 2011;32;3-4 DOI: 10.1542/pir.32-1-3 The online version

The Pediatrician as Teacher Lawrence F. Nazarian Pediatr. Rev. 2011;32;3-4 DOI: 10.1542/pir.32-1-3

The online version of this article, along with updated information and services, is located on the World Wide Web at:

http://pedsinreview.aappublications.org/cgi/content/full/32/1/3

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

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commentary

commentary Commentary The Pediatrician as Teacher The word “doctor” means “teacher,” and like all physicians,

Commentary

The Pediatrician as Teacher

commentary Commentary The Pediatrician as Teacher The word “doctor” means “teacher,” and like all physicians,

The word “doctor” means “teacher,” and like all physicians, pediatricians func- tion as teachers in many contexts. Ev- ery time a patient is cared for, some teaching is accomplished, even in a brief visit. When performing health maintenance or managing chronic ill- ness, teaching becomes a major com- ponent of care. Patients, parents, and caregivers are the students (although the complete physician will be learning constantly from those folks as well). In a pediatric office, physician part- ners teach and learn from each other, and that type of interchange extends to the entire health-care team. I acknowl- edge with gratitude the invaluable les- sons I have learned from nurses and nurse practitioners, and I hope I have repaid in kind. Secretaries, reception- ists, business personnel – we can teach all of them, and their contribution to our education is critical. Many in our profession have de- voted their careers to teaching, and those of us in practice who have learned so much from academic physi- cians, both in our training years and through our experiences in the office, are grateful for their dedication and expertise. However, the practitioner can provide a great deal of education to students and residents if there is a symbiotic relationship with an aca-

demic program. A student can be incor- porated into a busy office schedule, first as an observer, then in a more direct role. This time-honored appren- ticeship model works well, especially if the academic department can provide guidance and follow-up. Office teach- ing also works well for students in nursing and physician assistant pro- grams. Visiting a patient in the hospital offers opportunities for conversations with residents that can be mutually educational, and contributing time to round on the wards can be tremen- dously rewarding. Some of the most fruitful experiences I have enjoyed have come from the dual rounding system, in which an academic specialist and a general pediatrician form a teaching team in the hospital. The ability to complement each other’s perspectives makes for a full and balanced learning experience. Office-based pediatricians can contribute to conferences and grand rounds as well, especially when the topic involves activities they know intimately, such as telephone manage- ment or well child care, as well as subjects in which they might have a particular interest. The general public can benefit from the teaching pediatrician. From ad- dressing a group of nursery school teachers and parents to appearing on national television, we are in a position to pass along information that is accu- rate and evidence-based. Exerting this influence has become more important than ever with the proliferation of in- accurate information in the media, es- pecially on the Internet. Pediatrics in Review (PIR ) has as its mission to improve the health and wel-

fare of all children by educating pedi- atricians and other clinicians who care for children. As you are reading this commentary, authors are crafting arti- cles, reviewers are critiquing papers, editors are planning and refining mate- rial, and other staff are working in myriad ways to allow our readers to stay current across the whole spectrum

of pediatric medicine. We are grateful

for all of these contributions, many of which are made on a volunteer basis. We appreciate also the feedback we get from readers, which we take seriously and on which we follow up. It is important for readers to know that the Accreditation Council for Con- tinuing Medical Education sets stan- dards and establishes criteria for certi- fying organizations that grant credit for continuing medical education. The American Academy of Pediatrics (AAP) adheres to these guidelines, which are updated constantly, in its role as an educational institution. Adherence in- volves such activities as identifying learning gaps, making specific plans for filling those gaps, and monitoring the effects of learning and continuing ed- ucation on competence and actual practice. Making such measurements is

a considerable task, and techniques

vary with the type of education; medi- cal journals are different from single- session workshops and multiday con- ferences. Conflict of interest is another facet of education that is addressed by these standards. Be assured that all who are involved in the AAP’s educa- tional efforts are working hard to achieve the highest standards. We are also on the alert for new modalities to make our teaching more effective. Realizing that social networks

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3

commentary

are important to many of our readers, we recently debuted a website called “In the Loop” (http://intheloop.aap.org) that features social media links for many of the AAP’s publications as well as current news for each journal. Be sure to check it out! Both PIR and NeoReviews have pages on Facebook that amplify the ways in which we can communicate with our readers, and such involvement in networking will only grow. We would like to introduce a new

resource that should be of great help in assisting you as a teacher of patients and parents. The AAP has an online web- site (www.healthychildren.org) that contains a wealth of material on a broad range of pediatric topics written by experts for the lay public. Pediatric clinicians should familiarize themselves with this site and direct patients, par- ents, and caregivers to it. Material can be taken from the site and given out. When appropriate, we link resources on this site to specific articles published in

the journal, but you can help your patients at any time by going to the site yourself or directing them to it. Just as the AAP and PIR are working constantly to improve the ways in which we educate you, we encourage you to be aware of the importance of your role as a teacher and to take steps that will enhance this critical function.

Lawrence F. Nazarian, MD Editor-in-Chief

4 Pediatrics in Review Vol.32 No.1 January 2011

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The Pediatrician as Teacher Lawrence F. Nazarian Pediatr. Rev. 2011;32;3-4 DOI: 10.1542/pir.32-1-3

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Infants of Drug-dependent Mothers Lauren M. Jansson and Martha L. Velez Pediatr. Rev. 2011;32;5-13 DOI:

Infants of Drug-dependent Mothers Lauren M. Jansson and Martha L. Velez Pediatr. Rev. 2011;32;5-13 DOI: 10.1542/pir.32-1-5

The online version of this article, along with updated information and services, is located on the World Wide Web at:

http://pedsinreview.aappublications.org/cgi/content/full/32/1/5

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

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Article fetus and newborn

Infants of

Drug-dependent Mothers

Lauren M. Jansson, MD,* Martha L. Velez, MD*

Objectives After completing this article, readers should be able to:

1. Recognize the effects of maternal substance use on the developing fetus, neonate, and growing child.

 
 

2. Describe the effect of maternal substance use on the mother-infant dyad.

3. Discuss the factors that may serve as mediators and moderators of the effects of maternal substance use on the child.

4. Understand the complex context within which the substance-abusing mother and her infant must be considered.

5. Evaluate and manage the substance-exposed dyad.

Introduction

In utero substance exposure continues to pose a public health and societal dilemma. Prenatal exposure to legal and illegal substances is a substantial and preventable risk factor for developmental alterations in infants. Intrauterine substance exposure affects more newborns than many other common major medical conditions, making the problem of the substance-exposed infant an inevitable concern for all pediatricians. Of the 4.3 million infants born annually in the United States, between 800,000 and 1 million are born to women who used drugs during pregnancy; approximately 1 in 9 infants is exposed to alcohol, 1 in 5 is exposed to nicotine, and 1 in 20 is exposed to illegal drugs. Opioid use during pregnancy is a growing concern due to the rise in abuse of prescription opioids (eg, hydrocodone, oxycodone) in women of childbearing age. Currently, 5.4 million children live with a parent who has a substance use disorder, and 3.4 million live with a mother who has a substance use disorder in the United States. (1) Resumption of drug use following childbirth is an additional concern; in a recent report, cigarette, alcohol, binge alcohol, and marijuana use rates were higher in women with a child younger than 3 months of age (20.4%, 31.9%, 10.0%, and 3.8%, respectively) compared with rates of use in the third trimester of pregnancy (13.9%, 6.2%, 1.0%, and 1.4%, respectively). (2) Pregnant adolescents represent a special population because young women ages 15 to 17 years report a higher rate of use of illicit drugs and misuse of prescription drugs than same-age nonpregnant peers. (3) Even a woman who has decided not to use substances during a pregnancy may do so inadvertently during the early stages before the pregnancy is recognized. Initial studies examining specific effects of maternal drug use on the infant did not account for the wide spectrum of associated risk factors for birth outcomes, particularly psychosocial risk factors, or failed to estimate the proportion of risk attributable to a presumed biologic mechanism versus these other factors. For these reasons, the traditional teratology model has been replaced by a transactional or multiple-risk model in which the psychoactive substance exposure is considered a marker or risk indicator in a contextual framework to explain the outcome of the prenatally substance-exposed newborn. Multiple risk and protective factors have been investigated for their roles as mediators or moderators of the effects of maternal drug use on the developing child. Factors such as amount of drug, timing of use during gestation, use of several (illicit and licit) substances, and issues related to the postnatal caregiving environment need to be considered. Medical complications in the neonatal period, such as prematurity and low birthweight (LBW), can affect the expression of the effects of the substances in the infant and child. Furthermore,

 

*Department of Pediatrics, The Center for Addiction and Pregnancy, The Johns Hopkins University School of Medicine, Baltimore, MD.

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fetus and newborn infants of drug-dependent mothers

substance abuse frequently is associated with multiple social, psychosocial, behavioral, and biomedical maternal and child risk factors, including poverty, stress, psychiat- ric comorbidity, violence exposure, lack of social sup- port, physical abuse, sexually transmitted infections, poor nutrition, and poor medical care. The prevalence of psychiatric disorders among the population of substance-dependent women is of partic- ular importance because these disorders frequently war- rant the need for prescribed medications that have psy- choactive effects. It is estimated that nearly half of all substance-abusing pregnant women have a coexistent axis I disorder, as described in the Diagnostic and Statis- tical Manual of Mental Disorders . (4) Depression is es- pecially prevalent in drug-dependent pregnant popula- tions, and anxiety and personality disorders are frequent comorbid conditions. Psychotropic medications are pre- scribed for women nearly twice as often as they are for men, and these maternal medications can affect infant functioning, as can the disorder for which the medication is prescribed. The purpose of this review is to examine the current and relevant scientific literature regarding the effects of maternal substance use on the developing child and the factors that may serve as mediators and moderators of the effects of maternal substance use on the child as well as provide some recommendations for clinicians evaluating and treating substance-abusing mothers and their substance-exposed infants. The goal is to make clinicians aware of the severity of the potential effects of maternal drug use on the developing child, the myriad and largely indefinable mechanisms by which maternal substance use may affect the infant, and the importance of early and adequate diagnosis and treatment of the substance- exposed mother-child dyad. Improving the clinical ap- proach to these patients may allay the negative short- and long-term consequences of maternal drug use on the developing child.

Effects of Maternal Drug Use on the Developing Fetus

Research on the pediatric effects of maternal drug use poses complex challenges because it often is difficult to make this correlation accurately, given the multiple bio- logic and psychosocial factors that may act as mediators or moderators of the effects of drugs on the infant. Animal models traditionally have been used to define effects of in utero substance exposure. However, gener- alizing results from animal studies to humans is ham- pered by differences in timing of brain maturation. Drugs of abuse cross the placenta and may influence early

development through several pathophysiologic path- ways. Their teratologic effects are dependent on the intersection of the exposure, the temporal and regional emergence of critical developmental processes, and the sensitivity of the developing specific brain structure or neural circuit to the drug. Exposure during the first half of gestation may affect processes related to cytogenesis and histogenesis, whereas effects during the second half of gestation may compromise progressive events (eg, brain growth and differentiation) and regressive events (eg, programmed cell death). Alterations of these events have the capacity to modify brain development as well as the ability of the developing brain to recover from injury.

(5)

Drugs can affect fetal brain development through indirect and direct mechanisms. Indirect effects may be due to variations in maternal physiology and placental functioning. For example, potential indirect mechanisms of nicotine exposure include maternal and fetal undernu- trition caused by smoking-induced anorexia, hypoxia due to increased carboxyhemoglobin and vasoconstric- tion, placental hypertrophy, and reduced transplacental transport of nutrients. Direct effects of the drugs include alterations in the development of neurotransmitter and neuromodulator systems, many of which are present during early embryogenesis and have pleiotropic effects on brain development. Marijuana produces its psychoactive effects through spe- cific brain cannabinoid receptors that regulate multiple developmental processes such as neuronal proliferation, migration, differentiation, survival, and synaptogenesis. Methamphetamines are potent sympathomimetic agents that exert their action by releasing dopamine and serotonin, blocking monoamine reuptake mechanisms, and inhibiting monoamine oxidase, resulting in increases in synaptic con- centrations of the neurotransmitters dopamine and norepi- nephrine. Opioids are metabolized into morphine, and mechanisms of action are mediated by opioid, principally mu, receptors. Opioid receptors are present in several areas of the brain, and several mechanisms could be affected by opioid exposure. Morphine can affect migration and sur- vival of neurons in rats (6) and increase apoptosis in human fetal microglia and neurons. (7) Fetal programming is a mechanism that has been gaining consideration in linking adverse events occurring in utero and related outcomes (eg, enhanced risk for medical, behavioral, or psychiatric problems) in later life. Fetal programming, originally known as the ‘‘Barker” or ‘‘fetal origins hypothesis,” (8) assumes that nongenetic factors such as unfavorable intrauterine conditions can permanently organize or imprint physiologic and behav-

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fetus and newborn infants of drug-dependent mothers

ioral systems and disrupt normal fetal functioning, which may result in later disorders. This mechanism has been implicated in the causal pathway underlying long-term deficits observed in alcohol-exposed offspring. (9)(10) Research in animals and emerging studies in humans suggest that epigenetic changes in regulatory genes and growth-related genes play a significant role in fetal pro- gramming. These epigenetic changes are heritable but reversible alterations in gene expression caused by mech- anisms other than changes in DNA sequence. It is be- lieved that epigenetic changes can persist through mul- tiple cell divisions and cell differentiation and even be passed on to progeny. Based on this theory, maternal substance use could produce significant changes in the regulation of various offspring genes that may be involved in diverse functional systems through epigenetic mechanisms. For example, a study in mice indicated that maternal cocaine exposure during the second and third trimesters of gestation re- sulted in multiple alterations in the methylation states of offspring DNA with persistent effects, suggesting that maternal cocaine use could produce potentially profound structural and functional modifications in the epi- genomic programs. (11) How these potential mechanisms contribute individ- ually and collectively to altered brain growth and matu- ration has not been well established, but it is known that most drugs act through different mechanisms with indi- vidual developmental consequences. In the case of co- caine, the drug crosses the placenta and acts at the presynaptic level, affecting the fetus by blocking the reuptake of the neurotransmitters dopamine, norepi- nephrine, and serotonin; elevating circulating catechol- amine concentrations; and causing vasoconstriction in the fetoplacental unit. Cocaine affects neuronal forma- tion and proliferation and disrupts neuronal migration, resulting in changes to cortical architecture. In addition, cocaine has been implicated as an intrauterine stressor that alters fetal programming, changing developmental trajectories. (12) Finally, maternal and fetal genotypes and ecogenetic considerations (ie, the concept that the combination of a particular susceptible genome and drug/toxin exposure is necessary for adverse effects to become apparent) also may affect outcome. Effects of prenatal exposures have been shown to be sex-specific. For example, prenatal morphine exposure induces physiologic and behavioral changes involving the stress response in the adult rat that differ between sexes. (13) Prenatal exposure to alcohol alters hypothalamic- pituitary axis responsivity differently in male and female

offspring in both animals and in humans. (14) Prenatal exposure to cigarettes increases the risk for developmen- tal psychopathology in human boys but not girls. (15) Male infants have been found to be more vulnerable to maternal methadone use. (16)

Clinically Observable Effects of In Utero Substance Exposure on the Newborn

Regardless of mechanisms of harm and confounding by other risk factors, it is accepted that neonates exposed to substances during pregnancy are at increased risk for a variety of conditions that portend future developmental and other difficulties. The following are the most widely recognized clinical conditions associated with in utero drug exposure.

Drug-related Adverse Birth Outcomes

Nearly all drugs of abuse have been associated with drug-related adverse outcomes such as preterm birth, LBW, and growth restriction. Many substances used by drug-dependent women can shorten gestation and im- pair fetal growth without resulting in preterm deliveries or LBW, as traditionally defined.

Neonatal Abstinence Syndrome (NAS)

NAS is a group of signs indicating dysfunction of respi- ratory, gastrointestinal, or nervous system regulation that develops after the cessation of the maternal drug supply at delivery. Neonatal withdrawal is associated primarily with opiates, sedative-hypnotics, and alcohol, but most psychoactive drugs used during pregnancy, including antidepressants, antipsychotics, and nicotine, can produce “withdrawal-like symptoms” in the new- born. Other than for opioids, there are difficulties in ascribing any signs of neonatal withdrawal to any partic- ular substance because algorithms used to define NAS are specific to neonatal opioid withdrawal, and signs of with- drawal to other substances are likely to be qualitatively and quantitatively different. Nonopioid substances that have been described as having specific abstinence syn- dromes generally present with infants exhibiting signs that are described by the Finnegan Neonatal Abstinence Scoring System. (17) However, most newborns exposed to these substances do not reach cut-off values for phar- macologic treatment and may have symptoms not in- cluded in the Finnegan Scoring System. In addition, generally no specific treatments for nonopioid-exposed infants exist. The infant’s display of NAS can affect maternal functioning and interaction with the newborn, further compounding the threat to progressive neurode-

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fetus and newborn infants of drug-dependent mothers

velopment. Other factors, such as prematurity, can affect the course and presentation of NAS. (18)

Neurobehavioral and Regulatory Impairment

Signs displayed by drug-exposed infants that reflect dif- ficulties in their ability to maintain organized behavioral and physiologic responses to external or internal stimu- lation indicate neurobehavioral and regulatory impair- ment, alternatively labeled homeostatic instability or dysregulation. Frequently observed neurobehavioral problems of substance-exposed infants include tremors; irritability; difficulty being consoled; hypertonicity; in- creased startle response or exaggerated Moro reflex; and respiratory, feeding, and sleeping problems. Behavioral assessment of signs of regulatory dysfunction displayed by the substance-exposed infant has been facilitated by using the Neonatal Intensive Care Unit (NICU) Net- work Neurobehavioral Scale. (19) This scale, developed as a neurobehavioral assessment tool for the at-risk in- fant, is used to evaluate how stressors, such as in utero substance exposure, affect infant self-organizing neu- robehavioral capacities. A systematic assessment of the neurobehavioral functioning of the substance-exposed neonate in the domains of state control regulation, mo- tor and tone functioning, reactivity to sensory stimula- tion, and autonomic signs of stress, can define areas of concern that can be used to design an individualized care plan. (20)

Structural Changes

Congenital anomalies have been variably reported for almost all drugs of abuse. Aside from alcohol, which has a clearly defined pattern of birth defects, large outcome studies evaluating the correlation between congenital anomalies and periconceptional drug use generally find no positive associations. (21) Advances in brain magnetic resonance imaging-based methods have identified some alterations of brain structures and patterns of functional activation in offspring of mothers who used licit (eg, alcohol and tobacco) and illicit (eg, cocaine, metham-

phetamine, marijuana) drugs during pregnancy. Al- though these findings are limited by the complexities of separating the specific effects of each drug from other confounding variables and the impracticality of using such methods in the clinical setting, particularly during the neonatal period, these methods may advance the understanding of the underlying structures affected by prenatal drug exposure to improve diagnosis and provi- sion of therapeutic resources for affected infants, chil- dren, and young adults.

Postnatal Problems due to Environmental or Caregiving Deficiencies

Infant neurodevelopmental or behavioral problems can be created by an overstimulating or insensitive environ- ment or a caregiver’s style of interaction. When caregiv- ers are not trained or able to interpret and respond to physiologic or behavioral signs of dysregulation created by external or internal stimuli, the caregiver’s actions or interactive style can impair the recovery of the infant and perpetuate dysregulated responses. This impairment, in turn, can affect basic functions such as feeding, sleeping, and interactive patterns that may contribute to altered developmental trajectories. Neurodevelopmental diffi- culties also can be caused or exacerbated by maternal psychopathology or postnatal drug use, which may pro- vide the infant with further postnatal passive or active exposure to substances (eg, secondhand smoke or sub- stances via human milk).

The Effects of Individual Substances on the Neonate

Although it is difficult to ascribe any particular symptom to any particular substance, because most overlap (Table) and are nonspecific, full appreciation of the complexities and clinical status of the exposed neonate requires con- sideration of the effects of individual substances.

Table. Observed Effects of Substance Abuse in the Newborn

 

Nicotine Alcohol Marijuana Cocaine Opioids PCP

Methamphetamine Benzodiazepines

Prematurity

Yes

Yes

No

Yes

Yes/No No

Yes/No

Yes

Low birthweight

Yes

Yes

No

Yes

Yes/No No

Yes

Yes

Neurobehavioral symptoms Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

NAS

Yes

Yes

No

No?

Yes

Yes/No Yes?

Yes

Congenital malformations Yes/No Yes

No?

Yes/No No

Yes

Yes?

Yes/No

Yes/No both have been reported, ? controversial or unclear findings, NAS neonatal abstinence syndrome, PCP phencyclidine

 

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fetus and newborn infants of drug-dependent mothers

Nicotine

Nicotine has been described as a neuroteratogen that compromises critical neural pathways in the developing brain. (22) Nicotine crosses the placenta, and the fetus is exposed to concentrations that are 15% higher than in the maternal bloodstream. Cigarette use also involves exposure to substances that interfere with oxygen deliv- ery and use, such as carbon monoxide and hydrogen cyanide; these additional factors may participate in the overall effects of smoking. Nicotine exposure during gestation includes effects that have been found to be related to secondhand smoke as well as nicotine replace- ment therapies. (23) Neurobehavioral symptoms de- scribed in exposed neonates include impairment of arousal, irritability and hyperexcitability, hypertonicity, and tremors. (24)(25) Reports of sporadic congenital anomalies associated with nicotine consist principally of higher incidences of orofacial clefts, neural tube defects, and cryptorchidism, although large-scale studies have found no significant increase in gross malformations. (26) Prenatally nicotine-exposed infants are at increased risk for preterm birth and sudden infant death syndrome (27) as well as fetal growth restriction, which has been linked to subse- quent development of both neonatal and adult disease. (28) Dose-dependent LBW has been associated with maternal smoking. (29) Heavily nicotine-exposed infants have been described as having withdrawal syndromes.

(30)(31)

Alcohol

Alcohol exposure during gestation is a significant risk factor for poor infant outcomes. Alcohol passes through the placenta, and the amniotic fluid is a reservoir for ethanol, which increases availability of the drug to the fetus. Maternal alcohol use can produce preterm birth, LBW, and fetal alcohol spectrum disorder. Fetal alcohol syndrome is characterized by specific facial features, growth deficiency, central nervous system abnormalities, behavioral abnormalities, and intellectual disability. (32) A neonatal alcohol withdrawal phenomenon has been described in children born to alcoholic mothers and includes jitteriness, irritability, seizures, opisthotonus, abdominal distention, (33)(34) excessive mouthing movements, and reflex abnormalities. (35)

Marijuana

Delta 9 -tetrahydrocannabinol is the major psychoactive ingredient in cannabis. Cannabis constituents cross the placenta and are stored in amniotic fluid. Prolonged fetal exposure can result from regular marijuana use. Minor

physical anomalies (ocular hypertelorism and epican- thus) have been reported in heavy users of cannabis, but there is a lack of a definitive relationship between physical anomalies and prenatal cannabis exposure in general. Neurobehavioral effects of in utero cannabis exposure range from mild deficits in visual functioning, height- ened tremors, startling, jitteriness, hypotonia, and leth- argy (36) to difficulties with arousal, regulation, and excitability. (37) Although shorter gestational periods have been reported among heavy marijuana users, (38) neither LBW nor preterm birth have generally been reported.

Cocaine

Cocaine-exposed infants are at risk for preterm birth and LBW. Neurobehavioral signs at birth include jitteriness and tremors, high-pitched cry, irritability, excessive suck, hyperalertness, autonomic instability, (39) hypertonic- ity, and excitability. (40) Congenital anomalies have been reported previously in cocaine-exposed infants, but larger and more recent studies have disputed those find- ings. (39) A dose-response relationship for a negative association with motor and state regulation capabilities has been reported. (41)

Opioids

Opioids are narcotic, analgesic substances that have morphine-like effects and include narcotic pain killers, heroin, and methadone, a synthetic opiate with similar pharmacologic properties to morphine that is used to treat individuals who have opiate addictions. Most stud- ies report increased preterm birth and LBW related to opioid use, although few have controlled for associated risk factors. Those that have done so generally report no independent relationships between opiate use and growth parameters. The most notable opioid effect on the neonate is NAS, which may include tonal problems, tachypnea, feeding and sleeping problems, fever, and seizures among its signs. The tool used most commonly to evaluate opioid-related NAS is the Finnegan scale. (42) Evaluation of the opioid-exposed newborn using this scale is recommended every 3 to 4 hours during hospitalization, and surveillance should last for several days after birth. The scale contains 31 weighted (depend- ing on symptom and severity) items. Opioid agonist pharmacotherapy is recommended for infants who have Finnegan scores above a threshold level.

Phencyclidine

Infants exposed in utero to phencyclidine (PCP) have been reported to display dysmorphologic features that

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fetus and newborn infants of drug-dependent mothers

consist of microcephaly (43) and alterations in facial features. (44) Described neurobehavioral symptoms af- ter delivery consist of decreased attention, high-pitched cry, poor visual tracking, coarse flapping tremors, leth- argy, nystagmus/roving eye movements, poor feeding, and altered newborn reflexes. (43)(45) Although infants exposed to PCP generally are smaller and have lower gestational ages than nonexposed infants, PCP exposure is not associated with LBW or preterm birth. (46) An NAS has been described (47) and disputed (48) for PCP-exposed infants.

Methamphetamines

Despite concerns about infants exposed to this drug as rates of usage in the United States increase, there is a general dearth of reports involving in utero exposure. Isolated cases of cardiac defects, cleft lip, and biliary atresia have been reported. (49) Use during pregnancy also has been associated with increased rates of fetal distress and growth restriction, (50) resulting in small- for-gestational age size at birth. (50)(51)(52) Metham- phetamine exposure has been associated with preterm birth, (50) but this linkage has been disputed more recently. (52) Neurobehavioral patterns of decreased arousal, increased stress, and poor quality of movement (53) have been described, as has a withdrawal syndrome in a few infants (4%). (54)

Benzodiazepines

One of the most commonly prescribed class of drugs during pregnancy, despite the absence of complete knowledge of their potential adverse effects, benzodiaz- epines also are commonly abused licit drugs, and expo- sure often is unrecognized due to inconsistent screening policies. Benzodiazepines cross the placenta and accu- mulate in the fetus to varying degrees, depending on the specific drug and its properties. Withdrawal phenomena have been reported in exposed infants. Signs include hypoventilation, irritability, hypertonicity, and “floppy infant syndrome,” particularly after use in late gestation. (55)(56) These symptoms can appear within a few days to 3 weeks after birth and can last for several months. (57) There has been variable reporting on the relative risk of congenital anomalies in this group of infants. An increased risk of orofacial clefts was described in early case-control studies and refuted in later cohort studies. (58) Benzodiazepines appear to increase the risk of pre- term birth and LBW. (59)

Management

The drug-dependent mother and her infant are a com- plex and highly vulnerable dyad that present a challenge to any clinician. Due to the often multiple negative experiences and maladaptive behaviors of the mother and the frequently confusing constellation of signs and symp- toms of abstinence and neurobehavioral dysregulation of the infant, the dyad commonly is “out of sync” or “not bonding.” Thus, they require a caring and well-trained clinician to ensure a successful neonatal adaptation and

prevent the initiation of altered developmental and inter- actional trajectories. Provision of optimal care for the pair involves appropriate identification of the maternal sub- stance abuse and other difficulties, careful and frequent observation of the infant, and delineation of individual- ized care plans for the dyad. Lack of acknowledgment of the maternal addiction and its implications for the new- born, usually stemming from lack of knowledge of ad- dictions in general or lack of available resources postdis- charge, can affect the prognosis for the dyad negatively. All substance-exposed infants should receive support- ive care and evaluation for signs and symptoms of evolv- ing NAS and other regulatory problems. Standard sup- portive care for the exposed infant should include a quiet environment and gentle handling, swaddling, small and frequent feedings, and pacifier use. The individual func- tioning of each infant should be assessed thoroughly, evaluating the ability to regulate sleep/awake states; autonomic, sensory, motor, and interactive capacities; and displayed behaviors. Important behaviors include responses and sensitivities to auditory, tactile, and visual stimuli; motor capabilities; tremors and jitteriness; and style of communication, including eye contact, ability to calm with intervention, ability to signal needs, and signs

of stress or abstinence. The infant’s capacities and diffi-

culties in each area should be addressed in individual care

plans as well as in maternal-infant care. For infants experiencing significant NAS symptom- atology, pharmacotherapy is warranted. Medications used to treat the neurobehavioral symptoms related to prenatal exposure to psychoactive drugs vary widely among institutions. The most commonly used first-line

medications for opioid withdrawal are opioids (oral mor- phine solution, tincture of opium) and methadone. (60)

A major review advocates opioids as the drug of choice

for neonatal opioid withdrawal. (61) For polydrug- exposed infants, commonly employed medications are opioids, phenobarbital, and methadone. (60) Weight- based versus symptom-based treatment strategies can be employed, and examples of both have been described. (62)(63) Little empirically based evidence supports the

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fetus and newborn infants of drug-dependent mothers

use of one medication or one treatment strategy over the other, reflecting a paucity of randomized studies in this area. At the time of this writing, newer agents for the treatment of NAS, such as clonidine (64)(65) and bu- prenorphine, (66) are being explored and may have a role in the management of NAS. By examining the newborn in the presence of the mother and evaluating her perceptions and responses to newborn signaling, the clinician can assess and demon- strate the infant’s physiologic competencies and weak- nesses while simultaneously evaluating maternal respon- siveness and comprehension. Mothers and other caregivers can be taught to provide appropriate environ- ments (eg, not over- or understimulating) for the infant. Infants who have significant NAS require medication and prolonged hospitalization. In situations where mothers are able to stay with their infants or visit regularly, this period can be used as a time of prolonged evaluation of the dyad and an opportunity to provide ongoing parent- ing support and instruction. Teaching of simple con- cepts, such as the importance of infant sleep, cueing, and schedules, can provide a basis for improved parenting skills in the mother as the child grows. Maternal satisfac- tion with the diminution of NAS symptoms associated with her handling can allay some guilt and depression. Interventions for the drug-dependent mother and ex- posed infant have been described (67) and are useful in the care of the dyad for providing a basis for improved parenting and infant/child development. Drug-dependent women also require thoughtful and careful evaluation because their needs can be as complex as their difficulties. Evaluation for mood or other psychi- atric disorders, emotional availability to the newborn, violence exposure, community support systems, and his- tory of previous pregnancy outcomes is necessary. Addic- tion is a chronic disorder and must be addressed as such; all drug-using women should be referred to appropriate substance abuse treatment that will accept the infant. For women in treatment, conference (after consent) with treatment counselors to determine ongoing care plans is important. Mood disorders or other psychiatric comor- bidity should be evaluated and addressed in ongoing postpartum care, particularly because women who have depression are at increased risk for postpartum depres- sion. Postpartum guilt and anxiety, particularly for women who have infants experiencing NAS, is common, can interfere with dyadic communication, and must be gently addressed and monitored. Prejudicial or punitive attitudes, negative stereotyping, and conflicting advice have no place in the care of postpartum drug-dependent women because such attitudes only drive them away

Summary

• Nearly any psychoactive licit or illicit substance consumed by the pregnant woman is likely to result in enhanced risk of medical, developmental, and emotional/behavioral disability in the developing infant/child. These risks can be compounded by biologic and psychosocial factors associated with maternal addiction.

• Drug-dependent women do not use substances in isolation and they cannot escape the myriad complications of their internal and external environments and the attendant risks to the developing fetus and infant.

• The developmental trajectories of fetuses exposed to psychoactive substances may be altered by many factors, including disruption to neuroendocrine and neurotransmitter system development and fetal programming via stress hormone changes, resulting in altered set points for physiologic, metabolic, and behavioral outcomes. (69)

• Epigenetic models of developmental theory examining the intersecting influences of genes, physiology, and behavior with the physical, cultural, and social environment as well as other mechanisms have been implicated in the alteration of developmental trajectories. (5)

• These effects occur through the programming of cell fate and differentiation, in defining ultimate activity levels of specific functional systems, and in mediating environmental modulation of genetically based developmental programs. In this context, maternal substance use during gestation may directly or indirectly derail normal development by adversely modifying fetal/neonatal gene expression, resulting in disruption in brain development.

• The consequences of drug exposure can be seen at birth but sometimes do not emerge until later in life and may be produced at doses that are relatively harmless for adults.

• The role for all clinicians in the comprehensive care of the substance-exposed neonate should include thorough, comprehensive, and individual evaluation of the infant, the mother, and their interaction. Only through a willingness to understand and treat the mother who has drug addiction and the exposed infant as a pair, which may involve the extension of the boundaries of pediatric care, can we provide optimal care for substance-exposed infants, perhaps the most poorly understood, marginalized, and vulnerable segment of the pediatric population.

from treatment and other beneficial encounters at a time when treatment is most needed from those professionals most poised to help. Similarly, caregivers of the infant must refrain from stereotypical or prejudicial attitudes toward the mother. Referral to child protective or other

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fetus and newborn infants of drug-dependent mothers

monitoring services, when appropriate, may be neces- sary, particularly for women who have positive urine toxicology screening results that indicate recent drug use at delivery or substance-abusing women not in drug treatment. However, these services are not warranted for most abstinent and stable methadone-maintained women enrolled in comprehensive substance abuse treat- ment. Women receiving methadone maintenance may have difficulties with oversedation in the postpartum period due to changing medication needs and pain control and should be assessed for such reactions by pediatric clini-

cians who are likely to observe them. Communication with obstetric and mental health professionals is impor- tant in these cases. Breastfeeding is not contraindicated for women receiving methadone maintenance therapy but may not be advised for women relapsing to drug use close to term, women not in substance abuse treatment, or women experiencing difficulties in maintaining sobri- ety in an outpatient setting. Each woman desiring lacta- tion must be evaluated individually. (68) To view references for this article, visit http:// pedsinreview.aappublications.org and click on this ar- ticle title.

PIR Quiz

Quiz also available online at http://pedsinreview.aappublications.org.

1. You are seeing a family who is considering adopting a newborn boy who has been exposed to drugs in utero. They ask for information about how drug exposure affects medical and behavioral issues as children mature. Your best response is that:

A. Drug exposure effects manifest through physiologic rather than genetic mechanisms.

B. Drug exposure in the third trimester is the most detrimental to long-term outcome.

C. Effects of drug exposure in utero generally are the product of polydrug exposures and factors related to substance use.

D. There is a common mechanism by which drugs exert their intrauterine effects.

E. There is no difference in effects of drug exposure based on the sex of the fetus.

2. You are seeing a newborn in the nursery whose mother took prescribed benzodiazepines during pregnancy. One likely manifestation of benzodiazepine exposure in this baby is:

A. Cardiac defects.

B. Elevated bilirubin concentrations.

C. Hyperventilation.

D. Large-for-gestational age birthweight.

E. Withdrawal symptoms lasting for several months.

3. An infant was born at term with birthweight 2.1 kg. The most likely intrauterine drug exposure associated with this infant’s birthweight is:

A. Diazepam.

B. Fentanyl.

C. Marijuana.

D. Oxycodone.

E. Phencyclidine.

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fetus and newborn infants of drug-dependent mothers

4. An infant in the newborn nursery has tremors, poor feeding, and increased tone and is not easily consoled. An associated symptom of neonatal abstinence syndrome that might manifest in this infant is:

A. Cardiac arrest.

B. Hyperbilirubinemia.

C. Hypothermia.

D. Hypotonia.

E. Seizure.

5. A 3-year-old boy has been asked to leave several child care settings because of his extreme hyperactivity and inattention. His birth weight was 2.3 kg. His growth parameters show height at the 20th percentile, weight at the 10th percentile, and head circumference less than the 3rd percentile. He is just beginning to speak a few words, and his mother relates that his developmental skills are similar to the skills of his 18- month-old brother. Magnetic resonance imaging of his brain shows absent corpus callosum. The intrauterine drug exposure most likely associated with these findings is:

A. Alcohol.

B. Benzodiazepines.

C. Cocaine.

D. Marijuana.

E. Methamphetamines.

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Infants of Drug-dependent Mothers Lauren M. Jansson and Martha L. Velez Pediatr. Rev. 2011;32;5-13 DOI: 10.1542/pir.32-1-5

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Inflammatory Bowel Disease Sarah R. Glick and Ryan S. Carvalho Pediatr. Rev. 2011;32;14-25 DOI: 10.1542/pir.32-1-14

Inflammatory Bowel Disease Sarah R. Glick and Ryan S. Carvalho Pediatr. Rev. 2011;32;14-25 DOI: 10.1542/pir.32-1-14

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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

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Article gastrointestinal

Inflammatory Bowel Disease

Sarah R. Glick, MD,*

Objectives After completing this article, readers should be able to:

Ryan S. Carvalho, MD

1. Develop a differential diagnosis and plan an initial evaluation for the child or adolescent who presents with bloody diarrhea and abdominal pain.

   

2. Recognize that growth failure and pubertal delay may be an initial presentation of Crohn disease.

3. List the extraintestinal manifestations of inflammatory bowel disease (IBD).

4. Discuss the genetic advances in understanding the pathogenesis of IBD.

5. Describe the current treatments for IBD and the common adverse effects.

Introduction

IBD is a complex, multifactorial disease characterized by chronic inflammation in the intestinal tract of a genetically predisposed host. The spectrum of IBD in children primarily includes ulcerative colitis (UC) and Crohn disease (CD). With pediatric patients now accounting for 20% to 25% of newly diagnosed cases, it is becoming increasingly important for pediatricians to recognize the symptoms of IBD. (1) In this review, we discuss the epidemiology, clinical presentation, diagnosis, and complications of IBD, with specific emphasis on growth failure and pubertal delay because these are unique manifestations in children. We also describe newer, less invasive diagnostic techniques and current trends in management and advances in the pharmacologic treatment of affected children.

 

Epidemiology and Demographics

The epidemiologic patterns of pediatric IBD have evolved over the past few decades, with significant increases in both incidence and prevalence. The current incidence is 5 to 11 per 100,000 children, with a recent statewide survey from Wisconsin reporting the annual rate of diagnosis as 4.56 per 100,000 for CD and 2.14 per 100,000 for UC. (2) Canadian

Abbreviations

studies have reported an acceleration in new diagnoses from 9.5 per 100,000 in 1994 to 11.4 per 100,000 in 2005. The most significant increases were among the younger age groups, with the incidence rising 5% annually in children

5-ASA: 5-aminosalicylates

 

younger than 4 years of age and 7.6% annually in children ages 5 to 9 years. (3) The mean age at diagnosis of pediatric IBD in the United States is 12.5 years, (2) with 20% of children diagnosed before the age of 10 years and fewer than 5% diagnosed before age 5 years. Males seem overrepresented in new cases of pediatric CD, although an equal number of males and females receive a UC diagnosis. (4) Many risk factors have been associated with IBD, includ- ing family history, ethnicity, and tobacco use. Up to 25% of children who develop IBD have a positive family history of IBD. (5) Children who have a first-degree relative affected by either UC or CD have a 10 to 13 times higher risk for developing IBD. (5) Monozygotic twin concordance is ap- proximately 50% for CD and nearly 20% for UC. (6) In the United States, population-based studies histori-

CD:

EN:

ESR:

FC:

FL:

IBD:

Crohn disease erythema nodosum erythrocyte sedimentation rate calprotectin lactoferrin inflammatory bowel disease

IGF-1: insulin-like growth factor-1

MRI:

PG:

PSC:

SNP:

TNF:

UC:

VCE:

magnetic resonance imaging pyoderma gangrenosum primary sclerosing cholangitis single-nucleotide polymorphism tumor necrosis factor ulcerative colitis video capsule endoscopy

*Wright State University Boonshoft School of Medicine, Children’s Medical Center of Dayton, Dayton OH. The Ohio State University College of Medicine, Nationwide Children’s Hospital, Columbus, OH.

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gastrointestinal inflammatory bowel disease

cally have shown a higher prevalence of IBD in patients

of European or African descent than in patients of His-

panic or Asian descent. (7) Notably, Jewish ancestry (Ashkenazi more than Sephardic) is a significant risk factor for the development of IBD. However, more recent pediatric-specific population studies detected no differences in IBD frequency between ethnic groups. (2) The prevalence of IBD is highest in the industrialized world, including North America, northern Europe, and the United Kingdom. However, with progressive mod- ernization, the prevalence is now increasing in the devel- oping world. Tobacco use is linked closely with an in- creased risk of IBD. In smokers, the probability of developing CD is twice as high as for nonsmokers. (7) Passive exposure to smoking may be influential as well. (8)

Genetics

A genetic predisposition to IBD has been hypothesized

for decades because of the strong familial pattern of disease. Linkage analyses and genome-wide association studies have identified numerous IBD candidate genes. Many share a connection to the immune, inflammatory, or bacterial recognition pathways, which are fundamen- tal mechanisms in the pathogenesis of IBD. In 2001, the NOD2/CARD15 gene, located on chro- mosome 16q in the IBD1 susceptibility locus, was asso-

ciated with CD. Three high-risk single nucleotide poly- morphisms (SNPs) are suggested to alter recognition

of bacterial peptidoglycans in monocytes, macrophages,

gut epithelial cells, and Paneth cells. NOD2 mutations can impair the degradation of gut bacteria, leading to an accumulation of bacterial antigens and predisposing to

mucosal T-cell activation. Nearly 40% of white patients who have CD carry one

of these NOD2 SNPs compared with 20% of controls. (9)

These allelic variants also have phenotypic implications for those who have CD, with earlier age of onset, stric- turing disease, and ileal involvement occurring more frequently. The IBD5 locus on chromosome 5q31 is associated with a higher susceptibility toward CD. Patients who have CD and IBD5 locus polymorphisms may have more perianal disease, colonic disease, and importantly in pe- diatric patients, decreased weight and height at diagno- sis. (10) There also has been a weak association of the IBD5 locus with UC. The IBD3 locus on chromosome 6 contains the major histocompatibility complex genes, which also may contribute toward IBD predisposition. The DRB1*1502 gene has been associated with UC, and the DRB1*07 gene has been associated with CD, particularly in patients

who have ileal disease without a high-risk NOD2 poly- morphism. The DRB1*0103 allele has been linked to UC and colonic CD. Patients who have UC and this variant seem to have a greater predisposition toward more extensive and severe colonic involvement. There also seems to be an association between IBD3 locus variants and the extraintestinal manifestations of uveitis and peripheral arthropathy. (9) The field of IBD genetics is continuously expanding, but genetic testing is currently limited to research. In the future, children who have IBD may undergo genetic testing to quantify disease risk in family members or to predict phenotypic expression.

Causes

The precise causes of IBD remain unknown, but the current understanding involves a genetic predisposition combined with a dysregulation between the immune system and the antigenic environment in the gastrointes- tinal tract, leading to inflammation and damage. (11) The major pathogenic mechanism underlying CD is an excessive Th1 immune response, whereby CD4 T cells become upregulated and markedly resistant to apoptosis. (12) An excessive Th2 immune response has been impli- cated in patients who have UC. (13) Defective gastrointestinal mucosal integrity may lead to enhanced uptake of luminal bacteria, causing the normally protective mucosal immune system to be over- whelmed. This derangement may be a result of toler- ance to luminal antigens, a hyperreactive cell-mediated immune system, or specific gene mutations (such as NOD2 ). It has been postulated that the unchecked intestinal immune response to ubiquitous bacterial and enteric antigens could lead to the pathologic gross tissue injury characteristic of IBD. Activated immune cells secrete a variety of soluble mediators of inflammation, includ- ing cytokines (tumor necrosis factor [TNF]-alpha, interferon-gamma, transforming growth factor-beta, and interleukin-2, -5, -6, -12, and -18), arachidonic acid metabolites, reactive oxygen intermediates, streptolysins, and growth factors. (12) Activated neutrophils and mac- rophages may also release metalloproteinases, which di- gest collagen in the lamina propria and basement mem- brane and are markedly elevated in the fistulous tracts of those who have CD. The most persuasive argument for a pathogenic role of enteric flora comes from murine studies of IBD. (14)(15) The gut inflammation seen in mouse models of IBD depends on the presence of bacterial flora. No single infectious agent has been reproducibly associated with

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gastrointestinal inflammatory bowel disease

IBD, but several bacterial species, including Salmonella, Helicobacter, toxigenic Escherichia coli, Listeria, and Campylobacter , have been suggested to play a role in pathogenesis. Mycobacterium paratuberculosis has been strongly suspected in IBD development. (16) Viral the- ories have been proposed, including the potential for measles virus to cause a granulomatous vasculitis. (17) Another antigenic hypothesis in the development of IBD includes the phenomenon of dysbiosis, which is an al- tered balance between protective bacteria, such as Lacto- bacillus and Bifidobacterium , and aggressive organisms, including Bacteroides , Enterococcus , and invasive E coli.

(18)

tial presentation in children who have CD. Decreased bone density is seen in 25% of newly diagnosed children, even before initiation of corticosteroid therapy. (25)

Extraintestinal Manifestations

One third of patients who have IBD develop extra- intestinal manifestations, which may predate the onset of intestinal symptoms (Table 1). (26) Arthralgias and

arthritis are common extraintestinal manifestations of

CD. (26) Arthropathy also occurs in 20% to 25% of

patients who have UC and may be the presenting symp-

tom. Large joints, such as the knee, ankle, hip, and wrist,

typically are involved. A polyarticular arthropathy in- volves more than five joints; a pauciarticular form in- volves fewer joints and its disease course correlates with intestinal disease activity. (27) Ankylosing spondylitis associated with IBD runs a course independent of bowel disease activity and may progress to permanent deformity. Erythema nodosum (EN) and pyoderma gangreno- sum (PG), although rare, are the most frequent cutane- ous manifestations in IBD. EN occurs more commonly with CD; is characterized by tender, warm, red nodules or plaques; and typically is localized to the extensor surfaces of the lower extremities. PG occurs in fewer than 5% of UC patients and often is associated with more extensive colonic involvement. The lesions may appear initially as discrete pustules with surrounding erythema and subsequently extend peripherally, developing into an ulceration that has a well-defined border and a deep erythematous-to-violaceous color. PG tends to develop

Clinical Presentation

UC and CD can have varied yet overlapping presenta- tions. The cardinal symptoms of UC are diarrhea, rectal bleeding, and abdominal pain. Most children present with an insidious history of diarrhea without systemic signs of fever or weight loss. One third present with moderate symptoms, including hematochezia, abdomi- nal cramping associated with fecal urgency, malaise, low- grade or intermittent fevers, anorexia with weight loss,

mild anemia, and hypoalbuminemia. Only 10% of pa- tients present with severe colitis, characterized by five or more bloody stools per day; more profound anemia and hypoalbuminemia; fever; tachycardia; and a diffusely ten- der or distended abdomen. (19)(20) Children who have UC may develop symptoms of reflux or dyspepsia asso- ciated with inflammation of the upper gastrointestinal tract. (21) The classic presentation of ab-

dominal pain, diarrhea, and weight loss occurs in most children who have CD. Abdominal pain typically is crampy and can be diffuse or lo- calized to the right lower quadrant. (22) Stools can appear nonbloody or melanotic or can contain frank red blood. Chronic perianal disease, including tags, fissures, fistulae, and abscesses, may be present. (23) Re- current aphthous-stomatitis can also suggest the diagnosis. A decrease in height velocity may precede overt ab- dominal symptoms by 5 years, and growth failure may be the only sign of illness in 5% of children who receive the diagnosis of CD. (24) Poor appe- tite, fevers, and iron deficiency ane- mia are also commonly noted at ini-

Table 1. Extraintestinal Manifestations of Inflammatory Bowel Disease

System

Extraintestinal manifestations

Skeletal

Arthritis, arthralgia, ankylosing spondylitis, digital clubbing (hypertrophic osteoarthropathy), osteopenia, osteoporosis, aseptic necrosis

Cutaneous

Erythema nodosum, pyoderma gangrenosum, aphthous ulcers, vesiculopustular eruption, necrotizing vasculitis, metastatic Crohn disease

Ocular

Uveitis, episcleritis, corneal ulceration, retinal vascular disease

Hepatic

Primary sclerosing cholangitis, bile duct carcinoma, autoimmune chronic active hepatitis, fatty liver disease, cholelithiasis

Endocrine

Growth failure, pubertal delay

Hematologic

Autoimmune hemolytic anemia, thrombocytopenic purpura, thrombocytosis, thrombophlebitis, thromboembolism, arteritis

Renal

Nephrolithiasis (classically oxalate stones)

Cardiac

Pericarditis, myocarditis, heart block

Pancreatic

Acute pancreatitis (Crohn disease > ulcerative colitis)

Neurologic

Peripheral neuropathy, myelopathy, myasthenia gravis

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around sites of trauma and surgical scars. Although the emergence of EN usually follows intestinal disease activ- ity, PG runs an independent course, often necessitating potent therapy. Transient transaminase elevation occurs in some chil- dren who have IBD and may be related to medications or disease activity. Persistent elevations suggest the pres- ence of primary sclerosing cholangitis (PSC) or auto- immune hepatitis. PSC is more commonly associated with UC and can predate the onset of intestinal symp- toms in 50% of patients. (28) Typical symptoms in- clude chronic fatigue, anorexia, pruritus, and jaundice, although children may be asymptomatic. Elevated gamma- glutamyltranspeptidase and alkaline phosphatase values along with results of cholangiography and liver biopsy help confirm the diagnosis. (29)

Nutritional Considerations

Growth failure occurs in 15% to 40% of children who have IBD and is more frequent in CD than UC. The Z-score (or standard deviation score) is used as an objec- tive measurement of growth. The mean height Z-score at diagnosis of pediatric CD is 0.54, and a delay in diagnosis or presence of jejunal disease is negatively correlated with the Z-score. (4) Poor weight gain also may precede a diagnosis of IBD. Mean weight Z-score at diagnosis of pediatric CD is 1.06, with almost 30% of patients having weight Z-scores below the 3rd per- centile. In comparison, mean weight Z-score at diagnosis of UC is 0.32, with only 9% of patients falling below the 3rd percentile for age. (4) The cause of growth failure in IBD is multifactorial. Patients often experience abdominal pain and diarrhea related to eating, leading to food avoidance behaviors and a decrease in total energy intake. Elevated concen- trations of proinflammatory cytokines contribute to an- orexia and can cause growth hormone resistance, with inhibition of insulin-like growth factor-1 (IGF-1) pro- duction. (30) In CD, active inflammation in the small intestine can decrease the absorptive surface area, result- ing in a protein-losing enteropathy. Fat malabsorption contributes to the general energy-deficient state and may cause deficiencies in fat-soluble vitamins. Disease com- plications such as the presence of internal fistulae, surgi- cal bowel resections, or diverting ostomies can decrease nutrient absorption further.

Differential Diagnosis

The differential diagnosis for a child or adolescent pre- senting with abdominal pain and bloody diarrhea is broad. Infectious enterocolitis, pseudomembranous

colitis, lymphocytic colitis, eosinophilic enterocolitis, Henoch-Scho¨nlein purpura, and hemolytic-uremic syn- drome should be considered in addition to IBD. Intesti- nal malignancies such as non-Hodgkin lymphoma also should be considered. The periodic fevers syndromes, including TRAPS (TNF receptor-associated periodic syndrome) and PFAPA (periodic fever, aphthous stoma- titis, pharyngitis, and cervical adenitis), are rare but have some clinical overlap with IBD. Rheumatologic disor- ders, such as juvenile idiopathic arthritis, ankylosing spondylitis, and systemic lupus erythematosus, share many characteristics with pediatric IBD, specifically, weight loss, malaise, recurrent fevers, and joint involve- ment. Finally, intestinal tuberculosis and CD have similar clinical, radiographic, and endoscopic features and can be remarkably hard to differentiate. Intestinal tuberculo- sis typically involves the ileocolonic region, and the ul- cerative form is most common. A patient who has risk factors for tuberculosis should have a tuberculin skin test placed.

Diagnosis

A new diagnosis of IBD often is suggested by the clinical

history and findings on physical examination (Fig. 1). The history should focus on the nature and duration of symptoms; location and quality of abdominal symptoms; frequency and consistency of bowel movements; pres- ence of blood in stools; urgency, tenesmus, and night-

time awakening for bowel movements; and perianal, systemic (weight loss, fevers, fatigue), and extraintestinal symptoms (aphthous ulcers, skin lesions, joint pains, eye symptoms). A family history of IBD is of critical impor- tance. The physical examination should include measure- ments of height and weight as well as Sexual Maturity Rating staging. A complete evaluation includes examin- ing the mouth for aphthous lesions and performing a thorough abdominal examination. Physical findings may include abdominal tenderness, right lower quadrant mass

or fullness, pallor, and digital clubbing. A benign abdom-

inal examination does not exclude the diagnosis of IBD.

A rectal examination is mandatory, and the perianal area

must be checked for skin tags, fistulae, and fissures. Nutritional assessment should include measurements of growth velocity, height and weight Z-scores, and a comparison of absolute height with predicted mid-

parental height. A bone age radiograph can be obtained

if there is concern for significant growth delay. A dietary

history should be obtained, with calculation of protein, carbohydrate, fat, vitamin, and mineral intake and com- parison to recommended daily values. Serum concentra-

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gastrointestinal inflammatory bowel disease

gastrointestinal inflammatory bowel disease Figure 1. Evaluation of a patient suspected of having inflam- matory bowel

Figure 1. Evaluation of a patient suspected of having inflam- matory bowel disease (IBD). ESR erythrocyte sedimentation rate, UGI upper gastrointestinal, VCE video capsule endoscopy

tions of total protein, albumin, vitamin D, and iron should be measured. Depending on disease location, vitamin B 12 , folic acid, and micronutrients such as zinc also should be assessed. Measurements of hemoglobin, platelet count, eryth- rocyte sedimentation rate (ESR), and albumin classically show abnormalities in children who have new-onset IBD. Anemia is present in approximately 70% of patients, and ESR is elevated in nearly 75% of children who have moderate-to-severe disease. Only 4% of children who have moderate or severe IBD have normal test results at the time of diagnosis compared with 21% of patients who have mild CD and about 50% of those who have mild UC. (31) Thus, normal values in these domains should not delay further diagnostic evaluation if a high degree of suspicion for IBD exists. An infectious cause should be excluded before diag- nosing IBD. Screening stool studies should include:

culture for Salmonella , Shigella , E coli, Campylobacter , and Yersinia; examination for Giardia and Cryptospo- ridium ; and an assay for Clostridium difficile cytotoxin. If there is a history of immigration or overseas travel, stool should be checked for Entamoeba histolytica . Fecal markers, such as calprotectin (FC) and lacto- ferrin (FL), are released by neutrophils that have mi- grated into the intestinal wall and can be measured quantitatively in stool samples. (32) These markers are

used as noninvasive markers of gut inflammation. Al- though conditions other than IBD, such as infections, can cause inflammation and thus elevate these markers, measurement of FC and FL has a role in differentiating children who have IBD from those who have non- inflammatory gastrointestinal conditions, such as irrita- ble bowel syndrome. (33) The use of IBD serologic panels for population screening or as an isolated diagnostic tool is not recom- mended. False-positive results can create unwarranted anxiety and lead to excessive invasive testing. It should be noted that nearly one third of patients who have a posi- tive serologic panel do not have IBD. Serologic panels are most useful in children who have indeterminate coli- tis to differentiate CD from UC (Table 2). (34) Higher serologic antibody titers and a greater number of positive markers are associated with a more aggressive disease course. (35)(36) Notably, anti- Saccharomyces cerevisiae - positive CD patients are more likely to have perianal disease and ileal stricturing disease requiring resection. (37) Imaging studies play an important role in the diag- nosis of IBD. With CD, a barium upper gastrointestinal radiographic series may demonstrate stenosis, abnormal separation of bowel loops, and fistula formation. Com- puted tomography scan can assess for intestinal wall thickening and is important in the assessment of urgent complications of IBD, such as abscess formation and fistulizing or stricturing disease. Magnetic resonance im- aging (MRI) is beginning to play a larger role in children who have IBD because there is no radiation exposure. MRI has greater than 90% sensitivity and specificity for detecting CD of the small intestine and has the potential to distinguish colonic CD from UC because mucosal and full-thickness bowel wall inflammation enhance dif- ferently. (38)(39) Endoscopy, including esophagogastroduodenoscopy and colonoscopy with biopsy sampling, is the gold stan- dard for diagnosing IBD. Inflammation of the upper gastrointestinal tract can be seen in both UC and CD, although the presence of noncaseating granulomas in the stomach (versus nonspecific gastritis) is diagnostic of CD. Endoscopic features of UC include the characteristic continuous inflammation beginning in the rectum and extending a variable distance proximally into the large intestine. A sharp demarcation may exist between normal and diseased colon. The mucosal surface may be ery- thematous and granular, and there can be a loss of the normal vascular pattern with remarkable friability in areas of endoscope contact (Fig. 2). There may be small ero- sions, patches of exudates, and pseudopolyps. “Patchy”

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gastrointestinal inflammatory bowel disease

Table 2. Detection of Commercially Available Serologic Markers

Serologic Marker

Crohn Disease

Ulcerative Colitis

Controls

ASCA (anti-Saccharomyces cerevisiae antibody) immunoglobulin A and G

40% to 56%

0% to 7%

< 5%

ANCA (anti-neutrophil cytoplasmic antibody) histamine 1 protein, DNAase-specific

18% to 24%

60% to 80%

< 5%

Anti Omp C (outer membrane protein of Escherichia coli )

25%

6%

3%

colitis and relative rectal sparing can be consistent with early disease or partially treated UC. Biopsies may reveal crypt distortion with branching, shortening, or atrophy; there may also be crypt abscesses. Inflammatory changes are limited to the mucosal layer. Endoscopic features of CD include the characteristic skip lesions, in which areas of inflamed mucosa are in- terspersed with normal-appearing gut. “Cobblestoning” involves linear ulceration, with adjacent swelling giving tissue a cobblestone pattern (Fig. 3). Aphthae, exudates,

and stricturing may be present anywhere from the mouth to the anus, but the rectum typically is spared from gross inflammation. The terminal ileum is classically abnormal on gross inspection, and the ileocecal valve may be stenotic. The characteristic finding on biopsy is noncase- ating granulomas. Inflammation can extend through the full thickness of the bowel wall. Wireless video capsule endoscopy (VCE) is an excit- ing modality that can detect small bowel lesions in areas not accessible to traditional endoscopy. VCE is also

areas not accessible to traditional endoscopy. VCE is also Figure 2. A. Normal colonic mucosa and

Figure 2. A. Normal colonic mucosa and vascularity. B. Colon in a child who has ulcerative colitis, showing continuous inflammation, swelling, loss of vascular markings, and bleeding.

swelling, loss of vascular markings, and bleeding. Figure 3. A. Normal terminal ileum with lymphoid

Figure 3. A. Normal terminal ileum with lymphoid nodularity. B. Terminal ileum in a child who has Crohn disease, showing inflammation, cobblestoning, exudates, and bleeding.

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gastrointestinal inflammatory bowel disease

helpful in identifying disease recurrence, evaluating anas- tomotic sites, and detecting luminal complications such as malignancy. The drawbacks of VCE are difficulty with capsule ingestion in young children and risk of capsule retention.

Treatment

Medical Management

Immense progress has been made in the medical man- agement of pediatric IBD over the past decade. The primary goals of therapy are induction and maintenance

of remission, prevention of disease complications (such as fistula, stricture, abscess, and cancer), control of post- operative disease recurrence, maintenance of normal growth and development, and maximization of quality of life. Medications are selected based on the disease loca- tion and severity, the potential for adverse effects, and anticipated compliance. Current IBD medications in- clude corticosteroids, 5-aminosalicylates (5-ASA), im- munomodulators, biologic agents, antibiotics, and pro- biotics (Fig. 4). Moderate-to-severe symptoms initially are addressed most commonly with oral or intravenous corticosteroids, which inhibit the inflammatory cascade. The goal is to

use corticosteroids for as short a period as possible, then

change to nonsteroidal maintenance therapy. Budes- onide, an oral corticosteroid, is frequently employed in the treatment of mild-to-moderate CD because it is released in the distal small bowel and proximal colon, common sites of inflammation. Acute response to corti- costeroids is excellent, with 80% of IBD patients show- ing improvement, although corticosteroid dependency occurs in up to 50% of UC patients and 30% of CD patients. (40)(41) For adult patients who have mild-to-moderate UC, 5-ASA medications (sulfasalazine, mesalamine, balsala-

zide) are effective in inducing and maintaining remission

in 90% of cases. (42) Experience in children suggests

similar response rates. The exact mechanism of action

remains unknown but may involve decreased leukotriene production or scavenging of reactive oxygen species.

A new, once-daily 5-ASA medication, mesalamine

delayed-release tablets, has shown comparable efficacy

with the benefit of better compliance. However, the use

of 5-ASA medications in CD has become controversial

because a meta-analysis demonstrated no superiority to

placebo in maintaining remission. (43) The use of immunomodulators in children who have IBD has become the standard of care. Fifty percent of newly diagnosed children who have UC and 75% of those

of newly diagnosed children who have UC and 75% of those Figure 4. Treatment pyramid for

Figure 4. Treatment pyramid for ulcerative colitis (UC) and Crohn disease (CD) in children. TPN total parenteral nutrition, TNF- tumor necrosis factor-alpha, 6-MP 6- mercaptopurine, 5-ASA 5-aminosalicylates, IV intravenous

who have CD are given immunomodulators within 2 years of diagnosis. Immunomodulators such as azathio- prine and 6-mercaptopurine, which interfere with purine biosynthesis, have demonstrated good tolerance and can maintain remission in 75% of patients after discon- tinuation of corticosteroids. (44)(45) Because azathio- prine (which is metabolized to 6-mercaptopurine) and 6-mercaptopurine require 3 to 6 months to take effect, these medications often are started soon after diagnosis. Methotrexate is used in children who have CD and may be particularly useful when remission is not achieved with azathioprine or 6-mercaptopurine or in patients who experience intolerable adverse effects from those medications. (46) Methotrexate inhibits dihydrofolate reductase, an enzyme necessary for folic acid metabolism and thymidine synthesis. The drug is effective at provid- ing short-term symptom control, long-term remission, and steroid withdrawal. (47) Methotrexate usually is delivered as a weekly subcutaneous injection, and folic acid supplementation is recommended. Other immuno- modulators used infrequently in IBD treatment include tacrolimus and mycophenolate mofetil. For moderate-to-severe disease, biologic therapy is useful for induction and maintenance of remission. In- fliximab is a chimeric monoclonal antibody directed against the cytokine TNF-alpha that acts by inducing apoptosis of active T lymphocytes. A response rate of up to 90% is achieved in patients who have moderate-to- severe CD, even when disease is refractory to corticoste- roids and immunomodulators. (48) Those children who have refractory UC previously were treated with cyclo- sporine, but infliximab has become the treatment of choice because cyclosporine therapy has a high likelihood of eventual treatment failure and the need for colectomy in children. For patients who respond to infliximab, scheduled

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maintenance infusions are continued every 6 to 12 weeks. Gut mucosal healing has been demonstrated following infliximab therapy. Infliximab also plays an important role in treating fistulizing CD, which typically is more resistant to conventional therapies, and extraintestinal manifestations of IBD. PG, vasculitis, uveitis, EN, and arthritis have responded to this therapy. Infliximab is the only immunomodulator approved by the United States Food and Drug Administration for children who have CD. However, two other anti-TNF agents, adalimumab and certolizumab, appear effica- cious. Response rates are similar to infliximab, but be-

cause these antibodies are more fully humanized, allergic reactions may be less common. Adalimumab has shown efficacy in children who are intolerant or become unre- sponsive to infliximab. (49) Natalizumab (anti-alpha 4 integrin) inhibits the ad- hesion, migration, and activation of monocytes, macro- phages, and lymphocytes in a variety of tissues and has demonstrated clinical efficacy in treating children who have CD. (50) Three cases of progressive multifocal leukoencephalopathy associated with the human JC virus were described following trials in adults, which has cre- ated concern about its routine use. Nutritional therapy may be a primary or adjunctive treatment in CD. Exclusive enteral nutrition from ele- mental or polymeric formulas has been associated with short-term remission in up to 80% of children, equal to the response rate from corticosteroids. (51) The mecha- nism involves adequate suppression of bowel inflamma- tion and the induction of mucosal healing. (51) Improved growth and

development, without the adverse effects of corticosteroids, makes en- teral nutrition an excellent choice for first-line therapy in children who have active CD. However, after induction, long-term medica- tions, such as immunomodulators, are necessary to maintain remis- sion. Supplements such as iron, fo- lic acid, calcium, and vitamin D are required in certain situations. Antibiotics have specific indica- tions in IBD treatment. Metronida- zole is used to treat perirectal fistu- las, although recurrence rates are high and toxicity (eg, paresthesias) often limit long-term use. (52) Cip- rofloxacin is also useful in fistula treatment. Both antibiotics are pre-

scribed for treatment of pouchitis following colectomy or ileoanal pouch procedures in UC patients. (53) Rifaxi- min, a nonabsorbed oral antibiotic, has shown benefit in symptom reduction of abdominal pain and diarrhea in children who have IBD. (54) Probiotics have not been shown reproducibly to alter the natural history of CD, but for children who have newly diagnosed UC, probiotics are beneficial for main- taining remission when added to standard treatment regimens. (55) Probiotics are also helpful in the preven- tion and treatment of pouchitis. (56)(57) Safety in IBD patients is well established. Significant adverse effects exist for all of the previously described medications (Table 3). A favorable risk-benefit ratio is the goal when considering any therapy. Infliximab is contraindicated in patients who have active tuberculo- sis, opportunistic infection, history of demyelinating dis- ease, malignancy, congestive heart failure, or concurrent serious infection. Immunity to varicella should be as- certained before use of anti-TNF therapy. Recently, an aggressive malignancy, hepatosplenic T-cell lymphoma, has been described in young patients (mostly male) who were treated with a combination of infliximab and either azathioprine or 6-mercaptopurine. (58)

Surgical Management

Despite improvements in medical strategies, surgery maintains an important therapeutic role. Indications for surgery include uncontrolled gastrointestinal bleeding, bowel perforation, obstruction, intractable disease de-

Table 3. Adverse Effects of Medications Commonly Used to Treat Inflammatory Bowel Disease

Medication Class

Important Adverse Effects

Corticosteroids

Cushingoid facies, growth suppression, osteopenia, hypertension, hyperglycemia, acne, cataracts, hypothalamic-pituitary-adrenal axis suppression

5-Aminosalicylates

Hypersensitivity reaction, disease exacerbation, headache, diarrhea, rash, pneumonitis, interstitial nephritis

6-Mercaptopurine,

Bone marrow suppression, pancreatitis, hepatitis, rash, vasculitis; increased risk of lymphoma

azathioprine

Methotrexate

Hepatitis, liver fibrosis, rash, folic acid deficiency, nausea, vomiting, hair loss

Anti-tumor necrosis

Resurgence of tuberculosis, histoplasmosis, varicella, malignancies (including lymphoma), fatal lymphoproliferative syndromes, anaphylaxis, serum sickness syndrome, lupuslike syndrome, increased risk of serious infections

factor

Anti-integrin

Progressive multifocal leukomalacia

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spite standard therapy, and dysplasia. At times, surgical

resection is used to treat growth failure, especially if it allows the discontinuation of corticosteroids. The surgical procedure of choice in UC is resection of the entire colon with ileal pouch-anal anastomosis. This curative procedure can be performed either as a primary operation or in a staged approach, depending on the condition of the patient. Long-term results are excellent, and continence can be achieved in 89% of patients after

2 years with creation of a J-pouch reservoir. (59) The

major complication occurring after ileoanal pull-through is inflammation of the pouch (pouchitis), which occurs in 10% to 40% of children. (60)(61) In CD, segmental bowel resection is the most com- mon surgery and typically involves removing the diseased terminal ileum and adjacent inflamed colon. Short seg- ments of bowel that are narrowed from fibrosis can be treated with stricturoplasty. Perirectal disease also may necessitate surgery.

Adjunctive Therapies

Oral nutrition supplements and either nasogastric or gastrostomy feedings may be critically important in ad- dressing chronic undernutrition in children who have IBD. The administration of adequate calories with the addition of these supplements can help to reverse growth failure. Complementary and alternative medicine approaches are used by up to 40% of patients who have IBD. To prevent medication interactions and limit undue adverse effects, these therapies are not routinely recommended without physician consultation. The need for family education and reassurance cannot be overemphasized. Adolescents who have IBD may have a particularly difficult time because of issues related to growth failure, body image (eg, cushingoid features and acne from corticosteroids), and social invalidism from abdominal pain and diarrhea. Pubertal delay may also cause significant anxiety. Recent trials with growth hormone and IGF-1 have shown some promise in im- proving growth. In general, patient and family counseling and peer support groups are very helpful.

Prognosis and Disease Complications

Disease symptoms recur in up to one third of patients at

1 year and more than one half at 2 years after initiation of therapy. Factors that predispose to a relapse of CD include the number of previous strictures and the pres- ence of FC or FL in the stool. (62)(63)(64) In UC, a significant number of patients remain corticosteroid-

dependent after 1 year, and 5% may require colectomy.

(40)

Toxic megacolon, although rare in children, occurs in approximately 5% of adults who have severe UC and may be triggered by hypokalemia or opiate use. Colonic per- foration may occur and colectomy may become neces- sary. (65) Patients who have severe colitis (more than five bloody stools per day, fever, hypoalbuminemia, anemia) require hospitalization, bowel rest with parenteral nutri- tion support, intravenous corticosteroids, and very care- ful monitoring. Anecdotal experience supports the use of infliximab in reducing colectomy rates among patients who have severe colitis. The risk of colorectal cancer depends on the extent and duration of the disease. (66) The cumulative inci- dence of colorectal cancer in patients who have pancolitis is 5% to 10% after 20 years and 12% to 20% after 30 years of disease. Screening is recommended beginning 8 years after diagnosis. Patients who experience early-onset CD have a lower final adult height compared with predicted mid-parental height, with an average height reduction of 2.4 cm. Population studies have not shown a difference in final adult height in pediatric patients who have UC. (67) Osteopenia and osteoporosis can occur because of vita- min D deficiency, corticosteroid use, and high concen- trations of circulating inflammatory cytokines, which inhibit IGF-1. Abnormally low bone mineral density is found in nearly 50% of patients who have IBD. Maintain- ing disease remission, avoiding corticosteroids, exercis- ing, and ensuring adequate calcium and vitamin D in- take are imperative to optimize bone development and mineralization in the growing child, particularly during puberty. Dual-energy radiograph absorptiometry scans should be performed in children who experience growth failure and prolonged steroid use. (25)(68)(69)

Issues for the General Pediatrician

Children and adolescents who have IBD should avoid the use of nonsteroidal anti-inflammatory drugs (includ- ing ibuprofen) because their routine use can trigger a disease flare, enteropathy, or gastritis. Cautious use of acetaminophen is suggested for treatment of minor pain and fever. The casual use of antibiotics should be limited in children who have IBD to prevent the risk of C difficile colitis, which has been associated with increased morbid- ity. Children taking immunosuppressive medications and biologic therapy should be restricted from live vaccine administration. With administration of inactivated vac- cines, seroconversion is not always obtained if immuno- suppressive therapy is being used concomitantly. Mea-

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surement of growth velocity, evaluation of pubertal Sexual Maturity Rating staging, and annual-to-biannual eye examinations are recommended, even for asymptom- atic children who have IBD.

Summary

• Recent major advances have been made in the diagnosis and treatment of pediatric IBD, and understanding of its pathophysiology continues to evolve.

• The long-term outcome for children who have IBD continues to improve with better appreciation of genotype-phenotype correlations, earlier diagnosis, and more effective treatments.

• Although the incidence of pediatric IBD appears to be rising, the future for affected children and adolescents appears promising.

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gastrointestinal inflammatory bowel disease

PIR Quiz

Quiz also available online at http://pedsinreview.aappublications.org.

6. Which of the following symptoms or signs is seen in children who have Crohn disease, but not in children who have ulcerative colitis?

A. Anemia.

B. Arthritis.

C. Loose stools.

D. Perianal fistula.

E. Weight loss.

7. Which of the following infections can mimic the intestinal inflammation of Crohn disease?

A. Epstein-Barr virus.

B. Herpes simplex virus-1.

C. Measles virus.

D. Rotavirus.

E. Tuberculosis.

8. Which of the following tests is the “gold standard” for diagnosis of IBD?

A. Abdominal computed tomography scan.

B. Endoscopy and colonoscopy with biopsy.

C. Fecal lactoferrin.

D. Serologic panel.

E. Wireless capsule endoscopy.

9. A 15-year-old boy received the diagnosis of Crohn disease of the colon 6 months ago. He has had active disease despite 5 months of 6-mercaptopurine therapy and two courses of corticosteroid therapy. Of the following, which medication is most likely to induce remission?

A. Azathioprine.

B. Infliximab.

C. Mesalamine.

D. Metronidazole.

E. Rifaximin.

10. An adolescent girl who has ulcerative colitis has been successfully maintained on 6-mercaptopurine for 2 years and presents today for a health supervision visit. She asks which immunizations she can have in the future. Which of the following vaccines is contraindicated?

A. Human papillomavirus vaccine.

B. Influenza vaccine.

C. Measles, mumps, and rubella vaccine.

D. Pneumococcal vaccine.

E. Tetanus toxoid.

Pediatrics in Review Vol.32 No.1 January 2011 25

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Inflammatory Bowel Disease Sarah R. Glick and Ryan S. Carvalho Pediatr. Rev. 2011;32;14-25 DOI: 10.1542/pir.32-1-14

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Visual Diagnosis: Perceived Fevers and Back Pain in a 1-week-old Infant Delia L. Gold Pediatr.

Visual Diagnosis: Perceived Fevers and Back Pain in a 1-week-old Infant Delia L. Gold Pediatr. Rev. 2011;32;27-30 DOI: 10.1542/pir.32-1-27

The online version of this article, along with updated information and services, is located on the World Wide Web at:

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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

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visual diagnosis

visual diagnosis Perceived Fevers and Back Pain in a 1-week-old Infant Figure 1. Warm, confluent, blanching,

Perceived Fevers and Back Pain in a 1-week-old Infant

Perceived Fevers and Back Pain in a 1-week-old Infant Figure 1. Warm, confluent, blanching, erythematous, and

Figure 1. Warm, confluent, blanching, erythematous, and somewhat purpuric area covering the upper third of the infant’s back.

area covering the upper third of the infant’s back. Figure 2. Axillary erythema and induration. *Department

Figure 2. Axillary erythema and induration.

back. Figure 2. Axillary erythema and induration. *Department of Pediatrics, Nationwide Children’s Hospital,

*Department of Pediatrics, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH.

Delia L. Gold, MD*

Presentation

A 7-day-old female infant presents to the emergency

department with the complaints of perceived back pain and subjective fevers. Her mother also describes unex- plained skin color changes to her infant’s back and shoulders. For the past 2 days, the mother had noticed that her infant was fussy and would cry when her back was touched. She has no other systemic symptoms, no sick contacts, and no known history of trauma. The mother has no reported history of methicillin-resistant Staphylococcus aureus infection or colonization. This is the first time the mother has sought medical attention for her baby since discharge from the newborn nurs-

ery. The child was born by vacuum-assisted vaginal deliv- ery at 39 weeks’ gestation and weighed 3.8 kg. Labor had been induced because of maternal preeclampsia. Meconium-stained amniotic fluid was present on deliv- ery. Apgar scores were 3 and 8 at 1 and 5 minutes, respectively. The infant did not require resuscitation and was admitted directly to the newborn nursery, where she stayed for 3 days. The mother had adequate prenatal care and no serologic evidence of prenatal infections. Of note, because the mother had one prior spontaneous abortion, she had received Rho (D) immune globulin during this pregnancy. Physical examination reveals an afebrile, irritable infant. Examination of the skin demonstrates a warm, confluent, blanching, erythematous, and somewhat purpuric area covering the upper third of her back (Fig. 1). Areas of induration are scattered over the patient’s upper back and posterior axillae (Fig. 2). Shotty lymphadenopathy is noted in both axillae. The rest of the physical examination findings are unremark- able. After blood and cerebrospinal fluid specimens for culture are obtained in the emergency department, the infant is admitted to the infectious disease service for intravenous antibiotic therapy and further evaluation. Results of the initial laboratory examination, consisting

of a complete blood cell count, metabolic panel, coagu-

lation studies, and cerebrospinal fluid studies, appear to

be unremarkable. A clinical diagnosis is made.

Pediatrics in Review Vol.32 No.1 January 2011 27

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visual diagnosis

Diagnosis: Subcutaneous Fat Necrosis of the Newborn

The clinical diagnosis was based initially on the typical skin changes associated with subcutaneous fat necrosis of the newborn (SCFN) and the risk factors noted in the prenatal and birth history (maternal history of pre- eclampsia and Rh incompatibility, meconium-stained amniotic fluid, low Apgar scores). The diagnosis of SCFN subsequently was confirmed by skin biopsy.

The Condition

SCFN is an uncommon, often benign, self-limited pan- niculitis that develops typically in term or postterm new- borns in the first few postnatal weeks, primarily as a consequence of perinatal stress or complications. SCFN is characterized by erythematous, firm, indurated plaques or nodules usually located on the back, posterior surfaces of the arms, buttocks, and thighs, rarely involving the face or trunk. The plaques or nodules may become fluctuant due to liquefaction of fat or firm due to calcifi- cation. The lesions sometimes are painful. Resolution of the lesions may result in mild atrophy of the involved skin.

Cause

Although SCFN is a rare occurrence, numerous studies have explored possible causes. In most cases, SCFN is believed to result from perinatal complications such as asphyxia, meconium aspiration, seizures, obstetric trauma, maternal-fetal Rh factor incompatibility, and umbilical cord prolapse. Fetal factors such as sepsis, anemia, thrombocytosis, hypothermia, and a primary defect in subcutaneous fat may play a causative role. Maternal factors such as gestational diabetes, preeclamp- sia, or maternal exposure to cocaine or calcium antago- nists also may play a part. Perinatal asphyxia and meco- nium aspiration seem to be the most frequently recognized causative factors for development of SCFN. The prevalence of SCFN is increased in infants born by cesarean section, but some researchers have postu- lated that trauma such as pressure injury experienced in a vaginal delivery also can contribute to the development of SCFN by causing local ischemia to the affected tissues. The development of SCFN seems to be independent of the modalities of delivery, that is, vaginal delivery versus cesarean section. The elevated prevalence of this skin disorder in infants born via cesarean section might be related to the fetal stress that prompted the urgent sur- gical delivery rather than the mode of delivery.

Pathogenesis

The exact pathogenesis of SCFN is unknown but appears to be related to the relatively higher concentration of saturated fatty acids in neonatal fat compared with the higher proportion of unsaturated fatty acids in adult fat. Saturated fatty acids have a high melting point. Under cold stress, the saturated fat in neonates may solidify and crystallize, leading to subsequent adipocyte necrosis. It is postulated that fetal or neonatal distress around the time of delivery leads to cooling and hypoperfusion of subcu- taneous fat, thereby causing subcutaneous granuloma- tous inflammation and necrosis that results in the char- acteristic skin lesions of SCFN.

Diagnosis

The diagnosis of SCFN usually is suspected from findings on physical examination and the birth history, but the definitive diagnosis is based on skin biopsy findings. The skin biopsy performed on this infant during her hospital- ization yielded results that were consistent with SCFN (Fig. 3). A biopsy specimen of SCFN demonstrates fat necrosis, abundant histiocytes, and chronic inflammatory granulomatous formation with multinucleated giant cells. Both giant cells and necrotic adipocytes demon- strate needle-shaped crystals arranged radially. The differential diagnosis for SCFN primarily includes sclerema neonatorum (SN), skin cellulitis, and superficial trauma. SN is a distinct dermatologic condition seen in neonates that is characterized by hardening of the skin

in neonates that is characterized by hardening of the skin Figure 3. Biopsy sample of subcutaneous

Figure 3. Biopsy sample of subcutaneous tissue, with original magnification of 100x, shows flocculent, crystalline lipid within adipocytes (upper half of the image). Prominent acute inflammation with neutrophilic infiltration is present in the lower half.

28 Pediatrics in Review Vol.32 No.1 January 2011

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visual diagnosis

visual diagnosis Figure 4. Sclerema neonatorum, original magnification 100x. This section of subcutaneous tissue from a

Figure 4. Sclerema neonatorum, original magnification 100x. This section of subcutaneous tissue from a 3-day-old infant shows no inflammation and no fat necrosis. The wide connec- tive tissue septum shows separation of collagen due to edema.

that can adhere to underlying muscle and bone, causing difficulties with respiration and feeding. Unlike SCFN, this entity is associated with congenital anomalies and critical illness. A skin biopsy of SN demonstrates thick- ening of the connective tissue bands supporting the subcutaneous adipose tissue (Fig. 4) and a sparse inflam- matory infiltrate of lymphocytes, histiocytes, and multinucleate giant cells, in contrast to the pathologic findings in SCFN. SN is associated with a poor prognosis because it is related to severe clinical illness, usually following emergent delivery or surgery.

Associated Complications

SCFN generally follows an uncomplicated course, with spontaneous resolution and no medical intervention. However, certain uncommon but serious complications require investigation: hypercalcemia, hypoglycemia, thrombocytopenia, and hypertriglyceridemia. Hypercal- cemia is the most frequently reported complication of SCFN, but the exact incidence is unknown. Different hypotheses for the pathogenesis of hypercalcemia have been proposed, including bone resorption stimulated by elevated concentrations of parathyroid hormone or cal- cium release from resolving subcutaneous plaques. The accepted, most likely theory proposes that macrophages within the granulomas of the fat necrosis produce extra- renal 1,25-dihydroxyvitamin D3, a mechanism similar to that suggested for other granulomatous disorders, such as sarcoidosis and tuberculosis, that are associated with hypercalcemia.

Hypoglycemia, thrombocytopenia, and hypertriglyc- eridemia are observed very rarely in SCFN and often have no clinical consequence. In general, if the initial labora- tory tests do not reveal these metabolic and hematologic abnormalities, the studies do not need to be repeated. Patients who have SCFN and hypercalcemia should have their calcium values monitored weekly until the hyper- calcemia resolves or the lesions resolve.

Treatment

SCFN is most often self-limited, with resolution occur- ring within several weeks to 6 months. Usually, no specific treatment is needed for the lesions; rather, med- ical intervention focuses on possible complications. If the lesions are particularly large and fluctuant, fine-needle aspiration may prevent secondary infection, skin necrosis, and scarring. Although uncommon, hypercalcemia is the most frequently reported complication of SCFN and can be significant enough to cause seizures, renal failure, nephrolithiasis, cardiac toxicity and arrest, calcium dep- osition in the tissues, and even death. Hypercalcemia usually manifests when the lesions begin to resolve. If any of the signs of hypercalcemia are present, aggressive measures should be taken to correct the electrolyte ab- normality, including intravenous hydration with normal saline, administration of loop diuretics to decrease the calcium serum concentration, and dietary restriction of calcium and vitamin D. Corticosteroids, calcitonin, and bisphosphonates are alternative treatments that should be considered if the hypercalcemia is severe enough or is refractory to the previously cited measures. Because hypercalcemia is a rare yet serious complica- tion of SCFN, the physician should assess serial serum calcium concentrations. There is no definitive guideline on the duration of such assessment, but the consensus in the existing literature is that the serum calcium concen- tration should be checked weekly for 2 to 6 months after diagnosis or until the hypercalcemia disappears or the lesions resolve. The frequency of such tests can be deter- mined by the severity of the SCFN, the degree of hyper- calcemia, and the presence or absence of symptoms.

Patient Course

The infant remained afebrile for the duration of her 2-day hospitalization, and she was acting well and feed- ing appropriately before discharge. Cultures of urine, blood, and cerebrospinal fluid yielded negative results, and antibiotic therapy was discontinued. The infant ex- perienced mild hypercalcemia after discharge home. She was referred to an endocrinologist, and her serum cal- cium was monitored for 1 month, during which time the

Pediatrics in Review Vol.32 No.1 January 2011 29

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visual diagnosis

Summary

• SCFN of the newborn is an uncommon, benign disorder typically found in term, otherwise healthy neonates who have experienced perinatal stressors such as birth asphyxia, meconium aspiration, cord prolapse, hypothermia, and hypoxemia.

• Maternal factors such as preeclampsia, gestational diabetes, and in utero exposure to certain medications may play roles.

• Physical examination demonstrates firm, indurated, circumscribed, erythematous-to-purplish plaques or nodules, often on the back, shoulders, arms, thighs, or buttocks.

• Prognosis generally is very good, but rare complications such as hypercalcemia, thrombocytopenia, hypoglycemia, and hypertriglyceridemia have been reported.

• Hypercalcemia is the most common complication that can have potentially lethal effects on the renal, cardiovascular, and neurologic systems. Patients who have SCFN should have their calcium concentrations monitored weekly until the hypercalcemia disappears or the lesions resolve.

• Signs of hypercalcemia include irritability, lethargy, vomiting, hypotonia, dehydration, and failure to thrive. Parents of newborns who have SCFN should be educated about the signs and symptoms of hypercalcemia.

values returned to the normal range without medical intervention. The infant’s primary pediatrician and a dermatologist followed her progress after hospital dis- charge and documented no further complications and complete resolution of the lesions on her back. The patient is doing well at age 7 months.

ACKNOWLEDGMENTS. The author would like to thank Jonathan Thackeray, MD, Dwight Powell, MD, and Peter Baker, MD, at Nationwide Children’s Hospital in Columbus, Ohio, for their helpful input, photographs, and histologic slides.

Suggested Reading

Burden AD, Krafchik BR. Subcutaneous fat necrosis of the new- born: a review of 11 cases. Pediatr Dermatol. 1999;16:384–387 Ladoyanni E, Moss C, Brown RM, Ogboli M. Subcutaneous fat necrosis in a newborn associated with asymptomatic and uncom- plicated hypercalcemia. Pediatr Dermatol. 2009;26:217–219 Mahe E, Girszyn N, Hadj-Rabia S, et al. Subcutaneous fat necrosis of the newborn: a systematic evaluation of risk factors, clinical manifestations, complications and outcome of 16 children. Br J Dermatol. 2007;156:709–715 Tran JT, Sheth AP. Complications of subcutaneous fat necrosis of the newborn: a case report and review of the literature. Pediatr Dermatol. 2003;20:257–261 Zeb A, Darmstadt GL. Sclerema neonatorum: a review of nomen- clature, clinical presentation, histological features, differential diagnoses and management. J Perinatol. 2008;28:453–460

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Visual Diagnosis: Perceived Fevers and Back Pain in a 1-week-old Infant Delia L. Gold Pediatr. Rev. 2011;32;27-30 DOI: 10.1542/pir.32-1-27

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Focus on Diagnosis: A Primer on D-dimer Cristyn N. Camet and Donald L. Yee Pediatr.

Focus on Diagnosis: A Primer on D-dimer Cristyn N. Camet and Donald L. Yee Pediatr. Rev. 2011;32;31-33 DOI: 10.1542/pir.32-1-31

The online version of this article, along with updated information and services, is located on the World Wide Web at:

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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

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focus on diagnosis

focus on diagnosis A Primer on D-dimer Cristyn N. Camet, MD,* Donald L. Yee, MD †
focus on diagnosis A Primer on D-dimer Cristyn N. Camet, MD,* Donald L. Yee, MD †

A Primer on D-dimer

Cristyn N. Camet, MD,* Donald L. Yee,

MD

Introduction

The D-dimer antigen is a degrada- tion byproduct of the fibrinolytic process (Figure) and is commonly used as a biomarker in various clinical settings such as the evaluation of ve- nous thromboembolism (VTE) and disseminated intravascular coagula- tion (DIC). Much more literature on and collective experience with use of the D-dimer assay exists for adult than pediatric patients. However, thrombotic complications are be- coming increasingly recognized in infants and children, and reports on this assay’s utility in a variety of other pediatric applications are increasing. This review examines the biochemi- cal basis of D-dimer formation, issues raised by the varied testing methods used to measure D-dimer, and the scenarios in which this assay may pro- vide information useful for medical management.

D-dimer Formation

D-dimer formation begins with cleav- age of fibrinogen molecules by acti- vated thrombin into fibrin monomers, which then polymerize. Thrombin ac- tivates fibrin-bound factor XIII to form factor XIIIa that, in turn, cata- lyzes formation of covalent bonds be- tween D-domains of the polymerized fibrin. Finally, during fibrinolysis, plas- minogen is activated to plasmin, which cleaves the fibrin polymers at specific locations and releases fibrin degrada- tion products that vary in molecular weight and size but include moieties containing the exposed D-dimer anti-

*Pediatric Resident. Department of Pediatrics, Hematology-Oncology Section, Baylor College of Medicine, Houston, TX.

gen. Thus, D-dimer concentrations are increased under any conditions of increased fibrin formation, as with he- mostasis, thrombosis, and tissue repair.

Laboratory Considerations

A wide variety of testing methods has evolved over the years for detection of the D-dimer antigen, but the lack of standardization among these methods has been an ongoing source of con- cern. Although all modern commer- cially available assays use monoclonal antibodies specific for the D domain on factor XIIIa-cross-linked fibrin, they are not identical in the precise epitope (antigenic determinant) that they identify. The assays also differ in format, calibration methods, instru- mentation, sensitivity, and specificity. Ideally, only assays that have been val- idated in clinical studies of relevant test populations and for which specific cut- off values have been reliably deter- mined should be used. Unfortunately, this requirement is especially problem- atic in pediatrics due to the paucity of such validation testing and the reliance on reference ranges provided by stud- ies in adults when there are significant age-related differences in D-dimer val- ues. A recent study reported a six- to eightfold higher D-dimer reference range for newborns compared with adults. Although this difference largely resolves during infancy, subtle differ- ences persist into late childhood. Such findings are consistent with the con- cept of “developmental hemostasis” coined by Andrew and associates (1) to describe the physiologic, age-related variation in concentrations of many co- agulation proteins. However, develop- mental hemostasis places a significant burden on laboratories striving to pro- vide optimal care to pediatric patients because age-related reference ranges

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focus on diagnosis

focus on diagnosis Figure. Sequential process of fibrinogen cleavage, fibrin polymerization, cross-linking, and

Figure. Sequential process of fibrinogen cleavage, fibrin polymerization, cross-linking, and fibrinolysis that leads to degradation products containing the D-dimer antigen. This diagram is simplified by depicting only a single fibrin strand and degradation products of uniform composition. Adapted from Adam SS, Key NS, Greenberg CS. D-dimer antigen: current concepts and future prospects. Blood. 2009;113:2878 –

2887.

for the specific reagent/analyzer com- bination used in a given laboratory must be determined for many coagu- lation tests, including the D-dimer as- say. Otherwise, use of reference ranges based on studies of adults or different analyzer systems may lead to inaccu- rate interpretation of test results in pe- diatric patients.

Clinical Uses of D-dimer Antigen Assay

The D-dimer assay is commonly used in adult patients for assessment of possible VTE. In selected adult pa- tient populations, a normal D-dimer result is as sensitive for the exclusion of VTE as a negative imaging study. Specificity is much lower, however, because a positive D-dimer finding is not sufficient to diagnose VTE or dictate therapy; it only directs the

clinician toward more diagnostically specific imaging studies. Limited ret- rospective studies in children tend to support the assay’s high sensitivity in this setting but suggest that its spec- ificity for VTE may be even lower than in adults (specificity no higher than 57% among the limited number of pediatric patients studied). Other uses of the D-dimer assay in adults include stratifying risk for recur- rent VTE, especially in identifying pa- tients who would benefit from longer duration of anticoagulation therapy. Again, limited studies in children sug- gest that a markedly elevated D-dimer value is a marker for negative outcomes of VTE, including clot persistence, clot recurrence, and the long-term compli- cation known as the postthrombotic syndrome (characterized by limb

asymmetry, skin changes, and chronic pain in the most severe cases). A recent small study suggests a role for D-dimer in assessing the prognosis and cause of pediatric arterial ischemic stroke. (2) Strokes of cardioembolic subtype were associated with signifi- cantly higher D-dimer values than noncardioembolic subtypes (eg, arte- riopathies), consistent with the con- cept that a hypercoagulable state is more relevant to the former type of stroke. If confirmed in larger studies, the ability to distinguish between pediatric stroke subtypes could aid decision-making about the use of anti- thrombotic therapy as well as guide diagnostic approaches for new-onset childhood stroke. D-dimer is commonly used to as- sess for the presence of DIC, which may accompany extreme states such as sepsis, trauma, malignancy, and obstetric emergencies. DIC is char- acterized by continuous intravascular thrombin and fibrin formation that may lead to clinical bleeding caused by depletion of coagulation factors. However, the diagnosis of DIC is not based solely on the D-dimer result, but on a combination of laboratory values, including platelet count, fi- brinogen value, and prothrombin time, in addition to the detection of markers of fibrin formation (such as D-dimer). The test also has been used to guide decisions about the adequacy of anticoagulation therapy in patients who have rare thrombotic disorders such as severe protein C deficiency because a markedly elevated or rising D-dimer value can be a sign of devel- oping VTE or DIC in such patients. Inflammation and coagulation pathways are intimately linked, lead- ing to D-dimer elevation during in- flammatory disease states. An appli- cation of this association is the use of D-dimer to monitor outcomes in pa- tients who have systemic juvenile id-

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focus on diagnosis

iopathic arthritis (JIA). Elevated D-dimer values seen in JIA are be- lieved to result from cytokine- induced endothelial activation and are associated with disease activity and poor response to therapy. Persis- tently elevated D-dimer values, de- spite therapy with immune modula- tors, predict a poor outcome for these patients. D-dimer testing, thus, holds promise as a predictive tool to help target more intensive treatment for high-risk JIA patients early in the disease course. Elevated D-dimer has also been reported in the setting of other sys- temic vascular diseases such as Ka- wasaki disease, Henoch-Scho¨nlein purpura, and hemolytic-uremic syn- drome. In such cases, D-dimer values tend to correlate with disease stage, and it has been suggested that D-dimer measurement might serve as a prognostic tool for these condi- tions or to help differentiate among other diagnostic considerations. Of special relevance to the general pediatrician, elevated D-dimer con- centrations also have been associated with poorer outcomes in pediatric patients who develop community- acquired pneumonia (CAP). Patients who have CAP and elevated D-dimer concentrations may be at higher risk for developing parapneumonic effu- sion or empyema. Patients who expe- rience these complications may ex- hibit increased coagulation activity and fibrin deposition in the pleural space, leading to increased fibrinoly- sis and D-dimer formation. D-dimer values showed an increasing trend among groups of patients who had CAP, pneumonia with effusion, and empyema, respectively, and were higher than in healthy children.

However, further prospective studies are required.

Future Considerations

D-dimer is a widely available test, and an increasing number of applications for its use within adult medicine are evolving. Although additional valida- tion studies and studies of age- related changes in D-dimer values still need to be performed to allow for reliable and interpretable results for pediatricians, D-dimer measure- ment holds promise for monitoring of pediatric diseases. Prospective studies are required to examine the dynamics of D-dimer plasma concen- trations, such as time to normaliza- tion, so clinicians can interpret when an abnormal result is suggestive of significant new or ongoing disease rather than expected recovery from an elevated concentration after sur- gery or a resolving infection. Additional studies of the utility of D-dimer measurement in specific clinical situations are required. Can- didate disorders for such study in- clude inflammatory diseases such as other vasculitides and inflammatory bowel disease. Given the link be- tween inflammation and obesity, D-dimer could also prove useful in assessing vascular risk in obese chil- dren, as suggested by a recent study. (3) However, at present, rigorous studies of D-dimer applications in pediatric medicine are limited. Thus, caution should be exercised in inter- preting D-dimer results in the clinical care of pediatric patients because ref- erence ranges, cut-off values, and interpretation of clinical research studies in adults cannot be reliably extended to children. The D-dimer assay will have only limited utility in general pediatrics until the necessary

prospective clinical validation studies in children are performed.

References

1. Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood. 1992;80:1998 –2005 2. Bernard TJ, Fenton LZ, Apkon SD, et al. Biomarkers of hypercoagulability and inflammation in childhood-onset arterial ischemic stroke. J Pediatr. 2010;156:

651– 656 3. Balagopal P, George D, Sweeten S, et al. Response of fractional synthesis rate (FSR) of fibrinogen, concentration of D-dimer and fibrinolytic balance to physical activity- based intervention in obese children. J Thromb Haemost. 2008;6:1296 –1303

Suggested Reading

Adam SS, Key NS, Greenberg CS. D-dimer antigen: current concepts and future prospects. Blood. 2009;113:

2878 –2887 Biss TT, Branda˜o LR, Kahr WH, Chan AK, Williams S. Clinical probability score and D-dimer estimation lack utility in the diagnosis of childhood pulmonary embolism. J Thromb Haemost. 2009;7:

1633–1638

Bloom BJ, Alario AJ, Miller LC. Persistent elevation of fibrin D-dimer predicts long-term outcome in systemic juvenile idiopathic arthritis. J Rheumatol. 2009; 36:422– 426 Michelin E, Snijders D, Conte S, et al. Pro- coagulant activity in children with com- munity acquired pneumonia, pleural ef- fusion and empyema. Pediatr Pulmonol. 2008;43:472– 475 Monagle P, Barnes C, Ignjatovic V, et al. Developmental haemostasis—Impact for clinical haemostasis laboratories. Thromb Haemost. 2006;95:362–372 Rajpurkar M, Warrier I, Chitlur M, et al. Pulmonary embolism – experience at a single children’s hospital. Thromb Res. 2007;119:699 –703 Strouse JJ, Tamma P, Kickler TS, Takemoto CM. D-dimer for the diagnosis of ve- nous thromboembolism in children. Am J Hematol. 2009;84:62– 63

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Focus on Diagnosis: A Primer on D-dimer Cristyn N. Camet and Donald L. Yee Pediatr. Rev. 2011;32;31-33 DOI: 10.1542/pir.32-1-31

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Pediatrics in the Community: The Haiti Earthquake Sachin D. Shah and C. Andrew Aligne Pediatr.

Pediatrics in the Community: The Haiti Earthquake Sachin D. Shah and C. Andrew Aligne Pediatr. Rev. 2011;32;34 DOI: 10.1542/pir.32-1-34

The online version of this article, along with updated information and services, is located on the World Wide Web at:

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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

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pediatrics in the community

pediatrics in the community Disaster relief appeals to our noblest qualities as health-care professionals and
pediatrics in the community Disaster relief appeals to our noblest qualities as health-care professionals and

Disaster relief appeals to our noblest qualities as health-care professionals and compassionate human beings. The devastation caused by the January 2010 earthquake inspired many pedia- tricians to travel to Haiti. One of these was Dr Sachin Shah, a veteran of numerous international health experi- ences, who spent a week in Port-au- Prince helping to staff a field hospital. This facility, run by Project Medishare, (1) was a sophisticated operation boasting a 35-bed pediatrics ward that included a fully equipped neonatal in- tensive care unit/pediatric intensive care unit, a freestanding emergency department, and a separate operating tent (OR) with two operating theaters staffed by an orthopedist, neurosur- geon, and pediatric surgeon. “One of the most memorable children I cared for was a 2-year-old boy with congenital hydrocephalus, likely a consequence of a prenatal infection,” related Dr Shah. “He pre- sented with fever and severe abdom- inal pain with peritoneal signs. The

*University of Chicago, Chicago, Ill. University of Rochester, Rochester, NY

The Haiti Earthquake

Sachin D. Shah, MD,* C. Andrew Aligne, MD, MPH

month before, a neurosurgeon at our facility had placed a ventriculo- peritoneal (VP) shunt. A Gram stain of cerebrospinal fluid confirmed a shunt infection, and he was taken back to the OR where the VP shunt was removed by another neurosur- geon. Three days later, largely be- cause the neurosurgeon was leaving the next morning, the patient under- went an endoscopic third ventricu- lostomy. Although the care this child received was remarkable, it struck me how little we, in fact, accomplished. His hydrocephalus did not improve, and he was, perhaps, worse off than before our involvement.” Emergency medical relief services are important, and the rescue workers, physicians, nurses, and others who helped in Haiti did much good. How- ever, one needs to step back and ask why the devastation from the earth- quake was so enormous. Unfortu- nately, it was just one consequence of severe underlying problems. Hence, after all the heroic efforts in Haiti, the health situation there still is dismal. The country is a landscape dominated by the diseases of poverty: malaria, tet- anus, and tuberculosis. Basic sanitation remains an overwhelming need, with more than 100 people per toilet and difficult access to clean water. Malnu- trition is common. The volunteers who seemed to be making a lasting impact were those who addressed these basic needs with simple measures such as diphtheria- pertussis-tetanus vaccination or deliv- ery of portable, self-contained out- houses. Global health experts agree on the need to emphasize simple, cheap, and effective public health preventive

interventions over high-tech rescue care. In addition, we must favor broad- based grassroots improvements in in- frastructure, education, and economic development. Successful efforts in var- ious parts of the world show that progress is possible.

SECTION EDITOR’S NOTE. It is un- fortunate that overseas medical volun- teer experiences frequently end in the type of frustration described in this story. There is a tendency to think that the problems of poor countries are in- surmountable but that their health needs can be satisfied by emergency relief efforts. Both extremes are inaccu- rate. A recent book called Give a Little provides numerous examples of non- profit organizations engaged in effec- tive interventions to reduce poverty and illness both here and abroad. (2) Small contributions to the right orga- nizations can have a huge and lasting impact.

References

1. Project Medishare website. Accessed July 2010 at: www.projectmedishare.org 2. Smith W. Give a Little. New York, NY:

Hyperion; 2009

Suggested Reading

Crump JA, Sugarman J. Ethical consider- ations for short-term experiences by trainees in global health. JAMA. 2008; 300:1456 –1458

Hilts PJ. Rx for Survival. New York, NY:

Penguin Books; 2005

Packard RM. The Making of a Tropical Disease: A Short History of Malaria. Baltimore, Md: Johns Hopkins Uni- versity Press; 2007

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Index of Suspicion • Case 1: Recurrent Oral Ulcers in an Adolescent • Case 2:

Index of Suspicion • Case 1: Recurrent Oral Ulcers in an Adolescent • Case 2:

Visual Impairment in an Autistic Child • Case 3: Fever and Hepatosplenomegaly in an Infant Benjamin Bruins, Howard F. Fine, L. Nandini Moorthy, Ayesha Jain, Ashok K. Jain, Thomas W. Milligan and Rinku Patel Pediatr. Rev. 2011;32;35-40 DOI: 10.1542/pir.32-1-35

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index of suspicion

index of suspicion The reader is encouraged to write possible diagnoses for each case before turning

The reader is encouraged to write possible diagnoses for each case before turning to the discussion. We invite readers to contribute case presentations and discussions. Please inquire first by contacting Dr. Deepak Kamat at dkamat@med.wayne.edu.

by contacting Dr. Deepak Kamat at dkamat@med.wayne.edu. Frequently Used Abbreviations ALT: alanine
by contacting Dr. Deepak Kamat at dkamat@med.wayne.edu. Frequently Used Abbreviations ALT: alanine

Frequently Used Abbreviations

ALT:

alanine aminotransferase aspartate aminotransferase

AST:

BUN: blood urea nitrogen

CBC:

complete blood count central nervous system cerebrospinal fluid computed tomography

CNS:

CSF:

CT:

ECG: electrocardiography

ED:

emergency department

EEG: electroencephalography

ESR:

erythrocyte sedimentation rate gastrointestinal genitourinary

GI:

GU:

Hct:

hematocrit

Hgb:

hemoglobin

MRI:

magnetic resonance imaging

WBC: white blood cell

Case 1: Recurrent Oral Ulcers in an Adolescent Case 2: Visual Impairment in an Autistic Child Case 3: Fever and Hepatosplenomegaly in an Infant

Case 1 Presentation

A 16-year-old African American girl

presents with extremely painful re- current oral ulcers over the past 2 months. She reports similar painful ulcers of the genital area that have

whitish discharge and intermittent

low-grade fevers. A recent complaint

of blurry vision prompted a visit to an

ophthalmologist, who prescribed eye drops for “inflammation.” She de- nies sexual activity, drug use, nausea, vomiting, diarrhea, headaches, rash, joint pains, cough, or frequent infec- tions. Her past medical history is un- remarkable, but an older brother has human immunodeficiency virus (HIV) infection. Physical examination reveals a well- developed adolescent girl in no acute distress. Her vital signs are within age- appropriate limits. She has several well- demarcated aphthous ulcers in her buccal mucosa and oval ulcers with whitish discharge over her labia ma- jora. The remainder of the physical ex- amination yields no findings of note. Laboratory testing reveals normal findings on a complete metabolic panel, urinalysis, and serum immuno- globulin and complement assessment. Her Hgb is 11.5 g/dL (115 g/L) and her ESR is elevated at 55 mm/hr. Se- rologic testing reveals negative titers for herpes simplex virus (HSV) types 1 and 2; HIV; cytomegalovirus; Toxo- plasma; and hepatitis A, B, and C. HSV cultures from ulcers as well as gonococcus and Chlamydia DNA and rapid plasma reagin tests are negative. Antinuclear and antidouble-stranded DNA antibodies are negative. How- ever, a test for antiphospholipid anti- bodies is mildly positive to B2 glyco- protein. Biopsy results are consistent with vulvitis.

A discussion with the patient’s ophthalmologist confirms the clinical diagnosis and well-known complica- tion.

Case 2 Presentation

A 15-year-old Hispanic boy who has

a previous diagnosis of autism pre-

sents to the ophthalmology clinic with a 2-month history of vision problems. His parents report that he does not walk around freely because he cannot see, he holds on to walls, and he runs into the furniture. He is no longer able to transcribe words from the blackboard as he had done previously. He has stopped daily ac- tivities such as using the computer. However, he still can use a spoon and fork and dress himself. He has mild photosensitivity, and he rubs his eyes frequently. His appetite has re- mained unchanged. His past history includes being nonverbal and having developmental delay, moderate far- sightedness, and bilateral astigma- tism. He is obese, with a body mass index of 33. During an ophthalmo- logic examination, he is very uncoop- erative. There is no improvement af- ter a slight change is made in his eyeglass prescription. The ophthal- mologic examination conducted un- der general anesthesia shows normal intraocular pressure on both sides but keratinization of the bulbar con- junctiva and cornea bilaterally. Both corneas appear cloudy, and punctu- ate corneal staining is noted on both sides. There is a mild superior pannus present in both eyes. Funduscopic examination shows a normal cup-to- disc ratio on both sides, and the ret- inas appear normal. The cause of his

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index of suspicion

suspected disorder is confirmed by blood tests.

Case 3 Presentation

A 4-month-old boy presents with 3 weeks of intermittent high fevers and mild fussiness. He has no other signs. Initially, he was seen in the ED, and screening tests that included CBC, blood culture, serum electro- lytes, BUN, creatinine, liver en- zymes, and urinalysis and culture all yielded normal results. He was placed on antipyretic therapy only. For the next 2 weeks he continued to have fevers daily, despite taking acet- aminophen. Today his father notes that the boy’s abdomen also is “more full” than it used to be. The boy was born vaginally at term and has received his 2-month immunizations. Past medical and family histories have no findings of note. He lives at home with his mother and older sister in an old house on a farm in rural central Illi- nois and does not attend child care. Physical examination reveals a very thin, fussy, yet consolable infant whose temperature is 39.4°C, respi- rations are 40 breaths/min, heart rate is 130 beats/min, and blood pressure is 88/48 mm Hg. Abdomi- nal examination shows a firm and significantly distended abdomen as well as hepatosplenomegaly. The liver edge is palpated just above the right pelvic brim, and the spleen is palpable 3 cm below the left costal margin. Findings on the rest of the physical examination are normal. The patient is hospitalized and re- mains febrile until the diagnosis is made by additional laboratory evalu- ation.

Case 1 Discussion

This patient’s clinical presentation was consistent with Adamantiades-

Behc¸et disease (BD), and she was started on hydroxychloroquine, pen- toxifylline, and aspirin. In addition, given her age and the possibility of high-risk behaviors, sexually trans- mitted diseases were ruled out. After treatment was started, she developed panuveitis in the left eye, which did not resolve when topical corticoste- roids and methotrexate were added to the regimen. After missing an ap- pointment with the ophthalmolo- gist, she reported progressive wors- ening of vision in the right eye, new- onset paresthesias of the left upper extremity, and ataxia. Emergent ophthalmologic examination re- vealed severe retinal vasculitis of the right eye (Figure). Brain MRI and angiography showed subacute infarc- tion of her right medulla and pons, suggestive of small vessel CNS vascu- litis. She received intravenous cyclo- phosphamide and high-dose corti- costeroids as an inpatient, which re-

sulted in significant improvement in her clinical status.

Differential Diagnosis

The differential diagnosis for oral and genital ulcers includes common infections with HSV and lympho- granuloma venereum virus as well as syphilis and chancroid. Once sexually transmitted diseases are ruled out, BD and Crohn disease are important considerations.

The Condition

The prevalence of BD is low in the United States and is highest in indi- viduals of Middle Eastern and Japa- nese heritage. BD is correlated with the presence of human leukocyte an- tigen B51. Childhood BD has no sex bias, the age of presentation varies, and it represents 4% to 26% of all cases of BD. BD is a multisystemic autoim- mune condition characterized by a

is a multisystemic autoim- mune condition characterized by a Figure. Color fundus photographs of the right

Figure. Color fundus photographs of the right eye demonstrate vascular sheathing along the superotemporal arcade and marked cystoid macular edema. Note the perivascular yellow lipid exudation due to diffuse vasculitis in the mid-peripheral retina. The images are slightly blurred due to anterior segment inflammation, cataract, and vitreous haze.

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index of suspicion

classic triad of aphthous stomatitis, genital ulceration, and uveitis. The International Study Group has for- malized clinical criteria requiring at least three episodes of oral herpeti- form or aphthous ulcerations within a 12-month period observed directly by a physician or reported by the patient. In addition, two of the fol- lowing also must be demonstrated:

1) recurrent painful genital ulcers that heal with scarring; 2) ophthal- mic lesions, including anterior or posterior uveitis, hypopyon, or reti- nal vasculitis; 3) skin lesions, includ- ing erythema nodosum-like lesions, pseudofolliculitis, or papulopustular or acneiform lesions; and 4) positive results from pathergy skin testing, defined as the formation of a sterile erythematous papule 2 mm in diam- eter or larger that appears 48 hours following a skin prick with a sharp sterile needle. (1) The clinical presentation of child- hood BD is variable, and different organ systems can be involved. Oral ulcers (100%), genital ulcers (33% to 96%), skin lesions (35% to 100%), and ophthalmic lesions (27% to 92%) are common findings at presenta- tion. The ophthalmic findings in- clude recurrent or persistent anterior uveitis with or without posterior uve- itis, hypopyon, retinitis, papillitis, macular edema, and retinal vasculitis. Because it is a multisystem disease, additional clinical manifestations can involve nearly any organ system. GI involvement can range from abdom- inal pain to gastric or small bowel ulcerations with risk of perforation and can mimic Crohn disease. Pul- monary artery aneurysms with risk of massive hemoptysis as well as intersti- tial lung disease are found rarely in patients who have BD. Neuro-BD presents commonly as meningoen- cephalitis, but parenchymal lesions can lead to hemiparesis and cognitive changes. Arthritis, thrombophlebitis,

and vasculitis are other manifesta- tions of BD. The presence of anticar- diolipin antibodies may be related to retinal vascular disease.

Treatment and Prognosis

Treatment is tailored to clinical man- ifestations. Numerous agents are available to treat oral and genital ul- cers, including colchicine, pentoxi- fylline, thalidomide, corticosteroids, hydroxychloroquine, and azathio- prine. Uveitis is treated with ocular corticosteroids (with or without sys- temic corticosteroids), methotrex- ate, and anti-tumor necrosis factor (TNF) agents. Retinal and CNS vas- culitis often present therapeutic chal- lenges. Early recognition of these complications and aggressive treat- ment with topical and systemic im- munosuppressive medication (such as cytotoxic and anti-TNF agents) is critical to protect visual acuity and minimize long-term ocular and neu- rologic sequelae. A multidisciplinary approach involving the pediatrician, rheumatologist, and ophthalmolo- gist is ideal when treating children who have BD. The prognosis is guarded for chil- dren who present with active disease and severe ocular, CNS, and pulmo- nary involvement. Significant ocular involvement can result in irreversible visual loss leading to permanent blindness, especially when the pa- tient has posterior uveitis with syn- echiae and retinal vasculitis. Devas- tating complications can occur with occlusions and aneurysms of the CNS and cardiac and pulmonary vas- culature.

Lessons for the Clinician

BD presents challenges to the pe- diatrician in establishing early diag- nosis.

For patients who have multisystem diseases such as BD, it is essential to

perform a comprehensive history and physical examination, and care should be coordinated within a multidisciplinary team.

Once BD is diagnosed, it is critical to screen for common complica- tions, especially ocular involve- ment.

In addition to ocular involvement, the patient also can present with varied CNS findings.

Untreated systemic disease can be devastating and warrants prompt diagnosis and treatment.

(

Hospital of Philadelphia, Philadel- phia, PA; Howard F. Fine, MD, MHSC, L. Nandini Moorthy, MD, MS, UMDNJ/RWJ Medical School, New Brunswick, NJ )

Benjamin Bruins, MD, Children’s

Reference

1. Criteria for diagnosis of Behc¸et’s disease:

International Study Group for Behc¸et’s Dis- ease. Lancet. 1990;335:1070–1080

Case 2 Discussion

The findings of xerophthalmia and keratomalacia in this patient are char- acteristic of hypovitaminosis A. Vita- min A was undetectable in the serum, confirming the cause of the eye find- ings. A dietary history revealed ab- normal eating habits. The boy’s meals and snacks consisted of French fried potatoes and tortillas and were devoid of leafy vegetables, fruits, and animal sources of food. This diet pro- vided him less than 1% of the daily recommended dietary allowance (RDA) of vitamin A. There was no history or laboratory evidence to sug- gest fat malabsorption. He was pre- scribed a 10,000-IU vitamin A cap- sule daily for 60 days along with multivitamins, minerals, and lubri- cant eye drops. Within 1 month, his vision improved, he lost his photo- sensitivity, and he was no longer rub- bing his eyes. Slitlamp examination

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index of suspicion

showed clear corneas without stain-

ing. He could identify red, blue, green, and yellow colors. Visual acu- ity testing suggested that he saw 8-mm targets at 2 feet with glasses. Refraction showed that distance acu-

ity (20/600) could not be improved

with a change in eyeglass prescrip- tion. He was classified as being le- gally blind. His serum 25-hydroxyvitamin D concentration also was severely de- pressed ( 7 ng/mL [17.4 nmol/ L]), although serum calcium and phosphorus values were normal.

A radiograph of the knee revealed

mild osteopenia without signs of rickets. Prothrombin time, serum vi- tamin E concentration, and serum vitamin B 12 values were within normal range. He was given vitamin D3 (50,000 IU) once a week for 12 weeks. At the end of 3 months of treatment, his serum vitamin A and 25-hydroxyvitamin D values had normalized. Occupational therapy helped in expanding his food reper- toire, and he started consuming hamburger patties, fried chicken, sal- ads, oranges, gelatin desserts, and juices. This improved diet was able to meet 50% of his vitamin A RDA but was significantly deficient in vitamin D. He remained on multiple vitamin supplements.

Vitamin A

Vitamin A plays two roles in ocular metabolism: photo transduction and prevention of xerophthalmia. The

retina has two discrete photorecep- tors, the rods and the cones. The rod cells, containing rhodopsin, sense motion and allow for adaptation to dark. The cones contain iodopsin and detect color. The aldehyde form

of vitamin A serves as the precursor

for both of these visual pigments. In

vitamin A deficiency (VAD), synthe-

sis of rhodopsin is decreased, result-

ing in night blindness. By promoting

the integrity of lacrimal glands and

goblet cells in the surface epithelium

of the conjunctiva, vitamin A helps in

the production of a healthy tear film. The latter keeps the corneal surface

moist, preventing ocular dryness and

its related complications such as xe-

rophthalmia. Hypovitaminosis A can occur in either primary or secondary form.

A primary form occurs among pa-

tients whose diet lacks adequate amounts of fruits, liver, and leafy veg- etables. Secondary causes include fat malabsorption, disorders associated with exocrine pancreatic insuffi- ciency (eg, cystic fibrosis), chronic cholestasis, and abetalipoproteine- mia. Postsurgical causes include bari- atric procedures and short bowel syn- drome.

Clinical Manifestations of VAD

VAD, although rare in the United States, is a leading cause of morbidity and mortality, affecting millions of children in resource-poor countries. Approximately 250,000 to 500,000 children in developing countries be- come blind each year due to VAD, with the highest prevalence in South- east Asia and Africa. VAD is associ- ated with increased morbidity and mortality in various disease states, such as measles, due to an altered immune response. An initial symptom of hypovita- minosis A, weakened adaptation to the dark, can evolve to night blind- ness if untreated. Xerophthalmia, an- other clinical feature of VAD, occurs due to keratinization of ocular epi- thelium. The cornea dries, develops scaly layers of cells, and is more sus- ceptible to infections. As disease progresses, the cornea degenerates, turns hazy, and becomes wrinkled and soft (keratomalacia), resulting in irremediable blindness. Bitot spots, which are superficial,

irregular, or triangular-shaped foamy gray patches containing keratinized epithelial debris, are found on bulbar conjunctiva. In retrospect, the bilat- eral pannus described in this patient may have been Bitot spots. Other clinical features of VAD include poor overall growth, impaired immunity, and susceptibility to infections.

Treatment and Prevention of VAD

Recognizing the endemic prevalence of VAD states in resource-poor countries, the World Health Organi- zation has published age-specific dosing guidelines for prevention and treatment of VAD. Dietary recom- mendations include dark green leafy vegetables, carrots, sweet potatoes, and brightly colored fruits. Liver, beef, chicken, fortified milk, and ce- reals are other sources of vitamin A. If adequate intake cannot be assured, supplemental vitamin should be pro- vided.

Autism and Altered Eating Behavior

Autism is a developmental disorder characterized by impairment of com- munication and social interaction along with stereotypic and repetitive behaviors. Many children who have autism have feeding difficulties and limited food selection related to sen- sory regulatory difficulties, resulting in strong interest in some textures and taste and complete aversion to others. Affected children frequently are reported as insisting on routines and playing with food. Fewer than 50% of the parents of such children reported that their children ate bal- anced diets, and 6% of parents re- ported a poor appetite for most foods among their children. Such aberrant eating behaviors place some children who have autism at greater risk for both macronutrient and micronutri- ent deficiencies. Therefore, many nu-

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index of suspicion

tritional deficiency states such as scurvy, rickets, blindness, and early failure to thrive have been reported in these children.

Lessons for the Clinician

Clinicians should be cognizant of the abnormal eating habits of pa- tients who have autism.

A comprehensive dietary history and nutritional assessment may help in recognizing uncommon but classic vitamin deficiency states.

Even those who are overweight or obese can have micronutrient defi- ciencies.

Ayesha Jain, Texas A&M University,

College Station, TX; Ashok K. Jain, MD, and Thomas W. Milligan, MD, Driscoll Children’s Hospital, Corpus Christi, TX )

(

Case 3 Discussion

Hepatosplenomegaly results from a large array of conditions and gener- ally occurs because of inappropriate storage, infiltration, vascular conges- tion, or inflammation. Because the liver plays an important role in me- tabolism, metabolic abnormalities can result in storage of glycogen, lip- ids, proteins, and metals in the liver that cause hepatomegaly. Many of these conditions are accompanied by neurologic findings or deterioration, such as developmental delay or sei- zures. Similarly, splenomegaly can result from metabolic disorders. In this patient, an extensive metabolic evaluation yielded negative results. Hepatosplenomegaly caused by infiltration is likely due to tumors or conditions such as hemophagocytic syndromes and extramedullary he- matopoiesis. In this patient, the CBC was normal. In addition, abdominal ultrasonography and a contrast- enhanced CT scan of the abdomen

and pelvis revealed an enlarged liver (9 cm in length) that had normal echo- genicity and lacked any intra- or extra- hepatic masses or cysts as well as biliary ductal dilatation. The studies also showed an enlarged spleen (8 cm in length) without any retroperitoneal lymphadenopathy or ascitic fluid. Vascular congestion that results in an enlarged liver can be divided into suprahepatic (congestive heart fail- ure, hepatic vein thrombosis) and in- trahepatic (veno-occlusive disease, Alagille syndrome) conditions. The resulting portal hypertension also can cause congestive splenomegaly. Vascular congestion was ruled out for this child because of normal echo- cardiographic findings and normal flow pattern on Doppler abdominal ultrasonography. Inflammatory conditions, which commonly cause hepatosplenomegaly, usually are due to infections with vi- ruses, bacteria, fungi, or parasites and typically present with fever. Other causes of hepatosplenomegaly due to inflammation are toxins, drugs (non- steroidal anti-inflammatory drugs, isoniazid, propylthiouracil, sulfon- amides), and autoimmune diseases. In this patient, repeat CBC, complete metabolic panel, C-reactive protein, and ESR yielded normal results. In ad- dition, blood, urine, and CSF cultures as well as serologic tests for HIV, hep- atitis A, B, and C, Toxoplasma gondii, rubella virus, herpes simplex virus, cy- tomegalovirus, and Ebstein-Barr virus were negative. A purified protein de- rivative skin test for tuberculosis also yielded negative results. Screening im- mune evaluation, including serum concentrations of immunoglobulins and immune phenotyping, also had normal results. On day 7 of admission, urine was sent for Histoplasma capsu- latum and Blastomyces dermatitidis an- tigens and was positive for both. Based on clinical and epidemiologic evi-

dence, progressive disseminated his- toplasmosis (PDH) was diagnosed.

The Condition

H capsulatum is a dimorphic fungus found in the environment as a sapro- phyte mold in mycelial and micro- conidia (aerosolized fungal spore) forms and as yeast in host tissue. The organism is found primarily in the midwestern United States, specifi- cally near the Ohio and Mississippi river valleys. Soil rich with nitrate (from bird droppings or decayed wood) allows the fungus to thrive. H capsulatum infection causes symp- toms in fewer than 5% of infected people, with most presenting with an influenzalike illness. However, the microconidia can be inhaled into the alveoli, remain as spores, and lead to reinfection as they germinate and proliferate into the yeast phase. The yeast cells can gain access to the re- ticuloendothelial system via hilar lymph nodes and, thus, have the po- tential to seed any part of the body, particularly the GI system, skin, adre- nals, and CNS. This rare phenome- non occurs in 10% of cases and is known as PDH. PDH usually is seen in immuno- compromised individuals, specifically individuals who have HIV infec- tion, X-linked hyperimmunoglobulin (Ig)M syndrome, hyper-IgE syn- drome, and common variable immu- nodeficiency, but can occur in healthy young children. Positive culture from bone marrow, blood, sputum, or tissue is the gold standard for diagnosis. My- cologic media can take 1 to 6 weeks to grow the organisms. Polysaccharide antigen testing is a rapid and specific method for diagnosis and is used to monitor response to treatment. Be- cause cross-reactions occur with other mycoses, clinical and epidemiologic considerations, as with this patient, as- sist in differentiating the infections.

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index of suspicion

Treatment

Treatment for PDH involves intrave- nous (IV) amphotericin B, followed by long-term oral itraconazole. Al- though data for children are limited, based on international studies, some experts recommend IV amphotericin B for 2 to 3 weeks, followed by 3 to 6 months of oral itraconazole.

Clinical Course

This boy received IV amphotericin B for 2 weeks, and by the third day, his fever had subsided. On further inves- tigation, it was found that his father had complained of excess bird drop- pings on his truck 1 month earlier and was forced to cut down the trees in front of the farm. Two other out-

breaks of acute histoplasmosis had occurred in the county within the past 3 years. This patient continued to do well and was transitioned to oral itraconazole for 6 months. After 2 months of therapy, his spleen was no longer palpable, and the liver edge was within normal limits. Re- peat urine test for H capsulatum an- tigen at that time showed negative results.

Lessons for the Clinician

Massive hepatomegaly has a large differential diagnosis.

Concurrent splenomegaly usually is explained by involvement of the reticuloendothelial system.

In areas endemic for certain myco-

ses, failure to consider a fungal in- fection for prolonged fevers may delay the diagnosis. Most patients who develop PDH are immunocompromised, usually having defects with T-cell- mediated immunity. However, healthy children younger than the age of 2 years who have difficulty clearing the infection do develop PDH rarely.

( Rinku Patel, DO, Advocate Hope

Children’s Hospital, Oak Lawn, IL )

To view Suggested Reading lists, for these cases, visit http://pedsin review.aappublications.org and click on “Index of Suspicion”.

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Index of Suspicion • Case 1: Recurrent Oral Ulcers in an Adolescent • Case 2:

Visual Impairment in an Autistic Child • Case 3: Fever and Hepatosplenomegaly in an Infant Benjamin Bruins, Howard F. Fine, L. Nandini Moorthy, Ayesha Jain, Ashok K. Jain, Thomas W. Milligan and Rinku Patel Pediatr. Rev. 2011;32;35-40 DOI: 10.1542/pir.32-1-35

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