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Answer Key: 1. D; 2. A; 3. B; 4. E; 5. B; 6. B; 7. D; 8. B; 9. E;10. B; 11. E; 12. E

ArticlesAsthma Epidemiology, Pathophysiology,

and Initial Evaluation331

Vanessa L. Hill, Pamela Runge Wood

Thinking About HIV Infection337Evelyn P. Simpkins, George K. Siberry, Nancy Hutton

Coping With Death350Jennifer S. Linebarger, Olle Jane Z. Sahler, Kelsey A. Egan

Index of Suspicion357Case 1: Daniel H. Reirden

Case 2: Alexandra N. Menchise, Brian Knox, Rani Gereige

Case 3: Tamara Howard, Erica L. Thomas, Rosina Connelly

Case 4: Sarah Tyler, Katie McPeak

Research and Statistics: Cohort Studies364Raquel G. Hernandez, Peter C. Rowe

Pediatrics in the Community:Bulletproof: Using Media as a Tool for Advocacy371 Alexander Zusman, Tricia Michels Tayama

In Brief Parental Monitoring andDiscipline in Middle Childhood366

Cholelithiasis and Cholecystitis368

Clarification369

Internet-Only Article

Abstract appears on page 370.The Floppy Infant: Evaluation of Hypotoniae66Dawn E. Peredo, Mark C. Hannibal

Cover Art Conteste77

Cover: The artwork on the cover of this month’s issue is

by one of the winners of our 2007 Cover Art Contest,

9-year-old Amelia Broman of St. Cloud, Minn. Amelia’s

pediatrician is Kelly Fandel, MD.

contentsPediatricsinReview Vol.30No.9September 2009

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 ZanzolaMedical Copy Editor: Deborah K. KuhlmanEditorial Assistant: Sydney Sutherland

Editorial Office: Department of PediatricsUniversity of Rochester

School of Medicine & Dentistry 601 Elmwood Avenue, Box 777Rochester, NY [email protected]

Editorial BoardHugh D. Allen, Columbus, OH Margie Andreae, Ann Arbor, MI Richard Antaya, New Haven, CT Denise Bratcher, Kansas City, MO George R. Buchanan, Dallas, TX Brian Carter, Nashville, TN Latha Chandran, Stony Brook, NY David Cornfield, Stanford, CA Joseph Croffie, Indianapolis, IN B. Anne Eberhard, New Hyde Park, NY Leonard Feld, Charlotte, NC Rani Gereige, Tampa, FL

Mark Goldstein, Boston, MA Lindsey Grossman, Baltimore, MD Patricia Hamilton, London, UnitedKingdom HalB. Jenson, Springfield, MA DonaldLewis, Norfolk, VA Gregory Liptak, Syracuse, NY Blaise Nemeth, Madison, WI John Pascoe, Dayton, OH ThomasT. Sato, Milwaukee, WI Sarah E. Shea, Halifax, Nova Scotia NancySpector, Philadelphia,PA Surendra K. Varma, Lubbock, TX

Publisher: American Academy of PediatricsMichael J. Held, Director, Division of Scholarly Journals and Professional Periodicals

Pediatrics in ReviewPediatrics in Review(ISSN 0191-9601) is owned andcontrolled by theAmericanAcademy of Pediatrics. Itis published monthlyby theAmericanAcademy of Pediatrics, 141NorthwestPointBlvd., ElkGroveVillage,IL 60007-1098

Statementsand opinions expressed in Pediatrics in Review arethoseof theauthorsandnot necessarily those of theAmericanAcademy of Pediatrics or itsCommittees.Recommendationsincluded in this publication do notindicate an exclusive courseof treatmentor serve as a standard of medical care.Subscription price for2009 forprint andonline/onlineonly:AAP Fellow$163/$124; AAPCandidate Fellow$153/$114;Nonmember $204/$159;Allied HealthorResident $152/$103. Institutionscall for pricing (866-843-2271). For overseasdelivery,add $95. Current singleissue price is $10 domestic,$12 international.Replacement issuesmust be claimed within 6 monthsfrom thedate of issue andarelimited to three percalendaryear.Periodicalspostage paid at ARLINGTONHEIGHTS, ILLINOIS and at additionalmailing offices.© AMERICAN ACADEMY OF PEDIATRICS, 2009. Allrightsreserved. Printed inUSA. No part maybe duplicated or reproduced withoutpermission of theAmerican Academy of Pediatrics.POSTMASTER: Send address changes to PEDIATRICS IN REVIEW , American Academy of Pediatrics Customer Service Center, 141 NorthwestPoint Blvd., Elk Grove Village, IL 60007-1098.

Pediatrics in Review Print Issue Editorial Board DisclosuresThe American Academy of Pediatrics (AAP) Policy on Disclosure of FinancialRelationships and Resolution of Conflicts of Interest for AAP CME Activities isdesigned to ensure quality, objective, balanced, and scientifically rigorous AAPCME activities by identifying and resolving all potential conflicts of interest beforethe confirmation of service of those in a position to influence and/or control CMEcontent.

Every individual in a position to influence and/or control the content of AAPCME activities is required to disclose to the AAP, and subsequently to learners whether the individual has relevant financial relationships with manufacturers of commercial products and/or services discussed in the CME activities.Each of the editorial board members disclosed that the CME content he/sheedits/writes may include discussion/reference to generic pharmaceuticals, off-labelpharmaceutical use, investigational therapies, brand names, and manufacturers, if applicable.None of the editors had any relevant financial relationships to disclose, unless notedbelow. The AAP has taken steps to resolve any potential conflicts of interest.

Disclosures● Richard Antaya, MD, FAAP, disclosed that he participates in the Astellas Pharma,

US, Inc., speaker bureau, advisory board, and clinical trials; and in the Novartisspeaker bureau.

● Joseph Croffie, MD, MPH, FAAP, disclosed that he has research grants andserves on speaker bureaus of Sucampo Pharmaceuticals (Lubiprostone), BraintreeLabs (Miralax Halflytely), Medtronics (Bravo pH Capsule), Tap pharmaceuticals(Prevacid).

● Leonard Feld, MD, MMM, PhD, FAAP, disclosed that he is a speaker for andcommittee member of a Pediatric Board Review Course (sponsored by AbbottNutrition) through the AAP New York Chapter.

● Hal B. Jenson, MD, MBA, FAAP, disclosed that he is a speaker and vaccineadvisory board member for Merck Vaccines as well as a speaker for SanofiPasteur.

● Donald W. Lewis, MD, FAAP, disclosed that he is a consultant for and has aresearch grant from Astra Zeneca and Merck; and that he has research grants

from Ortho McNeil, Lilly, Bristol-Myers Squibb, GlaxoSmithKline, andBoehringer Ingelheim Pharmaceutical.

The printing and production of Pediatrics in Review issupported, in part, through an educational grant from Abbott Nutrition, a division of Abbott Laboratories.


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DOI: 10.1542/pir.30-9-3312009;30;331-336Pediatr. Rev.

Vanessa L. Hill and Pamela Runge WoodAsthma Epidemiology, Pathophysiology, and Initial Evaluation

http://pedsinreview.aappublications.org/cgi/content/full/30/9/331located on the World Wide Web at:

The online version of this article, along with updated information and services, is

Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2009 by the American Academy ofpublished, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1979. Pediatrics in Review is owned,Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly

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Asthma Epidemiology, Pathophysiology, andInitial Evaluation

Vanessa L. Hill, MD,*

Pamela Runge Wood,

MD†

Author Disclosure

Drs Hill and Wood

have disclosed no

financial relationships

relevant to this

article. This

commentary does not

contain a discussionof an unapproved/

investigative use of a

commercial

product/device.

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

1. Describe the underlying pathophysiology of asthma.

2. Discuss the role of atopy in the development of asthma.

3. Identify risk factors for death from asthma.

4. List conditions to be considered in the differential diagnosis of wheezing in children.

Introduction Asthma is a disease of airway inflammation characterized by hyperresponsiveness and

airflow obstruction that lead to symptoms such as cough and wheezing (Fig. 1). Child-

hood asthma continues to cause significant morbidity and burden in the United States.

This article reviews the pathophysiology, epidemiology, and recommendations for initial

evaluation of asthma. Recommendations are based on the 2007 Expert Panel Report 3:

Guidelines for the Diagnosis and Management of Asthma (“2007 Guidelines”). (1)

EpidemiologyPrevalence and Burden of Disease

The prevalence of asthma rose steadily from 1980 until the late 1990s, when it reached a

plateau. In 2007, 9% of children 0 to 17 years of age (6.7 million children) had asthma,

according to data from the National Health Interview Survey. The lifetime prevalence of

asthma in children is 13%. (2)

The burden of disease in the United States from pediatric asthma is alarming, according

to a recent report based on national surveys. In 2003, 12.8 million days of missed school

were attributed to asthma. In 2004, hospitalizations for asthma totaled 198,000 or 3% of

all pediatric admissions. Asthma resulted in 750,000 emergency department (ED) visits in

that same year (2.8% of all pediatric ED visits). Although children ages 0 to 4 years of age represent only a small proportion of the total asthma population, they account for a

sizeable proportion of the hospitalizations and ED visits. (3)

Natural HistoryThe natural history of asthma is variable. Most individuals who develop chronic asthma,

measured by a decrease in lung function and persistence of symptoms, have a genetic

predisposition. In addition, exposure of the airway epithelium to environmental insults in

such susceptible individuals contributes to the development, severity, and persistence of

asthma.

The Tucson Children’s Respiratory Study, a longitudinal

community-based study of 1,246 children who were fol-

lowed from birth until early adulthood, provides data on thenatural history of respiratory disease in children. (4) Data

from this study show that wheezing in the first 3 years after

birth often is associated with a lower respiratory tract infec-

tion, most commonly respiratory syncytial virus (RSV).

Thirty-two percent of all children have wheezing with acute

lower respiratory tract infections in the first year after birth,

17% in the second year, and 12% in the third year. More than

80% of infants who have a history of wheezing in the first

postnatal year do not wheeze after age 3 years.

*Assistant Professor of Pediatrics.†

Clinical Professor of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Tex.

Abbreviations

ED: emergency department

FEV 1

: forced expiratory volume in 1 second

Ig: immunoglobulin

IL: interleukin

RSV: respiratory syncytial virus

Th: T-helper

VCD: vocal cord dysfunction

Article allergy & immunology

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The investigators also identified three distinct wheez-

ing phenotypes that occur during childhood. “Transient

wheezers” are those infants whose wheezing is associated

with one or more lower respiratory tract infections and

who cease to wheeze after 3 years of age. “Nonatopic

wheezers” are children who have relatively more reac-

tive airways, a higher incidence of previous RSV infec-

tion, and persistent wheezing after age 3 years, which may

resolve over time. “Atopic wheezers” are the group of

children who are most likely to develop persistent asthma.Theyhavehigher immunoglobulin E (IgE) concentrations,

are prone to allergen-mediated airway hyperresponsive-

ness, and have more profound lung function deficits at an

early age compared with “nonatopic wheezers.” In gen-

eral, 60% of children who have asthma are symptom-free

by adulthood. However, only 5% to 30% of children who

have severe asthma or asthma associated with atopy out-

grow their asthma by adulthood. (5)

Mortality and Health Disparities Although mortality rates have fallen since 1999, asthma

remains a preventable cause of death in children. In

2004, the mortality rate from

asthma was 2.5 per 1 million chil-

dren for a total of 186 deaths per

year. Therefore, it is crucial to iden-

tify children at risk of death from

asthma. In general, the rate of

death from asthma is higher in se-

vere, uncontrolled disease. Specific

risk factors include: one or more

life-threatening exacerbations of

asthma, severe asthma requiring

chronic oral corticosteroids, poor

control of daily asthma symptoms

requiring frequent short-acting

beta2 agonist medication, abnor-mal forced expiratory volume in

1 second (FEV 1), frequent ED

visits, low socioeconomic status,

family dysfunction, and patient

psychological problems. (6)

Racial disparities are significant

in asthma. Prevalence rates for

asthma are highest among Puerto

Rican and African American chil-

dren. Compared with white chil-

dren, African American children

have higher rates of ED visits butlower outpatient and ambulatory

visits. African American children

continue to have higher rates of mortality than other

children, despite a downward trend in overall asthma

mortality rates. (3) Such disparity reflects limited access

to outpatient health services compared with other chil-

dren. (7)

PathophysiologyInherent to asthma is airway inflammation that is medi-

ated by a variety of cell subtypes, resulting in hyper-

responsive airways, ultimately limiting airflow and causing variable symptoms. Initial airway bronchoconstriction is

followed by airway edema and exaggerated mucus pro-

duction, accompanied by airway hyperresponsiveness,

and followed by chronic changes in the airway epithelium

(airway remodeling). Current medical management tar-

gets various points along this continuum. However, no

clear evidence suggests that early or aggressive treatment

with anti-inflammatory medications, such as inhaled cor-

ticosteroids, can prevent airway remodeling.

Airway inflammation is mediated by a variety of cyto-

kines and chemokines (cytokines that are specific for

chemotaxis and activation of leukocytes). Cytokines are

Figure 1. Mechanisms underlying the clinical symptoms of asthma. Adapted from the

National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. 2007.

allergy & immunology asthma epidemiology, pathophysiology, evaluation

332 Pediatrics in Review Vol.30 No.9 September 2009. Provided by Pakistan:AAP Sponsored on September 9, 2009http://pedsinreview.aappublications.orgDownloaded from

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produced by a number of cell types, including lympho-

cytes, eosinophils, and mast cells. Proinflammatory cyto-

kines (interleukin-4 [IL-4], IL-5, and IL-13), produced

primarily by the T-helper (Th)2 lymphocytes, are be-

lieved to trigger the intense inflammation of allergic

asthma. An imbalance between Th1 and Th2 lympho-

cytes (specifically, decreased Th1 activity with increased

Th2 activity) contributes to chronic inflammatory

asthma. Chemokines play a key role in inflammation.

These proteins recruit proinflammatory cells, including

Th2 lymphocytes, mast cells, neutrophils, and eosino-

phils. Eosinophils and mast cells have a distinct role in

asthma pathogenesis. These cell types produce proin-

flammatory cytokines as well as leukotrienes, which cause

bronchoconstriction.The airway epithelium is a target for infectious, nox-

ious, and environmental insults that cause injury via

influx of proinflammatory cells and cytokines (Fig. 2).

Both viral infections and airborne allergens can precipi-

tate a biphasic response that ultimately leads to asthma

symptoms. IgE plays a pivotal role in this process, as

shown by evidence that administration of anti-IgE

monoclonal antibodies reduces asthma symptoms and

improves lung function. (8) The IgE-mediated “early-

phase” or “immediate” response to an allergen challenge

causes mast cells and basophils to degranulate, precipi-

tating bronchospasm as well as the release of proinflam-matory cytokines and chemokines. This cascade of in-

flammatory responses results in the subsequent “late-

phase” obstruction of air flow, which occurs 4 to 12

hours following exposure to the environmental insult.

Bronchodilators can relax airway smooth muscle, if ad-

ministered during the initial period of bronchospasm.

However, due to the increased airway hyperresponsive-

ness and inflammation that occur with the late-phase

response, bronchodilator therapy is not as effective, and

anti-inflammatory medication is required.

Asthma also is characterized on a cellular level by

structural alterations in the airway epithelium. Airway

remodeling can occur and is associated with the follow-

ing changes in the underlying structural components of

the epithelium: mucous gland hyperplasia, thickening

of the epithelial basement membrane, fibrotic changes in

the sub-basement membrane, bronchial smooth muscle

hypertrophy, and eventually angiogenesis.

Clinical Aspects Asthma is characterized by intermittent, recurrent symp-

toms of airway obstruction that is at least partially revers-

ible. Common symptoms include cough (which may

be the only symptom), wheezing, difficulty breathing,

and “chest tightness.” Nighttime symptoms are com-

mon. In addition, symptoms often occur or worsen in the

presence of common asthma “triggers,” such as exercise,

changes in the weather, viral respiratory infections, and

exposure to allergens or airway irritants (eg, environmen-

tal tobacco smoke). To diagnose asthma, the physicianmust exclude other conditions. The diagnosis may be

particularly difficult in very young children because

wheezing is common in early childhood and many dis-

eases can cause symptoms similar to

those seen in asthma.

EvaluationInitial evaluation should begin with

a detailed medical history, in-

cluding the pattern of symptoms

and observed precipitating factors

(asthma triggers). Past medical his-tory should include information

about risk factors for asthma (par-

ticularly atopy), prior exacerba-

tions, treatments used, and their

effects. A positive family history of

parental asthma substantially in-

creases the risk of asthma in a child.

Evaluation also should include an

assessment of the impact of asthma

on the child and family. The phys-

ical examination of a child who has

asthma often yields normal find-

Figure 2. Cellular mechanisms involved in airway inflammation. ILinterleukin,

IgEimmunoglobulin E, LTB4leukotriene B4. From the National Asthma Education andPrevention Program. Expert Panel Report 2: Guidelines for the Diagnosis and Management

of Asthma. 1997.





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ings, although there may be signs of atopy, such as

eczema or allergic rhinitis, which are strongly associated

with asthma.

The 2007 Guidelines recommend objective measure-

ment of pulmonary function (spirometry) as part of the

initial evaluation. Most children older than age 6 or 7

years are capable of performing a forced expiratory ma-

neuver, if coached by an experienced technician. Some

centers can test children as young as 5 years of age.

Spirometry should be performed before and after admin-

istration of a short-acting bronchodilator. FEV 1 that

increases by 12% or more following the administration

of bronchodilators indicates reversible airway obstruc-

tion, even if baseline FEV 1 is normal. Spirometry results

may be normal, particularly in children who have mildasthma. Baseline chest radiography may be useful to rule

out other conditions, particularly in very young children

or in patients manifesting atypical signs and symptoms.

Differential DiagnosisThe differential diagnosis of asthma is broad and includes

upper airway disease as well as obstruction of large air-

ways and other causes of small airway obstruction. Upper

airway disease, such as allergic rhinitis or sinusitis, can

cause recurrent coughing, particularly at night, but often

has other signs or symptoms that help distinguish it from

asthma. Extrinsic or intrinsic obstruction of the largeairways (eg, tracheomalacia, vascular ring, mass, or for-

eign body) may present with signs and symptoms similar

to those of asthma. Specific findings, such as a change in

airway symptoms with position or failure of symptoms to

respond to usual asthma treatment, may be helpful in the

diagnosis. Individuals who have ingested a foreign body

often have a history of acute onset of symptoms follow-

ing a choking episode, but this history is more difficult to

elicit in very young children. Recurrent aspiration or

gastroesophageal reflux also can result in recurrent bouts

of coughing or other respiratory symptoms that might

be confused with asthma. A careful history that examinesthe pattern of symptoms and looks for evidence of

risk factors for reflux or aspiration, such as prematurity,

feeding difficulties, or neurologic impairment, may be

helpful.

Vocal cord dysfunction (VCD) presents with wheez-

ing or breathlessness associated with paradoxic vocal

cord adduction during inspiration and may be difficult to

distinguish clinically from asthma. Although VCD is a

distinct diagnosis, it also may coexist with asthma and

complicate its management. VCD, which is more com-

mon in adolescents and young adults, does not respond

to asthma medications and, therefore, should be in-

cluded in the differential diagnosis of atypical or difficult-

to-control asthma. The diagnosis may be suspected

based on clinical history and spirometry that shows a

flattened inspiratory loop. Definitive diagnosis usually is

made by a specialist and based on viewing of the vocal

cords during an episode.

A number of conditions that cause obstruction of the

small airways may result in wheezing or other symptoms

similar to those found in asthma. These include bronchi-

olitis, cystic fibrosis, congestive heart failure, and chronic

lung disease of prematurity. Recurrent episodes of bron-

chiolitis may occur in young children and sometimes are

difficult to distinguish from asthma. A detailed past med-

ical history and careful physical examination often help to

distinguish the latter three conditions from asthma. Asthma is particularly difficult to diagnose in infants

and toddlers. Recurrent wheezing episodes are common

in young children. Data from the Tucson Children’s

Respiratory Study showed that almost 50% of children

have at least onewheezing episode prior to age 6 years; in

most of these children, the wheezing is transient and

resolves prior to age 6 years. (4) These data were used to

build a “risk index” for asthma in young children. Spe-

cifically, children experiencing four or more episodes of

wheezing per year that last more than 1 day and affect

sleep are likely to develop asthma if they also have one

of the following major risk factors: 1) parental history of asthma, 2) atopic dermatitis, and 3) sensitization to

aeroallergens or two of the following minor risk factors:

1) sensitization to foods, 2) more than 4% eosinophilia,

or 3) wheezing apart from colds. According to the 2007

Guidelines, the young child who has a positive risk index

is at a high risk of developing asthma and should be

started on anti-inflammatory therapy.

In summary, asthma cannot be diagnosed based on a

single episode of wheezing, but rather requires observa-

tion of the pattern of symptoms over time. Individuals

manifesting atypical signs and symptoms or clinical

asthma that does not respond to asthma medications may

Summary

• The prevalence of asthma and the burden of diseaseremain high, despite efforts to improve publicawareness about and medical management of asthma.

• Asthma is a disease of airway inflammation that hasa variable natural history.

• Atopy is the most important risk factor for thedevelopment of asthma.





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require additional diagnostic studies (eg, specialized im-

aging of the chest or bronchoscopy) and referral to a

pulmonary specialist for additional evaluation.

NOTE. An article on the management of asthma will

be published in next month’s issue of Pediatrics in

Review .

References1. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of

Asthma. Full Report 2007. NIH Publication 07-4051. Bethesda,

Md: National Heart, Lung, and Blood Institute; 2007. Available at:http://www.nhlbi.nih.gov/guidelines/asthma/. Accessed June 20092. Bloom B, Cohen RA. Summary health statistics for U.S. chil-dren: National Health Interview Survey, 2007. National Center forHealth Statistics. Vital Health Stat . 2009;10(239). Available at: www.cdc.gov/nchs/nhis.htm. Accessed June 2009

3. Akinbami LJ. The state of childhood asthma, United States,1980–2005. Advance Data from Vital and Health Statistics ; No

381. Hyattsville, Md: National Center for Health Statistics; 2006. Available at: http://www.cdc.gov/nchs/data/ad/ad381.pdf. Ac-cessed June 20094. Taussig LM, Wright AL, Holberg CJ, Halonen M, Morgan WJ,Martinez FD. Tucson Children’s Respiratory Study: 1980 topresent. J Allergy Clin Immunol. 2003;111:661–6755. Phelan PD, Robertson CF, Olinsky A. The Melbourne AsthmaStudy: 1964–1999. J Allergy Clin Immunol. 2001;109:189–1946. Strunk RC. The fatality-prone asthmatic child and adolescent.Immunol Allergy Clin North Am. 1998;18:85–977. McDaniel M, Paxson C, Waldfogel J. Racial disparities in child-hood asthma in the United States: evidence from the NationalHealth Interview Survey, 1997 to 2003. Pediatrics. 2006;117:e868–e8778. Busse W, Corren J, Lanier BQ, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody for the treat-ment of severe allergic asthma. J Allergy Clin Immunol. 2001;108:184–190

PIR QuizQuiz also available online at pedsinreview.aappublications.org.

1. An 11-month-old boy presents with fever, runny nose, and difficulty breathing for 1 day. Physicalexamination shows an axillary temperature of 37.8°C, respiratory rate of 32 breaths/min, and heart rate of 110 beats/min. Diffuse expiratory wheezes are audible bilaterally. He had similar illness 2 months ago. Themother is concerned about her son developing asthma during his childhood. Which of the following is themost appropriate response to her concerns about her son?

A. If he has two more episodes of wheezing during the next year, his chances of having asthma duringchildhood are greater than 80%.

B. If he responds to bronchodilators such as albuterol, there is a greater than 80% risk that he will haveasthma during childhood.

C. If the respiratory infection is due to RSV, he should have less than a 20% risk of developing asthmaduring childhood.

D. More than 80% of infants who have a history of wheezing after respiratory infection in the first

postnatal year do not wheeze after age 3 years.E. More than 80% of infants younger than 1 year of age who have respiratory tract infections wheezeduring their illness.

2. A 3-year-old boy who has a previous history of allergic rhinitis and eczema presents to your office withcough and wheezing for 2 days. The symptoms started after he visited his uncle’s house and played with acat. Which of the following statements about his current state is true?

A. Airway inflammation has occurred due to action of cytokines and chemokines.B. Airway remodeling has occurred, characterized by mucous gland hyperplasia and bronchial smooth

muscle hypertrophy.C. Current illness represents the early phase of mast cell activation, causing bronchospasm.D. Eosinophils have been activated by IgE, causing IL-4 release.E. Th1 lymphocyte activation by IgA has caused airway hyperreactivity.





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3. A 6-year-old girl is brought in for evaluation of nighttime cough and wheezing after being exposed to

secondhand smoke. A pulmonary function test (PFT) using a forced expiratory maneuver to display a flow-volume curve is ordered. Which of the following statements is most accurate regarding PFT in thissituation?

A. Flattening of the inspiratory portion of the flow volume loop and decreased forced vital capacitysuggest the presence of asthma.

B. Increase in FEV 1

by at least 12% after administration of a bronchodilator is indicative of asthma.C. Normal PFT indicates that the patient does not have airway hyperresponsiveness and, therefore, retesting

with a bronchodilator is unnecessary.D. PFT assessment in those younger than age 8 years is unreliable due to lack of patient cooperation.E. PFT should be performed after challenging the patient with secondhand smoke and retesting after

administration of a bronchodilator.

4. A 15-year-old girl who has a known history of asthma is hospitalized for exacerbations of cough,wheezing, and shortness of breath. Her asthma has become increasingly unresponsive to bronchodilatorsand corticosteroids in the past 5 years. Flow-volume loop using a forced expiratory maneuver showsflattening of the inspiratory loop. Flexible fiberoptic laryngoscopy shows adduction of vocal cords andnarrowing of the subglottic area during inspiration. Which of the following is the most likely diagnosis?

A. Laryngomalacia.B. Subglottic hemangioma.C. Subglottic stenosis.D. Tethered vocal cord.E. Vocal cord dysfunction.

Find it in September NeoReviews™

The American Academy of Pediatrics online neonatology journal at http://neoreviews.aappublications.org

Educational Perspectives: Modeling Expertise in Medical Education—Leonard/Anderson

Thrombocytopenia in the Neonatal Intensive Care Unit—Saxonhouse/Sola-Visner

Immune-mediated Neutropenia in the Neonate—Black/Maheshwari

Preeclampsia and Neonatal Neutropenia—Moallem/Koenig

Index of Suspicion in the Nursery —Arevalo/Wetzel/Cabrera

Strip of the Month: September 2009—Druzin/Peterson





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Vanessa L. Hill and Pamela Runge WoodAsthma Epidemiology, Pathophysiology, and Initial Evaluation

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Evelyn P. Simpkins, George K. Siberry and Nancy HuttonThinking About HIV Infection

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Thinking About HIV InfectionEvelyn P. Simpkins, MD,*

George K. Siberry, MD,

MPH,† Nancy Hutton,

MD§

Author Disclosure

Drs Simpkins, Siberry,

and Hutton have

disclosed no financial

relationships relevant

to this article. This

commentary does notcontain a discussion

of an unapproved/

investigative use of a

commercial

product/device.

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

1. Recognize the important role that the general pediatrician plays in the prevention,

detection, and care of human immunodeficiency virus (HIV)-infected and -affected

patients.

2. Select the proper HIV testing plan for pediatric and adolescent patients based on age,

history, and physical assessment.

3. List the clinical conditions suggestive of HIV infection.

4. Provide counseling to reduce risk behaviors as part of routine adolescent health care.

5. Discuss comprehensive primary care for HIV-exposed infants.

Case Studies

Case Study 1 A 20-year-old woman, who is a recent emigrant from Ethiopia, brings in her 4-month-old

infant for a health supervision visit. The baby has had no immunizations, and his mother

reports having had no prenatal care. She is breastfeeding exclusively. The infant’s 25-year-old

father recently died after being very sick for 2 years. The mother states that he had “bad lungs.”

What are your next steps?

Case Study 2 A 17-year-old honor student comes to your office with a maculopapular rash on his face, trunk,

palms, and soles. He also complains of a sore throat and fever and states that he recently

returned from visiting his grandmother in Georgia. During his visit, he went hunting with his

uncles and his grandmother’s dog. During the interview, which involves asking routine

psychosocial questions in a nonthreatening manner (Table 1) to elicit sensitive information, he states that he has been sexually active with women for 2 years

and with men for 6 months. He does not use condoms with

either. He denies any contacts with sick persons or substance

abuse, including injection drug use (IDU). What are your

next steps?

IntroductionThe epidemiology, diagnosis, prevention, and treatment of

HIV infection and acquired immunodeficiency syndrome

(AIDS) in the pediatric and adolescent population have

changed dramatically over the past 25 years. In countries that

have good resources, such as the United States, rates of new infections in infants have plummeted with the implementa-

tion of effective screening and prevention strategies. Chil-

dren born with HIV early in the epidemic now are surviving

into young adulthood, facing unpredicted challenges and

opportunities in their physical health and social and emo-

tional well-being. Today’s adolescents are acquiring HIV at

an alarming rate. The role of the pediatrician varies with the

type of practice, the prevalence of HIV in the local commu-

*Fellow in Adolescent Medicine, Division of General Pediatrics & Adolescent Medicine.†Assistant Professor of Pediatrics, Division of General Pediatrics & Adolescent Medicine & Division of Infectious Diseases.§Associate Professor of Pediatrics, Division of General Pediatrics & Adolescent Medicine, Johns Hopkins University School of

Medicine, Baltimore, Md.

Abbreviations

AIDS: acquired immunodeficiency syndrome

CCR5: chemokine coreceptor 5

CD4: a glycoprotein on the surface of T helper cells

EIA: enzyme-linked immunoassay

HIV: human immunodeficiency virus

IDU: injection drug use

MMR: measles-mumps-rubella

mRNA: messenger RNA MTCT: mother-to-child transmission

NNRTI: non-nucleoside reverse transcriptase inhibitor

NRTI: nucleoside reverse transcriptase inhibitor

OI: opportunistic infection

PCP: Pneumocystis jiroveci pneumonia

PCR: polymerase chain reaction

PI: protease inhibitor

Article infectious diseases




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nity, and the ease of access to HIV specialty care and

consultation. All pediatricians should be prepared to

provide care for HIV-exposed newborns and their sib-

lings, to screen for and diagnose HIV infection in chil-

dren and adolescents, and to provide routine HIV pre-

vention counseling to adolescents. Many pediatricians

provide primary care for HIV-infected children and ad-

olescents in collaboration with HIV specialists (Table 2).

Epidemiology Worldwide, 33.2 million people live with HIV infection,2.5 million of whom are children younger than 15 years

of age. In 2007, 2.1 million AIDS deaths occurred, of

whom 330,000 were children. In the United States,

2,181 cases of AIDS were reported among children and

adolescents through age 24 years for the year 2006. Only

38 of these cases were in children younger than the age of

13 years, a sharp and steady reduction from the early

1990s when nearly 1,000 children annually were re-

ported as having AIDS. Clearly, the “pediatric” burden

of infection and disease now rests in the adolescent

population. Many children who had HIV at birth in the

1980s and early 1990s now are adolescents and youngadults living with HIV/AIDS. In addition, the number

of new cases of AIDS reported is increasing in all age

categories within the 13- to 24-year-old population.

Despite widespread availability of HIV testing and effec-

tive treatment, it is estimated that 25% of people living

with HIV/AIDS do not know that they are infected, a

proportion that increases to nearly 50% for infected

adolescents.

PathogenesisUnderstanding the basics of the HIV viral life cycle can

help pediatricians to employ HIV laboratory tests confi-

dently and to understand the current approach to HIV

prevention and treatment. HIV is a lentivirus in the

retrovirus family. Susceptible hosts are infected when the

virus enters the body and binds to CD4 receptors on host

T lymphocytes. Through a complex process of specific

HIV glycoprotein binding to host T-lymphocyte CD4

receptor and chemokine coreceptor 5 (CCR5) corecep-

tors, HIV fuses its envelope with the lymphocyte cell

membrane. Viral RNA and enzymes such as reverse

transcriptase enter the host cell, and the viral RNA isreverse transcribed into DNA. Viral DNA then enters the

nucleus of the host cell and is integrated into the cellular

genome.

When the host cell is activated, transcription takes

place, allowing viral DNA to be converted to genomic

and messenger RNA (mRNA). mRNA is translated into

viral proteins that combine with copies of genomic RNA

to become complete virions that subsequently are re-

leased from the host cell. The cycle of infection, replica-

tion, and release continues rapidly in the newly infected

host, creating billions of virions per day.

This initial viremic phase precedes antibody response

Table 1.

HEEADSSS* Interview forAdolescents

HomeEducation and employmentEatingActivitiesDrugsSexualitySuicide/depressionSafety

*The mnemonic HEEADSSS reminds the clinician of important as-pects of an adolescent’s life that require inquiry. Sensitive informationshould be elicited in a nonthreatening manner.

Table 2.

The Pediatrician’s Role inHIV Care

Health Maintenance Care

HIV-exposed newbornsImmunizationsGrowth and nutritional statusNeurodevelopment

Acute and Chronic Illness Care

Clinical syndromes suggestive of underlying HIV infection

Common problems in HIV-infected infants, children,and adolescents

Collaboration With HIV Specialist

Evaluation and stagingAntiretroviral treatmentPrevention of opportunistic infections

Counseling and Support

Primary and secondary HIV preventionCoping with diagnosis and prognosisAdherence with care and treatmentSchool and sports participationTransition to adult health careAdvance care planning and palliative care

Universal Precautions–Standard Precautions

infectious diseases HIV infection




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and is the period of highest infectivity due to the very

high viral load. During this time, dissemination of the

virus in the body and seeding of lymphoid organs is

widespread. The newly infected person may experience

acute retroviral syndrome, characterized by fever, lymph-

adenopathy, rash, myalgia, arthralgia, headache, diar-

rhea, oral ulcers, leukopenia, thrombocytopenia, and

transaminitis. During this “window period” between

host cell infection and host antibody response, an in-

fected person has a negative HIV antibody test result, but

HIV RNA testing results are positive. Seroconversion,

the demonstrated presence of HIV antibody, may occur

as early as 10 to 14 days after infection but usually occurs

within 3 or 4 weeks. Nearly all patients seroconvert

within 6 months of acquiring the infection. Infection with HIV is lifelong because HIV infects long-lived

memory T cells.

Preventing HIV Transmission to Children andAdolescentsHIV infection is transmitted by two principal modes in

the pediatric age group: mother-to-child and behavioral.

Mother-to-child transmission (MTCT) can occur ante-

partum through transplacental transfer; intrapartum

through exposure to maternal blood, amniotic fluid, and

cervicovaginal secretions during delivery; and postpar-

tum through breastfeeding. MTCT is preventable inalmost all cases by the proper use of combination anti-

retroviral therapy to achieve an undetectable viral load in

the mother, intrapartum maternal zidovudine, neonatal

zidovudine, and safe replacement infant feeding.

In addition, elective cesarean section prior to the

onset of labor can reduce MTCT risk in women who

have persistent viremia due to lack of or ineffective anti-

retroviral therapy during pregnancy. In the United

States, MTCT now occurs in fewer than 2% of births to

HIV-positive women, a decrease from 25% in nonbreast-

fed infants prior to the routine use of antiretroviral

therapy for the prevention of MTCT. It is important toremember that some infected infants escaped detection

early in the United States epidemic and now are being

identified as “new” cases in the adolescent age group.

Adolescents are exposed to HIV through risky behav-

iors that involve the exchange of infected blood or se-

men, such as unprotected sex (homosexual and hetero-

sexual) or injection drug use with sharing of needles or

syringes. Factors that increase the risk of sexual transmis-

sion include traumatic sex (voluntary or involuntary), in

which the genital, anal, or oral epithelium is compro-

mised (with those reporting receptive anal sex at highest

risk); active genital ulcer disease in either partner; and

(for females) douching before sex. Adolescent females

are at even higher risk than adult women of acquiring

sexually transmitted infections, including HIV, because

of the presence and vulnerability of the cervical ectro-

pion, an area of endocolumnar cells on the ectocervix

that regresses into the endocervical canal as the adoles-

cent matures. Behaviors that increase the likelihood of an

adolescent male or female being exposed to an HIV-

positive sexual partner include exchanging sex for money

or drugs, having multiple sex partners, and using recre-

ational drugs, including alcohol.

Studies of discordant partnerships (one person has

HIV infection, the other does not) reveal that consistent

and correct use of condoms made of latex, polyurethane,

or other synthetic materials offers a high degree of pro-tection from HIV and other sexually transmitted infec-

tions spread by the exchange of body fluids (as opposed

to infections spread by direct contact with lesions, such as

herpes simplex).

Testing for HIV Infection: Who, What,When?

The TestsSeveral laboratory tests are approved for screening and

diagnosing HIV infection (Table 3). The pediatrician

must select the correct test based on the patient’s age and

the clinical indication (Table 4). Most commercially available tests detect HIV antibody. For patients older

than age 18 months, the confirmed presence of antibody

to HIV is diagnostic of HIV infection. Standard HIV

antibody testing is performed on a blood specimen in

two steps: screening enzyme-linked immunoassay (EIA)

is performed and if reactive, a confirmatory test such as

Western blot is performed. Both steps must be positive

for the overall test result to be reported as positive.

Table 3. HIV TestsAntibody Tests in Laboratories

Enzyme-linked immunosorbent assayWestern blotImmunofluorescence assay

Antibody Tests in Clinical Settings (Rapid Tests)

BloodSaliva

Viral Detection Tests in Laboratories

DNA polymerase chain reaction (PCR) (qualitative)RNA PCR (quantitative)





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out. One of the tests looks for HIV. Have you ever heard

of that?”

The most important guideline is never lie . Partial

truthfulness can be supplemented at later visits or at older

ages. Deliberate misinformation, even under the guise of

protecting the child, leads to loss of trust and is very

difficult to undo.

Screening Pregnant WomenUniversal HIV counseling and voluntary HIV testing

using an opt-out approach is the recommended standard

of care for all pregnant women in the United States. This

practice provides the opportunity for HIV-positive

women to access HIV care for their own health and to

prevent HIV transmission to their babies. The opt-outapproach informs all pregnant women receiving care that

an HIV test will be performed unless she opposes testing.

Initial testing is performed early in pregnancy. Repeat

testing is recommended in the third trimester (before

36 weeks’ gestation) for women who live in high HIV

prevalence areas or for women who have specific high-

risk factors (exchange sex for money or drugs, IDU,

sexual partner who engages in IDU, new diagnosis of

sexually transmitted infection during pregnancy).

For women who have not received prenatal care,

intrapartum testing should be offered by using rapid test

kits or expedited EIA. Mothers who decline screening atany of these opportunities should be offered testing again

at every opportunity, including rapid antibody testing in

the immediate postpartum period. Practitioners also can

offer rapid antibody testing of newborns as an indicator

of HIV exposure when the mother’s status cannot be

determined. In most cases, maternal consent is needed

for testing newborns, but some states allow testing of

high-risk newborns without consent.

Testing HIV-Exposed InfantsInfants born to HIV-positive mothers should undergo

specific diagnostic testing; HIV DNA or RNA PCR should be used as part of their health maintenance care.

Testing is recommended at age 14 to 21 days, at 1 to 2

months, and again at 4 to 6 months. Due to the low

sensitivity of tests in the first 48 hours after birth, testing

is optional at birth. If performed, blood samples from the

umbilical cord should not be used because of possible

contamination with maternal blood. In nonbreastfed

infants, the sensitivity of HIV DNA PCR increases to

93% by 14 days of age. By 28 days, the sensitivity in-

creases to 96% and the specificity is 99%. Sensitivity and

specificity of the HIV RNA assay are similar. Any positive

test requires repeat confirmatory testing as soon as pos-

sible. Some practitioners use HIV DNA PCR for initial

testing and HIV RNA assay for confirmatory testing.

HIV infection is reasonably excluded when results of

two virologic tests are negative, the first at 14 days or

older and the second at 1 month of age or older. Defin-

itive exclusion requires negative results for two virologic

tests, the first at age 1 month or older and the second at

4 months of age or older. In older infants for whom early

testing was not performed, an alternate strategy is to

confirm the absence of HIV antibody. If infection al-

ready has been excluded definitively, HIV antibody test-

ing between 12 and 18 months of age to confirm the loss

of maternal antibody is optional.

Breastfeeding causes continued HIV exposure and is

not recommended in the United States where safe re-placement (formula) feeding can be provided. Testing

should continue throughout the period of breastfeeding

and for 6 months after cessation when an infant is breast-

fed.

Testing Children and AdolescentsHIV antibody tests are used for screening and diagnosis

in children older than age 18 months. All children of

HIV-positive mothers should be screened for HIV infec-

tion regardless of age or healthy appearance. Children or

adolescents who present with clinical conditions sugges-

tive of HIV infection should undergo HIV testing as partof the diagnostic evaluation, regardless of risk history.

All adolescents should be offered HIV testing as part

of routine health care. Annual testing is recommended

for those at high risk of acquiring HIV infection. Rapid

tests offer the advantage of providing test results at the

same visit. HIV-negative individuals can be reassured

and counseled to avoid future HIV exposure. HIV-

positive individuals can be engaged immediately into

care and support.

If a practitioner suspects acute infection or acute

retroviral syndrome, he or she should order HIV anti-

body and nucleic acid testing (HIV RNA) to look forevidence of infection. A positive nucleic acid test result in

the presence of a negative or indeterminate antibody test

result is consistent with acute HIV infection. Antibody

testing is recommended 10 to 12 weeks later to confirm

seroconversion.

Evaluation and Staging of the HIV-PositivePatient

Patients who have positive HIV test results should be

referred to an HIV specialist for comprehensive evalua-

tion (Table 5) so the clinical and immunologic stage of

disease can be assessed and treatment recommended.





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Initial evaluation of an HIV-infected pediatric patient

should include the mother’s medical history, child’s

medical history, family history, and social history. A com-

prehensive physical examination should be performed

and documented, including a developmental evaluation.

Assessment of HIV-infected adolescent patients (gener-

ally, 11 years of age and older), as for all adolescents,

should include a sexual history, substance use history,

and sexual maturity staging.

Initial laboratory testing in an HIV-positive patient

should include CD4 percentage and absolute cell counts,

plasma HIV RNA concentration (viral load), HIV geno-

type to assess for baseline resistance mutations, complete

blood count with differential count, serum chemistries

with liver and renal function tests, a lipid profile, andurinalysis. For children younger than 5 years of age, CD4

percentage is the preferred test for monitoring immune

status because the absolute CD4 cell count (number of

CD4 cells/mm3) in this age group varies with age-

related changes in absolute lymphocyte count. Screening

for hepatitis B and C infection as well as for tuberculosis

is recommended for all HIV-infected patients. In addi-

tion, sexually active adolescents should be screened for

Chlamydia infection, gonorrhea, syphilis, and human

papillomavirus infections. In contrast to the guidelines

for cervical cancer screening in healthy women, cervical

Papanicolaou smears are indicated routinely in all sexu-

ally active, HIV-infected adolescent girls, with colpos-

copy recommended for evaluation of abnormal results.

Similarly, most experts perform anal Pap smears in HIV-

infected adolescent men who have sex with men and

HIV-infected sexually active women; anoscopy is recom-

mended for evaluation of abnormal results.

HIV infection is a multisystem disease; clinical mani-

festations range from asymptomatic to complications

affecting virtually every organ system (Table 6). The

Centers for Disease Control and Prevention classification

system designates clinical categories based on the pa-

tient’s medical history and immunologic function cate-gories based on CD4 percentage (Table 7). This infor-

mation permits an estimated risk for future morbidity

and mortality and provides a rationale for instituting

specific opportunistic infection prophylaxis and initiating

or deferring antiretroviral therapy.

HIV-specific TreatmentAntiretroviral Therapy

The goal of anti-HIV therapy is to maximize the quality

and longevity of life through:

●

Complete suppression of viral replication (goal of nondetectable viral load )● Preservation or restoration of immunologic function

(goal of normal CD4 percentage or count )● Prevention of or improvement in clinical disease (goal

of asymptomatic state)

National treatmentguidelines for HIV-infectedchildren

and adolescents are updated routinely and are available on

the Internet (http://www.aidsinfo.nih.gov/Guidelines/).

Current recommendations are summarized in the text and

in Table 8. The pediatric treatment guidelines updated in

2008 recommend antiretroviral treatment for all infected

infants (12 months old); simplifies treatment initiationrecommendations into three age categories (12 months

old, 1 to 4 years old, and 5 years old) instead of four;

places greater emphasis on simplified, age-based CD4

thresholds for treatment initiation than on viral load; and is

consistent with adult guidelines for initiation of antiretrovi-

ral treatment in children 5 years of age and older. Clinical

and immune statuses are key predictors of morbidity and

mortality and form the basis for these recommendations.

Viral load is more useful for monitoring adherence and

effectiveness of therapy than as an indicator of when to

initiate antiretroviral therapy.

Treatment is recommended for: AIDS or severe symp-

Table 5. Evaluation and StagingHistory

Physical Assessment

Laboratory Assessment

Confirm HIV infectionHIV RNA (viral load)HIV resistance profile (genotype)CD4 percentage and absolute countComplete blood count with differential countChemistry panel (liver transaminases, bilirubin,

electrolytes, urea nitrogen, creatinine, calcium,phosphorus, glucose, cholesterol, triglycerides,amylase, lipase)

Coinfections: cytomegalovirus, Toxoplasma, hepatitisB and C, varicella

Urinalysis (dipstick and microscopic)

Tuberculin skin test

In sexually active individuals, screen for gonorrhea,Chlamydia infection, syphilis

Consider chest radiography, electrocardiography, dual-energy x-ray absorptiometry scan for bone mineraldensity





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Table 6. Relative Frequency of Clinical Conditions in Untreated HIV Infection

Body System or Illness Category* Specific Conditions

Relative Frequency

Common Uncommon

Infections: recurrent, severe, or Recurrent or chronic otitis, sinusitis Cunusual (opportunistic) Recurrent or severe pneumonia C

Recurrent or severe bacteremia COpportunistic infections, such as PCP, MAC, invasive candidal

infectionsC

Lymphoreticular system Generalized lymphadenopathy CHepatomegaly CSplenomegaly CParotid enlargement CLymphoid interstitial pneumonitis C

Growth Failure to thrive CWeight loss, wasting C

Stunting CDelayed puberty C

Neurologic Neurodevelopmental delay or regression CAbnormal tone (increased or decreased) CGait disturbance CPeripheral neuropathy UStroke U

Pulmonary Bacterial pneumonia CLymphoid interstitial pneumonitis CBronchiectasis UPneumothorax U

Cardiovascular Cardiomyopathy UPericardial effusion UConduction abnormalities UHypertension U

Vasculopathy UGastrointestinal Gastritis CDuodenitis CHepatitis UPancreatitis UCholecystitis UDiarrhea CGastrointestinal bleeding UAbdominal pain C

Renal Proteinuria CRenal tubular acidosis URenal failure UHypertension U

Hematologic Anemia CNeutropenia CThrombocytopenia C

Dermatologic Seborrhea CEczema CUrticaria UZoster CHerpes simplex infections CTinea corporis, capitis, unguium CBacterial infections CMolluscum contagiosum CWarts (HPV) C

Genital/Reproductive HPV-related dysplasia (cervical, anal) CPelvic inflammatory disease CDelayed puberty C

*Some conditions belong to more than one category. HPV human papillomavirus, MACMycobacterium avium complex, PCPPneumocystis jiroveci pneumonia





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toms, CD4 percentage of less than 25% (1 to 4 years) or

absolute CD4 count of less than 350 cells/mm3 (5 years

and older) regardless of symptoms, all infected infants

younger than 12 months of age, and all pregnant adoles-

cents.

Treatment is considered for: patients whose HIV

RNA is more than 100,000 copies/mL and who have

mild or absent symptoms and adequate CD4 cells (CD4

percentage of more than 25% [1 to 4 years] or absolute

CD4 count of more than 350 cells/mm3 [5 years and

older]).

Treatment can be deferred for: mild or absent symp-

toms and adequate CD4 values (CD4 percentage of

more than 25% [1 to 4 years] or absolute CD4 count of

less than 350 cells/mm3 [5 years andolder]) and RNA of

less than 100,000 copies/mL.

Antiretroviral therapy should be planned and moni-

tored in collaboration with an HIV

specialist. Strong evidence sup-

ports the use of triple-drug com-

bination antiretroviral therapy to

maximize virologic response and

minimize the emergence of viral

resistance. Initial therapy consists

of three drugs from two catego-

ries: one non-nucleoside reverse

transcriptase inhibitor (NNRTI)

OR protease inhibitor (PI) PLUS

two nucleoside or nucleotide

reverse transcriptase inhibitors

(NRTIs).

Important issues to consider whenselecting specific drugs include:

● Age, weight, sexual maturity stage of patient● Baseline HIV resistance pattern● Likelihood of developing resistance to selected drugs if

patient has difficulty adhering to the regimen (low

versus high barrier to resistance)● Likelihood of becoming pregnant while taking selected

drugs (eg, efavirenz)● Ease of administration (formulation, schedule, food

restrictions)

Planning treatment collaboratively with the patient

and family strengthens the therapeutic relationship and

promotes successful adherence and HIV control. Enlist-

ing adult support in the home is beneficial regardless of

the patient’s age. Frequent clinical follow-up with viral

load testing allows the clinician to identify problems early

and help patients and families find successful solutions.

Table 7. HIV Clinical Classification System

Clinical CategoriesN No symptoms*A Mild symptoms (eg, generalized

lymphadenopathy)B Moderate-to-severe symptoms

(eg, thrombocytopenia)C AIDS-defining conditions (eg,

Pneumocystis jiroveci pneumonia)

Immune Categories1 Normal CD4 >25%2 Moderate suppression CD4 15% to 24%3 Severe suppression CD4 350 cells/mm3

TREAT TREAT RNA100,000 copies/mLCONSIDER


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Patients in whom the virus shows no drug resistance and

in whom therapy is initiated with currently available

medicines should achieve a nondetectable viral load

within 3 to 6 months. Failure to achieve this goal

strongly suggests suboptimal adherence to the recom-

mended regimen rather than viral resistance.

Once HIV infection is controlled on a stable regimen,

most patients are seen every 3 to 4 months for routine

monitoring of viral load, CD4 cell response, and clinical

status, including evaluation for potential medication ad-

verse effects or toxicities. Patients who experience treat-

ment failure have additional treatment options, includ-

ing new drugs in existing classes (PIs, NNRTIs, NRTIs)

as well as new drug classes such as entry inhibitors (fusion

inhibitors and CCR5 antagonists) and integrase inhibi-tors.

Preventing Opportunistic InfectionsThe profound immunodeficiency caused by uncontrolled

HIV infection allows serious and life-threatening infections

to occur in children and adolescents. Evidence supports the

primary prevention of common opportunistic infections

(OIs) based on age and CD4 guidelines. Full recommen-

dations are available at http://aidsinfo.nih.gov.

Pneumocystis jiroveci pneumonia (PCP) is the most

common OI. Cotrimoxazole is recommended for all

HIV-exposed infants until HIV infection is reasonably excluded, for all HIV-infected infants until age 12

months, and for HIV-infected children and adolescents

older than 1 year of age whose CD4 values fall into the

severe immune suppression category (CD4 percentage

15% or CD4 count 200 cells/mm3).

Primary prevention of Mycobacterium avium complex

by using azithromycin or clarithromycin is recom-

mended at lower CD4 values (6 years old with CD4

count of 50 cells/mm3; ages 2 to 5 years with CD4

count of 75 cells/mm3; 1 to2 years with CD4 count of

500 cells/mm3; 1 year old with CD4 count of

750 cells/mm3

).Toxoplasmosis is less common in children than in

adults, but its prevention with daily cotrimoxazole is

recommended in HIV-infected children and adolescents

who are Toxoplasma immunoglobulin G-seropositive

and have severe immunosuppression (CD4 percentage

15% for children 6 years old; CD4 count100 cells/

mm3 for children 6 years old).

ImmunizationsThe 2009 immunization schedule for HIV-exposed in-

fants and for HIV-infected infants, children, and adoles-

cents is the same as for their healthy peers, with only a few

exceptions. Patients who have severely symptomatic ill-

ness or CD4 percentages of less than 15% or CD4 counts

of less than 200 cells/mm3 should not receive measles-

mumps-rubella (MMR) or varicella vaccines due to the

risk of opportunistic disease from the live attenuated

virus strains in the vaccines. HIV-infected children who

have higher CD4 counts should receive MMR and vari-

cella separately, not as the combined MMR-V. The

higher titer of varicella in MMR-V has not been tested for

safety in HIV-infected children. Annual influenza immu-

nization is recommended for all children older than age 6

months, but only the killed, injectable formulations of

the influenza vaccine are recommended for HIV-infected

children and adolescents.

HIV-infected children and adolescents need certainadditional vaccines and doses. Pneumococcal polysac-

charide vaccine is recommended in addition to the reg-

ular pneumococcal conjugate vaccine series. Specific and

comprehensive recommendations for immunizations in

HIV-infected children, adolescents, and adults are avail-

able at http://aidsinfo.nih.gov/.

Counseling and SupportPrimary and Secondary Prevention of HIV Infection

Health education messages to avoid HIV infection andto prevent its spread to others should be routine in every

pediatric and adolescent practice. It is important for

clinicians to be prepared to offer prevention counseling,

including abstinence and safe sex as best options for

preventing HIV transmission. Clinicians should be able

to teach all adolescents about correct use of male latex

condoms and emphasize that consistent use is essential

for prevention. Screening all patients ages 13 years and

older for HIV infection identifies asymptomatic patients

unaware of their HIV infection status, providing them

the opportunity to enroll in HIV-specific care for their

own benefit andto reduce the risk of transmitting HIV to

others. HIV-negative adolescents who engage in behav-

iors through which HIV can be transmitted should be

tested at least annually.

Coping With the Diagnosis and PrognosisLearning of a new diagnosis of HIV infection for oneself

or one’s child is emotionally devastating for most people.

While providing a listening ear and emotional support,

clinicians also can offer hope and reassurance about the

availability of effective treatment that can result in im-

proved quality of life and survival for people living with

HIV infection in the United States. Referral to the HIV





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specialist allows prompt access to specific medical care

and psychosocial supports.

Disclosure of HIV Infection StatusHIV infection remains a stigmatizing diagnosis. Igno-

rance, misinformation, and fear in families and commu-

nities cause people living with HIV infection to keep

their status a secret. However, this practice has negative

consequences, such as isolating the HIV-positive individ-

ual from social support and risking additional spread of

HIV to sexual partners. Planned disclosure to family

members and friends can increase practical and emo-

tional support for the HIV-positive person. Sexual part-

ners can make informed decisions about how to protect

themselves from exposure to HIV.In contrast to adolescents and adults, disclosure of

HIV status to children should be undertaken over time,

providing sequential pieces of practical health informa-

tion that match the developmental capacity of the child.

This process builds a strong foundation for children to

participate meaningfully in their HIV care.

Adherence to Care and TreatmentMost people do not adhere to the treatment recommen-

dations of their health-care practitioners all of the time.

Adolescence is a particularly vulnerable age for nonad-

herence in those who have chronic health conditionssuch as HIV infection. Poor adherence leads to poor

health outcomes in many diseases such as asthma and

diabetes. However, HIV treatment is unique in its re-

quirement for 90% to 100% adherence to drug regimens

to avoid the development of viral resistance and the loss

of future efficacy of anti-HIV drugs. The need for inten-

sive education and support for children and adolescents

living with HIV infection cannot be overstated.

School and Sports ParticipationChildren and adolescents who have HIV infection can

participate fully in the educational and extracurricularactivities in school. There is no obligation to notify

school personnel of a student’s HIV infection status. Any

sport may be played if the student’s health status allows.

For all athletes, regardless of HIV infection status, skin

lesions should be covered properly, and athletic person-

nel should use standard precautions when handling

blood or body fluids that have visible blood. Certain

high-contact sports (such as wrestling and boxing) may

create a situation that favors viral transmission (likely

bleeding plus skin breaks). Some experts advise athletes

who have a detectable viral load to avoid such high-

contact sports.

Transition to Adult Health CareChildren born with HIV infection in the United States

during the 1980s are now young adults. They continue

to be the pioneers who challenge our assumptions and

identify unmet needs for care and support services. No

one anticipated the current need to develop and imple-

ment programs to transition youth successfully to adult

HIV health-care clinicians. Practical concerns such as

transmitting a complete and coherent medical record

and psychological concerns such as the loss of long-term

supportive relationships must be addressed.

Advance Care Planning and Palliative Care Advance care planning is recommended for all who live

with chronic and life-threatening conditions. HIV-infected parents should plan for the care of their depen-

dent children. HIV-infected adolescents and young

adults should designate a person they trust to make

health-care decisions for them if they should become

unable to speak for themselves due to illness or injury.

One approach is to normalize this decision as part of

routine health care when reaching adulthood. This prac-

tice is particularly important for youth who have no

clearly identified next of kin, such as those who are

orphaned and have experienced sequential foster homes.

There continue to be patients who experience dis-

tressing medical complications of HIV infection that, if not reversed, lead to death. Integrating palliative care

with HIV-specific care reduces distress by managing

specific physical and emotional symptoms, encouraging

clear communication, and promoting effective decision-

making. This approach provides the best opportunity to

improve a patient’s quality of life regardless of how long

the patient survives.

Managing Potential HIV ExposureThe pediatrician may be called on to respond to ques-

tions about HIV exposure. Such questions may be about

occupational exposures, such as a needle stick injury to ahealth-care worker, or nonoccupational, such as a child

finding a discarded needle and syringe or an adolescent

who is a victim of sexual assault. The basic approach to

any of these scenarios is to assess the likelihood that

exposure to potentially infectious fluids actually oc-

curred, determine how severe or extensive the exposure

was, and evaluate the likelihood that the fluids are HIV-

contaminated. If the exposure is of high risk and the

source is known to be HIV-infected, postexposure pro-

phylaxis with antiretroviral drugs should begin as soon as

possible after the exposure, but no later than 72 hours.

Guidelines for evaluating risk and recommending post-





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exposure prophylaxis can be found at http://

aidsinfo.nih.gov.

Having a High Degree of SuspicionIn case study 1, the clinician is presented with a 4-month-

old infant of immigrant African parents whose father died

as a young man with “bad lungs” and whose mother is

breastfeeding exclusively. The clinician’s next steps in-

clude performing a careful history and physical examina-

tion to assess the infant’s growth and development and

to look for conditions suggestive of HIV infection. HIV

antibody testing should be recommended to the mother

for her own health and for planning the care of her baby.

If such testing cannot be arranged promptly, testing theinfant for HIV antibody would indicate the mother’s

HIV infection status. If the mother is HIV antibody-

negative and not engaging in risky behaviors, the infant

does not need additional HIV testing. However, if the

mother is HIV-positive, virologic testing of the infant

with HIV DNA or RNA PCR is indicated throughout

the period of breastfeeding and for 6 months after cessa-

tion. Counseling should be provided about the availabil-

ity of safe and affordable formula feeding and prompt

weaning recommended. Age-appropriate immuniza-

tions should be administered and cotrimoxazole pre-

scribed for PCP prophylaxis until HIV infection isexcluded.

Case study 2 involves a 17-year-old male who has a

rash, fever, and sore throat and recently has traveled to

Georgia, a trip that included a hunting trip. In addition,

the patient reports having sex with both females and

males and no condom use. The scenario leads to consid-

eration of Rocky Mountain spotted fever in the differen-

tial diagnosis. However, it is important to remember that

acute retroviral syndrome in adolescents presents with

fever 96% of the time and both rash and pharyngitis 70%

of the time. Additional signs and symptoms include

lymphadenopathy, myalgia, arthralgia, headache, diar-

rhea, oral ulcers, leucopenia, thrombocytopenia, and

transaminase elevation. In this patient, HIV antibody

testing and HIV RNA testing are indicated as part of

the medical evaluation. Counseling should be pro-

vided to reduce the risk of sexually transmitted infec-

tions.

Conclusion Although it is important to remember that HIV infection

is a multisystem disease requiring regular medical atten-

tion, including health maintenance care, it is equally

important to remember that some of the greatest chal-

lenges young people face have little to do with their

physical illness. Many are in the midst of social complex-

ities that neither they nor their families can begin to

navigate without support. Despite these challenges,

HIV-positive young people are resilient, strong, caring,

appreciative, and worthy of our respect. They are our

teachers, presenting diagnostic, therapeutic, and psycho-

social challenges that open new avenues for clinical in-

vestigation, stimulate our continuous professional devel-

opment, and remind us of our core human values. They

lead the way as we strive to find better ways to manage

their illness and improve the quality of their lives.

Suggested Reading and Useful WebsitesHIV EpidemiologyCenters for Disease Control and Prevention. HIV/AIDS Sur-

veillance Report, 2006 . Vol 18. Atlanta, Ga: United StatesDepartment of Health and Human Services, Centers for Dis-ease Control and Prevention; 2008:1–55. Available at: http:// www.cdc.gov/hiv/topics/surveillance/resources/reports/. Ac-cessed June 2009

HIV Disease Classification1994 revised classification system for human immunodeficiency

virus infection in children less than 13 years of age. MMWR Recomm Rep . 1994;43(RR-12):1–10. Available at: http:// www.cdc.gov/MMWR/preview/MMWRhtml/00032890.htm.

Accessed June 2009

Summary• Mother-to-child transmission of HIV can occur

during pregnancy, labor, delivery, and breastfeeding.Evidence-based interventions (routine screening of pregnant women, initiation of antiretroviral drugsfor mother’s treatment or prevention of MTCT, andavoiding breastfeeding) have reduced transmissionrates in the United States from 25% to 30% to lessthan 2%.

• Triple-drug combination antiretroviral therapyeffectively controls HIV infection and improvessurvival and quality of life for HIV-infected childrenand adolescents. Initial regimens use combinations

of two NRTIs together with an NNRTI or a ritonavir-boosted PI. These regimens have been shown toincrease CD4 counts and achieve virologicsuppression.

• Prevention of serious and opportunistic infectionsreduces morbidity and mortality in children andadolescents who have HIV infection. Recommendationsfor immunizations and chemoprophylaxis vary with the

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