01 Pediatrics in Review_Jan2008

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

Commentary

A Flood of Information3Lawrence F. Nazarian

Articles

Varicella-Zoster Virus Infections5Anne A. Gershon

Neutropenia in Pediatric Practice12George B. Segel, Jill S. Halterman

Index of Suspicion25Cherilyn Hall, Allen Friedland, Sumathi Sundar, Kathryn S. Torok,Mananda S. Bhende, Grace Pecson, Carolyn Leedy

Pediatrics in the Community:Community Pediatrics Training Initiative (CPTI)31Jeffrey Kaczorowski

In Brief

Inhalants33Internet-Only ArticleAbstract appears on page 35.

American Academy of PediatricsPolicy Statements on Bioethics:Summaries and Commentaries: Part 1e1Mark R. Mercurio, Mary B. Adam, Edwin N. Forman,Rosalind Ekman Ladd, Lainie Friedman Ross, Tomas J. Silber

Cover: The artwork on the cover of this month’sissue is by one of the winners of our 2005 CoverArt Contest, 11-year-old Elizabeth Emery of Ham-ilton, Va. Elizabeth’s pediatricians are with Ash-burn Pediatrics.

contentsPediatrics inReview� Vol.29 No.1 January 2008

Editor-in-Chief: Lawrence F. Nazarian,Rochester, NY

Associate Editors: Tina L. Cheng,Baltimore, MDJoseph A. Zenel, Portland, OR

Editor, In Brief: Henry M. Adam, Bronx, NYConsulting Editor: Janet Serwint, Baltimore, MDConsulting Editor Online and Multimedia

Projects: Laura Ibsen, Portland, OREditor Emeritus and Founding Editor:

Robert J. Haggerty, Canandaigua, NYManaging Editor: Luann ZanzolaMedical Copy Editor: Deborah K. KuhlmanEditorial Assistant: Sydney SutherlandEditorial Office: Department of Pediatrics

University of RochesterSchool of Medicine & Dentistry601 Elmwood Avenue, Box 777Rochester, NY [email protected]

Editorial BoardMargie Andreae, Ann Arbor, MIRichard Antaya, New Haven, CTLaurence A. Boxer, Ann Arbor, MILatha Chandran, Stony Brook, NYJoseph Croffie, Indianapolis, MDHoward Eigen, Indianapolis, INLeonard Feld, Charlotte, NCJeremy N. Friedman, Toronto, ONVincent A. Fulginiti,Tucson, AZMark Goldstein, Boston, MALindsey Grossman, Baltimore, MDRussell J. Hopp, Omaha, NEHal B. Jenson, Springfield, MAChris P. Johnson, San Antonio, TXJ. Jeffrey Malatack, Narberth, PABlaise Nemeth, Madison, WIJohn Pascoe, Dayton, OHDeWayne Pursley, Boston, MAThomas T. Sato, Milwaukee, WIBennett A. Shaywitz, New Haven, CTMichael Silberbach, Portland, ORNancy Spector, Philadelphia, PASurendra K. Varma, Lubbock, TXMaximilian Zach, Graz, AustriaPublisher: American Academy of PediatricsMichael J. Held, Director, Division of ScholarlyJournals and Professional Periodicals

Pediatrics in Review�Pediatrics in Review�(ISSN 0191-9601) is owned and controlled bythe American Academy of Pediatrics. It ispublished monthly by the American Academy ofPediatrics, 141 Northwest Point Blvd, Elk GroveVillage, IL 60007-1098Statements and opinions expressed in Pediatricsin Review� are those of the authors and notnecessarily those of the American Academy ofPediatrics or its Committees. Recommendationsincluded in this publication do not indicate anexclusive course of treatment or serve as astandard of medical care.Subscription price for 2008 for print and online/online only: AAP Fellow $163/$124; AAPCandidate Fellow $153/$114; Nonmember$204/$159; Allied Health or Resident $152/$103. Institutions call for pricing (866-843-2271). For overseas delivery, add $95. Currentsingle issue price is $10 domestic, $12international. Replacement issues must beclaimed within 6 months from the date of issueand are limited to three per calendar year.Periodicals postage paid at ARLINGTONHEIGHTS, ILLINOIS and at additional mailingoffices.© AMERICAN ACADEMY OF PEDIATRICS,2008. All rights reserved. Printed in USA. Nopart may be duplicated or reproduced withoutpermission of the American Academy ofPediatrics.POSTMASTER: Send addresschanges to PEDIATRICS INREVIEW�, American Academyof Pediatrics Customer ServiceCenter, 141 Northwest PointBlvd., Elk Grove Village, IL60007-1098.The printing and production ofPediatrics in Review� is madepossible, in part, by aneducational grant from RossProducts Division, AbbottLaboratories.

DOI: 10.1542/pir.29-1-3 2008;29;3-4 Pediatr. Rev.

Lawrence F. Nazarian A Flood of Information

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Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347. Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2008 by the American Academy of published, 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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CommentaryA Flood of InformationMany elements in our lives can over-whelm us and overload our circuits,including responsibilities, worries, andconflicting appointments. Even sometreats we enjoy can get to be too much,such as tomatoes in the garden at thepeak of the season, photographs wait-ing to be organized, and exceptionalbooks crying out to be read. Anotherflood that threatens to engulf us isinformation. Even if we ignore the ob-viously misleading or irrelevant rivers ofdata flowing toward our minds, there isenough worthwhile, relevant, desirableinformation coming our way to sweepus over the falls.

Restricting our focus to medicalknowledge, and even further to an un-derstanding of pediatric medicine, westill find that sector of the informationocean stretching out to the horizon andgetting bigger every year. There used tobe lectures, seminars, workshops, text-books, and journals. All of these sourceshave multiplied, and we have addedcontinuing medical education courses,teleconferences, CDs and DVDs, andthat infinite highway to knowledgeabout everything under the sun andbeyond, the Internet. No wonder manypractitioners feel they are lost at seaand going down for the third time.

Pediatrics in Review® (PIR) and thePREP program exist to throw you a lifepreserver and a compass. Our primarymission is to focus on the essentials ofpediatric medicine and to present cur-rent thinking about each aspect of thatbody of knowledge to keep readers upto date. We are fortunate to haveaccess to the content specifications ofthe American Board of Pediatrics,which has created a database that de-fines that core. In any given 5-year

period, PIR and the PREP Self-Assessment cover that content, allow-ing readers to refresh their knowledgein a constant, renewing fashion. In theprocess, steady readers are preparingthemselves for the cognitive testinginvolved in maintenance of certifica-tion.

We continue to recruit our materialfrom the best teachers in our professionand to spend countless hours makingwhat is written readable and lucid. Theindividuals who produce PIR at all lev-els know what it is like to come homeafter a long day and try to learn evenmore. With that sensitivity, we attemptto make our teaching as user-friendlyas we can.

Realizing that there are relevant andinteresting topics outside the core con-tent, we have expanded our horizons,adding two new sections in the last 2years. Many parents are using or askingabout therapies outside of conventionalmedicine, and we publish a regularseries on complementary and alterna-tive treatments. As strong believers inthe role of pediatricians in the widercommunity, we publish another regularfeature on community pediatrics thathighlights innovative and effective pro-grams in that area.

Our electronic edition has allowedus to broaden the spectrum of pediatricsubjects even further. By publishing oneor two articles each month in theonline-only format, we have creatednew space to give our readers insightsinto topics such as telemedicine, con-tinuing medical education, and theelectronic medical record. The elec-tronic capability has allowed us to pro-vide recordings of heart murmurs aswell as still and moving pictures. The

online edition also allows for RapidResponse, through which readers cangive us instant feedback on articles andwe can provide clarifications with equalspeed. We urge readers who are usingthe online journal to click the RapidResponse line every time they read anarticle to see if there is any informationthat has been added after publication.Most clarifications are published in theprint edition as well, but with an inev-itable lag time.

We have extended our reach beyondour borders in several ways. Cliniciansin developing countries can access theelectronic version of the journal free ofcharge. Authors from around the worldhave contributed material, especiallythrough “Index of Suspicion” cases,which have come from authors living in22 countries. We have published acommentary from Italy as part of anarticle on evaluation of athletes, andwe hope to bring you more of theseperspectives. PIR has been published inChinese, Italian, Hungarian, Polish, andSpanish, with a Turkish translationstarting up.

Residents rank among our most avidreaders, and we have a special relation-ship with these young physicians. Manyresidents have written “Index of Suspi-cion” cases, and each year we choose acase from their case-writing contest topublish. “Focus on Diagnosis,” now inits fourth year, is written exclusively byresidents, who share their knowledge ofcutting-edge diagnostic procedures. Allpediatric residents in the United Statesreceive a complementary subscriptionto PIR, funded mainly by an unre-stricted grant from Abbott Nutrition.

A great many people work hard tomake PIR what it is, and I would like to

commentary

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acknowledge the contributions of DrsTina Cheng and Joseph Zenel, our in-valuable Associate Editors; Drs HenryAdam and Janet Serwint, who preparethe “In Brief” articles; Dr Laura Ibsen,who provides media of all kinds; andour Medical Copy Editor Deb Kuhlman.AAP staff members Luann Zanzola,Susan Piscoran, Michael Held, and DrRobert Perelman give us constant sup-

port, as does our Editor Emeritus, DrRobert Haggerty. Our publishers, Cad-mus and Highwire, create the finalproduct. The whole operation is heldtogether by Sydney Sutherland, our Ed-itorial Assistant.

PIR is privileged to have an EditorialBoard of the finest pediatricians andteachers available anywhere, and I ex-tend to them my deep gratitude for the

countless hours they donate to makethis journal what it is.

Finally, thanks go out to our thou-sands of readers around the world. You,and especially the children for whomyou care, are why we exist.

Lawrence F. Nazarian, MDEditor-in-Chief

commentary

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Lawrence F. Nazarian A Flood of Information

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Anne A. Gershon Varicella-Zoster Virus Infections







Varicella-Zoster Virus InfectionsAnne A. Gershon, MD*

Author Disclosure

Dr Gershon has

disclosed that she

occasionally is a

consultant and

lecturer for Merck

and Company, Inc,

and GlaxoSmithKline.

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

1. Describe the natural history and pathogenesis of varicella and zoster and how thesediseases are related.

2. Explain to patients and parents the complex role of this virus in causing disease andhow the virus spreads.

3. Describe how best to manage patients who have these infections.4. Discuss how varicella vaccine works, how effective it is in preventing disease, and why

two doses of vaccine are now recommended.

The PathogenVaricella-zoster virus (VZV), a close but distinct relative of the other seven humanherpesviruses, including herpes simplex virus (HSV), causes two diseases. Varicella (chick-enpox), a generalized illness, is its primary infection, and zoster (shingles) is its secondaryinfection, caused by reactivation of VZV from latency. Varicella infection occurs in almostall people over their lifetimes. VZV becomes latent after varicella and usually persistssilently and indefinitely. VZV reactivates, however, to cause zoster in roughly 20% ofindividuals, with higher reactivation rates in immunocompromised patients and theelderly.

EpidemiologyIn the prevaccine era in the United States prior to 1995, approximately 4 million cases ofvaricella and 1 million cases of zoster occurred annually. Varicella was primarily a disease ofchildren younger than age 10 years and zoster an illness of adulthood. Childhood varicellainfection, however, is less common than adult infection in countries that have tropicalclimates. Varicella occurs in children who have no humoral or cellular immunity to VZV,termed “susceptibles.” Zoster occurs in individuals who previously have had varicella; theyusually have detectable specific antibody titers, but have low or absent cell-mediatedimmunity (CMI) to VZV.

VZV spreads primarily from the skin vesicles of persons who have varicella or zoster tothe respiratory tract of susceptible persons, who then become infected. Electron micro-scopic studies have shown a high concentration of well-formed, cell-free VZV in skinvesicles. (1) Respiratory spread is difficult to rule out entirely, but during disease, it is rareto isolate the virus from the throat, although it is common to isolate it from skin vesicles.VZV spreads as cell-free enveloped viral particles, or virions, which are present in skinvesicles and are small enough (approximately 200 nm in diameter) to be aerosolized. (2)The virus spreads by the airborne route and requires direct exposure to an infectedindividual for transmission.

Evidence for spread of VZV from skin is as follows. A 14% transmission rate of thevaccine (Oka) strain of VZV occurred when susceptible siblings were exposed to a recentlyimmunized child who had leukemia and had a vaccine-associated rash. No transmissionoccurred if the vaccinee had no rash, and VZV could not be isolated from the throats of anyof vaccinees, whether or not they had a vaccine-associated rash. Transmission rates weredirectly proportional to the number of skin lesions. Recent observations in otherwisehealthy children who contracted wild-type breakthrough varicella after immunization alsohave indicated that VZV spreads from skin. (3) Another recent study indicated that

*Professor of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY.

Article infectious diseases



children who had active varicella and were not excludedfrom school on day 1 after rash onset played a major rolein spreading the virus in their classrooms. (4) Finally,spread of VZV to observers during an autopsy indicatesthat transmission by other means than the respiratorytract must occur. (5)

VZV is highly communicable, and subclinical infec-tion is unusual; clinical infection develops in about 80%of susceptibles after family exposure. In contrast, inhealthy vaccinees, the Oka strain very rarely spreads toothers, even if a rash is present.

Patients who have zoster can transmit varicella toothers because the vesicular lesions contain infectiousVZV. About 100 years ago, during early attempts todevelop a VZV vaccine, children were inoculated withvesicular fluid from zoster patients, and they developedmild chickenpox. Zoster, however, is less contagiousthan varicella.

The incubation period of varicella ranges from 10 to23 days (average, 14 days). During the incubation pe-riod, VZV multiplies, spreads to regional lymph nodes,and causes viremia. Wild-type VZV has been isolatedfrom blood cultures just before and during very earlychickenpox in immunocompetent children. An attrac-tive, recently proposed pathogenetic mechanism is thatVZV reaches keratinocytes soon after infection by way ofVZV-infected CD4 memory T cells from infected tonsil-lar cells. These lymphocytes normally circulate throughthe skin, engaged in immune surveillance; some alsobecome infected with VZV as they circulate, spreadingthe virus in the body. In this model, overcoming innateimmunity in skin accounts for the 2- to 3-week incuba-tion period following infection, as reviewed by Gershonand associates. (6)

Second attacks of varicella are uncommon but mayoccur. Asymptomatic immunologic boosting of VZVimmunity occurs after re-exposure to VZV in varicella-immune individuals and may play a role in long-termmaintenance of immunity to VZV.

Patients who develop zoster usually have a history ofprevious varicella. Zoster can occur in childhood; theincidence is increased by a factor of as much as 20 inthose who had varicella in utero or before age 2 years,possibly because the immune response to VZV in younginfants is immature. Infants afflicted with the congenitalvaricella syndrome are at even greater risk for developingzoster.

The incidence of zoster is age-related and begins toincrease sharply at 50 years of age. (7) Loss of VZV CMI,which occurs during normal aging, is related to develop-ment of zoster. In keeping with this observation, zoster

can be prevented by immunization. Zoster also developscommonly in patients treated for cancer and after organtransplantation. Spinal trauma, irradiation, and cortico-steroid therapy are other precipitating factors for zoster.Children infected with human immunodeficiency virus(HIV) are at increased risk for developing zoster. Chil-dren who develop zoster should be screened (usually byhistory) for possible risk factors such as HIV infectionand underlying immunodeficiency; most often, however,no predisposing factors are identified.

On occasion, zoster occurs in healthy children oryoung adults. Presumably, such infection is the result ofa transient decrease in CMI to VZV, perhaps caused byanother inapparent viral infection. Low CMI to VZV is anecessary, but not sufficient, requirement for the devel-opment of zoster.

The DiseasesClinical Manifestations

Varicella usually is a mild-to-moderate illness in children.It often is more severe in adults. Even in children, how-ever, varicella cannot be counted on to be entirely be-nign. After a short or absent prodrome, skin lesionsappear. These start as macules and progress rapidly topapules, vesicles, pustules, and scabs. The rash is concen-trated on the trunk and head rather than on the extrem-ities; it normally evolves as a series of successive “crops”over 3 to 4 days. Most children have 250 to 500 super-ficial skin lesions, many of which are vesicular. Subclinicalelevations of hepatic transaminase concentrations are acommon, self-limited occurrence during varicella.

Zoster usually appears as a unilateral vesicular skineruption involving one to three dermatomes. Skin vesi-cles may be painful or pruritic, especially in adults. Zostergenerally is a milder disease in children than in adults.From 25% to 50% of persons older than 50 years of ageand the same proportion of immunocompromised pa-tients who acquire zoster experience serious pain, termedpost-herpetic neuralgia (PHN), after the rash has healed.The cause of PHN is unknown.

ComplicationsThe most common complication of varicella is bacterialsuperinfection of the skin, lungs, or bones, most often byStaphylococcus aureus or group A beta-hemolytic strepto-cocci (GAS). Such infections may be severe and evenfatal. Whether treatment with ibuprofen is associatedwith increased severity of GAS after varicella remainsunresolved. Therefore, this drug is not recommended fortreatment of fever accompanying varicella.

Central nervous system (CNS) complications, which

infectious diseases varicella



may precede or follow varicella, include transient cere-bellar ataxia, encephalitis, aseptic meningitis, and trans-verse myelitis. Most CNS complications are self-limited,except for encephalitis, which frequently is associatedwith severe sequelae if the patient survives. Other lessfrequent complications of chickenpox include arthritis,glomerulonephritis, myocarditis, and purpura fulminans.

Immunocompromised PatientsVaricella may be severe and even fatal in immunocom-promised patients, particularly those who have malig-nancy or congenital deficits in CMI, as well as in thosewho have undergone organ transplantation, have under-lying HIV infection, or are receiving high doses of corti-costeroids. Immunocompromised children who have se-vere varicella tend to have high fevers, extensive rasheslasting for more than 1 week, hepatitis, and primaryviral pneumonia, which may be fatal despite antiviraltherapy. Children who have leukemia have a 30% rate ofdisseminated varicella, with a 7% mortality rate. Severevaricella may occur in HIV-infected children, especiallyin those who have acquired immunodeficiency syndrome(AIDS). In most of these children, however, mild-to-moderate varicella occurs, although the illness often ismore severe than occurs in healthy hosts.

Congenital and Neonatal VaricellaAfter maternal VZV infection in the first or secondtrimester of pregnancy, approximately 2% of infants de-velop the congenital varicella syndrome. (8) Approxi-mately 100 affected infants have been described since1947; more than 95% of cases occurred after maternalvaricella and the remainder after possible maternal zos-ter. In the prevaccine era, an estimated 40 affected infantswere born annually in the United States. Cicatricial skinscars (in �60% of cases) are the most prominent abnor-malities. Other common manifestations include hypo-plastic limbs, chorioretinitis, microphthalmos, Hornersyndrome, cataract, nystagmus, cortical atrophy or men-tal retardation, zoster, and early death.

DiagnosisChickenpox generally is diagnosed clinically because ofthe characteristic vesicular rash and its distribution, aswell as through epidemiologic information such as his-tory of exposure and absence of prior varicella. Zosteralso presents with a distinct unilateral, dermatomal, ve-sicular rash that is diagnosed clinically. Laboratory diag-nosis can be used in questionable instances and is facili-tated by the accessibility of the virus in superficial skinlesions. (9) The diagnosis is made most definitively by

demonstration of specific viral antigens in skin scrapingsby immunofluorescence (DFA) using a commercialmonoclonal antibody to VZV conjugated to fluoresceinor by polymerase chain reaction (PCR). These diagnosticmethods are highly sensitive and rapid.

Diagnosis also may be made by isolating the virusfrom skin lesions, but this technique is more complicatedand expensive, is less sensitive, and takes longer thanDFA or PCR. VZV rarely can be isolated from cerebro-spinal fluid (CSF) and respiratory secretions. The pres-ence of VZV or antigens in secretions or tissues is diag-nostic of acute VZV infection because this virus is notshed by asymptomatic persons. The Tzanck test is notrecommended by this author because it lacks sensitivityand specificity.

Testing of skin scrapings, vesicular fluid, respiratorysecretions, and CSF by PCR is useful for diagnosingVZV, and PCR is replacing culture in many laboratories.PCR is available widely in commercial laboratories andcan distinguish between vaccine and wild-type VZV.

Many serologic tests measure antibodies to VZV,including fluorescent antibody to membrane antigen,latex agglutination, and enzyme-linked immunosorbentassay (ELISA). Antibody to VZV develops rapidly afterthe onset of varicella and persists indefinitely. Peak anti-body concentrations occur after 4 to 8 weeks. VZVinfections may be proven by a fourfold or greater rise inVZV antibody titer in acute and convalescent serumspecimens. Specific immunoglobulin M in one serumspecimen suggests recent VZV infection. Persistence ofVZV antibody in infants older than 8 months of agesuggests intrauterine varicella. Immunity to varicella ishighly likely if there is a positive antibody titer to VZV ina single serum sample in a healthy patient. CommercialELISAs, however, usually are not sufficiently sensitive toidentify the level of immunity that develops in vaccinees.After active immunization against VZV, antibody titersare significantly lower than after natural infection.

Serologic procedures for diagnosing zoster are limitedbecause of the nonspecific increases in antibody titeragainst VZV in some patients who have active HSVinfection. These viruses also share minor antigens, whichcan lead to an increase in VZV titer with HSV infection.Zoster occurs in the presence of serum VZV antibodies;elevations in titer, therefore, can be missed.

CMI responses play the major role in host defenseagainst the virus. CMI to VZV can be demonstrated invitro most practically by stimulation of lymphocytes withVZV antigens and by an interferon-gamma enzyme-linked immunosorbent spot (ELISPOT) assay. CMI re-




actions remain positive for years, although CMI oftenwanes in individuals older than 50 years of age.

TreatmentNonspecific treatment for varicella includes oral antihis-tamines, frequent bathing, calamine lotion, oatmealbaths, and the trimming of fingernails to discouragescratching. Fever should be controlled with acetamino-phen. Use of aspirin for this purpose may predispose toReye syndrome, and ibuprofen may predispose to GASinfection.

Indications for Specific TreatmentBecause most varicella infections are not serious and theillness usually is self-limited in otherwise healthy chil-dren, oral acyclovir (ACV) is not administered routinely.Further, the drug is not well absorbed from the gastro-intestinal tract. Specific therapy is reserved for those athigher risk for developing severe varicella or those whoalready have severe disease. Because controlled studies inchildren and adolescents given oral ACV for 5 days,starting within 24 hours of the rash of varicella, haveshown a modest benefit, prompt oral ACV therapy usu-ally is recommended for adolescents and young adults,who are at moderately high risk for developing severeillness. (10)(11)(12) The oral dose is 20 mg/kg qid forchildren and 1 g qid for adolescents. The antiviral activityof ACV depends on its phosphorylation by virus-inducedthymidine kinases.

Patients at serious risk for or who have severe orpotentially severe VZV infections should be treated withintravenous (IV) ACV (10 mg/kg per dose tid for adultsand adolescents and 500 mg/m2 per dose tid for chil-dren). Patients whose creatinine clearance is less than50 mL/min per 1.73 m2 are given one half to one thirdof this dosage, with slow infusion, making sure thathydration is adequate. ACV usually is tolerated very well,but adverse effects include phlebitis, rash, nausea, andneurologic symptoms. Children who are relatively im-munocompromised, such as those who have early, seem-ingly mild varicella and those who have early HIV infec-tion (not AIDS), may be given a closely monitoredtreatment trial of oral ACV and switched to IV ACV ifclinically necessary. In those who have zoster, IV or oralACV heals skin lesions rapidly and resolves pain.

Development of drug resistance to ACV is of potentialconcern. Resistance of VZV has been less of a problemthan with HSV; VZV resistant to ACV has been reportedonly rarely. A vaccinated child who had neuroblastomaand developed zoster due to the Oka strain that was

resistant to ACV after prolonged treatment has beendescribed.

Because data are few regarding the effectiveness ofACV for preventing chickenpox in susceptible healthychildren, its use for this purpose is discouraged.

Famciclovir, an orally administered prodrug of ACV,is converted to ACV in the body, with resulting higherdrug concentrations than oral ACV itself. Famciclovir isadministered three times a day for zoster (1,500 mg/d)for adults but is not approved either for children or fortreatment of varicella. Another oral prodrug of ACV,valacyclovir, achieves higher concentrations of ACV thandoes famciclovir, but also is not licensed in the UnitedStates for use in children or for varicella.

Foscarnet is used to treat VZV infections that areresistant to ACV; the drug inhibits synthesis of VZVDNA polymerase. The dose of IV foscarnet is180 mg/kg per day divided into two doses, adjusted ifnecessary for renal function. Toxicities include renaldamage and electrolyte imbalance.

PreventionControl Measures

It virtually is impossible to protect susceptible individualsfrom infection with VZV by avoidance because the agentis highly communicable. Transmission is expected todecrease, however, when VZV infection occurs in popu-lations that are highly vaccinated.

Children who have chickenpox should be excludedfrom school or child care from the time the diagnosis ismade until the lesions are crusted. Those who have zostermay attend school if the lesions can be covered or whenthey are crusted. The Table lists facts that can be helpfulin advising parents whose children are exposed to chick-enpox. Patients who have active VZV infection and arehospitalized should be isolated, preferably in a room thathas negative pressure ventilation, to minimize viral trans-mission.

Vaccination of individuals is particularly important ifthere are family members who cannot be vaccinated,such as a pregnant woman or immunocompromisedchildren. Transmission of the Oka strain from vaccinatedindividuals, even if they develop a rash, is extremely rareand has been reported after approximately 1 in 10 millionvaccinations.

Passive ImmunizationPassive immunization is used to protect exposed high-risk persons from developing severe VZV. Treatment isgiven to persons who have no history of previous VZVdisease, are at high risk for developing severe varicella,




and have had an intimate exposure to VZV within thepreceding 5 days. Formerly, passive immunization wasaccomplished by injection of varicella-zoster immuneglobulin (VZIG). VZIG is no longer being produced,however, because there was little demand for it after1995. A similar product is available from Canada(VariZIG™, Cangene Corporation, Winnipeg, Canada)and is recommended for neonates whose mothers haveactive varicella at or soon after delivery and for exposedsusceptible high-risk patients. (13) The product is avail-able in the United States under an investigational newdrug application expanded access protocol, with centralinstitutional review board approval. IV immune globulin400 mg/kg is an alternative should neither VZIG norVariZIG™ be available. (13)(14)

Active ImmunizationLive attenuated varicella vaccine was developed in Japanin 1974. (15) Since 1995, universal immunization ofhealthy children and adults in the United States who aresusceptible to varicella has been recommended by theCenters for Disease Control and Prevention (CDC).This vaccine is extremely safe and well-tolerated. About5% of healthy children develop a mild rash approximately4 to 6 weeks after immunization. Serious neurologicevents have not been related causally to varicella vaccine.Vaccinees who develop VZV rash within 2 to 3 weeks

after immunization are likely to have wild-type infectionand should be regarded so.

Live attenuated varicella vaccine is highly effective inhealthy children and adults. Universal vaccination hasdecreased the incidence, complications, morbidity, andmortality of varicella by roughly 80% in the UnitedStates.

Although varicella vaccine is highly effective, approx-imately 20% of children develop mild chickenpox afterexposure to wild VZV if they have received only one doseof vaccine. Severe varicella occurs only in about 3% ofthose who develop breakthrough varicella after vaccina-tion. The vaccine is also 80% effective in adults after twodoses. Severe wild-type varicella in vaccinated adults israre. (6)(14)(16)(17)

It is unclear whether breakthrough varicella is theresult more from primary or secondary vaccine failure,but primary vaccine failure seems to be the major factor.Loss of VZV antibodies occurs rarely in healthy vacci-nated children, even after a follow-up for as long as 20years. Between years 1 and 8 after immunization, therehas not been a decrease in protection of healthy children.There have been, however, numerous recent reports ofoutbreaks of varicella among immunized children inchild care facilities and schools. Most investigations ofoutbreaks have shown 80% to 85% vaccine effectiveness,but some show effectiveness as low as 45% to 55%. (6)(14) The children included in these studies had, for themost part, received only one dose of vaccine.

A recent investigation indicated a significant degree ofprimary vaccine failure (24%) in young children whoreceived only one dose of vaccine. (18) To decrease virustransmission, improve vaccine effectiveness, and preventaccumulation of susceptible young adults, two doses ofvaccine—previously recommended only for those olderthan 13 years of age—were recommended for all childrenby the CDC in June 2006. Catch-up varicella vaccinationalso is recommended for all children who received onlyone dose of varicella vaccine in the past. After a seconddose of varicella vaccine, there is a marked boost in bothhumoral and cellular immunity, and the second dose istolerated very well without significant complications.One small study indicated improved protection after twodoses compared with one dose over 10 years of follow-up. (19)

Another important recent advance for varicella immu-nization was the development of the combined measles-mumps-rubella-varicella (MMRV) vaccine, which wasapproved by the United States Food and Drug Admin-istration in 2005. MMRV contains about 10 times theamount of VZV as the monovalent formulation and is

Table. Information for ParentsWho Ask What to Do If TheirChild Is Exposed toChickenpox1. Some 80% of children who received one dose of

vaccine are completely protected from chickenpox.2. Only 3% to 4% of vaccinated children who received

one dose of vaccine develop full-blown chickenpox.3. Breakthrough chickenpox is just as contagious as

chickenpox in unvaccinated children unless the childhas fewer than 50 skin lesions (very mild infection).

4. All children should receive two doses of vaccine; thesecond dose can be administered as soon as 3months after the first and even after an exposureoccurs, in which case it might offer additionalprotection.

5. Rashes caused by the vaccine (Oka) strain (thatappear in weeks 2 through 6 after immunization)can be infectious to others, but transmission is veryrare (roughly 1/10 million vaccines), and contactcases uniformly are mild.




licensed only for children younger than 14 years of age.Currently, most infants and children will be immunizedwith two doses of MMRV after the shortage of thisvaccine is corrected. (20) Varicella vaccine also is rec-ommended for susceptible adults, especially for health-care workers and persons whose varicella-susceptiblefamily members are immunocompromised or pregnant.Varicella vaccine is recommended only for healthy per-sons. Zoster appears to be less of a problem after immu-nization than after natural infection. The CDC nowrecommends postexposure vaccination for healthyvaricella-susceptible exposed individuals.

Recently, a successful vaccine has been developed toprevent zoster in older adults; this vaccine is the Okastrain of VZV, given at a dose roughly 14 times greaterthan that in the monovalent formulation. One dose ofthis vaccine is recommended for healthy individuals olderthan age 60 years who have had varicella but not zoster.This vaccine is 50% to 60% protective against zoster andits major complication, PHN. (7)

SummaryAs a herpesvirus, VZV causes acute varicella, latent infec-tion, and zoster. The virus has the potential to causeserious infections, which may be difficult to treat. Com-plications include bacterial superinfections, CNS abnor-malities, and a host of more unusual problems such aspneumonia and hepatitis. Immunocompromised pa-tients, pregnant women and their infants, and the elderlyare at highest risk of developing severe and even fatalillnesses. In modern times, successful specific drug ther-apy has been developed. More recently, medical empha-sis has been on prevention of illness by vaccination. Dueto the three-pronged approaches of passive immuniza-tion, active immunization, and antiviral therapy, themorbidity and mortality from VZV infections have de-creased impressively in the past 20 years. With continueduse and “fine tuning” of these modalities, particularlyactive immunization, additional progress should bemade, resulting in the possibility of these infectionsbecoming unusual in the developed world.

References1. Chen JJ, Zhu Z, Gershon AA, Gershon MD. Mannose6-phosphate receptor dependence of varicella zoster virus infection

in vitro and in the epidermis during varicella and zoster. Cell.2004;119:915–9262. Hambleton S, Gershon AA. Preventing varicella-zoster disease.Clin Microbiol Rev. 2005;18:70–803. Seward JF, Zhang JX, Maupin TJ, Mascola L, Jumaan AO.Contagiousness of varicella in vaccinated cases: a household contactstudy. JAMA. 2004;292:704–7084. Ma H, Fontaine R. Varicella outbreak among primary schoolstudents–Beijing, China, 2004. MMWR Morbid Mortal Wkly Rep.2006;55(suppl 1):39–435. Paul N, Jacob ME. An outbreak of cadaver-acquired chickenpoxin a health care setting. Clin Infect Dis. 2006;43:599–6016. Gershon A, Takahashi M, Seward J. Varicella vaccine. In: Plot-kin S, Orenstein W, eds. Vaccines. 5th ed. Philadelphia, Pa: Saun-ders; 2008; in press7. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to preventherpes zoster and postherpetic neuralgia in older adults. N EnglJ Med. 2005;352:2271–22848. Gershon A. Chickenpox, Measles, and Mumps. 6th ed. Philadel-phia, Pa: Saunders; 20069. Gershon A, Chen J, LaRussa P, Steinberg S. Varicella-zostervirus. In: Murray PR, Baron E, Jorgensen J, Landry M, Pfaller M,eds. Manual of Clinical Microbiology. 9th ed. Washington, DC:ASM Press; 2007:1537–154810. Whitley RJ, Middlebrooks M, Gnann JW. Acyclovir: the pastten years. Adv Exp Med Biol. 1990;278:243–25311. Balfour HH, Rotbart H, Feldman S, et al. Acyclovir treatmentof varicella in otherwise healthy adolescents. J Pediatr. 1992;120:627–63312. Dunkel L, Arvin A, Whitley R, et al. A controlled trial of oralacyclovir for chickenpox in normal children. N Engl J Med. 1991;325:1539–154413. Centers for Disease Control. A new product (VariZIG) forpostexposure prophylaxis of varicella available under an investiga-tional new drug application expanded access protocol. MMWRMorbid Mortal Wkly Rep. 2006;55:209–21014. Centers for Disease Control. Prevention of varicella. MMWRMorbid Mortal Wkly Rep. 2007;56:1–4015. Takahashi M, Otsuka T, Okuno Y, Asano Y, Yazaki T, IsomuraS. Live vaccine used to prevent the spread of varicella in children inhospital. Lancet. 1974;2:1288–129016. Vazquez M, LaRussa P, Gershon A, Steinberg S, FreudigmanK, Shapiro E. The effectiveness of the varicella vaccine in clinicalpractice. N Engl J Med. 2001;344:955–96017. Vazquez M, LaRussa PS, Gershon AA, et al. Effectiveness overtime of varicella vaccine. JAMA. 2004;291:851–85518. Michalik D, La Russa P, Steinberg S, Wright P, Edwards KM,Gershon A. Primary immune failure after 1 dose of varicella vaccinemay be the main cause of breakthrough infections in healthy vacci-nated children. J Infect Dis. 2008; in press19. Kuter B, Matthews H, Shinefield H, et al. Ten year follow-upof healthy children who received one or two injections of varicellavaccine. Pediatr Infect Dis J. 2004;23:132–13720. Centers for Disease Control. Supply of vaccines containingvaricella-zoster virus. MMWR Morbid Mortal Wkly Rep. 2007;56:146–147




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

1. Infections of susceptible persons with the wild-type varicella-zoster virus (VZV) are transmitted primarilythrough:

A. Aerosols from skin lesions of infected individuals.B. Direct contact with a skin vesicle that has a damaged mucosal surface.C. Direct contact with a skin vesicle that has damaged skin.D. Respiratory droplets from individuals who have skin lesions.E. Respiratory droplets from subclinically infected individuals.

2. In a previously healthy 5-year-old child, the appearance of zoster most likely reflects a:

A. Life-threatening defect in cellular immunity.B. Life-threatening defect in humoral immunity.C. Primary VZV vaccine failure.D. Temporary phagocytic dysfunction.E. Transient defect in cellular immunity.

3. A previously healthy 10-year-old boy develops uncomplicated varicella. As part of his initial management,evidence-based practice supports the regular use of an appropriate dose of oral:

A. Acetaminophen.B. Acetylsalicylic acid.C. Acyclovir.D. Cephalexin.E. Ibuprofen.

4. An 11-month-old girl who has acute lymphoblastic leukemia in early remission was inadvertently exposedto varicella 1 day ago. To reduce the risk of life-threatening varicella, within 72 hours she should receive:

A. An increase in her dose of prednisone.B. Intravenous acyclovir.C. Oral acyclovir.D. Subcutaneous VZV vaccine (Oka strain).E. VariZIG™.

5. You are asked to speak with a group of medical students about varicella vaccine. Your most appropriatestatement is that after initial immunization:

A. Breakthrough varicella generally is severe.B. Neurologic complications remain a serious concern.C. Primary vaccine failure is relatively common.D. Transmission of attenuated virus is common.E. Zoster incidence is unchanged.





Anne A. Gershon Varicella-Zoster Virus Infections












Neutropenia in PediatricPracticeGeorge B. Segel, MD,* Jill

S. Halterman, MD, MPH†

Author Disclosure

Drs Segel and

Halterman did not

disclose any financial

relationships relevant

to this article.

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

1. Describe when a patient has true neutropenia, understanding the variation with ageand ethnic background.

2. Know the relative risk of infection at various values of the absolute neutrophil count.3. Discuss the differences between inherited and acquired causes of neutropenia.4. List the initial studies to evaluate patients who have neutropenia.

IntroductionThe significance of neutropenia is a common query to hematology specialists from primarycare physicians. Severe neutropenia is defined as an absolute neutrophil count (ANC) offewer than 500/mcL (0.5�109/L) and is a common and expected complication ofchemotherapy for childhood neoplasms. This article considers those patients who haveneutropenia unrelated to chemotherapy toxicity. This type of neutropenia may be notedwhen a complete blood count (CBC) is performed in a sick newborn, a febrile child, a childtaking chronic medication, or as part of a routine evaluation. Severe hereditary conditionssuch as Kostmann syndrome and certain immunodeficiency syndromes associated withneutropenia are rare, perhaps 1 per 100,000, and are more likely to present in neonates andinfants, although acquired conditions such as immune neutropenia and neutropeniarelated to infection also occur in this age group. A mild-to-moderate decrease in the ANC(percent neutrophils times the total white count) frequently is seen in viral illness or relatedto medication use as well as in some healthy persons of African ancestry. A number ofinherited conditions associated with neutropenia are associated with other congenitalanomalies such as dysplastic thumbs in Fanconi anemia, albinism in Chediak-Higashisyndrome, and dwarfism in the cartilage hair or Shwachman-Diamond syndromes.

When to Order a CBCA CBC is not ordered routinely for well children examined in the pediatrician’s office orwhen children present with common febrile illnesses such as upper respiratory tractinfections or otitis media. A CBC is warranted if clinical findings suggest a more severebacterial infection. Such clinical findings include, but are not limited to, recurrentinfections; prolonged or extreme fever (�103°F [39.5°C]); the spreading of localizedbacterial infection; infection of the lung, peritoneum, genitourinary tract, or centralnervous system; and suspicion of chronic inflammatory disease, immunodeficiency, ormalignancy. A CBC also may be warranted if a patient’s clinical course is atypical,prolonged, or complicated by signs and symptoms suggesting the development of asecondary bacterial infection.

Normal Values for the ANC and the Definition of NeutropeniaNormal values for the ANC vary by age, particularly during the first weeks after birth.Normal leukocyte counts and ANCs for children from birth to age 21 years are shown inTable 1. The ANC range is shown for each age, as well. The lower limit of normal is6,000/mcL (6.0�109/L) during the first 24 hours after birth, 5,000/mcL (5.0�109/L)for the first week, 1,500/mcL (1.5�109/L) during the second week, 1,000/mcL

*Professor, Department of Pediatrics, Division of Hematology Oncology.†Associate Professor of Pediatrics, Division of General Pediatrics, University of Rochester School of Medicine & Dentistry,Rochester, NY.

Article hematology/oncology

12 Pediatrics in Review Vol.29 No.1 January 2008

(1.0�109/L) between 2 weeks and 1 year of age, 1,500/mcL (1.5�109/L) from ages 1 year through 10 years,and 1,800/mcL (1.8�109/L) thereafter. However,most reports use 1,500/mcL (1.5�109/L) as the lowerlimit of normal for white adults. Adults and children ofAfrican extraction may have ANCs between 1,000 and1,500/mcL (1.0 and 1.5�109/L), which overlaps thevalues observed in patients who have “mild neutrope-nia.” We estimate from the data available that at least 3%to 5% of persons of African ancestry have ANCs below1,500/mcL (1/5�109/L).

Risk AssessmentFor patients older than 1 year of age, mild neutropenia isdefined as an ANC of 1,000 to 1,500/mcL (1.0 to1.5�109/L), moderate neutropenia as an ANC of500 to 1,000/mcL (0.5 to 1.0�109/L), and severeneutropenia as an ANC of less than 500/mcL(0.5�109/L). Usually, patients are highly susceptible tobacterial infection if the ANC is less than 500/mcL(0.5�109/L), with the risk of infection greatest at thelowest ANCs. Increased infection risk also is related tolonger durations of neutropenia and is highest if theneutrophil count remains low without recovery. If neu-trophils can be mobilized to respond, infection is lesslikely to occur, as can be seen in immune neutropenia, acondition in which there is myeloid hyperplasia andheightened neutrophil production. Although serious

bacterial infections are observed when the ANC is be-tween 500 and 1,000/mcL (0.5 and 1.0�109/L), theyare much less frequent or severe. There is little or noheightened infectious risk if the ANC is greater than1,000/mcL (1.0�109/L).

Pyogenic Infections Associated WithNeutropeniaModerate-to-severe neutropenia may portend an inade-quate neutrophil response to bacterial infection. Theclinical signs of neutropenia may include ulcerations ofthe oral mucosa or gingival inflammation. Otitis media,skin infections that include cellulitis and pustules, adeni-tis, pneumonia, and bacterial sepsis may occur. Thesource of the infection may be the child’s own skin orbowel flora. Perianal infection and ischiorectal fossa ab-scesses sometimes are seen. The most common offendingorganisms are Staphylococcus aureus and the gram-negative bacteria (see section on fever and neutropenia).

Initial Evaluation of the Patient Who HasNeutropeniaThe initial evaluation (Table 2) should include a historyand physical examination. It is critical to know whetherthe child has had recurrent bacterial infections, whetherthere is a family history of neutropenia or infection, andafter physical examination, whether there are any associ-ated congenital anomalies that suggest an inherited syn-

Table 1. Normal Blood Leukocyte Counts*

Age

Total Leukocytes Neutrophils Lymphocytes Monocytes Eosinophils

Mean (Range) Mean (Range) % Mean (Range) % Mean % Mean %

Birth 18.1 (9.0 to 30.0) 11.0 (6.0 to 26.0) 61 5.5 (2.0 to 11.0) 31 1.1 6 0.4 212 h 22.8 (13.0 to 38.0) 15.5 (6.0 to 28.0) 68 5.5 (2.0 to 11.0) 24 1.2 5 0.5 224 h 18.9 (9.4 to 34.0) 11.5 (5.0 to 21.0) 61 5.8 (2.0 to 11.5) 31 1.1 6 0.5 21 wk 12.2 (5.0 to 21.0) 5.5 (1.5 to 10.0) 45 5.0 (2.0 to 17.0) 41 1.1 9 0.5 42 wk 11.4 (5.0 to 20.0) 4.5 (1.0 to 9.5) 40 5.5 (2.0 to 17.0) 48 1.0 9 0.4 31 mo 10.8 (5.0 to 19.5) 3.8 (1.0 to 9.0) 35 6.0 (2.5 to 16.5) 56 0.7 7 0.3 36 mo 11.9 (6.0 to 17.5) 3.8 (1.0 to 8.5) 32 7.3 (4.0 to 13.5) 61 0.6 5 0.3 31 y 11.4 (6.0 to 17.5) 3.5 (1.5 to 8.5) 31 7.0 (4.0 to 10.5) 61 0.6 5 0.3 32 y 10.6 (6.0 to 17.0) 3.5 (1.5 to 8.5) 33 6.3 (3.0 to 9.5) 59 0.5 5 0.3 34 y 9.1 (5.5 to 15.5) 3.8 (1.5 to 8.5) 42 4.5 (2.0 to 8.0) 50 0.5 5 0.3 36 y 8.5 (5.0 to 14.5) 4.3 (1.5 to 8.0) 51 3.5 (1.5 to 7.0) 42 0.4 5 0.2 38 y 8.3 (4.5 to 13.5) 4.4 (1.5 to 8.0) 53 3.3 (1.5 to 6.8) 39 0.4 4 0.2 210 y 8.1 (4.5 to 13.5) 4.4 (1.8 to 8.0) 54 3.1 (1.5 to 6.5) 38 0.4 4 0.2 216 y 7.8 (4.5 to 13.0) 4.4 (1.8 to 8.0) 57 2.8 (1.2 to 5.2) 35 0.4 5 0.2 321 y 7.4 (4.5 to 11.0) 4.4 (1.8 to 7.7) 59 2.5 (1.0 to 4.8) 34 0.3 4 0.2 3

*Numbers of leukocytes are in thousands/mcL (�109/L), ranges are estimates of 95% confidence limits, and percentages refer to differential counts.Neutrophils include band cells at all ages and a small number of metamyelocytes and myelocytes in the first few postnatal days.From Dallman PR. Blood and blood-forming tissues. In: Rudolph AM, ed. Rudolph’s Pediatrics. 16th ed. New York, NY: Appleton-Century-Crofts;1977:1178, with permission.

hematology/oncology neutropenia

Pediatrics in Review Vol.29 No.1 January 2008 13

drome. Mouth ulcers may occur in association withneutropenia, and the presence of gingivitis is a goodindicator that the patient cannot mobilize adequate neu-trophils and, thus, may be susceptible to severe infection.If neutropenia is suspected, it is important to determine ifthe patient has isolated neutropenia or neutropenia asso-ciated with anemia or thrombocytopenia. The clinicalimplication of deficits of more than one cell type isdifferent from that of an isolated neutropenia. Anemia orthrombocytopenia in conjunction with neutropenia of-ten reflects a more generalized marrow failure syndromesuch as aplastic anemia or a marrow infiltrative processsuch as leukemia. The neutropenia must be confirmed byrepeating the CBC to avoid an extensive evaluation dueto a laboratory error.

It is reasonable to observe the patient who has a viralillness and mild-to-moderate neutropenia and otherwise

appears well. If the neutropenia persists or progressesafter 1 to 2 weeks, additional evaluation is necessary. Ifthe neutropenia is recurrent, obtaining blood counts twoto three times per week for several weeks can establishany cycles of neutropenia. If additional evaluation iswarranted, the presence of antineutrophil antibodiessuggests immune neutropenia, and quantifying immu-noglobulins, including IgG, IgA, and IgM, and thedistribution of lymphocyte subsets may indicate an un-derlying immunodeficiency syndrome. In addition,screening tests for systemic lupus erythematosus, includ-ing an antinuclear antibody titer and anti-double-stranded DNA, can be helpful. If a patient has severeneutropenia, referral to a hematologist is necessary. Ifsevere congenital neutropenia is suspected, assessing forthe HAX1 mutation for Kostmann disease and ELA2mutation for dominant or sporadic severe congenitalneutropenia is indicated. A detailed presentation of thepotential laboratory evaluation by hematology is shownin Table 3.

Acquired NeutropeniaInfection

When evaluating the child who has neutropenia, theacquired neutropenias are considered first because oftheir greater frequency (Table 4). The most commonunderlying cause for mild-to-moderate neutropenia istransient marrow suppression due to a variety of viralinfections. Neutropenia is seen in patients who haveEpstein-Barr virus, respiratory syncytial virus, influenza Aand B, hepatitis, and human herpesvirus 6 infectionsas well as the exanthems (to which most children areimmunized), including varicella, rubella, and rubeola.Neutropenia occurs often during the first few days of theviral illness and persists for 3 to 8 days. Severe bacterialinfection also may cause neutropenia rather than neutro-philia, which can be transient if the bacterial infection istreated effectively. Other bacterial or rickettsial diseasessuch as typhoid fever, tuberculosis, and Rocky Mountainspotted fever may cause neutropenia.

Drug-inducedA variety of medications (Table 5), including antibiotics,anticonvulsants, and anti-inflammatory agents, havebeen associated with neutropenia, a frequent reason forreferral to hematology. The dilemma is how to treat thepatient who requires the particular medication that iscausing a potentially dangerous adverse effect. If thedrug-induced neutropenia is idiosyncratic, its severityand persistence may be impossible to predict, and it isdifficult to avoid discontinuing the drug. A similar situ-

Table 2. Initial Evaluation forPatients Who HaveNeutropeniaHistory

● History of underlying disease, congenital anomalies,medication exposure, or recent infection or mouthulceration

● Other family members who have neutropenia andserious infections, hospitalizations, or blood diseases

Physical Examination

● Short stature, malnutrition, skeletal abnormalities● Abnormal skin pigmentation, dystrophic nails,

leukoplakia, warts, albinism, fine hair, eczema, skininfections, adenopathy, and organomegaly

CBC With Differential Count and ReticulocytePercentage

● Confirm the finding of neutropenia, evaluateneutrophil morphology, and assess whether red cellproduction is increased or decreased

● If the neutropenia resolves and is recurrent, repeattwo to three times per week for 6 weeks

Other Laboratory Tests

● Blood smear● Coombs test (direct antiglobulin test) for associated

hemolytic anemia● Immunoglobulins (IgA, IgG, IgM)● Serology (Epstein-Barr virus, cytomegalovirus,

respiratory syncytial virus, parvovirus, etc, asindicated clinically)

● Antineutrophil antibodies



ation exists for drug-induced immune neutropenia. If thedrug acts as a hapten, leading to production of an anti-body, the ANC should improve within 1 to 2 weeks aftercessation of drug administration. On the other hand, ifthe neutropenia is mild, it may be dose-related, and drugadministration could be titrated to permit continued use.

ImmuneNeonatal alloimmune neutropenia results from the trans-fer of fetal cells to the maternal circulation, causing themother to produce antibody to fetal antigens not presenton her own cells in a manner similar to Rh disease.A variety of neutrophil-specific antigens have been iden-tified and are designated HNA-1a (NA1), HNA-1b(NA2), HNA-2a (NB1), HNA-3a (5b), HNA-4a(MART), and HNA-5a (OND). Because the half-life ofIgG is approximately 5 to 6 weeks, alloimmune neutro-penia usually disappears after age 2 to 3 months. Ifinfections are associated with the neutropenia, granulo-cyte colony-stimulating factor (G-CSF) may be used tostimulate a heightened neutrophil count.

Passive transfer of maternal antibody also may causeneonatal neutropenia. Pregnant women who have eitherprimary immune neutropenia or immune neutropeniadue to a disease such as lupus may transfer IgG antineu-

trophil antibodies passively to the developing fetus. Thistype of neonatal neutropenia also is transient.

Primary autoimmune neutropenia of infancy andchildhood may be the cause of chronic neutropenia. Thediagnosis may be established in most patients with thedemonstration of antineutrophil antibodies by leukoag-glutination or immunofluorescence. These antibodiesmay develop as a result of “molecular mimicry,” whereinan epitope on the surface of an infecting virus stimulatesproduction of an antibody that then cross-reacts with asimilar antigen on the surface of the neutrophil, leadingto neutrophil destruction. Such antibodies often are di-rected against NA1. Marrow examination reveals my-eloid hyperplasia but with few mature neutrophils (pic-tures of normal bone marrow and marrow in immuneneutropenia are available in the online edition of thisissue of Pediatrics in Review [www.pedsinreview.org]).The neutropenia may be profound, and the child maydevelop ear, pulmonary, skin, or other infections. Suchinfections are treated primarily with antibiotics. How-ever, glucocorticoids such as prednisone may suppressthe immune destruction of neutrophils, and more re-cently, G-CSF has been used to heighten neutrophilproduction to overcome the antibody-induced destruc-tion. The initial dose of prednisone usually is 2 mg/kg

Table 3. Detailed Laboratory Evaluation of NeutropeniaTest Findings

CBC and Differential Count ANC less than lower limit for age (Table 1) � anemia and thrombocytopeniaReticulocyte % (Index) Increased if RBC destruction, as in Evans syndrome (or bleeding)

Decreased in marrow failure syndromesBlood Smear Confirms decreased ANC

Morphologic abnormalities of neutrophils, as in Chediak-Higashi syndromeAssociated RBC or platelet findings

Coombs Test (Direct Antiglobulin Test) Detects antibodies to RBC, as in Evans syndrome or systemic lupuserythematosus

ANA Anti-double-stranded DNA Screen for systemic lupus erythematosusAntineutrophil Antibody May be found in alloimmune or autoimmune neutropeniaIgG, IgA, IgM Screen for underlying immunodeficiency

IgG and IgA may be decreased and IgM elevatedLymphocyte Subtypes Decreased T, B, or NK cells in underlying immunodeficiencyMarrow Examination May show no maturation beyond the promyelocyte stage in severe

congenital neutropenia; myeloid hyperplasia with few or no bands ormature neutrophils in immune neutropenia

Cytogenetics may reveal a neoplastic clone, as in leukemiaDNA Analysis (HAX1, ELA2, Gfil)

(FANC, DKC, RPS19)Specific for genetic diagnosis—see Table 6 for specific genes

Serum Trypsinogen, Other Stool Fat Low serum trypsinogen and elevated stool fat found in Shwachman-Diamond syndrome

Nutritional Serum vitamin B12, RBC, and serum folic acid

ANA�antinuclear antibody, ANC�absolute neutrophil count, CBC�complete blood count, RBC�red blood cell.



per day administered orally in two divided doses, and theinitial dose of G-CSF is 5 mcg/kg administered subcu-taneously once a day. These therapies usually are admin-istered under the guidance of a pediatric hematologist.

Secondary autoimmune neutropenia more often af-fects adults and is seen in systemic autoimmune diseases,such as systemic lupus erythematosus, rheumatoid arthri-tis (Felty syndrome), or systemic sclerosis; in certaininfections, such as those due to human immunodefi-ciency virus, parvovirus B19, or Helicobacter pylori; or indrug-induced neutropenia. Secondary autoimmune neu-tropenia also has been reported in association with Wilmstumor and Hodgkin disease. Treatment of secondaryneutropenias is directed toward the primary disease. Ad-ministration of G-CSF may be considered if the neutro-penia is severe and protracted.

Chronic IdiopathicChronic idiopathic neutropenia likely represents a varietyof disorders and is not well characterized. Some of thepatients classified as having chronic idiopathic neutrope-nia actually may have immune neutropenia or familialbenign neutropenia. The “idiopathic” diagnosis may beconsidered when other known causes have been elimi-nated. The clinical severity appears to be related to the

severity of neutropenia, and the marrow findings are notconsistent. Ineffective or decreased production of neu-trophils may be seen in this condition. Many hematolo-gists watch patients whose conditions appear truly “idio-pathic” and whose neutropenia is mild and not associatedwith an increase in infections, keeping the evaluation to aminimum rather than pursuing a more extensive evalua-tion that often yields nothing. When therapy is indicated,glucocorticoids and G-CSF have been used.

SequestrationSplenomegaly and hypersplenism from any cause mayresult in mild neutropenia (1,000 to 1,500/mcL [1.0 to1.5�109/L]) due to sequestration. Enlarged spleensmay be present in patients who have chronic hemolyticanemias, liver disease, or portal hypertension and inmetabolic disorders such as Gaucher disease. These con-ditions also may result in anemia and thrombocytopenia.Results of the marrow examination are normal or showmild hyperplasia of all elements. Usually, this problemdoes not require treatment unless the cytopenias areprofound or management of the underlying conditionrequires treatment. In some cases, splenectomy is neces-sary.

Table 4. Acquired NeutropeniaCondition Pathogenesis Occurrence Associated Findings

Infection Viral marrow suppression orviral-induced immuneneutropenia

Common EBV/parvovirus/HHV6 and other viruses

Bacterial sepsis-endotoxinsuppression

Less common Severe infection

Drug-induced Direct marrow suppression Common Underlying conditionImmune destruction Less common

Autoimmune Primary (molecularmimicry)

Secondary (SLE, Evanssyndrome)

Common Monocytosis common

Newborn Immune Alloimmune—maternalsensitization

Rare Antigen difference in newborn andmother

Due to maternalautoimmune neutropenia

Maternal neutropenia

Chronic Idiopathic Ineffective or decreasedproduction

Common Consider also familial benignneutropenia

Often asymptomaticSequestration Hypersplenism Common if spleen is enlarged Mild neutropenia

Enlarged spleen—many causesNutritional Vitamin B12 or folic acid

deficiencyRare in children Marrow megaloblastic

Impaired DNA processing Hypersegmented neutrophils

EBV�Epstein-Barr virus, HHV�human herpesvirus, SLE�systemic lupus erythematosus.



Nutritional DeficiencyBoth vitamin B12 and folic acid deficiency may result inineffective hematopoiesis with megaloblastic erythropoi-esis. Patients who develop megaloblastic anemia gener-ally are adults. In addition to megaloblastic anemia, theimpairment in DNA processing may result in neutrope-nia. Neutrophil nuclear maturation is impaired, leadingto hypersegmentation of the neutrophil nuclei in theblood as well as ineffective marrow proliferation andmaturation. Treatment involves replacement of the defi-cient factor.

Inherited Neutropenia (Table 6)Severe Congenital

Severe congenital neutropenia may present as early asinfancy with umbilical infection, pyoderma, oral ulcers,pulmonary infections, or perineal infections of the labiaor perirectal area. The ANC is less than 500/mcL(0.5�109/L) and often less than 200/mcL (0.2�109/L). Severe congenital neutropenia may be inherited as an

autosomal recessive condition (Kostmann syndrome) in-volving mutations in the HAX1 gene that is involved insignal transduction. It also may be inherited as an auto-somal dominant condition, with mutations in the neu-trophil elastase gene (ELA2) or, more rarely, in the GFI1gene that targets ELA2. It has been suggested that suchgene mutations result in accelerated apoptosis of myeloidprecursors. Examination of the marrow reveals an arrestat the promyelocyte stage of development (a picture ofbone marrow in severe congenital neutropenia is avail-able in the online edition of this issue of Pediatrics inReview [www.pedsinreview.org]). Few or no myelo-cytes, metamyelocytes, bands, or mature neutrophils areseen, and there may be an associated monocytosis andeosinophilia in the blood. Affected patients have a veryhigh risk of developing a myelodysplastic syndrome oracute myelogenous leukemia, a consequence that hasbecome more evident as patients live longer with treat-ment using G-CSF. Table 7 describes G-CSF administra-tion.

Table 5. Partial List of Drugs Associated With Idiosyncratic NeutropeniaPossible Mechanism

DrugDirectSuppression

MetaboliteSuppression

ImmuneDestruction

Analgesics/Anti-inflammatory AgentsAminopyrine XIbuprofen XIndomethacin XPhenylbutazone X

AntibioticsChloramphenicol XPenicillins X XSulfonamides X

AnticonvulsantsPhenytoin XCarbamazepine X

Antithyroid AgentsPropylthiouracil X

Cardiovascular AgentsHydralazine XProcainamide XQuinidine X

Hypoglycemic AgentsChlorpropamide X

TranquilizersChlorpromazine XPhenothiazines X

OtherCimetidine, ranitidine XLevamisole X

Reproduced from Dinauer MC. The phagocyte system and disorders of granulopoiesis and granulocyte function. In: Nathan DG, Orkin SH, Look AT,Ginsburg D, eds Nathan and Oski’s Hematology of Infancy and Childhood. 6th ed. Philadelphia, Pa: WB Saunders Company; 2003:923–1010 with permission.



Table 6. Inherited NeutropeniaCondition Inheritance Pathogenesis Occurrence Associated Findings

Severe Congenital(Kostmann)

AR HAX1 mutationscausing disturbedregulation of myeloidhomeostasis

Marrow arrest at thepromyelocyte stage

Rare (1/1 to 200,000) ANC <500/mcL (0.5�109/L)Leukemia risk of 15% to 20%

Severe Congenital AD andsporadic

ELA2 mutations on theface of the moleculeopposite the activesite causingaccelerated apoptosis

GFI1 mutations targetELA2

Rare (1/1 to 200,000)

Two families

ANC <500/mcL (0.5�109/L)Leukemia risk of 5% to10%

2 T and B cellsMarrow has immature myeloid

cellsCyclic AD ELA2 mutations

clustering near theactive site of themolecule

0.5 to 1/106 21-day cycle with fever andmouth ulcers

Shwachman-DiamondSyndrome

AR SDS gene conversionfrom the pseudogene,resulting in failure ofneutrophil production

Defect in RNAprocessing

Decreased CD34 cells

1/50,000 Pancreatic exocrineinsufficiency, short stature,metaphyseal dysplasia,marrow failure, and leukemiarisk (15%)

Familial Benign AD Decreased marrowrelease

Common Africans and Yemenite JewsPeriodontal disease

Marrow Failure Syndromes:Fanconi AR Gene (FANC) defects in

DNA repair1/106 Dysplastic thumbs,

pancytopenia, otheranomalies

Dyskeratosis Congenita Usually XR(also AR andAD)

DKC1 (TERC or TERT inAD) mutations

Telomerase defect,ribosomal dysfunction

Abnormal skin pigmentation,leukoplakia, dystrophic nails

Blackfan DiamondSyndrome

Sporadic 75%AR and AD

RPS19 mutations thataffect a ribosomalprotein in 25% offamilies

? Mechanism oferythropoietic failure

Many patients respondto glucocorticoids

Erythroid failure syndromeNeutropenia in 25% to 40%Thumb and craniofacial

anomaliesIncreased RBC adenosine

deaminaseLeukemia risk of 2% to 3%

Dysgammaglobulinemia orHyper-IgM

XR (also AR) CD40 ligand mutations? Immune neutropenia,

but antineutrophilantibody is negative

2IgG, 2IgA, 1IgMMay have immune

thrombocytopenia andanemia

Neutropenia only seen in XRWHIM Syndrome and

MyelokathexisAD (also ?AR) Imbalance in pro- and

anti-apoptosisDefect in CXCR4

receptor leading tofailure of neutrophilsto leave the marrow

Case reports Warts, hypogammaglobulinemia,infections, and myelokathexis(WHIM)



CyclicCyclic neutropenia is characterized by approximately21-day cycles of changing neutrophil counts, with neu-tropenia spanning 3 to 6 days. The nadir of the neutro-phil count may be in the severe range. Fever and oralulcerations usually are seen during the nadir. Patientsalso may develop gingivitis, pharyngitis, and skin infec-tions. However, by the time the patient comes to medicalattention, the neutrophil count may be recovering.Therefore, diagnosing cyclic neutropenia may requireobtaining blood counts two to three times per week for4 to 6 weeks in an effort to observe the periodicity of thecycle.

More serious infections include pneumonia, necrotiz-ing enterocolitis with peritonitis, and Escherichia coli orClostridium sepsis. Marrow findings reflect the state ofneutropenia. Prior to the ANC nadir, the marrow mayresemble that associated with severe congenital neutro-penia before proceeding to a recovery phase. The peri-odicity of marrow activity also may be seen in the ery-throid series. As in severe congenital neutropenia,mutations occur in the ELA2 gene, but at differentlocations (Table 6). Also, there does not appear to be anincreased risk of myelodysplasia or acute myelogenousleukemia. Prophylactic G-CSF has been recommendedto prevent severe symptoms at the nadir of the cycle.

Table 6. Inherited Neutropenia Continued

Condition Inheritance Pathogenesis Occurrence Associated Findings

Chediak-Higashi Syndrome AR CHS1 ?defect inlysosomal fission

Abnormal proteintrafficking

Decreased neutrophilchemotaxis,degranulation,and killing

Rare 2NK and T-cell functionAlbinismNeurologic damage and giant

lysosomes

Reticular Dysgenesis AR Stem cell failure inlymphoid andmyeloid development

Rare Severe combinedimmunodeficiency withneutropenia

Cartilage Hair AR RMRP mutationsDefect in a ribonuclear

protein ribonuclease

Rare Fine hair, short-limbed,dwarfism, lymphopenia,2CD4 and 2CD8 cells

Infections, particularly varicellazoster

Metabolic GlycogenStorage Disease 1b

(also aminoacidopathies)

AR G6PT1 mutations(glucose-6-phosphatetranslocase) in 1b

1/105 live births Hypoglycemia, dyslipidemia,1uric acid,1lactic acid, andneutropenia in most patients

Griscelli Syndrome Type 2 AR RAB27A mutationsImpaired lytic granule

release

Rare Partial albinism, neutropenia,infections, andthrombocytopenia withhemophagocytosis and T-celldefect

Barth Syndrome XR TAZ mutation on the Xchromosome

Cardiolipin defect

Rare Dilated cardiomyopathySkeletal myopathyMitochondrial abnormalities

Wiscott-Aldrich Syndrome XR Mutations in the Cdc42binding site in theWASP gene

Results in X-linkedneutropenia

1 to 10/106 Impaired lymphoid developmentand maturation of monocytes

Associated with eczema,thrombocytopenia, andimmune deficiency

Selective IgA Deficiency Unknown ormultifactorial

Unknown Common (1/600) Infections of the upper andlower respiratory tracts inone third of patients

AR�autosomal recessive, AD�autosomal dominant, ANC�absolute neutrophil count, Ig�immunoglobulin, NK�natural killer, RBC�red blood cell,XR�X-linked recessive.



Shwachman-Diamond SyndromePatients who have Shwachman-Diamond syndrome usu-ally have a mild-to-moderate degree of neutropenia inassociation with exocrine pancreatic insufficiency, shortstature, metaphyseal dysplasia, marrow failure, and therisk of myelodysplasia and acute myelogenous leukemia.A defect in RNA processing leads to a failure of neutro-phil development. Malabsorption and failure to thriveare common problems, and affected patients may de-velop infections because of the neutropenia and a possi-ble defect in chemotaxis. G-CSF has been used when theneutropenia is symptomatic; pancreatic replacementtherapy is required.

Marrow Failure SyndromesFANCONI ANEMIA. Fanconi anemia is characterized

by pancytopenia (with all cell lines affected). It presentsmost commonly in the second half of the first decade oflife, and thrombocytopenia may precede the develop-ment of anemia and neutropenia. The marrow is hypo-plastic and resembles aplastic anemia. The disease ischaracterized by a defect in DNA repair leading to exten-sive chromosomal breakage, and there is hypersensitivityto DNA cross-linking agents such as diepoxybutane invitro. Affected patients have mutations in the FANCgenes, primarily in FANC A, C, and G. Clinically, pa-tients may have short stature; dysplastic thumbs; or heart,kidney, or eye abnormalities. They have a nearly 10% riskof developing a myelodysplastic syndrome or acute my-elogenous leukemia. The pancytopenia may respond toandrogen treatment, which is particularly difficult to usein young women. G-CSF and other cytokines may beeffective, but their efficacy may not be sustained. Theonly curative treatment for Fanconi anemia is stem celltransplantation.

DYSKERATOSIS CONGENITA (ZINSSER-ENGMAN-COLESYNDROME). This abnormality results from a mutationin the DKC1 gene that encodes dyskerin, a componentof the telomerase complex, which is responsible for theelongation of DNA. Affected patients exhibit abnormalskin pigmentation, leukoplakia, and dystrophic nails. Theskin and mucosal lesions appear in the second decade,and marrow failure develops in early adulthood. Patientsmay present with isolated neutropenia, but more often,all cell lines are affected. Hematopoietic growth factors,such as G-CSF, may be useful in treating the neutrope-nia. Abnormalities of T-helper cells and dysgamma-globulinemia may contribute to a susceptibility to infec-tion in some patients.

Syndromes Associated With Neutropenia andImmunodeficiency

A variety of syndromes include neutropenia and abnor-malities in T, B, or natural killer cell function. Thecombined problem of neutropenia and immunodefi-ciency makes patients who have these syndromes moresusceptible to infectious complications. One condition isthe hyper-IgM syndrome, in which concentrations ofIgG and IgA are diminished and IgM is heightened. Thenature of the neutropenia is not known, but may beimmune in origin, although antineutrophil antibodiesare negative. Other syndromes associated with neutrope-nia and immunodeficiency are listed in Table 6; theirassociated findings are particularly important for definingthese rare syndromes.

Fever and NeutropeniaA very difficult issue is how best to treat a patient who hasfever and neutropenia. Although detailed guidelines have

Table 7. Treatment of NeutropeniaGranulocyte Colony-stimulating Initially 5 mcg/kg per day subcutaneously

Factor If no response after 1 wk, the dose may be doubled repeatedly up to 100 mcg/kg per dayGlucocorticoids Prednisone 2 mg/kg per day PO for immune neutropeniaNutritional Vitamin B12 1,000 mcg each week for 5 to 6 wk, then q 1 mo subcutaneously if B12-

deficientFolic acid 1 mg/d PO

Splenectomy Prior immunization to encapsulated bacterial (pneumococcus, Haemophilus influenzaetype b, meningococcus) required

Prophylactic penicillin after splenectomy 125 mg bid <age 5 y; 250 mg bid >age 5 yMedication Revision If possible, reduce dosage or discontinue any medications associated with neutropeniaAntibiotics As appropriate for patient’s age, type and location of infection, and if possible, culture

resultsGranulocyte Transfusion May be useful in invasive bacterial or fungal infections for patients who have severe

neutropenia (ANC <500/mcL [0.5�109/L]) who are not responding to antibiotics



been formulated for patients who have chemotherapy-induced neutropenia, relatively few data are available forpatients who have neutropenia not associated with can-cer treatment. Fever is defined as a temperature greaterthan 101°F (38.3°C) or a temperature of at least 100.4°F(38°C) for longer than 1 hour. Most authors categorizethe severity of neutropenia into three groups (Table 8).The decision surrounding treatment and potential hos-pitalization depends on the likelihood of bacterial infec-tion, the location and severity of the infection, the sever-ity of the neutropenia, and the likelihood and timeframeof neutrophil recovery. Furthermore, the age of thepatient, the proximity of specialized medical care, andthe reliability of the guardians should be considered inthe management decision. Table 8 presents a startingpoint for consideration of “what to do” and is based onthe principles used in the care of neutropenic chemother-

apy patients and the concerns of pediatric hematologistsand infectious disease specialists.

Specific recommendations for initial broad-spectrumantibiotic coverage depend on the prevalence of organ-isms in each community and hospital and their suscepti-bility patterns. Approximately two thirds of isolated or-ganisms are gram-positive (Table 9). Initial antibiotictreatment may employ a single broad-spectrum antibi-otic such as ceftazidime or cefepime. Alternatively, anaminoglycoside can be combined with a beta-lactamdrug such as a third- or fourth-generation cephalosporinfor broad antibiotic coverage. The initial addition ofvancomycin is controversial, but should be done if resis-tant organisms are suspected because of their prevalencein the community.

When to discontinue antibiotic treatment is a partic-ular problem for physicians caring for patients who have

Table 8. Fever and NeutropeniaANC Etiology of Fever Management Outpatient/Hospital

1,000 to 1,500/mcL Viral (frequent) Supportive Outpatient

(1.0 to 1.5�109/L)Mild

Bacterial: URI(sinusitis, purulentrhinitis), otitismedia, local skininfections

Indicated PO antibiotics Outpatient

Bacterial pneumonia,systemicsymptoms, GUinfections,lymphadenitis

Blood culturesSpecific culturesBest estimate

antibioticsObservation for

progression

Outpatient unlessprogression

500 to 1,000/mcL Viral Supportive Outpatient

(0.5 to 1.0�109/L)Moderate

Bacterial: URI(sinusitis, purulentrhinitis), otitismedia, local skininfections

Blood and othercultures

Indicated PO or IVantibiotics

Outpatient/Hospital*

Bacterial pneumonia,systemicsymptoms, GUinfections,lymphadenitis

Blood culturesSpecific culturesSepsis evaluationParenteral broad-

spectrum antibiotics

Hospital

<500/mcL(0.5�109/L)Severe

Assume bacterial Blood culturesSpecific culturesSepsis evaluationParenteral broad-

spectrum antibiotics

Hospital

ANC�absolute neutrophil count, GU�genitourinary, IV�intravenous, PO�oral, URI�upper respiratory tract infection.*Either outpatient or hospital care may be appropriate for children who have moderate neutropenia and local infection, depending on the patient’s underlyingdisorder and the anticipated time for recovery of the ANC. Children who have congenital/chronic neutropenia likely would benefit from treatment in thehospital because recovery of the ANC is less likely without cytokine treatment. In contrast, neutropenia due to viral suppression, antibody effect, or somemedication exposures may allow a better response to localized bacterial infection and be managed on an outpatient basis.



neutropenia. If the blood cultures are negative and thechild becomes afebrile, antibiotics can be stopped, even ifthe neutropenia persists. Usually, antibiotics are contin-ued if the cultures are negative and the child remainsfebrile and neutropenic. Fever generally resolves quicklywith antibiotic therapy if the neutropenia resolves. If thecultures are positive and the child is no longer febrile andneutropenic, the prescribed antibiotic treatment may becompleted with oral antibiotics at home. If the culturesare positive and the child is afebrile but persistentlyneutropenic, the course of antibiotics usually is com-pleted in the hospital. The child then is observed for24 to 48 hours prior to discharge. The persistence ofneutropenia requires the additional evaluation describedin this article and consideration of treatment with G-CSF

if the neutropenia is profound and there are frequentinfections.

The Medical Emergency of Fever With SevereNeutropeniaHospitalization is required for patients who have severeneutropenia (specifically neutrophil counts less than500/mcL [0.5�109/L]), moderate neutropenia and se-vere infection, or any level of neutropenia combined withill appearance, as well as consultation with pediatrichematology and pediatric infectious disease services. Pa-tients who have immune neutropenia of infancy oftencan be treated as outpatients because they can mobilizeneutrophils transiently. The hematologist can help estab-lish the cause of the neutropenia, and the infectiousdisease specialist can help identify the type and suscepti-bility of the infecting bacteria in the specific community.If the patient is seen in the office, a blood culture (aerobicand anaerobic) and a urinalysis and urine culture (nocatheter should be used) can be obtained and the initialdose of antibiotics administered. If possible, an intrave-nous line should be kept open. The patient should betransported to the hospital by ambulance because septicshock may occur after administration of the first dose ofantibiotics.

On arrival at the emergency department, venous ac-cess should be ensured, and vital signs with oxygensaturation, a CBC with differential count and plateletcount, and a metabolic profile should be obtained. Norectal temperatures should be taken, rectal examinationsperformed, or rectal medications administered becauseof the risk of generating a perianal or perirectal infection.However, careful examination of the mouth, oral mu-cosa, lungs, abdomen, and perineal/perianal area is im-portant. A chest radiograph may be warranted if there arerespiratory signs or symptoms, but its usefulness may belimited because the lack of neutrophils may not producea visible infiltrate in patients who have severe neutro-penia.

Anticipatory Guidance for the Patient WhoHas NeutropeniaParents of patients who have neutropenia need to contacta health-care practitioner at the onset of any febrile illnessto assure prompt, appropriate care. The parents mustknow what is required for the evaluation (including thehistory and physical examination, blood counts andANC, blood and other cultures) and the initial treatment(usual antibiotic recommendation and route of adminis-tration for their child) because they may not be near amajor medical center, particularly when traveling. A per-

Table 9. Bacterial Causes ofFebrile Episodes inNeutropenic PatientsAerobic Bacteria (�90%)*Gram-positive Cocci (�45%)

StaphylococcusCoagulase-positive (S aureus)Coagulase-negative (S epidermidis and others)

StreptococcusS pneumoniaeS pyrogenesviridans group

Enterococcus faecalis/faeciumGram-positive bacilli (rare)

Corynebacterium spGram-negative Bacilli (�45%)

Escherichia coliKlebsiella spPseudomonas aeruginosa

Anaerobic Bacteria (4% to 5%) (Often Polymicrobial)

Gram-positive Cocci (normal mouth flora)PeptococciPeptostreptococci

Gram-negative BacilliBacteroides fragilisFusobacterium sp

*Percentages observed in patients receiving chemotherapy who wereimmunocompromised (Mathur P, Chaudry R, Kumar L, Kapil A,Dhawan B. A study of bacteremia in febrile neutropenic patients at atertiary-care hospital with special reference to anaerobes. Med Oncol.2002;19:267–272). Specific organisms were reported by Hughes WT,Armstrong D, Bodey GP, et al. 1997 guidelines for the use of antimi-crobial agents in neutropenic patients with unexplained fever. Infec-tious Diseases Society of America. Clin Infect Dis. 1997;25:551–573 and Merck & Co, Inc, Whitehouse Station, NJ, USA: 1995–2007(http://www.merck.com/mmpe/sec14/ch178/ch178j.html).



mission form may be necessary to allow carrying ofinjectable medications, such as G-CSF, syringes, andhypodermic needles on airplanes. Parents should carry acurrent written summary of the child’s condition andlaboratory values and the contact numbers of their pri-mary institution and physicians.

It is important to maintain good oral hygiene andappropriate preventive dental visits, particularly for pa-tients who have chronic neutropenia, to avoid chronicgingival or dental infection. Good skin care and promptcleansing of superficial cuts, abrasions, and bruises wherethe skin is broken help to prevent local infection. Allimmunizations can and should be given according tothe routine vaccination schedule, as long as the pa-tient’s neutropenia is not associated with an immunode-ficiency syndrome. Children who have impaired T- orB-lymphocyte function should not receive live orattenuated-live vaccines. Recommendations for the ad-ministration of specific vaccines can be found in theAmerican Academy of Pediatrics Red Book� and in the“Pink Book” produced by the Centers for Disease Con-trol and Prevention, “Epidemiology and Prevention ofVaccine-preventable Diseases.”

Child care and school attendance are reasonable formost children who have mild-to-moderate neutropenia,although contact with obviously ill children should beavoided. Children who have severe neutropenia or ahistory of serious infections with neutropenia requiregreater isolation to avoid exposure to infectious agents.Genetic counseling for the family of patients who haveinherited neutropenias is indicated, and siblings shouldbe tested for the disorder. Families of patients who haveneutropenia may experience significant stress due to feel-ing responsible for the disease if it is an inherited condi-tion or for exposing the child to infectious complications,caring for a child who has a chronic illness, and managingmultiple physician and hospital visits. Most pediatrichematology/oncology units have social workers, parentadvocates, and advanced-practice nurses who can pro-vide the types of support services required by patients andtheir parents.

SummaryNeutropenia unrelated to chemotherapy toxicity occursin a number of clinical settings. The most commonconditions associated with neutropenia are those that areacquired, including viral infection, neutropenia associ-ated with various medications, and immune neutropenia.Inherited neutropenias are rarer and often more pro-

found. These disorders include the dominant or sporadictypes of severe congenital neutropenia (often with mu-tations in the ELA2 gene), the recessive type or Kost-mann syndrome, and the marrow failure syndromes suchas Fanconi anemia. Cyclic neutropenia may be severe atthe nadir of the cycle. Of particular concern is the occur-rence of fever in conjunction with neutropenia. Thiscombination creates a medical emergency that must beaddressed with appropriate evaluation and prompt ad-ministration of antibiotics. The actual risk of severe in-fection and the likelihood of recovery depend not onlyon the level of the ANC, but on the duration of theneutropenia. If recovery from the neutropenia is notexpected, as in severe congenital types, G-CSF adminis-tration may be indicated.

To view an additional Suggested Reading list andfigures related to this article, visit www.pedsinreview.org and click on Neutropenia in Pediatric Practice.

Suggested ReadingAtallah E, Schiffer CA. Granulocyte transfusion. Curr Opin Hema-

tol. 2006;13:45–49Baehner RL. Drug-induced neutropenia and agranulocytosis. Up-

ToDate. 2007. Available at: www.uptodate.comBertuch AA, Strother D. Fever in children with non-chemotherapy-

induced neutropenia. UpToDate. 2007. Available at: www.up-todate.com

Bertuch AA, Strother D. Management of fever in children withnon-chemotherapy-induced neutropenia. UpToDate. 2007.Available at: www.uptodate.com

Beutler E, West C. Hematologic differences between African-American and whites: the roles of iron deficiency and alpha-thalassemia on hemoglobin levels and mean corpuscular vol-ume. Blood. 2005;106:740–745

Boxer LA. Neutrophil abnormalities. Pediatr Rev. 2003;24:52–62Boxer LA, Stein S, Buckley D, Bolyard AA, Dale DC. Strong

evidence for autosomal dominant inheritance of severe congen-ital neutropenia associated with ELA2 mutations. J Pediatr.2006;148:633–636

Hughes WT, Armstrong D, Bodey GP, et al. 1997 guidelines forthe use of antimicrobial agents in neutropenia patients withunexplained fever. Clin Infect Dis. 1997;25:551–573

Klein C, Grudzien M, Appaswamy G, et al. HAX1 deficiency causesautosomal recessive severe congenital neutropenia (Kostmanndisease). Nat Genet. 2007;39:86–92

Lehrnbecher T, Welte K. Haematopoietic growth factors in chil-dren with neutropenia. Br J Haematol. 2002;116:28–56

Palmblad JEW, von dem Borne AEG Jr. Idiopathic, immune,infectious and idiosyncratic neutropenias. Semin Hematol.2002;39:113–120

Skokowa J, Germeshausen M, Zeidler C, Welte K. Severe congen-ital neutropenia: inheritance and pathophysiology. Curr OpinHematol. 2007;14:22–28



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

6. A 6-year-old boy presents with a history of a temperature to 103°F (39.4°C) and ulcerations on his lipsand buccal mucosa 2 days ago. The child has some small, slightly ulcerated areas on his lips and isafebrile. His mother reports two similar episodes in the past 2 months. He has a white blood cell count of2.9�103/mcL (2.9�109/L), hemoglobin of 11.4 g/dL (114 g/L), and platelet count of 349�103/mcL(349�109/L). His differential count is 40% neutrophils, 49% lymphocytes, 9% monocytes, and 2%eosinophils. Of the following, the best laboratory test to evaluate this child is:

A. Antineutrophil antibodies.B. Blood counts two to three times a week for 4 to 6 weeks.C. Bone marrow aspiration.D. Herpes cultures.E. Repeat of the count in 1 week to see if it normalizes.

7. A previously well 3-year-old boy presents with 4 days of temperature up to 104°F (40°C). He is in noacute distress and does not appear ill. The only abnormal physical finding is mild rhinitis. A completeblood count reveals a white blood cell count of 1.5�103/mcL (1.5�109/L), hemoglobin of 12.8 g/dL(128 g/L), and platelet count of 349�103/mcL (349�109/L). His differential count is 2% neutrophils,80% lymphocytes, 10% monocytes, and 6% eosinophils. A blood culture is obtained. After a single doseof acetaminophen, the child becomes afebrile. Of the following, the most appropriate next step is to:

A. Give a dose of broad-spectrum antibiotics and admit the child for continuing intravenous antibiotics.B. Give a dose of ceftriaxone and see the child the following morning.C. Observe the child in the emergency department overnight.D. See the child the following morning but tell the parents to call sooner if he becomes more ill.E. Start amoxicillin and clavulanic acid orally and see the child the following morning.

8. The mother of a well 4-month-old child would like you to obtain a complete blood count to make sureher baby is “OK.” You determine that she has no specific anxieties or reasons for suspecting a problem. Ofthe following, the most appropriate response is to:

A. Explain that a routine complete blood count is obtained at 9 months of age.B. Explain that only a hemoglobin or hematocrit is measured routinely in well children at 9 to 12 months

of age.C. Explain that there is no reason to obtain any blood counts for well children at any time.D. Order a complete blood count.E. Order a complete blood count with a differential white blood cell count.

9. What is the most common underlying cause for mild-to-moderate neutropenia?

A. Exposure to medications such as antibiotics.B. Immune neutropenia.C. Shwachman-Diamond syndrome.D. Sequestration.E. Transient marrow suppression due to a viral infection.

10. At what age does alloimmune neutropenia usually resolve?

A. 2 to 3 days.B. 2 to 3 weeks.C. 5 to 6 weeks.D. 2 to 3 months.E. 6 to 7 months.




Bhende, Grace Pecson and Carolyn Leedy Cherilyn Hall, Allen Friedland, Sumathi Sundar, Kathryn S. Torok, Mananda S.

Index of Suspicion







The reader is encouraged to writepossible diagnoses for each case beforeturning to the discussion. We invitereaders to contribute casepresentations and discussions.Please inquire first by contacting Dr.Nazarian at [email protected].

Author Disclosure

Drs Hall, Friedland, Sundar, Torok,

Bhende, Pecson, and Leedy did not

disclose any financial relationships

relevant to these cases.

Case 1 PresentationA 12-year-old girl has had abdominalpain for 3 hours. The pain developedsuddenly and is severe, sharp, con-stant, and located in the epigastriumand lower quadrants, with no radia-tion. She has had five episodes ofbilious, nonbloody emesis. The painworsens with movement and vomit-ing, and she has found no way torelieve it. Her last bowel movementwas yesterday and was normal. Shehas had no fever, diarrhea, bloodystools, or back pain. Past medicalhistory reveals intermittent constipa-tion.

On physical examination, hertemperature is 96.3°F (35.7°C),heart rate is 106 beats/min, respira-tory rate is 14 breaths/min, andblood pressure is 103/60 mm Hg.Her abdomen is soft and slightly dis-tended, with hypoactive bowelsounds and both right and left lowerquadrant tenderness. Slight volun-tary guarding is noted. The rest ofthe physical findings are normal.

Her WBC is 9.6�103/mcL(9.6�109/L), Hgb is 11.4 g/dL(114 g/L), Hct is 33.3% (0.333),and platelet count is 406�103/mcL(406�109/L). Values for electro-lytes, BUN, creatinine, liver en-zymes, amylase, and lipase are withinnormal limits; a pregnancy test isnegative.

Abdominal/pelvic CT scan withintravenous contrast reveals a moder-ate amount of free fluid around thececum; the appendix is not visible.Pelvic and abdominal ultrasonogra-phy is read as normal, but the appen-dix is not visible.

Following intravenous hydration,she experiences persistent biliousvomiting and abdominal pain andundergoes a diagnostic laparoscopy,which is converted to an exploratorylaparotomy when no colon is locatedon the right side of her abdomen.

The cause of her pain and vomiting isrevealed at surgery.

Case 2 PresentationA 14-year-old girl is seen in the EDbecause of 2 days of lower abdominaland back pain. The pain is a constant,dull, bandlike ache of 9/10 in inten-sity. She denies fever, nausea, vomit-ing, diarrhea, melena, hematochezia,dysuria, hematuria, vaginal dis-charge, or constitutional symptoms.She is premenarchal and denies sex-ual activity.

She had an appendectomy at age 5years complicated by the develop-ment of necrotic bowel, requiring asmall bowel resection. After recover-ing from surgery, she developedchronic intermittent abdominal pain,ultimately diagnosed as being func-tional. She describes her current painas different from her chronic abdom-inal pain.

On physical examination, the girlis uncomfortable but in no apparentdistress and looks healthy. All vitalsigns are normal. Her breast develop-ment is at Sexual Maturity Rating 5.She is thin and easy to examine. Herback is straight, with no tendernessto palpation over the spine, paraspi-nal muscles, or costovertebral angles.Her abdominal examination reveals a10-cm linear, well-healed verticalscar down the midline and a slightlyprotuberant lower abdomen. Palpa-tion reveals a large, well-defined, firmmass extending from the pelvis half-way to the umbilicus in the mid-line.Mild pain is elicited on deep palpa-tion of the left lower quadrant, withno guarding or rebound tenderness.Additional examination reveals thediagnosis.

Case 3 PresentationA 6-month-old boy is readmitted be-cause of respiratory distress and hyp-

Frequently Used Abbreviations

ALT: alanine aminotransferaseAST: aspartate aminotransferaseBUN: blood urea nitrogenCBC: complete blood countCNS: central nervous systemCSF: cerebrospinal fluidCT: computed tomographyECG: electrocardiographyED: emergency departmentEEG: electroencephalographyESR: erythrocyte sedimentation

rateGI: gastrointestinalGU: genitourinaryHct: hematocritHgb: hemoglobinMRI: magnetic resonance imagingWBC: white blood cell

index of suspicion



oxia 1 day after a 2-week hospitaliza-tion for bronchiolitis with hypoxia.Despite resolution of signs of a respi-ratory tract infection, he was difficultto wean from supplemental oxygen,having percutaneous oxygen satura-tions of 88% to 92% in room air. Hewas discharged after his percutane-ous oxygen saturations remained at90% to 96% for 24 hours in room air.He was a small-for-gestational ageneonate, born via caesarean sectionat 36 weeks’ gestation for maternaldouble uterus, and remained in theneonatal intensive care unit for2 weeks for feeding and weight gain.He did not receive any mechanicalventilation, and his growth and de-velopment have been normal.

On physical examination, the pa-tient’s weight is in the 10th percen-tile, height is in the 5th percentile,and head circumference is below the3rd percentile. His blood pressure,heart rate, and respiratory rate arenormal. Percutaneous oxygen satura-tions in room air are 91%. He is re-ceiving 2 L of supplemental oxygenby nasal cannula and has no respira-tory distress. Wheezing is audible bi-laterally, and there is no heart mur-mur. He has a left facial nerve palsypresent since birth. Adequate perfu-sion and palpable pulses are noted inall extremities. The remaining physi-cal findings are normal.

A chest radiograph reveals multi-focal atelectasis, a left-sided aorticarch, and a cardiac silhouette thatmeasures at the upper limit of nor-mal. Additional evaluation revealsthe diagnosis.

Case 1 DiscussionAt laparotomy, intestinal malrotationwith small bowel obstruction at thelevel of the distal ileum was found.

The ConditionIntestinal malrotation is an anatomicanomaly caused by arrest of normalrotation and mesenteric fixation ofthe embryonic gut, a failure of nor-mal embryologic gut formation thatoccurs between the 5th and 10thweeks of gestation. The result of anonrotated gut is location of the co-lon on the left side and a narrow-based mesentery in the upper mid-abdomen that is fixed to the rightabdominal wall by adhesions knownas Ladd bands. Anomalies commonlyassociated with intestinal malrotationinclude duodenal atresia (50%) andjejunal atresia (33%). Disorders of in-testinal rotation and mesenteric fixa-tion to the posterior abdominal cav-ity are also common in infants andchildren who have congenital dia-phragmatic hernia, gastroschisis, andomphalocele.

Intestinal malrotation is believedto occur in 1 per 200 to 1 per 500 livebirths, with symptomatic malrota-tion occurring in 1 per 6,000 livebirths. Symptomatic malrotation isevident clinically in the first postnatalmonth in 64% of patients, and 82%are diagnosed in the first postnatalyear; 18% to 25% of symptomatic pa-tients are diagnosed at 1 year of ageand older. Because malrotation is dis-covered incidentally in some pa-tients, the true number of patientswho have malrotation that is neverdetected can only be estimated.

Malrotation can cause duodenalobstruction because of impingementon the bowel by the Ladd bands. Themost serious consequence is a mid-gut volvulus, a life-threatening con-dition in which the intestine twists onthe mesenteric stalk and compro-mises its blood supply, which canlead rapidly to infarction of the entiresmall bowel. Both duodenal obstruc-tion from Ladd bands and volvulusmay occur intermittently, character-ized by chronic and sometimes vague

complaints of abdominal pain with orwithout vomiting.

Symptomatic malrotation withvolvulus presents as duodenal ob-struction. In infancy, the clinical pic-ture includes bilious emesis, abdom-inal pain, diffuse tenderness, andbloody stool. Some clinicians warnthat the cause of bilious vomiting in aneonate should be considered me-chanical intestinal obstruction untilproven otherwise. Older childrenand adults can present with acute orchronic symptoms. Acute symptomsinclude bilious vomiting, diffuse ab-dominal pain, and bloody stool.

Among the chronic symptoms areintermittent vomiting and abdomi-nal pain, constipation, malabsorptionsyndrome, chronic diarrhea due toprotein-losing enteropathy, and fail-ure to thrive. Older children andadults who have chronic symptomsmay have received a previous diagno-sis of irritable bowel syndrome orcyclic vomiting. Some individualswho are diagnosed later in childhoodare believed to have been experienc-ing intermittent, self-resolving vol-vulus.

Differential DiagnosisThe differential diagnosis for intesti-nal malrotation varies according tothe age of presentation. In infancyand childhood, conditions to con-sider include necrotizing enterocoli-tis, pyloric stenosis, intussusception,ileus due to sepsis or meconium,Hirschsprung disease, appendicitis,and duodenal atresia. In older chil-dren and adults, similar symptomscan result from inflammatory bowelsyndrome, pancreatitis, or acute ab-dominal conditions such as appendi-citis.

DiagnosisDiagnostic evaluation generally re-quires a degree of suspicion for vol-vulus and, in a stable patient, can

index of suspicion



include abdominal radiography,upper GI radiographic series, or ab-dominal CT scan. Adjunctive imag-ing techniques are abdominal ultra-sonography and barium enema.Radiographs often reveal a gaslesscolon with a “double-bubble” signdue to duodenal obstruction. An ab-dominal radiograph was not per-formed in this patient because appen-dicitis was believed to be likely, andabdominal radiography would nothave been an optimal study for ap-pendicitis.

An upper GI contrast study usu-ally is considered the imaging studyof choice in a stable patient suspectedof having intestinal malrotation com-plicated by volvulus. An upper GIradiographic series reveals failure ofthe duodenal-jejunal junction tocross the midline and a corkscrewappearance of volvulus at the level ofthe duodenum. CT scan may revealduodenal obstruction (in the case ofmid-gut volvulus) or appear normalin the absence of volvulus. Ultra-sonographic findings suggestive ofvolvulus include identification of thesuperior mesenteric vein on the leftrather than the right.

TherapyIntestinal malrotation requires surgi-cal intervention. The Ladd proce-dure is recommended for intestinalmalrotation regardless of age orsymptoms. This operation includeslysis of adhesions, widening of themesenteric base, and positioning ofthe bowel in a place of nonrotation aswell as appendectomy and resectionof any necrotic bowel. The urgencyof the operation is dictated by thepresence of intestinal ischemiacaused by volvulus. In the setting ofmalrotation without volvulus, mostsurgeons advocate the Ladd proce-dure as a prophylactic maneuver toreduce the probability of volvulus.

This patient underwent a Ladd

procedure, and Doppler ultrasonog-raphy at the time of surgery showednormal blood flow to the distal il-eum. Postoperatively, she developedpancreatitis, which resolved after ap-proximately 1 week of bowel rest andfluid resuscitation. She was dis-charged with no additional compli-cations.

Lessons for the ClinicianMost symptomatic cases of malrota-tion occur during infancy and usuallypresent with bilious vomiting. Fewercases present after infancy and havevaried presentations related to inter-mittent volvulus, with symptomsthat include abdominal pain, vomit-ing, and diarrhea. Volvulus canmimic an acute abdominal inflamma-tory process, and diagnosis requires ahigh degree of suspicion becauseprogressive intestinal ischemia maybecome life-threatening. Patientswho present after infancy usuallyhave a history of chronic abdominalcomplaints. (Cherilyn Hall, MD,Allen Friedland, MD, SumathiSundar, MD, Christiana CareHealth System, Newark, Del.)

Case 2 DiscussionExamination of the patient’s genita-lia revealed a normal vulva and labiawith Sexual Maturity Rating 5 distri-bution of pubic hair. A bulging, blu-ish membrane that was firm to palpa-tion protruded from the introitus(Figure). Abdominal and pelvic ul-trasonography performed to confirmthe diagnosis of imperforate hymenrevealed a grossly dilated vagina filledwith homogeneous, echogenic mate-rial consistent with hematocolpos.No other urogenital abnormalitieswere present. The patient was admit-ted for a hymenectomy and evacua-tion of retained clotted blood. Afteran uncomplicated hymenectomy, the

patient was discharged in good con-dition with relief of pain.

The ConditionImperforate hymen is the most com-mon obstructive genital tract anom-aly occurring in females, having anincidence of 1 in 1,000 to 1 in10,000 individuals. Most commonly,imperforate hymen is detected dur-ing adolescence either during anevaluation for asymptomatic primaryamenorrhea or an investigation ofabdominal, back, or pelvic pain in thepremenarchal female. Other com-plaints include urinary retention andpain with defecation. The pain is dueto the collection of menstrual bloodin the vagina and uterus. An imper-forate hymen also can be detected onprenatal ultrasonography as hydro-colpos if it is associated with urinaryobstruction and a urogenital fistula,during a newborn examination as amucocolpos from maternal estrogen-induced secretions, or during ahealth supervision visit as a mem-brane that bulges when the child per-forms a Valsalva maneuver. The termhydrometrocolpos is used when bothvagina and uterus are dilated withfluid.

Imperforate hymen is a sporadiccongenital outflow obstructionanomaly resulting from the failure ofcanalization of the tissue joining themullerian ducts and the urogenitalsinus during development. Embryo-logically, the female genital tract in-volves the medial migration and mid-line (horizontal) fusion of the pairedmullerian (paramesonephric) ductsto form the uterus, cervix, and uppervagina and the vertical fusion of thedeveloping ductal system with theinvaginating urogenital sinus to formthe lower vagina and introitus. Hor-izontal fusion defects result in vaginalagenesis (also known as mullerianagenesis or Mayer-Rokitansky-Kuster-Hauser syndrome) and may

index of suspicion



have associated urinary system ab-normalities. Failure of vertical fusionresults in low obstruction abnormal-ities, such as imperforate hymen,transverse vaginal septum, and cervi-cal atresia, which usually are not as-sociated with urinary abnormalities.All of the previously noted condi-tions result in an accumulation ofmenstrual fluid above the level ofobstruction.

The ovarian structures are derivedfrom a separate embryologic source,the genital ridge. Therefore, ovarianhormonal and endocrinologic func-tion is normal in patients who havegenital outflow tract abnormalities,which causes an apparent discrepancybetween physical findings of ad-vanced secondary sexual characteris-tics and lack of menses.

An imperforate hymen is diag-nosed by genital examination, whichreveals a translucent thin membraneinferior to the urethral meatus thatbulges when the patient performs theValsalva maneuver. If hematocolposis present, a bluish discoloration isapparent behind the membrane. The

volume of blood that collects can begreat enough to fill and distend theuterus (hematometra), which maypresent as an abdominal or pelvicmass. Prolonged menses in a girl whohas an imperforate hymen may leadto hematosalpinges and retrogrademenses into the abdomen, whichmay cause intra-abdominal endome-triosis and adhesions.

Differential DiagnosisAlthough an imperforate hymenshould be obvious on physical exam-ination, several conditions maypresent with similar complaints andfindings. A history of primary amen-orrhea in the presence of a blind orabsent vagina indicates a variety ofdevelopmental anomalies of the gen-ital outflow tract, including imperfo-rate hymen, low-lying transverse vag-inal septum, cervical atresia, vaginal(mullerian) agenesis, and androgeninsensitivity syndrome (AIH). Ofthese conditions, imperforate hy-men, transverse septum, and cervicalatresia commonly present at the ex-pected time of menarche in a girl

who has well-developed secondarysexual characteristics and the com-plaint of cyclical lower abdominal,back, or pelvic pain. On examination,imperforate hymen appears typicallyas a thin, bulging blue membrane;transverse septa and cervical atresiacan be associated with a normal vag-inal opening but shortened vaginalcanal. Ultrasonography can helpevaluate the level and volume of se-questered menses; MRI provides su-perior anatomic detail to define thenature of anomalies further, includ-ing those of the upper urinary tract.Only in rare instances is laparoscopyrequired to clarify an anatomic devel-opmental anomaly.

Vaginal (mullerian) agenesis andAIH usually are asymptomatic pre-sentations of primary amenorrhea as-sociated with a vaginal anomaly. Pa-tients born with vaginal agenesisexperience variable uterine develop-ment, with only 2% to 7% having auterus that has a functioning endo-metrium. This group may presentwith cyclic or chronic abdominopel-vic pain due to hematometra, but thisclinical picture is the exception.

Extragenital anomalies are com-mon in vaginal agenesis and shouldbe screened for, particularly urologic(30%) and skeletal (15%) abnormali-ties. AIH differs from the other men-tioned anomalies in that it is a geneticdisorder of a chromosomal male(XY) but phenotypic female due toan androgen receptor mutation caus-ing androgen insensitivity in the tis-sues and resulting in a blind vagina,absent uterus, and testes in the ingui-nal canal. Imaging, along with evalu-ation of karyotype and hormone con-centrations, further delineates thisdisorder.

TreatmentHymenectomy is the definitive treat-ment for an imperforate hymen.Abdominal ultrasonography is rec-

Figure. External genitalia showing bulging hymeneal membrane.

index of suspicion



ommended before surgery to dem-onstrate that the true diagnosis is notan obstructing transverse septum orother genital anomaly. If abnormali-ties are present, the condition may bemore complex than a simple imper-forate hymen, and surgery should bedelayed until the appropriate evalua-tion is performed, including MRI ofthe abdomen and pelvis.

Surgical treatment of an imperfo-rate hymen is not an emergency pro-cedure. If a preadolescent is found tohave an imperforate hymen on exam-ination but otherwise is asymptom-atic, surgery often is delayed untilpuberty to allow the hymen to be-come estrogenized, optimizing thesurgical outcome. A more urgenthymenectomy is needed if the patientalso has urinary obstruction.

In addition to hymenectomy,treatment for an imperforate hy-men consists of evacuating copiousamounts of retained blood prod-ucts and suturing the vaginal epi-thelium to the hymeneal ring. Theoutcome of imperforate hymentreated with hymenectomy is excel-lent. Follow-up in patients whohave had imperforate hymentreated has shown normal preg-nancy rates and sexual function.Gynecologists have observed that ifendometriosis develops from retro-grade menses, it is more likely toresolve and have no significant ef-fect on fertility compared withspontaneous endometriosis occur-ring in the general population.

Lessons for the ClinicianA teenage girl who has lower abdom-inal pain and back pain may bring tomind an extensive differential diag-nosis, leading to extensive laboratoryand radiologic testing. However, thehistory and physical examination re-main the most useful tools at thephysician’s disposal to make the diag-nosis. In this case, the patient’s ad-

vanced breast development and lackof menses did not correlate and, inthe presence of recurring abdominaland back pain, led to the suspicion ofimperforate hymen. Imperforate hy-men is the most common cause ofvaginal outflow obstruction, and sur-gical repair can relieve the obstruc-tion and ensure commencement ofnormal menses. (Kathryn S. Torok,MD, Mananda S. Bhende, MD, Chil-dren’s Hospital of Pittsburgh, Pitts-burgh, Pa.)

Case 3 DiscussionThe baby continued to require sup-plemental oxygen and demonstratedrespiratory distress with feedings.A video swallow study showed noevidence of aspiration. CT scan of thechest performed to evaluate pulmo-nary anatomic abnormalities as acause for prolonged hypoxia revealeda vascular structure to the left of theaorta consistent with a duplicated su-perior vena cava or anomalous pul-monary venous connection. An ECGshowed right atrial enlargement andfindings consistent with right ven-tricular hypertrophy. Echocardiogra-phy confirmed the diagnosis of un-obstructed supracardiac total anom-alous pulmonary venous connection(TAPVC), with the pulmonary veinsdraining into the innominate vein.A large secundum atrial septal defect(ASD) with right-to-left shuntingalso was present.

The ConditionTAPVC is a cyanotic heart defect thatrepresents approximately 1% to 3% ofall congenital heart defects. Males areaffected more often than females (4:1). Some 33% of affected patientshave additional cardiac malforma-tions, and 33% have other noncardiacmalformations.

TAPVC results from a develop-mental error that prevents a direct

communication of the pulmonaryveins to the left atrium. The pulmo-nary veins drain into the systemic ve-nous system or directly into the rightatrium. In this malformation, anobligatory right-to-left shunt nearlyalways occurs at the atrial level. For-merly called total anomalous pulmo-nary venous return, the conditionmore appropriately is called TAPVC.The abnormality is the connection,not the return, because the veins canempty circuitously into the leftatrium or blood can flow into the leftatrium through an ASD.

The four types of TAPVC are basedon the location of the pulmonary veinconnection: supracardiac (50%, com-monly into the left innominate vein orright superior vena cava), cardiac (20%,commonly into the coronary sinus),infracardiac/subdiaphragmatic (20%,commonly into the portal vein, duc-tus venosus, hepatic vein, or inferiorvena cava), and mixed (10%).

The presence of an obstructedpulmonary venous connection affectsthe clinical presentation. Typically,tachypnea and cyanosis occur withinthe first few days after birth as pulmo-nary blood flow increases. The ob-structed flow causes pulmonaryedema and decreased lung compli-ance, which manifests as increasedwork of breathing and hypoxia.Feeding difficulties and other signs ofheart failure often are present. In ad-dition, there is a fixed and widely splitsecond heart sound due to a delay inpulmonary valve closure caused byright ventricular volume overload.Some infants also develop pulmonaryhypertension because of the obstruc-tion.

Without obstruction, there maybe no symptoms at birth. However,symptoms usually appear within thefirst postnatal year. Signs may includedyspnea on exertion and visible cya-nosis with crying. Examination usu-ally reveals a pulmonary murmur

index of suspicion



caused by increased flow across thevalve. The murmur may be difficultto hear if there is pulmonary veinobstruction. It can be distinguishedfrom pulmonic valve stenosis by theabsence of a pulmonary valve click.An ASD causes a similar pulmonaryflow murmur and fixed splitting ofthe second heart sound.

Rhonchi may be present in somepatients. As with this child, percuta-neous oxygen saturations may be de-creased only slightly because initialpulmonary blood flow remains highand a large interatrial connection al-lows oxygenated blood to flow intothe left atrium and systemic circula-tion. Progressive cyanosis resultsfrom increasing pulmonary edemathat impairs oxygenation and de-creasing right heart compliance thatincreases the interatrial right-to-leftshunt. Both obstructed and unob-structed types can cause congestiveheart failure, growth restriction, andmultiple pulmonary infections.

Chest radiography may show anenlarged heart with increased pulmo-nary flow, a “snowman” shape (insupracardiac TAPVC), or an en-larged upper right heart border.ECG shows right atrial and right ven-tricular enlargement. The diagnosisis confirmed by identifying a pulmo-nary venous connection to the sys-temic veins, coronary sinus, or rightatrium on echocardiography.

PrognosisMost patients who have TAPVC donot survive beyond the first yearwithout surgery. Emergent surgery

may be necessary for neonates whoare in cardiogenic shock due toTAPVC. Infants afflicted with infra-cardiac TAPVC die before 2 monthsafter birth without surgery. Advance-ments in surgical correction havelowered mortality rates to near zeroand increased long-term survival to98% at 7 years.

Cyanotic Heart DefectsMany nurseries routinely check per-cutaneous oxygen saturations atbirth. This screening is nearly 100%specific in detection of cyanotic heartdefects. (1) Without screening and ahigh level of suspicion, a subset ofpatients born with congenital heartdisease will be missed. Patients whomanifest cyanotic heart disease out-side of the neonatal period maypresent with growth restriction orfailure to thrive, a history of recurrentrespiratory infections, mild or epi-sodic cyanosis, or irritability.

As with this patient, persistent hy-poxemia despite resolution of an in-fectious respiratory process is a majorsign of cyanotic heart disease. In-deed, many patients who have cya-notic congenital heart defects areasymptomatic at birth because of thepresence of intracardiac mixing ofoxygenated and deoxygenated bloodthat increases the arterial oxygen sat-uration. Infants born with hypoplas-tic left heart syndrome or left heartobstruction or who experience in-creasing pulmonary blood flow as thepulmonary vascular resistance fallsnaturally (single ventricle withoutpulmonary stenosis, large ventricular

septal defect) eventually show signsand symptoms of heart failure or pul-monary edema. Unfortunately, forthose who have left heart obstruc-tion, symptoms of heart failure maybe subtle and the phase of decom-pensation rapid.

Signs and symptoms of congestiveheart failure include irritability, poorfeeding, failure to thrive, tachypneawithout respiratory distress (“happytachypnea”) or tachypnea with respi-ratory distress due to pulmonaryedema or pleural effusion, and hepa-tomegaly. Any patient suspected ofhaving a cyanotic heart defect or con-gestive heart failure should bescreened with a chest radiograph andECG. Echocardiography providesthe definitive diagnosis.

Lessons for the ClinicianRecognizing signs and symptoms ofcyanotic heart defects and earlysymptoms of congestive heart failureis critical to the early recognition,management, and surgical correctionof these lesions. (Grace Pecson, MD,Carolyn Leedy, MD, University ofTexas Southwestern Medical Center,Children’s Medical Center, Dallas,Tex.)

Reference1. Reich JD, Miller S, Brogdon B, et al. Theuse of pulse oximetry to detect congenitalheart disease. J Pediatr. 2003;142:268–272

To view Suggested Reading lists forthese cases, visit www.pedsinreview.organd click on Index of Suspicion.

index of suspicion




Bhende, Grace Pecson and Carolyn Leedy Cherilyn Hall, Allen Friedland, Sumathi Sundar, Kathryn S. Torok, Mananda S.

Index of Suspicion



Supplementary Material

DC1http://pedsinreview.aappublications.org/cgi/content/full/29/1/25/Supplementary material can be found at:







http://pedsinreview.aappublications.org/cgi/content/full/29/1/25/DC1





Jeffrey Kaczorowski Pediatrics in the Community: Community Pediatrics Training Initiative (CPTI)







Author Disclosure

Drs Kaczorowski and Aligne did not


relevant to this article.

Community Pediatrics TrainingInitiative (CPTI)Our inaugural story for Pediatrics inthe Community was in the January2007 edition of Pediatrics in Review.Dr Robert Haggerty provided the his-torical rationale for community pedi-atrics training (CPT) as part of thatfeature. Now, 1 year later, we askedDr Jeff Kaczorowski, Director of theCPTI at the American Academy ofPediatrics (AAP), to describe thepresent and future of CPT. As the sto-ries in this series have shown, some res-idents are having wonderful commu-nity experiences already and makinga difference in the lives of childrenin their communities. The challengeis how to make such experiences avail-able to all pediatric residents andpediatricians.—C. Andrew Aligne,MD, MPH, Section Editor

The CPTI was founded 8 years agoby a remarkable pediatrician namedAnne Dyson, and in 2005, CPTImoved to the AAP. Our ultimategoal is to ensure that all pediatrictraining programs develop and sus-tain quality community experiencesthat are fully integrated into resi-dency training. Maintaining a com-munity perspective is a critical part ofwhat we need to do in pediatrics toassure the health of all children in theUnited States.

Residents and young pediatriciansacross the country have told me thatthey want this kind of training, andnational surveys confirm this signifi-cant demand. Residents understandthat community and environmentalfactors play a major role in morbidi-ties such as obesity, mental healthproblems, child abuse, violence, andinjuries. Yet, many residency pro-grams are just beginning to developtraining experiences that involve get-ting outside the hospital into the

home and school environmentswhere children spend their days. Pro-grams that have these initial expo-sures often want to develop the nextlevel, particularly in the areas oflegislative/systems-level advocacyand community projects.

CPTI is working on many frontswith numerous partners to accom-plish its mission of developing qualityCPT experiences at beginning, aswell as more advanced, levels. CPTIis partnering with:

● the Ambulatory Pediatric Asso-ciation to cosponsor the PediatricAcademic Societies’ educationalscholars program for present or fu-ture faculty in academic pediatricswho have an interest and experi-ence in community pediatrics.

● the AAP CATCH (CommunityAccess to Child Health) programon grants for residency programsto plan and implement com-munity-based child health initia-tives, as well as visiting professor-ships in community pediatrics.

● the AAP Department of FederalAffairs to support five faculty-resident pairs annually to attendthe AAP Legislative Conferenceand then to implement an educa-tional activity on child advocacy incoordination with their local AAPchapter.

● the AAP Council on CommunityPediatrics to sponsor the Pediatricsfor the 21st Century (Peds-21) Symposium on CommunityPediatrics in October 2007, in-cluding a resident poster sessionfeaturing community-based initia-tives.

● the AAP Division of State Govern-ment Affairs and Department ofFederal Affairs to develop an advo-

pediatrics in the community



cacy guide for pediatricians, pediat-ric residents, and child health pro-fessionals, which will be available inthe spring of 2008.

● Pediatrics in Review to sponsor thisfeature.

CPTI has developed a number oftools to support residency programs,

including the Community PediatricsCurriculum Manual (2005), theCommunity-based Resident ProjectsToolkit (2005), and the CPTI Evalu-ation Toolkit (2007). CPTI will soonlaunch a searchable online databaseof community pediatrics training ac-tivities across the nation.

For more information on any of the

above or to join the CPTI listservto receive announcements aboutgrants and other opportunities, goto: http://www.aap.org/commpeds/cpti/or e-mail: [email protected].

Jeffrey Kaczorowski, MDDirector, CPTIAmerican Academy of Pediatrics

Figure. These children are participating in a program to help combat obesity and get children more active in Palo Alo, Calif. Theresidents involved were Heather Iezza, MD, and Maria Mosquera, MD.

pediatrics in the community




Jeffrey Kaczorowski Pediatrics in the Community: Community Pediatrics Training Initiative (CPTI)













Michael Crocetti and Janet R. Serwint Inhalants







In BriefInhalantsMichael Crocetti, MDBayview Medical CenterBaltimore, Md.

Author Disclosure

Drs Crocetti and Serwint did not


relevant to this In Brief.

Recognition and Prevention of InhalantAbuse. Anderson CE, Loomis GA. AmFam Physician. 2003;68:869–874

Adolescent Abuse of Other Drugs.Greene JP, Ahrendt D, Stafford EM.Adolesc Med. 2006;17:283–318

Inhalants of Abuse. Gussow LM. In: FordM, Delaney KA, Ling L, Erickson T,eds. Clinical Toxicology. Philadelphia,Pa: WB Saunders Co; 2001:651–656

Inhalant Abuse. National Institute onDrug Abuse. Research Reports. http://www.nida.nih.gov/ResearchReports/Inhalants/Inhalants.html. AccessedJanuary 15, 2007

Inhalant Abuse and Dependence AmongAdolescents in the United States.Wu L, Pilowsky DJ, Schlenger WE.J Am Acad Child Adolesc Psychiatry.2004;43:1206–1214

Inhalant Abuse. Williams JF, Storck M,and the Committee on SubstanceAbuse and Committee on NativeAmerican Child Health. Pediatrics.2007;119:1009–1017

Inhalants are volatile substances that,when sniffed or snorted, can induceeuphoric and hallucinogenic effects.These substances are lipid-soluble andafter inhalation are absorbed rapidlythrough the lungs, quickly entering thecentral nervous system (CNS). Inhalantsare classified as CNS depressants, butacute intoxication can lead to a senseof euphoria and excitability. “Sniffing”

involves inhaling vapors from an opencan or container, “bagging” describesinhaling vapors that have been cap-tured in a bag, and “huffing” consists ofinhaling volatile substances that havebeen soaked in a cloth. Bagging andhuffing are preferred methods becausethe user can inhale large concentra-tions of the drug.

Inhalant abuse reaches its peak be-tween grades 7 and 9 in the UnitedStates. Surveys of illicit drug use haverevealed that use of inhalants is secondto marijuana use among 8th and 10thgraders and that inhalants are the thirdmost widely used agents of abuseamong 12th graders. The Youth RiskBehavior Survey 2005 reported that theoverall prevalence of lifetime inhalantuse was about 12%. Some studies sug-gest that females are as likely as malesto use inhalants prior to 17 years of agebut that males in the 18- to 25-yearage group are more likely to do so.Rates of abuse have been reported to behigher among American Indians,whites, and Hispanics compared withAfrican Americans. Other research hasshown that a history of child abuse, ahistory of being in foster care, poorsocioeconomic status, failing grades,and dropping out of school are riskfactors associated with inhalant use.

Use of inhalants has been popularfor many years because these sub-stances are inexpensive, legal, and easyto obtain. Many can be found in com-mon household products stored in ga-rages, basements, and kitchens. Gener-ally, there are four classes of inhalants.Volatile solvents are liquids that vapor-ize at room temperature and can befound in paint thinners, gasoline, andglues. Aerosols include spray paints,deodorant, and hair sprays. Gases can

be found in many commercial products.Nitrous oxide is the most commonabused gas and can be found in butanelighters, propane tanks, whipped creamdispensers, and Freon™. Nitrites, whichdilate blood vessels and relax muscles,often are used as sexual enhancers.These substances are prohibited by theConsumer Product Safety Commissionbut can be found in small bottles underthe names “video head cleaner,” “roomdeodorizer,” or “liquid aroma.”

Inhalants produce a pleasurable ef-fect by depressing the CNS in a mannersimilar to that of alcohol. Research hasdemonstrated that toluene, found inglues, activates the brain’s dopaminesystem. Acute effects of inhalant useinclude excitation followed by drowsi-ness, disinhibition, lightheadedness,and agitation. High doses may lead toconfusion and delirium. These acuteeffects have a rapid onset but areshort-lived, and many adolescents in-hale the substances repeatedly to gainlonger-lasting effects. Repeated usemakes the user vulnerable to the differ-ent stages of inhalant intoxication.

Stage 1 is the excitability stage,stage 2 is the depressive phase, andstage 3 is further depression of theCNS. Stage 4 is the most worrisomestage, in which CNS depression canlead to coma, in addition to accidentsand trauma due to risk-taking behav-iors. Up to 50% of inhalant-relateddeaths are due to sudden sniffing deathsyndrome. Inhalants sensitize myocar-dial cell membranes to depolarization,and if the user is startled or engaging invigorous activity at the time, cate-cholamines are released, leading toventricular fibrillation. Inhalant-associated arrhythmias can occur aftera single inhalant use in otherwise

in brief



healthy adolescents. Sudden sniffingdeath is associated most often with theuse of toluene, propane, butane, andaerosols.

Diagnosing inhalant abuse is diffi-cult and relies on a high degree ofsuspicion, supported by a thorough his-tory and physical examination. Othercauses of acute intoxication or alteredmental status should be considered,such as hypoxia, hypoglycemia, ethanol,illicit drugs, trauma, and infection. In-haled hydrocarbons may be detected bygas chromatography within 10 hours ofuse, but this test is not readily availableat most medical facilities. Although notspecific, laboratory evaluation may re-veal hypokalemia, hypophosphatemia,hypocalcemia, metabolic acidosis, met-hemoglobinemia, and carbon monoxidetoxicity.

Laboratory evaluation should in-clude a complete blood count, basicmetabolic panel, calcium and phospho-rous measurements, hepatic panel, andurinalysis for clues to inhalant use andurine toxicology screen to detect otherillicit drug use. Consideration alsoshould be given to cardiac and muscleenzyme analysis and electrocardiogra-phy, arterial blood gas determination to

rule out methemoglobinemia, and brainimaging if neurologic signs are present.Treatment of an acute overdose is sup-portive, with particular attention paidto airway, breathing, and circulation.Unfortunately, no medication can re-verse the effects of most inhalants.

Long-term treatment of inhalantdependence involves counseling, strictabstinence, and drug treatment proto-cols such as 12-step programs andinpatient and outpatient therapy. How-ever, a recent survey found that manycenters are not adequately equipped totreat inhalant abuse or dependence.

Comment: Dr Crocetti’s In Brief onInhalants is really thought-provoking.He emphasizes the importance of con-sidering inhalant use when evaluatingpatients whose manifestations are ei-ther acute or chronic. Because inhal-ants are so easily available, they oftenare used initially by younger, elemen-tary school-age children; 3% of pa-tients have tried inhalants by 4th grade.Furthermore, those who reported firstuse by 13 to 14 years of age were sixtimes more likely to become dependenton inhalants than were those who be-gan using at 15 to 17 years of age.

Signs of inhalant use may be subtle.Clinicians need to be alert to odors onthe breath or clothes; discovery by par-ents of hidden empty cans; or signs ofslurred speech, nausea, and symptomssimilar to those of alcohol intoxication.Chronic users may exhibit a “huffer’srash,” which is a dermatitis around themouth or nose, with cracking of theskin and, sometimes, bacterial superin-fection.

Because the effects of inhalants areshort in duration, it is unusual forpatients to seek medical attention un-less they have developed chronic mor-bidity from long-term effects on thebrain, heart, lung, kidney, liver, or bonemarrow (suppression). Mortality canoccur both from the sudden sniffingsyndrome and through asphyxiation orsuffocation related to bagging or huff-ing. Education and prevention strate-gies for both children and their parentsmust begin during elementary school tominimize the morbidity and mortalityfrom this underdiagnosed form of drugabuse.

Janet R. Serwint, MDConsulting Editor

in brief




Michael Crocetti and Janet R. Serwint Inhalants












American Academy ofPediatrics Policy Statementson Bioethics: Summaries andCommentaries: Part 1Mark R. Mercurio, MD,

MA,* Mary B. Adam, MD,

MA,* Edwin N. Forman,

MD,* Rosalind Ekman

Ladd, PhD,* Lainie

Friedman Ross, MD, PhD,*

Tomas J. Silber, MD,

MAAS*

Author Disclosure

Drs Mercurio, Adam,

Forman, Ekman Ladd,

Friedman Ross, and

Silber did not disclose

any financial

relationships relevant

to this article.

IntroductionThe American Academy of Pediatrics (AAP) has a strong and longstanding interest in thefield of bioethics and periodically publishes policy statements pertaining to specific ethicalquestions relevant to pediatrics. The subjects addressed cover a wide range of topics, fromparental refusal of immunization to the care of critically ill children. These policies areauthored initially by the AAP’s Committee on Bioethics and undergo extensive internalreview by other committees prior to publication.

This article is the first in a series of three intended to familiarize readers with many of theAAP policies currently in place that address issues in bioethics. In this series, 16 policiespublished by the AAP are summarized, each followed by a brief commentary. Thecommentaries are intended to address, at least on a cursory level, some of the ethicalprinciples underlying the policies. Some briefly point out possible alternative viewpoints.

The policies referenced in this article represent the efforts of various committees andcommittee members over the years. Each of the summaries presented here, as well as thecommentaries that follow, represents the work of individuals serving on the ExecutiveCommittee of the Section on Bioethics, as indicated at the beginning of each summary.Understandably, some of the wording of these summaries is taken directly from thepublished policies. When quotations are used within a summary and not referenced, it canbe assumed that the quote is taken directly from the policy being summarized. For ease ofuse, the references for each policy are provided with each individual summary andcommentary.

Policies ReviewedPart 1 of this series reviews:

1. Informed Consent, Parental Permission, and Assent in Pediatric Practice2. Religious Objections to Medical Care3. Responding to Parental Refusals of Immunization of Children4. Sterilization of Minors With Developmental Disabilities5. Human Embryo Research

Part 2 of this series reviews:6. Guidelines on Foregoing Life-sustaining Medical Treatment7. Foregoing Life-sustaining Medical Treatment in Abused Children8. Do-Not-Resuscitate Orders for Pediatric Patients Who Require Anesthesia and

Surgery9. Do-Not-Resuscitate Orders in Schools

10. Ethical Issues with Genetic Testing in Pediatrics11. Ethics and Care of Critically Ill Infants and Children

Part 3 of this series reviews:12. Female Genital Mutilation13. Appropriate Boundaries in the Pediatrician-Family-Patient Relationship14. Infants With Anencephaly as Organ Sources: Ethical Considerations15. Palliative Care for Children16. Institutional Ethics Committees

*On behalf of the American Academy of Pediatrics Section on Bioethics.

Article policy statements

Pediatrics in Review Vol.29 No.1 January 2008 e1

Informed Consent, Parental Permission, andAssent in Pediatric PracticeCommittee on Bioethics. Informed consent, parentalpermission, and assent in pediatric practice. Pediatrics.1995;95:314–317. Available at: http://aappolicy.aappublications.org/cgi/content/abstract/pediatrics%3b95/2/314. Reaffirmed October 2006. Summary andcomment by Edwin N. Forman, MD, and RosalindEkman Ladd, PhD.

Summary of Policy StatementThis statement comments on the concept of informedconsent and its application and limitations in the practiceof pediatrics, where a triad exists: physician, parent(s),and patient. The policy analyzes the problematic issue ofwho should make health-care decisions. It lays out theelements and moral and legal underpinnings of informedconsent and consent by proxy (ie, by parents). Theconcepts of emancipated and mature minors are pre-sented.

The policy defines and defends the concept of assent.Although children cannot be treated as rational, auton-omous decision-makers, pediatricians should give seriousconsideration to the patient’s developing capacities forparticipating in decision-making. Children should beinvolved in discussions about their health care, even insituations in which one should not and does not solicittheir agreement to the proposed medical management.Four elements of assent are emphasized: 1) helping thechild achieve a developmentally appropriate awareness ofthe condition, 2) telling the child what should be ex-pected with tests and treatment, 3) assessing the child’sunderstanding and factors that influence his or her re-sponse, and 4) soliciting an expression of the child’swillingness to accept the proposed care. The policy notesthat physicians and parents should not solicit children’sviews without intending to weigh them seriously. Insituations in which the medical treatment is deemedessential and must be given despite the patient’s objec-tion, the child should be told of this fact.

The AAP argues for shared decision-making, pointsout limits on parental authority, and justifies the impor-tance of involving the child in decision-making by notingthat such actions foster trust, create better physician/patient relationships, and may improve long-term healthoutcomes. Specific steps are outlined in obtaining assent,depending on the patient’s developmental stage and themedical situation, and in cases of conflict resolution.Rejected are outright medical paternalism and total pa-rental authority.

CommentThis policy, which provides for a genuine form of childassent, is based clearly on Western values. Modeled afterthe informed consent requirement for competent adultpatients, it takes seriously an ethical duty to keep thechild informed in age-appropriate ways and to solicit anexpression of the child’s willingness (ie, assent), whenappropriate, to undergo the proposed treatment.

The policy is somewhat unclear about when it isappropriate to solicit assent. Dissent may be ethicallybinding in the case of nontherapeutic research or non-essential treatment, but the policy notes that it is decep-tive to ask for assent when treatment is necessary and thechild’s dissent will be overridden. On the other hand, itseems to recommend solicitation of the child’s willing-ness to accept treatment, even when it is deemed essentialand only parental permission is required, as one elementof involving the child in discussions about his or herhealth care.

Asking the child for assent recognizes the dignity andmoral status of the child. The model is to provide agradually increasing involvement of the child in makingchoices as the child grows in competence and movesfrom complete dependency on parents to independence.However, in our pluralistic society, the ideal of an indi-vidual as independent and free-thinking is not acceptedby all cultural groups. Some cultures expect decisions tobe made exclusively by parents or elders, whatever theage of the younger generation. In addition, the idea of aschool-age child expressing an opinion at variance withhis or her parents may constitute an upheaval of tradi-tional values when the parenting style is authoritarian.

In using the AAP policy, the pediatrician is followingWestern democratic values and should be sensitive to thefact that some families come from cultures that havedifferent views of the role of the child.

Religious Objections to Medical CareCommittee on Bioethics. Religious objectives to med-ical care. Pediatrics. 1997;99:279–281. Available at:http://aappolicy.aappublications.org/cgi/content/full/pediatrics;99/2/279. Reaffirmed October 2006. Sum-mary and comment by Mark R. Mercurio, MD, MA.

Summary of Policy StatementIn this statement, the Committee on Bioethics, speakingfor the AAP, addresses parental decisions not to seek oraccept medical care for their children based on religiousobjections. The major role that religion plays in the livesof many adults and children in the United States isrecognized, and the need for the pediatrician to be

policy statements bioethics

e2 Pediatrics in Review Vol.29 No.1 January 2008

sensitive to and have respect for religious tradition isacknowledged. However, the AAP “believes that all chil-dren deserve effective medical treatment that is likely toprevent substantial harm or suffering or death,” despitereligious objections that the parents may hold. If effortsat collaborative decision-making with parents are notsuccessful in getting their approval for appropriate med-ical treatment in such cases, a court order ultimatelyshould be sought. If the child’s life is in imminentdanger, the physician should intervene over parentalobjections.

The AAP’s position is consistent with that of theUnited States Supreme Court. As the AAP notes: “Con-stitutional guarantees of freedom of religion do notpermit children to be harmed through religious prac-tices, nor do they allow religion to be a valid legal defensewhen an individual harms or neglects a child.” (1) TheAAP opposes exemption, based on religion, from childabuse and neglect laws when children are not providednecessary medical care. Failure to seek medical care whena child is seriously ill should be considered child neglect,regardless of the motivation. Laws that would allow anexemption on religious grounds should be opposed orrepealed.

In the area of preventive care, a somewhat less forcefulstance is taken. Although the AAP strongly endorsesuniversal immunization, for example, it “does not sup-port the stringent application of medical neglect laws”when children do not receive those immunizations dueto parental refusal.

CommentAn ethical justification for the AAP position on thismatter could be presented as a rights-based argument.Every child, it could be argued, has a right to medicalcare that is “likely to prevent substantial harm or suffer-ing or death.” The child’s right creates obligations forthe parents, the physician, and society. The parents areobligated to bring the child for the needed treatment,which, in the opinion of the AAP, cannot be limited toprayer or other spiritual practices alone but should in-clude appropriate medical care.

The physician’s responsibility is either to provide thenecessary treatment if able or to attempt to procureappropriate medical treatment for the child. The policystates that the physician may withdraw from these cases ifcontinuing would violate his or her own moral precepts,“after securing acceptable alternative care.” However, apractitioner willing to withhold medical treatment likelyto prevent substantial harm would not seem to qualify asa provider of “acceptable alternative medical care.”

Society is obligated to facilitate the provision of theneeded treatment to the child, including passing andenforcing laws that support necessary treatment of chil-dren despite parental religious objections. However, itcould be argued, and rightly so, that society also isobligated to protect religious freedom. The courts oftenare asked to evaluate this tension between the parentalright to religious freedom (for themselves and theirchildren) and the child’s right to necessary medical care.In general, the courts have taken the position profferedby the AAP: If the treatment in question is “likely toprevent substantial harm or suffering or death,” thechild’s right to treatment outweighs the parental right toreligious freedom. This viewpoint is not intended toignore the parents’ right to religious freedom, but ratherto recognize another right that should be given priority.The choice of words within the AAP policy suggests,however, that if prevention of substantial harm is possiblebut perhaps not likely, the imperative to overrule parentalobjection to treatment may be less certain. Again, thecourts often have held this position.

The policy alludes briefly to the concept of the matureminor, including a recognition that as children grow intoadolescence, many have an increasing ability to contrib-ute to or make their own medical decisions. In a previousstatement, the Committee on Bioethics opined that “aschildren develop, they should gradually become the pri-mary guardians of personal health . . . assuming respon-sibility from their parents.” (2) Based on that under-standing, the policy at issue here states, “in selected cases,disputes may be avoided when a minor has the capacity tomake an independent decision in light of religious valuesand recommended medical therapy.” The pediatrician,indeed, may perceive less dispute, and the right path mayseem clearer, when a mature minor requests a recom-mended treatment that his or her parents seek to refuseon his or her behalf. However, what if the mature minorrefuses a lifesaving treatment, in accord with his or herparents, based on religious objections? It is not clear whatthe AAP would recommend in such a case.

A competent adult’s right to refuse treatment onreligious grounds is recognized widely. It is somewhatunclear exactly when that right obtains, particularly if webelieve that the development of decision-making capac-ity is a gradual process. It seems reasonable to suggest,nevertheless, that an individual’s right to refuse medicaltreatment on religious grounds should be recognized atthe same time as his or her right to refuse on any otherbasis.



References1. Walker v Superior Court, 763 P2d 852, 860 (Calif 1988), certdenied. 1989; 491 US 9052. Committee on Bioethics. American Academy of Pediatrics. In-formed consent, parental permission, and assent in pediatric prac-tice. Pediatrics. 1995;95:314–317

Responding to Parental Refusals ofImmunizationsDiekema DS and the Committee on Bioethics. Respond-ing to parental refusals of immunizations. Pediatrics.2005;115:1428–1431. Available at: http://aappolicy.aappublications.org/cgi/content/full/pediatrics;115/5/1428. Summary and comment by Lainie Friedman Ross,MD, PhD.

Summary of Policy StatementThis statement begins with the AAP’s strong endorse-ment of universal immunization, but acknowledges thatdespite their safety and efficacy profiles, some vaccinesare refused by some parents. Some parents refuse becauseof erroneous information; others refuse because of reli-gious or philosophical beliefs. (1)(2) Data from a peri-odic survey of AAP members found that 7 of 10 pedia-tricians reported that they had a parent refuse animmunization on behalf of a child in the 12 monthspreceding the survey, (3) similar to other recent data. (4)This statement recommends that when faced with arefusal, physicians should try to: 1) understand the par-ents’ perspective, 2) correct any misinformation, and3) encourage the parents to reconsider. It also asks thephysicians to consider whether the refusal exposes thechild to serious risk such that it constitutes medicalneglect and puts others at serious risk of harm, justifyingpublic health intervention. Because refusals rarely causeimminent threats to a child’s or a community’s health,the AAP recommends that physicians respect the refusals.The statement encourages physicians not to dismiss thesefamilies but to continue to work with them to ensure thattheir children have access to medical care and to maxi-mize opportunities to encourage vaccinations.

CommentThis statement takes an ethical and pragmatic position:Encourage universal immunization because that practiceserves the child’s best interest and because it promotesherd immunity (community benefit), but respect refus-als. The authors acknowledge that immunizations areneither 100% safe nor 100% effective but argue that thebenefit-to-harm calculation is extremely high and justi-fies universal immunization policies and practices. The

policy is clear that pediatricians generally should respectfamilies who refuse vaccines. The practice of respectingparental refusals of vaccinations also is addressed in an-other AAP statement, “Religious Objections to MedicalCare.” This latter statement notes that some religiousgroups deny children the benefits of routine preventivecare such as immunizations and states, “[t]he AAP doesnot support the stringent application of medical neglectlaws when children do not receive recommended immu-nizations.” (5) This stance is consistent with an attitudethat intervention by the state should be invoked onlywhen it offers the “least detrimental alternative.” (6)When most of the community is immunized, the risk tothe child is low, and state intervention cannot be justi-fied, even though outbreaks do occur with attendantserious consequences. (5)

With the development of new vaccines such as thehuman papillomavirus vaccine and continued work onhuman immunodeficiency virus vaccines, future policieswill need to consider whether these vaccines fit into ourcurrent model of public health interventions and state-mandated vaccination policies and how pediatric prac-tices will be able to deliver vaccines that should beprovided to adolescents.

References1. Salmon DA, Teret SP, MacIntyre CR, Salisbury D, Burgess MA,Halsey NA. Compulsory vaccination and conscientious or philo-sophical exemptions: past, present, and future. Lancet. 2006;367:436–4422. Salmon DA, Moulton LH, Omer SB, DeHart MP, Stokley S,Halsey NA. Factors associated with refusal of childhood vaccinesamong parents of school-aged children: a case-control study. ArchPediatr Adolesc Med. 2005;159:470–4763. American Academy of Pediatrics, Division of Health PolicyResearch. Periodic Survey of Fellows No 48: Immunization Admin-istration Practices. Elk Grove Village, Ill: American Academy ofPediatrics; 20014. Flanagan-Klygis EA, Sharp L, Frader JE. Dismissing the familywho refuses vaccines: a study of pediatrician attitudes. Arch PediatrAdolesc Med. 2005;159:929–9345. American Academy of Pediatrics Committee on Bioethics. Reli-gious objections to medical care. Pediatrics. 1997;99:279–2816. Goldstein J, Freud A, Solnit A. Before the Best Interests of theChild. New York, NY: Free Press; 1979

Sterilization of Minors With DevelopmentalDisabilitiesCommittee on Bioethics. Sterilization of minors withdevelopmental disabilities. Pediatrics. 1999;104:337–340. Available at: http://pediatrics.aappublications.org/cgi/content/full/104/2/337. Reaffirmed Octo-



ber 2006. Summary and comment by Tomas J. Silber,MD, MAAS.

Summary of Policy StatementThis statement, reviewing the history of and consider-ations leading to the parental request of sterilization for ason or daughter who has developmental disabilities, de-velops five recommendations, summarized as follows:

1. The AAP encourages pediatricians to use the devel-opment of secondary sexual characteristics in personswho have developmental disabilities as an opportunity toexplore the patients’ and caregivers’ understandings ofthe facts and implications of sexual maturation.

2. Consideration of sterilization should focus onwhether a need for permanent prevention of reproduc-tion exists. Concern about other consequences of sexualmaturity or aspects of sexuality among persons who havecognitive disabilities should focus on interventions sub-stantially less radical than sterilization. The AAP encour-ages pediatricians to familiarize themselves with the re-sources in their community to which they might referfamilies for additional information or for specialized ed-ucation and counseling on such matters as appropriateexpressions of affection and sexual drives, effective men-strual hygiene, sexual abuse avoidance training, and con-traception.

3. Whenever possible, pediatricians should involvetheir patients who have developmental disabilities indecisions about reproduction and should advocate forthe least permanent and intrusive method of contracep-tion consistent with the lowest risk for the patient.

4. When a minor who has developmental disabilitiesrequests sterilization and an assessment determines thatthe minor has adequate decision-making capacity to con-sent to the procedure, the minor’s views on the mattershould be respected. Such decisions generally benefitfrom the involvement of the adolescent’s family, otheradults close to the adolescent, or both.

5. Pediatricians should become familiar with the ap-plicable law about sterilization of persons who havedevelopmental disabilities. Pediatricians should establishrelations with local agencies and attorneys knowledge-able about the legal complexities of sterilization of per-sons who have developmental disabilities in their juris-diction. If sterilization is legally permissible on theauthority of parents or legal guardians and is chosen asthe best course of action, substantial effort should bemade to communicate to the patient the facts and impli-cations of the sterilization. To the extent possible, thepatient should participate in planning for the procedure.

CommentThis policy statement updates a previous AAP statemententitled, “Women Who Are Mentally Handicapped,”published in 1990. That statement was published as acompanion to a policy of the American College of Ob-stetricians & Gynecologists. The revised policy is basedon concepts developed in the earlier statements, but nowapplies them to both males and females. This is the policyto consult whenever parents or legal guardians approachpediatricians or other health-care professionals about thepossibility of surgical sterilization of children, adoles-cents, and young adults who have developmental disabil-ities.

Sterilization has a long history of abuse in the UnitedStates. However, by the middle of the 20th century, theUnited States Supreme Court prompted a major changein the legal landscape by declaring human procreation afundamental right. Since then, requests for authorizationto sterilize those who have developmental disabilitieshave been the object of scrutiny, limitations, and evenprohibition in many jurisdictions. In the 1970s, for ex-ample, regulations were enacted to prevent the use offederal funds to perform sterilization procedures onthose deemed mentally incompetent. It should come asno surprise that, at present, we face so many federal rules,state laws, and judicial rulings that pediatricians whoseadvice is requested find themselves facing “a confusingand contradictory array of restrictions on surgical steril-ization of persons with development disabilities.” In-deed, this confusion may not be a coincidence because anethical tension exists between the obligation to honorthe least restrictive alternatives for those who have cog-nitive disabilities and the concern about abuse and coer-cion leading to unwanted pregnancy or, worse, a preg-nancy that the child may not comprehend or may beterrified by. Moreover, those who love and care fordevelopmentally delayed children certainly may havetheir best interest at heart when they know that thoseindividuals are not capable of caring for offspring.

Although this statement gives guidance on how toproceed when sterilization becomes the choice, its majorstrength is that it develops the fundamental criteria re-quired to make that decision ethically permissible,namely, that the person lacks adequate mental capacity tomake decisions about his or her health care and is unableto interpret his or her own interests. Thus, there is amoral mandate before sterilization can be considered:Assessment of an individual’s capacity to decide mattersspecifically concerning reproduction and an obligation toobtain help from professionals experienced with evaluat-



ing the capabilities of persons with disabilities. Once thedecision has been reached, the advocacy work starts.

Human Embryo ResearchCommittee on Bioethics and Committee on PediatricResearch. Human embryo research. Pediatrics. 2001;108:813–816. Available at: http://aappolicy.aappublications.org/cgi/content/full/pediatrics%3b108/3/813. Reaffirmed January 2005. Summary and commentby Mary B. Adam, MD, MA.

Summary of Policy StatementOn behalf of the AAP, the AAP Committee on Bioethics,and the AAP Committee on Pediatric Research wrote apolicy statement asserting, “under certain conditions,research involving human embryos and pluripotent stemcells is of sufficient scientific importance that the Na-tional Institutes of Health should fund it and that federaloversight is morally preferable to the current unregulatedprivate sector.” According to the statement, embryos aredefined as “human organisms derived by fertilizationfrom one or more gametes or diploid cells.” (Embryosformed using a diploid cell is a reference to cloninghuman embryos.) Justification for use of human embryosincludes the possible identification of potential benefitsto children as a class as well as the more global potentialfor medical benefits.

The statement acknowledges that its position is con-troversial because some believe that research using hu-man embryos is morally problematic. Opponents to theAAP’s position object to the destruction of human em-bryos for research purposes because they view humans atall stages of development as deserving full human value.Those who object to the use of human embryos inresearch concede that even if that research may have greattherapeutic potential, the “ends do not justify themeans.”

Ethical concerns also arise regarding how the embryosare acquired for research and the possible moral complic-ity of researchers. The statement claims that using dis-carded embryos that are no longer needed by parents forassisted reproduction (clinical need) is less problematicthan the creation of embryos for the specific purpose ofresearch. However, the use of embryos that are no longerclinically needed as children for the couple using in vitrofertilization techniques still can cause “ethical problemsrelated to obtaining adequate informed consent fromdonors, ensuring privacy of donors, and decreasing po-tential or perceived conflicts of interest by those who mayrequest the donation and concerns about undue financialinducement to acquire embryos.” These concerns are

addressed by recommending limiting human embryoresearch to a set of eight conditions and suggesting agroup of considerations for obtaining informed consentfrom donor parents. The eight recommended conditionsare:

1. The embryos are already frozen and no longer areclinically needed.

2. A clear separation exists in the donor decisionprocess between the decision by the donors to createembryos for infertility treatment and the decision todonate frozen embryos for research purposes after theyare no longer clinically needed.

3. The decision to donate is strictly voluntary andwithout monetary inducements.

4. The physician responsible for fertility treatments isnot to be the person performing the research on the samefrozen embryos, and there should be no monetary rela-tionship, that is, transfer of funds in the research projectto the physician responsible for the fertility treatments.

5. There are to be no personal identifiers associatedwith the embryos used for research.

6. No restrictions can be placed by the donor on thetype of research performed.

7. The research performed on the frozen embryos canbe of no direct benefit to the original donors.

8. The embryo research does not involve research inreproductive cloning, transferring an altered embryo to awoman’s uterus, or using a human embryo in combina-tion with other human or animal embryos.

A unique status of the individual human embryo isacknowledged, and the following limitations are pro-posed as safeguards: 1) research is to be limited toembryos in the first 14 days after fertilization, and2) funding and additional oversight at the federal levelare appropriate, including the creation of a new Depart-ment of Health and Human Services committee to over-see human embryo research specifically and develop eth-ical guidelines for its use.

CommentThe moral standing of the embryo has generated signif-icant debate in the public sector, and this statement, notsurprisingly, created some controversy. Drs Chesney,Botkin, and Nelson responded for the Committees onPediatric Research and Bioethics to a letter to the editorof Pediatrics, stating, “Given the fundamental disagree-ments over the moral status of embryos, it probably isimpossible to develop a position on this subject that allwould consider acceptable.” (1) These fundamental dis-agreements are not scientific in origin because all partieswould agree that the human embryo is a being of human



origin. The disagreement, rather, is the result of differentperspectives on the meaning and ramifications of pro-tecting human value and dignity. Those who hold to aview that the human embryo is deserving of full moralrespect point out that various criteria have been usedwrongly during different periods of human history toidentify beings of human origin not believed to be wor-thy of full human value, dignity, and respect. Thesecriteria have included: location, ethnicity, mental capac-ity, stage of development, and sex (especially female sex).It is argued that a similar injustice is done when humanembryos are denied full protection because they aremembers of the human community. To do so wouldprovide a toehold for other potential abuses of humanbeings, a “slippery slope” argument. Those who holdthis view might agree that research has therapeutic po-tential but would say that the ends do not justify themeans.

On the other hand, the argument that the potentialfor scientific progress outweighs morally problematicconcerns is a utilitarian perspective. Research on noncon-senting human embryos, for whom there is no prospectof direct benefit and who would be destroyed in theprocess, could be acceptable from a utilitarian view if thepotential gain for others might outweigh the concern.A developmental perspective is another perspective thatmay be consistent with permitting research on humanembryos. In this view, one would assign different levels ofmoral status to human beings at different stages of de-velopment or capacity, with those individuals at theearliest stages of development being accorded less moralstatus (and, thus, more limited rights) than those later indevelopment.

The AAP recognizes the human embryo as unique, aspecial tissue deserving of respect, but by allowing theiruse in research up to 14 days after fertilization, placesembryos before 14 days of existence as having less moralworth than individuals at later developmental stages.This combining of a utilitarian and developmental per-spective permits the AAP to encourage lifting restrictionson federal funding for research on human embryos insome limited circumstances when the embryo is earlyenough in development, where potential benefit is seen,and where additional oversight is included. The state-ment does not specifically address protections or over-sight for embryos when the research is privately funded.

Other ethical issues in the statement flow out of avalue for the “unique” moral standing of the humanembryo. For example, the issue of the comodification ofhuman embryos is addressed. The Committee expressesconcern about the potential sale of human embryos and

recommends that no embryo be offered for research withmonetary inducements on the part of the physician re-sponsible for fertility treatments, donor parents, or re-searchers. This point of view is prudent because the saleof human gametes for financial profit (via Internet andnewspaper advertisements) is widespread. This issue alsohighlights the needs and challenges of oversight becausecreating embryos is not illegal, and human gametes areeasily procured for cash.

The AAP statement identifies parents as the “donors”who are entitled to represent the interests of the embryo.Parents are required to give their consent to donate theirembryos for research. However, no statement is includeddiscussing if one or both parents must agree with the “forresearch” designation. Concerns about the potential forcoercion of parents by researchers are part of the impetusto recommend that the donation be strictly voluntaryand without monetary inducements.

The limitations on the use of human embryos inresearch provided by the AAP’s statement include aprohibition on the use of embryos for reproductive clon-ing. There is no specific mention of the related researchissue of human “therapeutic” cloning. However, donorconsent in cases of therapeutic cloning would be prob-lematic because there is no separation of the decisionprocess to create the embryo and to use the embryo forresearch/therapeutic purposes (see recommendation 2).

The AAP’s position was challenged in a letter to theeditor. (2) The response included the following state-ment: “We feel that an ongoing debate on these topics ismeaningful, pertinent, appropriate, and a right of allAmerican citizens.” (1) Given the call for meaningfuldebate, this statement can be a launch point for discus-sions on what it means to be human. Do all beings ofhuman origin deserve full moral status, worth, and hu-man dignity? If not, why not? If so, how does one justifydrawing a line on the continuum of human develop-ment? Where do we draw the line? How do we safeguardagainst turning beings of human origin into commodi-ties or parts for sale? Are humans worth more than thesum of and sale of their parts? (3)(4)(5)

References1. Committee on Bioethics and Committee on Pediatric Research.Embryonic stem cell research. Pediatrics. 2002;109:990–9912. June P. Embryonic stem cell research. Pediatrics. 2002;109:990–9913. Devolder K. Creating and sacrificing embryos for stem cells.J Med Ethics. 2005;31:366–3704. Cheshire WP. Human embryo research and the language ofmoral uncertainty. Am J Bioethics. 2004;4:1–5



5. Cameron C, Williamson R. In the world of Dolly, when does ahuman embryo acquire respect? J Med Ethics. 2005;31:215–220

ConclusionThe AAP periodically publishes policy statements andguidelines addressing difficult ethical issues that physi-cians caring for children will continue to face. This reviewis intended to provide readers an overview of some ofthose guidelines and possibly stimulate additionalthought and dialogue within the profession. It is pre-sented by the AAP Section on Bioethics as part of itsmission to foster education in this area among pediatri-cians. As the commentaries suggest, there may not beunanimity about the positions taken, which is importantto recognize. The full text of each policy, as well as otherrelevant references and information, can be found on theweb site for the Section on Bioethics at http://www.aap.org/sections/bioethics.

The Section on Bioethics serves primarily an educa-tional role within the AAP and beyond. They organizeeducational forums in bioethics at the annual AAP Na-

tional Conference and Exhibition, publish a newsletterthat includes original articles in the area of bioethics, andcarry out other educational efforts intended primarily forpediatricians. In addition, they provide input to theBoard of Directors and other committees regarding pro-posed policy statements and guidelines. Membership inthe Section is open to all AAP Fellows who have aninterest in bioethics. Affiliate membership also is availableto physicians and other health professionals not eligiblefor AAP membership.

This is the first in a series of three articles on AAPpolicies that address ethical issues in pediatrics. The nexttwo articles will appear in subsequent issues of Pediatricsin Review.

ACKNOWLEDGMENTS. The authors would like tothank Marilyn A. Maxwell, MD, and Brenda Jean Mears,MD, their colleagues on the AAP Section on BioethicsExecutive Committee, for guidance and helpful com-ments in the preparation of this manuscript.



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