01 Pediatrics in Review - Jan2008

Editor-in-Chief: Lawrence F. Nazarian, Rochester, NY Associate Editors: Tina L. Cheng, Baltimore, MD Joseph A.
Zenel, Portland, OR Editor, In Brief: Henry M. Adam, Bronx, NY Consulting Editor: Janet Serwint, Baltimore, MD Consulting Editor Online and Multimedia Projects: Laura Ibsen, Portland, OR Editor Emeritus and Founding Editor: Robert J. Haggerty, Canandaigua, NY Managing Editor: Luann Zanzola Medical Copy Editor: Deborah K. Kuhlman Editorial Assistant: Sydney Sutherland Editorial Ofce: Department of Pediatrics University of Rochester School of Medicine & Dentistry 601 Elmwood Avenue, Box 777 Rochester, NY 14642 sydney_sutherland@urmc.rochester.edu Editorial Board Margie Andreae, Ann Arbor, MI Richard Antaya, New Haven, CT Laurence A. Boxer, Ann Arbor, MI Latha Chandran, Stony Brook, NY Joseph Crofe, Indianapolis, MD Howard Eigen, Indianapolis, IN Leonard Feld, Charlotte, NC Jeremy N. Friedman, Toronto, ON Vincent A. Fulginiti,Tucson, AZ Mark Goldstein, Boston, MA Lindsey Grossman, Baltimore, MD Russell J. Hopp, Omaha, NE Hal B. Jenson, Springeld, MA Chris P. Johnson, San Antonio, TX J. Jeffrey Malatack, Narberth, PA Blaise Nemeth, Madison, WI John Pascoe, Dayton, OH DeWayne Pursley, Boston, MA Thomas T. Sato, Milwaukee, WI Bennett A. Shaywitz, New Haven, CT Michael Silberbach, Portland, OR Nancy Spector, Philadelphia, PA Surendra K. Varma, Lubbock, TX Maximilian Zach, Graz, Austria Publisher: American Academy of Pediatrics Michael J. Held, Director, Division of Scholarly Journals and Professional Periodicals
PediatricsinReview
contents
Vol.29 No.1 January 2008
Commentary
3 5 12 25 31 33
A Flood of Information
Lawrence F. Nazarian
Articles
Varicella-Zoster Virus Infections
Anne A. Gershon
Neutropenia in Pediatric Practice

George B. Segel, Jill S. Halterman
Index of Suspicion
Cherilyn Hall, Allen Friedland, Sumathi Sundar, Kathryn S. Torok, Mananda S. Bhende, Grace Pecson, Carolyn Leedy
Pediatrics in the Community:

Community Pediatrics Training Initiative (CPTI)
Jeffrey Kaczorowski
Pediatrics in Review
(ISSN 0191-9601) is owned and controlled by the American Academy of Pediatrics. It is published monthly by the American Academy of Pediatrics, 141 Northwest Point Blvd, Elk Grove Village, IL 60007-1098 Statements and opinions expressed in Pediatrics in Review are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees. Recommendations included in this publication do not indicate an exclusive course of treatment or serve as a standard of medical care. Subscription price for 2008 for print and online/ online only: AAP Fellow $163/$124; AAP Candidate Fellow $153/$114; Nonmember $204/$159; Allied Health or Resident $152/ $103. Institutions call for pricing (866-8432271). For overseas delivery, add $95. Current single issue price is $10 domestic, $12 international. Replacement issues must be claimed within 6 months from the date of issue and are limited to three per calendar year. Periodicals postage paid at ARLINGTON HEIGHTS, ILLINOIS and at additional mailing ofces. AMERICAN ACADEMY OF PEDIATRICS, 2008. All rights reserved. Printed in USA. No part may be duplicated or reproduced without permission of the American Academy of Pediatrics. POSTMASTER: Send address changes to PEDIATRICS IN REVIEW , American Academy of Pediatrics Customer Service Center, 141 Northwest Point Blvd., Elk Grove Village, IL 60007-1098. The printing and production of Pediatrics in Review is made possible, in part, by an educational grant from Ross Products Division, Abbott Laboratories.
In Brief
Inhalants
Internet-Only Article
Abstract appears on page 35.
e1
American Academy of Pediatrics Policy Statements on Bioethics:

Summaries and Commentaries: Part 1
Mark R. Mercurio, Mary B. Adam, Edwin N. Forman, Rosalind Ekman Ladd, Lainie Friedman Ross, Tomas J. Silber
Answer Key:
1. A; 2. E; 3. A; 4. E; 5. C; 6. B; 7. A; 8. B; 9. E; 10. D
Cover: The artwork on the cover of this months issue is by one of the winners of our 2005 Cover Art Contest, 11-year-old Elizabeth Emery of Hamilton, Va. Elizabeths pediatricians are with Ashburn Pediatrics.
A Flood of Information Lawrence F. Nazarian Pediatr. Rev. 2008;29;3-4 DOI: 10.1542/pir.29-1-3
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/cgi/content/full/29/1/3
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2008 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.
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commentary
Commentary
A Flood of Information
Many elements in our lives can overwhelm us and overload our circuits, including responsibilities, worries, and conicting appointments. Even some treats we enjoy can get to be too much, such as tomatoes in the garden at the peak of the season, photographs waiting to be organized, and exceptional books crying out to be read. Another ood that threatens to engulf us is information. Even if we ignore the obviously misleading or irrelevant rivers of data owing toward our minds, there is enough worthwhile, relevant, desirable information coming our way to sweep us over the falls. Restricting our focus to medical knowledge, and even further to an understanding of pediatric medicine, we still nd that sector of the information ocean stretching out to the horizon and getting bigger every year. There used to be lectures, seminars, workshops, textbooks, and journals. All of these sources have multiplied, and we have added continuing medical education courses, teleconferences, CDs and DVDs, and that innite highway to knowledge about everything under the sun and beyond, the Internet. No wonder many practitioners feel they are lost at sea and going down for the third time. Pediatrics in Review (PIR) and the PREP program exist to throw you a life preserver and a compass. Our primary mission is to focus on the essentials of pediatric medicine and to present current thinking about each aspect of that body of knowledge to keep readers up to date. We are fortunate to have access to the content specications of the American Board of Pediatrics, which has created a database that denes that core. In any given 5-year period, PIR and the PREP SelfAssessment cover that content, allowing readers to refresh their knowledge in a constant, renewing fashion. In the process, steady readers are preparing themselves for the cognitive testing involved in maintenance of certication. We continue to recruit our material from the best teachers in our profession and to spend countless hours making what is written readable and lucid. The individuals who produce PIR at all levels know what it is like to come home after a long day and try to learn even more. With that sensitivity, we attempt to make our teaching as user-friendly as we can. Realizing that there are relevant and interesting topics outside the core content, we have expanded our horizons, adding two new sections in the last 2 years. Many parents are using or asking about therapies outside of conventional medicine, and we publish a regular series on complementary and alternative treatments. As strong believers in the role of pediatricians in the wider community, we publish another regular feature on community pediatrics that highlights innovative and effective programs in that area. Our electronic edition has allowed us to broaden the spectrum of pediatric subjects even further. By publishing one or two articles each month in the online-only format, we have created new space to give our readers insights into topics such as telemedicine, continuing medical education, and the electronic medical record. The electronic capability has allowed us to provide recordings of heart murmurs as well as still and moving pictures. The online edition also allows for Rapid Response, through which readers can give us instant feedback on articles and we can provide clarications with equal speed. We urge readers who are using the online journal to click the Rapid Response line every time they read an article to see if there is any information that has been added after publication. Most clarications are published in the print edition as well, but with an inevitable lag time. We have extended our reach beyond our borders in several ways. Clinicians in developing countries can access the electronic version of the journal free of charge. Authors from around the world have contributed material, especially through Index of Suspicion cases, which have come from authors living in 22 countries. We have published a commentary from Italy as part of an article on evaluation of athletes, and we hope to bring you more of these perspectives. PIR has been published in Chinese, Italian, Hungarian, Polish, and Spanish, with a Turkish translation starting up. Residents rank among our most avid readers, and we have a special relationship with these young physicians. Many residents have written Index of Suspicion cases, and each year we choose a case from their case-writing contest to publish. Focus on Diagnosis, now in its fourth year, is written exclusively by residents, who share their knowledge of cutting-edge diagnostic procedures. All pediatric residents in the United States receive a complementary subscription to PIR, funded mainly by an unrestricted grant from Abbott Nutrition. A great many people work hard to make PIR what it is, and I would like to
Pediatrics in Review Vol.29 No.1 January 2008 3
commentary
acknowledge the contributions of Drs Tina Cheng and Joseph Zenel, our invaluable Associate Editors; Drs Henry Adam and Janet Serwint, who prepare the In Brief articles; Dr Laura Ibsen, who provides media of all kinds; and our Medical Copy Editor Deb Kuhlman. AAP staff members Luann Zanzola, Susan Piscoran, Michael Held, and Dr Robert Perelman give us constant sup-
port, as does our Editor Emeritus, Dr Robert Haggerty. Our publishers, Cadmus and Highwire, create the nal product. The whole operation is held together by Sydney Sutherland, our Editorial Assistant. PIR is privileged to have an Editorial Board of the nest pediatricians and teachers available anywhere, and I extend to them my deep gratitude for the
countless hours they donate to make this journal what it is. Finally, thanks go out to our thousands of readers around the world. You, and especially the children for whom you care, are why we exist.
Lawrence F. Nazarian, MD Editor-in-Chief
4 Pediatrics in Review Vol.29 No.1 January 2008
A Flood of Information Lawrence F. Nazarian Pediatr. Rev. 2008;29;3-4 DOI: 10.1542/pir.29-1-3
Updated Information & Services Permissions & Licensing
including high-resolution figures, can be found at: http://pedsinreview.aappublications.org/cgi/content/full/29/1/3 Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pedsinreview.aappublications.org/misc/Permissions.shtml Information about ordering reprints can be found online: http://pedsinreview.aappublications.org/misc/reprints.shtml
Reprints
Varicella-Zoster Virus Infections Anne A. Gershon Pediatr. Rev. 2008;29;5-11 DOI: 10.1542/pir.29-1-5
Article
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Varicella-Zoster Virus Infections

Anne A. Gershon, MD*
Objectives
After completing this article, readers should be able to:
Author Disclosure Dr Gershon has disclosed that she occasionally is a consultant and lecturer for Merck and Company, Inc, and GlaxoSmithKline.
1. Describe the natural history and pathogenesis of varicella and zoster and how these diseases are related. 2. Explain to patients and parents the complex role of this virus in causing disease and how 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 Pathogen
Varicella-zoster virus (VZV), a close but distinct relative of the other seven human herpesviruses, including herpes simplex virus (HSV), causes two diseases. Varicella (chickenpox), a generalized illness, is its primary infection, and zoster (shingles) is its secondary infection, caused by reactivation of VZV from latency. Varicella infection occurs in almost all people over their lifetimes. VZV becomes latent after varicella and usually persists silently and indenitely. VZV reactivates, however, to cause zoster in roughly 20% of individuals, with higher reactivation rates in immunocompromised patients and the elderly.
Epidemiology
In the prevaccine era in the United States prior to 1995, approximately 4 million cases of varicella and 1 million cases of zoster occurred annually. Varicella was primarily a disease of children younger than age 10 years and zoster an illness of adulthood. Childhood varicella infection, however, is less common than adult infection in countries that have tropical climates. Varicella occurs in children who have no humoral or cellular immunity to VZV, termed susceptibles. Zoster occurs in individuals who previously have had varicella; they usually have detectable specic antibody titers, but have low or absent cell-mediated immunity (CMI) to VZV. VZV spreads primarily from the skin vesicles of persons who have varicella or zoster to the respiratory tract of susceptible persons, who then become infected. Electron microscopic studies have shown a high concentration of well-formed, cell-free VZV in skin vesicles. (1) Respiratory spread is difcult to rule out entirely, but during disease, it is rare to 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 skin vesicles 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 infected individual for transmission. Evidence for spread of VZV from skin is as follows. A 14% transmission rate of the vaccine (Oka) strain of VZV occurred when susceptible siblings were exposed to a recently immunized child who had leukemia and had a vaccine-associated rash. No transmission occurred if the vaccinee had no rash, and VZV could not be isolated from the throats of any of vaccinees, whether or not they had a vaccine-associated rash. Transmission rates were directly proportional to the number of skin lesions. Recent observations in otherwise healthy children who contracted wild-type breakthrough varicella after immunization also have 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. Pediatrics in Review Vol.29 No.1 January 2008 5
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children who had active varicella and were not excluded from school on day 1 after rash onset played a major role in spreading the virus in their classrooms. (4) Finally, spread of VZV to observers during an autopsy indicates that transmission by other means than the respiratory tract must occur. (5) VZV is highly communicable, and subclinical infection is unusual; clinical infection develops in about 80% of susceptibles after family exposure. In contrast, in healthy vaccinees, the Oka strain very rarely spreads to others, even if a rash is present. Patients who have zoster can transmit varicella to others because the vesicular lesions contain infectious VZV. About 100 years ago, during early attempts to develop a VZV vaccine, children were inoculated with vesicular uid from zoster patients, and they developed mild chickenpox. Zoster, however, is less contagious than varicella. The incubation period of varicella ranges from 10 to 23 days (average, 14 days). During the incubation period, VZV multiplies, spreads to regional lymph nodes, and causes viremia. Wild-type VZV has been isolated from blood cultures just before and during very early chickenpox in immunocompetent children. An attractive, recently proposed pathogenetic mechanism is that VZV reaches keratinocytes soon after infection by way of VZV-infected CD4 memory T cells from infected tonsillar cells. These lymphocytes normally circulate through the skin, engaged in immune surveillance; some also become infected with VZV as they circulate, spreading the virus in the body. In this model, overcoming innate immunity in skin accounts for the 2- to 3-week incubation period following infection, as reviewed by Gershon and associates. (6) Second attacks of varicella are uncommon but may occur. Asymptomatic immunologic boosting of VZV immunity occurs after re-exposure to VZV in varicellaimmune individuals and may play a role in long-term maintenance of immunity to VZV. Patients who develop zoster usually have a history of previous varicella. Zoster can occur in childhood; the incidence is increased by a factor of as much as 20 in those who had varicella in utero or before age 2 years, possibly because the immune response to VZV in young infants is immature. Infants aficted with the congenital varicella syndrome are at even greater risk for developing zoster. The incidence of zoster is age-related and begins to increase sharply at 50 years of age. (7) Loss of VZV CMI, which occurs during normal aging, is related to development of zoster. In keeping with this observation, zoster
can be prevented by immunization. Zoster also develops commonly in patients treated for cancer and after organ transplantation. Spinal trauma, irradiation, and corticosteroid therapy are other precipitating factors for zoster. Children infected with human immunodeciency virus (HIV) are at increased risk for developing zoster. Children who develop zoster should be screened (usually by history) for possible risk factors such as HIV infection and underlying immunodeciency; most often, however, no predisposing factors are identied. On occasion, zoster occurs in healthy children or young adults. Presumably, such infection is the result of a transient decrease in CMI to VZV, perhaps caused by another inapparent viral infection. Low CMI to VZV is a necessary, but not sufcient, requirement for the development of zoster.
The Diseases
Clinical Manifestations
Varicella usually is a mild-to-moderate illness in children. It often is more severe in adults. Even in children, however, varicella cannot be counted on to be entirely benign. After a short or absent prodrome, skin lesions appear. These start as macules and progress rapidly to papules, vesicles, pustules, and scabs. The rash is concentrated on the trunk and head rather than on the extremities; it normally evolves as a series of successive crops over 3 to 4 days. Most children have 250 to 500 supercial skin lesions, many of which are vesicular. Subclinical elevations of hepatic transaminase concentrations are a common, self-limited occurrence during varicella. Zoster usually appears as a unilateral vesicular skin eruption involving one to three dermatomes. Skin vesicles may be painful or pruritic, especially in adults. Zoster generally is a milder disease in children than in adults. From 25% to 50% of persons older than 50 years of age and the same proportion of immunocompromised patients who acquire zoster experience serious pain, termed post-herpetic neuralgia (PHN), after the rash has healed. The cause of PHN is unknown.
Complications
The most common complication of varicella is bacterial superinfection of the skin, lungs, or bones, most often by Staphylococcus aureus or group A beta-hemolytic streptococci (GAS). Such infections may be severe and even fatal. Whether treatment with ibuprofen is associated with increased severity of GAS after varicella remains unresolved. Therefore, this drug is not recommended for treatment of fever accompanying varicella. Central nervous system (CNS) complications, which
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may precede or follow varicella, include transient cerebellar ataxia, encephalitis, aseptic meningitis, and transverse myelitis. Most CNS complications are self-limited, except for encephalitis, which frequently is associated with severe sequelae if the patient survives. Other less frequent complications of chickenpox include arthritis, glomerulonephritis, myocarditis, and purpura fulminans.
Immunocompromised Patients
Varicella may be severe and even fatal in immunocompromised patients, particularly those who have malignancy or congenital decits in CMI, as well as in those who have undergone organ transplantation, have underlying HIV infection, or are receiving high doses of corticosteroids. Immunocompromised children who have severe varicella tend to have high fevers, extensive rashes lasting for more than 1 week, hepatitis, and primary viral pneumonia, which may be fatal despite antiviral therapy. Children who have leukemia have a 30% rate of disseminated varicella, with a 7% mortality rate. Severe varicella may occur in HIV-infected children, especially in those who have acquired immunodeciency syndrome (AIDS). In most of these children, however, mild-tomoderate varicella occurs, although the illness often is more severe than occurs in healthy hosts.
Congenital and Neonatal Varicella

After maternal VZV infection in the rst or second trimester of pregnancy, approximately 2% of infants develop the congenital varicella syndrome. (8) Approximately 100 affected infants have been described since 1947; more than 95% of cases occurred after maternal varicella and the remainder after possible maternal zoster. In the prevaccine era, an estimated 40 affected infants were born annually in the United States. Cicatricial skin scars (in 60% of cases) are the most prominent abnormalities. Other common manifestations include hypoplastic limbs, chorioretinitis, microphthalmos, Horner syndrome, cataract, nystagmus, cortical atrophy or mental retardation, zoster, and early death.
Diagnosis
Chickenpox generally is diagnosed clinically because of the characteristic vesicular rash and its distribution, as well as through epidemiologic information such as history of exposure and absence of prior varicella. Zoster also presents with a distinct unilateral, dermatomal, vesicular rash that is diagnosed clinically. Laboratory diagnosis can be used in questionable instances and is facilitated by the accessibility of the virus in supercial skin lesions. (9) The diagnosis is made most denitively by
demonstration of specic viral antigens in skin scrapings by immunouorescence (DFA) using a commercial monoclonal antibody to VZV conjugated to uorescein or by polymerase chain reaction (PCR). These diagnostic methods are highly sensitive and rapid. Diagnosis also may be made by isolating the virus from skin lesions, but this technique is more complicated and expensive, is less sensitive, and takes longer than DFA or PCR. VZV rarely can be isolated from cerebrospinal uid (CSF) and respiratory secretions. The presence of VZV or antigens in secretions or tissues is diagnostic of acute VZV infection because this virus is not shed by asymptomatic persons. The Tzanck test is not recommended by this author because it lacks sensitivity and specicity. Testing of skin scrapings, vesicular uid, respiratory secretions, and CSF by PCR is useful for diagnosing VZV, and PCR is replacing culture in many laboratories. PCR is available widely in commercial laboratories and can distinguish between vaccine and wild-type VZV. Many serologic tests measure antibodies to VZV, including uorescent antibody to membrane antigen, latex agglutination, and enzyme-linked immunosorbent assay (ELISA). Antibody to VZV develops rapidly after the onset of varicella and persists indenitely. Peak antibody concentrations occur after 4 to 8 weeks. VZV infections may be proven by a fourfold or greater rise in VZV antibody titer in acute and convalescent serum specimens. Specic immunoglobulin M in one serum specimen suggests recent VZV infection. Persistence of VZV antibody in infants older than 8 months of age suggests intrauterine varicella. Immunity to varicella is highly likely if there is a positive antibody titer to VZV in a single serum sample in a healthy patient. Commercial ELISAs, however, usually are not sufciently sensitive to identify the level of immunity that develops in vaccinees. After active immunization against VZV, antibody titers are signicantly lower than after natural infection. Serologic procedures for diagnosing zoster are limited because of the nonspecic increases in antibody titer against VZV in some patients who have active HSV infection. These viruses also share minor antigens, which can 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 defense against the virus. CMI to VZV can be demonstrated in vitro most practically by stimulation of lymphocytes with VZV antigens and by an interferon-gamma enzymelinked immunosorbent spot (ELISPOT) assay. CMI rePediatrics in Review Vol.29 No.1 January 2008 7
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actions remain positive for years, although CMI often wanes in individuals older than 50 years of age.
Treatment
Nonspecic treatment for varicella includes oral antihistamines, frequent bathing, calamine lotion, oatmeal baths, and the trimming of ngernails to discourage scratching. Fever should be controlled with acetaminophen. Use of aspirin for this purpose may predispose to Reye syndrome, and ibuprofen may predispose to GAS infection.
Indications for Specic Treatment

Because most varicella infections are not serious and the illness usually is self-limited in otherwise healthy children, oral acyclovir (ACV) is not administered routinely. Further, the drug is not well absorbed from the gastrointestinal tract. Specic therapy is reserved for those at higher risk for developing severe varicella or those who already have severe disease. Because controlled studies in children and adolescents given oral ACV for 5 days, starting within 24 hours of the rash of varicella, have shown a modest benet, prompt oral ACV therapy usually is recommended for adolescents and young adults, who are at moderately high risk for developing severe illness. (10)(11)(12) The oral dose is 20 mg/kg qid for children and 1 g qid for adolescents. The antiviral activity of ACV depends on its phosphorylation by virus-induced thymidine kinases. Patients at serious risk for or who have severe or potentially severe VZV infections should be treated with intravenous (IV) ACV (10 mg/kg per dose tid for adults and adolescents and 500 mg/m2 per dose tid for children). Patients whose creatinine clearance is less than 50 mL/min per 1.73 m2 are given one half to one third of this dosage, with slow infusion, making sure that hydration is adequate. ACV usually is tolerated very well, but adverse effects include phlebitis, rash, nausea, and neurologic symptoms. Children who are relatively immunocompromised, such as those who have early, seemingly mild varicella and those who have early HIV infection (not AIDS), may be given a closely monitored treatment trial of oral ACV and switched to IV ACV if clinically necessary. In those who have zoster, IV or oral ACV heals skin lesions rapidly and resolves pain. Development of drug resistance to ACV is of potential concern. Resistance of VZV has been less of a problem than with HSV; VZV resistant to ACV has been reported only rarely. A vaccinated child who had neuroblastoma and developed zoster due to the Oka strain that was
resistant to ACV after prolonged treatment has been described. Because data are few regarding the effectiveness of ACV for preventing chickenpox in susceptible healthy children, its use for this purpose is discouraged. Famciclovir, an orally administered prodrug of ACV, is converted to ACV in the body, with resulting higher drug concentrations than oral ACV itself. Famciclovir is administered three times a day for zoster (1,500 mg/d) for adults but is not approved either for children or for treatment of varicella. Another oral prodrug of ACV, valacyclovir, achieves higher concentrations of ACV than does famciclovir, but also is not licensed in the United States for use in children or for varicella. Foscarnet is used to treat VZV infections that are resistant to ACV; the drug inhibits synthesis of VZV DNA polymerase. The dose of IV foscarnet is 180 mg/kg per day divided into two doses, adjusted if necessary for renal function. Toxicities include renal damage and electrolyte imbalance.
Prevention
Control Measures
It virtually is impossible to protect susceptible individuals from infection with VZV by avoidance because the agent is highly communicable. Transmission is expected to decrease, however, when VZV infection occurs in populations that are highly vaccinated. Children who have chickenpox should be excluded from school or child care from the time the diagnosis is made until the lesions are crusted. Those who have zoster may attend school if the lesions can be covered or when they are crusted. The Table lists facts that can be helpful in advising parents whose children are exposed to chickenpox. Patients who have active VZV infection and are hospitalized should be isolated, preferably in a room that has negative pressure ventilation, to minimize viral transmission. Vaccination of individuals is particularly important if there are family members who cannot be vaccinated, such as a pregnant woman or immunocompromised children. Transmission of the Oka strain from vaccinated individuals, even if they develop a rash, is extremely rare and has been reported after approximately 1 in 10 million vaccinations.
Passive Immunization
Passive immunization is used to protect exposed highrisk persons from developing severe VZV. Treatment is given to persons who have no history of previous VZV disease, are at high risk for developing severe varicella,
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Table.
Information for Parents Who Ask What to Do If Their Child Is Exposed to Chickenpox
1. 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 child has fewer than 50 skin lesions (very mild infection). 4. All children should receive two doses of vaccine; the second dose can be administered as soon as 3 months after the rst and even after an exposure occurs, in which case it might offer additional protection. 5. Rashes caused by the vaccine (Oka) strain (that appear in weeks 2 through 6 after immunization) can be infectious to others, but transmission is very rare (roughly 1/10 million vaccines), and contact cases uniformly are mild.
and have had an intimate exposure to VZV within the preceding 5 days. Formerly, passive immunization was accomplished by injection of varicella-zoster immune globulin (VZIG). VZIG is no longer being produced, however, because there was little demand for it after 1995. A similar product is available from Canada (VariZIG, Cangene Corporation, Winnipeg, Canada) and is recommended for neonates whose mothers have active varicella at or soon after delivery and for exposed susceptible high-risk patients. (13) The product is available in the United States under an investigational new drug application expanded access protocol, with central institutional review board approval. IV immune globulin 400 mg/kg is an alternative should neither VZIG nor VariZIG be available. (13)(14)
Active Immunization
Live attenuated varicella vaccine was developed in Japan in 1974. (15) Since 1995, universal immunization of healthy children and adults in the United States who are susceptible to varicella has been recommended by the Centers for Disease Control and Prevention (CDC). This vaccine is extremely safe and well-tolerated. About 5% of healthy children develop a mild rash approximately 4 to 6 weeks after immunization. Serious neurologic events 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 infection and should be regarded so. Live attenuated varicella vaccine is highly effective in healthy children and adults. Universal vaccination has decreased the incidence, complications, morbidity, and mortality of varicella by roughly 80% in the United States. Although varicella vaccine is highly effective, approximately 20% of children develop mild chickenpox after exposure to wild VZV if they have received only one dose of vaccine. Severe varicella occurs only in about 3% of those who develop breakthrough varicella after vaccination. The vaccine is also 80% effective in adults after two doses. Severe wild-type varicella in vaccinated adults is rare. (6)(14)(16)(17) It is unclear whether breakthrough varicella is the result 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 vaccinated children, even after a follow-up for as long as 20 years. Between years 1 and 8 after immunization, there has not been a decrease in protection of healthy children. There have been, however, numerous recent reports of outbreaks of varicella among immunized children in child care facilities and schools. Most investigations of outbreaks 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 the most part, received only one dose of vaccine. A recent investigation indicated a signicant degree of primary vaccine failure (24%) in young children who received only one dose of vaccine. (18) To decrease virus transmission, improve vaccine effectiveness, and prevent accumulation of susceptible young adults, two doses of vaccinepreviously recommended only for those older than 13 years of agewere recommended for all children by the CDC in June 2006. Catch-up varicella vaccination also is recommended for all children who received only one dose of varicella vaccine in the past. After a second dose of varicella vaccine, there is a marked boost in both humoral and cellular immunity, and the second dose is tolerated very well without signicant complications. One small study indicated improved protection after two doses compared with one dose over 10 years of followup. (19) Another important recent advance for varicella immunization was the development of the combined measlesmumps-rubella-varicella (MMRV) vaccine, which was approved by the United States Food and Drug Administration in 2005. MMRV contains about 10 times the amount of VZV as the monovalent formulation and is
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licensed only for children younger than 14 years of age. Currently, most infants and children will be immunized with two doses of MMRV after the shortage of this vaccine is corrected. (20) Varicella vaccine also is recommended for susceptible adults, especially for healthcare workers and persons whose varicella-susceptible family members are immunocompromised or pregnant. Varicella vaccine is recommended only for healthy persons. Zoster appears to be less of a problem after immunization than after natural infection. The CDC now recommends postexposure vaccination for healthy varicella-susceptible exposed individuals. Recently, a successful vaccine has been developed to prevent zoster in older adults; this vaccine is the Oka strain of VZV, given at a dose roughly 14 times greater than that in the monovalent formulation. One dose of this vaccine is recommended for healthy individuals older than age 60 years who have had varicella but not zoster. This vaccine is 50% to 60% protective against zoster and its major complication, PHN. (7)
Summary
As a herpesvirus, VZV causes acute varicella, latent infection, and zoster. The virus has the potential to cause serious infections, which may be difcult to treat. Complications include bacterial superinfections, CNS abnormalities, and a host of more unusual problems such as pneumonia and hepatitis. Immunocompromised patients, pregnant women and their infants, and the elderly are at highest risk of developing severe and even fatal illnesses. In modern times, successful specic drug therapy has been developed. More recently, medical emphasis has been on prevention of illness by vaccination. Due to the three-pronged approaches of passive immunization, active immunization, and antiviral therapy, the morbidity and mortality from VZV infections have decreased impressively in the past 20 years. With continued use and ne tuning of these modalities, particularly active immunization, additional progress should be made, resulting in the possibility of these infections becoming unusual in the developed world.
References
1. Chen JJ, Zhu Z, Gershon AA, Gershon MD. Mannose
6-phosphate receptor dependence of varicella zoster virus infection
in vitro and in the epidermis during varicella and zoster. Cell. 2004;119:915926 2. Hambleton S, Gershon AA. Preventing varicella-zoster disease. Clin Microbiol Rev. 2005;18:70 80 3. Seward JF, Zhang JX, Maupin TJ, Mascola L, Jumaan AO. Contagiousness of varicella in vaccinated cases: a household contact study. JAMA. 2004;292:704 708 4. Ma H, Fontaine R. Varicella outbreak among primary school studentsBeijing, China, 2004. MMWR Morbid Mortal Wkly Rep. 2006;55(suppl 1):39 43 5. Paul N, Jacob ME. An outbreak of cadaver-acquired chickenpox in a health care setting. Clin Infect Dis. 2006;43:599 601 6. Gershon A, Takahashi M, Seward J. Varicella vaccine. In: Plotkin S, Orenstein W, eds. Vaccines. 5th ed. Philadelphia, Pa: Saunders; 2008; in press 7. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:22712284 8. Gershon A. Chickenpox, Measles, and Mumps. 6th ed. Philadelphia, Pa: Saunders; 2006 9. Gershon A, Chen J, LaRussa P, Steinberg S. Varicella-zoster virus. In: Murray PR, Baron E, Jorgensen J, Landry M, Pfaller M, eds. Manual of Clinical Microbiology. 9th ed. Washington, DC: ASM Press; 2007:15371548 10. Whitley RJ, Middlebrooks M, Gnann JW. Acyclovir: the past ten years. Adv Exp Med Biol. 1990;278:243253 11. Balfour HH, Rotbart H, Feldman S, et al. Acyclovir treatment of varicella in otherwise healthy adolescents. J Pediatr. 1992;120: 627 633 12. Dunkel L, Arvin A, Whitley R, et al. A controlled trial of oral acyclovir for chickenpox in normal children. N Engl J Med. 1991; 325:1539 1544 13. Centers for Disease Control. A new product (VariZIG) for postexposure prophylaxis of varicella available under an investigational new drug application expanded access protocol. MMWR Morbid Mortal Wkly Rep. 2006;55:209 210 14. Centers for Disease Control. Prevention of varicella. MMWR Morbid Mortal Wkly Rep. 2007;56:1 40 15. Takahashi M, Otsuka T, Okuno Y, Asano Y, Yazaki T, Isomura S. Live vaccine used to prevent the spread of varicella in children in hospital. Lancet. 1974;2:1288 1290 16. Vazquez M, LaRussa P, Gershon A, Steinberg S, Freudigman K, Shapiro E. The effectiveness of the varicella vaccine in clinical practice. N Engl J Med. 2001;344:955960 17. Vazquez M, LaRussa PS, Gershon AA, et al. Effectiveness over time of varicella vaccine. JAMA. 2004;291:851 855 18. Michalik D, La Russa P, Steinberg S, Wright P, Edwards KM, Gershon A. Primary immune failure after 1 dose of varicella vaccine may be the main cause of breakthrough infections in healthy vaccinated children. J Infect Dis. 2008; in press 19. Kuter B, Matthews H, Shineeld H, et al. Ten year follow-up of healthy children who received one or two injections of varicella vaccine. Pediatr Infect Dis J. 2004;23:132137 20. Centers for Disease Control. Supply of vaccines containing varicella-zoster virus. MMWR Morbid Mortal Wkly Rep. 2007;56: 146 147
infectious diseases
varicella
PIR Quiz
Quiz also available online at www.pedsinreview.org. 1. Infections of susceptible persons with the wild-type varicella-zoster virus (VZV) are transmitted primarily through: A. B. C. D. E. Aerosols from skin lesions of infected individuals. Direct contact with a skin vesicle that has a damaged mucosal surface. Direct contact with a skin vesicle that has damaged skin. Respiratory droplets from individuals who have skin lesions. Respiratory droplets from subclinically infected individuals.
2. In a previously healthy 5-year-old child, the appearance of zoster most likely reects a: A. B. C. D. E. Life-threatening defect in cellular immunity. Life-threatening defect in humoral immunity. Primary VZV vaccine failure. Temporary phagocytic dysfunction. 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. B. C. D. E. Acetaminophen. Acetylsalicylic acid. Acyclovir. Cephalexin. Ibuprofen.
4. An 11-month-old girl who has acute lymphoblastic leukemia in early remission was inadvertently exposed to varicella 1 day ago. To reduce the risk of life-threatening varicella, within 72 hours she should receive: A. B. C. D. E. An increase in her dose of prednisone. Intravenous acyclovir. Oral acyclovir. Subcutaneous VZV vaccine (Oka strain). VariZIG.
5. You are asked to speak with a group of medical students about varicella vaccine. Your most appropriate statement is that after initial immunization: A. B. C. D. E. Breakthrough varicella generally is severe. Neurologic complications remain a serious concern. Primary vaccine failure is relatively common. Transmission of attenuated virus is common. Zoster incidence is unchanged.
Varicella-Zoster Virus Infections Anne A. Gershon Pediatr. Rev. 2008;29;5-11 DOI: 10.1542/pir.29-1-5
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Article
hematology/oncology
Neutropenia in Pediatric Practice

George B. Segel, MD,* Jill S. Halterman, MD, MPH
Objectives
After completing this article, readers should be able to:
Author Disclosure Drs Segel and Halterman did not disclose any nancial relationships relevant to this article.
1. Describe when a patient has true neutropenia, understanding the variation with age and 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.
Introduction
The signicance of neutropenia is a common query to hematology specialists from primary care physicians. Severe neutropenia is dened as an absolute neutrophil count (ANC) of fewer than 500/mcL (0.5 109/L) and is a common and expected complication of chemotherapy for childhood neoplasms. This article considers those patients who have neutropenia unrelated to chemotherapy toxicity. This type of neutropenia may be noted when a complete blood count (CBC) is performed in a sick newborn, a febrile child, a child taking chronic medication, or as part of a routine evaluation. Severe hereditary conditions such as Kostmann syndrome and certain immunodeciency syndromes associated with neutropenia are rare, perhaps 1 per 100,000, and are more likely to present in neonates and infants, although acquired conditions such as immune neutropenia and neutropenia related 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 related to medication use as well as in some healthy persons of African ancestry. A number of inherited conditions associated with neutropenia are associated with other congenital anomalies such as dysplastic thumbs in Fanconi anemia, albinism in Chediak-Higashi syndrome, and dwarsm in the cartilage hair or Shwachman-Diamond syndromes.
When to Order a CBC

A CBC is not ordered routinely for well children examined in the pediatricians ofce or when children present with common febrile illnesses such as upper respiratory tract infections or otitis media. A CBC is warranted if clinical ndings suggest a more severe bacterial infection. Such clinical ndings include, but are not limited to, recurrent infections; prolonged or extreme fever ( 103F [39.5C]); the spreading of localized bacterial infection; infection of the lung, peritoneum, genitourinary tract, or central nervous system; and suspicion of chronic inammatory disease, immunodeciency, or malignancy. A CBC also may be warranted if a patients clinical course is atypical, prolonged, or complicated by signs and symptoms suggesting the development of a secondary bacterial infection.
Normal Values for the ANC and the Denition of Neutropenia

Normal values for the ANC vary by age, particularly during the rst weeks after birth. Normal leukocyte counts and ANCs for children from birth to age 21 years are shown in Table 1. The ANC range is shown for each age, as well. The lower limit of normal is 6,000/mcL (6.0 109/L) during the rst 24 hours after birth, 5,000/mcL (5.0 109/L) for the rst 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. 12 Pediatrics in Review Vol.29 No.1 January 2008
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Table 1.
Normal Blood Leukocyte Counts*

Total Leukocytes Neutrophils Mean 11.0 15.5 11.5 5.5 4.5 3.8 3.8 3.5 3.5 3.8 4.3 4.4 4.4 4.4 4.4 (Range) (6.0 to 26.0) (6.0 to 28.0) (5.0 to 21.0) (1.5 to 10.0) (1.0 to 9.5) (1.0 to 9.0) (1.0 to 8.5) (1.5 to 8.5) (1.5 to 8.5) (1.5 to 8.5) (1.5 to 8.0) (1.5 to 8.0) (1.8 to 8.0) (1.8 to 8.0) (1.8 to 7.7) % 61 68 61 45 40 35 32 31 33 42 51 53 54 57 59 Mean 5.5 5.5 5.8 5.0 5.5 6.0 7.3 7.0 6.3 4.5 3.5 3.3 3.1 2.8 2.5 Lymphocytes (Range) (2.0 to 11.0) (2.0 to 11.0) (2.0 to 11.5) (2.0 to 17.0) (2.0 to 17.0) (2.5 to 16.5) (4.0 to 13.5) (4.0 to 10.5) (3.0 to 9.5) (2.0 to 8.0) (1.5 to 7.0) (1.5 to 6.8) (1.5 to 6.5) (1.2 to 5.2) (1.0 to 4.8) % 31 24 31 41 48 56 61 61 59 50 42 39 38 35 34 Monocytes Mean 1.1 1.2 1.1 1.1 1.0 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.4 0.4 0.3 % 6 5 6 9 9 7 5 5 5 5 5 4 4 5 4 Eosinophils Mean 0.4 0.5 0.5 0.5 0.4 0.3 0.3 0.3 0.3 0.3 0.2 0.2 0.2 0.2 0.2 % 2 2 2 4 3 3 3 3 3 3 3 2 2 3 3 Mean 18.1 22.8 18.9 12.2 11.4 10.8 11.9 11.4 10.6 9.1 8.5 8.3 8.1 7.8 7.4 (Range) (9.0 to 30.0) (13.0 to 38.0) (9.4 to 34.0) (5.0 to 21.0) (5.0 to 20.0) (5.0 to 19.5) (6.0 to 17.5) (6.0 to 17.5) (6.0 to 17.0) (5.5 to 15.5) (5.0 to 14.5) (4.5 to 13.5) (4.5 to 13.5) (4.5 to 13.0) (4.5 to 11.0)
Age Birth 12 h 24 h 1 wk 2 wk 1 mo 6 mo 1y 2y 4y 6y 8y 10 y 16 y 21 y
*Numbers of leukocytes are in thousands/mcL ( 109/L), ranges are estimates of 95% condence limits, and percentages refer to differential counts. Neutrophils include band cells at all ages and a small number of metamyelocytes and myelocytes in the rst few postnatal days. From Dallman PR. Blood and blood-forming tissues. In: Rudolph AM, ed. Rudolphs Pediatrics. 16th ed. New York, NY: Appleton-Century-Crofts; 1977:1178, with permission.
(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 lower limit of normal for white adults. Adults and children of African extraction may have ANCs between 1,000 and 1,500/mcL (1.0 and 1.5 109/L), which overlaps the values observed in patients who have mild neutropenia. We estimate from the data available that at least 3% to 5% of persons of African ancestry have ANCs below 1,500/mcL (1/5 109/L).
bacterial infections are observed when the ANC is between 500 and 1,000/mcL (0.5 and 1.0 109/L), they are much less frequent or severe. There is little or no heightened infectious risk if the ANC is greater than 1,000/mcL (1.0 109/L).
Pyogenic Infections Associated With Neutropenia

Moderate-to-severe neutropenia may portend an inadequate neutrophil response to bacterial infection. The clinical signs of neutropenia may include ulcerations of the oral mucosa or gingival inammation. Otitis media, skin infections that include cellulitis and pustules, adenitis, pneumonia, and bacterial sepsis may occur. The source of the infection may be the childs own skin or bowel ora. Perianal infection and ischiorectal fossa abscesses sometimes are seen. The most common offending organisms are Staphylococcus aureus and the gramnegative bacteria (see section on fever and neutropenia).
Risk Assessment
For patients older than 1 year of age, mild neutropenia is dened as an ANC of 1,000 to 1,500/mcL (1.0 to 1.5 109/L), moderate neutropenia as an ANC of 500 to 1,000/mcL (0.5 to 1.0 109/L), and severe neutropenia as an ANC of less than 500/mcL (0.5 109/L). Usually, patients are highly susceptible to bacterial infection if the ANC is less than 500/mcL (0.5 109/L), with the risk of infection greatest at the lowest ANCs. Increased infection risk also is related to longer durations of neutropenia and is highest if the neutrophil count remains low without recovery. If neutrophils can be mobilized to respond, infection is less likely to occur, as can be seen in immune neutropenia, a condition in which there is myeloid hyperplasia and heightened neutrophil production. Although serious
Initial Evaluation of the Patient Who Has Neutropenia

The initial evaluation (Table 2) should include a history and physical examination. It is critical to know whether the child has had recurrent bacterial infections, whether there is a family history of neutropenia or infection, and after physical examination, whether there are any associated congenital anomalies that suggest an inherited synPediatrics in Review Vol.29 No.1 January 2008 13
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Table 2.
Initial Evaluation for Patients Who Have Neutropenia

History of underlying disease, congenital anomalies, medication exposure, or recent infection or mouth ulceration Other family members who have neutropenia and serious infections, hospitalizations, or blood diseases Short stature, malnutrition, skeletal abnormalities Abnormal skin pigmentation, dystrophic nails, leukoplakia, warts, albinism, ne hair, eczema, skin infections, adenopathy, and organomegaly
History
Physical Examination

CBC With Differential Count and Reticulocyte Percentage
Conrm the nding of neutropenia, evaluate neutrophil morphology, and assess whether red cell production is increased or decreased If the neutropenia resolves and is recurrent, repeat two to three times per week for 6 weeks 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, as indicated clinically) Antineutrophil antibodies
appears well. If the neutropenia persists or progresses after 1 to 2 weeks, additional evaluation is necessary. If the neutropenia is recurrent, obtaining blood counts two to three times per week for several weeks can establish any cycles of neutropenia. If additional evaluation is warranted, the presence of antineutrophil antibodies suggests immune neutropenia, and quantifying immunoglobulins, including IgG, IgA, and IgM, and the distribution of lymphocyte subsets may indicate an underlying immunodeciency syndrome. In addition, screening tests for systemic lupus erythematosus, including an antinuclear antibody titer and anti-doublestranded DNA, can be helpful. If a patient has severe neutropenia, referral to a hematologist is necessary. If severe congenital neutropenia is suspected, assessing for the HAX1 mutation for Kostmann disease and ELA2 mutation for dominant or sporadic severe congenital neutropenia is indicated. A detailed presentation of the potential laboratory evaluation by hematology is shown in Table 3.
Acquired Neutropenia
Infection
When evaluating the child who has neutropenia, the acquired neutropenias are considered rst because of their greater frequency (Table 4). The most common underlying cause for mild-to-moderate neutropenia is transient marrow suppression due to a variety of viral infections. Neutropenia is seen in patients who have Epstein-Barr virus, respiratory syncytial virus, inuenza A and B, hepatitis, and human herpesvirus 6 infections as well as the exanthems (to which most children are immunized), including varicella, rubella, and rubeola. Neutropenia occurs often during the rst few days of the viral illness and persists for 3 to 8 days. Severe bacterial infection also may cause neutropenia rather than neutrophilia, which can be transient if the bacterial infection is treated effectively. Other bacterial or rickettsial diseases such as typhoid fever, tuberculosis, and Rocky Mountain spotted fever may cause neutropenia.
Other Laboratory Tests

drome. Mouth ulcers may occur in association with neutropenia, and the presence of gingivitis is a good indicator that the patient cannot mobilize adequate neutrophils and, thus, may be susceptible to severe infection. If neutropenia is suspected, it is important to determine if the patient has isolated neutropenia or neutropenia associated with anemia or thrombocytopenia. The clinical implication of decits of more than one cell type is different from that of an isolated neutropenia. Anemia or thrombocytopenia in conjunction with neutropenia often reects a more generalized marrow failure syndrome such as aplastic anemia or a marrow inltrative process such as leukemia. The neutropenia must be conrmed by repeating the CBC to avoid an extensive evaluation due to a laboratory error. It is reasonable to observe the patient who has a viral illness and mild-to-moderate neutropenia and otherwise
Drug-induced
A variety of medications (Table 5), including antibiotics, anticonvulsants, and anti-inammatory agents, have been associated with neutropenia, a frequent reason for referral to hematology. The dilemma is how to treat the patient who requires the particular medication that is causing a potentially dangerous adverse effect. If the drug-induced neutropenia is idiosyncratic, its severity and persistence may be impossible to predict, and it is difcult to avoid discontinuing the drug. A similar situ-
hematology/oncology
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Table 3.
Detailed Laboratory Evaluation of Neutropenia

Findings ANC less than lower limit for age (Table 1) anemia and thrombocytopenia Increased if RBC destruction, as in Evans syndrome (or bleeding) Decreased in marrow failure syndromes Conrms decreased ANC Morphologic abnormalities of neutrophils, as in Chediak-Higashi syndrome Associated RBC or platelet ndings Detects antibodies to RBC, as in Evans syndrome or systemic lupus erythematosus Screen for systemic lupus erythematosus May be found in alloimmune or autoimmune neutropenia Screen for underlying immunodeciency IgG and IgA may be decreased and IgM elevated Decreased T, B, or NK cells in underlying immunodeciency May show no maturation beyond the promyelocyte stage in severe congenital neutropenia; myeloid hyperplasia with few or no bands or mature neutrophils in immune neutropenia Cytogenetics may reveal a neoplastic clone, as in leukemia Specic for genetic diagnosissee Table 6 for specic genes Low serum trypsinogen and elevated stool fat found in ShwachmanDiamond syndrome Serum vitamin B12, RBC, and serum folic acid
Test CBC and Differential Count Reticulocyte % (Index) Blood Smear Coombs Test (Direct Antiglobulin Test) ANA Anti-double-stranded DNA Antineutrophil Antibody IgG, IgA, IgM Lymphocyte Subtypes Marrow Examination
DNA Analysis (HAX1, ELA2, Gl) (FANC, DKC, RPS19) Serum Trypsinogen, Other Stool Fat Nutritional
ANA antinuclear antibody, ANC absolute neutrophil count, CBC complete blood count, RBC red blood cell.
ation exists for drug-induced immune neutropenia. If the drug acts as a hapten, leading to production of an antibody, the ANC should improve within 1 to 2 weeks after cessation of drug administration. On the other hand, if the neutropenia is mild, it may be dose-related, and drug administration could be titrated to permit continued use.
Immune
Neonatal alloimmune neutropenia results from the transfer of fetal cells to the maternal circulation, causing the mother to produce antibody to fetal antigens not present on her own cells in a manner similar to Rh disease. A variety of neutrophil-specic antigens have been identied 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 of IgG is approximately 5 to 6 weeks, alloimmune neutropenia usually disappears after age 2 to 3 months. If infections are associated with the neutropenia, granulocyte colony-stimulating factor (G-CSF) may be used to stimulate a heightened neutrophil count. Passive transfer of maternal antibody also may cause neonatal neutropenia. Pregnant women who have either primary immune neutropenia or immune neutropenia due to a disease such as lupus may transfer IgG antineu-
trophil antibodies passively to the developing fetus. This type of neonatal neutropenia also is transient. Primary autoimmune neutropenia of infancy and childhood may be the cause of chronic neutropenia. The diagnosis may be established in most patients with the demonstration of antineutrophil antibodies by leukoagglutination or immunouorescence. These antibodies may develop as a result of molecular mimicry, wherein an epitope on the surface of an infecting virus stimulates production of an antibody that then cross-reacts with a similar antigen on the surface of the neutrophil, leading to neutrophil destruction. Such antibodies often are directed against NA1. Marrow examination reveals myeloid hyperplasia but with few mature neutrophils (pictures of normal bone marrow and marrow in immune neutropenia are available in the online edition of this issue of Pediatrics in Review [www.pedsinreview.org]). The neutropenia may be profound, and the child may develop ear, pulmonary, skin, or other infections. Such infections are treated primarily with antibiotics. However, glucocorticoids such as prednisone may suppress the immune destruction of neutrophils, and more recently, G-CSF has been used to heighten neutrophil production to overcome the antibody-induced destruction. The initial dose of prednisone usually is 2 mg/kg
hematology/oncology
neutropenia
Table 4.
Acquired Neutropenia
Pathogenesis Viral marrow suppression or viral-induced immune neutropenia Bacterial sepsis-endotoxin suppression Direct marrow suppression Immune destruction Primary (molecular mimicry) Secondary (SLE, Evans syndrome) Alloimmunematernal sensitization Due to maternal autoimmune neutropenia Ineffective or decreased production Hypersplenism Vitamin B12 or folic acid deciency Impaired DNA processing Occurrence Common Less common Common Less common Common Associated Findings EBV/parvovirus/HHV6 and other viruses Severe infection Underlying condition Monocytosis common
Condition Infection
Drug-induced Autoimmune
Newborn Immune
Rare
Antigen difference in newborn and mother Maternal neutropenia Consider also familial benign neutropenia Often asymptomatic Mild neutropenia Enlarged spleenmany causes Marrow megaloblastic Hypersegmented neutrophils
Chronic Idiopathic Sequestration Nutritional
Common Common if spleen is enlarged Rare in children
EBV Epstein-Barr virus, HHV human herpesvirus, SLE systemic lupus erythematosus.
per day administered orally in two divided doses, and the initial dose of G-CSF is 5 mcg/kg administered subcutaneously once a day. These therapies usually are administered under the guidance of a pediatric hematologist. Secondary autoimmune neutropenia more often affects adults and is seen in systemic autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis (Felty syndrome), or systemic sclerosis; in certain infections, such as those due to human immunodeciency virus, parvovirus B19, or Helicobacter pylori; or in drug-induced neutropenia. Secondary autoimmune neutropenia also has been reported in association with Wilms tumor and Hodgkin disease. Treatment of secondary neutropenias is directed toward the primary disease. Administration of G-CSF may be considered if the neutropenia is severe and protracted.
severity of neutropenia, and the marrow ndings are not consistent. Ineffective or decreased production of neutrophils may be seen in this condition. Many hematologists watch patients whose conditions appear truly idiopathic and whose neutropenia is mild and not associated with an increase in infections, keeping the evaluation to a minimum rather than pursuing a more extensive evaluation that often yields nothing. When therapy is indicated, glucocorticoids and G-CSF have been used.
Sequestration
Splenomegaly and hypersplenism from any cause may result in mild neutropenia (1,000 to 1,500/mcL [1.0 to 1.5 109/L]) due to sequestration. Enlarged spleens may be present in patients who have chronic hemolytic anemias, liver disease, or portal hypertension and in metabolic disorders such as Gaucher disease. These conditions also may result in anemia and thrombocytopenia. Results of the marrow examination are normal or show mild hyperplasia of all elements. Usually, this problem does not require treatment unless the cytopenias are profound or management of the underlying condition requires treatment. In some cases, splenectomy is necessary.
Chronic Idiopathic
Chronic idiopathic neutropenia likely represents a variety of disorders and is not well characterized. Some of the patients classied as having chronic idiopathic neutropenia actually may have immune neutropenia or familial benign neutropenia. The idiopathic diagnosis may be considered when other known causes have been eliminated. The clinical severity appears to be related to the
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Table 5.
Partial List of Drugs Associated With Idiosyncratic Neutropenia

Possible Mechanism Direct Suppression Metabolite Suppression Immune Destruction X X X X X X X X X X X X X X X X X X X
Drug Analgesics/Anti-inammatory Agents Aminopyrine Ibuprofen Indomethacin Phenylbutazone Antibiotics Chloramphenicol Penicillins Sulfonamides Anticonvulsants Phenytoin Carbamazepine Antithyroid Agents Propylthiouracil Cardiovascular Agents Hydralazine Procainamide Quinidine Hypoglycemic Agents Chlorpropamide Tranquilizers Chlorpromazine Phenothiazines Other Cimetidine, ranitidine Levamisole
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 Oskis Hematology of Infancy and Childhood. 6th ed. Philadelphia, Pa: WB Saunders Company; 2003:9231010 with permission.
Nutritional Deciency
Both vitamin B12 and folic acid deciency may result in ineffective hematopoiesis with megaloblastic erythropoiesis. Patients who develop megaloblastic anemia generally are adults. In addition to megaloblastic anemia, the impairment in DNA processing may result in neutropenia. Neutrophil nuclear maturation is impaired, leading to hypersegmentation of the neutrophil nuclei in the blood as well as ineffective marrow proliferation and maturation. Treatment involves replacement of the decient factor.
Inherited Neutropenia (Table 6)

Severe Congenital
Severe congenital neutropenia may present as early as infancy with umbilical infection, pyoderma, oral ulcers, pulmonary infections, or perineal infections of the labia or 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) involving mutations in the HAX1 gene that is involved in signal transduction. It also may be inherited as an autosomal dominant condition, with mutations in the neutrophil elastase gene (ELA2) or, more rarely, in the GFI1 gene that targets ELA2. It has been suggested that such gene mutations result in accelerated apoptosis of myeloid precursors. Examination of the marrow reveals an arrest at the promyelocyte stage of development (a picture of bone marrow in severe congenital neutropenia is available in the online edition of this issue of Pediatrics in Review [www.pedsinreview.org]). Few or no myelocytes, metamyelocytes, bands, or mature neutrophils are seen, and there may be an associated monocytosis and eosinophilia in the blood. Affected patients have a very high risk of developing a myelodysplastic syndrome or acute myelogenous leukemia, a consequence that has become more evident as patients live longer with treatment using G-CSF. Table 7 describes G-CSF administration.
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Table 6.
Inherited Neutropenia
Inheritance AR Pathogenesis Occurrence Associated Findings Rare (1/1 to 200,000) ANC <500/mcL (0.5 109/L) HAX1 mutations causing disturbed Leukemia risk of 15% to 20% regulation of myeloid homeostasis Marrow arrest at the promyelocyte stage ELA2 mutations on the Rare (1/1 to 200,000) ANC <500/mcL (0.5 109/L) face of the molecule Leukemia risk of 5% to10% opposite the active site causing accelerated apoptosis 2 T and B cells GFI1 mutations target Two families Marrow has immature myeloid ELA2 cells ELA2 mutations 0.5 to 1/106 21-day cycle with fever and clustering near the mouth ulcers active site of the molecule 1/50,000 Pancreatic exocrine SDS gene conversion insufciency, short stature, from the pseudogene, metaphyseal dysplasia, resulting in failure of marrow failure, and leukemia neutrophil production risk (15%) Defect in RNA processing Decreased CD34 cells Decreased marrow Common Africans and Yemenite Jews release Periodontal disease Gene (FANC) defects in 1/106 DNA repair Dysplastic thumbs, pancytopenia, other anomalies Abnormal skin pigmentation, leukoplakia, dystrophic nails Erythroid failure syndrome Neutropenia in 25% to 40% Thumb and craniofacial anomalies Increased RBC adenosine deaminase Leukemia risk of 2% to 3% 2IgG, 2IgA, 1IgM May have immune thrombocytopenia and anemia Neutropenia only seen in XR Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM)
Condition Severe Congenital (Kostmann)
Severe Congenital
AD and sporadic
Cyclic
AD
Shwachman-Diamond Syndrome
AR
Familial Benign
AD
Marrow Failure Syndromes: Fanconi AR Dyskeratosis Congenita
Blackfan Diamond Syndrome
Dysgammaglobulinemia or Hyper-IgM
Usually XR DKC1 (TERC or TERT in (also AR and AD) mutations AD) Telomerase defect, ribosomal dysfunction Sporadic 75% RPS19 mutations that AR and AD affect a ribosomal protein in 25% of families ? Mechanism of erythropoietic failure Many patients respond to glucocorticoids XR (also AR) CD40 ligand mutations ? Immune neutropenia, but antineutrophil antibody is negative AD (also ?AR) Imbalance in pro- and Case reports anti-apoptosis Defect in CXCR4 receptor leading to failure of neutrophils to leave the marrow
WHIM Syndrome and Myelokathexis
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Table 6.
Inherited Neutropenia Continued

Inheritance Pathogenesis Occurrence Associated Findings 2NK and T-cell function Albinism Neurologic damage and giant lysosomes Rare CHS1 ?defect in lysosomal ssion Abnormal protein trafcking Decreased neutrophil chemotaxis, degranulation, and killing Stem cell failure in Rare lymphoid and myeloid development RMRP mutations Rare Defect in a ribonuclear protein ribonuclease
Condition
Chediak-Higashi Syndrome AR
Reticular Dysgenesis Cartilage Hair
AR AR
Metabolic Glycogen AR Storage Disease 1b (also aminoacidopathies) Griscelli Syndrome Type 2 AR
G6PT1 mutations (glucose-6phosphate translocase) in 1b RAB27A mutations Impaired lytic granule release
1/105 live births
Severe combined immunodeciency with neutropenia Fine hair, short-limbed, dwarsm, lymphopenia, 2CD4 and 2CD8 cells Infections, particularly varicella zoster Hypoglycemia, dyslipidemia, 1uric acid, 1lactic acid, and neutropenia in most patients Partial albinism, neutropenia, infections, and thrombocytopenia with hemophagocytosis and T-cell defect Dilated cardiomyopathy Skeletal myopathy Mitochondrial abnormalities Impaired lymphoid development and maturation of monocytes Associated with eczema, thrombocytopenia, and immune deciency Infections of the upper and lower respiratory tracts in one third of patients
Rare
Barth Syndrome
XR
Wiscott-Aldrich Syndrome XR
Selective IgA Deciency
Unknown or multifactorial
TAZ mutation on the X Rare chromosome Cardiolipin defect Mutations in the Cdc42 1 to 10/106 binding site in the WASP gene Results in X-linked neutropenia Unknown Common (1/600)
AR autosomal recessive, AD autosomal dominant, ANC absolute neutrophil count, Ig immunoglobulin, NK natural killer, RBC red blood cell, XR X-linked recessive.
Cyclic
Cyclic neutropenia is characterized by approximately 21-day cycles of changing neutrophil counts, with neutropenia spanning 3 to 6 days. The nadir of the neutrophil count may be in the severe range. Fever and oral ulcerations usually are seen during the nadir. Patients also may develop gingivitis, pharyngitis, and skin infections. However, by the time the patient comes to medical attention, the neutrophil count may be recovering. Therefore, diagnosing cyclic neutropenia may require obtaining blood counts two to three times per week for 4 to 6 weeks in an effort to observe the periodicity of the cycle.
More serious infections include pneumonia, necrotizing enterocolitis with peritonitis, and Escherichia coli or Clostridium sepsis. Marrow ndings reect the state of neutropenia. Prior to the ANC nadir, the marrow may resemble that associated with severe congenital neutropenia before proceeding to a recovery phase. The periodicity of marrow activity also may be seen in the erythroid series. As in severe congenital neutropenia, mutations occur in the ELA2 gene, but at different locations (Table 6). Also, there does not appear to be an increased risk of myelodysplasia or acute myelogenous leukemia. Prophylactic G-CSF has been recommended to prevent severe symptoms at the nadir of the cycle.
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Table 7.
Treatment of Neutropenia
Initially 5 mcg/kg per day subcutaneously If no response after 1 wk, the dose may be doubled repeatedly up to 100 mcg/kg per day Prednisone 2 mg/kg per day PO for immune neutropenia Vitamin B12 1,000 mcg each week for 5 to 6 wk, then q 1 mo subcutaneously if B12decient Folic acid 1 mg/d PO Prior immunization to encapsulated bacterial (pneumococcus, Haemophilus inuenzae type b, meningococcus) required Prophylactic penicillin after splenectomy 125 mg bid <age 5 y; 250 mg bid >age 5 y If possible, reduce dosage or discontinue any medications associated with neutropenia As appropriate for patients age, type and location of infection, and if possible, culture results 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
Granulocyte Colony-stimulating Factor Glucocorticoids Nutritional Splenectomy Medication Revision Antibiotics Granulocyte Transfusion
Shwachman-Diamond Syndrome
Patients who have Shwachman-Diamond syndrome usually have a mild-to-moderate degree of neutropenia in association with exocrine pancreatic insufciency, short stature, metaphyseal dysplasia, marrow failure, and the risk of myelodysplasia and acute myelogenous leukemia. A defect in RNA processing leads to a failure of neutrophil development. Malabsorption and failure to thrive are common problems, and affected patients may develop infections because of the neutropenia and a possible defect in chemotaxis. G-CSF has been used when the neutropenia is symptomatic; pancreatic replacement therapy is required.
Marrow Failure Syndromes

FANCONI ANEMIA. Fanconi anemia is characterized by pancytopenia (with all cell lines affected). It presents most commonly in the second half of the rst decade of life, and thrombocytopenia may precede the development of anemia and neutropenia. The marrow is hypoplastic and resembles aplastic anemia. The disease is characterized by a defect in DNA repair leading to extensive chromosomal breakage, and there is hypersensitivity to DNA cross-linking agents such as diepoxybutane in vitro. Affected patients have mutations in the FANC genes, primarily in FANC A, C, and G. Clinically, patients may have short stature; dysplastic thumbs; or heart, kidney, or eye abnormalities. They have a nearly 10% risk of developing a myelodysplastic syndrome or acute myelogenous leukemia. The pancytopenia may respond to androgen treatment, which is particularly difcult to use in young women. G-CSF and other cytokines may be effective, but their efcacy may not be sustained. The only curative treatment for Fanconi anemia is stem cell transplantation.
DYSKERATOSIS CONGENITA (ZINSSER-ENGMAN-COLE SYNDROME). This abnormality results from a mutation in the DKC1 gene that encodes dyskerin, a component of the telomerase complex, which is responsible for the elongation of DNA. Affected patients exhibit abnormal skin pigmentation, leukoplakia, and dystrophic nails. The skin and mucosal lesions appear in the second decade, and marrow failure develops in early adulthood. Patients may 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 neutropenia. Abnormalities of T-helper cells and dysgammaglobulinemia may contribute to a susceptibility to infection in some patients.
Syndromes Associated With Neutropenia and Immunodeciency

A variety of syndromes include neutropenia and abnormalities in T, B, or natural killer cell function. The combined problem of neutropenia and immunodeciency makes patients who have these syndromes more susceptible to infectious complications. One condition is the hyper-IgM syndrome, in which concentrations of IgG and IgA are diminished and IgM is heightened. The nature of the neutropenia is not known, but may be immune in origin, although antineutrophil antibodies are negative. Other syndromes associated with neutropenia and immunodeciency are listed in Table 6; their associated ndings are particularly important for dening these rare syndromes.
Fever and Neutropenia

A very difcult issue is how best to treat a patient who has fever and neutropenia. Although detailed guidelines have
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Table 8.
Fever and Neutropenia

Etiology of Fever Viral (frequent) Bacterial: URI (sinusitis, purulent rhinitis), otitis media, local skin infections Bacterial pneumonia, systemic symptoms, GU infections, lymphadenitis Management Supportive Indicated PO antibiotics Outpatient/Hospital Outpatient Outpatient
ANC 1,000 to 1,500/mcL (1.0 to 1.5 109/L) Mild
500 to 1,000/mcL (0.5 to 1.0 109/L) Moderate
Viral Bacterial: URI (sinusitis, purulent rhinitis), otitis media, local skin infections Bacterial pneumonia, systemic symptoms, GU infections, lymphadenitis Assume bacterial
Blood cultures Specic cultures Best estimate antibiotics Observation for progression Supportive Blood and other cultures Indicated PO or IV antibiotics Blood cultures Specic cultures Sepsis evaluation Parenteral broadspectrum antibiotics Blood cultures Specic cultures Sepsis evaluation Parenteral broadspectrum antibiotics
Outpatient unless progression
Outpatient Outpatient/Hospital*
Hospital
<500/mcL (0.5 109/L) Severe
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 patients underlying disorder and the anticipated time for recovery of the ANC. Children who have congenital/chronic neutropenia likely would benet from treatment in the hospital because recovery of the ANC is less likely without cytokine treatment. In contrast, neutropenia due to viral suppression, antibody effect, or some medication exposures may allow a better response to localized bacterial infection and be managed on an outpatient basis.
been formulated for patients who have chemotherapyinduced neutropenia, relatively few data are available for patients who have neutropenia not associated with cancer treatment. Fever is dened as a temperature greater than 101F (38.3C) or a temperature of at least 100.4F (38C) for longer than 1 hour. Most authors categorize the severity of neutropenia into three groups (Table 8). The decision surrounding treatment and potential hospitalization depends on the likelihood of bacterial infection, the location and severity of the infection, the severity of the neutropenia, and the likelihood and timeframe of neutrophil recovery. Furthermore, the age of the patient, the proximity of specialized medical care, and the reliability of the guardians should be considered in the management decision. Table 8 presents a starting point for consideration of what to do and is based on the principles used in the care of neutropenic chemother-
apy patients and the concerns of pediatric hematologists and infectious disease specialists. Specic recommendations for initial broad-spectrum antibiotic coverage depend on the prevalence of organisms in each community and hospital and their susceptibility patterns. Approximately two thirds of isolated organisms are gram-positive (Table 9). Initial antibiotic treatment may employ a single broad-spectrum antibiotic such as ceftazidime or cefepime. Alternatively, an aminoglycoside can be combined with a beta-lactam drug such as a third- or fourth-generation cephalosporin for broad antibiotic coverage. The initial addition of vancomycin is controversial, but should be done if resistant organisms are suspected because of their prevalence in the community. When to discontinue antibiotic treatment is a particular problem for physicians caring for patients who have
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Table 9.
Bacterial Causes of Febrile Episodes in Neutropenic Patients
if the neutropenia is profound and there are frequent infections.
The Medical Emergency of Fever With Severe Neutropenia

Hospitalization is required for patients who have severe neutropenia (specically neutrophil counts less than 500/mcL [0.5 109/L]), moderate neutropenia and severe infection, or any level of neutropenia combined with ill appearance, as well as consultation with pediatric hematology and pediatric infectious disease services. Patients who have immune neutropenia of infancy often can be treated as outpatients because they can mobilize neutrophils transiently. The hematologist can help establish the cause of the neutropenia, and the infectious disease specialist can help identify the type and susceptibility of the infecting bacteria in the specic community. If the patient is seen in the ofce, a blood culture (aerobic and anaerobic) and a urinalysis and urine culture (no catheter should be used) can be obtained and the initial dose of antibiotics administered. If possible, an intravenous line should be kept open. The patient should be transported to the hospital by ambulance because septic shock may occur after administration of the rst dose of antibiotics. On arrival at the emergency department, venous access should be ensured, and vital signs with oxygen saturation, a CBC with differential count and platelet count, and a metabolic prole should be obtained. No rectal temperatures should be taken, rectal examinations performed, or rectal medications administered because of the risk of generating a perianal or perirectal infection. However, careful examination of the mouth, oral mucosa, lungs, abdomen, and perineal/perianal area is important. A chest radiograph may be warranted if there are respiratory signs or symptoms, but its usefulness may be limited because the lack of neutrophils may not produce a visible inltrate in patients who have severe neutropenia.
Aerobic Bacteria ( 90%)* Gram-positive Cocci ( 45%) Staphylococcus Coagulase-positive (S aureus) Coagulase-negative (S epidermidis and others) Streptococcus S pneumoniae S pyrogenes viridans group Enterococcus faecalis/faecium Gram-positive bacilli (rare) Corynebacterium sp Gram-negative Bacilli ( 45%) Escherichia coli Klebsiella sp Pseudomonas aeruginosa Anaerobic Bacteria (4% to 5%) (Often Polymicrobial) Gram-positive Cocci (normal mouth ora) Peptococci Peptostreptococci Gram-negative Bacilli Bacteroides fragilis Fusobacterium sp
*Percentages observed in patients receiving chemotherapy who were immunocompromised (Mathur P, Chaudry R, Kumar L, Kapil A, Dhawan B. A study of bacteremia in febrile neutropenic patients at a tertiary-care hospital with special reference to anaerobes. Med Oncol. 2002;19:267272). Specic organisms were reported by Hughes WT, Armstrong D, Bodey GP, et al. 1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Infectious Diseases Society of America. Clin Infect Dis. 1997;25:551 573 and Merck & Co, Inc, Whitehouse Station, NJ, USA: 19952007 (http://www.merck.com/mmpe/sec14/ch178/ch178j.html).
neutropenia. If the blood cultures are negative and the child becomes afebrile, antibiotics can be stopped, even if the neutropenia persists. Usually, antibiotics are continued if the cultures are negative and the child remains febrile and neutropenic. Fever generally resolves quickly with antibiotic therapy if the neutropenia resolves. If the cultures are positive and the child is no longer febrile and neutropenic, the prescribed antibiotic treatment may be completed with oral antibiotics at home. If the cultures are positive and the child is afebrile but persistently neutropenic, the course of antibiotics usually is completed in the hospital. The child then is observed for 24 to 48 hours prior to discharge. The persistence of neutropenia requires the additional evaluation described in this article and consideration of treatment with G-CSF
Anticipatory Guidance for the Patient Who Has Neutropenia

Parents of patients who have neutropenia need to contact a health-care practitioner at the onset of any febrile illness to assure prompt, appropriate care. The parents must know what is required for the evaluation (including the history and physical examination, blood counts and ANC, blood and other cultures) and the initial treatment (usual antibiotic recommendation and route of administration for their child) because they may not be near a major medical center, particularly when traveling. A per-
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mission form may be necessary to allow carrying of injectable medications, such as G-CSF, syringes, and hypodermic needles on airplanes. Parents should carry a current written summary of the childs condition and laboratory values and the contact numbers of their primary institution and physicians. It is important to maintain good oral hygiene and appropriate preventive dental visits, particularly for patients who have chronic neutropenia, to avoid chronic gingival or dental infection. Good skin care and prompt cleansing of supercial cuts, abrasions, and bruises where the skin is broken help to prevent local infection. All immunizations can and should be given according to the routine vaccination schedule, as long as the patients neutropenia is not associated with an immunodeciency syndrome. Children who have impaired T- or B-lymphocyte function should not receive live or attenuated-live vaccines. Recommendations for the administration of specic vaccines can be found in the American Academy of Pediatrics Red Book and in the Pink Book produced by the Centers for Disease Control and Prevention, Epidemiology and Prevention of Vaccine-preventable Diseases. Child care and school attendance are reasonable for most children who have mild-to-moderate neutropenia, although contact with obviously ill children should be avoided. Children who have severe neutropenia or a history of serious infections with neutropenia require greater isolation to avoid exposure to infectious agents. Genetic counseling for the family of patients who have inherited neutropenias is indicated, and siblings should be tested for the disorder. Families of patients who have neutropenia may experience signicant stress due to feeling responsible for the disease if it is an inherited condition or for exposing the child to infectious complications, caring for a child who has a chronic illness, and managing multiple physician and hospital visits. Most pediatric hematology/oncology units have social workers, parent advocates, and advanced-practice nurses who can provide the types of support services required by patients and their parents.
found. These disorders include the dominant or sporadic types of severe congenital neutropenia (often with mutations in the ELA2 gene), the recessive type or Kostmann syndrome, and the marrow failure syndromes such as Fanconi anemia. Cyclic neutropenia may be severe at the nadir of the cycle. Of particular concern is the occurrence of fever in conjunction with neutropenia. This combination creates a medical emergency that must be addressed with appropriate evaluation and prompt administration of antibiotics. The actual risk of severe infection and the likelihood of recovery depend not only on the level of the ANC, but on the duration of the neutropenia. If recovery from the neutropenia is not expected, as in severe congenital types, G-CSF administration may be indicated. To view an additional Suggested Reading list and gures related to this article, visit www.pedsinreview. org and click on Neutropenia in Pediatric Practice.
Suggested Reading
Atallah E, Schiffer CA. Granulocyte transfusion. Curr Opin Hematol. 2006;13:45 49 Baehner RL. Drug-induced neutropenia and agranulocytosis. UpToDate. 2007. Available at: www.uptodate.com Bertuch AA, Strother D. Fever in children with non-chemotherapyinduced neutropenia. UpToDate. 2007. Available at: www.uptodate.com Bertuch AA, Strother D. Management of fever in children with non-chemotherapy-induced neutropenia. UpToDate. 2007. Available at: www.uptodate.com Beutler E, West C. Hematologic differences between AfricanAmerican and whites: the roles of iron deciency and alphathalassemia on hemoglobin levels and mean corpuscular volume. Blood. 2005;106:740 745 Boxer LA. Neutrophil abnormalities. Pediatr Rev. 2003;24:52 62 Boxer LA, Stein S, Buckley D, Bolyard AA, Dale DC. Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 mutations. J Pediatr. 2006;148:633 636 Hughes WT, Armstrong D, Bodey GP, et al. 1997 guidelines for the use of antimicrobial agents in neutropenia patients with unexplained fever. Clin Infect Dis. 1997;25:551573 Klein C, Grudzien M, Appaswamy G, et al. HAX1 deciency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet. 2007;39:86 92 Lehrnbecher T, Welte K. Haematopoietic growth factors in children 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;39:113120 Skokowa J, Germeshausen M, Zeidler C, Welte K. Severe congenital neutropenia: inheritance and pathophysiology. Curr Opin Hematol. 2007;14:2228
Summary
Neutropenia unrelated to chemotherapy toxicity occurs in a number of clinical settings. The most common conditions associated with neutropenia are those that are acquired, including viral infection, neutropenia associated with various medications, and immune neutropenia. Inherited neutropenias are rarer and often more pro-
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PIR Quiz
Quiz also available online at www.pedsinreview.org. 6. A 6-year-old boy presents with a history of a temperature to 103F (39.4C) and ulcerations on his lips and buccal mucosa 2 days ago. The child has some small, slightly ulcerated areas on his lips and is afebrile. His mother reports two similar episodes in the past 2 months. He has a white blood cell count of 2.9 103/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. B. C. D. E. Antineutrophil antibodies. Blood counts two to three times a week for 4 to 6 weeks. Bone marrow aspiration. Herpes cultures. 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 104F (40C). He is in no acute distress and does not appear ill. The only abnormal physical nding is mild rhinitis. A complete blood 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 dose of acetaminophen, the child becomes afebrile. Of the following, the most appropriate next step is to: A. B. C. D. E. Give a dose of broad-spectrum antibiotics and admit the child for continuing intravenous antibiotics. Give a dose of ceftriaxone and see the child the following morning. Observe the child in the emergency department overnight. See the child the following morning but tell the parents to call sooner if he becomes more ill. 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 sure her baby is OK. You determine that she has no specic anxieties or reasons for suspecting a problem. Of the 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. B. C. D. E. Exposure to medications such as antibiotics. Immune neutropenia. Shwachman-Diamond syndrome. Sequestration. Transient marrow suppression due to a viral infection.
10. At what age does alloimmune neutropenia usually resolve? A. B. C. D. E. 2 2 5 2 6 to to to to to 3 3 6 3 7 days. weeks. weeks. months. months.
Index of Suspicion Cherilyn Hall, Allen Friedland, Sumathi Sundar, Kathryn S. Torok, Mananda S. Bhende, Grace Pecson and Carolyn Leedy Pediatr. Rev. 2008;29;25-30 DOI: 10.1542/pir.29-1-25
index of suspicion
Case 1 Presentation
A 12-year-old girl has had abdominal pain for 3 hours. The pain developed suddenly and is severe, sharp, constant, and located in the epigastrium and lower quadrants, with no radiation. She has had ve episodes of bilious, nonbloody emesis. The pain worsens with movement and vomiting, and she has found no way to relieve it. Her last bowel movement was yesterday and was normal. She has had no fever, diarrhea, bloody stools, or back pain. Past medical history reveals intermittent constipation. On physical examination, her temperature is 96.3F (35.7C), heart rate is 106 beats/min, respiratory rate is 14 breaths/min, and blood pressure is 103/60 mm Hg. Her abdomen is soft and slightly distended, with hypoactive bowel sounds and both right and left lower quadrant tenderness. Slight voluntary guarding is noted. The rest of the physical ndings 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 electrolytes, BUN, creatinine, liver enzymes, amylase, and lipase are within normal limits; a pregnancy test is negative. Abdominal/pelvic CT scan with intravenous contrast reveals a moderate amount of free uid around the cecum; the appendix is not visible. Pelvic and abdominal ultrasonography is read as normal, but the appendix is not visible. Following intravenous hydration, she experiences persistent bilious vomiting and abdominal pain and undergoes a diagnostic laparoscopy, which is converted to an exploratory laparotomy when no colon is located on the right side of her abdomen.
The cause of her pain and vomiting is revealed at surgery.
Case 2 Presentation
A 14-year-old girl is seen in the ED because of 2 days of lower abdominal and back pain. The pain is a constant, dull, bandlike ache of 9/10 in intensity. She denies fever, nausea, vomiting, diarrhea, melena, hematochezia, dysuria, hematuria, vaginal discharge, or constitutional symptoms. She is premenarchal and denies sexual activity. She had an appendectomy at age 5 years complicated by the development of necrotic bowel, requiring a small bowel resection. After recovering from surgery, she developed chronic intermittent abdominal pain, ultimately diagnosed as being functional. She describes her current pain as different from her chronic abdominal pain. On physical examination, the girl is uncomfortable but in no apparent distress and looks healthy. All vital signs are normal. Her breast development is at Sexual Maturity Rating 5. She is thin and easy to examine. Her back is straight, with no tenderness to palpation over the spine, paraspinal muscles, or costovertebral angles. Her abdominal examination reveals a 10-cm linear, well-healed vertical scar down the midline and a slightly protuberant lower abdomen. Palpation reveals a large, well-dened, rm mass extending from the pelvis halfway to the umbilicus in the mid-line. Mild pain is elicited on deep palpation of the left lower quadrant, with no guarding or rebound tenderness. Additional examination reveals the diagnosis.
The reader is encouraged to write possible diagnoses for each case before turning to the discussion. We invite readers to contribute case presentations and discussions. Please inquire rst by contacting Dr. Nazarian at LFredN@aol.com.
Author Disclosure Drs Hall, Friedland, Sundar, Torok, Bhende, Pecson, and Leedy did not disclose any nancial relationships relevant to these cases.
Frequently Used Abbreviations

alanine aminotransferase aspartate aminotransferase blood urea nitrogen complete blood count central nervous system cerebrospinal uid computed tomography electrocardiography emergency department electroencephalography erythrocyte sedimentation rate GI: gastrointestinal GU: genitourinary Hct: hematocrit Hgb: hemoglobin MRI: magnetic resonance imaging WBC: white blood cell ALT: AST: BUN: CBC: CNS: CSF: CT: ECG: ED: EEG: ESR:
Case 3 Presentation
A 6-month-old boy is readmitted because of respiratory distress and hypPediatrics in Review Vol.29 No.1 January 2008 25
index of suspicion
oxia 1 day after a 2-week hospitalization for bronchiolitis with hypoxia. Despite resolution of signs of a respiratory tract infection, he was difcult to wean from supplemental oxygen, having percutaneous oxygen saturations of 88% to 92% in room air. He was discharged after his percutaneous oxygen saturations remained at 90% to 96% for 24 hours in room air. He was a small-for-gestational age neonate, born via caesarean section at 36 weeks gestation for maternal double uterus, and remained in the neonatal intensive care unit for 2 weeks for feeding and weight gain. He did not receive any mechanical ventilation, and his growth and development have been normal. On physical examination, the patients weight is in the 10th percentile, height is in the 5th percentile, and head circumference is below the 3rd percentile. His blood pressure, heart rate, and respiratory rate are normal. Percutaneous oxygen saturations in room air are 91%. He is receiving 2 L of supplemental oxygen by nasal cannula and has no respiratory distress. Wheezing is audible bilaterally, and there is no heart murmur. He has a left facial nerve palsy present since birth. Adequate perfusion and palpable pulses are noted in all extremities. The remaining physical ndings are normal. A chest radiograph reveals multifocal atelectasis, a left-sided aortic arch, and a cardiac silhouette that measures at the upper limit of normal. Additional evaluation reveals the diagnosis.
The Condition
Intestinal malrotation is an anatomic anomaly caused by arrest of normal rotation and mesenteric xation of the embryonic gut, a failure of normal embryologic gut formation that occurs between the 5th and 10th weeks of gestation. The result of a nonrotated gut is location of the colon on the left side and a narrowbased mesentery in the upper midabdomen that is xed to the right abdominal wall by adhesions known as Ladd bands. Anomalies commonly associated with intestinal malrotation include duodenal atresia (50%) and jejunal atresia (33%). Disorders of intestinal rotation and mesenteric xation to the posterior abdominal cavity are also common in infants and children who have congenital diaphragmatic hernia, gastroschisis, and omphalocele. Intestinal malrotation is believed to occur in 1 per 200 to 1 per 500 live births, with symptomatic malrotation occurring in 1 per 6,000 live births. Symptomatic malrotation is evident clinically in the rst postnatal month in 64% of patients, and 82% are diagnosed in the rst postnatal year; 18% to 25% of symptomatic patients are diagnosed at 1 year of age and older. Because malrotation is discovered incidentally in some patients, the true number of patients who have malrotation that is never detected can only be estimated. Malrotation can cause duodenal obstruction because of impingement on the bowel by the Ladd bands. The most serious consequence is a midgut volvulus, a life-threatening condition in which the intestine twists on the mesenteric stalk and compromises its blood supply, which can lead rapidly to infarction of the entire small bowel. Both duodenal obstruction from Ladd bands and volvulus may occur intermittently, characterized by chronic and sometimes vague
complaints of abdominal pain with or without vomiting. Symptomatic malrotation with volvulus presents as duodenal obstruction. In infancy, the clinical picture includes bilious emesis, abdominal pain, diffuse tenderness, and bloody stool. Some clinicians warn that the cause of bilious vomiting in a neonate should be considered mechanical intestinal obstruction until proven otherwise. Older children and adults can present with acute or chronic symptoms. Acute symptoms include bilious vomiting, diffuse abdominal pain, and bloody stool. Among the chronic symptoms are intermittent vomiting and abdominal pain, constipation, malabsorption syndrome, chronic diarrhea due to protein-losing enteropathy, and failure to thrive. Older children and adults who have chronic symptoms may have received a previous diagnosis of irritable bowel syndrome or cyclic vomiting. Some individuals who are diagnosed later in childhood are believed to have been experiencing intermittent, self-resolving volvulus.
Differential Diagnosis
The differential diagnosis for intestinal malrotation varies according to the age of presentation. In infancy and childhood, conditions to consider include necrotizing enterocolitis, pyloric stenosis, intussusception, ileus due to sepsis or meconium, Hirschsprung disease, appendicitis, and duodenal atresia. In older children and adults, similar symptoms can result from inammatory bowel syndrome, pancreatitis, or acute abdominal conditions such as appendicitis.
Case 1 Discussion
At laparotomy, intestinal malrotation with small bowel obstruction at the level of the distal ileum was found.
Diagnosis
Diagnostic evaluation generally requires a degree of suspicion for volvulus and, in a stable patient, can
index of suspicion
include abdominal radiography, upper GI radiographic series, or abdominal CT scan. Adjunctive imaging techniques are abdominal ultrasonography and barium enema. Radiographs often reveal a gasless colon with a double-bubble sign due to duodenal obstruction. An abdominal radiograph was not performed in this patient because appendicitis was believed to be likely, and abdominal radiography would not have been an optimal study for appendicitis. An upper GI contrast study usually is considered the imaging study of choice in a stable patient suspected of having intestinal malrotation complicated by volvulus. An upper GI radiographic series reveals failure of the duodenal-jejunal junction to cross the midline and a corkscrew appearance of volvulus at the level of the duodenum. CT scan may reveal duodenal obstruction (in the case of mid-gut volvulus) or appear normal in the absence of volvulus. Ultrasonographic ndings suggestive of volvulus include identication of the superior mesenteric vein on the left rather than the right.
procedure, and Doppler ultrasonography at the time of surgery showed normal blood ow to the distal ileum. Postoperatively, she developed pancreatitis, which resolved after approximately 1 week of bowel rest and uid resuscitation. She was discharged with no additional complications.
patient was discharged in good condition with relief of pain.
The Condition
Imperforate hymen is the most common obstructive genital tract anomaly occurring in females, having an incidence of 1 in 1,000 to 1 in 10,000 individuals. Most commonly, imperforate hymen is detected during adolescence either during an evaluation for asymptomatic primary amenorrhea or an investigation of abdominal, back, or pelvic pain in the premenarchal female. Other complaints include urinary retention and pain with defecation. The pain is due to the collection of menstrual blood in the vagina and uterus. An imperforate hymen also can be detected on prenatal ultrasonography as hydrocolpos if it is associated with urinary obstruction and a urogenital stula, during a newborn examination as a mucocolpos from maternal estrogeninduced secretions, or during a health supervision visit as a membrane that bulges when the child performs a Valsalva maneuver. The term hydrometrocolpos is used when both vagina and uterus are dilated with uid. Imperforate hymen is a sporadic congenital outow obstruction anomaly resulting from the failure of canalization of the tissue joining the mullerian ducts and the urogenital sinus during development. Embryologically, the female genital tract involves the medial migration and midline (horizontal) fusion of the paired mullerian (paramesonephric) ducts to form the uterus, cervix, and upper vagina and the vertical fusion of the developing ductal system with the invaginating urogenital sinus to form the lower vagina and introitus. Horizontal fusion defects result in vaginal agenesis (also known as mullerian agenesis or Mayer-RokitanskyKuster-Hauser syndrome) and may
Lessons for the Clinician

Most symptomatic cases of malrotation occur during infancy and usually present with bilious vomiting. Fewer cases present after infancy and have varied presentations related to intermittent volvulus, with symptoms that include abdominal pain, vomiting, and diarrhea. Volvulus can mimic an acute abdominal inammatory process, and diagnosis requires a high degree of suspicion because progressive intestinal ischemia may become life-threatening. Patients who present after infancy usually have a history of chronic abdominal complaints. (Cherilyn Hall, MD, Allen Friedland, MD, Sumathi Sundar, MD, Christiana Care Health System, Newark, Del.)
Therapy
Intestinal malrotation requires surgical intervention. The Ladd procedure is recommended for intestinal malrotation regardless of age or symptoms. This operation includes lysis of adhesions, widening of the mesenteric base, and positioning of the bowel in a place of nonrotation as well as appendectomy and resection of any necrotic bowel. The urgency of the operation is dictated by the presence of intestinal ischemia caused by volvulus. In the setting of malrotation without volvulus, most surgeons advocate the Ladd procedure as a prophylactic maneuver to reduce the probability of volvulus. This patient underwent a Ladd
Case 2 Discussion
Examination of the patients genitalia revealed a normal vulva and labia with Sexual Maturity Rating 5 distribution of pubic hair. A bulging, bluish membrane that was rm to palpation protruded from the introitus (Figure). Abdominal and pelvic ultrasonography performed to conrm the diagnosis of imperforate hymen revealed a grossly dilated vagina lled with homogeneous, echogenic material consistent with hematocolpos. No other urogenital abnormalities were present. The patient was admitted for a hymenectomy and evacuation of retained clotted blood. After an uncomplicated hymenectomy, the
index of suspicion
Figure. External genitalia showing bulging hymeneal membrane.
have associated urinary system abnormalities. Failure of vertical fusion results in low obstruction abnormalities, such as imperforate hymen, transverse vaginal septum, and cervical atresia, which usually are not associated with urinary abnormalities. All of the previously noted conditions result in an accumulation of menstrual uid above the level of obstruction. The ovarian structures are derived from a separate embryologic source, the genital ridge. Therefore, ovarian hormonal and endocrinologic function is normal in patients who have genital outow tract abnormalities, which causes an apparent discrepancy between physical ndings of advanced secondary sexual characteristics and lack of menses. An imperforate hymen is diagnosed by genital examination, which reveals a translucent thin membrane inferior to the urethral meatus that bulges when the patient performs the Valsalva maneuver. If hematocolpos is present, a bluish discoloration is apparent behind the membrane. The
volume of blood that collects can be great enough to ll and distend the uterus (hematometra), which may present as an abdominal or pelvic mass. Prolonged menses in a girl who has an imperforate hymen may lead to hematosalpinges and retrograde menses into the abdomen, which may cause intra-abdominal endometriosis and adhesions.
Differential Diagnosis
Although an imperforate hymen should be obvious on physical examination, several conditions may present with similar complaints and ndings. A history of primary amenorrhea in the presence of a blind or absent vagina indicates a variety of developmental anomalies of the genital outow tract, including imperforate hymen, low-lying transverse vaginal septum, cervical atresia, vaginal (mullerian) agenesis, and androgen insensitivity syndrome (AIH). Of these conditions, imperforate hymen, transverse septum, and cervical atresia commonly present at the expected time of menarche in a girl
who has well-developed secondary sexual characteristics and the complaint of cyclical lower abdominal, back, or pelvic pain. On examination, imperforate hymen appears typically as a thin, bulging blue membrane; transverse septa and cervical atresia can be associated with a normal vaginal opening but shortened vaginal canal. Ultrasonography can help evaluate the level and volume of sequestered menses; MRI provides superior anatomic detail to dene the nature of anomalies further, including those of the upper urinary tract. Only in rare instances is laparoscopy required to clarify an anatomic developmental anomaly. Vaginal (mullerian) agenesis and AIH usually are asymptomatic presentations of primary amenorrhea associated with a vaginal anomaly. Patients born with vaginal agenesis experience variable uterine development, with only 2% to 7% having a uterus that has a functioning endometrium. This group may present with cyclic or chronic abdominopelvic pain due to hematometra, but this clinical picture is the exception. Extragenital anomalies are common in vaginal agenesis and should be screened for, particularly urologic (30%) and skeletal (15%) abnormalities. AIH differs from the other mentioned anomalies in that it is a genetic disorder of a chromosomal male (XY) but phenotypic female due to an androgen receptor mutation causing androgen insensitivity in the tissues and resulting in a blind vagina, absent uterus, and testes in the inguinal canal. Imaging, along with evaluation of karyotype and hormone concentrations, further delineates this disorder.
Treatment
Hymenectomy is the denitive treatment for an imperforate hymen. Abdominal ultrasonography is rec-
index of suspicion
ommended before surgery to demonstrate that the true diagnosis is not an obstructing transverse septum or other genital anomaly. If abnormalities are present, the condition may be more complex than a simple imperforate hymen, and surgery should be delayed until the appropriate evaluation is performed, including MRI of the abdomen and pelvis. Surgical treatment of an imperforate hymen is not an emergency procedure. If a preadolescent is found to have an imperforate hymen on examination but otherwise is asymptomatic, surgery often is delayed until puberty to allow the hymen to become estrogenized, optimizing the surgical outcome. A more urgent hymenectomy is needed if the patient also has urinary obstruction. In addition to hymenectomy, treatment for an imperforate hymen consists of evacuating copious amounts of retained blood products and suturing the vaginal epithelium to the hymeneal ring. The outcome of imperforate hymen treated with hymenectomy is excellent. Follow-up in patients who have had imperforate hymen treated has shown normal pregnancy rates and sexual function. Gynecologists have observed that if endometriosis develops from retrograde menses, it is more likely to resolve and have no signicant effect on fertility compared with spontaneous endometriosis occurring in the general population.
vanced breast development and lack of menses did not correlate and, in the presence of recurring abdominal and back pain, led to the suspicion of imperforate hymen. Imperforate hymen is the most common cause of vaginal outow obstruction, and surgical repair can relieve the obstruction and ensure commencement of normal menses. (Kathryn S. Torok, MD, Mananda S. Bhende, MD, Childrens Hospital of Pittsburgh, Pittsburgh, Pa.)
Case 3 Discussion
The baby continued to require supplemental oxygen and demonstrated respiratory distress with feedings. A video swallow study showed no evidence of aspiration. CT scan of the chest performed to evaluate pulmonary anatomic abnormalities as a cause for prolonged hypoxia revealed a vascular structure to the left of the aorta consistent with a duplicated superior vena cava or anomalous pulmonary venous connection. An ECG showed right atrial enlargement and ndings consistent with right ventricular hypertrophy. Echocardiography conrmed the diagnosis of unobstructed supracardiac total anomalous pulmonary venous connection (TAPVC), with the pulmonary veins draining into the innominate vein. A large secundum atrial septal defect (ASD) with right-to-left shunting also was present.
The Condition Lessons for the Clinician

A teenage girl who has lower abdominal pain and back pain may bring to mind an extensive differential diagnosis, leading to extensive laboratory and radiologic testing. However, the history and physical examination remain the most useful tools at the physicians disposal to make the diagnosis. In this case, the patients adTAPVC is a cyanotic heart defect that represents approximately 1% to 3% of all congenital heart defects. Males are affected more often than females (4: 1). Some 33% of affected patients have additional cardiac malformations, and 33% have other noncardiac malformations. TAPVC results from a developmental error that prevents a direct
communication of the pulmonary veins to the left atrium. The pulmonary veins drain into the systemic venous system or directly into the right atrium. In this malformation, an obligatory right-to-left shunt nearly always occurs at the atrial level. Formerly called total anomalous pulmonary venous return, the condition more appropriately is called TAPVC. The abnormality is the connection, not the return, because the veins can empty circuitously into the left atrium or blood can ow into the left atrium through an ASD. The four types of TAPVC are based on the location of the pulmonary vein connection: supracardiac (50%, commonly into the left innominate vein or right superior vena cava), cardiac (20%, commonly into the coronary sinus), infracardiac/subdiaphragmatic (20%, commonly into the portal vein, ductus venosus, hepatic vein, or inferior vena cava), and mixed (10%). The presence of an obstructed pulmonary venous connection affects the clinical presentation. Typically, tachypnea and cyanosis occur within the rst few days after birth as pulmonary blood ow increases. The obstructed ow causes pulmonary edema and decreased lung compliance, which manifests as increased work of breathing and hypoxia. Feeding difculties and other signs of heart failure often are present. In addition, there is a xed and widely split second heart sound due to a delay in pulmonary valve closure caused by right ventricular volume overload. Some infants also develop pulmonary hypertension because of the obstruction. Without obstruction, there may be no symptoms at birth. However, symptoms usually appear within the rst postnatal year. Signs may include dyspnea on exertion and visible cyanosis with crying. Examination usually reveals a pulmonary murmur
index of suspicion
caused by increased ow across the valve. The murmur may be difcult to hear if there is pulmonary vein obstruction. It can be distinguished from pulmonic valve stenosis by the absence of a pulmonary valve click. An ASD causes a similar pulmonary ow murmur and xed splitting of the second heart sound. Rhonchi may be present in some patients. As with this child, percutaneous oxygen saturations may be decreased only slightly because initial pulmonary blood ow remains high and a large interatrial connection allows oxygenated blood to ow into the left atrium and systemic circulation. Progressive cyanosis results from increasing pulmonary edema that impairs oxygenation and decreasing right heart compliance that increases the interatrial right-to-left shunt. Both obstructed and unobstructed types can cause congestive heart failure, growth restriction, and multiple pulmonary infections. Chest radiography may show an enlarged heart with increased pulmonary ow, a snowman shape (in supracardiac TAPVC), or an enlarged upper right heart border. ECG shows right atrial and right ventricular enlargement. The diagnosis is conrmed by identifying a pulmonary venous connection to the systemic veins, coronary sinus, or right atrium on echocardiography.
may be necessary for neonates who are in cardiogenic shock due to TAPVC. Infants aficted with infracardiac TAPVC die before 2 months after birth without surgery. Advancements in surgical correction have lowered mortality rates to near zero and increased long-term survival to 98% at 7 years.
Cyanotic Heart Defects

Many nurseries routinely check percutaneous oxygen saturations at birth. This screening is nearly 100% specic in detection of cyanotic heart defects. (1) Without screening and a high level of suspicion, a subset of patients born with congenital heart disease will be missed. Patients who manifest cyanotic heart disease outside of the neonatal period may present with growth restriction or failure to thrive, a history of recurrent respiratory infections, mild or episodic cyanosis, or irritability. As with this patient, persistent hypoxemia despite resolution of an infectious respiratory process is a major sign of cyanotic heart disease. Indeed, many patients who have cyanotic congenital heart defects are asymptomatic at birth because of the presence of intracardiac mixing of oxygenated and deoxygenated blood that increases the arterial oxygen saturation. Infants born with hypoplastic left heart syndrome or left heart obstruction or who experience increasing pulmonary blood ow as the pulmonary vascular resistance falls naturally (single ventricle without pulmonary stenosis, large ventricular
septal defect) eventually show signs and symptoms of heart failure or pulmonary edema. Unfortunately, for those who have left heart obstruction, symptoms of heart failure may be subtle and the phase of decompensation rapid. Signs and symptoms of congestive heart failure include irritability, poor feeding, failure to thrive, tachypnea without respiratory distress (happy tachypnea) or tachypnea with respiratory distress due to pulmonary edema or pleural effusion, and hepatomegaly. Any patient suspected of having a cyanotic heart defect or congestive heart failure should be screened with a chest radiograph and ECG. Echocardiography provides the denitive diagnosis.
Lessons for the Clinician

Recognizing signs and symptoms of cyanotic heart defects and early symptoms of congestive heart failure is critical to the early recognition, management, and surgical correction of these lesions. (Grace Pecson, MD, Carolyn Leedy, MD, University of Texas Southwestern Medical Center, Childrens Medical Center, Dallas, Tex.)
Reference
1. Reich JD, Miller S, Brogdon B, et al. The
use of pulse oximetry to detect congenital heart disease. J Pediatr. 2003;142:268 272
Prognosis
Most patients who have TAPVC do not survive beyond the rst year without surgery. Emergent surgery
To view Suggested Reading lists for these cases, visit www.pedsinreview.org and click on Index of Suspicion.
Index of Suspicion Cherilyn Hall, Allen Friedland, Sumathi Sundar, Kathryn S. Torok, Mananda S. Bhende, Grace Pecson and Carolyn Leedy Pediatr. Rev. 2008;29;25-30 DOI: 10.1542/pir.29-1-25
Updated Information & Services Supplementary Material
including high-resolution figures, can be found at: http://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 Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pedsinreview.aappublications.org/misc/Permissions.shtml Information about ordering reprints can be found online: http://pedsinreview.aappublications.org/misc/reprints.shtml
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Pediatrics in the Community: Community Pediatrics Training Initiative (CPTI) Jeffrey Kaczorowski Pediatr. Rev. 2008;29;31-32 DOI: 10.1542/pir.29-1-31
pediatrics in the community
Community Pediatrics Training Initiative (CPTI)

Author Disclosure Drs Kaczorowski and Aligne did not disclose any nancial relationships relevant to this article.
Our inaugural story for Pediatrics in the Community was in the January 2007 edition of Pediatrics in Review. Dr Robert Haggerty provided the historical rationale for community pediatrics training (CPT) as part of that feature. Now, 1 year later, we asked Dr Jeff Kaczorowski, Director of the CPTI at the American Academy of Pediatrics (AAP), to describe the present and future of CPT. As the stories in this series have shown, some residents are having wonderful community experiences already and making a difference in the lives of children in their communities. The challenge is how to make such experiences available to all pediatric residents and pediatricians.C. Andrew Aligne, MD, MPH, Section Editor The CPTI was founded 8 years ago by a remarkable pediatrician named Anne Dyson, and in 2005, CPTI moved to the AAP. Our ultimate goal is to ensure that all pediatric training programs develop and sustain quality community experiences that are fully integrated into residency training. Maintaining a community perspective is a critical part of what we need to do in pediatrics to assure the health of all children in the United States. Residents and young pediatricians across the country have told me that they want this kind of training, and national surveys conrm this signicant demand. Residents understand that community and environmental factors play a major role in morbidities such as obesity, mental health problems, child abuse, violence, and injuries. Yet, many residency programs are just beginning to develop training experiences that involve getting outside the hospital into the
home and school environments where children spend their days. Programs that have these initial exposures often want to develop the next level, particularly in the areas of legislative/systems-level advocacy and community projects. CPTI is working on many fronts with numerous partners to accomplish its mission of developing quality CPT experiences at beginning, as well as more advanced, levels. CPTI is partnering with:
the Ambulatory Pediatric Association to cosponsor the Pediatric Academic Societies educational scholars program for present or future faculty in academic pediatrics who have an interest and experience in community pediatrics. the AAP CATCH (Community Access to Child Health) program on grants for residency programs to plan and implement community-based child health initiatives, as well as visiting professorships in community pediatrics. the AAP Department of Federal Affairs to support ve facultyresident pairs annually to attend the AAP Legislative Conference and then to implement an educational activity on child advocacy in coordination with their local AAP chapter. the AAP Council on Community Pediatrics to sponsor the Pediatrics for the 21st Century (Peds21) Symposium on Community Pediatrics in October 2007, including a resident poster session featuring community-based initiatives. the AAP Division of State Government Affairs and Department of Federal Affairs to develop an advoPediatrics in Review Vol.29 No.1 January 2008 31
pediatrics in the community
Figure. These children are participating in a program to help combat obesity and get children more active in Palo Alo, Calif. The residents involved were Heather Iezza, MD, and Maria Mosquera, MD.
cacy guide for pediatricians, pediatric residents, and child health professionals, which will be available in the spring of 2008. Pediatrics in Review to sponsor this feature.
CPTI has developed a number of tools to support residency programs,
including the Community Pediatrics Curriculum Manual (2005), the Community-based Resident Projects Toolkit (2005), and the CPTI Evaluation Toolkit (2007). CPTI will soon launch a searchable online database of community pediatrics training activities across the nation. For more information on any of the
above or to join the CPTI listserv to receive announcements about grants and other opportunities, go to: http://www.aap.org/commpeds/ cpti/or e-mail: cpti@aap.org. Jeffrey Kaczorowski, MD Director, CPTI American Academy of Pediatrics
Pediatrics in the Community: Community Pediatrics Training Initiative (CPTI) Jeffrey Kaczorowski Pediatr. Rev. 2008;29;31-32 DOI: 10.1542/pir.29-1-31
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Inhalants Michael Crocetti and Janet R. Serwint Pediatr. Rev. 2008;29;33-34 DOI: 10.1542/pir.29-1-33
in brief
In Brief
Inhalants
Michael Crocetti, MD Bayview Medical Center Baltimore, Md. involves inhaling vapors from an open can or container, bagging describes inhaling vapors that have been captured in a bag, and hufng consists of inhaling volatile substances that have been soaked in a cloth. Bagging and hufng are preferred methods because the user can inhale large concentrations of the drug. Inhalant abuse reaches its peak between grades 7 and 9 in the United States. Surveys of illicit drug use have revealed that use of inhalants is second to marijuana use among 8th and 10th graders and that inhalants are the third most widely used agents of abuse among 12th graders. The Youth Risk Behavior Survey 2005 reported that the overall prevalence of lifetime inhalant use was about 12%. Some studies suggest that females are as likely as males to use inhalants prior to 17 years of age but that males in the 18- to 25-year age group are more likely to do so. Rates of abuse have been reported to be higher among American Indians, whites, and Hispanics compared with African Americans. Other research has shown that a history of child abuse, a history of being in foster care, poor socioeconomic status, failing grades, and dropping out of school are risk factors associated with inhalant use. Use of inhalants has been popular for many years because these substances are inexpensive, legal, and easy to obtain. Many can be found in common household products stored in garages, basements, and kitchens. Generally, there are four classes of inhalants. Volatile solvents are liquids that vaporize at room temperature and can be found in paint thinners, gasoline, and glues. Aerosols include spray paints, deodorant, and hair sprays. Gases can be found in many commercial products. Nitrous oxide is the most common abused gas and can be found in butane lighters, propane tanks, whipped cream dispensers, and Freon. Nitrites, which dilate blood vessels and relax muscles, often are used as sexual enhancers. These substances are prohibited by the Consumer Product Safety Commission but can be found in small bottles under the names video head cleaner, room deodorizer, or liquid aroma. Inhalants produce a pleasurable effect by depressing the CNS in a manner similar to that of alcohol. Research has demonstrated that toluene, found in glues, activates the brains dopamine system. Acute effects of inhalant use include excitation followed by drowsiness, disinhibition, lightheadedness, and agitation. High doses may lead to confusion and delirium. These acute effects have a rapid onset but are short-lived, and many adolescents inhale the substances repeatedly to gain longer-lasting effects. Repeated use makes the user vulnerable to the different stages of inhalant intoxication. Stage 1 is the excitability stage, stage 2 is the depressive phase, and stage 3 is further depression of the CNS. Stage 4 is the most worrisome stage, in which CNS depression can lead to coma, in addition to accidents and trauma due to risk-taking behaviors. Up to 50% of inhalant-related deaths are due to sudden snifng death syndrome. Inhalants sensitize myocardial cell membranes to depolarization, and if the user is startled or engaging in vigorous activity at the time, catecholamines are released, leading to ventricular brillation. Inhalantassociated arrhythmias can occur after a single inhalant use in otherwise
Author Disclosure Drs Crocetti and Serwint did not disclose any nancial relationships relevant to this In Brief.
Recognition and Prevention of Inhalant Abuse. Anderson CE, Loomis GA. Am Fam Physician. 2003;68:869 874 Adolescent Abuse of Other Drugs. Greene JP, Ahrendt D, Stafford EM. Adolesc Med. 2006;17:283318 Inhalants of Abuse. Gussow LM. In: Ford M, Delaney KA, Ling L, Erickson T, eds. Clinical Toxicology. Philadelphia, Pa: WB Saunders Co; 2001:651 656 Inhalant Abuse. National Institute on Drug Abuse. Research Reports. http:// www.nida.nih.gov/ResearchReports/ Inhalants/Inhalants.html. Accessed January 15, 2007 Inhalant Abuse and Dependence Among Adolescents 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 Substance Abuse and Committee on Native American Child Health. Pediatrics. 2007;119:1009 1017
Inhalants are volatile substances that, when sniffed or snorted, can induce euphoric and hallucinogenic effects. These substances are lipid-soluble and after inhalation are absorbed rapidly through the lungs, quickly entering the central nervous system (CNS). Inhalants are classied as CNS depressants, but acute intoxication can lead to a sense of euphoria and excitability. Snifng
in brief
healthy adolescents. Sudden snifng death is associated most often with the use of toluene, propane, butane, and aerosols. Diagnosing inhalant abuse is difcult and relies on a high degree of suspicion, supported by a thorough history and physical examination. Other causes of acute intoxication or altered mental status should be considered, such as hypoxia, hypoglycemia, ethanol, illicit drugs, trauma, and infection. Inhaled hydrocarbons may be detected by gas chromatography within 10 hours of use, but this test is not readily available at most medical facilities. Although not specic, laboratory evaluation may reveal hypokalemia, hypophosphatemia, hypocalcemia, metabolic acidosis, methemoglobinemia, and carbon monoxide toxicity. Laboratory evaluation should include a complete blood count, basic metabolic panel, calcium and phosphorous measurements, hepatic panel, and urinalysis for clues to inhalant use and urine toxicology screen to detect other illicit drug use. Consideration also should be given to cardiac and muscle enzyme analysis and electrocardiography, arterial blood gas determination to
rule out methemoglobinemia, and brain imaging if neurologic signs are present. Treatment of an acute overdose is supportive, with particular attention paid to airway, breathing, and circulation. Unfortunately, no medication can reverse the effects of most inhalants. Long-term treatment of inhalant dependence involves counseling, strict abstinence, and drug treatment protocols such as 12-step programs and inpatient and outpatient therapy. However, a recent survey found that many centers are not adequately equipped to treat inhalant abuse or dependence. Comment: Dr Crocettis In Brief on Inhalants is really thought-provoking. He emphasizes the importance of considering inhalant use when evaluating patients whose manifestations are either acute or chronic. Because inhalants are so easily available, they often are used initially by younger, elementary school-age children; 3% of patients have tried inhalants by 4th grade. Furthermore, those who reported rst use by 13 to 14 years of age were six times more likely to become dependent on inhalants than were those who began using at 15 to 17 years of age.
Signs of inhalant use may be subtle. Clinicians need to be alert to odors on the breath or clothes; discovery by parents of hidden empty cans; or signs of slurred speech, nausea, and symptoms similar to those of alcohol intoxication. Chronic users may exhibit a huffers rash, which is a dermatitis around the mouth or nose, with cracking of the skin and, sometimes, bacterial superinfection. Because the effects of inhalants are short in duration, it is unusual for patients to seek medical attention unless they have developed chronic morbidity from long-term effects on the brain, heart, lung, kidney, liver, or bone marrow (suppression). Mortality can occur both from the sudden snifng syndrome and through asphyxiation or suffocation related to bagging or huffing. Education and prevention strategies for both children and their parents must begin during elementary school to minimize the morbidity and mortality from this underdiagnosed form of drug abuse.
Janet R. Serwint, MD Consulting Editor
Inhalants Michael Crocetti and Janet R. Serwint Pediatr. Rev. 2008;29;33-34 DOI: 10.1542/pir.29-1-33
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Article
policy statements
American Academy of Pediatrics Policy Statements on Bioethics: Summaries and

Commentaries: Part 1
Mark 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*
Introduction
The American Academy of Pediatrics (AAP) has a strong and longstanding interest in the eld of bioethics and periodically publishes policy statements pertaining to specic ethical questions relevant to pediatrics. The subjects addressed cover a wide range of topics, from parental refusal of immunization to the care of critically ill children. These policies are authored initially by the AAPs Committee on Bioethics and undergo extensive internal review by other committees prior to publication. This article is the rst in a series of three intended to familiarize readers with many of the AAP policies currently in place that address issues in bioethics. In this series, 16 policies published by the AAP are summarized, each followed by a brief commentary. The commentaries are intended to address, at least on a cursory level, some of the ethical principles underlying the policies. Some briey point out possible alternative viewpoints. The policies referenced in this article represent the efforts of various committees and committee members over the years. Each of the summaries presented here, as well as the commentaries that follow, represents the work of individuals serving on the Executive Committee 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 the published policies. When quotations are used within a summary and not referenced, it can be assumed that the quote is taken directly from the policy being summarized. For ease of use, the references for each policy are provided with each individual summary and commentary.
Author Disclosure Drs Mercurio, Adam, Forman, Ekman Ladd, Friedman Ross, and Silber did not disclose any nancial relationships relevant to this article.
Policies Reviewed
Part 1 of this series reviews: 1. Informed Consent, Parental Permission, and Assent in Pediatric Practice 2. Religious Objections to Medical Care 3. Responding to Parental Refusals of Immunization of Children 4. Sterilization of Minors With Developmental Disabilities 5. Human Embryo Research Part 2 of this series reviews: 6. Guidelines on Foregoing Life-sustaining Medical Treatment 7. Foregoing Life-sustaining Medical Treatment in Abused Children 8. Do-Not-Resuscitate Orders for Pediatric Patients Who Require Anesthesia and Surgery 9. Do-Not-Resuscitate Orders in Schools 10. Ethical Issues with Genetic Testing in Pediatrics 11. Ethics and Care of Critically Ill Infants and Children Part 3 of this series reviews: 12. Female Genital Mutilation 13. Appropriate Boundaries in the Pediatrician-Family-Patient Relationship 14. Infants With Anencephaly as Organ Sources: Ethical Considerations 15. Palliative Care for Children 16. Institutional Ethics Committees
*On behalf of the American Academy of Pediatrics Section on Bioethics. Pediatrics in Review Vol.29 No.1 January 2008 e1
policy statements
bioethics
Informed Consent, Parental Permission, and Assent in Pediatric Practice

Committee on Bioethics. Informed consent, parental permission, and assent in pediatric practice. Pediatrics. 1995;95:314 317. Available at: http://aappolicy. aappublications.org/cgi/content/abstract/pediatrics% 3b95/2/314. Reafrmed October 2006. Summary and comment by Edwin N. Forman, MD, and Rosalind Ekman Ladd, PhD.
Comment
This policy, which provides for a genuine form of child assent, is based clearly on Western values. Modeled after the informed consent requirement for competent adult patients, it takes seriously an ethical duty to keep the child informed in age-appropriate ways and to solicit an expression of the childs willingness (ie, assent), when appropriate, to undergo the proposed treatment. The policy is somewhat unclear about when it is appropriate to solicit assent. Dissent may be ethically binding in the case of nontherapeutic research or nonessential treatment, but the policy notes that it is deceptive to ask for assent when treatment is necessary and the childs dissent will be overridden. On the other hand, it seems to recommend solicitation of the childs willingness to accept treatment, even when it is deemed essential and only parental permission is required, as one element of involving the child in discussions about his or her health care. Asking the child for assent recognizes the dignity and moral status of the child. The model is to provide a gradually increasing involvement of the child in making choices as the child grows in competence and moves from complete dependency on parents to independence. However, in our pluralistic society, the ideal of an individual as independent and free-thinking is not accepted by all cultural groups. Some cultures expect decisions to be made exclusively by parents or elders, whatever the age of the younger generation. In addition, the idea of a school-age child expressing an opinion at variance with his or her parents may constitute an upheaval of traditional values when the parenting style is authoritarian. In using the AAP policy, the pediatrician is following Western democratic values and should be sensitive to the fact that some families come from cultures that have different views of the role of the child.
Summary of Policy Statement

This statement comments on the concept of informed consent and its application and limitations in the practice of pediatrics, where a triad exists: physician, parent(s), and patient. The policy analyzes the problematic issue of who should make health-care decisions. It lays out the elements and moral and legal underpinnings of informed consent and consent by proxy (ie, by parents). The concepts of emancipated and mature minors are presented. The policy denes and defends the concept of assent. Although children cannot be treated as rational, autonomous decision-makers, pediatricians should give serious consideration to the patients developing capacities for participating in decision-making. Children should be involved in discussions about their health care, even in situations in which one should not and does not solicit their agreement to the proposed medical management. Four elements of assent are emphasized: 1) helping the child achieve a developmentally appropriate awareness of the condition, 2) telling the child what should be expected with tests and treatment, 3) assessing the childs understanding and factors that inuence his or her response, and 4) soliciting an expression of the childs willingness to accept the proposed care. The policy notes that physicians and parents should not solicit childrens views without intending to weigh them seriously. In situations in which the medical treatment is deemed essential and must be given despite the patients objection, the child should be told of this fact. The AAP argues for shared decision-making, points out limits on parental authority, and justies the importance of involving the child in decision-making by noting that such actions foster trust, create better physician/ patient relationships, and may improve long-term health outcomes. Specic steps are outlined in obtaining assent, depending on the patients developmental stage and the medical situation, and in cases of conict resolution. Rejected are outright medical paternalism and total parental authority.
e2 Pediatrics in Review Vol.29 No.1 January 2008
Religious Objections to Medical Care

Committee on Bioethics. Religious objectives to medical care. Pediatrics. 1997;99:279 281. Available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics;99/2/279. Reafrmed October 2006. Summary and comment by Mark R. Mercurio, MD, MA.

In this statement, the Committee on Bioethics, speaking for the AAP, addresses parental decisions not to seek or accept medical care for their children based on religious objections. The major role that religion plays in the lives of many adults and children in the United States is recognized, and the need for the pediatrician to be
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sensitive to and have respect for religious tradition is acknowledged. However, the AAP believes that all children deserve effective medical treatment that is likely to prevent substantial harm or suffering or death, despite religious objections that the parents may hold. If efforts at collaborative decision-making with parents are not successful in getting their approval for appropriate medical treatment in such cases, a court order ultimately should be sought. If the childs life is in imminent danger, the physician should intervene over parental objections. The AAPs position is consistent with that of the United States Supreme Court. As the AAP notes: Constitutional guarantees of freedom of religion do not permit children to be harmed through religious practices, nor do they allow religion to be a valid legal defense when an individual harms or neglects a child. (1) The AAP opposes exemption, based on religion, from child abuse and neglect laws when children are not provided necessary medical care. Failure to seek medical care when a child is seriously ill should be considered child neglect, regardless of the motivation. Laws that would allow an exemption on religious grounds should be opposed or repealed. In the area of preventive care, a somewhat less forceful stance is taken. Although the AAP strongly endorses universal immunization, for example, it does not support the stringent application of medical neglect laws when children do not receive those immunizations due to parental refusal.
Comment
An ethical justication for the AAP position on this matter could be presented as a rights-based argument. Every child, it could be argued, has a right to medical care that is likely to prevent substantial harm or suffering or death. The childs right creates obligations for the parents, the physician, and society. The parents are obligated to bring the child for the needed treatment, which, in the opinion of the AAP, cannot be limited to prayer or other spiritual practices alone but should include appropriate medical care. The physicians responsibility is either to provide the necessary treatment if able or to attempt to procure appropriate medical treatment for the child. The policy states that the physician may withdraw from these cases if continuing would violate his or her own moral precepts, after securing acceptable alternative care. However, a practitioner willing to withhold medical treatment likely to prevent substantial harm would not seem to qualify as a provider of acceptable alternative medical care.
Society is obligated to facilitate the provision of the needed treatment to the child, including passing and enforcing laws that support necessary treatment of children despite parental religious objections. However, it could be argued, and rightly so, that society also is obligated to protect religious freedom. The courts often are asked to evaluate this tension between the parental right to religious freedom (for themselves and their children) and the childs right to necessary medical care. In general, the courts have taken the position proffered by the AAP: If the treatment in question is likely to prevent substantial harm or suffering or death, the childs right to treatment outweighs the parental right to religious freedom. This viewpoint is not intended to ignore the parents right to religious freedom, but rather to 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 possible but perhaps not likely, the imperative to overrule parental objection to treatment may be less certain. Again, the courts often have held this position. The policy alludes briey to the concept of the mature minor, including a recognition that as children grow into adolescence, many have an increasing ability to contribute to or make their own medical decisions. In a previous statement, the Committee on Bioethics opined that as children develop, they should gradually become the primary guardians of personal health . . . assuming responsibility from their parents. (2) Based on that understanding, the policy at issue here states, in selected cases, disputes may be avoided when a minor has the capacity to make an independent decision in light of religious values and recommended medical therapy. The pediatrician, indeed, may perceive less dispute, and the right path may seem clearer, when a mature minor requests a recommended treatment that his or her parents seek to refuse on his or her behalf. However, what if the mature minor refuses a lifesaving treatment, in accord with his or her parents, based on religious objections? It is not clear what the AAP would recommend in such a case. A competent adults right to refuse treatment on religious grounds is recognized widely. It is somewhat unclear exactly when that right obtains, particularly if we believe that the development of decision-making capacity is a gradual process. It seems reasonable to suggest, nevertheless, that an individuals right to refuse medical treatment on religious grounds should be recognized at the same time as his or her right to refuse on any other basis.
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References
1. Walker v Superior Court, 763 P2d 852, 860 (Calif 1988), cert
denied. 1989; 491 US 905
2. Committee on Bioethics. American Academy of Pediatrics. Informed consent, parental permission, and assent in pediatric practice. Pediatrics. 1995;95:314 317
Responding to Parental Refusals of Immunizations

Diekema DS and the Committee on Bioethics. Responding 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.

This statement begins with the AAPs strong endorsement of universal immunization, but acknowledges that despite their safety and efcacy proles, some vaccines are refused by some parents. Some parents refuse because of erroneous information; others refuse because of religious or philosophical beliefs. (1)(2) Data from a periodic survey of AAP members found that 7 of 10 pediatricians reported that they had a parent refuse an immunization on behalf of a child in the 12 months preceding the survey, (3) similar to other recent data. (4) This statement recommends that when faced with a refusal, physicians should try to: 1) understand the parents perspective, 2) correct any misinformation, and 3) encourage the parents to reconsider. It also asks the physicians to consider whether the refusal exposes the child to serious risk such that it constitutes medical neglect and puts others at serious risk of harm, justifying public health intervention. Because refusals rarely cause imminent threats to a childs or a communitys health, the AAP recommends that physicians respect the refusals. The statement encourages physicians not to dismiss these families but to continue to work with them to ensure that their children have access to medical care and to maximize opportunities to encourage vaccinations.
policy is clear that pediatricians generally should respect families who refuse vaccines. The practice of respecting parental refusals of vaccinations also is addressed in another AAP statement, Religious Objections to Medical Care. This latter statement notes that some religious groups deny children the benets of routine preventive care such as immunizations and states, [t]he AAP does not support the stringent application of medical neglect laws when children do not receive recommended immunizations. (5) This stance is consistent with an attitude that intervention by the state should be invoked only when it offers the least detrimental alternative. (6) When most of the community is immunized, the risk to the child is low, and state intervention cannot be justied, even though outbreaks do occur with attendant serious consequences. (5) With the development of new vaccines such as the human papillomavirus vaccine and continued work on human immunodeciency virus vaccines, future policies will need to consider whether these vaccines t into our current model of public health interventions and statemandated vaccination policies and how pediatric practices will be able to deliver vaccines that should be provided to adolescents.
References
1. Salmon DA, Teret SP, MacIntyre CR, Salisbury D, Burgess MA,
Halsey NA. Compulsory vaccination and conscientious or philosophical exemptions: past, present, and future. Lancet. 2006;367: 436 442 2. Salmon DA, Moulton LH, Omer SB, DeHart MP, Stokley S, Halsey NA. Factors associated with refusal of childhood vaccines among parents of school-aged children: a case-control study. Arch Pediatr Adolesc Med. 2005;159:470 476 3. American Academy of Pediatrics, Division of Health Policy Research. Periodic Survey of Fellows No 48: Immunization Administration Practices. Elk Grove Village, Ill: American Academy of Pediatrics; 2001 4. Flanagan-Klygis EA, Sharp L, Frader JE. Dismissing the family who refuses vaccines: a study of pediatrician attitudes. Arch Pediatr Adolesc Med. 2005;159:929 934 5. American Academy of Pediatrics Committee on Bioethics. Religious objections to medical care. Pediatrics. 1997;99:279 281 6. Goldstein J, Freud A, Solnit A. Before the Best Interests of the Child. New York, NY: Free Press; 1979
Comment
This statement takes an ethical and pragmatic position: Encourage universal immunization because that practice serves the childs best interest and because it promotes herd immunity (community benet), but respect refusals. The authors acknowledge that immunizations are neither 100% safe nor 100% effective but argue that the benet-to-harm calculation is extremely high and justies universal immunization policies and practices. The
Sterilization of Minors With Developmental Disabilities

Committee on Bioethics. Sterilization of minors with developmental disabilities. Pediatrics. 1999;104:337 340. Available at: http://pediatrics.aappublications. org/cgi/content/full/104/2/337. Reafrmed Octo-
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ber 2006. Summary and comment by Tomas J. Silber, MD, MAAS.
Comment
This policy statement updates a previous AAP statement entitled, Women Who Are Mentally Handicapped, published in 1990. That statement was published as a companion to a policy of the American College of Obstetricians & Gynecologists. The revised policy is based on concepts developed in the earlier statements, but now applies them to both males and females. This is the policy to consult whenever parents or legal guardians approach pediatricians or other health-care professionals about the possibility of surgical sterilization of children, adolescents, and young adults who have developmental disabilities. Sterilization has a long history of abuse in the United States. However, by the middle of the 20th century, the United States Supreme Court prompted a major change in the legal landscape by declaring human procreation a fundamental right. Since then, requests for authorization to sterilize those who have developmental disabilities have been the object of scrutiny, limitations, and even prohibition in many jurisdictions. In the 1970s, for example, regulations were enacted to prevent the use of federal funds to perform sterilization procedures on those deemed mentally incompetent. It should come as no surprise that, at present, we face so many federal rules, state laws, and judicial rulings that pediatricians whose advice is requested nd themselves facing a confusing and contradictory array of restrictions on surgical sterilization of persons with development disabilities. Indeed, this confusion may not be a coincidence because an ethical tension exists between the obligation to honor the least restrictive alternatives for those who have cognitive disabilities and the concern about abuse and coercion leading to unwanted pregnancy or, worse, a pregnancy that the child may not comprehend or may be terried by. Moreover, those who love and care for developmentally delayed children certainly may have their best interest at heart when they know that those individuals are not capable of caring for offspring. Although this statement gives guidance on how to proceed when sterilization becomes the choice, its major strength is that it develops the fundamental criteria required to make that decision ethically permissible, namely, that the person lacks adequate mental capacity to make decisions about his or her health care and is unable to interpret his or her own interests. Thus, there is a moral mandate before sterilization can be considered: Assessment of an individuals capacity to decide matters specically concerning reproduction and an obligation to obtain help from professionals experienced with evaluatPediatrics in Review Vol.29 No.1 January 2008 e5

This statement, reviewing the history of and considerations leading to the parental request of sterilization for a son or daughter who has developmental disabilities, develops ve recommendations, summarized as follows: 1. The AAP encourages pediatricians to use the development of secondary sexual characteristics in persons who have developmental disabilities as an opportunity to explore the patients and caregivers understandings of the facts and implications of sexual maturation. 2. Consideration of sterilization should focus on whether a need for permanent prevention of reproduction exists. Concern about other consequences of sexual maturity or aspects of sexuality among persons who have cognitive disabilities should focus on interventions substantially less radical than sterilization. The AAP encourages pediatricians to familiarize themselves with the resources in their community to which they might refer families for additional information or for specialized education and counseling on such matters as appropriate expressions of affection and sexual drives, effective menstrual hygiene, sexual abuse avoidance training, and contraception. 3. Whenever possible, pediatricians should involve their patients who have developmental disabilities in decisions about reproduction and should advocate for the least permanent and intrusive method of contraception consistent with the lowest risk for the patient. 4. When a minor who has developmental disabilities requests sterilization and an assessment determines that the minor has adequate decision-making capacity to consent to the procedure, the minors views on the matter should be respected. Such decisions generally benet from the involvement of the adolescents family, other adults close to the adolescent, or both. 5. Pediatricians should become familiar with the applicable law about sterilization of persons who have developmental disabilities. Pediatricians should establish relations with local agencies and attorneys knowledgeable about the legal complexities of sterilization of persons who have developmental disabilities in their jurisdiction. If sterilization is legally permissible on the authority of parents or legal guardians and is chosen as the best course of action, substantial effort should be made to communicate to the patient the facts and implications of the sterilization. To the extent possible, the patient should participate in planning for the procedure.
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ing the capabilities of persons with disabilities. Once the decision has been reached, the advocacy work starts.
Human Embryo Research

Committee on Bioethics and Committee on Pediatric Research. Human embryo research. Pediatrics. 2001; 108:813 816. Available at: http://aappolicy. aappublications.org/cgi/content/full/pediatrics%3b108/ 3/813. Reafrmed January 2005. Summary and comment by Mary B. Adam, MD, MA.

On behalf of the AAP, the AAP Committee on Bioethics, and the AAP Committee on Pediatric Research wrote a policy statement asserting, under certain conditions, research involving human embryos and pluripotent stem cells is of sufcient scientic importance that the National Institutes of Health should fund it and that federal oversight is morally preferable to the current unregulated private sector. According to the statement, embryos are dened as human organisms derived by fertilization from one or more gametes or diploid cells. (Embryos formed using a diploid cell is a reference to cloning human embryos.) Justication for use of human embryos includes the possible identication of potential benets to children as a class as well as the more global potential for medical benets. The statement acknowledges that its position is controversial because some believe that research using human embryos is morally problematic. Opponents to the AAPs position object to the destruction of human embryos for research purposes because they view humans at all stages of development as deserving full human value. Those who object to the use of human embryos in research concede that even if that research may have great therapeutic potential, the ends do not justify the means. Ethical concerns also arise regarding how the embryos are acquired for research and the possible moral complicity of researchers. The statement claims that using discarded embryos that are no longer needed by parents for assisted reproduction (clinical need) is less problematic than the creation of embryos for the specic purpose of research. However, the use of embryos that are no longer clinically needed as children for the couple using in vitro fertilization techniques still can cause ethical problems related to obtaining adequate informed consent from donors, ensuring privacy of donors, and decreasing potential or perceived conicts of interest by those who may request the donation and concerns about undue nancial inducement to acquire embryos. These concerns are
addressed by recommending limiting human embryo research to a set of eight conditions and suggesting a group of considerations for obtaining informed consent from donor parents. The eight recommended conditions are: 1. The embryos are already frozen and no longer are clinically needed. 2. A clear separation exists in the donor decision process between the decision by the donors to create embryos for infertility treatment and the decision to donate frozen embryos for research purposes after they are no longer clinically needed. 3. The decision to donate is strictly voluntary and without monetary inducements. 4. The physician responsible for fertility treatments is not to be the person performing the research on the same frozen embryos, and there should be no monetary relationship, that is, transfer of funds in the research project to the physician responsible for the fertility treatments. 5. There are to be no personal identiers associated with the embryos used for research. 6. No restrictions can be placed by the donor on the type of research performed. 7. The research performed on the frozen embryos can be of no direct benet to the original donors. 8. The embryo research does not involve research in reproductive cloning, transferring an altered embryo to a womans uterus, or using a human embryo in combination with other human or animal embryos. A unique status of the individual human embryo is acknowledged, and the following limitations are proposed as safeguards: 1) research is to be limited to embryos in the rst 14 days after fertilization, and 2) funding and additional oversight at the federal level are appropriate, including the creation of a new Department of Health and Human Services committee to oversee human embryo research specically and develop ethical guidelines for its use.
Comment
The moral standing of the embryo has generated significant debate in the public sector, and this statement, not surprisingly, created some controversy. Drs Chesney, Botkin, and Nelson responded for the Committees on Pediatric Research and Bioethics to a letter to the editor of Pediatrics, stating, Given the fundamental disagreements over the moral status of embryos, it probably is impossible to develop a position on this subject that all would consider acceptable. (1) These fundamental disagreements are not scientic in origin because all parties would agree that the human embryo is a being of human
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origin. The disagreement, rather, is the result of different perspectives on the meaning and ramications of protecting human value and dignity. Those who hold to a view that the human embryo is deserving of full moral respect point out that various criteria have been used wrongly during different periods of human history to identify beings of human origin not believed to be worthy of full human value, dignity, and respect. These criteria have included: location, ethnicity, mental capacity, stage of development, and sex (especially female sex). It is argued that a similar injustice is done when human embryos are denied full protection because they are members of the human community. To do so would provide a toehold for other potential abuses of human beings, a slippery slope argument. Those who hold this view might agree that research has therapeutic potential but would say that the ends do not justify the means. On the other hand, the argument that the potential for scientic progress outweighs morally problematic concerns is a utilitarian perspective. Research on nonconsenting human embryos, for whom there is no prospect of direct benet and who would be destroyed in the process, could be acceptable from a utilitarian view if the potential gain for others might outweigh the concern. A developmental perspective is another perspective that may be consistent with permitting research on human embryos. In this view, one would assign different levels of moral status to human beings at different stages of development or capacity, with those individuals at the earliest stages of development being accorded less moral status (and, thus, more limited rights) than those later in development. The AAP recognizes the human embryo as unique, a special tissue deserving of respect, but by allowing their use in research up to 14 days after fertilization, places embryos before 14 days of existence as having less moral worth than individuals at later developmental stages. This combining of a utilitarian and developmental perspective permits the AAP to encourage lifting restrictions on federal funding for research on human embryos in some limited circumstances when the embryo is early enough in development, where potential benet is seen, and where additional oversight is included. The statement does not specically address protections or oversight for embryos when the research is privately funded. Other ethical issues in the statement ow out of a value for the unique moral standing of the human embryo. For example, the issue of the comodication of human embryos is addressed. The Committee expresses concern about the potential sale of human embryos and
recommends that no embryo be offered for research with monetary inducements on the part of the physician responsible for fertility treatments, donor parents, or researchers. This point of view is prudent because the sale of human gametes for nancial prot (via Internet and newspaper advertisements) is widespread. This issue also highlights the needs and challenges of oversight because creating embryos is not illegal, and human gametes are easily procured for cash. The AAP statement identies parents as the donors who are entitled to represent the interests of the embryo. Parents are required to give their consent to donate their embryos for research. However, no statement is included discussing if one or both parents must agree with the for research designation. Concerns about the potential for coercion of parents by researchers are part of the impetus to recommend that the donation be strictly voluntary and without monetary inducements. The limitations on the use of human embryos in research provided by the AAPs statement include a prohibition on the use of embryos for reproductive cloning. There is no specic mention of the related research issue of human therapeutic cloning. However, donor consent in cases of therapeutic cloning would be problematic because there is no separation of the decision process to create the embryo and to use the embryo for research/therapeutic purposes (see recommendation 2). The AAPs position was challenged in a letter to the editor. (2) The response included the following statement: We feel that an ongoing debate on these topics is meaningful, pertinent, appropriate, and a right of all American citizens. (1) Given the call for meaningful debate, this statement can be a launch point for discussions on what it means to be human. Do all beings of human origin deserve full moral status, worth, and human dignity? If not, why not? If so, how does one justify drawing a line on the continuum of human development? Where do we draw the line? How do we safeguard against turning beings of human origin into commodities or parts for sale? Are humans worth more than the sum of and sale of their parts? (3)(4)(5)
References
1. Committee on Bioethics and Committee on Pediatric Research.
Embryonic stem cell research. Pediatrics. 2002;109:990 991
2. June P. Embryonic stem cell research. Pediatrics. 2002;109:

990 991
3. Devolder K. Creating and sacricing embryos for stem cells.

J Med Ethics. 2005;31:366 370
4. Cheshire WP. Human embryo research and the language of

moral uncertainty. Am J Bioethics. 2004;4:15
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5. Cameron C, Williamson R. In the world of Dolly, when does a

human embryo acquire respect? J Med Ethics. 2005;31:215220
Conclusion
The AAP periodically publishes policy statements and guidelines addressing difcult ethical issues that physicians caring for children will continue to face. This review is intended to provide readers an overview of some of those guidelines and possibly stimulate additional thought and dialogue within the profession. It is presented by the AAP Section on Bioethics as part of its mission to foster education in this area among pediatricians. As the commentaries suggest, there may not be unanimity about the positions taken, which is important to recognize. The full text of each policy, as well as other relevant references and information, can be found on the web site for the Section on Bioethics at http:// www.aap.org/sections/bioethics. The Section on Bioethics serves primarily an educational role within the AAP and beyond. They organize educational forums in bioethics at the annual AAP Na-
tional Conference and Exhibition, publish a newsletter that includes original articles in the area of bioethics, and carry out other educational efforts intended primarily for pediatricians. In addition, they provide input to the Board of Directors and other committees regarding proposed policy statements and guidelines. Membership in the Section is open to all AAP Fellows who have an interest in bioethics. Afliate membership also is available to physicians and other health professionals not eligible for AAP membership. This is the rst in a series of three articles on AAP policies that address ethical issues in pediatrics. The next two articles will appear in subsequent issues of Pediatrics in Review. ACKNOWLEDGMENTS. The authors would like to thank Marilyn A. Maxwell, MD, and Brenda Jean Mears, MD, their colleagues on the AAP Section on Bioethics Executive Committee, for guidance and helpful comments in the preparation of this manuscript.

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Editor-in-Chief: Lawrence F. Nazarian, Rochester, NY Associate Editors: Tina L. Cheng, Baltimore, MD Joseph A.

Neutropenia in Pediatric Practice

Pediatrics in the Community:

American Academy of Pediatrics Policy Statements on Bioethics:

A Flood of Information Lawrence F. Nazarian Pediatr. Rev. 2008;29;3-4 DOI: 10.1542/pir.29-1-3

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Lawrence F. Nazarian, MD Editor-in-Chief

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A Flood of Information Lawrence F. Nazarian Pediatr. Rev. 2008;29;3-4 DOI: 10.1542/pir.29-1-3

Updated Information & Services Permissions & Licensing

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Varicella-Zoster Virus Infections

After completing this article, readers should be able to:

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Congenital and Neonatal Varicella

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Indications for Specic Treatment

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Updated Information & Services Permissions & Licensing

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Neutropenia in Pediatric Practice

After completing this article, readers should be able to:

When to Order a CBC

Normal Values for the ANC and the Denition of Neutropenia

Normal Blood Leukocyte Counts*

Pyogenic Infections Associated With Neutropenia

Initial Evaluation of the Patient Who Has Neutropenia

Initial Evaluation for Patients Who Have Neutropenia

CBC With Differential Count and Reticulocyte Percentage

Other Laboratory Tests

Detailed Laboratory Evaluation of Neutropenia

Chronic Idiopathic Sequestration Nutritional

Common Common if spleen is enlarged Rare in children

Partial List of Drugs Associated With Idiosyncratic Neutropenia

Inherited Neutropenia (Table 6)

Condition Severe Congenital (Kostmann)

Marrow Failure Syndromes: Fanconi AR Dyskeratosis Congenita

Blackfan Diamond Syndrome

WHIM Syndrome and Myelokathexis

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

Inherited Neutropenia Continued

Reticular Dysgenesis Cartilage Hair

Metabolic Glycogen AR Storage Disease 1b (also aminoacidopathies) Griscelli Syndrome Type 2 AR

1/105 live births

Selective IgA Deciency

Marrow Failure Syndromes

Syndromes Associated With Neutropenia and Immunodeciency

Fever and Neutropenia

Fever and Neutropenia

ANC 1,000 to 1,500/mcL (1.0 to 1.5 109/L) Mild

500 to 1,000/mcL (0.5 to 1.0 109/L) Moderate

Outpatient unless progression

<500/mcL (0.5 109/L) Severe