Pediatrics in Reviw 2013

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Editor-in-Chief: Joseph A. Zenel, Sioux Falls, SD Associate Editor: Tina L. Cheng, Baltimore, MD Editor, In Brief: Henry M. Adam, Bronx, NY Consulting Editor, In Brief: Janet Serwint, Baltimore, MD Editor, Index of Suspicion: Deepak M. Kamat, Detroit, MI Consulting Editor Online and Multimedia Projects: Laura Ibsen, Portland, OR Editor, CME: Paula Algranati, Longmeadow, MA Editor Emeritus: Lawrence F. Nazarian, Rochester, NY Founding Editor: Robert J. Haggerty, Canandaigua, NY Managing Editor: Luann Zanzola Medical Copyediting: Dartmouth Journal Services Editorial Associates: Kathleen Bernard, Erin Carlson
Editorial Board Hugh D. Allen, Columbus, OH Denise Bratcher, Kansas City, MO Brian Carter, Nashville, TN Joseph Croffie, Indianapolis, IN B. Anne Eberhard, New Hyde Park, NY Philip Fischer, Rochester, MN Lynn Garfunkel, Rochester, NY Rani Gereige, Miami, FL Lindsey Grossman, Springfield, MA Jacob Hen, Bridgeport, CT Jeffrey D. Hord, Akron, OH Michael Macknin, Cleveland, OH Susan Massengill, Charlotte, NC Jennifer Miller, Gainesville, FL Blaise Nemeth, Madison, WI Carrie A. Phillipi, Portland, OR Mobeen Rathore, Jacksonville, FL E. Steve Roach, Columbus, OH Thomas L. Sato, Milwaukee, WI Sarah E. Shea, Halifax, Nova Scotia Andrew Sirotnak, Denver, CO Alfred Tenore, Udine, Italy Miriam Weinstein, Toronto, ON

Pediatrics in Review® Vol.34 No.4 April 2013
Articles

contents
Kawasaki Disease

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

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 2013 for print and online/online only: AAP/CPS Member $188/$144; AAP National Affiliate Member $149/$101; Nonmember $236/$183; Allied Health or In-training $175/$118. Institutions call for pricing (866-843-2271). For overseas delivery, add $120. Current single issue price is $10 domestic, $12 international. Replacement issues must be claimed within 6 months from the date of issue and are limited to three per calendar year. Periodicals postage paid at ARLINGTON HEIGHTS, ILLINOIS and at additional mailing offices. © AMERICAN ACADEMY OF PEDIATRICS, 2013. 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. Pediatrics in Review Print Issue Editorial Board Disclosures The American Academy of Pediatrics (AAP) Policy on Disclosure of Financial Relationships and Resolution of Conflicts of Interest for AAP CME Activities is designed to ensure quality, objective, balanced, and scientifically rigorous AAP CME activities by identifying and resolving all potential conflicts of interest before the confirmation of service of those in a position to influence and/or control CME content. All individuals in a position to influence and/or control the content of AAP CME activities are required to disclose to the AAP and subsequently to learners that the individual either has no relevant financial relationships or any financial relationships with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in CME activities. Commercial interest is defined as any entity producing, marketing, reselling or distributing health-care goods or services consumed by, or used on, patients. Each of the editorial board members, reviewers, question writers, PREP Coordinating Committee members and staff has disclosed, if applicable, that the CME content he/ she edits/writes/reviews may include discussion/reference to generic pharmaceuticals, off-label pharmaceutical use, investigational therapies, brand names, and manufacturers. None of the editors, board members, reviewers, question writers, PREP Coordinating Committee members, or staff has any relevant financial relationships to disclose, unless noted below. The AAP has taken steps to resolve any potential conflicts of interest. Disclosures • Athos Bousvaros, MD, MPH, FAAP, disclosed that he has research grants from Merck and UCB; and that he is a paid consultant and on the speaker bureau for Millennium. • Blaise Nemeth, MD, MS, FAAP, has disclosed he has an unrestricted educational grant for fellowship from Biomet. • Richard Sills, MD, FAAP, disclosed that he receives a research grant from Novartis. • Miriam Weinstein, MD, disclosed that she is a consultant for Pediapharm and SunCorp. She also has received honoraria from Dermik and Leo Pharma.

151 163 172 173 185

Mary Beth F. Son, Jane W. Newburger

Pelvic Inflammatory Disease
Maria Trent

Corrections How to Approach Neutropenia in Childhood
Kelly Walkovich, Laurence A. Boxer

Visual Diagnosis: Obese 11-month-old Female
With Round Facies
Nancy L. Beck, Alba E. Morales, R.F. Buchmann, R.J. Birusingh

Index of Suspicion
Case 1: Fatigue, Weakness, Body Aches, and Metabolic Alkalosis in a 15-year-old Boy Case 2: Refractory Hypotension, Tachycardia, Hyperglycemia, and Metabolic Acidosis in an Afebrile Teen
Case 1: Darshita Bhatia, Matthew B. McDonald Case 2: Gunjan Kamdar Tiyyagura, Janienne Kondrich

192

In Brief

196

Bacillus Cereus
Senthilkumar Sankararaman, Sujithra Velayuthan

Online-only Article
Abstract appears on page 198.

e13
Pediatrics in Review® is supported, in part, through an educational grant from Abbott Nutrition, a division of Abbott Laboratories, Inc. Cover: The artwork on the cover of this month’s issue is by one of the winners of our 2012 Cover Art Contest, 7-year-old Megan A. of San Diego, CA. Megan’s pediatrician is Rachel Ireland, MD.

Visual Diagnosis: A 3-month-old Male
With Wheezing
Kamakshya P. Patra, Suman Shekar, Robert D. Jackson, Ernest A. Kiel, Jon D. Wilson

Pediatrics in Review offers 36 CME articles per year. A maximum of one AMA PRA Category 1 CreditTM is earned after achieving a 60% score on each designated quiz. CME statements: The American Academy of Pediatrics (AAP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAP designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity is acceptable for a maximum of 1.00 AAP credit. These credits can be applied toward the AAP CME/CPD* Award available to Fellows and Candidate Members of the AAP. The American Academy of Physician Assistants accepts certificates of participation for educational activities certified for AMA PRA Category 1 CreditsTM from organizations accredited by ACCME. Physician assistants may claim a maximum of 1.00 hour of Category 1 credit for completing this program. This program is accredited for 1.00 NAPNAP CE contact hour; pharmacology (Rx) contact hours to be determined per the National Association of Pediatric Nurse Practitioners (NAPNAP) Continuing Education Guidelines.

Answer key appears on page 198, the last page of the journal.

It has been established that each CME activity will take the learner approximately 1 hour to complete. *Continuing Professional Development How to complete this activity: Pediatrics in Review can be accessed and reviewed in print or online at http://pedsinreview.aappublications.org. Learners can claim credit monthly online upon completion of each CME article. The deadline for completing this activity is December 31, 2015. Credit will be recorded in the year in which it is submitted. It is estimated that it will take approximately 1 hour to complete each CME article. This activity is not considered to have been completed until the learner documents participation in that activity to the provider via online submission of answers. Course evaluations are online.

Article

collagen vascular disorders

Kawasaki Disease
Mary Beth F. Son, MD,* Jane W. Newburger, MD, MPH†

Practice Gap
1. Clinicians should not dismiss the diagnosis of Kawasaki disease (KD) in children with symptoms commonly attributed to viral illness. For example, severe headache and photophobia should signal the possibility of aseptic meningitis even in the presence of KD. And, right upper quadrant pain may indicate hydrops of the gallbladder. 2. A challenging subset of patients who do not meet the classic case definition are said to have incomplete KD. Patients who have incomplete KD are more likely to be infants and older children and, as such, are also at higher risk for coronary artery lesions (CAL). Of note, infants younger than 6 months of age are at high risk for development of CAL, yet often have fewer clinical features to facilitate the diagnosis. For these reasons, echocardiography is recommended for infants younger than age 6 months with fever of unclear etiology persisting for 7 or more days and elevated inflammatory markers.

Author Disclosure Drs Son and Newburger have disclosed no financial relationships relevant to this article. This commentary does contain discussion of unapproved/ investigative use of a commercial product/ device.

Objectives
1. 2. 3. 4.

After reading this article, readers should be able to:

Describe the clinical manifestations of Kawasaki disease. Formulate a differential diagnosis for patients with suspected Kawasaki disease. Describe the laboratory values typically seen in Kawasaki disease. Discuss the role of echocardiography in the management of patients who have Kawasaki disease and describe the cardiac complications of the disease. 5. Define primary treatment of Kawasaki disease with intravenous immunoglobulin and aspirin.

Case Study
A 3-year-old previously healthy Hispanic girl is brought to her pediatrician’s office with a history of 6 days of fever. The fever has been present daily and has been unremitting, despite administration of antipyretic medications. She has been irritable with decreased appetite. Her mother noticed an erythematous, nonpruritic rash covering her torso 1 day after fever onset. She has developed red eyes in the past 2 days. She has no siblings and attends child care. On examination, the girl is febrile to 38.9°C and tachycardic at 140 beats per minute. Her blood pressure while crying is 110/60 mm Hg. Her weight is 14.5 kg. She has conjunctival injection with limbal Abbreviations sparing and without exudate. Her lips appear erythematous and cracked, and her oropharynx is diffusely erythematous AHA: American Heart Association without exudate. She does not have significant cervical chain ASA: aspirin lymphadenopathy. A polymorphous maculopapular rash CAL: coronary artery lesions covers her torso and extremities. The dorsa of her hands CRP: C-reactive protein and feet appear swollen. EBV: Epstein-Barr virus She has a total white blood cell count of 15,600/mm3, ESR: erythrocyte sedimentation rate a hemoglobin level of 9.8 g/dL, and a platelet count of IVIG: intravenous immunoglobulin 3. The differential count of the white blood 670,000/mm KD: Kawasaki disease cells is 81% neutrophils and 14% lymphocytes. She has mild LAD: left anterior descending artery transaminitis with an alanine aminotransferase level of 68 RCA: right coronary artery U/L; her aspartate aminotransferase level is normal. Her
*Department of Pediatrics, National University Hospital, Singapore. † Department of Cardiology, Children’s Hospital Boston, Boston, MA.

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C-reactive protein (CRP) level is 9.8 mg/dL and her erythrocyte sedimentation rate (ESR) is 65 mm/hour. There are 25 white cells per high-power field on urinalysis.

Epidemiology
KD was first described in 1967 by a Japanese pediatrician, Dr Tomisaku Kawasaki, as the mucocutaneous lymph node syndrome. (1) At that time, the cardiac involvement of KD was not apparent, nor was effective treatment described. Within a few years, autopsy cases of patients who had KD demonstrated coronary artery aneurysms and thrombosis, and the cardiac complications of KD became evident. Since Dr Kawasaki’s initial report, KD has been described in children around the world, and in virtually all races; however, Japanese children are at the highest risk. Since 1970, Japan has collected epidemiologic data about KD nearly every 2 years via nationwide surveys. Interestingly, although the birth rate has declined, the numbers of patients diagnosed with KD and the incidence rate in Japan have risen rapidly since the 1990s. There have been three documented epidemics of KD in Japan, in 1979, 1982, and 1986. In 2010, the incidence rate of KD in Japan was 239.6 per 100,000 children age 0 to 4 years, which exceeds the highest rate during any of the epidemics and is the highest rate recorded. The reason for the linear increase in the incidence rate of KD in Japan is unclear. Similar to prior surveys in Japan, the most recent survey in 2009–2010 found that the incidence rate was highest among children age 6 to 11 months and was higher in boys than in girls. As compared with a survey performed in 1999–2000, the proportion of children with coronary artery dilation and aneurysms decreased from 6% to 3%; however, the incidence of giant aneurysms in patients who had KD did not decrease concomitantly. Infants, particularly those younger than 6 months, as well as children at least age 5 years had an increased relative risk of developing CAL. In contrast to Japan, hospitalization rates associated with KD in the United States have been relatively stable over the past decade. The rate in 1997 was 17.5 per 100,000 children younger than age 5 years, and in 2006, 20.8 per 100,000 children younger than age 5 years. Most hospitalizations occurred in children younger than age 3 years. Children of Asian/Pacific Islander descent had the highest hospitalization rate, demonstrating the likely role of genetics in the pathogenesis of KD. An underlying genetic predisposition is supported further by the findings that siblings of children who have KD have a 10-fold increased risk for the disease, and the parents of children who have KD in Japan today are twice as likely, compared with other adults, to have had KD when they were children. Risk factors for poor coronary artery outcomes have been studied in several populations. Demographic factors, such as young age, particularly younger than 6 months and

Overview
Kawasaki disease (KD) is an acute febrile illness of childhood characterized by vasculitis of medium-sized, extraparenchymal arteries, with a predilection for coronary arteries. KD is the leading cause of acquired heart disease in developed countries, although rheumatic heart disease continues to dominate in the developing world. The natural history and treatment of KD are well described, but its etiology remains obscure, hampering efforts to identify a specific diagnostic test and targeted treatments. In the absence of a specific diagnostic test, KD remains a diagnosis based on clinical criteria. All signs and symptoms of KD resolve following the acute illness, but coronary artery lesions (CALs) develop in 3% to 5% of children treated with intravenous immunoglobulin (IVIG), and up to 25% of untreated children. Its prognosis is predicated entirely on the presence and severity of CALs, which can range from mild dilation to giant aneurysms (Fig 1). It is unclear if children who have normal-appearing coronary arteries during the acute phase of the disease will be at risk for endothelial dysfunction and accelerated atherosclerosis later in the life.

Figure 1. Selective right coronary angiogram demonstrating

multiple aneurysms in a child who has KD.
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older than 9 years, male gender, Asian and Pacific Islander race, and Hispanic ethnicity have been associated with poor clinical outcomes. Laboratory parameters, such as neutrophilia, thrombocytopenia, hyponatremia, elevated CRP, and transaminitis, have all been associated with poor response to IVIG and the development of CAL. (2) Essentially, patients with evidence of significant and widespread inflammation are at the highest risk.

Pathogenesis
KD’s etiology remains unknown. Many aspects of KD mimic infectious processes, such as toxin-mediated illnesses and viral illnesses. Seasonal peaks have occurred in the United States and Japan, with increased incidence in localized areas, suggesting a transmissible vector. Researchers have looked painstakingly and unsuccessfully for an etiologic infectious agent, including Epstein-Barr virus (EBV), adenovirus, human coronavirus, human bocavirus, Yersinia pseudotuberculosis, herpes viruses, and others. Toxins, such as those produced by Staphylococcus aureus and Streptococcus pyogenes, have been postulated as the causative agents of KD because the rash can resemble an erythroderma, similar to the toxic shock syndromes and staphylococcal scalded skin syndrome. Additionally, the efficacy of treatment with IVIG could be explained by immunoglobulin binding of the toxins, although antigenindependent mechanisms have been postulated as well. Toxins act as superantigens, which nonselectively activate large numbers of T cells, leading to massive cytokine release and inflammation. Studies looking at the role of superantigens in KD have been conflicting. Specifically, isolation of superantigen-producing organisms, isolation of superantigen proteins, and the presence of an immunologic signature of superantigen activity have varied across studies. To date, no unique agent has been proven to cause KD. An alternative hypothesis posits that many infectious agents trigger a final common pathway in genetically susceptible hosts, which is supported by the finding that many patients diagnosed as having KD have documented concomitant infections. The interplay of infection and vascular inflammation has been described in other forms of vasculitis, such as hepatitis B and polyarteritis nodosa, hepatitis C and cryoglobulinemia, and Staphylococcus and granulomatosis with polyangitis (Wegener’s). Therefore, the hypothesis that infectious agents may trigger the inflammatory cascade in KD has face validity. Both the innate and adaptive arms of the immune system have been evaluated in the pathogenesis of KD. The innate immune system includes epithelial barriers and phagocytic cells that provide protection against infection, whereas the adaptive immune response is mediated by

antigen-specific lymphocytes stimulated by infectious agents. There is evidence that the innate immune system plays a significant role in the pathogenesis of KD. One study reported that neutrophils are important actors in the initial attack on coronary artery walls. (3) In a murine model of coronary arteritis induced by Lactobacillus casei cell wall extract, Toll-like receptor 2 and its downstream adaptor protein, MyD88, are required for the development of coronary artery lesions, establishing a role for the innate immune system. (4) Two recent studies demonstrated increased expression levels of innate immunityassociated genes during the acute phase of KD. (5)(6) T cells also play an important role in KD. CD8þ T cells have been found in the coronary arteries from autopsy specimens. Studies of acute and subacute sera in patients who have KD showed a decrease in the population of T regulatory cells in the acute phase, with normalization following treatment with IVIG, indicating that impaired immunoregulation has a possible role in the development of KD. Recent genome-wide association studies have described functional single-nucleotide polymorphisms in the ITPKC (inositol 1,4,5 triphosphate 3-kinase C) gene that are associated with increased risks for susceptibility to KD, more severe coronary artery disease, and resistance to IVIG. (7) ITPKC acts as a negative regulator of T-cell activation through the calcineurin/NFAT signaling pathway, and alterations in signaling may contribute to immune hyperreactivity in KD. To date, the role of B cells in the pathogenesis of KD has not been clearly elucidated. Immunoglobulin A plasma cells have been found in lung tissue and coronary arteries from fatal cases of KD, but the precise role of the immunoglobulin A plasma cells remains to be determined. Furthermore, a recent study using the murine model with Lactobacillus casei cell wall extract–induced coronary arteritis indicated that B cells are not required for development of CALs. (8)

Clinical Manifestations
Classic clinical criteria with supportive clinical and laboratory findings are listed in Table 1. (9) With the exception of fever, the features of KD can fluctuate, and a thorough medical history is required to determine their presence during the period of illness. Children who have at least 4 days of fever (3 days in expert hands) and 4 or 5 of the principal criteria meet the case definition of KD. The case definition also includes children with fewer than four criteria if they have coronary artery disease. The hallmark of KD is fever, typically above 39°C, which has abrupt onset and may not remit with antipyretic
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Clinical and Laboratory Features of Kawasaki Disease
Table 1.

Epidemiologic case definition (classic clinical criteria) • Fever of at least 5 days’ duration • Presence of at least 4 of the following principal features: B Changes in extremities B Polymorphous exanthem B Bilateral conjunctival injection B Changes in lips and oral cavity B Cervical lymphadenopathy • Exclusion of other diseases with similar findings (Table 2) Other clinical and laboratory findings • Cardiovascular findings B Congestive heart failure, myocarditis, pericarditis, or valvular regurgitation B Coronary artery abnormalities B Aneurysms of medium-sized noncoronary arteries B Raynaud phenomenon B Peripheral gangrene • Musculoskeletal system B Arthritis B Arthralgia • Gastrointestinal tract B Diarrhea, vomiting, abdominal pain B Hepatic dysfunction B Hydrops of the gallbladder • Respiratory tract B Pulmonary nodules and interstitial infiltrates B Pleural effusion • Central nervous system B Extreme irritability B Aseptic meningitis B Peripheral facial nerve palsy B Sensorineural hearing loss • Genitourinary system B Urethritis/meatitis B Testicular swelling • Other findings B Erythema and induration at Bacille Calmette-Guerin site B Anterior uveitis B Desquamating rash in groin • Laboratory findings in acute Kawasaki disease (KD) B Neutrophilia with immature forms B Elevated erythrocyte sedimentation rate B Elevated C-reactive protein (CRP) level B Elevated serum a1-antitrypsin level B Anemia B Abnormal plasma lipids B Hypoalbuminemia B Thrombocytosis after first week of illness B Sterile pyuria B Elevated serum transaminases B Pleocytosis of cerebrospinal fluid B Leukocytosis in synovial fluid
Reprinted with permission from Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110(17):2751.

medications. In the absence of treatment, fever typically lasts 11 to 12 days, with rare cases of prolonged fever lasting more than 3 weeks. Although some children treated with IVIG experience immediate improvement during the infusion, others defervesce 1 to 2 days after receiving IVIG. Approximately 15% of children treated with IVIG have persistent or recrudescent fever more than 36 hours after completion of the first IVIG infusion. More than 90% of children who have KD develop bilateral, nonexudative conjunctivitis that spares the limbus (ie, with clearing around the iris (Fig 2). Anterior uveitis also may be detected on slit-lamp examination during the acute phase of the disease. Oropharyngeal manifestations are common and include a diffusely erythematous oropharynx, red fissured lips, and a strawberry tongue (Fig 3). Discrete oral ulcers and tonsillar exudates are not seen typically in KD. KD rash usually appears within 5 days of fever onset, and often starts as desquamation in the perineal area that evolves into a diffuse, erythematous, maculopapular rash. Morbilliform rashes, erythema multiforma, and erythroderma also can occur. Bullous or vesicular lesions suggest an alternative diagnosis. Children afflicted with KD develop firm swelling of the hands and feet, as well as erythema of the palms and soles in the acute phase of the disease. Characteristic, although not pathognomonic, periungual peeling from the fingers and the toes (Fig 4) begins 2 to 3 weeks after the onset of the fever. Cervical lymph node enlargement is the least common criterion found in patients who have KD. The enlargement is usually unilateral, located in the anterior cervical chain, nonfluctuant, and nontender. The diameter of the involved node

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Incomplete KD
A challenging subset of patients who do not meet the classic case definition are said to have incomplete or atypical KD. Children who have incomplete KD do not have atypical features; rather, they have some of the classic features of KD but not enough to meet the case definition. Patients who have incomplete KD are more likely to be infants and older children, and, as such, also are at higher risk for CALs. Considering the cardiac consequences of failing to treat incomplete KD and the comparative safety of IVIG treatment, the American Heart Association (AHA) published an algorithm for the evaluation and treatment of suspected incomplete KD to assist clinicians (Fig 5). The algorithm uses laboratory values and echocardiography in those children who have only a few clinical features of the disease, and also recommends consultation with a KD expert if needed. A multicenter retrospective study of patients who have KD with aneurysms presenting before day 21 of illness found that application of the AHA algorithm would have resulted in referral of 97% of patients for IVIG treatment. (10) Of note, infants younger than age 6 months are at high risk for development of CALs, yet often have few clinical features to facilitate the diagnosis. For these reasons, it is recommended that infants younger than age 6 months who have had ‡7 days of fever of unclear etiology and elevated inflammatory markers undergo echocardiography.

Figure 2. Bilateral nonexudative limbal sparing conjunctivitis is found in up to 90% of children who have KD. Courtesy of Annette L. Baker, NP.

should be ‡1.5 cm. Imaging typically reveals a group of matted nodes without abscess formation. Children who have KD can have a myriad of other signs and symptoms, including myalgias, arthralgias, and arthritis. Neurologic involvement can include significant irritability, likely because of meningeal inflammation, transient facial palsies, and sensorineural hearing loss. Gastrointestinal complaints occur in up to 30% of patients and include abdominal pain, vomiting, diarrhea, acalculous distention of the gallbladder (hydrops), and hepatomegaly. Rarely, hemophagocytic lymphohistiocytosis, a lifethreatening complication in which activated macrophages and T cells cause a cytokine storm, can occur in KD.

Differential Diagnosis
Because KD is a self-limited febrile illness, infections dominate the list of differential diagnoses (Table 2). Measles, adenovirus, enterovirus, and EBV can mimic the clinical presentation of KD. Measles does not occur typically in countries with widespread vaccination; a travel or contact history should be sought in cases in which coryza and cough are conspicuous. Children who have adenoviral or enteroviral illnesses typically are less ill compared with children who have KD, and laboratory studies show less evidence of inflammation, with lower white blood cell counts and inflammatory markers. White blood cell indices typically reveal lymphocytosis. EBV is associated commonly with an exudative pharyngitis and diffuse lymphadenopathy, neither of which is seen typically in KD. The conjunctivitis and rash of KD can be quite prominent and may appear consistent with StevensJohnson syndrome. The absence of other clinical features of KD, or findings of skin pain, skin necrosis, or blisters, favors the diagnosis of Stevens-Johnson syndrome.
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Figure 3. Oropharyngeal changes, including a strawberry tongue, as pictured, are common in children who have KD. Courtesy of Annette L. Baker, NP.

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Evaluation for Suspected KD
Laboratory Studies
Children who have KD typically have leukocytosis with a predominance of neutrophils and immature forms. Many of these children have a normocytic normochromic anemia, with the average hematocrit at presentation being 2 SDs below the norm for age. A sudden drop in hemoglobin concentration following IVIG may be attributable to hemolytic anemia. Platelet counts usually are elevated by the end of the first week of illness (450,000/mm3), and may evolve into significant thrombocytosis, with platelet counts averaging 700,000/mm3 by the third week. Platelet counts exceeding 1 million/mm3 are not uncommon. Relatively lower platelet counts at the time of presentation are a risk factor for later development of CAL, likely reflecting greater adherence of platelets to an activated endothelium. Rarely, marked thrombocytopenia at diagnosis may be attributable to diffuse intravascular coagulation. Inflammatory markers are elevated in nearly all cases of KD. The ESR and CRP should be assessed at diagnosis. The ESR following treatment with IVIG often is high, because the protein load from the infusion elevates the ESR, obscuring the extent of disease activity. Nonetheless, measurements of the ESR can be helpful in assessing the degree of inflammation at diagnosis. CRP levels are unaffected by IVIG and can be used in both the acute and subacute phases to gauge the degree of inflammation. Transaminases are elevated in approximately 40% of patients with KD, and a mild hyperbilirubinemia can occur. Plasma gammaglutamyl transpeptidase levels are elevated in approximately two thirds of patients who have KD. Sterile pyuria (ie, dipstick negative) of ‡12 white blood cells/mL is present in approximately 80% of patients who have KD. Such pyuria may be found also in children who have other febrile illnesses, but the magnitude is greater in patients who have KD. (12) Other laboratory findings, such as hypoalbuminemia and hyponatremia, reflect more severe illness and can be associated with capillary leak. Lipid panels in patients who have KD are markedly altered, with decreased levels of total cholesterol, as well as apolipoprotein A1 and high-density lipoprotein. Markers of cardiac damage or dysfunction, such as troponins and B-type natriuretic peptide, also may be elevated, but are not obtained routinely. Although laboratory studies are not a component of the classic criteria for KD, they are included in the algorithm for treatment of suspected incomplete KD, because

Figure 4. Periungual peeling, first from the finger nailbeds and then the toes, is typically seen 2 to 3 weeks after onset of the fever. Courtesy of Annette L. Baker, NP.

Toxin-mediated syndromes triggered by staphylococcal or streptococcal infections usually are characterized by visceral organ involvement, including renal insufficiency and significant hepatic dysfunction that are quite unusual in KD. Hypotension is also quite prominent in the toxinmediated illnesses. Scarlet fever can be evaluated with rapid streptococcal antigen testing; fever caused by group A Streptococcus is usually not associated with conjunctivitis and usually improves significantly within 24 hours of initiation of antibiotics. Rocky Mountain spotted fever presenting with fever and rash can appear similar to KD and occurs in specific geographic regions in the United States; treatment for this potentially fatal infection should not be withheld while KD is being considered. Acrodynia can cause irritability and extremity changes similar to KD; an ingestion history of mercury should be sought if these are prominent manifestations. Children who have systemic-onset juvenile idiopathic arthritis present with fever and rash, and coronary dilation on echocardiography has been described in this population; however, the ocular and oropharyngeal signs of KD are quite unusual in the systemic form of arthritis. Concomitant infections do not preclude the diagnosis of KD. In one study from Toronto, over 30% of children who had typical KD had laboratory evidence of at least one infection. (11) Patients who have KD have nonspecific symptoms as well, such as headache, abdominal pain, and malaise. Clinicians should not dismiss the diagnosis of KD in children who have symptoms that are attributed commonly to viral illnesses.
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Figure 5. Evaluation of suspected incomplete Kawasaki disease (KD). (1) In the absence of gold standard for diagnosis, this algorithm

cannot be evidence-based but rather represents the informed opinion of the expert committee. Consultation with an expert should be sought any time assistance is needed. (2) Infants £6 months old on day ‡7 of fever without other explanation should undergo laboratory testing and, if evidence of systemic inflammation is found, echocardiography, even if the infants have no clinical criteria. (3) Patient characteristics suggesting KD are listed in Table 1. Characteristics suggesting disease other than KD include exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, or generalized adenopathy. Consider alternative diagnoses (see Table 2). (4) Supplemental laboratory criteria include albumin £3.0 g/dL, anemia for age, elevation of alanine aminotransferase, platelets after 7 days ‡450,000/mm3, white blood cell count ‡15,000/mm3, and urine ‡10 white blood cells/highpower field. (5) Can treat before performing echocardiography. (6) Echocardiography is considered positive for purposes of this algorithm if any of 3 conditions are met: z score of LAD or RCA ‡2.5, coronary arteries meet Japanese Ministry of Health criteria for aneurysms, or ‡3 other suggestive features exist, including perivascular brightness, lack of tapering, decreased left ventricular function, mitral regurgitation, pericardial effusion, or z scores in LAD or RCA of 2.0 to 2.5. (7) If echocardiography is positive, treatment should be given to children within 10 days of fever onset and those beyond day 10 with clinical and laboratory signs (CRP, ESR) of ongoing inflammation. (8) Typical peeling begins under nail bed of fingers and then toes. Figure and legend reprinted with permission from Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110(17):2748. CRP=C-reactive protein; echo=echocardiography; ESR=erythrocyte sedimentation rate; f/u=follow-up; LAD=left anterior descending artery; RCA=right coronary artery.

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Differential Diagnosis of Kawasaki Disease
Table 2.

Infections • Viral B Measles B Adenovirus B Enterovirus B Epstein-Barr virus • Bacterial B Scarlet fever B Cervical lymphadenitis B Rocky Mountain spotted fever B Leptospirosis Toxin-mediated diseases • Staphlycoccal scalded skin syndrome • Toxic shock syndrome (associated with Staphylococcus or Streptococcus) Hypersensitivity reactions • Drug hypersensitivity reactions • Stevens-Johnson syndrome Other • Systemic onset juvenile idiopathic arthritis • Acrodynia (mercury toxicity)

many of the laboratory abnormalities described previously are seen consistently in KD. The child has echocardiography performed. Her coronary artery dimensions are within normal limits for age, but her left anterior descending artery does not taper normally. Her left ventricular function is normal, and no pericardial effusion is seen.

Cardiac Imaging
Echocardiography is an excellent imaging modality for evaluating coronary artery dimensions, myocardial function, valve regurgitation, and pericardial effusion. The procedure is noninvasive, and in experienced hands has high sensitivity and specificity for dilation in the proximal coronary arteries. Sedation often is required in younger children to obtain optimal images. If the diagnosis is clear, treatment for KD should not be withheld while waiting to schedule or obtain the results of echocardiography. Two-dimensional echocardiography should be performed with the highest-frequency probe available to produce high-resolution images. Standard views for cardiac echocardiography include parasternal, apical, subcostal, and suprasternal notch windows. Patients who have definite or suspected KD should undergo assessment of each coronary artery, including the left main coronary artery, left anterior descending artery (LAD), left circumflex coronary artery, right coronary
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artery (RCA), and posterior descending coronary artery. The proximal LAD and RCA are affected most commonly by coronary artery aneurysms. Coronary arteries should be evaluated with respect to their size and appearance. The size of an artery should be measured from internal edge to internal edge, avoiding areas of branching that can be associated with areas of natural dilation. The widely used Japanese Ministry of Health criteria classify coronary artery sizes according to age, with an internal lumen diameter greater than 3 mm abnormal in children less than age 5 years, and internal lumen diameter greater than 4 mm abnormal in children age ‡5 years. Additionally, artery segments that are ‡1.5 times larger than the adjacent section and those segments having an irregular coronary lumen also are considered abnormal. Because coronary artery dimensions change with the size of the child, body surface area–adjusted coronary dimensions (z scores) also should be obtained for the left main coronary artery, LAD, and RCA. The other coronary arteries do not have established z scores, and as such, the Japanese Ministry of Health criteria may be applied to those segments. Aneurysms can be classified as small (<5 mm internal diameter), medium (5–8 mm internal diameter), and giant (>8 mm internal diameter) when using absolute dimensions. The appearance of the coronary arteries is informative as well. In most children who have KD, coronary diameters are greatest on the first echocardiography performed early in the disease. (13) Larger baseline measurements predict the development of worsening CALs over the ensuing 4 to 6 weeks in a subset of children. If coronary artery dimensions are normal in the subacute period (up to 6 weeks), it is highly unlikely that the child will develop dilatation of coronary vessels thereafter, unless the disease relapses or recurs. In addition to documenting findings in the coronary arteries, echocardiography provides assessment of left ventricular and valve function. Left ventricular systolic dysfunction (ie, ejection fraction >2 SDs below normal) occurs in 20% of children who have acute KD. Histologic studies suggest that myocarditis is universal in patients who have KD and can be severe enough to produce a clinical picture consistent with shock. The myocarditis improves rapidly with administration of IVIG. The pericardium should be assessed with echocardiography for evidence of effusion. Last, although mitral regurgitation is seen in 27% of patients early in the course of KD, aortic regurgitation is less common (1%). Echocardiography should be obtained at diagnosis, 1 to 2 weeks later, and 6 weeks post discharge. Children who have persistent or recrudescent fever or who have

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known CALs need more frequent monitoring to inform treatment decisions, and close follow-up with a pediatric cardiologist is essential. AHA recommendations suggest follow-up echocardiography at 1 year in children who never had coronary sequelae; however, echocardiography should be performed more frequently among those who have CALs. Although echocardiography is the preferred method of visualizing the coronary arteries early after KD, coronary angiography is used in children who have significant coronary artery aneurysms using techniques of computed tomography, magnetic resonance angiography, or cardiac catheterization. Based on the clinical findings, the child is diagnosed as having KD and is prescribed IVIG at 2 g/kg and aspirin (ASA) 80 to 100 mg/kg per day divided every 6 hours.

Treatment
Once the diagnosis of KD is confirmed, treatment with highdose IVIG (2 g/kg) and high-dose ASA (80 to 100 mg/kg per day divided into 4 doses) should be instituted promptly. Ideally, treatment is administered within the first 7 days of illness, and by day 10 (as defined by the first day of fever) at the latest. Treatment with IVIG after day 10 of illness is reserved for those with ongoing fever and evidence of systemic inflammation on laboratory studies. To avoid infusion reactions, premedication with standard dosing of diphenhydramine should be considered strongly. Additionally, IVIG should be administered slowly, over 8 to 12 hours, to avoid hemodynamic instability. IVIG can be associated with lowgrade fevers within the first 48 hours of its administration. Hemolytic reactions to IVIG are well described. Approximately 15% of children who have KD will have recurrent or persistent fever after the first dose of IVIG and are considered resistant to IVIG and at higher risk for CALs. The treatment of these children remains an area of controversy, because studies to evaluate treatment strategies for IVIG resistance are limited. Most clinicians administer another dose of IVIG (2 g/kg) 48 hours after the first dose if fever persists or is recrudescent. Because KD is a vasculitis, corticosteroids have undergone trials in KD. Steroids can be administered as “primary” therapy when given at the time of the first dose of IVIG, or as “secondary” therapy when given for IVIG resistance. Furthermore, corticosteroids can be given in high-“pulse” doses of 30 mg/kg of intravenous methylprednisolone, or in lower doses (0.5 to 2.0 mg/kg per day) of prednisolone orally. The use of corticosteroids in KD has an interesting history, because an early report raised the possibility of steroids worsening coronary artery disease; however, subsequent studies indicated a likely beneficial effect in

children. Most recently, a study by Kobayashi et al (14) involving high-risk Japanese children showed that primary therapy with a combination of corticosteroids (prednisolone 2 mg/kg per day) and IVIG provided protection against poor coronary outcomes. However, this regimen has not been tested in non-Japanese populations, and the protocol involved a prolonged course of intravenous corticosteroid with concomitant hospitalization. The optimal regimen of corticosteroids for IVIG resistance has yet to be determined, and the lack of consensus has fostered considerable practice variation across centers. Other therapies used in IVIG resistance include infliximab, a tumor necrosis factor inhibitor (5 mg/kg per dose). Retrospective data indicate that infliximab may decrease the number of days of fever, but may not alter coronary artery outcomes. Results of a prospective trial using infliximab as primary therapy are awaited. There are reports from Japan and the United States that calcineurin inhibitors, such as cyclosporine A, may be effective in patients with IVIG resistance. There are very few indications for ASA in childhood given the risk of Reye syndrome, but KD remains one of them. Studies have shown that use of ASA does not affect the development of CALs (15); however, all of the major clinical trials to study treatment of KD have used ASA. Use of other nonsteroidal anti-inflammatory drugs, such as ibuprofen, has not been studied recently. In treating KD, ASA is given at high (anti-inflammatory) doses of 80 to 100 mg/kg per day, divided into every-6hour dosing initially, followed by antithrombotic doses of 3 to 5 mg/kg per day in once-daily dosing. There is practice variation in duration of high-dose ASA administration. Some practitioners give high-dose ASA until patients are afebrile for 48 hours, whereas others continue with high-dose ASA for 2 weeks. Lowdose ASA typically is discontinued if echocardiography findings are normal at the 6-week visit. Children who have persistent CAL at 6 weeks are continued on low-dose ASA, and yearly influenza vaccinations are strongly recommended in those cases to decrease the risk of Reye syndrome. Patients who are not fully vaccinated should receive immunizations according to the guidelines put forth in the American Academy of Pediatrics’ Red Book, which state that measles and varicella-containing vaccinations are contraindicated for 11 months after administration of IVIG for KD. (16) For those patients who have moderate to large aneurysms, a second antiplatelet agent may be added to ASA. Children who have giant aneurysms require anticoagulation with low-molecular-weight heparin or warfarin, in addition to ASA. Such regimens are best implemented
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with the collaboration of pediatric hematologists or coagulation services. The role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in children who have KD remains an area of research. Statins have both cholesterol-lowering and immunomodulatory properties. In a small study of 11 children who had KD and CALs, use of a statin for 3 months resulted in improved flowmediated dilation (an indication of endothelial health) and CRP levels. (17) Although these results are of interest, larger-scale clinical trials are needed before one can recommend use of statins in the earliest phases of KD. However, the threshold for use of statins in children who have aneurysms is lower because of data suggesting susceptibility of these patients to atherosclerosis. The patient tolerates her IVIG infusion without complication and defervesces within the subsequent 48 hours. Her tachycardia resolves. The conjunctival injection improves significantly, as does the rash. Upon discharge, she is well appearing and prescribed ASA 40.5 mg daily. She is scheduled for an appointment in 2 weeks for echocardiography and laboratory studies.

Prognosis and Long-Term Management
The prognosis of KD relates entirely to the extent and severity of cardiac disease. With timely IVIG treatment, the incidence of CAL in treated children has fallen to less than 5%, and only 1% of children develop giant aneurysms. Coronary aneurysms regress to normal lumen diameter via proliferation of myofibroblasts in more than one half of affected arterial segments. However, endothelial function is impaired in these segments even after regression. Stenoses at the proximal and distal ends of aneurysms can develop over time and increase the risk of myocardial ischemia. Stenotic lesions are more likely to form in giant aneurysms, as compared with smaller lesions. Management of children who have significant coronary artery disease may require a combination of beta-blockers to decrease oxidative stress, as well as anticoagulation therapy. These children are followed closely with assessment of coronary function (eg, exercise stress echocardiography in children old enough to run on a treadmill, dobutamine cardiac magnetic resonance imaging for younger children) and structure (echocardiography, coronary angiography). In those who develop symptoms of angina or findings of reversible ischemia on stress testing, percutaneous coronary intervention, for example with coronary stents, and coronary artery bypass surgery may be indicated. A recent report from Japan that followed patients who had giant aneurysms into adulthood found that long-term survival is
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relatively good among patients with giant aneurysms, despite their need for multiple catheterizations and surgeries. (18) Mortality from KD is low (<0.5%), with the highest risk occurring in the first year after illness onset because of acute myocardial infarction among patients who have giant aneurysms. Sluggish blood flow through a dilated arterial segment and activation of platelets and endothelium contribute to the risk for myocardial infarction. Children who have myocardial infarction may present with pallor, vomiting, and abdominal pain; older children may complain of chest pain. Rupture of coronary artery aneurysms is very rare, and generally occurs within the first few months of illness. Severe myocarditis leading to hemodynamic compromise or arrhythmias can lead to death in the first week of illness. Fortunately, most children who have KD do well after a single dose of IVIG, with rapid clinical improvement and reassuring echocardiographic findings. The risk of premature atherosclerosis among patients with always-normal coronary arteries will not be known definitively until large cohorts of middle-aged patients who have KD are assembled. In the interim, all children with a history of KD, even those without apparent coronary artery involvement, should undergo assessment of risk factors, such as hyperlipidemia and hypertension, and be counseled regarding a healthy lifestyle and avoidance of modifiable cardiac risk factors, such as obesity, smoking, and a sedentary lifestyle.

Summary
• Patients who have acute Kawasaki disease (KD) should be treated promptly with intravenous immunoglobulin (IVIG) to prevent coronary artery abnormalities (based on strong research evidence). (19) • Patients who have persistent or recrudescent fever following primary therapy with IVIG should receive another dose of IVIG at 2 g/kg (based primarily on consensus). (9) Other secondary therapies to consider include corticosteroids (14)(20) and infliximab (21) (based on some research evidence). • Echocardiography is an excellent modality for assessing coronary artery changes in children who have early KD (based primarily on consensus). • In patients who have KD and always-normal coronary arteries, preventive cardiology counseling and followup are recommended until further studies delineate the long-term consequences on endothelial health (9) (based on some research evidence as well as consensus). • In patients who have KD and coronary aneurysms, cardiologic follow-up is tailored to the degree of coronary artery involvement and involves assessment of coronary function and structure (based on strong research evidence). (9)

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References
1. Kawasaki T Acute febrile mucocutaneous syndrome with
lymphoid involvement with specific desquamation of the fingers and toes in children [in Japanese]. Arerugi. 1967;16(3):178–222 2. Kobayashi T, Inoue Y, Takeuchi K, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation. 2006;113(22):2606–2612 3. Takahashi K, Oharaseki T, Naoe S, et al. Neutrophilic involvement in the damage to coronary arteries in acute stage of Kawasaki disease. Pediatr Int. 2005;47(3):305–310 4. Rosenkranz ME, Schulte DJ, Agle LM, et al. TLR2 and MyD88 contribute to Lactobacillus casei extract-induced focal coronary arteritis in a mouse model of Kawasaki disease. Circulation. 2005; 112(19):2966–2973 5. Onoyama S, Ihara K, Yamaguchi Y, et al. Genetic susceptibility to Kawasaki disease: analysis of pattern recognition receptor genes. Hum Immunol. 2012;73(6):654–660 6. Popper SJ, Shimizu C, Shike H, et al. Gene-expression patterns reveal underlying biological processes in Kawasaki disease. Genome Biol. 2007;8(12):R261 7. Onouchi Y, Gunji T, Burns JC, et al. ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nat Genet. 2008;40(1):35–42 8. Schulte DJ, Yilmaz A, Shimada K, et al. Involvement of innate and adaptive immunity in a murine model of coronary arteritis mimicking Kawasaki disease. J Immunol. 2009;183(8):5311–5318 9. Newburger JW, Takahashi M, Gerber MA, et al; Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease; Council on Cardiovascular Disease in the Young; American Heart Association; American Academy of Pediatrics. Diagnosis, treatment, and longterm management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110 (17):2747–2771 10. Yellen ES, Gauvreau K, Takahashi M, et al. Performance of 2004 American Heart Association recommendations for treatment of Kawasaki disease. Pediatrics. 2010;125(2). Available at: www. pediatrics.org/cgi/content/full/125/2/e234 11. Benseler SM, McCrindle BW, Silverman ED, Tyrrell PN, Wong J, Yeung RS. Infections and Kawasaki disease: implications

for coronary artery outcome. Pediatrics. 2005;116(6). Available at: www.pediatrics.org/cgi/content/full/116/6/e760 12. Shike H, Kanegaye JT, Best BM, Pancheri J, Burns JC. Pyuria associated with acute Kawasaki disease and fever from other causes. Pediatr Infect Dis J. 2009;28(5):440–443 13. McCrindle BW, Li JS, Minich LL, et al; Pediatric Heart Network Investigators. Coronary artery involvement in children with Kawasaki disease: risk factors from analysis of serial normalized measurements. Circulation. 2007;116(2):174–179 14. Kobayashi T, Saji T, Otani T, et al; RAISE study group investigators. Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial. Lancet. 2012;379(9826):1613–1620 15. Durongpisitkul K, Gururaj VJ, Park JM, Martin CF. The prevention of coronary artery aneurysm in Kawasaki disease: a metaanalysis on the efficacy of aspirin and immunoglobulin treatment. Pediatrics. 1995;96(6):1057–1061 16. American Academy of Pediatrics. Kawasaki disease. In: Pickering LK, ed. Red Book: 2012. Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012:454–460. 17. Hamaoka A, Hamaoka K, Yahata T, et al. Effects of HMG-CoA reductase inhibitors on continuous post-inflammatory vascular remodeling late after Kawasaki disease. J Cardiol. 2010;56(2): 245–253 18. Suda K, Iemura M, Nishiono H, et al. Long-term prognosis of patients with Kawasaki disease complicated by giant coronary aneurysms: a single-institution experience. Circulation. 2011;123 (17):1836–1842 19. Newburger JW, Takahashi M, Beiser AS, et al. A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med. 1991;324(23):1633–1639 20. Newburger JW, Sleeper LA, McCrindle BW, et al; Pediatric Heart Network Investigators. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med. 2007;356(7):663–675 21. Burns JC, Mason WH, Hauger SB, et al. Infliximab treatment for refractory Kawasaki syndrome. J Pediatr. 2005;146(5): 662–667

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PIR Quiz
This quiz is available online at http://www.pedsinreview.aappublications.org. NOTE: Learners can take Pediatrics in Review quizzes and claim credit online only. No paper answer form will be printed in the journal.

New Minimum Performance Level Requirements
Per the 2010 revision of the American Medical Association (AMA) Physician’s Recognition Award (PRA) and credit system, a minimum performance level must be established on enduring material and journal-based CME activities that are certified for AMA PRA Category 1 CreditTM. In order to successfully complete 2013 Pediatrics in Review articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of 60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity. In Pediatrics in Review, AMA PRA Category 1 CreditTM may be claimed only if 60% or more of the questions are answered correctly. If you score less than 60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved.

1. A 3-year-old boy has had an unremitting fever for 4 days. Which of the clinical findings below best supports Kawasaki disease (KD) as the explanation for his fever? A. B. C. D. E. Bilateral cervical lymph node enlargement Bilateral nonexudative conjunctivitis Periungual peeling of fingers and toes Tonsillar exudate Vesicles on the palms and soles

2. You are aware that other conditions can cause a similar clinical pattern. In your evaluation of this child, which of the following conditions is initially most likely to be confused with KD? A. Adenoviral infection B. Pauciarticular juvenile arthritis C. Rubella D. Staphylococcal scarlet fever E. Varicella-zoster 3. You order laboratory tests to add further diagnostic insights. Which of the following findings strengthen your impression that the child has KD? A. B. C. D. E. Elevated erythrocyte sedimentation rate Lymphocytosis Microcytic anemia Neutropenia Thrombocytopenia

4. A 3-year-old girl meets clinical criteria for KD. You realize that the greatest threat to her is coronary artery disease. The best choice for initial imaging of the coronary arteries is A. B. C. D. E. Cardiac catheterization Computed tomography Magnetic resonance angiography Radionuclide imaging Two-dimensional echocardiography

5. Although her echocardiography shows no coronary artery lesions, you realize that the girl is at risk for developing coronary artery disease and requires preventive therapy. The treatment that lowers the incidence of coronary artery disease in KD the most is high-dose A. B. C. D. E. Aspirin Corticosteroids Cyclosporine A Infliximab Intravenous immune globulin

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Article

adolescent medicine/gynecology

Pelvic Inflammatory Disease
Maria Trent, MD, MPH*

Practice Gaps
1. The U. S. Centers for Disease Control and Prevention (CDC) provides evidence-based, expert-driven guidelines for effective management of pelvic inflammatory disease (PID); however, clinician adherence to the guidelines has been problematic. 2. PID practice guideline adherence is an international problem, as evidenced by a 2012 audit in the United Kingdom demonstrating that 55.5% of patients with PID did not receive care according to the British Association of Sexual Health and HIV treatment recommendations. Clinician behavior can be enhanced with the use of institutionally driven protocols, especially those that include onsite dispensing of a full course of medications. 3. Women seeking infertility services who report a history of unexplained and untreated abdominal pain are significantly more likely to have tubal infertility than women without such history; therefore caution should be used in dismissing mild symptoms (mild non-specific abdominal pain, vaginal discharge, bleeding or dyspareunia) among sexually active patients who may be at risk for PID.

Author Disclosure Dr Trent has disclosed no financial relationships relevant to this article. This commentary does not contain discussion of unapproved/ investigative use of a commercial product/ device.

Objectives
1. 2. 3. 4.

After completing this article, readers should be able to:

Describe the epidemiology and pathogenesis of pelvic inflammatory disease (PID). Recognize the clinical features of PID. Develop a management strategy for adolescent patients who have PID. Carefully weigh the options for the disposition of patients who have PID.

Prologue
Justine is a 17-year-old girl who presents for evaluation of lower abdominal pain that has been increasing over the past few days. Earlier today she was eating and drinking, but has developed some nausea in the past couple of hours without vomiting. She has had soft, regular bowel movements that are free of blood and mucus. She denies dysuria, but has had some light vaginal discharge that started about 1 week ago. Justine continues to have regular periods. She also reAbbreviations: cently started having sex with her boyfriend of 9 months. The couple uses condoms about 60% of the time. She reCDC: Centers for Disease Control and Prevention ports that when they had sex 2 days ago it was painful. CPP: chronic pelvic pain Her partner does not have any symptoms. CT: computed tomography Her mom is aware that she is having sex, though not IM: intramuscular happy about it. The HEADSSS assessment (Home/EnviIUD: intrauterine device ronment, Education/Employment/Eating, Activity, Diet/ IV: intravenous Drugs, Sexuality, Suicide/Depression, Safety/Exposure to KOH: potassium hydroxide Violence) reveals that Justine is an adolescent from a 2NAAT: nucleic acid amplification testing parent, working-class family. She is a cheerleader and a soloPEACH: Pelvic Inflammatory Evaluation and Clinical ist in her church choir. She tried alcohol once at a party, but Health otherwise does not engage in any alcohol, tobacco, or drug PID: pelvic inflammatory disease use. She is a strong student with plans to attend college to STI: sexually transmitted infection become a nurse. Her mother is in the waiting room.
*Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD.

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On clinical examination, the patient’s temperature is 100.1°F, blood pressure 110/65 mm Hg, heart rate is 78 beats per minute, respirations 24/minute, and BMI 21. Clinical examination is remarkable for a soft abdomen with bowel sounds, but marked pain on light and deep palpation in the left lower quadrant with rebound tenderness and guarding. Pelvic examination reveals female genitalia without external lesions and a sexual maturity rating of Tanner V. On the speculum examination, there is discharge in the vault and covering the cervix. There is no frank pus emerging from the os. On bimanual examination, she has cervical and left adnexal tenderness. There is no palpable adnexal fullness, enlargement, or mass. Pregnancy testing is negative. Urine dipstick shows a specific gravity of 1.020, pH of 5, small amount of blood and trace leukocytes without nitrites. Urine is sent for culture and endocervical specimens are collected for Neisseria gonorrhoeae and Chlamydia trachomatis nucleic acid amplification testing (NAAT). Vaginal swabs are obtained for a wet prep, potassium hydroxide (KOH) prep, and NAAT testing for Trichomonas vaginalis. Vaginal pH is 5.5. Office-based wet prep reveals red blood cells and sheets of white blood cells, but no evidence of bacterial vaginosis (clue cells) or T vaginalis infection. KOH prep is negative.

episode of PID increases the risk of these long-term complications. Available international data have shown that the impact of PID among women in developing countries also is significant. For example, hospitalization data from subSaharan Africa indicate that PID accounts for 17% to 40% of all gynecologic admissions, that 80% of infertility is associated with previous PID, and that 30% to 50% of women of reproductive age are infertile. (5) Future fertility is of cross-cultural value to adolescents and their families (6)(7) and the pediatric clinician’s ability to diagnose and treat adolescent patients who have PID appropriately is critical for fertility preservation and prevention of long-term sequelae.

Pathogenesis
The term PID refers to a spectrum of clinical disorders of the upper reproductive tract, including endometritis, salpingitis, tubo-ovarian abscesses, and pelvic peritonitis. These health states are caused when organisms ascend from the lower reproductive tract (vagina/cervix) into the endometrium, fallopian tubes, and related structures. Although PID is classified as a sexually transmitted infection and occurs rarely in female patients who have never initiated intercourse, the polymicrobial etiology of PID may include STIs, genital flora, enteric organisms, and agents typically causing respiratory infections. The role of N. gonorrhoeae and C trachomatis as causative agents in PID has been well established in the literature; however, new data from women clinically diagnosed as having mild-moderate PID indicates that almost 70% of patients have non–C trachomatis/nonN. gonorrhoeae PID. (8) Although recommended laboratory testing for patients suspected of having PID still centers on C trachomatis and N. gonorrhoeae testing, Mycoplasma genitalium and Ureaplasma urealyticum have long been associated with laparoscopically confirmed PID and tubal infertility. Organisms recovered from the upper genital tract of women who have PID include Gardnerella vaginalis, Actinomyces israelii, Prevotella bivia, Escherichia coli, Campylobacter fetus, and group B-D streptococci, staphylococci, Bacteroides species, and Peptostreptococcus species. Respiratory organisms recovered in patients who have PID have included Haemophilus influenzae, Streptococcus pneumoniae, and group A streptococcus. The development of abscesses and pelvic peritonitis are late clinical events resulting from the mix of anaerobic and facultative bacteria that often cause infection in conjunction with STIs.

Clinical Problem
This patient meets the current diagnostic criteria for a presumptive diagnosis of pelvic inflammatory disease (PID). Although there are problems with following epidemiologic trends for PID as a nonreportable sexually transmitted infection (STI), available data suggest that prevention efforts have reduced the rates of PID in the United States through asymptomatic STI screening and early treatment. Currently, an estimated 800,000 cases occur annually. (1) Despite the reduction in overall cases, PID rates remain disproportionately higher among adolescent girls and minority women. (2)(3) As an example, the general risk of acquiring salpingitis for a 15-year-old sexually active girl is 1 in 8, whereas that for a 24-year-old woman is 1 in 80. (4) PID is of particular clinical and public health importance because it is associated with significant short- and long-term sequelae. Short-term sequelae include the development of tubo-ovarian abscesses requiring triple antibiotic therapy, perihepatitis, periappendicitis, and protracted hospitalization. Long-term sequelae include ectopic pregnancy, chronic pelvic pain (CPP), and tubal infertility because of scarring. Further, each
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Clinical factors associated with the ascension of microbes from the lower reproductive tract include frequency of intercourse, bacteriospermia (bacteria in semen), menstrual timing, diagnostic and therapeutic surgical procedures that disrupt the normal cervical barrier (e.g., abortion, intrauterine device [IUD] insertion, hysterosalpingogram), nonuse of hormonal contraceptives, hygiene practices (e.g., douching), and disturbance of normal vaginal flora from bacterial vaginosis. Hormonal contraceptive users generally have a lower risk for the development of PID. Use of hormonal contraceptives increases the cervical mucus barrier and reduces the frequency and amplitude of subendometrial myometrial contractions, compared with those observed with ovulatory cycles. Although it has been noted that diagnostic and therapeutic surgical procedures account for up to 12% of PID cases, the risk of PID associated with the IUD is limited primarily to the first 20 days after insertion. Postsurgical infection rates have led to protocols for STI screening before or during placement of IUDs and the prescription of prophylactic antibiotics following surgical procedures (e.g., abortion) are standard of care. (9)

Diagnosis
The clinical diagnosis of PID is notoriously imprecise, but the use of surgical procedures that allow for greater precision (such as laparoscopy) are no longer considered a part of standard assessment. To complicate matters further, patients often do not present with the classically described PID presentation. An acute presentation with severe lower abdominal pain resulting in a shuffling gait or the “chandelier sign” on clinical examination is rare. The heterogeneity of infectious agents now causing PID is thought to contribute to the varied clinical presentations for which symptoms can range from mild to severe. Although infertility as an adverse outcome has been well documented in patients who have PID both prospectively and in retrospective studies of women with infertility, there is an additional subset of infertile women who experience the sequelae of PID without the classic findings. Women seeking infertility services who report a history of unexplained and untreated abdominal pain were significantly more likely to have tubal infertility than women without such a history. (10) Thus, caution should be used in dismissing mild symptoms (mild nonspecific abdominal pain, vaginal discharge, bleeding, or dyspareunia) among sexually active patients who may be at risk for PID. Patients without the classic features of PID who are at risk for an STI and who have positive STI screening

N. gonorrhoeae/C trachomatis) or bacterial vaginosis are significantly more likely to have histopathology consistent with endometritis. (11) As a result, nonclassical “silent” or subclinical infection has emerged as an important phenomenon in clinical practice. Over time, the diagnostic criteria for PID in the Centers for Disease Control and Prevention (CDC) Sexually Transmitted Disease Treatment Guidelines (Table 1) have broadened to account for these observations and to increase the sensitivity of the clinical examination. The CDC currently recommends that empiric treatment for PID should be initiated for sexually active women at risk for STIs who present with lower abdominal or pelvic pain and who meet the minimum criteria of having uterine, adnexal, or cervical motion tenderness without an alternative explanation for their symptoms. Additional supportive criteria include fever (>38.3°C), abnormal cervical or vaginal mucopurulent discharge, white blood cells on saline microscopy, an elevated sedimentation rate or C-reactive protein, and existing documentation of C trachomatis or N. gonorrhoeae infection at the time of clinical assessment (Table 1). (12) Laboratory evaluation of the patient suspected of having PID should be sufficiently broad to detect other common medical conditions that might be contributing

Table 1.

Diagnostic Criteria for Pelvic Inflammatory Disease Based on the Centers for Disease Control (CDC) Guidelines

Sexually Active Female Patients At Risk for Sexually Transmitted Infections Pelvic or Lower Abdominal Pain No Other Cause Identified Minimum diagnostic criteria Uterine tenderness OR Adnexal tenderness OR Cervical motion tenderness Supportive clinical findings Fever (>38.3˚C) Abnormal cervical or vaginal mucopurulent discharge White blood cells on saline microscopy Elevated sedimentation rate and/or C-reactive protein Known positivity for Gonococcus (N. gonorrhoeae) or C trachomatis
Workowski KA, Berman S, Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010;59:1–110.

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to the patient’s clinical status. Specimen collection for screening asymptomatic patients has become increasingly easy in nonclinical settings, given the availability of vaginal and urine-based NAAT testing. However, it is still important that the pediatric clinician be prepared and equipped to perform a complete and thorough evaluation, including a speculum examination for visualization of the cervix and vagina and collection of endocervical and vaginal specimens, followed by a bimanual examination. It is critical also for pediatricians to conduct a sufficiently detailed, nonjudgmental, confidential, and adolescentcentered clinical history. This evaluation should include a 12-point review of systems, sexual and reproductive history, and psychosocial assessment to reduce the imprecision involved in diagnosing PID, while enhancing clinical decision making. Useful laboratory tests include a pregnancy test, endocervical N. gonorrhoeae/C trachomatis screening, wet prep and KOH prep, vaginal pH, urinalysis, and urine culture. A pregnancy test is important to determine if the patient’s discomfort may derive from an intrauterine or ectopic pregnancy and to aid decision-making for the final disposition of the patient (need for hospitalization, medications prescribed). The complete blood count and erythrocyte sedimentation rate or C-reactive protein may be useful in determining the degree of inflammation and severity of illness. A wet prep with KOH is useful for determining the presence of red blood cells, white blood cells, clue cells (bacterial vaginosis), T vaginalis organisms, or yeast. The vaginal pH may be elevated and the whiff test can be positive if the patient has bacterial vaginosis. A small subset of patients may have a concurrent urinary tract infection; so collection of a clean-catch urine specimen for urinalysis (and culture if urinalysis is positive) will allow for appropriate antibiotic coverage to treat 1 or both infections. In addition to the listed testing, pelvic sonography is indicated for individuals suspected of having an ectopic pregnancy, tubo-ovarian abscess, or other severe illness. In patients who also report having experienced sexual assault or abuse at the time of the PID assessment, it will be important to obtain bacterial cultures simultaneously for confirmation of positive NAATs. The NAATs are not approved for use in legal cases despite their high sensitivity and speci ficity in diagnosing N. gonorrhoeae/ C trachomatis infection. More specific diagnostic tests for PID include laparoscopy, endometrial biopsy to assess histopathology for evidence of endometritis, and transvaginal sonography or magnetic resonance imaging to assess for thickened,
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fluid-filled tubes and free pelvic fluid or tubo-ovarian abscesses. Doppler imaging studies can help to determine the presence of tubal hyperemia suggestive of pelvic infection. Given the proximity of the bowel and bladder to the uterus and contiguous structures, the differential diagnosis of PID is quite extensive (Table 2). Additional radiologic or consultative services may be required to exclude other serious conditions or PID-related complications. Short-term complications of PID include perihepatitis (Fitz-Hugh-Curtis syndrome) and periappendicitis. Although the pathogenesis of perihepatitis is unclear, up to 15% of patients who have PID will experience this finding. Patients usually present with mild to severe right upper quadrant abdominal pain, and examination reveals tenderness to palpation, guarding, and mild enlargement of the liver. In these cases, abdominal ultrasound and chest radiography may be indicated to assess for liver/gall bladder disease and pleural effusions, respectively. Transaminases may be slightly elevated but usually are within normal limits. Perihepatitis is most often associated with

Table 2.

Differential Diagnosis of Acute Pelvic Pain by Systems
System Gynecologic Condition Pelvic inflammatory disease • Endometritis • Salpingitis • Perihepatitis • Periappendicitis • Tubo-ovarian abscess Ectopic pregnancy Intrauterine pregnancy Endometriosis Hemorrhagic ovarian cyst Ovarian cyst Ovarian tumor Ovarian torsion Tubal torsion Septic abortion Vaginal foreign bodies Hematometrocolpos Chemical irritants Urinary tract infection Acute pyelonephritis Acute appendicitis Acute cholecystitis Mesenteric lymphadenitis Pelvic thrombophlebitis Functional abdominal pain Sexual assault Sexual abuse

Urinary Gastrointestinal Heme/Vascular Other

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a N. gonorrhoeae or C trachomatis infection, which will further solidify the diagnosis of PID when frank genital symptomatology is not present. Patients who have acute salpingitis are also at risk for developing periappendicitis. Most diagnoses of periappendicitis are diagnosed postoperatively in patients found to have tubal abnormalities intraoperatively, positive STI testing, and the absence of an inflammatory mass consistent with a true appendicitis. If appendicitis is suspected, however, blood work to assess inflammation, computed tomography (CT), and surgical consultations are warranted. In this instance, patients should have ultrasonography before CT to assess for other ovarian causes, such as ectopic pregnancy, tubal or ovarian torsion, and tubo-ovarian abscess, particularly if they are at low risk for appendicitis. CT is notoriously poor for diagnosing reproductive health problems involving ovarian structures and this stepwise approach prevents unnecessary radiation exposure. It is also recommended highly that patients who have PID be tested for syphilis and HIV infection. Because many patients may be seen in urgent care or emergency department settings that do not perform HIV testing, it will be important for clinicians to counsel and test patients for HIV during the post-PID reassessment visit. Now that the burden for the consent process has been improved in many regions of the country, performing HIV testing while the patient is getting other blood work drawn during the baseline evaluation is easier. Many adolescent-focused practices now offer confidential rapid oral or serum HIV testing, which may enhance acceptance of HIV testing.

Table 3.

Recommended Medication Regimens for Treatment of Pelvic Inflammatory Disease

Parenteral treatment Regimen A Cefoxitin 2 g IV every 6 h OR Cefotetan 2 g IV every 12 h Doxycycline 100 mg po BID 3 14 d – Metronidazole 500 mg po BID 3 14 d Regimen B Clindamycin 900 mg IVD Gentamicin loading dose IV or IM (2 mg/kg), followed by a maintenance dose (1.5 mg/kg) every 8 h OR Gentamicin single daily dosing (3–5 mg/kg/d) Alternate regimen Ampicillin/sulbactam 3 g IV every 6 h D Doxycycline 100 mg po BID 3 14 d Oral treatment Regimen A Ceftriaxone 250 mg IM (single dose) D Doxycycline 100 mg po BID 3 14 d – Metronidazole 500 mg po BID 3 14 d Regimen B Cefoxitin 2 g IM D Probenecid 1 g po (single dose) Doxycycline 100 mg po BID 3 14 d – Metronidazole 500 mg po BID 3 14 d Alternate regimen Other parenteral third-generation cephalosporin (eg, ceftizoxime or cefotaxime) D Doxycycline 100 mg po BID 3 14 d – Metronidazole 500 mg po BID 3 14 d
BID¼twice a day, d¼day(s), h¼hour(s), IM¼intramuscular, IV¼intravenous, po¼by mouth. Workowski KA, Berman S, Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010;59:1–110

Management
The CDC provides evidence-based, expert-guided recommendations for both inpatient and outpatient treatment approaches based on the illness severity. Although older CDC STD treatment guidelines indicated that all adolescents with PID should be hospitalized for treatment, 2010 guidelines recommend hospitalization for patients presenting with surgical emergencies, pregnancy, lack of response to antimicrobial therapy, inability to follow or tolerate an outpatient regimen, severe illness (e.g., fever, nausea/vomiting), or suspected or confirmed tubo-ovarian abscess. The antibiotic regimens for PID treatment have not changed in recent years and efficacy has been demonstrated in both laboratory and clinical studies. It is important to note that in 2007, the CDC recommended discontinuation of fluoroquinolones for PID treatment

because of N. gonorrhoeae resistance. Although there are also general concerns about N. gonorrhoeae resistance to available cephalosporins, the CDC maintains the use of these strategies as the optimal approach to medication management. The currently recommended treatment regimens per the CDC are outlined in Table 3. (12) For patients having more complicated infections, such as a tubo-ovarian abscess, additional anaerobic coverage with antibiotics, such as clindamycin, is indicated. In this instance, clindamycin should be continued at discharge to complete 14 days of therapy using the oral preparation. (12) Most patients who have an IUD in place can be
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treated effectively using the antibiotics without removing the IUD. In addition to the antibiotic regimens, the CDC recommends that all patients who have PID be reassessed within 72 hours of initiating therapy. Outpatients who are not clinically well or at least improving by 72 hours may require additional evaluation and/or hospitalization for parenteral therapy. (12) The clinician should suspect a tubo-ovarian abscess, peritonitis, or other cause for the pelvic pain. In this instance, a repeat bimanual examination and ultrasonography are important next steps in management. Adolescent medicine or gynecologic consultation also may be indicated to assist with management of patients on a general pediatric service.

Does Outpatient Treatment Work for Adolescents?
Although much of what we know about PID and its complications has been gleaned from the work of Weström in Lund, Sweden, (13) the PEACH (Pelvic Inflammatory Disease Evaluation and Clinical Health) Trial has provided seminal data on the microbiology, histopathology, clinical management, and longitudinal outcomes for women who have PID in the United States. This trial has greatly influenced the decision to treat adolescents with mild to moderate disease in the outpatient setting. Even so, it remains to be seen whether or not this approach is optimal for adolescents who may find self-management in the outpatient setting challenging. The trial examined primarily whether or not women with mild to moderate PID receiving antibiotics in the hospital for a few days followed by outpatient therapy did better than those receiving oral antibiotics in the outpatient setting. Because women in the inpatient and outpatient treatment arms appeared to have similar outcomes, the study and the cost-effectiveness analyses that emerged using PEACH trial data concluded that it would not be cost-effective to treat patients of any age with mild to moderate disease as inpatients. (14) Although this may be true given the low-cost nature of outpatient treatment with doxycycline, there are several issues that the pediatrician must consider when interpreting the data in the context of managing adolescent patients: 1. The PEACH trial was an efficacy trial and not an effectiveness trial, which means that data is unavailable on those who were unable to undergo the rigors of the trial (eg, endometrial biopsy), were ineligible, or refused to participate. Patients were also called
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every 3 months for 7 years to assess trial outcomes, which may have influenced patient behaviors following PID. Translational studies to evaluate effectiveness of outcomes among “all comers” in a real world context have yet to be performed. 2. In the STD treatment guidelines, the CDC indicates there are no differences for younger patients with PID. However, further analysis of the PEACH trial data indicates that although the study was open to adolescents as young as 14 years, the mean age of the 208 patients younger than 19 years who actually enrolled in the trial was 17.8 (SD 1) years. (15) This observation suggests that the findings may not be applicable to early and middle adolescents who have PID. 3. Overall, women in the PEACH trial did not fare well over the course of the 7 years: 21% had PID again, 19% experienced infertility, and 43% experienced CPP. (15,16) Adolescents had a shorter time to pregnancy and recurrent disease than adult women(15) and those who had recurrent PID were 5 times more likely to experience CPP. (17) 4. Finally, many adolescents hospitalized in pediatric centers with adolescent care units often receive additional clinical services beyond intravenous (IV) antibiotics. Such enhanced care often includes nursing education and support, assistance disclosing the PID diagnosis to parents or guardians, social work consultation, risk reduction counseling, assistance with partner notification and treatment, and scheduling of outpatient follow-up appointments before hospital discharge. It is simply unclear how this adolescent-specific standard of care approach or inclusion of a short evidence-based STI risk reduction intervention during hospitalization may have changed the longitudinal outcomes for patients in the trial. Despite these considerations and the fact that adolescents represent only about one fourth of all patients diagnosed as having PID, universal inpatient hospitalization with an optimized evidence-based behavioral intervention is unlikely to reemerge as a standard treatment recommendation. Still, pediatricians must realize that the responsibility for final disposition is theirs. Use of inpatient therapy for adolescents who have PID who by CDC standards have mild-moderate disease and are “unable to follow or tolerate” an outpatient management plan or have severe disease should be admitted for shortterm management. Based on these criteria, some institutions have created guidelines supporting admission of

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adolescents <15 years of age because of concerns about the developmental capacity of early adolescents to follow an outpatient treatment plan without adult support. (18) Another major problem affecting both adolescents and adult women facing a PID diagnosis in the outpatient setting is inadequate treatment by clinicians. A single-center study demonstrated that 40% of adolescent patients with PID in a large academic center received inadequate care per CDC guidelines in 2005. (19) Additional analyses published in 2011 using the National Hospital Ambulatory Survey have since shown that the problem is even more pervasive for all women in the United States, and that 70% of patients receive inadequate care for PID based on CDC guidelines. Most notable was that the prescribed antibiotic regimens were problematic, and that many women received neither antibiotics nor analgesia for treatment. Among all women, adolescents fared the worst. (20) Sadly, adherence to guidelines is an international problem. A 2012 audit in the United Kingdom demonstrated that 55.5% of patients who had PID did not receive care according to the British Association of Sexual Health and HIV treatment recommendations. (21) Fortunately, clinician behavior can be enhanced with the use of institutionally driven treatment protocols, especially those that include onsite dispensing of full courses of medications. (18)(22) An additional consideration for pediatricians is that management of PID in the outpatient setting requires several critical behaviors by patients to be most effective. An adolescent girl will need to (1) take the antibiotics twice daily for 14 days; (2) return for follow-up care within 72 hours; (3) notify her partner so that he can be treated while she is being treated; (4) temporarily abstain from sexual intercourse until both she and her partner are treated; and (5) make lifestyle changes to prevent a future episode of PID through enhanced partner communication and condom use. Even if the clinician prescribes a course of treatment consistent with the CDC recommendations and the adolescent professes the self-efficacy for following the recommendations, adolescents often do not adhere without support. Many adolescents with PID have already had an STI or pregnancy and few are using contraception; (23) so the 72-hour visit becomes a critical time to ensure PID recovery and engage in STI risk reduction and family planning counseling. Fortunately, some brief interventions for PID have been devised that improve the rates of partner treatment and can

be administered in any setting through which patients can access a computer. The 6-minute PID Outreach video was developed by using the tenets of the Health Belief Model and has been found in a randomized controlled trial to increase partner treatment. (23) The video intervention is publically accessible at the following Internet address: http://www.youtube.com/watch?v¼lGuXF8vpujQ Research on easier alternative treatment strategies is promising. One Brazilian trial has demonstrated that ceftriaxone 250 mg intramuscularly (IM) plus 1 g of azithromycin given orally at baseline and repeated in 2 weeks is as effective in 14-day cure rates as the standard CDC-recommended regimen of ceftriaxone 250 mg IM plus oral doxycycline 100 mg twice daily for 14 days. (24) There have been no confirmatory studies, and longitudinal outcomes using this method have not been explored. If proven to be clinically effective, this approach may improve adherence for adolescents who struggle with medication completion and enhance adherence to the 72-hour follow-up visit.

Prognosis
The prognosis for PID is highly dependent on the ability of adolescents to seek and receive timely care and to prevent future episodes of STI or PID. Each episode (and its degree of severity) contributes to the potential development of sequelae, such as infertility. (25)(26) Sexually active adolescents who have had PID must not only engage in active biannual screening for STIs to reduce the risk for developing another episode of PID, but also make a commitment to consistent condom use. For those who have recurrent STIs or PID, the mean time to the next diagnosis is about 1 year. (27) Use of evidence-based interventions that support and empower adolescents to negotiate sexual decision-making and use of condoms may be important adjuncts to clinical practices that better allow for successful outpatient treatment of adolescents with PID.

Epilogue
Justine is diagnosed with PID and is given ceftriaxone 250 mg IM and 100 mg of doxycycline orally with a plan for her to complete 14 days of twice-daily oral doxycycline. In addition to the testing for N. gonorrhoeae and C trachomatis, she also has syphilis and HIV testing. While waiting for her prescriptions, she is counseled on partner notification and treatment, afforded the opportunity to watch the PID outreach video online to aid in self-management at home, and scheduled for a follow-up visit
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within 72 hours. She discloses her diagnosis to her mother, who is upset but extremely supportive. As Justine is leaving the office, she vomits and small pill fragments are seen in the emesis. Given her inability to tolerate outpatient therapy, Justine is admitted to the hospital’s adolescent unit for short-term management with IV antibiotics. You realize that her boyfriend, who came to visit her during the hospitalization, also is your patient. You arrange to screen him for STIs and treat him for urethritis during the visit, pending the results of her STI testing. Her STI testing is positive for C trachomatis. You counsel them both individually and together about the risks for PID and provide condoms at the end of your conversations. Justine makes the anticipated rapid recovery within 72 hours of initiating IV antibiotics. You reinforce the importance of completing all medications to clear the infection. You make arrangements to see Justine 3 days after discharge in your office to reassess her clinical status, provide risk reduction and family planning counseling, and follow-up on pending laboratory results.

4. Nongonococcal urethritis and other selected sexually transmitted
diseases of public health importance. Report of a WHO Scientific Group. World Health Organ Tech Rep Ser. 1981;660:1–142 5. Wasserheit JN. The significance and scope of reproductive tract infections among Third World women. Suppl Int J Gynecol Obstet. 1989;3:145–168 6. Trent M, Lehmann HP, Qian Q, Thompson CB, Ellen JM, Frick KD. Adolescent and parental utilities for the health states associated with pelvic inflammatory disease. Sex Transm Infect. 2011;87(7):583–587 7. Trent M, Millstein SG, Ellen JM. Gender-based differences in fertility beliefs and knowledge among adolescents from high sexually transmitted disease-prevalence communities. J Adolesc Health. 2006;38(3):282–287 8. Haggerty CL, Taylor BD. Mycoplasma genitalium: an emerging cause of pelvic inflammatory disease. Infect Dis Obstet Gynecol. 2011;2011:959816 9. Meirik O. Intrauterine devices—upper and lower genital tract infections. Contraception. 2007;75(suppl 6):S41–S47 10. Wølner-Hanssen P. Silent pelvic inflammatory disease: is it overstated? Obstet Gynecol. 1995;86(3):321–325 11. Wiesenfeld HC, Sweet RL, Ness RB, Krohn MA, Amortegui AJ, Hillier SL. Comparison of acute and subclinical pelvic inflammatory disease. Sex Transm Dis. 2005;32(7):400–405 12. Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010 [published correction appears in MMWR Recomm Rep. 2011;60(1):18]. MMWR Recomm Rep. 2010;59(RR-12):1–110 13. Weström L. Effect of acute pelvic inflammatory disease on fertility. Am J Obstet Gynecol. 1975;121(5):707–713 14. Smith KJ, Ness RB, Roberts MS. Hospitalization for pelvic inflammatory disease: a cost-effectiveness analysis. Sex Transm Dis. 2007;34(2):108–112 15. Trent M, Haggerty CM, Jennings JJ, et al. Adverse adolescent reproductive health outcomes after pelvic inflammatory disease. Arch Pediatr Adolesc Med. 2011;165:49–54 16. Ness RB, Soper DE, Holley RL, et al. Effectiveness of inpatient and outpatient treatment strategies for women with pelvic inflammatory disease: results from the Pelvic Inflammatory Disease Evaluation and Clinical Health (PEACH) Randomized Trial. Am J Obstet Gynecol. 2002;186(5):929–937 17. Trent M, Bass D, Ness RB, Haggerty C. Recurrent PID, subsequent STI, and reproductive health outcomes: findings from the PID evaluation and clinical health (PEACH) study. Sex Transm Dis. 2011;38(9):879–881 18. Trent M, Judy SL, Ellen JM, Walker A. Use of an institutional intervention to improve quality of care for adolescents treated in pediatric ambulatory settings for pelvic inflammatory disease. J Adolesc Health. 2006;39(1):50–56 19. Trent M, Ellen JM, Walker A. Pelvic inflammatory disease in adolescents: care delivery in pediatric ambulatory settings. Pediatr Emerg Care. 2005;21(7):431–436 20. Shih TY, Gaydos CA, Rothman RE, Hsieh YH. Poor provider adherence to the Centers for Disease Control and Prevention treatment guidelines in US emergency department visits with a diagnosis of pelvic inflammatory disease. Sex Transm Dis. 2011; 38(4):299–305 21. Oroz C, Bailey H, Hollows K, Lee J, Mullan H, Theobald N; UK BASHH SAS Group. A national audit on the management of pelvic inflammatory disease in UK genitourinary medicine clinics. Int J STD AIDS. 2012;23(1):53–54

Summary
• Pelvic inflammatory disease (PID) is a common upper reproductive health disorder disproportionately affecting adolescents. • Common adverse reproductive health consequences associated with PID include tubal infertility, chronic pelvic pain, and ectopic pregnancy • Centers for Disease Control and Prevention (CDC) provides evidence-based and expert-driven treatment guidelines for effective management of PID, but clinician adherence to the guidelines has been poor. • Clinicians should determine carefully the need for inpatient versus outpatient dispositions based on severity of illness and the adolescent’s ability to tolerate an outpatient treatment regimen.

References
1. Sutton MY, Sternberg M, Zaidi A, St Louis ME, Markowitz LE. Trends in pelvic inflammatory disease hospital discharges and ambulatory visits, United States, 1985-2001. Sex Transm Dis. 2005;32(12):778–784 2. Velebil P, Wingo PA, Xia Z, Wilcox LS, Peterson HB. Rate of hospitalization for gynecologic disorders among reproductive-age women in the United States. Obstet Gynecol. 1995;86(5):764–769 3. Chandra A, Martinez GM, Mosher WD, Abma JC, Jones J. Fertility, family planning, and reproductive health of U.S. women: data from the 2002 National Survey of Family Growth. Vital Health Stat 23. 2005;(25):1–160
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22. Shrier LA, Moszczenski SA, Emans SJ, Laufer MR, Woods ER. Three years of a clinical practice guideline for uncomplicated pelvic inflammatory disease in adolescents. J Adolesc Health. 2000;27(1): 57–62 23. Trent M, Chung SE, Burke M, Walker A, Ellen JM. Results of a randomized controlled trial of a brief behavioral intervention for pelvic inflammatory disease in adolescents. J Pediatr Adolesc Gynecol. 2010;23(2):96–101 24. Savaris RF, Teixeira LM, Torres TG, Edelweiss MI, Moncada J, Schachter J. Comparing ceftriaxone plus azithromycin or

doxycycline for pelvic inflammatory disease: a randomized controlled trial. Obstet Gynecol. 2007;110(1):53–60 25. Hillis SD, Joesoef R, Marchbanks PA, Wasserheit JN, Cates W Jr, Westrom L. Delayed care of pelvic inflammatory disease as a risk factor for impaired fertility. Am J Obstet Gynecol. 1993;168(5):1503–1509 26. Weström L. Effect of pelvic inflammatory disease on fertility. Venereology. 1995;8(4):219–222 27. Trent M, Chung SE, Forrest L, Ellen JM. Subsequent sexually transmitted infection after outpatient treatment of pelvic inflammatory disease. Arch Pediatr Adolesc Med. 2008;162(11):1022–1025

PIR Quiz
This quiz is available online at http://www.pedsinreview.aappublications.org. NOTE: Learners can take Pediatrics in Review quizzes and claim credit online only. No paper answer form will be printed in the journal.

New Minimum Performance Level Requirements
Per the 2010 revision of the American Medical Association (AMA) Physician’s Recognition Award (PRA) and credit system, a minimum performance level must be established on enduring material and journal-based CME activities that are certified for AMA PRA Category 1 CreditTM. In order to successfully complete 2013 Pediatrics in Review articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of 60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity. In Pediatrics in Review, AMA PRA Category 1 CreditTM may be claimed only if 60% or more of the questions are answered correctly. If you score less than 60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved.

1. You counsel a 16-year-old girl who has fever and cervical motion tenderness on pelvic examination. You note on review of her medical chart that this is the third episode with a similar presentation. In addition to treating her acute condition, you are MOST likely to discuss her risk for A. B. C. D. E. Appendicitis Ectopic pregnancy Menorrhagia Septic shock Vaginitis

2. A 17-year-old girl presents with lower abdominal pain, fever, and adnexal tenderness. Testing for gonococcus and Chlamydia trachomatis is negative. She eats lunch without difficulty while waiting for laboratory results. You are MOST likely to tell her that she A. B. C. D. E. Does not have a serious infection Needs abdominal magnetic resonance imaging Should be hospitalized for intravenous antibiotics. Should take antibiotics to treat a pelvic inflammatory infection Will be admitted for laparoscopy

3. An 18-year-old woman has fever, moderate lower abdominal pain, vaginal discharge, and adnexal tenderness. Although uncomfortable, she has been keeping down solid foods, as well as the ibuprofen tablets she has taken for her pain. An office pregnancy test is positive. Appropriate management of this patient would be A. B. C. D. E. Immediate computed tomographic scanning Hospital admission for further evaluation and therapy Injection of ceftriaxone after cultures are obtained Outpatient antibiotic therapy that is safe during pregnancy Urgent blood work to assess inflammation

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4. A 14-year-old girl has severe right upper quadrant abdominal pain, and examination reveals tenderness to palpation and guarding. Abdominal ultrasonography shows no gallbladder disease. She is most likely to also have A. Ascites B. Jaundice C. Liver failure D. Mild hepatomegaly E. Pancreatitis 5. An 18-year-old woman has fever, lower abdominal pain, vaginal discharge, and adnexal tenderness. She is able to eat without emesis. You elect to treat her with antibiotics as an outpatient. She has no allergies to medications. You give her an injection of ceftriaxone and a prescription for doxycycline. In addition, you are MOST likely to prescribe A. B. C. D. E. Amoxicillin Ciprofloxacin Erythromycin Metronidazole Repeat dose of ceftriaxone in 24 hours

Corrections
In the December 2012 article “Hypertension” (Brady T. Pediatr Rev. 2012;33(12):541–552), figure 1’s caption should include, “Reprinted from Feld LG, Corey H. Hypertension in childhood. Pediatr Rev. 2007;28(8):283–298) and Adapted from The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents. Pediatrics. 2004;114:555–576.” The journal regrets this error. In the January 2013 article “Adolescent Sexuality” (Tulloch T, Kaufman M. Pediatr Rev. 2013;34(1):29–38), there is an error in the table on page 32. The pregnancy rate for the United Kingdom should read 43.0. The journal regrets the error.

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4. A 14-year-old girl has severe right upper quadrant abdominal pain, and examination reveals tenderness to palpation and guarding. Abdominal ultrasonography shows no gallbladder disease. She is most likely to also have A. Ascites B. Jaundice C. Liver failure D. Mild hepatomegaly E. Pancreatitis 5. An 18-year-old woman has fever, lower abdominal pain, vaginal discharge, and adnexal tenderness. She is able to eat without emesis. You elect to treat her with antibiotics as an outpatient. She has no allergies to medications. You give her an injection of ceftriaxone and a prescription for doxycycline. In addition, you are MOST likely to prescribe A. B. C. D. E. Amoxicillin Ciprofloxacin Erythromycin Metronidazole Repeat dose of ceftriaxone in 24 hours

Corrections
In the December 2012 article “Hypertension” (Brady T. Pediatr Rev. 2012;33(12):541–552), figure 1’s caption should include, “Reprinted from Feld LG, Corey H. Hypertension in childhood. Pediatr Rev. 2007;28(8):283–298) and Adapted from The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents. Pediatrics. 2004;114:555–576.” The journal regrets this error. In the January 2013 article “Adolescent Sexuality” (Tulloch T, Kaufman M. Pediatr Rev. 2013;34(1):29–38), there is an error in the table on page 32. The pregnancy rate for the United Kingdom should read 43.0. The journal regrets the error.

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Article

hematology/oncology

How to Approach Neutropenia in Childhood
Kelly Walkovich, MD, Laurence A. Boxer, MD

Practice Gaps
1. Patients presenting with recurrent fevers, mouth ulcers and gingivitis should be evaluated for neutropenia. 2. The use of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in the management of cyclic neutropenia and severe congenital neutropenia has dramatically decreased clinical symptoms and has decreased mortality from infectious causes.

Author Disclosure Dr Walkovich has disclosed no financial relationships relevant to this article. Dr. Boxer has disclosed that he owns stocks/ bonds in Amgen Inc.; serves as a consultant and on the speaker bureau of Alexion Pharmaceuticals; and is a consultant for Vidara Therapeutics. This commentary does not contain discussion of unapproved/ investigative use of a commercial product/ device.

Objectives

After completing this article, readers should be able to:

1. Recognize patients who have concerning features of history, physical examination, or laboratory results that warrant further investigation for possible neutropenia or other immunodeficiency. 2. Define mild, moderate, and severe neutropenia. 3. Understand that neutropenia can arise from acquired or intrinsic conditions. Know which causes of neutropenia are most commonly encountered in childhood. 4. Recognize why disorders of neutrophil production and release from the bone marrow carry more risk for bacterial infection than peripheral neutropenia associated with normal bone marrow morphology. 5. Understand why neutropenic patients undergoing immunosuppressive therapy are more at risk for a serious bacterial infection than patients who have isolated neutropenia. 6. Understand the impact that treatment with recombinant human granulocyte colonystimulating factor has had on the outcome of patients who have severe congenital and cyclic neutropenia. 7. Know when to refer to a pediatric hematologist/oncologist. A case study is provided to illustrate key aspects of the care of patients who have neutropenia.

Case Abbreviations:
AIN: AML: ANC: CBC: MDS: rhG-CSF: SCN: SDS: WBC: autoimmune neutropenia acute myelogenous leukemia absolute neutrophil count complete blood cell count myelodysplastic syndrome recombinant human granulocyte colonystimulating factor severe congenital neutropenia Shwachman-Diamond syndrome white blood cell count

A 13-month-old boy presents to his primary care physician for his standard 1-year well-child check. He has had four episodes of otitis media since starting child care, all of which resolved with standard antibiotics. His mother reports that he has been healthy recently, with the exception of a viral upper respiratory tract infection that he and his older siblings experienced a few weeks ago. His physical examination is unremarkable, with no oral lesions, gingivitis, lymphadenopathy, hepatosplenomegaly, or rashes. He has normal forearms and thumbs. A screening complete blood cell count (CBC) with differential is obtained, which shows the following: white blood cell (WBC) count, 5.6/mm3; hemoglobin, 13.8 g/dL; platelets, 212,000/mm3; and absolute neutrophil count (ANC),

Department of Pediatrics, University of Michigan, Ann Arbor, MI.

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300/mm3. Repeat CBC with differential 1 week later continues to show a normal total WBC count with persistent severe neutropenia. He is referred to a pediatric hematologist/oncologist for further evaluation and management. Antineutrophil antibody testing result is positive, and he is diagnosed as having autoimmune neutropenia of infancy. This case represents a classic presentation of autoimmune neutropenia of infancy. The management usually is supportive because the risk for infection in 80% of the patients is no greater than that for normal children. More importantly, lymphocyte and monocyte function are normal; thus, affected children can receive live vaccines.

Table 1.

Clinical Features Meriting Further Immunologic Evaluation

Introduction
The differential diagnosis for a patient presenting with recurrent infections and the question of an immunodeficiency is challenging. Similarities in the clinical presentation of neutrophil, antibody, and cellular immune defects, as well as complement disorders, can prove difficult for the physician attempting to establish a diagnosis. Infants and children who are brought to the pediatrician for “repeated infections” must be evaluated carefully. Most patients who have recurrent infections do not have an identifiable phagocyte defect or broader immunodeficiency. Instead, the patients often have anatomic variations, allergy-related illness, social exposures (such as child care), or other risk factors for recurrent infections. Given the low probability of identifying a discrete immune defect, the pediatrician faces the difficult decision of which patients merit a complete evaluation and referral to a pediatric immunologist or pediatric hematologist/ oncologist. In general, evaluations and referrals, particularly for neutrophil disorders, should be initiated for those who have had at least one of the listed clinical features in Table 1 within a 1-year period. Once the decision is reached that an evaluation is warranted, a thorough clinical history, physical examination (including plotting a growth curve), and laboratory screening for immunodeficiency disorders should aid in determining the diagnosis. If the CBC reveals absolute neutropenia, further studies are required to establish the basis for the low ANC. Patients who experience recurrent bacterial infections but have a normal neutrophil count warrant evaluation for qualitative neutrophil disorders or other immunodeficiencies (Table 2). The remainder of this article will focus on neutropenia in childhood.
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• More than two systemic bacterial infections (sepsis, meningitis, osteomyelitis) • More than two serious respiratory infections (pneumonia) • Multiple bacterial infections (cellulitis, draining otitis media, lymphadenitis) • Unusual infections involving the liver or a brain abscess • Infections caused by unusual pathogens (eg, Aspergillus pneumonia, disseminated candidiasis, infection with Serratia marcescens, Nocardia species, Burkholderia cepacia) • Infections of unusual severity • Chronic gingivitis or recurring aphthous ulcers

Neutropenia
Neutropenia is defined as a decrease in the absolute numbers of circulating segmented neutrophils and band forms in the blood. Obtaining a CBC with a differential count identifies this condition. The ANC is determined by multiplying the total WBC count by the percentage of segmented and band forms. The ANC for the general population normally ranges between 1.5 and 8.0 Â 109/L. It is important to note that this normal range was generated primarily by using data from white children and may not be as applicable to other ethnic groups. For example, as many as 30% of the African-American population may have ANC levels as low as 0.8 Â 109/L (0.8.0 Â 109/L) and still be considered healthy. Regardless of ethnicity, ANCs vary widely in healthy individuals. The relative proportion of neutrophils and lymphocytes in the blood changes with age. Neutrophils predominate at birth but decrease rapidly in the first few days after birth. During infancy, neutrophils constitute 20% to 30% of the circulating leukocyte populations. Approximately equal numbers of neutrophils and lymphocytes are found in the peripheral circulation by the time a child reaches w5 years of age, and the characteristic 70% predominance of neutrophils that occurs in adulthood usually is attained at puberty. In healthy children, therefore, 20% to 70% of the total circulating WBCs may be neutrophils. Individual patients who have neutropenia may be characterized as having acute or chronic neutropenia. Acute neutropenia is neutropenia of less than 3 months’ duration, whereas chronic neutropenia is neutropenia of 4 or more months’ duration. Severe acute neutropenia

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Table 2.

Causes and Mechanisms of Recurrent Infection in Primary Immunodeficiency States
Disorders Humoral immunodeficiency (predominantly B-cell defects) Cellular immunodeficiency states (predominantly T-cell defects) Severe combined immunodeficiency Wiskott-Aldrich syndrome Ataxia-telangiectasia Splenic insufficiency or absence Complement deficiencies Neutrophil dysfunction syndromes, including chronic granulomatous disease and leukocyte adhesion deficiency Neutropenia (<0.5 3 109/L) Deficiency Impaired opsonization; failure of lysis and agglutination of bacteria; failure to neutralize bacterial toxins Absent T-cell cooperation for B-cell synthesis of antibodies to T cell–specific antigens Absent T-cell and B-cell response Decreased antibody response to carbohydrate antigens T helper cell deficiency; immunoglobulin deficiency Defective opsonization; defective clearing of encapsulated organisms Defective opsonization Impaired neutrophil bactericidal activity arising from failure to generate hydrogen peroxide by phagocytes; gingivitis, perirectal ulcers, delayed umbilical cord separation Inadequate numbers of phagocytes

developing over hours or days and arising from chemotherapy, marrow failure, or marrow exhaustion often is associated with a greater risk of bacterial infection than severe chronic neutropenia. Chronic neutropenia arises from reduced production, increased destruction, or an excessive splenic sequestration of neutrophils. Patients also can be defined as having mild neutropenia when the ANC is 1.0 to 1.5 Â 109/L, moderate neutropenia when the ANC is 0.5 to 1.0 Â 109/L, and severe neutropenia when the ANC is less than 0.5 Â 109/L. (1) The classification of neutropenia as mild, moderate, or severe predicts the risk for pyogenic infections in patients who have neutropenia resulting from disorders of bone marrow production. Neutropenia associated with monocytopenia, lymphocytopenia, or hypogammaglobulinemia increases the risk for infection compared with isolated neutropenia. Neutropenia may be characterized further by whether it is acquired (Table 3) or arising from an intrinsic defect affecting production of myeloid progenitor cells (Table 4). Susceptibility to bacterial infections, even in the presence of severe neutropenia, varies. In general, disorders of neutrophil production and release from the bone marrow carry more risk for bacterial infections than peripheral neutropenia associated with normal marrow morphology. Some patients who have chronic neutropenia and an ANC of less than 0.5 Â 109/L do not experience serious infection, probably because other parts of their immune system remain intact, including T- and B-cell function, although they will often suffer from gingivitis.

In contrast, neutropenic patients receiving cytotoxic or immunosuppressive drugs, particularly in conjunction with malignancies, are more likely to develop serious bacterial infections than those whose neutropenia is isolated because the cytotoxic agents and immune suppression compromise both the function and numbers of lymphocyte and monocytes. Cancer chemotherapy also can compromise the integrity of the skin and mucous membranes as well as the nutritional status of the patient, which further predisposes the patient to infection. Patients who have neutropenia are infected most frequently by endogenous flora. Colonization by various nosocomial organisms is also often observed. The types of pyogenic infections occurring most frequently among patients who have profound neutropenia are cellulitis and abscesses or furunculosis, pneumonia, and septicemia. In addition, stomatitis, gingivitis, perirectal inflammation, and otitis media are common. Occasionally, diffuse intestinal lesions develop, which can cause abdominal pain and diarrhea. These lesions may be related to bacterial overgrowth in the intestines. The most common pathogens isolated from patients who have neutropenia are Staphylococcus aureus, Gram-negative organisms, Staphylococcus epidermidis, streptococci, and enterococci. Often, the signs and symptoms of local infections and inflammation, such as exudate, abscess formation, and regional lymphopathy, are diminished in neutropenic patients because of a paucity of neutrophils to mediate the inflammatory response. Other signs and symptoms, such as redness, pain, tenderness, and warmth,
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Table 3.

Acquired Causes of Neutropenia
Etiologic Factors/Agents Viruses, bacteria, protozoa, rickettsia, fungi Phenothiazines, sulfonamides, anticonvulsants, penicillins, aminopyrine Alloimmune, autoimmune Hypersplenism Malignancy (eg, lymphoma, metastatic solid tumor) Suppression of myeloid cell production Stem cell destruction and depletion Malnutrition; congenital deficiency of vitamin B12 absorption, transport, and storage; vitamin avoidance Bone marrow replacement with malignant cells Dysplastic maturation of stem cells Impaired regulation of myeloid proliferation and reduced size of postmitotic pool Impaired myeloid proliferation and/or maturation Acquired stem cell defect to secondary to mutation of PIG-A gene Associated Findings Redistribution from circulating to marginating pools, impaired production, accelerated destruction Hypersensitivity reaction (fever, lymphadenopathy, rash, hepatitis, nephritis, pneumonitis, aplastic anemia), antineutrophil antibodies Variable arrest from metamyelocyte to segmented neutrophils in bone marrow Anemia, thrombocytopenia, neutropenia Presence of immature myeloid and erythroid precursors in peripheral blood Bone marrow hypoplasia, anemia, thrombocytosis Pancytopenia Megaloblastic anemia, hypersegmented neutrophils Pancytopenia, leukocytosis Bone marrow hypoplasia with megaloblastoid red cell precursors, thrombocytopenia Maternal preeclampsia None Pancytopenia, thrombosis

Cause Infection Drug-induced

Immune neutropenia Reticuloendothelial sequestration Bone marrow replacement Cancer chemotherapy or radiation therapy to bone marrow Aplastic anemia Vitamin B12 or folate deficiency Acute leukemia, chronic myelogenous leukemia Myelodysplasia Prematurity with birthweight <2 kg Chronic idiopathic neutropenia Paroxysmal nocturnal hemoglobinuria

Reprinted with permission from Newburger PE, Boxer LA. Leukopenia. In: Kliegman RM, Stanton BF, St Gene IW III, Schor NF, Behrman RE, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Elsevier Saunders; 2011:748.

accompanied by fever, are mediated by inflammatory cytokines and generally are present.

Evaluation of Children Who Have Neutropenia
Evaluation begins with confirmation of neutropenia according to age-appropriate standards of neutrophil counts. When patients have ANCs less than 1.0 Â 109/L, a manual differential count should be requested to determine whether blasts or immature neutrophils are present in the peripheral smear, which might indicate acute leukemia. The general pediatrician should obtain a thorough history to establish the onset of neutropenia; the type, frequency, and severity of infections; drug history for toxic exposures; and family history of recurrent infection or unexplained infant deaths.
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The physical examination should note growth and development; phenotypic abnormalities; and the presence of bacterial infections at various sites in the body, including mucous membranes, gingiva, skin, tympanic membranes, and rectum. Lymphadenopathy, hepatosplenomegaly, and signs of possible underlying disease also should be noted. The presence of petechiae and purpura suggesting thrombocytopenia might indicate a more generalized disease process. The patient’s temperature should be recorded, but rectal temperatures should be avoided in the neutropenic patient to prevent possible injury to the mucous membranes and subsequent spread of bacteria into the circulation. The severity and duration of the neutropenia determine the extent of laboratory evaluation. If the child

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Table 4.

Intrinsic Disorders of Myeloid Precursor Cells
Inheritance (Gene) AD (ELA2) AD (ELA2, GFL1, others) X-linked (WAS) AR (HAX1) AR (SBDS) Telomerase defects: XL (DKC1), AD (TER), AR (TERT) AR (LYST) Clinical Features (Including Static Neutropenia Unless Otherwise Noted) Periodic oscillation (21-day cycles) in ANC Risk of MDS and AML neutropenic variant of WAS Neurologic abnormalities, risk of MDS and AML Pancreatic insufficiency, variable neutropenia, other cytopenias, metaphysical dysostosis Nail dystrophy, leukoplakia, reticulated hyperpigmentation of the skin; 30%–60% develop bone marrow failure Partial albinism, giant granules in myeloid cells, platelet storage pool defect, impaired natural killer cell function, hemophagocytic lymphohistiocytosis Partial albinism, impaired natural killer cell function, hemophagocytic lymphohistiocytosis Developmental delay, facial dysmorphism, retinopathy Cyclic neutropenia, partial albinism Partial albinism, decreased B and T cells Hepatic enlargement, growth retardation, impaired neutrophil motility Structural heart defects, urogenital abnormalities, venous angiectasia Episodic neutropenia, dilated cardiomyopathy, methylglutaconic aciduria, pancytopenia Vacuolization of erythroid and myeloid precursors, ringed sideroblasts, pancytopenia Hypogammaglobulinemia, other immune system defects Decreased IgA Absent humoral and cellular immune function Absent IgG, elevated IgM, autoimmune cytopenia Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) Lymphopenia, short-limbed dwarfism, metaphysical chondrodysplasia, fine sparse hair Lymphopenia, pancytopenia, spondyloepiphyseal dysplasia, growth retardation, renal failure

Syndrome Primary disorder of myelopoiesis Cyclic neutropenia Severe congenital neutropenia Kostmann syndrome Disorders of ribosomal function Shwachman-Diamond syndrome Dyskeratosis congenita Disorders of granule sorting ´ diak-Higashi syndrome Che

Griscelli syndrome, type II Cohen syndrome Hermansky-Pudlak syndrome, type II p14 deficiency Disorders of metabolism Glycogen storage disease type 1b Glucose-6-phosphate catalytic subunit 3 deficiency Barth syndrome Pearson syndrome Neutropenia in disorders of immune function Common variable immunodeficiency IgA deficiency Severe combined immunodeficiency Hyper-IgM syndrome WHIM syndrome Cartilage-hair hyperplasia Schimke immune-osseous dysplasia

AR (RAB27a) AR (COH1) AR (AP3P1) Probable AR (MAPBPIP) AR (G6PT1) AR (G6PC3) XL (TAZ1) Mitochondrial (DNA deletions) Familial sporadic (TNFRSF13B) Unknown (Unknown or TNFRSF13B) AR, XL (multiple loci) XL (HIGM1) AD (CXCR4) AR (RMKP) Probable AR (SMARCAL1)

Reprinted with permission and modified from Newburger PE, Boxer LA. Leukopenia. In: Kliegman RM, Stanton BF, St Gene IW III, Schor NF, Behrman RE, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Elsevier Saunders; 2011:748. AD¼autosomal dominant; AML¼acute myelogenous leukemia; ANC¼absolute neutrophil count; AR¼autosomal recessive; Ig¼immunoglobulin; MDS¼myelodysplastic syndrome; WAD¼Wiskott-Aldrich syndrome; XL¼X linked.

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is neutropenic at the time of examination shortly after a viral infection, a CBC should be performed 3 to 4 weeks later to evaluate recovery of the ANC. For the infant who remains asymptomatic despite the persistence of neutropenia, studies should be initiated to determine whether the patient’s serum contains antineutrophil antibody. Bone marrow examination usually is not needed in the patient who has acute-onset neutropenia, is not experiencing more than the usual childhood bacterial infections, and who has no history of chronic gingivitis or recurrent mouth ulcers. In contrast, children who have a clinical history consistent with infections due to chronic neutropenia, such as gingivitis in infancy, require more extensive evaluation by a pediatric hematologist/oncologist (Table 5). The specialist will obtain weekly CBCs for 6 weeks to establish whether there is a cycle of 21 days (–4 days) of neutropenia, which differentiates cyclic neutropenia from severe congenital neutropenia. Bone marrow aspirate and bone marrow cytogenetics are required to evaluate the risk for leukemia as well as to assess cellular morphology and the extent of myeloid cell maturation. Children presenting with pancytopenia require a bone marrow aspiration and biopsy to aid in the diagnosis and to assess bone marrow cellularity. Additional marrow studies, including cytogenetic analysis, flow analysis, and special stains for detecting leukemia and other malignant disorders, are required in certain cases. Selection of other laboratory tests is determined by the duration and severity of the neutropenia and by the findings obtained on the physical examination. Children who present with a history consistent with malabsorption and neutropenia should be evaluated for Shwachman-Diamond syndrome (SDS). These patients also require studies to evaluate the status of their pancreatic enzymes, as well as skeletal evaluation to assess the possibility of metaphyseal chondrodysplasia. All children who have chronic neutropenia associated with recurrent infections should have growth curves plotted to evaluate the effect of the infections on their growth. Antinuclear antibody determination, red blood cell folate concentration, and serum vitamin B12 level assessments are indicated for patients in whom collagen vascular disease (antinuclear antibody) and nutritional deficiencies (folate, vitamin B12) are suspected. More extensive immunologic evaluation by a pediatric immunologist is indicated for selected patients suspected of having a concurrent immunodeficiency.

over a few days and occurs when neutrophil use is rapid and production is compromised. Infectious diseases are among the most common causes of acute neutropenia in children, with viral infection being the major cause of acute neutropenia in childhood. Viruses commonly causing neutropenia include respiratory syncytial virus, varicella, influenza A and B, measles, rubella, and Epstein-Barr virus. Neutropenia occurs often during the first 24 to 48 hours of illness and usually persists for 3 to 8 days, which corresponds to the period of acute viremia. Significant neutropenias may be associated also with bacterial, protozoal, rickettsia, and severe fungal infections. The mechanisms responsible for neutropenia in acute bacterial infections include: 1) redistribution of neutrophils from the peripheral blood circulating pool to the marginating pool (neutrophils adherent to endothelium of low-flow exchange vessels) after release of cytokines that increase expression of the protein’s intracellular adhesion molecule-1 and -2 on endothelium; 2) increased use of neutrophils at sites of infection; and 3) in some cases, decreased production of neutrophils. Sepsis is a particularly serious cause of neutropenia, especially among babies and children. Premature neonates are especially prone to exhausting their marrow reserve pool of segmented neutrophils and bands and rapidly succumbing to bacterial sepsis. In contrast, marrow reserves in older children and adults can increase during infection.

Drug-induced Neutropenia
Drugs can induce severe neutropenia by immunologic, toxic, and hypersensitivity-mediated mechanisms; often the mechanism is incompletely understood. This form of neutropenia must be distinguished from that seen with viral infections and from the severe neutropenia that accompanies administration of large doses of cytotoxic drugs or which follows radiation therapy. Only 10% of drug-induced neutropenia occurs in children. The higher frequency in adults aged older than 60 years likely reflects the use of multiple medications. Once neutropenia occurs, the most effective therapeutic measure is withdrawal of nonessential drugs, particularly drugs suspected of being myeloid-toxic. Often, the neutropenia will respond to withdrawal of the offending drug. If the neutropenia fails to improve with drug withdrawal and the patient subsequently experiences signs and symptoms related to severe neutropenia, subcutaneous administration of 5 mg/kg of recombinant human granulocyte colonystimulating factor (rhG-CSF) should be considered.

Acquired Neutropenias
Infection
A large number of acquired conditions may be associated with neutropenia (Table 3). Acute neutropenia evolves
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Immune Neutropenia
Immune neutropenias are associated with the presence of circulating antineutrophil antibodies. The antibodies are

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Table 5.

Diagnostic Approach for Patients Who Have Leukopenia
Associated Clinical Diagnosis

Evaluation Initial evaluation by the generalist History of acute or chronic neutropenia General medical history Physical examination: stomatitis, gingivitis, dental defects, congenital anomalies

Spleen size History of drug exposure Complete blood count with differential and reticulocyte counts If ANC <1,000/mL Evaluation of acute-onset neutropenia Repeat blood counts in 3–4 weeks Serology and cultures for infectious agents Discontinue drug(s) associated with neutropenia Test for the presence of antineutrophil antibodies and occasionally test for antibodies to red cells and platelets Measure quantitative Igs (G, A, and M), lymphocyte subsets If ANC <500 /mL on three separate tests Bone marrow aspiration and biopsy, with cytogenetics Serial CBCs (3/week for 6 weeks) Exocrine pancreatic function Skeletal radiographs If ALC <1,000/mL Repeat blood counts in 3-4 weeks If ALC <1,000/mL on three separate tests HIV-1 antibody test Quantitative Igs (G, A, and M), lymphocyte subsets If there is pancytopenia Bone marrow aspiration and biopsy Bone marrow cytogenetics Vitamin B12 and folate levels

Congenital syndromes (Shwachman-Diamond, WiskottAldrich, Fanconi anemia, dyskeratosis congenita, glycogen storage disease type lb, disorders of vesicular transport, glucose-6-phosphate catalytic subunit 3 deficiency, immunodeficiencies Hypersplenism Drug-associated neutropenia Neutropenia, aplastic anemia, autoimmune cytopenias

Transient myelosuppression (eg, viral) Active chronic infection with viruses (eg, EBV, CMV), bacteria, mycobacteria, rickettsia Drug-associated neutropenia Autoimmune neutropenia, Evans syndrome Neutropenia associated with disorders of immune function Severe congenital neutropenia, cyclic neutropenia, Shwachman-Diamond syndrome, myelokathexis; chronic or benign or idiopathic neutropenia Cyclic neutropenia Shwachman-Diamond syndrome Shwachman-Diamond syndrome, cartilage-hair hypoplasia, Fanconi anemia Transient leukopenia (eg, viral) HIV-1 infection, AIDS Congenital or acquired disorders of immune function Bone marrow replacement by malignancy, fibrosis, granulomata, storage cells Myelodysplasia, leukemia Vitamin deficiencies

Reprinted with permission and modified from Newburger PE, Boxer LA. Leukopenia. In: Kliegman RM, Stanton BF, St Gene IW III, Schor NF, Behrman RE, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Elsevier Saunders; 2011:747. ALC¼absolute lymphocyte count; ANC¼absolute neutrophil count; CBC¼complete blood count; CMV¼cytomegalovirus; EBV¼Epstein-Barr virus; HIV¼human immunodeficiency virus; Ig¼immunoglobulin.

directed against specific neutrophil antigens genetically controlled independently of the human leukocyte antigen system. The antibodies mediate neutrophil destruction by complement-mediated lysis or splenic phagocytosis of antibody-coated neutrophils. The assays used most commonly to detect neutrophil antibodies are indirect immunofluorescence assays that identify

surface antigens on the neutrophil and microcapillary agglutination assays that evaluate the ability of the antibody to clump neutrophils. Usually a combination of immunofluorescence and microcapillary agglutination assays, along with a panel of fresh neutrophils with known antigen specificity, are used to ensure identification of the antineutrophil antibodies. Often, neutrophil
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antibodies are present at low titers or bind to neutrophilspecific antigens with low avidity. Thus, neutrophil antibody testing may require up to three attempts to achieve detection. The presence of antibodies directed against red blood cell and platelet antigens and occasionally neutrophil antigens characterize Evans syndrome. These antibodies can lead to pancytopenia. The disorder is frequently seen in common variable immunodeficiency and other immunodeficiency states. Treatment relies on administration of prednisone to improve the blood counts. Management decisions are best made under the direction of a pediatric hematologist/oncologist.

contains a reduced number of segmented neutrophils. Symptomatic treatment with antibiotics is satisfactory in most infants. Among patients treated with rhG-CSF for severe infection or for surgical preparation, neutrophil counts may be increased. When history is combined with the detection of neutrophil-specific antibodies, most patients can be diagnosed readily without stressful investigations, including the need for bone marrow aspiration. Most importantly, these infants can be immunized with live viral vaccines because the cellular immune system is intact, which includes normal T- and B-cell function.

Sequestration/Hypersplenism Alloimmune Neonatal Neutropenia
This form of neonatal neutropenia occurs after transplancental transfer of maternal alloantibodies directed against an antigen of the infant’s neutrophils. This disorder is present in 0.2% of pregnancies. (2) Prenatal sensitization induces maternal immunoglobulin G antibodies to neutrophil antigens of the fetal cells. Symptomatic infants may present with delayed separation of the umbilical cord, mild skin infections, fever, and pneumonia within the first 2 weeks after birth; these conditions resolve with antibiotic therapy. The neutropenia often is severe and associated with fever and infections due to the usual microbes that cause neonatal disease. By 7 weeks after birth, the infant’s neutrophil count generally returns to normal, reflecting the duration of survival of the maternal antibody in the infant’s circulation. Usually, treatment consists of supportive care and appropriate antibiotics for infections. If the infection is severe, rhG-CSF may be used. Splenic enlargement resulting from intrinsic splenic disease, such as storage diseases or systemic disorders that cause splenic hyperplasia arising from inflammation, neoplasia, or hemolytic anemias, can lead to neutropenia. Most often, the neutropenia is mild to moderate and is accompanied by corresponding degrees of thrombocytopenia and anemia. Cytopenias often are improved by successfully treating the underlying disease. In selected cases, splenectomy may be a necessary option to restore the neutrophil count, but this procedure results in increased risk for infections by encapsulated bacterial infections. Splenectomy should be avoided in patients who have combined variable immunodeficiency because of the high risk for predisposing the patient to sepsis.

Marrow Replacement, Cancer Chemotherapy and Radiation Effects, and Aplastic Anemia
As seen in Table 3, various acquired bone marrow disorders lead to neutropenia and are accompanied by anemia and thrombocytopenia. Hematologic malignancies and metastatic solid tumors suppress myelopoiesis by infiltrating the bone marrow. Neutropenia often accompanies myelodysplastic disorders, which are characterized by peripheral cytopenias and macrocytic blood cells. Cancer chemotherapy and radiation to the bone marrow can damage bone marrow stem cells and prevent their development into mature neutrophils, red blood cells, and platelets. Aplastic anemia can arise from T cell–mediated damage to stem cells, leading to neutropenia and other cytopenias. Management of acquired transient neutropenia associated with malignancies, chemotherapy, or immunosuppressive chemotherapy requires prompt attention to the treatment of infections with broad-spectrum antibiotics to cover S aureus and Pseudomonas aeruginosa. Frequently, the infections are heralded only by fever, and sepsis can cause early death. Empiric treatment of fever

Autoimmune Neutropenia of Infancy
Primary autoimmune neutropenia (AIN) is observed most commonly in infants and is caused by granulocyte-specific autoantibodies. In many patients, AIN is diagnosed only after an expensive and burdening investigation and unnecessary treatment with rhG-CSF, as AIN is not well known among physicians. Primary AIN is diagnosed typically in infants between the ages of 5 and 15 months. In 90% of infants, AIN is not associated with an increased risk of repeated pyogenic infections, even in the presence of severe neutropenia. Previously, many of these patients were categorized as having chronic benign neutropenia of childhood. Typically, 95% of infants undergo spontaneous remission within 7 to 30 months. Often, screening must be repeated for antibodies several times until the antibodies are detected, because they are not always observed in the serum. The bone marrow typically is normocellular or hypercellular and usually
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with broad-spectrum antibiotics is imperative, even before the results of blood cultures are known.

Ineffective Myelopoiesis
Ineffective myelopoiesis may result from congenital or acquired vitamin B12 or folic acid deficiency. Although vitamin deficiencies are rare in pediatrics, neutropenia may appear in an infant who has starvation or marasmus and in adolescents who have anorexia nervosa or have experienced extended use of antibiotics, such as trimethoprimsulfamethoxazole, which can lead to folate deficiency.

Intrinsic Disorders of Myeloid Cell Maturation and Proliferation
The intrinsic disorders of proliferation and maturation of myeloid stem cells are rare (Table 4). Affected patients frequently benefit from rhG-CSF therapy. Congenital disorders that have severe neutropenia as a clinical feature include severe combined immunodeficiency syndromes, hyper–immunoglobulin M syndrome, common variable immunodeficiencies, glycogen storage disease type 1b, SDS, cyclic neutropenia, and severe congenital neutropenia.

tract. Cyclic neutropenia frequently is called cyclic hematopoiesis because of the cycling of other blood cells, such as platelets, reticulocytes, and monocytes. Cyclic neutropenia is diagnosed by obtaining blood counts two to three times a week for 2 months. The requirement for repeated blood counts is necessary because some of the elastase mutations overlap with those in patients who have severe congenital neutropenia. The diagnosis can be confirmed with molecular genetic studies demonstrating mutations in the elastase gene. Affected patients are treated with daily rhG-CSF, and their cycle of profound neutropenia changes from a 21-day interval to a 9- to 11-day interval with 1 day of profound neutropenia. Such patients no longer are at risk for fatal infections with Clostridia or Gram-negative organisms, and antibiotic use associated with inflammatory disease is diminished. (3)

Severe Congenital Neutropenia
Severe congenital neutropenia (SCN) is characterized by an arrest in myeloid maturation at the promyelocyte stage of the bone marrow, resulting in an ANC of less than 0.2 Â 109/L on at least three separate occasions over a 1-month period. The disorder occurs with a frequency of 1 per 1 million. This condition is inherited both as an autosomal dominant disorder, which is associated with mutation in the elastase gene in 60% of patients, and as an autosomal recessive disorder in consanguineous populations. The autosomal recessive disorder is commonly called Kostmann disease. Many other genetic causes of congenital neutropenia disorders have been identified (Table 4). Patients who have SCN experience a predictable pattern of infection and inflammation. Mouth ulcers, gingivitis, otitis media, respiratory infections, cellulitis, and skin abscesses are the most common conditions. Pneumonia and deep tissue abscesses occur frequently and are life-threatening. The onset of mouth ulcers and gingivitis, the most common finding, occurs in early childhood. Mild hepatosplenomegaly is common. Peripheral blood eosinophilia and monocytosis and a bone marrow test result demonstrating arrest of myeloid cell maturation at the promyelocyte stage are associated with profound neutropenia. The observed “maturational arrest” in the bone marrow differentiates SCN from idiopathic and immune neutropenia. The platelet count often is mildly elevated, and patients have anemia associated with chronic inflammatory disease. In the past, two-thirds of patients died of fatal infections before reaching adolescence. rhG-CSF has had a major impact on the management and outcomes of SCN in that morbidity and mortality from infectious complications have been significantly diminished. (3)
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Cyclic Neutropenia
Cyclic neutropenia is a rare congenital granulopoietic disorder. The mode of inheritance is autosomal dominant, and the disorder is characterized by regular, periodic oscillations, with the number of peripheral neutrophils ranging from normal to neutropenic values. The nadir of the neutropenia count is accompanied by an elevated monocyte count. The reciprocity between the neutrophil and monocyte counts allows for differentiation from idiopathic neutropenia, in which such a relationship does not exist. The mean oscillatory period of the cycle is 21 days (–4 days) of profound neutropenia. The estimated frequency of this condition is w0.6 per 1 million. Cyclic neutropenia arises from a mutation in the neutrophil elastase gene. Patients may experience oral ulcers, stomatitis, or cutaneous infections associated with lymph node enlargement during the neutropenic phase. Occasionally, patients develop severe abdominal pain from different intestinal lesions. Serious infections occur occasionally and may lead to pneumonia or recurrent ulcerations in the oral, vaginal, and rectal mucosa. Approximately 10% of patients who had cyclic neutropenia before the availability of rhG-CSF developed fatal Clostridium perfringens or Gram-negative infection, likely arising from dissemination of organisms from ulcers or translocation of bacteria from the gastrointestinal

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Before the availability of rhG-CSF, leukemic transformation occurred in some surviving patients diagnosed as having SCN and SDS. After many years of clinical use of rhG-CSF, it has been documented that w10% to 20% of patients who are diagnosed as having SCN develop myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), which appears independently from rhG-CSF use. The onset of MDS can be insidious, with patients developing thrombocytopenia, anemia, or a change in the dose of rhG-CSF required to maintain the target ANC. Cytogenetic analysis of unstimulated bone marrow cells frequently documents loss of the entire chromosome 7 homolog (monosomy 7) or a partial deletion involving the long arm. Some patients have trisomy 21. Activating ras oncogene mutations have been identified retrospectively in patients who developed MDS/AML. At the minimum, CBCs with differential counts every 3 months and annual bone marrow aspirations with cytogenetic evaluation should be performed to adequately manage patients who have severe congenital neutropenia. It is important to differentiate cyclic neutropenia from severe congenital neutropenia. Patients who have cyclic neutropenia are not at risk for leukemia and do not require annual bone marrow studies. Currently, more than 95% of patients who have SCN respond to rhG-CSF. The 5% of patients who do not respond to rhG-CSF with a sufficient increase in ANC should be considered as candidates for stem cell transplantation from a human leukocyte antigen–identical sibling or a matched unrelated donor. Additional scenarios that prompt consideration for stem cell transplantation include the requirement for high (greater than 8 mg/kg) rhG-CSF doses to maintain an adequate neutrophil count; detection of a cytogenetic abnormality or MDS on bone marrow evaluation; and, in rare instances, select gene mutations known to be associated with a high rate of leukemic conversion. For patients who have SCN and MDS/AML, traditional chemotherapy is ineffective and associated with high mortality. Stem cell transplantation has proven to be the only successful treatment once patients who have SCN convert to MDS/AML. Therapy for fever in severe chronic neutropenia is dictated by the clinical manifestations and the degree of neutropenia. Superficial infections in children who have mild to moderate neutropenia may be treated with appropriate oral antibiotics. Patients who have neutropenia with an ANC of less than 0.5 Â 109/L and fevers higher than 38°C should be hospitalized and receive broad-spectrum intravenous antibiotics. Management of acquired transient neutropenia associated with malignancies, chemotherapy, or immunosuppressive chemotherapy requires prompt attention to the
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treatment of infections with broad-spectrum antibiotics to cover S aureus and P aeruginosa. Frequently, the infections are heralded only by fever, and sepsis is a cause of early death. Empiric treatment of fever with broad-spectrum antibiotics is imperative even before the results of blood cultures are known.

Summary
• Patients presenting with recurrent fevers, mouth ulcers, and gingivitis should be evaluated for neutropenia. • Neutropenia can be defined as mild when the absolute neutrophil count (ANC) is 1.0 to 1.5 3 103/mL (1.0– 1.5 3 109/L), moderate when the ANC is 0.5 to 1.0 3 103/mL (0.5–1.0 3 109/L), and severe when the ANC is less than 0.5 3103/mL (0.5 3 109/L). • The most commonly encountered causes of neutropenia in childhood are viral-induced neutropenia and immune-mediated neutropenia. • Patients who have disorders of neutrophil production and release from the bone marrow carry a greater risk of bacterial infection than patients who have peripheral neutropenia associated with a normal bone marrow because the bone marrow is not able to produce new neutrophils sufficiently in times of need (ie, infection). • Patients receiving immunosuppressive therapy (eg, chemotherapy) are at significantly higher risk for serious bacterial infection compared with those who have isolated neutropenia due to the compounding T-cell and B-cell dysfunction. • The use of recombinant human granulocyte colonystimulating factor in the management of cyclic neutropenia and severe congenital neutropenia has dramatically decreased clinical symptoms and has decreased mortality from infectious causes.

References
1. Dale DC, Cottle TE, Fier CJ, et al. Severe chronic neutropenia:
treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol. 2003;72(2): 82–93 2. Levine DH, Madyastha PR. Isoimmune neonatal neutropenia. Am J Perinatol. 1986;3(3):231–233 3. Dale DC, Bonilla MA, Davis MW, et al. A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia. Blood. 1993;81(10):2496–2502

Suggested Reading
Andrès E, Zimmer J, Mecili M, Weitten T, Alt M, Maloisel F. Clinical presentation and management of drug-induced agranulocytosis. Expert Rev Hematol. 2011;4(2):143–151

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hematology/oncology neutropenia

Boxer LA, Newburger PE. A molecular classification of congenital neutropenia syndromes. Pediatr Blood Cancer. 2007;49(5): 609–614 Dale DC, Person RE, Bolyard AA, et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood. 2000;96(7):2317–2322 Donadieu J, Fenneteau O, Beaupain B, Mahlaoui N, Chantelot CB. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis. 2011;6:26 Fioredda F, Calvillo M, Bonanomi S, et al. Congenital and acquired neutropenias consensus guidelines on therapy and follow-up in childhood from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica). Am J Hematol. 2011;57:10–17 Grann VR, Ziv E, Joseph CK, et al. Duffy (Fy), DARC, and neutropenia among women from the United States,

Europe and the Caribbean. Br J Haematol. 2008;143(2): 288–293 Klein C. Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes. Annu Rev Immunol. 2011;29:399–413 Levine DH, Madyastha PR. Isoimmune neonatal neutropenia. Am J Perinatol. 1986;3(3):231–233 Newburger PE, Boxer LA. Leukopenia. In: Kliegman RM, Stanton BF, St Gene IW III, Schor NF, Behrman RE, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Elsevier Saunders; 2011:746–751 Newburger PE, Pindyck TN, Zhu Z, et al. Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE mutation and paternal haplotype: evidence for phenotype determination by modifying genes. Pediatr Blood Cancer. 2010;55(2):314–317

PIR Quiz
This quiz is available online at http://www.pedsinreview.aappublications.org. NOTE: Learners can take Pediatrics in Review quizzes and claim credit online only. No paper answer form will be printed in the journal.

New Minimum Performance Level Requirements
Per the 2010 revision of the American Medical Association (AMA) Physician’s Recognition Award (PRA) and credit system, a minimum performance level must be established on enduring material and journal-based CME activities that are certified for AMA PRA Category 1 CreditTM. In order to successfully complete 2013 Pediatrics in Review articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of 60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity. In Pediatrics in Review, AMA PRA Category 1 CreditTM may be claimed only if 60% or more of the questions are answered correctly. If you score less than 60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved.

1. A previously well 2-year-old white boy has had a fever for 2 days. He has had no other symptoms. His examination is normal. An emergency department physician orders a complete blood count and differential with the following results: white blood cell count, 4,326/mm3 (4.326 3 109/L); neutrophils, 10%; bands, 1%; lymphocytes, 78%; monocytes, 7%; eosinophils, 2%; and basophils, 2%. This patient has: A. A normal neutrophil count B. Lymphopenia C. Mild neutropenia D. Moderate neutropenia E. Severe neutropenia 2. Which finding usually associated with inflammation is most likely to be absent in a severely neutropenic 3year-old girl with a community-acquired methicillin-resistant Staphylococcus aureus infection of her forearm? A. Abscess formation B. Erythema C. Fever D. Tenderness E. Warmth

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3. Which of the following infants is most likely to have an underlying condition associated with clinically significant neutropenia? A 6-month-old boy with a history of: A. B. C. D. E. A single bout of enterococcal urinary tract infection A single bout of enteroviral meningitis A single bout of S aureus septic arthritis Recurrent aphthous ulcers Recurrent wheezing

4. Which of the following patients who has severe neutropenia will have the best outcome without treatment? A 12-month-old girl: A. B. C. D. E. Receiving chemotherapy for acute lymphoblastic leukemia Who has autoimmune neutropenia of infancy With cyclic neutropenia With Kostmann disease With Shwachman-Diamond syndrome

5. Recombinant human granulocyte colony-stimulating factor is most effective in correcting the neutropenia of patients who have: A. Autoimmune neutropenia of infancy B. Myelodysplastic syndrome/acute myelogenous leukemia C. Sequestration/hypersplenism D. Severe congenital neutropenia E. Severe influenza infections

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visual diagnosis

Obese 11-month-old Female With Round Facies
Nancy L. Beck, MD,* Alba E. Morales, MD,† R.F. Buchmann, DO,‡ R.J. Birusingh, DOx

Case Presentation
An 11-month-old girl presents to the clinic for a mild respiratory illness. Her parents also voice concern about their daughter’s appearance and offer a photograph of her taken at age 9 months (Fig 1). Both parents are slim and healthy. On examination, the infant is noted to have a round face, generalized fine body hair, acne, and central obesity (Fig 2). She currently weighs 9.6 kg (50th percentile for age), her length is 69 cm (10th percentile), and her head circumference is 43 cm (10th percentile). She was born by uncomplicated vaginal delivery having a birthweight of 3.125 kg (25th percentile) and a length of 48 cm (75th percentile). Review of the girl’s growth curves reveals the absence of linear growth during the previous month (Fig 3). The child’s vital signs are normal for her age. She has mild nasal congestion. Her genitalia appear normal, but her neurologic examination shows delayed gross motor skills. She is able to pull to stand but does not cruise or walk. Based on a suspected diagnosis, the patient undergoes several laboratory examinations.

Figure 1. The patient at age 9 months.

Author Disclosure Drs Beck, Morales, Buchmann, and Birusingh have disclosed no financial relationships relevant to this article. This commentary does contain a discussion of an unapproved/ investigative use of a commercial product/device. The editors and staff have been gratified by the large number of submissions by readers from all over the world to the Visual Diagnosis column. At the present time, the journal has so many cases in production that we cannot accept new manuscripts for awhile. We will indicate in the journal when readers can resume sending offers to write cases and discussions.

Figure 2. The patient at age 11 months.

*Assistant Professor, Division of Endocrinology, Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, TX. † Associate Professor, Division of Diabetes and Endocrine, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR. ‡ Assistant Professor, Radiology and Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR. x Assistant Professor, Pediatric Pathology, University of Arkansas for Medical Sciences, Little Rock, AR.

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Figure 3. Growth chart reveals cessation of linear growth.
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visual diagnosis

Diagnosis: Cushing Syndrome Due to an Adrenal Adenoma
Midnight salivary cortisol levels were 29.2 nmol/L (reference <0.3–4.3) and 33.4 nmol/L on consecutive nights. An overnight dexamethasone (0.3 mg/m2) suppression test revealed an 8 AM serum cortisol level of 25.4 mg/dL (701 nmol/L) (reference <3 mg/dL or 83 nmol/L). The plasma cortisol concentration at 4 PM was 29.4 mg/dL (811 nmol/L). The results of renal and thyroid function tests were normal. Serum corticotropin levels obtained on two occasions were undetectable. The combination of poor growth and abnormal cortisol production, with undetectable corticotropin levels, prompted imaging studies of the adrenal glands. Abdominal magnetic resonance imaging (MRI) (Fig 4) demonstrated a 5.2 Â 4.8 Â 3.9 cm mass in the left retroperitoneum in close association with the tail of the pancreas, but the exact organ of origin was difficult to determine. Surgical resection and pathologic examination revealed an adrenal adenoma.

The differential diagnosis for CS in the pediatric age group includes obesity primarily. Although CS is rare, obesity is becoming increasingly more commonplace in the pediatric population. Thus, pediatricians face the challenge of differentiating between conventional obesity and CS, with the objective of refraining from an unnecessarily extensive evaluation of an obese patient while not missing a diagnosis of CS. The least invasive screen for CS is cessation of linear growth, which is virtually always present.

Pathophysiology
The clinical features are related to excess glucocorticoid distribution in the affected individual. The most common cause of CS, in both children and adults, is protracted use of topical, inhaled, or oral corticosteroids. Childhood CS of endogenous origin most commonly is caused by pituitary or adrenocortical tumors. Two useful approaches to determining the source of endogenous hypercortisolism are: 1. Differentiating corticotropin-independent CS from corticotropin-dependent CS. 2. Determining the most likely causes based on the age of the patient. Corticotropin-dependent causes of CS include: 1. Cushing disease, which derives from a corticotropinsecreting pituitary adenoma. 2. Ectopic corticotropin syndrome, which almost invariably coincides with neoplastic disease and is extremely rare in childhood. Corticotropin-independent causes of CS are: 1. Exogenous glucocorticoids. 2. Adrenocortical adenoma or carcinoma. 3. Disorders of primary adrenocortical hyperplasia: a. Primary pigmented adrenocortical disease b. Corticotropin-independent macronodular adrenal hyperplasia, and c. McCune-Albright syndrome Likely causes include the following disorders, based on age:

Discussion
Cushing syndrome (CS) in childhood and adolescence is rare. “Cushing syndrome ” refers to glucocorticoid excess of any origin. “ Cushing disease ” speci fi cally pertains to excessive production of corticotropin by the pituitary gland, resulting in overstimulation of the adrenal gland and resultant excess cortisol production. The stereotypical features of CS seen in adults usually are not present initially in children; instead, growth arrest and BMI increase are almost universally present. Additional symptoms and signs, which may or may not be present, include acne; purple striae; hirsutism; virilization; lethargy or depression with emotional lability; headache; hypertension; myopathy; osteoporosis; a “buffalo hump,” which is a dorsocervical fat pad; easy bruising; and facial fullness. Untreated CS may lead to severe short stature, glucose intolerance or diabetes mellitus, severe osteoporosis, psychiatric abnormalities (depression, psychosis, anxiety), gonadal dysfunction, skin abnormalities, dyslipidemia, cataracts, brain atrophy, and recurrent infections due to immune suppression. Serial photographs can provide visual documentation of the progression of changes in appearance consistent with CS.

Infancy
CS in infancy often is associated with McCune-Albright syndrome, resulting from sporadic mutations of the GNAS1 gene. This gene encodes the a-subunit of the G protein found on receptors present in various
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visual diagnosis

puberty, pituitary gigantism or acromegaly, or any combination of these.

Age £4 Years
Adrenocortical tumors should be considered. The incidence is highest in children under age 4 years. These tumors are rare in the pediatric population in general but appear to be most prevalent in Brazil.

Age ‡5 Years (mean age of presentation, 13–14 years)
Cushing disease represents approximately 80% of pediatric CS. The disorder almost never is seen in children younger than age 6 years. Cushing disease occurs predominantly in boys before puberty, and in girls after puberty. Pituitary microadenomas vastly outnumber macroadenomas.

Figure 4. Coronal T1-weighted image (left) of the abdomen and pelvis demonstrates a well-defined 5.0-cm oval mass (arrows) in the left retroperitoneum. Axial fatsuppressed T2-weighted image (right) demonstrates the 5.0-cm oval mass (white arrows) with intermediate to high signal intensity. The mass occupies the left retroperitoneum and displaces the left kidney (brown arrow) posteriorly.

tissues. The mutation causes permanent activation of the receptor and, consequently, autonomous hyperfunctioning of endocrine organs, which may result in hyperthyroidism, CS, gonadotropin-independent precocious

Teenage Years and Early Adulthood (mean age of diagnosis, 20 years)
Primary pigmented adrenocortical disease, also known as micronodular adrenal disease, should be in the differential. Diagnosis is based upon the finding of numerous small adrenocortical nodules, with intervening atrophic adrenal cortex. This is a rare disorder in all ages.

Differential Diagnosis
Childhood obesity and CS may present with overlapping signs and symptoms. However, children who have CS will have almost complete lack of linear growth, which can appear pronounced on a growth chart plot. Children who have “uncomplicated” obesity will be tall for age. Bone age usually is delayed in individuals who have CS and frequently is advanced in childhood obesity.

Laboratory Examination
To confirm endogenous CS, confirmation of hypercortisolism is necessary. The following studies are employed: 1. 24-hour urinary free cortisol excretion. This test is the gold standard for confirming hypercortisolism but should be repeated two or three times to be certain of the results. Normal levels are less than 70 mg/m2 per day (1,931 nmol/L) for boys and less than 31.9 mg/m2 per day (880 nmol/L) for girls. Levels above

Figure 5. Gross photograph of adrenal adenoma. Cut section

shows a yellow, slightly lobulated appearance.
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visual diagnosis

Figure 6. Low-power magnification view showing a thick

capsule (hematoxylin and eosin, magnification 32).

the normal values merit further evaluation, and levels more than four times the normal value are considered unequivocally diagnostic. 2. Midnight plasma and salivary cortisol levels. Based on circadian rhythm, cortisol reaches its peak values at approximately 6 to 8 AM and its nadir at approximately midnight. In patients who have CS, cortisol secretion remains elevated throughout the 24-hour period. Various studies have found plasma cutoff levels from more than or equal to 1.8 to more than or equal to 7.2 mg/dL (50–199 nmol/L) to be diagnostic of CS. Midnight sleeping plasma cortisol has the greatest sensitivity of all tests for CS in children. This

Figure 8. Age 15 months (2 months after surgery).

Figure 7. High-power magnification view highlighting two morphological types of cells. One has a pale staining cytoplasm (center of field), and the other has a deeper, eosinophilic staining cytoplasm (upper right-hand corner) (hematoxylin and eosin, magnification 320).

procedure requires hospitalization and placement of an indwelling catheter. Midnight salivary cortisol testing is as sensitive a test as the plasma cortisol test; cutoff values of approximately 0.3 mg/dL (8.3 nmol/L) provide diagnostic accuracy comparable to that of midnight plasma cortisol and urinary free cortisol determinations. 3. Low-dose dexamethasone suppression test. A dose of 0.5 mg dexamethasone is given orally every 6 hours for 48 hours total. Plasma cortisol is measured at baseline and 48 hours after the first dose. Plasma cortisol should be undetectable (<50 nmol/L or <2 mg/dL) at 48 hours. 4. One milligram overnight dexamethasone suppression test. One milligram (or 15 mg/kg body weight in children) of dexamethasone is administered at 11 PM, and a plasma cortisol level is measured at 8 AM the following morning. A normal (suppressed) cortisol level after dexamethasone is less than 2 mg/dL or less than 55 nmol/L; concentrations more than 10 mg/dL (276 nmol/L) are strongly suggestive of CS; and values between 2 and 10 mg/dL (55–276 nmol/L) are considered equivocal. This test has a false-positive rate of 15% to 20%, with sensitivity as low as 55%, so results must be interpreted cautiously. Once the diagnosis of CS has been established, differentiation between corticotropin-dependent and corticotropin-independent conditions should be made.
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Management
In patients who have CS due to exposure to exogenous steroids, symptoms will resolve after withdrawal or reduction of corticosteroid dose. For adrenocortical tumors, surgical excision should be performed. Glucocorticoid replacement is required preand postoperatively because of suppression of the contralateral adrenal gland. Treatment for primary pigmented adrenocortical disease (micronodular adrenal disease) is bilateral adrenalectomy. First-line therapy for Cushing disease is transsphenoidal pituitary surgery to remove the microadenoma, while retaining the normal pituitary tissue. Hypopituitarism is a possible complication. If surgery is unsuccessful in returning cortisol levels to normal, pituitary radiation may be used as a secondary therapy.

Patient Course
Based on the clinical and laboratory findings, the patient was diagnosed as having CS. Surgery revealed a unilateral, intact encapsulated tumor (Figs 5 and 6). Pathologic analysis of the tumor revealed a benign adrenal adenoma (Fig 7). Two days after surgery, the 8 AM cortisol level was within normal limits. She was discharged on a physiologic dose of hydrocortisone, which was later discontinued. At age 15 months (Fig 8), her cortisol level was normal. Her weight had decreased by 0.3 kg; her growth velocity was 12 cm/year (normal). At age 2 years, her cushingoid features had resolved (Fig 9), her gross motor skills were appropriate for age, and she continued to have appropriate growth and development. Her pediatrician and an endocrinologist follow her progress.

Figure 9. At age 2 years, with growth normalization.

Measurement of a morning corticotropin level is the initial test. Undetectable levels of corticotropin are found in patients who have adrenocortical tumors or nodular adrenal hyperplasia. The finding of undetectable corticotropin levels should prompt computed tomography or MRI examination of the adrenal gland to locate adrenocortical tumors or nodularity. Detectable levels of corticotropin are found in Cushing disease and ectopic corticotropin syndrome. A corticotropin-releasing hormone stimulation test consists of administration of 1 mg/kg or 100 mg intravenously, and provokes an increase of more than 35% in plasma corticotropin or cortisol levels from baseline in patients who have Cushing disease, but no response in patients who have ectopic corticotropin secretion. After biochemical testing indicates Cushing disease, pituitary MRI should be performed in an attempt to localize the position of an adenoma. However, most pediatric corticotropin-secreting pituitary tumors are microadenomas, which often do not enhance on MRI. In these cases, bilateral inferior petrosal sinus sampling for corticotropin is performed. This technique is used to predict the site of the microadenoma before surgery.
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Summary
• Cushing syndrome (CS) is a constellation of findings caused by an excess of cortisol. • The most common cause of CS is exogenous corticosteroid administration. • Cushing disease is hypercortisolemia specifically due to excess corticotropin production by the pituitary gland. • Cessation of linear growth is nearly always present in CS, whereas children who have other causes of obesity usually have normal or advanced progression of height. • Diagnostic approaches include determination of likely causes by patient age and determining whether the disorder is corticotropin-dependent. • Prognosis and treatment are dependent on the cause of CS.

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Suggested Reading
Batista DL, Riar J, Keil M, Stratakis CA. Diagnostic tests for children who are referred for the investigation of Cushing syndrome. Pediatrics. 2007;120(3):e575–e586 Chan LF, Storr HL, Grossman AB, Savage MO. Pediatric Cushing’s syndrome: clinical features, diagnosis, and treatment. Arq Bras Endocrinol Metabol. 2007;51(8):1261–1271

Savage MO, Chan LF, Grossman AB, Storr HL. Work-up and management of paediatric Cushing’s syndrome. Curr Opin Endocrinol Diabetes Obes. 2008;15(4):346–351 Storr HL, Chan LF, Grossman AB, Savage MO. Paediatric Cushing’s syndrome: epidemiology, investigation and therapeutic advances. Trends Endocrinol Metab. 2007;18(4): 167–174

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index of suspicion

Case 1: Fatigue, Weakness, Body Aches, and Metabolic Alkalosis in a 15-year-old Boy Case 2: Refractory Hypotension, Tachycardia, Hyperglycemia, and Metabolic Acidosis in an Afebrile Teen
Case 1
The reader is encouraged to write possible diagnoses for each case before turning to the discussion.

Presentation

The editors and staff of Pediatrics in Review find themselves in the fortunate position of having too many submissions for the Index of Suspicion column. Our publication slots for Index of Suspicion are filled through 2013. Because we do not think it is fair to delay publication longer than that, we have decided not to accept new cases for the present. We will make an announcement in Pediatrics in Review when we resume accepting new cases. We apologize for having to take this step, but we wish to be fair to all authors. We are grateful for your interest in the journal.

A 15-year-old boy presents with a 4-day history of fatigue, intermittent mild headache, and a 1-day history of generalized weakness, body aches, sleepiness, dizziness, and three episodes of nonbilious, nonbloody emesis. He denies cough, shortness of breath, palpitations, or chest pain, as well as abdominal pain, joint pain, rash, vision changes, weight loss, polyuria, polydipsia, or change in urine color. He currently takes methylphenidate for attention-deficit/ hyperactivity disorder and sertraline for depression. He denies any overthe-counter or illicit drug use. Physical examination reveals a well-developed, tired-appearing adolescent. His temperature is 100.6°F with otherwise normal vital signs,

Frequently Used Abbreviations:
ALT: AST: BUN: CBC: CNS: CSF: CT: ECG: ED: EEG: ESR: GI: GU: Hct: Hgb: MRI: WBC: alanine aminotransferase aspartate aminotransferase blood urea nitrogen complete blood count central nervous system cerebrospinal fluid computed tomography electrocardiography emergency department electroencephalography erythrocyte sedimentation rate gastrointestinal genitourinary hematocrit hemoglobin magnetic resonance imaging white blood cell

including blood pressure. Physical examination of the heart, lungs, and abdomen are within normal limits. His proximal muscle strength is 4 of 5; the rest of his neurologic examination is within normal limits. Initial laboratory examination includes the following levels: sodium, 133 mmol/L; potassium, 2.4 mmol/L; chloride, 90 mmol/L; bicarbonate, 30 mmol/L; BUN, 9 mg/dL; creatinine, 0.5 mg/dL; glucose, 103 mg/dL; calcium, 9.4 mg/dL; magnesium, 2.0 mg/dL;and phosphorus, 4.3 mg/dL. CBCs, liver function test results, and hepatic enzyme levels are normal. ECG shows a prolonged QT interval at 550 milliseconds. On admission, the patient receives a potassium bolus, followed by maintenance intravenous (IV) fluids containing potassium chloride. He has no vomiting or diarrhea on his first hospital day. A follow-up laboratory examination of his chemistry studies shows persistence of his initial abnormalities.

Author Disclosure Drs Bhatia, McDonald, Tiyyagura and Kondrich have disclosed no financial relationships relevant to this article. This commentary does not contain discussion of unapproved/ investigative use of a commercial product/device.

Case 2

Presentation

A 19-year-old female presents to the ED 3 hours after intentional ingestion of an unknown substance. On initial presentation, she is afebrile, with a blood pressure of 100/59 mm Hg, respiratory rate of 20 breaths per minute, heart rate of 110 beats per minute, and oxygen saturation of 99% on room air. She is alert, oriented, and conversational. Within 20 minutes of arrival to the ED, her blood pressure drops to 61/ 24 mm Hg, for which she receives

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index of suspicion

a total of 8 L of normal saline. An ECG shows sinus tachycardia but no other abnormalities. Initial CBC, basic metabolic panel, hepatic function panel, and levels of amylase, lipase, salicylate, and acetaminophen are all within normal limits. Serum b-human chorionic gonadotropin measurement is negative. Urine toxicology screen is negative for benzodiazepines, opioids, cocaine, phencyclidine, and barbiturates. Despite repeated fluid boluses over the next 4 hours, the girl remains hypotensive but awake and alert. Several doses of activated charcoal are administered. She then begins to complain of a closing sensation in her throat, and her voice grows hoarse. On examination, her lips have become edematous, and she has a swollen uvula. She receives epinephrine intramuscularly, diphenhydramine intravenously, and hydrocortisone intravenously. She is then intubated and started on a norepinephrine drip. At this point, she is transferred to the PICU, and additional history reveals the source of her presentation.

urine electrolytes demonstrate high levels of potassium and chloride despite low serum levels. In children who have metabolic alkalosis with chloride loss secondary to vomiting or diarrhea, the urine chloride concentration should be low because of chloride retention. The clinical picture of elevated urine chloride in conjunction with a hypochloremic metabolic alkalosis suggests either ongoing diuretic therapy or a renal tubular disorder mimicking diuretic therapy, which would include diseases such as Bartter syndrome and Gitelman syndrome. Both of these conditions have hyperreninemiaand hyperaldosteronism-associated hypokalemia. However, this patient’s overall clinical presentation, including age of presentation, normal growth and development, and hypocalciuria, make Gitelman syndrome the more likely diagnosis.

Bartter syndrome. The spectrum of symptoms ranges from being asymptomatic to the extremes of tetany and rhabdomyolysis. These symptoms do not seem to correlate with the degree of hypokalemia. Gitelman syndrome is characterized by hypokalemia and metabolic alkalosis. These patients have hyperreninemia and hyperaldosteronemia but are not hypertensive. Serum calcium levels are normal, with low or normal serum magnesium levels. In Gitelman syndrome, a low urinary calcium level is a hallmark, compared with patients who have Bartter syndrome, in whom hypercalciuria predisposes to nephrocalcinosis.

Pathogenesis
The pathophysiology in Gitelman syndrome is a loss of function of the thiazide-sensitive sodium chloride cotransporter (TSC) located in the distal convoluted tubule, which leads to defective sodium and chloride reabsorption. Bartter syndrome is caused by a mutation affecting the Na-K-2Cl cotransporter in the loop of Henle. These mutations mimic the physiology seen in patients taking thiazide and loop diuretics. In Gitelman syndrome, the impaired reabsorption of sodium and chloride at the TSC effectively leads to some degree of hypovolemia. Hypovolemia in turn activates the renin-angiotensin system, ultimately increasing levels of aldosterone to maintain intravascular volume. The increase in aldosterone results in hypokalemia and metabolic alkalosis, as potassium and hydrogen ions are excreted in exchange for sodium. Despite the upregulation of the reninangiotensin system, children who have Gitelman syndrome have normal or low blood pressure. Filtered calcium reabsorption is coupled to the Na-K-Cl channel, which is dysfunctional in Bartter syndrome. In
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The Condition
Gitelman syndrome is one of two rare inherited forms of hypokalemichypochloremic metabolic alkalosis caused by disorders of the renal tubular electrolyte transport. The other is Bartter syndrome, which has a similar presentation and overlapping physiology. The inheritance pattern in children born with Gitelman syndrome is autosomal recessive but may be sporadic. The prevalence is difficult to assess but is estimated to be 1:40,000. There is no ethnic or gender predilection. Gitelman syndrome presents typically in adolescence and early adulthood. The most common presenting symptoms in patients who have Gitelman syndrome are salt craving, musculoskeletal complaints such as muscle weakness and cramps, and constitutional complaints such as fatigue and dizziness. Notably absent are the features of polydipsia, polyuria, and growth retardation seen in

Case 1

Discussion

This child had an initial laboratory evaluation hallmarked by a hyponatremic, hypokalemic, hypochloremic metabolic alkalosis that persisted despite normal saline infusion and potassium correction. Furthermore, he denied GI losses or diuretic use. In addition, he was not hypertensive, as would be expected in primary hyperaldosteronism. Because of the unexplained hypokalemic metabolic alkalosis, ongoing renal loss was suspected, and spot urine electrolyte testing revealed the following: sodium, 193 mmol/L; potassium, 61 mmol/L; chloride, 272 mmol/L; and calcium, 0.5 mg/dL. These

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index of suspicion

Bartter syndrome, this impaired reabsorption leads to urinary calcium wasting and hyercalciuria, in contrast with Gitelman syndrome, in which marked hypocalciuria occurs. Lastly, hypermagnesiuria leading to hypomagnesemia is often seen in Gitelman syndrome, but the pathophysiologic mechanism is unclear.

Treatment
The treatment of Gitelman syndrome is geared toward correcting hypokalemia and hypomagnesemia if needed. Patients benefit from oral magnesium and a potassium-sparing diuretic such as amiloride or spironolactone to counteract distal tubular potassium secretion.

grandfather’s amlodipine tablets (10 mg each) after learning that her boyfriend was unfaithful. In the PICU, she developed hyperglycemia and worsening metabolic acidosis. Her symptoms of refractory hypotension, angioedema, hyperglycemia, and metabolic acidosis were consistent with calcium channel blocker (CCB) toxicity. She received treatment and improved slowly.

Pathophysiology
Calcium plays an important role in intracellular signaling. In the myocardium, it enters via L-type calcium channels and affects excitation– contraction coupling. In sinoatrial tissue, it functions in action potential generation. In vascular smooth muscle, calcium is important in maintaining tone. The dihydropyridines, such as amlodipine and nifedipine, primarily block the vascular smooth muscle L-type calcium channels and are strong vasodilators that have little negative inotropic or conduction effects on the myocardium. In contrast, nondihydropyridines, such as verapamil and diltiazem, preferentially block the L-type calcium channels in the myocardium, and thus are weak vasodilators but have a strong negative effect on cardiac conduction and contractility. The selectivity can be lost as the dose of either type of CCB is increased. CCBs also block L-type calcium channels in the pancreas, preventing the release of insulin. In addition, they can cause insulin resistance, leading to hyperglycemia, but with impaired cellular glucose uptake. These effects, when combined with impaired glucose delivery from decreased perfusion, cause acidosis and can worsen cardiac function. Generally, patients taking more than five to 10 times the recommended dose of a CCB will manifest symptoms of toxicity. In children

Lessons for the Clinician
• Analysis of urine electrolytes, including chloride, is essential in distinguishing the etiology of hypochloremic, hypokalemic metabolic alkalosis. • Gitelman syndrome is a rare, inheritable cause of renal tubular dysfunction at the thiazide-sensitive sodium chloride cotransporter in the distal convoluted tubule, leading to hypokalemic, hypochloremic metabolic alkalosis. • Gitelman syndrome presents in adolescence or adulthood, with a spectrum ranging from an asymptomatic state to severe fatigue and a potential for tetany and rhabdomyolysis. (Darshita Bhatia, MD, Matthew B. McDonald III, MD, St Christopher’s Hospital for Children, Philadelphia, PA)

younger than 6 years, ingestion of only one pill has resulted in severe toxicity. Most CCBs have a large volume of distribution and are primarily protein bound. CCBs are metabolized by hepatic enzymes, which can become saturated in the setting of an overdose. These factors allow large quantities of the drug to enter the circulation and amplify the clinical effects. Also, many CCBs are prepared in an extended-release formulation, prolonging the period of toxicity. Dihydropyridine toxicity results in arterial vasodilation and hypotension with reflex tachycardia, whereas nondihydropyridine toxicity causes decreased contractility, bradycardia, and conduction abnormalities. Hypoperfusion may result in altered mental status, seizures, renal failure, liver infarction, respiratory depression, and metabolic acidosis. The decline in neurologic status often is precipitous and occurs in the setting of severely decreased cerebral perfusion. Patients often maintain a surprisingly normal mental status, even with other manifestations of CCB toxicity, due to the neuroprotective nature of these agents. Angioedema and noncardiogenic pulmonary edema related to CCB toxicity have been described in case reports.

Differential Diagnosis
b-blocker toxicity commonly is in the differential diagnosis for CCB ingestion. b-blockers inhibit calcium entry into cardiac myocytes by preventing cellular signaling that leads to the opening of L-type calcium channels. Both CCBs and b-blockers ultimately prevent intracellular calcium entry and cause decreased cardiac contractility as well as decreased sinoatrial and atrioventricular node depolarization, leading to diminished cardiac output. b-blockers more commonly produce changes in mental status due

Case 2

Discussion

On the morning of presentation, this patient had ingested 20 of her
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index of suspicion

to their lipophilic nature. b-blockers also may cause hypoglycemia, whereas CCBs cause hyperglycemia. Other specific differences exist between individual drugs. Despite these differences, management of CCB or b-blocker intoxication is nearly identical.

Management
Management of CCB overdose is directed at maintenance or improvement of cardiac output and peripheral vascular tone. If CCB ingestion is suspected, the patient must undergo immediate evaluation. CCBs can cause significant morbidity and mortality with an overdose, even with normal initial vital signs. The patient should be placed on a cardiac monitor, and IV access should be obtained. If the patient is hypotensive and there is no evidence of congestive heart failure or pulmonary edema, fluid boluses of 20 mL/kg of isotonic crystalloid should be given. GI decontamination with activated charcoal given within the first two hours of ingestion is indicated to minimize systemic absorption. In the case of sustained-release CCB ingestion, whole bowel irrigation should be initiated. Although many drugs have been used to treat CCB toxicity, no single intervention has proven completely effective. Symptomatic bradycardia is treated with atropine. Administration of calcium ion (chloride or gluconate) may improve cardiac contractility and hypotension because such therapy increases the transmembrane concentration gradient

of calcium and can overcome the receptor blockade partly. Vasopressors also play an important role in the treatment of CCB lipid poisoning. These agents all provide differing stimulation of both the b1-adrenergic receptors on the myocardium or a1-adrenergic receptors on the peripheral vasculature, and the choice of sympathomimetic agent should be based on both the patient and the pharmacologic profile of the CCB type ingested. Glucagon has inotropic and chronotropic effects and has proven useful in CCB overdose. These effects are believed to be due in part to an increase in cardiac cyclic adenosine monophosphate. Phosphodiesterase inhibitors such as milrinone also increase intracellular cardiac cyclic adenosine monophosphate concentrations by preventing its breakdown. Hyperinsulinemia-euglycemia therapy, using the administration of high-dose insulin with glucose, has become a mainstay of treatment for patients who have severe CCB poisoning. CCBs both inhibit the release of insulin from the pancreas as well as force the myocardium to become dependent on carbohydrate metabolism. Insulin is believed to improve contractility by assisting the myocardium to use carbohydrate as fuel. IV emulsion also has been used as adjuvant therapy. Lipid emulsion therapy has been shown to have some benefit against poisoning from lipophilic medications but should be started after discussion with a poison control center clinician.

The most severe cases of CCB poisoning may be refractory to pharmacologic intervention and require advanced hemodynamic support, such as cardiac pacing, intra-aortic balloon pump, or extracorporeal membrane oxygenation. Every patient who manifests any signs or symptoms of CCB toxicity should be monitored in a PICU, and any patient who has a reported ingestion of a sustained release formulation should be observed for 24 hours, given the potential for delayed toxicity.

Lessons for the Clinician
• Patients who take a calcium channel blocker overdose, compared with a b-blocker overdose, are more likely to maintain a normal mental status. • Because calcium channel blockers prevent insulin release, hyperglycemia can be seen in overdose. • Ingestion of only one pill in young children has resulted in severe toxicity. (Gunjan Kamdar Tiyyagura, MD, Yale Department of Pediatric Emergency Medicine, New Haven, CT; Janienne Kondrich, MD, NYU School of Medicine, Bellevue Hospital Center, Division of Pediatric Emergency Medicine, New York, NY) To view Suggested Reading lists for these cases, visit http://pedsinreview. aappublications.org and click on “Index of Suspicion” link.

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in brief

In Brief
Bacillus cereus
Senthilkumar Sankararaman, Sujithra Velayuthan Louisiana State University Health Sciences Center, Shreveport, LA
Tokieda K, Morikawa Y, Maeyama K, Mori K, Ikeda K. Clinical manifestations of Bacillus cereus meningitis in newborn infants. J Paediatr Child Health. 1999; 35(6):582–584

Author Disclosure Drs Sankararaman and Velayuthan have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.

Bottone EJ. Bacillus cereus, a volatile human pathogen. Clin Microbiol Rev. 2010;23(2):382–398 Drobniewski FA. Bacillus cereus and related species. Clin Microbiol Rev. 1993;6(4):324–338 Gaur AH, Patrick CC, McCullers JA, et al. Bacillus cereus bacteremia and meningitis in immunocompromised children. Clin Infect Dis. 2001;32(10): 1456–1462 Hilliard NJ, Schelonka RL, Waites KB. Bacillus cereus bacteremia in a preterm neonate. J Clin Microbiol. 2003;41(7):3441–3444 Kuroki R, Kawakami K, Qin L, et al. Nosocomial bacteremia caused by biofilm-forming Bacillus cereus and Bacillus thuringiensis. Intern Med. 2009;48(10):791–796 Sasahara T, Hayashi S, Morisawa Y, et al. Bacillus cereus bacteremia outbreak due to contaminated hospital linens. Eur J Microbiol Infect Dis. 2011;30(2):219–226 Stenfors Arnesen LP, Fagerlund A, Granum PE. From soil to gut: Bacillus cereus and its food poisoning toxins. FEMS Microbiol Rev. 2008;32(4): 579–606
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Bacillus cereus is an aerobic and facultatively anaerobic, motile, spore-forming gram-positive rod. Widely distributed in the environment, including in soil, dust, air, fomites, and water, B cereus often is discarded as a saprophytic contaminant when recovered from blood and other biological specimens. Studies suggest that as many as 0.5% of all blood culture samples may be contaminated with B cereus. B cereus is well known for its role in causing self-limited gastroenteritis of two types: an emetic syndrome with a relatively short incubation period of 1 to 6 hours and a diarrheal syndrome with an incubation period of 6 to 24 hours. The emetic syndrome (commonly associated with the ingestion of fried rice contaminated with preformed emetic toxin) resembles the vomiting illness caused by Staphylococcus aureus enterotoxins, whereas the diarrheal syndrome is clinically similar to the food poisoning caused by Clostridium perfringens. These gastrointestinal (GI) manifestations usually are self-limited, and the symptoms last less than 24 hours. Over the last 3 decades, B cereus has been recognized increasingly as a cause of potentially fatal systemic infections outside the GI tract, particularly in high-risk patients, such as neonates, patients with central lines, immunocompromised individuals, injection drug users, and chronically debilitated patients. Serious systemic infections caused by B cereus include bacteremia, septicemia,

meningitis, cerebral abscess, pneumonia, and endocarditis. In vulnerable high-risk patients, prompt recognition and aggressive management of these systemic infections are required to reduce both morbidity and mortality. Localized infections with B cereus have been reported in posttraumatic wounds, surgical wounds, and burns. Ocular infections, such as panophthalmitis, endophthalmitis, and corneal abscess, also have been documented. B cereus exists in two forms: spores and vegetative cells. Natural reservoirs for B cereus include fresh and salt water sources, decaying organic material, vegetables, and fomites. When adverse conditions prevail, the bacillus sporulates and the endospores are highly resistant to harsh environmental conditions. Common methods of decontamination, such as heating, desiccation, chemical exposure, and radiation, do not destroy the spores. Furthermore, alcohol-based hand sanitizers used in intensive care units are not sporicidal. Control measures during an outbreak of B cereus from contaminated linens in a Japanese hospital included autoclaving the linens, increased use of gloves in patient care and use of strong alkaline detergents to clean the washing machines. Under favorable conditions, such as contact with organic material or animal or human hosts, the spores germinate into their vegetative form. In the microbiological laboratory, B cereus can be identified as either gram-positive or gram-variable, catalasepositive, motile, spore-forming rods that grow as irregular, b-hemolytic colonies on sheep blood agar. Species differentiation from other closely related Bacillus species, such as B anthracis, B

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in brief

thuringiensis, and B mycoides, is based on phenotypic differences and genetic sequencing results. B cereus produces a variety of exotoxins, which are responsible for the pathogenesis of disease and most of the clinical manifestations of disease. The emetic syndrome is caused by cereulide, a small ring peptide that acts as a heat- and pH-stable emetic toxin. The exact mechanism of this toxin’s action in humans is unknown, but in animal models, cereulide binds to the 5HT3 (serotonin) receptors in the duodenum and stimulates the afferent vagus nerve endings, resulting in vomiting. The diarrheal syndrome is associated with three heat labile enterotoxins (hemolysin BL [HBL], nonhemolytic enterotoxin [NHE], and cytotoxin K), which are produced by certain toxigenic strains of B cereus. The mechanism of action of these enterotoxins is not understood clearly. HBL and NHE are presumed to cause diarrhea by the formation of pores in the plasma membrane of the epithelial cells of the small intestine. The manifestations of systemic B cereus disease result from the action of other potent exotoxins that function as proteases, phospholipases, lecithinases, and hemolysins, producing extensive tissue damage and necrosis of visceral organs, including the brain, lungs, and eyes. B cereus also has the ability to produce b-lactamases, which render it resistant to penicillins and cephalosporins.

The microbe is susceptible to vancomycin, aminoglycosides, clindamycin, carbapenems, chloramphenicol, and erythromycin. In high-risk populations, early aggressive treatment reduces further dissemination of the bacilli and subsequent production of its toxins. In view of the fulminant course and poor outcome associated with systemic disease in the context of severe immunocompromise, the use of two antibiotics should be considered in particularly vulnerable patients. Although there are no standard guidelines for the antimicrobial treatment of serious B cereus infections, vancomycin generally is considered the drug of first choice. B cereus is ubiquitous in the hospital environment also. Contamination of linens, ventilator supplies, diapers, washing machines, steamed towels, intravenous fluids, and alcohol prep pads are some of the well-documented sources of outbreaks in intensive care units. B cereus has been isolated also from the hands of intensive care personnel, from endotracheal secretions, and from the umbilical cords of neonates. The presence of invasive devices, such as intravenous lines (both peripheral and central), umbilical lines, ventriculoperitoneal shunts, prosthetic heart valves, and pacemakers, predisposes to the dissemination of the bacillus because B cereus produces biofilms that adhere easily to these devices, producing chronic persistent infection. From the biofilm, the bacilli can be released

periodically into the blood stream (planktonic form), resulting in bacteremia and dissemination to distant organs. Because antibiotic therapy typically destroys the planktonic bacilli but not the biofilm, prolonged antibiotic therapy is indicated in high-risk patients, along with the removal of the infected devices. For deep-seated visceral abscesses (eg, cerebral abscesses), surgical drainage often is needed in addition to antimicrobial treatment. When the microbiological laboratory preliminarily reveals gram-positive bacilli in a gram stain or blood culture, Listeria monocytogenes often is presumed to be the likely pathogen because physicians are more familiar with L monocytogenes causing serious infections than with B cereus. Unfortunately, ampicillin, typically used to treat L monocytogenes, is ineffective against B cereus. Clinicians should be aware also that penicillins and third-generation cephalosporins, often chosen as empirical therapy for serious infections, are not effective against B cereus. Because of its ubiquity, B cereus often is ignored or dismissed as a contaminant when found in a culture specimen. Whenever in doubt, a culture positive for B cereus should be repeated, and appropriate antimicrobial therapy should be started expectantly in high-risk patients. Persistent recovery of the bacillus from the same site or source confirms true infection rather than contamination and mandates continued aggressive treatment.

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visual diagnosis

A 3-month-old Male With Wheezing
Kamakshya P. Patra, MD, Suman Shekar, MD, Robert D. Jackson, MD, Ernest A. Kiel, MD, Jon D. Wilson, MD

Presentation
A 3-month-old boy presents to the emergency department with difficulty breathing and wheezing for the past week. His medical history is notable for being born at term via normal vaginal delivery, followed by an uneventful neonatal period. There is a family history of asthma in both parents. The patient’s mother has recently recovered from a viral upper respiratory tract infection. On physical examination, the infant’s vital signs include a temperature of 99°F, heart rate of 192 beats per minute, respiratory rate of 77 breaths per minute, blood pressure of 50/36 mm Hg, and 95% oxygen saturation in room air. The extremities are cool to touch, the peripheral pulses are thready, and the capillary refill time is 5 seconds. A gallop rhythm and a grade 3/6 holosystolic murmur with radiation to the left axilla are present. There are bibasilar crackles and wheezes. The liver edge is palpable 5 cm below the right costal margin, with a total span of 8 cm. There is generalized hypotonia and head lag. There are no obvious facial abnormalities. The rest of his physical findings are normal. A chest radiograph shows an enlarged cardiac silhouette (Fig 1). Complete blood cell count and metabolic profile results are normal for age. The serum creatine kinase level is elevated at 438 U/L (normal: 22–198 U/L). Electrocardiography demonstrates a short PR interval with tall and broad QRS complexes (Fig 2). Further tests confirm the suspected underlying diagnosis.

Figure 1. Chest radiograph demonstrates a large cardiac

silhouette.

Author Disclosure Drs Patra, Shekar, Jackson, Kiel, and Wilson have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.

Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, Shreveport, LA.

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visual diagnosis

with glycogen deposition (Fig 4). Electron microscopy demonstrated lakes of granular material, consistent with glycogen deposition within the sarcoplasm and accumulation within the lysosomes (Fig 5).

Discussion
Pompe disease, or glycogen storage disorder type II, develops due to a deficiency of the enzyme acid a-1,4 glucosidase (acid maltase or acid a-glucosidase [GAA]). This lysosomal enzyme normally is responsible for cleaving a-1,4 and a-1,6 linkages of glycogen, producing glucose. Deficiency of this enzyme leads to the buildup and deposition of lysosomal glycogen in various tissues, with cardiac, skeletal, and smooth muscle cells most severely affected. Figure 2. Electrocardiogram demonstrates high-voltage QRS complexes and shortened Pompe disease is a panethnic auPR intervals. tosomal recessive disorder with an estimated incidence of 1 in 40,000 live births. The GAA enzyme gene is located on chromosome Diagnosis: Pompe Disease 17q25.2. More than 200 mutations have been identified. Doppler echocardiography demonstrated severe mitral There are two variants of Pompe disease: infantile-onset regurgitation and a concentric, hypertrophied left ventriand late-onset. These different phenotypic expressions are cle (Fig 3). Results of a muscle biopsy confirmed the susthought to be due to genetic heterogeneity and varipected diagnosis of Pompe disease. A cross-section of able levels of residual enzyme activity. The infantile-onset skeletal muscle fibers demonstrated markedly abnormal variant typically presents between 8 and 12 weeks of age peripheral and intersarcomeric cytoplasmic clearing with and is uniformly fatal if untreated. Infantile-onset Pompe abnormal cytoplasmic material that is peroxidase aciddisease presents with cardiomegaly (92%), respiratory disSchiff (PAS) stain positive and diastase sensitive, consistent tress (78%), muscle weakness (63%), feeding difficulties (57%), and failure to thrive (53%). Macroglossia is often present. Mental function is normal, yet loss of muscle strength leads to developmental delay or loss of developmental milestones. The median age for death is w8.7 months (range: 0.3–73 months). The median age when ventilatory support becomes necessary is w5.9 months (range: 0.1–31 months). The survival rates at ages 12 months and 18 months are 26% and 12%, respectively. The ventilator-free survival rates at ages 12 months and 18 months are 16.9% and 6.7%. Late-onset Pompe disease is less severe and has a more insidious course. The heart and liver are not affected. Skeletal muscle involvement is prominent, with a predilection for the lower limbs. Vascular disorders such as dilative arteriopathy, carotid artery dissection, and basilar artery dolichoectasia have been reported in late-onset disease. The mean age for developing symptoms in Figure 3. Echocardiogram shows concentric left ventricular late-onset Pompe disease is 28 – 14 years. hypertrophy. Arrow points to the hypertrophied septum.
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visual diagnosis

Figure 4. Skeletal muscle fibers seen in cross-section. The arrow

points to abnormal peripheral and intersarcomeric cytoplasmic material that is peroxidase acid-Schiff (PAS) positive and diastase sensitive, consistent with glycogen. (Frozen section PAS and PAS with diastase; original magnification 2003).

The biochemical findings of Pompe disease may include elevated levels of creatine kinase, aldolase, aspartate aminotransferase, and lactate dehydrogenase. A chest radiograph frequently shows an enlarged cardiac silhouette. Electrocardiographic hallmarks include a high-voltage QRS complex and shortened PR intervals. Echocardiography demonstrates characteristic thickening of the ventricles and interventricular septum. Such thickening can

cause ventricular outflow tract obstruction as well as limitation of diastolic filling. The cardiac manifestations of infantile-onset Pompe disease can include both hypertrophic and dilated cardiomyopathy, and often a combination of the two. Serum creatine kinase levels are not always elevated in late-onset disease. The confirmatory test for diagnosis of Pompe disease is an enzyme assay that demonstrates GAA enzyme activity. This procedure usually is performed in muscle, cultured skin fibroblasts, dried blood spots, leukocytes, or blood mononuclear cells. Although a muscle biopsy has the diagnostic advantage of obtaining a faster result, it requires anesthesia, which carries a risk; in addition, it is possible to biopsy an unaffected area of muscle. In Pompe disease, muscle biopsy results should demonstrate vacuolar myopathy. Vacuoles (abnormal spaces that appear empty) within the muscle cell are PAS positive and are digestible by diastase. The muscle tissue tests positive for acid phosphatase. The presence of vacuoles is consistent with glycogen storage within lysosomes. Electron microscopy reveals glycogen accumulation within the lysosomes and cytoplasm of the muscle. Prenatal diagnosis is available if the mutation in the family is known. If the genetic defect is unknown, GAA activity can be assayed in cultured amniocytes or chorionic villus samples.

Differential Diagnosis
The differential diagnosis of infantile-onset Pompe disease includes other causes of cardiac failure or hypotonia in infants. Causes of cardiac failure include myocarditis, endocardial fibroelastosis, Danon disease, and mitochondrial disorders. Causes of hypotonia include spinal muscular atrophy, carnitine uptake disorders, mitochondrial disorders, glycogen storage disorder type IIIa and IV, hypothyroidism, peroxisomal disorders and other inborn errors of metabolism, and congenital muscular dystrophies. Frequently, an infant who has Pompe disease may present with wheezing and be misdiagnosed as having bronchiolitis. The same error can be made in infants who have dilated cardiomyopathy and left heart failure.

Management
Pompe disease is treated with enzyme replacement therapy, diet (high-protein, low-carbohydrate), exercise, and supportive care. Administration of recombinant GAA, approved by the US Food and Drug Administration in 2006, is effective in improving cardiac and skeletal muscle function. The recommended dosage in children 1 month to 3.5 years of age is 20 mg/kg given intravenously over w4 hours every 2 weeks. Adverse effects include severe
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Figure 5. Electron microscopy of muscle fiber cross-section

reveals granular material (arrow) consistent with glycogen deposition within the sarcoplasm and accumulation within the lysosomes.

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visual diagnosis

hypersensitivity reaction, acute cardiorespiratory failure, and infusion reaction. Early GAA treatment is associated with a 99% reduction of death, extended ventilation-free survival, regression or stabilization of cardiomyopathy, and improved motor milestones. The treatment outcome in infantile-onset Pompe disease is affected by the cross-reactive immunologic material (CRIM) status of the patient. In Pompe disease, endogenous GAA protein is present. The total absence of GAA is described as CRIM negative; the presence of any GAA band is described as CRIM positive. CRIMnegative patients quickly develop inhibitory antibodies to the enzyme, thereby attenuating response to therapy. Gene therapy is still in its nascent stage. Respiratory syncytial virus prophylaxis and influenza vaccination are important for infants who have Pompe disease. Pompe disease is a multiorgan disorder and should be managed by a multidisciplinary team that includes a biochemical geneticist, intensivist, cardiologist, pulmonologist, neurologist, orthopedist, respiratory therapist, physical therapist, occupational therapist, and metabolic dietitian.

documentation of regressing ventricular hypertrophy. He has had no further hospitalizations for cardiorespiratory symptoms.

Summary
• Pompe disease is an autosomal recessive, panethnic glycogen storage disorder with a spectrum of genotypic-phenotypic patterns that results from the deficiency of the enzyme acid a-glucosidase. • There are two forms of Pompe disease: infantile-onset and late-onset. The former is a more severe type and is characterized by hypotonia, cardiomegaly, and hepatomegaly. • The diagnosis is corroborated by hallmark electrocardiographic changes, as well as findings on echocardiography and muscle biopsy. • A multidisciplinary approach, including cardiology, respiratory, occupational and physical therapy, nutrition, and general pediatrics services, is imperative to achieve optimal quality of life. • Enzyme replacement therapy has radically transformed the quality of life and survival of the patients who have Pompe disease.

Patient Course
The patient was initially thought to have bronchiolitis because he had wheezing, a positive family history for asthma, and a recent viral upper respiratory tract infection. Interpretation of the chest radiograph suggested that his “wheezing” was due to heart failure. That finding, plus the patient’s generalized hypotonia, suggested underlying Pompe disease. The patient was treated with inotropic support and mechanical ventilation for 72 hours. Enzyme replacement therapy was initiated. Eventually, the patient was discharged from the hospital treated with furosemide and carvedilol (a cardioselective b-blocker and a1-blocker), which were later discontinued. He is currently 14 months old and is receiving biweekly enzyme replacement therapy. His cardiac function has improved, with echocardiographic

Suggested Reading
Katzin LW, Amato AA. Pompe disease: a review of the current diagnosis and treatment recommendations in the era of enzyme replacement therapy. J Clin Neuromuscul Dis. 2008;9(4):421–431 Kishnani PS, Corzo D, Leslie ND, et al. Early treatment with alglucosidase alpha prolongs long-term survival of infants with Pompe disease. Pediatr Res. 2009;66(3):329–335 Kishnani PS, Goldenberg PC, DeArmey SL, et al. Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants. Mol Genet Metab. 2010;99(1):26–33 Tinkle BT, Leslie N. Glycogen storage disease type II (Pompe disease). In: Pagon RA, Bird TD, Dolan CR, et al, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993. Available at: http://www.ncbi.nlm.nih.gov/books/ NBK1261/. Accessed September 26, 2012 van der Ploeg AT, Reuser AJ. Pompe’s disease. Lancet. 2008;372 (9646):1342–1353

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