January 2015 Evidence-Based Management Volume 12, Number 1 Authors

Of Kawasaki Disease In The Kara K. Seaton, MD Fellow, Pediatric Emergency Medicine, Children’s Hospital and Clinics of Minnesota, Minneapolis, MN Emergency Department Anupam Kharbanda, MD Director of Research, Emergency and Trauma Services, Abstract Children’s Hospital and Clinics of Minnesota, Minneapolis, MN Peer Reviewers Kawasaki disease, also known as mucocutaneous lymph node syn- Catherine Sellinger, MD, FAAP Associate Director, Pediatric Emergency Services, Children’s drome, was first described in Japan in 1967. It is currently the leading Hospital at Montefiore; Assistant Professor of Pediatrics, Albert cause of acquired heart disease in children in the United States. Un- Einstein College of Medicine, Bronx, NY treated Kawasaki disease may lead to the formation of coronary artery Michael J. Stoner, MD Assistant Professor of Pediatrics, The Ohio State University aneurysms and sudden cardiac death in children. This vasculitis pres- College of Medicine; Attending Physician, Pediatric Emergency ents with fever for ≥ 5 days, plus a combination of key criteria. Because Medicine, Nationwide Children’s Hospital, Columbus, OH each of the symptoms commonly occurs in other childhood illnesses, CME Objectives the disease can be difficult to diagnose, especially in children who Upon completion of this article, you should be able to: present with an incomplete form of the disease. At this time, the etiol- 1. Describe the clinical features and risks associated with ogy of the disease remains unknown, and there is no single diagnostic Kawasaki disease. 2. Identify epidemiologic trends in Kawasaki disease in high- test to confirm the diagnosis. This issue reviews the presentation, diag- risk populations. nostic criteria, and management of Kawasaki disease in the emergency 3. Assess the differences between complete and incomplete presentations of Kawasaki disease. department. Emergency clinicians should consider Kawasaki disease 4. Discuss the initial treatment of Kawasaki disease and as a diagnosis in pediatric patients presenting with prolonged fever, as possible options for treating resistant disease. prompt evaluation and management can significantly decrease the risk Prior to beginning this activity, see “Physician CME of serious cardiac sequelae. Information” on the back page.

Editor-in-Chief Ilene Claudius, MD Therapeutics; Research Director, Melissa Langhan, MD, MHS Christopher Strother, MD Associate Professor of Emergency Pediatric Emergency Medicine, BC Associate Professor of Pediatrics, Assistant Professor, Director, Adam E. Vella, MD, FAAP Medicine, Keck School of Medicine Children's Hospital, Vancouver, BC, Fellowship Director, Pediatric Undergraduate and Emergency Associate Professor of Emergency of the University of Southern Canada Emergency Medicine, Director of Simulation, Icahn School of Medicine, Pediatrics, and Medical California, Los Angeles, CA Education, Pediatric Emergency Medicine at Mount Sinai, New Alson S. Inaba, MD, FAAP Education, Director Of Pediatric Medicine, Yale School of Medicine, York, NY Ari Cohen, MD Associate Professor of Pediatrics, Emergency Medicine, Icahn New Haven, CT School of Medicine at Mount Sinai, Chief of Pediatric Emergency University of Hawaii at Mãnoa AAP Sponsor New York, NY Medicine Services, Massachusetts John A. Burns School of Medicine, Robert Luten, MD General Hospital; Instructor in Division Head of Pediatric Professor, Pediatrics and Martin I. Herman, MD, FAAP, FACEP Associate Editor-in-Chief Pediatrics, Harvard Medical Emergency Medicine, Kapiolani Emergency Medicine, University of Professor of Pediatrics, Attending Physician, Emergency Medicine Vincent J. Wang, MD, MHA School, Boston, MA Medical Center for Women and Florida, Jacksonville, FL Children, Honolulu, HI Department, Sacred Heart Associate Professor of Pediatrics, Marianne Gausche-Hill, MD, Garth Meckler, MD, MSHS Children’s Hospital, Pensacola, FL Keck School of Medicine of the FACEP, FAAP Madeline Matar Joseph, MD, FAAP, Associate Professor of Pediatrics, University of Southern California; Professor of Clinical Medicine, FACEP University of British Columbia; International Editor Associate Division Head, David Geffen School of Medicine Professor of Emergency Medicine Division Head, Pediatric Lara Zibners, MD, FAAP Division of Emergency Medicine, at the University of California at and Pediatrics, Chief and Medical Emergency Medicine, BC Honorary Consultant, Paediatric Children's Hospital Los Angeles, Los Angeles; Vice Chair and Chief, Director, Pediatric Emergency Children's Hospital, Vancouver, Emergency Medicine, St Mary's Los Angeles, CA Division of Pediatric Emergency Medicine Division, University BC, Canada Hospital, Imperial College Trust; Medicine, Harbor-UCLA Medical of Florida Medical School- Editorial Board Joshua Nagler, MD EM representative, Steering Group Center, Los Angeles, CA Jacksonville, Jacksonville, FL Assistant Professor of Pediatrics, ATLS ®-UK, Royal College of Jeffrey R. Avner, MD, FAAP Michael J. Gerardi, MD, FAAP, Stephanie Kennebeck, MD Harvard Medical School; Surgeons, London, England Professor of Clinical Pediatrics FACEP, President-Elect Associate Professor, University Fellowship Director, Division of and Chief of Pediatric Emergency Associate Professor of Emergency of Cincinnati Department of Emergency Medicine, Boston Pharmacology Editor Medicine, Albert Einstein College Medicine, Icahn School of Pediatrics, Cincinnati, OH Children’s Hospital, Boston, MA James Damilini, PharmD, MS, of Medicine, Children’s Hospital at Medicine at Mount Sinai; Director, BCPS Montefiore, Bronx, NY Anupam Kharbanda, MD, MS James Naprawa, MD Pediatric Emergency Medicine, Research Director, Associate Associate Clinical Professor Clinical Pharmacy Specialist, Steven Bin, MD Goryeb Children's Hospital, Fellowship Director, Department of Pediatrics, The Ohio State Emergency Medicine, St. Associate Clinical Professor, Morristown Medical Center, of Pediatric Emergency Medicine, University College of Medicine; Joseph's Hospital and Medical Division of Pediatric Emergency Morristown, NJ Children's Hospitals and Clinics of Attending Physician, Emergency Center, Phoenix, AZ Medicine, UCSF Benioff Children’s Sandip Godambe, MD, PhD Minnesota, Minneapolis, MN Department, Nationwide Children’s Quality Editor Hospital, University of California, Vice President, Quality & Patient Hospital, Columbus, OH Tommy Y. Kim, MD, FAAP, FACEP San Francisco, CA Safety, Professor of Pediatrics and Steven Choi, MD Assistant Professor of Emergency Steven Rogers, MD Richard M. Cantor, MD, FAAP, Emergency Medicine, Attending Medical Director of Quality, Medicine and Pediatrics, Loma Assistant Professor, University of Director of Pediatric Cardiac FACEP Physician, Children's Hospital Linda University Medical Center and Connecticut School of Medicine, Inpatient Services, The Children’s Professor of Emergency Medicine of the King's Daughters Health Children’s Hospital, Loma Linda, CA; Attending Emergency Medicine and Pediatrics, Director, Pediatric System, Norfolk, VA Hospital at Montefiore; Assistant California Emergency Physicians, Physician, Connecticut Children's Professor of Pediatrics, Albert Emergency Department, Medical Ran D. Goldman, MD Riverside, CA Medical Center, Hartford, CT Director, Central New York Einstein College of Medicine, Professor, Department of Pediatrics, Bronx, NY Poison Control Center, Golisano University of British Columbia; Children's Hospital, Syracuse, NY Co-Lead, Division of Translational Case Presentation Since it was first described, Kawasaki disease has been well characterized. Affected children generally A 3-year-old girl presents to the emergency department have fever for at least 5 days, plus 4 of 5 key criteria. for evaluation of fever. Her mother reports that the child These criteria include conjunctival injection, oral has had a fever for the past 5 days, with temperatures mucosal changes, polymorphous rash, distal extremity 5,6 ranging from 38.3°C (101°F) to 40°C (104°F). The child changes, and cervical lymphadenopathy. Nonspe- has some rhinorrhea, but no significant cough. She has cific symptoms, such as vomiting, joint pain, cough, been complaining of abdominal pain and had 2 episodes of decreased oral intake, rhinorrhea, and abdominal pain, nonbilious vomiting in the last 2 days. She was evalu- may also be present, and may make the diagnosis ated at her pediatrician’s office 2 days ago, and she was more challenging. To add to the diagnostic challenge, diagnosed with a viral illness. Her mother reports the some patients may develop an incomplete form of the subsequent development of a red rash that started on disease. These children will not meet all of the clinical the child’s face and chest, and it is now present on her criteria of Kawasaki disease, but they may still develop trunk, back, and extremities. Her lips are cracked, and her the cardiovascular complications. Incomplete Kawasaki mother attributes this to poor oral intake over the past few disease accounts for 15% to 20% of Kawasaki disease days. Today, the child was noted to have red eyes, without diagnoses, and it is more common in children aged < 6 5 discharge, and redness in the genital area. The mother has months and in children aged > 5 years. not noticed swelling of the extremities or peeling skin. The No single laboratory test can be used to establish remainder of the review of systems is negative. The child the diagnosis of Kawasaki disease, although labora- was previously healthy, with no prior hospitalizations, tory testing can be used to distinguish this disease and she is fully immunized. She attends a small, in-home from other disease entities. Thus, the diagnosis must daycare, but none of the other children there have been be made using a combination of a thorough history, sick. On physical examination, the child appears tired physical examination, and laboratory results. If some and ill, although she is not in distress. Her temperature of the diagnostic criteria are met and Kawasaki dis- at triage is 39.8°C (103.6°F). She is tachycardic, with ease is suspected, the current recommendations are to a heart rate of 166 beats/min; and tachypneic, with a obtain an echocardiogram to assess coronary artery respiratory rate of 48 breaths/min. Her eyes are injected involvement. Ideally, this should be done within 10 bilaterally, without purulent discharge. Her tympanic days of the onset of fever to minimize the risk of car- membranes are normal. She has dry, fissured lips. She has diovascular complications. shotty cervical lymphadenopathy. Her lungs are clear to Kawasaki disease is rarely fatal, but virtually auscultation, and the cardiovascular examination reveals all deaths result from cardiac sequelae. In fact, this tachycardia without murmurs. Her abdomen is soft and disease has now surpassed rheumatic heart disease mildly tender to palpation throughout, with no hepato- as the leading acquired heart disease in children in 5 splenomegaly. Her extremities are warm, well perfused, the United States. Coronary artery aneurysms occur and without swelling. Her skin is notable for a fine, ery- in 15% to 25% of untreated children. Coronary artery thematous, maculopapular rash on the face, chest, back, aneurysm has been known to lead to myocardial and extremities. The patient’s ill appearance and history infarction, ischemic heart disease, and sudden car- of prolonged fever are concerning for the possibility of diac death. Peak mortality occurs 15 to 45 days after Kawasaki disease, but you aren’t sure that she meets all of the development of fever. However, sudden cardiac the criteria. You wonder if there are infections you should death has been documented years after the diagnosis worry about. Are there laboratory tests you could order of Kawasaki disease. In-hospital mortality is cur- 7 that would help you differentiate Kawasaki disease from rently estimated to be 0.17% in the United States. infection? What about diagnostic imaging tests? Should you start any medications? Are there any other complica- Critical Appraisal Of The Literature tions that you should be concerned about? A literature search was performed using both Introduction PubMed and Ovid. The initial search on PubMed us- ing the term Kawasaki disease resulted in 8170 articles. Kawasaki disease was initially described in Japan in This was then decreased to 3458 articles by limiting 1967 by Tomisaku Kawasaki.1-4 Originally known as the results to children (aged birth to 18 years) and mucocutaneous lymph node syndrome, it is an acute, articles published in English. A similar search in self-limited, febrile vasculitis of infancy and child- Ovid using the same terms produced 4593 articles. hood. Kawasaki disease primarily affects small- and Guidelines from the American Academy of Pediat- medium-sized arteries, including the coronary arter- rics (AAP) in partnership with the American Heart ies. Although it is a self-limited disease, early diagno- Association (AHA) were reviewed. Search of the sis and treatment is critical to preventing the forma- Cochrane Database of Systematic Reviews produced tion of coronary artery aneurysms, which may lead to reviews of Kawasaki disease treatment using intra- acquired cardiovascular disease and sudden death. venous immunoglobulin (IVIG) and aspirin. The ref-

Copyright © 2015 EB Medicine. All rights reserved. 2 www.ebmedicine.net • January 2015 erences in the strongest articles were also reviewed dren.11 Europe and Oceania reported significantly lower to explore the most relevant historical articles. rates. Hospital admission rates from England averaged Kawasaki disease was first discovered in Japan, 8.4 per 100,000.14 Australian statistics from the 1990s and the incidence of the disease is significantly showed an annual incidence of 3.7 per 100,000 children higher in Asian populations. As a result, many of aged < 5 years.15 the published studies have come from Japan. How- ever, for our purposes, only those studies published Etiology And Pathophysiology in English were reviewed. Despite all of the research that has been performed A review of the literature for the etiology and in the last 40 years, the exact etiology of Kawasaki pathogenesis of Kawasaki disease produced mixed disease remains a mystery. Clinical and epidemio- results. Although there are many studies examining logical data are suggestive of an infectious agent, but the etiology of the disease, the evidence presented such an agent has never been identified. The self- within these studies was weak overall. In contrast, limited nature of the illness and associated symp- the evidence in support of the optimal treatment of toms of fever, rash, and conjunctivitis are common Kawasaki disease is much stronger. Many of these to many viral illnesses. Younger children are dis- studies have been performed using a prospective, proportionately affected, which is also the case with randomized approach. In addition, several meta-anal- many infectious diseases. Epidemiological data have yses on the topic are available and were reviewed. shown that the disease is most common in the win- ter and spring, and occurs in community outbreaks Epidemiology, Etiology, And Pathophysiology with a wave-like geographic spread.16 All of these factors are characteristic of an infectious etiology. Epidemiology Many infectious agents have been proposed as Kawasaki disease is the second most common vascu- having a causative role in Kawasaki disease, including litis condition in children. It is also the leading cause multiple viruses, bacteria, spirochetes, and rickettsia. of acquired heart disease in children in the United However, none have been confirmed as the definitive States.8 It is slightly more prevalent in males than in source. Other theories have been proposed as well. One females, at a rate of approximately 1.5 to 1.9 Although theory has suggested that selective expansion of spe- Kawasaki disease has been described in all ethnici- cific T-cell receptor families in Kawasaki disease might ties, it is most prevalent in children of Asian ancestry. be the result of a bacterial superantigen. A 1993 study The United States Centers for Disease Control and found toxic shock syndrome toxin-1 (TSST-1) in 11 out of Prevention reported estimates of disease occurrence 16 patients with Kawasaki disease.17 However, follow- in 9 to 19 per 100,000 children aged < 5 years in the up studies by different authors failed to show similar continental United States, with an estimated 5447 results.18 A more recent prospective, multicenter trial related hospitalizations in 2009.10 Rates are highest in did not show a higher prevalence of supertoxin-produc- Asian/Pacific Islanders, followed by blacks, whites, ing bacteria in Kawasaki disease patients compared to and American Indians.3 The rate of hospitalization febrile controls.19 In addition, the immune response in for Kawasaki disease among Asian/Pacific Islander Kawasaki disease has now been shown to be oligoclo- children in the United States is 30.3 per 100,000, nal.20,21 The oligoclonal response is more consistent with while the rate for white, non-Hispanic children in the an immune response to a common antigen, rather than United States is 12 per 100,000.11 Within the United the polyclonal response typically seen when a superan- States, Hawaii has higher rates of Kawasaki disease, tigen is present. with one study showing an estimated rate of 47.7 per In 2005, another theory was presented when 100,000 children aged < 5 years.12 The significantly researchers reported a novel human coronavirus in higher rates in Hawaii are likely related to the high respiratory samples from 8 out of 11 patients with proportion of the population with Asian- or Pacific- Kawasaki disease, but in only 1 of 22 control pa- Islander ancestry. tients.22 This was called the New Haven coronavirus Worldwide, the highest incidence of Kawasaki (HCoV-NH), named for its place of discovery. Un- disease is in Japan, where it was first described. In 2007 fortunately, this virus was later found to be the same and 2008, an epidemiologic study in Japan estimated as a previously reported coronavirus, HCoV NL-63, the incidence of Kawasaki disease at 216.7 per 100,000 and multiple follow-up studies from both the United children aged 0 to 4 years, which is > 10 times the States and Asia have been unable to find an associa- incidence in the United States.13 In other parts of Asia, tion between this virus and Kawasaki disease.22-25 rates of Kawasaki disease are lower compared to those Studies have also attempted to link Kawasaki seen in Japan, but they are still higher than rates in the disease to various environmental causes (including United States. A 2012 review reported that Hong Kong pollutants, toxins, and heavy metals), but no conclu- had an incidence of 39 per 100,000 children aged < 5 sive evidence has been found. A significant overlap years, Beijing had an incidence of 55 per 100,000, and in symptoms has been observed in both Kawasaki Korea’s annual incidence was 113.1 per 100,000 chil- disease and acrodynia (mercury toxicity), but a link

January 2015 • www.ebmedicine.net 3 Reprints: www.ebmedicine.net/pempissues between the 2 conditions has not been proven. viral infections, and they will resolve on their own More recent immunologic research has revealed in time without long-term consequences. Rash as- infiltration of immunoglobulin A (IgA) plasma cells sociated with fever may be seen in viral exanthems, in coronary artery walls, as well as in the respiratory as well as in Epstein-Barr virus and acute strepto- tract, pancreas, and kidneys of patients with Kawa- coccal infections. Adenovirus may present quite saki disease.20 In addition, CD8 lymphocytes have similarly to Kawasaki disease, with symptoms such also been noted as part of the inflammatory response as fever, rash, conjunctival changes, mucous mem- in coronary artery aneurysms.26 These patterns of brane changes, and adenopathy. A study by Barone inflammatory cell infiltration support the theory of et al noted that children with adenovirus are more an immune response to a microbial agent. Similar likely to have purulent conjunctivitis or exudative findings of IgA plasma cells in the respiratory tract pharyngitis compared to children with Kawasaki are seen in respiratory illnesses such as influenza disease, although the study was small.31 Rash, fever, or respiratory syncytial virus, suggesting that the and conjunctival changes are also seen in measles, portal of entry for the microbial agent may be the and, although many children are vaccinated against respiratory tract.26 Further immunologic study has this disease, several outbreaks have recently been revealed the presence of intracytoplasmic inclusion reported. Fever can also be seen in drug hypersen- (ICI) bodies within the ciliated bronchial epithe- sitivity reactions, so a complete medication history lium.27 Similar inclusion bodies were not detected should be taken at presentation. in control patients. A single monoclonal antibody detected approximately 85% of the ICI bodies in pa- Prehospital Care tients with fatal Kawasaki disease, suggesting that a single agent or closely related agents may be respon- Many children with suspected Kawasaki disease will 28 sible for the disease. No structures representing initially present to their pediatricians or be brought known bacterial, fungal, or parasitic elements were identified within the ICI bodies.28 Despite our improved understanding of the Table 1. Differential Diagnosis Of Prolonged immune system activation that occurs in Kawasaki Fever In Pediatric Patients disease, it is still somewhat unclear how it leads to coronary artery aneurysms. Patients with Kawasaki Infectious disease have been found to have stimulation of the • Systemic viral infection cytokine cascade and endothelial cell activation. It • Pneumonia is this endothelial activation that leads to coronary • Urinary tract infection arteritis and aneurysms, although the exact mecha- • Infective endocarditis nism of how this occurs still needs to be elucidated. • Osteomyelitis Various studies have shown elevated levels of • Lyme disease matrix metalloproteinase-929 and vascular endothe- • Rocky Mountain spotted fever • Human immunodeficiency virus lial growth factor30 in Kawasaki disease patients, • Malaria both of which may contribute to the development of aneurysms. Endocrinologic • Thyrotoxicosis Differential Diagnosis Immunologic When children present with Kawasaki disease in its • Immunodeficiency classic form, it is not difficult for an astute emergen- Oncologic cy clinician to make the correct diagnosis. However, • Leukemia children presenting with < 5 days of fever, or those • Lymphoma with incomplete Kawasaki disease may prove to be • Other neoplasm more of a diagnostic challenge. Fever is a very com- mon complaint in pediatric patients, with a broad Rheumatologic differential diagnosis. (See Table 1.) Accurately • Juvenile idiopathic arthritis differentiating fever due to viral or bacterial illnesses • Systemic lupus erythematosus from fever due to Kawasaki disease is critical. This • Kawasaki disease is especially true since patient outcomes are signifi- • Familial Mediterranean fever cantly improved when patients are treated within 10 days of the onset of fever. Gastroenterologic • Inflammatory bowel disease It is important to consider a variety of diagnoses when thinking about children with fever. (See Table Toxicologic 2, page 5.) Many fevers will be caused by nonspecific • Drug-related fever

Copyright © 2015 EB Medicine. All rights reserved. 4 www.ebmedicine.net • January 2015 to the hospital directly by parents. For children who Physical Examination are transported via emergency medical services, pre- In addition to fever, the diagnostic criteria for com- hospital care should focus on supportive measures. plete Kawasaki disease include the presence of 4 out Assessment of the airway, breathing, and circulation of 5 supporting signs and symptoms. (See Table 3, is of primary importance, with close monitoring of page 6.) These include conjunctival injection, oro- vital signs during transport. A few children may pharyngeal changes, polymorphous rash, extrem- develop shock in association with Kawasaki disease. ity changes, and lymphadenopathy. Conjunctival For these children, obtaining intravenous access and injection is common, and it occurs in an estimated initiating fluid resuscitation takes precedence. When 80% to 90% of patients with Kawasaki disease.3 It is possible, these children should be transported to a most commonly bilateral, painless, and nonpurulent. facility with a pediatric intensive care unit. It typically involves the bulbar conjunctiva and is described as limbic sparing. It is rarely painful.5 (See Emergency Department Evaluation Figure 1, page 6.) Oropharyngeal mucous membrane changes are History found in approximately 80% to 90% of patients with 3 The diagnosis of Kawasaki disease should be con- Kawasaki disease. These include obvious changes sidered in all children presenting with prolonged such as dry, fissured, or erythematous lips, which fever, especially if it has been present for ≥ 5 days. are easily observed. (See Figure 2, page 6.) However, It is important to note that symptoms may present changes can be more subtle. Children may develop sequentially rather than simultaneously, and, thus, strawberry tongue, in which the tongue becomes some of the diagnostic symptoms may be resolved bright red with prominent papillae. Other changes prior to presentation to the emergency department.5 may include nonexudative pharyngitis or erythema When considering a diagnosis of Kawasaki disease, of the posterior oropharynx. ask the caregivers about all recent symptoms, even if Polymorphous rash is present in approximately they are not currently present. 80% to 90% of patients, and it often develops early in 3 The presence of ≥ 5 days of fever is essential for the course of the disease. A wide variety of cutane- the diagnosis of Kawasaki disease. In affected children, ous eruptions have been described, including rashes fevers are often high, commonly > 39°C (102.2°F), and that appear as diffuse and macular, scarlatiniform, potentially > 40°C (104°F).5 The fever may not respond scaling plaques, or even resembling erythema to antipyretic drugs, and it generally persists for an multiforme. (See Figure 3, page 7.) The rash is less average of 10 to 14 days without treatment, but may commonly urticarial, and almost never appears as 3 continue for as long as 3 to 4 weeks.3 Once treatment vesicles or bullae. The rash is often found on the for Kawasaki disease is initiated, fever usually resolves truck or extremities, and may be present in the peri- within 48 hours. neal area.

Table 2. Comparison Of Kawasaki Disease And Other Similarly Presenting Diseases

Disease Features First-Line Treat- Complications ment Kawasaki disease Fever (> 5 days) plus: Intravenous immuno- • Coronary artery aneurysms • Conjunctivitis globulin plus aspirin • Sudden cardiac death • Oropharyngeal changes • Polymorphous rash • Extremity changes • Lymphadenopathy Adenovirus Fever plus: Supportive care • Pneumonia • Rash • Conjunctivitis • Lymphadenopathy • Pharyngitis Group A Streptococcus Fever plus: Antibiotics • Rheumatic heart disease • Pharyngitis • Postinfection glomerulonephritis • Rash Measles Fever plus: Supportive care • Pneumonia • Rash • Otitis media with or without hearing loss • Conjunctivitis • Encephalitis • Rhinorrhea • Subacute sclerosing panencephalitis • Pharyngitis

January 2015 • www.ebmedicine.net 5 Reprints: www.ebmedicine.net/pempissues Interestingly, children who have previously to the palms of the hands and the soles of the feet.3 received the bacillus Calmette-Guérin (BCG) vac- (See Figure 4, page 7.) Erythema is often sharply de- cine will often have erythema, induration, or crust- marcated at the wrist and ankle. The hands and feet ing at the site of injection.32,33 The mechanism for can be painful, and, in younger children, this may inflammation at this site is not well understood. It manifest as refusal to bear weight or use the affected is known to be a very specific finding for Kawasaki limbs. Such changes occur in 80% to 90% of children disease, and it can be considered a strong indication during the acute phase of illness.3 Desquamation of of Kawasaki disease in the presence of incomplete the fingers and toes is also common in children.(See or atypical criteria. This finding is rarely observed in Figure 5, page 7.) One recent study reported that the United States, as children in the United States do 68% of children diagnosed with Kawasaki disease not routinely receive the BCG vaccine. However, the had desquamation of the fingers, toes, or both.35 BCG vaccine is commonly used in other countries. However, this occurs late in the disease, often 2 to 3 Although it does not prevent pulmonary tuberculo- weeks after the onset of illness, making it less useful sis, the BCG vaccine is used to provide infants and for diagnosing Kawasaki disease in the acute phase. young children with protection against tuberculo- Lymphadenopathy is the least common of the diag- sis, meningitis, and disseminated tuberculosis.34 In nostic criteria. It occurs in only 50% to 60% of patients countries where tuberculosis is endemic, the vaccine with Kawasaki disease.3,36 The adenopathy of Kawasaki is routinely given to neonates as soon as possible af- disease is most commonly unilateral and found in the ter birth. Therefore, emergency clinicians should be cervical chain. Classic criteria cite the lymphadenopathy aware of this finding when evaluating children who as consisting of ≥ 1 lymph node with a diameter of at were born in or who have lived in countries where least 1.5 cm.5 the BCG vaccination is common. Extremity changes are another criterion for Kawasaki disease, but a wide variety of changes can Figure 2. Oropharyngeal Mucous Membrane occur. Erythema and/or edema of the hands and feet Changes may be present.5 The entirety of the hands and feet may be affected, but erythema may also be limited

Figure 1. Conjunctival Injection

This figure was published inZitelli and Davis' Atlas of Pediatric Physi- This figure was published inZitelli and Davis' Atlas of Pediatric Physi- cal Diagnosis, 6th edition, Torok K, Rosen P, Kawasaki Disease, cal Diagnosis, 6th edition, Torok K, Rosen P, Kawasaki Disease, pages 289-291, Copyright Elsevier 2012. Used with permission. pages 289-291, Copyright Elsevier 2012. Used with permission.

Table 3. Features Of Kawasaki Disease In Children*

Diagnostic Criteria Description Time of Occurrence Occurrence Rate Fever Duration ≥ 5 days Acute phase 100% Conjunctivitis Bilateral, painless, nonpurulent Acute phase 80%-90% Oropharyngeal changes Erythema, pharyngitis, fissured lips, strawberry tongue Acute phase 80%-90% Polymorphous rash Diffuse, often macular, may be scarlatiniform, possible perineal Acute phase 80%-90% involvement Extremity changes May include erythema, edema, or desquamation Acute phase and/or 2-3 weeks 80%-90% after onset Lymphadenopathy Cervical region, usually unilateral Acute phase 50%-60%

*Complete Kawasaki disease is defined as fever for ≥ 5 days plus 4 of the 5 diagnostic criteria. Reprinted from the Journal of the American Academy of Dermatology, Volume 69, Issue 4, Stephanie Byers, MD, Stanford T. Shulman, MD, and Amy S. Paller, MD, Kawasaki disease, Part I. Diagnosis, clinical features, and pathogenesis, pages 501.e1-501.e11. Copyright 2013, with permission from Elsevier.

Copyright © 2015 EB Medicine. All rights reserved. 6 www.ebmedicine.net • January 2015 Outside of the diagnostic criteria, there are other Arthritis and arthralgias can occur, usually early in symptoms that are commonly reported in patients with the course. Arthritis may be oligoarticular or polyarticu- Kawasaki disease. Irritability is quite common. Although lar.40 The cardiovascular examination in children with children who have viral illnesses may also be irritable, Kawasaki disease can reveal tachycardia, hyperdynamic the irritability of children with Kawasaki disease is often precordium, murmurs, or a gallop.5 more pronounced.5 The irritability may resemble that Gastrointestinal complaints are common, but are often seen in bacterial or viral meningitis.37 Because of this, nonspecific. Complaints may include abdominal pain, some theorize that the irritability may be the result of vomiting, or diarrhea, and may occur in up to one-third aseptic meningitis, which is found in approximately of patients.3 One study found that vomiting was associ- 25% of patients with Kawasaki disease. One study found ated with an increased risk of treatment resistance to that 50% of patients were described as irritable by their IVIG, although this study was small and retrospective parents in the 10 days prior to the diagnosis of Kawa- in nature.41 Nonspecific gastrointestinal complaints saki disease, and these patients were more likely to be are common in viral illnesses, and so are not as useful younger in age.38 However, marked irritability has been in making a definitive diagnosis of Kawasaki disease. noted in infants with normal cerebrospinal fluid studies, Less commonly, hepatomegaly and jaundice can occur. so further research in this area is needed to determine There have been rare reports of obstructive jaundice the cause of such pronounced irritability.39 due to gall bladder hydrops and cholestasis associated with Kawasaki disease.42 Increasingly, Kawasaki disease has been recog- nized as an etiology of shock in some children.43 These Figure 3. Diffuse Macular Rash children often require intravenous fluids, pressors, and admission to a pediatric intensive care unit. Children presenting with Kawasaki disease with shock show a significantly higher inflammatory response than chil- dren with Kawasaki disease without shock, despite the time to presentation being equal.43 Kawasaki disease has also been indicated as a cause of multiple organ dysfunction syndrome. A retrospective review at one institution revealed that, over an 8-year period, 11 chil- dren had been admitted to the pediatric intensive care unit with shock and were later diagnosed with Kawasaki

Figure 5. Desquamation Of Fingers

This figure was published inZitelli and Davis' Atlas of Pediatric Physi- cal Diagnosis, 6th edition, Torok K, Rosen P, Kawasaki Disease, pages 289-291, Copyright Elsevier 2012. Used with permission.

Figure 4. Erythema Of The Extremities

This figure was published inZitelli and Davis' Atlas of Pediatric Physi- cal Diagnosis, 6th edition, Torok K, Rosen P, Kawasaki Disease, pages 289-291, Copyright Elsevier 2012. Used with permission. To view a full-color version of this issue's photos, scan the QR code with a smartphone or tablet or go to: www.ebmedicine.net/KawasakiDiseaseSigns.

This figure was published inZitelli and Davis' Atlas of Pediatric Physi- cal Diagnosis, 6th edition, Torok K, Rosen P, Kawasaki Disease, pages 289-291, Copyright Elsevier 2012. Used with permission.

January 2015 • www.ebmedicine.net 7 Reprints: www.ebmedicine.net/pempissues disease.44 Eight of these patients (72.7%) had evidence peptidase.5,45 The mechanism behind liver func- of multiple organ dysfunction syndrome, with hemody- tion abnormalities in Kawasaki disease patients is namic instability, and neurologic, gastrointestinal, and not well understood. Theories for how this occurs renal dysfunction. Three children developed respiratory include vasculitis within the liver vessels, toxin- failure, requiring intubation or requiring noninvasive mediated effects, oxidant stress, and inflammatory ventilatory support. In addition, 7 out of 11 of the chil- cell infiltration, but further research in these areas is dren developed coronary artery aneurysms. All of these needed.46 children survived after proper treatment for Kawasaki disease, suggesting that prompt recognition and treat- Lipid And Albumin Levels ment of Kawasaki disease in patients with shock can Plasma cholesterol and high-density lipoprotein result in favorable outcomes.44 levels can be markedly depressed in affected pa- tients.47 Hypoalbuminemia is another common Diagnostic Testing finding, and it has been associated with more severe disease.48 The pathophysiology of this finding is Making a definitive diagnosis of Kawasaki disease that microvascular inflammation leads to increased can be a challenge, especially in atypical cases. microvascular permeability, which, in turn, results Although there is no single diagnostic test to con- in vascular leak, decreased serum levels of albumin, 48 firm the diagnosis, there are many diagnostic tests and, ultimately, peripheral edema. that can help to differentiate Kawasaki disease from other entities. Sodium Levels Hyponatremia has also been documented in patients Laboratory Studies with Kawasaki disease. This was first described in Inflammatory Markers the United States in a 1982 retrospective study of pa- Since Kawasaki disease is characterized by acute tients with Kawasaki disease, which found that 6 of 11 patients had hyponatremia at the time of hospital inflammation, it is necessary to assess patients for 49 elevated inflammatory markers. This includes the admission. Lim et al prospectively studied 50 pa- acute phase reactants, such as C-reactive protein tients with Kawasaki disease and found that 26% (13 patients) had hyponatremia during the acute phase (CRP) and erythrocyte sedimentation rate (ESR). 50 These are nearly universally elevated, with ESR of illness. Even higher rates of hyponatremia have being elevated in approximately 60% of Kawasaki been reported in some studies. Watanabe et al con- ducted a study of 146 Kawasaki patients, and they disease patients, and CRP being elevated in as many 51 as 80% of affected patients. Guidelines (such as those found that 44% of the patients had hyponatremia. from the AAP) recommend testing both the CRP and It has been suggested that patients with hyponatre- ESR levels for best results.5 The AAP guidelines sug- mia have higher levels of inflammation overall, al- though the exact pathophysiology of hyponatremia gest that elevations of CRP ≥ 3.0 mg/dL and ESR ≥ 50,51 40 mm/h can be used in the evaluation of both com- in Kawasaki disease is not well understood. plete and incomplete Kawasaki disease.5 Treatment Brain Natriuretic Peptide Levels with IVIG can lead to elevations in the ESR, so this test should not be used as the primary determiner of Elevated serum N-terminal brain natriuretic peptide inflammation in treated patients. (NTproBNP) levels have been investigated for use in diagnosing Kawasaki disease. Brain natriuretic Complete Blood Count peptide (BNP) is synthesized within myocytes as Leukocytosis is a common finding, with elevations proBNP and is released into circulation during in white blood cell (WBC) counts > 15,000/mm3 periods of ventricular stress. The N-terminal section 5 is cleaved, releasing both the active BNP and the found in at least half of patients. Thrombocytosis is 52 another characteristic finding of Kawasaki disease. inactive NTproBNP into circulation. BNP has an Platelet counts often exceed 500,000/mm3, and may extremely short half-life, being degraded in 5 to 10 be as high as 1,000,000/mm3. Thrombocytosis de- minutes. NTproBNP has a significantly longer half- velops later than some findings, typically appearing life than BNP (25 to 125 minutes) making it more during the second week of illness, and peaking in easily detectable in circulation. Although NTproBNP the third or fourth week. levels are frequently elevated in children with Kawa- saki disease, these levels vary with age, making it 52,53 Liver Function Tests difficult to use this laboratory test in diagnosis. Liver panel abnormalities can occur in patients with In practice, given the complexity of this marker, it is Kawasaki disease. Up to 40% of patients will show not routinely used. mild to moderate elevations in serum transaminases. Urinalysis An even higher number (approximately 60% to 67%) will have elevated plasma gamma-glutamyl trans- Sterile pyuria can be found in approximately one- third of affected patients. Early research reported

Copyright © 2015 EB Medicine. All rights reserved. 8 www.ebmedicine.net • January 2015 that urine obtained via suprapubic tap was normal, treated within 10 days of the onset of fever.57-59 Howev- indicating urethritis as the primary cause of pyuria.5 er, more recent studies have shown much higher rates. However, more recent research indicates that upper Tse et al examined echocardiograms from 178 patients urinary structures, including the bladder and kid- with Kawasaki disease, noting that 34% had lesions on ney, may be involved.54,55 initial evaluation.60 Baer et al studied initial echocar- diograms of 100 patients with Kawasaki disease, and Lumbar Puncture they found that 44% of patients had either ectasia or Although lumbar puncture is not routinely recom- aneurysms present at the time of the initial evaluation.61 mended for evaluation of Kawasaki disease, it is The dramatic increase in lesions at the time of diagnosis occasionally performed. Of those children who is thought to be related to changing the definition of undergo this procedure, between one-third and lesions from absolute measurements to a measurement one-half will show signs of cerebrospinal fluid that is adjusted for body surface area.61 pleocytosis.37 This includes a predominance of Perivascular echocardiographic brightness (PEB) mononuclear cells and normal cerebrospinal fluid has been proposed as a criterion for diagnosing incom- protein and glucose levels. plete Kawasaki disease in some patients. Prior research suggested that perivascular brightness was a predic- Cardiovascular Testing tor of coronary artery aneurysms.62 However, PEB is Children with Kawasaki disease may have changes somewhat subjective and dependent on the individual on electrocardiography (ECG), although these are echocardiographer. A more recent attempt to quantita- often nonspecific. Changes may include arrhyth- tively define PEB and its use in diagnosing incomplete mias, nonspecific T-wave changes, PR-interval pro- Kawasaki disease did not confirm PEB to be a reliable longation, or QT-interval prolongation.5 These ECG diagnostic criterion.63 findings are most likely to be found during the acute In addition to coronary artery lesions, children phase and in the first month following diagnosis, can develop other cardiac problems, and initial and they frequently normalize after recovery.56 echocardiography should assess for such problems. The most critical imaging to obtain in children with Myocarditis is common during the acute phase of the Kawasaki disease is echocardiography. This is usually illness, and decreased ventricular contractility can performed transthoracically, and should be done in occur.5 As many as 50% to 70% of patients will have all patients with a definitive or suspected diagnosis wall motion abnormalities related to myocardial in- of Kawasaki disease. Ideally, initial echocardiography flammation, although this seems to be independent of should be performed on the day of diagnosis. Echocar- the risk of coronary artery aneurysms.64 Pericarditis, diography can be helpful in formally diagnosing cases valvular regurgitation, and pericardial effusion have of incomplete Kawasaki disease. It is noninvasive and also been documented.65,66 does not involve radiation. It is both highly sensitive and specific for detecting coronary artery lesions. Risk Classification Guidelines from the AHA and the AAP recommend prompt echocardiography once Kawasaki disease is Although several risk classification criteria have diagnosed or suspected, although delays in obtaining been proposed, the most commonly applied in the 5 imaging should not delay initiation of treatment. The United States are those proposed by Beiser et al.67 AAP stresses the importance of this examination being These criteria are generally used to predict which performed by an experienced echocardiographer in patients are at a high risk of developing coronary order to best visualize all segments of the coronary artery aneurysms among patients who were treated arteries and accurately assess vessel diameter. Ectasia with IVIG within 10 days of the onset of fever. The of the arteries is defined as vessels that are larger than scoring system uses baseline neutrophil and band normal without segmental aneurysms. The AHA defines counts, hemoglobin, platelet count, and temperature aneurysms as small if they are < 5 mm in diameter, on the day after the patient receives IVIG to catego- medium if the diameter is 5 to 8 mm, and giant if the di- rize patients into high-risk and low-risk categories. 5 ameter is > 8 mm. The most commonly affected vessel The negative predictive value of the score appears to is the proximal segment of the left anterior descending be appropriate, as no patients in the low-risk group artery, followed by the proximal right coronary artery, developed coronary artery aneurysms. However, the left main coronary artery, and the left circumflex artery, positive predictive value of the tool is relatively in- respectively. The least commonly affected vessel is the adequate, with only 13% of high-risk patients devel- 5 distal segment of the right coronary artery. oping coronary artery aneurysms.67 Thus, although It should be noted that a normal initial echocar- this may be a helpful tool for predicting low-risk diogram should not be used to exclude the diagnosis patients, it should not be used to guide treatment or of Kawasaki disease, especially if physical examina- follow-up decisions. tion findings and laboratory tests are consistent with Egami et al devised a scoring system to predict the diagnosis. Early studies estimated the prevalence treatment resistance to IVIG.68 Using multivariate logis- of coronary artery lesions to be 2% to 4% in patients January 2015 • www.ebmedicine.net 9 Reprints: www.ebmedicine.net/pempissues Clinical Pathway For Emergency Department Management Of Kawasaki Disease

• Consider alternative diagnosis Fever for ≥ 5 days? NO • Discharge if appropriate • Recommend follow-up with primary YES care physician if fever persists

≥ 4 diagnostic criteria present? • Conjunctivitis • Mucous membrane changes • Polymorphous rash • Extremity changes • Cervical lymphadenopathy

NO YES

2-3 diagnostic criteria present? Obtain laboratory testing • Conjunctivitis • CRP/ESR • Mucous membrane changes • CBC • Polymorphous rash • ALT • Extremity changes • Albumin • Cervical lymphadenopathy • Urinalysis

NO YES

Laboratory tests consistent with Kawa- saki disease? (eg, CRP ≥ 3.0 mg/dL NO Evaluate for Consider alter- and ESR ≥ 40 mm/h) incomplete Ka- native diagnosis wasaki disease YES • Consider alternative diagnosis (Class II) • Monitor for fever for 2-3 days • Recommend follow-up with primary • Start treatment with IVIG and high- care physician if fever persists dose ASA (Class I) • If suspicion for Kawasaki disease • Obtain echocardiogram expeditiously remains high, consider obtaining an (Class II) echocardiogram Consider other treatment options • IVIG plus corticosteroids (Class II) • Infliximab(Class II) • Continue low-dose ASA (Class III) NO Fever resolved within 48 h? YES • Abciximab (Class III) • Follow-up echocardiogram (Class I)

Abbreviations: ALT, alanine aminotransferase; ASA, acetyl salicylic acid (aspirin); CBC, complete blood count; CRP, C-reactive protein; ED, emergency department; ESR, erythrocyte sedimentation rate; IVIG, intravenous immunoglobulin. Class Of Evidence Definitions

Each action in the clinical pathways section of Pediatric Emergency Medicine Practice receives a score based on the following definitions.

Class I Class II Class III Indeterminate • Always acceptable, safe • Safe, acceptable • May be acceptable • Continuing area of research • Definitely useful • Probably useful • Possibly useful • No recommendations until further research • Proven in both efficacy and effectiveness • Considered optional or alternative treat- Level of Evidence: ments Level of Evidence: Level of Evidence: • Generally higher levels of evidence • Evidence not available • One or more large prospective studies are • Nonrandomized or retrospective studies: Level of Evidence: • Higher studies in progress present (with rare exceptions) historic, cohort, or case control studies • Generally lower or intermediate levels of • Results inconsistent, contradictory • High-quality meta-analyses • Less robust randomized controlled trials evidence • Results not compelling • Study results consistently positive and • Results consistently positive • Case series, animal studies, compelling consensus panels • Occasionally positive results

This clinical pathway is intended to supplement, rather than substitute for, professional judgment and may be changed depending upon a patient’s individual needs. Failure to comply with this pathway does not represent a breach of the standard of care. Copyright © 2015 EB Medicine. 1-800-249-5770. No part of this publication may be reproduced in any format without written consent of EB Medicine.

Copyright © 2015 EB Medicine. All rights reserved. 10 www.ebmedicine.net • January 2015 tic regression, they found that age, total days of symp- incomplete disease, with an odds ratio of 1.447 (95% 73 toms, platelet count, CRP, and alanine aminotransferase confidence interval [CI], 1.158-1.808;P = .001). This can be used to predict which patients are likely to be re- included analysis of > 20 studies, for a total of 4504 sistant to IVIG therapy. In the initial study, the score had Kawasaki disease patients and 32,519 controls. How- a sensitivity of 78% and a specificity of 76%. Although ever, the analysis did not address the issue of delay this may be helpful in anticipating treatment resistance, in diagnosis and treatment. it was designed for use in Japan, so treatment resistance A second large study reported the differences patterns will vary. Several recent studies have investi- between complete and incomplete Kawasaki disease at gated the use of the Egami score in North America. The a single center in North America. Manlhiot et al retro- studies found that, when applied to a North American spectively reviewed 955 patients with Kawasaki disease, cohort, the Egami score had adequate specificity, but a finding that 77% presented with complete Kawasaki low sensitivity for predicting IVIG resistance.69,70 Thus, disease while the remaining 23% fell into the incom- 74 this scoring system may be inadequate for detecting plete category. Although this study also showed that patients at risk of treatment resistance in the North the time to diagnosis and treatment was delayed for pa- American population. tients with incomplete disease, there was no significant difference in the rate of development of coronary artery Incomplete Kawasaki Disease aneurysms between the 2 groups (13% vs 11%).74 Within the literature, there is some debate regard- The evidence of incomplete Kawasaki disease as ing the diagnosis of incomplete Kawasaki disease. an independent predictor of aneurysm development Generally, a patient is diagnosed with incomplete is complicated by the difficulty in making a diagnosis disease if Kawasaki disease is suspected but fails to of incomplete Kawasaki disease. It is well documented fulfill the conventional diagnostic criteria.5 These that a longer duration of fever and delay in treatment patients typically display prolonged fever in addi- increase the risk of aneurysm development. Thus, emer- tion to 2 to 3 of the principal criteria, failing to meet gency clinicians who suspect Kawasaki disease should the more traditional definition of at least 4 principal proceed with further evaluation, including laboratory criteria. In these situations, emergency clinicians testing and echocardiography. The AHA reports that should be suspicious of Kawasaki disease. It is conventional diagnostic criteria should be considered important to note that laboratory findings should be as a guideline for Kawasaki disease, and that all patients supportive of the diagnosis of Kawasaki disease, if with fever for ≥ 5 days plus 2 to 3 criteria should be 5 no alternative diagnosis is found in the course of the promptly evaluated. The AAP and AHA provide a frame- evaluation. By most estimates, approximately 20% work for decisions regarding the evaluation of children 5 of patients with Kawasaki disease will likely fall into with suspected incomplete Kawasaki disease. the category of incomplete disease.71 Prior research indicates that children with incom- Treatment plete Kawasaki disease may be at higher risk for the development of coronary artery aneurysms. However, Initial Treatment it is not clear whether this relates to the disease itself or Since the etiology of Kawasaki disease remains un- to the delay in diagnosis that often occurs in cases of clear, the goals of treatment focus on the prevention incomplete disease. Sudo et al examined a large cohort of coronary artery aneurysm development. Early of patients with Kawasaki disease in Japan to study the identification and treatment of Kawasaki disease has epidemiologic differences between patients with com- been shown to reduce the development of coronary plete versus incomplete forms of Kawasaki disease.72 Of artery aneurysms. Treatment should be started as the more than 23,000 patients in the study, 80% fell into soon as a diagnosis of Kawasaki disease is made. the category of complete disease, and the other 20% fell Current recommendations suggest treatment should along a spectrum of having 1 to 4 supporting criteria. be given within 10 days of the onset of fever, and, The patients with incomplete Kawasaki disease had ideally, within 7 days of the onset of fever.5 Initial an increased incidence of coronary artery aneurysms treatment in the United States generally includes compared to the typical Kawasaki disease patients IVIG in combination with high-dose aspirin.75 (13.1% vs 8.8%).72 It should be noted that these patients also tended to be hospitalized later in the course of Intravenous Immunoglobulin their disease and were less likely to receive IVIG than Evidence for the use of IVIG in Kawasaki disease is 72 the children with more typical disease. The authors at- strong. The use of IVIG in Kawasaki disease began in tributed the higher incidence of aneurysms to the delay the 1980s. Several randomized controlled studies dur- in diagnosis and treatment, as well as to the increased ing that time showed a significant reduction in coro- use of echocardiography for establishing a diagnosis of nary artery aneurysm development in children receiv- 72 Kawasaki disease. ing IVIG plus aspirin compared to aspirin alone.57,76 Further, a meta-analysis found that there was Newburger et al used an IVIG dose of 400 mg/kg/day an increased risk of coronary artery aneurysms in for 4 days.57 A follow-up randomized controlled study

January 2015 • www.ebmedicine.net 11 Reprints: www.ebmedicine.net/pempissues several years later showed that a single infusion of Japan, more-moderate doses of aspirin (30-50 mg/kg/ 2 g/kg of IVIG was more effective at preventing day) are given during the febrile phase of the illness.11 58 aneurysms than the traditional 4-dose regimen. This Low-dose aspirin is then continued for 6 to 8 weeks until infusion is generally given over a period of 10 to 12 follow-up echocardiography is normal. For children who hours. More recently, a meta-analysis of randomized develop coronary artery lesions, low-dose aspirin may be controlled trials has shown that treatment with IVIG continued indefinitely for its antiplatelet effects. Despite compared to placebo significantly reduced the risk of the lack of evidence to support the use of aspirin, the 77 coronary artery aneurysms at 30 days. In addition, AHA and the AAP continue to recommend its use in com- the single, higher dose of IVIG was associated with bination with IVIG.5 a reduction in the duration of fever when compared with the multiple-dose regimen.58,77 Corticosteroids The efficacy of IVIG for the treatment of Kawasaki The use of corticosteroids as a routine part of a treat- disease is well established, although the mechanism of ment regimen for Kawasaki disease is still under action is not clearly understood. IVIG is thought to work debate. This treatment dates back to before the use primarily through a generalized anti-inflammatory ac- of IVIG as primary treatment. In 1979, Kato et al tion. Several mechanisms have been proposed, includ- published their research on the treatment of Kawa- ing regulation of Fc-receptor function, suppression of saki disease, exploring 5 different treatment options, proinflammatory cytokine production, inhibition of the including the use of prednisone as monotherapy. complement system, and inhibition of tumor necrosis The research showed a substantially higher rate of 11 factor (TNF) production. However, strong evidence to coronary artery aneurysms in children treated with support these theories is still needed. corticosteroids alone (prednisolone 2-3 mg/kg/day) IVIG is considered to be a safe treatment, although compared to aspirin alone (64.7% vs 11%).80 The it is not without side effects. Common side effects of prednisolone group also had significantly higher the infusion include headaches, fever, chills, myalgias, rates of coronary artery lesions compared to those nausea, vomiting, changes in blood pressure, and tachy- treated with a combination of steroids plus aspirin 78 cardia. If such side effects occur, they can generally or no treatment. However, this study had significant be managed by slowing the infusion and by providing limitations. It was a relatively small sample, with supportive care. Serious side effects are uncommon, a total of 92 patients. There was no randomization, but can include acute renal failure, aseptic meningitis, and the size of each treatment group varied signifi- neutropenia, anaphylaxis, and autoimmune hemo- cantly, with some groups having as few as 7 pa- 78 lytic anemia. In addition, IVIG is also a pooled-blood tients. Despite these limitations, this study led to the product and thus carries the risk of transfusion-related near-abandonment of corticosteroids as a part of the infections as well. treatment for Kawasaki disease. More recently, the question of using corticosteroids Aspirin in combination with IVIG for primary treatment has Aspirin has long been used as part of the treatment been explored. Newburger et al conducted a multi- for Kawasaki disease. It is theorized that since aspi- center, randomized, placebo-controlled, double-blinded rin has anti-inflammatory effects as well as anti- study in the United States to compare standard therapy platelet effects, it should be useful in the treatment (IVIG plus high-dose aspirin) to standard therapy plus of Kawasaki disease. However, there is insufficient methylprednisolone.81 The findings showed no sig- evidence in the literature to show that aspirin at nificant difference in the number of days spent in the any dose reduces the incidence of coronary artery hospital, the duration of fever, rates of initial treatment 5 aneurysms. A Cochrane review of the literature failure, or the incidence of coronary artery aneurysms. identified only 1 randomized controlled trial exam- Based on this evidence, they concluded that cortico- ining the use of aspirin in Kawasaki disease. This steroids are not useful as a routine adjunct to IVIG in single study failed to demonstrate an added benefit standard-risk Kawasaki patients. of aspirin plus IVIG compared to IVIG alone to re- There is continued interest in the use of steroids 79 duce the development of coronary artery lesions. for patients who are considered to be at a high risk Given the lack of randomized controlled trials, the of treatment resistance. A randomized trial from Cochrane review was unable to support or negate a single institution in Japan explored the use of the use of aspirin in the treatment of Kawasaki dis- standard treatment plus corticosteroids in patients 79 ease. Despite this, many centers continue to use predicted to be at a high risk of refractory disease.82 aspirin in conjunction with IVIG. A total of 48 patients out of 122 were predicted to Without sufficient evidence for its use, there are no have Kawasaki disease that was refractory to treat- consistent recommendations on aspirin dosing. In North ment, and they were randomized to receive standard America, aspirin is generally started at high doses (80-100 therapy of IVIG plus aspirin or standard therapy of mg/kg/day) and divided into 4 doses. The dose is then IVIG plus a single dose of intravenous methylpred- 5,6 decreased to 3 to 5 mg/kg/day after defervescence. In nisolone (30 mg/kg). Significantly more patients in

Copyright © 2015 EB Medicine. All rights reserved. 12 www.ebmedicine.net • January 2015 the standard treatment plus methylprednisolone 5 mg/kg of infliximab and 2 patients were treated group had a prompt defervescence compared to with 10 mg/kg. Of the 16 patients who were febrile patients who received standard therapy alone (86.4% prior to treatment with infliximab, 13 had cessa- versus 23.1%). In addition, the group that received tion of fever after treatment. The limitations of this steroids had a 9% rate of coronary artery aneurysms study include its small size and retrospective nature. on echocardiogram at 1 month compared to 39% in However, given the overall favorable response to the standard treatment group. This study, performed treatment in these patients, the authors of the study by Ogata et al, was well designed, but limited in its concluded that further research was warranted. application due to its small size.82 A follow-up study by Burns et al investigated the A second Japanese study by Kobayashi et al use of infliximab for resistant Kawasaki disease using a used a larger, multicenter approach.83 As in the prior multicenter, randomized, prospective approach.85 This study, this one addressed the use of corticosteroids study compared infliximab 5 mg/kg to a second dose of as an adjunct to the standard initial therapy for IVIG 2 g/kg in patients who had persistent fever after an patients classified as being at high risk. In this case, initial dose of IVIG. In this study, 8 of 12 patients given patients were randomized to standard treatment a second dose of IVIG had prompt resolution of fever of IVIG (123 patients) or standard treatment plus compared to 11 of 12 patients treated with infliximab. steroids (125 patients). The steroid regimen included There were no differences in adverse outcomes be- intravenous prednisolone (2 mg/kg/day in divided tween the 2 groups. Although further research is need- doses) for 5 days followed by a 15-day oral prednis- ed, infliximab is generally safe and should be considered olone taper. The results showed only 3% of patients as an alternative therapy in treatment-resistant disease. treated with corticosteroids developed coronary artery aneurysms, compared to 23% of patients who Abciximab received the standard treatment. Abciximab (ReoPro®), another monoclonal anti- It should be noted that the Newburger et al study body, has been investigated for use in patients who did not separate patients into risk categories, but used develop aneurysms. Abciximab inhibits the gly- a general group of patients with Kawasaki disease.81 In coprotein IIb/IIIa inhibitor. It has previously been comparison, both the Ogata et al and Kobayashi et al used in adults to prevent thrombotic complications studies examined only patients characterized as high and promote vascular remodeling in acute coronary risk (by applying the Egami criteria). This suggests that, disease.86 Case reports have shown improvement although corticosteroids do not need to be given to all in coronary artery aneurysms in children treated Kawasaki patients, there may be a select group of high- with abciximab. A retrospective study compared risk patients who would benefit from the addition of 9 patients with coronary artery aneurysms who corticosteroids to the standard therapy. received standard therapy to 6 patients with similar lesions who received standard therapy plus abcix- Treatment Resistance imab. In this study, standard therapy was defined as Although the standard therapy of IVIG plus high- IVIG 2 g/kg plus aspirin 80 to 100 mg/kg/day. The dose aspirin is effective for most patients with patients who received abciximab had a significantly Kawasaki disease, it is estimated that approximately higher rate of resolution of their aneurysms com- 10% to 20% of patients will fail to respond to this pared to the patients who received standard therapy therapy.5 Second-line therapy usually consists of (68% vs 37%).86 Although these results are encourag- retreatment with IVIG, potentially in combination ing, the study was very small and was performed in with corticosteroids. Persistent fever and elevations a retrospective fashion. Further study on the use of of inflammatory markers place patients at a high abciximab for Kawasaki disease is needed, prefer- risk of developing coronary artery aneurysms and ably in the form of prospective trials. other cardiac complications. Therefore, the choice of treatment for resistant disease becomes important. Special Populations

Infliximab In addition to having a propensity to occur in certain Infliximab (Remicade®) is a monoclonal antibody populations, Kawasaki disease has been noted to be directed against tumor necrosis factor alpha-1 (TNF- affected by genetics. Children whose parents had alpha) and blocks its function. Infliximab was theo- Kawasaki disease have a slightly higher risk of de- rized to work in Kawasaki disease, as TNF-alpha veloping the disease.87 Siblings of children affected levels are known to be elevated in patients with this by Kawasaki disease are at significantly higher disease.75 To explore the effectiveness of infliximab risk for developing Kawasaki disease themselves. as a treatment for recalcitrant Kawasaki disease, Familial studies in Japan show siblings of affected Burns et al published a case series of 16 patients children to have 10 times the relative risk for devel- treated with infliximab after they failed to respond opment of the disease.88 Such cases were also more to IVIG.84 In this series, 14 patients were treated with likely to have recurrent disease.87

January 2015 • www.ebmedicine.net 13 Reprints: www.ebmedicine.net/pempissues Researchers in North America studied clusters of nificantly different from the mean periostin level of families with multiple cases of Kawasaki disease in sib- 42,549 ng/mL in all patients with Kawasaki disease lings or cousins.89 The researchers obtained information (P = .0086).91 Although promising, this was a small from 2 hospitals, as well as from families who contacted study, and the results need to be validated. a Kawasaki disease research program. They were able to identify 9 families in which 2 siblings were diagnosed Disposition with Kawasaki disease, for a total of 18 affected children. They also identified 9 other families with 24 affected Patients with suspected Kawasaki disease, either children. Many of these cases were separated by both complete or incomplete, should be admitted to an time and geography, so the researchers were unable appropriate pediatric inpatient facility. Treatment for to identify a clear pattern of inheritance. Despite this, Kawasaki disease involves, at a minimum, an infu- clinicians should be aware of the tendency for Kawasaki sion of IVIG, which is typically given over a period of disease to run in families, as this may lead to a more hours. Side effects of this medication may include fe- timely diagnosis and reduce the risk of coronary artery ver, headache, urticaria, nausea, vomiting, and blood aneurysm development. pressure instability. Although uncommon, anaphy- laxis, Stevens-Johnson syndrome, and nephrotoxicity Emerging Research have been reported, so it is in the best interest of the patient to be admitted for monitoring during treat- To date, there is no definitive test for Kawasaki ment. In addition, most hospitals will keep children in disease, leading to potentially dangerous delays in the hospital until the fever resolves, as children with diagnosis and treatment. Prior research has shown ongoing fevers may be resistant to traditional treat- that delays in diagnosis increase the risk of compli- ments. Ideally, children should be admitted to a unit cations (including coronary artery aneurysms) and with the capability for pediatric echocardiography mortality. To this end, several researchers have been and access to a pediatric cardiologist for complete working to find a more definitive laboratory test evaluation of the heart and coronary artery aneu- to help emergency clinicians make the diagnosis of rysms. Children who present with myocarditis, im- Kawasaki disease. paired ventricular function, or giant coronary artery Kentsis et al have been studying urine proteomics aneurysms in the setting of acute Kawasaki disease in an attempt to find a sensitive diagnostic test for should be managed at a facility with a pediatric cardi- making the diagnosis of Kawasaki disease.90 The study ology service and pediatric intensive care unit. looked at a total of 107 patients, of whom 53 had a Children with Kawasaki disease can be discharged diagnosis of Kawasaki disease and 54 had Kawasaki-like after completion of therapy provided there is resolu- symptoms, but a different final diagnosis (such as viral tion of fever. High-dose aspirin (80-100 mg/kg/day illness). The researchers identified that filamin C, which in the United States) is generally continued for 48 to is associated with myocardial and endothelial damage, 72 hours after defervescence. All children with Kawa- and meprin A, which is an immune modulator, were saki disease should be discharged on low-dose aspirin present in high concentrations in the urine of patients (3-5 mg/kg/day), which should be maintained for a with Kawasaki disease compared to patients with other minimum of 6 to 8 weeks following diagnosis. Echo- febrile diagnoses. This was true for both the complete cardiography should be repeated at 2 weeks post di- and incomplete forms of Kawasaki disease. In addition, agnosis, and then again at 6 to 8 weeks post diagnosis. the diagnostic performance of these tests was superior Aspirin can be discontinued at that time if no coronary to the diagnostic performance of ESR, CRP, or a combi- artery abnormalities are found on echocardiography. nation of the 2 tests. In addition, the levels of meprin A Recurrence rates of Kawasaki disease are low. Large and filamin C present in the urine were found to decline epidemiologic studies done in Japan estimate a recur- after treatment with IVIG.90 Future research is needed to rence rate of 3% to 4%.11,92 Similar studies estimate a validate these findings. recurrence rate of 2% in the North American popula- Reindel et al investigated serum periostin lev- tion.93,94 Recurrence tends to be more common in els as a possible biomarker for diagnosing Kawa- children aged < 3 years of age at the time of the initial saki disease.91 The authors hypothesized that, since episode.94 Emergency clinicians need to be aware of the periostin plays a role in vascular and cardiac dam- risk of recurrence when evaluating a patient with a his- age, it might be elevated in patients with Kawasaki tory of Kawasaki disease. disease. In this study, the researchers compared serum periostin levels of 30 control patients (15 Long-Term Prognosis afebrile controls, 15 febrile controls) to the periostin levels of 27 patients with Kawasaki disease (12 with Since Kawasaki disease was first described more coronary artery aneurysms, 15 without coronary than 40 years ago, outcomes have improved signifi- artery aneurysms). The mean periostin level in all cantly. With proper identification and treatment, the control patients was 5647 ng/mL, which was sig- incidence of coronary artery lesions has declined

Copyright © 2015 EB Medicine. All rights reserved. 14 www.ebmedicine.net • January 2015 to approximately 3% to 5%, from an initial rate of lesions will regress within 1 to 2 years.5,6 Coronary 25% to 30% previously.95 Long-term management arteries may develop areas of stenosis, and these le- of children following diagnosis of Kawasaki disease sions are frequently progressive. Depending on the depends largely on whether or not they develop type, location, and size of the lesion, these children coronary artery lesions. Risk stratification schemes may require long-term antiplatelet or anticoagula- exist to help guide follow-up. These can be found in tion therapy and frequent evaluations by a pediatric the AHA guidelines on Kawasaki disease, and they cardiologist. (See Table 4, page 15.) are summarized in Table 4. Mortality rates for Kawasaki disease are general- Children who are promptly diagnosed and ly low, and they are currently estimated to be 0.01% treated and who do not develop coronary artery to 0.2% currently.94 Mortality peaks between 15 and lesions are considered at low risk. These children are 45 days after the onset of disease, and it is most thought to have long-term cardiac outcomes similar often due to coronary artery thrombosis.5,94 Myo- to the population without Kawasaki disease.5 These cardial infarction can occur secondary to thrombotic patients are generally treated with a 6- to 8-week occlusion of an aneurysm or stenotic vessel, and the course of antiplatelet therapy, and are followed by highest risk of this occurs within the first year after cardiology every 3 to 5 years after the first year. diagnosis.5 Other causes of death include conges- Despite proper recognition and treatment, a small tive heart failure, arrhythmias, or coronary artery percentage of children develop coronary artery rupture.94 As children with Kawasaki disease age, aneurysms. It is estimated that 50% to 70% of such there is a recognized risk of late myocardial infarc-

Table 4. American Academy Of Pediatrics Risk Stratification And Recommendations On Follow-Up

Risk Level (I-V) Pharmacological Therapy Physical Activity Follow-Up and Invasive Testing Diagnostic Testing I (no coronary artery None beyond first 6-8 wk No restrictions beyond first Cardiovascular risk assess- None recommended changes at any stage of 6-8 wk ment, counseling at 5-y illness) intervals II (transient coronary ar- None beyond first 6-8 weeks No restrictions beyond first Cardiovascular risk assess- None recommended tery ectasia, disappears 6-8 wk ment, counseling at 5-y within first 6-8 wk) intervals III (1 small-medium coronary Low-dose aspirin (3-5 mg/ For patients aged < 11 y, Annual cardiology follow-up Angiography, if noninvasive artery aneurysm/major kg/day), at least until no restriction beyond first with echocardiogram test suggests ischemia coronary artery) aneurysm regression is 6-8 wk; patients aged + ECG, combined with documented 11-20 y, physical activity cardiovascular risk assess- guided by biennial stress ment, counseling; biennial test, evaluation of myo- stress test/evaluation of cardial perfusion scan; myocardial perfusion scan contact or high-impact sports discouraged for patients taking antiplate- let agents IV (large or giant coronary Long-term antiplatelet Contact or high-impact Biannual follow-up with First angiography at 6-12 artery aneurysm, or multi- therapy and warfarin sports should be avoided echocardiogram + ECG; mo or sooner, if clini- ple or complex aneurysms (target INR 2-2.5) or because of risk of bleeding; annual stress test/ cally indicated; repeated in same coronary artery, low–molecular-weight other physical activity evaluation of myocardial angiography if noninvasive without obstruction) heparin (target anti- recommendations guided perfusion scan test, clinical, or labora- factor Xa level 0.5-1 by stress test/evaluation of tory findings suggest U/mL), should be com- myocardial perfusion scan ischemia; elective repeat bined in giant aneurysms outcome angiography under some circumstances V (coronary artery obstruc- Long-term low-dose aspirin; Contact or high-impact Biannual follow-up with Angiography recommended tion) warfarin or low-molecular- sports should be avoided echocardiogram and to address therapeutic weight heparin if giant because of risk of bleeding; ECG; annual stress test/ options aneurysm persists; con- other physical activity evaluation of myocardial sider use of low-molecular- recommendations guided perfusion scan weight consumption by stress test/myocardial perfusion scan outcome

Abbreviations: ECG, electrocardiogram; INR, international normalized ratio. Reproduced with permission from Pediatrics, Vol. 114, Issue 6, pages 1708-1733, Copyright © 2004 by the AAP.

January 2015 • www.ebmedicine.net 15 Reprints: www.ebmedicine.net/pempissues Risk Management Pitfalls In Kawasaki Disease

1. “I thought the child had a viral illness, so I treat- 4. “I was unsure of the diagnosis, so I waited to ed her with antipyretics and discharged her.” start treatment with IVIG.” Fevers are common in children, and many Delays in making the diagnosis and delays in children with fever will likely have a viral starting treatment significantly increase the illness. Many of the other symptoms of risk of developing coronary artery aneurysms. Kawasaki disease are found in viral illnesses, If the emergency clinician has a high suspicion such as rash and conjunctivitis. However, for Kawasaki disease and laboratory values Kawasaki disease should be considered in all support the diagnosis, treatment should be patients with parental report of prolonged initiated promptly. Echocardiogram should be fever. Failure to recognize and treat Kawasaki performed as soon as possible, but this should disease in a timely manner can have catastrophic not delay treatment. consequences. 5. “I know that the guidelines recommend echo- 2. “The child did not meet the criteria for all of cardiography for assessment of coronary arter- the symptoms on presentation to the ED, so I ies when the suspicion is high for Kawasaki thought she could not have Kawasaki disease.” disease, so I delayed treatment to obtain the The diagnosis of incomplete Kawasaki disease imaging.” can be difficult. It is necessary to have a high Ideally, initial echocardiography should be index of suspicion with regard to Kawasaki performed on the day of diagnosis. Guidelines disease in children with a fever lasting ≥ 5 days. from the AHA and the AAP recommend It is important to note that symptoms may prompt echocardiography once Kawasaki present sequentially rather than simultaneously, disease is diagnosed or suspected, although and, thus, some of the diagnostic symptoms delays in obtaining imaging should not delay may be resolved prior to presentation to the ED. initiation of treatment. If a patient has fever plus 2 to 3 of the diagnostic criteria, further evaluation with laboratory 6. “The patient failed to respond to initial stan- studies and possibly an echocardiogram is dard treatment of IVIG and aspirin, and I warranted to evaluate for Kawasaki disease. By didn’t know what to choose next.” most estimates, approximately 20% of patients Although the standard therapy of IVIG plus with Kawasaki disease will fall into the category high-dose aspirin is effective for most patients of incomplete disease. with Kawasaki disease, it is estimated that approximately 10% to 20% of patients will fail 3. “I suspected Kawasaki disease, but I was to respond to this therapy. Second-line therapy unsure of the diagnosis, so I waited for the usually consists of retreatment with IVIG, laboratory tests to return before beginning potentially in combination with corticosteroids. any treatment.” Although further research is needed, infliximab There is no single diagnostic test to confirm is generally safe and should be considered as an the diagnosis of Kawasaki disease. Diagnosis alternative therapy in treatment-resistant disease. centers on the presence of the criteria for Kawasaki disease, which include fever for at 7. “I ordered an echocardiogram for the patient, least 5 days, plus 4 of 5 of the following key but there were no findings, so I ruled out Ka- criteria: conjunctival injection, oral mucosal wasaki disease.” changes, polymorphous rash, distal extremity It should be noted that a normal initial changes, and cervical lymphadenopathy. echocardiogram should not be used to exclude Treatment should not be delayed if the diagnosis the diagnosis of Kawasaki disease, especially if can be confirmed by the history and physical physical examination findings and laboratory examination. Early identification and treatment tests are consistent with the diagnosis. of Kawasaki disease has been shown to reduce the development of coronary artery aneurysms.

Copyright © 2015 EB Medicine. All rights reserved. 16 www.ebmedicine.net • January 2015 tion, often occurring years later. This may occur due Case Conclusion to thrombosis of aneurysms or progressive steno- 96 sis. Although the risks are significantly higher in After evaluating this 3-year-old patient, you had some patients with known coronary artery lesions, there concerns that the patient had incomplete Kawasaki disease. may be an increase in patients without such lesions, Review of the diagnostic criteria revealed that this patient 93 but these risks have yet to be fully defined. In the had the characteristic criteria of 5 days of fever, and met 3 meantime, emergency clinicians should be aware of of the supporting diagnostic criteria (conjunctivitis, oral these risks when assessing adults with a history of mucous membrane changes, and polymorphous rash). Kawasaki disease. You discussed this possibility with the mother, and pro- ceeded with laboratory workup. The patient’s laboratory Summary tests showed a white blood cell count of 18,900/mm3, but normal hemoglobin of 12.3 g/dL and normal platelet count Kawasaki disease is an acute, febrile vasculitis of of 320,000/mm3. She was mildly hyponatremic, with a childhood, primarily affecting small- to medium- sodium level of 132 mEq/L, although the remainder of her sized arteries. It is a self-limited disease, but can result electrolyte levels were normal. Her inflammatory markers in the development of coronary artery aneurysms if were extremely elevated, with a CRP of > 25 mg/dL and an left untreated. Despite significant research, the exact ESR of 87 mm/h. She was mildly hypoalbuminemic, with etiology of the disease remains unknown. In the an albumin level of 2.7 g/dL. Her liver enzymes revealed a United States, clinical criteria for diagnosis of com- normal AST of 54 U/L, but an elevated ALT of 131 U/L. plete Kawasaki disease include fever for ≥ 5 days and Her urinalysis was positive for leukocyte esterase and nega- at least 4 of 5 supporting symptoms. These symptoms tive for nitrites. Urine also had 10 to 25 WBC/HPF and 0 include conjunctival injection, oral mucosal changes, RBC/HPF. Blood and urine cultures remained negative. polymorphous rash, distal extremity changes, and These laboratory results were consistent with a diagno- cervical lymphadenopathy. Emergency clinicians sis of incomplete Kawasaki disease, so you admitted the should be aware that a smaller proportion of chil- patient for treatment. You consulted cardiology to obtain dren will present with incomplete Kawasaki disease, an echocardiogram. In the meantime, she was started on comprised of fever for ≥ 5 days plus 2 to 3 of the sup- IVIG 2 g/kg and high-dose aspirin of 100 mg/kg/day. The porting symptoms. These patients will typically have echocardiogram showed no coronary artery aneurysms. laboratory findings that support the diagnosis. However, she was noted to have mildly decreased left ven- All children with suspected or confirmed Kawasaki tricular function, mild mitral insufficiency, and a small disease should have echocardiography performed pericardial effusion. She continued to have a fever for 48 to assess for coronary artery abnormalities. Primary hours after IVIG administration, and was given a second treatment for Kawasaki disease includes IVIG infusion. dose, after which she promptly defervesced. Her cardiac Despite a lack of strong evidence in its favor, many function subsequently improved. She was discharged institutions continue to include high-dose aspirin as home on low-dose aspirin, and was scheduled for follow- part of the treatment protocol. Treatment should ideally up with a pediatric cardiologist. be started within 10 days of the onset of fever. Patients who have persistent fever despite treatment may need repeated IVIG infusion or treatment with corticosteroids. In addition, infliximab and abciximab are currently be- ing investigated for use in resistant disease, although Time- And Cost-Effective further studies are needed. Children who are untreated Strategies or have delays in diagnosis and treatment are at an increased risk for development of coronary artery aneu- rysms, thrombosis, and sudden cardiac death. • If the suspicion for Kawasaki disease is high or if the diagnosis is confirmed (patient meets criteria for Kawasaki disease), treatment should not be delayed while awaiting echocardiogra- phy. Ideally, initial echocardiography should be performed on the day of diagnosis to assess for coronary artery aneurysm.

• Children who have symptoms consistent with incomplete Kawasaki disease, but whose labora- tory testing is not definitive, should be referred for echocardiography. The presence of coronary artery ectasia or perivascular echo brightness can aid in finalizing the diagnosis, ensuring that the child can be treated in a timely manner.

January 2015 • www.ebmedicine.net 17 Reprints: www.ebmedicine.net/pempissues References disease in England: ethnicity, deprivation, and respiratory pathogens. Pediatr Infect Dis J. 2009;28(1):21-24. (Epidemio- logic study; 1704 patients) Evidence-based medicine requires a critical ap- 15. Royle JA, Williams K, Elliott E, et al. Kawasaki disease in praisal of the literature based upon study methodol- Australia, 1993-95. Arch Dis Child. 1998;78(1):33-39. (Epide- ogy and number of subjects. Not all references are miologic study; 139 cases) equally robust. The findings of a large, prospective, 16. Rowley AH, Shulman ST. New developments in the search random­ized, and blinded trial should carry more for the etiologic agent of Kawasaki disease. Curr Opin Pedi- weight than a case report. atr. 2007;19(1):71-74. (Review article) To help the reader judge the strength of each ref- 17. Leung DY, Meissner HC, Fulton DR, et al. Toxic shock syn- erence, pertinent information about the study will be drome toxin-secreting Staphylococcus aureus in Kawasaki syndrome. Lancet. 1993;342(8884):1385-1388. (Prospective included in bold type following the reference,­ where cohort study; 31 patients) available. The most informative references cited in this 18. Terai M, Miwa K, Williams T, et al. The absence of evidence paper, as determined by the author, will be noted by of staphylococcal toxin involvement in the pathogenesis of an asterisk (*) next to the number of the reference. Kawasaki disease. J Infect Dis. 1995;172(2):558-561. (Prospec- tive case-control study; 48 patients) 1.* Kawasaki T. Acute febrile mucocutaneous syndrome with 19. Leung DY, Meissner HC, Shulman ST, et al. Prevalence of lymphoid involvement with specific desquamation of the superantigen-secreting bacteria in patients with Kawasaki fingers and toes in children.Arerugi . 1967;16(3):178-122. disease. J Pediatr. 2002;140(6):742-746. 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Incomplete clinical manifestation as patients with Kawasaki disease whose parents had the same a risk factor for coronary artery abnormalities in Kawasaki disease. Arch Pediatr Adolesc Med. 2004;158 (12):1166-1169. disease: a meta-analysis. Eur J Pediatr. 2013;172(3):343-349. (Retrospective cohort study; 65 patients) (Meta-analysis; 20 studies, 4504 patients, 32,519 controls) 88. Hirata S, Nakamura Y, Yanagawa H. Incidence rate of recur- 74. Manlhiot C, Christie E, McCrindle BW, et al. Complete and rent Kawasaki disease and related risk factors: from the re- incomplete Kawasaki disease: two sides of the same coin. sults of a nationwide surveys of Kawasaki disease in Japan. Eur J Pediatr. 2012;171(4):657-662. (Retrospective review; 955 Acta Paediatr. 2001;90(1):40-44. (Epidemiologic study; 10,679 patients) patients) 75. Dominguez SR, Anderson MS. Advances in the treatment 89. Dergun M, Kao A, Hauger S, et al. Familial occurance of of Kawasaki disease. Curr Opin Pediatr. 2013;25(1):103-109. Kawasaki syndrome in North America. Arch Pediatr Adolesc (Review) Med. 2005;159(9):876-881. (Retrospective cohort study; 42 patients) 76. Furusho K, Kamiya T, Nakano H, et al. High-dose intra- venous gammaglobulin for Kawasaki disease. Lancet. 90. Kentsis A, Shulman A, Ahmed S, et al. Urine proteomics 1984;2(8411):1055-1058. (Multicenter control trial; 85 pa- for discovery of improved diagnostic markers of Kawasaki tients) disease. EMBO Mol Med. 2013;5(2):210-220. (Retrospective case-control study; 107 patients) 77.* Oates-Whitehead RM, Baumer JH, Haines L, et al. Intrave- nous immunoglobulin for the treatment of Kawasaki disease 91. Reindel R, Kim KY, Baker SC, et al. Periostin is upregulated in children. Cochrane Database Syst Rev. 2003;(4):CD004000. in coronary arteriopathy in Kawasaki disease and is a poten- (Meta-analysis and review) tial diagnostic biomarker. Pediatr Infect Dis J. 2014;33(6):659- 661. (Case-control study; 57 patients) 78. Orbach H, Katz U, Sherer Y, et al. Intravenous immunoglob- ulin: adverse effects and safe administration. Clin Rev Allergy 92. Yanagawa H, Nakamura Y, Yashiro M, et al. Update of the Immunol. 2005;29(3):173-184. (Review) epidemiology of Kawasaki disease in Japan--from the results of 1993-94 nationwide survey. J Epidemiol. 1996;6(3):148-157. 79. Baumer JH, Love S, Gupta A, et al. Salicylate for the treat- (Epidemiologic study; 11,458 cases) ment of Kawasaki disease in children. Cochrane Database Syst Rev. 2006;(4):CD004175. (Meta-analysis and review) 93. Belay ED, Maddox RA, Holman RC, et al. Kawasaki syn- drome and risk factors for coronary artery abnormalities: 80. Kato H, Koike S, Yokoyama T. Kawasaki disease: effect United States, 1994-2003. Pediatr Infect Dis J. 2006;25(3):245- of treatment on coronary artery involvement. Pediatrics. 249. (Epidemiologic study; 3115 patients) 1979;63(2):175-179. (Prospective case-control study; 92 patients) 94. Bayers S, Shulman ST, Paller AS. Kawasaki disease: part II. Complications and treatment. J Am Acad Dermatol. 81. Newburger JW, Sleeper LA, McCrindle BW, et al. Random- 2013;69(4):513.e511-e518. (Review) ized trial of pulsed corticosteroid therapy for primary treat- ment of Kawasaki disease. N Engl J Med. 2007;356(7):663-675. 95. Fukazawa R. Long-term prognosis of Kawasaki dis- (Prospective multicenter randomized trial; 199 patients) ease: increased cardiovascular risk? Curr Opin Pediatr. 2010;22(5):587-592. (Review) 82. Ogata S, Ogihara Y, Honda T, et al. Corticosteroid pulse combination therapy for refractory Kawasaki disease: a ran- 96. Daniels LB, Gordon JB, Burns JC. Kawasaki disease: late car- domized trial. Pediatrics. 2012;129(1):e17-e23. (Prospective diovascular sequelae. Curr Opin Cardiol. 2012;27(6):572-577. randomized trial; 122 patients) (Review)

Copyright © 2015 EB Medicine. All rights reserved. 20 www.ebmedicine.net • January 2015 CME Questions 5. Lymphadenopathy in Kawasaki disease: a. Is usually axillary b. Occurs in 80% to 90% of children with Take This Test Online! Kawasaki disease c. Requires antibiotic management Current subscribers receive CME credit absolutely d. Is usually unilateral free by completing the following test. Each issue includes 4 AMA PRA Category 1 CreditsTM, 4 ACEP 6. Elevation of which of the following labora- Category I credits, 4 AAP Prescribed credits, and 4 Take This Test Online! tory results aids in the diagnosis of Kawasaki AOA Category 2A or 2B credits. Monthly online disease? testing is now available for current and archived a. Sodium issues. To receive your free CME credits for this b. Albumin issue, scan the QR code below with your smart- c. Cholesterol phone or visit www.ebmedicine.net/P0115. d. CRP

7. Incomplete Kawasaki disease may be diag- nosed when a child presents with: a. Myocarditis of unknown etiology b. Fever and rash and the patient is an Asian/ Pacific Islander c. Fever for ≥ 5 days plus 2 to 3 of the 1. Diagnostic clinical criteria for Kawasaki dis- diagnostic criteria ease include all of the following EXCEPT: d. Two to 3 of the diagnostic criteria without a. Conjunctivitis fever b. Oropharyngeal changes c. Vomiting 8. In the United States, what is the standard treat- d. Extremity changes ment for Kawasaki disease? a. Supportive care 2. Rates of Kawasaki disease are highest in which b. IVIG plus aspirin population? c. Corticosteroids a. Asian/Pacific Islanders d. Aciximab b. Hispanics c. Blacks 9. At this time, an option for treatment of resis- d. Whites tant disease is: a. Propranolol 3. The polymorphous rash associated with Kawa- b. Infliximab saki disease is commonly: c. Dialysis a. Vesicular d. Ampicillin b. Bullous c. Diffuse macular 10. The risk of a child developing Kawasaki dis- d. Urticarial ease is significantly increased if: a. The child has a sibling with Kawasaki 4. Which finding in patients who have previously disease received the BCG vaccination is highly specific b. The child is unimmunized for Kawasaki disease? c. The child attends daycare a. Jaundice d. The child has congenital heart disease b. Erythema at the BCG injection site c. Shock d. Arthritis

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January 2015 • www.ebmedicine.net 23 Reprints: www.ebmedicine.net/pempissues Physician CME Information

Date of Original Release: January 1, 2015. Date of most recent review: December 15, 2014. Termination date: January 1, 2018.

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