Download Evidence-Based Management Of Kawasaki Disease

Evidence-Based Management
Of Kawasaki Disease In The
Emergency Department
January 2015
Volume 12, Number 1
Authors
Kara K. Seaton, MD
Fellow, Pediatric Emergency Medicine, Children’s Hospital and
Clinics of Minnesota, Minneapolis, MN
Anupam Kharbanda, MD
Director of Research, Emergency and Trauma Services,
Children’s Hospital and Clinics of Minnesota, Minneapolis, MN
Abstract
Peer Reviewers
Kawasaki disease, also known as mucocutaneous lymph node syndrome, was first described in Japan in 1967. It is currently the leading
cause of acquired heart disease in children in the United States. Untreated Kawasaki disease may lead to the formation of coronary artery
aneurysms and sudden cardiac death in children. This vasculitis presents with fever for ≥ 5 days, plus a combination of key criteria. Because
each of the symptoms commonly occurs in other childhood illnesses,
the disease can be difficult to diagnose, especially in children who
present with an incomplete form of the disease. At this time, the etiology of the disease remains unknown, and there is no single diagnostic
test to confirm the diagnosis. This issue reviews the presentation, diagnostic criteria, and management of Kawasaki disease in the emergency
department. Emergency clinicians should consider Kawasaki disease
as a diagnosis in pediatric patients presenting with prolonged fever, as
prompt evaluation and management can significantly decrease the risk
of serious cardiac sequelae.
Editor-in-Chief
Catherine Sellinger, MD, FAAP
Associate Director, Pediatric Emergency Services, Children’s
Hospital at Montefiore; Assistant Professor of Pediatrics, Albert
Einstein College of Medicine, Bronx, NY
Michael J. Stoner, MD
Assistant Professor of Pediatrics, The Ohio State University
College of Medicine; Attending Physician, Pediatric Emergency
Medicine, Nationwide Children’s Hospital, Columbus, OH
CME Objectives
Upon completion of this article, you should be able to:
1.
Describe the clinical features and risks associated with
Kawasaki disease.
2. Identify epidemiologic trends in Kawasaki disease in highrisk populations.
3. Assess the differences between complete and incomplete
presentations of Kawasaki disease.
4. Discuss the initial treatment of Kawasaki disease and
possible options for treating resistant disease.
Prior to beginning this activity, see “Physician CME
Information” on the back page.
Ilene Claudius, MD
Therapeutics; Research Director,
Associate Professor of Emergency
Pediatric Emergency Medicine, BC
Adam E. Vella, MD, FAAP
Medicine, Keck School of Medicine
Children's Hospital, Vancouver, BC,
Associate Professor of Emergency
of the University of Southern
Canada
Medicine, Pediatrics, and Medical
California, Los Angeles, CA
Alson S. Inaba, MD, FAAP
Education, Director Of Pediatric
Ari Cohen, MD
Associate Professor of Pediatrics,
Emergency Medicine, Icahn
University of Hawaii at Mãnoa
School of Medicine at Mount Sinai, Chief of Pediatric Emergency
Medicine Services, Massachusetts
John A. Burns School of Medicine,
New York, NY
General Hospital; Instructor in
Division Head of Pediatric
Associate Editor-in-Chief
Pediatrics, Harvard Medical
Emergency Medicine, Kapiolani
School, Boston, MA
Medical Center for Women and
Vincent J. Wang, MD, MHA
Children, Honolulu, HI
Associate Professor of Pediatrics, Marianne Gausche-Hill, MD,
Melissa Langhan, MD, MHS
Associate Professor of Pediatrics,
Fellowship Director, Pediatric
Emergency Medicine, Director of
Education, Pediatric Emergency
Medicine, Yale School of Medicine,
New Haven, CT
Editorial Board
Joshua Nagler, MD
Assistant Professor of Pediatrics,
Harvard Medical School;
Fellowship Director, Division of
Emergency Medicine, Boston
Children’s Hospital, Boston, MA
Keck School of Medicine of the
University of Southern California;
Associate Division Head,
Division of Emergency Medicine,
Children's Hospital Los Angeles,
Los Angeles, CA
Jeffrey R. Avner, MD, FAAP
Professor of Clinical Pediatrics
and Chief of Pediatric Emergency
Medicine, Albert Einstein College
of Medicine, Children’s Hospital at
Montefiore, Bronx, NY
FACEP, FAAP
Madeline Matar Joseph, MD, FAAP,
Professor of Clinical Medicine,
FACEP David Geffen School of Medicine
Professor of Emergency Medicine
at the University of California at
and Pediatrics, Chief and Medical
Los Angeles; Vice Chair and Chief,
Director, Pediatric Emergency
Division of Pediatric Emergency
Medicine Division, University
Medicine, Harbor-UCLA Medical
of Florida Medical SchoolCenter, Los Angeles, CA
Jacksonville, Jacksonville, FL
Michael J. Gerardi, MD, FAAP,
FACEP, President-Elect
Associate Professor of Emergency
Medicine, Icahn School of
Medicine at Mount Sinai; Director,
Pediatric Emergency Medicine,
Goryeb Children's Hospital,
Morristown Medical Center,
Morristown, NJ
Stephanie Kennebeck, MD
Associate Professor, University
of Cincinnati Department of
Pediatrics, Cincinnati, OH
Anupam Kharbanda, MD, MS
Research Director, Associate
Fellowship Director, Department
of Pediatric Emergency Medicine,
Children's Hospitals and Clinics of
Minnesota, Minneapolis, MN
Steven Bin, MD
Associate Clinical Professor,
Division of Pediatric Emergency
Medicine, UCSF Benioff Children’s Sandip Godambe, MD, PhD
Hospital, University of California,
Vice President, Quality & Patient
Tommy Y. Kim, MD, FAAP, FACEP
San Francisco, CA
Safety, Professor of Pediatrics and Assistant Professor of Emergency
Emergency Medicine, Attending
Richard M. Cantor, MD, FAAP,
Medicine and Pediatrics, Loma
Physician, Children's Hospital
FACEP
Linda University Medical Center and
of the King's Daughters Health
Professor of Emergency Medicine
Children’s Hospital, Loma Linda, CA;
System, Norfolk, VA
and Pediatrics, Director, Pediatric
California Emergency Physicians,
Emergency Department, Medical
Ran D. Goldman, MD
Riverside, CA
Director, Central New York
Professor, Department of Pediatrics,
Poison Control Center, Golisano
University of British Columbia;
Children's Hospital, Syracuse, NY
Co-Lead, Division of Translational
Christopher Strother, MD
Assistant Professor, Director,
Undergraduate and Emergency
Simulation, Icahn School of
Medicine at Mount Sinai, New
York, NY
AAP Sponsor
Robert Luten, MD
Martin I. Herman, MD, FAAP, FACEP
Professor, Pediatrics and
Emergency Medicine, University of Professor of Pediatrics, Attending
Physician, Emergency Medicine
Florida, Jacksonville, FL
Department, Sacred Heart
Garth Meckler, MD, MSHS
Children’s Hospital, Pensacola, FL
Associate Professor of Pediatrics,
University of British Columbia;
International Editor
Division Head, Pediatric
Lara Zibners, MD, FAAP
Emergency Medicine, BC
Honorary Consultant, Paediatric
Children's Hospital, Vancouver,
Emergency Medicine, St Mary's
BC, Canada
Hospital, Imperial College Trust;
EM representative, Steering Group
ATLS®-UK, Royal College of
Surgeons, London, England
Pharmacology Editor
James Damilini, PharmD, MS,
BCPS
James Naprawa, MD
Clinical Pharmacy Specialist,
Associate Clinical Professor
Emergency Medicine, St.
of Pediatrics, The Ohio State
Joseph's Hospital and Medical
University College of Medicine;
Center, Phoenix, AZ
Attending Physician, Emergency
Department, Nationwide Children’s Quality Editor
Hospital, Columbus, OH
Steven Choi, MD
Steven Rogers, MD
Medical Director of Quality,
Assistant Professor, University of
Director of Pediatric Cardiac
Connecticut School of Medicine,
Inpatient Services, The Children’s
Attending Emergency Medicine
Hospital at Montefiore; Assistant
Physician, Connecticut Children's
Professor of Pediatrics, Albert
Medical Center, Hartford, CT
Einstein College of Medicine,
Bronx, NY
Case Presentation
Since it was first described, Kawasaki disease has
been well characterized. Affected children generally
have fever for at least 5 days, plus 4 of 5 key criteria.
These criteria include conjunctival injection, oral
mucosal changes, polymorphous rash, distal extremity
changes, and cervical lymphadenopathy.5,6 Nonspecific symptoms, such as vomiting, joint pain, cough,
decreased oral intake, rhinorrhea, and abdominal pain,
may also be present, and may make the diagnosis
more challenging. To add to the diagnostic challenge,
some patients may develop an incomplete form of the
disease. These children will not meet all of the clinical
criteria of Kawasaki disease, but they may still develop
the cardiovascular complications. Incomplete Kawasaki
disease accounts for 15% to 20% of Kawasaki disease
diagnoses, and it is more common in children aged < 6
months and in children aged > 5 years.5
No single laboratory test can be used to establish
the diagnosis of Kawasaki disease, although laboratory testing can be used to distinguish this disease
from other disease entities. Thus, the diagnosis must
be made using a combination of a thorough history,
physical examination, and laboratory results. If some
of the diagnostic criteria are met and Kawasaki disease is suspected, the current recommendations are to
obtain an echocardiogram to assess coronary artery
involvement. Ideally, this should be done within 10
days of the onset of fever to minimize the risk of cardiovascular complications.
Kawasaki disease is rarely fatal, but virtually
all deaths result from cardiac sequelae. In fact, this
disease has now surpassed rheumatic heart disease
as the leading acquired heart disease in children in
the United States.5 Coronary artery aneurysms occur
in 15% to 25% of untreated children. Coronary artery
aneurysm has been known to lead to myocardial
infarction, ischemic heart disease, and sudden cardiac death. Peak mortality occurs 15 to 45 days after
the development of fever. However, sudden cardiac
death has been documented years after the diagnosis
of Kawasaki disease. In-hospital mortality is currently estimated to be 0.17% in the United States.7
A 3-year-old girl presents to the emergency department
for evaluation of fever. Her mother reports that the child
has had a fever for the past 5 days, with temperatures
ranging from 38.3°C (101°F) to 40°C (104°F). The child
has some rhinorrhea, but no significant cough. She has
been complaining of abdominal pain and had 2 episodes of
nonbilious vomiting in the last 2 days. She was evaluated at her pediatrician’s office 2 days ago, and she was
diagnosed with a viral illness. Her mother reports the
subsequent development of a red rash that started on
the child’s face and chest, and it is now present on her
trunk, back, and extremities. Her lips are cracked, and her
mother attributes this to poor oral intake over the past few
days. Today, the child was noted to have red eyes, without
discharge, and redness in the genital area. The mother has
not noticed swelling of the extremities or peeling skin. The
remainder of the review of systems is negative. The child
was previously healthy, with no prior hospitalizations,
and she is fully immunized. She attends a small, in-home
daycare, but none of the other children there have been
sick. On physical examination, the child appears tired
and ill, although she is not in distress. Her temperature
at triage is 39.8°C (103.6°F). She is tachycardic, with
a heart rate of 166 beats/min; and tachypneic, with a
respiratory rate of 48 breaths/min. Her eyes are injected
bilaterally, without purulent discharge. Her tympanic
membranes are normal. She has dry, fissured lips. She has
shotty cervical lymphadenopathy. Her lungs are clear to
auscultation, and the cardiovascular examination reveals
tachycardia without murmurs. Her abdomen is soft and
mildly tender to palpation throughout, with no hepatosplenomegaly. Her extremities are warm, well perfused,
and without swelling. Her skin is notable for a fine, erythematous, maculopapular rash on the face, chest, back,
and extremities. The patient’s ill appearance and history
of prolonged fever are concerning for the possibility of
Kawasaki disease, but you aren’t sure that she meets all of
the criteria. You wonder if there are infections you should
worry about. Are there laboratory tests you could order
that would help you differentiate Kawasaki disease from
infection? What about diagnostic imaging tests? Should
you start any medications? Are there any other complications that you should be concerned about?
Critical Appraisal Of The Literature
A literature search was performed using both
PubMed and Ovid. The initial search on PubMed using the term Kawasaki disease resulted in 8170 articles.
This was then decreased to 3458 articles by limiting
the results to children (aged birth to 18 years) and
articles published in English. A similar search in
Ovid using the same terms produced 4593 articles.
Guidelines from the American Academy of Pediatrics (AAP) in partnership with the American Heart
Association (AHA) were reviewed. Search of the
Cochrane Database of Systematic Reviews produced
reviews of Kawasaki disease treatment using intravenous immunoglobulin (IVIG) and aspirin. The ref-
Introduction
Kawasaki disease was initially described in Japan in
1967 by Tomisaku Kawasaki.1-4 Originally known as
mucocutaneous lymph node syndrome, it is an acute,
self-limited, febrile vasculitis of infancy and childhood. Kawasaki disease primarily affects small- and
medium-sized arteries, including the coronary arteries. Although it is a self-limited disease, early diagnosis and treatment is critical to preventing the formation of coronary artery aneurysms, which may lead to
acquired cardiovascular disease and sudden death.
Copyright © 2015 EB Medicine. All rights reserved.
2
www.ebmedicine.net • January 2015
erences in the strongest articles were also reviewed
to explore the most relevant historical articles.
Kawasaki disease was first discovered in Japan,
and the incidence of the disease is significantly
higher in Asian populations. As a result, many of
the published studies have come from Japan. However, for our purposes, only those studies published
in English were reviewed.
A review of the literature for the etiology and
pathogenesis of Kawasaki disease produced mixed
results. Although there are many studies examining
the etiology of the disease, the evidence presented
within these studies was weak overall. In contrast,
the evidence in support of the optimal treatment of
Kawasaki disease is much stronger. Many of these
studies have been performed using a prospective,
randomized approach. In addition, several meta-analyses on the topic are available and were reviewed.
dren.11 Europe and Oceania reported significantly lower
rates. Hospital admission rates from England averaged
8.4 per 100,000.14 Australian statistics from the 1990s
showed an annual incidence of 3.7 per 100,000 children
aged < 5 years.15
Etiology And Pathophysiology
Despite all of the research that has been performed
in the last 40 years, the exact etiology of Kawasaki
disease remains a mystery. Clinical and epidemiological data are suggestive of an infectious agent, but
such an agent has never been identified. The selflimited nature of the illness and associated symptoms of fever, rash, and conjunctivitis are common
to many viral illnesses. Younger children are disproportionately affected, which is also the case with
many infectious diseases. Epidemiological data have
shown that the disease is most common in the winter and spring, and occurs in community outbreaks
with a wave-like geographic spread.16 All of these
factors are characteristic of an infectious etiology.
Many infectious agents have been proposed as
having a causative role in Kawasaki disease, including
multiple viruses, bacteria, spirochetes, and rickettsia.
However, none have been confirmed as the definitive
source. Other theories have been proposed as well. One
theory has suggested that selective expansion of specific T-cell receptor families in Kawasaki disease might
be the result of a bacterial superantigen. A 1993 study
found toxic shock syndrome toxin-1 (TSST-1) in 11 out of
16 patients with Kawasaki disease.17 However, followup studies by different authors failed to show similar
results.18 A more recent prospective, multicenter trial
did not show a higher prevalence of supertoxin-producing bacteria in Kawasaki disease patients compared to
febrile controls.19 In addition, the immune response in
Kawasaki disease has now been shown to be oligoclonal.20,21 The oligoclonal response is more consistent with
an immune response to a common antigen, rather than
the polyclonal response typically seen when a superantigen is present.
In 2005, another theory was presented when
researchers reported a novel human coronavirus in
respiratory samples from 8 out of 11 patients with
Kawasaki disease, but in only 1 of 22 control patients.22 This was called the New Haven coronavirus
(HCoV-NH), named for its place of discovery. Unfortunately, this virus was later found to be the same
as a previously reported coronavirus, HCoV NL-63,
and multiple follow-up studies from both the United
States and Asia have been unable to find an association between this virus and Kawasaki disease.22-25
Studies have also attempted to link Kawasaki
disease to various environmental causes (including
pollutants, toxins, and heavy metals), but no conclusive evidence has been found. A significant overlap
in symptoms has been observed in both Kawasaki
disease and acrodynia (mercury toxicity), but a link
Epidemiology, Etiology, And Pathophysiology
Epidemiology
Kawasaki disease is the second most common vasculitis condition in children. It is also the leading cause
of acquired heart disease in children in the United
States.8 It is slightly more prevalent in males than in
females, at a rate of approximately 1.5 to 1.9 Although
Kawasaki disease has been described in all ethnicities, it is most prevalent in children of Asian ancestry.
The United States Centers for Disease Control and
Prevention reported estimates of disease occurrence
in 9 to 19 per 100,000 children aged < 5 years in the
continental United States, with an estimated 5447
related hospitalizations in 2009.10 Rates are highest in
Asian/Pacific Islanders, followed by blacks, whites,
and American Indians.3 The rate of hospitalization
for Kawasaki disease among Asian/Pacific Islander
children in the United States is 30.3 per 100,000,
while the rate for white, non-Hispanic children in the
United States is 12 per 100,000.11 Within the United
States, Hawaii has higher rates of Kawasaki disease,
with one study showing an estimated rate of 47.7 per
100,000 children aged < 5 years.12 The significantly
higher rates in Hawaii are likely related to the high
proportion of the population with Asian- or PacificIslander ancestry.
Worldwide, the highest incidence of Kawasaki
disease is in Japan, where it was first described. In 2007
and 2008, an epidemiologic study in Japan estimated
the incidence of Kawasaki disease at 216.7 per 100,000
children aged 0 to 4 years, which is > 10 times the
incidence in the United States.13 In other parts of Asia,
rates of Kawasaki disease are lower compared to those
seen in Japan, but they are still higher than rates in the
United States. A 2012 review reported that Hong Kong
had an incidence of 39 per 100,000 children aged < 5
years, Beijing had an incidence of 55 per 100,000, and
Korea’s annual incidence was 113.1 per 100,000 chilJanuary 2015 • www.ebmedicine.net
3
Reprints: www.ebmedicine.net/pempissues
between the 2 conditions has not been proven.
More recent immunologic research has revealed
infiltration of immunoglobulin A (IgA) plasma cells
in coronary artery walls, as well as in the respiratory
tract, pancreas, and kidneys of patients with Kawasaki disease.20 In addition, CD8 lymphocytes have
also been noted as part of the inflammatory response
in coronary artery aneurysms.26 These patterns of
inflammatory cell infiltration support the theory of
an immune response to a microbial agent. Similar
findings of IgA plasma cells in the respiratory tract
are seen in respiratory illnesses such as influenza
or respiratory syncytial virus, suggesting that the
portal of entry for the microbial agent may be the
respiratory tract.26 Further immunologic study has
revealed the presence of intracytoplasmic inclusion
(ICI) bodies within the ciliated bronchial epithelium.27 Similar inclusion bodies were not detected
in control patients. A single monoclonal antibody
detected approximately 85% of the ICI bodies in patients with fatal Kawasaki disease, suggesting that a
single agent or closely related agents may be responsible for the disease.28 No structures representing
known bacterial, fungal, or parasitic elements were
identified within the ICI bodies.28
Despite our improved understanding of the
immune system activation that occurs in Kawasaki
disease, it is still somewhat unclear how it leads to
coronary artery aneurysms. Patients with Kawasaki
disease have been found to have stimulation of the
cytokine cascade and endothelial cell activation. It
is this endothelial activation that leads to coronary
arteritis and aneurysms, although the exact mechanism of how this occurs still needs to be elucidated.
Various studies have shown elevated levels of
matrix metalloproteinase-929 and vascular endothelial growth factor30 in Kawasaki disease patients,
both of which may contribute to the development
of aneurysms.
viral infections, and they will resolve on their own
in time without long-term consequences. Rash associated with fever may be seen in viral exanthems,
as well as in Epstein-Barr virus and acute streptococcal infections. Adenovirus may present quite
similarly to Kawasaki disease, with symptoms such
as fever, rash, conjunctival changes, mucous membrane changes, and adenopathy. A study by Barone
et al noted that children with adenovirus are more
likely to have purulent conjunctivitis or exudative
pharyngitis compared to children with Kawasaki
disease, although the study was small.31 Rash, fever,
and conjunctival changes are also seen in measles,
and, although many children are vaccinated against
this disease, several outbreaks have recently been
reported. Fever can also be seen in drug hypersensitivity reactions, so a complete medication history
should be taken at presentation.
Prehospital Care
Many children with suspected Kawasaki disease will
initially present to their pediatricians or be brought
Table 1. Differential Diagnosis Of Prolonged
Fever In Pediatric Patients
Infectious
• Systemic viral infection
• Pneumonia
• Urinary tract infection
• Infective endocarditis
• Osteomyelitis
• Lyme disease
• Rocky Mountain spotted fever
• Human immunodeficiency virus
• Malaria
Endocrinologic
• Thyrotoxicosis
Differential Diagnosis
Immunologic
• Immunodeficiency
When children present with Kawasaki disease in its
classic form, it is not difficult for an astute emergency clinician to make the correct diagnosis. However,
children presenting with < 5 days of fever, or those
with incomplete Kawasaki disease may prove to be
more of a diagnostic challenge. Fever is a very common complaint in pediatric patients, with a broad
differential diagnosis. (See Table 1.) Accurately
differentiating fever due to viral or bacterial illnesses
from fever due to Kawasaki disease is critical. This
is especially true since patient outcomes are significantly improved when patients are treated within 10
days of the onset of fever.
It is important to consider a variety of diagnoses
when thinking about children with fever. (See Table
2, page 5.) Many fevers will be caused by nonspecific
Copyright © 2015 EB Medicine. All rights reserved.
Oncologic
• Leukemia
• Lymphoma
• Other neoplasm
Rheumatologic
• Juvenile idiopathic arthritis
• Systemic lupus erythematosus
• Kawasaki disease
• Familial Mediterranean fever
Gastroenterologic
• Inflammatory bowel disease
Toxicologic
• Drug-related fever
4
www.ebmedicine.net • January 2015
Physical Examination
to the hospital directly by parents. For children who
are transported via emergency medical services, prehospital care should focus on supportive measures.
Assessment of the airway, breathing, and circulation
is of primary importance, with close monitoring of
vital signs during transport. A few children may
develop shock in association with Kawasaki disease.
For these children, obtaining intravenous access and
initiating fluid resuscitation takes precedence. When
possible, these children should be transported to a
facility with a pediatric intensive care unit.
In addition to fever, the diagnostic criteria for complete Kawasaki disease include the presence of 4 out
of 5 supporting signs and symptoms. (See Table 3,
page 6.) These include conjunctival injection, oropharyngeal changes, polymorphous rash, extremity changes, and lymphadenopathy. Conjunctival
injection is common, and it occurs in an estimated
80% to 90% of patients with Kawasaki disease.3 It is
most commonly bilateral, painless, and nonpurulent.
It typically involves the bulbar conjunctiva and is
described as limbic sparing. It is rarely painful.5 (See
Figure 1, page 6.)
Oropharyngeal mucous membrane changes are
found in approximately 80% to 90% of patients with
Kawasaki disease.3 These include obvious changes
such as dry, fissured, or erythematous lips, which
are easily observed. (See Figure 2, page 6.) However,
changes can be more subtle. Children may develop
strawberry tongue, in which the tongue becomes
bright red with prominent papillae. Other changes
may include nonexudative pharyngitis or erythema
of the posterior oropharynx.
Polymorphous rash is present in approximately
80% to 90% of patients, and it often develops early in
the course of the disease.3 A wide variety of cutaneous eruptions have been described, including rashes
that appear as diffuse and macular, scarlatiniform,
scaling plaques, or even resembling erythema
multiforme. (See Figure 3, page 7.) The rash is less
commonly urticarial, and almost never appears as
vesicles or bullae.3 The rash is often found on the
truck or extremities, and may be present in the perineal area.
Emergency Department Evaluation
History
The diagnosis of Kawasaki disease should be considered in all children presenting with prolonged
fever, especially if it has been present for ≥ 5 days.
It is important to note that symptoms may present
sequentially rather than simultaneously, and, thus,
some of the diagnostic symptoms may be resolved
prior to presentation to the emergency department.5
When considering a diagnosis of Kawasaki disease,
ask the caregivers about all recent symptoms, even if
they are not currently present.
The presence of ≥ 5 days of fever is essential for
the diagnosis of Kawasaki disease. In affected children,
fevers are often high, commonly > 39°C (102.2°F), and
potentially > 40°C (104°F).5 The fever may not respond
to antipyretic drugs, and it generally persists for an
average of 10 to 14 days without treatment, but may
continue for as long as 3 to 4 weeks.3 Once treatment
for Kawasaki disease is initiated, fever usually resolves
within 48 hours.
Table 2. Comparison Of Kawasaki Disease And Other Similarly Presenting Diseases
Disease
Features
First-Line Treatment
Complications
Kawasaki disease
Fever (> 5 days) plus:
• Conjunctivitis
• Oropharyngeal changes
• Polymorphous rash
• Extremity changes
• Lymphadenopathy
Intravenous immunoglobulin plus aspirin
• Coronary artery aneurysms
• Sudden cardiac death
Adenovirus
Fever plus:
• Rash
• Conjunctivitis
• Lymphadenopathy
• Pharyngitis
Supportive care
• Pneumonia
Group A Streptococcus
Fever plus:
• Pharyngitis
• Rash
Antibiotics
• Rheumatic heart disease
• Postinfection glomerulonephritis
Measles
Fever plus:
• Rash
• Conjunctivitis
• Rhinorrhea
• Pharyngitis
Supportive care
•
•
•
•
January 2015 • www.ebmedicine.net
5
Pneumonia
Otitis media with or without hearing loss
Encephalitis
Subacute sclerosing panencephalitis
Reprints: www.ebmedicine.net/pempissues
Interestingly, children who have previously
received the bacillus Calmette-Guérin (BCG) vaccine will often have erythema, induration, or crusting at the site of injection.32,33 The mechanism for
inflammation at this site is not well understood. It
is known to be a very specific finding for Kawasaki
disease, and it can be considered a strong indication
of Kawasaki disease in the presence of incomplete
or atypical criteria. This finding is rarely observed in
the United States, as children in the United States do
not routinely receive the BCG vaccine. However, the
BCG vaccine is commonly used in other countries.
Although it does not prevent pulmonary tuberculosis, the BCG vaccine is used to provide infants and
young children with protection against tuberculosis, meningitis, and disseminated tuberculosis.34 In
countries where tuberculosis is endemic, the vaccine
is routinely given to neonates as soon as possible after birth. Therefore, emergency clinicians should be
aware of this finding when evaluating children who
were born in or who have lived in countries where
the BCG vaccination is common.
Extremity changes are another criterion for
Kawasaki disease, but a wide variety of changes can
occur. Erythema and/or edema of the hands and feet
may be present.5 The entirety of the hands and feet
may be affected, but erythema may also be limited
to the palms of the hands and the soles of the feet.3
(See Figure 4, page 7.) Erythema is often sharply demarcated at the wrist and ankle. The hands and feet
can be painful, and, in younger children, this may
manifest as refusal to bear weight or use the affected
limbs. Such changes occur in 80% to 90% of children
during the acute phase of illness.3 Desquamation of
the fingers and toes is also common in children. (See
Figure 5, page 7.) One recent study reported that
68% of children diagnosed with Kawasaki disease
had desquamation of the fingers, toes, or both.35
However, this occurs late in the disease, often 2 to 3
weeks after the onset of illness, making it less useful
for diagnosing Kawasaki disease in the acute phase.
Lymphadenopathy is the least common of the diagnostic criteria. It occurs in only 50% to 60% of patients
with Kawasaki disease.3,36 The adenopathy of Kawasaki
disease is most commonly unilateral and found in the
cervical chain. Classic criteria cite the lymphadenopathy
as consisting of ≥ 1 lymph node with a diameter of at
least 1.5 cm.5
Figure 2. Oropharyngeal Mucous Membrane
Changes
Figure 1. Conjunctival Injection
This figure was published in Zitelli and Davis' Atlas of Pediatric Physical Diagnosis, 6th edition, Torok K, Rosen P, Kawasaki Disease,
pages 289-291, Copyright Elsevier 2012. Used with permission.
This figure was published in Zitelli and Davis' Atlas of Pediatric Physical Diagnosis, 6th edition, Torok K, Rosen P, Kawasaki Disease,
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
involvement
Acute phase
80%-90%
Extremity changes
May include erythema, edema, or desquamation
Acute phase and/or 2-3 weeks
after onset
80%-90%
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
symptoms that are commonly reported in patients with
Kawasaki disease. Irritability is quite common. Although
children who have viral illnesses may also be irritable,
the irritability of children with Kawasaki disease is often
more pronounced.5 The irritability may resemble that
seen in bacterial or viral meningitis.37 Because of this,
some theorize that the irritability may be the result of
aseptic meningitis, which is found in approximately
25% of patients with Kawasaki disease. One study found
that 50% of patients were described as irritable by their
parents in the 10 days prior to the diagnosis of Kawasaki disease, and these patients were more likely to be
younger in age.38 However, marked irritability has been
noted in infants with normal cerebrospinal fluid studies,
so further research in this area is needed to determine
the cause of such pronounced irritability.39
Arthritis and arthralgias can occur, usually early in
the course. Arthritis may be oligoarticular or polyarticular.40 The cardiovascular examination in children with
Kawasaki disease can reveal tachycardia, hyperdynamic
precordium, murmurs, or a gallop.5
Gastrointestinal complaints are common, but are often
nonspecific. Complaints may include abdominal pain,
vomiting, or diarrhea, and may occur in up to one-third
of patients.3 One study found that vomiting was associated with an increased risk of treatment resistance to
IVIG, although this study was small and retrospective
in nature.41 Nonspecific gastrointestinal complaints
are common in viral illnesses, and so are not as useful
in making a definitive diagnosis of Kawasaki disease.
Less commonly, hepatomegaly and jaundice can occur.
There have been rare reports of obstructive jaundice
due to gall bladder hydrops and cholestasis associated
with Kawasaki disease.42
Increasingly, Kawasaki disease has been recognized as an etiology of shock in some children.43 These
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 children 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 children had been admitted to the pediatric intensive care
unit with shock and were later diagnosed with Kawasaki
Figure 3. Diffuse Macular Rash
Figure 5. Desquamation Of Fingers
This figure was published in Zitelli and Davis' Atlas of Pediatric Physical 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 in Zitelli and Davis' Atlas of Pediatric Physical 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 in Zitelli and Davis' Atlas of Pediatric Physical 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
peptidase.5,45 The mechanism behind liver function abnormalities in Kawasaki disease patients is
not well understood. Theories for how this occurs
include vasculitis within the liver vessels, toxinmediated effects, oxidant stress, and inflammatory
cell infiltration, but further research in these areas is
needed.46
disease.44 Eight of these patients (72.7%) had evidence
of multiple organ dysfunction syndrome, with hemodynamic instability, and neurologic, gastrointestinal, and
renal dysfunction. Three children developed respiratory
failure, requiring intubation or requiring noninvasive
ventilatory support. In addition, 7 out of 11 of the children developed coronary artery aneurysms. All of these
children survived after proper treatment for Kawasaki
disease, suggesting that prompt recognition and treatment of Kawasaki disease in patients with shock can
result in favorable outcomes.44
Lipid And Albumin Levels
Plasma cholesterol and high-density lipoprotein
levels can be markedly depressed in affected patients.47 Hypoalbuminemia is another common
finding, and it has been associated with more severe
disease.48 The pathophysiology of this finding is
that microvascular inflammation leads to increased
microvascular permeability, which, in turn, results
in vascular leak, decreased serum levels of albumin,
and, ultimately, peripheral edema.48
Diagnostic Testing
Making a definitive diagnosis of Kawasaki disease
can be a challenge, especially in atypical cases.
Although there is no single diagnostic test to confirm the diagnosis, there are many diagnostic tests
that can help to differentiate Kawasaki disease from
other entities.
Sodium Levels
Hyponatremia has also been documented in patients
with Kawasaki disease. This was first described in
the United States in a 1982 retrospective study of patients with Kawasaki disease, which found that 6 of
11 patients had hyponatremia at the time of hospital
admission.49 Lim et al prospectively studied 50 patients with Kawasaki disease and found that 26% (13
patients) had hyponatremia during the acute phase
of illness.50 Even higher rates of hyponatremia have
been reported in some studies. Watanabe et al conducted a study of 146 Kawasaki patients, and they
found that 44% of the patients had hyponatremia.51
It has been suggested that patients with hyponatremia have higher levels of inflammation overall, although the exact pathophysiology of hyponatremia
in Kawasaki disease is not well understood.50,51
Laboratory Studies
Inflammatory Markers
Since Kawasaki disease is characterized by acute
inflammation, it is necessary to assess patients for
elevated inflammatory markers. This includes the
acute phase reactants, such as C-reactive protein
(CRP) and erythrocyte sedimentation rate (ESR).
These are nearly universally elevated, with ESR
being elevated in approximately 60% of Kawasaki
disease patients, and CRP being elevated in as many
as 80% of affected patients. Guidelines (such as those
from the AAP) recommend testing both the CRP and
ESR levels for best results.5 The AAP guidelines suggest that elevations of CRP ≥ 3.0 mg/dL and ESR ≥
40 mm/h can be used in the evaluation of both complete and incomplete Kawasaki disease.5 Treatment
with IVIG can lead to elevations in the ESR, so this
test should not be used as the primary determiner of
inflammation in treated patients.
Brain Natriuretic Peptide Levels
Elevated serum N-terminal brain natriuretic peptide
(NTproBNP) levels have been investigated for use
in diagnosing Kawasaki disease. Brain natriuretic
peptide (BNP) is synthesized within myocytes as
proBNP and is released into circulation during
periods of ventricular stress. The N-terminal section
is cleaved, releasing both the active BNP and the
inactive NTproBNP into circulation.52 BNP has an
extremely short half-life, being degraded in 5 to 10
minutes. NTproBNP has a significantly longer halflife than BNP (25 to 125 minutes) making it more
easily detectable in circulation. Although NTproBNP
levels are frequently elevated in children with Kawasaki disease, these levels vary with age, making it
difficult to use this laboratory test in diagnosis.52,53
In practice, given the complexity of this marker, it is
not routinely used.
Complete Blood Count
Leukocytosis is a common finding, with elevations
in white blood cell (WBC) counts > 15,000/mm3
found in at least half of patients.5 Thrombocytosis is
another characteristic finding of Kawasaki disease.
Platelet counts often exceed 500,000/mm3, and may
be as high as 1,000,000/mm3. Thrombocytosis develops later than some findings, typically appearing
during the second week of illness, and peaking in
the third or fourth week.
Liver Function Tests
Liver panel abnormalities can occur in patients with
Kawasaki disease. Up to 40% of patients will show
mild to moderate elevations in serum transaminases.
An even higher number (approximately 60% to 67%)
will have elevated plasma gamma-glutamyl transCopyright © 2015 EB Medicine. All rights reserved.
Urinalysis
Sterile pyuria can be found in approximately onethird of affected patients. Early research reported
8
www.ebmedicine.net • January 2015
treated within 10 days of the onset of fever.57-59 However, more recent studies have shown much higher rates.
Tse et al examined echocardiograms from 178 patients
with Kawasaki disease, noting that 34% had lesions on
initial evaluation.60 Baer et al studied initial echocardiograms of 100 patients with Kawasaki disease, and
they found that 44% of patients had either ectasia or
aneurysms present at the time of the initial evaluation.61
The dramatic increase in lesions at the time of diagnosis
is thought to be related to changing the definition of
lesions from absolute measurements to a measurement
that is adjusted for body surface area.61
Perivascular echocardiographic brightness (PEB)
has been proposed as a criterion for diagnosing incomplete Kawasaki disease in some patients. Prior research
suggested that perivascular brightness was a predictor of coronary artery aneurysms.62 However, PEB is
somewhat subjective and dependent on the individual
echocardiographer. A more recent attempt to quantitatively define PEB and its use in diagnosing incomplete
Kawasaki disease did not confirm PEB to be a reliable
diagnostic criterion.63
In addition to coronary artery lesions, children
can develop other cardiac problems, and initial
echocardiography should assess for such problems.
Myocarditis is common during the acute phase of the
illness, and decreased ventricular contractility can
occur.5 As many as 50% to 70% of patients will have
wall motion abnormalities related to myocardial inflammation, although this seems to be independent of
the risk of coronary artery aneurysms.64 Pericarditis,
valvular regurgitation, and pericardial effusion have
also been documented.65,66
that urine obtained via suprapubic tap was normal,
indicating urethritis as the primary cause of pyuria.5
However, more recent research indicates that upper
urinary structures, including the bladder and kidney, may be involved.54,55
Lumbar Puncture
Although lumbar puncture is not routinely recommended for evaluation of Kawasaki disease, it is
occasionally performed. Of those children who
undergo this procedure, between one-third and
one-half will show signs of cerebrospinal fluid
pleocytosis.37 This includes a predominance of
mononuclear cells and normal cerebrospinal fluid
protein and glucose levels.
Cardiovascular Testing
Children with Kawasaki disease may have changes
on electrocardiography (ECG), although these are
often nonspecific. Changes may include arrhythmias, nonspecific T-wave changes, PR-interval prolongation, or QT-interval prolongation.5 These ECG
findings are most likely to be found during the acute
phase and in the first month following diagnosis,
and they frequently normalize after recovery.56
The most critical imaging to obtain in children with
Kawasaki disease is echocardiography. This is usually
performed transthoracically, and should be done in
all patients with a definitive or suspected diagnosis
of Kawasaki disease. Ideally, initial echocardiography
should be performed on the day of diagnosis. Echocardiography can be helpful in formally diagnosing cases
of incomplete Kawasaki disease. It is noninvasive and
does not involve radiation. It is both highly sensitive and
specific for detecting coronary artery lesions.
Guidelines from the AHA and the AAP recommend
prompt echocardiography once Kawasaki disease is
diagnosed or suspected, although delays in obtaining
imaging should not delay initiation of treatment.5 The
AAP stresses the importance of this examination being
performed by an experienced echocardiographer in
order to best visualize all segments of the coronary
arteries and accurately assess vessel diameter. Ectasia
of the arteries is defined as vessels that are larger than
normal without segmental aneurysms. The AHA defines
aneurysms as small if they are < 5 mm in diameter,
medium if the diameter is 5 to 8 mm, and giant if the diameter is > 8 mm.5 The most commonly affected vessel
is the proximal segment of the left anterior descending
artery, followed by the proximal right coronary artery,
left main coronary artery, and the left circumflex artery,
respectively. The least commonly affected vessel is the
distal segment of the right coronary artery.5
It should be noted that a normal initial echocardiogram should not be used to exclude the diagnosis
of Kawasaki disease, especially if physical examination findings and laboratory tests are consistent with
the diagnosis. Early studies estimated the prevalence
of coronary artery lesions to be 2% to 4% in patients
January 2015 • www.ebmedicine.net
Risk Classification
Although several risk classification criteria have
been proposed, the most commonly applied in the
United States are those proposed by Beiser et al.67
These criteria are generally used to predict which
patients are at a high risk of developing coronary
artery aneurysms among patients who were treated
with IVIG within 10 days of the onset of fever. The
scoring system uses baseline neutrophil and band
counts, hemoglobin, platelet count, and temperature
on the day after the patient receives IVIG to categorize patients into high-risk and low-risk categories.
The negative predictive value of the score appears to
be appropriate, as no patients in the low-risk group
developed coronary artery aneurysms. However, the
positive predictive value of the tool is relatively inadequate, with only 13% of high-risk patients developing coronary artery aneurysms.67 Thus, although
this may be a helpful tool for predicting low-risk
patients, it should not be used to guide treatment or
follow-up decisions.
Egami et al devised a scoring system to predict
treatment resistance to IVIG.68 Using multivariate logis9
Reprints: www.ebmedicine.net/pempissues
Clinical Pathway For Emergency Department
Management Of Kawasaki Disease
Fever for ≥ 5 days?
NO
YES
• Consider alternative diagnosis
• Discharge if appropriate
• Recommend follow-up with primary
care physician if fever persists
≥ 4 diagnostic criteria present?
• Conjunctivitis
• Mucous membrane changes
• Polymorphous rash
• Extremity changes
• Cervical lymphadenopathy
YES
NO
Obtain laboratory testing
• CRP/ESR
• CBC
• ALT
• Albumin
• Urinalysis
2-3 diagnostic criteria present?
• Conjunctivitis
• Mucous membrane changes
• Polymorphous rash
• Extremity changes
• Cervical lymphadenopathy
NO
Consider alternative diagnosis
YES
Laboratory tests consistent with Kawasaki disease? (eg, CRP ≥ 3.0 mg/dL
and ESR ≥ 40 mm/h)
Evaluate for
incomplete Kawasaki disease
(Class II)
NO
• Consider alternative diagnosis
• Monitor for fever for 2-3 days
• Recommend follow-up with primary
care physician if fever persists
• If suspicion for Kawasaki disease
remains high, consider obtaining an
echocardiogram
YES
• Start treatment with IVIG and highdose ASA (Class I)
• Obtain echocardiogram expeditiously
(Class II)
Consider other treatment options
• IVIG plus corticosteroids (Class II)
• Infliximab (Class II)
• Abciximab (Class III)
NO
Fever resolved within 48 h?
YES
• Continue low-dose ASA (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
• Always acceptable, safe
• Definitely useful
• Proven in both efficacy and effectiveness
Level of Evidence:
• One or more large prospective studies are
present (with rare exceptions)
• High-quality meta-analyses
• Study results consistently positive and
compelling
Class II
• Safe, acceptable
• Probably useful
Level of Evidence:
• Generally higher levels of evidence
• Nonrandomized or retrospective studies:
historic, cohort, or case control studies
• Less robust randomized controlled trials
• Results consistently positive
Class III
• May be acceptable
• Possibly useful
• Considered optional or alternative treatments
Level of Evidence:
• Generally lower or intermediate levels of
evidence
• Case series, animal studies, consensus panels
• Occasionally positive results
Indeterminate
• Continuing area of research
• No recommendations until further research
Level of Evidence:
• Evidence not available
• Higher studies in progress
• Results inconsistent, contradictory
• Results not compelling
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
incomplete disease, with an odds ratio of 1.447 (95%
confidence interval [CI], 1.158-1.808; P = .001).73 This
included analysis of > 20 studies, for a total of 4504
Kawasaki disease patients and 32,519 controls. However, the analysis did not address the issue of delay
in diagnosis and treatment.
A second large study reported the differences
between complete and incomplete Kawasaki disease at
a single center in North America. Manlhiot et al retrospectively reviewed 955 patients with Kawasaki disease,
finding that 77% presented with complete Kawasaki
disease while the remaining 23% fell into the incomplete category.74 Although this study also showed that
the time to diagnosis and treatment was delayed for patients with incomplete disease, there was no significant
difference in the rate of development of coronary artery
aneurysms between the 2 groups (13% vs 11%).74
The evidence of incomplete Kawasaki disease as
an independent predictor of aneurysm development
is complicated by the difficulty in making a diagnosis
of incomplete Kawasaki disease. It is well documented
that a longer duration of fever and delay in treatment
increase the risk of aneurysm development. Thus, emergency clinicians who suspect Kawasaki disease should
proceed with further evaluation, including laboratory
testing and echocardiography. The AHA reports that
conventional diagnostic criteria should be considered
as a guideline for Kawasaki disease, and that all patients
with fever for ≥ 5 days plus 2 to 3 criteria should be
promptly evaluated.5 The AAP and AHAprovide a framework for decisions regarding the evaluation of children
with suspected incomplete Kawasaki disease.5
tic regression, they found that age, total days of symptoms, platelet count, CRP, and alanine aminotransferase
can be used to predict which patients are likely to be resistant to IVIG therapy. In the initial study, the score had
a sensitivity of 78% and a specificity of 76%. Although
this may be helpful in anticipating treatment resistance,
it was designed for use in Japan, so treatment resistance
patterns will vary. Several recent studies have investigated the use of the Egami score in North America. The
studies found that, when applied to a North American
cohort, the Egami score had adequate specificity, but a
low sensitivity for predicting IVIG resistance.69,70 Thus,
this scoring system may be inadequate for detecting
patients at risk of treatment resistance in the North
American population.
Incomplete Kawasaki Disease
Within the literature, there is some debate regarding the diagnosis of incomplete Kawasaki disease.
Generally, a patient is diagnosed with incomplete
disease if Kawasaki disease is suspected but fails to
fulfill the conventional diagnostic criteria.5 These
patients typically display prolonged fever in addition to 2 to 3 of the principal criteria, failing to meet
the more traditional definition of at least 4 principal
criteria. In these situations, emergency clinicians
should be suspicious of Kawasaki disease. It is
important to note that laboratory findings should be
supportive of the diagnosis of Kawasaki disease, if
no alternative diagnosis is found in the course of the
evaluation. By most estimates, approximately 20%
of patients with Kawasaki disease will likely fall into
the category of incomplete disease.71
Prior research indicates that children with incomplete Kawasaki disease may be at higher risk for the
development of coronary artery aneurysms. However,
it is not clear whether this relates to the disease itself or
to the delay in diagnosis that often occurs in cases of
incomplete disease. Sudo et al examined a large cohort
of patients with Kawasaki disease in Japan to study the
epidemiologic differences between patients with complete versus incomplete forms of Kawasaki disease.72 Of
the more than 23,000 patients in the study, 80% fell into
the category of complete disease, and the other 20% fell
along a spectrum of having 1 to 4 supporting criteria.
The patients with incomplete Kawasaki disease had
an increased incidence of coronary artery aneurysms
compared to the typical Kawasaki disease patients
(13.1% vs 8.8%).72 It should be noted that these patients
also tended to be hospitalized later in the course of
their disease and were less likely to receive IVIG than
the children with more typical disease.72 The authors attributed the higher incidence of aneurysms to the delay
in diagnosis and treatment, as well as to the increased
use of echocardiography for establishing a diagnosis of
Kawasaki disease.72
Further, a meta-analysis found that there was
an increased risk of coronary artery aneurysms in
January 2015 • www.ebmedicine.net
Treatment
Initial Treatment
Since the etiology of Kawasaki disease remains unclear, the goals of treatment focus on the prevention
of coronary artery aneurysm development. Early
identification and treatment of Kawasaki disease has
been shown to reduce the development of coronary
artery aneurysms. Treatment should be started as
soon as a diagnosis of Kawasaki disease is made.
Current recommendations suggest treatment should
be given within 10 days of the onset of fever, and,
ideally, within 7 days of the onset of fever.5 Initial
treatment in the United States generally includes
IVIG in combination with high-dose aspirin.75
Intravenous Immunoglobulin
Evidence for the use of IVIG in Kawasaki disease is
strong. The use of IVIG in Kawasaki disease began in
the 1980s. Several randomized controlled studies during that time showed a significant reduction in coronary artery aneurysm development in children receiving IVIG plus aspirin compared to aspirin alone.57,76
Newburger et al used an IVIG dose of 400 mg/kg/day
for 4 days.57 A follow-up randomized controlled study
11
Reprints: www.ebmedicine.net/pempissues
several years later showed that a single infusion of
2 g/kg of IVIG was more effective at preventing
aneurysms than the traditional 4-dose regimen.58 This
infusion is generally given over a period of 10 to 12
hours. More recently, a meta-analysis of randomized
controlled trials has shown that treatment with IVIG
compared to placebo significantly reduced the risk of
coronary artery aneurysms at 30 days.77 In addition,
the single, higher dose of IVIG was associated with
a reduction in the duration of fever when compared
with the multiple-dose regimen.58,77
The efficacy of IVIG for the treatment of Kawasaki
disease is well established, although the mechanism of
action is not clearly understood. IVIG is thought to work
primarily through a generalized anti-inflammatory action. Several mechanisms have been proposed, including regulation of Fc-receptor function, suppression of
proinflammatory cytokine production, inhibition of the
complement system, and inhibition of tumor necrosis
factor (TNF) production.11 However, strong evidence to
support these theories is still needed.
IVIG is considered to be a safe treatment, although
it is not without side effects. Common side effects of
the infusion include headaches, fever, chills, myalgias,
nausea, vomiting, changes in blood pressure, and tachycardia.78 If such side effects occur, they can generally
be managed by slowing the infusion and by providing
supportive care. Serious side effects are uncommon,
but can include acute renal failure, aseptic meningitis,
neutropenia, anaphylaxis, and autoimmune hemolytic anemia.78 In addition, IVIG is also a pooled-blood
product and thus carries the risk of transfusion-related
infections as well.
Japan, more-moderate doses of aspirin (30-50 mg/kg/
day) are given during the febrile phase of the illness.11
Low-dose aspirin is then continued for 6 to 8 weeks until
follow-up echocardiography is normal. For children who
develop coronary artery lesions, low-dose aspirin may be
continued indefinitely for its antiplatelet effects. Despite
the lack of evidence to support the use of aspirin, the
AHA and the AAP continue to recommend its use in combination with IVIG.5
Corticosteroids
The use of corticosteroids as a routine part of a treatment regimen for Kawasaki disease is still under
debate. This treatment dates back to before the use
of IVIG as primary treatment. In 1979, Kato et al
published their research on the treatment of Kawasaki disease, exploring 5 different treatment options,
including the use of prednisone as monotherapy.
The research showed a substantially higher rate of
coronary artery aneurysms in children treated with
corticosteroids alone (prednisolone 2-3 mg/kg/day)
compared to aspirin alone (64.7% vs 11%).80 The
prednisolone group also had significantly higher
rates of coronary artery lesions compared to those
treated with a combination of steroids plus aspirin
or no treatment. However, this study had significant
limitations. It was a relatively small sample, with
a total of 92 patients. There was no randomization,
and the size of each treatment group varied significantly, with some groups having as few as 7 patients. Despite these limitations, this study led to the
near-abandonment of corticosteroids as a part of the
treatment for Kawasaki disease.
More recently, the question of using corticosteroids
in combination with IVIG for primary treatment has
been explored. Newburger et al conducted a multicenter, randomized, placebo-controlled, double-blinded
study in the United States to compare standard therapy
(IVIG plus high-dose aspirin) to standard therapy plus
methylprednisolone.81 The findings showed no significant difference in the number of days spent in the
hospital, the duration of fever, rates of initial treatment
failure, or the incidence of coronary artery aneurysms.
Based on this evidence, they concluded that corticosteroids are not useful as a routine adjunct to IVIG in
standard-risk Kawasaki patients.
There is continued interest in the use of steroids
for patients who are considered to be at a high risk
of treatment resistance. A randomized trial from
a single institution in Japan explored the use of
standard treatment plus corticosteroids in patients
predicted to be at a high risk of refractory disease.82
A total of 48 patients out of 122 were predicted to
have Kawasaki disease that was refractory to treatment, and they were randomized to receive standard
therapy of IVIG plus aspirin or standard therapy of
IVIG plus a single dose of intravenous methylprednisolone (30 mg/kg). Significantly more patients in
Aspirin
Aspirin has long been used as part of the treatment
for Kawasaki disease. It is theorized that since aspirin has anti-inflammatory effects as well as antiplatelet effects, it should be useful in the treatment
of Kawasaki disease. However, there is insufficient
evidence in the literature to show that aspirin at
any dose reduces the incidence of coronary artery
aneurysms.5 A Cochrane review of the literature
identified only 1 randomized controlled trial examining the use of aspirin in Kawasaki disease. This
single study failed to demonstrate an added benefit
of aspirin plus IVIG compared to IVIG alone to reduce the development of coronary artery lesions.79
Given the lack of randomized controlled trials, the
Cochrane review was unable to support or negate
the use of aspirin in the treatment of Kawasaki disease.79 Despite this, many centers continue to use
aspirin in conjunction with IVIG.
Without sufficient evidence for its use, there are no
consistent recommendations on aspirin dosing. In North
America, aspirin is generally started at high doses (80-100
mg/kg/day) and divided into 4 doses. The dose is then
decreased to 3 to 5 mg/kg/day after defervescence.5,6 In
Copyright © 2015 EB Medicine. All rights reserved.
12
www.ebmedicine.net • January 2015
the standard treatment plus methylprednisolone
group had a prompt defervescence compared to
patients who received standard therapy alone (86.4%
versus 23.1%). In addition, the group that received
steroids had a 9% rate of coronary artery aneurysms
on echocardiogram at 1 month compared to 39% in
the standard treatment group. This study, performed
by Ogata et al, was well designed, but limited in its
application due to its small size.82
A second Japanese study by Kobayashi et al
used a larger, multicenter approach.83 As in the prior
study, this one addressed the use of corticosteroids
as an adjunct to the standard initial therapy for
patients classified as being at high risk. In this case,
patients were randomized to standard treatment
of IVIG (123 patients) or standard treatment plus
steroids (125 patients). The steroid regimen included
intravenous prednisolone (2 mg/kg/day in divided
doses) for 5 days followed by a 15-day oral prednisolone taper. The results showed only 3% of patients
treated with corticosteroids developed coronary
artery aneurysms, compared to 23% of patients who
received the standard treatment.
It should be noted that the Newburger et al study
did not separate patients into risk categories, but used
a general group of patients with Kawasaki disease.81 In
comparison, both the Ogata et al and Kobayashi et al
studies examined only patients characterized as high
risk (by applying the Egami criteria). This suggests that,
although corticosteroids do not need to be given to all
Kawasaki patients, there may be a select group of highrisk patients who would benefit from the addition of
corticosteroids to the standard therapy.
5 mg/kg of infliximab and 2 patients were treated
with 10 mg/kg. Of the 16 patients who were febrile
prior to treatment with infliximab, 13 had cessation of fever after treatment. The limitations of this
study include its small size and retrospective nature.
However, given the overall favorable response to
treatment in these patients, the authors of the study
concluded that further research was warranted.
A follow-up study by Burns et al investigated the
use of infliximab for resistant Kawasaki disease using a
multicenter, randomized, prospective approach.85 This
study compared infliximab 5 mg/kg to a second dose of
IVIG 2 g/kg in patients who had persistent fever after an
initial dose of IVIG. In this study, 8 of 12 patients given
a second dose of IVIG had prompt resolution of fever
compared to 11 of 12 patients treated with infliximab.
There were no differences in adverse outcomes between the 2 groups. Although further research is needed, infliximab is generally safe and should be considered
as an alternative therapy in treatment-resistant disease.
Abciximab
Abciximab (ReoPro®), another monoclonal antibody, has been investigated for use in patients who
develop aneurysms. Abciximab inhibits the glycoprotein IIb/IIIa inhibitor. It has previously been
used in adults to prevent thrombotic complications
and promote vascular remodeling in acute coronary
disease.86 Case reports have shown improvement
in coronary artery aneurysms in children treated
with abciximab. A retrospective study compared
9 patients with coronary artery aneurysms who
received standard therapy to 6 patients with similar
lesions who received standard therapy plus abciximab. In this study, standard therapy was defined as
IVIG 2 g/kg plus aspirin 80 to 100 mg/kg/day. The
patients who received abciximab had a significantly
higher rate of resolution of their aneurysms compared to the patients who received standard therapy
(68% vs 37%).86 Although these results are encouraging, the study was very small and was performed in
a retrospective fashion. Further study on the use of
abciximab for Kawasaki disease is needed, preferably in the form of prospective trials.
Treatment Resistance
Although the standard therapy of IVIG plus highdose aspirin is effective for most patients with
Kawasaki disease, it is estimated that approximately
10% to 20% of patients will fail to respond to this
therapy.5 Second-line therapy usually consists of
retreatment with IVIG, potentially in combination
with corticosteroids. Persistent fever and elevations
of inflammatory markers place patients at a high
risk of developing coronary artery aneurysms and
other cardiac complications. Therefore, the choice of
treatment for resistant disease becomes important.
Special Populations
Infliximab
Infliximab (Remicade®) is a monoclonal antibody
directed against tumor necrosis factor alpha-1 (TNFalpha) and blocks its function. Infliximab was theorized to work in Kawasaki disease, as TNF-alpha
levels are known to be elevated in patients with this
disease.75 To explore the effectiveness of infliximab
as a treatment for recalcitrant Kawasaki disease,
Burns et al published a case series of 16 patients
treated with infliximab after they failed to respond
to IVIG.84 In this series, 14 patients were treated with
January 2015 • www.ebmedicine.net
In addition to having a propensity to occur in certain
populations, Kawasaki disease has been noted to be
affected by genetics. Children whose parents had
Kawasaki disease have a slightly higher risk of developing the disease.87 Siblings of children affected
by Kawasaki disease are at significantly higher
risk for developing Kawasaki disease themselves.
Familial studies in Japan show siblings of affected
children to have 10 times the relative risk for development of the disease.88 Such cases were also more
likely to have recurrent disease.87
13
Reprints: www.ebmedicine.net/pempissues
nificantly different from the mean periostin level of
42,549 ng/mL in all patients with Kawasaki disease
(P = .0086).91 Although promising, this was a small
study, and the results need to be validated.
Researchers in North America studied clusters of
families with multiple cases of Kawasaki disease in siblings or cousins.89 The researchers obtained information
from 2 hospitals, as well as from families who contacted
a Kawasaki disease research program. They were able to
identify 9 families in which 2 siblings were diagnosed
with Kawasaki disease, for a total of 18 affected children.
They also identified 9 other families with 24 affected
children. Many of these cases were separated by both
time and geography, so the researchers were unable
to identify a clear pattern of inheritance. Despite this,
clinicians should be aware of the tendency for Kawasaki
disease to run in families, as this may lead to a more
timely diagnosis and reduce the risk of coronary artery
aneurysm development.
Disposition
Patients with suspected Kawasaki disease, either
complete or incomplete, should be admitted to an
appropriate pediatric inpatient facility. Treatment for
Kawasaki disease involves, at a minimum, an infusion of IVIG, which is typically given over a period of
hours. Side effects of this medication may include fever, headache, urticaria, nausea, vomiting, and blood
pressure instability. Although uncommon, anaphylaxis, Stevens-Johnson syndrome, and nephrotoxicity
have been reported, so it is in the best interest of the
patient to be admitted for monitoring during treatment. In addition, most hospitals will keep children in
the hospital until the fever resolves, as children with
ongoing fevers may be resistant to traditional treatments. Ideally, children should be admitted to a unit
with the capability for pediatric echocardiography
and access to a pediatric cardiologist for complete
evaluation of the heart and coronary artery aneurysms. Children who present with myocarditis, impaired ventricular function, or giant coronary artery
aneurysms in the setting of acute Kawasaki disease
should be managed at a facility with a pediatric cardiology service and pediatric intensive care unit.
Children with Kawasaki disease can be discharged
after completion of therapy provided there is resolution of fever. High-dose aspirin (80-100 mg/kg/day
in the United States) is generally continued for 48 to
72 hours after defervescence. All children with Kawasaki disease should be discharged on low-dose aspirin
(3-5 mg/kg/day), which should be maintained for a
minimum of 6 to 8 weeks following diagnosis. Echocardiography should be repeated at 2 weeks post diagnosis, and then again at 6 to 8 weeks post diagnosis.
Aspirin can be discontinued at that time if no coronary
artery abnormalities are found on echocardiography.
Recurrence rates of Kawasaki disease are low. Large
epidemiologic studies done in Japan estimate a recurrence rate of 3% to 4%.11,92 Similar studies estimate a
recurrence rate of 2% in the North American population.93,94 Recurrence tends to be more common in
children aged < 3 years of age at the time of the initial
episode.94 Emergency clinicians need to be aware of the
risk of recurrence when evaluating a patient with a history of Kawasaki disease.
Emerging Research
To date, there is no definitive test for Kawasaki
disease, leading to potentially dangerous delays in
diagnosis and treatment. Prior research has shown
that delays in diagnosis increase the risk of complications (including coronary artery aneurysms) and
mortality. To this end, several researchers have been
working to find a more definitive laboratory test
to help emergency clinicians make the diagnosis of
Kawasaki disease.
Kentsis et al have been studying urine proteomics
in an attempt to find a sensitive diagnostic test for
making the diagnosis of Kawasaki disease.90 The study
looked at a total of 107 patients, of whom 53 had a
diagnosis of Kawasaki disease and 54 had Kawasaki-like
symptoms, but a different final diagnosis (such as viral
illness). The researchers identified that filamin C, which
is associated with myocardial and endothelial damage,
and meprin A, which is an immune modulator, were
present in high concentrations in the urine of patients
with Kawasaki disease compared to patients with other
febrile diagnoses. This was true for both the complete
and incomplete forms of Kawasaki disease. In addition,
the diagnostic performance of these tests was superior
to the diagnostic performance of ESR, CRP, or a combination of the 2 tests. In addition, the levels of meprin A
and filamin C present in the urine were found to decline
after treatment with IVIG.90 Future research is needed to
validate these findings.
Reindel et al investigated serum periostin levels as a possible biomarker for diagnosing Kawasaki disease.91 The authors hypothesized that, since
periostin plays a role in vascular and cardiac damage, it might be elevated in patients with Kawasaki
disease. In this study, the researchers compared
serum periostin levels of 30 control patients (15
afebrile controls, 15 febrile controls) to the periostin
levels of 27 patients with Kawasaki disease (12 with
coronary artery aneurysms, 15 without coronary
artery aneurysms). The mean periostin level in all
control patients was 5647 ng/mL, which was sigCopyright © 2015 EB Medicine. All rights reserved.
Long-Term Prognosis
Since Kawasaki disease was first described more
than 40 years ago, outcomes have improved significantly. With proper identification and treatment, the
incidence of coronary artery lesions has declined
14
www.ebmedicine.net • January 2015
lesions will regress within 1 to 2 years.5,6 Coronary
arteries may develop areas of stenosis, and these lesions are frequently progressive. Depending on the
type, location, and size of the lesion, these children
may require long-term antiplatelet or anticoagulation therapy and frequent evaluations by a pediatric
cardiologist. (See Table 4, page 15.)
Mortality rates for Kawasaki disease are generally low, and they are currently estimated to be 0.01%
to 0.2% currently.94 Mortality peaks between 15 and
45 days after the onset of disease, and it is most
often due to coronary artery thrombosis.5,94 Myocardial infarction can occur secondary to thrombotic
occlusion of an aneurysm or stenotic vessel, and the
highest risk of this occurs within the first year after
diagnosis.5 Other causes of death include congestive heart failure, arrhythmias, or coronary artery
rupture.94 As children with Kawasaki disease age,
there is a recognized risk of late myocardial infarc-
to approximately 3% to 5%, from an initial rate of
25% to 30% previously.95 Long-term management
of children following diagnosis of Kawasaki disease
depends largely on whether or not they develop
coronary artery lesions. Risk stratification schemes
exist to help guide follow-up. These can be found in
the AHA guidelines on Kawasaki disease, and they
are summarized in Table 4.
Children who are promptly diagnosed and
treated and who do not develop coronary artery
lesions are considered at low risk. These children are
thought to have long-term cardiac outcomes similar
to the population without Kawasaki disease.5 These
patients are generally treated with a 6- to 8-week
course of antiplatelet therapy, and are followed by
cardiology every 3 to 5 years after the first year.
Despite proper recognition and treatment, a small
percentage of children develop coronary artery
aneurysms. It is estimated that 50% to 70% of such
Table 4. American Academy Of Pediatrics Risk Stratification And Recommendations On Follow-Up
Risk Level (I-V)
Pharmacological Therapy
Physical Activity
Follow-Up and
Diagnostic Testing
Invasive Testing
I (no coronary artery
changes at any stage of
illness)
None beyond first 6-8 wk
No restrictions beyond first
6-8 wk
Cardiovascular risk assessment, counseling at 5-y
intervals
None recommended
II (transient coronary artery ectasia, disappears
within first 6-8 wk)
None beyond first 6-8 weeks
No restrictions beyond first
6-8 wk
Cardiovascular risk assessment, counseling at 5-y
intervals
None recommended
III (1 small-medium coronary
artery aneurysm/major
coronary artery)
Low-dose aspirin (3-5 mg/
kg/day), at least until
aneurysm regression is
documented
For patients aged < 11 y,
no restriction beyond first
6-8 wk; patients aged
11-20 y, physical activity
guided by biennial stress
test, evaluation of myocardial perfusion scan;
contact or high-impact
sports discouraged for
patients taking antiplatelet agents
Annual cardiology follow-up
with echocardiogram
+ ECG, combined with
cardiovascular risk assessment, counseling; biennial
stress test/evaluation of
myocardial perfusion scan
Angiography, if noninvasive
test suggests ischemia
IV (large or giant coronary
artery aneurysm, or multiple or complex aneurysms
in same coronary artery,
without obstruction)
Long-term antiplatelet
therapy and warfarin
(target INR 2-2.5) or
low–molecular-weight
heparin (target antifactor Xa level 0.5-1
U/mL), should be combined in giant aneurysms
Contact or high-impact
sports should be avoided
because of risk of bleeding;
other physical activity
recommendations guided
by stress test/evaluation of
myocardial perfusion scan
outcome
Biannual follow-up with
echocardiogram + ECG;
annual stress test/
evaluation of myocardial
perfusion scan
First angiography at 6-12
mo or sooner, if clinically indicated; repeated
angiography if noninvasive
test, clinical, or laboratory findings suggest
ischemia; elective repeat
angiography under some
circumstances
V (coronary artery obstruction)
Long-term low-dose aspirin;
warfarin or low-molecularweight heparin if giant
aneurysm persists; consider use of low-molecularweight consumption
Contact or high-impact
sports should be avoided
because of risk of bleeding;
other physical activity
recommendations guided
by stress test/myocardial
perfusion scan outcome
Biannual follow-up with
echocardiogram and
ECG; annual stress test/
evaluation of myocardial
perfusion scan
Angiography recommended
to address therapeutic
options
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 treated her with antipyretics and discharged her.”
Fevers are common in children, and many
children with fever will likely have a viral
illness. Many of the other symptoms of
Kawasaki disease are found in viral illnesses,
such as rash and conjunctivitis. However,
Kawasaki disease should be considered in all
patients with parental report of prolonged
fever. Failure to recognize and treat Kawasaki
disease in a timely manner can have catastrophic
consequences.
4. “I was unsure of the diagnosis, so I waited to
start treatment with IVIG.”
Delays in making the diagnosis and delays in
starting treatment significantly increase the
risk of developing coronary artery aneurysms.
If the emergency clinician has a high suspicion
for Kawasaki disease and laboratory values
support the diagnosis, treatment should be
initiated promptly. Echocardiogram should be
performed as soon as possible, but this should
not delay treatment.
5. “I know that the guidelines recommend echocardiography for assessment of coronary arteries when the suspicion is high for Kawasaki
disease, so I delayed treatment to obtain the
imaging.”
Ideally, initial echocardiography should be
performed on the day of diagnosis. Guidelines
from the AHA and the AAP recommend
prompt echocardiography once Kawasaki
disease is diagnosed or suspected, although
delays in obtaining imaging should not delay
initiation of treatment.
2. “The child did not meet the criteria for all of
the symptoms on presentation to the ED, so I
thought she could not have Kawasaki disease.”
The diagnosis of incomplete Kawasaki disease
can be difficult. It is necessary to have a high
index of suspicion with regard to Kawasaki
disease in children with a fever lasting ≥ 5 days.
It is important to note that symptoms may
present sequentially rather than simultaneously,
and, thus, some of the diagnostic symptoms
may be resolved prior to presentation to the ED.
If a patient has fever plus 2 to 3 of the diagnostic
criteria, further evaluation with laboratory
studies and possibly an echocardiogram is
warranted to evaluate for Kawasaki disease. By
most estimates, approximately 20% of patients
with Kawasaki disease will fall into the category
of incomplete disease.
6. “The patient failed to respond to initial standard treatment of IVIG and aspirin, and I
didn’t know what to choose next.”
Although the standard therapy of IVIG plus
high-dose aspirin is effective for most patients
with Kawasaki disease, it is estimated that
approximately 10% to 20% of patients will fail
to respond to this therapy. Second-line therapy
usually consists of retreatment with IVIG,
potentially in combination with corticosteroids.
Although further research is needed, infliximab
is generally safe and should be considered as an
alternative therapy in treatment-resistant disease.
3. “I suspected Kawasaki disease, but I was
unsure of the diagnosis, so I waited for the
laboratory tests to return before beginning
any treatment.”
There is no single diagnostic test to confirm
the diagnosis of Kawasaki disease. Diagnosis
centers on the presence of the criteria for
Kawasaki disease, which include fever for at
least 5 days, plus 4 of 5 of the following key
criteria: conjunctival injection, oral mucosal
changes, polymorphous rash, distal extremity
changes, and cervical lymphadenopathy.
Treatment should not be delayed if the diagnosis
can be confirmed by the history and physical
examination. Early identification and treatment
of Kawasaki disease has been shown to reduce
the development of coronary artery aneurysms.
Copyright © 2015 EB Medicine. All rights reserved.
7. “I ordered an echocardiogram for the patient,
but there were no findings, so I ruled out Kawasaki disease.”
It should be noted that a normal initial
echocardiogram should not be used to exclude
the diagnosis of Kawasaki disease, especially if
physical examination findings and laboratory
tests are consistent with the diagnosis.
16
www.ebmedicine.net • January 2015
Case Conclusion
tion, often occurring years later. This may occur due
to thrombosis of aneurysms or progressive stenosis.96 Although the risks are significantly higher in
patients with known coronary artery lesions, there
may be an increase in patients without such lesions,
but these risks have yet to be fully defined.93 In the
meantime, emergency clinicians should be aware of
these risks when assessing adults with a history of
Kawasaki disease.
After evaluating this 3-year-old patient, you had some
concerns that the patient had incomplete Kawasaki disease.
Review of the diagnostic criteria revealed that this patient
had the characteristic criteria of 5 days of fever, and met 3
of the supporting diagnostic criteria (conjunctivitis, oral
mucous membrane changes, and polymorphous rash).
You discussed this possibility with the mother, and proceeded with laboratory workup. The patient’s laboratory
tests showed a white blood cell count of 18,900/mm3, but
normal hemoglobin of 12.3 g/dL and normal platelet count
of 320,000/mm3. She was mildly hyponatremic, with a
sodium level of 132 mEq/L, although the remainder of her
electrolyte levels were normal. Her inflammatory markers
were extremely elevated, with a CRP of > 25 mg/dL and an
ESR of 87 mm/h. She was mildly hypoalbuminemic, with
an albumin level of 2.7 g/dL. Her liver enzymes revealed a
normal AST of 54 U/L, but an elevated ALT of 131 U/L.
Her urinalysis was positive for leukocyte esterase and negative for nitrites. Urine also had 10 to 25 WBC/HPF and 0
RBC/HPF. Blood and urine cultures remained negative.
These laboratory results were consistent with a diagnosis of incomplete Kawasaki disease, so you admitted the
patient for treatment. You consulted cardiology to obtain
an echocardiogram. In the meantime, she was started on
IVIG 2 g/kg and high-dose aspirin of 100 mg/kg/day. The
echocardiogram showed no coronary artery aneurysms.
However, she was noted to have mildly decreased left ventricular function, mild mitral insufficiency, and a small
pericardial effusion. She continued to have a fever for 48
hours after IVIG administration, and was given a second
dose, after which she promptly defervesced. Her cardiac
function subsequently improved. She was discharged
home on low-dose aspirin, and was scheduled for followup with a pediatric cardiologist.
Summary
Kawasaki disease is an acute, febrile vasculitis of
childhood, primarily affecting small- to mediumsized arteries. It is a self-limited disease, but can result
in the development of coronary artery aneurysms if
left untreated. Despite significant research, the exact
etiology of the disease remains unknown. In the
United States, clinical criteria for diagnosis of complete Kawasaki disease include fever for ≥ 5 days and
at least 4 of 5 supporting symptoms. These symptoms
include conjunctival injection, oral mucosal changes,
polymorphous rash, distal extremity changes, and
cervical lymphadenopathy. Emergency clinicians
should be aware that a smaller proportion of children will present with incomplete Kawasaki disease,
comprised of fever for ≥ 5 days plus 2 to 3 of the supporting symptoms. These patients will typically have
laboratory findings that support the diagnosis.
All children with suspected or confirmed Kawasaki
disease should have echocardiography performed
to assess for coronary artery abnormalities. Primary
treatment for Kawasaki disease includes IVIG infusion.
Despite a lack of strong evidence in its favor, many
institutions continue to include high-dose aspirin as
part of the treatment protocol. Treatment should ideally
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 being investigated for use in resistant disease, although
further studies are needed. Children who are untreated
or have delays in diagnosis and treatment are at an
increased risk for development of coronary artery aneurysms, thrombosis, and sudden cardiac death.
Time- And Cost-Effective
Strategies
• 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 echocardiography. 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 laboratory 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. (Epidemiologic study; 1704 patients)
Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are
equally robust. The findings of a large, prospective,
random­ized, and blinded trial should carry more
weight than a case report.
To help the reader judge the strength of each reference, pertinent information about the study will be
included in bold type following the ref­erence, where
available. The most informative references cited in this
paper, as determined by the author, will be noted by
an asterisk (*) next to the number of the reference.
15. Royle JA, Williams K, Elliott E, et al. Kawasaki disease in
Australia, 1993-95. Arch Dis Child. 1998;78(1):33-39. (Epidemiologic study; 139 cases)
16. Rowley AH, Shulman ST. New developments in the search
for the etiologic agent of Kawasaki disease. Curr Opin Pediatr. 2007;19(1):71-74. (Review article)
17. Leung DY, Meissner HC, Fulton DR, et al. Toxic shock syndrome toxin-secreting Staphylococcus aureus in Kawasaki
syndrome. Lancet. 1993;342(8884):1385-1388. (Prospective
cohort study; 31 patients)
18. Terai M, Miwa K, Williams T, et al. The absence of evidence
of staphylococcal toxin involvement in the pathogenesis of
Kawasaki disease. J Infect Dis. 1995;172(2):558-561. (Prospective case-control study; 48 patients)
1.* Kawasaki T. Acute febrile mucocutaneous syndrome with
lymphoid involvement with specific desquamation of the
fingers and toes in children. Arerugi. 1967;16(3):178-122.
(Retrospective review; 50 patients)
19. Leung DY, Meissner HC, Shulman ST, et al. Prevalence of
superantigen-secreting bacteria in patients with Kawasaki
disease. J Pediatr. 2002;140(6):742-746. (Prospective multicenter cohort study; 82 patients)
2.
Shike H, Burns JC, Shimizu S. Translation of Dr. Tomisaku
Kawasaki’s original report of fifty patients in 1967. Pediatr
Infec Dis J. 2002;21(11):993-995. (Translation of original
research; 50 patients)
20. Rowley AH, Shulman ST, Mask CA, et al. IgA plasma cell
infiltration of proximal respiratory tract, pancreas, kidney,
and coronary artery in acute Kawasaki disease. J Infect Dis.
2000;182(4):1183-1191. (Case-control study; 28 patients)
3.
Bayers S, Shulman ST, Paller AS. Kawasaki disease: part I.
Diagnosis, clinical features, and pathogenesis. J Am Acad
Dermatol. 2013;69(4):501. (Review article)
21. Rowley AH, Shulman ST, Spike BT, et al. Oligoclonal IgA
response in the vascular wall in acute Kawasaki diease. J Immunol. 2001;166(2):1334-1343. (Histopathologic study)
4.
Kawasaki T, Kosaki F, Okawa S, et al. A new infantile acute
febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatrics. 1974;54(3):271-276. (Retrospective review, 50 patients)
22. Esper F, Shapiro ED, Weibel C, et al. Association between a
novel human coronavirus and Kawasaki disease. J Infect Dis.
2005;191(4):499-502. (Case-control study; 33 patients)
23. Ebihara T, Endo R, Ma X, et al. Lack of association between
New Haven coronavirus and Kawasaki disease. J Infect Dis.
2005;192(2):351-352. (Case-control study; 227 patients)
5.* Newburger JW, Takahashi M, Committee on Rheumatic
Fever, Endocarditis, and Kawasaki Disease, et al. Diagnosis,
treatment, and long-term management of Kawasaki disease:
a statement for health professionals from the Committee
on Rheumatic Fever, Endocarditis, and Kawasaki Disease,
Council on Cardiovascular Disease in the Young, American
Heart Association. Pediatrics. 2004;114(6):1708-1733. (Consensus statement, USA)
6. 24. Belay ED, Erdman DD, Anderson LJ, et al. Kawasaki disease
and human coronavirus. J Infect Dis. 2005;192(2):352-353.
(Retrospective case-control study; 17 patients)
25. Chang LY, Chiang BL, Kao CL, et al. Lack of association
between infection with a novel human coronavirus (HCoV),
HCoV-NH, and Kawasaki disease in Taiwan. J Infect Dis.
2006;193(2):283-286. (Prospective cohort study; 53 patients)
Dajani AS, Taubert KA, Gerber MA, et al. Diagnosis and
therapy of Kawasaki disease in children. Circulation.
1993;87(5):1776-1780. (Review article)
7. Chang RK. Hospitalizations for Kawasaki disease among
children in the United States, 1988-1997. Pediatrics.
2002;109(6):e87. (Epidemiologic study)
8. Eleftheriou D, Levin M, Shingadia D, et al. Management of
Kawasaki disease. Arch Dis Child. 2014;99(1):74-83. (Review)
9.
Holman RC, Belay ED, Christensen KY, et al. Hospitalizations for Kawasaki syndrome among children in the United
States, 1997-2007. Pediatr Infect Dis J. 2010;29(6):483-488.
(Epidemiologic study)
26. Brown TJ, Crawford SE, Cornwall ML, et al. CD8 T lymphocytes and macrophages infiltrate coronary artery aneurysms
in acute Kawasaki disease. J Infect Dis. 2001;184(7):940-943.
(Histopathologic study; 8 patients)
27. Rowley AH, Baker SC, Shulman ST, et al. Cytoplasmic inclusion bodies are detected by synthetic antibody in ciliated
bronchial epithelium during acute Kawasaki disease. J Infect
Dis. 2005;192(10):1757-1766. (Histopathologic study)
28. Rowley AH, Baker SC, Shulman ST, et al. Ultrastructural,
immunofluorescence, and RNA evidence support the hypothesis of a “new” virus associated with Kawasaki disease.
J Infect Dis. 2011;203(7):1021-1030. (Histopathologic study; 4
patients)
10. Centers for Disease Control and Prevention: Kawasaki Syndrome. 2013; Available at: http://www.cdc.gov/kawasaki/.
Accessed July 14, 2014. (Government report)
29. Takeshita S, Tokutomi T, Kawase H, et al. Elevated serum
levels of matrix metalloproteinase-9 (MMP-9) in Kawasaki
disease. Clin Exp Immunol. 2001;125(2):340-344. (Prospective
case-control study; 38 patients)
11. Luca NJ, Yeung RS. Epidemiology and management of Kawasaki disease. Drugs. 2012;72(8):1029-1038. (Review article)
12. Holman RC, Shahriari A, Effler PV, et al. Kawasaki sydrome
hospitalizations among children in Hawai and Connecticut.
Arch Pediatr Adolesc Med. 2000;154(8):804-808. (Epidemiologic study, retrospective analysis; 175 patients)
30. Yasukawa K, Terai M, Shulman ST, et al. Systemic production of vascular endothelial growth factor and fms-like tyrosine kinase-1 receptor in acute Kawasaki disease. Circulation.
2002;105(6):766-769. (Histopathologic study)
13. Nakamura Y, Yashiro M, Uehara R, et al. Epidemiologic features of Kawasaki disease in Japan: results of the 2007-2008
nationwide survey. J Epidemiol. 2010;20(4):302-307. (Epidemiologic study; 23,337 cases)
31. Barone SR, Pontrelli LR, Krilov LR. The differentiation of
classic Kawasaki disease, atypical Kawasaki disease, and
acute adenoviral infection: use of clinical features and a
rapid direct fluorescent antigen test. Arch Pediatr Adolesc
14. Harnden A, Mayon-White R, Perera R, et al. Kawasaki
Copyright © 2015 EB Medicine. All rights reserved.
18
www.ebmedicine.net • January 2015
Med. 2000;154(5):453-456. (Retrospective case-control study;
43 patients)
51. Watanabe T, Abe Y, Sato S, et al. Hyponatremia in Kawasaki
disease. Pediatr Nephrol. 2006;21(6):778-781. (Cohort study;
114 patients)
32. Uehara R, Igarashi H, Yashiro M, et al. Kawasaki disease
patients with redness or crust formation at the Bacille
Calmette-Guerin inoculation site. Pediatr Infect Dis J.
2010;29(5):430-433. (Epidemiologic data analysis study;
15,524 patients)
52. Shiraishi M, Fuse S, Mori T, et al. N-terminal pro-brain
natriuretic peptide as a useful diagnostic marker of acute
Kawasaki disease in children. Circ J. 2013;77(8):2097-2101.
(Prospective case-control study; 655 patients)
33. Lai CC, Lee PC, Wang CC, et al. Reaction at the bacillus
Calmette--Guerin inoculation site in patients with Kawasaki
disease. Pediatr Neonatol. 2013;54(1):43-48. (Retrospective
study; 145 patients)
53. McNeal-Davidson A, Fournier A, Spigelblatt L, et al. Value
of amino-terminal pro B-natriuretic peptide in diagnosing
Kawasaki disease. Pediatr Int. 2012;54(5):627-633. (Prospective case-control, 130 patients)
34. World Health Organization. BCG vaccine. WHO position
paper. Wkly Epidemiol Rec. 2004;79(4):27-38. (Position paper)
54. Shike H, Kanegaye JT, Best BM, et al. Pyuria associated with
acute Kawasaki disease and fever from other causes. Pediatr
Infect Dis J. 2009;28(5):440-443. (Prospective case-control
study; 222 patients)
35. Wang S, Best BM, Burns JC. Periungual desquamation
in patients with Kawasaki disease. Pediatr Infect Dis J.
2009;28(6):538-539. (Retrospective review; 243 patients)
55. Watanabe T. Kidney and urinary tract involvement in Kawasaki disease. Int J Pediatr. 2013;2013:831834. (Review article)
36. Saundankar J, Yim D, Itotoh B, et al. The epidemiology and
clinical features of Kawasaki disease in Australia. Pediatrics.
2014;133(4):e1009-e1014. (Epidemiologic study; 353 cases)
56. Ichida F, Fatica NS, O’Loughlin JE, et al. Correlation of
electrocardiographic and echocardiographic changes in
Kawasaki syndrome. Am Heart J. 1988;116(3):812-819. (Retrospective cohort study; 44 patients)
37. Dengler LD, Capparelli EV, Bastian JF, et al. Cerebrospinal
fluid profile in patients with acute Kawasaki disease. Pediatr
Infect Dis J. 1998;17(6):478-481. (Retrospective review; 46
patients)
57. Newburger JW, Takahashi M, Burns JC, et al. The treatment
of Kawasaki syndrome with intravenous gamma globulin.
N Engl J Med. 1986;315(6):341-347. (Prospective multicenter
randomized trial; 158 patients)
38. Baker AL, Lu M, Minich LL, et al. Associated symptoms in
the ten days before diagnosis of Kawasaki disease. J Pediatr.
2009;154(4):592-595. (Prospective study; 198 patients)
58. Newburger JW, Takahashi M, Beiser AS, et al. A single intravenous infusion of gamma globulin as compared with four
infusions in the treatment of acute Kawasaki syndrome. N
Engl J Med. 1991;324(23):1633-1639. (Prospective multicenter
randomized trial; 549 patients)
39. Bradley DJ, Glode MP. Kawasaki disease. The mystery continues. West J Med. 1998;168(1):23-29. (Review article)
40. Gong GW, McCrindle BW, Ching JC, et al. Arthritis presenting during the acute phase of Kawasaki disease. J Pediatr.
2006;148(6):800-805. (Retrospective study; 414 patients)
59. Barron KS, Murphy DJ, Jr, Silverman ED, et al. Treatment of
Kawasaki syndrome: a comparison of two dosage regimens
of intravenously administered immune globulin. J Pediatr.
1990;117(4):638-644. (Prospective multicenter trial; 44 patients)
41. Yun SH, Yang NR, Park SA. Associated symptoms of Kawasaki disease. Korean Circ J. 2011;41(7):394-398. (Retrospective
cohort study; 121 patients)
42. Ibanez-Alcalde M, Sanchez-Forte M, Gimenez-Sanchez F,
et al. Cholestasis as the initial feature of Kawasaki disease.
Pediatr Infect Dis J. 2012;31(7):766-767. (Retrospective case
study; 31 patients)
60. Tse SM, Silverman ED, McCrindle BW, et al. Early treatment with intravenous immunoglobulin in patients with
Kawasaki disease. J Pediatr. 2002;140(4):450-455. (Prospective
case-control study; 178 patients)
43. Kanegaye JT, Wilder MS, Molkara D, et al. Recognition of a Kawasaki disease shock syndrome. Pediatrics.
2009;123(5):e783-e789. (Prospective cohort study; 187
patients)
61. Baer AZ, Rubin LG, Shapiro CA, et al. Prevalence of coronary artery lesions on the initial echocardiogram in Kawasaki syndrome. Arch Pediatr Adolesc Med. 2006;160(7):686-690.
(Retrospective study; 100 patients)
44. Gatterre P, Oualha M, Dupic L, et al. Kawasaki disease: an
unexpected etiology of shock and multiple organ dysfunction syndrome. Intensive Care Med. 2012;38(5):872-878. (Retrospective study; 11 patients)
62. Newburger JW, Taubert KA, Shulman ST, et al. Summary
and abstracts of the Seventh International Kawasaki Disease
Symposium: December 4-7, 2001, Hakone, Japan. Pediatr Res.
2003;53(1):153-157. (Summary)
45. Tremoulet AH, Jain S, Chandrasekar D, et al. Evolution of
laboratory values in patients with Kawasaki disease. Pediatr
Infect Dis J. 2011;30(12):1022-1026. (Retrospective cohort
study; 380 patients)
63. Yu JJ, Jang WS, Ko HK, et al. Perivascular brightness of coronary arteries in Kawasaki disease. J Pediatr. 2011;159(3):454457. (Prospective case-control study; 58 patients)
64. Crystal MA, Syan SK, Yeung RS, et al. Echocardiographic
and electrocardiographic trends in children with acute
Kawasaki disease. Can J Cardiol. 2008;24(10):776-780. (Retrospective cohort study; 176 patients)
46. Eladawy M, Dominguez SR, Anderson MS, et al. Abnormal
liver panel in acute kawasaki disease. Pediatr Infect Dis J.
2011;30(2):141-144. (Retrospective review; 259 patients)
47. Newburger JW, Burns JC, Beiser AS, et al. Altered lipid profile after Kawasaki syndrome. Circulation. 1991;84(2):625-631.
(Prospective cohort study; 105 patients)
65. Frazier A, Hunt EA, Holmes K. Pediatric cardiac emergencies: children are not small adults. J Emerg Trauma Shock.
2011;4(1):89-96. (Review)
48. Terai M, Honda T, Yasukawa K, et al. Prognostic impact
of vascular leakage in acute Kawasaki disease. Circulation.
2003;108(3):325-330. (Prospective case-control study; 103
patients)
66. Yim D, Curtis N, Cheung M, et al. An update on Kawasaki
disease II: clinical features, diagnosis, treatment and outcomes. J Paediatr Child Health. 2013;49(8):614-623. (Review)
67. Beiser AS, Takahashi M, Baker AL, et al. A predictive instrument for coronary artery aneurysms in Kawasaki disease. US
Multicenter Kawasaki Disease Study Group. Am J Cardiol.
1998;81(9):1116-1120. (Retrospective cohort study with validation; 212 patients)
49. Laxer RM, Petty RE. Hyponatremia in Kawasaki disease.
Pediatrics. 1982;70(4):655. (Retrospective review; 11 patients)
50. Lim GW, Lee M, Kim HS, et al. Hyponatremia and syndrome
of inappropriate antidiuretic hormone secretion in Kawasaki disease. Korean Circ J. 2010;40(10):507-513. (Prospective
cohort study; 50 patients)
January 2015 • www.ebmedicine.net
68. Egami K, Muta H, Ishii M, et al. Prediction of resistance to
19
Reprints: www.ebmedicine.net/pempissues
intravenous immunoglobulin treatment in patients with
Kawasaki disease. J Pediatr. 2006;149(2):237-240. (Retrospective cohort study; 320 patients)
83. Kobayashi T, Saji T, Otani T, et al. Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery
abnormalities in severe Kawasaki disease (RAISE study):
a randomised, open-label, blinded-endpoints trial. Lancet.
2012;379(9826):1613-1620. (Prospective, multicenter randomized trial; 248 patients)
69. Tremoulet AH, Best BM, Song S, et al. Resistance to intravenous immunoglobulin in children with Kawasaki disease.
J Pediatr. 2008;153(1):117-121. (Retrospective study; 362
patients)
84. Burns JC, Mason WH, Hauger SB, et al. Infliximab treatment
for refractory Kawasaki syndrome. J Pediatr. 2005;146(5):662667. (Retrospective cohort study; 16 patients)
70. Sleeper LA, Minich LL, McCrindle BM, et al. Evaluation
of Kawasaki disease risk-scoring systems for intravenous
immunoglobulin resistance. J Pediatr. 2011;158(5):831-835.
(Retrospective study; 198 patients)
85. Burns JC, Best BM, Mejias A, et al. Infliximab treatment of
intravenous immunoglobulin-resistant Kawasaki disease. J
Pediatr. 2008;153(6):833-838. (Prospective multicenter randomized trial; 24 patients)
71. Forsey J, Mertens L. Atypical Kawasaki disease--a clinical
challenge. Eur J Pediatr. 2012;171(4):609-611. (Editorial comment)
86. Williams RV, Wilke VM, Tani LY, et al. Does Abciximab
enhance regression of coronary aneurysms resulting from
Kawasaki disease? Pediatrics. 2002;109(1):E4. (Prospective
cohort study; 15 patients)
72. Sudo D, Monobe Y, Yashiro M, et al. Coronary artery lesions
of incomplete Kawasaki disease: a nationwide survey in
Japan. Eur J Pediatr. 2012;171(4):651-656. (Epidemiologic
study)
87. Uehara R, Yashiro M, Nakamura Y, et al. Clinical features of
patients with Kawasaki disease whose parents had the same
disease. Arch Pediatr Adolesc Med. 2004;158 (12):1166-1169.
(Retrospective cohort study; 65 patients)
73. Ha KS, Jang G, Lee J. Incomplete clinical manifestation as
a risk factor for coronary artery abnormalities in Kawasaki
disease: a meta-analysis. Eur J Pediatr. 2013;172(3):343-349.
(Meta-analysis; 20 studies, 4504 patients, 32,519 controls)
88. Hirata S, Nakamura Y, Yanagawa H. Incidence rate of recurrent Kawasaki disease and related risk factors: from the results of a nationwide surveys of Kawasaki disease in Japan.
Acta Paediatr. 2001;90(1):40-44. (Epidemiologic study; 10,679
patients)
74. Manlhiot C, Christie E, McCrindle BW, et al. Complete and
incomplete Kawasaki disease: two sides of the same coin.
Eur J Pediatr. 2012;171(4):657-662. (Retrospective review; 955
patients)
89. Dergun M, Kao A, Hauger S, et al. Familial occurance of
Kawasaki syndrome in North America. Arch Pediatr Adolesc
Med. 2005;159(9):876-881. (Retrospective cohort study; 42
patients)
75. Dominguez SR, Anderson MS. Advances in the treatment
of Kawasaki disease. Curr Opin Pediatr. 2013;25(1):103-109.
(Review)
76. Furusho K, Kamiya T, Nakano H, et al. High-dose intravenous gammaglobulin for Kawasaki disease. Lancet.
1984;2(8411):1055-1058. (Multicenter control trial; 85 patients)
90. Kentsis A, Shulman A, Ahmed S, et al. Urine proteomics
for discovery of improved diagnostic markers of Kawasaki
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. Intravenous immunoglobulin for the treatment of Kawasaki disease
in children. Cochrane Database Syst Rev. 2003;(4):CD004000.
(Meta-analysis and review)
91. Reindel R, Kim KY, Baker SC, et al. Periostin is upregulated
in coronary arteriopathy in Kawasaki disease and is a potential diagnostic biomarker. Pediatr Infect Dis J. 2014;33(6):659661. (Case-control study; 57 patients)
78. Orbach H, Katz U, Sherer Y, et al. Intravenous immunoglobulin: adverse effects and safe administration. Clin Rev Allergy
Immunol. 2005;29(3):173-184. (Review)
92. Yanagawa H, Nakamura Y, Yashiro M, et al. Update of the
epidemiology of Kawasaki disease in Japan--from the results
of 1993-94 nationwide survey. J Epidemiol. 1996;6(3):148-157.
(Epidemiologic study; 11,458 cases)
79. Baumer JH, Love S, Gupta A, et al. Salicylate for the treatment 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 syndrome and risk factors for coronary artery abnormalities:
United States, 1994-2003. Pediatr Infect Dis J. 2006;25(3):245249. (Epidemiologic study; 3115 patients)
80. Kato H, Koike S, Yokoyama T. Kawasaki disease: effect
of treatment on coronary artery involvement. Pediatrics.
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.
2013;69(4):513.e511-e518. (Review)
81. Newburger JW, Sleeper LA, McCrindle BW, et al. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med. 2007;356(7):663-675.
(Prospective multicenter randomized trial; 199 patients)
95. Fukazawa R. Long-term prognosis of Kawasaki disease: 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 randomized trial. Pediatrics. 2012;129(1):e17-e23. (Prospective
randomized trial; 122 patients)
Copyright © 2015 EB Medicine. All rights reserved.
96. Daniels LB, Gordon JB, Burns JC. Kawasaki disease: late cardiovascular sequelae. Curr Opin Cardiol. 2012;27(6):572-577.
(Review)
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 Kawasaki disease
c. Requires antibiotic management
d. Is usually unilateral
Take This Test Online!
Current subscribers receive CME credit absolutely
free by completing the following test. Each issue
includes 4 AMA PRA Category 1 CreditsTM, 4 ACEP
Category I credits, 4 AAP Prescribed credits, and 4
Take This Test Online!
AOA Category 2A or 2B credits. Monthly online
testing is now available for current and archived
issues. To receive your free CME credits for this
issue, scan the QR code below with your smartphone or visit www.ebmedicine.net/P0115.
6. Elevation of which of the following laboratory results aids in the diagnosis of Kawasaki
disease?
a. Sodium
b. Albumin
c. Cholesterol
d. CRP
7. Incomplete Kawasaki disease may be diagnosed 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 diagnostic criteria
d. Two to 3 of the diagnostic criteria without fever
1. Diagnostic clinical criteria for Kawasaki disease include all of the following EXCEPT:
a. Conjunctivitis
b. Oropharyngeal changes
c. Vomiting
d. Extremity changes
8. In the United States, what is the standard treatment for Kawasaki disease?
a. Supportive care
b. IVIG plus aspirin
c. Corticosteroids
d. Aciximab
2. Rates of Kawasaki disease are highest in which
population?
a. Asian/Pacific Islanders
b. Hispanics
c. Blacks
d. Whites
9. At this time, an option for treatment of resistant disease is:
a. Propranolol
b. Infliximab
c. Dialysis
d. Ampicillin
3. The polymorphous rash associated with Kawasaki disease is commonly:
a. Vesicular
b. Bullous
c. Diffuse macular
d. Urticarial
10. The risk of a child developing Kawasaki disease is significantly increased if:
a. The child has a sibling with Kawasaki disease
b. The child is unimmunized
c. The child attends daycare
d. The child has congenital heart disease
4. Which finding in patients who have previously
received the BCG vaccination is highly specific
for Kawasaki disease?
a. Jaundice
b. Erythema at the BCG injection site
c. Shock
d. Arthritis
January 2015 • www.ebmedicine.net
21
Reprints: www.ebmedicine.net/pempissues
SPECIAL SAVINGS:
The 2012-2015 Lifelong Learning
And Self-Assessment Study Guides
The
Ultimate
LLSA Prep
Receive FREE article reprints,* CME, and
more when you order yours today!
Includes
FULL Article
Reprints*
*Due to copyright restrictions, the tables
from one article in the 2014 LLSA and two
articles in the 2013 LLSA are not included.
2
DESCRIPTION
AMOUNT
The 2015 Lifelong Learning And Self-Assessment Study Guide
$199 $50
$149 Off
The 2014 Lifelong Learning and Self-Assessment Study Guide
$199 $50
$149 Off
The 2013 Lifelong Learning And Self-Assessment Study Guide $199 $50
$149 Off
The 2012 Lifelong Learning And Self-Assessment Study Guide $199 $50
$149 Off
•
Full reprints of the original articles* FREE
•
35 AMA PRA Category 1 Credits or 35 ACEP Category I CME Credits. FREE
•
A handy summary of key points so you get the "must know" information for each article.
INCLUDED
•
An in-depth discussion of each article to clarify and elaborate on the key points. INCLUDED
•
Sample questions to help you quiz yourself on your knowledge of the material. INCLUDED
•
Answers and explanations to the sample questions that drive home the main points. INCLUDED
TM
• A critical discussion and critique of the article that answers the question, “What does this article really tell us?”
INCLUDED
• 100% money-back guarantee: If, for any reason, you are not completely satisfied, simply call us to receive a full and immediate refund. No questions asked.
INCLUDED
E A S Y
WAYS TO
ORDER
1. Go online to: www.ebmedicine.net/NHLAG
2. Call 1-800-249-5770 or 678-366-7933
Use Promotion Code: NHLAG at checkout to secure your discount
Copyright © 2015 EB Medicine. All rights reserved.
22
www.ebmedicine.net • January 2015
Your pediatric patients
require special attention.
Renew your subscription now
to continue enhancing their care.
Don’t wait – contact us today to continue receiving high-quality, evidence-based
issues of Pediatric Emergency Medicine Practice – the only publication that truly
focuses on pediatrics in emergency medicine. You can renew your subscription now for only $199 (a savings of $100 from our regular rate) and get a free
download of the Pediatric Emergency Medicine Practice Audio Series Vol. II!
Your subscription to Pediatric Emergency Medicine Practice includes:
• Monthly print & online issues of Pediatric Emergency Medicine Practice, featuring current clinical reports from the leading minds in pediatric EM care
• 48 AMA PRA Category 1 CreditsTM, 48 ACEP Category I credits, 48 AAP Prescribed credits, and 48 AOA Category 2A or 2B credits per year
• Online access to archived issues, CME testing, and CME tracking
• Up to 144 additional CME credits online at www.ebmedicine.net
3 Ways to Order…
1) Call 1-800-249-5770 2) Go online to www.ebmedicine.net/RHPAC 3) Detach lower portion and mail to:
5550 Triangle Pkwy, Ste 150 / Norcross, GA 30092
n

Yes! Renew my Pediatric Emergency Medicine Practice subscription with this exclusive subscriber discount. I also
receive a copy of the Pediatric Emergency Medicine Practice Audio Series Vol. II when I renew via this special offer.
Please check one: n One-year subscription (12 issues) – only $199 (a $100 savings)
n Two-year subscription (24 issues) – only $378 (a $220 savings)
Name:_____________________________________________________________________
Address:___________________________________________________________________
City:__________________________ State:_______ ZIP:____________________________
Phone #:__________________ Email:___________________________________________
Promotion Code:
RHPAC
n Check enclosed (made payable to EB Medicine) / Charge my n Visa n MC n AmEx
Card #:______________________________________________ Exp. date: ____________
Signature: _________________________________________________________________
EB Medicine * 5550 Triangle Parkway, Suite 150 / Norcross, GA 30092 * 1-800-249-5770 * www.ebmedicine.net/RHPAC
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.
Accreditation: EB Medicine is accredited by the Accreditation Council for Continuing
Medical Education (ACCME) to provide continuing medical education for physicians. This
activity has been planned and implemented in accordance with the Essential Areas and
Policies of the ACCME.
Credit Designation: EB Medicine designates this enduring material for a maximum of 4
AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate
with the extent of their participation in the activity.
ACEP Accreditation: Pediatric Emergency Medicine Practice is also approved by the
American College of Emergency Physicians for 48 hours of ACEP Category I credit per
annual subscription.
AAP Accreditation: This continuing medical education activity has been reviewed by the
American Academy of Pediatrics and is acceptable for a maximum of 48 AAP credits per
year. These credits can be applied toward the AAP CME/CPD Award available to Fellows
and Candidate Fellows of the American Academy of Pediatrics.
Pediatric Emergency
Medicine Practice
Has Gone Mobile!
You can now view all Pediatric Emergency
Medicine Practice content on your iPhone
or Android smartphone. Simply visit
www.ebmedicine.net from your mobile
device, and you’ll automatically be
directed to our mobile site.
On our mobile site, you can:
•
View all issues of Pediatric Emergency Medicine
Practice since inception
•
Take CME tests for all Pediatric Emergency
Medicine Practice issues published within the last
3 years – that’s over 100 AMA Category 1 CreditsTM!
•
View your CME records, including scores, dates of
completion, and certificates
•
And more!
Check out our mobile site, and give us your
feedback! Simply click the link at the bottom of the
mobile site to complete a short survey to tell us
what features you’d like us to add or change.
AOA Accreditation: Pediatric Emergency Medicine Practice is eligible for up to 48
American Osteopathic Association Category 2A or 2B credit hours per year.
Needs Assessment: The need for this educational activity was determined by a survey
of medical staff, including the editorial board of this publication; review of morbidity and
mortality data from the CDC, AHA, NCHS, and ACEP; and evaluation of prior activities
for emergency physicians.
Target Audience: This enduring material is designed for emergency medicine physicians,
physician assistants, nurse practitioners, and residents.
Goals: Upon completion of this activity, you should be able to: (1) demonstrate medical
decision-making based on the strongest clinical evidence; (2) cost-effectively diagnose
and treat the most critical ED presentations; and (3) describe the most common
medicolegal pitfalls for each topic covered.
Discussion of Investigational Information: As part of the newsletter, faculty may be
presenting investigational information about pharmaceutical products that is outside
Food and Drug Administration approved labeling. Information presented as part of this
activity is intended solely as continuing medical education and is not intended to promote
off-label use of any pharmaceutical product.
Faculty Disclosure: It is the policy of EB Medicine to ensure objectivity, balance,
independence, transparency, and scientific rigor in all CME-sponsored educational
activities. All faculty participating in the planning or implementation of a sponsored
activity are expected to disclose to the audience any relevant financial relationships
and to assist in resolving any conflict of interest that may arise from the relationship.
Presenters must also make a meaningful disclosure to the audience of their discussions
of unlabeled or unapproved drugs or devices. In compliance with all ACCME
Essentials, Standards, and Guidelines, all faculty for this CME activity were
asked to complete a full disclosure statement. The information received is as
follows: Dr. Seaton, Dr. Kharbanda, Dr. Sellinger, Dr. Stoner, Dr. Vella, Dr. Wang, Dr.
Damilini, and their related parties report no significant financial interest or other
relationship with the manufacturer(s) of any commercial product(s) discussed in
this educational presentation.
Commercial Support: This issue of Pediatric Emergency Medicine Practice did not receive
any commercial support.
Earning Credit: Two Convenient Methods: (1) Go online to www.ebmedicine.net/CME
and click on the title of this article. (2) Mail or fax the CME Answer And Evaluation Form
with your June and December issues to EB Medicine.
Hardware/Software Requirements: You will need a Macintosh or PC with internet
capabilities to access the website.
Additional Policies: For additional policies, including our statement of conflict of interest,
source of funding, statement of informed consent, and statement of human and animal
rights, visit http://www.ebmedicine.net/policies.
CEO & Publisher: Stephanie Williford Director of Editorial: Dorothy Whisenhunt Content Editors: Erica Carver, Jenique Meekins Editorial Assistant: Lesley Wood
Office Manager: Kiana Collier Member Services Representative: Paige Banks Director of Business Development: Susan Woodard Account Manager: Cory Shrider
Director of Marketing: Robin Williford Marketing Coordinator: Katherine Johnson
Direct all questions to:
EB Medicine
Phone: 1-800-249-5770 or 678-366-7933
Fax: 1-770-500-1316
5550 Triangle Parkway, Suite 150
Norcross, GA 30092
E-mail: [email protected]
Website: EBMedicine.net
To write a letter to the editor, email: [email protected]
Subscription Information:
1 year (12 issues) including evidence-based print issues;
48 AMA PRA Category 1 CreditsTM, 48 ACEP Category 1 Credits, 48 AAP Prescribed
credits, and 48 AOA Category 2A or 2B credit; and full online access to searchable
archives and additional free CME: $299
(Call 1-800-249-5770 or go to www.ebmedicine.net/subscribe to order)
Single issues with CME may be purchased at
www.ebmedicine.net/PEMPissues
Pediatric Emergency Medicine Practice (ISSN Print: 1549-9650, ISSN Online: 1549-9669, ACID-FREE) is published monthly (12 times per year) by EB Medicine. 5550 Triangle Parkway, Suite 150, Norcross,
GA 30092. Opinions expressed are not necessarily those of this publication. Mention of products or services does not constitute endorsement. This publication is intended as a general guide and is intended
to supplement, rather than substitute, professional judgment. It covers a highly technical and complex subject and should not be used for making specific medical decisions. The materials contained herein
are not intended to establish policy, procedure, or standard of care. Pediatric Emergency Medicine Practice is a trademark of EB Medicine. Copyright © 2015 EB Medicine All rights reserved. No part of this
publication may be reproduced in any format without written consent of EB Medicine. This publication is intended for the use of the individual subscriber only, and may not be copied in whole or in part or
redistributed in any way without the publisher’s prior written permission – including reproduction for educational purposes or for internal distribution within a hospital, library, group practice, or other entity.
Copyright © 2015 EB Medicine. All rights reserved.
24
www.ebmedicine.net • January 2015
Thank you for purchasing this
Pediatric Emergency Medicine Practice article.
Your article includes 4 AMA PRA Category 1 CreditsTM, 4 ACEP
Category 1 credits, 4 AAP Prescribed credits, and 4 AOA Category
2A or 2B credits. You have 2 options to receive credit:
1. Go to www.ebmedicine.net/CME, click the title of the article
you purchased.
2. Mail or fax the Answer & Evaluation Form on the next page to
EB Medicine at the address or fax below.
If you have any questions or comments, please contact us at
1-800-249-5770 or [email protected].
5550 Triangle Parkway, STE 150
Fax: 1-770-500-1316
Norcross, GA 30092
1-800-249-5770
Outside U.S.: 1-678-366-7933
Email: [email protected]
Website: www.ebmedicine.net
Pediatric Emergency Medicine Practice CME Answer & Evaluation Form
Please print the following information clearly:
Title of Article: ____________________________________________________________________________
Month and Year of Publication: ________________________________________________________________
Name: __________________________________________________________________________________
Address: _________________________________________________________________________________
_______________________________________________________________________________________
Phone number: ____________________________________________________________________________
E-mail address (required): ___________________________________________________________________
Please write your email address clearly. Certificates will be sent by email.
Check here if you need your certificate mailed: †
Accreditation: Please see the article for accreditation information.
Earning Credit: To receive credit for this issue, please mail this completed form to 5550 Triangle Pkwy, Ste 150 / Norcross, GA 30092 or fax to
770-500-1316. You must complete both the Answer and Evaluation Form below to receive credit. Results will be kept confidential. CME certificates will be emailed
to each participant scoring higher than 70% (please check the box above if you need your certificate mailed). Alternatively, you can take the CME test online at
www.ebmedicine.net/CME. If you have any questions, please call 1-800-249-5770 or e-mail [email protected].
Subscribing: Pediatric Emergency Medicine Practice subscribers receive 12 monthly print issues, 48 CME credits per year, and full online access to searchable
archives, CME testing, and 144 additional CME credits. To subscribe, call 1-800-249-5770 or enter Promotion Code AFP to save $50 at
http://ebmedicine.net/subscribe. Subscribing is optional and you are under no obligation. You can receive CME credit for this issue whether you choose to
subscribe or not.
Please fill in the appropriate box for
the correct answer for each question.
The test questions appear at the end of the
issue. Each question has only one correct
answer. If there are fewer questions on your
issue than listed here, leave the additional
questions blank. Please make a copy of the
completed answer form for your files
and return it to EB Medicine at the address
or fax number below.
1.
2.
3.
4.
5.
6.
7.
8.
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[b]
[b]
[b]
[b]
[b]
[b]
[b]
[b]
[c]
[c]
[c]
[c]
[c]
[c]
[c]
[c]
[d]
[d]
[d]
[d]
[d]
[d]
[d]
[d]
[e]
[e]
[e]
[e]
[e]
[e]
[e]
[e]
9.
10.
11.
12.
13.
14.
15.
16.
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[b]
[b]
[b]
[b]
[b]
[b]
[b]
[b]
[c] [d] [e]
[c] [d] [e]
[c] [d] [e]
[c] [d] [e]
[c] [d] [e]
[c] [d] [e]
[c] [d] [e]
[c] [d] [e]
Please take a few moments to complete this Evaluation Form. Your opinions will ensure continuing program relevance and quality.
Enter the extent to which you agree with the following statements.
Response codes: 5=strongly agree; 4=agree; 3=neutral; 2=disagree; 1=strongly disagree
1. ____ The overall activity content was pertinent to my needs and expectations.
2. ____ The information was presented in an impartial and unbiased manner.
3. ____ I learned information that will enhance my professional effectiveness.
4. ____ Adequate faculty disclosure was given.
5. ____ The test questions were clear and appropriate.
6. ____ The information presented in this CME quiz was objective, balanced, and of scientific rigor.
7. ____ The authors were NOT biased in their discussion of any commercial product or service.
8. ____ The content in this activity is useful in my everyday practice.
9. ____ The first CME objective (listed on the cover of the article) was met for this activity.
10. ____ The second CME objective (listed on the cover of the article) was met for this activity.
11.What clinical information did you learn that was of value to you? ___________________________________________________
12. How did the clinical information you learned impact positively or change the way you care for your patients? _________________
13. For future activities, what personal professional gap would you like us to fill? _________________________________________
14. What do you like MOST about Pediatric Emergency Medicine Practice? ____________________________________________
15. What do you like LEAST about Pediatric Emergency Medicine Practice? ____________________________________________
16. Please provide any additional comments. _____________________________________________________________________
5550 Triangle Pkwy, Ste 150 • Norcross, GA 30092 • 1-800-249-5770 • Fax: 770-500-1316 • [email protected] • www.ebmedicine.net
ANNOUNCING:
Pediatric Emergency Medicine Practice
5550 Triangle Pkwy, Ste 150 Norcross, GA 30092
1-800-249-5770 or 1-678-366-7933 / Fax: 1-770-500-1315
[email protected]www.ebmedicine.net
Shipping information:
Name: ___________________________________________________________
Address: _________________________________________________________
________________________________________________________________
City, State, ZIP: __________________________________________________
Phone number: ___________________________________________________
E-mail address: ___________________________________________________
We respect your privacy, and we hate spam as much as you do! We will

never share your email address, and you can easily opt out at any time.
Subscription Discount Offer
Yes! Start my Pediatric Emergency Medicine Practice subscription with
this exclusive discount. Promotion Code SAMPP. Please check one:
o One-year subscription (12 issues)—only $199 (a $100 savings) OR
o Two-year subscription (24 issues)—only $378 (a $220 savings)
Payment options:
Bill my: o Visa
o Mastercard
o American Express
Card # __________________________________________ Exp. ______
Signature (required): _________________________________________
OR
o Check enclosed (made payable to EB Medicine)
Phone: ___________________________________________________
Email: ____________________________________________________
We respect your privacy, and we hate spam as much as you do! We will
never share your email address and you can easily opt out at any time.
I also receive An Evidence-Based Approach to
Pediatric Emergencies—a $149 book—free.
DESCRIPTION
Pediatric Emergency Medicine Practice: 12 monthly evidence-based print issues per year
48 AMA PRA Category 1 CreditsTM, 48 ACEP Category 1 credits, and 48 AAP Prescribed
CME credits per year
Full online access to searchable archives, CME testing, and an additional 144 AMA PRA
Category 1 CreditsTM per year or 144 ACEP Category 1, AAP Prescribed CME credits
Our Guarantee: If you do not receive practice-improving information in each and every
Pediatric Emergency Medicine Practice issue, simply call us to receive a full, cheerful, and
immediate refund. No questions asked.
Bonus Book: An Evidence-Based Approach To Pediatric Emergencies
Get up to speed with these compelling chapters: The Nightmare Neonate: LifeThreatening Events In The First Month Of Life, The Young Febrile Child: Evidence-Based
Diagnostic And Therapeutic Strategies, Acute Abdominal Pain In Children: “Classic”
Presentations Vs. Reality, and The Critically Ill Or Comatose Infant: An Organized Approach.
Your Pediatric Emergency Medicine PRACTICE subscription gives you:
• An evidence-based approach to the most common -- and the most critical -- patient presentations
• Diagnosis and treatment recommendations solidly based in the current literature
• Risk management pitfalls that help you avoid costly errors
• Management algorithms that help you practice more efficiently -- and effectively
• A cost- and time-effective way to stay up to date and earn CME
Four Easy Ways To Order:
1.
2.
3.
4.
Call toll free: 1-800-249-5770
Fax this form to 770-500-1316
Mail this form to EB Medicine / 5550 Triangle Pkwy, Ste 150 / Norcross GA 30092
Go to http://ebmedicine.net/subscribe and enter Promotion Code SAMPP
This is not a bill. You are under no obligation to pay. This is an offer to subscribe at an exclusive discounted rate.
AMOUNT
$199 $100
off!
FREE
FREE
INCLUDED
INCLUDED
INCLUDED