Evidence-Based Management January 2015

Volume 12, Number 1

Of Kawasaki Disease In The Authors

Kara K. Seaton, MD

Emergency Department
Fellow, Pediatric Emergency Medicine, Childrens Hospital and
Clinics of Minnesota, Minneapolis, MN
Anupam Kharbanda, MD
Director of Research, Emergency and Trauma Services,
Abstract Childrens Hospital and Clinics of Minnesota, Minneapolis, MN
Peer Reviewers

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

Editor-in-Chief
Adam E. Vella, MD, FAAP
Associate Professor of Emergency
Medicine, Pediatrics, and Medical
Education, Director Of Pediatric
Emergency Medicine, Icahn
School of Medicine at Mount Sinai, Chief of Pediatric Emergency
New York, NY
Associate Editor-in-Chief
Vincent J. Wang, MD, MHA
Associate Professor of Pediatrics, Marianne Gausche-Hill, MD,
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
Editorial Board
Jeffrey R. Avner, MD, FAAP
Professor of Clinical Pediatrics
and Chief of Pediatric Emergency
Medicine, Albert Einstein College
of Medicine, Childrens Hospital at
Montefiore, Bronx, NY
Steven Bin, MD
Associate Clinical Professor,
Division of Pediatric Emergency
Medicine, UCSF Benioff Childrens Sandip Godambe, MD, PhD
Hospital, University of California, Vice President, Quality & Patient
San Francisco, CA
Richard M. Cantor, MD, FAAP,
FACEP
Professor of Emergency Medicine
and Pediatrics, Director, Pediatric
Emergency Department, Medical
Director, Central New York
Poison Control Center, Golisano
Children's Hospital, Syracuse, NY
Ilene Claudius, MD
Associate Professor of Emergency
Medicine, Keck School of Medicine
of the University of Southern
California, Los Angeles, CA
Alson S. Inaba, MD, FAAP
Ari Cohen, MD
Medicine Services, Massachusetts
General Hospital; Instructor in
Pediatrics, Harvard Medical
School, Boston, MA
FACEP, FAAP
Professor of Clinical Medicine,
David Geffen School of Medicine
at the University of California at
Los Angeles; Vice Chair and Chief,
Division of Pediatric Emergency
Medicine, Harbor-UCLA Medical
Center, Los Angeles, CA
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
Safety, Professor of Pediatrics and Assistant Professor of Emergency
Emergency Medicine, Attending
Physician, Children's Hospital
of the King's Daughters Health
System, Norfolk, VA
Ran D. Goldman, MD
Professor, Department of Pediatrics,
University of British Columbia;
Co-Lead, Division of Translational
Therapeutics; Research Director,
Pediatric Emergency Medicine, BC
Children's Hospital, Vancouver, BC,
Canada
Associate Professor of Pediatrics,
University of Hawaii at Mnoa
John A. Burns School of Medicine,
Division Head of Pediatric
Emergency Medicine, Kapiolani
Medical Center for Women and
Children, Honolulu, HI
Madeline Matar Joseph, MD, FAAP,
FACEP University of British Columbia;
Professor of Emergency Medicine
and Pediatrics, Chief and Medical
Director, Pediatric Emergency
Medicine Division, University
of Florida Medical School-
Jacksonville, Jacksonville, FL
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
Tommy Y. Kim, MD, FAAP, FACEP
Medicine and Pediatrics, Loma
Linda University Medical Center and
Childrens Hospital, Loma Linda, CA;
California Emergency Physicians,
Riverside, CA
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
Robert Luten, MD
Professor, Pediatrics and
Emergency Medicine, University of Professor of Pediatrics, Attending
Florida, Jacksonville, FL
Garth Meckler, MD, MSHS
Associate Professor of Pediatrics,
Division Head, Pediatric
Emergency Medicine, BC
Children's Hospital, Vancouver,
BC, Canada
Joshua Nagler, MD
Assistant Professor of Pediatrics,
Harvard Medical School;
Fellowship Director, Division of
Emergency Medicine, Boston
Childrens Hospital, Boston, MA James Damilini, PharmD, MS,
James Naprawa, MD
Associate Clinical Professor
of Pediatrics, The Ohio State
University College of Medicine;
Attending Physician, Emergency
Department, Nationwide Childrens Quality Editor
Hospital, Columbus, OH
Steven Rogers, MD
Assistant Professor, University of
Connecticut School of Medicine,
Attending Emergency Medicine
Physician, Connecticut Children's
Medical Center, Hartford, CT
Christopher Strother, MD
Assistant Professor, Director,
Undergraduate and Emergency
Simulation, Icahn School of
Medicine at Mount Sinai, New
York, NY
AAP Sponsor
Martin I. Herman, MD, FAAP, FACEP
Physician, Emergency Medicine
Department, Sacred Heart
Childrens Hospital, Pensacola, FL
International Editor
Lara Zibners, MD, FAAP
Honorary Consultant, Paediatric
Emergency Medicine, St Mary's
Hospital, Imperial College Trust;
EM representative, Steering Group
ATLS-UK, Royal College of
Surgeons, London, England
Pharmacology Editor
BCPS
Clinical Pharmacy Specialist,
Emergency Medicine, St.
Joseph's Hospital and Medical
Center, Phoenix, AZ
Steven Choi, MD
Medical Director of Quality,
Director of Pediatric Cardiac
Inpatient Services, The Childrens
Hospital at Montefiore; Assistant
Professor of Pediatrics, Albert
Einstein College of Medicine,
Bronx, NY
Case Presentation
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 38.3C (101F) to 40C (104F). 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 evalu-
ated at her pediatricians 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 childs 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 39.8C (103.6F). 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 hepato-
splenomegaly. Her extremities are warm, well perfused,
and without swelling. Her skin is notable for a fine, ery-
thematous, maculopapular rash on the face, chest, back,
and extremities. The patients ill appearance and history
of prolonged fever are concerning for the possibility of
Kawasaki disease, but you arent 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 complica-
tions that you should be concerned about?
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 child-
hood. Kawasaki disease primarily affects small- and
medium-sized arteries, including the coronary arter-
ies. Although it is a self-limited disease, early diagno-
sis and treatment is critical to preventing the forma-
tion of coronary artery aneurysms, which may lead to
acquired cardiovascular disease and sudden death.
Copyright 2015 EB Medicine. All rights reserved. 2
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 Nonspe-
cific 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 labora-
tory 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 dis-
ease 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 car-
diovascular 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 car-
diac 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 cur-
rently estimated to be 0.17% in the United States.7
Critical Appraisal Of The Literature
A literature search was performed using both
PubMed and Ovid. The initial search on PubMed us-
ing 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 Pediat-
rics (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 intra-
venous immunoglobulin (IVIG) and aspirin. The ref-
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. How-
ever, 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-anal-
yses on the topic are available and were reviewed.
Epidemiology, Etiology, And Pathophysiology
Epidemiology
Kawasaki disease is the second most common vascu-
litis 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 ethnici-
ties, 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 Pacific-
Islander 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
Koreas annual incidence was 113.1 per 100,000 chil-
January 2015 www.ebmedicine.net
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 epidemio-
logical data are suggestive of an infectious agent, but
such an agent has never been identified. The self-
limited nature of the illness and associated symp-
toms of fever, rash, and conjunctivitis are common
to many viral illnesses. Younger children are dis-
proportionately affected, which is also the case with
many infectious diseases. Epidemiological data have
shown that the disease is most common in the win-
ter 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 spe-
cific 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, follow-
up studies by different authors failed to show similar
results.18 A more recent prospective, multicenter trial
did not show a higher prevalence of supertoxin-produc-
ing bacteria in Kawasaki disease patients compared to
febrile controls.19 In addition, the immune response in
Kawasaki disease has now been shown to be oligoclo-
nal.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 superan-
tigen 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 pa-
tients.22 This was called the New Haven coronavirus
(HCoV-NH), named for its place of discovery. Un-
fortunately, 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 associa-
tion 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 conclu-
sive evidence has been found. A significant overlap
in symptoms has been observed in both Kawasaki
disease and acrodynia (mercury toxicity), but a link
3 Reprints: www.ebmedicine.net/pempissues
between the 2 conditions has not been proven. viral infections, and they will resolve on their own
More recent immunologic research has revealed in time without long-term consequences. Rash as-
infiltration of immunoglobulin A (IgA) plasma cells sociated with fever may be seen in viral exanthems,
in coronary artery walls, as well as in the respiratory as well as in Epstein-Barr virus and acute strepto-
tract, pancreas, and kidneys of patients with Kawa- coccal infections. Adenovirus may present quite
saki disease.20 In addition, CD8 lymphocytes have similarly to Kawasaki disease, with symptoms such
also been noted as part of the inflammatory response as fever, rash, conjunctival changes, mucous mem-
in coronary artery aneurysms.26 These patterns of brane changes, and adenopathy. A study by Barone
inflammatory cell infiltration support the theory of et al noted that children with adenovirus are more
an immune response to a microbial agent. Similar likely to have purulent conjunctivitis or exudative
findings of IgA plasma cells in the respiratory tract pharyngitis compared to children with Kawasaki
are seen in respiratory illnesses such as influenza disease, although the study was small.31 Rash, fever,
or respiratory syncytial virus, suggesting that the and conjunctival changes are also seen in measles,
portal of entry for the microbial agent may be the and, although many children are vaccinated against
respiratory tract.26 Further immunologic study has this disease, several outbreaks have recently been
revealed the presence of intracytoplasmic inclusion reported. Fever can also be seen in drug hypersen-
(ICI) bodies within the ciliated bronchial epithe- sitivity reactions, so a complete medication history
lium.27 Similar inclusion bodies were not detected should be taken at presentation.
in control patients. A single monoclonal antibody
detected approximately 85% of the ICI bodies in pa- Prehospital Care
tients with fatal Kawasaki disease, suggesting that a
single agent or closely related agents may be respon- Many children with suspected Kawasaki disease will
sible for the disease.28 No structures representing initially present to their pediatricians or be brought
known bacterial, fungal, or parasitic elements were
identified within the ICI bodies.28
Despite our improved understanding of the Table 1. Differential Diagnosis Of Prolonged
immune system activation that occurs in Kawasaki Fever In Pediatric Patients
disease, it is still somewhat unclear how it leads to
coronary artery aneurysms. Patients with Kawasaki Infectious
disease have been found to have stimulation of the Systemic viral infection
cytokine cascade and endothelial cell activation. It Pneumonia
is this endothelial activation that leads to coronary Urinary tract infection
arteritis and aneurysms, although the exact mecha- Infective endocarditis
nism of how this occurs still needs to be elucidated. Osteomyelitis
Lyme disease
Various studies have shown elevated levels of
Rocky Mountain spotted fever
matrix metalloproteinase-929 and vascular endothe-
Human immunodeficiency virus
lial growth factor30 in Kawasaki disease patients,
Malaria
both of which may contribute to the development
of aneurysms. Endocrinologic
Thyrotoxicosis
Differential Diagnosis
Immunologic
Immunodeficiency
When children present with Kawasaki disease in its
classic form, it is not difficult for an astute emergen-
Oncologic
cy clinician to make the correct diagnosis. However,
Leukemia
children presenting with < 5 days of fever, or those Lymphoma
with incomplete Kawasaki disease may prove to be Other neoplasm
more of a diagnostic challenge. Fever is a very com-
mon complaint in pediatric patients, with a broad Rheumatologic
differential diagnosis. (See Table 1.) Accurately Juvenile idiopathic arthritis
differentiating fever due to viral or bacterial illnesses Systemic lupus erythematosus
from fever due to Kawasaki disease is critical. This Kawasaki disease
is especially true since patient outcomes are signifi- Familial Mediterranean fever
cantly improved when patients are treated within 10
Gastroenterologic
days of the onset of fever.
Inflammatory bowel disease
It is important to consider a variety of diagnoses
when thinking about children with fever. (See Table Toxicologic
2, page 5.) Many fevers will be caused by nonspecific Drug-related fever

Copyright 2015 EB Medicine. All rights reserved. 4 www.ebmedicine.net January 2015

to the hospital directly by parents. For children who
are transported via emergency medical services, pre-
hospital 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.
Emergency Department Evaluation
History
The diagnosis of Kawasaki disease should be con-
sidered 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 > 39C (102.2F), and
potentially > 40C (104F).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
Kawasaki disease Fever (> 5 days) plus:
Conjunctivitis
Oropharyngeal changes
Polymorphous rash
Extremity changes
Lymphadenopathy
Adenovirus Fever plus:
Rash
Conjunctivitis
Lymphadenopathy
Pharyngitis
Group A Streptococcus Fever plus:
Pharyngitis
Rash
Measles Fever plus:
Rash
Conjunctivitis
Rhinorrhea
Pharyngitis
January 2015 www.ebmedicine.net
Physical Examination
In addition to fever, the diagnostic criteria for com-
plete Kawasaki disease include the presence of 4 out
of 5 supporting signs and symptoms. (See Table 3,
page 6.) These include conjunctival injection, oro-
pharyngeal changes, polymorphous rash, extrem-
ity 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 cutane-
ous 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 peri-
neal area.
First-Line Treat- Complications
ment
Intravenous immuno- Coronary artery aneurysms
globulin plus aspirin Sudden cardiac death
Supportive care Pneumonia
Antibiotics Rheumatic heart disease
Postinfection glomerulonephritis
Supportive care Pneumonia
Otitis media with or without hearing loss
Encephalitis
Subacute sclerosing panencephalitis
5 Reprints: www.ebmedicine.net/pempissues
 Interestingly, children who have previously
received the bacillus Calmette-Gurin (BCG) vac-
cine will often have erythema, induration, or crust-
ing 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 tuberculo-
sis, the BCG vaccine is used to provide infants and
young children with protection against tuberculo-
sis, meningitis, and disseminated tuberculosis.34 In
countries where tuberculosis is endemic, the vaccine
is routinely given to neonates as soon as possible af-
ter 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 de-
marcated 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 diag-
nostic 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 Physi- This figure was published in Zitelli and Davis' Atlas of Pediatric Physi-
cal Diagnosis, 6th edition, Torok K, Rosen P, Kawasaki Disease, cal Diagnosis, 6th edition, Torok K, Rosen P, Kawasaki Disease,
pages 289-291, Copyright Elsevier 2012. Used with permission. pages 289-291, Copyright Elsevier 2012. Used with permission.

Table 3. Features Of Kawasaki Disease In Children*

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

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

Copyright 2015 EB Medicine. All rights reserved. 6 www.ebmedicine.net January 2015

 Outside of the diagnostic criteria, there are other
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 Kawa-
saki 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
Figure 3. Diffuse Macular Rash
This figure was published in Zitelli and Davis' Atlas of Pediatric Physi-
cal Diagnosis, 6th edition, Torok K, Rosen P, Kawasaki Disease,
pages 289-291, Copyright Elsevier 2012. Used with permission.
Figure 4. Erythema Of The Extremities
This figure was published in Zitelli and Davis' Atlas of Pediatric Physi-
cal Diagnosis, 6th edition, Torok K, Rosen P, Kawasaki Disease,
pages 289-291, Copyright Elsevier 2012. Used with permission.
January 2015 www.ebmedicine.net
Arthritis and arthralgias can occur, usually early in
the course. Arthritis may be oligoarticular or polyarticu-
lar.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 associ-
ated 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 recog-
nized 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 chil-
dren with Kawasaki disease without shock, despite the
time to presentation being equal.43 Kawasaki disease
has also been indicated as a cause of multiple organ
dysfunction syndrome. A retrospective review at one
institution revealed that, over an 8-year period, 11 chil-
dren had been admitted to the pediatric intensive care
unit with shock and were later diagnosed with Kawasaki
Figure 5. Desquamation Of Fingers
This figure was published in Zitelli and Davis' Atlas of Pediatric Physi-
cal Diagnosis, 6th edition, Torok K, Rosen P, Kawasaki Disease,
pages 289-291, Copyright Elsevier 2012. Used with permission.
To view a full-color version of this issue's photos, scan
the QR code with a smartphone or tablet or go to:
www.ebmedicine.net/KawasakiDiseaseSigns.
7 Reprints: www.ebmedicine.net/pempissues
disease.44 Eight of these patients (72.7%) had evidence
of multiple organ dysfunction syndrome, with hemody-
namic 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 chil-
dren developed coronary artery aneurysms. All of these
children survived after proper treatment for Kawasaki
disease, suggesting that prompt recognition and treat-
ment of Kawasaki disease in patients with shock can
result in favorable outcomes.44
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 con-
firm the diagnosis, there are many diagnostic tests
that can help to differentiate Kawasaki disease from
other entities.
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 sug-
gest that elevations of CRP 3.0 mg/dL and ESR
40 mm/h can be used in the evaluation of both com-
plete 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.
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 de-
velops 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 trans-
Copyright 2015 EB Medicine. All rights reserved. 8
peptidase.5,45 The mechanism behind liver func-
tion abnormalities in Kawasaki disease patients is
not well understood. Theories for how this occurs
include vasculitis within the liver vessels, toxin-
mediated effects, oxidant stress, and inflammatory
cell infiltration, but further research in these areas is
needed.46
Lipid And Albumin Levels
Plasma cholesterol and high-density lipoprotein
levels can be markedly depressed in affected pa-
tients.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
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 pa-
tients 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 pa-
tients 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 con-
ducted a study of 146 Kawasaki patients, and they
found that 44% of the patients had hyponatremia.51
It has been suggested that patients with hyponatre-
mia have higher levels of inflammation overall, al-
though the exact pathophysiology of hyponatremia
in Kawasaki disease is not well understood.50,51
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 half-
life than BNP (25 to 125 minutes) making it more
easily detectable in circulation. Although NTproBNP
levels are frequently elevated in children with Kawa-
saki 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.
Urinalysis
Sterile pyuria can be found in approximately one-
third of affected patients. Early research reported
www.ebmedicine.net January 2015
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 kid-
ney, may be involved.54,55
Lumbar Puncture
Although lumbar puncture is not routinely recom-
mended 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 arrhyth-
mias, nonspecific T-wave changes, PR-interval pro-
longation, 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. Echocar-
diography 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 di-
ameter 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 echocar-
diogram should not be used to exclude the diagnosis
of Kawasaki disease, especially if physical examina-
tion 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
treated within 10 days of the onset of fever.57-59 Howev-
er, 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 echocar-
diograms 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 incom-
plete Kawasaki disease in some patients. Prior research
suggested that perivascular brightness was a predic-
tor of coronary artery aneurysms.62 However, PEB is
somewhat subjective and dependent on the individual
echocardiographer. A more recent attempt to quantita-
tively 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 in-
flammation, 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
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 catego-
rize 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 in-
adequate, with only 13% of high-risk patients devel-
oping 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 logis-
9 Reprints: www.ebmedicine.net/pempissues
 Clinical Pathway For Emergency Department
Management Of Kawasaki Disease

Consider alternative diagnosis

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

4 diagnostic criteria present?

Conjunctivitis
Mucous membrane changes
Polymorphous rash
Extremity changes
Cervical lymphadenopathy

NO YES

2-3 diagnostic criteria present? Obtain laboratory testing

Conjunctivitis CRP/ESR
Mucous membrane changes CBC
Polymorphous rash ALT
Extremity changes Albumin
Cervical lymphadenopathy Urinalysis

NO YES

Laboratory tests consistent with Kawa-

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

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

Class Of Evidence Definitions

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

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

Copyright 2015 EB Medicine. All rights reserved. 10 www.ebmedicine.net January 2015

tic regression, they found that age, total days of symp-
toms, platelet count, CRP, and alanine aminotransferase
can be used to predict which patients are likely to be re-
sistant 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 investi-
gated 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 regard-
ing 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 addi-
tion 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 incom-
plete 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 com-
plete 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 at-
tributed 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
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. How-
ever, 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 retro-
spectively reviewed 955 patients with Kawasaki disease,
finding that 77% presented with complete Kawasaki
disease while the remaining 23% fell into the incom-
plete category.74 Although this study also showed that
the time to diagnosis and treatment was delayed for pa-
tients 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, emer-
gency 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 frame-
work for decisions regarding the evaluation of children
with suspected incomplete Kawasaki disease.5
Treatment
Initial Treatment
Since the etiology of Kawasaki disease remains un-
clear, 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 dur-
ing that time showed a significant reduction in coro-
nary artery aneurysm development in children receiv-
ing 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 ac-
tion. Several mechanisms have been proposed, includ-
ing 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 tachy-
cardia.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 hemo-
lytic anemia.78 In addition, IVIG is also a pooled-blood
product and thus carries the risk of transfusion-related
infections as well.
Aspirin
Aspirin has long been used as part of the treatment
for Kawasaki disease. It is theorized that since aspi-
rin has anti-inflammatory effects as well as anti-
platelet 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 exam-
ining 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 re-
duce 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 dis-
ease.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
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 com-
bination with IVIG.5
Corticosteroids
The use of corticosteroids as a routine part of a treat-
ment 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 Kawa-
saki 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 signifi-
cantly, with some groups having as few as 7 pa-
tients. 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 multi-
center, 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 sig-
nificant 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 cortico-
steroids 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 treat-
ment, and they were randomized to receive standard
therapy of IVIG plus aspirin or standard therapy of
IVIG plus a single dose of intravenous methylpred-
nisolone (30 mg/kg). Significantly more patients in
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 prednis-
olone 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 high-
risk patients who would benefit from the addition of
corticosteroids to the standard therapy.
Treatment Resistance
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.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.
Infliximab
Infliximab (Remicade) is a monoclonal antibody
directed against tumor necrosis factor alpha-1 (TNF-
alpha) and blocks its function. Infliximab was theo-
rized 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
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 cessa-
tion 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 be-
tween the 2 groups. Although further research is need-
ed, infliximab is generally safe and should be considered
as an alternative therapy in treatment-resistant disease.
Abciximab
Abciximab (ReoPro), another monoclonal anti-
body, has been investigated for use in patients who
develop aneurysms. Abciximab inhibits the gly-
coprotein 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 abcix-
imab. 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 com-
pared to the patients who received standard therapy
(68% vs 37%).86 Although these results are encourag-
ing, the study was very small and was performed in
a retrospective fashion. Further study on the use of
abciximab for Kawasaki disease is needed, prefer-
ably in the form of prospective trials.
Special Populations
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 de-
veloping 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 devel-
opment of the disease.88 Such cases were also more
likely to have recurrent disease.87
13 Reprints: www.ebmedicine.net/pempissues
 Researchers in North America studied clusters of
families with multiple cases of Kawasaki disease in sib-
lings 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.
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 compli-
cations (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 combi-
nation 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 lev-
els as a possible biomarker for diagnosing Kawa-
saki disease.91 The authors hypothesized that, since
periostin plays a role in vascular and cardiac dam-
age, 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 sig-
Copyright 2015 EB Medicine. All rights reserved. 14
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.
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 infu-
sion of IVIG, which is typically given over a period of
hours. Side effects of this medication may include fe-
ver, headache, urticaria, nausea, vomiting, and blood
pressure instability. Although uncommon, anaphy-
laxis, Stevens-Johnson syndrome, and nephrotoxicity
have been reported, so it is in the best interest of the
patient to be admitted for monitoring during treat-
ment. In addition, most hospitals will keep children in
the hospital until the fever resolves, as children with
ongoing fevers may be resistant to traditional treat-
ments. 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 aneu-
rysms. Children who present with myocarditis, im-
paired ventricular function, or giant coronary artery
aneurysms in the setting of acute Kawasaki disease
should be managed at a facility with a pediatric cardi-
ology service and pediatric intensive care unit.
Children with Kawasaki disease can be discharged
after completion of therapy provided there is resolu-
tion 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 Kawa-
saki 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. Echo-
cardiography should be repeated at 2 weeks post di-
agnosis, 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 recur-
rence rate of 3% to 4%.11,92 Similar studies estimate a
recurrence rate of 2% in the North American popula-
tion.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 his-
tory of Kawasaki disease.
Long-Term Prognosis
Since Kawasaki disease was first described more
than 40 years ago, outcomes have improved signifi-
cantly. With proper identification and treatment, the
incidence of coronary artery lesions has declined
www.ebmedicine.net January 2015
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
lesions will regress within 1 to 2 years.5,6 Coronary
arteries may develop areas of stenosis, and these le-
sions are frequently progressive. Depending on the
type, location, and size of the lesion, these children
may require long-term antiplatelet or anticoagula-
tion therapy and frequent evaluations by a pediatric
cardiologist. (See Table 4, page 15.)
Mortality rates for Kawasaki disease are general-
ly 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 Myo-
cardial 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 conges-
tive heart failure, arrhythmias, or coronary artery
rupture.94 As children with Kawasaki disease age,
there is a recognized risk of late myocardial infarc-

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

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

Abbreviations: ECG, electrocardiogram; INR, international normalized ratio.

Reproduced with permission from Pediatrics, Vol. 114, Issue 6, pages 1708-1733, Copyright 2004 by the AAP.

January 2015 www.ebmedicine.net 15 Reprints: www.ebmedicine.net/pempissues

 Risk Management Pitfalls In Kawasaki Disease
1. I thought the child had a viral illness, so I treat-
ed 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.
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.
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. 16
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 echo-
cardiography for assessment of coronary arter-
ies 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.
6. The patient failed to respond to initial stan-
dard treatment of IVIG and aspirin, and I
didnt 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.
7. I ordered an echocardiogram for the patient,
but there were no findings, so I ruled out Ka-
wasaki 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.
www.ebmedicine.net January 2015
tion, often occurring years later. This may occur due
to thrombosis of aneurysms or progressive steno-
sis.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.
Summary
Kawasaki disease is an acute, febrile vasculitis of
childhood, primarily affecting small- to medium-
sized 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 com-
plete 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 chil-
dren will present with incomplete Kawasaki disease,
comprised of fever for 5 days plus 2 to 3 of the sup-
porting 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 be-
ing 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 aneu-
rysms, thrombosis, and sudden cardiac death.
January 2015 www.ebmedicine.net
Case Conclusion
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 pro-
ceeded with laboratory workup. The patients 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 nega-
tive 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 diagno-
sis 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 ven-
tricular 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 follow-
up with a pediatric cardiologist.
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 echocardiogra-
phy. Ideally, initial echocardiography should be
performed on the day of diagnosis to assess for
coronary artery aneurysm.
Children who have symptoms consistent with
incomplete Kawasaki disease, but whose labora-
tory testing is not definitive, should be referred
for echocardiography. The presence of coronary
artery ectasia or perivascular echo brightness
can aid in finalizing the diagnosis, ensuring that
the child can be treated in a timely manner.
17 Reprints: www.ebmedicine.net/pempissues
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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)
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)
39. Bradley DJ, Glode MP. Kawasaki disease. The mystery con-
tinues. West J Med. 1998;168(1):23-29. (Review article)
40. Gong GW, McCrindle BW, Ching JC, et al. Arthritis present-
ing during the acute phase of Kawasaki disease. J Pediatr.
2006;148(6):800-805. (Retrospective study; 414 patients)
41. Yun SH, Yang NR, Park SA. Associated symptoms of Kawa-
saki 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)
43. Kanegaye JT, Wilder MS, Molkara D, et al. Recogni-
tion of a Kawasaki disease shock syndrome. Pediatrics.
2009;123(5):e783-e789. (Prospective cohort study; 187
patients)
44. Gatterre P, Oualha M, Dupic L, et al. Kawasaki disease: an
unexpected etiology of shock and multiple organ dysfunc-
tion syndrome. Intensive Care Med. 2012;38(5):872-878. (Ret-
rospective study; 11 patients)
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)
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 pro-
file after Kawasaki syndrome. Circulation. 1991;84(2):625-631.
(Prospective cohort study; 105 patients)
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)
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 Kawa-
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cohort study; 50 patients)
January 2015 www.ebmedicine.net
51. Watanabe T, Abe Y, Sato S, et al. Hyponatremia in Kawasaki
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52. Shiraishi M, Fuse S, Mori T, et al. N-terminal pro-brain
natriuretic peptide as a useful diagnostic marker of acute
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53. McNeal-Davidson A, Fournier A, Spigelblatt L, et al. Value
of amino-terminal pro B-natriuretic peptide in diagnosing
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tive case-control, 130 patients)
54. Shike H, Kanegaye JT, Best BM, et al. Pyuria associated with
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55. Watanabe T. Kidney and urinary tract involvement in Kawa-
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56. Ichida F, Fatica NS, OLoughlin JE, et al. Correlation of
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57. Newburger JW, Takahashi M, Burns JC, et al. The treatment
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58. Newburger JW, Takahashi M, Beiser AS, et al. A single intra-
venous infusion of gamma globulin as compared with four
infusions in the treatment of acute Kawasaki syndrome. N
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randomized trial; 549 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 pa-
tients)
60. Tse SM, Silverman ED, McCrindle BW, et al. Early treat-
ment with intravenous immunoglobulin in patients with
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case-control study; 178 patients)
61. Baer AZ, Rubin LG, Shapiro CA, et al. Prevalence of coro-
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62. Newburger JW, Taubert KA, Shulman ST, et al. Summary
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Symposium: December 4-7, 2001, Hakone, Japan. Pediatr Res.
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63. Yu JJ, Jang WS, Ko HK, et al. Perivascular brightness of coro-
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64. Crystal MA, Syan SK, Yeung RS, et al. Echocardiographic
and electrocardiographic trends in children with acute
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spective cohort study; 176 patients)
65. Frazier A, Hunt EA, Holmes K. Pediatric cardiac emergen-
cies: children are not small adults. J Emerg Trauma Shock.
2011;4(1):89-96. (Review)
66. Yim D, Curtis N, Cheung M, et al. An update on Kawasaki
disease II: clinical features, diagnosis, treatment and out-
comes. J Paediatr Child Health. 2013;49(8):614-623. (Review)
67. Beiser AS, Takahashi M, Baker AL, et al. A predictive instru-
ment for coronary artery aneurysms in Kawasaki disease. US
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dation; 212 patients)
68. Egami K, Muta H, Ishii M, et al. Prediction of resistance to
19 Reprints: www.ebmedicine.net/pempissues
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Kawasaki disease. J Pediatr. 2006;149(2):237-240. (Retrospec-
tive cohort study; 320 patients)
69. Tremoulet AH, Best BM, Song S, et al. Resistance to intrave-
nous immunoglobulin in children with Kawasaki disease.
J Pediatr. 2008;153(1):117-121. (Retrospective study; 362
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)
71. Forsey J, Mertens L. Atypical Kawasaki disease--a clinical
challenge. Eur J Pediatr. 2012;171(4):609-611. (Editorial com-
ment)
72. Sudo D, Monobe Y, Yashiro M, et al. Coronary artery lesions
of incomplete Kawasaki disease: a nationwide survey in
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study)
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)
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)
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 intra-
venous gammaglobulin for Kawasaki disease. Lancet.
1984;2(8411):1055-1058. (Multicenter control trial; 85 pa-
tients)
77.* Oates-Whitehead RM, Baumer JH, Haines L, et al. Intrave-
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in children. Cochrane Database Syst Rev. 2003;(4):CD004000.
(Meta-analysis and review)
78. Orbach H, Katz U, Sherer Y, et al. Intravenous immunoglob-
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79. Baumer JH, Love S, Gupta A, et al. Salicylate for the treat-
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80. Kato H, Koike S, Yokoyama T. Kawasaki disease: effect
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82. Ogata S, Ogihara Y, Honda T, et al. Corticosteroid pulse
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randomized trial; 122 patients)
Copyright 2015 EB Medicine. All rights reserved. 20
83. Kobayashi T, Saji T, Otani T, et al. Efficacy of immunoglobu-
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84. Burns JC, Mason WH, Hauger SB, et al. Infliximab treatment
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91. Reindel R, Kim KY, Baker SC, et al. Periostin is upregulated
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93. Belay ED, Maddox RA, Holman RC, et al. Kawasaki syn-
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94. Bayers S, Shulman ST, Paller AS. Kawasaki disease: part
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95. Fukazawa R. Long-term prognosis of Kawasaki dis-
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96. Daniels LB, Gordon JB, Burns JC. Kawasaki disease: late car-
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(Review)
www.ebmedicine.net January 2015
CME Questions 5. Lymphadenopathy in Kawasaki disease:
a. Is usually axillary
b. Occurs in 80% to 90% of children with
Take This Test Online!
Kawasaki disease
c. Requires antibiotic management
Current subscribers receive CME credit absolutely
d. Is usually unilateral
free by completing the following test. Each issue
includes 4 AMA PRA Category 1 CreditsTM, 4 ACEP
6. Elevation of which of the following labora-
Category I credits, 4 AAP Prescribed credits, and 4
Take This Test Online! tory results aids in the diagnosis of Kawasaki
AOA Category 2A or 2B credits. Monthly online
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d. CRP

7. Incomplete Kawasaki disease may be diag-

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

January 2015 www.ebmedicine.net 21 Reprints: www.ebmedicine.net/pempissues

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