1. No category

Diagnosis and therapy of Kawasaki disease in children.
A S Dajani, K A Taubert, M A Gerber, S T Shulman, P Ferrieri, M Freed, M Takahashi, F Z Bierman,
A W Karchmer and W Wilson
Circulation. 1993;87:1776-1780
doi: 10.1161/01.CIR.87.5.1776
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1993 American Heart Association, Inc. All rights reserved.
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1776
AHA Medical/Scientific Statement
Special Report
Diagnosis and Therapy of
Kawasaki Disease in Children
Adnan S. Dajani, MD, Chairman; Kathryn A. Taubert, PhD; Michael A. Gerber, MD;
Stanford T. Shulman, MD; Patricia Ferrieri, MD; Michael Freed, MD; Masato Takahashi, MD;
Fredrick Z. Bierman, MD; Adolf W. Karchmer, MD; Walter Wilson, MD;
Shahbudin H. Rahimtoola, MD; David T. Durack, MD, DPhil, (Liaison, Infectious Diseases
Society of America); Georges Peter, MD (Liaison, American Academy of Pediatrics, Committee
on Infectious Diseases), Members, Committee on Rheumatic Fever, Endocarditis, and Kawasaki
Disease, Council on Cardiovascular Disease in the Young, American Heart Association
awasaki disease, a generalized vasculitis of unknown etiology, is a leading cause of acquired
heart disease in children in the United States.
It occurs more often in boys than in girls, with a ratio of
about 1.5:1. Eighty percent of cases occur in children
less than 5 years of age, and most are in children under
2. The onset of the disease is rare after 8 years of age.
Less than 2% of patients have recurrences.' Within the
United States, children of all racial backgrounds are
affected, although the highest incidence is in children of
Asian ancestry. Kawasaki disease has been reported
worldwide.
Kawasaki disease was initially described by Dr.
Tomisaku Kawasaki2 in 1967 in Japan and was found to
be an important cause of cardiac disease in children
shortly thereafter. More than 115,000 cases were reported in Japan from that time through 1991 (T. Kawasaki, written communication, 1992). Annual attack
rates in Japan have been as high as 67 per 100,000
children under 5 years of age.3 In the United States
annual attack rates vary between 6-9 per 100,000
children less than 5 years of age.4-6 This is reflected in
an estimate of at least 2,000 cases per year in the United
K
States.6
In the United States Kawasaki disease occurs yearround, with a greater number of cases observed in
winter and spring. Reports from Japan, where the most
complete epidemiological surveillance data have been
collected, show that epidemics occurred in 1979, 1982,
and 1985. Epidemics have also been reported in the
United States and other countries.
The epidemiology of Kawasaki disease suggests that a
microbial agent is the cause of this disease. The clinical
presentation is also highly suggestive of an infectious
etiology; rickettsiae, viruses (primarily Epstein-Barr virus and retroviruses), several bacteria (e.g., group A
streptococci, other streptococci, and propionibacteria),
Address for reprints: Kathryn A. Taubert, PhD, American Heart
Association, 7272 Greenville Avenue, Dallas, TX 75231-4596.
"Diagnosis and Therapy of Kawasaki Disease in Children" was
approved by the AHA's Steering Committee on February 18,
1993.
and candidae have been suggested as etiologic agents.
To date, however, an etiologic agent has not been
documented. Epidemiological observations suggest that
Kawasaki disease may be associated with living near
bodies of water or exposure to house dust mites or
recently shampooed carpets. Critical data to substantiate these possible associations are lacking. Although an
infectious etiology has been suggested, person-to-person transmission has not been documented, even in
day-care centers, a common source for outbreaks has
not been defined, and cases among siblings are very
rare.
This statement discusses the diagnosis of Kawasaki
disease and its treatment during the acute phase. Longterm follow-up of patients with cardiac involvement will
be addressed in a subsequent publication by this
committee.
Diagnosis of Kawasaki Disease
In the absence of a specific diagnostic test for Kawasaki disease, clinical criteria have been established to
assist the physician in making the diagnosis.7 Other
clinical and laboratory findings observed in patients
with this disease are frequently helpful. Table 1 describes the clinical and laboratory features of Kawasaki
disease.
Principal Clinical Findings
Fever and at least four of the fiveprincipal clinicalfeatures
should be present to establish the diagnosis of Kawasaki
disease. Patients with fever and fewer than four principal
features can be diagnosed as having Kawasaki disease
when coronary artery disease is detected by two-dimensional echocardiography or coronary angiography.
The fever is generally high and spiking, and persists in
the untreated patient for 1-2 weeks or longer. With
appropriate treatment the fever usually resolves in a
short period of time. Kawasaki disease should be considered in the differential diagnosis of a young child
with unexplained fever.
Changes in the extremities are distinctive. Erythema
of the palms and soles and/or firm, sometimes painful
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Kawasaki Disease in Children AHA Scientific Council
1777
TABLE 1. Clinical and Laboratory Features of Kawasaki Disease
Diagnostic criteria (principal clinical findings*)
Fever of at least 5 days' durationt
Presence of four of the following principal features:
Changes in extremities
Polymorphous exanthem
Bilateral conjunctival injection
Changes in the lips and oral cavity
Cervical lymphadenopathy
Exclusion of other diseases with similar findings (Table 2)
Other clinical and laboratory findings
Cardiac findings
Pancarditis, in early stages of disease
Coronary artery abnormalities, usually beyond 10 days of onset of illness
Noncardiac findings
Respiratory tract
Musculoskeletal system
Preceding respiratory illness
Arthritis, arthralgia
Otitis media
Pulmonary infiltrates
Gastrointestinal tract
Diarrhea, vomiting, abdominal pain
Other findings
Hepatic dysfunction
Erythema and induration at
Hydrops of the gallbladder
Bacille Calmette-Guerin (BCG) inoculation site
Auditory abnormalities
Central nervous system
Testicular swelling
Extreme irritability
Peripheral gangrene
Aseptic meningitis
Aneurysms of medium-sized noncoronary arteries
Laboratory findings
Neutrophilia with immature forms
Elevated erythrocyte sedimentation rate
Positive C-reactive protein
Elevated serum a-1-antitrypsin
Anemia
Hypoalbuminemia
Elevated serum immunoglobulin E
Thrombocytosis
Proteinuria
Sterile pyuria
Elevated serum transaminases
*Patients with fever and fewer than four principal clinical features can be diagnosed as having Kawasaki disease
when coronary artery disease is detected by two-dimensional echocardiography or coronary angiography.
tMany experts believe that, in the presence of classic features, the diagnosis of Kawasaki disease can be made by
experienced practitioners before the fifth day of fever.
induration of the hands or feet often occurs in the early
phase of the disease. Desquamation of the fingers and
toes usually begins 1-3 weeks after onset of fever in the
periungual region and may extend to include the palms
and soles. Approximately 1-2 months after the onset of
fever, deep transverse grooves across the nails (Beau's
lines) may appear.
A polymorphous exanthema usually appears within 5
days of the onset of fever. The rash may take various
forms, including an urticarial exanthema, a maculopapular morbilliform eruption, a scarlatiniform erythroderma, an erythema-multiforme-like rash, or, rarely, a
fine micropustular eruption. Bullous eruptions have not
been described. The rash is usually extensive with
involvement of the trunk and extremities and accentuation in the perineal region.
Bilateral conjunctival injection usually begins shortly
after the onset of fever. It typically involves the bulbar
conjunctivae much more than the palpebral or tarsal
conjunctivae, is not associated with an exudate, and is
usually painless.
Changes of the lips and oral cavity include erythema
and cracking of the lips, strawberry tongue, and erythema of the orophyaryngeal mucosa. Oral or lingual
ulcerations are not seen.
Cervical lymphadenopathy is considered a principal
finding when at least one lymph node is more than 1.5 cm
in diameter. The lymphadenopathy is generally unilateral
and the nodes are usually firm and slightly tender. There
may be some overlying erythema but the nodes are
nonfluctuant. Among the five principal clinical features,
cervical lymphadenopathy is the least common.
Because the principal clinical findings to fulfill the
diagnostic criteria are not specific, other diseases with
similar clinical features should be excluded (Table 2).
Consideration of measles as a possible diagnosis is
particularly important because cases have been misdiagnosed as Kawasaki disease and appropriate control
measures have not been taken promptly.
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Circulation Vol 87, No S May 1993
TABLE 2. Differential Diagnosis of Kawasaki Disease: Diseases
and Disorders With Similar Clinical Findings
Measles
Scarlet fever
Drug reactions
Stevens-Johnson syndrome
Other febrile viral exanthemas
Rocky Mountain spotted fever
Staphylococcal scalded skin syndrome
Toxic shock syndrome
Juvenile rheumatoid arthritis
Leptospirosis
Mercury poisoning
Other Clinical and Laboratory Findings
Cardiac Findings. Cardiovascular manifestations
can
be prominent in the acute phase of the illness and are
the leading cause of long-term morbidity and mortality.
In this phase the pericardium, myocardium, endocardium, and coronary arteries may all be involved.
Pericardial effusion is detected by echocardiography
in approximately 30% of patients with Kawasaki disease. It rarely progresses to tamponade and usually
resolves spontaneously without specific therapy.
Clinically recognizable myocarditis is common. Signs
include tachycardia out of proportion to the degree of
fever. A gallop rhythm may be heard. The electrocardiogram is abnormal in one third of children with
Kawasaki disease, showing decreased R wave voltage,
ST segment depression, and T wave flattening or inversion. Myocardial inflammation may cause slowed conduction, resulting in prolonged PR or QT intervals or
both. Local areas of ischemia may occur and predispose
to atrial or, more commonly, ventricular arrhythmias.
Congestive cardiac failure can also occur.
Coronary arterial abnormalities develop in approximately 20% of children with untreated Kawasaki disease and are the most common cause of both short- and
long-term morbidity and mortality. Aneurysms have
been detected within 3 days of onset of illness but more
commonly occur from 10 days to 4 weeks after the onset
of symptoms. The appearance of aneurysms more than
6 weeks after the onset of illness is uncommon. Factors
associated with an increased risk of developing coronary
arterial aneurysms include male gender; age less than 1
year; other signs or symptoms of pericardial, myocardial, or endocardial involvement, including arrhythmias;
prolonged period of inflammation, including fever for
more than 10 days; and recurrence of fever after an
afebrile period of at least 24 hours.
Abnormalities of the coronary arteries include ectasia (coronary size larger than normal for age, [normal
artery size ranges from 1-2 mm in newborns
and infants to 4.5-5.0 mm in teenagers8'9], or aneurysms
that may be fusiform or saccular (near-equal axial and
lateral diameters). Patients with giant aneurysms (internal diameter of at least 8 mm) have the worst prognosis
and are at the greatest risk of developing coronary
thrombosis, stenosis, or myocardial infarction. Giant
aneurysms generally do not resolve. Coronary abnormalities are usually detected by high-resolution cardiac
ultrasound. Angiography is sometimes used for diagno-
coronary
sis, particularly in patients with suspected or definite
echocardiographic changes or ischemia. Expertise is
needed for a complete coronary artery evaluation and
usually requires a qualified pediatric cardiologist because of considerable normal variations in the coronary
arteries.
Myocardial infarction is the principal cause of death
in Kawasaki disease. It may occur during the acute
illness but happens more commonly within a year and
may occur even later in patients who have giant aneurysms. Symptoms of myocardial infarction include unconsolable crying, vomiting, dyspnea, cardiovascular
collapse, and shock. Chest pain has been described by
children who can communicate the symptom. The majority of documented cases of infarction occur during
sleep or while at rest.10 Mortality from infarction has
been reported to be approximately 25%.10
In patients with coronary arterial abnormalities, aneurysms of other medium-sized muscular arteries, including the renal, brachial, and femoral arteries, can
occur during the acute phase of the illness but more
commonly are detected more than a year after the acute
illness. Children with giant coronary aneurysms more
likely have other arterial involvement.
Valvar involvement, primarily mitral regurgitation,
has been described in about 1% of children with Kawasaki disease."1 Very rarely, regurgitation is severe
enough to require valve replacement.12'13
Noncardiac Findings. Multiple noncardiac clinical
findings may be observed in patients with Kawasaki
disease. Arthritis or arthralgia can occur in the first
week of the illness and is usually polyarticular, involving
the knees, ankles, and hands. Commonly a pauciarticular arthritis involving the knees, ankles, or hips appears
during the second or third week of illness. Arthritis is
more common in older girls.
Infants with Kawasaki disease are often more irritable than infants with other febrile illnesses. Signs and
symptoms suggestive of aseptic meningitis may be present in some patients. A mononuclear pleocytosis in the
cerebrospinal fluid is found in at least one fourth of the
patients who undergo lumbar puncture.
Diarrhea, vomiting, and abdominal pain are common
features. Mild to moderate elevations of serum transaminases with mild obstructive jaundice are occasionally
noted. Acute acalculous distention of the gallbladder
(hydrops) commonly occurs during the first 2 weeks of
illness and can be identified by abdominal ultrasound.
Preceding or concurrent respiratory symptoms such
as cough, rhinorrhea, otitis media, or pulmonary infiltrates are often observed.
Other less common findings include erythema and
induration at the site of a recent vaccination with
Bacille Calmette-Guerin (BCG). Auditory abnormalities, testicular swelling, and peripheral gangrene have
also been reported.
Laboratory Findings. During the acute phase of the
illness, patients with Kawasaki disease typically have
neutrophilia, often including immature forms, increased
acute phase reactants, mild anemia, hypoalbuminemia,
and elevated serum immunoglobulin E levels. Thrombocytosis is frequently seen after the first week of the
illness and may be marked. Proteinuria, probably secondary to fever, and sterile pyuria, probably a reflection
of urethral involvement, are common.
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Kawasaki Disease in Children AHA Scientific Council
TABLE 3. Recommended Therapy During the Acute Stage of
Kawasaki Disease
Intravenous gamma globulin
2 glkg as single infusion over 12 hours (preferred)
or
400 mg/kg per day for 4 days; each dose infused over 2 hours
(alternate)
plus
Aspirin
80-100 mg/kg per day orally in four equally divided doses until
patient is afebrile*
then
3-5 mg/kg orally once daily for up to 6-8 weekst
*Some clinicians recommend high-dose aspirin until the 14th
day of illness.
tDiscontinue aspirin 6-8 weeks after onset of illness if no
coronary arterial abnormalities are observed on echocardiogram.
Continue indefinitely if there are coronary arterial abnormalities.
Some patients who do not fulfill the criteria outlined
in Table 1 have been diagnosed subsequently as having
"atypical" or "incomplete" Kawasaki disease. Patients
with fever and fewer than four principal clinical findings
can be diagnosed as having Kawasaki disease when
coronary artery disease is detected. Some children with
prolonged unexplained febrile illnesses, especially when
associated with subsequent peripheral desquamation,
may indeed have had atypical Kawasaki disease and
should be reevaluated carefully for possible development of coronary artery disease.
Therapy During Acute Stage
Initial therapy for Kawasaki disease is currently directed at reducing inflammation, particularly in the
coronary arterial wall and myocardium. Later, therapy
is directed toward preventing coronary thrombosis by
inhibiting platelet aggregation. Specific therapy awaits
discovery of the etiologic agent.
When possible, patients with Kawasaki disease
should be treated within the first 10 days of onset of
illness with intravenous gamma globulin and high-dose
aspirin (Table 3). The beneficial effect of intravenous
gamma globulin on coronary abnormalities was first
reported in Japan.14 A multicenter randomized controlled trial in the United States demonstrated that
defervescence and resolution of inflammation were
more pronounced and coronary arterial abnormalities
were significantly less frequent in patients treated with
intravenous gamma globulin plus aspirin than in patients treated with aspirin alone.15 A subsequent US
trial compared a single 2 g/kg dose of intravenous
gamma globulin to the dosage of 400 mg/kg per day for
4 days; both groups also received 100 mg/kg of aspirin
per day. Children treated with the single-infusion regimen had significantly fewer coronary arterial abnormalities 2 weeks after enrollment than children treated with
the 4-day infusion. By the seventh week after enrollment, the difference between the two groups was not
significant. Children treated with the single-infusion
regimen also had a more rapid defervescence and
return of acute phase reactants to normal.16 Intravenous
gamma globulin has been reported to reduce the likelihood of development of giant coronary artery aneu-
1779
rysms17 and appears to have a direct beneficial effect on
abnormalities in cardiac function associated with the
acute phase of Kawasaki disease.18
High-dose aspirin alone hastens the resolution of
acute manifestations of Kawasaki disease, particularly
fever. The combination of aspirin at 80-100 mg/kg per
day and intravenous gamma globulin has a more rapid
anti-inflammatory effect than aspirin alone and appears
to decrease the rate of development of coronary abnormalities. In children with Kawasaki disease, absorption
of aspirin may be impaired and monitoring serum
concentrations can be helpful in apparent nonresponders or in certain other circumstances.
After the child has become afebrile, aspirin should be
reduced to 3-5 mg/kg given as a single daily dose for its
antithrombotic effect. Low-dose aspirin is continued for
approximately 6-8 weeks and then discontinued if no
coronary arterial abnormalities have been detected by
echocardiography. To reduce the risk of Reye's syndrome,
aspirin therapy should be interrupted if the patient develops varicella or influenza, although the magnitude of such
a risk is unknown. The use of dipyridamole to alter
platelet activity should be considered during this interval
if the patient is at high risk for myocardial infarction, that
is, has developed significant coronary arterial abnormalities. If coronary arterial abnormalities are detected, lowdose aspirin therapy should be continued indefinitely and
the patient referred to a pediatric cardiologist for longterm follow-up.
Some Japanese and American investigators have attempted to target intravenous gamma globulin therapy
only to those patients thought to be at highest risk of
developing coronary arterial abnormalities by constructing risk scoring systems. None of these scoring
systems is sensitive or specific enough to enable early
prediction of which patients will develop coronary abnormalities. Therefore, the current recommendation is
that all children diagnosed with Kawasaki disease within
10 days of onset of fever should receive intravenous
gamma globulin and high-dose aspirin as early as
possible.
Administration of parenteral live virus vaccines (measles, mumps, and rubella) should be delayed for at least
5 months after intravenous gamma globulin treatment
because passively acquired antibodies may interfere
with effective immunization.19 During a measles outbreak, however, it may be prudent to administer measles vaccine earlier to a previously unimmunized child
and repeat the vaccination at a later time. Schedules for
administration of other routine childhood vaccinations
should not be interrupted. To reduce the risk of Reye's
syndrome in patients on long-term aspirin therapy,
administration of influenza vaccine is recommended.
Unresolved therapeutic issues. The mechanism of action of intravenous gamma globulin in Kawasaki disease
is unknown. Gamma globulin may act by blockade or
modulation of Fc receptors, by providing a specific
antibody against an etiologic agent or toxin, by an
anti-idiotypic mechanism resulting in suppression of
antibody function, synthesis, or both, or by downregulation of cytokine production.
Because the mechanism of action of intravenous
gamma globulin is unknown, standardization of intravenous gamma globulin preparations is not possible. It is
unclear whether all commercially available intravenous
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Circulation Vol 87, No S May 1993
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3. Yanagawa H: Results of nationwide surveys of Kawasaki disease,
in Shigematsu I, Yanagawa H, Kawasaki T (eds): Kawasaki Disease
Epidemiological Data Book. Tokyo, Soft Science-sha Publications,
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4. Shulman ST, McAuley JB, Pachman LM, Miller ML, Ruschhaupt
DG: Risk of coronary abnormalities due to Kawasaki disease in urban
area with small Asian population. Am J Dis Child 1987;141:420-425
5. Rauch AM, Kaplan SL, Nihill MR, Pappas PG, Hurwitz ES,
Schonberger LB: Kawasaki syndrome clusters in Harris County,
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6. Taubert KA, Rowley AH, Shulman ST: A nationwide survey of
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EL, Millard D, Randolph MF, Shulman ST, Taubert KA,
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9. Arjunan K, Daniels SR, Meyer RA, Schwartz DC, Barran H,
Kaplan S: Coronary artery caliber in normal children and patients
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10. Kato H, Ichinose E, Kawasaki T: Myocardial infarction in
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11. Akagi T, Kato H, Inoue 0, Sato N, Imamura K: Valvular heart
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12. Gidding SS, Shulman ST, Ilbawi M, Crussi F, Duffy CE: Mucocutaneous lymph node syndrome (Kawasaki disease): Delayed aortic
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13. Kitamura S, Kawashima Y, Kawachi K, Harima R, Ihara K,
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18. Newberger JW, Sanders SP, Burns JC, et al: Left ventricular contractility and function in Kawasaki syndrome. Circulation 1989;79:
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gamma globulin preparations or various lots of the same
preparation are equally effective.
The optimal dose of intravenous gamma globulin for
treatment of acute Kawasaki disease remains undetermined. Two US studies using a single dose of 1 g/kg
intravenous gamma globulin have been reported. One
study was uncontrolled,20 and the other comparing
doses of 1 g/kg to 400 mg/kg per day for 4 days involved
a small number of patients.21 No trials comparing single
doses of 1 g/kg and 2 g/kg have been reported.
Intravenous gamma globulin therapy should be considered for patients in whom the diagnosis of Kawasaki
disease is made after the tenth day of illness if they have
signs of ongoing inflammation or evolving coronary
artery disease. Prolonged fever is associated with increased risk of coronary arterial abnormalities, including giant aneurysms. However, there are no available
data from controlled studies on the benefit of intravenous gamma globulin in this circumstance.
Some patients who present within 10 days of onset of
illness already have coronary arterial abnormalities.
These patients should receive aspirin and intravenous
gamma globulin, although there are no data available on
the acute or long-term benefits of such therapy.
Intravenous gamma globulin therapy may not always
result in a prompt anti-inflammatory response. Some
patients have persistent fever 24 hours after completion
of the infusion. Other patients have an initial defervescence for at least 24 hours and then a recurrence of the
fever. In both circumstances, retreatment with intravenous gamma globulin should be considered, although
the benefit of retreatment to decrease the risk of
coronary arterial sequelae has not been determined.
Treatment of atypical or incomplete Kawasaki disease
with intravenous gamma globulin is based on clinical
judgment. To identify such patients with certainty will
not be possible until the etiology of the illness is discovered and a specific diagnostic test developed. Infants,
particularly those under 6 months of age, frequently lack
full diagnostic criteria for Kawasaki disease, and a high
index of suspicion is necessary to make the diagnosis in
these patients. Because these young infants are at an
extremely high risk of developing coronary arterial abnormalities, early diagnosis and institution of appropriate
therapy is particularly important. Overuse of intravenous
gamma globulin should be discouraged because this
treatment is expensive and has potential side-effects.
When possible, patients with questionable diagnoses
should be referred to a pediatric facility with established
expertise in the diagnosis and management of Kawasaki
disease before therapy is initiated.
Additional Reading
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