Kawasaki disease is a febrile, exanthematous, multisystem vasculitis of importance, because approximately 20% of untreated children will develop coronary artery abnormalities. Most cases of Kawasaki disease occur in children younger than 12 years of age. The illness is characterized by fever and the following clinical features: (1) bilateral bulbar conjunctival injection without exudate; (2) erythematous mouth and pharynx, strawberry tongue, and red, cracked lips; (3) a polymorphous, generalized, erythematous rash that can be morbilliform, maculopapular, or scarlatiniform or may resemble erythema multiforme; (4) changes in the peripheral extremities consisting of induration of the hands and feet with erythematous palms and soles, often with later periungual desquamation; and (5) acute, nonsuppurative, usually unilateral, cervical lymphadenopathy with at least one node 1.5 cm in diameter. For diagnosis of classic Kawasaki disease, patients should have fever for at least 4 days and at least 4 of these 5 features without alternative explanation for the findings. The epidemiologic case definition also allows diagnosis of Kawasaki disease when a person has fewer than 4 principal clinical criteria in the presence of coronary artery aneurysms. Irritability, abdominal pain, diarrhea, and vomiting commonly are associated features. Other findings include urethritis with sterile pyuria (70% of cases), mild anterior uveitis (25%-50%), mild hepatic dysfunction (40%), arthritis or arthralgia (10%-20%), meningismus with cerebrospinal fluid pleocytosis (25%), pericardial effusion of at least 1 mm (less than 5%), gallbladder hydrops (less than 10%), and myocarditis manifested by congestive heart failure (less than 5%). Fine desquamation in the groin area can occur in the acute phase of disease.¹

Incomplete Kawasaki disease can be diagnosed in febrile patients when fever plus fewer than 4 of the characteristic features are present. Patients with fewer than 4 of the characteristic features and who have additional findings not listed above (eg, purulent conjunctivitis) should not be considered to have incomplete Kawasaki disease. Incomplete Kawasaki disease is more common in infants younger than 12 months of age than in older children. Infants with Kawasaki disease also have a higher risk of developing coronary artery aneurysms than do older children, making diagnosis and timely Treatment especially important in this age group. The laboratory findings of incomplete cases are similar to findings of classic cases. Therefore, although laboratory findings in Kawasaki disease are nonspecific, they may prove useful in increasing or decreasing the likelihood of incomplete Kawasaki disease. If coronary artery ectasia or dilatation is evident, the diagnosis is confirmed. A normal early echocardiographic study does not exclude the diagnosis but may be useful in evaluation of patients with suspected incomplete Kawasaki disease. Incomplete Kawasaki disease should be considered in any child with unexplained fever for 5 days or longer in association with 2 or more of the principal features of this illness and supportive laboratory data (eg, erythrocyte sedimentation rate [ESR] 40 mm/hour or greater or C-reactive protein [CRP] concentration 3.0 mg/dL or greater). Fig 3.2 shows the American Heart Association algorithm for diagnosis and Treatment of suspected incomplete Kawasaki disease.





Without aspirin and Immune Globulin Intravenous (IGIV) therapy, fever can last 2 weeks or longer. After fever resolves, patients can remain anorectic and/or irritable for 2 to 3 weeks. During this phase, desquamation of the groin, fingers, and toes and fine desquamation of other areas may occur. Recurrent disease occurring months to years later develops in approximately 2% of patients.

Coronary artery abnormalities can be demonstrated with 2-dimensional echocardiography in 20% to 25% of patients who are not treated within 10 days of onset of fever. Increased risk of developing coronary artery aneurysms is associated with male sex; age younger than 12 months or older than 8 years; fever for more than 10 days; high baseline neutrophil (greater than 30 000 cells/mm³) and band count; low hemoglobin concentration (less than 10 g/dL); hypoalbuminemia, hyponatremia, or thrombocytopenia at presentation; fever persisting after IGIV administration; and persistence of elevated ESR or CRP for more than 30 days or recurrent elevations. Hispanic ethnicity also has been associated with high risk of coronary artery aneurysms, which may be related to delayed diagnosis and Treatment. Aneurysms of the coronary arteries have been demonstrated by echocardiography as early as 5 to 7 days after onset of illness but more typically occur between 1 and 4 weeks after onset of illness; their initial appearance later than 6 weeks is uncommon. Giant coronary artery aneurysms (diameter 8 mm or greater) are likely to be associated with long-term complications. Aneurysms occurring in other medium-sized arteries (eg, iliac, femoral, renal, and axillary vessels) are uncommon and generally do not occur in the absence of significant coronary abnormalities. In addition to coronary artery disease, carditis can involve the pericardium, myocardium, or endocardium, and mitral or aortic regurgitation or both can develop. Carditis generally resolves when fever resolves.

In children with mild coronary artery dilation or ectasia, coronary artery dimensions often return to baseline within 6 to 8 weeks after onset of disease. Approximately 50% of coronary aneurysms (fewer giant aneurysms) regress to normal luminal size within 1 to 2 years, although this process can be accompanied by development of coronary stenosis. In addition, regression of aneurysm(s) may result in a poorly compliant, fibrotic vessel wall.

The current case-fatality rate in the United States and Japan is less than 0.1% to 0.2%. The principal cause of death is myocardial infarction resulting from coronary artery occlusion attributable to thrombosis or progressive stenosis. Rarely, a large coronary artery aneurysm may rupture. The relative risk of mortality is highest within 6 weeks of onset of symptoms, but myocardial infarction and sudden death can occur months to years after the acute episode. There is hypothetical concern that the vasculitis of Kawasaki disease may predispose to premature coronary artery disease.

Etiology

The cause is unknown. Epidemiologic and clinical features suggest an infectious cause.

Epidemiology

Peak age of occurrence in the United States is between 18 and 24 months. Fifty percent of patients are younger than 2 years of age, and 80% are younger than 5 years of age; children older than 8 years of age less commonly develop the disease. In children younger than 6 months of age, the diagnosis often is delayed, because the symptom complex of Kawasaki disease is incomplete. The prevalence of coronary artery abnormalities is higher when diagnosis and Treatment are delayed beyond the 10th day of illness. The male-to-female ratio is approximately 1.5:1. In the United States, 3000 to 5000 cases are estimated to occur each year; the incidence is highest in those of Asian background. Kawasaki disease first was described in Japan, where a pattern of endemic occurrence with superimposed epidemic outbreaks was recognized. A similar pattern of steady or increasing endemic disease with occasional sharply defined community-wide epidemics has been recognized in North America and Hawaii. Clusters generally occur during winter and spring. No evidence indicates person-to-person or common-source spread, although the incidence is slightly higher in siblings of children with the disease.

The incubation period is unknown.

Diagnostic Tests

No specific diagnostic test is available. The diagnosis is established by fulfillment of the clinical criteria (see Clinical Manifestations) and clinical or laboratory exclusion of other possible illnesses, such as measles, parvovirus B19 infection, adenovirus or enterovirus infections, staphylococcal or streptococcal toxin-mediated disease, rickettsial exanthems, drug reactions (eg, Stevens-Johnson syndrome), leptospirosis, systemic onset juvenile idiopathic arthritis, and reactive arthritis. A greatly increased ESR and serum CRP concentration during the first 2 weeks of illness and an increased platelet count (greater than 450 000/mm³) on days 10 to 21 of illness are almost universal laboratory features. ESR and platelet count usually are normal within 6 to 8 weeks; CRP concentration returns to normal much sooner.

Treatment

Management during the acute phase is directed at decreasing inflammation of the myocardium and coronary artery wall and providing supportive care. Therapy should be initiated when the diagnosis is established or strongly suspected, optimally within the first 10 days of illness. Once the acute phase has passed, therapy is directed at prevention of coronary artery thrombosis. Specific recommendations for therapy include the following measures.

Immune Globulin Intravenous

Therapy with high-dose IGIV and aspirin initiated within 10 days of the onset of fever substantially decreases progression to coronary artery dilation and aneurysms, compared with Treatment with aspirin alone, and results in more rapid resolution of fever and other clinical and laboratory indicators of acute inflammation. Therapy with IGIV should be initiated as soon as possible; its efficacy when initiated later than the 10th day of illness or after detection of aneurysms has been evaluated in only one controlled trial. However, therapy with IGIV and aspirin should be provided for patients diagnosed after day 10 who have manifestations of continuing inflammation (eg, fever or elevated ESR or CRP concentration) or of evolving coronary artery disease. Despite prompt Treatment with IGIV and aspirin, 2% to 4% of patients develop coronary artery abnormalities.

Dose

A dose of 2 g/kg as a single dose, given over 10 to 12 hours, has been proven to reduce the risk of coronary artery aneurysm from 17% to 4%. Few complications occur from this regimen.

ReTreatment

Up to 20% of patients who receive IGIV and aspirin therapy have persistent fever after IGIV or recurrence of fever after an initial period of being afebrile. In these situations, reTreatment with IGIV (2 g/kg) within 24 to 48 hours of persistent or recrudescent fever and continued aspirin therapy generally is given. Persistent or recrudescent fever is associated with high concentrations of proinflammatory cytokines and an increased risk of coronary artery abnormalities. The benefit and possible detriment of use of systemic corticosteroids in Treatment of Kawasaki disease are controversial. Corticosteroids are not beneficial for primary therapy. For the limited number of patients who are refractory to at least 2 doses of IGIV, rescue therapy of intravenous methylprednisolone (usually 30 mg/kg/day for 1 to 3 days) or infliximab (5 mg/kg as one infusion) may be administered in attempt to reduce inflammation and improve coronary artery outcomes. Lack of data on use of these modalities precludes definitive recommendations.

Aspirin

Aspirin is used for anti-inflammatory and antithrombotic actions, although aspirin alone does not decrease risk of coronary artery abnormalities. The optimal dose or duration of aspirin Treatment is unknown. Aspirin is administered in doses of 80 to 100 mg/kg per day in 4 divided doses once the diagnosis is made. Children with acute Kawasaki disease have decreased aspirin absorption and increased clearance and rarely achieve therapeutic serum concentrations. In most children, it is not necessary to monitor aspirin concentrations. After fever is controlled for 48 hours (usually around the 14th day of illness), the aspirin dose is decreased to 3 to 5 mg/kg per day for antithrombotic activity. Aspirin is discontinued if no coronary artery abnormalities have been detected by 6 to 8 weeks after onset of illness. Low-dose aspirin therapy should be continued indefinitely for people in whom coronary artery abnormalities are present. Because of the theoretical risk of Reye syndrome in patients with influenza or varicella receiving salicylates, parents of children receiving aspirin should be instructed to contact their child's physician promptly if the child develops symptoms of or is exposed to either disease. In general, ibuprofen should be avoided in children with coronary aneurysms taking aspirin for its antiplatelet effects, because ibuprofen antagonizes the platelet inhibition that is induced by aspirin. The child and household contacts should be given influenza vaccine at diagnosis of Kawasaki disease according to seasonal recommendations.

Cardiac Care

An echocardiogram should be obtained at the time of diagnosis and then 1 to 2 and 6 to 8 weeks after onset. Children at higher risk-for example, those with persistent or recrudescent fever after initial IGIV or baseline coronary abnormalities-should have more frequent echocardiograms to guide the need for additional therapies. Children also should be assessed during this time for arrhythmias, congestive heart failure, and valvular regurgitation. The care of patients with significant cardiac abnormalities should involve a pediatric cardiologist experienced in management of patients with Kawasaki disease and in assessing echocardiographic studies of coronary arteries in children. Long-term management of Kawasaki disease should be based on the extent of coronary artery involvement. In patients with persistent moderately large coronary artery abnormalities that are not large enough to require anticoagulation, prolonged low-dose aspirin and clopidogrel (1 mg/kg/day) are recommended in combination. Development of giant coronary artery aneurysms (diameter 8 mm or larger) usually requires addition of anticoagulant therapy, such as warfarin or low-molecular weight heparin, to prevent thrombosis. Anticoagulation also sometimes is used in young infants with coronary artery aneurysms measuring less than 8 mm in diameter but for whom the size is equivalent to giant aneurysms when body surface area is considered. For example, a 3-month-old infant with coronary arteries 6 or 7 mm in diameter often would be a candidate for anticoagulation.

Subsequent Immunization

Measles and varicella-containing vaccines should be deferred for 11 months after high-dose IGIV for Treatment of Kawasaki disease. If the child's risk of exposure to measles or varicella is high, the child should be immunized and then reimmunized at least 11 months after administration of IGIV (see Measles). The schedule for administration of inactivated childhood vaccines should not be interrupted.

Isolation of the Hospitalized Patient

Standard precautions are indicated.

Control Measures

None.

Footnotes

1 . Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, Treatment and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation . 2004;110(17):2747-2771 (also in Pediatrics . 2004;114[6]:1708-1733)