Kawasaki disease is a vasculitis of medium-sized arteries, most significantly the coronary arteries, which are involved in about 20% of untreated patients. Early manifestations include acute myocarditis with heart failure, arrhythmias, endocarditis, and pericarditis. Coronary artery aneurysms may subsequently form. Giant coronary artery aneurysms (> 8 mm internal diameter on echocardiography), though rare, have the greatest risk of causing cardiac tamponade, thrombosis, or infarction. Kawasaki disease is the leading cause of acquired heart disease in children. Extravascular tissue also may become inflamed, including the upper respiratory tract, pancreas, biliary tract, kidneys, mucous membranes, and lymph nodes.
Etiology of Kawasaki Disease
The etiology of Kawasaki disease is unknown, but the epidemiology and clinical presentation suggest an infection or, more likely, an abnormal immunologic response to an infection in genetically predisposed children. Autoimmune disease is also a possibility. Children of Japanese descent have a particularly high incidence, but Kawasaki disease occurs worldwide. In the US, 3000 to 5000 cases occur annually. The male:female ratio is about 1.5:1. Eighty percent of patients are < 5 years (peak, 18 to 24 months) of age. Cases in adolescents, adults, and infants < 4 months of age are rare.
Cases occur year-round but most often in spring or winter. Clusters have been reported in communities without clear evidence of person-to-person spread. About 2% of patients have recurrences, typically months to years later. There is no known prevention.
Symptoms and Signs of Kawasaki Disease
The illness tends to progress in stages, beginning with fever lasting at least 5 days, usually unremittent and > 39° C (about 102.2° F), and is associated with irritability, occasional lethargy, or intermittent colicky abdominal pain. Usually within a day or two of fever onset, bilateral bulbar conjunctival injection appears without exudate.
Within 5 days, a polymorphous, erythematous macular rash appears, primarily over the trunk, often with accentuation in the perineal region. The rash may be urticarial, morbilliform, erythema multiforme, or scarlatiniform. It is accompanied by injected pharynx; reddened, dry, fissured lips; and a red strawberry tongue.
During the first week, pallor of the proximal portion of the fingernails or toenails (leukonychia partialis) may occur. Erythema or a purple-red discoloration and variable edema of the palms and soles usually appear on about the 3rd to 5th day. Although edema may be slight, it is often tense, hard, and nonpitting. Periungual, palmar, plantar, and perineal desquamation begins on about the 10th day. The superficial layer of the skin sometimes comes off in large casts, revealing new normal skin.
Tender, nonsuppurative cervical lymphadenopathy (≥ 1 node ≥ 1.5 cm in diameter) is present throughout the course in about 50% of patients. The illness may last from 2 to 12 weeks or longer. Incomplete or atypical cases can occur, especially in younger infants, who have higher risk of developing coronary artery disease. These findings manifest in about 90% of patients.
Other less specific findings indicate involvement of many systems. Arthritis or arthralgias (mainly involving large joints) occur in about 33% of patients. Other clinical features include urethritis, aseptic meningitis, hepatitis, otitis, vomiting, diarrhea, hydrops of the gallbladder, upper respiratory symptoms, and anterior uveitis.
Cardiac manifestations usually begin in the subacute phase of the syndrome about 1 to 4 weeks after onset as the rash, fever, and other early acute clinical symptoms begin to subside.
Diagnosis of Kawasaki Disease
Serial ECG and echocardiography
Testing to rule out other disorders: complete blood count, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, rheumatoid factor, albumin, liver enzymes, throat and blood cultures, urinalysis, chest x-ray
Diagnosis of Kawasaki disease is by clinical criteria ( see Table: Criteria for Diagnosis of Kawasaki Disease Criteria for Diagnosis of Kawasaki Disease ). Similar symptoms can result from scarlet fever Scarlet fever Streptococci are gram-positive aerobic organisms that cause many disorders, including pharyngitis, pneumonia, wound and skin infections, sepsis, and endocarditis. Symptoms vary with the organ... read more , staphylococcal exfoliative syndromes, measles Measles Measles is a highly contagious viral infection that is most common among children. It is characterized by fever, cough, coryza, conjunctivitis, an enanthem (Koplik spots) on the oral mucosa... read more , drug reactions, and juvenile idiopathic arthritis Juvenile Idiopathic Arthritis (JIA) Juvenile idiopathic arthritis is a group of rheumatic diseases that begins by age 16. Arthritis, fever, rash, adenopathy, splenomegaly, and iridocyclitis are typical of some forms. Diagnosis... read more . Less common mimics are leptospirosis Leptospirosis Leptospirosis is an infection caused by one of several pathogenic serotypes of the spirochete Leptospira. Symptoms are biphasic. Both phases involve acute febrile episodes; the 2nd phase... read more and Rocky Mountain spotted fever Rocky Mountain Spotted Fever (RMSF) Rocky Mountain spotted fever (RMSF) is caused by Rickettsia rickettsii and transmitted by ixodid ticks. Symptoms are high fever, severe headache, and rash. (See also Overview of Rickettsial... read more .
Criteria for Diagnosis of Kawasaki Disease
Diagnosis is made if fever of ≥ 5 days has occurred and 4 of the following 5 criteria are noted:
1. Bilateral nonexudative conjunctival injection
2. Changes in the lips, tongue, or oral mucosa (injection, drying, fissuring, red strawberry tongue)
3. Changes in the peripheral extremities (edema, erythema, desquamation)
4. Polymorphous truncal exanthem
5. Cervical lymphadenopathy (at least 1 node ≥ 1.5 cm in diameter)
Some febrile children who have fewer than 4 of the 5 diagnostic criteria nonetheless develop vasculitic complications, including coronary artery aneurysms. Such children are considered to have atypical (or incomplete) Kawasaki disease. Atypical Kawasaki disease should be considered, and testing should be initiated if the child has had ≥ 5 days of fever > 39° C (about 102.2° F) plus ≥ 2 of the 5 criteria for Kawasaki disease.
Laboratory tests are not diagnostic but may be done to exclude other disorders. Patients generally undergo complete blood count, antinuclear antibody, rheumatoid factor, erythrocyte sedimentation rate (ESR), and throat and blood cultures. Leukocytosis, often with a marked increase in immature cells, is common acutely. Other hematologic findings include a mild normocytic anemia, thrombocytosis (≥ 450,000/mcL [≥ 450,000 × 109/L]) in the 2nd or 3rd week of illness, and elevated ESR or C-reactive protein. Antinuclear antibody, rheumatoid factor, and cultures are negative. Other abnormalities, depending on the organ systems involved, include sterile pyuria, elevated liver enzymes, proteinuria, reduced serum albumin, and cerebrospinal fluid pleocytosis.
Consultation with a pediatric cardiologist is important. At diagnosis, ECG and echocardiography are done. Because abnormalities may not appear until later, these tests are repeated 2 to 3 weeks, 6 to 8 weeks, and perhaps 6 to 12 months after onset. ECG may show arrhythmias, decreased voltage, or left ventricular hypertrophy. Echocardiography should detect coronary artery aneurysms, valvular regurgitation, pericarditis, or myocarditis. Coronary arteriography occasionally is useful in patients with aneurysms and abnormal stress test results.
Prognosis for Kawasaki Disease
Without therapy, mortality may approach 1%, usually occurring within 6 weeks of onset. With adequate therapy, the mortality rate in the US is 0.17%. Long duration of fever increases cardiac risk. Deaths most commonly result from cardiac complications and can be sudden and unpredictable: > 50% occur within 1 month of onset, 75% within 2 months, and 95% within 6 months but may occur as long as 10 years later. Effective therapy reduces acute symptoms and, more importantly, lowers the incidence of coronary artery aneurysms from 20% to < 5%.
In the absence of coronary artery disease, the prognosis for complete recovery is excellent. About two thirds of coronary aneurysms regress within 1 year, although it is unknown whether residual coronary stenosis remains. Giant coronary aneurysms are less likely to regress and require more intensive follow-up and therapy.
Treatment of Kawasaki Disease
High-dose IV immune globulin (IVIG)
Children should be treated by or in close consultation with an experienced pediatric cardiologist, pediatric infectious disease specialist, or pediatric rheumatologist. Because infants with atypical Kawasaki disease are at high risk of coronary artery aneurysms, treatment should not be delayed. Therapy is started as soon as possible, optimally within the first 10 days of illness, with a combination of high-dose IVIG (single dose of 2 g/kg given over 10 to 12 hours) and oral high-dose aspirin 20 to 25 mg/kg orally 4 times a day. The aspirin dose is reduced to 3 to 5 mg/kg once a day after the child has been afebrile for 4 to 5 days; some authorities prefer to continue high-dose aspirin until the 14th day of illness. Aspirin metabolism is erratic during acute Kawasaki disease, which partially explains the high dose requirements. Some authorities monitor serum aspirin levels during high-dose therapy, especially if therapy is given for 14 days and/or fever persists despite IVIG treatment.
Most patients have a brisk response over the first 24 hours of therapy. A small fraction continue to be ill with fever for several days and require repeated dosing with IVIG. An alternative regimen, which may lead to slightly slower resolution of symptoms but may benefit patients with cardiac dysfunction who could not tolerate the volume of a 2 g/kg IGIV infusion, is IVIG 400 mg/kg once a day for 4 days (again in combination with high-dose aspirin). The efficacy of IVIG/aspirin therapy when begun > 10 days after onset of illness is unknown, but therapy should still be considered.
After the child’s symptoms have abated for 4 to 5 days, aspirin 3 to 5 mg/kg once a day is continued for at least 8 weeks after onset until repeated echocardiographic testing is completed. If there are no coronary artery aneurysms and signs of inflammation are absent (shown by normalization of ESR and platelets), aspirin may be stopped. Because of its antithrombotic effect, aspirin is continued indefinitely for children with coronary artery abnormalities. Children with giant coronary aneurysms may require additional anticoagulant therapy (eg, warfarin, antiplatelet drugs).
Children who receive IVIG therapy may have a lower response rate to live viral vaccines. Thus, measles-mumps-rubella vaccine should generally be delayed for 11 months after IVIG therapy, and varicella vaccine should be delayed for ≥ 11 months. If the risk of measles exposure is high, vaccination should proceed, but revaccination (or serologic testing) should be done 11 months later.
A small risk of Reye syndrome exists in children receiving long-term aspirin therapy during outbreaks of influenza or varicella; thus, annual influenza vaccination is especially important for children (≥ 6 months of age) receiving long-term aspirin therapy. Further, parents of children receiving aspirin should be instructed to contact their child’s physician promptly if the child is exposed to or develops symptoms of influenza or varicella. Temporary interruption of aspirin may be considered (with substitution of dipyridamole for children with documented aneurysms).
Kawasaki disease is a childhood systemic vasculitis of unknown etiology.
The most serious complications involve the heart and include acute myocarditis with heart failure, arrhythmias, and coronary artery aneurysms.
Children have fever, cutaneous rash (which later desquamates), oral and conjunctival inflammation, and lymphadenopathy; atypical cases with fewer of these classic criteria can occur.
Diagnosis is made by clinical criteria; children meeting criteria should have a serial ECG and echocardiography and consult with a specialist.
Early use of high-dose aspirin and IV immune globulin relieves symptoms and helps prevent cardiac complications.
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