Mary Beth Son and Jane W. Newburger
Kawasaki disease (KD), an acute febrile illness of childhood, was described in Japan in 1967 by Dr. Tomasaku Kawasaki as the mucocutaneous lymph node syndrome.1 A vasculitis of medium-sized vessels, KD has a predilection for the coronary arteries, and 20% to 25% of untreated children develop coronary artery aneurysms. Fortunately, a regimen of intravenous immunoglobulin and aspirin reduces the incidence of coronary artery abnormalities to less than 5%.2 Nonetheless, KD is a leading cause of acquired heart disease in children in North America and Japan. Furthermore, the etiology of KD remains elusive, impeding the development of targeted therapy and diagnostic testing.
EPIDEMIOLOGY AND SPECIFIC POPULATIONS AT RISK
The Japanese Ministry of Health has collected epidemiologic data on Kawasaki disease (KD) since 1970 with nationwide surveys every 2 years. In total, over 225,000 cases of KD were reported in Japan between 1970 and 2006.3-5The incidence of KD in Japan from 2005 to 2006 was 184.6 per 100,000 in children younger than 5 years of age.3
In the United States, Holman et al6 reported a hospitalization rate for Kawasaki disease (KD) in the United States in 2000 as 17.1 per 100,000 children less than 5 years of age, with a median age at admission of 2 years. Children of Asian and Pacific Islander heritage had the highest hospitalization rate at 39 per 100,000 children.
Risk factors for poor coronary artery outcomes have been identified in a number of studies. Young age, male sex and a number of laboratory parameters, including neutrophilia, thrombocytopenia, hyponatremia, elevated C reactive protein, and transaminitis have been associated with poor response to intravenous immunoglobulin or the development of coronary artery aneurysms.7-11 In short, younger, sicker children with worse systemic inflammation are at higher risk.
PATHOPHYSIOLOGY AND GENETICS
Despite years of extensive research, the etiology of Kawasaki disease (KD) remains obscure. Many aspects of the disease implicate an infectious trigger in the pathogenesis. KD is a disease of childhood, rarely seen in adults or infants less than 2 months of age. Discrete seasonal peaks with increased incidence in selected geographic areas suggest a transmittable vector.5,12 Many of the clinical features of KD resemble other childhood infections with exanthems (see below). However, no single etiologic agent has emerged as the clear culprit.
Similarities between Kawasaki disease and toxin-mediated diseases, such as toxic shock syndrome and streptococcal toxic shock syndrome, led to the proposition that the features of Kawasaki disease are mediated by superantigens.
However, studies of T cells and attempts at isolating superantigen-producing bacteria in Kawasaki disease patients have yielded conflicting results.
Classic clinical criteria, as well as supportive clinical and laboratory findings, are summarized in Table 488-1. In brief, the epidemiologic case definition of Kawasaki disease (KD) includes at least 4 days of fever (3 days in expert hands), together with 4 or 5 principal clinical criteria. Those with fewer than 4 principal clinical criteria may meet the case definition if they have coronary artery disease. Incomplete KD, in which fewer than 4 principal clinical criteria are evident, is associated with a rate of coronary aneurysms that is similar to that of complete disease. Because the diagnosis of incomplete KD is particularly challenging, the latest American Heart Association recommendations, endorsed by the American Academy of Pediatrics, provide an algorithm for evaluation and treatment of suspected incomplete KD (Fig. 488-1).2
Table 488-1. Clinical and Laboratory Features of Kawasaki Disease
Fever is the hallmark of KD. Children with KD tend to have daily, high fevers (> 39°C) that are of abrupt onset. Without intravenous immunoglobulin treatment, the average duration of fever is 11 to 12 days, with rare patients remaining febrile for as long as 4 weeks. Patients who receive appropriate therapy tend to defervesce within 2 to 3 days of intravenous immunoglobulin administration. The clinical features that accompany fever in KD patients may appear and subside at differing times over the course of illness, highlighting the importance of medical history.
More than 90% of children with Kawasaki disease (KD) develop bilateral, marked conjunctival injection in a limbus-sparing pattern. Patients with KD develop mucosal changes in their oropharynx; diffuse erythema of the oropharynx, a strawberry tongue, and cracked, reddened lips are characteristic of KD, whereas exudative tonsillitis or discrete oral lesions suggest other etiologies. Typically, the rash is erythematous and begins in the perineal area with some desquamation; morbilliform and erythema multiforme lesions can also occur. Vesicular or bullous lesions suggest other diagnoses. Extremity changes in the acute phase of KD include erythema of the palms and soles, as well as edema of the hands and feet. In the convalescent phase of KD, usually 2 weeks after fever onset, periungual peeling occurs on the fingers, followed by the toes. The least common manifestation of KD is cervical lymphadenopathy, specifically a single large (> 1.5 cm) unilateral node that is usually nontender, without erythema or warmth. Diffuse lymphadenopathy is more likely explained by another diagnosis.
A variety of signs and symptoms may support the diagnosis of Kawasaki disease (KD). Patients with KD are usually irritable, perhaps reflecting central nervous system inflammation. Children with KD may complain of arthralgias; reported rates of frank arthritis range from 7.5% to 31% in KD patients.13Gastrointestinal complaints are also common and include abdominal pain, nausea, and vomiting. Hydrops of the gallbladder can present with abdominal pain or jaundice or can be clinically silent.
FIGURE 488-1. Evaluation of suspected incomplete Kawasaki disease. (1) In the absence of gold standard for diagnosis, this algorithm cannot be evidence based but rather represents the informed opinion of the expert committee. Consultation with an expert should be sought anytime assistance is needed. (2) Infants 6 months old or younger on day 7 or more of fever without other explanation should undergo laboratory testing, and if evidence of systemic inflammation is found, should have an echocardiogram, even if the infants have no clinical criteria. (3) Patient characteristics suggesting Kawasaki disease are listed in Table 488-1. Characteristics suggesting disease other than Kawasaki disease include exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, or generalized lymphadenopathy. Consider alternative diagnoses (see eTable 488.1 ). (4) Supplemental laboratory criteria include albumin less than or equal to 3.0 g/dL, anemia for age, elevation of alanine aminotransferase, platelets after 7 days greater than or equal to 450,000/mm3, white blood cell count greater than or equal to 15,000/m3, and urine greater than or equal to 10 white blood cells per high power field. (5) The child can be treated before the echocardiogram. (6) Echocardiogram is considered positive for purposes of this algorithm if any of 3 conditions are met: z score of left anterior descending (LAD) coronary artery or right coronary artery (RCA) greater than or equal to 2.5, coronary arteries meet Japanese Ministry of Health criteria for aneurysms, or 3 or more other suggestive features exist, including perivascular brightness, lack of tapering, decreased LV function, mitral regurgitation, pericardial effusion, or z scores in LAD or RCA of 2 to 2.5. (7) If the echocardiogram is positive, treatment should be given to children within 10 days of fever onset and for those beyond day 10 with clinical and laboratory signs (C-reactive protein, erythrocyte sedimentation rate) of ongoing inflammation. (8) Typical peeling begins under nail bed of fingers and then toes.
As fever and rash are the most common features of Kawasaki disease (KD), the differential diagnosis is dominated by infectious diseases of childhood (eTable 488.1 ). Common viral infections such as adenovirus, enterovirus, and Epstein Barr virus can mimic KD. As the rash of KD is frequently morbilliform, measles is a differential diagnosis, but is less commonly encountered in developed countries because of widespread vaccination. Diseases with exanthems such as scarlet fever, Rocky Mountain spotted fever, leptospirosis, staphylococcal scalded skin syndrome, and toxic shock syndrome should be considered when evaluating a child for KD. Drug hypersensitivity syndromes, including Stevens-Johnson syndrome are also possible. In some children who appear at first to have KD, with fever, rash, joint pain, and coronary artery changes, the symptoms may ultimately evolve into systemic onset juvenile idiopathic arthritis.14 Rarely, mercury poisoning or acrodynia, with its swollen, erythematous hands and feet, may mimic KD.
Laboratory studies in patients with Kawasaki disease (KD) may demonstrate leukocytosis, anemia, and, in the later stages of the acute phase, a pronounced thrombocytosis with platelet counts from 500,000 to 1,000,000/mm. Inflammatory markers are nearly always elevated in KD, with the erythrocyte sedimentation rate usually greater than or equal to 40 mm/hour and the C-reactive protein usually greater than or equal to 3.0 mg/dL. Elevation of the erythrocyte sedimentation rate may lag behind that of C-reactive protein, so both should be measured. Further supportive laboratory findings are listed in Table 488-1.
Echocardiography is the cornerstone of diagnosis of coronary artery abnormalities in children with KD. Taken together with Doppler imaging, echocardiographic imaging is also used to assess mitral and, more rarely, aortic regurgitation, left ventricular function, and pericardial effusion. At the time of presentation, within 10 days of illness, children with KD have enlarged coronary artery dimensions compared to afebrile normal children. Coronary artery dimensions are generally described in terms of their absolute diameter, as well as in standard deviation units (z scores) adjusted for body surface area. Echocardiography should be performed at the time of diagnosis, at 2 weeks, and then approximately 6 to 8 weeks after illness onset.2 Children with documented coronary artery abnormalities or persistent fever may require more frequent imaging.
Once the diagnosis of Kawasaki disease (KD) has been established, intravenous immunoglobulin (IVIG) should be administered at a dose of 2 g per kilogram over 8 to 12 hours.54,55 Treatment with IVIG should be instituted no later than day 10, and ideally by day 7 of illness; the first day of fever in KD is considered day 1. Administration of IVIG beyond day 10 of illness should be reserved for children with persistent fever or those with coronary artery lesions and evidence of ongoing systemic inflammation on laboratory testing.
The American Heart Association/American Academy of Pediatrics statement on treatment of KD recommends aspirin in high doses for its anti-inflammatory effects (80–100 milligrams per kilogram per day divided into 4 doses) followed by low-dose aspirin (3–5 milligrams per kilogram per day) for antiplatelet effects. High dose aspirin is continued until the child has been afebrile for 48 hours, although some centers continue high-dose aspirin until the child is beyond 14 days of illness, and afebrile for 48 hours. Most children with KD are maintained on low-dose aspirin therapy until 6 to 8 weeks after illness onset, at which point aspirin therapy may be discontinued if the child’s echocardiogram is normal. Patients with coronary artery abnormalities on follow-up echocardiogram may be maintained on low-dose aspirin indefinitely, and annual influenza vaccinations are recommended in such patients. Reye syndrome has been reported in patients who received high-dose aspirin therapy for KD;58,59 the risks conferred by daily low-dose aspirin as chronic therapy are uncertain. Aspirin should be temporarily discontinued in children who have been exposed to varicella or influenza; other antiplatelet agents, such as clopidogrel, can be used in children with coronary lesions. Lastly, administration of measles and varicella immunizations should be delayed for 11 months after IVIG treatment, which may render the vaccines less immunogenic.
Approximately 15% of KD patients have persistent or recrudescent fever after a single dose of intravenous immunoglobulin (IVIG) (so-called IVIG resistance) and are candidates for secondary therapy.16,60-66The subset of patients with IVIG resistance is at increased risk for developing coronary abnormalities.60,64 Although specific recommendations for patients with persistent or recrudescent fever after 1 dose of IVIG are hampered by lack of prospective trials, additional IVIG, at a dose of 2 g/kg, is generally administered. Recently, infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α, has been used increasingly in the IVIG-resistant population and is reported to shorten fever duration;73-76 delineation of its efficacy in reducing the prevalence of coronary aneurysms awaits further study.
Virtually all serious morbidity and mortality derive from the cardiac effects of Kawasaki disease (KD). The most important complication of KD is coronary artery aneurysms, which may lead to myocardial ischemia, infarction, and sudden death. Prior to the development of an effective treatment for Kawasaki disease, 20% to 25% of affected children developed coronary artery aneurysms, with a 2% mortality rate.2 Fortunately, a regimen of intravenous immunoglobulin and aspirin reduces the rate of coronary lesions to less than 5%, with only 1% of children developing giant aneurysms.54,55 The mortality rate in recent studies is less than 0.5%.77,78
Coronary aneurysms are created by the intense inflammatory process in the acute phase of Kawasaki disease. Classification of coronary artery aneurysms of the left circumflex, distal right coronary, distal left anterior descending, and the posterior descending arteries continue to rely on Japanese Ministry of Health criteria which may underestimate the prevalence of coronary artery dilation.79 When using absolute dimensions, aneurysms may be classified as small (less than 5 mm internal diameter), medium (5–8 mm internal diameter), and giant (greater than 8 mm internal diameter). Regression to normal lumen diameter occurs via myointimal proliferation in approximately half of coronary artery aneurysms;80 regression is most likely in patients with aneurysms less than 8 mm in internal diameter and with a fusiform morphology, in distal vessels, and in young children. Stenotic lesions, usually occurring at the proximal and distal ends of aneurysms, form in the chronic phase and are associated with myocardial ischemia.81
Myocardial infarction occurs most frequently in children with giant aneurysms.84,85 The combination of sluggish blood flow through an enlarged lumen, enhanced platelet activation due to shear stress at the proximal and distal sites of the aneurysm, and marked thrombocytosis significantly increase the risk for thrombus formation in the subacute phase. Although the relative risk of myocardial infarctions is highest in the first year,86 deaths from myocardial infarction continue to occur late after the onset of illness.86-88 Rupture of coronary aneurysms is a very rare complication occurring in rapidly expanding, inflamed coronary arteries, usually within the first 6 weeks of illness.89
KD affects not only the coronary arteries, but also cardiac muscle and heart valves. Children with KD may have depressed left ventricular function by echocardiography in the acute phase of the disease. Mitral regurgitation secondary to valvulitis occurs in approximately 1 in 4 children during the acute phase;91 late mitral regurgitation results from papillary muscle dysfunction in children with ischemic heart disease.86 Aortic root dilation97 and mild aortic regurgitation91,97,98 occur in KD but are usually not progressive.
KD may produce long-term systemic abnormalities, including diminished reactivity and greater stiffness of the peripheral arteries;99 increased intimal medial thickness of the carotid arteries;100 and dyslipidemia.101,102 These findings are most pronounced in patients with coronary aneurysms. An unfavorable lipid profile is found, however, even among patients in whom coronary involvement has not detected in any stage of illness.101,102 Data are conflicting on the long-term effects of acute KD on arterial health among patients who never had coronary involvement.
The prognosis for children with Kawasaki disease (KD) is determined by the extent of coronary artery involvement and consequent risk of myocardial ischemia.2 For this reason, recommendations for frequency of follow-up and types of testing, exercise, and medications for children after KD are stratified according to their coronary artery status (eTable 488.2 ).2 All children should have a lipid profile 1 year after KD onset. In addition, children and their families should be encouraged to follow a heart-healthy diet, exercise regularly, and avoid smoking.108