Kawasaki Disease

Authors: Angela M. Fimbres, M.D., Stanford T. Shulman, M.D.

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History

Epidemiology

Kawasaki disease is an acute, self-limited vasculitis of unknown etiology with a striking predilection for the coronary arteries of infants and young children. First described in Japan in 1967 by Tomisaku Kawasaki, the disease is now known to occur in the Americas, Europe, and Asia in children of all races. Kawasaki disease is markedly more prevalent in Japan and in children of Japanese descent, with an annual incidence of 174 cases per 100,000 children <5 years old, about 10 times the rate in the United States (7). In the U.S., the incidence of Kawasaki disease has recently been estimated using hospital discharge data. An estimated 4248 hospitalizations associated with Kawasaki disease occurred in the U.S. in the year 2000, with a median age of 2 years. The incidence of Kawasaki disease was highest among Asians and Pacific Islanders and lowest in Caucasians. Boys outnumbered girls by 3:2, and 76% of children were under age 5 years. In-hospital mortality was 0.17%. Virtually all of the very few deaths in patients with Kawasaki disease result from its cardiac sequelae. The peak mortality occurs 15-45 days after the onset of fever. However, sudden death from myocardial infarction may occur many years later in individuals who as children developed coronary artery aneurysms and subsequent stenoses. Cases of ischemic heart disease in young adults have been attributed to “missed” Kawasaki disease in childhood (2,8,10,12).

Recurrence rates and the importance of genetic factors in Kawasaki disease are best documented in Japan, where the recurrence rate is approximately 3%. The proportion of cases with a positive family history is about 1%. The risk of occurrence in twins is about 13%. These data suggest that a genetic predisposition interacts with an etiologic agent in the environment to cause disease. The occasional occurrence of Kawasaki disease in children of parents who also had Kawasaki disease in childhood also supports the contribution of genetic factors. Reported association of Kawasaki disease with exposure to carpet-cleaning fluids has not been confirmed (10,12).

Clinical Manifestations

Clinical criteria have been established to assist physicians in diagnosing Kawasaki disease since there is no specific diagnostic test. The classic, or typical, diagnosis of Kawasaki disease has been based on the presence of ≥5 days of fever and ≥4 of the 5 principal clinical features. Those features are: 1) changes in the hands and feet (erythema, edema, later peeling), 2) polymorphous exanthema, 3) bilateral bulbar conjunctival injection usually without exudate, 4) changes in the lips and oral cavity (erythema, strawberry tongue), and 5) unilateral cervical lymphadenopathy. Of course, exclusion of other diseases with similar findings is necessary. Patients with ≥5 days of fever and only 3 principal features can be diagnosed as having classic Kawasaki disease when coronary artery disease is detected by 2-dimensional echocardiography or coronary angiography. The fever typically is high spiking and remittent. In the absence of therapy, fever persists for a mean of 11 days. With appropriate therapy, fever usually resolves within 2 days of treatment (10,12).

Changes in the extremities include erythema of the palms and soles or firm, sometimes painful induration of the hands and feet and later desquamation of the fingers and toes. The desquamation usually begins in the periungual region within 2-3 weeks after the onset of fever and may extend to include the palms and soles. In addition, 1-2 months after the onset of fever, deep transverse grooves across the nails may appear. These are known as Beau’s lines. An erythematous rash usually appears within 5 days of the onset of fever. The rash may take various forms, but the most common is a nonspecific diffuse rash with scattered macules and erythematous papules. Bullous and vesicular eruptions have not been described and should prompt the physician to consider other diagnoses if present. Occasionally seen are urticarial exanthems, a scarlatiniform rash, erythroderma, erythema multiforme, or rarely, a fine micropustular eruption. Accentuation of the rash occurs in the perineal region where early desquamation may begin. Bilateral painless conjunctival injection usually begins shortly after the onset of fever. It typically involves the bulbar conjunctivae and is usually not associated with an exudate or conjunctival edema. Changes of the lips and oral cavity are protean in nature and include erythema, dryness, fissuring, peeling, cracking and bleeding of the lips; a “strawberry tongue” with erythema and prominent papillae; and diffuse erythema of the oropharyngeal mucosa. Oral ulcers and pharyngeal exudate are not seen. Cervical lymphadenopathy is the least common of the principal clinical features. It is usually unilateral, confined to the anterior cervical triangle and is defined as ≥1.5 cm in diameter. The lymph nodes are often firm and non-tender, with no overlying erythema or evidence of suppuration (10,12).

Multiple other clinical findings can be seen in patients with Kawasaki disease. Arthritis or arthralgia can occur in the first week and tend to involve multiple joints, especially the ankles. Children with Kawasaki disease typically are more irritable than are children with other febrile illnesses. Gastrointestinal complaints, including diarrhea, vomiting, and abdominal pain occur in approximately one third of patients. Hepatomegaly and jaundice can occur as well as acute acalculous distention of the gallbladder. In addition, up to 15% of patients with Kawasaki disease have abnormal chest radiograph findings (10,12).

Laboratory Diagnosis

Leukocytosis is typical during the acute stage of the illness, with a predominance of immature and mature granulocytes. About 50% of patients with Kawasaki disease have white blood cell counts >15 000/mm3. Anemia may develop, especially with prolonged duration of active inflammation. Elevation of the acute phase reactants, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), is nearly universal in Kawasaki disease. Both the ESR and CRP should be measured, if possible, because of the potential for discordance of the values. In patients who have already been treated with intravenous immune globulin (IVIG), ESR is not useful as a marker of ongoing inflammation since an elevation can be the result of the IVIG therapy itself. A characteristic in the subacute stage of illness is thrombocytosis, with platelet counts ranging from 500 000 to >1 million/mm3. This peaks in about the third week and gradually returns to normal by 4-8 weeks after onset of illness. Mild to moderate elevations in serum transaminases occur in ≤40% of patients and mild hyperbilirubinemia in about 10%. Hypoalbuminemia and hyponatremia are common and are associated with more severe and more prolonged acute disease. Urinalysis reveals mild to moderate sterile pyuria in about one third of patients. If patients with Kawasaki disease undergo lumbar puncture, approximately half show evidence of aseptic meningitis with a predominance of mononuclear cells, as well as normal glucose and protein levels (10,12).

Laboratory tests can provide diagnostic support in patients whose clinical presentation is suggestive of but not diagnostic of Kawasaki disease. A moderately to markedly elevated CRP (≥3 mg/dl) or ESR (>40 mm/hr), for example, is nonspecific but is nearly universally seen in Kawasaki disease while unlikely in viral infections. Past experience suggests that Kawasaki disease is unlikely if platelet counts and acute phase reactants are normal after day 7 of fever. It is important to remember that in young infants the manifestations of Kawasaki disease can be very subtle and difficult to recognize. Thus, the American Heart Association (AHA) published an algorithm to assist in making the diagnosis in these complicated patients (10).

Pathogens

Although the etiology of Kawasaki disease remains elusive, clinical and epidemiologic features strongly suggest an infectious cause. Laboratory features also suggest an infectious agent as the cause of the inflammation. Kawasaki disease is a generalized vasculitis affecting medium-sized arteries throughout the body, preferentially involving the coronary arteries. An influx of neutrophils is found early after onset with a rapid transition to large mononuclear cells in concert with CD8 lymphocytes and IgA plasma cells. Active inflammation is replaced over several weeks to months by progressive fibrosis, with scar formation. A self-limited, generally nonrecurring illness that manifests itself by fever fits well with an infectious etiology or trigger. However, despite extensive efforts to identify an infectious agent in Kawasaki disease with conventional bacterial and viral cultures and serologic methods, researchers have not yet been successful but are making progress. Recent investigations have discovered that the immune response in Kawasaki disease is oligoclonal (antigen driven, i.e., similar to a response to a conventional antigen) rather than polyclonal, and immunoglobulin A (IgA) plasma cells play a central role. The prominence of IgA plasma cells in the respiratory tract of fatal acute stage Kawasaki disease patients, similar to findings in fatal viral respiratory infections, suggests a respiratory pathogen, and viral-like particles as well as intracytoplasmic inclusions have been identified in bronchial epithelial cells (11,12).

SUSCEPTIBILITY IN VITRO AND IN VIVO

Not applicable.

ANTIMICROBIAL THERAPY

No antimicrobial agents exist for Kawasaki disease.

ADJUNCTIVE THERAPY

IVIG Plus Aspirin

The current standard therapy for Kawasaki disease is a combination of aspirin and IVIG. In 1983, Japanese investigators reported that children with Kawasaki disease treated with IVIG had faster resolution of fever and developed fewer coronary-artery abnormalities than historical controls. A multicenter randomized trial in the U.S. showed that children treated with IVIG and high-dose aspirin had significantly faster resolution of fever and other inflammatory markers than children treated with high dose aspirin alone and confirmed that coronary artery abnormalities were reduced by about 85%. Subsequent studies have confirmed that initial therapy with IVIG and high dose aspirin should be the standard therapy for Kawasaki disease. During the acute phase of illness, aspirin is administered at 80-100 mg/kg per day in 4 doses with IVIG. High-dose aspirin and IVIG appear to have an additive anti-inflammatory effect. Most clinicians continue high-dose aspirin until day 14 of illness if the child remains afebrile. When high-dose aspirin is discontinued, therapy is continued with low-dose aspirin at 3-5 mg/kg per day until the patient shows no evidence of coronary changes by 6-8 weeks after the onset of illness. This applies to children who have no coronary abnormalities on initial echocardiogram. For children who develop coronary abnormalities, aspirin or clopidogrel (Plavix) may be continued indefinitely. Aspirin has anti-inflammatory properties at high doses and antiplatelet activity at low doses but alone does not appear to lower the frequency of the development of coronary abnormalities. Because Reye syndrome is a risk in children who take salicylates while they are infected with varicella or influenza, parents should be instructed to contact their child’s physician immediately if the child develops symptoms of or is exposed to influenza or varicella (2,10,12).

The efficacy of IVIG in reducing the prevalence of coronary artery abnormalities in Kawasaki disease is well established despite the fact that the mechanism of action is unknown. IVIG appears to have a generalized anti-inflammatory effect. Patients with Kawasaki disease should be treated with IVIG, 2 g/kg in a single infusion together with high-dose aspirin. Whenever possible, this therapy should be started within the first 10 days of illness, with the first day of fever considered the first day of illness. IVIG should also be considered for children presenting with Kawasaki disease after the 10th day of illness if they have persistent fever with no other explanation or evidence of ongoing inflammation such as elevated ESR or CRP, with or without coronary abnormalities. Measles and varicella immunizations should be deferred for 11 months after a child receives IVIG. Even when treated appropriately within the first 10 days of illness, approximately 5% of children with Kawasaki disease develop some coronary artery dilation and 1% develop giant aneurysms, defined as greater than 8 mm internal diameter (10).

Corticosteroids

Despite steroids being highly effective in treating other forms of vasculitis, their use in Kawasaki disease has been limited. Although early studies showed a possible detrimental effect of steroids, subsequent studies have shown neither clear benefit nor definite ill effects. A recent study examined the effect of adding a 30 mg/kg dose of IV methylprednisolone to the initial 2 gm/kg dose of IVIG and aspirin on coronary artery outcomes. The results did not support the addition of a single pulsed dose of steroids to conventional therapy because no significant effect was seen on the development of coronary artery abnormalities. However, there was a potential benefit in the small subset of patients who required retreatment with IVIG because of persistent or recurrent fever and were therefore more at risk for coronary abnormalities (9). More studies will need to be performed in order to delineate this further.

Failure of Therapy

Approximately 10% of patients with Kawasaki disease fail to respond to initial IVIG therapy. Failure to respond is usually defined as persistent or recrudescent fever ≥36 hours after completion of the initial IVIG infusion. Most experts recommend retreatment with IVIG at the same dose. Treatment of patients with true IVIG-refractory Kawasaki disease, defined as persistent fevers and/or elevated inflammatory markers despite having received 2 courses of IVIG, is controversial. There is no universally accepted “next step” in therapy. Some clinicians use a third dose of IVIG. Pulse methylprednisolone has also been used to treat patients who are IVIG refractory and has been shown to reduce fever, but the effect of steroids on development of coronary abnormalities is still uncertain. The most commonly used steroid regimen for highly refractory Kawasaki disease is intravenous pulse methylprednisolone, 30 mg/kg for 2-3 hours, administered once daily for 3 days (4).

Alternative Agents

A class of agents that may play a role in the treatment of patients with refractory Kawasaki disease is monoclonal antibodies to proinflammatory cytokines. Serum levels of the pro-inflammatory cytokine tumor necrosis factor (TNF)-α are elevated acutely in patients with Kawasaki disease. A chimeric murine/human IgG1 monoclonal antibody that binds specifically to human TNF-α-1, infliximab (Remicade®), is being studied for treatment of children who fail to become afebrile after initial IVIG treatment. Infliximab is effective in a wide variety of immunologic disorders in which inflammation is mediated by TNF-α. Although its effectiveness in reducing the prevalence of coronary artery aneurysms is still unproven, anecdotal evidence has shown that some patients with refractory Kawasaki disease have responded rapidly and completely to a single infusion of infliximab (3). Therapy with infliximab or other agents directed at TNF-α might be considered as adjunctive therapy in patients who are IVIG refractory. Cytotoxic agents such as cyclophosphamide and methotrexate have been used occasionally for the treatment of refractory Kawasaki disease as they are used widely to treat other severe vasculitides. However, the risk of using these agents may exceed the benefits for the majority of patients, and they are not routinely recommended currently. Because controlled data are lacking, the roles of these adjunctive therapies for IVIG refractory patients remain uncertain. Ongoing research into various treatment modalities is needed to guide clinicians in treating IVIG-refractory patients (3,4,10).

Interventional Measures

Attempts at excision of the coronary artery aneurysm have not been successful and have caused deaths. Surgical management of Kawasaki disease comprises primarily coronary artery bypass grafts for obstructive lesions. Catheter interventions such as balloon angioplasty, rotational ablation, and stent placement have been performed in a relatively small number of children with Kawasaki disease. Catheter intervention for patients with Kawasaki disease should be considered when ischemic symptoms are present and in patients with ≥75% stenosis with or without ischemia in the LAD. Approximately 20 patients with Kawasaki disease have undergone cardiac transplantation for severe myocardial dysfunction, severe ventricular arrhythmias, and severe coronary arterial lesions. This should be considered for individuals with severe, irreversible myocardial dysfunction and coronary lesions for which interventional catheterization procedures or coronary bypass are not feasible (8,10,12).

ENDPOINTS FOR MONITORING THERAPY

Cardiac imaging is a critical part of the evaluation of all patients with suspected Kawasaki disease and echocardiography has been determined to be the ideal imaging modality for cardiac assessment. The initial echocardiogram should be performed as soon as the diagnosis is suspected, but initiation of treatment should not be delayed by the timing of the study. Cardiac evaluation of patients suspected to have Kawasaki disease should focus on imaging the left main coronary artery (LMCA), left anterior descending (LAD), left circumflex coronary artery (LCX), right coronary artery (RCA), and the posterior descending coronary arteries. Maximal efforts should be made to visualize all major coronary segments. The most common sites of coronary aneurysms include the proximal LAD and proximal RCA, followed by the LMCA, then LCX, and finally the distal RCA and the junction between the RCA and posterior descending coronary artery. In addition, assessment of left ventricular function should be part of the echocardiographic evaluation of all patients with suspected Kawasaki disease as some degree of myocarditis is almost universal. This may manifest as chest pain and/or tachycardia that can occur out of proportion to the degree of fever, valvular dysfunction, and EKG changes. The presence of a pericardial effusion is common in Kawasaki disease and should also be noted (10).

Large cohort studies from Japan and North America have established the following features of the natural history of Kawasaki disease. Coronary artery aneurysms occur in 20-25% of untreated children. Other cardiovascular complications include myocarditis, pericarditis with effusion, and valvulitis, the latter occurring in about 1% of patients and most commonly involving the mitral valve. Resolution of aneurysms 1-2 years after onset of the disease has been observed in about 50% of vessels with coronary aneurysms. The likelihood that an aneurysm will resolve is determined in large part by its initial size, with smaller aneurysms having a greater likelihood of regression, and shape, with saccular aneurysms less likely to regress than tubular. Vessels that do not undergo resolution are at risk for later development of stenosis or occlusion by thrombus and/or myointimal proliferation. Rupture of a coronary aneurysm can occur within the first few months after Kawasaki disease, but this is exceedingly rare. The worst prognosis occurs in children with giant aneurysms (≥ 8mm diameter). In these aneurysms, thrombosis is promoted by the sluggish and turbulent blood flow within the dilated vascular space and the frequent occurrence of stenotic lesions at the proximal or distal end of the aneurysms. Myocardial infarction caused by thrombotic occlusion of an abnormal coronary artery is the principal cause of death from Kawasaki disease. The greatest risk of myocardial infarction occurs in the first year after onset of the disease. It is generally believed that if coronary aneurysms are not identified by complete and adequate echocardiograms in the first 1-2 months after diagnosis, it is unlikely that new aneurysms will develop at a later time. Children without known cardiac sequelae during the first month of Kawasaki disease appear to return to their previous state of health, without signs or symptoms of cardiac impairment. However, there is limited evidence of possible long-term endothelial dysfunction in children without obvious coronary involvement, the significance of which is unknown (10,12).

Echocardiography should be performed at the time of diagnosis and then usually at 2 and 6 weeks after disease onset. Children are stratified according to their relative risk of myocardial ischemia. Patient management can then be individualized according to risk level as recommended by the AHA (10). In children at higher risk of coronary abnormalities, such as those with persistent or recurrent fever, or with clear coronary abnormalities, more frequent imaging may be necessary to guide management. Patients without coronary artery changes on echo at any stage of the illness should still be counseled periodically about cardiovascular risk factors (e.g., hypertension, diet, exercise) since the future risk for atherosclerotic heart disease in this category of patients is still undetermined.

Patients who have small solitary aneurysms should take long-term aspirin therapy until the aneurysms regress and should be followed by a pediatric cardiologist or other physician experienced in the management of Kawasaki disease. Patients who have giant aneurysms or multiple complex aneurysms should be considered for long term antiplatelet therapy and anticoagulation therapy. The choice of regimen depends on the degree of coronary enlargement. Regimens include combinations of aspirin, clopidogrel, low molecular weight heparin, and warfarin. Treatment with aspirin is usually sufficient for aneurysms with a maximum dimension of 5 mm, whereas patients with giant aneurysms are generally treated with a combination of aspirin or clopidogrel and warfarin, aiming for an INR of 2.0 to 2.5, or low molecular weight heparin. These severely affected patients should be followed by a cardiologist and have echocardiograms, EKGs, and stress tests performed at regular intervals. Other noninvasive tests may be widely used in the future to assess coronary stenoses, aneurysms, and occlusions. Multislice spiral computed tomography (MSCT) has been used successfully to image the distal segments of coronary arteries in adolescents and young adults to identify small areas of stenosis and aneurysm. Coronary MR angiography (CMRA) also has been shown to define coronary artery aneurysms accurately as well as thickened vessel walls in free-breathing sedated children. In the future, these tests may be useful noninvasive alternatives for children who would otherwise need frequent catheterizations as they grow older (5,10).

VACCINES

No vaccines are available for Kawasaki disease.

PREVENTION OR INFECTION CONTROL MEASURES

Not applicable.

CONTROVERSIES, CAVEATS, OR COMMENTS

Some patients do not fulfill the clinical criteria for Kawasaki disease and are diagnosed based on echocardiographic findings of coronary artery abnormalities. Therefore, the conventional diagnostic criteria should be viewed as guidelines to prevent overdiagnosis but may result in failure to recognize incomplete forms of Kawasaki disease. Incomplete, or atypical, Kawasaki disease is more common in young infants than in older children, making accurate diagnosis especially important because these patients are at higher risk of developing coronary abnormalities. Echocardiography is also useful in diagnosing patients with Kawasaki disease who only have some of the classic features. Although aneurysms rarely form before day 10 of illness, pericardial effusion, mitral regurgitation, decreased LV function and/or echo-brightness of the coronary artery wall (which may be evidence of arteritis) can be present in the acute stage of Kawasaki disease before the formation of aneurysms and can help clinicians recognize incomplete Kawasaki disease patients. Incomplete Kawasaki disease should be considered in all infants and children with unexplained fever for ≥5 days associated with only 2 or 3 of the principal clinical features of Kawasaki disease. In addition, supplemental lab criteria including hypoalbuminemia, anemia, elevated transaminases, and urinalysis showing pyuria can be used to support the diagnosis. Because young infants may present with fever and little else, echocardiography should be considered in any infant aged <6 months with fever of ≥ 7 days’ duration, laboratory evidence of systemic inflammation, and no other explanation for the febrile illness (10,12).

Exciting advances have been made by Rowley and colleagues towards discovering the etiologic agent of Kawasaki disease. By studying tissue samples from fatal cases of Kawasaki disease, it was found that oligoclonal IgA plasma cells infiltrate inflamed tissues, including coronary arteries. Synthetic versions of these oligoclonal antibodies bind to an antigen in acutely Kawasaki disease-inflamed ciliated bronchial epithelium but not in ciliated bronchial epithelium from infant controls. Both light and electron microscopy studies have demonstrated that the antigen is localized to cytoplasmic inclusion bodies in tissues inflamed by acute Kawasaki disease. The presence of these inclusion bodies and their composition and appearance are highly suggestive of infection with an intracellular pathogen, such as a virus (11).

Recent studies have focused on identifying risk factors for IVIG-refractory Kawasaki disease in order to be able to predict which children may not respond. In one such study, a high band count, low serum albumin, and presence of coronary artery abnormalities at diagnosis were seen significantly more often in non-responders (1). In addition, an elevated CRP, total bilirubin, and aspartate aminotransferase (AST) have been seen more often in IVIG non-responders. Work is underway to develop a reliable scoring model to accurately predict who will become a nonresponder. However, a question remains as to the appropriate therapy in patients whose scores predict high risk for IVIG unresponsiveness (6).

Although great progress has been made in the treatment of Kawasaki disease, much is left to learn about the etiology of the illness. Until an etiologic agent is identified and a diagnostic test is devised, children with Kawasaki disease will still be misdiagnosed (underdiagnosed and overdiagnosed) and some with Kawasaki disease will go untreated, with resultant potentially serious morbidity or even mortality. Priorities for research are the development of a diagnostic test, identification of genetic markers of susceptibility to Kawasaki disease, identification of prognostic factors, development of improved therapies, and of course, discovering the etiology of Kawasaki disease. The ultimate goal of Kawasaki disease research is to prevent the grave cardiac consequences and critical to this is the elucidation of the causative agent.

REFERENCES

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