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Kawasaki disease, an acute febrile illness of childhood, was described in Japan in 1967 by Dr. Tomasaku Kawasaki as the mucocutaneous lymph node syndrome. A vasculitis of medium-sized vessels, Kawasaki disease 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%. Nonetheless, Kawasaki disease is the leading cause of acquired heart disease in children in North America and Japan. Furthermore, the etiology of Kawasaki disease remains elusive, impeding the development of targeted therapy and diagnostic testing.
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EPIDEMIOLOGY AND SPECIFIC POPULATIONS AT RISK
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The Japanese Ministry of Health collects epidemiologic data on Kawasaki disease every 2 years with nationwide surveys and has done so since 1970. In total, approximately 300,000 cases of Kawasaki disease were reported in Japan between 1970 and 2012. In addition to endemic disease, 3 epidemics of Kawasaki disease occurred in Japan in 1979, 1982, and 1986, with an incidence of 196.1 cases per 100,000 children less than 5 years of age in 1982, the most severe of the epidemics. Interestingly, there have been no recent epidemics, but surveys reveal a steady increase in the incidence of Kawasaki disease. The incidence of Kawasaki disease in Japan in 2012 was 264.8 per 100,000 in children younger than 5 years of age, the highest reported incidence to date.
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In contrast to Japan, rates of Kawasaki disease in the United States have been stable for approximately the past 2 decades. The hospitalization rates for Kawasaki disease in the United States were 19 per 100,000 children less than 5 years of age in 2009, 19.6 per 100,000 children in 2003, and 17.5 per 100,000 children in 1997. Children of Asian and Pacific Islander heritage have consistently higher hospitalization rates in the United States, a finding consistent with the hypothesis that Kawasaki disease results from unidentified environmental triggers in genetically susceptible hosts. Furthermore, siblings of patients with Kawasaki disease may be at higher risk for developing the disease, and parents of affected children in Japan are twice as likely to have a history of Kawasaki disease themselves.
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RISK FACTORS FOR POOR OUTCOMES
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Risk factors for poor coronary artery outcomes have been identified in a number of studies. A study using the Centers for Disease Control and Prevention (CDC) passive surveillance system for Kawasaki disease found that coronary artery aneurysms were significantly associated with age less than 1 year or greater than 9 years, male sex, Asian and Pacific Islander race, and Hispanic ethnicity. A number of investigators have created predictive models to identify risk factors for poor clinical outcome. 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. Increased diameter of the coronary arteries on baseline echocardiogram may also predict the subsequent development of coronary artery aneurysms. In short, younger, sicker children with worse systemic inflammation are at higher risk.
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Despite years of extensive research, the etiology of Kawasaki disease remains unknown. Many aspects of the disease implicate an infectious trigger in the pathogenesis. Kawasaki disease 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 vector borne transmission. Many of the clinical features of Kawasaki disease resemble other childhood infections with exanthems (see below). These observations led to the investigation of many infectious agents as the causative factor, including the Epstein-Barr virus, adenovirus, human coronavirus NL63, human bocavirus, Yersinia pseudotuberculosis, herpesviruses, and others. However, no single etiologic agent has emerged as the clear culprit.
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Similarities between Kawasaki disease and toxin-mediated diseases, such as toxic shock syndrome and streptococcal toxic shock syndrome, suggest that the features of Kawasaki disease are mediated by superantigens. Superantigens are proteins that can bind to the major histocompatibility complex on antigen-presenting cells and to T-cell receptors at sites other than conventional peptide-binding clefts, enabling simultaneous activation of many T cells. Binding of the T cell occurs at the variable region of the β chain (V β region). The resultant massive release of cytokines likely produces many of the features of toxic shock syndrome, streptococcal toxic shock syndrome, and other toxin-mediated syndromes.
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Detection of superantigen activity is best determined by V β skewing, which is the finding of a disproportionate number of T cells that express a particular family of V β T-cell receptor genes. However, studies of T cells and attempts at isolating superantigen-producing bacteria in Kawasaki disease patients have yielded conflicting results, as some studies have found evidence of V β skewing in the peripheral blood, the intestinal wall mucosa, and coronary arteries, whereas other studies have shown an absence of V β skewing. A study of serologic responses to superantigens revealed an increase in immunoglobulin (Ig) M antibodies to multiple toxins, indicating that more than 1 superantigen could be involved in the pathogenesis of Kawasaki disease. Despite the wealth of data regarding superantigens in Kawasaki disease, their role remains controversial.
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Studies of other immunologic mechanisms at work in Kawasaki disease, including oligoclonal IgA plasma cells, toll-like receptors and adaptor proteins, CD25+/CD4+ regulatory T cells, and genetic variations in interleukin-4 and chemokine (C-C motif) receptor 5, have yielded intriguing but inconclusive results.
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Genome-wide association studies have identified susceptibility genes to Kawasaki disease. For example, polymorphisms in the inositol 1,4,5-triphosphate 3-kinase (ITPKC) gene have been associated with increased risk for Kawasaki disease as well as for development of coronary artery aneurysms, and have been described in Japanese and US populations. ITPKC is a negative regulator of the Ca++/NFAT signal pathway, and polymorphisms lead to sustained activation of T cells and resultant cytokine expression. This mechanism lends validity to the use of cyclosporine (a downregulator of NFAT) as a possible treatment for Kawasaki disease (see Treatment section). Other candidate genes for Kawasaki disease as identified by genome-wide association studies include CASP3, BLK, and FCGR2A. Lastly, associations of single nucleotide polymorphisms in the human leukocyte antigen (HLA) class II region (HLA-DQB2 and HLA-DOB) with Kawasaki disease have been reported.
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CLINICAL MANIFESTATIONS
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Classic clinical criteria, as well as supportive clinical and laboratory findings, are summarized in Table 482-1. In brief, the epidemiologic case definition of Kawasaki disease 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 Kawasaki disease, 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 Kawasaki disease is particularly challenging, the American Heart Association recommendations, endorsed by the American Academy of Pediatrics, provide an algorithm for evaluation and treatment of suspected incomplete Kawasaki disease (Fig. 482-1).
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Kawasaki disease is a vasculitis, and its features indicate systemic inflammation, likely incited in part by tumor necrosis factor and interleukin-1. Fever is the hallmark of Kawasaki disease. Children with Kawasaki disease 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 3 to 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 Kawasaki disease patients may appear and subside at differing times over the course of illness, highlighting the importance of a complete medical history.
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More than 90% of children with Kawasaki disease develop bilateral, marked conjunctival injection in a limbal sparing pattern. Anterior uveitis, detected by a slit lamp examination, also occurs in the acute phase of the disease. Patients with Kawasaki disease develop mucosal changes in their oropharynx; diffuse erythema of the oropharynx, a strawberry tongue, and cracked, reddened lips are characteristic of Kawasaki disease, 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 Kawasaki disease include erythema of the palms and soles, as well as edema of the hands and feet. In the convalescent phase of Kawasaki disease, usually 2 weeks after fever onset, periungual peeling occurs on the fingers, followed by the toes. The least common manifestation of Kawasaki disease is cervical lymphadenopathy, specifically a single large (> 1.5 cm) unilateral node or, by computed tomography or ultrasound, a cluster of nodes, that is usually nontender, without erythema or warmth. Diffuse lymphadenopathy is more likely explained by another diagnosis.
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A variety of signs and symptoms may support the diagnosis of Kawasaki disease. Patients with Kawasaki disease are usually irritable, perhaps reflecting central nervous system inflammation. Children with Kawasaki disease may complain of arthralgias; reported rates of frank arthritis range from 7.5% to 31% in Kawasaki disease patients.Although large joints of the lower extremities are most likely to be involved, small-joint arthritis has been reported as well. Gastrointestinal 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. Possible etiologies for acalculous distension of the gallbladder include vasculitis, serositis, or compression of the cystic duct by inflamed mesenteric lymph nodes.
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As fever and rash are the most common features of Kawasaki disease, the differential diagnosis is dominated by infectious diseases of childhood (Table 482-2). Common viral infections such as adenovirus, enterovirus, and Epstein-Barr virus can mimic Kawasaki disease. As the rash of Kawasaki disease is frequently morbilliform, measles is a differential diagnosis but is less commonly encountered in developed countries due to 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 Kawasaki disease. The toxin-mediated shock syndromes are characterized by hemodynamic instability that is also seen in Kawasaki disease shock syndrome, a recently described entity whereby children present with signs of Kawasaki disease as well as prominent hypotension, requiring vasoactive medications and/or transfer to a higher level of care. Drug hypersensitivity syndromes, including Stevens-Johnson syndrome, are also possible. In some children who appear at first to have Kawasaki disease with fever, rash, joint pain, and coronary artery changes may ultimately evolve into systemic-onset juvenile idiopathic arthritis. Rarely, mercury poisoning or acrodynia, with its swollen, erythematous hands and feet, may mimic Kawasaki disease. Although cervical chain lymphadenopathy is the least common manifestation of Kawasaki disease, it can be the presenting symptom in lymph node–first Kawasaki disease. In this scenario, children are treated for presumed bacterial lymphadenitis but do not defervesce with appropriate antimicrobials and typically develop other signs of Kawasaki disease during their clinical course.
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Complicating the diagnosis of Kawasaki disease is the finding that up to one-third of patients have confirmed intercurrent illnesses. Additionally, patients with Kawasaki disease frequently present with nonspecific symptoms. Thus, the examining physician should not discount the possibility of Kawasaki disease in a patient with nonspecific complaints if stigmata of this disease are present.
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Importantly, any child < 6 months of age with unexplained fevers for 7 or more days and signs of systemic inflammation on laboratory studies should be evaluated with an echocardiogram, as incomplete Kawasaki disease is more likely in infants who are also at higher risk for poor coronary artery outcomes. Early identification and treatment of these infants are critical to decrease long-term morbidity from coronary artery aneurysms.
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Laboratory studies in patients with Kawasaki disease 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. Thrombocytopenia in the early phase of Kawasaki disease may be a sign of consumption or evidence of an activated endothelium with platelet adherence, and has been identified as a poor prognostic factor. Inflammatory markers are nearly always elevated in Kawasaki disease, with the erythrocyte sedimentation rate usually greater than or equal to 40 mm/h 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 at diagnosis. Assessment of systemic inflammation following treatment with intravenous immunoglobulin should include C-reactive protein only, as the erythrocyte sedimentation rate will be elevated due to the intravenous immunoglobulin and should not be interpreted as a sign of worsening inflammation. Further supportive laboratory findings include transaminitis, hyperbilirubinemia, elevated plasma gamma-glutamyl transpeptidase, hypoalbuminemia, and sterile pyuria (see Table 482-1).
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ELECTROCARDIOGRAPHY AND PLAIN RADIOGRAPHS OF THE CHEST
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Electrocardiography in patients with Kawasaki disease may reveal sinus tachycardia, prolongation of the PR and QT intervals, or nonspecific ST- and T-wave changes. Plain radiographs of the chest tend to be unrevealing, although rare children have pulmonary infiltrates or effusions. Cardiomegaly is rarely present in the acute phase.
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Echocardiography is the cornerstone of diagnosis of coronary artery abnormalities in children with Kawasaki disease. Taken together with Doppler imaging, echocardiographic imaging is also used to assess mitral and, more rarely, aortic regurgitation, left ventricular function, and pericardial effusion.
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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. The widely used 1984 Japanese Ministry of Health criteria for coronary artery aneurysms include any of the following: an internal lumen diameter of greater than 3 mm in children less than 5 years of age or greater than 4 mm in children 5 years of age or older, an internal lumen diameter that is greater than or equal to 1.5 times that of an adjacent segment, or a coronary lumen that is clearly irregular. Many natural history studies of coronary aneurysms in the Japanese literature are based on these definitions. In a more recent revision of the Japanese Ministry of Health criteria, the size of an aneurysm is classified according to internal lumen dimensions: small, ≤ 4 mm; medium, > 4 to ≤ 8 mm; and giant, > 8 mm. For children age ≥ 5 years, aneurysm size can also be determined by the ratio of the internal diameter compared to an adjacent segment: small, 1.5×; medium, 1.5× to 4×; and giant, > 4×.
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Coronary artery dimensions are related to body size, and use of z-scores has demonstrated that the Japanese Ministry of Health criteria underestimate the prevalence of coronary artery dilation in Kawasaki disease patients. Aneurysms are considered small when z-scores are ≥ 2.5 to < 5, medium if z-scores are ≥ 5 to < 10, and large if z-scores are either ≥ 10. Coronary artery z-scores are considered in the American Heart Association criteria for treatment of suspected incomplete Kawasaki disease (see below), as well as for choice of antithrombotic agents. There are 3 coronary artery z-score calculators in common use in North America. At larger coronary dimensions, these calculators can vary considerably in their calculated z-scores, potentially affecting therapeutic decisions about the need for anticoagulation. Moreover, the z-score calculators do not apply to all arterial segments (eg, the distal right coronary, distal left anterior descending, and the posterior descending arteries). For this reason, classification of coronary aneurysms continues to rely on both z-scores and Japanese Ministry of Health criteria.
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At the time of presentation, within the first 10 days of illness, children with Kawasaki disease have enlarged coronary artery dimensions, adjusted for body surface area, compared to afebrile normal children. In addition to coronary artery enlargement, arterial walls may appear bright, and the arteries may not taper normally. Abnormalities on echocardiography form an important criterion for intravenous immunoglobulin treatment of children with suspected Kawasaki disease with incomplete criteria (see Fig. 482-1). Echocardiography should be performed at the time of diagnosis, at 2 weeks, and then approximately 5 to 6 weeks after illness onset. Children with documented coronary artery abnormalities or persistent fever require more frequent imaging surveillance; more aggressive anti-inflammatory therapy is initiated in those with expanding aneurysms. In addition, echocardiographic surveillance as often as twice weekly may be prudent for detection of coronary thrombosis in children with giant aneurysms who are early in the disease.
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Standard Therapy: Intravenous Immunoglobulin and Aspirin
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Once the diagnosis of Kawasaki disease has been established, intravenous immunoglobulin (IVIG) should be administered at a dose of 2 g/kg over 8 to 12 hours. Treatment with IVIG should be instituted no later than day 10, and ideally by day 7, of illness; the first day of fever in Kawasaki disease 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. In general, IVIG is well tolerated. Use of premedications (diphenhydramine and acetaminophen) and using a slow rate of administration decrease infusion reactions. IVIG-related hemolysis is dependent on dose and recipient blood type (non-O is protected).
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Aspirin was the first agent to be used in the treatment of Kawasaki disease, and subsequent studies evaluating the efficacy of IVIG and other treatments have included aspirin in the treatment regimen. However, the use of aspirin alone does not decrease the frequency of coronary artery lesions. Aspirin is recommended in medium (30–50 mg/kg/d divided into 4 doses) or high doses (80–100 mg/kg/d divided into 4 doses) for anti-inflammatory effects followed by low-dose aspirin (3–5 mg/kg/d) for antiplatelet effects. There is practice variation among experts in the field with respect to the duration of medium- to high-dose aspirin use. Most commonly, low-dose aspirin is instituted after the patient has been afebrile for 48 hours, but some centers continue higher dose aspirin until the child is both afebrile and beyond day 14 of illness, whichever is longer. Most children with Kawasaki disease are maintained on low-dose aspirin therapy until 6 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 Kawasaki disease; the risks conferred by daily low-dose aspirin as chronic therapy are uncertain, although likely very low. 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 live vaccines, including the measles and varicella immunizations, should be delayed for 11 months after IVIG treatment, as it may render the vaccines less immunogenic.
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Rescue Therapy and Primary Intensification
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Two strategies have been implemented to decrease the incidence of coronary artery aneurysms in children with Kawasaki disease. One strategy is to administer “rescue therapy” to the approximately 15% to 20% of patients who have persistent or recrudescent fever after a single dose of IVIG (so-called IVIG resistance). Importantly, the subset of patients with IVIG resistance is at increased risk for developing coronary artery abnormalities. 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. Infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α, has been used in the IVIG-resistant population and is reported to shorten fever duration and hospital days. However, there is no evidence to demonstrate that use of infliximab in IVIG resistance reduces the prevalence of coronary aneurysms. Other treatments include intravenous methylprednisolone, oral corticosteroids, and cyclosporine. In severe cases, cyclophosphamide and plasma exchange can be considered.
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Primary Intensification
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As coronary artery aneurysms develop dynamically with peak coronary artery dimensions typically in the first 6 weeks of illness, the need to aggressively treat coronary artery inflammation early in the course of disease seems paramount. Accordingly, intensification of primary treatment (ie, treatment administered with the first dose of IVIG) has also been implemented as a strategy to improve coronary artery outcomes. Unfortunately, North American trials of primary intensification have not yielded positive results. Adding a single dose of methylprednisolone (30 mg/kg) to initial IVIG treatment did not lead to improvement of coronary artery aneurysms in a multicenter trial. Similarly, a trial of infliximab administered with the initial IVIG dose did not lead to decreased IVIG resistance, the primary end point. In contrast, the RAISE trial (Randomized Controlled Trial to Assess Immunoglobulin plus Steroid Efficacy for Kawasaki Disease) in Japan used corticosteroids (2 mg/kg/d) in a high-risk cohort and demonstrated improved coronary artery outcomes as well as decreased IVIG resistance. It seems likely that North American trials of more intensive primary therapy were negative, in part, because they included unselected Kawasaki disease patients, whereas the Japanese RAISE trial enrolled only children at high risk for aneurysms. Currently in North America, both rescue therapies and approaches to primary intensification remain center dependent and subject to significant variation.
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Virtually all serious morbidity and mortality derive from the cardiac effects of Kawasaki disease. The most important complication of Kawasaki disease 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. Fortunately, a regimen of IVIG and aspirin reduces the rate of coronary lesions to less than 5%, with only 1% of children developing giant aneurysms. The mortality rate in recent studies is less than 0.5%.
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Coronary aneurysms created by the intense inflammatory process in the acute phase of Kawasaki disease evolve in their shape and dimension over years after illness onset. Regression to normal lumen diameter occurs via myofibroblastic proliferation in approximately half of coronary artery aneurysms; 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. Rarely, stenotic lesions can give rise to new aneurysm formation years after disease resolution secondary to hemodynamic factors such as sheer stress. Stenotic lesions are most likely to occur at the points of entrance to or exit from giant aneurysms; patients with small aneurysms are at much lower risk to develop stenosis.
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Myocardial Infarction
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Myocardial infarction occurs most frequently in children with giant aneurysms. 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 increases the risk for thrombus formation in the subacute phase. Although the relative risk of myocardial infarctions is highest in the first year, deaths from myocardial infarction continue to occur late after the onset of illness. Myocardial infarctions may be accompanied by symptoms of pallor, crying, vomiting, and abdominal pain. Children older than 4 years may complain of chest pain. Of note, myocardial infarctions are silent in more than one-third of patients with Kawasaki disease. Rupture of coronary aneurysms is a very rare complication occurring in rapidly expanding, inflamed coronary arteries, usually within the first 6 weeks of illness.
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Other Cardiac Involvement
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Kawasaki disease affects not only the coronary arteries, but also cardiac muscle and heart valves. Children with Kawasaki disease may have depressed left ventricular function by echocardiography in the acute phase of the disease, and cardiac biopsies as well as nuclear imaging studies have shown that myocarditis is extremely common. Indeed, myocarditis and arrhythmias are the leading causes of death in the first week of Kawasaki disease. Mitral regurgitation secondary to valvulitis occurs in approximately 1 in 4 children during the acute phase; late mitral regurgitation results from papillary muscle dysfunction in children with ischemic heart disease. Aortic root dilation and mild aortic regurgitation occur in Kawasaki disease but are usually not progressive.
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Kawasaki disease may produce long-term systemic abnormalities, including diminished reactivity and greater stiffness of the peripheral arteries; increased intimal medial thickness of the carotid arteries; and dyslipidemia. These findings are most pronounced in patients with coronary aneurysms. Data are conflicting on the long-term effects of acute Kawasaki disease on arterial health among patients who never had coronary involvement. Some studies report endothelial dysfunction in these patients, whereas others found normal arterial reactivity and no evidence of arterial stiffness. Two studies have shown that myocardial flow reserve is altered in patients with Kawasaki disease regardless of coronary artery status. Lastly, an unfavorable lipid profile can be found, even among patients in whom coronary involvement has not been detected in any stage of illness.
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The prognosis for children with Kawasaki disease is determined by the extent of coronary artery involvement and consequent risk of myocardial ischemia. For this reason, recommendations for frequency of follow-up and types of testing, exercise, and medications for children after Kawasaki disease are stratified according to their coronary artery status (Table 482-3). Because even patients who never had coronary abnormalities may be at higher risk for later atherosclerotic coronary artery disease, preventive cardiology assessment and counseling are of paramount importance. All children should have a lipid profile 1 year after Kawasaki disease onset. In addition, children and their families should be encouraged to follow a heart-healthy diet, exercise regularly, and avoid smoking.
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