Chapter 488. Kawasaki Disease

Mary Beth Son; Jane W. Newburger

Kawasaki Disease: Introduction

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 2006.3-5 In addition to endemic disease, 3 epidemics of KD occurred in Japan in 1979, 1982, and 1986, with an incidence of 196.1 KD 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 recent surveys have revealed an increase in the incidence of KD.4,5 The incidence of KD in Japan from 2005 to 2006 was 184.6 per 100,000 in children younger than 5 years of age.3 The highest incidence of KD was in children younger than 1 year of age, with a peak incidence of 6 to 8 months, and cardiac abnormalities occurred most commonly in infants and in children older than 4 years.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. A subsequent study of KD in Hawaiian children revealed an incidence higher than the national findings, with an incidence of 45.2 per 100,000 children less than 5 years of age from 1996 to 2001.7 Furthermore, that study revealed a striking discrepancy amongst ethnicities in patients less than 5 years of age, with an incidence of 35.3 per 100,000 white children and 70.9 per 100,000 Asian and Pacific Islander children residing in Hawaii. The incidence of KD in Japanese Americans living in Hawaii was 197.7 per 100,000 children, higher than the incidence in Japan during the last epidemic. Siblings of patients with KD may be at higher risk for developing the disease,8 and parents of affected children in Japan are twice as likely to have a history of KD themselves.9 These findings are consistent with the hypothesis that KD results from unidentified environmental triggers in genetically susceptible hosts.

Risk factors for poor coronary artery outcomes have been identified in a number of studies. Using the CDC passive surveillance system for Kawasaki disease, Belay et al. 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.10 One study posited that African American ethnicity is protective against the development of coronary artery aneurysms.11 Furthermore, 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.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). 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.13-29 However, no single etiologic agent has emerged as the clear culprit. Rowley and colleagues have posited that KD is likely caused by either a single infectious agent or a group of closely related agents,30 based on their findings of oligoclonal IgA-secreting plasma cells31,32 and cytoplasmic inclusion bodies33 in the respiratory tract of patients with KD.

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. 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.

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,34-40 whereas other studies have shown an absence of V β skewing.41-45 A recent study of serological responses to superantigens revealed an increase in IgM antibodies to multiple toxins, indicating that more than one superantigen could be involved in the pathogenesis of Kawasaki disease.46 Despite the wealth of data regarding superantigens in Kawasaki disease, their role remains controversial.

Studies of other immunologic mechanisms at work in Kawasaki disease, including oligoclonal IgA plasma cells, Toll-like receptors and adaptor proteins,47 CD25+ CD4+ regulatory T cells,48 and genetic variations in interleukin-4 and chemokine (C-C motif) receptor 5,49,50 have yielded intriguing but inconclusive results.

Clinical Features

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

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Table 488-1. Clinical and Laboratory Features of Kawasaki Disease

Epidemiologic Case Definition (classic clinical criteria)

Fever of at least 5 days’ duration

Presence of at least 4 of the following principal features:

Changes in extremities

Polymorphous exanthem

Bilateral conjunctival injection

Changes in the lips and oral cavity

Cervical lymphadenopathy

Exclusion of other diseases with similar findings (eTable 488.1)

Other Clinical Findings

Cardiovascular findings

Congestive heart failure, myocarditis, pericarditis, or valvular regurgitation

Coronary artery abnormalities

Aneurysms of medium-sized noncoronary arteries

Raynaud phenomenon

Peripheral gangrene

Musculoskeletal system

Arthritis, arthralgia

Gastrointestinal tract

Diarrhea, vomiting, abdominal pain

Hepatic dysfunction

Hydrops of the gallbladder

Respiratory tract

Pulmonary nodules and interstitial infiltrates

Pleural effusion

Central nervous system

Extreme irritability

Aseptic meningitis

Peripheral facial nerve palsy

Sensorineuronal hearing loss

Genitourinary system

Urethritis/meatitis

Testicular swelling

Other findings

Erythema and induration at Bacille Calmette-Guerin inoculation site

Anterior uveitis

Desquamating rash in groin

Laboratory findings

Neutrophilia with immature forms

Elevated erythrocyte sedimentation rate

Elevated C-reactive protein

Elevated serum α1-antitrypsin

Anemia

Abnormal plasma lipids

Hypoalbuminemia

Thrombocytosis after first week

Sterile pyuria

Elevated serum transaminases

Pleocytosis of cerebrospinal fluid

Leukocytosis in synovial fluid

Reprinted with permission from 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;110:2747-2771.

Figure 488-1.

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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.

Kawasaki disease (KD) is a vasculitis, and its principal features indicate systemic inflammation, likely incited in part by tumor necrosis factor and interleukin-1. 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. Anterior uveitis, detected by a slit lamp examination, also occurs in the acute phase of the disease. 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.13 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.

Differential Diagnosis

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.

eTable 488.1. Differential Diagnosis of Kawasaki Disease: Diseases and Disorders with Similar Clinical Findings

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eTable 488.1. Differential Diagnosis of Kawasaki Disease: Diseases and Disorders with Similar Clinical Findings

Viral infections (eg, measles, adenovirus, enterovirus, Epstein Barr virus)

Scarlet fever

Staphylococcal scalded skin syndrome

Toxic shock syndrome

Bacterial cervical lymphadenitis

Drug hypersensitivity reactions

Stevens-Johnson syndrome

Juvenile rheumatoid arthritis

Rocky Mountain spotted fever

Leptospirosis

Mercury hypersensitivity reaction (acrodynia)

*Reprinted with permission from Circulation. 2004; 110:2747-2771.

Complicating the diagnosis of Kawasaki disease (KD) is the finding that up to one third of patients with KD have confirmed intercurrent illnesses.51-53 Additionally, patients with KD frequently present with nonspecific symptoms. Thus, the examining physician should not discount the possibility of KD in a patient with nonspecific complaints if stigmata of this disease are present. Furthermore, any child with unexplained fevers for 5 or more days should be evaluated for KD.

Diagnostic Evaluation

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. 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.14 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, include transaminitis, hyperbilirubinemia, elevated plasma gamma-glutamyl transpeptidase, hypoalbuminemia, and sterile pyuria (Table 488-1).

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.

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, adjusted for body surface area, 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. 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 (Fig. 488-1). 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.

Treatment

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.

Aspirin was the first agent to be used in the treatment of KD, and subsequent studies evaluating the efficacy of IVIG and other treatments have included aspirin in the treatment regimen.54,55 However, the use of aspirin alone does not decrease the frequency of coronary artery lesions.56,57 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. There is practice variation among experts in the field with respect to the duration of high-dose aspirin use. Most commonly, low-dose aspirin is instituted after the patient has been afebrile for 48 hours, but some centers continue high-dose aspirin until the child is both afebrile and beyond day 14 of illness, whichever is longer. 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.16,60-66 The 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. Other treatments include intravenous methylprednisolone, oral corticosteroids, cyclophosphamide, cyclosporine, methotrexate, and plasma exchange.66-72 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.

Complications

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 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 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. 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.79 Presently, z scores are available only for the left main coronary artery, the left anterior descending coronary artery, and the right coronary artery. 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. 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).

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. 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 Rarely, stenotic lesions can give rise to new aneurysm formation years after disease resolution secondary to hemodynamic factors such as sheer stress.82 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.83

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 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.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,90,91 and cardiac biopsies92-94 as well as nuclear imaging studies95,96 have shown that myocarditis is extremely common. Indeed, myocarditis and arrhythmias are the leading causes of death in the first week of Kawasaki disease, and children with acute Kawasaki disease occasionally present in cardiogenic shock.2 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. Some studies report endothelial dysfunction in these patients,99,100,103 whereas others found normal arterial reactivity and no evidence of arterial stiffness.104,105 Lastly, 2 studies have shown that myocardial flow reserve is altered in patients with Kawasaki disease regardless of coronary artery status.106,107

Long-Term Management

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 Because even patients who never had coronary abnormalities may be at higher risk for later atherosclerotic coronary artery disease, preventive cardiology assessment and counseling is of paramount importance. 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

eTable 488.2. Risk Stratification

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eTable 488.2. Risk Stratification

Risk Level

Pharmacologic Therapy

Physical Activity

Follow-up and Diagnostic Testing

Invasive Testing

I (No coronary artery changes at any stage of illness)

None beyond initial 6 to 8 weeks

No restrictions beyond initial 6 to 8 weeks

Cardiovascular risk assessment and counseling at 5-year intervals

None recommended

II (Transient coronary artery ectasia that disappears within initial 6 to 8 weeks)

None beyond initial 6 to 8 weeks

No restrictions beyond initial 6 to 8 weeks

Cardiovascular risk assessment and counseling at 3- to 5-year intervals

None recommended

III (Small to medium solitary coronary artery aneurysm)

Low-dose aspirin (3 to 5 mg/kg per day), at least until aneurysm regression is documented.

For patients in first decade of life, no restriction beyond initial 6 to 8 weeks. For second decade, physical activity guided by stress testing every other year. Contact or high-impact sports discouraged for patients on antiplatelet agents.

Annual cardiology follow-up with echocardiogram and ECG, combined with cardiovascular risk assessment and counseling. Stress testing with radioisotope perfusion scan or stress echocardiogram every other year.

Angiography, if noninvasive test suggests ischemia

IVa (One or more large or giant coronary artery aneurysms), or

Long-term antiplatelet therapy and warfarin (target INR 2.0–2.5) or LMW heparin (target: antifactor Xa level 0.5–1.0 units/mL) should be combined in giant aneurysms.

Contact or high-impact sports, isometrics, and weight training should be avoided because of the risk of bleeding. Other physical activity recommendations guided by outcome of stress testing or myocardial perfusion scan.

Biannual follow-up with echocardiogram and ECG. Annual pharmacologic or exercise stress testing.

Initial angiography at 6 to 12 months. Repeated angiography if noninvasive test, clinical or laboratory findings suggest ischemia. Elective repeated angiography under some circumstances (see text).

IVb (Multiple or complex aneurysms, without obstruction)

V (Coronary artery obstruction)

Long-term low-dose aspirin. Warfarin or LMW heparin if giant aneurysm persists. Use of beta-blockers should be considered to reduce myocardial oxygen consumption

Biannual follow-up with echocardiogram and ECG. Annual pharmacologic or exercise stress testing.

Angiography is recommended to address therapeutic options.

INR, International Normalized Ratio; LMW, low molecular weight.

Reprinted with permission from Circulation. 2004;110:2747-2771.

References

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Chapter 488. Kawasaki Disease

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Kawasaki Disease: Introduction

Epidemiology and Specific Populations at Risk

Pathophysiology and Genetics

Clinical Features

Figure 488-1.

Differential Diagnosis

Diagnostic Evaluation

Treatment

Complications

Long-Term Management

References

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