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(Circulation. 2004;110:2747-2771.)
© 2004 American Heart Association, Inc.

AHA Scientific Statement

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

Jane W. Newburger, MD, MPH; Masato Takahashi, MD; Michael A. Gerber, MD; Michael H. Gewitz, MD; Lloyd Y. Tani, MD; Jane C. Burns, MD; Stanford T. Shulman, MD; Ann F. Bolger, MD; Patricia Ferrieri, MD; Robert S. Baltimore, MD; Walter R. Wilson, MD; Larry M. Baddour, MD; Matthew E. Levison, MD; Thomas J. Pallasch, DDS; Donald A. Falace, DMD; Kathryn A. Taubert, PhD

	Abstract

Top Abstract Introduction Epidemiology Etiology and Pathogenesis Pathology Diagnosis Cardiac Findings Treatment Long-Term Follow-Up Summary References

 
Background— Kawasaki disease is an acute self-limited vasculitis of childhood that is characterized by fever, bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, and cervical lymphadenopathy. Coronary artery aneurysms or ectasia develop in 15% to 25% of untreated children and may lead to ischemic heart disease or sudden death.

Methods and Results— A multidisciplinary committee of experts was convened to revise the American Heart Association recommendations for diagnosis, treatment, and long-term management of Kawasaki disease. The writing group proposes a new algorithm to aid clinicians in deciding which children with fever for 5 days and 4 classic criteria should undergo echocardiography, receive intravenous gamma globulin (IVIG) treatment, or both for Kawasaki disease. The writing group reviews the available data regarding the initial treatment for children with acute Kawasaki disease, as well for those who have persistent or recrudescent fever despite initial therapy with IVIG, including IVIG retreatment and treatment with corticosteroids, tumor necrosis factor- antagonists, and abciximab. Long-term management of patients with Kawasaki disease is tailored to the degree of coronary involvement; recommendations regarding antiplatelet and anticoagulant therapy, physical activity, follow-up assessment, and the appropriate diagnostic procedures to evaluate cardiac disease are classified according to risk strata.

Conclusions— Recommendations for the initial evaluation, treatment in the acute phase, and long-term management of patients with Kawasaki disease are intended to assist physicians in understanding the range of acceptable approaches for caring for patients with Kawasaki disease. The ultimate decisions for case management must be made by physicians in light of the particular conditions presented by individual patients.

Key Words: AHA Scientific Statements • vasculitis • aneurysm • diagnosis • therapy

	Introduction

Top Abstract Introduction Epidemiology Etiology and Pathogenesis Pathology Diagnosis Cardiac Findings Treatment Long-Term Follow-Up Summary References

 
Kawasaki disease is an acute, self-limited vasculitis of unknown etiology that occurs predominantly in infants and young children. First described in Japan in l967 by Tomisaku Kawasaki, the disease is now known to occur in both endemic and community-wide epidemic forms in the Americas, Europe, and Asia in children of all races.¹ Kawasaki disease is characterized by fever, bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, and cervical lymphadenopathy. Coronary artery aneurysms or ectasia develop in 15% to 25% of untreated children with the disease and may lead to myocardial infarction (MI), sudden death, or ischemic heart disease.^2,3 In the United States, Kawasaki disease has surpassed acute rheumatic fever as the leading cause of acquired heart disease in children.⁴ Treatment of Kawasaki disease in the acute phase is directed at reducing inflammation in the coronary artery wall and preventing coronary thrombosis, whereas long-term therapy in individuals who develop coronary aneurysms is aimed at preventing myocardial ischemia or infarction.

A new feature of these recommendations is an algorithm for the evaluation and treatment of patients in whom incomplete or atypical Kawasaki disease is suspected (refer to Criteria for Treatment of Kawasaki Disease later in this statement and Figure 1). We attempt to summarize the current state of knowledge of the management of patients with Kawasaki disease. The recommendations are evidence based and derived from published data wherever possible. The levels of evidence on which recommendations are based are classified as follows: level A (highest), multiple randomized clinical trials; level B (intermediate), limited number of randomized trials, nonrandomized studies, and observational registries; and level C (lowest), primarily expert consensus.

View larger version (33K): [in this window] [in a new window]   Figure 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 on day 7 of fever without other explanation should undergo laboratory testing and, if evidence of systemic inflammation is found, an echocardiogram, even if the infants have no clinical criteria. (3) Patient characteristics suggesting Kawasaki disease are listed in Table 1. Characteristics suggesting disease other than Kawasaki disease include exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, or generalized adenopathy. Consider alternative diagnoses (see Table 2). (4) Supplemental laboratory criteria include albumin 3.0 g/dL, anemia for age, elevation of alanine aminotransferase, platelets after 7 d 450 000/mm3, white blood cell count 15 000/mm3, and urine 10 white blood cells/high-power field. (5) Can treat before performing echocardiogram. (6) Echocardiogram is considered positive for purposes of this algorithm if any of 3 conditions are met: z score of LAD or RCA 2.5, coronary arteries meet Japanese Ministry of Health criteria for aneurysms, or 3 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 2–2.5. (7) If the echocardiogram is positive, treatment should be given to children within 10 d of fever onset and those beyond day 10 with clinical and laboratory signs (CRP, ESR) of ongoing inflammation. (8) Typical peeling begins under nail bed of fingers and then toes.

Recommendations for initial evaluation, treatment in the acute phase, and long-term management of patients with Kawasaki disease are intended to assist physicians in understanding the range of acceptable approaches for caring for patients with Kawasaki disease. Where published data do not define well the best medical practices, our report provides practical interim recommendations. Ultimately, management decisions must be individualized to a patient’s specific circumstances.

	Epidemiology

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In the past, Kawasaki disease may have masqueraded as other illnesses, and old reports on infantile polyarteritis nodosa describe pathological findings that are identical to those of fatal Kawasaki disease.^5–8 Kawasaki disease is markedly more prevalent in Japan and in children of Japanese ancestry, with an annual incidence of 112 cases per 100 000 children <5 years old.⁹ In the United States, the incidence of Kawasaki disease has been best estimated from hospital discharge data.^10,11 An estimated 4248 hospitalizations associated with Kawasaki disease occurred in the United States in 2000, with a median age of 2 years.¹⁰ Race-specific incidence rates derived from administrative data indicate that Kawasaki disease is most common among Americans of Asian and Pacific Island descent (32.5/100 000 children <5 years old), intermediate in non-Hispanic African Americans (16.9/100 000 children <5 years old) and Hispanics (11.1/100 000 children <5 years old), and lowest in whites (9.1/100 000 children <5 years old).¹⁰ These estimates are similar to those reported in smaller studies.^12,13 Recent reports have emphasized the occurrence of Kawasaki disease in older children, who may have a higher prevalence of cardiovascular complications related to late diagnosis.^14–16

Rates of recurrence and familial occurrence of Kawasaki disease are best documented in the literature from Japan; these rates may be lower in other races and ethnicities. In Japan, the recurrence rate of Kawasaki disease has been reported to be 3%.¹⁷ The proportion of cases with a positive family history is 1%.^17,18 Within 1 year after onset of the first case in a family, the rate in a sibling is 2.1%, which is a relative risk of 10-fold as compared with the unaffected Japanese population; 50% of the second cases develop within 10 days of the first case.¹⁹ The risk of occurrence in twins is 13%.^19,20 Higher rates of Kawasaki disease in the siblings of index cases and twins suggest a possible role for genetic predisposition that interacts with exposure to the etiologic agent or agents in the environment.^19–22 The reported occurrence of Kawasaki disease in children of parents who themselves had the illness in childhood also supports the contribution of genetic factors.^23–26

In the United States, Kawasaki disease is more common during the winter and early spring months; boys outnumber girls by 1.5 to 1.7:1; and 76% of children are <5 years old.^10,11 Reported associations of Kawasaki disease with antecedent respiratory illness and exposure to carpet-cleaning fluids have not been consistently confirmed.^{12,13,27–30} Other factors that are reportedly associated with Kawasaki disease include having preexisting eczema,³¹ using a humidifier,³⁰ and living near a standing body of water.³²

The case fatality rate in Kawasaki disease in Japan is 0.08%.¹⁷ The standardized mortality ratio (the observed number of deaths divided by the expected number of deaths based on vital statistics in Japan) in patients diagnosed between 1982 and 1992 was 1.25 (95% CI, 0.84 to 1.85) overall and 2.35 (95% CI, 0.96 to 5.19) for boys with cardiac sequelae.³³ In the United States, the in-hospital mortality rate is 0.17% (the investigators used administrative data that may include readmissions for coronary disease).¹⁵ Virtually all deaths in patients with Kawasaki disease result from its cardiac sequelae.³⁴ The peak mortality occurs 15 to 45 days after the onset of fever; during this time well-established coronary vasculitis occurs concomitantly with a marked elevation of the platelet count and a hypercoagulable state.³⁵ However, sudden death from MI may occur many years later in individuals who as children had coronary artery aneurysms and stenoses. Many cases of fatal and nonfatal MI in young adults have been attributed to "missed" Kawasaki disease in childhood.³⁶

	Etiology and Pathogenesis

Top Abstract Introduction Epidemiology Etiology and Pathogenesis Pathology Diagnosis Cardiac Findings Treatment Long-Term Follow-Up Summary References

 
The etiology of Kawasaki disease remains unknown, although clinical and epidemiological features strongly suggest an infectious cause. A self-limited, generally nonrecurring illness that manifests itself by fever, rash, enanthem, conjunctival injection, and cervical adenopathy fits well with an infectious etiology or trigger. The epidemiological features noted above, including age distribution, winter–spring seasonality, occurrence of community outbreaks with wave-like geographic spread, and apparent epidemic cycles, are suggestive of a transmissible childhood disease. The laboratory features also suggest infection. However, efforts to identify an infectious agent in Kawasaki disease with conventional bacterial and viral cultures and serological methods, as well as with animal inoculation, have failed to identify an infectious cause.

An attractive hypothesis is that Kawasaki disease is caused by a ubiquitous infectious agent that produces clinically apparent disease only in certain genetically predisposed individuals, particularly Asians. Its rarity in the first few months of life and in adults suggests an agent to which the latter are immune and from which very young infants are protected by passive maternal antibodies. Because little evidence exists of person-to-person transmission, this hypothesis assumes that most infected children experience asymptomatic infection with only a small fraction developing overt clinical features of Kawasaki disease. The genetic basis of susceptibility is currently unknown.

The hypothesis that Kawasaki disease is related to a bacterial superantigenic toxin has been suggested because of the reported selective expansion of Vß2 and Vß8 T-cell receptor families, but this theory remains controversial.^37–40 A recent prospective multicenter study failed to show a significant difference in the prevalence of toxin-producing strains between patients with Kawasaki disease and febrile controls.⁴¹ Recent investigations support an alternative hypothesis: The immune response in Kawasaki disease is oligoclonal (antigen driven, ie, similar to a response to a conventional antigen) rather than polyclonal (as found typically in superantigen-driven responses), and immunoglobulin A (IgA) plasma cells play a central role.^42–44

It also is possible that Kawasaki disease results from an immunologic response that is triggered by any of several different microbial agents. Support for this hypothesis includes documented infection by different microorganisms in different individual cases, failure to detect a single microbiological or environmental agent after almost 3 decades of study, and analogies to other syndromes caused by multiple agents (eg, aseptic meningitis). This hypothesis is somewhat difficult to reconcile with the distinctive clinical/laboratory picture of Kawasaki disease and with its epidemiological features, however.

Efforts to associate Kawasaki disease with exposure to drugs or to such environmental pollutants as toxins, pesticides, chemicals, and heavy metals have failed, although clinical similarities between Kawasaki disease and acrodynia (mercury hypersensitivity) are notable.

Striking immune perturbations occur in acute Kawasaki disease, including marked cytokine cascade stimulation and endothelial cell activation. The key steps leading to coronary arteritis are still being clarified, but endothelial cell activation, CD68⁺ monocyte/macrophages, CD8⁺ (cytotoxic) lymphocytes, and oligoclonal IgA plasma cells appear to be involved.^43,45 The prominence of IgA plasma cells in the respiratory tract, which is similar to findings in fatal viral respiratory infections, suggests a respiratory portal of entry of an etiologic agent or agents.⁴⁴ Enzymes including matrix metalloproteinases that are capable of damaging arterial wall integrity may be important in the development of aneurysmal dilatation.⁴⁶ Vascular endothelial growth factor (VEGF), monocyte chemotactic and activating factor (MCAF or MCP-1), tumor necrosis factor- (TNF-), and various interleukins also appear to play important roles in the vasculitic process.^47–54

	Pathology

Top Abstract Introduction Epidemiology Etiology and Pathogenesis Pathology Diagnosis Cardiac Findings Treatment Long-Term Follow-Up Summary References

 
Although the coronary arteries virtually always are involved in autopsy cases, Kawasaki disease is a generalized systemic vasculitis involving blood vessels throughout the body. Aneurysms may occur in other extraparenchymal muscular arteries, such as the celiac, mesenteric, femoral, iliac, renal, axillary, and brachial arteries.⁵⁵ The early stages in the formation and development of arteritis in Kawasaki disease have been well studied morphologically in relatively large muscular arteries.⁵⁵ The media of affected vessels demonstrate edematous dissociation of the smooth muscle cells, which is most obvious toward the exterior. Endothelial cell swelling and subendothelial edema are seen, but the internal elastic lamina remains intact. An influx of neutrophils is found in the early stages (7 to 9 days after onset), with a rapid transition to large mononuclear cells in concert with lymphocytes (predominantly CD8⁺ T cells) and IgA plasma cells.^42–45 Destruction of the internal elastic lamina and eventually fibroblastic proliferation occur at this stage. Matrix metalloproteinases are prominent in the remodeling process.⁵⁶ Active inflammation is replaced over several weeks to months by progressive fibrosis, with scar formation.

Arterial remodeling or revascularization may occur in Kawasaki disease with coronary arteritis. Progressive stenosis in the disease results from active remodeling with intimal proliferation and neoangiogenesis; the intima is markedly thickened and consists of linearly arranged microvessels, a layer that is rich in smooth muscle cells, and fibrous layers. Several growth factors are prominently expressed at the inlet and outlet of aneurysms, where they are activated by high shear stress.⁵⁷

During the clinical course of Kawasaki disease, vomiting and abdominal pain are seen often. Kurashige and colleagues described the intestinal tract in 31 fatal cases, but in only 3 patients was mesenteric arteritis found.⁵⁸ Using biopsy specimens of the jejunal mucosa, Nagata et al studied cell surface phenotypes of mononuclear cells and enterocytes.⁵⁹ Both HLA-DR⁺CD3⁺ (activated T cells) and DR⁺CD4⁺ cells (activated helper T cells) were significantly increased in the lamina propria of patients with acute Kawasaki disease as compared with controls. In contrast, CD8⁺ cells (suppressor/cytotoxic T cells) were significantly reduced in both the epithelium and the lamina propria of individuals with Kawasaki disease as compared with controls. During the convalescent phase of the disease, these cell patterns returned to normal.⁵⁹ Hydrops of the gallbladder may be clinically apparent in patients with Kawasaki disease. A study of surgically removed gallbladders revealed a nonspecific severe perivascular inflammatory cell infiltration⁶⁰; distinct arteritis in the gallbladder wall has not been well documented.

Lymphadenopathy, an early finding in patients with Kawasaki disease, usually disappears by autopsy. Pathological findings in lymph nodes include thrombotic arteriolitis and severe lymphadenitis with necrosis.⁵⁵ Lymph node biopsies performed in the first week of the illness revealed abnormal hyperplasia of the endothelium of the postcapillary venule and hyperplasia of reticular cells around the postcapillary venule.¹

	Diagnosis

Top Abstract Introduction Epidemiology Etiology and Pathogenesis Pathology Diagnosis Cardiac Findings Treatment Long-Term Follow-Up Summary References

 
In the absence of a specific diagnostic test or pathognomonic clinical feature, clinical criteria have been established to assist physicians in diagnosing Kawasaki disease. Other clinical and laboratory findings observed in patients with this disease are frequently helpful in diagnosis. Table 1 describes the clinical and laboratory features of Kawasaki disease according to the epidemiological case definition.

View this table: [in this window] [in a new window]   TABLE 1. Clinical and Laboratory Features of Kawasaki Disease

Principal Clinical Findings
The classic diagnosis of Kawasaki disease has been based on the presence of 5 days of fever and 4 of the 5 principal clinical features (see Table 1).³ Typically, all of the clinical features are not present at a single point in time, and watchful waiting is sometimes necessary before a diagnosis can be made. Patients with fever for 5 days and <4 principal features can be diagnosed as having Kawasaki disease when coronary artery disease is detected by 2D echocardiography (2DE) or coronary angiography. In the presence of 4 principal criteria, the diagnosis of Kawasaki disease can be made on day 4 of illness. Kawasaki disease should be considered in the differential diagnosis of a young child with unexplained fever for 5 days that is associated with any of the principal clinical features of this disease.

The fever typically is high spiking and remittent, with peak temperatures generally >39°C (102°F) and in many cases >40°C (104°F). In the absence of appropriate therapy, fever persists for a mean of 11 days, but it may continue for 3 to 4 weeks and, rarely, even longer. With appropriate therapy, the fever usually resolves within 2 days.

Changes in the extremities are distinctive. Erythema of the palms and soles or firm, sometimes painful induration of the hands or feet, or both erythema and induration often occur in the acute phase of the disease. Desquamation of the fingers and toes usually begins in the periungual region within 2 to 3 weeks after the onset of fever and may extend to include the palms and soles. Approximately 1 to 2 months after the onset of fever, deep transverse grooves across the nails (Beau’s lines) may appear.

An erythematous rash usually appears within 5 days of the onset of fever. The rash may take various forms; the most common is a nonspecific, diffuse maculopapular eruption. Occasionally seen are an urticarial exanthem, a scarlatiniform rash, an erythroderma, an erythema-multiforme–like rash, or, rarely, a fine micropustular eruption. Bullous and vesicular eruptions have not been described. The rash usually is extensive, with involvement of the trunk and extremities and accentuation in the perineal region, where early desquamation may occur.

Bilateral conjunctival injection usually begins shortly after the onset of fever. It typically involves the bulbar conjunctivae (sparing the limbus, an avascular zone around the iris) much more often than the palpebral or tarsal conjunctivae; is not associated with an exudate, conjunctival edema or corneal ulceration; and usually is painless. Mild acute iridocyclitis or anterior uveitis may be noted by slit lamp; it resolves rapidly and rarely is associated with photophobia or eye pain.

Changes of the lips and oral cavity include (1) erythema, dryness, fissuring, peeling, cracking, and bleeding of the lips; (2) a "strawberry tongue" that is indistinguishable from that associated with streptococcal scarlet fever, with erythema and prominent fungiform papillae; and (3) diffuse erythema of the oropharyngeal mucosae. Oral ulcerations and pharyngeal exudates are not seen.

Cervical lymphadenopathy is the least common of the principal clinical features. It is usually unilateral and confined to the anterior cervical triangle, and its classic criteria include 1 lymph node that is >1.5 cm in diameter. Imaging studies frequently demonstrate multiple enlarged nodes without suppuration.⁶¹ The lymph nodes often are firm and nonfluctuant, are not associated with marked erythema of the overlying skin, and are nontender or only slightly tender. Occasionally, the lymph node swelling of Kawasaki disease can be confused with bacterial adenitis.

Because the principal clinical findings that fulfill the diagnostic criteria are not specific, other diseases with similar clinical features should be excluded (Table 2).

View this table: [in this window] [in a new window]   TABLE 2. Differential Diagnosis of Kawasaki Disease: Diseases and Disorders With Similar Clinical Findings

Other Clinical and Laboratory Findings
Cardiac Findings
Cardiovascular manifestations can be prominent in the acute phase of Kawasaki disease and are the leading cause of long-term morbidity and mortality. During this phase, the pericardium, myocardium, endocardium, valves, and coronary arteries all may be involved. Cardiac auscultation of the infant or child with Kawasaki disease in the acute phase often reveals a hyperdynamic precordium, tachycardia, a gallop rhythm, and an innocent flow murmur in the setting of anemia, fever, and depressed myocardial contractility secondary to myocarditis. Children with significant mitral regurgitation may have a pansystolic regurgitant murmur that is typical of this condition. Occasionally, patients with Kawasaki disease and poor myocardial function may present with low cardiac output syndrome or shock. Electrocardiography may show arrhythmia, prolonged PR interval, or nonspecific ST and T wave changes.

Noncardiac Findings
Multiple noncardiac clinical findings may be observed in patients with Kawasaki disease. Arthritis or arthralgia can occur in the first week of the illness and tends to involve multiple joints, including the small interphalangeal joints as well as large weight-bearing joints. Arthritis or arthralgia developing after the 10th day of illness favors large weight-bearing joints, especially the knees and ankles.

Children with Kawasaki disease often are more irritable than are children with other febrile illnesses. Transient unilateral peripheral facial nerve palsy occurs rarely. Transient high-frequency sensorineural hearing loss (20 to 35 dB) can occur during acute Kawasaki disease,^62,63 but persistent sensorineural hearing loss is rare.⁶⁴ Gastrointestinal complaints, including diarrhea, vomiting, and abdominal pain, occur in approximately one third of patients. Rarely, Kawasaki disease can present as an acute surgical abdomen.⁶⁵ Hepatic enlargement and jaundice can occur. Acute acalculous distention of the gallbladder (hydrops) occurs in 15% of patients during the first 2 weeks of the illness and can be identified by abdominal ultrasound.⁶⁰ Erythema and induration at the site of a previous vaccination with Bacille Calmette-Guérin (BCG) is common in Japan, where BCG is used widely.⁶⁶ Rare findings include testicular swelling, pulmonary nodules⁵⁰ and infiltrates,⁶⁷ pleural effusions, and hemophagocytic syndrome.⁶⁸

Laboratory Findings
Leukocytosis is typical during the acute stage of Kawasaki disease, with a predominance of immature and mature granulocytes. Approximately 50% of patients have white blood cell counts >15 000/mm³. Leukopenia is rare. Anemia may develop, usually with normal red blood cell indexes, particularly with more prolonged duration of active inflammation. Severe hemolytic anemia requiring transfusions is rare and may be related to intravenous immunoglobulin (IVIG) infusion.^69–72 Elevation of acute phase reactants, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), is nearly universal in Kawasaki disease, usually returning to normal by 6 to 10 weeks after onset of the illness. Because the degree of elevation of ESR and CRP may show a discrepancy in some patients at the time of presentation, both should be measured.⁷³ Furthermore, elevation of ESR (but not of CRP) can be caused by IVIG therapy per se; therefore, ESR should not be used as the sole determinant of the degree of inflammatory activity in IVIG–treated patients.

A characteristic feature of the later phases of the illness is thrombocytosis, with platelet counts ranging from 500 000 to >1 million/mm³. Thrombocytosis rarely is present in the first week of the illness, usually appears in the second week, and peaks in the third week with a gradual return to normal by 4 to 8 weeks after onset in uncomplicated cases. The mean peak platelet count is 700 000/mm³. Thrombocytopenia is seen rarely in the acute stage and may be a sign of disseminated intravascular coagulation. A low platelet count at illness presentation is a risk factor for coronary aneurysms (see Risk Scores for Predicting Aneurysms). In patients with arthritis, arthrocentesis typically yields purulent-appearing fluid with a white blood cell count of 125 000 to 300 000/mm³, a normal glucose level, and negative Gram stain and cultures.⁷⁴ Plasma lipids are markedly altered in acute Kawasaki disease, with depressed plasma cholesterol, high-density lipoprotein (HDL), and apolipoprotein AI.^75–78

Mild to moderate elevations in serum transaminases occur in 40% of patients and mild hyperbilirubinemia in 10%.⁷⁹ Plasma gammaglutamyl transpeptidase is elevated in 67% of patients.⁸⁰ Hypoalbuminemia is common and is associated with more severe and more prolonged acute disease. Urinalysis reveals intermittent mild to moderate sterile pyuria in 33% of patients, although suprapubic urine generally does not show pyuria, which suggests urethritis. In children who undergo lumbar puncture, 50% demonstrate evidence of aseptic meningitis with a predominance of mononuclear cells, as well as normal glucose and protein levels.⁸¹

Elevation of serum cardiac troponin I, a marker that is specific for myocardial damage, has been reported in acute Kawasaki disease, which is consistent with myocardial cell injury in the early phase of the disease.^82,83 Such elevation was not confirmed in another study.⁸⁴ Troponin assays do not play a role in the routine management of children with Kawasaki disease.

Laboratory tests, even though they are nonspecific, can provide diagnostic support in patients with clinical features that are suggestive but not diagnostic of Kawasaki disease. A moderately to markedly elevated CRP or ESR, which is almost universally seen in children with Kawasaki disease, is uncommon in viral infections. Platelet counts usually are >450 000/mm³ in patients evaluated after day 7 of illness. Clinical experience suggests that Kawasaki disease is unlikely if platelet counts and acute-phase inflammatory reactants (ie, ESR and CRP) are normal after day 7 of illness. In addition, low white blood cell count, lymphocyte predominance, and low platelet count in the absence of disseminated intravascular coagulation suggest a viral etiology.

Incomplete (Atypical) Kawasaki Disease
Some patients who do not fulfill the criteria outlined in Table 1 have been diagnosed as having "incomplete" or "atypical" Kawasaki disease, a diagnosis that often is based on echocardiographic findings of coronary artery abnormalities. The term "incomplete" may be preferable to "atypical" because these patients lack sufficient clinical signs of the disease to fulfill the classic criteria; they do not demonstrate atypical clinical features. The phrase "atypical Kawasaki disease" should be reserved for patients who have a problem, such as renal impairment, that generally is not seen in Kawasaki disease. The conventional diagnostic criteria should be viewed as guidelines that are particularly useful in preventing overdiagnosis but may result in failure to recognize incomplete forms of illness. Incomplete Kawasaki disease is more common in young infants than in older children, making accurate diagnosis and timely treatment especially important in these young patients who are at substantial risk of developing coronary abnormalities.⁸⁵ The laboratory findings of incomplete cases appear to be similar to those of classic cases. Therefore, although laboratory findings in Kawasaki disease are nondiagnostic, they may prove useful in heightening or reducing the suspicion of incomplete Kawasaki disease.

Echocardiography also may be useful in evaluating children with protracted fever and some features of Kawasaki disease. Although aneurysms rarely form before day 10 of illness, perivascular brightness, ectasia, and lack of tapering of the coronary arteries in the acute stage of Kawasaki disease may represent coronary arteritis before the formation of aneurysms. Decreased left ventricular (LV) contractility, mild valvular regurgitation (most commonly mitral regurgitation), and pericardial effusion also may be seen in an echocardiogram of a person with acute Kawasaki disease.

Incomplete Kawasaki disease should be considered in all children with unexplained fever for 5 days associated with 2 or 3 of the principal clinical features of Kawasaki disease (see Criteria for Treatment of Kawasaki Disease and Figure 1). Because young infants may present with fever and few, if any, principal clinical features, 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.

Common Pitfalls in Diagnosis
Certain common pitfalls in the diagnosis of Kawasaki disease should be noted. Children may present with only fever and a unilateral enlarged cervical lymph node. The rash and mucosal changes that follow often are mistaken for a reaction to antibiotics that are administered for presumed bacterial lymphadenitis. Sterile pyuria may be mistaken for a partially treated urinary tract infection with sterile urine cultures. The young infant may present with fever, rash, and cerebrospinal fluid pleocytosis and be misdiagnosed with viral meningitis. Occasionally, a child may present with an acute abdomen and be admitted to a surgical service. Kawasaki disease should be considered in the differential diagnosis of every child with fever of at least several days’ duration, rash, and nonpurulent conjunctivitis, especially in children <1 year old and in adolescents, in whom the diagnosis is frequently missed.

Risk Scores for Predicting Aneurysms
Several scoring systems have been developed to identify children at highest risk for coronary artery abnormalities.^86–89 Duration of fever, presumably reflecting the severity of ongoing vasculitis, has been confirmed as a powerful predictor of coronary artery aneurysms in various studies.^87–89 Harada et al^90,91 developed a risk score to use at the time a child presents with Kawasaki disease to determine the risk of future coronary aneurysms. At some centers in Japan, the Harada score is used to determine whether IVIG treatment will be used. Intravenous gamma globulin is given to children who fulfill 4 of the following criteria, assessed within 9 days of onset of illness: (1) white blood cell count >12 000/mm³; (2) platelet count <350 000/mm³; (3) CRP >3+; (4) hematocrit <35%; (5) albumin <3.5 g/dL; (6) age 12 months; and (7) male sex. For children with <4 risk factors but continuing acute symptoms, the risk score is reassessed daily. In North America, where IVIG is recommended for all children with Kawasaki disease, Beiser et al⁹² constructed a predictive instrument for the development of coronary artery lesions among patients treated with high-dose IVIG within the first 10 days of the onset of illness using data from a US multicenter database of patients with acute Kawasaki disease. The risk factors that Beiser and associates used in the sequential classification instrument included baseline neutrophil and band counts, hemoglobin concentration, platelet count, and temperature on the day after IVIG infusion. This instrument allowed the clinician to identify within 1 day of treatment the low-risk children in whom extensive and frequent cardiac testing may be unnecessary. Its positive predictive value was less satisfactory, however; the frequencies of the development of coronary artery abnormalities in boys and girls who were classified as high risk were only 13.8% and 5.5%, respectively. Because of the imperfect performance of scoring systems, all patients who are diagnosed with Kawasaki disease should be treated with IVIG.

Criteria for Treatment of Kawasaki Disease
The original guidelines for the diagnosis of Kawasaki disease were created by a committee that was appointed by the Japanese Ministry of Health in 1970. At that time, the coronary artery complications of Kawasaki disease were not yet appreciated. In addition, neither effective treatment nor a noninvasive method of assessing coronary artery abnormalities existed. The case definition was created, therefore, for epidemiological surveillance and to establish the extent of the clinical syndrome now known as Kawasaki disease in Japan. The case definition intentionally was made restrictive to exclude patients with rheumatic fever and Stevens-Johnson syndrome.

More than 3 decades later, the clinical landscape has changed dramatically. Echocardiographic screening for coronary enlargement has shown that a substantial number of children with Kawasaki disease and coronary artery abnormalities are not identified by the classic case definition.^93–95 Thus, although the present case definition provides a specific tool for epidemiological surveillance, it may not be the optimal method for aiding clinicians in the recognition of children with a systemic vasculitis that requires prompt treatment. Given the potential seriousness of the complications, together with the efficacy and safety of early treatment, high sensitivity of the treatment criteria is more important than is high specificity. We have therefore devised an algorithm to aid clinicians in deciding whether a child with signs and symptoms suggestive of Kawasaki disease should be treated with IVIG. To strive for the greatest sensitivity while maintaining sufficient specificity to prevent widescale overuse of IVIG, we have attempted to base our recommendations on laboratory and echocardiographic data derived from the population of patients with Kawasaki disease who meet the classic epidemiological case definition.

The 1993 American Heart Association guidelines on Kawasaki disease suggested that the diagnosis could be made on day 4 of fever, with day 1 by convention being the first day of fever.³ In the presence of 4 of 5 classic criteria (Table 1), US and Japanese experts agree that only 4 days of fever are necessary before initiating treatment.

It is also broadly agreed that Kawasaki disease can be diagnosed in the absence of full criteria when coronary abnormalities are present. The definition of coronary artery abnormalities has changed since the original Japanese Ministry of Health criteria were devised. In particular, coronary artery dimensions, adjusted for body surface area, provide a more accurate assessment of the size of the proximal right coronary artery (RCA) or left anterior descending coronary artery (LAD) as compared with expected population norms.^96,97 A z score 2.5 (ie, a coronary dimension that is 2.5 SDs above the mean for body surface area) in 1 of these arterial segments would be expected to occur in 0.6% of the population without Kawasaki disease, and a z score 3.0 in 1 of these segments would be expected to occur in 0.1% of the population without Kawasaki disease. Having a coronary artery z score 2.5 in both the proximal RCA and LAD would be uncommon in the general population. Because of anatomic variation in the left main coronary artery (LMCA), its z score must be interpreted with caution. Occasional cases of coronary prominence in patients with other disorders have been noted. Clinical experience, however, suggests that coronary enlargement in other febrile illnesses is rare, whereas coronary enlargement in Kawasaki disease is relatively common. Thus, coronary artery z scores should be incorporated into the recommendations for the evaluation and treatment of Kawasaki disease.

The present writing group proposes a scheme to aid the clinician in deciding which patients with fever and <4 classic criteria should undergo echocardiography or receive IVIG treatment or both for Kawasaki disease (Figure 1). In the absence of a gold standard for diagnosis, this algorithm cannot be evidence based but rather represents the informed opinion of a committee of experts (evidence level C). We offer this opinion as guidance to clinicians until an evidence-based algorithm or a specific diagnostic test for Kawasaki disease becomes available.

	Cardiac Findings

Top Abstract Introduction Epidemiology Etiology and Pathogenesis Pathology Diagnosis Cardiac Findings Treatment Long-Term Follow-Up Summary References

 
Coronary Aneurysms
Echocardiography
The major sequelae of Kawasaki disease are related to the cardiovascular and, more specifically, the coronary arterial system, so cardiac imaging is a critical part of the evaluation of all patients with suspected Kawasaki disease. Because it is noninvasive and has a high sensitivity and specificity for the detection of abnormalities of the proximal LMCA and RCA, echocardiography is the ideal imaging modality for cardiac assessment (evidence level C). Evaluation of the cardiovascular sequelae of Kawasaki disease requires serial cardiac ultrasound studies and should be performed using equipment with appropriate transducers and supervised by an experienced echocardiographer. 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 (ie, waiting for sedation). This initial study establishes a baseline for longitudinal follow-up of coronary artery morphology, LV and left valvular function, and the evolution and resolution of pericardial effusion when present. Because detailed echocardiographic imaging is compromised if a child is uncooperative, sedation often is required for younger children (eg, chloral hydrate 65 to 100 mg/kg, maximum 1000 mg, or other short-acting sedative or hypnotic agents).

The 2D imaging should be performed with the highest frequency transducer possible. Imaging with high-frequency transducers should be attempted even in older children, as these probes allow for higher-resolution, detailed evaluation of the coronary arteries. Studies should be recorded in a dynamic video or digital cine format because the normal translational movement of the heart facilitates the display of the coronary artery anatomy. Such recordings will allow future review and comparison with subsequent studies. In addition to standard imaging from parasternal, apical, subcostal, and suprasternal notch windows, 2DE evaluation of patients with suspected Kawasaki disease should focus on imaging the LMCA, LAD, left circumflex coronary artery (LCX), RCA (proximal, middle, and distal segments), and posterior descending coronary arteries. Multiple imaging planes and transducer positions are required for the optimal visualization of all major coronary segments (Table 3, Figure 2). Maximal efforts should be made to visualize all major coronary segments. In order of highest to lowest frequency, 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.

View this table: [in this window] [in a new window]   TABLE 3. Echocardiographic Views of Coronary Arteries in Patients With Kawasaki Disease

View larger version (127K): [in this window] [in a new window]   Figure 2. 2D echocardiogram. AO indicates aorta; PA, pulmonary artery; LAD, left anterior descending coronary artery; CX, circumflex coronary artery; and L MAIN, left main coronary artery.

Evaluation of the coronary arteries should include quantitative assessment of the internal vessel diameters. Measurements should be made from inner edge to inner edge and should exclude points of branching, which may have normal focal dilation. The number and location of aneurysms and the presence or absence of intraluminal thrombi also should be assessed. Aneurysms are classified as saccular if axial and lateral diameters are nearly equal or as fusiform if symmetric dilatation with gradual proximal and distal tapering is seen. When a coronary artery is larger than normal (dilated) without a segmental aneurysm, the vessel is considered ectatic. Care must be taken in making the diagnosis of ectasia because of considerable normal variation in coronary artery distribution and dominance. In the last American Heart Association statement,^3,98 aneurysms were classified as small (<5 mm internal diameter), medium (5 to 8 mm internal diameter), or giant (>8 mm internal diameter). The Japanese Ministry of Health criteria classify coronary arteries as abnormal if the internal lumen diameter is >3 mm in children <5 years old or >4 mm in children 5 years old; if the internal diameter of a segment measures 1.5 times that of an adjacent segment; or if the coronary lumen is clearly irregular.⁹⁹ Current statistics on the prevalence of coronary artery abnormalities secondary to Kawasaki disease are based on these criteria. Although the Japanese Ministry of Health criteria are not based on an individual patient’s body size, coronary artery dimensions in children without Kawasaki disease have been shown to increase with indexes of body size, such as body surface area or body length.

More recently, de Zorzi and colleagues showed that the body surface area–adjusted coronary dimensions of some people with Kawasaki disease whose coronary arteries were considered "normal" are larger than expected in the acute, convalescent, and late phases when compared with references established for body size.⁹⁶ Figure 3 shows coronary internal diameters according to body surface area in the population without Kawasaki disease. Because use of the Japanese Ministry of Health criteria may result in both underdiagnosis and underestimation of the true prevalence of coronary dilation, coronary vessel measurements adjusted for body surface area should be compared with those of the population without Kawasaki disease. Of note, z scores are available for only the LMCA, proximal LAD, and proximal RCA, so that the Japanese Ministry of Health criterion of "size 1.5 times that of the surrounding segment" is still useful for diagnosing aneurysms in peripheral sites. Enlargement of the LMCA caused by Kawasaki disease does not involve the orifice and rarely occurs without associated ectasia of the LAD, LCX, or both arteries. In addition to measuring coronary artery dimensions, imaging the coronary arteries also may reveal the lack of normal tapering and perivascular echogenicity or "brightness."²³

View larger version (21K): [in this window] [in a new window]   Figure 3. Mean and prediction limits for 2 and 3 SDs for size of (A) LAD, (B) proximal RCA, and (C) LMCA according to body surface area for children <18 years old. LMCA z scores should not be based on dimension at orifice and immediate vicinity; enlargement of LMCA secondary to Kawasaki disease usually is associated with ectasia of LAD, LCX, or both.

Although the echocardiographic examination of patients with Kawasaki disease is focused on the coronary arteries, other information can and should be obtained. Histological evidence suggests that myocarditis is universal in acute Kawasaki disease, and other studies have shown depressed ventricular contractility to be common early in the course of Kawasaki disease. Therefore, assessment of LV function should be a part of the echocardiographic evaluation of all patients with suspected Kawasaki disease. LV end-diastolic and end-systolic dimensions and a shortening fraction should be measured from standard M-mode tracings. Apical imaging allows the estimation of LV end-diastolic and end-systolic volumes and an ejection fraction. Although loading conditions influence these measurements, they are more readily measured than are complex indexes of contractility and are adequate for routine clinical follow-up. Evaluating regional wall motion may be useful, especially in children with coronary artery abnormalities. The aortic root also should be imaged, measured, and compared with references for body surface area because evidence exists that mild aortic root dilation is common among patients with Kawasaki disease.¹⁰⁰ Because pericarditis may be associated with the vasculitis and myocarditis seen in patients with Kawasaki disease, the presence or absence of a pericardial effusion should be noted.

Standard pulsed and color flow Doppler interrogation should be performed to assess the presence and degree of valvular regurgitation (in particular for mitral and aortic valves). Color flow Doppler with a low Nyquist limit setting from a favorable angle of view may allow coronary flow to be demonstrated and may be useful in positively identifying coronary artery lumens.

It is important to recognize the limitations of echocardiography in the evaluation and follow-up of patients with Kawasaki disease. Although echocardiographic detection of thrombi and coronary artery stenosis has been reported, the sensitivity and specificity of echocardiography for identifying these abnormalities is unclear. In addition, the visualization of coronary arteries becomes progressively more difficult as a child grows and body size increases. Angiography, intravascular ultrasound (IVUS), transesophageal echocardiography, and other modalities including magnetic resonance angiography (MRA) and ultrafast computed tomography (CT) may be of value in the assessment of selected patients (see below).

For uncomplicated cases, echocardiographic evaluation should be performed at the time of diagnosis, at 2 weeks, and at 6 to 8 weeks after onset of the disease. More frequent echocardiographic evaluation is needed to guide management in children at higher risk (eg, those who are persistently febrile or who exhibit coronary abnormalities, ventricular dysfunction, pericardial effusion, or valvular regurgitation). Recent studies have shown that repeat echocardiography performed 1 year after the onset of the illness is unlikely to reveal coronary artery enlargement in patients whose echocardiographic findings were normal at 4 to 8 weeks.^101,102 Because abnormalities in coronary artery function,^103–105 coronary flow reserve,¹⁰⁶ and aortic root dilation¹⁰⁰ remain potential concerns even among patients in whom coronary dilatation was never detected, repeat echocardiography beyond 8 weeks in patients with previously normal findings should be considered optional. Follow-up echocardiograms should identify the progression or regression of coronary abnormalities, evaluate ventricular and valvular function, and assess the presence or evolution of pericardial effusions.

Other Noninvasive Tests
Magnetic resonance imaging (MRI) and MRA may delineate coronary artery aneurysms in the proximal coronary artery segments and provide data regarding flow profile (evidence level C).^107–109 A recent small series in patients with Kawasaki disease demonstrated that coronary MRA accurately diagnosed all coronary artery aneurysms, coronary occlusions, and coronary stenoses present on x-ray angiography.¹¹⁰ MRI and MRA may be used to image peripheral artery aneurysms. Ultrafast CT also has been used to assess coronary aneurysms.^111,112 Further larger studies in patients with Kawasaki disease are needed to establish the reliability of MRA and ultrafast CT for the detection of coronary artery aneurysms and stenoses in distal segments, as well as for the presence of collateral circulation.

Cardiac stress testing for reversible ischemia is indicated to assess the existence and functional consequences of coronary artery abnormalities in children with Kawasaki disease and coronary aneurysms (evidence level A). The types of stress tests reported in children with Kawasaki disease include nuclear perfusion scans with exercise,^113,114 exercise echocardiography,^115,116 and stress echocardiography with pharmacological agents such as dobutamine,^117,118 dipyridamole, or adenosine.¹¹⁹ More recently, MRI stress imaging with quantification of regional perfusion has detected significant coronary stenoses.¹²⁰ Myocardial perfusion also can be assessed by myocardial contrast echocardiography, taking gas-filled microbubbles to measure the microcirculatory flow and hence capillary density in different myocardial regions.¹²¹ With stress, the myocardial blood volume fraction decreases distal to a stenosis, causing a perfusion defect on myocardial contrast echocardiography.^122,123

The predictive value of stress tests for coronary artery disease requiring intervention is a function of the probability of significant disease in the population tested (Bayes’ theorem). For example, false-positive tests are more likely in patients with a previously low probability of coronary disease. Used appropriately, stress test results may guide a clinician’s decision to refer a patient for invasive evaluation (ie, cardiac catheterization), as well as for catheter or surgical intervention. The choice of stress modality should be guided by institutional expertise with particular techniques, as well as by the age of the child (eg, pharmacological stress should be used in young children in whom traditional exercise protocols are not feasible).

Cardiac Catheterization and Angiography
Coronary angiography offers a more detailed definition of coronary artery anatomy than does cardiac ultrasound, making it possible to detect coronary artery stenosis or thrombotic occlusion and to determine the extent of collateral artery formation in patients with Kawasaki disease (Figure 4). Before recommending coronary angiography to a patient, a physician must compare the potential benefits of the procedure with its risks and cost. In patients with mild ectasia or small fusiform aneurysms demonstrated by echocardiography, coronary angiography is unlikely to provide any further useful information and is not recommended (evidence level C). Patients with more complex coronary artery lesions may benefit from coronary angiography after the acute inflammatory process has resolved. Practices regarding the timing of cardiac catheterization for such patients vary greatly from center to center; coronary angiography is generally recommended 6 to 12 months after the onset of illness or sooner if indicated clinically (evidence level C). In long-term follow-up, the decision to perform angiography may be guided by echocardiographic imaging of coronary arteries, ventricular regional wall motion abnormalities, and clinical signs or noninvasive studies indicating myocardial ischemia. The failure to image distal coronary arteries in a patient in whom large proximal aneurysms have regressed may be an indication for another imaging modality, including cardiac angiography, to guide the appropriate use of antithrombotic agents (evidence level C). Patients who have undergone surgical revascularization or catheter intervention may have a repeat cardiac catheterization so that the efficacy of the treatment can be evaluated (evidence level C).

View larger version (137K): [in this window] [in a new window]   Figure 4. Coronary angiogram demonstrating giant aneurysm of the LAD with obstruction and giant aneurysm of the RCA with area of severe narrowing in 6-year-old boy.

Additional techniques used during cardiac catheterization may detect structural or functional changes in the coronary artery wall. Patients with angiographically documented regression of coronary artery aneurysms have shown abnormal thickening of the intima-media complex by IVUS¹²⁴ and abnormal vasoreactivity in response to various vasodilators.^125,126 The long-term clinical implications of these anatomical and functional changes are unknown at this time.

Aneurysms can occur in arteries outside the coronary system, most commonly the subclavian, brachial, axillary, iliac, or femoral vessels, and occasionally in the abdominal aorta and renal arteries.¹²⁷ For this reason, abdominal aortography and subclavian arteriography are recommended in patients with Kawasaki disease undergoing coronary arteriography for the first time (evidence level C).

Myocarditis
Myocarditis has been demonstrated in autopsy and myocardial biopsy studies to be a common feature of early Kawasaki disease.^34,128 Myocardial inflammation has been documented in 50% to 70% of patients using ⁶⁷Ga citrate scans (planar or single photon emission CT)¹²⁹ and ^99mTc-labeled white blood cell scans.^130–132 The severity of myocarditis does not appear to be associated with the risk of coronary artery aneurysms, however.^133,134

Although the majority of patients with Kawasaki disease has abnormal myocardial contractility by echocardiographic assessment at presentation, myocardial mechanics improve rapidly after IVIG therapy, with a high concordance between the clinical and myocardial responses to therapy.¹³⁵ The speed of recovery suggests that depressed contractility in patients with Kawasaki disease is caused by rapidly reversible mechanisms such as those involving circulating toxins or activated cytokines. It is also possible that the inflammatory infiltrate found between the muscle fibers on postmortem examination in early Kawasaki disease may resolve quickly.

The occurrence of myocarditis during the acute phase of Kawasaki disease has fostered concern about the potential long-term effects of the disease on myocardial function. Biopsy of the right ventricular myocardium was performed in 201 patients with Kawasaki disease to assess the evolution and course of myocardial change.¹³⁶ The interval between onset of the disease and myocardial biopsy ranged from 2 months to 11 years. Myocardial abnormalities, including fibrosis and cellular disarrangement, as well as abnormal branching and hypertrophy of myocytes, were detected at all time periods after onset of the disease; their severity was unrelated to the presence of coronary artery abnormalities. In addition, electron microscopic examination of endomyocardial biopsies has demonstrated ultrastructural abnormalities late after Kawasaki disease.¹³⁷

Despite the concerns raised about histopathologic abnormalities on myocardial biopsy, long-term myocardial contractility and function measured by echocardiography appear to be normal, except among patients with ischemic heart disease.¹³⁵ Assessment of the full impact of Kawasaki disease on heart function must await follow-up studies of these children into adulthood.

Valvular Regurgitation
Mitral regurgitation may result from transient papillary muscle dysfunction, MI, or valvulitis. The appearance of mitral regurgitation after the acute stage usually is secondary to myocardial ischemia, although late-onset valvulitis unrelated to ischemia has been documented.¹³⁸ Kato et al² reported 6 patients (1.0% of their series) with mitral regurgitation in the acute or subacute stage of Kawasaki disease, with resolution in 3 patients, death from MI in 2, and persistence from papillary muscle dysfunction in 1.

Aortic regurgitation has been documented angiographically by Nakano and colleagues¹³⁹ in 5% of children with Kawasaki disease and was attributed to valvulitis. Other investigators have observed a much lower incidence of aortic regurgitation in the acute phase,² but late-onset aortic regurgitation has been reported as an exceedingly rare finding after Kawasaki disease and may be associated with the need for aortic valve replacement.^2,138,140 Approximately 4% of a consecutive series with Kawasaki disease had mild aortic regurgitation as seen by echocardiogram.¹⁰⁰

	Treatment

Top Abstract Introduction Epidemiology Etiology and Pathogenesis Pathology Diagnosis Cardiac Findings Treatment Long-Term Follow-Up Summary References

 
Initial Treatment
Aspirin
Aspirin has been used in the treatment of Kawasaki disease for many years. Although aspirin has important anti-inflammatory (at high doses) and antiplatelet (at low doses) activity, it does not appear to lower the frequency of the development of coronary abnormalities.¹⁴¹ During the acute phase of illness, aspirin is administered at 80 to 100 mg/kg per day in 4 doses with IVIG (see next section). High-dose aspirin and IVIG appear to possess an additive anti-inflammatory effect. Practices regarding the duration of high-dose aspirin administration vary across institutions, and many centers reduce the aspirin dose after the child has been afebrile for 48 to 72 hours. Other clinicians continue high-dose aspirin until day 14 of illness and 48 to 72 hours after fever cessation. When high-dose aspirin is discontinued, clinicians begin low-dose aspirin (3 to 5 mg/kg per day) and maintain it until the patient shows no evidence of coronary changes by 6 to 8 weeks after the onset of illness (evidence level C). For children who develop coronary abnormalities, aspirin may be continued indefinitely (evidence level B). Of note, the concomitant use of ibuprofen antagonizes the irreversible platelet inhibition that is induced by aspirin¹⁴²; thus, in general, ibuprofen should be avoided in children with coronary aneurysms taking aspirin for its antiplatelet effects (evidence level B).

Reye syndrome is a risk in children who take salicylates while they are experiencing active infection with varicella or influenza, and has been reported in patients taking high-dose aspirin for a prolonged period after Kawasaki disease.^143,144 It is unclear whether the low-d