AMERICAN ACADEMY OF PEDIATRICS AMERICAN HEART … · Characteristics suggesting disease other than Kawasaki disease include exudative conjunctivitis, exudative pharyngitis, discrete

AMERICAN ACADEMY OF PEDIATRICS

AMERICAN HEART ASSOCIATION

ENDORSED CLINICAL REPORTGuidance for the Clinician in Rendering Pediatric Care

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; and Kathryn A. Taubert, PhD

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 CardiovascularDisease in the Young, American Heart Association

ABSTRACT. Background. Kawasaki disease is anacute self-limited vasculitis of childhood that is charac-terized by fever, bilateral nonexudative conjunctivitis,erythema of the lips and oral mucosa, changes in theextremities, rash, and cervical lymphadenopathy. Coro-nary artery aneurysms or ectasia develop in �15% to 25%of untreated children and may lead to ischemic heartdisease or sudden death.

Methods and Results. A multidisciplinary committeeof experts was convened to revise the American HeartAssociation recommendations for diagnosis, treatment,and long-term management of Kawasaki disease. Thewriting group proposes a new algorithm to aid cliniciansin deciding which children with fever for >5 days and<4 classic criteria should undergo electrocardiography,receive intravenous gamma globulin (IVIG) treatment, orboth for Kawasaki disease. The writing group reviewsthe available data regarding the initial treatment for chil-dren with acute Kawasaki disease, as well for those whohave persistent or recrudescent fever despite initial ther-apy with IVIG, including IVIG retreatment and treat-ment with corticosteroids, tumor necrosis factor-� antag-onists, and abciximab. Long-term management ofpatients with Kawasaki disease is tailored to the degreeof coronary involvement; recommendations regardingantiplatelet and anticoagulant therapy, physical activity,follow-up assessment, and the appropriate diagnosticprocedures to evaluate cardiac disease are classified ac-cording to risk strata.

Conclusions. Recommendations for the initial evalu-ation, treatment in the acute phase, and long-term man-agement of patients with Kawasaki disease are intendedto assist physicians in understanding the range of accept-able approaches for caring for patients with Kawasakidisease. The ultimate decisions for case management

must be made by physicians in light of the particularconditions presented by individual patients. Pediatrics2004;114:1708–1733; AHA Scientific Statements, vasculitis,therapy, aneurysm, diagnosis.

ABBREVIATIONS. MI, myocardial infarction; CI, confidenceinterval; Ig, immunoglobulin; TNF-�, tumor necrosis actor-�; 2D,2-dimensional; 2DE, 2-dimensional echocardiography; IVIG, intra-venous immunoglobulin; ESR, erythrocyte sedimentation rate;CRP, C-reactive protein; LV, left ventricular; RCA, right coronaryartery; LAD, left anterior descending coronary artery; LMCA, leftmain coronary artery; LCX, left circumflex coronary artery; IVUS,intravascular ultrasound; MRA, magnetic resonance angiography;CT, computed tomography; MRI, magnetic resonance imaging; IL,interleukin; INR, international normalized ratio; tPA, tissue plas-minogen activator; ECG, electrocardiogram.

Kawasaki disease is an acute, self-limited vas-culitis of unknown etiology that occurs pre-dominantly in infants and young children.

First described in Japan in l967 by Tomisaku Ka-wasaki, the disease is now known to occur in bothendemic and community-wide epidemic forms in theAmericas, Europe, and Asia in children of all races.1Kawasaki disease is characterized by fever, bilateralnonexudative conjunctivitis, erythema of the lips andoral mucosa, changes in the extremities, rash, andcervical lymphadenopathy. Coronary artery aneu-rysms or ectasia develop in �15% to 25% of un-treated children with the disease and may lead tomyocardial infarction (MI), sudden death, or isch-emic heart disease.2,3 In the United States, Kawasakidisease has surpassed acute rheumatic fever as theleading cause of acquired heart disease in children.4Treatment of Kawasaki disease in the acute phase isdirected at reducing inflammation in the coronaryartery wall and preventing coronary thrombosis,whereas long-term therapy in individuals who de-velop coronary aneurysms is aimed at preventingmyocardial ischemia or infarction.

A new feature of these recommendations is an

This report was approved by the American Heart Association ScienceAdvisory and Coordinating Committee on June 16, 2004.This report was copublished in the October 26, 2004 issue of Circulation.The guidance in this report does not indicate an exclusive course of treat-ment or serve as a standard of medical care. Variations, taking into accountindividual circumstances, may be appropriate.doi:10.1542/peds.2004-2182PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad-emy of Pediatrics.

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algorithm for the evaluation and treatment of pa-tients in whom incomplete or atypical Kawasaki dis-ease is suspected (refer to “Criteria for Treatment ofKawasaki Disease” later in this statement and Fig 1).We attempt to summarize the current state of knowl-edge of the management of patients with Kawasakidisease. The recommendations are evidence based

and derived from published data wherever possible.The levels of evidence on which recommendationsare based are classified as follows: level A (highest),multiple randomized clinical trials; level B (interme-diate), limited number of randomized trials, nonran-domized studies, and observational registries; andlevel C (lowest), primarily expert consensus.

Fig 1. Evaluation of suspected incomplete Kawasaki disease. (1) In the absence of gold standard for diagnosis, this algorithm cannot beevidence based but rather represents the informed opinion of the expert committee. Consultation with an expert should be sought anytimeassistance is needed. (2) Infants �6 months old on day �7 of fever without other explanation should undergo laboratory testing and, ifevidence of systemic inflammation is found, an echocardiogram, even if the infants have no clinical criteria. (3) Patient characteristicssuggesting Kawasaki disease are listed in Table 1. Characteristics suggesting disease other than Kawasaki disease include exudativeconjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, or generalized adenopathy. Consider alternativediagnoses (see Table 2). (4) Supplemental laboratory criteria include albumin �3.0 g/dL, anemia for age, elevation of alanine amino-transferase, platelets after 7 days �450 000/mm3, white blood cell count �15 000/mm3, and urine �10 white blood cells/high-powerfield. (5) Can treat before performing echocardiogram. (6) Echocardiogram is considered positive for purposes of this algorithm if any of3 conditions are met: z score of LAD or RCA �2.5, coronary arteries meet Japanese Ministry of Health criteria for aneurysms, or �3 othersuggestive features exist, including perivascular brightness, lack of tapering, decreased LV function, mitral regurgitation, pericardialeffusion, 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 daysof fever onset and those beyond day 10 with clinical and laboratory signs (CRP, ESR) of ongoing inflammation. (8) Typical peeling beginsunder nail bed of fingers and then toes.

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Recommendations for initial evaluation, treatmentin the acute phase, and long-term management ofpatients with Kawasaki disease are intended to assistphysicians in understanding the range of acceptableapproaches for caring for patients with Kawasakidisease. Where published data do not define well thebest medical practices, our report provides practicalinterim recommendations. Ultimately, managementdecisions must be individualized to a patient’s spe-cific circumstances.

EPIDEMIOLOGYIn the past, Kawasaki disease may have masquer-

aded as other illnesses, and old reports on infantilepolyarteritis nodosa describe pathological findingsthat are identical to those of fatal Kawasaki dis-ease.5–8 Kawasaki disease is markedly more preva-lent in Japan and in children of Japanese ancestry,with an annual incidence of �112 cases per 100 000children �5 years old.9 In the United States, theincidence of Kawasaki disease has been best esti-mated from hospital discharge data.10,11 An esti-mated 4248 hospitalizations associated with Ka-wasaki disease occurred in the United States in 2000,with a median age of 2 years.10 Race-specific inci-dence rates derived from administrative data indi-cate that Kawasaki disease is most common amongAmericans 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 000children �5 years old).10 These estimates are similarto those reported in smaller studies.12,13 Recent re-ports have emphasized the occurrence of Kawasakidisease in older children, who may have a higherprevalence of cardiovascular complications relatedto late diagnosis.14–16

Rates of recurrence and familial occurrence of Ka-wasaki disease are best documented in the literaturefrom Japan; these rates may be lower in other racesand ethnicities. In Japan, the recurrence rate of Ka-wasaki disease has been reported to be �3%.17 Theproportion of cases with a positive family history is�1%.17,18 Within 1 year after onset of the first case ina family, the rate in a sibling is 2.1%, which is arelative risk of �10-fold as compared with the unaf-fected Japanese population; �50% of the secondcases develop within 10 days of the first case.19 Therisk of occurrence in twins is �13%.19,20 Higher ratesof Kawasaki disease in the siblings of index cases andtwins suggest a possible role for genetic predisposi-tion that interacts with exposure to the etiologicagent or agents in the environment.19–22 The reportedoccurrence of Kawasaki disease in children of par-ents who themselves had the illness in childhoodalso supports the contribution of genetic factors.23–26

In the United States, Kawasaki disease is morecommon during the winter and early spring months;boys outnumber girls by �1.5 to 1.7:1; and 76% ofchildren are �5 years old.10,11 Reported associationsof Kawasaki disease with antecedent respiratory ill-ness and exposure to carpet-cleaning fluids have notbeen consistently confirmed.12,13,27–30 Other factors

that are reportedly associated with Kawasaki diseaseinclude having preexisting eczema,31 using a humid-ifier,30 and living near a standing body of water.32

The case fatality rate in Kawasaki disease in Japanis 0.08%.17 The standardized mortality ratio (the ob-served number of deaths divided by the expectednumber of deaths based on vital statistics in Japan) inpatients diagnosed between 1982 and 1992 was 1.25(95% confidence interval [CI]: 0.84–1.85) overall and2.35 (95% CI: 0.96–5.19) for boys with cardiac sequel-ae.33 In the United States, the in-hospital mortalityrate is �0.17% (the investigators used administrativedata that may include readmissions for coronary dis-ease).15 Virtually all deaths in patients with Ka-wasaki disease result from its cardiac sequelae.34 Thepeak mortality occurs 15 to 45 days after the onset offever; during this time well-established coronaryvasculitis occurs concomitantly with a marked ele-vation of the platelet count and a hypercoagulablestate.35 However, sudden death from MI may occurmany years later in individuals who as children hadcoronary artery aneurysms and stenoses. Many casesof fatal and nonfatal MI in young adults have beenattributed to “missed” Kawasaki disease in child-hood.36

ETIOLOGY AND PATHOGENESISThe etiology of Kawasaki disease remains un-

known, although clinical and epidemiological fea-tures strongly suggest an infectious cause. A self-limited, generally nonrecurring illness that manifestsitself by fever, rash, enanthem, conjunctival injection,and cervical adenopathy fits well with an infectiousetiology or trigger. The epidemiological featuresnoted above, including age distribution, winter-spring seasonality, occurrence of community out-breaks with wave-like geographic spread, and ap-parent epidemic cycles, are suggestive of atransmissible childhood disease. The laboratory fea-tures also suggest infection. However, efforts to iden-tify an infectious agent in Kawasaki disease withconventional bacterial and viral cultures and serolog-ical methods, as well as with animal inoculation,have failed to identify an infectious cause.

An attractive hypothesis is that Kawasaki diseaseis caused by a ubiquitous infectious agent that pro-duces clinically apparent disease only in certain ge-netically predisposed individuals, particularlyAsians. Its rarity in the first few months of life and inadults suggests an agent to which the latter are im-mune and from which very young infants are pro-tected by passive maternal antibodies. Because littleevidence exists of person-to-person transmission,this hypothesis assumes that most infected childrenexperience asymptomatic infection with only a smallfraction developing overt clinical features of Ka-wasaki disease. The genetic basis of susceptibility iscurrently unknown.

The hypothesis that Kawasaki disease is related toa bacterial superantigenic toxin has been suggestedbecause of the reported selective expansion of V�2and V�8 T-cell receptor families, but this theory re-mains controversial.37–40 A recent prospective multi-center study failed to show a significant difference in

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the prevalence of toxin-producing strains betweenpatients with Kawasaki disease and febrile con-trols.41 Recent investigations support an alternativehypothesis: The immune response in Kawasaki dis-ease is oligoclonal (antigen driven, ie, similar to aresponse to a conventional antigen) rather than poly-clonal (as found typically in superantigen-driven re-sponses), and immunoglobulin A (IgA) plasma cellsplay a central role.42–44

It also is possible that Kawasaki disease resultsfrom an immunologic response that is triggered byany of several different microbial agents. Support forthis hypothesis includes documented infection bydifferent microorganisms in different individualcases, failure to detect a single microbiological orenvironmental agent after almost 3 decades of study,and analogies to other syndromes caused by multi-ple agents (eg, aseptic meningitis). This hypothesis issomewhat difficult to reconcile with the distinctiveclinical/laboratory picture of Kawasaki disease andwith its epidemiological features, however.

Efforts to associate Kawasaki disease with expo-sure to drugs or to such environmental pollutants astoxins, pesticides, chemicals, and heavy metals havefailed, although clinical similarities between Ka-wasaki disease and acrodynia (mercury hypersensi-tivity) are notable.

Striking immune perturbations occur in acute Ka-wasaki disease, including marked cytokine cascadestimulation and endothelial cell activation. The keysteps leading to coronary arteritis are still being clar-ified, but endothelial cell activation, CD68� mono-cyte/macrophages, CD8� (cytotoxic) lymphocytes,and oligoclonal IgA plasma cells appear to be in-volved.43,45 The prominence of IgA plasma cells inthe respiratory tract, which is similar to findings infatal viral respiratory infections, suggests a respira-tory portal of entry of an etiologic agent or agents.44

Enzymes including matrix metalloproteinases thatare capable of damaging arterial wall integrity maybe important in the development of aneurysmal di-latation.46 Vascular endothelial growth factor(VEGF), monocyte chemotactic and activating factor(MCAF or MCP-1), tumor necrosis actor-� (TNF-�),and various interleukins also appear to play impor-tant roles in the vasculitic process.47–54

PATHOLOGYAlthough the coronary arteries virtually always

are involved in autopsy cases, Kawasaki disease is ageneralized systemic vasculitis involving blood ves-sels throughout the body. Aneurysms may occur inother extraparenchymal muscular arteries such asthe celiac, mesenteric, femoral, iliac, renal, axillary,and brachial arteries.55 The early stages in the forma-tion and development of arteritis in Kawasaki dis-ease have been well studied morphologically in rel-atively large muscular arteries.55 The media ofaffected vessels demonstrate edematous dissociationof the smooth muscle cells, which is most obvioustoward the exterior. Endothelial cell swelling andsubendothelial edema are seen, but the internal elas-tic lamina remains intact. An influx of neutrophils isfound in the early stages (7–9 days after onset), with

a rapid transition to large mononuclear cells in con-cert with lymphocytes (predominantly CD8� T cells)and IgA plasma cells.42–45 Destruction of the internalelastic lamina and eventually fibroblastic prolifera-tion occur at this stage. Matrix metalloproteinasesare prominent in the remodeling process.56 Activeinflammation is replaced over several weeks tomonths by progressive fibrosis, with scar formation.

Arterial remodeling or revascularization may oc-cur in Kawasaki disease with coronary arteritis. Pro-gressive stenosis in the disease results from activeremodeling with intimal proliferation and neoangio-genesis; the intima is markedly thickened and con-sists of linearly arranged microvessels, a layer that isrich in smooth muscle cells, and fibrous layers. Sev-eral growth factors are prominently expressed at theinlet and outlet of aneurysms, where they are acti-vated by high shear stress.57

During the clinical course of Kawasaki disease,vomiting and abdominal pain are seen often.Kurashige and colleagues58 described the intestinaltract in 31 fatal cases, but in only 3 patients wasmesenteric arteritis found. Using biopsy specimensof the jejunal mucosa, Nagata et al59 studied cellsurface phenotypes of mononuclear cells and entero-cytes. Both HLA-DR�CD3� (activated T cells) andDR�CD4� cells (activated helper T cells) were sig-nificantly increased in the lamina propria of patientswith acute Kawasaki disease as compared with con-trols. In contrast, CD8� cells (suppressor/cytotoxic Tcells) were significantly reduced in both the epithe-lium and the lamina propria of individuals withKawasaki disease as compared with controls. Duringthe convalescent phase of the disease, these cell pat-terns returned to normal.59 Hydrops of the gallblad-der may be clinically apparent in patients with Ka-wasaki disease. A study of surgically removedgallbladders revealed a nonspecific severe perivas-cular inflammatory cell infiltration60; distinct arteritisin the gallbladder wall has not been well docu-mented.

Lymphadenopathy, an early finding in patientswith Kawasaki disease, usually disappears by au-topsy. Pathological findings in lymph nodes includethrombotic arteriolitis and severe lymphadenitiswith necrosis.55 Lymph node biopsies performed inthe first week of the illness revealed abnormal hy-perplasia of the endothelium of the postcapillaryvenule and hyperplasia of reticular cells around thepostcapillary venule.1

DIAGNOSISIn the absence of a specific diagnostic test or pa-

thognomonic clinical feature, clinical criteria havebeen established to assist physicians in diagnosingKawasaki disease. Other clinical and laboratory find-ings observed in patients with this disease are fre-quently helpful in diagnosis. Table 1 describes theclinical and laboratory features of Kawasaki diseaseaccording to the epidemiological case definition.

Principal Clinical FindingsThe 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 Typi-cally, all of the clinical features are not present at asingle point in time, and watchful waiting is some-times necessary before a diagnosis can be made.Patients with fever for �5 days and �4 principalfeatures can be diagnosed as having Kawasaki dis-ease when coronary artery disease is detected by2-dimensional (2D) echocardiography (2DE) or cor-

onary angiography. In the presence of �4 principalcriteria, the diagnosis of Kawasaki disease can bemade on day 4 of illness. Kawasaki disease should beconsidered in the differential diagnosis of a youngchild with unexplained fever for �5 days that isassociated with any of the principal clinical featuresof this disease.

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

Changes in the extremities are distinctive. Ery-thema of the palms and soles or firm, sometimespainful induration of the hands or feet, or both ery-thema and induration often occur in the acute phaseof the disease. Desquamation of the fingers and toesusually begins in the periungual region within 2 to 3weeks after the onset of fever and may extend toinclude the palms and soles. Approximately 1 to 2months after the onset of fever, deep transversegrooves across the nails (Beau’s lines) may appear.

An erythematous rash usually appears within 5days of the onset of fever. The rash may take variousforms; the most common is a nonspecific, diffusemaculopapular eruption. Occasionally seen are anurticarial exanthem, a scarlatiniform rash, an eryth-roderma, an erythema-multiforme-like rash, or,rarely, a fine micropustular eruption. Bullous andvesicular eruptions have not been described. Therash usually is extensive, with involvement of thetrunk and extremities and accentuation in the peri-neal region, where early desquamation may occur.

Bilateral conjunctival injection usually beginsshortly after the onset of fever. It typically involvesthe bulbar conjunctivae (sparing the limbus, an avas-cular zone around the iris) much more often than thepalpebral or tarsal conjunctivae; is not associatedwith an exudate, conjunctival edema or corneal ul-ceration; and usually is painless. Mild acute iridocy-clitis or anterior uveitis may be noted by slit lamp; itresolves rapidly and rarely is associated with photo-phobia or eye pain.

Changes of the lips and oral cavity include (1)erythema, dryness, fissuring, peeling, cracking, andbleeding of the lips; (2) a “strawberry tongue” that isindistinguishable from that associated with strepto-coccal scarlet fever, with erythema and prominentfungiform papillae; and (3) diffuse erythema of theoropharyngeal mucosae. Oral ulcerations and pha-ryngeal exudates are not seen.

Cervical lymphadenopathy is the least common ofthe principal clinical features. It is usually unilateraland confined to the anterior cervical triangle, and itsclassic criteria include �1 lymph node that is �1.5cm in diameter. Imaging studies frequently demon-strate multiple enlarged nodes without suppura-tion.61 The lymph nodes often are firm and nonfluc-tuant, are not associated with marked erythema ofthe overlying skin, and are nontender or only slightlytender. Occasionally, the lymph node swelling of

TABLE 1. Clinical and Laboratory Features of Kawasaki Dis-ease

Epidemiological case definition (classic clinical criteria)*Fever persisting at least 5 days†Presence of at least 4 principal features:

Changes in extremitiesAcute: Erythema of palms, soles; edema of hands, feetSubacute: Periungual peeling of fingers, toes in weeks 2

and 3Polymorphous exanthemBilateral bulbar conjunctival injection without exudateChanges in lips and oral cavity: Erythema, lips cracking,

strawberry tongue, diffuse injection of oral andpharyngeal mucosae

Cervical lymphadenopathy (�1.5-cm diameter), usuallyunilateral

Exclusion of other diseases with similar findings‡Other clinical and laboratory findings

Cardiovascular findingsCongestive heart failure, myocarditis, pericarditis, valvular

regurgitationCoronary artery abnormalitiesAneurysms of medium-size noncoronary arteriesRaynaud’s phenomenonPeripheral gangrene

Musculoskeletal systemArthritis, arthralgia

Gastrointestinal tractDiarrhea, vomiting, abdominal painHepatic dysfunctionHydrops of gallbladder

Central nervous systemExtreme irritabilityAseptic meningitisSensorineural hearing loss

Genitourinary systemUrethritis/meatitis

Other findingsErythema, induration at BCG inoculation siteAnterior uveitis (mild)Desquamating rash in groin

Laboratory findings in acute Kawasaki diseaseLeukocytosis with neutrophilia and immature formsElevated ESRElevated CRPAnemiaAbnormal plasma lipidsHypoalbuminemiaHyponatremiaThrombocytosis after week 1§Sterile pyuriaElevated serum transaminasesElevated serum gamma glutamyl transpeptidasePleocytosis of cerebrospinal fluidLeukocytosis in synovial fluid

Patients with fever at least 5 days and �4 principal criteria can bediagnosed with Kawasaki disease when coronary artery abnor-malities are detected by 2DE or angiography.† In the presence of �4 principal criteria, Kawasaki disease diag-nosis can be made on day 4 of illness. Experienced clinicians whohave treated many Kawasaki disease patients may establish diag-nosis before day 4.‡ See Table 2.§ Some infants present with thrombocytopenia and disseminatedintravascular coagulation.


Kawasaki disease can be confused with bacterial ad-enitis.

Because the principal clinical findings that fulfillthe diagnostic criteria are not specific, other diseaseswith similar clinical features should be excluded (Ta-ble 2).

Other Clinical and Laboratory Findings

Cardiac FindingsCardiovascular manifestations can be prominent

in the acute phase of Kawasaki disease and are theleading cause of long-term morbidity and mortality.During this phase, the pericardium, myocardium,endocardium, valves, and coronary arteries all maybe involved. Cardiac auscultation of the infant orchild with Kawasaki disease in the acute phase oftenreveals a hyperdynamic precordium, tachycardia, agallop rhythm, and an innocent flow murmur in thesetting of anemia, fever, and depressed myocardialcontractility secondary to myocarditis. Children withsignificant mitral regurgitation may have a pansys-tolic regurgitant murmur that is typical of this con-dition. Occasionally, patients with Kawasaki diseaseand poor myocardial function may present with lowcardiac output syndrome or shock. Electrocardiogra-phy may show arrhythmia, prolonged PR interval, ornonspecific ST and T wave changes.

Noncardiac FindingsMultiple noncardiac clinical findings may be ob-

served in patients with Kawasaki disease. Arthritisor arthralgia can occur in the first week of the illnessand tends to involve multiple joints, including thesmall interphalangeal joints as well as large weight-bearing joints. Arthritis or arthralgia developing af-ter the 10th day of illness favors large weight-bearingjoints, especially the knees and ankles.

Children with Kawasaki disease often are moreirritable than are children with other febrile illnesses.Transient unilateral peripheral facial nerve palsy oc-curs rarely. Transient high-frequency sensorineuralhearing loss (20–35 dB) can occur during acute Ka-wasaki disease,62,63 but persistent sensorineuralhearing 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 surgicalabdomen.65 Hepatic enlargement and jaundice canoccur. 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 ab-dominal ultrasound.60 Erythema and induration atthe site of a previous vaccination with BacilleCalmette-Guerin (BCG) is common in Japan, whereBCG is used widely.66 Rare findings include testicu-lar swelling, pulmonary nodules50 and infiltrates,67

pleural effusions, and hemophagocytic syndrome.68

Laboratory FindingsLeukocytosis is typical during the acute stage of

Kawasaki disease, with a predominance of immatureand mature granulocytes. Approximately 50% of pa-tients have white blood cell counts �15 000/mm3.Leukopenia is rare. Anemia may develop, usuallywith normal red blood cell indexes, particularly withmore prolonged duration of active inflammation. Se-vere hemolytic anemia requiring transfusions is rareand may be related to intravenous immunoglobulin(IVIG) infusion.69–72 Elevation of acute phase reac-tants, such as erythrocyte sedimentation rate (ESR)and C-reactive protein (CRP), is nearly universal inKawasaki disease, usually returning to normal by 6to 10 weeks after onset of the illness. Because thedegree of elevation of ESR and CRP may show adiscrepancy in some patients at the time of presen-tation, both should be measured.73 Furthermore, el-evation of ESR (but not of CRP) can be caused byIVIG therapy per se; therefore, ESR should not beused as the sole determinant of the degree of inflam-matory activity in IVIG-treated patients.

A characteristic feature of the later phases of theillness is thrombocytosis, with platelet counts rang-ing from 500 000 to �1 million/mm3. Thrombocyto-sis rarely is present in the first week of the illness,usually appears in the second week, and peaks in thethird week with a gradual return to normal by 4 to 8weeks after onset in uncomplicated cases. The meanpeak platelet count is �700 000/mm3. Thrombocyto-penia is seen rarely in the acute stage and may be asign of disseminated intravascular coagulation. Alow platelet count at illness presentation is a riskfactor for coronary aneurysms (see “Risk Scores forPredicting Aneurysms”). In patients with arthritis,arthrocentesis typically yields purulent-appearingfluid with a white blood cell count of 125 000 to300 000/mm3, a normal glucose level, and negativeGram stain and cultures.74 Plasma lipids are mark-edly altered in acute Kawasaki disease, with de-pressed plasma cholesterol, high-density lipoprotein(HDL), and apolipoprotein AI.75–78

Mild to moderate elevations in serum transami-nases occur in �40% of patients and mild hyperbil-irubinemia in �10%.79 Plasma gammaglutamyltranspeptidase is elevated in �67% of patients.80 Hy-poalbuminemia is common and is associated withmore severe and more prolonged acute disease. Uri-nalysis reveals intermittent mild to moderate sterilepyuria in �33% of patients, although suprapubicurine generally does not show pyuria, which sug-gests urethritis. In children who undergo lumbarpuncture, �50% demonstrate evidence of asepticmeningitis with a predominance of mononuclearcells, as well as normal glucose and protein levels.81

Elevation of serum cardiac troponin I, a marker

TABLE 2. Differential Diagnosis of Kawasaki Disease: Dis-eases and Disorders With Similar Clinical Findings

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

Scarlet feverStaphylococcal scalded skin syndromeToxic shock syndromeBacterial cervical lymphadenitisDrug hypersensitivity reactionsStevens-Johnson syndromeJuvenile rheumatoid arthritisRocky Mountain spotted feverLeptospirosisMercury hypersensitivity reaction (acrodynia)


that is specific for myocardial damage, has been re-ported in acute Kawasaki disease, which is consistentwith myocardial cell injury in the early phase of thedisease.82,83 Such elevation was not confirmed in an-other study.84 Troponin assays do not play a role inthe routine management of children with Kawasakidisease.

Laboratory tests, even though they are nonspecific,can provide diagnostic support in patients with clin-ical features that are suggestive but not diagnostic ofKawasaki disease. A moderately to markedly ele-vated CRP or ESR, which is almost universally seenin children with Kawasaki disease, is uncommonin viral infections. Platelet counts usually are�450 000/mm3 in patients evaluated after day 7 ofillness. Clinical experience suggests that Kawasakidisease is unlikely if platelet counts and acute-phaseinflammatory reactants (ie, ESR and CRP) are normalafter day 7 of illness. In addition, low white bloodcell count, lymphocyte predominance, and low plate-let count in the absence of disseminated intravascu-lar coagulation suggest a viral etiology.

Incomplete (Atypical) Kawasaki DiseaseSome patients who do not fulfill the criteria out-

lined in Table 1 have been diagnosed as having“incomplete” or “atypical” Kawasaki disease, a di-agnosis that often is based on echocardiographicfindings of coronary artery abnormalities. The term“incomplete” may be preferable to “atypical,” be-cause these patients lack sufficient clinical signs ofthe disease to fulfill the classic criteria; they do notdemonstrate atypical clinical features. The phrase“atypical Kawasaki disease” should be reserved forpatients who have a problem, such as renal impair-ment, that generally is not seen in Kawasaki disease.The conventional diagnostic criteria should beviewed as guidelines that are particularly useful inpreventing overdiagnosis but may result in failure torecognize incomplete forms of illness. IncompleteKawasaki disease is more common in young infantsthan in older children, making accurate diagnosisand timely treatment especially important in theseyoung patients who are at substantial risk of devel-oping coronary abnormalities.85 The laboratory find-ings of incomplete cases appear to be similar to thoseof classic cases. Therefore, although laboratory find-ings in Kawasaki disease are nondiagnostic, theymay prove useful in heightening or reducing thesuspicion of incomplete Kawasaki disease.

Echocardiography also may be useful in evaluat-ing children with protracted fever and some featuresof Kawasaki disease. Although aneurysms rarelyform before day 10 of illness, perivascular bright-ness, ectasia, and lack of tapering of the coronaryarteries in the acute stage of Kawasaki disease mayrepresent coronary arteritis before the formation ofaneurysms. Decreased left ventricular (LV) contrac-tility, mild valvular regurgitation (most commonlymitral regurgitation), and pericardial effusion alsomay be seen in an echocardiogram of a person withacute Kawasaki disease.

Incomplete Kawasaki disease should be consid-ered in all children with unexplained fever for �5

days associated with 2 or 3 of the principal clinicalfeatures of Kawasaki disease (see “Criteria for Treat-ment of Kawasaki Disease” and Fig 1). Becauseyoung infants may present with fever and few, ifany, principal clinical features, echocardiographyshould be considered in any infant aged �6 monthswith fever of �7 days’ duration, laboratory evidenceof systemic inflammation, and no other explanationfor the febrile illness.

Common Pitfalls in DiagnosisCertain common pitfalls in the diagnosis of Ka-

wasaki disease should be noted. Children maypresent with only fever and a unilateral enlargedcervical lymph node. The rash and mucosal changesthat follow often are mistaken for a reaction to anti-biotics that are administered for presumed bacteriallymphadenitis. Sterile pyuria may be mistaken for apartially treated urinary tract infection with sterileurine cultures. The young infant may present withfever, rash, and cerebrospinal fluid pleocytosis andbe misdiagnosed with viral meningitis. Occasionally,a child may present with an acute abdomen and beadmitted to a surgical service. Kawasaki diseaseshould be considered in the differential diagnosis ofevery child with fever of at least several days’ dura-tion, rash, and nonpurulent conjunctivitis, especiallyin children �1 year old and in adolescents, in whomthe diagnosis is frequently missed.

Risk Scores for Predicting AneurysmsSeveral scoring systems have been developed to

identify children at highest risk for coronary arteryabnormalities.86–89 Duration of fever, presumably re-flecting the severity of ongoing vasculitis, has beenconfirmed as a powerful predictor of coronary arteryaneurysms in various studies.87–89 Harada et al90,91

developed a risk score to use at the time a childpresents with Kawasaki disease to determine the riskof future coronary aneurysms. At some centers inJapan, the Harada score is used to determinewhether IVIG treatment will be used. Intravenousgamma globulin is given to children who fulfill 4 ofthe following criteria, assessed within 9 days of onsetof 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 �4risk factors but continuing acute symptoms, the riskscore is reassessed daily. In North America, whereIVIG is recommended for all children with Kawasakidisease, Beiser et al92 constructed a predictive instru-ment for the development of coronary artery lesionsamong patients treated with high-dose IVIG withinthe first 10 days of the onset of illness using datafrom a US multicenter database of patients withacute Kawasaki disease. The risk factors that Beiserand associates used in the sequential classificationinstrument included baseline neutrophil and bandcounts, hemoglobin concentration, platelet count,and temperature on the day after IVIG infusion. Thisinstrument allowed the clinician to identify within 1day of treatment the low-risk children in whom ex-tensive and frequent cardiac testing may be unnec-


essary. Its positive predictive value was less satisfac-tory, however; the frequencies of the development ofcoronary artery abnormalities in boys and girls whowere classified as high risk were only 13.8% and5.5%, respectively. Because of the imperfect perfor-mance of scoring systems, all patients who are diag-nosed with Kawasaki disease should be treated withIVIG.

Criteria for Treatment of Kawasaki DiseaseThe original guidelines for the diagnosis of Ka-

wasaki disease were created by a committee that wasappointed by the Japanese Ministry of Health in1970. At that time, the coronary artery complicationsof Kawasaki disease were not yet appreciated. Inaddition, neither effective treatment nor a noninva-sive method of assessing coronary artery abnormal-ities existed. The case definition was created, there-fore, for epidemiological surveillance and toestablish the extent of the clinical syndrome nowknown as Kawasaki disease in Japan. The case defi-nition intentionally was made restrictive to excludepatients with rheumatic fever and Stevens-Johnsonsyndrome.

More than 3 decades later, the clinical landscapehas changed dramatically. Echocardiographicscreening for coronary enlargement has shown that asubstantial number of children with Kawasaki dis-ease and coronary artery abnormalities are not iden-tified by the classic case definition.93–95 Thus, al-though the present case definition provides a specifictool for epidemiological surveillance, it may not bethe optimal method for aiding clinicians in the rec-ognition of children with a systemic vasculitis thatrequires prompt treatment. Given the potential seri-ousness of the complications, together with the effi-cacy and safety of early treatment, high sensitivity ofthe treatment criteria is more important than is highspecificity. We have therefore devised an algorithmto aid clinicians in deciding whether a child withsigns and symptoms suggestive of Kawasaki diseaseshould be treated with IVIG. To strive for the great-est sensitivity while maintaining sufficient specificityto prevent widescale overuse of IVIG, we have at-tempted to base our recommendations on laboratoryand echocardiographic data derived from the popu-lation of patients with Kawasaki disease who meetthe classic epidemiological case definition.

The 1993 American Heart Association guidelineson Kawasaki disease suggested that the diagnosiscould be made on day 4 of fever, with day 1 byconvention being the first day of fever.3 In the pres-ence of 4 of 5 classic criteria (Table 1), US and Japa-nese experts agree that only 4 days of fever arenecessary before initiating treatment.

It is also broadly agreed that Kawasaki disease canbe diagnosed in the absence of full criteria whencoronary abnormalities are present. The definition ofcoronary artery abnormalities has changed since theoriginal Japanese Ministry of Health criteria weredevised. In particular, coronary artery dimensions,adjusted for body surface area, provide a more accu-rate assessment of the size of the proximal rightcoronary artery (RCA) or left anterior descending

coronary artery (LAD) as compared with expectedpopulation norms.96,97 A z score �2.5 (ie, a coronarydimension that is �2.5 SDs above the mean for bodysurface area) in 1 of these arterial segments would beexpected to occur in �0.6% of the population with-out Kawasaki disease, and a z score �3.0 in 1 of thesesegments would be expected to occur in �0.1% of thepopulation without Kawasaki disease. Having a cor-onary artery z score �2.5 in both the proximal RCAand LAD would be uncommon in the general pop-ulation. Because of anatomic variation in the leftmain coronary artery (LMCA), its z score must beinterpreted with caution. Occasional cases of coro-nary prominence in patients with other disordershave been noted. Clinical experience, however, sug-gests that coronary enlargement in other febrile ill-nesses is rare, whereas coronary enlargement in Ka-wasaki disease is relatively common. Thus, coronaryartery z scores should be incorporated into the rec-ommendations for the evaluation and treatment ofKawasaki disease.

The present writing group proposes a scheme toaid the clinician in deciding which patients withfever and �4 classic criteria should undergo echo-cardiography or receive IVIG treatment or both forKawasaki disease (Fig 1). In the absence of a goldstandard for diagnosis, this algorithm cannot be ev-idence based but rather represents the informedopinion of a committee of experts (evidence level C).We offer this opinion as guidance to clinicians untilan evidence-based algorithm or a specific diagnostictest for Kawasaki disease becomes available.

CARDIAC FINDINGS

Coronary Aneurysms

EchocardiographyThe major sequelae of Kawasaki disease are re-

lated to the cardiovascular and, more specifically, thecoronary arterial system, so cardiac imaging is acritical part of the evaluation of all patients withsuspected Kawasaki disease. Because it is noninva-sive and has a high sensitivity and specificity for thedetection of abnormalities of the proximal LMCAand RCA, echocardiography is the ideal imagingmodality for cardiac assessment (evidence level C).Evaluation of the cardiovascular sequelae of Ka-wasaki disease requires serial cardiac ultrasoundstudies and should be performed using equipmentwith appropriate transducers and supervised by anexperienced echocardiographer. The initial echocar-diogram should be performed as soon as the diag-nosis is suspected, but initiation of treatment shouldnot be delayed by the timing of the study (ie, waitingfor sedation). This initial study establishes a baselinefor longitudinal follow-up of coronary artery mor-phology, LV and left valvular function, and the evo-lution and resolution of pericardial effusion whenpresent. Because detailed echocardiographic imag-ing is compromised if a child is uncooperative, seda-tion often is required for younger children (eg, chlo-ral hydrate 65–100 mg/kg, maximum 1000 mg, orother short-acting sedative or hypnotic agents).

The 2D imaging should be performed with the


highest-frequency transducer possible. Imaging withhigh-frequency transducers should be attemptedeven in older children, because these probes allowfor higher-resolution, detailed evaluation of the cor-onary arteries. Studies should be recorded in a dy-namic video or digital cine format, because the nor-mal translational movement of the heart facilitatesthe display of the coronary artery anatomy. Suchrecordings will allow future review and comparisonwith subsequent studies. In addition to standard im-aging from parasternal, apical, subcostal, and su-prasternal notch windows, 2DE evaluation of pa-tients with suspected Kawasaki disease should focuson imaging the LMCA, LAD, left circumflex coro-nary artery (LCX), RCA (proximal, middle, and dis-tal segments), and posterior descending coronary ar-teries. Multiple imaging planes and transducerpositions are required for the optimal visualizationof all major coronary segments (Table 3, Fig 2). Max-imal efforts should be made to visualize all majorcoronary segments. In order of highest to lowestfrequency, common sites of coronary aneurysms in-clude the proximal LAD and proximal RCA, fol-lowed by the LMCA, then LCX, and finally the distalRCA and the junction between the RCA and poste-rior descending coronary artery.

Evaluation of the coronary arteries should includequantitative assessment of the internal vessel diam-eters. Measurements should be made from inneredge to inner edge and should exclude points ofbranching, which may have normal focal dilation.The number and location of aneurysms and the pres-ence or absence of intraluminal thrombi also shouldbe assessed. Aneurysms are classified as saccular ifaxial and lateral diameters are nearly equal or asfusiform if symmetric dilatation with gradual proxi-mal and distal tapering is seen. When a coronaryartery is larger than normal (dilated) without a seg-mental aneurysm, the vessel is considered ectatic.Care must be taken in making the diagnosis of ecta-sia because of considerable normal variation in cor-onary artery distribution and dominance. In the last

American Heart Association statement,3,98 aneu-rysms were classified as small (�5-mm internal di-ameter), medium (5- to 8-mm internal diameter), orgiant (�8-mm internal diameter). The Japanese Min-istry of Health criteria classify coronary arteries asabnormal if the internal lumen diameter is �3 mm inchildren �5 years old or �4 mm in children �5 yearsold; if the internal diameter of a segment measures�1.5 times that of an adjacent segment; or if thecoronary lumen is clearly irregular.99 Current statis-tics on the prevalence of coronary artery abnormali-ties secondary to Kawasaki disease are based onthese criteria. Although the Japanese Ministry ofHealth criteria are not based on an individual pa-tient’s body size, coronary artery dimensions in chil-dren without Kawasaki disease have been shown toincrease with indexes of body size, such as bodysurface area or body length.

More recently, de Zorzi and colleagues96 showedthat the body surface area–adjusted coronary dimen-sions of some people with Kawasaki disease whosecoronary arteries were considered “normal” arelarger than expected in the acute, convalescent, andlate phases when compared with references estab-lished for body size. Figure 3 shows coronary inter-nal diameters according to body surface area in thepopulation without Kawasaki disease. Because useof the Japanese Ministry of Health criteria may resultin both underdiagnosis and underestimation of thetrue prevalence of coronary dilation, coronary vesselmeasurements adjusted for body surface area shouldbe compared with those of the population withoutKawasaki disease. Of note, z scores are available foronly 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” isstill useful for diagnosing aneurysms in peripheralsites. Enlargement of the LMCA caused by Kawasakidisease does not involve the orifice and rarely occurswithout associated ectasia of the LAD, LCX, or botharteries. In addition to measuring coronary arterydimensions, imaging the coronary arteries also mayreveal the lack of normal tapering and perivascularechogenicity or “brightness.”23

Although the echocardiographic examination ofpatients with Kawasaki disease is focused on thecoronary arteries, other information can and shouldbe obtained. Histological evidence suggests thatmyocarditis is universal in acute Kawasaki disease,and other studies have shown depressed ventricularcontractility to be common early in the course ofKawasaki disease. Therefore, assessment of LV func-tion should be a part of the echocardiographic eval-uation of all patients with suspected Kawasaki dis-ease. LV end-diastolic and end-systolic dimensionsand a shortening fraction should be measured fromstandard M-mode tracings. Apical imaging allowsthe estimation of LV end-diastolic and end-systolicvolumes and an ejection fraction. Although loadingconditions influence these measurements, they aremore readily measured than are complex indexes ofcontractility and are adequate for routine clinicalfollow-up. Evaluating regional wall motion may beuseful, especially in children with coronary artery

TABLE 3. Echocardiographic Views of Coronary Arteries inPatients With Kawasaki Disease

LMCA: Precordial short axis at level of aortic valve; precordiallong axis of left ventricle (superior tangential); subcostal LVlong axis

LAD: Precordial short axis at level of aortic valve; precordialsuperior tangential long axis of left ventricle; precordial shortaxis of left ventricle

Left circumflex: Precordial short axis at level of aortic valve;apical 4-chamber

RCA, proximal segment: Precordial short axis at level of aorticvalve; precordial long axis (inferior tangential) of leftventricle; subcostal coronal projection of right ventricularoutflow tract; subcostal short axis at level of atrioventriculargroove

RCA, middle segment: Precordial long axis of left ventricle(inferior tangential); apical 4-chamber; subcostal LV long axis;subcostal short axis at level of atrioventricular groove

RCA, distal segment: Apical 4-chamber (inferior); subcostalatrial long axis (inferior)

Posterior descending coronary artery: Apical 4-chamber(inferior); subcostal atrial long axis (inferior); precordial longaxis (inferior tangential) imaging posterior interventriculargroove


abnormalities. The aortic root also should be imaged,measured, and compared with references for bodysurface area because evidence exists that mild aorticroot dilation is common among patients with Ka-wasaki disease.100 Because pericarditis may be asso-ciated with the vasculitis and myocarditis seen inpatients with Kawasaki disease, the presence or ab-sence of a pericardial effusion should be noted.

Standard pulsed and color flow Doppler interro-gation should be performed to assess the presenceand degree of valvular regurgitation (in particularfor mitral and aortic valves). Color flow Dopplerwith a low Nyquist limit setting from a favorableangle of view may allow coronary flow to be dem-onstrated and may be useful in positively identifyingcoronary artery lumens.

It is important to recognize the limitations of echo-cardiography in the evaluation and follow-up of pa-tients with Kawasaki disease. Although echocardio-graphic detection of thrombi and coronary arterystenosis has been reported, the sensitivity and spec-ificity of echocardiography for identifying these ab-normalities is unclear. In addition, the visualizationof coronary arteries becomes progressively more dif-ficult as a child grows and body size increases. An-giography, intravascular ultrasound (IVUS), trans-esophageal echocardiography, and other modalitiesincluding magnetic resonance angiography (MRA)and ultrafast computed tomography (CT) may be ofvalue in the assessment of selected patients (see be-low).

For uncomplicated cases, echocardiographic eval-uation should be performed at the time of diagnosis,at 2 weeks, and at 6 to 8 weeks after onset of thedisease. More frequent echocardiographic evaluationis needed to guide management in children at higherrisk (eg, those who are persistently febrile or who

exhibit coronary abnormalities, ventricular dysfunc-tion, pericardial effusion, or valvular regurgitation).Recent studies have shown that repeat echocardiog-raphy performed 1 year after the onset of the illnessis unlikely to reveal coronary artery enlargement inpatients whose echocardiographic findings werenormal at 4 to 8 weeks.101,102 Because abnormalitiesin coronary artery function,103–105 coronary flow re-serve,106 and aortic root dilation100 remain potentialconcerns even among patients in whom coronarydilatation was never detected, repeat echocardiogra-phy beyond 8 weeks in patients with previouslynormal findings should be considered optional. Fol-low-up echocardiograms should identify the pro-gression or regression of coronary abnormalities,evaluate ventricular and valvular function, and as-sess the presence or evolution of pericardial effu-sions.

Other Noninvasive TestsMagnetic resonance imaging (MRI) and MRA may

delineate coronary artery aneurysms in the proximalcoronary artery segments and provide data regard-ing flow profile (evidence level C).107–109 A recentsmall series in patients with Kawasaki disease dem-onstrated that coronary MRA accurately diagnosedall coronary artery aneurysms, coronary occlusions,and coronary stenoses present on x-ray angiogra-phy.110 MRI and MRA may be used to image periph-eral artery aneurysms. Ultrafast CT also has beenused to assess coronary aneurysms.111,112 Furtherlarger studies in patients with Kawasaki disease areneeded to establish the reliability of MRA and ultra-fast CT for the detection of coronary artery aneu-rysms and stenoses in distal segments, as well as forthe presence of collateral circulation.

Cardiac stress testing for reversible ischemia is

Fig 2. 2D echocardiogram. AO indicates aorta; PA, pulmonary artery; CX, circumflex coronary artery; L MAIN, left main coronaryartery.


indicated to assess the existence and functional con-sequences of coronary artery abnormalities in chil-dren with Kawasaki disease and coronary aneu-rysms (evidence level A). The types of stress testsreported in children with Kawasaki disease includenuclear perfusion scans with exercise,113,114 exerciseechocardiography,115,116 and stress echocardiogra-phy with pharmacological agents such as dobut-amine,117,118 dipyridamole, or adenosine.119 More re-cently, MRI stress imaging with quantification ofregional perfusion has detected significant coronarystenoses.120 Myocardial perfusion also can be as-sessed by myocardial contrast echocardiography,taking gas-filled microbubbles to measure the micro-

circulatory flow and hence capillary density in dif-ferent myocardial regions.121 With stress, the myo-cardial blood volume fraction decreases distal to astenosis, causing a perfusion defect on myocardialcontrast echocardiography.122,123

The predictive value of stress tests for coronaryartery disease requiring intervention is a function ofthe probability of significant disease in the popula-tion tested (Bayes’ theorem). For example, false-pos-itive tests are more likely in patients with a previ-ously low probability of coronary disease. Usedappropriately, stress test results may guide a clini-cian’s decision to refer a patient for invasive evalu-ation (ie, cardiac catheterization), as well as for cath-eter or surgical intervention. The choice of stressmodality should be guided by institutional expertisewith particular techniques, as well as by the age ofthe child (eg, pharmacological stress should be usedin young children in whom traditional exercise pro-tocols are not feasible).

Cardiac Catheterization and AngiographyCoronary angiography offers a more detailed def-

inition of coronary artery anatomy than does cardiacultrasound, making it possible to detect coronaryartery stenosis or thrombotic occlusion and to deter-mine the extent of collateral artery formation in pa-tients with Kawasaki disease (Fig 4). Before recom-mending coronary angiography to a patient, aphysician must compare the potential benefits of theprocedure with its risks and cost. In patients withmild ectasia or small fusiform aneurysms demon-strated by echocardiography, coronary angiographyis unlikely to provide any further useful informationand is not recommended (evidence level C). Patientswith more complex coronary artery lesions may ben-efit from coronary angiography after the acute in-flammatory process has resolved. Practices regard-ing the timing of cardiac catheterization for suchpatients vary greatly from center to center; coronaryangiography is generally recommended 6 to 12months after the onset of illness or sooner if indi-cated clinically (evidence level C). In long-term fol-low-up, the decision to perform angiography may beguided by echocardiographic imaging of coronaryarteries, ventricular regional wall motion abnormal-ities, and clinical signs or noninvasive studies indi-cating myocardial ischemia. The failure to image dis-tal coronary arteries in a patient in whom largeproximal aneurysms have regressed may be an indi-cation for another imaging modality, including car-diac angiography, to guide the appropriate use ofantithrombotic agents (evidence level C). Patientswho have undergone surgical revascularization orcatheter intervention may have a repeat cardiac cath-eterization so that the efficacy of the treatment can beevaluated (evidence level C).

Additional techniques used during cardiac cathe-terization may detect structural or functionalchanges in the coronary artery wall. Patients withangiographically documented regression of coronaryartery aneurysms have shown abnormal thickeningof the intima-media complex by IVUS124 and abnor-mal vasoreactivity in response to various vasodila-

Fig 3. Mean and prediction limits for 2 and 3 SDs for size of LAD(A), proximal RCA (B), and LMCA (C) according to body surfacearea for children �18 years old. LMCA z scores should not bebased on dimension at orifice and immediate vicinity; enlarge-ment of LMCA secondary to Kawasaki disease usually is associ-ated with ectasia of LAD, LCX, or both.


tors.125,126 The long-term clinical implications ofthese anatomical and functional changes are un-known at this time.

Aneurysms can occur in arteries outside the coro-nary system, most commonly the subclavian, bra-chial, axillary, iliac, or femoral vessels, and occasion-ally in the abdominal aorta and renal arteries.127 Forthis reason, abdominal aortography and subclavianarteriography are recommended in patients with Ka-wasaki disease undergoing coronary arteriographyfor the first time (evidence level C).

MyocarditisMyocarditis has been demonstrated in autopsy

and myocardial biopsy studies to be a common fea-ture of early Kawasaki disease.34,128 Myocardial in-flammation has been documented in 50% to 70% ofpatients using 67Ga citrate scans (planar or single-photon emission CT)129 and 99mTc-labeled whiteblood cell scans.130–132 The severity of myocarditisdoes not appear to be associated with the risk ofcoronary artery aneurysms, however.133,134

Although the majority of patients with Kawasakidisease has abnormal myocardial contractility byechocardiographic assessment at presentation, myo-cardial mechanics improve rapidly after IVIG ther-apy, with a high concordance between the clinicaland myocardial responses to therapy.135 The speedof recovery suggests that depressed contractility inpatients with Kawasaki disease is caused by rapidlyreversible mechanisms such as those involving cir-culating toxins or activated cytokines. It is also pos-sible that the inflammatory infiltrate found betweenthe muscle fibers on postmortem examination inearly Kawasaki disease may resolve quickly.

The occurrence of myocarditis during the acutephase of Kawasaki disease has fostered concern

about the potential long-term effects of the diseaseon myocardial function. Biopsy of the right ventric-ular myocardium was performed in 201 patientswith Kawasaki disease to assess the evolution andcourse of myocardial change.136 The interval be-tween onset of the disease and myocardial biopsyranged from 2 months to 11 years. Myocardial ab-normalities, including fibrosis and cellular disar-rangement, as well as abnormal branching and hy-pertrophy of myocytes, were detected at all timeperiods after onset of the disease; their severity wasunrelated to the presence of coronary artery abnor-malities. In addition, electron microscopic examina-tion of endomyocardial biopsies has demonstratedultrastructural abnormalities late after Kawasaki dis-ease.137

Despite the concerns raised about histopathologicabnormalities on myocardial biopsy, long-term myo-cardial contractility and function measured by echo-cardiography appear to be normal, except amongpatients with ischemic heart disease.135 Assessmentof the full impact of Kawasaki disease on heart func-tion must await follow-up studies of these childreninto adulthood.

Valvular RegurgitationMitral regurgitation may result from transient

papillary muscle dysfunction, MI, or valvulitis. Theappearance of mitral regurgitation after the acutestage usually is secondary to myocardial ischemia,although late-onset valvulitis unrelated to ischemiahas been documented.138 Kato et al2 reported 6 pa-tients (1.0% of their series) with mitral regurgitationin the acute or subacute stage of Kawasaki disease,with resolution in 3 patients, death from MI in 2, andpersistence from papillary muscle dysfunction in 1.

Aortic regurgitation has been documented angio-

Fig 4. Coronary angiogram demonstrating giant aneurysm of the LAD with obstruction and giant aneurysm of the RCA with area ofsevere narrowing in 6-year-old boy.


graphically by Nakano and colleagues139 in �5% ofchildren with Kawasaki disease and was attributedto valvulitis. Other investigators have observed amuch lower incidence of aortic regurgitation in theacute phase,2 but late-onset aortic regurgitation hasbeen reported as an exceedingly rare finding afterKawasaki disease and may be associated with theneed for aortic valve replacement.2,138,140 Approxi-mately 4% of a consecutive series with Kawasakidisease had mild aortic regurgitation as seen byechocardiogram.100

TREATMENT

Initial Treatment

AspirinAspirin has been used in the treatment of Ka-

wasaki disease for many years. Although aspirin hasimportant anti-inflammatory (at high doses) and an-tiplatelet (at low doses) activity, it does not appear tolower the frequency of the development of coronaryabnormalities.141 During the acute phase of illness,aspirin is administered at 80 to 100 mg/kg per day in4 doses with IVIG (see next section). High-dose as-pirin and IVIG appear to possess an additive anti-inflammatory effect. Practices regarding the durationof high-dose aspirin administration vary across insti-tutions, and many centers reduce the aspirin doseafter the child has been afebrile for 48 to 72 hours.Other clinicians continue high-dose aspirin until day14 of illness and �48 to 72 hours after fever cessation.When high-dose aspirin is discontinued, cliniciansbegin low-dose aspirin (3–5 mg/kg per day) andmaintain it until the patient shows no evidence ofcoronary changes by 6 to 8 weeks after the onset ofillness (evidence level C). For children who developcoronary abnormalities, aspirin may be continuedindefinitely (evidence level B). Of note, the concom-itant use of ibuprofen antagonizes the irreversibleplatelet inhibition that is induced by aspirin142; thus,in general, ibuprofen should be avoided in childrenwith coronary aneurysms taking aspirin for its anti-platelet effects (evidence level B).

Reye syndrome is a risk in children who takesalicylates while they are experiencing active infec-tion with varicella or influenza and has been re-ported in patients taking high-dose aspirin for a pro-longed period after Kawasaki disease.143,144 It isunclear whether the low-dose therapy used for anti-platelet effect increases the risk of Reye syndrome.Children who are taking salicylates long-term shouldreceive an annual influenza vaccine.145 Althoughvaccine manufacturers recommend that salicylatesbe avoided for 6 weeks after the administration ofvaricella vaccine, physicians need to weigh the the-oretical risks associated with varicella vaccineagainst the known risks of wild-type varicella inchildren receiving long-term salicylate therapy.145

Some physicians substitute another antiplatelet med-ication for aspirin during the 6-week period. Parentsof the children receiving salicylates should be in-structed to contact their child’s physician promptly ifthe child develops symptoms of or is exposed toeither influenza or varicella.

IVIGThe efficacy of IVIG administered in the acute

phase of Kawasaki disease in reducing the preva-lence of coronary artery abnormalities is well estab-lished.141,146–148 The mechanism of action of IVIG intreating Kawasaki disease is unknown. IVIG appearsto have a generalized anti-inflammatory effect. Thepossible mechanisms of action include modulation ofcytokine production, neutralization of bacterial su-perantigens or other etiologic agents, augmentationof T-cell suppressor activity, suppression of antibodysynthesis, and provision of anti-idiotypic antibodies.

A variety of dose regimens have been used inJapan and the United States. Two meta-analyseshave demonstrated a dose-response effect, withhigher doses given in a single infusion having thegreatest efficacy.141,148 Furthermore, peak adjustedserum IgG levels are lower among patients whosubsequently develop coronary artery abnormalitiesand are inversely related to fever duration and lab-oratory indexes of acute inflammation.147,149 The as-sociation of lower peak IgG levels with worse out-comes lends further support to the concept of arelationship between serum IgG concentration andtherapeutic effectiveness.

Patients should be treated with IVIG, 2 g/kg in asingle infusion (evidence level A), together with as-pirin (see previous section).3 This therapy should beinstituted within the first 10 days of illness and, ifpossible, within 7 days of illness. Treatment of Ka-wasaki disease before day 5 of illness appears nomore likely to prevent cardiac sequelae than doestreatment on days 5 to 7, but it may be associatedwith an increased need for IVIG retreatment.150,151

IVIG also should be administered to children pre-senting after the 10th day of illness (ie, children inwhom the diagnosis was missed earlier) if they haveeither persistent fever without other explanation152

or aneurysms and ongoing systemic inflammation,as manifested by elevated ESR or CRP (evidencelevel C).

Gamma globulin is a biological product madefrom pooled donor plasma, and potentially impor-tant product-manufacturing differences exist. Per-haps for this reason, adverse effects appear to varyconsiderably among products.153–155 The results ofclinical studies comparing the efficacy of immuneglobulin products have conflicted,156,157 with moststudies failing to find a significant difference be-tween brands. Within the US health care system, theuse of high-dose IVIG is cost-effective.130 In Japan,however, some centers treat only children who arepredicted to be at high risk for developing coronaryartery disease,90 although practices have been chang-ing since 1996 with the approval by the JapaneseMinistry of Health of the 2 g/kg regimen.

Measles and varicella immunizations should bedeferred for 11 months after a child receives high-dose IVIG.145 A child in whom the risk of exposure tomeasles is high, however, may be vaccinated earlierand then be reimmunized �11 months after IVIGadministration if the child has an inadequate sero-logical response. Even when treated with high-dose


IVIG regimens within the first 10 days of illness,�5% of children with Kawasaki disease develop atthe least transient coronary artery dilation and 1%develop giant aneurysms.98,141,148 Additional poten-tially beneficial treatments are discussed below, butthe optimal treatment awaits delineation of the spe-cific agent or agents and pathogenetic mechanisms ofKawasaki disease.

SteroidsAlthough corticosteroids are the treatment of

choice in other forms of vasculitis, their use has beenlimited in children with Kawasaki disease.158 Corti-costeroids were used as the initial therapy for Ka-wasaki disease long before the first report of IVIGefficacy by Furusho et al146 in 1984. Although anearly study by Kato et al159 suggested that steroidsexert a detrimental effect when used as the initialtherapy for Kawasaki disease, subsequent studieshave shown either no ill effects or possible benefit. Ina randomized trial of high-dose intravenous methyl-prednisolone plus heparin as compared with heparinalone, Kijima et al160 found that steroid therapy wasassociated with a greater rate of improvement incoronary abnormalities. In a randomized trial in 100children treated with intravenous prednisolone fol-lowed by an oral taper versus low-dose IVIG (300mg/kg per day for 3 consecutive days), Nonaka andcolleagues161 reported shorter fever duration in thesteroid group but no significant difference in theprevalence of coronary aneurysms. In a retrospectivereview, Shinohara et al162 found that treatment reg-imens that included prednisolone were associatedwith significantly shorter fever duration and a lowerprevalence of coronary artery aneurysms. Most re-cently, a small randomized trial examined whetherthe addition of 30 mg/kg of intravenous methyl-prednisolone to conventional therapy with IVIG (2g/kg) and aspirin improved outcomes.163 Patientswho received steroids had a shorter duration of feverand shorter hospital stays, as well as a lower meanESR and median CRP 6 weeks after the onset ofillness. No differences between treatment groups incoronary outcomes were noted, with limited statisti-cal power. Children to whom corticosteroids andIVIG were administered, compared with those whoreceived IVIG alone, had reduced levels of cytokines,including interleukin-2 (IL-2), IL-6, IL-8, and IL-10within 24 hours of IVIG administration.164 Atpresent, the usefulness of steroids in the initial treat-ment of Kawasaki disease is not well established(evidence level C). A National Heart, Lung, andBlood Institute–funded, multicenter randomized,placebo-blind trial that is in progress will providemore information on the effectiveness of such treat-ment.

PentoxifyllinePentoxifylline is a methyl xanthine compound that

specifically inhibits TNF-� messenger RNA tran-scription. Because TNF-� appears to be important inthe inflammatory cascade in Kawasaki disease, pen-toxifylline has been assessed as a therapeutic adjunctto standard therapy. In a small clinical trial in which

all patients were treated with a low-dose regimen ofIVIG plus aspirin, the individuals who receivedhigh-dose pentoxifylline appeared to have fewer an-eurysms and therapy was well tolerated.165 A recentstudy reported the pharmacokinetics of an oral pe-diatric suspension of pentoxifylline in children withacute Kawasaki disease.166 The drug was well toler-ated, and no toxicities were noted. The role of pen-toxifylline in the initial treatment of Kawasaki dis-ease is uncertain (evidence level C).

Treatment of Patients Who Failed to Respond to InitialTherapy

IVIGApproximately �10% of patients with Kawasaki

disease fail to defervesce with initial IVIG thera-py.156,167,168 Failure to respond usually is defined aspersistent or recrudescent fever �36 hours after com-pletion of the initial IVIG infusion. Most expertsrecommend retreatment with IVIG, 2 g/kg (evidencelevel C). The putative dose-response effect of IVIGforms the theoretical basis for this approach.

SteroidsCorticosteroids also have been used to treat pa-

tients who have failed to respond to initial therapyfor Kawasaki disease.158 Several small case serieshave described children with Kawasaki disease withrecrudescent or persistent fever despite IVIG treat-ment in whom the administration of steroid therapywas associated with an improvement in symptomsand the absence of a significant progression in coro-nary artery abnormalities or adverse effects.168–170 Ina recent small randomized trial, Hashino et al171

compared the efficacy and safety of additional IVIGtherapy with pulse steroid therapy in patients withIVIG-resistant Kawasaki disease. Seventeen patientswho did not respond to an initial infusion of 2 g/kgIVIG plus aspirin followed by an additional IVIGinfusion of 1 g/kg were randomized to receive eithera single additional dose of IVIG (1 g/kg) or pulsesteroid therapy. Patients in the steroid group had ashorter duration of fever and lower medical costs.No significant difference in the incidence of coronaryartery aneurysms was noted between the 2 groups,but power to detect a difference was limited.

Studies of steroids in the initial therapy for Ka-wasaki disease, as well as in therapy for patientswith persistent or recrudescent fever despite treat-ment with IVIG and aspirin, have shown that corti-costeroids reduce fever. The effects of steroids oncoronary artery abnormalities are still uncertain,however. Until multicenter controlled trials areavailable, the present writing group recommendsthat steroid treatment be restricted to children inwhom �2 infusions of IVIG have been ineffective inalleviating fever and acute inflammation (evidencelevel C). The most commonly used steroid regimen isintravenous pulse methylprednisolone, 30 mg/kgfor 2 to 3 hours, administered once daily for 1 to 3days.


Other TreatmentsPlasma exchange has been reported in an uncon-

trolled clinical trial to be an effective therapy inpatients who are refractory to IVIG and to lower theincidence of coronary artery aneurysms.172 Of note,treatment assignment was not randomized, and fewdetails about the comparability of treatment groupswere provided in this short report. Earlier reports ofdramatic response to this mode of treatment consistof small case series.173,174 Because of its risks, plasmaexchange is not in general recommended (evidencelevel C).

Ulinastatin is a human trypsin inhibitor purifiedfrom human urine that has been used in Japan as anadjunctive therapy for acute Kawasaki disease. This67 000-Dalton glycoprotein inhibits neutrophil elas-tase as well as prostaglandin H2 synthase at themessenger RNA level.175 Ulinastatin has been pro-posed as useful in IVIG-refractory patients,175 but itseffectiveness is unproven, and additional experiencewith this agent is necessary before it can be recom-mended (evidence level C).

Abciximab, a platelet glycoprotein IIb/IIIa receptorinhibitor, has been used to treat patients in the acuteor subacute phase of Kawasaki disease who havelarge coronary aneurysms.176 Patients who receivedabciximab plus standard therapy as compared withhistorical controls treated with standard therapyalone showed a greater regression in maximum an-eurysm diameter, suggesting that treatment with ab-ciximab might promote vascular remodeling. Pro-spective controlled trials are needed, but abciximabtherapy may be considered in patients with largeaneurysms in the acute or subacute phase (evidencelevel C).

A new class of agents that may play a role in thetreatment of patients with refractory Kawasaki dis-ease is monoclonal antibodies to various proinflamma-tory cytokines.177 A humanized monoclonal anti-body against TNF-�, infliximab, is being studied in aclinical trial of treatment for children who fail tobecome afebrile after initial IVIG treatment. Al-though its effectiveness in reducing the prevalence ofcoronary artery aneurysms is unproven, therapywith infliximab or other agents directed at TNF-�might be considered in patients who are resistant toIVIG and steroids (evidence level C).

Cytotoxic agents such as cyclophosphamide, in con-junction with oral steroids, have been suggested asuseful for the treatment of exceptional patients withparticularly refractory acute Kawasaki disease.168

This therapy is used widely to treat other severevasculitides. Cyclosporin A was reported to be inef-fective in halting the progression of obliterative pan-arteritis in a single case report of fatal Kawasakidisease.178 Of note, the risks of cytotoxic agents ex-ceed the benefits for the vast majority of patientswith Kawasaki disease (evidence level C).

In summary, because controlled data are lacking,the relative roles of repeated doses of IVIG, cortico-steroids, TNF-� antagonists, plasma exchange, abcix-imab, and agents such as cyclophosphamide for pa-

tients with refractory Kawasaki disease remainuncertain.

Prevention of Thrombosis in Patients With CoronaryDisease

The management of coronary disease in patientswith Kawasaki disease depends on the severity andextent of coronary involvement. No prospective dataexist to guide clinicians in choosing an optimal reg-imen, so recommendations are based on knownpathophysiology, retrospective case series in chil-dren with Kawasaki disease, and extrapolation fromexperience in adults with coronary disease. Thera-peutic regimens used in patients with Kawasaki dis-ease depend on the severity of coronary involvementand include antiplatelet therapy with aspirin, with orwithout dipyridamole or clopidogrel; anticoagulanttherapy with warfarin or low-molecular-weight hep-arin; or a combination of anticoagulant and antiplate-let therapy, usually warfarin plus aspirin.

Platelet activation is a profound component of theacute illness and persists throughout the convales-cent and chronic phases. As a result, antiplateletagents play a critical role in managing patients atevery stage. Low-dose aspirin may be appropriatefor asymptomatic patients with mild and stable dis-ease. As the extent and severity of the coronaryartery enlargement increase, the combination of as-pirin with other antiplatelet agents (eg, clopidogrel,dipyridamole) aimed at antagonizing adenosine-5�diphosphate may be more effective in suppressingplatelet activation. Clopidogrel in combination withaspirin has been shown to be more effective thaneither agent alone in preventing vascular events inboth coronary and cerebral territories in adults (theClopidogrel in Unstable Angina to Prevent RecurrentEvents study).179–182 Most experts believe that a pre-dominantly platelet-directed approach is appropri-ate in the setting of stable, mild-to-moderate disease(evidence level C).

When a coronary aneurysm expands rapidly, therisk of thrombosis is particularly high. For this rea-son, the use of heparin with aspirin has been advo-cated (evidence level C). The goals for treatment inthis group include prevention of thrombosis, as wellas modification of the evolution of the derangementof the coronary shape and size, which may relate tothe remodeling effects of endothelial damage andthrombosis.

The coronary aneurysm presents increasingly ab-normal flow conditions, which are unlike other com-mon clinical conditions such as atherosclerosis.183

Within the aneurysm itself, the vessel dilatation re-sults in low blood flow velocities and relative stasisof flow, which predispose the aneurysm to chronicthrombus formation. Additional severe abnormali-ties of coronary flow may arise over time secondaryto incremental stenoses at the proximal or distal orproximal and distal ends of the aneurysm. This com-bination of stenosis at the aneurysm inlet, in imme-diate proximity to a dilated, low-velocity region, is apowerful stimulus to thrombus formation. Plateletsare activated by the high shear stress that occurs atthe stenosis and then are stimulated further as they


decelerate and linger within the turbulent, low-ve-locity regions distal to the stenosis. The poststenoticturbulence also is responsible for endothelial activa-tion that results from gradients in the region of shearstress. Thus, progressive stenosis of these chronicallyhypercoagulable segments augments both the plate-let and endothelial mechanisms for thrombosis. Fi-nally, the presence of chronic thrombus in the aneu-rysm presents fibrin and clotting precursors that canamplify the thrombotic cascade. Patients with giantaneurysms, with or without stenosis, are at the high-est risk for coronary thrombosis.

The most common antithrombotic regimen for pa-tients with giant aneurysms is low-dose aspirin to-gether with warfarin, maintaining an internationalnormalized ratio (INR) of 2.0 to 2.5 (evidence levelC). Some physicians substitute a therapeutic dose oflow-molecular-weight heparin for warfarin, al-though this therapy requires twice-daily subcutane-ous injections.

Treatment of Coronary ThrombosisOnce thrombosis is initiated in proximity to a seg-

ment at risk, it may progress rapidly and create athrombus burden unlike that which occurs in adultatherosclerotic coronary occlusion. Coronary occlu-sion in adults with atherosclerosis involves plaquerupture or inflammation that exposes lipids and theextracellular matrix to the coagulation system. Ka-wasaki disease-associated acute thrombosis is notrelated to this form of plaque instability or rupture.Therefore, established thrombolytic protocols foradults with atherosclerotic coronary disease may not

necessarily be optimal for the Kawasaki disease pop-ulation.

The treatment of acute coronary occlusion in pa-tients with Kawasaki disease should target multiplesteps in the coagulation cascade (Table 4). In casereports, streptokinase,184,185 urokinase,186–188 and tis-sue plasminogen activator (tPA)189,190 each has beenadministered to infants and children with coronarythrombosis with varying success rates (evidencelevel C). Because no randomized, controlled trialshave been performed in children, the treatment ofinfants and children with coronary thrombosis isderived from studies in adults with acute coronarysyndromes. The goals of therapy include reestablish-ing coronary patency, salvaging the myocardium,and improving survival.191 In adult trials, treatmentwith streptokinase has demonstrated a lower inci-dence of bleeding than have other agents (eg,Gruppo Italiano per lo Studio della Sopravvivenzanell’Infarto [GISSI-1], Second International Study ofInfarct Survival [ISIS-2]),192,193 but potential allergiccomplications limit its use in patients with a historyof streptococcal pharyngitis within the past 6months. Better coronary patency rates are achievedwith tPA than with streptokinase in adults (GlobalUtilization of Streptokinase and Tissue PlasminogenActivator for Occluded Coronary Arteries [GUSTO-1]).194–196 Tenecteplase-tPA is 14 times more fibrinspecific than is tPA and may be more fibrinolytic atthe site of the thrombus. Its longer association withthe fibrin-rich clot and higher fibrin specificity maylead to the enhanced dissolution of older clots (�4hours), with fewer bleeding complications as com-

TABLE 4. Antiplatelet, Anticoagulant, and Thrombolytic Medications

Medication Route Dosage

Aspirin Oral Antiplatelet dose: 3–5 mg/kg every dayClopidogrel Oral 1 mg/kg per day* to max (adult dose) of 75 mg/dayDipyridamole Oral 2–6 mg/kg per day in 3 divided doses†Unfractionated heparin Intravenous Load: 50 U/kg

Infusion: 20 U/kg/hAdjust dosage to achieve desired therapeutic level, usually

plasma heparin level�0.35–0.7 in antifactor Xa activityor aPTT 60–85 s

Low-molecular-weight heparin Subcutaneous Infants �12 monthsTreatment: 3 mg/kg per day, divided every 12 hProphylaxis: 1.5 mg/kg per day, divided every 12 h

Children/adolescentsTreatment: 2 mg/kg per day, divided every 12 h

Prophylaxis: 1.5 mg/kg per day, divided every 12 hProphylaxis: 1 mg/kg per day, divided every 12 hProphylaxis: 1.5 mg/kg per day, divided every 12 h

Adjust dose to achieve desired therapeutic level, usuallyantifactor Xa � 0.5–1.0 U/mL

Abciximab Intravenous Bolus: 0.25 mg/kgInfusion: 0.125 �g/kg per min for 12 h

Streptokinase Intravenous Bolus: 1000–4000 U/kg over 30 minInfusion: 1000–1500 U/kg per h

tPA Intravenous Bolus: 1.25 mg/kgInfusion: 0.1–0.5 mg/kg per h for 6 h, then reassess

Urokinase Intravenous Bolus: 4400 U/kg over 10 minInfusion: 4400 U/kg per h

Warfarin Oral 0.1 mg/kg per day, given every day (0.05–0.34 mg/kg perday; adjust dose to achieve desired INR, usually 2.0–2.5)

No published studies in children.† Clopidogrel is preferred to dipyridamole, based on adult studies.


pared with tPA (Assessment of the Safety and Effi-cacy of a New Thrombolytic [ASSENT-2]).197 Allthrombolytic regimens include aspirin and eitherheparin or low-molecular-weight heparin.

The platelet glycoprotein IIb/IIIa receptor partici-pates in the final common pathway for platelet ag-gregation. Inhibition of this receptor has shown greatpromise for improving outcomes when administeredwith aspirin and heparin, both with and without theuse of thrombolytics in adults with acute coronarysyndromes.198–200 Reduced-dose thrombolytic ther-apy in combination with the administration of a gly-coprotein IIb/IIIa inhibitor, such as abciximab, re-stores antegrade flow as effectively as does full-dosethrombolytic therapy, but it is associated with lowerrates of reocclusion and reinfarction (evidence levelC). Mechanical restoration of coronary blood flow(ie, the use of immediate coronary angioplasty orstent placement) is effective in adults and has beenused in a small number of children (evidence levelC).23 The choice of method to reestablish perfusion inchildren with Kawasaki disease and coronary throm-bosis should be based on that which can be admin-istered with the greatest expertise in a timely fashion.

Surgical and Catheter Coronary InterventionsThe current recommendations for surgical and

catheter interventions summarize the current opin-ions of experts based on limited data. The presentwriting group recommends that decisions about in-tervention in individual patients be made in concertwith experienced adult interventional cardiologistsand cardiac surgeons.

Surgical ManagementAttempts at excision or plication of the coronary

artery aneurysm have not been successful and havecaused deaths. Surgical management in Kawasakidisease comprises primarily coronary artery bypassgrafts for obstructive lesions.201–203 The diameter andlength of internal mammary grafts increase with thesomatic growth of children as compared with thetendency of saphenous vein grafts to shorten some-what over time. In a recently published series, thepatency rates of arterial grafts (primarily the left andright internal mammary arteries) were 94%, 82%,and 78% at 1, 5, and 10 years, respectively, whereaspatency rates for venous grafts were 82%, 63%, and36%, respectively.202 No early deaths occurred, andonly 2 patients died at late follow-up of mean 6.7 �4.5 years, 1 with sudden death and the other in atraffic accident. Freedom from cardiac events afterbypass was �70% at 10 years. Although the resultsduring the first decade after coronary artery bypasssurgery in childhood are encouraging, the arterialgraft patency rate in later adult life is still unknown.

The indications for coronary bypass graft proce-dures in children have not been established in clini-cal trials, but such surgery should be consideredwhen reversible ischemia is present on stress-imag-ing test results, the myocardium to be perfusedthrough the graft is still viable, and no appreciablelesions are present in the artery distal to the plannedgraft site (evidence level C). One panel of experts

stated that surgical revascularization may be consid-ered under the following conditions: severe occlu-sion of the main trunk of the LMCA, severe occlusionof �1 major coronary artery, severe occlusion in theproximal segment of the LAD, collateral coronaryarteries in jeopardy, or all of the above.204 Mostexperts agree that surgery is indicated after recurrentMI because the prognosis is so unfavorable.205,206

Interventional Cardiac Catheterization TechniquesCatheter interventions including balloon angio-

plasty, rotational ablation, and stent placement havebeen performed in a relatively small number of chil-dren with Kawasaki disease. Most of the experiencehas been accumulated in Japan. In general, balloonangioplasty has not been successful even with high-pressure balloons when it is done �2 years after theacute illness because of dense fibrosis and calcifica-tion in the arterial wall.207,208 The relatively highballoon pressures that are necessary under these cir-cumstances can lead to late neoaneurysm forma-tion.208 For this reason, if percutaneous transluminalcoronary angioplasty cannot be performed with aballoon pressure of �10 atm, then rotational ablationor bypass surgery is advisable as an alternative pro-cedure.209 IVUS imaging has been found to be auseful tool for evaluating internal vessel morphologybefore and after percutaneous transluminal coronaryangioplasty.207 Stent placement has been useful inolder children with mild calcification and in childrenwith giant aneurysms. Rotational ablation and stentplacement have met with a success rate �80% ac-cording to a collective experience in Japan.210

The recommendations for catheter intervention forpatients with Kawasaki disease recently formulatedby the Research Committee of the Japanese Ministryof Health, Labor, and Welfare209 state that catheterintervention should be considered in patients pre-senting with ischemic symptoms, patients withoutischemic symptoms but with reversible ischemia onstress test, and patients without ischemia but with�75% stenosis in the LAD (evidence level C). Bypasssurgery is preferred in patients with severe LV dys-function. Catheter intervention is contraindicated forindividuals who have vessels with multiple, ostial, orlong-segment lesions (evidence level C).

Cardiac TransplantationA small number of patients with Kawasaki disease

have undergone cardiac transplantation for severemyocardial dysfunction, severe ventricular arrhyth-mias, and severe coronary arterial lesions for whichinterventional catheterization or coronary artery by-pass procedures were not feasible.211 The timing oftransplant has ranged from a few weeks or months toas long as 12 years after acute Kawasaki disease.Almost half of the transplant patients had undergoneprevious bypass grafting procedures without expe-riencing improvement in myocardial function. Thisprocedure should be considered only for individualswith severe, irreversible myocardial dysfunction andcoronary lesions for which interventional catheter-ization procedures or coronary artery bypass are notfeasible (evidence level C).


LONG-TERM FOLLOW-UP

Natural History

Regression and Evolution of Coronary LesionsCoronary artery lesions resulting from Kawasaki

disease change dynamically with time. Angiographicresolution 1 to 2 years after onset of the disease hasbeen observed in �50% to 67% of vessels with cor-onary aneurysms.2,212 The likelihood that an aneu-rysm will resolve appears to be determined in largemeasure by its initial size, with smaller aneurysmshaving a greater likelihood of regression.213,214 Otherfactors that are positively associated with the regres-sion of aneurysms include age at onset of Kawasakidisease �1 year, fusiform rather than saccular aneu-rysm morphology, and aneurysm location in a distalcoronary segment.212 Vessels that do not undergoapparent resolution of abnormalities may demon-strate persistence of aneurysmal morphology, devel-opment of stenosis or occlusion, or abnormal tortu-osity. Rupture of a coronary aneurysm can occurwithin the first few months after Kawasaki disease,but this is an exceedingly rare occurrence.

Course of Patients With Persistent Coronary ArteryAbnormalities

Whereas aneurysm size tends to diminish withtime, stenotic lesions that are secondary to markedmyointimal proliferation are frequently progres-sive.2,127,215 The prevalence of stenosis continues torise almost linearly over time.2,215 The highest rate ofprogression to stenosis occurs among patients whoseaneurysms are large.215 The worst prognosis occursin children with so-called giant aneurysms (ie, thosewith a maximum diameter �8 mm).215–219 In theseaneurysms, thrombosis is promoted by the combina-tion of sluggish blood flow within the massivelydilated vascular space and the frequent occurrence ofstenotic lesions at the proximal or distal end of theaneurysms.

MI caused by thrombotic occlusion in an aneurys-mal, a stenotic, or both types of coronary artery is theprincipal cause of death from Kawasaki disease.206

The highest risk of MI occurs in the first year afteronset of the disease, and most fatal attacks are asso-ciated with obstruction in either the LMCA or boththe RCA and LAD.206 Serial stress tests and myocar-dial imaging are mandatory in the management ofpatients with Kawasaki disease and significant cor-onary artery disease so that the need for coronaryangiography and for surgical or transcatheter inter-vention can be determined.

The carotid artery wall in patients with coronaryartery lesions 6 to 20 years after the onset of Ka-wasaki disease has been found to be less distensibleand thicker than that in control patients.220 Thesechanges of arterial properties in patients with Ka-wasaki disease are not associated with major alter-ations of the lipid profile and are postulated to besecondary to the changes in arterial walls after adiffuse vasculitis. Extrapolation from these findingsin carotid arteries suggests that the coronary arteriesmay be predisposed to accelerated atherosclerosis inpatients with Kawasaki disease and coronary artery

lesions. A similar study has not yet been performedin children with Kawasaki disease who did not de-velop coronary abnormalities.

Late cardiac sequelae of Kawasaki disease mayfirst manifest in adulthood.221,222 A history of a Ka-wasaki disease-like illness in childhood should besought in patients who present with coronary aneu-rysms in the absence of generalized atheroscleroticdisease. Some adult patients may be unable to recallan illness that occurred so early in life, however.

Course of Patients With Spontaneous Regression ofAneurysms

Approximately 50% of the vascular segments withcoronary artery aneurysms in Kawasaki diseaseshow angiographic regression of aneurysms. Thisregression usually occurs by myointimal prolifera-tion, although more rarely the mechanism of regres-sion can be organization and recanalization of athrombus.34,223,224 Pathological examination revealsfibrous intimal thickening despite a normal coronaryartery lumen diameter. Similarly, transluminal (in-travascular) ultrasound of regressed coronary aneu-rysms shows marked symmetrical or asymmetricalmyointimal thickening.124,225,226 Regressed coronaryartery aneurysms are not only histopathologicallyabnormal, but they also show reduced vascular re-activity to isosorbide dinitrate and constriction withacetylcholine, indicating endothelial dysfunc-tion.104,125,126,226 A recent follow-up study with IVUSsuggested a significant correlation between the initialdiameters of the coronary arteries and intima-medialthickness �10 years later.225

Course After Kawasaki Disease Without DetectableCoronary Lesions

Although coronary artery aneurysms produce themost serious sequelae of Kawasaki disease, vascularinflammation during the acute stage of the illness isdiffuse. Generalized endothelial dysfunction hasbeen suggested by the observation that plasma 6-ke-to-prostaglandin F1 remains generally undetectableduring the 8 weeks after the onset of Kawasaki dis-ease.227 In addition, Kawasaki disease produces al-tered lipid metabolism that persists beyond clinicalresolution of the disease.75,77,228 Children with Ka-wasaki disease with normal coronary arteries alsohave been reported to have higher brachial-radialartery mean pulse wave velocity than do childrenwithout Kawasaki disease, suggesting increased ar-terial stiffness.228 Histological data concerning thelong-term status of the coronary arteries in childrenwho never had demonstrable abnormalities are fewand difficult to interpret.223,229

Some investigators in Japan have studied coronaryphysiology in the population without aneurysms.Among children with a history of Kawasaki diseasebut with normal epicardial coronary arteries, lowermyocardial flow reserve and higher total coronaryresistance compared with normal controls werefound by Muzik et al.106 Children without a historyof coronary aneurysms after Kawasaki disease alsohave been reported to have abnormal endothelium-dependent brachial artery reactivity.103 The data con-


flict regarding the impairment of long-term endothe-lium-dependent relaxation of the epicardial coronaryarteries among children in whom coronary arterydilation was never detected.105,230

From a purely clinical perspective, children with-out known cardiac sequelae during the first month ofKawasaki disease appear to return to their previous(usually excellent) state of health, without signs orsymptoms of cardiac impairment.2 Meaningfulknowledge about long-term myocardial function,late-onset valvar regurgitation, and coronary arterystatus in this population must await their carefulsurveillance in future decades.

Risk StratificationClinical experience with Kawasaki disease permits

the stratification of patients according to their rela-tive risk of myocardial ischemia. Risk-level catego-ries are listed below and are summarized in Table 5.This stratification allows for patient management tobe individualized with respect to medical therapy toreduce the risk of thrombosis, physical activity, fre-quency of clinical follow-up and diagnostic testing,and indications for cardiac catheterization and coro-nary angiography. With careful clinical follow-up 10to 20 years after the onset of Kawasaki disease, pa-tients with no coronary artery changes on echocar-diography at any stage of the illness seem to dem-onstrate a risk for clinical cardiac events that issimilar to that in the population without Kawasakidisease,2 but research studies suggest subclinical ab-normalities of endothelial function and myocardialflow reserve.103,231–233 Furthermore, patients withKawasaki disease seem to have a more adverse car-diovascular risk profile, with higher blood pressureand greater adiposity, as compared with control chil-dren.234 The risk level for a given patient with coro-nary artery involvement may change over time be-cause of the changes in coronary artery morphology.For example, the development of thrombosis or ste-nosis associated with an aneurysm increases therisk for myocardial ischemia. Aneurysms also mayregress to normal internal lumen diameter overtime; optimal management of patients with re-gressed aneurysms is controversial because struc-tural and functional coronary artery abnormalitiespersist.57,126,226,235,236 The following suggestions forlong-term management are based on a consensus ofexperts and serve as a guide to clinicians until long-term studies and prospective trials facilitate evi-dence-based practice (evidence level C).

Risk LevelsRisk Level I—Patients with no coronary artery changes on

echocardiography at any stage of the illness

• No antiplatelet therapy is needed beyond the ini-tial 6 to 8 weeks after the onset of illness.

• No restriction of physical activity is necessary after6 to 8 weeks.

• Because the degree of future risk for ischemicheart disease in this category of patients is stillundetermined, periodic assessment and counsel-

ing about known cardiovascular risk factors every5 years is suggested.

• Coronary angiography is not recommended.Risk Level II—Patients with transient coronary artery

ectasia or dilatation (disappearing within the initial 6 to 8weeks after the onset of illness)

• No antiplatelet therapy is needed beyond the ini-tial 6 to 8 weeks after the onset of illness.

• No restriction of physical activity is necessary after6 to 8 weeks.

• Risk assessment and counseling is recommendedat 3- to 5-year intervals.

• Coronary angiography is not recommended.Risk Level III—Patients with isolated (solitary) small to

medium (�3-mm but �6-mm, or z score between 3 and 7)coronary artery aneurysm in �1 coronary arteries onechocardiography or angiography

• Long-term antiplatelet therapy with aspirinshould be administered, at least until the aneu-rysms regress.

• Physical activity without restriction in infants andchildren in the first decade of life is permitted afterthe initial 6 to 8 weeks. Stress tests with myocar-dial perfusion evaluation may be useful in thesecond decade to guide recommendations forphysical activity. Participation in competitive col-lision or high-impact sports is discouraged in chil-dren receiving antiplatelet therapy.

• Annual follow-up by a pediatric cardiologist withechocardiogram and electrocardiogram (ECG) isrecommended. Stress tests with myocardial perfu-sion imaging is recommended every 2 years inpatients �10 years old.

• Coronary angiography is indicated if myocardialischemia is demonstrated by stress tests withimaging.Risk Level IV—Patients with �1 large coronary artery

aneurysm (�6 mm), including giant aneurysms, and patientsin whom a coronary artery contains multiple (segmented) orcomplex aneurysms without obstruction

• Long-term antiplatelet therapy is recommended.Adjunctive therapy with warfarin with a targetINR of 2.0:2.5 is recommended for patients withgiant aneurysms. Daily subcutaneous injections oflow-molecular-weight heparin merits consider-ation as an alternative to warfarin for infants andtoddlers, in whom blood drawing for INR testingis difficult. Low-molecular-weight heparin alsomay be used as a bridge during the initial phase ofwarfarin therapy or during the reintroduction ofwarfarin after the interruption of therapy for thepurpose of elective surgery; therapeutic levels areassessed by measuring antifactor Xa levels. Someexperts recommend a combination of aspirin andclopidogrel for patients with multiple or complexaneurysms.

• Recommendations about physical activity shouldbe guided by annual stress tests with myocardialperfusion evaluation. Collision or high-impactsports should be discouraged because of the risk ofbleeding. Participation in noncontact dynamic or


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recreational sports is encouraged if no evidenceexists of stress-induced myocardial ischemia.

• Cardiology evaluation with echocardiogram andECG should be done at 6-month intervals. Stresstests with myocardial perfusion evaluation shouldbe performed annually. The patient should bemonitored for known risk factors of atherosclero-sis and his or her family should be counseledaccordingly.

• Cardiac catheterization with selective coronary an-giography should be performed 6 to 12 monthsafter recovery from the acute illness, or sooner ifclinically indicated, to delineate the complex cor-onary artery anatomy. Follow-up angiographymay be indicated if noninvasive studies suggestmyocardial ischemia. In addition, elective cardiaccatheterization in the absence of noninvasive evi-dence of myocardial ischemia may be useful torule out subclinical major coronary artery obstruc-tions in some situations, such as when the patientexperiences atypical chest pain, the ability to per-form dynamic stress testing is limited by age,unique activity restrictions or insurability recom-mendations are needed, or the anatomy or size ofthe aneurysm cannot be clearly defined by echo-cardiography for decisions regarding anticoagula-tion.

• For females of childbearing age, reproductivecounseling is strongly recommended.Risk Level V—Patients with coronary artery obstruction

confirmed by angiography

• Long-term antiplatelet therapy with or withoutadjunctive therapy with warfarin anticoagulationis recommended (see “Risk Level IV”).

• �-Adrenergic-blocking drugs should be consid-ered to reduce myocardial oxygen consumption.

• Recommendations about dynamic physical activi-ties should be based on the patient’s responseto stress testing. Collision or high-impact sportsshould be discouraged because of the risk of bleed-ing. Patients should avoid a sedentary lifestyle.

• Cardiology evaluation with an echocardiogramand ECG should be obtained at 6-month intervals.Stress tests with myocardial perfusion evaluationshould be performed annually. The patient shouldbe monitored for known risk factors of atheroscle-rosis and his or her family should be counseledaccordingly.

• Cardiac catheterization with selective coronary an-giography is recommended to address the thera-peutic options of bypass grafting or catheter inter-vention and to identify the extent of collateralperfusion. Repeat cardiac catheterization may beindicated when new onset or worsening myocar-dial ischemia is suggested by noninvasive diag-nostic testing or clinical presentation. If the patienthas undergone surgical revascularization or acatheter intervention, then repeat cardiac catheter-ization may be indicated to evaluate the efficacy ofthe treatment.

• For females of childbearing age, reproductivecounseling is strongly recommended.

SUMMARYKawasaki disease is the leading cause of acquired

heart disease in children in the United States. Coro-nary artery aneurysms or ectasia develop in �15% to25% of untreated children; treatment with IVIG inthe acute phase of the disease reduces this risk to�5%. Treatment with high-dose IVIG is recom-mended for children with fever of 4 days’ durationand 4 of 5 classic clinical criteria, as well as for thosewith fewer clinical criteria in whom coronary abnor-malities are noted by echocardiogram. This scientificstatement proposes a new algorithm to aid cliniciansin deciding which children with fever for �5 daysand �4 classic criteria should undergo echocardiog-raphy, receive IVIG treatment, or both for Kawasakidisease. For patients with persistent or recurrent fe-ver after initial IVIG infusion, IVIG retreatment maybe useful. We reviewed the available data regardingother therapies for children with IVIG-resistant Ka-wasaki disease, including treatment with corticoste-roids, TNF-� antagonists, and abciximab. Angio-graphic resolution occurs in �50% of aneurysmalarterial segments, but these segments show persis-tent histological and functional abnormalities. Theremainder may continue to be aneurysmal, oftenwith the development of progressive stenosis or oc-clusion. The long-term management of patients withKawasaki disease should be tailored to the degree ofcoronary involvement. The present writing groupmade recommendations for each risk level regardingantiplatelet and anticoagulant therapies, physical ac-tivity, follow-up assessment, and the appropriate di-agnostic procedures that may be performed to eval-uate cardiac disease. The risk level for a given patientwith coronary arterial involvement may change overtime because of the changes in coronary artery mor-phology. Our statement on the initial evaluation,treatment in the acute phase, and long-term manage-ment of patients with Kawasaki disease is intendedto provide practical interim recommendations untilevidence-based data are available to define best med-ical practices.

DISCLOSUREThe American Heart Association makes every effort to avoid

any actual or potential conflicts of interest that may arise as aresult of an outside relationship or a personal, professional, orbusiness interest of a member of the writing panel. Specifically, allmembers of the writing group are required to complete and sub-mit a Disclosure Questionnaire showing all such relationships thatmight be perceived as real or potential conflicts of interest.

Dr Jane W. Newburger has received research grants from Phil-ips Medical and Pfizer and is a National Heart, Lung, and BloodInstitute Advisory Council member; Dr Masato Takahashi hasreceived a research grant from Sonofi-Synthelabo; and Dr Jane C.Burns has received a research grant from Centocor. No disclosureswere made by the remaining authors of this report: Dr Michael A.Gerber, Dr Michael H. Gewitz, Dr Lloyd Y. Tani, Dr Stanford T.Shulman, Dr Ann F. Bolger, Dr Patricia Ferrieri, Dr Robert S.Baltimore, Dr Walter R. Wilson, Dr Larry M. Baddour, Dr Mat-thew E. Levison, Dr Thomas J. Pallasch, Dr Donald A. Falace, andDr Kathryn A. Taubert.

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