Levels of evidence are defined at the end of the "Major Recommendations" field.
Diagnosis
In the absence of a specific diagnostic test or pathognomonic clinical feature, clinical criteria have been established to assist physicians in diagnosing Kawasaki disease. Other clinical and laboratory findings observed in patients with this disease are frequently helpful in diagnosis. The table below describes the clinical and laboratory features of Kawasaki disease according to the epidemiological case definition.
Table. Clinical and Laboratory Features of Kawasaki Disease
Epidemiological case definition (classic clinical criteria)*
- Fever persisting at least 5 days**
- Presence of at least 4 principal features:
- Changes in extremities
- Acute: Erythema of palms, soles; edema of hands, feet
- Subacute: Periungual peeling of fingers, toes in weeks 2 and 3
- Polymorphous exanthem
- Bilateral bulbar conjunctival injection without exudate
- Changes in lips and oral cavity: Erythema, lips cracking, strawberry tongue, diffuse injection of oral and pharyngeal mucosae
- Cervical lymphadenopathy (>1.5-cm diameter), usually unilateral
- Exclusion of other diseases with similar findings (refer to Table 2 in the original guideline document)
Other clinical and laboratory findings
- Cardiovascular findings
- Congestive heart failure, myocarditis, pericarditis, valvular regurgitation
- Coronary artery abnormalities
- Aneurysms of medium-size noncoronary arteries
- Raynaud's phenomenon
- Peripheral gangrene
- Musculoskeletal system
- Gastrointestinal tract
- Diarrhea, vomiting, abdominal pain
- Hepatic dysfunction
- Hydrops of gallbladder
- Central nervous system
- Extreme irritability
- Aseptic meningitis
- Sensorineural hearing loss
- Genitourinary system
- Other findings
- Erythema, induration at Bacille Calmette-Guerin (BCG) inoculation site
- Anterior uveitis (mild)
- Desquamating rash in groin
Laboratory findings in acute Kawasaki disease
- Leukocytosis with neutrophilia and immature forms
- Elevated erythrocyte sedimentation rate
- Elevated C-reactive protein
- Anemia
- Abnormal plasma lipids
- Hypoalbuminemia
- Hyponatremia
- Thrombocytosis after week 1***
- Sterile pyuria
- Elevated serum transaminases
- Elevated serum gamma glutamyl transpeptidase
- Pleocytosis of cerebrospinal fluid
- Leukocytosis in synovial fluid
*Patients with fever at least 5 days and <4 principal criteria can be diagnosed with Kawasaki disease when coronary artery abnormalities detected by 2-D echocardiography or angiography.
**In presence of >4 principal criteria, Kawasaki disease diagnosis can be made on day 4 of illness. Experienced clinicians who have treated many Kawasaki disease patients may establish diagnosis before day 4.
***Some infants present with thrombocytopenia and disseminated intravascular coagulation.
Incomplete (Atypical) Kawasaki Disease
Some patients who do not fulfill the criteria outlined in the previous table have been diagnosed as having "incomplete" or "atypical" Kawasaki disease, a diagnosis that often is based on echocardiographic findings of coronary artery abnormalities. The term "incomplete" may be preferable to "atypical" because these patients lack sufficient clinical signs of the disease to fulfill the classic criteria; they do not demonstrate atypical clinical features. The phrase "atypical Kawasaki disease" should be reserved for patients who have a problem, such as renal impairment, that generally is not seen in Kawasaki disease. The conventional diagnostic criteria should be viewed as guidelines that are particularly useful in preventing overdiagnosis but may result in failure to recognize incomplete forms of illness. Incomplete Kawasaki disease is more common in young infants than in older children, making accurate diagnosis and timely treatment especially important in these young patients who are at substantial risk of developing coronary abnormalities. The laboratory findings of incomplete cases appear to be similar to those of classic cases. Therefore, although laboratory findings in Kawasaki disease are nondiagnostic, they may prove useful in heightening or reducing the suspicion of incomplete Kawasaki disease.
Echocardiography also may be useful in evaluating children with protracted fever and some features of Kawasaki disease. Although aneurysms rarely form before day 10 of illness, perivascular brightness, ectasia, and lack of tapering of the coronary arteries in the acute stage of Kawasaki disease may represent coronary arteritis before the formation of aneurysms. Decreased left ventricular (LV) contractility, mild valvular regurgitation (most commonly mitral regurgitation), and pericardial effusion also may be seen in an echocardiogram of a person with acute Kawasaki disease.
Incomplete Kawasaki disease should be considered in all children with unexplained fever for >5 days associated with 2 or 3 of the principal clinical features of Kawasaki disease (see "Criteria for Treatment of Kawasaki Disease" below, and Figure 1 in the original guideline document). Because young infants may present with fever and few, if any, principal clinical features, echocardiography should be considered in any infant aged <6 months with fever of >7 days' duration, laboratory evidence of systemic inflammation, and no other explanation for the febrile illness.
Common Pitfalls in Diagnosis
Certain common pitfalls in the diagnosis of Kawasaki disease should be noted. Children may present with only fever and a unilateral enlarged cervical lymph node. The rash and mucosal changes that follow often are mistaken for a reaction to antibiotics that are administered for presumed bacterial lymphadenitis. Sterile pyuria may be mistaken for a partially treated urinary tract infection with sterile urine cultures. The young infant may present with fever, rash, and cerebrospinal fluid pleocytosis and be misdiagnosed with viral meningitis. Occasionally, a child may present with an acute abdomen and be admitted to a surgical service. Kawasaki disease should be considered in the differential diagnosis of every child with fever of at least several days' duration, rash, and nonpurulent conjunctivitis, especially in children <1 year old and in adolescents, in whom the diagnosis is frequently missed.
Risk Scores for Predicting Aneurysms
Several scoring systems have been developed to identify children at highest risk for coronary artery abnormalities. Duration of fever, presumably reflecting the severity of ongoing vasculitis, has been confirmed as a powerful predictor of coronary artery aneurysms in various studies. Harada et al developed a risk score to use at the time a child presents with Kawasaki disease to determine the risk of future coronary aneurysms. At some centers in Japan, the Harada score is used to determine whether intravenous gamma globulin (IVIG) treatment will be used. Intravenous gamma globulin is given to children who fulfill 4 of the following criteria, assessed within 9 days of onset of illness: (1) white blood cell count >12,000/mm3; (2) platelet count <350,000/mm3; (3) C-reactive protein (CRP) >3+; (4) hematocrit <35%; (5) albumin <3.5 g/dL; (6) age <12 months; and (7) male sex. For children with <4 risk factors but continuing acute symptoms, the risk score is reassessed daily. In North America, where IVIG is recommended for all children with Kawasaki disease, Beiser et al constructed a predictive instrument for the development of coronary artery lesions among patients treated with high-dose IVIG within the first 10 days of the onset of illness using data from a U.S. multicenter database of patients with acute Kawasaki disease. The risk factors that Beiser and associates used in the sequential classification instrument included baseline neutrophil and band counts, hemoglobin concentration, platelet count, and temperature on the day after IVIG infusion. This instrument allowed the clinician to identify within 1 day of treatment the low-risk children in whom extensive and frequent cardiac testing may be unnecessary. Its positive predictive value was less satisfactory, however; the frequencies of the development of coronary artery abnormalities in boys and girls who were classified as high risk were only 13.8% and 5.5%, respectively. Because of the imperfect performance of scoring systems, all patients who are diagnosed with Kawasaki disease should be treated with IVIG.
Criteria for Treatment of Kawasaki Disease
The original guidelines for the diagnosis of Kawasaki disease were created by a committee that was appointed by the Japanese Ministry of Health in 1970. At that time, the coronary artery complications of Kawasaki disease were not yet appreciated. In addition, neither effective treatment nor a noninvasive method of assessing coronary artery abnormalities existed. The case definition was created, therefore, for epidemiological surveillance and to establish the extent of the clinical syndrome now known as Kawasaki disease in Japan. The case definition intentionally was made restrictive to exclude patients with rheumatic fever and Stevens-Johnson syndrome.
More than 3 decades later, the clinical landscape has changed dramatically. Echocardiographic screening for coronary enlargement has shown that a substantial number of children with Kawasaki disease and coronary artery abnormalities are not identified by the classic case definition. Thus, although the present case definition provides a specific tool for epidemiological surveillance, it may not be the optimal method for aiding clinicians in the recognition of children with a systemic vasculitis that requires prompt treatment. Given the potential seriousness of the complications, together with the efficacy and safety of early treatment, high sensitivity of the treatment criteria is more important than is high specificity. The guideline developers have therefore devised an algorithm to aid clinicians in deciding whether a child with signs and symptoms suggestive of Kawasaki disease should be treated with IVIG. To strive for the greatest sensitivity while maintaining sufficient specificity to prevent wide-scale overuse of IVIG, the guideline developers have attempted to base their recommendations on laboratory and echocardiographic data derived from the population of patients with Kawasaki disease who meet the classic epidemiological case definition.
The 1993 American Heart Association guidelines on Kawasaki disease suggested that the diagnosis could be made on day 4 of fever, with day 1 by convention being the first day of fever. In the presence of 4 of 5 classic criteria (see Table above "Clinical and Laboratory Features of Kawasaki Disease"), US and Japanese experts agree that only 4 days of fever are necessary before initiating treatment.
It is also broadly agreed that Kawasaki disease can be diagnosed in the absence of full criteria when coronary abnormalities are present. The definition of coronary artery abnormalities has changed since the original Japanese Ministry of Health criteria were devised. In particular, coronary artery dimensions, adjusted for body surface area, provide a more accurate assessment of the size of the proximal right coronary artery (RCA) or left anterior descending coronary artery (LAD) as compared with expected population norms. A z score >2.5 (i.e., a coronary dimension that is >2.5 SDs above the mean for body surface area) in 1 of these arterial segments would be expected to occur in approximately 0.6% of the population without Kawasaki disease, and a z score >3.0 in 1 of these segments would be expected to occur in approximately 0.1% of the population without Kawasaki disease. Having a coronary artery z score >2.5 in both the proximal RCA and LAD would be uncommon in the general population. Because of anatomic variation in the left main coronary artery (LMCA), its z score must be interpreted with caution. Occasional cases of coronary prominence in patients with other disorders have been noted. Clinical experience, however, suggests that coronary enlargement in other febrile illnesses is rare, whereas coronary enlargement in Kawasaki disease is relatively common. Thus, coronary artery z scores should be incorporated into the recommendations for the evaluation and treatment of Kawasaki disease.
The present writing group proposes a scheme to aid the clinician in deciding which patients with fever and <4 classic criteria should undergo echocardiography or receive IVIG treatment or both for Kawasaki disease (see Figure 1 in the original guideline document and "Evaluation of Suspected Incomplete Kawasaki Disease" below). In the absence of a gold standard for diagnosis, this algorithm cannot be evidence based but rather represents the informed opinion of a committee of experts (evidence level C). The writing group offers this opinion as guidance to clinicians until an evidence-based algorithm or a specific diagnostic test for Kawasaki disease becomes available.
Evaluation of Suspected Incomplete Kawasaki Disease (Algorithm: see Figure 1 in original guideline document)
- In the absence of gold standard for diagnosis, this algorithm cannot be evidence based but rather represents the informed opinion of the expert committee. Consultation with an expert should be sought anytime assistance is needed.
- Infants <6 months old on day >7 of fever without other explanation should undergo laboratory testing and, if evidence of systemic inflammation is found, an echocardiogram, even if the infants have no clinical criteria.
- Patient characteristics suggesting Kawasaki disease are listed in the table above entitled "Clinical and Laboratory Features of Kawasaki Disease." Characteristics suggesting disease other than Kawasaki disease include exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, or generalized adenopathy. Consider alternative diagnoses (see Table 2 in the original guideline document).
- Supplemental laboratory criteria include albumin <3.0 g/dL, anemia for age, elevation of alanine aminotransferase, platelets after 7 days >450,000/mm3, white blood cell count >15,000/mm3, and urine >10 white blood cells/high-power field.
- Can treat before performing echocardiogram.
- Echocardiogram is considered positive for purposes of this algorithm if any of 3 conditions are met: z score of LAD or RCA >2.5, coronary arteries meet Japanese Ministry of Health criteria for aneurysms, or >3 other suggestive features exist, including perivascular brightness, lack of tapering, decreased LV function, mitral regurgitation, pericardial effusion, or z scores in LAD or RCA of 2 to 2.5.
- If the echocardiogram is positive, treatment should be given to children within 10 days of fever onset and those beyond day 10 with clinical and laboratory signs (CRP, erythrocyte sedimentation rate [ESR]) of ongoing inflammation.
- Typical peeling begins under nail bed of fingers and then toes.
Cardiac Findings
Coronary Aneurysms
Echocardiography
The major sequelae of Kawasaki disease are related to the cardiovascular and, more specifically, the coronary arterial system, so cardiac imaging is a critical part of the evaluation of all patients with suspected Kawasaki disease. Because it is noninvasive and has a high sensitivity and specificity for the detection of abnormalities of the proximal LMCA and RCA, echocardiography is the ideal imaging modality for cardiac assessment (evidence level C). Evaluation of the cardiovascular sequelae of Kawasaki disease requires serial cardiac ultrasound studies and should be performed using equipment with appropriate transducers and supervised by an experienced echocardiographer. The initial echocardiogram should be performed as soon as the diagnosis is suspected, but initiation of treatment should not be delayed by the timing of the study (i.e., waiting for sedation). This initial study establishes a baseline for longitudinal follow-up of coronary artery morphology, LV and left valvular function, and the evolution and resolution of pericardial effusion when present. Because detailed echocardiographic imaging is compromised if a child is uncooperative, sedation often is required for younger children (e.g., chloral hydrate 65 to 100 mg/kg, maximum 1,000 mg, or other short-acting sedative or hypnotic agents).
The 2 dimensional (2D) imaging should be performed with the highest frequency transducer possible. Imaging with high-frequency transducers should be attempted even in older children, as these probes allow for higher-resolution, detailed evaluation of the coronary arteries. Studies should be recorded in a dynamic video or digital cine format because the normal translational movement of the heart facilitates the display of the coronary artery anatomy. Such recordings will allow future review and comparison with subsequent studies. In addition to standard imaging from parasternal, apical, subcostal, and suprasternal notch windows, 2 dimensional echocardiography (2DE) evaluation of patients with suspected Kawasaki disease should focus on imaging the LMCA, LAD, left circumflex coronary artery (LCX), RCA (proximal, middle, and distal segments), and posterior descending coronary arteries. Multiple imaging planes and transducer positions are required for the optimal visualization of all major coronary segments (refer to the table below titled "Echocardiographic Views of Coronary Arteries in Patients with Kawasaki Disease" and to Figure 2 of the original guideline document titled "2D Echocardiogram"). Maximal efforts should be made to visualize all major coronary segments. In order of highest to lowest frequency, common sites of coronary aneurysms include the proximal LAD and proximal RCA, followed by the LMCA, then LCX, and finally the distal RCA and the junction between the RCA and posterior descending coronary artery.
Evaluation of the coronary arteries should include quantitative assessment of the internal vessel diameters. Measurements should be made from inner edge to inner edge and should exclude points of branching, which may have normal focal dilation. The number and location of aneurysms and the presence or absence of intraluminal thrombi also should be assessed. Aneurysms are classified as saccular if axial and lateral diameters are nearly equal or as fusiform if symmetric dilatation with gradual proximal and distal tapering is seen. When a coronary artery is larger than normal (dilated) without a segmental aneurysm, the vessel is considered ectatic. Care must be taken in making the diagnosis of ectasia because of considerable normal variation in coronary artery distribution and dominance. In the last American Heart Association statement, aneurysms were classified as small (<5 mm internal diameter), medium (5 to 8 mm internal diameter), or giant (>8 mm internal diameter). The Japanese Ministry of Health criteria classify coronary arteries as abnormal if the internal lumen diameter is >3 mm in children <5 years old or >4 mm in children >5 years old; if the internal diameter of a segment measures >1.5 times that of an adjacent segment; or if the coronary lumen is clearly irregular. Current statistics on the prevalence of coronary artery abnormalities secondary to Kawasaki disease are based on these criteria. Although the Japanese Ministry of Health criteria are not based on an individual patient's body size, coronary artery dimensions in children without Kawasaki disease have been shown to increase with indexes of body size, such as body surface area or body length.
More recently, de Zorzi and colleagues showed that the body surface area-adjusted coronary dimensions of some people with Kawasaki disease whose coronary arteries were considered "normal" are larger than expected in the acute, convalescent, and late phases when compared with references established for body size. Figure 3 of the original guideline document shows coronary internal diameters according to body surface area in the population without Kawasaki disease. Because use of the Japanese Ministry of Health criteria may result in both underdiagnosis and underestimation of the true prevalence of coronary dilation, coronary vessel measurements adjusted for body surface area should be compared with those of the population without Kawasaki disease. Of note, z scores are available for only the LMCA, proximal LAD, and proximal RCA, so that the Japanese Ministry of Health criterion of "size 1.5 times that of the surrounding segment" is still useful for diagnosing aneurysms in peripheral sites. Enlargement of the LMCA caused by Kawasaki disease does not involve the orifice and rarely occurs without associated ectasia of the LAD, LCX, or both arteries. In addition to measuring coronary artery dimensions, imaging the coronary arteries also may reveal the lack of normal tapering and perivascular echogenicity or "brightness."
Although the echocardiographic examination of patients with Kawasaki disease is focused on the coronary arteries, other information can and should be obtained. Histological evidence suggests that myocarditis is universal in acute Kawasaki disease, and other studies have shown depressed ventricular contractility to be common early in the course of Kawasaki disease. Therefore, assessment of LV function should be a part of the echocardiographic evaluation of all patients with suspected Kawasaki disease. LV end-diastolic and end-systolic dimensions and a shortening fraction should be measured from standard M-mode tracings. Apical imaging allows the estimation of LV end-diastolic and end-systolic volumes and an ejection fraction. Although loading conditions influence these measurements, they are more readily measured than are complex indexes of contractility and are adequate for routine clinical follow-up. Evaluating regional wall motion may be useful, especially in children with coronary artery abnormalities. The aortic root also should be imaged, measured, and compared with references for body surface area because evidence exists that mild aortic root dilation is common among patients with Kawasaki disease. Because pericarditis may be associated with the vasculitis and myocarditis seen in patients with Kawasaki disease, the presence or absence of a pericardial effusion should be noted.
Standard pulsed and color flow Doppler interrogation should be performed to assess the presence and degree of valvular regurgitation (in particular for mitral and aortic valves). Color flow Doppler with a low Nyquist limit setting from a favorable angle of view may allow coronary flow to be demonstrated and may be useful in positively identifying coronary artery lumens.
It is important to recognize the limitations of echocardiography in the evaluation and follow-up of patients with Kawasaki disease. Although echocardiographic detection of thrombi and coronary artery stenosis has been reported, the sensitivity and specificity of echocardiography for identifying these abnormalities is unclear. In addition, the visualization of coronary arteries becomes progressively more difficult as a child grows and body size increases. Angiography, intravascular ultrasound (IVUS), transesophageal echocardiography, and other modalities including magnetic resonance angiography (MRA) and ultrafast computed tomography (CT) may be of value in the assessment of selected patients (see below).
For uncomplicated cases, echocardiographic evaluation should be performed at the time of diagnosis, at 2 weeks, and at 6 to 8 weeks after onset of the disease. More frequent echocardiographic evaluation is needed to guide management in children at higher risk (e.g., those who are persistently febrile or who exhibit coronary abnormalities, ventricular dysfunction, pericardial effusion, or valvular regurgitation). Recent studies have shown that repeat echocardiography performed 1 year after the onset of the illness is unlikely to reveal coronary artery enlargement in patients whose echocardiographic findings were normal at 4 to 8 weeks. Because abnormalities in coronary artery function, coronary flow reserve, and aortic root dilation remain potential concerns even among patients in whom coronary dilatation was never detected, repeat echocardiography beyond 8 weeks in patients with previously normal findings should be considered optional. Follow-up echocardiograms should identify the progression or regression of coronary abnormalities, evaluate ventricular and valvular function, and assess the presence or evolution of pericardial effusions.
Other Noninvasive Tests
Magnetic resonance imaging (MRI) and MRA may delineate coronary artery aneurysms in the proximal coronary artery segments and provide data regarding flow profile (evidence level C). A recent small series in patients with Kawasaki disease demonstrated that coronary MRA accurately diagnosed all coronary artery aneurysms, coronary occlusions, and coronary stenoses present on x-ray angiography. Magnetic resonance imaging and MRA may be used to image peripheral artery aneurysms. Ultrafast computed tomography (CT) also has been used to assess coronary aneurysms. Further larger studies in patients with Kawasaki disease are needed to establish the reliability of MRA and ultrafast CT for the detection of coronary artery aneurysms and stenoses in distal segments, as well as for the presence of collateral circulation.
Cardiac stress testing for reversible ischemia is indicated to assess the existence and functional consequences of coronary artery abnormalities in children with Kawasaki disease and coronary aneurysms (evidence level A). The types of stress tests reported in children with Kawasaki disease include nuclear perfusion scans with exercise, exercise echocardiography, and stress echocardiography with pharmacological agents such as dobutamine, dipyridamole, or adenosine. More recently, MRI stress imaging with quantification of regional perfusion has detected significant coronary stenoses. Myocardial perfusion also can be assessed by myocardial contrast echocardiography, taking gas-filled microbubbles to measure the microcirculatory flow and hence capillary density in different myocardial regions. With stress, the myocardial blood volume fraction decreases distal to a stenosis, causing a perfusion defect on myocardial contrast echocardiography.
The predictive value of stress tests for coronary artery disease requiring intervention is a function of the probability of significant disease in the population tested (Bayes' theorem). For example, false-positive tests are more likely in patients with a previously low probability of coronary disease. Used appropriately, stress test results may guide a clinician's decision to refer a patient for invasive evaluation (i.e., cardiac catheterization), as well as for catheter or surgical intervention. The choice of stress modality should be guided by institutional expertise with particular techniques, as well as by the age of the child (e.g., pharmacological stress should be used in young children in whom traditional exercise protocols are not feasible).
Table: Echocardiographic Views of Coronary Arteries in Patients with Kawasaki Disease
|
Left main coronary artery
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- Precordial short axis at level of aortic valve
- Precordial long axis of left ventricle (superior tangential)
- Subcostal left ventricular long axis
|
|
Left anterior descending coronary artery
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- Precordial short axis at level of aortic valve
- Precordial superior tangential long axis of left ventricle
- Precordial short axis of left ventricle
|
|
Left circumflex
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- Precordial short axis at level of aortic valve
- Apical 4-chamber
|
|
Right coronary artery, proximal segment
|
- Precordial short axis at level of aortic valve
- Precordial long axis (inferior tangential) of left ventricle
- Subcostal coronal projection of right ventricular outflow tract
- Subcostal short axis at level of atrioventricular groove
|
|
Right coronary artery, middle segment
|
- Precordial long axis of left ventricle (inferior tangential)
- Apical 4-chamber
- Subcostal left ventricular long axis
- Subcostal short axis at level of atrioventricular groove
|
|
Right coronary artery, distal segment
|
- Apical 4-chamber (inferior)
- Subcostal atrial long axis (inferior)
|
|
Posterior descending coronary artery
|
- Apical 4-chamber (inferior)
- Subcostal atrial long axis (inferior)
- Precordial long axis (inferior tangential) imaging
- Posterior interventricular groove
|
Cardiac Catheterization and Angiography
Coronary angiography offers a more detailed definition of coronary artery anatomy than does cardiac ultrasound, making it possible to detect coronary artery stenosis or thrombotic occlusion and to determine the extent of collateral artery formation in patients with Kawasaki disease (see figure 4 of the original guideline document for a sample coronary angiogram). Before recommending coronary angiography to a patient, a physician must compare the potential benefits of the procedure with its risks and cost. In patients with mild ectasia or small fusiform aneurysms demonstrated by echocardiography, coronary angiography is unlikely to provide any further useful information and is not recommended (evidence level C). Patients with more complex coronary artery lesions may benefit-from coronary angiography after the acute inflammatory process has resolved. Practices regarding the timing of cardiac catheterization for such patients vary greatly from center to center; coronary angiography is generally recommended 6 to 12 months after the onset of illness or sooner if indicated clinically (evidence level C). In long-term follow-up, the decision to perform angiography may be guided by echocardiographic imaging of coronary arteries, ventricular regional wall motion abnormalities, and clinical signs or noninvasive studies indicating myocardial ischemia. The failure to image distal coronary arteries in a patient in whom large proximal aneurysms have regressed may be an indication for another imaging modality, including cardiac angiography, to guide the appropriate use of antithrombotic agents (evidence level C). Patients who have undergone surgical revascularization or catheter intervention may have a repeat cardiac catheterization so that the efficacy of the treatment can be evaluated (evidence level C).
Additional techniques used during cardiac catheterization may detect structural or functional changes in the coronary artery wall. Patients with angiographically documented regression of coronary artery aneurysms have shown abnormal thickening of the intima-media complex by IVUS and abnormal vasoreactivity in response to various vasodilators. The long-term clinical implications of these anatomical and functional changes are unknown at this time.
Aneurysms can occur in arteries outside the coronary system, most commonly the subclavian, brachial, axillary, iliac, or femoral vessels, and occasionally in the abdominal aorta and renal arteries. For this reason, abdominal aortography and subclavian arteriography are recommended in patients with Kawasaki disease undergoing coronary arteriography for the first time (evidence level C).
Myocarditis
Myocarditis has been demonstrated in autopsy and myocardial biopsy studies to be a common feature of early Kawasaki disease. Myocardial inflammation has been documented in 50 to 70% of patients using 67Ga citrate scans (planar or single photon emission computed tomography) and 99mTc-labeled white blood cell scans. The severity of myocarditis does not appear to be associated with the risk of coronary artery aneurysms, however.
Although the majority of patients with Kawasaki disease have abnormal myocardial contractility by echocardiographic assessment at presentation, myocardial mechanics improve rapidly after IVIG therapy, with a high concordance between the clinical and myocardial responses to therapy. The speed of recovery suggests that depressed contractility in patients with Kawasaki disease is caused by rapidly reversible mechanisms such as those involving circulating toxins or activated cytokines. It is also possible that the inflammatory infiltrate found between the muscle fibers on postmortem examination in early Kawasaki disease may resolve quickly.
The occurrence of myocarditis during the acute phase of Kawasaki disease has fostered concern about the potential long-term effects of the disease on myocardial function. Biopsy of the right ventricular myocardium was performed in patients with Kawasaki disease to assess the evolution and course of myocardial change. The interval between onset of the disease and myocardial biopsy ranged from 2 months to 11 years. Myocardial abnormalities, including fibrosis and cellular disarrangement, as well as abnormal branching and hypertrophy of myocytes, were detected at all time periods after onset of the disease; their severity was unrelated to the presence of coronary artery abnormalities. In addition, electron microscopic examination of endomyocardial biopsies has demonstrated ultrastructural abnormalities late after Kawasaki disease.
Despite the concerns raised about histopathologic abnormalities on myocardial biopsy, long-term myocardial contractility and function measured by echocardiography appear to be normal, except among patients with ischemic heart disease. Assessment of the full impact of Kawasaki disease on heart function must await follow-up studies of these children into adulthood.
Valvular Regurgitation
Mitral regurgitation may result from transient papillary muscle dysfunction, myocardial infarction (MI), or valvulitis. The appearance of mitral regurgitation after the acute stage usually is secondary to myocardial ischemia, although late-onset valvulitis unrelated to ischemia has been documented. Kato et al reported 6 patients (1.0% of their series) with mitral regurgitation in the acute or subacute stage of Kawasaki disease, with resolution in 3 patients, death from MI in 2, and persistence from papillary muscle dysfunction in 1.
Aortic regurgitation has been documented angiographically by Nakano and colleagues in approximately 5% of children with Kawasaki disease and was attributed to valvulitis. Other investigators have observed a much lower incidence of aortic regurgitation in the acute phase, but late-onset aortic regurgitation has been reported as an exceedingly rare finding after Kawasaki disease and may be associated with the need for aortic valve replacement. Approximately 4% of a consecutive series with Kawasaki disease had mild aortic regurgitation as seen by echocardiogram.
Treatment
Initial Treatment
Aspirin
Aspirin has been used in the treatment of Kawasaki disease for many years. Although aspirin has important anti-inflammatory (at high doses) and antiplatelet (at low doses) activity, it does not appear to lower the frequency of the development of coronary abnormalities. During the acute phase of illness, aspirin is administered at 80 to 100 mg/kg per day in 4 doses with IVIG (see section below titled "IVIG"). High-dose aspirin and IVIG appear to possess an additive anti-inflammatory effect. Practices regarding the duration of high-dose aspirin administration vary across institutions, and many centers reduce the aspirin dose after the child has been afebrile for 48 to 72 hours. Other clinicians continue high-dose aspirin until day 14 of illness and >48 to 72 hours after fever cessation. When high-dose aspirin is discontinued, clinicians begin low-dose aspirin (3 to 5 mg/kg per day) and maintain it until the patient shows no evidence of coronary changes by 6 to 8 weeks after the onset of illness (evidence level C). For children who develop coronary abnormalities, aspirin may be continued indefinitely (evidence level B). Of note, the concomitant use of ibuprofen antagonizes the irreversible platelet inhibition that is induced by aspirin; thus, in general, ibuprofen should be avoided in children with coronary aneurysms taking aspirin for its antiplatelet effects (evidence level B).
Reye syndrome is a risk in children who take salicylates while they are experiencing active infection with varicella or influenza, and has been reported in patients taking high-dose aspirin for a prolonged period after Kawasaki disease. It is unclear whether the low-dose therapy used for antiplatelet effect increases the risk of Reye syndrome. Children who are taking salicylates long-term should receive an annual influenza vaccine. Although vaccine manufacturers recommend that salicylates be avoided for 6 weeks after the administration of varicella vaccine, physicians need to weigh the theoretical risks associated with varicella vaccine against the known risks of wild-type varicella in children receiving long-term salicylate therapy. Some physicians substitute another antiplatelet medication for aspirin during the 6-week period. Parents of the children receiving salicylates should be instructed to contact their child's physician promptly if the child develops symptoms of or is exposed to either influenza or varicella.
IVIG
The efficacy of IVIG administered in the acute phase of Kawasaki disease in reducing the prevalence of coronary artery abnormalities is well-established. The mechanism of action of IVIG in treating Kawasaki disease is unknown. IVIG appears to have a generalized anti-inflammatory effect. The possible mechanisms of action include modulation of cytokine production, neutralization of bacterial superantigens or other etiologic agents, augmentation of T-cell suppressor activity, suppression of antibody synthesis, and provision of anti-idiotypic antibodies.
A variety of dose regimens have been used in Japan and the United States. Two meta-analyses have demonstrated a dose-response effect, with higher doses given in a single infusion having the greatest efficacy. Furthermore, peak adjusted serum IgG levels are lower among patients who subsequently develop coronary artery abnormalities and are inversely related to fever duration and laboratory indexes of acute inflammation. The association of lower peak IgG levels with worse outcomes lends further support to the concept of a relationship between serum IgG concentration and therapeutic effectiveness.
Patients should be treated with IVIG, 2 g/kg in a single infusion (evidence level A), together with aspirin (see section above titled "Aspirin"). This therapy should be instituted within the first 10 days of illness and, if possible, within 7 days of illness. Treatment of Kawasaki disease before day 5 of illness appears no more likely to prevent cardiac sequelae than does treatment on days 5 to 7, but it may be associated with an increased need for IVIG retreatment. IVIG also should be administered to children presenting after the 10th day of illness (i.e., children in whom the diagnosis was missed earlier) if they have either persistent fever without other explanation or aneurysms and ongoing systemic inflammation, as manifested by elevated ESR or CRP (evidence level C).
Gamma globulin is a biological product made from pooled donor plasma, and potentially important product-manufacturing differences exist. Perhaps for this reason, adverse effects appear to vary considerably among products. The results of clinical studies comparing the efficacy of immune globulin products have conflicted, with most studies failing to find a significant difference between brands. Within the US healthcare system, the use of high-dose IVIG is cost-effective. In Japan, however, some centers treat only children who are predicted to be at high risk for developing coronary artery disease, although practices have been changing since 1996 with the approval by the Japanese Ministry of Health of the 2 g/kg regimen.
Measles and varicella immunizations should be deferred for 11 months after a child receives high-dose IVIG. A child in whom the risk of exposure to measles is high, however, may be vaccinated earlier and then be reimmunized >11 months after IVIG administration if the child has an inadequate serological response. Even when treated with high-dose IVIG regimens within the first 10 days of illness, approximately 5% of children with Kawasaki disease develop at the least transient coronary artery dilation and 1% develop giant aneurysms. Additional potentially beneficial treatments are discussed below, but the optimal treatment awaits delineation of the specific agent or agents and pathogenetic mechanisms of Kawasaki disease.
Steroids
Although corticosteroids are the treatment of choice in other forms of vasculitis, their use has been limited in children with Kawasaki disease. Corticosteroids were used as the initial therapy for Kawasaki disease long before the first report of IVIG efficacy by Furusho et al in 1984. Although an early study by Kato et al suggested that steroids exert a detrimental effect when used as the initial therapy for Kawasaki disease, subsequent studies have shown either no ill effects or possible benefit. In a randomized trial of high-dose intravenous methylprednisolone plus heparin as compared with heparin alone, Kijima et al found that steroid therapy was associated with a greater rate of improvement in coronary abnormalities. In a randomized trial in 100 children treated with intravenous prednisolone followed by an oral taper versus low-dose IVIG (300 mg/kg per day for 3 consecutive days), Nonaka and colleagues reported shorter fever duration in the steroid group but no significant difference in the prevalence of coronary aneurysms. In a retrospective review, Shinohara et al found that treatment regimens that included prednisolone were associated with significantly shorter fever duration and a lower prevalence of coronary artery aneurysms. Most recently, a small randomized trial examined whether the addition of 30 mg/kg of intravenous methylprednisolone to conventional therapy with IVIG (2 g/kg) and aspirin improved outcomes. Patients who received steroids had a shorter duration of fever and shorter hospital stays, as well as a lower mean erythrocyte sedimentation rate and median C-reactive protein 6 weeks after the onset of illness. No differences between treatment groups in coronary outcomes were noted, with limited statistical power. Children to whom corticosteroids and IVIG were administered, compared with those who received IVIG alone, had reduced levels of cytokines, including interleukin-2 (IL-2), IL-6, IL-8, and IL-10 within 24 hours of IVIG administration. At present, the usefulness of steroids in the initial treatment of Kawasaki disease is not well established (evidence level C). A National Heart, Lung, and Blood Institute-funded, multicenter randomized, placebo-blind trial that is in progress will provide more information on the effectiveness of such treatment.
Pentoxifylline
Pentoxifylline is a methyl xanthine compound that specifically inhibits tumor necrosis factor (TNF)-alpha messenger RNA transcription. Because TNF-alpha appears to be important in the inflammatory cascade in Kawasaki disease, pentoxifylline has been assessed as a therapeutic adjunct to standard therapy. In a small clinical trial in which all patients were treated with a low-dose regimen of IVIG plus aspirin, the individuals who received high-dose pentoxifylline appeared to have fewer aneurysms and therapy was well tolerated. A recent study reported the pharmacokinetics of an oral pediatric suspension of pentoxifylline in children with acute Kawasaki disease. The drug was well tolerated and no toxicities were noted. The role of pentoxifylline in the initial treatment of Kawasaki disease is uncertain (evidence level C).
Treatment of Patients Who Failed to Respond to Initial Therapy
IVIG
Approximately >10% of patients with Kawasaki disease fail to defervesce with initial IVIG therapy. Failure to respond usually is defined as persistent or recrudescent fever >36 hours after completion of the initial IVIG infusion. Most experts recommend retreatment with IVIG, 2 g/kg (evidence level C). The putative dose-response effect of IVIG forms the theoretical basis for this approach.
Steroids
Corticosteroids also have been used to treat patients who have failed to respond to initial therapy for Kawasaki disease. Several small case series have described children with Kawasaki disease with recrudescent or persistent fever despite IVIG treatment in whom the administration of steroid therapy was associated with an improvement in symptoms and the absence of a significant progression in coronary artery abnormalities or adverse effects. In a recent small randomized trial, Hashino et al compared the efficacy and safety of additional IVIG therapy with pulse steroid therapy in patients with IVIG-resistant Kawasaki disease. Seventeen patients who did not respond to an initial infusion of 2 g/kg IVIG plus aspirin followed by an additional IVIG infusion of 1 g/kg were randomized to receive either a single additional dose of IVIG (1 g/kg) or pulse steroid therapy. Patients in the steroid group had a shorter duration of fever and lower medical costs. No significant difference in the incidence of coronary artery aneurysms was noted between the 2 groups, but power to detect a difference was limited.
Studies of steroids in the initial therapy for Kawasaki disease, as well as in therapy for patients with persistent or recrudescent fever despite treatment with IVIG and aspirin, have shown that corticosteroids reduce fever. The effects of steroids on coronary artery abnormalities are still uncertain, however. Until multicenter controlled trials are available, the present writing group recommends that steroid treatment be restricted to children in whom >2 infusions of IVIG have been ineffective in alleviating fever and acute inflammation (evidence level C). The most commonly used steroid regimen is intravenous pulse methylprednisolone, 30 mg/kg for 2 to 3 hours, administered once daily for 1 to 3 days.
Other Treatments
Plasma exchange has been reported in an uncontrolled clinical trial to be an effective therapy in patients who are refractory to IVIG and to lower the incidence of coronary artery aneurysms. Of note, treatment assignment was not randomized, and few details about the comparability of treatment groups were provided in this short report. Earlier reports of dramatic response to this mode of treatment consist of small case series. Because of its risks, plasma exchange is not in general recommended (evidence level C).
Ulinastatin is a human trypsin inhibitor purified from human urine that has been used in Japan as an adjunctive therapy for acute Kawasaki disease. This 67,000-Da glycoprotein inhibits neutrophil elastase as well as prostaglandin H2-synthase at the messenger RNA level. Ulinastatin has been proposed as useful in IVIG-refractory patients, but its effectiveness is unproven and additional experience with this agent is necessary before it can be recommended (evidence level C).
Abciximab, a platelet glycoprotein IIb/IIIa receptor inhibitor, has been used to treat patients in the acute or subacute phase of Kawasaki disease who have large coronary aneurysms. Patients who received abciximab plus standard therapy as compared with historical controls treated with standard therapy alone showed a greater regression in maximum aneurysm diameter, suggesting that treatment with abciximab might promote vascular remodeling. Prospective controlled trials are needed, but abciximab therapy may be considered in patients with large aneurysms in the acute or subacute phase (evidence level C).
A new class of agents that may play a role in the treatment of patients with refractory Kawasaki disease is monoclonal antibodies to various proinflammatory cytokines. A humanized monoclonal antibody against TNF-alpha, infliximab, is being studied in a clinical trial of treatment for children who fail to become afebrile after initial IVIG treatment. Although its effectiveness in reducing the prevalence of coronary artery aneurysms is unproven, therapy with infliximab or other agents directed at TNF-alpha might be considered in patients who are resistant to IVIG and steroids (evidence level C).
Cytotoxic agents such as cyclophosphamide, in conjunction with oral steroids, have been suggested as useful for the treatment of exceptional patients with particularly refractory acute Kawasaki disease. This therapy is used widely to treat other severe vasculitides. Cyclosporin A was reported to be ineffective in halting the progression of obliterative panarteritis in a single case report of fatal Kawasaki disease. Of note, the risks of cytotoxic agents exceed the benefits for the vast majority of patients with Kawasaki disease (evidence level C).
In summary, because controlled data are lacking, the relative roles of repeated doses of IVIG, corticosteroids, TNF-alpha antagonists, plasma exchange, abciximab, and agents such as cyclophosphamide for patients with refractory Kawasaki disease remain uncertain.
Prevention of Thrombosis in Patients with Coronary Disease
The management of coronary disease in patients with Kawasaki disease depends on the severity and extent of coronary involvement. No prospective data exist to guide clinicians in choosing an optimal regimen, so recommendations are based on known pathophysiology, retrospective case series in children with Kawasaki disease, and extrapolation from experience in adults with coronary disease. Therapeutic regimens used in patients with Kawasaki disease depend on the severity of coronary involvement and include antiplatelet therapy with aspirin, with or without dipyridamole or clopidogrel; anticoagulant therapy with warfarin or low-molecular-weight heparin; or a combination of anticoagulant and antiplatelet therapy, usually warfarin plus aspirin.
Platelet activation is a profound component of the acute illness and persists throughout the convalescent and chronic phases. As a result, antiplatelet agents play a critical role in managing patients at every stage. Low-dose aspirin may be appropriate for asymptomatic patients with mild and stable disease. As the extent and severity of the coronary artery enlargement increase, the combination of aspirin with other antiplatelet agents (e.g., clopidogrel, dipyridamole) aimed at antagonizing adenosine-5' diphosphate may be more effective in suppressing platelet activation. Clopidogrel in combination with aspirin has been shown to be more effective than either agent alone in preventing vascular events in both coronary and cerebral territories in adults (the Clopidogrel in Unstable Angina to Prevent Recurrent Events study). Most experts believe that a predominantly platelet-directed approach is appropriate in the setting of stable, mild-to-moderate disease (evidence level C).
When a coronary aneurysm expands rapidly, the risk of thrombosis is particularly high. For this reason, the use of heparin with aspirin has been advocated (evidence level C). The goals for treatment in this group include prevention of thrombosis, as well as modification of the evolution of the derangement of the coronary shape and size, which may relate to the remodeling effects of endothelial damage and thrombosis.
The coronary aneurysm presents increasingly abnormal flow conditions, which are unlike other common clinical conditions such as atherosclerosis. Within the aneurysm itself, the vessel dilatation results in low blood flow velocities and relative stasis of flow, which predispose the aneurysm to chronic thrombus formation. Additional severe abnormalities of coronary flow may arise over time secondary to incremental stenoses at the proximal or distal or proximal and distal ends of the aneurysm. This combination of stenosis at the aneurysm inlet, in immediate proximity to a dilated, low-velocity region, is a powerful stimulus to thrombus formation. Platelets are activated by the high shear stress that occurs at the stenosis and then are stimulated further as they decelerate and linger within the turbulent, low-velocity regions distal to the stenosis. The post-stenotic turbulence also is responsible for endothelial activation that results from gradients in the region of shear stress. Thus, progressive stenosis of these chronically hypercoagulable segments augments both the platelet and endothelial mechanisms for thrombosis. Finally, the presence of chronic thrombus in the aneurysm presents fibrin and clotting precursors that can amplify the thrombotic cascade. Patients with giant aneurysms, with or without stenosis, are at the highest risk for coronary thrombosis.
The most common antithrombotic regimen for patients with giant aneurysms is low-dose aspirin together with warfarin, maintaining an international normalized ratio (INR) of 2.0 to 2.5 (evidence level C). Some physicians substitute a therapeutic dose of low-molecular-weight heparin for warfarin, although this therapy requires twice-daily subcutaneous injections.
Treatment of Coronary Thrombosis
Once thrombosis is initiated in proximity to a segment at risk, it may progress rapidly and create a thrombus burden unlike that which occurs in adult atherosclerotic coronary occlusion. Coronary occlusion in adults with atherosclerosis involves plaque rupture or inflammation that exposes lipids and the extracellular matrix to the coagulation system. Kawasaki disease-associated acute thrombosis is not related to this form of plaque instability or rupture. Therefore, established thrombolytic protocols for adults with atherosclerotic coronary disease may not necessarily be optimal for the Kawasaki disease population.
The treatment of acute coronary occlusion in patients with Kawasaki disease should target multiple steps in the coagulation cascade (See Table 4 in the original guideline document for routes and dosages for antiplatelet, anticoagulant, and thrombolytic medications). In case reports, streptokinase, urokinase, and tissue plasminogen activator (tPA) each has been administered to infants and children with coronary thrombosis with varying success rates (evidence level C). Because no randomized controlled trials have been performed in children, the treatment of infants and children with coronary thrombosis is derived from studies in adults with acute coronary syndromes. The goals of therapy include reestablishing coronary patency, salvaging the myocardium, and improving survival. In adult trials, treatment with streptokinase has demonstrated a lower incidence of bleeding than have other agents, but potential allergic complications limit its use in patients with a history of streptococcal pharyngitis within the past 6 months. Better coronary patency rates are achieved with tPA than with streptokinase in adults. Tenecteplase-tPA is 14 times more fibrin specific than is tPA and may be more fibrinolytic at the site of the thrombus. Its longer association with the fibrin-rich clot and higher fibrin specificity may lead to the enhanced dissolution of older clots (>4 hours), with fewer bleeding complications as compared with tPA. All thrombolytic regimens include aspirin and either heparin or low-molecular-weight heparin.
The platelet glycoprotein IIb/IIIa receptor participates in the final common pathway for platelet aggregation. Inhibition of this receptor has shown great promise for improving outcomes when administered with aspirin and heparin, both with and without the use of thrombolytics in adults with acute coronary syndromes. Reduced-dose thrombolytic therapy in combination with the administration of a glycoprotein IIb/IIIa inhibitor, such as abciximab, restores antegrade flow as effectively as does full-dose thrombolytic therapy, but it is associated with lower rates of reocclusion and reinfarction (evidence level C). Mechanical restoration of coronary blood flow (i.e., the use of immediate coronary angioplasty or stent placement) is effective in adults and has been used in a small number of children (evidence level C). The choice of method to reestablish perfusion in children with Kawasaki disease and coronary thrombosis should be based on that which can be administered with the greatest expertise in a timely fashion.
Surgical and Catheter Coronary Interventions
The current recommendations for surgical and catheter interventions summarize the current opinions of experts based on limited data. The present writing group recommends that decisions about intervention in individual patients be made in concert with experienced adult interventional cardiologists and cardiac surgeons.
Surgical Management
Attempts at excision or placation of the coronary artery aneurysm have not been successful and have caused deaths. Surgical management in Kawasaki disease comprises primarily coronary artery bypass grafts for obstructive lesions. The diameter and length of internal mammary grafts increase with the somatic growth of children as compared with the tendency of saphenous vein grafts to shorten somewhat over time. In a recently published series, the patency rates of arterial grafts (primarily the left and right internal mammary arteries) were 94%, 82%, and 78% at 1, 5, and 10 years, respectively, whereas patency rates for venous grafts were 82%, 63%, and 36%, respectively. No early deaths occurred, and only 2 patients died at late follow-up of mean 6.7+4.5 years, 1 with sudden death and the other in a traffic accident. Freedom from cardiac events after bypass was approximately 70% at 10 years. Although the results during the first decade after coronary artery bypass surgery in childhood are encouraging, the arterial graft patency rate in later adult life is still unknown.
The indications for coronary bypass graft procedures in children have not been established in clinical trials, but such surgery should be considered when reversible ischemia is present on stress-imaging test results, the myocardium to be perfused through the graft is still viable, and no appreciable lesions are present in the artery distal to the planned graft site (evidence level C). One panel of experts stated that surgical revascularization may be considered under the following conditions: severe occlusion of the main trunk of the LMCA, severe occlusion of >1 major coronary artery, severe occlusion in the proximal segment of the LAD, collateral coronary arteries in jeopardy, or all of the above. Most experts agree that surgery is indicated after recurrent MI because the prognosis is so unfavorable.
Interventional Cardiac Catheterization Techniques
Catheter interventions including balloon angioplasty, rotational ablation, and stent placement have been performed in a relatively small number of children with Kawasaki disease. Most of the experience has been accumulated in Japan. In general, balloon angioplasty has not been successful even with high-pressure balloons when it is done >2 years after the acute illness because of dense fibrosis and calcification in the arterial wall. The relatively high balloon pressures that are necessary under these circumstances can lead to late neoaneurysm formation. For this reason, if percutaneous transluminal coronary angioplasty cannot be performed with a balloon pressure of <10 atmospheres, then rotational ablation or bypass surgery is advisable as an alternative procedure. IVUS imaging has been found to be a useful tool for evaluating internal vessel morphology before and after percutaneous transluminal coronary angioplasty. Stent placement has been useful in older children with mild calcification and in children with giant aneurysms. Rotational ablation and stent placement have met with a success rate >80% according to a collective experience in Japan.
The recommendations for catheter intervention for patients with Kawasaki disease recently formulated by the Research Committee of the Japanese Ministry of Health, Labor, and Welfare state that catheter intervention should be considered in patients presenting with ischemic symptoms, patients without ischemic symptoms but with reversible ischemia on stress test, and patients without ischemia but with >75% stenosis in the LAD (evidence level C). Bypass surgery is preferred in patients with severe LV dysfunction. Catheter intervention is contraindicated for individuals who have vessels with multiple, ostial, or long-segment lesions (evidence level C).
Cardiac Transplantation
A small number of patients with Kawasaki disease have undergone cardiac transplantation for severe myocardial dysfunction, severe ventricular arrhythmias, and severe coronary arterial lesions for which interventional catheterization or coronary artery bypass procedures were not feasible. The timing of transplant has ranged from a few weeks or months to as long as 12 years after acute Kawasaki disease. Almost half of the transplant patients had undergone previous bypass grafting procedures without experiencing improvement in myocardial function. This procedure should be considered only for individuals with severe, irreversible myocardial dysfunction and coronary lesions for which interventional catheterization procedures or coronary artery bypass are not feasible (evidence level C).
Long-Term Follow-Up
Risk Stratification
Clinical experience with Kawasaki disease permits the stratification of patients according to their relative risk of myocardial ischemia. Risk-level categories are listed below and are summarized in Table 5 of the original guideline document. This stratification allows for patient management to be individualized with respect to medical therapy to reduce the risk of thrombosis, physical activity, frequency of clinical follow-up and diagnostic testing, and indications for cardiac catheterization and coronary angiography. With careful clinical follow-up 10 to 20 years after the onset of Kawasaki disease, patients with no coronary artery changes on echocardiography at any stage of the illness seem to demonstrate a risk for clinical cardiac events that is similar to that in the population without Kawasaki disease, but research studies suggest sub-clinical abnormalities of endothelial function and myocardial flow reserve. Furthermore, patients with Kawasaki disease seem to have a more adverse cardiovascular risk profile, with higher blood pressure and greater adiposity, as compared with control children. The risk level for a given patient with coronary artery involvement may change over time because of the changes in coronary artery morphology. For example, the development of thrombosis or stenosis associated with an aneurysm increases the risk for myocardial ischemia. Aneurysms also may regress to normal internal lumen diameter over time; optimal management of patients with regressed aneurysms is controversial because structural and functional coronary artery abnormalities persist. The following suggestions for long-term management are based on a consensus of experts and serve as a guide to clinicians until long-term studies and prospective trials facilitate evidence-based practice (evidence level C).
Risk Levels
Risk Level I - Patients with no coronary artery changes on echocardiography at any stage of the illness
- No antiplatelet therapy is needed beyond the initial 6 to 8 weeks after the onset of illness
- No restriction of physical activity is necessary after 6 to 8 weeks.
- Because the degree of future risk for ischemic heart disease in this category of patients is still undetermined, periodic assessment and counseling about known cardiovascular risk factors every 5 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 8 weeks after the onset of illness)
- No antiplatelet therapy is needed beyond the initial 6 to 8 weeks after the onset of illness.
- No restriction of physical activity is necessary after 6 to 8 weeks.
- Risk assessment and counseling is recommended at 3- to 5-year interviews
- 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 on echocardiography or angiography
- Long-term antiplatelet therapy with aspirin should be administered, at least until the aneurysms regress.
- Physical activity without restriction in infants and children in the first decade of life is permitted after the initial 6 to 8 weeks. Stress tests with myocardial perfusion evaluation may be useful in the second decade to guide recommendations for physical activity. Participation in competitive collision or high-impact sports is discouraged in children receiving antiplatelet therapy.
- Annual follow-up by a pediatric cardiologist with echocardiogram and electrocardiogram (ECG) is recommended. Stress tests with myocardial perfusion imaging is recommended every 2 years in patients >10 years.
- Coronary angiography is indicated if myocardial ischemia is demonstrated by stress tests with imaging.
Risk Level IV - Patients with >1 large coronary artery aneurysm (>6 mm), including giant aneurysms, and patients in whom a coronary artery contains multiple (segmented) or complex aneurysms without obstruction
- Long-term antiplatelet therapy is recommended. Adjunctive therapy with warfarin with a target INR of 2.0:2.5 is recommended for patients with giant aneurysms. Daily subcutaneous injections of low-molecular-weight heparin merits consideration as an alternative to warfarin for infants and toddlers, in whom blood drawing for INR testing is difficult. Low-molecular-weight heparin also may be used as a bridge during the initial phase of warfarin therapy or during the reintroduction of warfarin after the interruption of therapy for the purpose of elective surgery; therapeutic levels are assessed by measuring antifactor Xa levels. Some experts recommend a combination of aspirin and clopidogrel for patients with multiple or complex aneurysms.
- Recommendations about physical activity should be guided by annual stress tests with myocardial perfusion evaluation. Collision or high-impact sports should be discouraged because of the risk of bleeding. Participation in non-contact dynamic or recreational sports is encouraged if no evidence exists of stress-induced myocardial ischemia.
- Cardiology evaluation with echocardiogram and ECG should be done at 6-month intervals. Stress tests with myocardial perfusion evaluation should be performed annually. The patient should be monitored for known risk factors of atherosclerosis and his or her family should be counseled accordingly.
- Cardiac catheterization with selective coronary angiography should be performed 6 to 12 months after recovery from the acute illness, or sooner if clinically indicated, to delineate the complex coronary artery anatomy. Follow-up angiography may be indicated if noninvasive studies suggest myocardial ischemia. In addition, elective cardiac catheterization in the absence of noninvasive evidence of myocardial ischemia may be useful to rule out subclinical major coronary artery obstructions in some situations, such as when the patient experiences atypical chest pain, the ability to perform dynamic stress testing is limited by age, unique activity restrictions or insurability recommendations are needed, or the anatomy or size of the aneurysm cannot be clearly defined by echocardiography for decisions regarding anticoagulation.
- For females of childbearing age, reproductive counseling is strongly recommended.
Risk Level V - Patients with coronary artery obstruction confirmed by angiography
- Long-term antiplatelet therapy with or without adjunctive therapy with warfarin anticoagulation is recommended (see Risk Level IV)
- Beta-adrenergic-blocking drugs should be considered to reduce myocardial oxygen consumption.
- Recommendations about dynamic physical activities should be based on the patient's response to stress testing. Collision or high-impact sports should be discouraged because of the risk of bleeding. Patients should avoid a sedentary lifestyle.
- Cardiology evaluation with an echocardiogram and ECG should be obtained at 6-month intervals. Stress tests with myocardial perfusion evaluation should be performed annually. The patient should be monitored for known risk factors of atherosclerosis and his or her family should be counseled accordingly.
- Cardiac catheterization with selective coronary angiography is recommended to address the therapeutic options of bypass grafting or catheter intervention and to identify the extent of collateral perfusion. Repeat cardiac catheterization may be indicated when new onset or worsening myocardial ischemia is suggested by noninvasive diagnostic testing or clinical presentation. If the patient has undergone surgical revascularization or a catheter intervention, then repeat cardiac catheterization may be indicated to evaluate the efficacy of the treatment.
- For females of childbearing age, reproductive counseling is strongly recommended.
Summary
Kawasaki disease is the leading cause of acquired heart disease in children in the United States. Coronary artery aneurysms or ectasia develop in approximately 15 to 25% of untreated children; treatment with IVIG in the acute phase of the disease reduces this risk to <5%. Treatment with high-dose IVIG is recommended for children with fever of 4 days' duration and 4 of 5 classic clinical criteria, as well as for those with fewer clinical criteria in whom coronary abnormalities are noted by echocardiogram. This scientific statement proposes a new algorithm to aid clinicians in deciding which children with fever for >5 days and <4 classic criteria should undergo echocardiography, receive IVIG treatment, or both for Kawasaki disease. For patients with persistent or recurrent fever after initial IVIG infusion, IVIG retreatment may be useful. We reviewed the available data regarding other therapies for children with IVIG-resistant Kawasaki disease, including treatment with corticosteroids, TNF-alpha antagonists, and abciximab. Angiographic resolution occurs in approximately 50% of aneurysmal arterial segments, but these segments show persistent histological and functional abnormalities. The remainder may continue to be aneurysmal, often with the development of progressive stenosis or occlusion. The long-term management of patients with Kawasaki disease should be tailored to the degree of coronary involvement. The present writing group made recommendations for each risk level regarding antiplatelet and anticoagulant therapies, physical activity, follow-up assessment, and the appropriate diagnostic procedures that may be performed to evaluate cardiac disease. The risk level for a given patient with coronary arterial involvement may change over time because of the changes in coronary artery morphology. The statement on the initial evaluation, treatment in the acute phase, and long-term management of patients with Kawasaki disease is intended to provide practical interim recommendations until evidence-based data are available to define best medical practices.
Definitions
Levels of Evidence
Level A (highest): multiple randomized clinical trials
Level B (intermediate): limited number of randomized trials, nonrandomized studies, and observational registries
Level C (lowest): primarily expert consensus
