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Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation

Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation
Literature review current through: Jan 2024.
This topic last updated: Feb 06, 2023.

INTRODUCTION — Kawasaki disease (KD; also called mucocutaneous lymph node syndrome) is a vasculitis of unknown etiology that generally occurs in infancy and childhood. The acute illness is self-limited and is characterized by high fever; nonexudative conjunctivitis; inflammation of the oral mucosa; rash; cervical adenopathy; and findings in the extremities, including swollen hands and feet, red palms and soles, and, later, subungual peeling. (See "Kawasaki disease: Clinical features and diagnosis" and "Kawasaki disease: Epidemiology and etiology".)

Children with KD are at risk for serious cardiovascular sequelae, particularly coronary artery abnormalities (CAAs), which can lead to myocardial ischemia, infarction, and sudden death. The risk of developing CAAs is highest among children with KD who are not treated early in the disease with high-dose intravenous immune globulin (IVIG). Thus, initial management of patients with KD is focused on early diagnosis and treatment with IVIG. (See "Kawasaki disease: Initial treatment and prognosis".)

The clinical features and evaluation of cardiac sequelae of KD, including CAA, will be reviewed here. Other aspects of KD are discussed in greater detail separately:

(See "Cardiovascular sequelae of Kawasaki disease: Management and prognosis".)

(See "Kawasaki disease: Epidemiology and etiology".)

(See "Kawasaki disease: Clinical features and diagnosis".)

(See "Kawasaki disease: Initial treatment and prognosis".)

PATHOLOGY — The cardiovascular histopathology has been described in only a few small autopsy series [1,2], as mortality is rare in the contemporary era of treatment with intravenous immune globulin (IVIG; in-hospital mortality in the United States ranges from 0 to 0.17 percent [3,4]). In these studies, early KD is manifested as a panarteritis without fibrinoid necrosis. Infiltration of inflammatory cells (ie, neutrophils, lymphocytes, macrophages, and plasma cells) leads to dissociation and disruption of the media and internal elastic lamina. Studies using immunohistochemical techniques demonstrate that neutrophil infiltration in the coronary arterial wall peaks prior to infiltrations of CD68+ monocytes/macrophages, CD3+ lymphocytes, and CD20+ lymphocytes [5]. Aneurysms occur primarily in the coronary arteries. However, patients with giant coronary aneurysms sometimes also have peripheral aneurysms in extraparenchymal, medium-sized muscular arteries, such as the axillary, brachial, iliac, or femoral arteries.

In addition to coronary arteritis, cardiac involvement during the acute phase of KD includes inflammation in the pericardium, myocardium, atrioventricular conduction system, heart valves, and endocardium. Fulminant myocarditis and arrhythmias were reported to cause early deaths among the initial reported case series of KD [1,2]. In addition to data from autopsy series, which are skewed to the most severe cases, right ventricular endomyocardial biopsies have suggested that myocarditis is common, with late persistence of myocyte hypertrophy, disarray, and fibrosis [6,7].

Autopsy studies from the 1990s and 2000s of deaths occurring one month after onset of disease (ie, convalescent phase) described progressive neointimal proliferation, neoangiogenesis, and fibrosis with scar formation, whereas autopsies among patients who died several years later after the diagnosis of KD typically show severe coronary artery stenosis [1,2]. The late coronary artery histology among patients with aneurysms is characterized by replacement of medial smooth muscle with fibroblasts and extracellular matrix, and destruction of the internal elastic lamina [8]. Growth factors are expressed at areas of high sheer stress, such as the inlet and outlet of aneurysms [9].

In a subsequent report of an autopsy series of patients with coronary aneurysms, three pathologic processes were observed: necrotizing arteritis (mediated by neutrophils), subacute/chronic vasculitis (mediated by lymphocytes, plasma cells, and eosinophils), and luminal myofibroblastic proliferation, which can promote coronary artery stenosis [10]. In contrast to earlier studies, this report found complete absence of atherosclerotic changes within coronary aneurysms.

The late histopathology in KD differs from that described in routine adult atherosclerotic heart disease. As a result, the natural history and responses to coronary interventions in KD cannot be directly extrapolated from the large adult coronary literature.

PHYSICAL EXAMINATION FINDINGS — During the acute phase of illness, common findings on cardiac examination in children with KD include [11]:

Tachycardia out of proportion to the degree of fever.

Hyperdynamic precordium.

Gallop rhythm (movie 1).

Murmurs – Innocent flow murmurs are common in children with KD resulting from fever and/or anemia at the time of presentation. One-quarter of patients during the acute phase of KD have mitral regurgitation that may be detected by a regurgitant murmur at the apex (movie 2). Mitral regurgitation in acute KD generally results from valvulitis, whereas late mitral regurgitation is more likely to reflect papillary muscle dysfunction associated with ischemic heart disease. (See 'Valvular regurgitation' below.)

ACUTE COMPLICATIONS

KD shock syndrome — KD shock syndrome (KDSS) is an uncommon presentation of KD, occurring in <10 percent of cases [12,13]. It is characterized by warm shock with low peripheral vascular resistance. Patients with KDSS have a heightened risk of coronary aneurysms [12,13]. They also commonly have evidence of depressed left ventricular (LV) function and/or mitral regurgitation on echocardiography. (See 'Coronary artery abnormalities' below and 'Ventricular dysfunction' below and 'Valvular regurgitation' below.)

Characteristic laboratory findings in patients with KDSS include [12,14]:

Elevated troponin

Elevated lactate

Low platelet count

Elevated D-dimer

Elevated C-reactive protein

Hyponatremia

Low albumin

Elevated hepatic enzymes

Coagulopathy

Patients with KDSS are more likely to be resistant to intravenous immunoglobulin (IVIG) compared with classic KD [12,14].

Infants <6 months of age may be particularly ill at presentation. Some have cold, pale, or cyanotic digits of the hands and feet with reduced blood perfusion. Peripheral gangrene may, in rare cases, cause loss of fingers or toes during this acute period. Rarely, young infants may develop fusiform aneurysms of the brachial arteries, which are palpable or visible in the axillae. (See 'Peripheral artery aneurysms' below.)

The differential diagnosis for KDSS includes coronavirus disease 2019 (COVID-19)-related multisystem inflammatory syndrome in children (MIS-C), toxic shock syndrome, septic shock, and myocarditis. Rarely, KD can present with hemophagocytic syndrome or macrophage activation syndrome [15-18]. (See "Kawasaki disease: Complications", section on 'Shock' and "Kawasaki disease: Complications", section on 'Macrophage activation syndrome'.)

Coronary artery abnormalities — Coronary artery abnormalities (CAAs) are the most serious complication of KD and are usually first detected by echocardiography. They are classified based upon Z-score (coronary diameter adjusted for body surface area) (table 1) [11]. (See 'Coronary artery abnormality classification' below.)

In the first weeks after KD onset, approximately 25 percent of KD patients overall and >50 percent of infants younger than age six months have coronary aneurysms (ie, Z-scores ≥2.5) and approximately 1 percent develop giant coronary aneurysms (ie, Z-scores ≥10 or absolute dimension ≥8 mm) [19-22]. Coronary artery thrombosis and progressive stenosis within the aneurysm may cause late ischemic heart disease [23,24]. The risk of myocardial ischemia, myocardial infarction, and sudden death is highest among patients with a history of large or giant aneurysms. (See 'Long-term complications' below.)

Features — CAAs are located in the epicardial coronary arteries, most commonly in the proximal left anterior descending and proximal right coronary arteries, followed in frequency by the left main coronary artery, circumflex coronary artery, distal right coronary artery, and at the take-off of the posterior descending coronary artery from the right coronary artery [25]. The predilection for CAAs at branch points suggests a pathologic role for sheer stress.

CAAs can be saccular, fusiform, or ectatic (diffusely dilated without a segmental aneurysm) in shape, and their shape and size evolve over time. For example, an aneurysm that first appears to be ectatic can evolve to a segmented or beaded shape over weeks.

Risk factors — Reported risk factors associated with CAA include [19,26-40]:

Late diagnosis and delayed treatment with intravenous immune globulin (IVIG). IVIG treatment administered during the first 10 days of illness reduces the prevalence of CAAs fivefold [32,41]. (See "Kawasaki disease: Initial treatment and prognosis", section on 'Intravenous immune globulin'.)

Age <1 year and >9 years. Infants, particularly those <6 months, have the highest risk of aneurysms, even with prompt IVIG treatment [20]. In addition, since many infants present with atypical disease, diagnosis and treatment may be delayed. It is not clear whether children >9 years old have an increased susceptibility to coronary artery dilation or whether the increased risk of CAA is primarily due to a delay in administration of IVIG [42].

Male sex.

Long duration of fever (ie, ≥14 days).

Failure to respond to initial IVIG therapy manifested by persistent and recrudescent fever. (See "Kawasaki disease: Initial treatment and prognosis", section on 'Refractory KD'.)

Abnormal laboratory findings, including [19,30-32]:

Low hematocrit (ie, <35 percent)

Low serum albumin

Low serum sodium (ie, <135 mEq/L)

Elevated alanine aminotransferase

Elevated C-reactive protein and erythrocyte sedimentation rate

Elevated white blood cell count (>12,000/mm3)

Low baseline serum immunoglobulin G

Elevations in interleukin (IL)-6 and IL-8

Genetic polymorphisms including but not limited to matrix metalloproteinase haplotypes [43], endothelial growth factor and its receptors [44], calcium signaling pathways [45], and the transforming growth factor beta signaling pathway [46].

In the United States, the risk of CAAs appears to vary among ethnic groups. In one report based upon national surveillance data from 1994 to 2003 that included 3115 children with KD, Asian and Pacific Islander race and Hispanic ethnicity were associated with an increased risk of CAAs [36]. In an analysis from the Pediatric Health Information System that identified 4811 patients with KD from 2001 to 2006, the highest rate of CAAs was reported in Native Americans, but the number of such patients with KD was small [33]. The second highest rate of CAAs was in Hispanic patients (5.9 percent), followed by White non-Hispanic patients (3.4 percent), and the lowest rates were seen in Black and Asian patients (1.8 percent in both groups).

Identifying children at the highest risk for development of CAA at the time of presentation would be clinically useful as it could guide management decisions (eg, administering adjuvant antiinflammatory therapies in addition to IVIG). Risk scores have been developed based on demographic and clinical data from Japanese children [47-49]. While these perform well for Japanese children, they have poor sensitivity for predicting IVIG resistance and CAA in North American populations. An alternative risk score has been developed using data from a North American cohort [50]. The score performed well in a retrospective validation cohort, but prospective validation studies are needed. The approach to identifying children at high risk for IVIG resistance and the use of additional antiinflammatory therapy in this setting are discussed in greater detail separately. (See "Kawasaki disease: Initial treatment and prognosis", section on 'Identification of patients at high risk for IVIG resistance' and "Kawasaki disease: Initial treatment and prognosis", section on 'Additional therapy for patients at high risk for IVIG resistance'.)

Natural history — The natural course of CAAs is determined in large part by the severity of coronary artery disease during the acute phase of KD. Aneurysms may increase in size over the first four to six weeks after illness onset. After reaching a peak diameter, approximately 50 to 75 percent of aneurysms regress to normal lumen diameter [51-54]. Regression generally occurs within two years after the initial onset of KD; after this time, further regression is unlikely. The likelihood that an aneurysm will regress to normal lumen diameter is most strongly related to its maximum diameter; giant aneurysms are least likely to regress [53,55,56]. Aneurysms are also more likely to regress in younger children, at a more distal location, or if they are fusiform in shape [52].

Although internal lumen diameter is normal in regressed aneurysmal segments, myointimal thickening is evident by late intravascular ultrasound [57-59] and is directly related to the initial coronary diameter during the early months after disease onset [58]. Multiple studies have also demonstrated impaired coronary and peripheral vascular reactivity [59-62]. Thus, the term "regression" most often indicates remodeling rather than a true return to normal status.

In patients with persistent aneurysms, myointimal proliferation at the aneurysm entrance or exit progresses steadily over time [51,63,64]. Approximately one-half of aneurysms of maximum diameter ≥6 mm developed stenosis by 15 years follow-up in one study [65]. Aneurysmal arterial segments are also prone to increased tortuosity, calcification, and thrombotic occlusion. Because the arterial wall calcifies over time, the very rare event of aneurysm rupture is generally confined to the earliest months after illness onset.

Ventricular dysfunction — Evidence of mild to moderate ventricular dysfunction is noted on echocardiography during the acute phase in one-quarter to one-half of patients with KD [66,67]. Rarely, function is severely depressed. Depressed myocardial contractility may be caused by direct myocardial inflammation (ie, myocarditis) or from indirect negative inotropic effects of the systemic inflammatory response, whereas ischemic cardiomyopathy may occur in patients after myocardial infarction. Depressed ventricular function during the acute phase is often manifested by a third heart sound gallop, which may become more prominent with hydration [68]. In rare cases, it may progress to heart failure. For patients without ischemic cardiomyopathy, ventricular function usually improves rapidly following treatment with IVIG [68].

In a study of 198 patients with KD, echocardiographic evaluation demonstrated left ventricular (LV) dysfunction in 20 percent of patients at diagnosis [66]. Myocardial function generally improved rapidly after IVIG administration, and systolic function normalized among patients without ischemic myocardial disease. However, patients with LV dysfunction were more likely to have coronary artery dilation one and five weeks after diagnosis.

The LV dysfunction is due to impairment of both load-dependent and load-independent measures of LV contractility [67]. In analyses of diastolic function, relaxation has been found to be impaired during acute KD, and such abnormalities were seen long-term among patients with coronary aneurysms even in the absence of systolic dysfunction [69].

Valvular regurgitation — Mitral regurgitation of mild or moderate severity is present in approximately one-quarter of patients at baseline echocardiographic evaluation, with the incidence diminishing in the convalescent phase [66]. Aortic regurgitation is reported, but is less common, occurring in approximately 1 percent of patients during the first five weeks of illness [66]. Mild aortic root dilation is common in the first three weeks of the disease and persists during the first year of follow-up [66,70].

Pericardial effusion — Pericardial effusions of greater than 1 mm occur in fewer than 5 percent of patients [66], although rare patients can develop pericardial tamponade [71]. Tamponade can also be a complication of rupture of a giant aneurysm into the pericardial space [72-74].

Peripheral artery aneurysms — Peripheral artery aneurysms (PAAs) occur in <5 percent of patients with KD, chiefly in patients with giant CAAs or other manifestations of severe KD [75]. In patients who have indications for coronary angiography, it is reasonable to examine the peripheral arteries angiographically at the same time to evaluate for PAAs (see 'Coronary angiography' below). We suggest not routinely screening with full-body magnetic resonance angiography (MRA) for the sole purpose of detecting PAAs, because they rarely cause morbidity or mortality.

PAAs most commonly occur in the axillary, brachial, and iliac arteries [2,75,76]. They rarely may present with associated arterial thrombosis, causing limb ischemia and gangrene [77,78]. The vasculitis of KD generally spares visceral vessels, so involvement of other organ systems is unusual. Nonetheless, any vascular bed may be affected. Case reports have included KD presenting as a cerebrovascular accident (eg, acute encephalopathy [79], stroke [80]), gastrointestinal obstruction [81] or pseudo-obstruction [82], or acute abdominal catastrophe [83].

In a single-center study of 1148 patients with KD who underwent risk-based screening for PAAs, 14 percent (n = 162) were assessed to be at high risk on the basis of having giant CAAs, progressive CAAs, or refractory KD despite two courses of IVIG [75]. High-risk patients underwent evaluation with full-body MRA and/or peripheral angiography early in the disease course (median of 30 days after onset). Among these high-risk patients, PAAs were identified in 14 percent (2 percent of the entire cohort). PAAs occurred in 37 percent of patients with giant CAAs, 9 percent of patients with medium CAAs, and no patients with small CAAs or normal coronaries. In most affected patients, multiple peripheral arteries were involved, most commonly the axillary, common iliac, brachial, internal iliac, and/or subclavian arteries. The PAAs were asymptomatic in most patients and did not change management in any patient (all affected patients were already on systemic anticoagulation). Over follow-up of 3 to 18 months, 93 percent of PAAs regressed to some degree, with 80 percent regressing to normal. Longer-term follow-up of this cohort may help further characterize the natural history of PAAs in KD.

LONG-TERM COMPLICATIONS — Long-term cardiovascular complications of KD include accelerated atherosclerosis, myocardial ischemia, and arrythmia. These complications occur only in patients who had CAAs in the acute phase of the illness.

Accelerated atherosclerosis — The risk for early atherosclerotic cardiovascular disease (ASCVD) in patients with KD varies depending on the presence and persistence of CAAs:

Persistent aneurysms – Patients who have persistent aneurysms are at high risk for early atherosclerosis and ischemic heart disease [84,85]. The thresholds for treatment of atherosclerotic risk factors are lower in such patients than in the general population, as summarized in the figure (algorithm 1) and discussed in detail separately. (See "Overview of the management of the child or adolescent at risk for atherosclerosis".)

As described below, myocardial infarction as a consequence of KD occurs almost exclusively in patients with aneurysms. (See 'Myocardial infarction' below.)

Regressed aneurysms – Patients who have regressed aneurysms are at moderate risk for early ASCVD [84,85]. The thresholds for treatment of atherosclerotic risk factors are lower in such patients than in the general population, as summarized in the figure (algorithm 1) and discussed in detail separately. (See "Overview of the management of the child or adolescent at risk for atherosclerosis".)

Long-term follow-up studies of patients with CAAs due to KD have shown abnormalities in preclinical markers of atherosclerosis (eg, flow-mediated dilation, measures of vascular stiffness, and carotid intima-media thickness [cIMT]) [86,87]. Studies using intravascular ultrasound have demonstrated thickened intima in patients at the site of CAAs [57,58]. In a study of six patients who died after age 15, histopathologic findings included intimal thickening, and thrombotic occlusion in four of six persistent aneurysms, and in one patient there were advanced atherosclerotic changes [88]. Ultrasound findings of carotid atherosclerosis have been reported, independent of dyslipidemia, 6 to 20 years after KD was diagnosed among patients with CAAs [89]. In patients at ≥10-year follow-up, coronary angiographic findings revealed increased peripheral arterial stiffness, diminished vascular reactivity, and calcification [59,90]. In addition, patients who have persistent CAAs may have ongoing low-grade systemic inflammation, with higher levels of CRP than patients with KD who never had aneurysms or normal controls [91,92].

Patients who never had CAAs – Patients who never had CAAs do not appear to be at increased risk for atherosclerotic CVD compared with the general pediatric population [86,93-96]. The optimal follow-up for patients with a history of KD without CAAs has been an area of controversy. We agree with the 2017 guidelines of the American Heart Association, which recommend that this population be given the same routine counseling for ASCVD risk reduction as is given to the general population (ie, encouraging physical activity and heart-healthy diet) [11]. (See "Cardiovascular sequelae of Kawasaki disease: Management and prognosis", section on 'Long-term follow-up' and "Pediatric prevention of adult cardiovascular disease: Promoting a healthy lifestyle and identifying at-risk children", section on 'Promoting a heart-healthy lifestyle'.)

A 10- to 21-year follow-up study of 594 patients with KD demonstrated few cardiovascular events in patients without CAAs [51]. In a follow-up of Japanese children who had KD between July 1982 and December 1992, the standardized mortality ratio for patients without cardiac sequelae was not higher than that of the general population [94]. Two studies in North America have shown no changes in vascular function in KD patients who never had CAAs [95,96]. Late coronary artery calcification suggestive of atherosclerosis on low-dose non-contrast CT scanning is absent in patients who had no coronary artery dilation during the acute phase [90,97].

Studies evaluating indirect measures of early atherosclerosis in patients who never had any documented CAAs have had conflicting results. Several studies reported abnormal endothelium-dependent brachial artery reactivity, higher brachial-radial artery mean pulse wave Doppler velocity, lower myocardial flow reserve, and higher total coronary resistance [97-100]. Other studies have failed to show long-term abnormalities of peripheral vascular function in patients with either normal or mildly ectatic coronary artery dimensions [86,93,95]. One study that measured cIMT over 15 years found that cIMT was initially increased in patients who never had CAAs compared with normal controls; however, the difference normalized at a later age [87]. Studies of coronary endothelial function in which acetylcholine was administered in the epicardial coronary arteries have also shown conflicting results [101,102]. A systematic review and meta-analysis of 30 studies concluded that surrogate markers for atherosclerosis do not appear to be increased in KD patients who never had CAAs [86].

The extent to which the process and risk factors for atherosclerosis are related to the long-term course of KD vasculopathy is not completely understood. Further data with longer follow-up into adulthood are needed.

Myocardial infarction — Ischemic heart disease is a complication of KD limited solely to patients with CAAs [103,104]. Affected patients may present with chest pain, abdominal pain, pallor, diaphoresis, or inconsolable crying without an obvious cause. These symptoms warrant prompt evaluation. However, in one study, more than one-third of patients with myocardial infarction were asymptomatic and the infarct was identified on routine follow-up imaging [103].

Myocardial infarction is the principal cause of KD mortality and occurs most frequently among patients with giant CAAs [103]. The risk of myocardial infarction is highest in the first 6 to 12 months of the disease and declines after the first two years [103,104]; however, the risk persists into adulthood [23,104,105]. Indeed, "missed" KD in childhood can present with myocardial infarction in adulthood [106].

In a single-institution retrospective study of 1073 patients with KD followed for a median of 6.7 years between 1980 and 2012, myocardial ischemia, acute myocardial infarction (AMI), or death occurred in 13 patients (48 percent) with giant aneurysms, one patient (2 percent) with a medium aneurysm, and no patients with small aneurysms [53]. Of the patients who developed AMI, 67 percent occurred within the first year of KD onset. In another study from Japan of 245 patients with giant aneurysms, approximately one-half required coronary artery bypass grafting by a median of 20 years from onset of KD [107].

As discussed separately, ongoing monitoring with echocardiography and electrocardiogram is recommended, with the most intense monitoring in the first few months after the initial illness. (See "Cardiovascular sequelae of Kawasaki disease: Management and prognosis", section on 'Long-term follow-up'.)

Arrhythmia — Beyond the acute/subacute phase of illness, arrhythmia in KD occurs chiefly as a consequence of myocardial ischemia or infarction. Patients with arrhythmia may present with syncope or palpitations. Ventricular arrhythmias are likely indicators of underlying myocardial damage and are associated with increased risk of sudden death [11,104,108]. In a study of 60 patients with KD who were followed for a median of 16 years after suffering AMI, 28 percent had documented nonsustained ventricular tachycardia (NSVT), 7 percent had sustained VT, and 12 percent required treatment with antiarrhythmic agents [104]. Of the six patients in this cohort who died suddenly, four had prior documented NSVT.

CARDIAC EVALUATION

General approach — In our practice, all patients who are early in the course of KD undergo cardiac testing that includes echocardiography and ECG. When echocardiography is inadequate to image the coronary arteries, ultrafast computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) are used to fully delineate the coronary arterial tree.

Long-term management and follow-up of patients with KD is stratified according to their maximal aneurysm severity as assessed once acute management is completed and the coronary arteries are no longer enlarging (table 2). (See "Cardiovascular sequelae of Kawasaki disease: Management and prognosis", section on 'Management' and "Cardiovascular sequelae of Kawasaki disease: Management and prognosis", section on 'Long-term follow-up'.)

Patients with coronary aneurysms undergo stress testing with myocardial perfusion imaging on a regular basis to evaluate for inducible ischemia (table 2).

For patients with a history of giant coronary aneurysms, advanced imaging by cardiac catheterization, CTA, or MRA is performed during the first year after disease onset and then serially at an interval dependent upon clinical status and results of stress testing. If a cardiac catheterization is performed for evaluation of coronary anatomy, subsequent advanced imaging modalities are generally noninvasive (eg, CTA or MRA) unless a catheter intervention is needed or noninvasive coronary imaging provides inadequate data to guide management. Exposure to ionizing radiation should be minimized wherever possible. The interval for follow-up testing is discussed in a separate topic review. (See "Cardiovascular sequelae of Kawasaki disease: Management and prognosis", section on 'Frequency of follow-up'.)

Our approach is generally consistent with the 2017 guidelines of the American Heart Association [11].

Distinguishing KD from MIS-C — With the emergence of the coronavirus disease 2019 (COVID-19) pandemic, a novel syndrome called COVID-19-related multisystem inflammatory syndrome in children (MIS-C; also called pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2; PIMS-TS]) has been recognized [109]. MIS-C has considerable overlap with KD and KD shock syndrome. It can be challenging to differentiate between KD and MIS-C, especially as more of the pediatric population have been exposed to SARS-CoV-2. In general, the following features help to differentiate KD from MIS-C [110-112]:

KD occurs predominantly in early childhood (<5 years old), whereas MIS-C more commonly occurs in school-age children and adolescents

Gastrointestinal symptoms (diarrhea, vomiting, abdominal pain, even colitis) are strikingly prominent in MIS-C and are less common in KD

Inflammatory markers (especially C-reactive protein, ferritin, and D-dimer) tend to be more elevated and platelets and absolute lymphocyte count are lower in MIS-C compared with KD

Patients with MIS-C are more likely to present with shock and depressed left ventricular (LV) function compared with patients with KD

This issue is discussed in greater detail separately. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis", section on 'Differentiating MIS-C and Kawasaki disease'.)

The approach to evaluating for suspected MIS-C is summarized in the figure (algorithm 2) and discussed in greater detail separately. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis", section on 'Evaluation'.)

Echocardiography

Initial evaluation — Echocardiography should be performed in all patients with KD as soon as the diagnosis is suspected in order to establish a baseline for longitudinal follow-up. In addition, in a subset of patients with fever and incomplete criteria, findings on echocardiography are helpful in the decision of whether intravenous immune globulin (IVIG) should be administered (algorithm 3) [11]. (See "Kawasaki disease: Clinical features and diagnosis" and "Incomplete (atypical) Kawasaki disease", section on 'Criteria for treatment'.)

Echocardiography has a high sensitivity and specificity for detecting proximal coronary arterial dilatation in the acute phase of illness and other noncoronary artery abnormalities [113]. Children <2 years of age may need to be sedated to obtain adequate images.

Echocardiography also detects other noncoronary artery abnormalities including depressed ventricular function, valvular regurgitation, and pericardial effusions. (See 'Ventricular dysfunction' above and 'Valvular regurgitation' above and 'Pericardial effusion' above.)

Follow-up studies — Repeat echocardiograms are usually obtained at one to two weeks and again four to six weeks after discharge. More frequent echocardiography may be warranted for higher-risk patients (ie, those with abnormalities on baseline echocardiography or persistent or recrudescent fever).

For children with giant aneurysms, we perform echocardiography to monitor for thrombus formation at least twice weekly during the period when coronary arteries are enlarging, then once weekly in the highest-risk period (ie, first 45 days of illness), then monthly until the third month of disease, and then once every three months until the end of the first year after illness onset.

Patients who do not have CAAs in the first month after KD onset and who do not have lingering or recurrent signs or symptoms do not need further cardiac testing [114,115].

Coronary artery abnormality classification — Coronary artery abnormalities (CAAs) are classified according to the diameter of the internal lumen, normalized for body surface area as a Z-score (table 1) [11,116]:

No involvement – Z-score always <2 and no more than a 0.9 decrease in Z-score during follow-up

Dilation only – Z-score 2 to <2.5 or if Z-score initially <2, a ≥1 decrease in Z-score during follow-up

Small aneurysm – Z-score ≥2.5 to <5

Medium aneurysm – Z-score ≥5 to <10 and absolute dimension <8 mm

Large or giant aneurysm – Z-score ≥10 or absolute dimension ≥8 mm

Some children who have coronary artery dimensions within the normal range (ie, Z-score <2) have substantial reduction in coronary artery dimension over time, suggesting that the coronary artery was initially dilated [117,118]. Such patients are categorized as "dilation only" despite always having coronary artery dimensions within the normal range (ie, Z-score <2).

Z-scores can be computed by several different methods. The Boston Children's Hospital Z-score system is based on data gathered from healthy children [119]. Other online calculators are available through the referenced website [120]. For large absolute coronary dimensions, these Z-score calculators can produce very different values, potentially affecting the decision to prescribe an anticoagulant [121].

In Japan, criteria for aneurysms are based upon absolute dimensions [122,123]: small aneurysms have internal lumen diameter ≤4 mm, medium aneurysms >4 to ≤8 mm, and giant aneurysms >8 mm. In addition, the ratio of the aneurysms internal diameter to that of an adjacent segment is used to classify aneurysm severity by Japanese criteria; a ratio of 1.5 is considered a small aneurysm, 1.5 to 4 a medium aneurysm, and >4 a giant aneurysm.

In a multicenter study in which echocardiograms were read in a central core laboratory [19], the median Z-score at the time of presentation was 1.43, significantly higher than the expected population median of 0. For most patients, Z-scores decreased at one and five weeks following the baseline evaluation, although they were still increased compared with the normal afebrile population. In one in four patients, at least one echocardiogram in the five-week observation period included a proximal right coronary artery or left anterior descending coronary artery Z-score of 2.5; 5 percent had at least one Z-score ≥5. Coronary artery segments with Z-scores <2.5 at initial evaluation usually do not dilate over the ensuing weeks. Perivascular brightness of the coronary artery walls, lack of tapering, and ectasia (coronary Z-scores 2 to 2.5) are thought to be soft signs of KD, although their predictive validity is unproven.

CTA and MRA — In patients with clinically significant CAAs, echocardiography alone may not be sufficient to fully evaluate the extent of disease. In this setting, CTA and MRA are often used to obtain high-resolution coronary images [124-129]. CTA and MRA are particularly useful for detecting distal lesions and coronary artery stenosis. Because aneurysms and stenosis in KD can worsen over time, we typically perform coronary CTA in patients with large or complex aneurysms approximately 12 months after illness onset. Cardiac catheterization is performed earlier if there are clinical or noninvasive induced signs of ischemia. (See 'Coronary angiography' below.)

Both CTA and MRA are optimized with a slow heart rate, and intravenous beta blockade may be necessary in young children to obtain the best images. Anesthesia is needed to perform both types of noninvasive angiography when children are unable to stay still. CTA exposes children to ionizing radiation. Although the radiation doses are ever decreasing, this is still a risk in children who require repeated studies. However, the quality of coronary imaging is generally superior to that of cardiac MRA. Nonetheless, MRA has several advantages over ultrafast CTA because it can be combined with dobutamine- or adenosine-stress testing and can also delineate areas affected by myocardial infarction using delayed enhancement.

Electrocardiography — The electrocardiogram (ECG) may show arrhythmia, slight prolongation of the PR and QT intervals, or nonspecific ST and T wave changes. In patients with aneurysms, myocardial infarction can be indicated by ECG abnormalities, supported by elevation in biochemical markers of myocardial necrosis (eg, troponin, creatinine kinase MB dimers [CK-MB]) and myocardial imaging studies showing new loss of viable myocardium or new regional wall motion abnormality. (See "Diagnosis of acute myocardial infarction" and "Troponin testing: Clinical use".)

Stress testing for inducible ischemia — Patients with aneurysms are advised to undergo periodic testing for inducible ischemia in order to detect and, if present, to quantify the degree of coronary insufficiency. The interval for testing is discussed in a separate topic review. (See "Cardiovascular sequelae of Kawasaki disease: Management and prognosis", section on 'Frequency of follow-up'.)

Based upon small case series, stress testing appears to be a useful tool for evaluating children with KD who have CAAs [130-143]. Because the risk of false-positive testing is highest when the probability of disease is low, we suggest not performing stress testing in patients without a history of aneurysms.

The choice of testing technique is based upon the child’s ability to cooperate, potential risks (such as radiation exposure or anesthesia), institutional preference, and experience in adults. (See "Selecting the optimal cardiac stress test".)

The following principles should be considered when determining the most appropriate technique for stress testing:

Exercise stress testing is generally preferred over pharmacologic stress testing because it is more physiologic. However, pharmacologic stress testing is appropriate for children who are unable to cooperate with the exercise protocol.

The predictive value of exercise stress testing is enhanced with the use of noninvasive imaging. This is particularly true for pharmacologic stress testing, which always combines ECG analysis with imaging because the sensitivity of using only ECG monitoring to detect inducible ischemia in this setting is unacceptably low. (See "Selecting the optimal cardiac stress test", section on 'Exercise ECG alone or in combination with an imaging modality?'.)

Imaging techniques for stress testing include echocardiography, single-photon emission computed tomography (SPECT), MRA, and positron emission tomography (PET). In weighing the relative merits of imaging techniques, stress echocardiography compared with SPECT perfusion imaging has a higher success rate, greater specificity, and avoids radiation exposure and the need for placement of an intravenous line; the latter is a major advantage for younger children. However, stress echocardiography is dependent upon acoustic windows and, compared with SPECT imaging, has greater interobserver variability and lower sensitivity. For patients with KD with left main or multivessel disease leading to "balanced ischemia," SPECT imaging may be less sensitive than stress echocardiography. Dobutamine MRA avoids radiation exposure and can assess both perfusion and wall motion abnormalities but has the downside of usually requiring general anesthesia. Pediatric experience with pharmacologic stress testing using PET is growing. PET is a powerful modality for assessing myocardial perfusion viability and ischemic burden. Like SPECT perfusion imaging, PET imaging involves radiation but has a lower radiation dose than does SPECT.

Coronary angiography — Because cardiac catheterization with angiography has a greater risk than noninvasive methods and exposes children to ionizing radiation, it should be restricted to patients with clinically significant CAAs in whom:

Noninvasive testing cannot provide equivalent imaging without greater risk

Symptoms or noninvasive evidence of ischemia suggest that coronary revascularization may be indicated (see "Cardiovascular sequelae of Kawasaki disease: Management and prognosis", section on 'Coronary revascularization procedures')

Angiographic imaging is otherwise needed to guide therapy, including the choice of optimal antithrombotic therapy (eg, warfarin plus aspirin versus only antiplatelet therapy) (see "Cardiovascular sequelae of Kawasaki disease: Management and prognosis", section on 'Myocardial infarction and coronary thrombosis')

At some centers, cardiac catheterization is also routinely performed to assess coronary status after surgical revascularization or percutaneous coronary intervention.

Selective coronary angiography has historically been the "gold standard" for evaluation of coronary architecture in children with KD. In fact, serial angiography in Japanese patients has defined the natural history of the disease. Coronary angiography offers detailed definition of the coronary lumen anatomy and blood flow characteristics, including collateral flow. It can detect and quantify stenosis, obstruction, and aneurysms of the coronary arteries and the collateral circulation (movie 3 and movie 4 and movie 5). Intraluminal ultrasound performed at the time of cardiac catheterization can add information about the structure of the coronary arterial wall, and measurements of coronary flow reserve with adenosine stress may also be useful. Intravenous or intracoronary infusion of vasoactive drugs such as nitroglycerin, isosorbide dinitrate, acetylcholine, or ergotamine with computer-based vascular edge detection and quantitative measurement can provide information on vascular function.

If cardiac catheterization is performed, subclavian arteriograms should be performed to delineate the anatomy of the internal mammary arteries and to evaluate for peripheral artery aneurysms (PAAs) in the brachial, subclavian, and/or axillary arteries [63]. Similarly, abdominal aortography is useful to evaluate for PAAs in the iliac and femoral arteries. (See 'Peripheral artery aneurysms' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kawasaki disease" and "Society guideline links: Lipid disorders and atherosclerosis in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Kawasaki disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

Acute cardiovascular complications

Coronary artery abnormalities (CAAs) – The major acute cardiovascular complication of Kawasaki disease (KD) is a CAA, which can include dilation, aneurysm, and/or stenosis. Approximately one-quarter of all KD patients and more than one-half of infants <6 months old have CAAs during the acute illness. CAAs are classified based upon Z-score (coronary diameter adjusted for body surface area) (table 1). (See 'Coronary artery abnormalities' above and 'Coronary artery abnormality classification' above.)

Risk factors for CAAs include age <12 months, prolonged duration of fever (≥14 days), and late diagnosis/delayed treatment with intravenous immune globulin (IVIG). (See 'Risk factors' above.)

Aneurysms typically increase over the first four to six weeks after illness onset, and approximately one-half regress to normal lumen diameter over the subsequent two years. The likelihood that an aneurysm will regress to normal lumen diameter is most strongly related to its maximum diameter; giant aneurysms are least likely to regress. The highest risk of morbidity and mortality is associated with large or giant CAAs. (See 'Natural history' above.)

Other acute cardiovascular complications – Other cardiovascular complications that can be seen in patients with KD during the acute phase include:

-Shock (see 'KD shock syndrome' above)

-Depressed ventricular function(see 'Ventricular dysfunction' above)

-Valvular regurgitation(see 'Valvular regurgitation' above)

-Pericardial effusion(see 'Pericardial effusion' above)

-Peripheral artery aneurysms (PAAs) (see 'Peripheral artery aneurysms' above)

Late cardiovascular complications – Late complications are generally limited to patients who had moderate or large/giant CAAs in the acute phase. (See 'Long-term complications' above.)

Early atherosclerotic cardiovascular disease (ASCVD) – Patients with CAAs may be at risk for early ASCVD. The thresholds for treatment of atherosclerotic risk factors are lower in such patients than in the general population (algorithm 1). Patients who never had CAAs do not appear to be at increased risk for cardiovascular disease compared with the general pediatric population. (See 'Accelerated atherosclerosis' above.)

Myocardial infarction – Myocardial infarction occurs most frequently among patients with giant CAAs. The risk is highest within the first 6 to 12 months after the onset of illness, but it persists into adulthood. Affected patients may present with chest pain, abdominal pain, pallor, diaphoresis, or inconsolable crying without an obvious cause. (See 'Myocardial infarction' above.)

Arrhythmia – Beyond the acute/subacute phase of illness, arrhythmia in KD occurs chiefly as a consequence of myocardial ischemia or infarction. (See 'Arrhythmia' above.)

Cardiac evaluation – In all patients with KD, cardiac testing includes electrocardiogram (ECG) and echocardiography (see 'Cardiac evaluation' above):

ECG – The ECG in acute KD may show arrhythmia, slight prolongation of the PR and QT intervals, or nonspecific ST and T wave changes. (See 'Electrocardiography' above.)

Echocardiography – Echocardiography has a high sensitivity and specificity for detecting proximal CAAs in the acute phase of illness. Echocardiography also detects other cardiac abnormalities including depressed myocardial contractility, valvular regurgitation, and pericardial effusions. (See 'Echocardiography' above.)

Repeat echocardiograms are usually performed at one to two weeks and again four to six weeks after discharge. Patients who do not have CAAs in the first month after KD onset and who do not have lingering or recurrent signs or symptoms do not need further cardiac testing. (See 'Follow-up studies' above.)

Other noninvasive imaging – If the acoustic windows are poor on echocardiography and do not permit adequate images of the coronary arteries, computed tomographic angiography (CTA) or magnetic resonance angiography (MRA) may be used to fully delineate the coronary arterial tree. (See 'CTA and MRA' above.)

Stress testing – Patients with coronary aneurysms undergo stress testing with myocardial perfusion imaging on a regular basis to evaluate for inducible ischemia (table 2). (See 'Stress testing for inducible ischemia' above and "Cardiovascular sequelae of Kawasaki disease: Management and prognosis", section on 'Frequency of follow-up'.)

  1. Fujiwara H, Hamashima Y. Pathology of the heart in Kawasaki disease. Pediatrics 1978; 61:100.
  2. Naoe S, Takahashi K, Masuda H, Tanaka N. Kawasaki disease. With particular emphasis on arterial lesions. Acta Pathol Jpn 1991; 41:785.
  3. Holman RC, Curns AT, Belay ED, et al. Kawasaki syndrome hospitalizations in the United States, 1997 and 2000. Pediatrics 2003; 112:495.
  4. Chang RK. Hospitalizations for Kawasaki disease among children in the United States, 1988-1997. Pediatrics 2002; 109:e87.
  5. Takahashi K, Oharaseki T, Naoe S, et al. Neutrophilic involvement in the damage to coronary arteries in acute stage of Kawasaki disease. Pediatr Int 2005; 47:305.
  6. Yutani C, Okano K, Kamiya T, et al. Histopathological study on right endomyocardial biopsy of Kawasaki disease. Br Heart J 1980; 43:589.
  7. Yutani C, Go S, Kamiya T, et al. Cardiac biopsy of Kawasaki disease. Arch Pathol Lab Med 1981; 105:470.
  8. Burns JC. Kawasaki Disease update. Indian J Pediatr 2009; 76:71.
  9. Suzuki A, Miyagawa-Tomita S, Komatsu K, et al. Active remodeling of the coronary arterial lesions in the late phase of Kawasaki disease: immunohistochemical study. Circulation 2000; 101:2935.
  10. Orenstein JM, Shulman ST, Fox LM, et al. Three linked vasculopathic processes characterize Kawasaki disease: a light and transmission electron microscopic study. PLoS One 2012; 7:e38998.
  11. McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation 2017; 135:e927.
  12. Kanegaye JT, Wilder MS, Molkara D, et al. Recognition of a Kawasaki disease shock syndrome. Pediatrics 2009; 123:e783.
  13. Taddio A, Rossi ED, Monasta L, et al. Describing Kawasaki shock syndrome: results from a retrospective study and literature review. Clin Rheumatol 2017; 36:223.
  14. Lamrani L, Manlhiot C, Elias MD, et al. Kawasaki Disease Shock Syndrome vs Classical Kawasaki Disease: A Meta-analysis and Comparison With SARS-CoV-2 Multisystem Inflammatory Syndrome. Can J Cardiol 2021; 37:1619.
  15. Chen Y, Shang S, Zhang C, et al. Hemophagocytic lymphohistiocytosis at initiation of kawasaki disease and their differential diagnosis. Pediatr Hematol Oncol 2010; 27:244.
  16. Palazzi DL, McClain KL, Kaplan SL. Hemophagocytic syndrome after Kawasaki disease. Pediatr Infect Dis J 2003; 22:663.
  17. Simonini G, Pagnini I, Innocenti L, et al. Macrophage activation syndrome/Hemophagocytic Lymphohistiocytosis and Kawasaki disease. Pediatr Blood Cancer 2010; 55:592.
  18. Titze U, Janka G, Schneider EM, et al. Hemophagocytic lymphohistiocytosis and Kawasaki disease: combined manifestation and differential diagnosis. Pediatr Blood Cancer 2009; 53:493.
  19. McCrindle BW, Li JS, Minich LL, et al. Coronary artery involvement in children with Kawasaki disease: risk factors from analysis of serial normalized measurements. Circulation 2007; 116:174.
  20. Salgado AP, Ashouri N, Berry EK, et al. High Risk of Coronary Artery Aneurysms in Infants Younger than 6 Months of Age with Kawasaki Disease. J Pediatr 2017; 185:112.
  21. Newburger JW, Sleeper LA, McCrindle BW, et al. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med 2007; 356:663.
  22. Ogata S, Tremoulet AH, Sato Y, et al. Coronary artery outcomes among children with Kawasaki disease in the United States and Japan. Int J Cardiol 2013; 168:3825.
  23. Burns JC, Shike H, Gordon JB, et al. Sequelae of Kawasaki disease in adolescents and young adults. J Am Coll Cardiol 1996; 28:253.
  24. Suda K, Iemura M, Nishiono H, et al. Long-term prognosis of patients with Kawasaki disease complicated by giant coronary aneurysms: a single-institution experience. Circulation 2011; 123:1836.
  25. Kitamura S, Kameda Y, Seki T, et al. Long-term outcome of myocardial revascularization in patients with Kawasaki coronary artery disease. A multicenter cooperative study. J Thorac Cardiovasc Surg 1994; 107:663.
  26. Minich LL, Sleeper LA, Atz AM, et al. Delayed diagnosis of Kawasaki disease: what are the risk factors? Pediatrics 2007; 120:e1434.
  27. Muta H, Ishii M, Sakaue T, et al. Older age is a risk factor for the development of cardiovascular sequelae in Kawasaki disease. Pediatrics 2004; 114:751.
  28. Song D, Yeo Y, Ha K, et al. Risk factors for Kawasaki disease-associated coronary abnormalities differ depending on age. Eur J Pediatr 2009; 168:1315.
  29. Kim T, Choi W, Woo CW, et al. Predictive risk factors for coronary artery abnormalities in Kawasaki disease. Eur J Pediatr 2007; 166:421.
  30. Beiser AS, Takahashi M, Baker AL, et al. A predictive instrument for coronary artery aneurysms in Kawasaki disease. US Multicenter Kawasaki Disease Study Group. Am J Cardiol 1998; 81:1116.
  31. Sabharwal T, Manlhiot C, Benseler SM, et al. Comparison of factors associated with coronary artery dilation only versus coronary artery aneurysms in patients with Kawasaki disease. Am J Cardiol 2009; 104:1743.
  32. Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 1986; 315:341.
  33. Son MB, Gauvreau K, Ma L, et al. Treatment of Kawasaki disease: analysis of 27 US pediatric hospitals from 2001 to 2006. Pediatrics 2009; 124:1.
  34. Nakamura Y, Yashiro M, Uehara R, et al. Use of laboratory data to identify risk factors of giant coronary aneurysms due to Kawasaki disease. Pediatr Int 2004; 46:33.
  35. Koren G, Lavi S, Rose V, Rowe R. Kawasaki disease: review of risk factors for coronary aneurysms. J Pediatr 1986; 108:388.
  36. Belay ED, Maddox RA, Holman RC, et al. Kawasaki syndrome and risk factors for coronary artery abnormalities: United States, 1994-2003. Pediatr Infect Dis J 2006; 25:245.
  37. Stockheim JA, Innocentini N, Shulman ST. Kawasaki disease in older children and adolescents. J Pediatr 2000; 137:250.
  38. Momenah T, Sanatani S, Potts J, et al. Kawasaki disease in the older child. Pediatrics 1998; 102:e7.
  39. Uehara R, Belay ED, Maddox RA, et al. Analysis of potential risk factors associated with nonresponse to initial intravenous immunoglobulin treatment among Kawasaki disease patients in Japan. Pediatr Infect Dis J 2008; 27:155.
  40. Manlhiot C, Yeung RS, Clarizia NA, et al. Kawasaki disease at the extremes of the age spectrum. Pediatrics 2009; 124:e410.
  41. Furusho K, Kamiya T, Nakano H, et al. High-dose intravenous gammaglobulin for Kawasaki disease. Lancet 1984; 2:1055.
  42. Yeo Y, Kim T, Ha K, et al. Incomplete Kawasaki disease in patients younger than 1 year of age: a possible inherent risk factor. Eur J Pediatr 2009; 168:157.
  43. Shimizu C, Matsubara T, Onouchi Y, et al. Matrix metalloproteinase haplotypes associated with coronary artery aneurysm formation in patients with Kawasaki disease. J Hum Genet 2010; 55:779.
  44. Kariyazono H, Ohno T, Khajoee V, et al. Association of vascular endothelial growth factor (VEGF) and VEGF receptor gene polymorphisms with coronary artery lesions of Kawasaki disease. Pediatr Res 2004; 56:953.
  45. Onouchi Y, Gunji T, Burns JC, et al. ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms. Nat Genet 2008; 40:35.
  46. Shimizu C, Jain S, Davila S, et al. Transforming growth factor-beta signaling pathway in patients with Kawasaki disease. Circ Cardiovasc Genet 2011; 4:16.
  47. Kobayashi T, Inoue Y, Takeuchi K, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation 2006; 113:2606.
  48. Sleeper LA, Minich LL, McCrindle BM, et al. Evaluation of Kawasaki disease risk-scoring systems for intravenous immunoglobulin resistance. J Pediatr 2011; 158:831.
  49. Tremoulet AH, Best BM, Song S, et al. Resistance to intravenous immunoglobulin in children with Kawasaki disease. J Pediatr 2008; 153:117.
  50. Son MBF, Gauvreau K, Tremoulet AH, et al. Risk Model Development and Validation for Prediction of Coronary Artery Aneurysms in Kawasaki Disease in a North American Population. J Am Heart Assoc 2019; 8:e011319.
  51. Kato H, Sugimura T, Akagi T, et al. Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of 594 patients. Circulation 1996; 94:1379.
  52. Takahashi M, Mason W, Lewis AB. Regression of coronary aneurysms in patients with Kawasaki syndrome. Circulation 1987; 75:387.
  53. Lin MT, Sun LC, Wu ET, et al. Acute and late coronary outcomes in 1073 patients with Kawasaki disease with and without intravenous γ-immunoglobulin therapy. Arch Dis Child 2015; 100:542.
  54. Friedman KG, Gauvreau K, Hamaoka-Okamoto A, et al. Coronary Artery Aneurysms in Kawasaki Disease: Risk Factors for Progressive Disease and Adverse Cardiac Events in the US Population. J Am Heart Assoc 2016; 5.
  55. Fujiwara T, Fujiwara H, Hamashima Y. Size of coronary aneurysm as a determinant factor of the prognosis in Kawasaki disease: clinicopathologic study of coronary aneurysms. Prog Clin Biol Res 1987; 250:519.
  56. Nakano H, Ueda K, Saito A, Nojima K. Repeated quantitative angiograms in coronary arterial aneurysm in Kawasaki disease. Am J Cardiol 1985; 56:846.
  57. Sugimura T, Kato H, Inoue O, et al. Intravascular ultrasound of coronary arteries in children. Assessment of the wall morphology and the lumen after Kawasaki disease. Circulation 1994; 89:258.
  58. Tsuda E, Kamiya T, Kimura K, et al. Coronary artery dilatation exceeding 4.0 mm during acute Kawasaki disease predicts a high probability of subsequent late intima-medial thickening. Pediatr Cardiol 2002; 23:9.
  59. Iemura M, Ishii M, Sugimura T, et al. Long term consequences of regressed coronary aneurysms after Kawasaki disease: vascular wall morphology and function. Heart 2000; 83:307.
  60. Kurisu Y, Azumi T, Sugahara T, et al. Variation in coronary arterial dimension (distensible abnormality) after disappearing aneurysm in Kawasaki disease. Am Heart J 1987; 114:532.
  61. Matsumura K, Okuda Y, Ito T, et al. Coronary angiography of Kawasaki disease with the coronary vasodilator dipyridamole: assessment of distensibility of affected coronary arterial wall. Angiology 1988; 39:141.
  62. Sugimura T, Kato H, Inoue O, et al. Vasodilatory response of the coronary arteries after Kawasaki disease: evaluation by intracoronary injection of isosorbide dinitrate. J Pediatr 1992; 121:684.
  63. Suzuki A, Kamiya T, Kuwahara N, et al. Coronary arterial lesions of Kawasaki disease: cardiac catheterization findings of 1100 cases. Pediatr Cardiol 1986; 7:3.
  64. Kamiya T, Suzuki A, Ono Y, et al. Angiographic follow-up study of coronary artery lesion in the cases with a history of Kawasaki disease - with a focus on the follow-up more than ten years after the onset of the disease. In: Kawasaki Disease. Proceedings of the 5th International Kawasaki Disease Symposium, Kato H (Ed), Elsevier Science B.V., Amsterdam 1995. p.569.
  65. Tsuda E, Kamiya T, Ono Y, et al. Incidence of stenotic lesions predicted by acute phase changes in coronary arterial diameter during Kawasaki disease. Pediatr Cardiol 2005; 26:73.
  66. Printz BF, Sleeper LA, Newburger JW, et al. Noncoronary cardiac abnormalities are associated with coronary artery dilation and with laboratory inflammatory markers in acute Kawasaki disease. J Am Coll Cardiol 2011; 57:86.
  67. Moran AM, Newburger JW, Sanders SP, et al. Abnormal myocardial mechanics in Kawasaki disease: rapid response to gamma-globulin. Am Heart J 2000; 139:217.
  68. Newburger JW, Sanders SP, Burns JC, et al. Left ventricular contractility and function in Kawasaki syndrome. Effect of intravenous gamma-globulin. Circulation 1989; 79:1237.
  69. Selamet Tierney ES, Newburger JW, Graham D, et al. Diastolic function in children with Kawasaki disease. Int J Cardiol 2011; 148:309.
  70. Ravekes WJ, Colan SD, Gauvreau K, et al. Aortic root dilation in Kawasaki disease. Am J Cardiol 2001; 87:919.
  71. Ozdogu H, Boga C. Fatal cardiac tamponade in a patient with Kawasaki disease. Heart Lung 2005; 34:257.
  72. Kuppuswamy M, Gukop P, Sutherland G, Venkatachalam C. Kawasaki disease presenting as cardiac tamponade with ruptured giant aneurysm of the right coronary artery. Interact Cardiovasc Thorac Surg 2010; 10:317.
  73. Imai Y, Sunagawa K, Ayusawa M, et al. A fatal case of ruptured giant coronary artery aneurysm. Eur J Pediatr 2006; 165:130.
  74. Maresi E, Passantino R, Midulla R, et al. Sudden infant death caused by a ruptured coronary aneurysm during acute phase of atypical Kawasaki disease. Hum Pathol 2001; 32:1407.
  75. Zhao QM, Chu C, Wu L, et al. Systemic Artery Aneurysms and Kawasaki Disease. Pediatrics 2019; 144.
  76. Hoshino S, Tsuda E, Yamada O. Characteristics and Fate of Systemic Artery Aneurysm after Kawasaki Disease. J Pediatr 2015; 167:108.
  77. Tomita S, Chung K, Mas M, et al. Peripheral gangrene associated with Kawasaki disease. Clin Infect Dis 1992; 14:121.
  78. Ozdemir E, Peterson RE. Systemic arterial aneurysm complicated by thrombosis in an infant with resistant Kawasaki disease. Ann Pediatr Cardiol 2019; 12:147.
  79. Tabarki B, Mahdhaoui A, Selmi H, et al. Kawasaki disease with predominant central nervous system involvement. Pediatr Neurol 2001; 25:239.
  80. Suda K, Matsumura M, Ohta S. Kawasaki disease complicated by cerebral infarction. Cardiol Young 2003; 13:103.
  81. Mele T, Evans M. Intestinal obstruction as a complication of Kawasaki disease. J Pediatr Surg 1996; 31:985.
  82. Akikusa JD, Laxer RM, Friedman JN. Intestinal pseudoobstruction in Kawasaki disease. Pediatrics 2004; 113:e504.
  83. Zulian F, Falcini F, Zancan L, et al. Acute surgical abdomen as presenting manifestation of Kawasaki disease. J Pediatr 2003; 142:731.
  84. Kavey RE, Allada V, Daniels SR, et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation 2006; 114:2710.
  85. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics 2011; 128 Suppl 5:S213.
  86. Dietz SM, Tacke CE, Hutten BA, Kuijpers TW. Peripheral Endothelial (Dys)Function, Arterial Stiffness and Carotid Intima-Media Thickness in Patients after Kawasaki Disease: A Systematic Review and Meta-Analyses. PLoS One 2015; 10:e0130913.
  87. Dietz SM, Tacke CE, de Groot E, et al. Extracardial Vasculopathy After Kawasaki Disease: A Long-Term Follow-up Study. J Am Heart Assoc 2016; 5.
  88. Takahashi K, Oharaseki T, Naoe S. Pathological study of postcoronary arteritis in adolescents and young adults: with reference to the relationship between sequelae of Kawasaki disease and atherosclerosis. Pediatr Cardiol 2001; 22:138.
  89. Noto N, Okada T, Yamasuge M, et al. Noninvasive assessment of the early progression of atherosclerosis in adolescents with Kawasaki disease and coronary artery lesions. Pediatrics 2001; 107:1095.
  90. Kahn AM, Budoff MJ, Daniels LB, et al. Calcium scoring in patients with a history of Kawasaki disease. JACC Cardiovasc Imaging 2012; 5:264.
  91. Cheung YF, Ho MH, Tam SC, Yung TC. Increased high sensitivity C reactive protein concentrations and increased arterial stiffness in children with a history of Kawasaki disease. Heart 2004; 90:1281.
  92. Mitani Y, Sawada H, Hayakawa H, et al. Elevated levels of high-sensitivity C-reactive protein and serum amyloid-A late after Kawasaki disease: association between inflammation and late coronary sequelae in Kawasaki disease. Circulation 2005; 111:38.
  93. Selamet Tierney ES, Gal D, Gauvreau K, et al. Vascular health in Kawasaki disease. J Am Coll Cardiol 2013; 62:1114.
  94. Nakamura Y, Aso E, Yashiro M, et al. Mortality among persons with a history of kawasaki disease in Japan: mortality among males with cardiac sequelae is significantly higher than that of the general population. Circ J 2008; 72:134.
  95. McCrindle BW, McIntyre S, Kim C, et al. Are patients after Kawasaki disease at increased risk for accelerated atherosclerosis? J Pediatr 2007; 151:244.
  96. Gupta-Malhotra M, Gruber D, Abraham SS, et al. Atherosclerosis in survivors of Kawasaki disease. J Pediatr 2009; 155:572.
  97. Cheung YF, Yung TC, Tam SC, et al. Novel and traditional cardiovascular risk factors in children after Kawasaki disease: implications for premature atherosclerosis. J Am Coll Cardiol 2004; 43:120.
  98. Dhillon R, Clarkson P, Donald AE, et al. Endothelial dysfunction late after Kawasaki disease. Circulation 1996; 94:2103.
  99. Ooyanagi R, Fuse S, Tomita H, et al. Pulse wave velocity and ankle brachial index in patients with Kawasaki disease. Pediatr Int 2004; 46:398.
  100. Muzik O, Paridon SM, Singh TP, et al. Quantification of myocardial blood flow and flow reserve in children with a history of Kawasaki disease and normal coronary arteries using positron emission tomography. J Am Coll Cardiol 1996; 28:757.
  101. Mitani Y, Okuda Y, Shimpo H, et al. Impaired endothelial function in epicardial coronary arteries after Kawasaki disease. Circulation 1997; 96:454.
  102. Yamakawa R, Ishii M, Sugimura T, et al. Coronary endothelial dysfunction after Kawasaki disease: evaluation by intracoronary injection of acetylcholine. J Am Coll Cardiol 1998; 31:1074.
  103. Kato H, Ichinose E, Kawasaki T. Myocardial infarction in Kawasaki disease: clinical analyses in 195 cases. J Pediatr 1986; 108:923.
  104. Tsuda E, Hirata T, Matsuo O, et al. The 30-year outcome for patients after myocardial infarction due to coronary artery lesions caused by Kawasaki disease. Pediatr Cardiol 2011; 32:176.
  105. Kato H, Inoue O, Kawasaki T, et al. Adult coronary artery disease probably due to childhood Kawasaki disease. Lancet 1992; 340:1127.
  106. Rizk SR, El Said G, Daniels LB, et al. Acute myocardial ischemia in adults secondary to missed Kawasaki disease in childhood. Am J Cardiol 2015; 115:423.
  107. Tsuda E, Hamaoka K, Suzuki H, et al. A survey of the 3-decade outcome for patients with giant aneurysms caused by Kawasaki disease. Am Heart J 2014; 167:249.
  108. Tsuda E, Arakaki Y, Shimizu T, et al. Changes in causes of sudden deaths by decade in patients with coronary arterial lesions due to Kawasaki disease. Cardiol Young 2005; 15:481.
  109. Centers for Disease Control and Prevention. Multisystem Inflammatory Syndrome (MIS). 2021. Available at: https://www.cdc.gov/mis/index.html (Accessed on November 11, 2021).
  110. Whittaker E, Bamford A, Kenny J, et al. Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. JAMA 2020; 324:259.
  111. Bar-Meir M, Guri A, Godfrey ME, et al. Characterizing the differences between multisystem inflammatory syndrome in children and Kawasaki disease. Sci Rep 2021; 11:13840.
  112. Fernández-Cooke E, Grasa CD, Domínguez-Rodríguez S, et al. Prevalence and Clinical Characteristics of SARS-CoV-2 Confirmed and Negative Kawasaki Disease Patients During the Pandemic in Spain. Front Pediatr 2020; 8:617039.
  113. Capannari TE, Daniels SR, Meyer RA, et al. Sensitivity, specificity and predictive value of two-dimensional echocardiography in detecting coronary artery aneurysms in patients with Kawasaki disease. J Am Coll Cardiol 1986; 7:355.
  114. Wang Q, Morikawa Y, Akahoshi S, et al. Follow-Up Duration of Echocardiography in Patients with Kawasaki Disease with No Initial Coronary Aneurysms. J Pediatr 2022; 244:133.
  115. de Ferranti SD, Gauvreau K, Friedman KG, et al. Association of Initially Normal Coronary Arteries With Normal Findings on Follow-up Echocardiography in Patients With Kawasaki Disease. JAMA Pediatr 2018; 172:e183310.
  116. Manlhiot C, Millar K, Golding F, McCrindle BW. Improved classification of coronary artery abnormalities based only on coronary artery z-scores after Kawasaki disease. Pediatr Cardiol 2010; 31:242.
  117. Crystal MA, Manlhiot C, Yeung RS, et al. Coronary artery dilation after Kawasaki disease for children within the normal range. Int J Cardiol 2009; 136:27.
  118. Dallaire F, Fournier A, Breton J, et al. Marked variations in serial coronary artery diameter measures in Kawasaki disease: a new indicator of coronary involvement. J Am Soc Echocardiogr 2012; 25:859.
  119. Colan SD. Normal echocardiographic values for cardiovascular structures, Appendix 1. In: Echocardiography in Pediatric and Congenital Heart Disease, Lai WW, Cohen MS, Geva T, Mertens L (Eds), Wiley-Blackwell, West Sussex, UK 2009. p.765.
  120. Parameter(z) Coronary Artery Z-Scores. Available at: http://www.parameterz.com/sites/coronary-arteries (Accessed on May 18, 2016).
  121. Ronai C, Baker AL, Friedman KG, et al. Prevalence of Undiagnosed Structural Heart Disease in Children Undergoing Echocardiography for Kawasaki Disease. Clin Pediatr (Phila) 2016; 55:557.
  122. Research Committee on Kawasaki Disease. Report of Subcommittee on Standardization of Diagnostic Criteria and Reporting of Coronary Artery Lesions in Kawasaki Disease. Ministry of Health and Welfare; Tokyo, Japan, 1984.
  123. JCS Joint Working Group. Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2008)--digest version. Circ J 2010; 74:1989.
  124. Greil GF, Stuber M, Botnar RM, et al. Coronary magnetic resonance angiography in adolescents and young adults with kawasaki disease. Circulation 2002; 105:908.
  125. Danias PG, Stuber M, Botnar RM, et al. Coronary MR angiography clinical applications and potential for imaging coronary artery disease. Magn Reson Imaging Clin N Am 2003; 11:81.
  126. Mavrogeni S, Papadopoulos G, Douskou M, et al. Magnetic resonance angiography is equivalent to X-ray coronary angiography for the evaluation of coronary arteries in Kawasaki disease. J Am Coll Cardiol 2004; 43:649.
  127. Sohn S, Kim HS, Lee SW. Multidetector row computed tomography for follow-up of patients with coronary artery aneurysms due to Kawasaki disease. Pediatr Cardiol 2004; 25:35.
  128. Schmidt WA. Use of imaging studies in the diagnosis of vasculitis. Curr Rheumatol Rep 2004; 6:203.
  129. Han BK, Lesser A, Rosenthal K, et al. Coronary computed tomographic angiographic findings in patients with Kawasaki disease. Am J Cardiol 2014; 114:1676.
  130. Kondo C, Hiroe M, Nakanishi T, Takao A. Detection of coronary artery stenosis in children with Kawasaki disease. Usefulness of pharmacologic stress 201Tl myocardial tomography. Circulation 1989; 80:615.
  131. Jan SL, Hwang B, Fu YC, et al. Comparison of 201Tl SPET and treadmill exercise testing in patients with Kawasaki disease. Nucl Med Commun 2000; 21:431.
  132. Pahl E, Sehgal R, Chrystof D, et al. Feasibility of exercise stress echocardiography for the follow-up of children with coronary involvement secondary to Kawasaki disease. Circulation 1995; 91:122.
  133. Henein MY, Dinarevic S, O'Sullivan CA, et al. Exercise echocardiography in children with Kawasaki disease: ventricular long axis is selectively abnormal. Am J Cardiol 1998; 81:1356.
  134. Noto N, Ayusawa M, Karasawa K, et al. Dobutamine stress echocardiography for detection of coronary artery stenosis in children with Kawasaki disease. J Am Coll Cardiol 1996; 27:1251.
  135. Kimball TR, Witt SA, Daniels SR. Dobutamine stress echocardiography in the assessment of suspected myocardial ischemia in children and young adults. Am J Cardiol 1997; 79:380.
  136. Bezold LI, Lewin MB, Vick GW 3rd, Pignatelli R. Update on new technologies in pediatric echocardiography. Tex Heart Inst J 1997; 24:278.
  137. Mühling O, Jerosch-Herold M, Näbauer M, Wilke N. Assessment of ischemic heart disease using magnetic resonance first-pass perfusion imaging. Herz 2003; 28:82.
  138. Kaul S, Ito H. Microvasculature in acute myocardial ischemia: part I: evolving concepts in pathophysiology, diagnosis, and treatment. Circulation 2004; 109:146.
  139. Zilberman MV, Witt SA, Kimball TR. Is there a role for intravenous transpulmonary contrast imaging in pediatric stress echocardiography? J Am Soc Echocardiogr 2003; 16:9.
  140. Ishii M, Himeno W, Sawa M, et al. Assessment of the ability of myocardial contrast echocardiography with harmonic power Doppler imaging to identify perfusion abnormalities in patients with Kawasaki disease at rest and during dipyridamole stress. Pediatr Cardiol 2002; 23:192.
  141. Noto N, Kamiyama H, Karasawa K, et al. Long-term prognostic impact of dobutamine stress echocardiography in patients with Kawasaki disease and coronary artery lesions: a 15-year follow-up study. J Am Coll Cardiol 2014; 63:337.
  142. Tedla BA, Burns JC, Tremoulet AH, et al. Exercise Stress Echocardiography in Kawasaki Disease Patients with Coronary Aneurysms. Pediatr Cardiol 2023; 44:381.
  143. Stagnaro N, Moscatelli S, Cheli M, et al. Dobutamine Stress Cardiac MRI in Pediatric Patients with Suspected Coronary Artery Disease. Pediatr Cardiol 2023; 44:451.
Topic 5772 Version 56.0

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