Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation

INTRODUCTION — 

Kawasaki disease (KD; previously called mucocutaneous lymph node syndrome) is one of the most common forms of systemic vasculitis in children. 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 (table 1).

Children with KD are at risk for serious cardiovascular sequelae, particularly coronary artery abnormalities (CAAs), which can lead to myocardial ischemia, infarction, arrhythmia, and sudden cardiac 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 timely treatment with IVIG. (See "Kawasaki disease: Initial treatment and prognosis", section on 'Intravenous immune globulin'.)

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: Pathogenesis, epidemiology, and etiology".)

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

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

ACUTE CARDIOVASCULAR COMPLICATIONS

KD shock syndrome — KD shock syndrome (KDSS) is an uncommon presentation of KD, occurring in <10 percent of cases [1,2]. It is characterized by warm shock with low peripheral vascular resistance. Patients with KDSS have a heightened risk of coronary aneurysms [1,2]. 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 [1,3]:

●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 [1,3].

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 toxic shock syndrome, septic shock, myocarditis, and coronavirus disease 2019 (COVID-19)-related multisystem inflammatory syndrome in children (MIS-C). Rarely, KD can present with hemophagocytic syndrome or macrophage activation syndrome [4-7]. (See "Kawasaki disease: Clinical features and diagnosis", section on 'Other manifestations'.)

Coronary artery abnormalities — Coronary artery abnormalities (CAAs) (movie 1A-B) are a 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 2) [8]. (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) [9-12]. Coronary artery thrombosis and progressive stenosis within the aneurysm may cause late ischemic heart disease [13,14]. 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 [15]. 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 [9,16-30]:

●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 [22,31]. (See "Kawasaki disease: Initial treatment and prognosis", section on 'Intravenous immune globulin'.)

●Coronary artery dilation on initial baseline echocardiogram [32,33].

●Age <1 year or >9 years. Infants, particularly those <6 months, have the highest risk of CAAs, even with prompt IVIG treatment [10]. 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 [34].

●Male sex.

●Among North American populations, Asian ancestry is a risk factor for CAAs [26,32].

●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 [9,20-22]:

•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 [35], endothelial growth factor and its receptors [36], calcium signaling pathways [37], and the transforming growth factor beta signaling pathway [38].

Identifying children at the highest risk for developing CAAs at the time of presentation would be clinically useful as it could guide management decisions (eg, administering adjuvant anti-inflammatory therapies in addition to IVIG). Risk scores have been developed based on demographic and clinical data from Japanese children [39-41]. 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 [32]. 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 anti-inflammatory 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 [42-45]. 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 [44,46,47]. Aneurysms are also more likely to regress in younger children, at a more distal location, or if they are fusiform in shape [43].

Although internal lumen diameter is normal in regressed aneurysmal segments, myointimal thickening is evident by late intravascular ultrasound [48-50] and is directly related to the initial coronary diameter during the early months after disease onset [49]. Multiple studies have also demonstrated impaired coronary and peripheral vascular reactivity [50-53]. 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 [42,54,55]. Approximately one-half of aneurysms of maximum diameter ≥6 mm developed stenosis by 15 years follow-up in one study [56]. 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 [57,58]. 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 [59]. In rare cases, it may progress to heart failure. For patients without ischemic cardiomyopathy, ventricular function usually improves rapidly following treatment with IVIG [59].

In a study of 198 patients with KD, echocardiographic evaluation demonstrated left ventricular (LV) dysfunction in 20 percent of patients at diagnosis [57]. 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 [58]. 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 [60].

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 [57]. Aortic regurgitation is reported, but is less common, occurring in approximately 1 percent of patients during the first five weeks of illness [57]. Mild aortic root dilation is common in the first three weeks of the disease and persists during the first year of follow-up [57,61].

Pericardial effusion — Pericardial effusions of greater than 1 mm occur in fewer than 5 percent of patients [57], although rare patients can develop pericardial tamponade [62]. Tamponade can also be a complication of rupture of a giant aneurysm into the pericardial space [63-65].

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 [66]. 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 [66-68]. They rarely may present with associated arterial thrombosis, causing limb ischemia and gangrene [69,70]. 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 [71], stroke [72]), gastrointestinal obstruction [73] or pseudo-obstruction [74], or acute abdominal catastrophe [75].

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 [66]. 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 occur only in patients who had coronary artery abnormalities (CAAs) during the acute phase of the illness; patients with large or giant aneurysms (ie, Z-score ≥10) are at particularly high risk. Long-term complications can include myocardial ischemia, myocardial infarction (MI), arrythmia, and accelerated atherosclerotic coronary artery disease (CAD).  

For patients who never had CAAs, the risk of long-term cardiovascular disease is similar to that of the general population [42,76].

In a long-term follow-up study of a >6500 patients diagnosed with KD between 1982 to 1992 who were enrolled in a Japanese registry and followed for an average of 30 years, there were 68 deaths (1 percent) over the follow-up period, a mortality rate that was not different from the general population [76]. There were nine deaths that were directly attributed to KD-related cardiac disease (all nine were in males). In these patients, death occurred as early as 11 months after being diagnosed with KD to as late as 26 years later. All but one patient had CAAs during the acute illness.

In another large registry study involving 1651 patients with KD-associated CAAs, there were no complications among those with small CAAs over medium follow-up of two years [77]. Among patients with medium CAAs (n = 357), only one patient (0.3 percent) experienced long-term complications (chronic ischemia leading to heart failure and death). Among patients with large CAAs (n = 440), major adverse cardiac events (including MI, need for coronary revascularization, heart transplantation, or cardiovascular death) occurred in approximately 10 percent of patients over median follow-up of five years; this included seven deaths (1.6 percent). Independent risk factors for adverse cardiac events included location of the aneurysm in the left anterior descending or right coronary (as opposed to left main or circumflex branches), aneurysm Z-score ≥20, and complex coronary artery architecture (eg, multiple aneurysms in a coronary artery, as opposed to an isolated coronary aneurysm).

Atherosclerotic coronary artery disease

●Patients without coronary involvement – Patients with KD without coronary involvement do not appear to be at increased risk for atherosclerotic CAD compared with the general population [42,76,78-82]. We agree with the 2017 guidelines of the American Heart Association, which recommend that this population be given the same routine counseling for atherosclerotic cardiovascular disease (ASCVD) risk reduction as is given to the general population (ie, encouraging physical activity and heart-healthy diet) [8]. (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'.)

●Patients with CAAs – It is uncertain whether patients with CAAs are at increased risk of accelerated atherosclerotic CAD [78-80,83-89]. Atherosclerosis has been posited by some investigators as a mechanism for endothelial dysfunction [85], increased carotid intima-medial thickness [78], and increased aortic stiffness and elasticity [90-92]. Moreover, long-term systemic inflammation in patients with giant aneurysms could augment atherosclerosis risk [93]. Intravascular ultrasound late after KD has shown changes that would be diagnostic of atherosclerosis in the general adult population; however, its diagnostic validity for assessing atherosclerosis is uncertain in arterial segments in KD affected by severe arteriosclerosis [94]. Moreover, autopsy studies have not shown atherosclerosis within aneurysmal segments but rather luminal myofibroblastic proliferation, thrombosis, and inflammatory changes [95].

Enhanced screening to detect ASCVD risk factors (eg, dyslipidemia, hypertension, diabetes mellitus, obesity), as well as more aggressive management of these risk factors in patients with persistent and regressed aneurysms, is recommended by the American Heart Association [96] and the National Heart, Lung, and Blood Institute [97]. Such preventive measures seem reasonable to protect coronary arteries already damaged from KD from acquiring atherosclerotic disease as patients age. (See "Cardiovascular sequelae of Kawasaki disease: Management and prognosis", section on 'Counseling and screening for risk factors'.)

In particular, the threshold for statin therapy is lower in this population since observational data suggest that statins may have benefits for KD-related coronary artery disease based upon their pleiotropic effects [8,98,99]. (See "Dyslipidemia in children and adolescents: Management", section on 'Statin therapy'.)

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.

Myocardial infarction — Ischemic heart disease is a complication of KD limited solely to patients with CAAs [100,101]. 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 [100].

Myocardial infarction is the principal cause of KD mortality and occurs most frequently among patients with giant CAAs [100]. The risk of myocardial infarction is highest in the first 6 to 12 months of the disease and declines after the first two years [100,101]; however, the risk persists into adulthood [13,101,102]. Indeed, "missed" KD in childhood can present with myocardial infarction in adulthood [103].

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 [44]. 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 [104].

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 [8,101,105]. 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 [101]. 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) is 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 3). (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 3).

For patients with a history of giant coronary aneurysms, advanced imaging by cardiac catheterization, CTA, or magnetic resonance angiography (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 (AHA) [8].

Distinguishing KD from MIS-C — During the coronavirus disease 2019 (COVID-19) pandemic, a novel syndrome called multisystem inflammatory syndrome in children (MIS-C; also called pediatric inflammatory multisystem syndrome PIMS]) emerged [106]. MIS-C has considerable overlap with KD and KD shock syndrome (KDSS) (table 4). Distinguishing between KD (particularly KDSS), and MIS-C can be challenging. Most children now have antibodies to SARS-CoV-2 so this finding is not helpful in making the distinction. 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'.)

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 1) [8]. (See "Kawasaki disease: Clinical features and diagnosis".)

Echocardiography has a high sensitivity and specificity for detecting proximal coronary arterial dilatation in the acute phase of illness and other noncoronary artery abnormalities [107]. 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 [108,109].

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 2) [8,110]:

●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 [111,112]. 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 [113]; the AHA KD guidelines are based upon Z-score cut-offs using this calculator [8]. Other online calculators are available through the referenced website [114]. For large absolute coronary dimensions, these Z-score calculators can produce very different values, potentially affecting the decision to prescribe an anticoagulant [115,116].

In Japan, criteria for aneurysms are based upon absolute dimensions [117,118]: 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 aneurysm's 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. However, the Z-score criteria above have better sensitivity for detection of coronary artery enlargement [119].

In a multicenter study in which echocardiograms were read in a central core laboratory [9], 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.

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 [120-125]. CTA is 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 of CTA 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 [126-139]. Because the risk of false-positive testing is highest when the probability of disease is low, we suggest not performing stress testing in asymptomatic 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".)

●Imaging techniques for stress testing include echocardiography, single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), 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. Stress MRI avoids radiation exposure and can assess both perfusion and wall motion abnormalities. MRI is also the most reliable modality for assessing right ventricular ischemia. 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. (See "Selecting the optimal cardiac stress test".)

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 does not provide adequate imaging

●Symptoms or noninvasive evidence of ischemia suggest that coronary revascularization may be indicated (see "Cardiovascular sequelae of Kawasaki disease: Management and prognosis", section on 'Revascularization in patients with stable CAD')

●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 'Management of acute MI')

Cardiac catheterization is also commonly 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 2 and movie 1A and movie 1B). 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.

In addition to angiographic imaging, cardiac catheterization is used to perform tests of coronary artery function and structure that are routine during catheterization of adults with atherosclerotic CAD. The functional importance of stenotic coronary lesions is assessed with fractional flow reserve; because there are few data establishing standards in children, cut-points for significant ischemia are taken from adults with atherosclerosis. Invasive intravascular imaging (intravascular ultrasound or optical coherence tomography), can provide virtual histology and define intracoronary characteristics such as myointimal thickening, calcification, and eccentricity [94,140].

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 [54]. 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 5^th to 6^th 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 10^th to 12^th 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) as summarized in the table (table 2). (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), higher laboratory markers of the systemic inflammatory response (eg, C-reactive protein), 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 most commonly occur in patients who had large/giant CAAs in the acute phase. (See 'Long-term complications' above.)

•Atherosclerotic coronary artery disease (CAD)

-Patients without CAAs – Patients with KD without coronary involvement do not appear to be at increased risk for atherosclerotic CAD compared with the general population. (See 'Atherosclerotic coronary artery disease' above.)

-Patients with CAAs – It is uncertain whether patients with CAAs are at increased risk of accelerated atherosclerotic CAD. Nevertheless, enhanced screening to detect atherosclerotic risk factors (eg, dyslipidemia, hypertension, diabetes mellitus, obesity), as well as more aggressive management of these risk factors is generally warranted in patients with persistent and regressed aneurysms. (See 'Atherosclerotic coronary artery disease' 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. The risk persists into adulthood, though it lessen after two years from illness onset. Affected patients may present with chest pain; abdominal pain; pallor; diaphoresis; or, in infants and young children, 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 – During the acute KD illness, the ECG may show arrhythmia, slight prolongation of the PR and QT intervals, or nonspecific ST and T wave changes. ECG is also important for detecting myocardial ischemia or infarction in patients with large/giant aneurysms. (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 3). (See 'Stress testing for inducible ischemia' above and "Cardiovascular sequelae of Kawasaki disease: Management and prognosis", section on 'Frequency of follow-up'.)

•Cardiac catheterization – Invasive testing is performed when noninvasive testing does not provide adequate imaging, symptoms or noninvasive evidence of ischemia suggest the need for coronary revascularization, or other catheterization data are needed for clinical management. (See 'Coronary angiography' above.)