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Cardiovascular sequelae of Kawasaki disease - UpToDate https://www.uptodate.com/contents/cardiovascular-sequelae-of-kawasa...

Official reprint from UpToDate


www.uptodate.com 2017 UpToDate

Cardiovascular sequelae of Kawasaki disease

Authors: Jane W Newburger, MD, MPH, Sarah D de Ferranti, MD, MPH, David R Fulton, MD
Section Editor: John K Triedman, MD
Deputy Editor: Carrie Armsby, MD, MPH

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2017. | This topic last updated: Aug 03, 2017.

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".)

Approximately one in five patients who are not treated early in the disease with high-dose intravenous
immune globulin (IVIG) develops coronary artery aneurysms (CAAs), which can lead to myocardial
ischemia, infarction, and sudden death. As a result, initial management of patients with KD is focused on
early diagnosis and treatment with IVIG. (See "Kawasaki disease: Initial treatment and prognosis".)

The cardiac sequelae of KD, including CAAs and their management, will be reviewed here. Other aspects
of KD are discussed in greater detail separately:

(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 pan-arteritis 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]. Coronary artery 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

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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.

CARDIOVASCULAR MANIFESTATIONS

Acute phase Common cardiovascular symptoms during the acute phase 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.)

Infrequently, patients may present with KD shock syndrome, most often characterized by warm shock with
low peripheral vascular resistance [12]. The differential diagnosis in such patients includes toxic shock
syndrome, sepsis, and for those with severe myocardial dysfunction, viral-induced acute fulminant
myocarditis. Rarely, KD can present with hemophagocytic syndrome [13-16]. (See "Kawasaki disease:
Complications", section on 'Macrophage activation syndrome' and "Kawasaki disease: Complications",
section on 'Shock'.)

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. Finally, young infants may develop fusiform aneurysms of the
brachial arteries, which are palpable or visible in the axillae.

Late manifestations Late manifestations of KD are restricted to cardiac symptoms and events, which
occur solely in patients who had coronary artery disease in the acute phase of the illness.

In the convalescent and late phases of KD, patients with significant coronary disease are often
asymptomatic. Those with large or giant coronary aneurysms who present with the following findings need
to be emergently evaluated because they are at risk for ischemic heart disease [17,18]:

Angina (more easily ascertained in older children)


Abdominal pain or vomiting occurring outside the context of a viral syndrome and in association with
pallor and diaphoresis

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Inconsolable crying without obvious cause


Episodes of syncope

In a Japanese cross-sectional survey, symptoms during acute myocardial infarction were not detected in
more than one-third of patients, and the diagnosis was later identified by electrocardiographic
abnormalities indicative of infarction [17]. (See 'Myocardial infarction and coronary thrombosis' below and
"Criteria for the diagnosis of acute myocardial infarction".)

Children without coronary dilation or aneurysms during the acute or subacute phase are extremely
unlikely to have ischemia or other late cardiac manifestations. The rates of noncardiac diseases in
individuals who have had KD are similar to those in the general population.

In a long-term study that evaluated coronary arterial calcification in 70 patients with KD, those who never
had coronary artery aneurysms had no evidence of coronary artery calcification at >10 years after onset of
KD [19]. In contrast, coronary calcification was observed in 10 of 14 patients with initial coronary
aneurysm.

CARDIOVASCULAR COMPLICATIONS The major complication of KD is coronary artery aneurysms


(CAAs), which may result in myocardial ischemia, myocardial infarction, and sudden death. Other
cardiovascular complications include decreased myocardial function in the acute phase, valvular
regurgitation, pericardial effusion, and peripheral artery aneurysms [20]. Infants younger than one year of
age with KD have the highest risk of developing cardiac complications.

Coronary artery aneurysm CAA is the most serious complication of KD and is usually first diagnosed
by echocardiography. CAAs are detected during the acute phase of KD in 30 to 40 percent of patients and
they persist beyond one month in 10 to 20 percent [21,22]. Coronary artery thrombosis and progressive
stenosis within the aneurysm may cause late ischemic heart disease [20,23]. Indeed, "missed" KD in
childhood can present with myocardial infarction in adulthood [24]. (See 'Echocardiography' 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 [26-41]:

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 [32,42].

Age <1 year and >9 years. Infants, particularly those <6 months, have the highest risk of aneurysms,
even with prompt IVIG treatment. In addition, since many infants present with atypical disease,
diagnosis and treatment may be delayed. It is unclear whether patients >9 years 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 [43].

Male sex.

Long duration of fever (ie, 14 days).

Failure to respond to initial IVIG therapy manifested by persistent and recrudescent fever. (See

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"Kawasaki disease: Initial treatment and prognosis", section on 'Refractory KD'.)

Abnormal laboratory findings, including low hematocrit (ie, <35 percent), low serum albumin, low
serum sodium (ie, <135 mEq/L), elevated alanine aminotransferase (ALT), elevated C-reactive
protein (CRP) and erythrocyte sedimentation rate (ESR), elevated white blood cell count
(>12,000/mm3), low baseline serum immunoglobulin G (IgG), and elevations in interleukin (IL)-6 and
IL-8 [30-33].

Genetic polymorphisms including but not limited to matrix metalloproteinase haplotypes [44],
endothelial growth factor and its receptors [45], calcium signaling pathways [46], and the transforming
growth factor (TGF) beta signaling pathway [47].

In the United States, the risk of CAAs appears to vary among ethnic groups:

In one report based upon national Kawasaki syndrome surveillance data from 1994 to 2003 that
identified 3115 children with KD, Asian and Pacific Islander race and Hispanic ethnicity were
associated with an increased risk of CAAs [37].

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 American Indians, but the number of such
patients with KD was small [34]. The second highest rate of CAAs was in Hispanics (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).

Natural course 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 [21,48-50]. Regression generally occurs within two to five 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 [21,51,52]. Aneurysms are also more likely to regress in younger children, at a more
distal location, or if they are fusiform in shape [49].

Although internal lumen diameter is normal in regressed aneurysmal segments, myointimal thickening is
evident by late intravascular ultrasound [53-55] and is directly related to the initial coronary diameter
during the early months after disease onset [54]. Multiple studies have also demonstrated impaired
coronary and peripheral vascular reactivity [55-58].

In patients with persistent aneurysms, myointimal proliferation at the aneurysm entrance or exit
progresses steadily over time [48,59,60]. Approximately half of aneurysms of maximum diameter 6 mm
developed stenoses by 15 years follow-up in one study [61]. 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.

Prognosis The prognosis of CAAs depends upon the size of the aneurysm. Small aneurysms
generally have a favorable prognosis with a low risk of myocardial ischemic events and/or mortality
[50,62]. In contrast, giant CAAs (ie, those with an internal diameter >8 mm or with a Z-score 10) have a
high risk of morbidity and mortality [48,50]. Up to one-half of such aneurysms become obstructed, and are
associated with myocardial infarction, arrhythmias, or sudden death [21,48,50]. (See 'Echocardiography'
below and 'Myocardial infarction and coronary thrombosis' below and 'Coronary revascularization
procedures' below.)

Among patients who develop aneurysms, mortality is highest between 15 and 45 days after onset of KD
[17]. Because coronary artery thrombosis is the leading cause of death in KD, medications to prevent

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thrombosis form the cornerstone of therapy for patients with aneurysms [11]. (See 'Prevention of coronary
thrombosis' below.)

In a retrospective study of 1073 patients with KD followed at a single institution from 1980 to 2012, giant
aneurysms occurred in 27 patients (2.5 percent) [21]. In long-term follow-up (median 6.7 years),
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.
Of the patients who developed AMI, 67 percent occurred within the first year of KD onset. Treatment with
IVIG was associated with a greater likelihood of coronary regression within one month after KD onset, but
no association was seen between IVIG treatment and late coronary outcomes.

Among patients with giant aneurysms, 10-year survival rates are 85 to 95 percent [23,63]. Most fatalities
occur in the first year after disease onset. Rates of coronary intervention at 10 to 15 years after disease
onset are approximately 30 to 40 percent [23,63].

Myocardial dysfunction In the acute phase of KD, depressed myocardial contractility may be caused
by myocarditis, whereas ischemic cardiomyopathy may occur in patients after myocardial infarction.
Depressed myocardial contractility may progress to heart failure during the acute illness, and is often
manifested by a third heart sound gallop, which may become more prominent with hydration [64].

In a study of 198 patients with KD, echocardiographic evaluation demonstrated left ventricular (LV)
dysfunction in 20 percent of patients at diagnosis [65]. 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 [66]. 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 [67].

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 [65]. Aortic regurgitation is reported, but is less common, occurring in approximately 1
percent of patients during the first five weeks of illness [65]. Mild aortic root dilation is common in the first
three weeks of the disease and persists during the first year of follow-up [65,68].

Pericardial effusion Pericardial effusions of greater than 1 mm occur in fewer than 5 percent of
patients [65], although rare patients can develop pericardial tamponade [69]. Tamponade can also be a
complication of rupture of a giant aneurysm into the pericardial space [70-72].

Noncoronary vascular involvement Aneurysms can occur in peripheral medium-sized, muscular,


extraparenchymal arteries, such as the axillary, brachial, or iliac arteries [2]. Such peripheral artery
aneurysms only occur among Kawasaki patients with giant CAAs. Peripheral arterial obstruction can lead
to ischemia and gangrene; this complication generally accompanies other manifestations of severe
disease such as giant CAAs and aneurysms in peripheral arteries [73].

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 [74], stroke [75]), gastrointestinal obstruction [76] or
pseudo-obstruction [77], or acute abdominal catastrophe [78].

Long-term complications

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Risk for atherosclerosis The risk of atherosclerosis is dependent upon whether the patient has
persistent CAAs, regressed aneurysms, or never had coronary abnormalities:

Persistent aneurysms Patients who have persistent aneurysms are considered to be at high risk
for early atherosclerotic disease.

Regressed aneurysms Patients who have regressed aneurysms are considered to be at moderate
risk for early atherosclerotic disease.

In patients with persistent or regressed aneurysms, the thresholds for treatment of risk factors for
adult atherosclerotic heart disease are lower than in the general population (algorithm 1). (See 'Long-
term follow-up' below.)

Data to support this approach are indirect as prospective evidence is lacking. Long-term follow-up
studies of patients with CAAs due to KD have shown abnormalities in surrogate markers of
atherosclerosis risk, including flow-mediated dilation, measures of vascular stiffness, and carotid
intima-media thickness (cIMT) [79,80]. Studies using intravascular ultrasound have demonstrated
thickened intima in patients at the site of CAAs [53,54]. 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 [81].
Ultrasound findings of carotid atherosclerosis have been reported, independent of dyslipidemia, 6 to
20 years after KD was diagnosed among patients with CAAs [82]. In patients at 10-year follow-up,
coronary angiographic findings revealed increased peripheral arterial stiffness and diminished
vascular reactivity [55]. 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 [83,84].

Patients who never had coronary artery abnormalities It is likely that patients who never had
coronary artery abnormalities are not at increased risk for cardiovascular disease compared with the
general pediatric population. A 10- to 21-year follow-up study of 594 patients with KD demonstrated
few cardiovascular events in patients without CAAs [48]. 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 [85]. Two studies in North
America have shown no changes in vascular function in KD patients who never had coronary
aneurysms [86,87]. Late coronary artery calcification suggestive of atherosclerosis on low-dose
noncontrast CT scanning is absent in patients who had no coronary artery dilation during the acute
phase [88].

Studies evaluating indirect measures of early atherosclerosis in patients who never had any
documented coronary artery abnormalities 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 [88-91].
Other studies have failed to show long-term abnormalities of peripheral vascular function in patients
with either normal or mildly ectatic coronary artery dimensions [79,86,92]. One study that measured
cIMT over 15 years found that cIMT was initially increased in patients who never had coronary artery
abnormalities compared with normal controls; however, the difference normalized at a later age [80].
Studies of coronary endothelial function in which acetylcholine was administered in the epicardial
coronary arteries have also shown conflicting results [93,94]. 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 coronary artery abnormalities [79].

The optimal follow-up for patients with a history of KD without coronary abnormalities is a topic of
great controversy. (See 'Long-term follow-up' below.)

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Myocardial function Because myocarditis is a nearly universal phenomenon in early KD [1,2,6,7],


some investigators have expressed concern about long-term myocardial sequelae even in patients who
never had coronary artery abnormalities [95]. However, prospectively gathered data are needed to verify
whether this should be a long-term concern.

EVALUATION

General approach In our practice, all patients with KD undergo cardiac testing that includes
echocardiography and ECG. When echocardiography is inadequate to image the coronary arteries, CTA
or MRA is used to fully delineate the coronary arterial tree.

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

For patients with a history of giant coronary aneurysms, advanced imaging by cardiac catheterization,
CTA, or MRA is performed one 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 at one year,
subsequent advanced imaging modalities are noninvasive (eg, CTA or MRA) unless a catheter
intervention is needed or noninvasive coronary imaging provides inadequate data to guide management.

For asymptomatic patients with giant aneurysms and negative stress tests, advanced imaging is generally
performed every three to five years. Exposure to ionizing radiation should be minimized wherever
possible.

Echocardiography

Initial evaluation Echocardiography should be performed as soon as the diagnosis of KD 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 2) [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 [96]. To obtain the best images,
children <2 years of age are usually sedated.

Echocardiography also detects other noncoronary artery abnormalities including depressed myocardial
contractility, valvular lesions, and pericardial effusions. (See 'Myocardial dysfunction' above and 'Valvular
regurgitation' above and 'Pericardial effusion' above.)

Follow-up studies Echocardiography is usually repeated at approximately two and six weeks after
onset of illness. Frank aneurysms are often not seen until after 10 days of illness.

Importantly, in children at higher risk for coronary artery aneurysms (CAAs) (ie, because of abnormalities
on baseline echocardiography or persistent or recrudescent fever), more frequent echocardiography is
helpful in guiding appropriate therapy. For children with giant CAAs, we perform echocardiography for
surveillance of thrombus formation at least twice weekly during the period of time that coronary arteries
are enlarging, then once weekly in the high-risk period of the first 45 days of illness, monthly until the third
month of disease, and then once every three months until the end of the first year after illness onset.

Coronary aneurysm criteria and classification CAA size is classified according to internal lumen
diameter, normalized for body surface area as Z-scores or standard deviation units [11,97]:

Small aneurysm: Z-score 2.5 to <5

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Medium aneurysm: Z-scores of 5 to <10


Large aneurysm or giant aneurysm: Z-scores 10 or absolute dimension >8 mm, respectively

Z-scores can be computed by several different methods. The Boston Children's Hospital Z-score system
is based on data gathered from normal children over 12 years [98]. Other online calculators are available
through the referenced website [99]. For large absolute coronary dimensions, these Z-score calculators
can produce very different values, potentially affecting the decision to prescribe an anticoagulant [100].

In Japan, criteria for aneurysms are based upon absolute dimensions [101,102]: 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 [33], 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.

Other noninvasive tests to image coronary artery anatomy Although echocardiography has high
sensitivity and specificity for detection of proximal CAAs in the early phases of KD in infants and young
children, our impression is that it is less sensitive for detecting distal lesions and coronary artery stenosis,
which steadily worsen over time in coronary arterial segments affected by aneurysms. For this reason,
ultrafast computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) are used
to obtain high-resolution coronary images [103-108].

Both CTA and MRA imaging 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 dosages 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 the territory affected by myocardial
infarction using delayed enhancement. In patients with significant CAAs, we obtain MRAs (often
dobutamine stress MRAs with delayed enhancement) over CTAs. We repeat coronary MRAs
approximately every two years.

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 "Criteria for the
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. Only small case series have reported the results of stress testing in children with KD and
aneurysms [109-120]. Thus, the choice of testing technique is based upon the larger adult literature, the
ability of a child to cooperate, potential risks (such as radiation exposure or anesthesia), and the
institutional experience. Because the risk of false positive testing is highest when the probability of

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disease is low, we do not recommend stress testing in patients without a history of aneurysms. (See
"Selecting the optimal cardiac stress test".)

In determining the most appropriate stress test to detect ischemia in children with CAAs, the following
should be considered:

Exercise stress testing is preferred to pharmacologic stress testing because it is more physiologic.
However, if children are unable to cooperate with the exercise protocol, pharmacological stress
testing using dobutamine MRA avoids radiation exposure and can assess both perfusion and wall
motion abnormalities. This testing is usually done under anesthesia. Pediatric experience with
pharmacologic stress testing using positron emission tomography is growing.

Exercise testing for inducible ischemia with only ECG monitoring for ischemic changes has a
relatively low mean sensitivity and specificity in adult series.

The predictive value of exercise stress testing is enhanced with the use of noninvasive imaging. In
weighing the relative merits of imaging techniques, stress echocardiography compared with SPECT
(single photon emission computed tomography) 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.

Coronary angiography 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.

Because cardiac catheterization with angiography has a greater risk than noninvasive methods and
exposes children to ionizing radiation, its use should be restricted to patients with 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 'Coronary revascularization procedures' below.)

Angiographic imaging is otherwise needed to guide therapy, including the choice of optimal
antithrombotic therapy (eg, warfarin plus aspirin versus only antiplatelet therapy). (See 'Myocardial
infarction and coronary thrombosis' below.)

Some clinicians perform routine cardiac catheterization to assess status after surgical revascularization or
percutaneous coronary intervention. Because aneurysms in KD may evolve and regress over time, we
generally recommend cardiac catheterization or 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.

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When cardiac catheterization is first performed, subclavian arteriograms should be performed to delineate
the anatomy of the internal mammary arteries and to exclude brachial artery aneurysms [59]. Similarly,
abdominal aortography is useful to image arteries arising from the descending aorta, including the iliac
and femoral arteries, to detect any abnormality.

MANAGEMENT The management of cardiovascular sequelae of KD includes prevention of coronary


thrombosis, treatment of patients with myocardial infarction and coronary thrombosis, and in some severe
rare cases, cardiac transplantation.

There are no available randomized trials of antithrombotic therapy in children with KD and coronary artery
aneurysms (CAA). Management is based largely upon adult data for secondary prevention of coronary
artery disease [121]. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular
disease".)

The management approach described in the following sections is generally consistent with the 2017
guidelines of the American Heart Association [11].

Prevention of coronary thrombosis Factors that contribute to the development of coronary arterial
thrombosis during the first weeks of KD are activation of platelets and of the endothelium, and formation of
coronary artery aneurysms (CAAs), which results in stagnant blood flow. To reduce the risk of coronary
arterial thrombosis, all patients with KD are treated with low-dose (antiplatelet) aspirin until it is clear that
aneurysms will not develop (after one month) or unless there are contraindications to its use.

The antithrombotic regimen for patients with persistent CAAs is based upon adult data for secondary
prevention of coronary artery disease, as well as first principles, because there are no available data from
randomized trials of antithrombotic therapy in children with KD and CAAs [121]. The following approach is
consistent with the American Heart Association (AHA) statement on the prevention and management of
thrombosis in pediatric and congenital heart disease [121]:

Low-dose aspirin therapy (3 to 5 mg/kg per day) is administrated to all patients with persistent
coronary artery disease. During episodes of influenza or chicken pox, other antiplatelet agents (eg,
clopidogrel) should be temporarily substituted for aspirin due to the risk of Reye syndrome in this
setting. Long-term therapy with ibuprofen should be avoided because it antagonizes aspirin-induced
platelet inhibition [122].

Based upon the size of the aneurysm and age of the patient, other anticoagulation and antiplatelet
therapy may be added. The guidelines below are those used in our practice. (See 'Coronary
aneurysm criteria and classification' above.)

Small CAAs Patients with small CAAs (ie, Z-score 2.5 to <5) are generally managed with low-
dose aspirin alone.

Moderate CAAs In some patients with moderate CAAs (ie, Z-score 5 to <10), additional
antiplatelet therapy (eg, clopidogrel) is added to aspirin. In the absence of any evidence-based
data, the decision to use dual antiplatelet therapy is made on a case-by-case basis in those with
Z-scores between 7 and 9.

Large and giant CAAs Among patients with large and giant CAAs (ie, Z-score 10 or
maximum internal diameter of 8 mm), a lower rate of myocardial infarction has been noted
when aspirin is combined with anticoagulation (ie, warfarin or heparin) [123]. In general, the goal
of therapy is an international normalized ratio (INR) between 2 and 3, although particularly
severe aneurysms may be managed with an INR goal between 2.5 and 3.5. To date, there have
been no publications on the use of novel oral anticoagulants in children with KD.

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Frequent evaluation with echocardiography and electrocardiography (ECG) should be performed


in patients with giant aneurysms. A worsening of ventricular function or a change in ECG should
raise suspicion for coronary thrombosis. (See 'Follow-up studies' above.)

- Infants In infants, anticoagulation treatment should be based on the criterion of Z-score


10 rather than maximum internal diameter of 8 mm [97]. Low-molecular-weight heparin
(LMWH) is preferred over warfarin because of its predictable anticoagulant response. In one
study of patients with giant CAAs (defined as a Z-score 10), there was no difference in the
frequency of thrombotic coronary artery occlusions between LMWH and warfarin therapy.
Severe bleeding was more frequently observed in patients treated with warfarin, but minor
bleeding was more frequent in patients treated with LMWH. In our experience, patients
treated with both aspirin and warfarin have a high risk of both thrombosis and bleeding
(sometimes in the same patient), and careful monitoring is recommended. (See
'Echocardiography' above and "Management of thrombosis in the newborn", section on
'Anticoagulant therapy'.)

- Triple therapy In rare circumstances (eg, a young infant with giant CAAs who had
coronary thrombosis treated with thrombolysis), triple therapy with aspirin, an additional
antiplatelet agent (eg, clopidogrel), and anticoagulation (eg, warfarin or LMWH) is
sometimes used for a limited period of time. In such instances, the risks of bleeding must be
balanced against the risks of coronary thrombosis and occlusion.

Women with CAAs should have reproductive counseling during adolescence and, once pregnant,
should follow anticoagulation guidelines similar to those for the obstetric patient with a prosthetic
heart valve. Outcomes of pregnancy in women with CAAs in a small series appear to be excellent
[124]. (See "Management of pregnant women with prosthetic heart valves", section on
'Anticoagulation during pregnancy for mechanical heart valves'.)

Myocardial infarction and coronary thrombosis Myocardial infarction is the principal cause of KD
mortality and occurs most frequently among patients with giant CAAs [17]. Although the relative risk of
myocardial infarction is highest in the first 6 to 12 months of the disease and declines after the first two
years [17,18], risk continues into adulthood [18,20,125]. As noted above, ongoing monitoring with
echocardiography and ECG is recommended, with the most intense monitoring in the first few months
after the initial illness [121]. (See 'Follow-up studies' above.)

Because myocardial infarction is rare in KD subjects, principles of treatment are derived from those used
in the adult population with atherosclerotic coronary artery disease [121]. (See "Overview of the acute
management of ST elevation myocardial infarction" and "Overview of the acute management of non-ST
elevation acute coronary syndromes".)

We have treated children with coronary thrombosis as follows:

For patients who present with acute thrombotic occlusion of a coronary artery and who are large
enough for use of adult-sized catheters, immediate angiography with mechanical restoration of
myocardial blood flow is the procedure of choice. (See "Primary percutaneous coronary intervention
in acute ST elevation myocardial infarction: Periprocedural management".)

For younger children who are not candidates for mechanical restoration of flow in the cardiac
catheterization laboratory, we administer systemic alteplase (recombinant tissue-type plasminogen
[tPA], dosing at 0.5 mg/kg per hour intravenously for six hours), low-dose aspirin (3 to 5 mg/kg per
day), and heparin (initial dosing at 10 units/kg per hour, which is adjusted to a targeted activated
partial thromboplastin time [aPTT] between 50 and 70 seconds). Echocardiographic imaging then is
performed to reassess the thrombus, and alteplase may be continued for longer if the thrombus has

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not resolved. (See "Fibrinolysis for acute ST elevation myocardial infarction: Initiation of therapy".)

For some patients with a particularly large thrombus burden, alteplase is intravenously administered
at half dosing (0.25 mg/kg per hour), together with abciximab (platelet glycoprotein IIb/IIIA inhibitor, as
an initial bolus of 0.25 mg/kg bolus over 30 minutes, followed by an infusion of 0.125 micrograms/kg
per minute for 12 hours).

When echocardiographic surveillance during the acute or subacute phase of disease reveals a new
mural, nonocclusive thrombus, abciximab together is administered with low-dose heparin (10 units/kg
per hour) to prevent clot extension.

Following acute myocardial infarction, we may treat patients with beta blockers, angiotensin-
converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), and aldosterone
blockers in addition to their antithrombotic regimen, in accordance with standard postmyocardial
infarction therapy in adults. (See "Overview of the non-acute management of ST elevation myocardial
infarction", section on 'Further medical therapy'.)

Long-term outcome in patients with KD after myocardial infarction is highly related to ejection fraction, with
30-year survival after myocardial infarction being poor for patients with ejection fraction 45 percent [18].

Coronary revascularization procedures Coronary artery revascularization, either by percutaneous


coronary intervention (PCI) or coronary artery bypass grafting (CABG) procedure, is performed to relieve
symptoms of angina and to reduce the risk of myocardial infarction or sudden death in patients with
evidence of reversible ischemia on stress testing [23]. The decision to perform a coronary
revascularization procedure in a patient with KD is based on consensus of experts, clinical experience in
adults with atherosclerotic coronary artery disease, and retrospective reviews in patients with KD
[126-130].

There are no randomized clinical trials assessing the relative merits of PCI versus CABG procedure in KD.
A retrospective Japanese survey suggested that patients who undergo PCI as a first revascularization
procedure, compared with those whose first procedure is surgical, had similar rates of mortality and acute
myocardial infarction. However, the PCI group was more likely to undergo repeat revascularization
procedures [131]. The re-interventions rate was especially high in patients whose CABG procedures were
performed in the absence of ischemic findings, presumably because competitive flow caused graft failure.

The Research Committee of the Japanese Ministry of Health, Labour and Welfare recommends PCI for
patients with the following findings [132]:

Ischemic symptoms
Reversible ischemia on stress testing
75 percent stenosis of the left anterior descending coronary artery

Performance of PCI in the child or adolescent after KD should be performed by an adult interventional
cardiologist, relying on support from pediatric specialists in smaller children. Interventional catheterization
procedures used in patients with KD are similar to those in adults. However, because affected vessels
become calcified, rotational ablation and stent placement are generally preferred to percutaneous
transluminal coronary angioplasty after a few years have passed since disease onset.

The above Japanese committee recommends CABG procedure rather than PCI for patients with the
following findings [132]:

Severe left ventricular dysfunction


Coronary lesions with multiple, ostial, or long-segment coronary artery stenoses

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Surgical revascularization is most often performed in children who either have symptoms of angina, or
who have clinically relevant obstruction in two or more major coronary arteries or in the left main coronary
artery, and thus are considered to be at high risk for myocardial infarction. CABG procedures are only
performed when the myocardium to be supplied is viable and the artery beyond the planned graft site is
not stenotic [133]. In the contemporary era, almost all grafts are derived from systemic arteries (ie, internal
mammary or radial artery) rather than saphenous veins, because these are able to grow in size as the
child matures [126-128]. Grafts have better long-term patency when performed in the older child, but
subsequent use of PCI can extend graft longevity, and children as young as one year of age have
undergone surgical revascularization. In a single-center experience, 25-year survival after CABG
procedure was 95 percent, but only 60 percent of patients had escaped reoperation or PCI by this time
[128].

Cardiac transplantation Cardiac transplantation is reserved for patients with end-stage ischemic
cardiomyopathy who are not candidates for coronary revascularization procedures [134]. (See "Indications
and contraindications for cardiac transplantation in adults".)

LONG-TERM FOLLOW-UP We agree with the American Heart Association (AHA) recommendations
for the frequency of follow-up assessments and physical activity restrictions based upon the coronary
artery status of the patient [11]. Guidelines for long-term assessment and counseling are available on the
AHA website.

Counseling and screening for risk factors All patients with KD and their families should be
counseled on risk factors for atherosclerotic coronary disease, regardless of severity of coronary disease
in the acute phase of their illness. Screening and counseling regarding the risk of atherosclerotic coronary
disease should involve all of the following:

Assessment of cardiovascular risk factors Thresholds for treatment of risk factors (eg,
hyperlipidemia, hypertension), which are lower than for the normal pediatric population, have been
proposed in accordance with severity of coronary involvement (algorithm 1). As patients with
persistent aneurysms approach adulthood, we believe that they should be treated according to adult
guidelines for secondary prevention of cardiovascular disease. (See "Risk factors and development of
atherosclerosis in childhood" and "Prevention of cardiovascular disease events in those with
established disease or at high risk".)

Screening for dyslipidemia Patients >2 years old should be screened for dyslipidemia by either a
fasting lipid profile, or lipid profile with directly measured low-density lipoprotein (LDL) cholesterol one
year after the acute phase of their disease. If the results are normal, repeat lipid screening is
performed every five years. (See "Dyslipidemia in children: Definition, screening, and diagnosis",
section on 'Lipid screening'.)

Promoting a healthy lifestyle We stress the importance of a heart-healthy diet, regular exercise,
and avoidance of smoking including passive smoking. (See "Pediatric prevention of adult
cardiovascular disease: Promoting a healthy lifestyle and identifying at-risk children".)

In patients who never had coronary artery aneurysms (CAAs), the optimal frequency and intensity of
follow-up is uncertain [95,135]. Available data suggest, however, that such individuals are at low risk of
adult coronary artery disease [19]. Because the risk conferred by KD will not be known until the earliest
Japanese cohorts reach middle-age adulthood, patients should receive regularly updated information as
new studies are published regarding the natural history after KD without coronary enlargement in any
stage. They should receive routine preventive cardiology counseling at visits with their primary care
provider. With continued surveillance, the long-term repercussions of KD, including its effects on risks of
coronary artery, valvular, and myocardial disease, will be more fully elucidated, and will inform clinicians
on how best to manage these patients long-term.

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Participation in competitive sports Exercise recommendations in patients with a history of KD are


tailored to the degree of coronary involvement. All patients with KD should avoid a sedentary lifestyle, and
counseling should proactively address the importance of regular aerobic exercise.

In general, we follow the 2015 AHA and American College of Cardiology (ACC) guidelines for sports
participation in patients with coronary artery disease, including KD [136]:

Patients without coronary abnormalities at any stage of the disease, and those with transient coronary
artery ectasia who do not have evidence of exercise-induced ischemia or arrhythmia, can resume
participation in all competitive sports after symptoms have resolved, generally at approximately six to
eight weeks after illness onset. Risk reassessment is recommended every three to five years.

In patients with aneurysms, exercise recommendations are guided by findings on stress testing with
myocardial perfusion imaging and evaluation of left ventricular (LV) function:

Patients who have had a recent myocardial infarction or revascularization procedure are
restricted from competitive sports until their recovery is complete, at which time exercise and
myocardial function are reevaluated. If LV ejection fraction is normal and exercise testing reveals
no reversible ischemia or arrhythmia, participation in class IA and IB sports (figure 1) is
permitted. (See "Risk of sudden cardiac death in athletes", section on 'Coronary heart disease'
and "Cardiac rehabilitation: Indications, efficacy, and safety in patients with coronary heart
disease".)

Collision sports should be avoided in patients receiving antiplatelet or anti-thrombotic therapy.

Patients with small to moderate CAAs without exercise-induced ischemia or arrhythmias may
participate in low- to moderate-intensity sports (classes IA, IB, IIA, and IIB) (figure 1).

Patients with one or more large CAAs should undergo annual stress testing and activity should
be guided by results.

Immunizations Patients with KD should receive all routine childhood vaccinations. Annual influenza
vaccination is especially imperative in patients with KD on chronic aspirin therapy because of the
association of aspirin therapy and influenza with Reye syndrome. Other antiplatelet agents (eg,
clopidogrel) should be temporarily substituted for aspirin during episodes of influenza or chicken pox. (See
"Standard immunizations for children and adolescents: Overview" and "Seasonal influenza in children:
Prevention with vaccines".)

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

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SUMMARY AND RECOMMENDATIONS Cardiovascular complications are the major cause of


mortality and morbidity in patients with Kawasaki disease (KD).

The major complication of KD is coronary artery aneurysms (CAAs). Patients also can develop
decreased myocardial contractility in the acute phase, valvular regurgitation, pericardial effusion, and
peripheral artery aneurysms. Myocardial infarction and ischemia, the two most serious sequelae, only
develop in patients with coronary disease. (See 'Cardiovascular complications' above.)

The highest risk of morbidity and mortality is associated with large or giant CAAs (internal diameter
Z-score 10 or >8 mm). Up to one-half of giant aneurysms become obstructed, and are associated
with myocardial infarction, arrhythmias, or sudden death. Risk factors associated with CAAs include
late diagnosis and delayed treatment with intravenous immune globulin (IVIG), age <1 year and >9
years, male gender, prolonged fever, failure to respond to initial IVIG therapy, and laboratory findings
suggestive of persistent and severe inflammation. (See 'Coronary artery aneurysm' above.)

Typically, aneurysms increase over the first four to six weeks after illness onset, and approximately 50
percent will regress to normal lumen diameter over the next 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. (See 'Natural course' above.)

Patients who have regressed or persistent aneurysms are assumed to be an "at-risk" population for
early atherosclerotic disease, with myofibroblastic proliferation in the coronary arterial wall; however,
available data suggest that patients who never had coronary involvement in the acute phase are at
low risk of adult coronary artery disease. (See 'Risk for atherosclerosis' above.)

In all patients with KD, cardiac testing includes echocardiography and electrocardiography. When
echocardiography is inadequate to image the coronary arteries, computed tomographic angiography
(CTA) or magnetic resonance angiography (MRA) is used to fully delineate the coronary arterial tree.
(See 'Evaluation' above.)

Patients with coronary aneurysms should undergo stress testing with myocardial perfusion imaging to
detect inducible ischemia on an annual basis. For patients with a history of giant coronary aneurysms,
advanced imaging by cardiac catheterization, CTA, or MRA is performed one 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 at one year, subsequent advanced imaging modalities should be
noninvasive (eg, CTA or MRA) unless a catheter intervention is needed or noninvasive coronary
imaging provides inadequate data to guide management. For asymptomatic patients with giant
aneurysms and negative stress tests, advanced imaging is generally performed every three to five
years. Exposure to ionizing radiation should be minimized wherever possible. (See 'General
approach' above.)

The management of cardiovascular sequelae of KD includes prevention of coronary thrombosis,


treatment of patients with myocardial infarction and coronary thrombosis, and in some severe rare
cases, cardiac transplantation. (See 'Management' above.)

We recommend all patients with KD and persistent CAAs receive antithrombotic therapy to
prevent coronary thrombosis (Grade 1B). We tailor our therapy based on the size of the CAAs. In
our practice, all patients receive low-dose aspirin therapy. Other antiplatelet agents (eg,
clopidogrel) may be added to the drug regimen of patients with moderate CAAs. Patients with
large or giant CAAs are treated with aspirin together with anticoagulation (ie, warfarin or low-
molecular-weight heparin). (See 'Prevention of coronary thrombosis' above.)

In patients who suffer a myocardial infarction, we recommend emergent therapy for reperfusion
and revascularization (Grade 1A). The therapeutic intervention is dependent on the size of the

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patient. In patients large enough for use of adult-size catheters, we recommend immediate
angiography and mechanical restoration of blood flow (Grade 1A). In smaller patients, systemic
alteplase (recombinant tissue-type plasminogen [tPA]) at a rate of 0.5 mg/kg per hour
intravenously for six hours is administered together with aspirin and heparin. (See 'Myocardial
infarction and coronary thrombosis' above.)

In patients with clinical signs of coronary ischemia including reversible ischemia with exertion, we
suggest that coronary artery revascularization intervention be performed (Grade 2C). (See
'Coronary revascularization procedures' above.)

The long-term follow-up care of patients with KD is based on the coronary artery status of the patient
and includes assessment of other cardiovascular risk factors, screening for dyslipidemia, promoting a
heart healthy diet, and physical activity counseling. Guidelines for long-term assessment and
counseling are available on the American Heart Association website. (See 'Long-term follow-up'
above.)

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Circulation 2015; 132:e310.

Topic 5772 Version 40.0

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GRAPHICS

Risk stratification and management for children with conditions


predisposing to accelerated atherosclerosis and early cardiovascular
disease from the 2011 NHLBI Expert Panel

Step 1: Risk stratification by disease state or condition.


Step 2: Assess all cardiovascular risk factors. If there are 2 comorbidities at a moderate risk cut point,
move tier II patient to tier I for subsequent management.
Step 3: Tier-specific treatment goals/cut points defined for high and moderate risks.
Step 4: Initial therapy: For tier I, initial management is therapeutic lifestyle change PLUS disease-specific
management. For tier II, initial management is therapeutic lifestyle change.
Step 5: For tier I conditions, if goals are not met, consider pharmacological therapy.

NHLBI: National Heart, Lung, and Blood Institute; HIV: human immunodeficiency virus; CV: cardiovascular; RF:
risk factor; CVD: cardiovascular disease; BP: blood pressure; BMI: body mass index; FG: fasting glucose; LDL-C:
low density lipoprotein cholesterol; TG: triglycerides; HDL-C: high density lipoprotein cholesterol; HgbA1c:

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hemoglobin A1c.
* Though not included in the 2011 NHLBI recommendations, a 2015 American Heart Association statement
advocates including major depressive disorder and bipolar disorder in adolescents as moderate risk conditions for
premature CVD.

Modified from:
1. Daniels SR, Benuck I, Christakis DA, et al. Expert panel on integrated guidelines for cardiovascular health
and risk reduction in children and adolescents: Full report, 2011. National Heart Lung and Blood Institute.
Available at: http://www.nhlbi.nih.gov/guidelines/cvd_ped/peds_guidelines_full.pdf.
2. Goldstein BI, Carnethon MR, Matthews KA, et al. Major Depressive Disorder and Bipolar Disorder
Predispose Youth to Accelerated Atherosclerosis and Early Cardiovascular Disease: A Scientific Statement
From the American Heart Association. Circulation 2015; 132:965.

Graphic 54963 Version 7.0

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Evaluation of suspected incomplete Kawasaki disease (KD)*

KD: Kawasaki disease; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; Echo: echocardiogram;
LAD: left anterior descending artery; RCA: right coronary artery; LV: left ventricle.
* In the absence of gold standard for diagnosis, this algorithm cannot be evidence based, but rather
represents the informed opinion of the expert committee. Consultation with an expert should be sought any
time assistance is needed.
Infants 6 months old on day 7 of fever without other explanation should undergo laboratory testing and,
if evidence of systemic inflammation is found, an echocardiogram, even if the infants have no clinical criteria.
Fever may be absent or missed in some infants and children. Thus, seemingly afebrile children who have
other findings consistent with KD should still be evaluated.
Patient characteristics suggesting disease other than KD include exudative conjunctivitis, exudative
pharyngitis, discrete intraoral lesions, bullous or vesicular rash, or generalized adenopathy. Consider
alternative diagnoses.
Supplemental laboratory criteria include albumin 3 g/dL, anemia for age, elevation of alanine
aminotransferase, platelets after seven days 450,000/mm , white blood cell count 15,000/mm 3, and
3

urine 10 white blood cells/high power field.


Can treat before performing echocardiogram.
Echocardiogram is considered positive for purposes of this algorithm if any of three conditions are met:
Z-score of LAD or RCA 2.5, coronary arteries meet Japanese Ministry of Health criteria for aneurysms, or 3
other suggestive features exist, including perivascular brightness, lack of tapering, decreased LV function,
mitral regurgitation, pericardial effusion, or Z-scores in LAD or RCA of 2 to 2.5.
Typical peeling begins under nailbed of fingers and then toes.
If the echocardiogram is positive, treatment should be given to children within 10 days of fever onset and
those beyond day 10 with clinical and laboratory signs (CRP, ESR) of ongoing inflammation.

Reproduced with permission from Pediatrics, Vol. 114, Pages 1708-33, Copyright 2004 by the AAP.

Graphic 79349 Version 18.0

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Classification of sports based on peak static and dynamic components


during competition

This classification is based on peak static and dynamic components achieved during competition;
however, higher values may be reached during training. The increasing dynamic component is
defined in terms of the estimated percentage of maximal oxygen uptake (VO 2max ) achieved and
results in an increasing cardiac output. The increasing static component is related to the estimated
percentage of maximal voluntary contraction reached and results in an increasing blood pressure
load. The lowest total cardiovascular demands (cardiac output and blood pressure) are shown in
the palest color, with increasing dynamic load depicted by increasing blue intensity and increasing
static load by increasing red intensity. Note the graded transition between categories, which should
be individualized on the basis of player position and style of play.

* Danger of bodily collision (see related table on sports according to risk of impact and
educational background)
Increased risk if syncope occurs. [1]

Reference:
1. Mitchell JH, Haskell W, Snell P, Van Camp SP. Task Force 8: classification of sports. J Am Coll
Cardiol 2005; 45:1364.
Reproduced from: Levine BD, Baggish AL, Kovacs RJ. Eligibility and Disqualification Recommendations for
Competitive Athletes With Cardiovascular Abnormalities: Task Force 1: Classification of Sports: Dynamic,
Static, and Impact: A Scientific Statement From the American Heart Association and American College of
Cardiology. J Am Coll Cardiol 2015; 66:2350. Illustration used with the permission of Elsevier Inc. All
rights reserved.

Graphic 105651 Version 2.0

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Contributor Disclosures
Jane W Newburger, MD, MPH Grant/Research Support: Bristol-Myers-Squibb [Anticoagulation
(Apixiban)]. Sarah D de Ferranti, MD, MPH Nothing to disclose David R Fulton, MD Nothing to
disclose John K Triedman, MD Consultant/Advisory Boards: Biosense Webster [supraventricular and
ventricular topics (EP mapping and ablation systems)]. Carrie Armsby, MD, MPH Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy

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