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Vol.
29 No. 9, September 2008

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Cardiovascular
Disorders

Collagen
Vascular and Other Multisystem Disorders

(Pediatrics in Review. 2008;29:308-316.)
© 2008 American Academy
of Pediatrics

Kawasaki Disease

Angela M. Fimbres, MD,
MPH*
Stanford T. Shulman, MD
* Fellow, Pediatric
Infectious Diseases, Feinberg School of Medicine, Northwestern University,
Chicago, Ill

Professor of Pediatrics, Feinberg School of Medicine, Northwestern University,
Chicago, Ill

Objectives

Top
Objectives
Introduction
Epidemiology
Causes and Pathogenesis
Diagnosis
Laboratory Evaluation
Incomplete or Atypical KD
Differential Diagnosis
Cardiac Imaging
Treatment
Long-term Follow-up and Outcome
Conclusion
Suggested
Reading

After completing this
article, readers should be able to:

Describe the clinical and laboratory manifestations of
Kawasaki disease (KD).

Describe the features of atypical, or incomplete, KD.

Discuss the value of high-dose aspirin and intravenous immune
globulin (IVIG) in the treatment of KD and possible therapies
for IVIG-refractory KD.

Identify the cardiac complications of KD and the
importance of evaluation and follow-up.

Delineate the prognosis and management of KD.

Introduction

Top
Objectives
Introduction
Epidemiology
Causes and Pathogenesis
Diagnosis
Laboratory Evaluation
Incomplete or Atypical KD
Differential Diagnosis
Cardiac Imaging
Treatment
Long-term Follow-up and Outcome
Conclusion
Suggested
Reading

Kawasaki disease (KD)
is an acute, self-limited vasculitis of unknown cause that has a
striking predilection for the coronary arteries of infants and young
children. First described in Japan in 1967 by Tomisaku Kawasaki, the
disease now is known to occur in the Americas, Europe, and Asia in
children of all races. In retrospect, the entity known as infantile
polyarteritis nodosa likely is a part of the continuum of KD, and
clinically mild KD probably was confused with diseases such as
measles or scarlet fever before the advent of vaccines and
antibiotics. In fact, old reports on infantile polyarteritis nodosa
describe pathologic findings that are identical to those of fatal
KD.

Epidemiology

Top
Objectives
Introduction
Epidemiology
Causes and Pathogenesis
Diagnosis
Laboratory Evaluation
Incomplete or Atypical KD
Differential Diagnosis
Cardiac Imaging
Treatment
Long-term Follow-up and Outcome
Conclusion
Suggested
Reading

KD is markedly more
prevalent in Japan and in children of Japanese ethnicity, having an
annual incidence of 150 cases per 100,000 children younger than 5
years of age, about 10 times the rate in the United States. In the
United States, the incidence of KD has been estimated recently by
using hospital discharge data. An estimated 4,248 hospitalizations
associated with KD occurred in the United States in the year 2000,
with a median age of 2 years. The incidence of KD was highest among
Asians and Pacific Islanders and lowest in white children. Boys
outnumbered girls by 3:2, and 76% of children were younger than age 5
years. In-hospital mortality was 0.17%. Virtually all deaths in
patients who have KD result from cardiac sequelae. The peak mortality
occurs 15 to 45 days after the onset of fever. However, sudden death
from myocardial infarction (MI) may occur many years later in
individuals who developed coronary artery aneurysms and stenoses in
childhood. Many cases of ischemic heart disease in young adults have
been attributed to "missed" KD in childhood.

Recurrence rates and the importance of genetic factors in KD are
documented best in Japan, where the recurrence rate is approximately
3%. The proportion of cases that have a positive family history
is approximately 1%. The risk of occurrence in twins is approximately
13%. These data suggest that a genetic predisposition interacts
with an environmental etiologic agent to cause disease. The
occasional occurrence of KD in children of parents who had KD
in childhood also supports the contribution of genetic factors.
Reported associations of KD with respiratory illnesses and exposure
to carpet-cleaning fluids have not been confirmed.

Causes
and Pathogenesis

Top
Objectives
Introduction
Epidemiology
Causes and Pathogenesis
Diagnosis
Laboratory Evaluation
Incomplete or Atypical KD
Differential Diagnosis
Cardiac Imaging
Treatment
Long-term Follow-up and Outcome
Conclusion
Suggested
Reading

Although the cause of
KD remains elusive, clinical and epidemiologic features strongly
suggest an infectious source. A self-limited, generally nonrecurring
illness that manifests with fever fits well with an infectious cause
or trigger. Laboratory features also suggest an infectious agent as
the cause of the inflammation. However, despite extensive efforts to
identify an infectious agent in KD with conventional bacterial and
viral cultures and serologic methods, researchers have not yet been
successful in finding such an agent, although they are making
progress. Recent investigations have discovered that the immune
response in KD is oligoclonal or antigen-driven (ie, similar to a
response to a conventional antigen) rather than polyclonal, and
immunoglobulin A (IgA) plasma cells play a central role. The
prominence of IgA plasma cells in the respiratory tracts of patients
who had fatal acute-stage KD, which is similar to findings in
fatal viral respiratory infections, suggests a respiratory
pathogen.

KD is a generalized vasculitis affecting all blood vessels throughout
the body, but preferentially involving the coronary arteries.
The early stages in the development of vasculitis have been
well studied in large muscular arteries. An influx of neutrophils
is found early after onset, with a rapid transition to large
mononuclear cells in concert with lymphocytes and IgA plasma
cells. Active inflammation is replaced over several weeks to
months by progressive fibrosis, with scar formation.

Diagnosis

Top
Objectives
Introduction
Epidemiology
Causes and Pathogenesis
Diagnosis
Laboratory Evaluation
Incomplete or Atypical KD
Differential Diagnosis
Cardiac Imaging
Treatment
Long-term Follow-up and Outcome
Conclusion
Suggested
Reading

Clinical criteria have
been established to assist physicians in diagnosing KD because there
is no definitive diagnostic test. The classic diagnosis of KD has
been based on the presence of five or more days of fever and four or
more of the five principal clinical features (Table 1).
Those features are 1) changes in the hands and feet (erythema, edema,
peeling), 2) polymorphous exanthema, 3) bilateral bulbar conjunctival
injection without exudate, 4) changes in the lips and oral cavity
(erythema, strawberry tongue), and 5) cervical lymphadenopathy. Of
course, exclusion of other diseases that have similar findings is
necessary. Patients who have fever for 5 or more days and only three
principal features can be diagnosed as having classic KD when
coronary artery disease is detected by two-dimensional
echocardiography or coronary angiography. The fever typically is
high-spiking and remittent. In the absence of therapy, fever persists
for a mean of 11 days. With appropriate therapy, fever usually
resolves within 2 days.

Table 1. Diagnostic Criteria for Kawasaki Disease

Fever for at least 5 days and
four of the five following criteria:

Bilateral conjunctival injection

Changes of the mucous membranes of the upper
respiratory tract: injected pharynx; infected, fissured
lips; strawberry tongue

Polymorphous rash

Changes of the extremities: peripheral edema,
peripheral erythema, periungual desquamation

Cervical
adenopathy

Changes in the extremities include erythema of the palms and
soles or firm, sometimes painful induration of the hands and feet and later
desquamation of the fingers and toes. The desquamation usually begins in the
periungual region within 2 to 3 weeks after the onset of fever and may extend to
include the palms and soles. In addition, 1 to 2 months after the
onset of fever, deep transverse grooves across the nails, known as
Beau lines, may appear.

An erythematous rash usually appears within 5 days of the onset of
fever. The rash may have various forms, but most common is a
nonspecific diffuse rash consisting of scattered macules and
erythematous papules. Bullous and vesicular eruptions have
not been described in KD; if they are present, the physician should consider
other diagnoses. Occasionally seen in KD are urticarial
exanthems, a scarlatiniform rash, erythroderma, erythema multiforme,
or rarely, a fine micropustular eruption. The rash is accentuated in
the perineal region, where early desquamation may begin.

Bilateral painless conjunctival injection usually begins shortly
after the onset of fever, typically involving the bulbar conjunctivae
and usually not associated with an exudate or conjunctival edema.
Changes of the lips and oral cavity are protean and include
erythema, dryness, fissuring, peeling, cracking, and bleeding
of the lips; a "strawberry tongue" that has erythema and prominent
papillae; and diffuse erythema of the oropharyngeal mucosa.
Oral ulcers and pharyngeal exudate are not seen.

Cervical lymphadenopathy is the least common of the principal
clinical features. It usually is unilateral, is confined to the
anterior cervical triangle, and is defined as 1.5 cm or more in
diameter. The lymph nodes often are firm and nontender and have no
overlying erythema.

Multiple other clinical findings can be seen in patients who have
KD. Arthritis or arthralgia can occur in the first week and tends to
involve multiple joints. Children who have KD often are more
irritable than are children who have other febrile illnesses.
Gastrointestinal complaints, including diarrhea, vomiting, and
abdominal pain, occur in approximately one third of patients.
Hepatomegaly and jaundice can develop, as can acute acalculous
distention of the gallbladder. In addition, up to 15% of affected
patients have abnormal findings on chest radiography.

Laboratory Evaluation

Top
Objectives
Introduction
Epidemiology
Causes and Pathogenesis
Diagnosis
Laboratory Evaluation
Incomplete or Atypical KD
Differential Diagnosis
Cardiac Imaging
Treatment
Long-term Follow-up and Outcome
Conclusion
Suggested
Reading

Leukocytosis is
typical during the acute stage of the illness, with a predominance of
immature and mature granulocytes. About 50% of patients who have KD
have white blood cell counts greater than 15.0x103/mcL (15.0x109/L). Anemia may develop,
especially with a prolonged duration of active inflammation. Elevated
values for the acute-phase reactants, such as erythrocyte
sedimentation rate (ESR) and C-reactive protein (CRP), are nearly
universal in KD. Both the ESR and CRP should be measured, if
possible, because of the potential for discordance of the values.
For patients who already have been treated with intravenous
immune globulin (IVIG), ESR is not useful as a marker of
inflammation because an elevation can be the result of the IVIG
therapy.

Thrombocytosis is a characteristic in the subacute stage of
illness, with platelet counts ranging from 500.0 to 1,000.0x103/mcL (500.0 to 1,000.0x109/L) or more. Thrombocytosis peaks in
the third week and gradually returns to normal by 4 to 8 weeks after onset of
illness. Mild-to-moderate elevations in serum transaminases occur
in 40% or fewer of patients, and mild hyperbilirubinemia is seen
in approximately 10%. Hypoalbuminemia is common and is associated
with more severe and more prolonged acute disease. Urinalysis
reveals mild-to-moderate sterile pyuria in about one third of
patients. If those who have KD undergo lumbar puncture, approximately
50% have evidence of aseptic meningitis, with a predominance of
mononuclear cells, as well as normal glucose and protein
concentrations.

Laboratory tests can provide diagnostic support for patients whose
clinical presentations are suggestive but not diagnostic of KD. A
moderately-to-markedly elevated CRP (30.0 mg/L
[3.0 mg/dL]) or ESR (>40 mm/hr), for example, is nonspecific
but nearly universal in KD, while unlikely in viral infections.
Past experience suggests that KD is unlikely if platelet counts
and acute-phase reactant values are normal after the seventh
day of fever.

Incomplete or Atypical KD

Top
Objectives
Introduction
Epidemiology
Causes and Pathogenesis
Diagnosis
Laboratory Evaluation
Incomplete or Atypical
KD
Differential Diagnosis
Cardiac Imaging
Treatment
Long-term Follow-up and Outcome
Conclusion
Suggested
Reading

Some patients do not
fulfill the clinical criteria for KD and are diagnosed based on
echocardiographic findings of coronary artery abnormalities.
Therefore, the conventional diagnostic criteria should be viewed as
guidelines to prevent overdiagnosis, but strict adherence to the
criteria may result in failure to recognize incomplete forms of KD.
Incomplete, or atypical, KD is more common in young infants than in
older children, making accurate diagnosis especially important
because these patients are at higher risk for developing coronary
abnormalities. Echocardiography is useful in diagnosing KD among
patients who have only some of the classic features. Although
aneurysms rarely form before day 10 of illness, some evidence of
arteritis can be present in the acute stage of KD before the
formation of aneurysms.

Incomplete KD should be considered in all infants and children who
have unexplained fever for 5 or more days associated with two or
three of the principal clinical features of KD. In addition,
supplemental laboratory criteria, including albumin, hemoglobin,
and transaminase measurements as well as urinalysis, can be
used to support the diagnosis. Because young infants may present
with fever and little else, echocardiography should be considered
in any infant younger than 6 months who has fever lasting 7
days or more, laboratory evidence of systemic inflammation, and
no other explanation for the febrile illness. An algorithm for the
evaluation of children suspected of having incomplete KD is presented
in the Figure.

View larger
version (43K):
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this window]
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Figure. Evaluation of suspected
incomplete Kawasaki disease (KD). 1) In the absence of a gold
standard for diagnosis, this algorithm cannot be evidence-based but
rather represents the informed opinion of the Expert Committee.
Consultation with an expert should be sought anytime assistance is
needed. 2) Infants 6 months old on day 7 of fever with no other
explanation should undergo laboratory testing and, if evidence of
systemic inflammation is found, echocardiography, even if the
infants have no clinical criteria. 3) Characteristics suggesting KD
are listed in Table 1.
Characteristics suggesting disease other than KD include exudative
conjunctivitis, exudative pharyngitis, discrete intraoral lesions,
bullous or vesicular rash, or generalized adenopathy. Consider
alternative diagnoses (see Table 2).
4) Supplemental laboratory criteria include albumin value of 3.0
g/dL (30.0 g/L), anemia for age, elevation of alanine
aminotransferase, platelet count of more than 450.0x103/mcL (450.0x109/L) after 7 days, white
blood cell count 15.0x103/mcL (15.0x109/L), and 10 white blood
cells/high-power field in the urine. 5) Can treat before performing
echocardiography (Echo). 6) Echocardiography is considered positive
for purposes of this algorithm if any of three conditions are met: z
score for left anterior descending or right coronary artery of 2.5;
coronary arteries meet Japanese Ministry of Health criteria for
aneurysms; or three other suggestive features exist, including
perivascular brightness, lack of tapering, decreased left
ventricular function, mitral regurgitation, pericardial effusion, or
z scores in left anterior descending or right coronary artery of 2
to 2.5. 7) If echocardiography is positive, children should be
treated within 10 days of fever onset and those beyond day 10 with
clinical and laboratory signs (C-reactive protein, erythrocyte
sedimentation rate) of ongoing inflammation. 8) Typical peeling
begins under nail bed of fingers and then toes. CRP=C-reactive
protein, ESR=erythrocyte sedimentation rate. Reprinted with
permission from Newburger JW, Takahashi M, Gerber MA, et al.
Diagnosis, treatment, and long-term management of Kawasaki disease:
a statement for health professionals from the Committee on Rheumatic
Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular
Disease in the Young, American Heart Association. Pediatrics.
2004;114:1708–1733.

Differential Diagnosis

Top
Objectives
Introduction
Epidemiology
Causes and Pathogenesis
Diagnosis
Laboratory Evaluation
Incomplete or Atypical KD
Differential Diagnosis
Cardiac Imaging
Treatment
Long-term Follow-up and Outcome
Conclusion
Suggested
Reading

Other febrile
illnesses of childhood can mimic KD (Table 2).
Measles, group A streptococcal or staphylococcal infections,
and drug hypersensitivity reactions are the illnesses that resemble
KD most closely. In addition, the differential diagnosis includes
Stevens-Johnson syndrome, adenovirus infection, Rocky Mountain
spotted fever, and Epstein-Barr virus infection. However, certain
clinical features strongly suggest KD. Conjunctival injection
in KD primarily is bulbar and usually is not accompanied by
exudate. Lip redness and swelling can be severe enough to cause
cracking and bleeding, and "strawberry tongue" is characteristic.
Oral ulcers and exudative pharyngitis are not features of the
illness. Tense swelling of the hands and feet is distinctive
and rarely seen in other childhood febrile illnesses. Perineal
accentuation of the rash is common in KD but not in other disorders.
Vesicles, bullae, petechiae, and purpura are not seen. KD should
be considered in the differential diagnosis of every child who
has fever of at least several days’ duration, rash, and
nonpurulent conjunctivitis, especially in children younger than
1 year of age and in adolescents, in whom the diagnosis frequently
is missed and treatment delayed.

Table 2. Differential Diagnosis of Kawasaki Disease

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

Scarlet fever

Staphylococcal scalded skin syndrome

Toxic shock syndrome

Bacterial cervical lymphadenitis

Drug hypersensitivity

Stevens-Johnson syndrome

Juvenile idiopathic arthritis

Leptospirosis

Mercury hypersensitivity reaction
(acrodynia)

Cardiac Imaging

Top
Objectives
Introduction
Epidemiology
Causes and Pathogenesis
Diagnosis
Laboratory Evaluation
Incomplete or Atypical KD
Differential Diagnosis
Cardiac Imaging
Treatment
Long-term Follow-up and Outcome
Conclusion
Suggested
Reading

Cardiac imaging is
critical in the evaluation of all patients who are suspected of
having KD, and echocardiography has been determined to be the ideal
imaging modality for cardiac assessment. Initial echocardiography
should be performed as soon as the diagnosis is suspected, but
treatment should not be delayed by the timing of the study. Cardiac
evaluation of patients suspected of having KD should focus on maximal
efforts to see all major coronary segments: the left main coronary
artery (LMCA), left anterior descending artery (LAD), left circumflex
coronary artery (LCX), right coronary artery (RCA), and the posterior
descending coronary arteries. The most common sites of coronary
aneurysms include the proximal LAD and proximal RCA, followed by the
LMCA, then LCX, and finally the distal RCA and the junction
between the RCA and the posterior descending coronary artery. In
addition, assessment of left ventricular function should be a part
of the echocardiographic evaluation of all patients in whom KD
is suspected because some degree of myocarditis is almost universal.
Myocarditis may manifest as chest pain or tachycardia that can
occur out of proportion to the degree of fever, valvular dysfunction,
and electrocardiographic changes. The presence of any pericardial
effusion also should be noted on echocardiography.

Treatment

Top
Objectives
Introduction
Epidemiology
Causes and Pathogenesis
Diagnosis
Laboratory Evaluation
Incomplete or Atypical KD
Differential Diagnosis
Cardiac Imaging
Treatment
Long-term Follow-up and Outcome
Conclusion
Suggested
Reading

The current standard
therapy for KD is a combination of aspirin and IVIG. In 1983,
Japanese investigators reported that children treated with IVIG had
faster resolving fever and developed fewer coronary artery
abnormalities than did "historic" controls. A multicenter randomized
trial in the United States showed that children treated with IVIG and
high-dose aspirin had significantly faster resolution of fever and
other inflammatory markers than did children treated with high-dose
aspirin alone and confirmed that coronary artery abnormalities were
reduced by about 85%. Subsequent studies have confirmed that initial
therapy with IVIG and high-dose aspirin should be the standard
therapy for KD.

During the acute phase of illness, aspirin is administered at 80
to 100 mg/kg per day in four doses along with IVIG. High-dose aspirin
and IVIG appear to have an additive anti-inflammatory effect. Most
clinicians continue high-dose aspirin until day 14 of illness if the
child remains afebrile. When high-dose aspirin is discontinued,
therapy is continued with low-dose aspirin at 3 to 5 mg/kg per day
until the patient shows no evidence of coronary changes by 6 to 8
weeks after the onset of illness. This regimen applies to children
who have no coronary abnormalities on initial echocardiography.

For children who develop coronary abnormalities, aspirin may be
continued indefinitely. Aspirin has anti-inflammatory properties at
high doses and antiplatelet activity at low doses but alone does not
appear to lower the frequency of the development of coronary
abnormalities. Because Reye syndrome is a risk in children who take
salicylates while they are infected with varicella or influenza,
parents should be instructed to contact their child's physician
immediately if the child develops symptoms of or is exposed to
influenza or varicella. Children on aspirin therapy should receive
influenza immunizations routinely.

The efficacy of IVIG in reducing the prevalence of coronary artery
abnormalities in KD is well established, despite the mechanism of
action being unknown. IVIG appears to have a generalized
anti-inflammatory effect. Patients who have KD should be treated
with IVIG (2 g/kg in a single infusion) together with high-dose
aspirin. Whenever possible, this therapy should be started within
the first 10 days of illness, with the first day of fever considered
the first day of illness. IVIG also should be administered to
children presenting with KD after the 10th day of illness if
they have persistent fever with no other explanation or evidence
of ongoing inflammation such as an elevated ESR or CRP, with or
without coronary abnormalities. Measles and varicella immunizations
should be deferred for 11 months after a child receives IVIG.
Even when treated appropriately within the first 10 days of
illness, approximately 5% of children who have KD develop some
coronary artery dilation, and 1% develop giant aneurysms, defined
as a greater than 8 mm internal diameter.

Despite steroids being highly effective in treating other forms of
vasculitis, their use in KD has been limited. Steroids were the
initial therapy for KD before the discovery of the efficacy of IVIG.
Although early studies may have shown a detrimental effect of
steroids, subsequent studies have shown neither benefit nor ill
effects. A recent investigation examined the effect on coronary
artery outcomes of pairing the initial dose of IVIG with a dose of
intravenous methylprednisolone. The results did not support the
addition of a single pulsed dose of steroids to conventional therapy
because no significant effect was seen on the development of coronary
artery abnormalities. However, there was a potential benefit in the
subset of patients who required retreatment with IVIG because of
persistent or recurrent fever and, therefore, were at greater risk
for coronary abnormalities. More studies will need to be performed to
delineate this effect further.

Approximately 10% of patients who have KD fail to respond to
initial IVIG therapy. Failure to respond usually is defined as persistent or
recrudescent fever 36 hours or more after completion of the initial IVIG
infusion. Most experts recommend retreatment with IVIG at the same
dose. Treatment of patients who have true IVIG-refractory KD,
defined as persistent fevers or elevated inflammatory markers
despite having received two courses of IVIG, is controversial.
There is no universally accepted "next step" in therapy. Some
clinicians use a third dose of IVIG. Steroids also have been used to
treat patients whose disease is refractory to IVIG. Steroids
have been shown to reduce fever, but the steroid effect on
coronary abnormalities remains uncertain. The steroid regimen used
most commonly is intravenous pulse methylprednisolone, 30 mg/kg
for 2 to 3 hours, administered once daily for 3 days.

A class of agents that may play a role in the treatment of patients
who have refractory KD is monoclonal antibodies to proinflammatory
cytokines. A monoclonal antibody against tumor necrosis factor-alpha,
infliximab, is being studied for treatment of children who fail
to become afebrile after initial IVIG treatment. Although its
effectiveness in reducing the prevalence of coronary artery
aneurysms remains unproven, therapy with infliximab or other
agents directed at tumor necrosis factor-alpha might be considered
for patients who are refractory to IVIG.

Cytotoxic agents such as cyclophosphamide and methotrexate have
been suggested as being useful for the treatment of refractory
KD because they are used widely to treat other severe vasculitides.
However, the risk of using cytotoxic agents may exceed the benefits
for most patients, and they are not recommended routinely at
this point. Because controlled data are lacking, the roles for
these adjunctive therapies for IVIG-refractory patients remain
uncertain. Ongoing research into various treatments is needed
to guide clinicians in treating IVIG-refractory patients.

Long-term Follow-up and Outcome

Top
Objectives
Introduction
Epidemiology
Causes and Pathogenesis
Diagnosis
Laboratory Evaluation
Incomplete or Atypical KD
Differential Diagnosis
Cardiac Imaging
Treatment
Long-term Follow-up and Outcome
Conclusion
Suggested
Reading

The following features
of the natural history of KD have been established, based on large
series of patients from Japan and North America. Coronary artery
aneurysms occur in 20% to 25% of untreated children. Other
cardiovascular complications include myocarditis, pericarditis with
effusion, and valvulitis, the latter occurring in about 1% of
patients, most commonly involving the mitral valve. Resolution of
aneurysms 1 to 2 years after disease onset has been observed in
approximately 50% of vessels that have coronary aneurysms. The
likelihood that an aneurysm will resolve is determined, in large
part, by its initial size, with smaller aneurysms having a greater
likelihood of regression. Vessels in which resolution does not occur
are at risk for developing stenosis or occlusion by thrombus or
myointimal proliferation. A coronary aneurysm can rupture within the
first few months after KD, but this complication is exceedingly rare.
The worst prognosis is noted in children who have giant aneurysms,
where thrombosis is promoted by the sluggish and turbulent blood
flow within the dilated vascular space and by the frequent
occurrence of stenotic lesions at the proximal or distal end of the
aneurysms.

MI caused by thrombotic occlusion of an abnormal coronary artery
is the principal cause of death from KD. The greatest risk of
MI occurs in the first year after disease onset. The general
belief is that if coronary aneurysms are not identified by complete
and adequate echocardiography in the first 1 to 2 months after
diagnosis, the development of new aneurysms is unlikely. Children
who have no known cardiac sequelae during the first month of KD
appear to return to their previous state of health without signs or
symptoms of cardiac impairment. However, limited evidence suggests
possible long-term endothelial dysfunction in children who have no
obvious coronary involvement, the significance of which is
unknown.

Echocardiography should be performed at the time of diagnosis and
subsequently usually at 2 and 6 weeks after disease onset. Children
are stratified according to their relative risk of myocardial
ischemia. Treatment can be individualized according to risk level, as
recommended by the American Heart Association (Table 3).
For children at higher risk, such as those who have persistent fever
or coronary abnormalities, more frequent imaging may be necessary to
guide management. Patients who have no coronary artery changes on
echocardiography at any stage of the illness still should be
counseled periodically about cardiovascular risk factors (eg,
hypertension, diet, exercise) because the future risk for ischemic
heart disease in this category of patients remains undetermined.

Table 3. Management of Kawasaki Disease

Risk Level

Pharmacologic Therapy

Physical Activity

Follow-up and Diagnostic Testing

Invasive Testing

I (no coronary artery changes at any stage
of illness)

None beyond first 6 to 8 weeks

No restrictions beyond first 6 to 8
weeks

Cardiovascular risk assessment, counseling
at 5-year intervals

None recommended

Il (transient coronary artery ectasia
disappears within first 6 to 8 weeks)

None beyond first 6 to 8 weeks

No restrictions beyond first 6 to 8
weeks

Cardiovascular risk assessment, counseling
at 3- to 5-year intervals

None recommended

III (1 small-to-medium coronary artery
aneurysm/major coronary artery)

Low-dose aspirin (3 to 5 mg/kg per day),
at least until aneurysm regression documented

For patients <11 years old, no
restriction; patients 11 to 20 years old, physical activity guided
by biennial stress test, evaluation of myocardial perfusion scan;
contact or high-impact sports discouraged for patients taking
antiplatelet agents

Annual cardiology follow-up of
echocardiography+ECG combined with cardiovascular risk assessment,
counseling; biennial stress test/evaluation of myocardial perfusion
scan

Angiography, if noninvasive test suggests
ischemia

IV (1
large or giant coronary artery aneurysm, multiple, or complex
aneurysms in same coronary artery without obstruction)

Long-term antiplatelet therapy and
warfarin (target International Normalized Ratio 2.0 to 2.5) or
low-molecular-weight heparin (target antifactor Xa level 0.5 to 1.0
U/mL) should be combined in giant aneurysms

Contact or high-impact sports should be
avoided because of risk of bleeding; other physical activity
recommendations guided by stress test/evaluation of myocardial
perfusion scan

Biannual follow-up with
echocardiography+ECG; annual stress test/evaluation of myocardial
perfusion scan

First angiography at 6 to 12 months or
sooner if clinically indicated; repeat angiography if noninvasive
test, clinical, or laboratory findings suggest ischemia; elective
repeat angiography under some circumstances

V (coronary artery obstruction)

Long-term low-dose aspirin; warfarin or
low-molecular- weight heparin if giant aneurysm persists; consider
use of beta blockers to reduce myocardial oxygen consumption

Contact or high-impact sports should be
avoided because of risk of bleeding; other physical activity
recommendations guided by stress test/myocardial perfusion scan

Biannual follow-up with
echocardiography+ECG; annual stress test/evaluation of myocardial
perfusion scan

Angiography recommended to address
therapeutic options

ECG=electrocardiography. Adapted from Newburger JW, Takahashi
M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki
disease: a statement for health professionals from the Committee on Rheumatic
Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in
the Young, American Heart Association. Pediatrics. 2004; 114:1708–1733.

Patients who have small solitary aneurysms should take long-term
aspirin therapy until the aneurysms regress and be followed by
a pediatric cardiologist or other physician experienced in the
management of KD. Patients who have giant aneurysms or multiple
complex aneurysms should be considered candidates for long-term
antiplatelet therapy and anticoagulation therapy. The choice of
regimen depends on the degree of coronary enlargement. Regimens
include combinations of aspirin, clopidogrel, heparin, and warfarin.
Treatment with aspirin usually is sufficient for aneurysms that
have a maximum diameter of 5 mm, whereas patients who have giant
aneurysms generally are treated with a combination of aspirin
and warfarin, aiming for an International Normalized Ratio of
2.0 to 2.5. Such severely affected patients should be followed
by a cardiologist and have echocardiography, electrocardiography,
and stress tests performed at regular intervals.

Other noninvasive tests may be used widely in the future to assess
coronary stenoses, aneurysms, and occlusions. Multislice spiral
computed tomography scan (MSCT) has been used successfully to "image"
the distal segments of coronary arteries in adolescents and young
adults to identify small areas of stenosis and aneurysm. Coronary
magnetic resonance angiography (CMRA) also has been shown to define
coronary artery aneurysms accurately as well as thickened vessel
walls in free-breathing sedated children. In the future, MSCT and
CMRA may be useful noninvasive alternatives for children who
otherwise would need frequent catheterizations as they grow
older.

Attempts at excising coronary artery aneurysms have been unsuccessful
and have caused deaths. The primary surgical management of KD
is coronary artery bypass grafts for obstructive lesions. Catheter
interventions such as balloon angioplasty, rotational ablation,
and stent placement have been performed in a relatively small
number of children who have KD. Catheter intervention for patients
who have KD should be considered when ischemic symptoms are
present and in patients who have 75% or more stenosis with or
without ischemia in the LAD. Approximately 20 patients who have
KD have undergone cardiac transplantation for severe myocardial
dysfunction, severe ventricular arrhythmias, and severe coronary
arterial lesions. Cardiac transplantation should be considered
for individuals who have severe, irreversible myocardial dysfunction
and coronary lesions for which interventional catheterization
procedures or coronary bypass are not feasible.

Conclusion

Top
Objectives
Introduction
Epidemiology
Causes and Pathogenesis
Diagnosis
Laboratory Evaluation
Incomplete or Atypical KD
Differential Diagnosis
Cardiac Imaging
Treatment
Long-term Follow-up and Outcome
Conclusion
Suggested
Reading

Although great
progress has been made in the treatment of KD, much is left to learn
about the cause of the illness. Until an etiologic agent is
identified and a definitive diagnostic test devised, children who
have KD still will be misdiagnosed (under- and overdiagnosed), and
some who have KD will be untreated, suffering potentially serious
morbidity or even mortality. Priorities for research are developing a
diagnostic test, identifying genetic markers for susceptibility to
KD, identifying prognostic factors, developing improved therapies,
and discovering the cause of KD. The ultimate goal of KD research is
to prevent the grave cardiac consequences of the disease, and
critical to this goal is elucidation of the causative agent.

Footnotes

Author Disclosure

Drs Fimbres and Shulman have disclosed no financial relationships
relevant to this article. This commentary does not contain a
discussion of an unapproved/investigative use of a commercial
product/device.

Suggested Reading

Top
Objectives
Introduction
Epidemiology
Causes and Pathogenesis
Diagnosis
Laboratory Evaluation
Incomplete or Atypical KD
Differential Diagnosis
Cardiac Imaging
Treatment
Long-term Follow-up and Outcome
Conclusion
Suggested
Reading

Burns JC, Glode MP. Kawasaki syndrome.
Lancet.2004; 364 :533 –544[CrossRef][Medline]

Danford D. Is there a role for corticosteroids in
treatment of Kawasaki disease? Commentary on article by Newburger, Sleeper, and
McCrindle. AAP Grand Rounds.2007; 17 (5):50[Free Full Text]

Freeman AF, Shulman ST. Refractory Kawasaki
disease. Pediatr Infect Dis J.2004; 23 :463 –464[Medline]

Greil GF, Seeger A, Miller S, et al. Coronary
magnetic resonance angiography and vessel wall imaging in children with Kawasaki
disease. Pediatr Radiol.2007; 37 :666 –673[CrossRef][Medline]

Li SC. Is there a role for corticosteroids in
treatment of Kawasaki disease? Commentary on article by Newburger, Sleeper, and
McCrindle. AAP Grand Rounds.2007; 17 (5):50[Free Full Text]

Newburger JW, Fulton DR. Kawasaki disease.
Curr Opin Pediatr.2004; 16 :508 –514[CrossRef][Medline]

Newburger JW, Sleeper LA, McCrindle BW, et al.
Randomized trial of pulsed corticosteroid therapy for primary treatment of
Kawasaki disease. N Engl J Med.2007; 356 :663 –675[Abstract/Free Full Text]

Newburger JW, Takahashi M, Gerber MA, et al.
Diagnosis, treatment, and long-term management of Kawasaki disease: a statement
for health professionals from the Committee on Rheumatic Fever, Endocarditis,
and Kawasaki Disease, Council on Cardiovascular disease in the Young, American
Heart Association. Pediatrics.2004; 14 :1708 –1733

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