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Kawasaki disease (KD), an acute febrile illness of childhood,
was described in Japan in 1967 by Dr. Tomasaku Kawasaki as the mucocutaneous
lymph node syndrome.1 A vasculitis of medium-sized vessels,
KD has a predilection for the coronary arteries, and 20% to
25% of untreated children develop coronary artery aneurysms.
Fortunately, a regimen of intravenous immunoglobulin and aspirin
reduces the incidence of coronary artery abnormalities to less than 5%.2 Nonetheless,
KD is a leading cause of acquired heart disease in children in North
America and Japan. Furthermore, the etiology of KD remains elusive,
impeding the development of targeted therapy and diagnostic testing.
+++
Epidemiology
and Specific Populations at Risk
++
The Japanese Ministry of Health has collected epidemiologic data on
Kawasaki disease (KD) since 1970 with nationwide surveys every 2
years. In total, over 225,000 cases of KD were reported in Japan
between 1970 and 2006.3-5 In addition to endemic disease,
3 epidemics of KD occurred in Japan in 1979, 1982, and 1986, with an
incidence of 196.1 KD cases per 100,000 children less than 5 years
of age in 1982, the most severe of the epidemics. Interestingly,
there have been no recent epidemics, but recent surveys have revealed
an increase in the incidence of KD.4,5 The incidence of
KD in Japan from 2005 to 2006 was 184.6 per 100,000 in children
younger than 5 years of age.3 The highest incidence of
KD was in children younger than 1 year of age, with a peak incidence
of 6 to 8 months, and cardiac abnormalities occurred most commonly
in infants and in children older than 4 years.3
++
In the United States, Holman et al6 reported a hospitalization
rate for Kawasaki disease (KD) in the United States in 2000 as 17.1
per 100,000 children less than 5 years of age, with a median age
at admission of 2 years. Children of Asian and Pacific Islander
heritage had the highest hospitalization rate at 39 per 100,000
children. A subsequent study of KD in Hawaiian children revealed
an incidence higher than the national findings, with an incidence
of 45.2 per 100,000 children less than 5 years of age from 1996
to 2001.7 Furthermore, that study revealed a striking discrepancy
amongst ethnicities in patients less than 5 years of age, with an
incidence of 35.3 per 100,000 white children and 70.9 per 100,000
Asian and Pacific Islander children residing in Hawaii. The incidence
of KD in Japanese Americans living in Hawaii was 197.7 per 100,000
children, higher than the incidence in Japan during the last epidemic. Siblings
of patients with KD may be at higher risk for developing the disease,8 and
parents of affected children in Japan are twice as likely to have
a history of KD themselves.9 These findings are consistent
with the hypothesis that KD results from unidentified environmental triggers
in genetically susceptible hosts.
++
Risk factors for poor coronary artery outcomes have been identified
in a number of studies. Using the CDC passive surveillance system
for Kawasaki disease, Belay et al. found that coronary artery aneurysms
were significantly associated with age less than 1 year or greater
than 9 years, male sex, Asian and Pacific Islander race, and Hispanic
ethnicity.10 One study posited that African American ethnicity
is protective against the development of coronary artery aneurysms.11 Furthermore,
a number of investigators have created predictive models to identify
risk factors for poor clinical outcome. Young age, male sex and
a number of laboratory parameters, including neutrophilia, thrombocytopenia, hyponatremia,
elevated C reactive protein, and transaminitis have been associated
with poor response to intravenous immunoglobulin or the development
of coronary artery aneurysms.7-11 In short, younger, sicker
children with worse systemic inflammation are at higher risk.
+++
Pathophysiology
and Genetics
++
Despite years of extensive research, the etiology of Kawasaki disease
(KD) remains obscure. Many aspects of the disease implicate an infectious
trigger in the pathogenesis. KD is a disease of childhood, rarely
seen in adults or infants less than 2 months of age. Discrete seasonal
peaks with increased incidence in selected geographic areas suggest
a transmittable vector.5,12 Many of the clinical features
of KD resemble other childhood infections with exanthems (see below). These
observations led to the investigation of many infectious agents
as the causative factor, including the Epstein-Barr virus, adenovirus,
human coronavirus NL63, human bocavirus, Yersinia pseudotuberculosis,
herpesviruses, and others.13-29 However, no single etiologic agent
has emerged as the clear culprit. Rowley and colleagues have posited
that KD is likely caused by either a single infectious agent or
a group of closely related agents,30 based on their findings
of oligoclonal IgA-secreting plasma cells31,32 and cytoplasmic
inclusion bodies33 in the respiratory tract of patients with
KD.
++
Similarities between Kawasaki disease and toxin-mediated diseases,
such as toxic shock syndrome and streptococcal toxic shock syndrome,
led to the proposition that the features of Kawasaki disease are
mediated by superantigens. Superantigens are proteins that can bind to
the major histocompatibility complex on antigen-presenting cells
and to T-cell receptors at sites other than conventional peptide-binding
clefts, enabling simultaneous activation of many T cells. Binding
of the T cell occurs at the variable region of the β chain
(V β region). The resultant massive release of
cytokines likely produces many of the features of toxic shock syndrome,
streptococcal toxic shock syndrome, and other toxin-mediated syndromes.
++
Detection of superantigen activity is best determined by V β skewing,
which is the finding of a disproportionate number of T cells that
express a particular family of V β T-cell receptor
genes. However, studies of T cells and attempts at isolating superantigen-producing bacteria
in Kawasaki disease patients have yielded conflicting results, as
some studies have found evidence of V β skewing
in the peripheral blood, the intestinal wall mucosa, and coronary
arteries,34-40 whereas other studies have shown an absence
of V β skewing.41-45 A recent study of
serological responses to superantigens revealed an increase in IgM
antibodies to multiple toxins, indicating that more than one superantigen
could be involved in the pathogenesis of Kawasaki disease.46 Despite
the wealth of data regarding superantigens in Kawasaki disease,
their role remains controversial.
++
Studies of other immunologic mechanisms at work in Kawasaki disease,
including oligoclonal IgA plasma cells, Toll-like receptors and
adaptor proteins,47 CD25+ CD4+ regulatory
T cells,48 and genetic variations in interleukin-4 and
chemokine (C-C motif) receptor 5,49,50 have yielded intriguing
but inconclusive results.
++
Classic clinical criteria, as well as supportive clinical and
laboratory findings, are summarized in Table 488-1.
In brief, the epidemiologic case definition of Kawasaki disease (KD)
includes at least 4 days of fever (3 days in expert hands), together
with 4 or 5 principal clinical criteria. Those with fewer than 4 principal
clinical criteria may meet the case definition if they have coronary
artery disease. Incomplete KD, in which fewer than 4 principal clinical
criteria are evident, is associated with a rate of coronary aneurysms
that is similar to that of complete disease. Because the diagnosis
of incomplete KD is particularly challenging, the latest American
Heart Association recommendations, endorsed by the American Academy
of Pediatrics, provide an algorithm for evaluation and treatment
of suspected incomplete KD (Fig. 488-1).2
++
++
++
Kawasaki disease (KD) is a vasculitis, and its principal features
indicate systemic inflammation, likely incited in part by tumor
necrosis factor and interleukin-1. Fever is the hallmark of KD.
Children with KD tend to have daily, high fevers (> 39˚C)
that are of abrupt onset. Without intravenous immunoglobulin treatment,
the average duration of fever is 11 to 12 days, with rare patients
remaining febrile for as long as 4 weeks. Patients who receive appropriate
therapy tend to defervesce within 2 to 3 days of intravenous immunoglobulin
administration. The clinical features that accompany fever in KD
patients may appear and subside at differing times over the course
of illness, highlighting the importance of medical history.
++
More than 90% of children with Kawasaki disease (KD)
develop bilateral, marked conjunctival injection in a limbus-sparing
pattern. Anterior uveitis, detected by a slit lamp examination,
also occurs in the acute phase of the disease. Patients with KD
develop mucosal changes in their oropharynx; diffuse erythema of the
oropharynx, a strawberry tongue, and cracked, reddened lips are
characteristic of KD, whereas exudative tonsillitis or discrete
oral lesions suggest other etiologies. Typically, the rash is erythematous
and begins in the perineal area with some desquamation; morbilliform
and erythema multiforme lesions can also occur. Vesicular or bullous
lesions suggest other diagnoses. Extremity changes in the acute
phase of KD include erythema of the palms and soles, as well as
edema of the hands and feet. In the convalescent phase of KD, usually
2 weeks after fever onset, periungual peeling occurs on the fingers,
followed by the toes. The least common manifestation of KD is cervical
lymphadenopathy, specifically a single large (> 1.5 cm) unilateral
node that is usually nontender, without erythema or warmth. Diffuse
lymphadenopathy is more likely explained by another diagnosis.
++
A variety of signs and symptoms may support the diagnosis of
Kawasaki disease (KD). Patients with KD are usually irritable, perhaps reflecting
central nervous system inflammation. Children with KD may complain
of arthralgias; reported rates of frank arthritis range from 7.5% to
31% in KD patients.13 Although large joints of
the lower extremities are most likely to be involved, small joint
arthritis has been reported as well. Gastrointestinal complaints
are also common and include abdominal pain, nausea, and vomiting.
Hydrops of the gallbladder can present with abdominal pain or jaundice
or can be clinically silent. Possible etiologies for acalculous
distension of the gallbladder include vasculitis, serositis, or
compression of the cystic duct by inflamed mesenteric lymph nodes.
+++
Differential
Diagnosis
++
As fever and rash are the most common features of Kawasaki disease
(KD), the differential diagnosis is dominated by infectious diseases
of childhood (eTable 488.1). Common viral infections such as adenovirus,
enterovirus, and Epstein Barr virus can mimic KD. As the rash of
KD is frequently morbilliform, measles is a differential diagnosis, but
is less commonly encountered in developed countries because of widespread
vaccination. Diseases with exanthems such as scarlet fever, Rocky
Mountain spotted fever, leptospirosis, staphylococcal scalded skin syndrome,
and toxic shock syndrome should be considered when evaluating a
child for KD. Drug hypersensitivity syndromes, including Stevens-Johnson
syndrome are also possible. In some children who appear at first
to have KD, with fever, rash, joint pain, and coronary artery changes,
the symptoms may ultimately evolve into systemic onset juvenile
idiopathic arthritis.14 Rarely, mercury poisoning or acrodynia,
with its swollen, erythematous hands and feet, may mimic KD.
++
++
Complicating the diagnosis of Kawasaki disease (KD) is the finding that
up to one third of patients with KD have confirmed intercurrent illnesses.51-53 Additionally,
patients with KD frequently present with nonspecific symptoms. Thus,
the examining physician should not discount the possibility of KD
in a patient with nonspecific complaints if stigmata of this disease
are present. Furthermore, any child with unexplained fevers for
5 or more days should be evaluated for KD.
+++
Diagnostic Evaluation
++
Laboratory studies in patients with Kawasaki disease (KD) may
demonstrate leukocytosis, anemia, and, in the later stages of the
acute phase, a pronounced thrombocytosis with platelet counts from 500,000
to 1,000,000/mm. Thrombocytopenia in the early phase of Kawasaki
disease may be a sign of consumption or evidence of an activated
endothelium with platelet adherence, and has been identified as
a poor prognostic factor.14 Inflammatory markers are nearly always
elevated in KD, with the erythrocyte sedimentation rate usually
greater than or equal to 40 mm/hour and the C-reactive
protein usually greater than or equal to 3.0 mg/dL. Elevation
of the erythrocyte sedimentation rate may lag behind that of C-reactive protein,
so both should be measured. Further supportive laboratory findings
are listed in Table 488-1, include transaminitis,
hyperbilirubinemia, elevated plasma gamma-glutamyl transpeptidase, hypoalbuminemia,
and sterile pyuria (Table 488-1).
++
Electrocardiography in patients with Kawasaki disease may reveal sinus
tachycardia, prolongation of the PR and QT intervals, or nonspecific
ST and T wave changes. Plain radiographs of the chest tend to be
unrevealing, although rare children have pulmonary infiltrates or
effusions.
++
Echocardiography is the cornerstone of diagnosis of coronary
artery abnormalities in children with KD. Taken together with Doppler imaging,
echocardiographic imaging is also used to assess mitral and, more
rarely, aortic regurgitation, left ventricular function, and pericardial
effusion. At the time of presentation, within 10 days of illness,
children with KD have enlarged coronary artery dimensions, adjusted
for body surface area, compared to afebrile normal children. Coronary
artery dimensions are generally described in terms of their absolute
diameter, as well as in standard deviation units (z scores)
adjusted for body surface area. In addition to coronary artery enlargement,
arterial walls may appear bright, and the arteries may not taper
normally. Abnormalities on echocardiography form an important criterion
for intravenous immunoglobulin treatment of children with suspected
Kawasaki disease with incomplete criteria (Fig.
488-1). Echocardiography should be performed at the time of
diagnosis, at 2 weeks, and then approximately 6 to 8 weeks after
illness onset.2 Children with documented coronary artery
abnormalities or persistent fever may require more frequent imaging.
++
Once the diagnosis of Kawasaki disease (KD) has been established, intravenous
immunoglobulin (IVIG) should be administered at a dose of 2 g per
kilogram over 8 to 12 hours.54,55 Treatment with IVIG should
be instituted no later than day 10, and ideally by day 7 of illness;
the first day of fever in KD is considered day 1. Administration
of IVIG beyond day 10 of illness should be reserved for children
with persistent fever or those with coronary artery lesions and
evidence of ongoing systemic inflammation on laboratory testing.
++
Aspirin was the first agent to be used in the treatment of KD,
and subsequent studies evaluating the efficacy of IVIG and other
treatments have included aspirin in the treatment regimen.54,55 However,
the use of aspirin alone does not decrease the frequency of coronary
artery lesions.56,57 The American Heart Association/American
Academy of Pediatrics statement on treatment of KD recommends aspirin
in high doses for its anti-inflammatory effects (80–100
milligrams per kilogram per day divided into 4 doses) followed by
low-dose aspirin (3–5 milligrams per kilogram per day)
for antiplatelet effects. High dose aspirin is continued until the
child has been afebrile for 48 hours, although some centers continue high-dose
aspirin until the child is beyond 14 days of illness, and afebrile
for 48 hours. There is practice variation among experts in the field
with respect to the duration of high-dose aspirin use. Most commonly,
low-dose aspirin is instituted after the patient has been afebrile
for 48 hours, but some centers continue high-dose aspirin until
the child is both afebrile and beyond day 14 of illness, whichever
is longer. Most children with KD are maintained on low-dose aspirin
therapy until 6 to 8 weeks after illness onset, at which point aspirin
therapy may be discontinued if the child’s echocardiogram is
normal. Patients with coronary artery abnormalities on follow-up echocardiogram
may be maintained on low-dose aspirin indefinitely, and annual influenza vaccinations
are recommended in such patients. Reye syndrome has been reported
in patients who received high-dose aspirin therapy for KD;58,59 the
risks conferred by daily low-dose aspirin as chronic therapy are uncertain.
Aspirin should be temporarily discontinued in children who have
been exposed to varicella or influenza; other antiplatelet agents,
such as clopidogrel, can be used in children with coronary lesions. Lastly,
administration of measles and varicella immunizations should be
delayed for 11 months after IVIG treatment, which may render the
vaccines less immunogenic.
++
Approximately 15% of KD patients have persistent or
recrudescent fever after a single dose of intravenous immunoglobulin (IVIG)
(so-called IVIG resistance) and are candidates for secondary therapy.16,60-66 The
subset of patients with IVIG resistance is at increased risk for developing
coronary abnormalities.60,64 Although specific recommendations
for patients with persistent or recrudescent fever after 1 dose
of IVIG are hampered by lack of prospective trials, additional IVIG,
at a dose of 2 g/kg, is generally administered. Other treatments
include intravenous methylprednisolone, oral corticosteroids, cyclophosphamide,
cyclosporine, methotrexate, and plasma exchange.66-72 Recently,
infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α,
has been used increasingly in the IVIG-resistant population and
is reported to shorten fever duration;73-76 delineation
of its efficacy in reducing the prevalence of coronary aneurysms
awaits further study.
++
Virtually all serious morbidity and mortality derive from the
cardiac effects of Kawasaki disease (KD). The most important complication
of KD is coronary artery aneurysms, which may lead to myocardial
ischemia, infarction, and sudden death. Prior to the development
of an effective treatment for Kawasaki disease, 20% to
25% of affected children developed coronary artery aneurysms,
with a 2% mortality rate.2 Fortunately, a regimen
of intravenous immunoglobulin and aspirin reduces the rate of coronary
lesions to less than 5%, with only 1% of children
developing giant aneurysms.54,55 The mortality rate in
recent studies is less than 0.5%.77,78
++
Coronary artery dimensions are generally described in terms of their
absolute diameter, as well as in standard deviation units (z scores)
adjusted for body surface area. The widely used Japanese
Ministry of Health criteria for coronary artery aneurysms include
any of the following: an internal lumen diameter of greater than
3 mm in children less than 5 years of age or greater than 4 mm in
children 5 years of age or older, an internal lumen diameter that
is greater than or equal to 1.5 times that of an adjacent segment,
or a coronary lumen that is clearly irregular. Coronary artery dimensions
are related to body size, and use of z scores has
demonstrated that the Japanese Ministry of Health criteria underestimate
the prevalence of coronary artery dilation in Kawasaki disease patients.79 Presently, z scores
are available only for the left main coronary artery, the left anterior
descending coronary artery, and the right coronary artery. Classification
of coronary artery aneurysms of the left circumflex, distal right
coronary, distal left anterior descending, and the posterior descending
arteries continue to rely on Japanese Ministry of Health criteria.
When using absolute dimensions, aneurysms may be classified as small
(less than 5 mm internal diameter), medium (5–8 mm internal
diameter), and giant (greater than 8 mm internal diameter).
++
Coronary aneurysms created by the intense inflammatory process in
the acute phase of Kawasaki disease evolve in their shape and dimension
over years after illness onset. Coronary aneurysms are created by
the intense inflammatory process in the acute phase of Kawasaki
disease. Classification of coronary artery aneurysms of the left
circumflex, distal right coronary, distal left anterior descending,
and the posterior descending arteries continue to rely on Japanese
Ministry of Health criteria which may underestimate the prevalence
of coronary artery dilation.79 When using absolute
dimensions, aneurysms may be classified as small (less than 5 mm
internal diameter), medium (5–8 mm internal diameter),
and giant (greater than 8 mm internal diameter). Regression to normal
lumen diameter occurs via myointimal proliferation in approximately
half of coronary artery aneurysms;80 regression is most
likely in patients with aneurysms less than 8 mm in internal diameter
and with a fusiform morphology, in distal vessels, and in young
children. Stenotic lesions, usually occurring at the proximal and
distal ends of aneurysms, form in the chronic phase and are associated
with myocardial ischemia.81 Rarely, stenotic lesions can
give rise to new aneurysm formation years after disease resolution
secondary to hemodynamic factors such as sheer stress.82 Stenotic
lesions are most likely to occur at the points of entrance to or exit
from giant aneurysms; patients with small aneurysms are at much
lower risk to develop stenosis.83
++
Myocardial infarction occurs most frequently in children with
giant aneurysms.84,85 The combination of sluggish blood
flow through an enlarged lumen, enhanced platelet activation due
to shear stress at the proximal and distal sites of the aneurysm, and
marked thrombocytosis significantly increase the risk for thrombus
formation in the subacute phase. Although the relative risk of myocardial
infarctions is highest in the first year,86 deaths from
myocardial infarction continue to occur late after the onset of
illness.86-88 Myocardial infarctions may be accompanied
by symptoms of pallor, crying, vomiting, and abdominal pain. Children
older than 4 years may complain of chest pain. Of note, myocardial
infarctions are silent in more than one third of patients with Kawasaki
disease. Rupture of coronary aneurysms is a very rare complication
occurring in rapidly expanding, inflamed coronary arteries, usually
within the first 6 weeks of illness.89
++
KD affects not only the coronary arteries, but also cardiac muscle
and heart valves. Children with KD may have depressed left ventricular function
by echocardiography in the acute phase of the disease,90,91 and
cardiac biopsies92-94 as well as nuclear imaging studies95,96 have
shown that myocarditis is extremely common. Indeed, myocarditis
and arrhythmias are the leading causes of death in the first week
of Kawasaki disease, and children with acute Kawasaki disease occasionally
present in cardiogenic shock.2 Mitral regurgitation secondary
to valvulitis occurs in approximately 1 in 4 children during the
acute phase;91 late mitral regurgitation results from papillary
muscle dysfunction in children with ischemic heart disease.86 Aortic
root dilation97 and mild aortic regurgitation91,97,98 occur
in KD but are usually not progressive.
++
KD may produce long-term systemic abnormalities, including diminished
reactivity and greater stiffness of the peripheral arteries;99 increased
intimal medial thickness of the carotid arteries;100 and
dyslipidemia.101,102 These findings are most pronounced
in patients with coronary aneurysms. An unfavorable lipid profile
is found, however, even among patients in whom coronary involvement
has not detected in any stage of illness.101,102 Data are
conflicting on the long-term effects of acute KD on arterial health
among patients who never had coronary involvement. Some studies
report endothelial dysfunction in these patients,99,100,103 whereas
others found normal arterial reactivity and no evidence of arterial
stiffness.104,105 Lastly, 2 studies have shown that myocardial
flow reserve is altered in patients with Kawasaki disease regardless
of coronary artery status.106,107
++
The prognosis for children with Kawasaki disease (KD) is determined
by the extent of coronary artery involvement and consequent risk
of myocardial ischemia.2 For this reason, recommendations for
frequency of follow-up and types of testing, exercise, and medications
for children after KD are stratified according to their coronary
artery status (eTable 488.2).2 Because
even patients who never had coronary abnormalities may be at higher
risk for later atherosclerotic coronary artery disease, preventive
cardiology assessment and counseling is of paramount importance. All children should have a lipid profile
1 year after KD onset. In addition, children and their families should
be encouraged to follow a heart-healthy diet, exercise regularly,
and avoid smoking.108
++