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Kawasaki
disease is a vasculitis, sometimes involving the coronary
arteries, that tends to occur in infants and children between ages
1 and 8 yr. It is characterized by prolonged fever, exanthem,
conjunctivitis, mucous membrane inflammation, and lymphadenopathy.
Coronary artery aneurysms may develop and rupture or cause MI.
Diagnosis is by clinical criteria; once the disease is diagnosed,
echocardiography is performed. Treatment is aspirin and IV immune
globulin. Coronary thrombosis may require fibrinolysis or
percutaneous interventions.
Kawasaki
disease (KD) is a vasculitis of medium-sized arteries, most
significantly the coronary arteries, which are involved in about
20% of untreated patients. Early manifestations include acute
myocarditis with heart failure, arrhythmias, endocarditis, and
pericarditis. Coronary artery aneurysms may subsequently form.
Giant coronary artery aneurysms (>
8 mm internal diameter on echocardiogram), though rare, have the
greatest risk of producing cardiac tamponade, thrombosis, or
infarction. KD is the leading cause of acquired heart disease in
children. Extravascular tissue may also become inflamed, including
the upper respiratory tract, pancreas, biliary tract, and kidneys.
The
etiology is unknown, but the epidemiology and clinical
presentation suggest an infection or an abnormal immunologic
response to an infection in genetically predisposed children.
Children of Japanese descent have a particularly high incidence,
but KD occurs worldwide. In the US, 3000 to 5000 cases occur
annually. The male:female ratio is about 1.5:1. Eighty percent of
patients are < 5 yr (peak, 18 to 24
mo). Cases in teenagers, adults, and infants <
4 mo are rare. Cases occur year-round, but most often in spring or
winter. Clusters have been reported in communities without clear
evidence of person-to-person spread. About 2% of patients have
recurrences, typically months to years later.
Symptoms
and Signs
The
illness tends to progress in stages, beginning with fever lasting
at least 5 days, usually remittent and >
39° C, associated with irritability,
occasional lethargy, or intermittent colicky abdominal pain.
Usually within a day or two of fever onset, bilateral bulbar
conjunctival injection appears without exudate. Within 5 days, a
polymorphous, erythematous macular rash appears, primarily over
the trunk, often with accentuation in the perineal region. The
rash may be urticarial, morbilliform, erythema multiforme, or
scarlatiniform. It is accompanied by injected pharynx; reddened,
dry, fissured lips; and a red strawberry tongue. During the 1st
week, pallor of the proximal portion of the fingernails or
toenails (leukonychia partialis) may occur. Erythema or a
purple-red discoloration and variable edema of the palms and soles
usually appear on about the 3rd to 5th day. Although edema may be
slight, it is often tense, hard, and nonpitting. Periungual,
palmar, and plantar and perineal desquamation begins on about the
10th day. The superficial layer of the skin sometimes comes off in
large casts, revealing new normal skin. Tender, nonsuppurative
cervical lymphadenopathy (≥ 1
node, ≥ 1.5 cm in size) is
present throughout the course in about 50% of patients. The
illness may last from 2 to 12 wk or longer. Incomplete or atypical
cases can occur, especially in younger infants, who have higher
risk of developing coronary artery disease. These findings
manifest in about 90% of patients.
Other
less specific findings indicate involvement of many systems.
Arthritis or arthralgias (mainly involving large joints) occur in
about 1⁄3 of patients. Other clinical
features include urethritis, aseptic meningitis, hepatitis, otitis,
vomiting, diarrhea, hydrops of the gallbladder, and anterior
uveitis.
Cardiac
manifestations usually begin in the subacute phase of the syndrome
about 1 to 4 wk after onset, as the rash, fever, and other early
acute clinical symptoms begin to subside.
Diagnosis
Diagnosis
is by clinical criteria (see Table 3: Miscellaneous
Disorders in Infants and Children: Criteria for Diagnosis of
Kawasaki Disease). Similar symptoms can result from scarlet
fever, staphylococcal exfoliative syndromes, measles, drug
reactions, and juvenile RA; less common mimics are leptospirosis
and Rocky Mountain spotted fever.
Laboratory
tests are not diagnostic but may be obtained to exclude other
disorders. Patients generally undergo CBC, antinuclear antibody
(ANA), rheumatoid factor (RF), ESR, and throat and blood culture.
Leukocytosis, often with a marked increase in immature cells, is
common acutely. Other hematologic findings include a mild
normocytic anemia, thrombocytosis (≥
450,000/μL) in the 2nd or 3rd wk
of illness, and elevated ESR or C-reactive protein. ANA, RF, and
cultures are negative. Other abnormalities, depending on the organ
systems involved, include sterile pyuria, elevated liver enzymes,
proteinuria, and CSF pleocytosis.
Consultation
with a pediatric cardiologist is important. At diagnosis, ECG and
echocardiography are performed; because abnormalities may not
appear until later, these tests are repeated at 2 to 3 wk, 6 to 8
wk, and perhaps at 6 to 12 mo after onset. ECG may show
arrhythmias, decreased voltage, or left ventricular hypertrophy.
Echocardiography should detect coronary artery aneurysms, valvular
regurgitation, pericarditis, or myocarditis. Coronary
arteriography is occasionally useful in patients with aneurysms
and abnormal stress testing.
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Table
3
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Criteria
for Diagnosis of Kawasaki Disease
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Diagnosis
is made if fever of ≥
5 days has occurred and 4 of the following 5
criteria are noted:
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1.
Bilateral nonexudative conjunctival injection
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2.
Changes in the lips, tongue, or oral mucosa
(injection, drying, fissuring, red strawberry
tongue)
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3.
Changes in the peripheral extremities (edema,
erythema, desquamation)
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4.
Polymorphous truncal exanthem
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5.
Cervical lymphadenopathy (at least one node ≥
1.5 cm in diameter)
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Prognosis
Without
therapy, mortality may approach 1%, usually occurring within 6 wk
of onset. The mortality rate is <
0.01% in the US with adequate therapy. Long duration of fever
increases cardiac risk. Deaths most commonly result from cardiac
complications and can be sudden and unpredictable: >
50% occur within 1 mo of onset, 75% within 2 mo, and 95% within 6
mo but may occur as long as 10 yr later. Effective therapy reduces
acute symptoms and, more importantly, the incidence of coronary
artery aneurysms from 20% to < 5%.
In the absence of coronary artery disease, the prognosis for
complete recovery is excellent. About 2⁄3
of coronary aneurysms regress within 1 yr, although it is unknown
whether residual coronary stenosis remains. Giant coronary
aneurysms are less likely to regress and require more intensive
follow-up and therapy.
Treatment
Children
should be treated by or in close consultation with an experienced
pediatric cardiologist and/or pediatric infectious disease
specialist. Therapy is started as soon as possible, optimally
within the 1st 10 days of illness, with a combination of high-dose
immune globulin IV (IGIV), a single dose of 2 g/kg given over
10 to 12 h, and oral high-dose aspirin, 20 to 25 mg/kg po qid. The
aspirin dose is reduced to 3 to 5 mg/kg once/day after the child
has been afebrile for 4 to 5 days; some authorities prefer to
continue high-dose aspirin until the 14th day of illness. Aspirin
metabolism is erratic during acute KD, which partially explains
the high dose requirements. Some authorities monitor serum aspirin
levels during high-dose therapy, especially if therapy is given
for 14 days.
Most
patients have a brisk response over the 1st 24 h of therapy. A
small fraction continues to be ill with fever for several days and
requires repeated dosing with IGIV. An alternative regimen, which
may lead to slightly slower resolution of symptoms but may benefit
those with cardiac dysfunction who could not tolerate the volume
of a 2 g/kg IGIV infusion, is IGIV 400 mg/kg once/day for 4 days
(again in combination with high-dose aspirin). The efficacy of
IGIV/aspirin therapy when begun >
10 days after onset of illness is unknown, but therapy should
still be considered.
After
the child has improved for 4 to 5 days, aspirin 3 to 5 mg/kg/day
is continued for at least 8 wk after onset until repeated
echocardiographic testing is completed. If there are no coronary
artery aneurysms and signs of inflammation are absent
(demonstrated by normalization of ESR and platelets), aspirin may
be stopped. Because of its antithrombotic effect, aspirin is
continued indefinitely for children with coronary artery
abnormalities. Children with giant coronary aneurysms may require
additional anticoagulant therapy - eg, warfarin, dipyridamole
Children
who receive IGIV therapy may have a lower response rate to live
viral vaccines. Thus, measles-mumps-rubella vaccine should
generally be delayed for 11 mo after IGIV administration, and
varicella vaccine should be delayed for ≥
11 mo. If the risk of measles exposure is high, vaccination should
proceed, but revaccination (or serologic testing) should be
performed 11 mo later.
A
small risk of Reye's syndrome exists in children receiving
long-term aspirin during outbreaks of influenza or varicella;
thus, annual influenza vaccination is indicated for children (≥
6 mo of age) receiving long-term aspirin therapy. Further, parents
of children receiving aspirin should be instructed to contact
their child's physician promptly if the child is exposed to or
develops symptoms of influenza or varicella. Temporary
interruption of aspirin may be considered (with substitution of dipyridamole
(PERSANTINE)for children with documented aneurysms).
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