Download Kawasaki disease

Kawasaki disease
Author: Doctor Alfred Mahr1
Creation date: June 2001
Update: June 2004
Scientific Editor: Professor Loïc Guillevin
1
Service de médecine interne, CHU Hôpital Cochin, 27 Rue du Faubourg Saint-Jacques, 75014 Paris
France. [email protected].
Abstract
Key words
Disease name and synonyms
Excluded diseases
Diagnostic criteria/definition
Differential diagnosis
Epidemiology
Clinical description
Management including treatment
Etiology
Diagnostic methods
Unresolved questions
References
Abstract
Mucocutaneous lymph node syndrome, or Kawasaki disease (KD), is an infantile vasculitis of mediumand small-sized arteries. It is a disorder affecting predominantly children younger than 4 years and more
frequently subjects of Asian origin. KD is an acute illness characterized by high fever, conjunctivitis, oral
mucosal changes, cheilitis, cervical lymph nodes, rash, and reddening of the palms and soles with
subsequent desquamation. The disease generally resolves spontaneously within several days. However,
approximately 20% of all untreated patients develop coronary aneurysms that are potentially lifethreatening. As there is no specific laboratory test, KD is diagnosed based on clinical criteria and,
possibly, on the detection of coronary aneurysms by echocardiography or by coronary angiography.
Treatment of KD combines a single course of intravenous immunoglobulins and aspirin. Instituted during
the acute phase of the illness, this treatment reduces the frequency of coronary artery-lesions to less than
5%. Some patients unresponsive to this treatment may receive Infliximab as alternative therapy. The
etiology of KD remains unknown but might be infectious. Nevertheless, no specific agent has yet been
recognized.
Key words
Kawasaki disease, Kawasaki syndrome, mucocutaneous lymph node syndrome, vasculitis, coronary
aneurysms, acquired ischemic heart disease of childhood
Disease name and synonyms
Kawasaki disease (KD), Kawasaki syndrome,
mucocutaneous lymph node syndrome
Excluded diseases
Infantile polyarteritis nodosa
Diagnostic criteria/definition
Diagnostic guidelines for KD were established by
the Japanese Kawasaki Disease Research
Committee [1]. Accordingly, the diagnosis of KD
Mahr A. Kawasaki disease. Orphanet Encyclopedia, June 2004:
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can be retained in the presence of fever lasting
for more than 5 days in association with 4 of the
following 5 criteria:
1)
polymorphous rash;
2)
bilateral nonexudative conjunctivitis;
3)
changes of the oral mucosa (cheilitis
and/or "strawberry" tongue and/or pharyngitis);
4)
non-purulent cervical lymphadenopathy
(at least 1.5 cm);
5)
changes of the hands and feet
(erythema on the palms or soles and/or
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indurative edema and/or desquamation from the
fingertips).
When coronary abnormalities are present, KD
can be diagnosed in patients with fever and only
3 of the other diagnostic criteria. However,
because these diagnostic guidelines are not
entirely specific to KD, other diseases with
similar symptoms have previously to be
excluded. A small subset of children present with
"atypical" or "incomplete" KD, as defined by the
presence of fever and fewer than 4 of the other
features. Atypical cases are more difficult to
recognize and, unfortunately, at greatest risk for
coronary disease [2-4].
Differential diagnosis
The differential diagnosis of KD encompasses a
multitude of diseases including bacterial
infections (toxic shock syndrome, staphylococcal
scalded
skin
syndrome,
scarlet
fever,
rickettsiosis,
leptospirosis,
yersinia),
viral
exanthema (measles, adenovirus, Epstein-Barr
virus, cytomegalovirus, parvovirus, retrovirus),
drug-induced skin reaction (Stevens - Johnson
syndrome), connective tissue disease (systemic
onset juvenile rheumatoid arthritis, Reiter's
syndrome) or other vasculitides (infantile
polyarteritis nodosa) [2-5].
Epidemiology
Since the initial description in 1967 by the
Japanese pediatrician T. Kawasaki [6], more
than 170,000 children have been diagnosed with
KD in Japan. Recently, series from European
countries such as the UK and Italy have been
published [23]. In 80%, the affected individuals
are 4 years old with a peak incidence between 6
months and 2 years [2-4]. KD is uncommon
before 3 months and in children over 4 years,
even if it has also been observed occasionally in
children older than 10 years [7] or in young
adults [8]. Although described in subjects of all
ethnic origins, the incidence of KD is highest in
Asians or individuals of Asian ancestry. In
Japan, the estimated incidence rate exceeds
1,000/1,000,000 under 5 years old [9]. In the
United States, an annual incidence of up to
150/1,000,000 children under 5 years old has
been reported, with the highest incidence among
Asian Americans (333/1,000,000) followed by
black (234/1,000,000) and white Americans
(127/1,000,000) [10]. The incidence in Europe is
compatible to that in USA. Occurrence in siblings
is rare, at approximately 2% [11]. KD epidemics
have been recorded in many countries with, in
particular, 3 large-scale outbreaks in Japan in
1979, 1982 and 1986. KD recurrences are
uncommon, occurring in only about 1-3% of the
patients [3]. KD is more common in males, with a
M:F ratio of 1.5:1. Seasonal variation in the
Mahr A. Kawasaki disease. Orphanet Encyclopedia, June 2004:
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disease incidence has been reported, with peak
occurrence in the spring and winter months.
Clinical description
Clinical presentation. KD is an acute-onset
illness characterized by high fever with
mucocutaneous changes and adenitis. Fever is
a constant feature of KD and generally the first
symptom of the disease; it ranges between 38°
and 40°C and frequently has irregular spikes; it
is often abrupt in onset and unresponsive to
antibiotic therapy. Mucocutaneous changes are
seen in approximately 90% of the patients and
they coincide with the onset of fever or within the
hours or days thereafter. The mucosal signs
variably include intense bilateral non-exudative
conjunctivitis predominantly involving the bulbar
conjunctivae; cheilitis with crusting, bleeding lips;
"strawberry" tongue; or diffuse erythema of the
oropharynx. The skin involvement includes a
rash, and changes of the hands and feet
associating a clearly delimited erythema of the
palms and soles, whereas the dorsa of the
hands and feet and the fingers and toes become
swollen and indurated. The rash has a
remarkably polymorphous presentation and can
be morbilliform, scarlatiniform or multiform. It is
widespread over the body, affecting the face, the
trunk and limbs. However, in some cases, and
especially in infants and young children, the rash
may preferentially involve the perineal area.
Lymphadenitis is less frequent, occurring in
approximately 50 - 60% of the patients. Most
frequently, the adenitis presents as a large, firm,
unilateral lymph node of the cervical or
submandibular area; in some cases, it may
become the most prominent feature of the
disease
[2-4,
12].
Associated manifestations. In addition to the
previously cited major signs, many other
features have been observed in association with
KD: aseptic meningitis, vomiting, diarrhea, gall
bladder hydrops, sterile pyuria, hepatitis,
arthralgia or arthritis, and/or uveitis [2-4, 12].
Irritability (out of proportion to the degree of fever
or other signs) is present in the majority of
children with KD that can be related to aseptic
meningitis.
Disease course
KD has a typically triphasic course.
The acute phase is self-limited with the fever and
the other acute signs of inflammation subsiding
spontaneously after 1 - 2 weeks.
The following subacute phase lasts 1-2 weeks
and is characterized by the desquamation of the
hand and feet with peeling starting at the tips of
the fingers and toes and subsequently involving
the entire hands and feet. The conjunctivitis may
persist during this phase.
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The convalescent phase starts when all clinical
signs have resolved and end when the
laboratory abnormalities have returned to
normal, usually 4 - 6 weeks after disease onset.
Beau's lines, corresponding to transverse
grooves of the fingernails, may develop 1 - 2
months after KD onset [2-4, 12].
Cardiovascular complications
Initially described as a harmless disease [6], it
rapidly became evident that KD was fatal for 12% of the affected individuals with death most
commonly attributed to ischemic heart disease
[12]. KD was subsequently recognized as a
systemic vasculitis of small- and medium-sized
arteries with a marked predilection for the
coronary arteries [13]. During the acute phase of
the disease, the spectrum of cardiovascular
manifestations comprises myocarditis, valvulitis,
pericarditis or arrhythmia. However, cardiac
involvement during this stage is most commonly
asymptomatic but rarely is manifested by
congestive heart failure. The most characteristic
feature of cardiovascular involvement in KD is
the formation of coronary aneurysms that may
occur during the subacute phase of the disease
and thus when the acute clinical symptoms have
already subsided.
Aneurysms develop in approximately 20% of
untreated patients [14]. Angiographic studies
showed that the aneurysms, which are
principally located in the proximal portions of the
coronary arteries, are commonly associated with
other abnormalities, such as vessel dilatation,
stenosis or thrombosis. The most severe
coronary lesions are giant aneurysms, which are
defined by an internal lumen of more than 8 mm
[15].
More
rarely,
aneurysms
involve
extracoronary arteries, and approximately 2% of
the patients present with aneurysms in the
axillary, iliac, renal and/or intermammarian
arteries [14]. The coronary artery disease may
lead to fatal myocardial infarction or rupture of
an aneurysm, with most of the deaths occurring
within the first 2 months following disease onset
[14]. Peripheral ischemia is a rare but severe
complication of KD that leads either to death or
gangrene [16]. It is unclear what factors account
for the occurrence of severe cardiovascular
disease in some patients. Male gender, age of
less than 1 year at disease onset, prolonged
fever duration and highly elevated laboratory
markers of inflammation have been cited as
predictors of the occurrence of coronary
aneurysms [2-4].
Management including treatment
The current standard of treatment of KD
combines
high-dose
intravenous
immunoglobulins (IVIG) and aspirin administered
Mahr A. Kawasaki disease. Orphanet Encyclopedia, June 2004:
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within the first 10 days of disease onset [2-4, 17].
It has been demonstrated in several therapeutic
studies that, compared to aspirin alone, this
treatment shortens the duration of the acute
signs of the disease and reduces the occurrence
of coronary aneurysms and the frequency of
long-term coronary abnormalities [18, 19].
Among the various protocols that have been
tried, a single, high dose of IVIG (2 g/kg)
appeared to be the most efficacious regimen
[20]. Aspirin was the first medication widely used
to treat KD. Although it has never been proven
that this drug has a preventive effect on the
coronary abnormalities, it continues to be given
for its anti-inflammatory and anti-thrombotic
properties.
Most
commonly,
aspirin
is
administered at an anti-inflammatory dose (80100 mg/kg/d in four divided doses) until the fever
subsides and is subsequently reduced to an antiplatelet aggregation dose (3 - 10 mg/kg/d) until
being discontinued by 6 weeks after disease
onset unless coronary abnormalities persist [24]. Thus, the efficacy of the standard treatment
with IVIG and aspirin has only been studied for
administration within the first 10 days of illness
and, although the precise mechanism of this
therapy remains unknown, it is unlikely that it
may still be beneficial when the inflammatory
response has already subsided [3, 17].
With regard to the atypical presentation in some
patients and the importance of early initiation of
therapy, this combined treatment should be
given to all patients for whom a high index of
suspicion exists and other diagnoses have been
reasonably excluded [2-4]. In about 10% of the
patients, the fever persists or recurs after the
completion of the initial therapy with IVIG and
aspirin. The management of these patients is not
well defined, but most authors have
recommended treating again with 1 g/kg of IVIG
[17]. Steroids have been abandoned for the
treatment of KD since it was advanced that they
would favor the formation of coronary aneurysms
[21]. More recently, however, the use of steroids
has been reconsidered in selected patients, e.g.
for patients with IVIG-refractory disease [22].
Other medications include anticoagulants that
should be given to patients with giant coronary
aneurysms. Inotropic agents may be required for
congestive heart failure. The long-term follow-up
of children with KD mainly depends on the
presence or not of persistent coronary
aneurysms beyond the convalescent phase.
Small- to medium-sized aneurysms may
completely regress within 1-2 years, whereas
giant aneurysms generally do not resolve or
progress to stenotic lesions and may ultimately
necessitate
percutaneous
or
surgical
angioplasty. In developed countries, KD has
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become the major cause of acquired heart
disease of childhood [2-4].
Recently, a patient unresponsive to treatment
with IVIG and high dose aspirin was treated with
infliximab. After the first dose, reduction of fever
was observed and his laboratory measures
improved [24].
Etiology
Despite intense investigation, the etiology of KD
remains unknown. The young age at onset, the
clinical presentation and the occurrence of
outbreaks would point to an infectious, and, in
particular, a viral origin. However, none of the
various viruses (parvovirus B19, Epstein - Barr
virus, human herpesvirus 6 or other
Herpesviruses, retrovirus, measles virus) that
have been incriminated as potential causative
agents could be clearly correlated to KD. Toxinproducing bacteria were implicated because of
clinical similarities with the toxic shock syndrome
and because of immunological evidence that
would suggest an underlying superantigenmediated
mechanism.
However,
further
investigation provided conflicting results, and
could not confirm the immunological findings or
the relationship between staphylococcal or
streptococcal infection and KD. An interesting
hypothesis refers to the role of IgA plasma cells:
these have been found in the vascular walls of
KD patients, and an oligoclonal pattern has been
demonstrated, consistent with an antigen-driven
immune response [25]. Pro-inflammatory
cytokines have been shown to play a role in the
disease pathogenesis, and a recent study has
provided preliminary evidence for an increased
frequency of alleles associated with elevated
TNF- levels [26]. Autoantibodies in KD have
not been found consistently except antiendothelial cell antibodies (AECA) [27]. A
genetic factor conferring susceptibility to KD
would be supported by the higher incidence in
children of Asian ancestry but no particular
human leukocyte antigen phenotype (HLA) could
be
identified.
Furthermore,
different
environmental risk factors have been identified in
affected children such as a significantly higher
exposure to carpet cleaning and proximity to
septic water, but the significance of these results
remains unknown [2-4].
Diagnostic methods
No specific test is available to diagnose KD.
Laboratory findings mainly reflect an intense
immune response with leukocytosis, highly
elevated erythrocyte sedimentation rate and Creactive protein level, and thrombocytosis. A
mild elevation of liver enzymes and sterile pyuria
are also commonly observed [2-4]. An
interesting finding, possibly related to a cross
Mahr A. Kawasaki disease. Orphanet Encyclopedia, June 2004:
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reactivity of T cells between epitopes of
mycobacterial and human heat shock proteins, is
the development of erythema and induration at
sites of BCG immunization [23] Two-dimensional
echocardiography may show coronary artery
aneurysms which are a highly suggestive but
delayed finding as they generally become visible
only during the subacute phase of the illness.
During the acute phase, echocardiography may
detect coronary dilatation, pericardial effusion,
mitral insufficiency and/or left ventricular
insufficiency. Because of the high sensitivity of
two-dimensional echocardiography in detecting
proximal coronary aneurysms [2], coronary
angiography is generally reserved for patients
with large or multiple aneurysms on
echocardiograms, in order to fully investigate the
extent of the coronary involvement [4].
Consequently, the diagnosis of KD relies, for the
most part, on clinical criteria and, in particular,
on the major features that have been outlined by
the Japanese Kawasaki Disease Research
Committee [1]. However, with regard to the
existence of atypical presentations, the
diagnosis should be considered in all children
with an undiagnosed febrile illness presenting
with any of the diagnostic criteria of KD [2, 4].
Unresolved questions
The long-term consequences of KD are a matter
of debate. The results of several studies tend to
support that arteries with resolved aneurysms
remain functionally impaired, but it is unclear if
these abnormalities predispose to accelerated
atherosclerosis. Further investigation should also
be undertaken to define the optimal
management
of
immunoglobulin-refractory
disease. Finally, the development of a diagnostic
test and a specific treatment awaits the
discovery of the etiological agent of KD.
References
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Committee: Diagnostic guidelines of Kawasaki
disease, 4th edition, 1984.
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al. Increased frequency of alleles associated
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