CONTINUING MEDICAL EDUCATION
Kawasaki disease
Part I. Diagnosis, clinical features, and pathogenesis
Stephanie Bayers, BSBA, a Stanford T. Shulman, MD,c and Amy S. Paller,
MDa,b
Chicago, Illinois
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Date of release: October 2013
Expiration date: October 2016
© 2013 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2013.07.002
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501.e1
501.e2 Bayers, Shulman, and Paller J AM ACAD DERMATOL
OCTOBER 2013

Kawasaki disease, or mucocutaneous lymph node syndrome, most commonly affects children between
6 months and 5 years of age. Approximately 90% of patients have mucocutaneous manifestations.
This article will focus on the epidemiology of Kawasaki disease in the United States as it relates to
other countries, the diagnosis of Kawasaki disease, its clinical course, and the currently accepted
theories of pathogenesis. A particular focus is given to the various dermatologic manifestations that
may occur. ( J Am Acad Dermatol 2013;69:501.e1e11.)

Key words: diagnosis; epidemiology; Kawasaki disease; mucocutaneous lymph node

syndrome; pathogenesis; pediatric; vasculitis.

Kawasaki disease (KD), incidence has remained

first described by Tomisaku CAPSULE SUMMARY steady in the United States
Kawasaki in 1967, is an for the past 20 years, it
acute systemic vasculitis of d
Polymorphous eruptions, a scarlatiniform has been increasing in most
the small- and medium- groin area dermatitis, erythema and other countries.5,8,11-17 KD
sized arteries.1,2 Also called is most often seen in
muco- cutaneous lymph edema of the hands and feet, oral children be- tween 6
node syn- drome, mucosa changes, conjunctival injection, months and 5 years of age,
approximately 90% of and cervical lymphadenopathy are key regardless of ethnic- ity,
patients have mucocuta- mucocutaneous signs of Kawasaki although the peak inci-
neous manifestations, lead- dence is about 6 months
ing to an important role in disease. of age in Japan versus 13
early diagnosis by d
Nail changes, alopecia, peripheral to 24 months of age in the
dermatol- ogists.3 As such, gangrene, psoriasiform lesions, and skin United States.9,18,19
practicing dermatologists changes at the site of bacillus Nevertheless, neonates,
must be fa- miliar with the older children, and adults
signs, symp- toms, and CalmetteeGuérin vaccination are other with KD have been
ramifications of KD, potential cutaneous manifestations. described.20-27 The male to
especially because early female ratio of KD is 1.5:1,
diagnosis and intervention d
The underlying molecular basis remains and the disease tends to
is critical to the prevention unclear, but the pathogenesis appears to occur more often in winter
of cardiovascular morbidity involve infection, immune system and spring in nontropical
and mortality. activation and inflammation, and genetic climates.5,6,8,19,28,29
susceptibility.
EPIDEMIOLOGY
Key points
d The typical age at presentation is 6 months
DIAGNOSIS
Key points
to 5 years of age
d Fever plus 4 other criteria are required for
d The highest incidence of Kawasaki disease is
the diagnosis of classical Kawasaki disease
d Atypical and incomplete forms of Kawasaki
in Asian countries
d In the United States, the incidence of Kawa-
disease do not necessarily meet all of the
diagnostic criteria
saki disease is highest in Asian ethnic groups
d No laboratory result is specific for Kawasaki

KD has been described in all ethnicities, but
worldwide it is most common in Asia, especially
in Japan, China, and Korea.4-8 In the United
States, KD affects 17 to 20.8 per 100,000 children
under 5 years of age, with the highest incidence in
the Hawaiian population and Asian/Pacific
Islanders, followed in descending order by
African Americans, whites, and American Indians
and Alaskan Natives.9-13 While the
disease, but laboratory studies help to rule
out Kawasaki disease and predict the risk of
complications
d The clinical course can be divided into 3
distinct phases
d If possible, it is best to make a diagnosis of
Kawasaki disease within 10 days of the onset
of illness

From the Department of Dermatologya and the Division of
Dermatology, Department of Pediatricsb; and the Division of
Infectious Diseases, Department of Pediatrics,c Northwestern
University Feinberg School of Medicine, Chicago.
Funding sources: None.
Conflicts of interest: None declared.
Reprints not available from the authors.
Correspondence to: Amy S. Paller, MD, Department of
Dermatology, 676 N St Clair St, Ste 1600, Chicago, IL
60611-2941. E-mail: apaller@northwestern.edu.
0190-9622/$36.00
J AM ACAD DERMATOL
VOLUME 69, NUMBER 4
Abbreviations used:
AHA: American Heart
Association ALT: alanine
aminotransferase BCG: bacillus
CalmetteeGuérin CRP: C-reactive
protein
ESR: erythrocyte sedimentation
rate IVIG: intravenous
immunoglobulin KD: Kawasaki
disease
WBC: white blood cell
The diagnostic criteria for classical KD include
fever for at least 5 days accompanied by at least 4
of 5 criteria, which are largely
mucocutaneous (Table I).30 Concurrence of these
signs is not re- quired for diagnosis. Fever,
occurring in 80% to 90% of patients, is typically
high-grade, does not respond to antipyretic drugs,
and generally lasts 10 to 14 days or longer without
treatment.3,10 In Japan, the diag- nostic guidelines
include fever as a sixth, equal criterion, and
patients must meet 5 of 6 criteria for diagnosis;
the fever may also last \5 days in cases where
early intravenous immunoglobulin (IVIG) is
provided per Japanese criteria.31 The incidence of
each of the diagnostic criteria in adults appears to
be similar to that in children.26 Other common
clinical findings that are not required for
diagnosis are presented in Table II.4,10,32 Children
more frequently develop cheilitis and meningitis;
adults more often have arthralgia and
lymphadenopathy.26 The typical differential
diagnosis includes febrile exanthema, acute
streptococcal and staphylococcal infections, and
drug hypersensitivity reactions.
During the course of KD, laboratory value
alter- ations may occur, although none are specific
for the disease (Table III).3,7,9,30,33 The elevated
white blood cell (WBC) count mainly reflects
neutrophilia with lymphopenia. Thrombocytosis
tends to develop in the second week of the illness,
with resolution after 4 to 8 weeks.9,30,34 The few
patients who are throm- bocytopenic at
presentation are at increased risk of developing
coronary aneurysms.30,35 Eosinophils, on the
other hand, are elevated early and continue to
rise until later in the disease course.33 In untreated
patients, the erythrocyte sedimentation rate (ESR)
and C-reactive protein (CRP) levels usually are
ele- vated at presentation and return to normal in
6 to 10 weeks; if ESR, CRP, and platelet count
normalize after the first week without any
treatment, a diagnosis of KD is unlikely.30
Alternatively, in the IVIG-treated patient, ESR
becomes artificially elevated and loses its
usefulness for determining the disease course; in
these patients, only CRP levels should be moni-
tored.30 Abnormal laboratory values have been
found to correlate with the development of
coronary artery lesions after KD (Table IV).36
Patients with
Bayers, Shulman, and Paller 501.e3
WBCs, neutrophils, and CRP levels that continue
to increase after IVIG therapy also portend a
higher risk for coronary artery complications.37
Incomplete and atypical forms of KD have
been described for patients who do not meet
clinical criteria but have no other diagnosis that
fits their symp- toms.38,39 According to the 2004
American Heart Association (AHA) guidelines, a
patient with at least 5 days of fever, 2 or 3
additional clinical diagnostic criteria, and
abnormal laboratory values typical of KD should
be diagnosed with incomplete KD. 30,34,40 These
patients may be outside the normal age range for
KD; nevertheless, infants younger than 6 months
old often also have incomplete presentations with
transient or subtle signs and symptoms,34,38 and
these infants have a high risk for developing
coronary artery complications.41,42 In very young
infants, prolonged fever may bethe only
manifestation of incomplete KD.
Echocardiography may be useful to verify the
diagno- sis of KD in atypical or incomplete
cases.38 The AHA specifies that the term ‘ atypical’’
should be used for those patients who have a
sign or symptom not typically seen in KD, such as
renal impairment.30
The clinical course for KD has been divided into
3
phases: acute, subacute, and convalescent. The
acute phase lasts from the onset of fever until its
resolution, and without treatment lasts for an
average of 11 days.3,10,43 Once the fever resolves,
the suba- cute phase begins and lasts until all of
the clinical features of KD have resolved, which
typically takes about 2 weeks.3,10,43 Finally, the
convalescent phase starts after the subacute phase
and is considered to be complete once the ESR
and platelet count have normalized,3,10,43 usually 4
to 8 weeks after fever onset.
Cutaneous eruption
A variety of dermatologic findings have been
described, including a polymorphous
erythematous, usually diffuse eruption that may
be macular, scar- latiniform, erythema
multiformeelike, morbilliform, or characterized
by scaling plaques (Figs 1-4).30,43-48
Uncommonly, the eruption presents as an
urticarial exanthem, erythroderma, or rarely a
micropustular eruption,30 but it is almost never
vesicular or bul- lous.10,30 It has been described as
nonpruritic and may or may not be tender. 44,47 In
almost all cases, the eruption occurs on the trunk
and extremities, often with perineal accentuation.
In 1 retrospective re- view, up to 67% of 58
patients with KD developed a perineal rash within
the first week, most often beginning in the diaper
area (Fig 5).44,49,50 The perineal component of the
rash is often scarlatini- form, may or may not be
tender, and desquamates early during the acute
phase of the disease
501.e4 Bayers, Shulman, and Paller J AM ACAD DERMATOL
OCTOBER 2013

Table I. Diagnostic criteria of Kawasaki disease

Clinical feature Percent of patients affected Phase in disease course
Fever for $ 5 days 80-90 Acute
Changes in distal extremities, including erythema and edema of the 80-90 Acute and subacute
hands and feet and periungual desquamation of the fingers and toes
Polymorphous eruption 80-90 Acute
Changes in lips and oral cavity, including erythema of the lips and oral 80-90 Acute
mucosa, fissured lips, strawberry tongue, and diffuse oropharyngeal
mucosal injection
Nonexudative bilateral conjunctival injection (5% are exudative) 80-90 Acute
Cervical lymphadenopathy, usually unilateral 50-60 Acute

Table II. Nonmucocutaneous clinical findings of Table III. Abnormal laboratory values found in
Kawasaki disease4,10,32 Kawasaki disease3,7,9,30,33
Marked irritability Elevated Decreased
Diarrhea Erythrocyte sedimentation rate Albumin
Bile duct inflammation (normalizes in 6-10 weeks)
Hepatitis C-reactive protein (normalizes Hemoglobin
Gall bladder hydrops in 2-5 days with treatment)
Jaundice Alanine aminotransferase Sodium
Pancreatitis Aspartate aminotransferase Potassium
Aseptic meningitis Gamma-glutamyl Total cholesterol
Anterior uveitis transpeptidase
Arthralgias or arthritis White blood cell count High-density lipoprotein
Respiratory symptoms Neutrophil count Lymphocyte count
Otitis media or tympanitis Platelet count ([450,000/mm3
Urethritis or meatitis starting in week 2 of illness;
Facial nerve palsies resolves after 4-8 weeks)
Eosinophil count (elevated in
the acute phase and peaks in
the convalescent phase of
course.3,10,30,51-54 A cutaneous eruption is present
Kawasaki disease)
in 80% to 90% of patients early in the disease
course. Psoriasiform skin lesions may develop
during the acute to convalescent phase of KD.
This association has been postulated to be related desquamation is not helpful in making an early
to proinflammatory cytokine production during diagnosis, given its late onset during the
acute KD that leads to a vigorous T cell subacute phase of disease.
response.66 Of 10 patients described in 1 report, 7
developed typical psoriasiform lesions on the
trunk, knees, and elbows, while 3 developed a Erythema and edema of the hands and feet
pustular eruption on the trunk and extremities.66 Erythema and edema may develop over the
entire hands and feet or just on the palms and
soles and may be painful (Figs 3 and 6).30 The
Periungual desquamation erythema is often well demarcated with a sharp
Periungual desquamation of the fingers distinction from uninvolved skin proximal to
and/or toes, one of the most common the wrist and ankle. Pain may manifest as a
dermatologic find- ings, is seen in the subacute refusal to bear weight or hold objects. These
phase, typically 2 to 3 weeks after the onset of findings occur in the acute phase and thus may
fever.10,30,47,55 It tends to follow erythema and be seen upon initial presentation in 80% to 90%
edema of the hands and/or feet. If severe, of patients.
desquamation may extend to the palms and
soles.30,44 Kawasaki55 identified periungual Conjunctival injection
desqua- mation in 49 of his 50 original patients. Conjunctival injection occurs in 80% to 90% of
The periun- gual desquamation most commonly patients with KD. It is painless, bilateral, and
occurs on both the upper and lower extremities, involves the bulbar conjunctivae more frequently
but in some cases may occur just on the fingers than the palpebral conjunctivae.30,50 The limbic
or toes.55 Periungual region is
J AM ACAD DERMATOL Bayers, Shulman, and Paller 501.e5
VOLUME 69, NUMBER 4

Table IV. Laboratory abnormalities associated with

coronary artery lesions36
Elevated neutrophil count
Elevated platelet count
Elevated platelet distribution width
Elevated mean platelet volume
Elevated erythrocyte sedimentation rate
Elevated cardiac troponin I
Elevated endothelin-1
Low albumin
Low hemoglobin

Fig 3. Erythema multiformeelike lesions on the palms

of a patient with Kawasaki disease.

Fig 1. Scarlatiniform eruption of Kawasaki disease.

Fig 4. Morbilliform eruption in a patient with

Kawasaki disease. Note the dry, fissured lips.

be incorrectly diagnosed, KD does not respond

Fig 2. Erythema multiformeelike eruption on the trunk
of a toddler with Kawasaki disease.
typically spared.30 Conjunctival injection usually
occurs during the acute phase of illness.
Purulence is a more common feature of
adenovirus infection, which is often in the
differential diagnosis of KD.50,56
Lymphadenopathy
Lymphadenopathy, another diagnostic
criterion, occurs in 50% to 60% of patients and
therefore occurs less often than the other
diagnostic signs. It is almost always unilateral
and located in the cervical region. 30,45,46,57 The
lymph node is firm and non- fluctuant, but may
be tender and have some overly- ing erythema.
Although bacterial lymphadenitis may
to antibiotic drugs.10 There may be multiple
lymph nodes; 1 study found a mean of 6
enlarged lymph nodes per patient with the
majority located in the upper jugular, middle
jugular, and posterior triangle regions.19
Bacillus CalmetteeGuérin vaccination site
ftndings
In patients who have received bacillus
CalmetteeGuérin (BCG) vaccination, erythema,
in- duration, and/or crusting at the vaccination site
may occur during the acute phase of KD. Rarely,
the inoculation site may feature necrotic
ulcerations.58 Although uncommon in the United
States, it is important to be aware of this finding
for patients who have lived in a country in which
BCG vaccine is
501.e6 Bayers, Shulman, and Paller
Fig 5. Perineal dermatitis in a patient with Kawasaki
disease. Perineal eruption with desquamation occurs
in the acute phase of disease in 80% to 90% of
patients.
Fig 6. Edema of the fingers and palm in a patient
with Kawasaki disease. Note the swelling of the
fingers, leading to deep creases in the fold areas.
Edema of the hands and/ or feet occurs in the acute
phase of Kawasaki disease, may be painful, and may
manifest as a refusal to hold objects or bear weight.
routinely provided. Erythema or crusting at the
BCG site is such a strong, relatively specific
finding for KD that it may be considered an
indicator of the diag- nosis in incomplete or
atypical cases.40,59-61 No reactivity occurs when
KD patients are tested with other intradermal
antigens.59
Oropharyngeal mucosal ftndings
Findings of the oropharyngeal mucosa in KD
can take many forms, including dryness and
fissuring of the lips, erythema of the lips (Figs 4
and 7), oral cavity, buccal mucosa, and
pharyngeal mucosa, nonexudative inflammation
of the throat, and straw- berry tongue.3,10,45-47,62
Just 1 of these findings is sufficient to meet this
diagnostic criterion. Lip and oral cavity changes
occur in 80% to 90% of patients.
Other nail ftndings
While not part of the diagnostic criteria,
various nail abnormalities occur in patients with
KD
J AM ACAD DERMATOL
OCTOBER 2013
Fig 7. Lip erythema and fissuring with bleeding in a
patient with Kawasaki disease. Oropharyngeal
findings occur in 80% to 90% of patients, including
redness of the lips, tongue, and throat and lip
fissuring and dryness.
(Table V). Color changes can affect up to 75% of
patients with KD and have been described as
orange- brown or white.63 The discoloration is
transverse, appears 5 to 8 days after the onset of
fever, begins more commonly in the fingernails than
in the toe- nails, and fades in 2 to 4 weeks.63
Leukonychia striata may occur independently of
orange-brown chromo- nychia and may be partial,
with white discoloration localized to the proximal
portion of the nail.63,64 Nail color changes
spontaneously resolve.63 Beau’s lines are another
important nail finding. These deep transverse
grooves across the nails occur in the convalescent
phase of KD, 1 to 2 months after the onset of fever,
and may occur without previous color changes.3,10,30
Onychomadesis, in which the nails separate from
the matrix, has been described during resolution of
the periungual desquamation.64,65 Similar to Beau’s
lines, these nail findings resolve, and proximal
nails regrow normally.63,65 Detachment of the
skin beneath the hyponychium has also been
reported in the febrile period, with or without
associated desquamation.10 Pincer nail de- formity,
with transverse curling of the nail along the
longitudinal axis, rarely occurs and resolves
spontaneously.63
Rare cutaneous consequences
Alopecia has been reported in 2 cases of KD.
Krishnamurthy et al47 described 1 case of alopecia
areata without nail pitting during the acute phase
of KD in a 10-year-old male, and Nabavizadeh et
al67 described diffuse hair loss in a 26-month-old
patient. Peripheral gangrene has been described in
at least 12 patients, particularly in patients who
did not receive
J AM ACAD DERMATOL
VOLUME 69, NUMBER 4
Table V. Other nail findings3,10,30,63-65
Onycholysis
Onychomadesis (after periungual desquamation begins to
resolve)
Detachment of skin beneath hyponychium in the acute
phase (no association with desquamation)
Pincer nail deformity (transverse curling of nail along the
longitudinal axis)
Nail shedding
IVIG or who had delayed therapy; these patients
tend to have a poorer coronary artery
prognosis.68,69 Findings that are not typically
associated with KD and therefore should
prompt consideration of an alternative diagnosis
include exudative pharyngitis, conjunctival
exudate (although present in 5% of KD cases),
discrete intraoral lesions (such as ulcers,
vesicles, or Koplik spots), and generalized
lymphadenopathy.
Noncutaneous features
A variety of noncutaneous features that are not
part of the diagnostic criteria may be seen in asso-
ciation with KD. The prevalence of arthritis and
arthralgia is estimated to range from 7.5% to
30%.70,71 Arthritis may be polyarticular or
oligoarticular and mainly involves the large
joints; it is often quite painful.70 Gastrointestinal
complaints, mainly ab- dominal pain, diarrhea,
and vomiting, are another common feature that
may be seen71,72
in up to one-third
of patients. If urinalysis is performed, sterile
pyuria is a likely finding.73
PATHOGENESIS
Key points
d An infectious etiology is likely, but a specific
agent has not yet been identified
d The immune system is extensively involved
in disease pathogenesis
d While genetics are clearly implicated, iden-
tified genetic loci have been population-
specific
The etiology of KD is still unclear. It is most
likely an immune response to an infectious
organism in a genetically susceptible host, but
the causative infec- tious organism has not been
identified. Genetic polymorphisms have been
associated with KD and extensive immune
activation has been shown. The rationale for an
infectious etiology is supported by
epidemiologic features. Cases tend to occur
close to each other temporally, have a
predilection for winter and spring,
predominantly affect children, have a similar
clinical course to infectious processes,
Bayers, Shulman, and Paller 501.e7
Table VI. Potential roles of gene products
associated with Kawasaki disease83,99-110
Role Gene product
Impacts T cell function ITPKC
Impacts response to FcgIIIB
intravenous immunoglobulin
Induces nuclear factor-kappaB NOD1
activation
Inflammasome component, NLRP1
activated by bacteria
Implicated in development of PELI1, VEGFA, ANGPT1,
coronary artery lesions and ANGPT2
Involved in immune response BLK and CD40
Unknown CASP3, TGFb pathway
genes, NAALADL2,
ZFHX3, DAB1, and
SMAD3
and are self-limited.4,10,30 EpsteineBarr virus,
Mycoplasma pneumoniae, varicella zoster virus,
and human adenoviruses have all been suggested
as causative but have not been confirmed.74-77
Intracytoplasmic inclusion bodies have been
found in ciliated bronchial epithelium, and
monoclonal immunoglobulin A has detected a
specific antigen in the coronary arteries, bronchial
epithelium, and inflamed tissues in KD patients as
evidence for KD being an immune response to an
organism.78-82
The vasculitis of KD is nongranulomatous
with histology revealing an infiltration of
macrophages,
neutrophils, and CD81 T cells.78,83-85 While CD81 T
cells are observed in postmortem tissue, studies
of
the peripheral blood have shown elevations of
CD41 T cells, with decreased CD8 1 and
CD41CD251 T cells instead.9 Several markers of
immune activation are increased in patients,
suggesting their involve- ment in the pathogenesis
of KD.83,86-90 These include tumor necrosis
factorealfa, nuclear factor-kappaB, interleukin
(IL)-17, transforming growth factore beta,
granulocyte colony stimulating factor, IL-1b, IL-
6, follistatin-like protein 1, Toll-like receptor 2,
and Toll-like receptor 4. Of these, nuclear factor-
kappaB, tumor necrosis factorealfa, and IL-6 are
significantly elevated in patients who develop
coro- nary artery complications.90,91 KD patients
also have significant elevations in levels of the
adipokine resistin.87,92,93 IVIG nonresponders
have signifi- cantly higher resistin on admission
compared to responders, and successful treatment
with IVIG leads to a decrease in resistin levels.87
Omentin, another adipokine involved in
inflammation, is also elevated in KD patients
when compared to healthy controls.94
Adiponectin is elevated in some studies but de-
pressed in others, leading to controversy about
its
501.e8 Bayers, Shulman, and Paller
role.87,92,93 Finally, reactive oxygen species
increase with disease activity, and normalize with
IVIG ther- apy, suggesting a role for oxidative
stress in patho- genesis.95-98
Genotype likely also plays a role in
susceptibility to KD. Certain ethnicities (eg,
Japanese) have higher rates of KD, and these
rates are not affected by moving to the United
States. A sibling of a patient with a history of KD
is 6 to 30 times more likely to develop KD, and
the child of an affected individual is 2 times more
likely.9,99-101 Although gene associa- tions have
been population-specific, several genes have
been linked to KD (Table VI), including some
strongly linked single-nucleotide polymorphisms
from genome-wide association studies (ie,
inositol 1,4,5-trisphosphate 3-kinase C [ITPKC],
caspase 3, apoptosis-related cysteine peptidase
[CASP3], trans- forming growth factorebeta
pathway genes; Fc fragment of immunoglobulin
G, low affinity IIa, receptor [FCGR2A], and Fc
gamma IIIB [FcgIIIB]).83,99-110 ITPKC, FCGR2A,
and FcgIIIB pol-
ymorphisms have been identified in several
different ethnic groups. The role of products of
these impli- cated genes remains unclear, but
determination of their relevance may have
implications for future treatment.
CONCLUSION
KD is a vasculitic disorder that virtually
always occurs in infants and younger children and
is the most common cause of acquired heart
disease in the United States. Given the importance
of the mucocu- taneous changes for diagnosis and
the many cuta- neous manifestations of the
disorder, the dermatologist must be familiar with
the signs of KD, particularly because early
treatment with IVIG markedly reduces the risk of
cardiac complications.
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