Kawasaki disease

Kawasaki Disease
Dr.Sid Kaithakkoden MD
MBBS,DCH,DNB,MD,MRCPCH.FCPS
alavisaid@aol.com

25-Feb-15
Introduction
 Acute multi system disease affecting infants &
children with prominent vasculitis of large &
medium sized vessels
 Acute self-limited vasculitis of childhood,
characterized by
 Fever
 Bilateral non exudative conjunctivitis
 Erythema of the lips and oral mucosa
 Changes in the extremities
 Rash
 Cervical lymphadenopathy

25-Feb-15
 KD - The leading cause for acquired heart
disease in children
 Coronary artery aneurysms or ectasia
develop in 15% to 25% of untreated
children & can lead to
ischemic heart disease or
sudden death

25-Feb-15
Historical Perspective
 1967 - Tomisaku Kawasaki reports a series of 50
patients and establishes the clinical criteria for
diagnosis (in Japanese)
 1974 - first English language report of Kawasaki
syndrome by Kawasaki
 1976 - first series of American patients reported by
Melish, Hawaii
 1977 - landing and Larson establish that Kawasaki
disease and infantile polyarteritis nodosa are
pathologically indistinguishable
 1988 - American academy of pediatrics endorses
high does IVGG plus ASA as recommended therapy
for Kawasaki disease

25-Feb-15
Epidemiology
 More prevalent in Japan and in children of
Japanese ancestry (annual incidence of 112
cases per 100 000 children <5 years old)
 Age of onset -
 Peak age - 2 to 5 yrs
 80 - 85 % < 5 yrs
 Rare > 11 yrs

25-Feb-15
Aetiology and Pathogenesis
 Aetiology of KD remains unknown, (although
clinical and epidemiological features strongly
suggest an infectious cause)
 Hypothesis - KD is caused by a ubiquitous
infectious agent that produces clinically
apparent disease only in certain genetically
predisposed individuals, particularly Asians

25-Feb-15
 Its rarity in the first few months of life and in adults
suggests an agent to which the latter are immune
and from which very young infants are protected by
passive maternal antibodies
 Little evidence exists of person-to-person
transmission
 Hypothesis assumes that most infected children
experience asymptomatic infection with only a small
fraction developing overt clinical features of
Kawasaki disease
 The genetic basis of susceptibility is currently
unknown

25-Feb-15
Pathology
 Generalized systemic vasculitis involving
blood vessels throughout the body
 Aneurysms may occur in other
extraparenchymal muscular arteries (celiac,
mesenteric, femoral, iliac, renal, axillary, and
brachial arteries)
 Media of affected vessels demonstrate
edematous dissociation of the smooth
muscle cells

25-Feb-15
 Endothelial cell swelling and subendothelial
edema are seen, but the internal elastic lamina
remains intact
 Influx of neutrophils is found in the early stages
(7 to 9 days after onset), with a rapid transition to
large mononuclear cells in concert with
lymphocytes (predominantly CD8+ T cells) and
IgA plasma cells
 Destruction of the internal elastic lamina and
eventually fibroblastic proliferation
 Active inflammation is replaced over several
weeks to months by progressive fibrosis, with
scar formation

25-Feb-15
Clinical Features
1. Prolonged fever – FUO/PUO
2. Bilateral non exudative conjunctivitis
3. Erythema of the lips and oral mucosa
4. Changes in the extremities – oedema,
peeling
5. Rash – non-vesicular
6. Cervical lymphadenopathy – unilateral

25-Feb-15
 1: Fever in KD
 First day of fever is considered first day of illness,
although other features may develop first
 High-spiking (~40 C) and remittent
 Fever of ≥5 days generally distinguishes Kawasaki
disease from self-limiting viral infections (don't have to
wait 5 days before starting treatment)
 Untreated the fever usually lasts 1-2 weeks
 Defervescence within 1-2 days of treatment with IVIG

25-Feb-15
 2: Conjunctivitis in KD
Begins shortly after the fever
Resolves promptly - may have disappeared
by presentation
Non-purulent conjunctival injection
Bulbar conjunctivitis with limbic sparing
Anterior uveitis may occur (in up to 80%)

25-Feb-15
 3: Oropharyngeal changes
Erythema, dryness, swelling and peeling of
lips - lipstick sign
Lips may bleed
Erythema of oropharyngeal mucosa
Strawberry tongue
No Koplik’s spots or oral ulceration or
exudates in KD

25-Feb-15
 4: Changes in the extremities
Oedema of hands and feet, especially in
infants
Peeling of fingers and toes (often periungual)
is NOT a feature of the acute presentation
Peeling of hands and feet in sub acute phase
(1-2 weeks)
Beau’s lines in nails; occasionally nail is lost

25-Feb-15
 5: Polymorphous rash
 Generally occurs with onset of fever and fades within
a week
 Morbilliform rash or erythematous plaques at flexor
creases
 Erythema and desquamation of the inguinal/perineal
area
 Occurs early (desquamation of hands and feet is a
later sign)
 The presence of - petechiae or purpura, vesicles or
bullae, crusting, pruritis - search for an alternative
diagnosis

25-Feb-15
 5: Lymphadenopathy in KD
50-80% of cases
>1.5cm, usually more obvious
May be unilateral single node
May be erythematous, but non-fluctuant and
no pus

25-Feb-15
Other clinical features or KD
 Irritability
 Aseptic meningitis (~25% ) (CSF - ↑ lymph's, N
glucose/protein)
 Arthritis - probably less common since IVIG treatment
 Hydrops of the gallbladder (RUQ pain, seen on USS)
 Sterile pyuria, urethritis and diarrhoea
 Pulmonary infiltrates or pneumonitis
 Inflammation at site of BCG scar
 Cross-reactivity of T cells in KD patients between
specific epitopes of Mycobacterial and human heat
shock proteins

25-Feb-15
Kawasaki disease - diagnostic criteria
 Fever of ≥ 5 days duration + four of five
criteria
Oropharyngeal changes (90%+ of cases)
Changes in peripheral extremities (90%+ of
cases)
Cervical lymphadenopathy (~75% of cases)
Polymorphous rash (95%+ of cases)
Bilateral non-purulent conjunctivitis (90%+ of
cases)

25-Feb-15
Kawasaki Disease: Diagnostic Criteria
Criterion Description
Fever Duration of 5 days or more plus 4 of the following:
1 Conjunctivitis Bilateral, bulbar, non-suppurative
2 Lymphadenopathy Cervical, >1.5 cm
3 Rash Polymorphous, no vesicles or crusts
4 Changes of lips or oral
mucosa
Red cracked lips; "strawberry" tongue; or diffuse erythema
of oropharynx
5 Changes of extremities Initial stage: erythema and oedema of palms and soles
Convalescent stage: peeling of skin from fingertips
KD may be diagnosed with fewer than 4 of these features if coronary artery aneurysms
are detected.

25-Feb-15
Diagnostic problems in Kawasaki
disease
 Atypical or incomplete cases
Most common in infants - greatest risk of CAA
Children may have fever and < 4 clinical signs
Reports of coronary AN with 3 diagnostic
features
Occasionally only prolonged fever is present,
and diagnosis is only made after an ECHO

25-Feb-15
 Atypical or Incomplete KD
Recognition is difficult
KD should be in the DD of prolonged fever in
infants
Sequential clinical features: incomplete
becomes complete Use other clues (irritability,
BCG scar indurations etc.)
Balance between risk of KD and risk of IVIG
Tend to err on side of treatment

25-Feb-15
 Recurrent Kawasaki Disease
Much rarer than parents or clinicians think
2% in Japanese; ~<1% in UK and N America
Must fulfil diagnostic criteria again in full
Skin peeling with subsequent febrile illnesses
is common
Increased rate of heart damage in second
episode of KD

25-Feb-15
DD
 Streptococcal infection (scarlet fever, toxic
shock-like syndrome)
 Staphylococcal infection (toxic shock syndrome,
scalded skin syndrome)
 Viral exanthemas (Measles, rubella, roseola
infantum, Epstein Barr virus, influenza A and B,
adenovirus)
 Mycoplasma pneumonia
 Stevens-Johnson syndrome
 Systemic idiopathic juvenile arthritis

25-Feb-15
Initial Investigations for Suspected
Kawasaki Disease
 Full blood count and film
 Erythrocyte sedimentation rate
 C reactive protein
 Blood cultures
 ASOT and anti DNase B
 Nose and throat swab, stool culture
(superantigen toxin typing if staphylococcus
aureus and/or ß haemolytic streptococci
detected)
 Renal and liver function tests

25-Feb-15
 Coagulation screen
 Autoantibody profile (antinuclear antibodies; Extractable
nuclear antibodies; Rheumatoid factor; antineutrophil
cytoplasmic antibodies)
 Serology (IgG and IgM) for mycoplasma pneumoniae,
enterovirus, adenovirus, measles, parvovirus, Epstein–
Barr virus, cytomegalovirus
 Urine microscopy and culture
 Dip test of urine for blood and protein
 Electrocardiogram and echocardiogram
 Consider serology for rickettsiae and leptospirosis if
history suggestive
 Consider chest x ray

25-Feb-15
Complications
 Irritability and aseptic meningitis
 Gallbladder hydrops
 Hepatitis
 Otitis media
 Pancreatitis
 Myositis
 Pericarditis and myocarditis
 Aneurysm formation can lead to peripheral gangrene,
cerebral infarction and cardiac arterial aneurysm (this
may lead to thrombosis, myocardial infarction and
dysrrhythmia)

25-Feb-15
Cardiac complications
 20–40% of untreated KD patients develop coronary
artery abnormalities
 50% of these lesions regress within five years, and in
most with mild CAA (3–4 mm) regression occurs within
two years
 Giant aneurysms (>8 mm) are unlikely to resolve, and
some may develop stenosis with risk of coronary
thrombosis, myocardial infarction, and death
 In 1993, a report from the BPSU indicated a mortality
rate of 3.7% in the UK for KD

25-Feb-15
Newburger, J. W. et al. Circulation 2004;110:2747-2771
Coronary angiogram demonstrating giant aneurysm of the LAD with obstruction and giant
aneurysm of the RCA with area of severe narrowing in 6-year-old boy

25-Feb-15
Mean and prediction limits for 2 and 3 SDs for size of (A) LAD, (B) proximal RCA, and (C)
LMCA according to body surface area for children

25-Feb-15
Straight lateral view of a selective right coronary artery angiogram demonstrating a giant
aneurysm just distal to the coronary ostium. Multiple small aneurysms are noted throughout the
course of the right coronary artery and posterior descending artery

25-Feb-15
Selective left coronary artery angiogram in slight left anterior oblique view with caudal
angulation. The left main coronary artery appears normal and trifurcates into the left anterior
descending (LAD), ramus and circumflex branches. The giant aneurysm in the LAD appears
globular in this view and is densely opacified. The ramus aneurysm is long and saccular,
located inferior to LAD

25-Feb-15
Recommended guideline for the
management of Kawasaki disease in the UK
 Establish diagnosis
 (1) Complete Kawasaki disease (any age)
 (2) Incomplete Kawasaki (<1 year)
 Treatment
 IVIG 2 g/kg as a single infusion over 12 hours
 Aspirin 30–50 mg/kg/day in 4 divided doses for 2
weeks (7.5 – 12.5 mg/kg QDS)
 Echocardiography and ECG
 Aspirin 2–5 mg/kg/day when fever settled (disease
defervescence) continuing for a minimum of 6 weeks

25-Feb-15
Disease defervescence:
Repeat echocardiography at 2 and 6 weeks
No CAA CAA <8 mm, no stenoses CAA > 8 mm and/or stenoses
Stop aspirin at 6
weeks
Continue aspirin Lifelong aspirin 2–5 mg/kg/day
Lifelong follow up at
least every 2 years
Repeat echocardiography and
ECG at 6 monthly intervals
Consider warfarin
Discontinue aspirin if resolves Consider coronary aneurysm
angiography and exercise stress
testing
Consider exercise stress test if
multiple aneurysms
Repeat echocardiography and ECG at
6 monthly intervals
Specific advice on minimizing
atheroma risk factors
Specific advice on minimizing
atheroma risk factors
Lifelong follow up Lifelong follow up
No disease defervescence within 48 hours, or disease recrudescence within 2
weeks:
Seek expert advice to consider:
• Second dose of IVIG at 2 gm/kg/day
• Pulsed methylprednisolone at 600 mg/m2 twice daily for 3 days or
prednisolone 2 mg/kg/day once daily, weaning over 6 weeks

25-Feb-15
● Treatment can be commenced before full 5 days
of fever if sepsis excluded
● Treatment should also be given if the
presentation is >10 days from fever onset
● Incomplete cases >1 year old treated at
discretion of clinician--seek expert advice
● Refer to paediatric cardiologist
● Other specific interventions such as positron
emission tomography scanning, addition of
calcium channel blocker therapy, and coronary
angioplasty at discretion of paediatric
cardiologist

25-Feb-15
Evaluation of suspected incomplete Kawasaki disease
Supplemental laboratory
criteria:
1. albumin 3.0 g/dL
2. anaemia for age
3. elevation of ALT
4. platelets after 7 day
450 000/mm3
5. WBC 15 000/mm3
6. urine - 10 WBC/HPF

25-Feb-15
Risk Level
Pharmacological
Therapy
Physical Activity
Follow-Up and
Diagnostic Testing
Invasive Testing
I (no coronary artery
changes at any stage of
illness)
None beyond 1st 6–8 weeks No restrictions beyond 1st 6–
8 weeks
Cardiovascular risk
assessment, counseling at
5-y intervals
None recommended
II (transient coronary
artery ectasia disappears
within 1st 6–8 weeks)
None beyond 1st 6–8 weeks No restrictions beyond 1st 6–
8 weeks
Cardiovascular risk
assessment, counseling at
3- to 5-y intervals
None recommended
III (1 small–medium
coronary artery
aneurysm/major coronary
artery)
Low-dose aspirin (3–5
mg/kg aspirin/d), at least
until aneurysm regression
documented
For patients <11 y old, no
restriction beyond 1st 6–8
weeks; patients 11–20 y 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
with echocardiogram +
ECG, combined with
cardiovascular risk
assessment, counseling;
biennial stress test/evaluation
of myocardial perfusion scan
Angiography, if noninvasive
test suggests ischemia
IV large or giant coronary
artery aneurysm, or
multiple or complex
aneurysms in same
coronary artery, without
obstruction)
Long-term antiplatelet
therapy and Warfarin (target
INR 2.0–2.5) or low-
molecular-weight heparin
(target: antifactor Xa level
0.5–1.0 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
outcome
Biannual follow-up with
echocardiogram + ECG;
annual stress test/evaluation
1st angiography at 6–12 mo
or sooner if clinically
indicated; repeated
angiography if noninvasive
test, clinical, or laboratory
findings suggest ischemia;
elective repeat angiography
under some circumstances
(see text)
V (coronary artery
obstruction)
Long-term low-dose aspirin;
warfarin or low-molecular-
weight heparin if giant
aneurysm persists; consider
use of ß-blockers to reduce
myocardial O2 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 outcome
Biannual follow-up with
echocardiogram and ECG;
annual stress test/evaluation
Angiography recommended
to address therapeutic
options
Risk Stratification

25-Feb-15
KEY PRACTICE POINTS
 Kawasaki disease should be considered in the DD
of every child with prolonged fever accompanied by
rash and non-purulent conjunctivitis
 especially in children < 1 year old and in adolescents,
in whom the diagnosis is frequently missed
 Diagnostic pitfalls include mistaking:
 rash and mucosal changes for an antibiotic reaction
 sterile pyuria for partially treated urinary tract infection
 cerebrospinal fluid (CSF) pleocytosis for viral
meningitis

25-Feb-15
 The diagnosis is guided by:
 the number of positive clinical criteria
 the age of the child (those under 6 months with
persistent fever for seven days and evidence of
inflammation needing an echocardiogram even in the
absence of positive clinical criteria)
 the absence of clinical features suggesting another
diagnosis, and
 the laboratory C reactive protein (CRP) and
erythrocyte sedimentation rate (ESR) results

25-Feb-15
 In those with raised CRP and/or,do other
supplementary investigations contribute to the
decision as to whether to treat with IVIG
 WBC
 PLT
 S albumin
 ALT
 Urine –WBC
 Echocardiography

25-Feb-15
Vaccination post KD
 IVIG can block replication of live viral vaccines &
subsequent actively acquired immunity
 Current recommendation - live vaccines be
deferred for at least three months following
treatment with IVIG
 Autoimmune diseases including the systemic
vasculitides flare in response to live and non-live
vaccine preparations
 Defer immunisation with all vaccines for at least
three months following an episode of KD

25-Feb-15
Areas of Future Research
 Epidemiology including incidence, management, complication rate,
and case fatality rate
 Investigation of superantigen dependent or independent pathways of
T cell activation in the acute and convalescent phases of the illness
 Investigation of a viral aetiopathogenesis, in particular herpes
viruses, using degenerate polymerase chain reaction methodology
 Investigation of host genetic determinants of susceptibility and
outcome in KD
 Correlation of coronary and/or peripheral arterial involvement with
clinical presentation
 Evaluation of the potential of circulating endothelial microparticles as
a laboratory diagnostic test and predictor of those at risk of coronary
arterial aneurysm formation
 Examination of B lymphocyte homing receptor expression of
circulating antibody secreting B lymphocytes in acute and
convalescent KD.

Areas of Future Research
 Inflixumab – TNF alpha antagonist- in the
RX of KD
 Biomarker for diagnosis of KD –
Urinary protiens – Flamin C & Mephrin A
THRIL – activated macrophage

Kawasaki disease

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