Kawasaki's disease is a systemic vasculitis that commonly affects children under 5 years old and can lead to coronary artery aneurysms if left untreated. It is characterized by a fever for at least 5 days along with at least 4 of 5 principal symptoms including bilateral non-exudative conjunctivitis, changes to the lips and oral cavity, polymorphous rash, changes to the extremities, and cervical lymphadenopathy over 1.5cm. Atypical presentations with fewer symptoms or in unusual age groups can be missed but are important to identify to prevent cardiac complications through early treatment with intravenous immunoglobulin and aspirin. Delayed or missed diagnosis is associated with increased risks of aneurysm formation, treatment

1. 1
Kawasaki's Disease
Dr Hugh Reid
Emergency Medicine Advanced Trainee
Newcastle, Australia
May 2013

2. 2
川
kawa river
崎
saki promontory

3. Kawasaki's Disease
Typical and Atypical Presentations
Dr. Tomisaku Kawasaki, Aged 87

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Kawasaki's disease
Otherwise known as:
“ Muco-Cutaneous Lymph Node syndrome”

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Kawasaki's systemic vasculitis
MCLN syndrome: Odds Ratio
Conjunctival injection 7.95 muco-
Extremity change 6.97
cutaneous
Oropharyngeal changes 5.21
muco-
Rash 2.43
cutaneous
Cervical LN > 15mm 1.51 [ least
common ]

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Non Standard KD symptoms
In addition there are > 30 clinical findings attributed to
the underlying multi-system vasculitis, including
CNS / Resp / CVS / GIT / GU / Msk /Skin
Why bother with all these symptoms ? – atypical
Kawasaki's can be diagnosed with 5 days of fever
and 2/5 typical signs. You won't remember them all.
Just remember to “be suspicious”

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Non Standard KD symptoms
GITDiarrhea, abdominal pain, vomiting, liver dysfunction,
pancreatitis, Hydrops gallbladder,parotitis, cholangitis,
intussusception, intestinal pseudo- obstruction,
ascites, splenic infarction.
MSS Polyarthritis and arthralgia.
CVS Myocarditis, pericarditis, tachycardia, valvular heart
disease.
GU Urethritis, prostatitis, cystitis, priapism, Interstitial
nephritis, orchitis, nephrotic syndrome.

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Non Standard KD symptoms
CNS Lethargy, semicoma, aseptic
meningitis, and sensorineural
deafness.
Resp Shortness of breath, influenza-like
illness, plural effusion, atelectasis.
Skin Erythema and induration at BCG
vaccine site, Beau's lines, and finger
gangrene.
Atypical Kawasaki's can be diagnosed with 5 days of fever and 2/5 typical signs

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Timing of Kawasaki Symptoms

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Pathophysiology of KD
Kawasaki disease fits nicely in the spectrum
between an infectious disease and a true
autoimmune disease, with an infectious trigger
leading to a prolonged self-directed immune
response.

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Pathophysiology of KD
A normal Ag stimulates one in a million T cells.
A Super Antigen [ SAg. ] is a protein which can
stimulate a large proportion of T cells - up to
10% of the body's T Cells,
In normal people this stimulation peters out fairly
quickly. But in Kawasaki's patients, a genetic
predisposition allows this massive T
Lymphocyte population to persist, rather than
suffering apoptosis [ siblings have a 10 fold risk
for KD ].

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Pathophysiology of KD
Coronary arteries contain large numbers of Toll
like receptors [ no-one knows why yet ]
Toll like receptors are part of the innate immune
system and are designed to recognise parts of
Gram Positive bacteria cell walls.
Hyperstimulated T cells stimulate these Toll like
receptors on the coronary arteries, via TNF,
stimulating matrix metalloproteinases [ MMP ]
which dissolve elastin, causing aneurysm
formation

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Pathophysiology of KD
Summary
Super antigens affect genetically predisposed
people and persist in these people. They
stimulate a massive inflammatory response,
causing the signs which we can see, and most
importantly, stimulate Toll like receptors in the
coroanry arteries which switch on MMPs which
dissolve elastin in the arteries, casusing
aneurysms.

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History of Kawasaki Disease
The original case was observed in January 1961in a 4
year old boy;
Diagnosis: “God only knows ... I didn't see another one
until February 1962 and then realized that this was
a unique clinical entity not in the textbooks... I
encountered five more patients from
February to July 1962.
I presented the seven patients at a meeting of the
Japan Medical Society. I belonged to both the Chiba
and Tokyo branches of the Society, and I chose Chiba
because I thought I would get a more friendly
reception, but...

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History of Kawasaki Disease
...the Tokyo professors denied the existence of a new
entity and thought it a mild form of Stevens-Johnson
syndrome. They indicated they had also been observing
similar cases. The professor of pediatrics at Tokyo
University denied the new syndrome, all respected his
opinion, but then he died and Kawasaki disease became
recognized as a new diagnosis”.
Nothing has changed … !!

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History of Kawasaki Disease
Clinical presentation recognised early but not the
complications - c.f. early assertion by Dr Kawasaki that it was
a self limiting disease without sequelae !
Coronary artery thrombosis first recognized in 1965 on
autopsy of one of his patients previously diagnosed with
MCLNS – final resolution in 1970 with 10 autopsy cases of
sudden death after diagnosis of KD
First Japanese report of 50 cases, 1967
By the time of the first English-language publication by Dr.
Kawasaki in 1974, the link between KD and coronary artery
vasculitis was well-established.

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Natural History of untreated KD
Coronary arteries: BADNESS
Acute: Dilatation / frankly Aneurysmal / Thrombose / Infarction
Chronic: Fibrotic / Stenosis / persistent aneurysm
Coronary artery aneurysms in 15% to 25% of children*
Acute: 2% mortality rate, peak mortality ~ 15-45 days after onset of
fever
[ Mortality highest in < 12 monthers and > 9 year olds - because no-one thinks
of it ]
Longer Term: 146 aneurysms: 50% regressed, 25% persist,
16% stenose, 3% died; of stenoses, 40% infarcted [ of whom
half died ], and 25% required CABG; aneurysms ? Stent, can't graft
[ Source: Dr N.
Collins ]
* AHA Scientific Staement 2004

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Natural History of Untreated KD
Most common in:
Japanese 112 /
100,000
Asian and Pacific Islanders 32 / 100,000
Lowest in whites 9 / 100,000
Commonest cause of acquired heart disease in the
Industrialised world
Commonest age 1- 4 yrs – median 22 months

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Age Distribution
< 6 months 6-12 mo 1-4 yrs 5-9 yrs > 9 yrs
0
10
20
30
40
50
60
70
Age Distribution of KD
Age at diagnosis
Percentage

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Natural History of Untreated KD*
Commonest age 1- 4 yrs – median 22 months but
children as young as 1 month and as old as 20 years
have been diagnosed with KD.
Children < 6 months and > 9 years were 2.5 times more
likely to be diagnosed after day 12. Young infants are
more likely to have severe disease with a 50%
aneurysm rate, whereas older children [ > 9 years ]
are more likely to have atypical presentations, so are
less likely to be diagnosed, or to be diagnosed too
late, where response to treatment rates are much
lower, aneurysm rates higher, and presumably
mortality, as well.
* Manlhiot et al, Pediatrics 2009:124:e140

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TYPICAL KAWASAKI'S DISEASE – 2004 AHA Criteria
Fever persisting at least 5 days and at least 4 of the following
5 features:
conjunctival injection
Changes in extremities:
Changes in lips and oral cavity
Polymorphous exanthema
Marked cervical lymphadenopathy (≥1.5 cm in diameter),
In the presence of ≥4 principal criteria, the diagnosis of
Kawasaki disease can be made on day 4 of illness.

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Bilateral, painless conjunctival injection,
often with limbic sparing [ diffferent blood supply ],
bulbar > palpebral [ ie opposite of conjunctivitis ], without
exudate
VASCULITIS

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Limbic sparing

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Changes in extremities: Acute: Erythema and oedema
of hands and
feet
VASCULITIS

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VASCULITIS – ERYTHEMA +
OEDEMA

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VASCULITIS

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TYPICAL KAWASAKI'S DISEASE – 2004 AHA Criteria
Mouth: Changes in lips and oral cavity: Erythema and
cracking of lips, strawberry tongue, diffuse injection of oral
and pharyngeal mucosae
VASCULITIS

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34. 34
VASCULITIS

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TYPICAL KAWASAKI'S DISEASE – 2004 AHA Criteria
Rash
Polymorphous exanthema
Erythematous / Maculopapular
Urticarial /Scarlitiniform
Erythroderma / EM
Micropustular
NOT bullous
NOT vesicular

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TYPICAL KAWASAKI'S DISEASE – 2004 AHA Criteria
Marked Lymphadenopathy
Marked
cervical
lymphadenopathy
(≥1.5 cm in diameter),
usually unilateral

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Cervical Lymphadenopathy

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Cervical Lymphadenopathy

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Cervical Lymphadenopathy

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TYPICAL KAWASAKI'S DISEASE – 2004 AHA Criteria
Fever persisting at least 5 days and at least 4 of the following
5 features:
Conjunctival injection
Changes in extremities:
Changes in lips and oral cavity
Polymorphous exanthema
Marked cervical lymphadenopathy (≥1.5 cm in diameter),
In the presence of ≥4 principal criteria, the diagnosis of
Kawasaki disease can be made on day 4 of illness.

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Incomplete kawasaki's Disease
Typically, not all of the clinical features are
present at a single point in time, and watchful
waiting is sometimes necessary before a
diagnosis can be made.
Patients with fever for ≥5 days and <4 principal
features can be diagnosed as having Kawasaki
disease when coronary artery disease is
detected by echocardiography.

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Incomplete Kawasaki's Disease
Kawasaki disease should be considered in the
differential diagnosis of a young child with unexplained
fever for ≥5 days that is associated with any of the
principal clinical features of this disease.
Incomplete kawasaki's – fever 5/7 and 2/5 criteria, no
other reasonable explanation for the illness, and
laboratory findings consistent with severe systemic
inflammation.
We should bear in mind that five of the patients in
Kawasaki’s original series of 50 would not have
satisifed the current clinical case definition, and that a
multitude of other symptoms have since been described
in children who have turned out to have KD.

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Diagnostics
Inflammatory markers – CRP, ESR
raised WCC
massive thrombocytosis >750 [esp. late ]
low platelet count [ cytokine storm ]
Low serum Na, albumin from vascular leak
Echo obvious dilation / aneurysm
> 3mm lumen diameter
increased vessel wall thickness = oedema
increased signal intensity

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Diagnostics - Echo

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Diagnostics

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Diagnostics

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Diagnostics - IVUS

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Too late
Desquamation commences around week 3, and
duration of fever is the most important predictor of
poor coronary outcome

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Too late

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Treatment
IVIG – but treatment failure is not uncommon –
up to 10-15% of children don't respond [in
terms of inflammatory markers ] and are at risk
of developing aneuryms. Can repeat IVIG,
steroids, TNF blockers, but...
5% of children develop aneurysms despite being
treated:
? because of treatment resistance
? delay in diagnosis

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Summary
Kawasaki's Disease is a bad disease, with a
significant mortality because...
delayed or missed diagnosis is associated with
increased aneurysm formation, treatment
failure and morbidity and mortality.
Special attention:
Atypical presentations:
Unusual age groups:

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Summary - Special attention
Atypical presentations:
2 / 5 signs and fever, multitude of non-
standard symptoms
“ not all fever with rash is viral
Unusual age groups:
< 12 months,
> 5 years, and up to 20 years !
Nick Collins: Chest pain in a young adult
? missed KD in childhood – do an ECG !