KAWASAKI DISEASE

NINFA JOSON-VILLANUEVA, MD, FPPS, FPCC

Pediatric Cardiologist
KAWASAKI DISEASE

Definition/Epidemiology/Etiology/ Pathology
Clinical Criteria
typical manifestations/clinical phases
associated findings/laboratory
Atypical KD
Complications
Treatment
Natural History/ Follow-up
 KAWASAKI
DISEASE
Mucocutaneous Lymph Node
Syndrome
an acute, self-limited, multisystem
vasculitis of infancy and childhood
Infantile Polyarteritis Nodosa
KAWASAKI DISEASE

1967: Dr. Tomisaku Kawasaki

KAWASAKI DISEASE: Epidemiology

In Japan: incidence of 184.6

cases/100,000 children/year in <5y/o
in developed countries, KD replaced
Acute Rheumatic Fever as the most
common cause of acquired HD in
children
Myocardial Infarct in young adults:
could be missed KD in childhood
KAWASAKI DISEASE: Epidemiology

Peak onset: 6-11 months

80% are under 4y/o
Male/female ratio:1.35:1
Recurrence rate: 3%
KAWASAKI DISEASE

ETIOLOGY: still UNKNOWN

clinical & epidemiological features
suggest infectious cause
Probable immunologic response
triggered by several different
microbial agents
Kawasaki Disease: Recent Researches

identification of cytoplasmic
inclusion bodies (aggregates of
viral proteins & RNA) &
virus-like particles in KD tissues

Rowley & colleagues (IKI 2008)

 KAWASAKI DISEASE

Possible role of genetic

predisposition:
1% with positive family history
50% of 2nd cases develop within 10 days of the
first case
13% occurrence in twins

Genomic studies: functional single nucleotide

polymorphism of ITPKC gene that confers
susceptiblity to KD (Onouchi, 2008)
 KAWASAKI DISEASE:
Pathology

Generalized systemic vasculitis

involving blood vessels throughout the
body
Active inflammation--- progressive
fibrosis---scar formation
In coronary arteries: arterial
remodelling or revascularization
KAWASAKI DISEASE: Diagnostic Criteria
FEVER for at least 5 days
AND 4 of the following:
1. Conjunctival injection
2. Changes in the oral mucosa
(mouth & lips)
3. Changes in the peripheral extremities
4. Polymorphous rash
5. Cervical lymphadenopathy
AND illness not explained by other known
disease process.
Atypical or Incomplete
Kawasaki Disease
children with KD manifested
with fever & fewer than 4 of the
diagnostic clinical features
also at risk for coronary
aneurysm
KAWASAKI DISEASE: FEVER
High spiking and
remittent
Average duration=
11 days (5-23 days)
May extend to 3-4
weeks without
treatment
 KAWASAKI DISEASE: EYE CHANGES

Bulbar conjunctivae
are more affected
No exudates
No conjunctival
edema
No corneal ulceration
No Pain
Spares the limbus (avascular
zone around the iris)
Eye Changes in Kawasaki Disease
 KAWASAKI DISEASE:
ORAL MUCOSA CHANGES
Appear within 1-3
days after onset of
fever
a) diffuse erythema of
the oropharyngeal
mucosae
b) Lips: erythema,
dryness, fissuring,
peeling, cracking &
bleeding
KAWASAKI DISEASE:ORAL MUCOSA CHANGES

c) Strawberry tongue with prominent papillae

& erythema
*No oral ulcerations, pharyngeal exudates &
Kopliks spots
KAWASAKI DISEASE:
CHANGES IN THE PERIPHERAL EXTREMITIES

Acute Phase:
a) induration (swelling) of hands & feet
(dorsal edema); sometimes painful
KAWASAKI DISEASE:
Changes in the Peripheral Extremities

Acute phase:
b) Erythema of
palms & soles;
abrupt change to
normal skin at
wrist & ankle
(stocking & glove
areas)
KAWASAKI DISEASE:
Changes in the Peripheral Extremities

Subacute phase
(2 weeks after onset):
periungal desquamation of
fingers & toes

Convalescent phase
(1 to 2 months after onset):
transverse grooves across
nails (Beaus lines)
Desquamation of palms & fingers in
the subacute phase of KD
KAWASAKI DISEASE:
RASH

Polymorphous rash on trunk &

extremities
most common: non-specific diffuse
maculopapular erythematous rash
No bullous & vesicular eruptions
KAWASAKI DISEASE: RASH

Quite common: groin

erythema & desquamation
KAWASAKI DISEASE:
CERVICAL LYMPHADENOPATHY
Least common feature (50-75%)
Usually unilateral & confined to
the anterior cervical triangle
Classic criterion:
1 lymph node
> 1.5 cm in size
Nonfluctuant, nonpurulent &
nontender; no marked erythema
KAWASAKI DISEASE:Other findings

Musculoskeletal Arthritis
Arthralgia

Genitourinary Urethritis
meatitis

Gastrointestinal tract Diarrhea

Vomiting
abdominal pain
hepatic dysfunction
gallbladder hydrops

Central Nervous System Extreme hyperirritability

Aseptic meningitis
Sensorineural loss
KAWASAKI DISEASE:
Cardiovascular Findings
Congestive heart failure
Myocarditis, pericarditis, valvulitis
Coronary artery findings: arteritis
Aneurysms of medium-size
noncoronary arteries
Raynauds phenomenon
Peripheral gangrene
 KAWASAKI DISEASE

Erythema and
induration on
BCG site

Rare findings: Testicular swelling, pulmonary

nodules and infiltrates, pleural effusions, and
hemophagocyctic syndrome
 KAWASAKI DISEASE

Gangrene of toes
KAWASAKI DISEASE:
CLINICAL PHASES
1. Acute Febrile Phase
(1-10 days)
2. Subacute Phase
(11-20 days)
3. Convalescent Phase
(21-60 days)
4. Chronic Phase (7 years)
KAWASAKI DISEASE: ACUTE PHASE
Signs & symptoms:
fever
conjunctival injection
erythema of the oral
mucosa
erythema & swelling of
the hands & feet
cervical lymphadenopathy
rashes
aseptic meningitis
diarrhea
hepatic dysfunction

CARDIAC
myocarditis
pericardial effusion
coronary arteritis
KAWASAKI DISEASE: SUBACUTE PHASE

1-2 weeks which lasts up to 4

weeks after onset of fever
resolution of fever, rash &
lympadenopathy
irritability, anorexia &
conjunctival injection may
persists

Prominent features: Desquamation

of fingers
Thrombocytosis

CARDIAC: Coronary Artery

Aneurysm - highest risk for
death
KAWASAKI DISEASE:
Convalescent Phase

usually 6-8 weeks after onset of

illness
when all the clinical signs have
disappeared
continues until the ESR returns to
normal
KAWASAKI DISEASE:
Common Pitfalls in Diagnosis
MISTAKEN FOR:

Fever + enlarged lymph node: Allergy

presumed bacterial adenitis; given
antibiotics after which developed
rash & mucosal changes
Sterile pyuria Partially-treated UTI

Fever+ rash +CSF pleocytosis Viral meningitis

Fever + abdominal pain Acute abdomen

KAWASAKI DISEASE:
Differential Diagnosis
Viral infections (measles, adenovirus,
enterovirus, Epstein-Barr virus)
Scarlet fever
Staphylococcal scalded skin syndrome
Toxic shock syndrome
Bacterial cervical lymphadenitis
Drug hypersensitivity reactions
Steven-Johnson syndrome
Juvenile Rheumatoid Arthritis
Leptospirosis
Mercury hypersensitivity reaction
(acrodynia)
Kawasaki Disease: Cardiac Complications

Acute phase (30%)

Myocarditis
Pericarditis
Mitral insufficiency
CHF
Subacute phase
Mitral insufficiency
Coronary aneurysm
Coronary thrombosis with infarction
Convalescent
Coronary & peripheral aneurysms may persist
Chronic
Angina pectoris &/or myocardial insufficiency
may develop
KAWASAKI DISEASE: Cardiac Complications

Higher risk of coronary artery

lesions in patients < 6 mons old
20-25% of untreated cases
develop coronary artery
abnormalities
Mortality rate drops from 1-2% to
0.08% with IVIG
Death usually due to myocardial
infarction secondary to:
a) Thrombosis of a coronary aneurysm
b) Rupture of a large coronary artery
KAWASAKI DISEASE: Risk Factors for developing
Coronary Artery Aneurysms

1. Male gender
2. Very young infants, particularly < 6 months
where disease is atypical
3. Older age (> 5y/o), partly because of the
delay in recognition and treatment
4. Prolonged fever (>16 days) & fever despite
IVIG therapy
5. Recurrence of fever after an afebrile period
of at least 48 hours

Koren G, et al , J Pediatr (1986)

Beiser AS, et al, Am J Cardiol (!998)
Daniels SR, et al Am J Dis Child
(1987)
KAWASAKI DISEASE: Risk Factors for developing
Coronary Artery Aneurysms

6. Anemia
7. Thrombocytopenia early in the disease &
thrombocytosis in a later stage
8. WBC >30,000/mm2
9. ESR > 101 mm/hr and high CRP
10. Elevated ESR and CRP > 30 days or
recurrent elevation
11. Low serum albumin & adjusted IgG
levels

Koren G, et al , J Pediatr (1986)

Beiser AS, et al, Am J Cardiol (!998)
Daniels SR, et al Am J Dis Child
(1987)
 KAWASAKI DISEASE:
2D-echocardiography

Structural abnormalities
in the coronary arteries
Valvular abnormalities
Pericardial effusion

Dilated left coronary artery

KAWASAKI DISEASE: Angiography

Left coronary
angiogram (LAO):
huge aneurysm of
left anterior
descending artery
KAWASAKI DISEASE: Angiography

Multiple aneurysms in coronary arteries

Kawasaki Disease: Cardiac Imaging

CT scan
coronary aneurysms, stenosis, intimal
hypertrophy, wall abnormalities
MRI
myocardial ischemia
Multi-slice CT scan
 KAWASAKI DISEASE: Treatment

1. ASPIRIN
Anti-inflammatory dose in acute
phase= 80-100 mg/kg/day given
every 6 hours
Antiplatelet / anti-thrombotic dose:
3-5 mg/kg/day single dose 2-3
days after the fever lyzes; given
for 6 weeks & continued indefinitely
if coronary abnormalities are
observed
KAWASAKI DISEASE: Treatment

2. IV Immunoglobulin
Acute phase:
2 g/kg given single infusion for
12 hours OR
400 mg/kg/day for 4 days
leads to rapid defervescence of
fever & more rapid normalization of
acute phase reactants compared to
treatment with ASA alone
improves myocardial function
KAWASAKI DISEASE
Mechanism of action of IVIG:
UNKNOWN
With generalized anti-inflammatory
effect
Possible:
1. Modulation of cytokine production
2. Neutralization of bacterial superantigens or
other etiologic agents
3. Augmentation of T-cell suppressor activity
4. Suppression of antibody synthesis
5. Provision of anti-idiotypic antibodies

Circulation, 2004; 110

Kawasaki Disease:Treatment
3. Heparin/ Warfarin
Indicated in large coronary
aneurysms with or without thrombus
IV heparin or subcutaneous low
molecular weight (LMWH) heparin
Warfarin dose titrated to target INR
of 2 2.5; should be given with low
dose aspirin
Disadvantage: interactions with Vit K
rich food and many drugs
Kawasaki Disease: Treatment
4. Corticosteroids- ONLY indicated for
IVIG resistant patients
(15% of patients have resistance to 1st
IVIG)
Varying responses to addition of
steroids to IVIG

IKI 2008:T. Suzuki et al: as prime therapy, beneficial in those who have
high risk of being IVIG non-responders
H. Suzuki et al: worse coronary outcomes
KAWASAKI DISEASE
TREATMENT of Patients Who Failed
to Respond to Initial Therapy:

Retreatment with IVIG 2g/kg

Steroids: should be restricted to

children in whom 2 infusions of IVIG
have been given
IV Methylprednisolone: 30 mg/kg for
2-3 hours once daily for 1 to 3 days

Circulation 2004;110
KAWASAKI DISEASE
TREATMENT of Patients Who Failed to
Respond to Initial Therapy:
Infliximab (anti-TNF-alpha agent)- given
with 2nd dose of IVIG in IVIG resistant
patients
Others: Plasma exchange
Ulinastatin
Abciximab
Monoclonal antibodies
Cytototoxic agents: cyclophosphamide

Circulation, 2004:110
KAWASAKI DISEASE: Treatment

4. Anti-CHF regimen when necessary

inotropes
diuretics
vasodilators
KAWASAKI DISEASE:
Treatment Failure

persistent or recrudescent
fever 36 hours after
completion of initial IVIG
infusion
KAWASAKI DISEASE:Prevention of
Thrombosis in Patients with
Coronary Disease

1. Antiplatelet therapy: Aspirin,

dipyridamole, clopidogrel
2. Anticoagulant therapy: Warfarin,
heparin
KAWASAKI DISEASE: Surgical &
Catheter Coronary Interventions
Cardiac Catheterization:
Balloon angioplasty
Rotational Ablation
Stent Placement

Coronary artery bypass grafts for obstructive

lesions

Indications for Cardiac Transplantation:

Severe myocardial dysfunction
Severe ventricular arrhythmia
Severe coronary lesions
KAWASAKI DISEASE:
Long-Term Follow-up

Spontaneous regression of
aneurysms (50-70%) in 1-2
years
Factors which favor regression:
< 1 year age of onset of KD
Aneurysm: small size, fusiform
morphology, location in distal
coronary segment
Kawasaki Disease:
Long-Term Follow-up

Atherosclerosis, lipid
abnormalities, late coronary
artery lesions
Need for counselling for healthy
life-style (proper diet & exercise)

B. McCrindle (IKS, 2008)

KAWASAKI DISEASE:
Important Parameters for Follow-up

1. After baseline 2D-echo, repeat study:

2-4 weeks after onset of illness
4-6 months after illness
9-12 months after illness
OR as deemed clinically indicated
KAWASAKI DISEASE:
Important Parameters for Follow-up

2. After baseline ESR & Platelet Count

REPEAT
2-3 weeks after onset of illness
6-8 weeks following onset
guide in discontinuation of salicylates

3. ECG as necessary
Summary
Kawasaki Disease is an acute multisystem
vasculitis of infancy and childhood.
The standard criteria for diagnosis
includes: fever for 5days or more plus the
presence of 4/5 of the ff: nonpurulent
conjunctivitis, oral mucosal changes,
unilateral cervical lymphadenopathy,
polymorphous rashes and swelling of
hands/feet.
Summary
Treatment is intravenous immunoglobulin
and aspirin.
Long-term follow-up of children with
Kawasaki Disease is advisable.
Thank you.