Kawasaki Disease July 3, 2013

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

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: presumed bacterial adenitis; given antibiotics after which developed rash & mucosal changes

Allergy

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


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


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.

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Kawasaki Disease July 3, 2013