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
Genitourinary Gastrointestinal tract
Arthritis Arthralgia
Urethritis meatitis Diarrhea Vomiting abdominal pain hepatic dysfunction gallbladder hydrops Extreme hyperirritability Aseptic meningitis Sensorineural loss

Central Nervous System

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 Acute Febrile Phase (1-10 days) 2. Subacute Phase (11-20 days) 3. Convalescent Phase (21-60 days)
1.
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 Desquamation

Prominent features: 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 Sterile pyuria Allergy

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

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
1.

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. 7.

Anemia 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. 2. 3. 4. 5.

Modulation of cytokine production Neutralization of bacterial superantigens or other etiologic agents Augmentation of T-cell suppressor activity Suppression of antibody synthesis 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. 2.

Antiplatelet therapy: Aspirin, dipyridamole, clopidogrel 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.