What are the new guidelines for treating pediatric patients suspected of having Kawasaki disease?

New Guidelines for Kawasaki Disease

Diagnostic Criteria and Recognition

The American Heart Association recommends diagnosing Kawasaki disease (KD) based on fever ≥5 days plus at least 4 of 5 principal clinical features: bilateral non-purulent conjunctival injection, oral mucosal changes (including strawberry tongue and cracked lips), polymorphous rash, extremity changes (erythema or edema of hands/feet), and cervical lymphadenopathy ≥1.5 cm. 1, 2, 3

Incomplete Kawasaki Disease Algorithm

For children with fever ≥5 days but only 2-3 principal features, the following stepwise approach is critical:

• Immediately measure ESR and CRP if only 2-3 clinical features are present 1, 2, 3
• If ESR ≥40 mm/hour and/or CRP ≥3.0 mg/dL, obtain: complete blood count with differential, serum albumin, serum transaminases, and urinalysis 1, 2
• Perform urgent echocardiography if laboratory evidence of inflammation is present or if ≥3 supplemental laboratory criteria are met 1, 2, 3
• Incomplete KD is particularly common in infants <1 year, who paradoxically have the highest risk of coronary artery aneurysms if untreated 1, 4

Critical pitfall: Children with fever ≥7 days without clear etiology should undergo laboratory assessment even without KD features, and echocardiography should be performed if inflammation is documented 1

Initial Treatment Protocol

All patients meeting diagnostic criteria should receive IVIG 2 g/kg as a single infusion over 10-12 hours combined with high-dose aspirin 80-100 mg/kg/day divided into four doses, initiated as early as possible within the first 10 days of fever onset. 1, 2, 3

Aspirin Dosing Regimen

• High-dose aspirin (80-100 mg/kg/day in 4 divided doses) should be continued until the patient is afebrile for 48-72 hours 1, 2
• Transition to low-dose aspirin (3-5 mg/kg/day as single daily dose) after defervescence and continue for 6-8 weeks if no coronary abnormalities are present 1, 2
• Continue low-dose aspirin indefinitely if coronary artery abnormalities develop 1, 2

Treatment Timing Considerations

• IVIG should still be administered to children presenting after day 10 of illness if they have ongoing systemic inflammation (ESR or CRP elevation) together with persistent fever or coronary artery aneurysms (Z score >2.5) 1, 5
• Treatment within 10 days significantly reduces coronary artery abnormality risk from 15-25% to approximately 5% for any abnormality and 1% for giant aneurysms 1, 4
• The research evidence confirms that delayed treatment beyond 10 days increases risk of coronary abnormalities, though neither occurrence nor resolution timing of lesions correlates strictly with IVIG timing once abnormalities develop 5

Management of IVIG-Resistant Disease

IVIG resistance, defined as persistent or recrudescent fever ≥36 hours after completion of initial IVIG infusion, occurs in 10-20% of patients and requires escalation of therapy. 1, 2

Treatment Algorithm for IVIG Resistance

First-line for resistance: Administer a second dose of IVIG 2 g/kg as a single infusion 1, 2

Second-line options (if fever persists after second IVIG dose):

• Intravenous methylprednisolone 20-30 mg/kg (maximum 1 gram) daily for 1-3 days, or 1, 2
• Infliximab 5 mg/kg IV as a single infusion over 2 hours (both show similar efficacy) 1, 2

Third-line option: Cyclosporine 4-6 mg/kg/day orally for highly refractory cases, with monitoring for hyperkalemia (occurred in 32% of patients in trials) 2

Primary Intensification for High-Risk Patients

• For patients predicted to be IVIG-resistant using validated risk scores, adding corticosteroids to initial IVIG therapy reduces coronary artery aneurysms 2
• Major caveat: Japanese risk-stratification scores (Kobayashi, Egami) have poor sensitivity in non-Japanese populations, making it difficult to identify which patients benefit from primary steroid therapy 2
• The RAISE protocol (prednisolone 2 mg/kg/day IV for 5 days followed by oral taper) has shown efficacy in high-risk Japanese patients 2

Long-Term Anticoagulation Based on Coronary Artery Status

The American Heart Association stratifies long-term management based on maximal coronary artery dimensions:

No Coronary Abnormalities

• Low-dose aspirin 3-5 mg/kg/day until 6-8 weeks after disease onset, then discontinue 1, 2

Small Coronary Aneurysms (Z score 2.5-5)

• Low-dose aspirin indefinitely 1, 2

Moderate Aneurysms (Z score 5-10 or absolute dimension 4-6 mm)

• Low-dose aspirin plus clopidogrel 1 mg/kg/day (maximum 75 mg/day) 1, 2

Giant Aneurysms (Z score ≥10 or absolute dimension ≥8 mm)

• Low-dose aspirin plus warfarin with target INR 2.0-3.0, or 1, 2
• Low-dose aspirin plus therapeutic-dose low-molecular-weight heparin for infants or children where warfarin monitoring is difficult 1, 2

Monitoring and Follow-Up

Echocardiography should be performed at diagnosis, 2 weeks, and 6-8 weeks after treatment initiation. 1, 3

• The highest risk for coronary artery thrombosis occurs within the first 3 months, with peak incidence at 15-45 days 2
• Frequent echocardiography and ECG evaluation during the first 3 months are essential, especially for patients with giant coronary aneurysms 2
• CRP is more accurate than ESR for monitoring inflammation after IVIG therapy, as IVIG elevates ESR 1

Important Safety Considerations and Pitfalls

Annual influenza vaccination is mandatory for children on long-term aspirin therapy due to Reye's syndrome risk during influenza infection 1, 2, 3

Ibuprofen must be avoided in children taking aspirin as it antagonizes the irreversible antiplatelet effect of aspirin 1, 2

Measles, mumps, rubella, and varicella immunizations should be deferred for 11 months after high-dose IVIG administration due to interference with vaccine efficacy 1, 2

Coombs-positive hemolytic anemia can complicate IVIG administration, especially in individuals with AB blood type, requiring monitoring 1

Aseptic meningitis may occur after IVIG infusion but resolves quickly without neurological sequelae 1

Diagnostic Pitfalls to Avoid

• Do not dismiss KD because conjunctivitis is absent—incomplete KD is more common in infants <1 year who have paradoxically higher rates of coronary aneurysms 1, 2
• Do not attribute strawberry tongue and rash solely to antibiotic reaction if the patient was initially treated for presumed bacterial infection—this is a classic missed diagnosis scenario 2
• Features that help exclude KD include: exudative conjunctivitis or pharyngitis, discrete intraoral lesions, bullous or vesicular rash, and generalized lymphadenopathy 1
• Young infants (<6 months) with prolonged fever (≥7 days) require echocardiography even with minimal clinical features due to high risk of coronary complications 2, 4