What is the role of steroids in treating Kawasaki disease?

Steroids in Kawasaki Disease

Primary Treatment Recommendation

For high-risk Kawasaki disease patients predicted to be IVIG-resistant (using validated scoring systems), add corticosteroids to initial IVIG and aspirin therapy to reduce coronary artery abnormalities and treatment failure. 1

The 2017 American Heart Association guidelines establish that adding corticosteroid therapy to IVIG and aspirin in primary therapy lowers the prevalence of coronary artery abnormalities, duration of fever, and inflammation among children at highest risk for IVIG resistance. 1 However, a critical caveat exists: Japanese scoring systems (Kobayashi, Egami, Sano) have low sensitivity in North American populations, making risk stratification outside Japan challenging. 1

Evidence-Based Steroid Regimens

For Primary Treatment in High-Risk Patients

Two validated regimens exist for initial therapy:

• RAISE protocol (strongest evidence): Intravenous prednisolone 2 mg/kg/day for 5 days followed by oral taper over weeks, combined with IVIG 2 g/kg and aspirin 30 mg/kg/day. 1 The RAISE study (248 patients) demonstrated lower incidence of coronary artery abnormalities, lower coronary artery Z scores, and more rapid fever resolution. 1

• Pulse methylprednisolone: Single dose of 30 mg/kg IV with IVIG 2 g/kg and aspirin. 1 Multiple Japanese studies showed lower incidence of coronary abnormalities and treatment resistance compared to IVIG alone. 1

The Post-RAISE study (2018) verified these findings in 724 predicted IVIG non-responders, showing coronary artery abnormalities in only 5.9% using AHA criteria and 3.8% using Japanese criteria. 2

For IVIG-Resistant Disease (Rescue Therapy)

After first IVIG failure, consider steroids as an alternative to second IVIG dose, particularly with cardiac involvement:

• Pulse methylprednisolone: 30 mg/kg/day IV for 3 consecutive days, followed by oral taper. 1, 3 Studies show shorter fever duration and lower medical costs compared to IVIG retreatment. 1

• Longer prednisolone course: 2 mg/kg/day IV tapered over 2 weeks after CRP normalizes. 1 A retrospective study of 359 IVIG-resistant patients showed significantly lower rates of persistent fever and coronary abnormalities with this regimen. 1

After second IVIG failure, steroids become a primary option before considering other immunosuppressives. 1, 3 The 2004 AHA guidelines recommend restricting steroids to children in whom 2 infusions of IVIG have been ineffective, though the 2017 update acknowledges earlier use in high-risk patients. 1

Critical Limitations and Pitfalls

The major limitation is identifying high-risk patients outside Japan. 1 The Kobayashi, Egami, and Sano scoring systems have insufficient accuracy in North American populations, making it difficult to determine which patients warrant primary steroid therapy. 1 Until better predictive instruments are developed for heterogeneous populations, routine primary steroid use in all patients cannot be recommended. 1

For standard-risk patients, a North American trial showed no benefit. 1 The Pediatric Heart Network's randomized trial of single-dose pulse methylprednisolone (30 mg/kg) added to IVIG showed similar coronary outcomes overall, though post-hoc analysis suggested benefit in highest-risk subgroups. 1

Practical Algorithm

Step 1: Risk stratification at diagnosis

• If high-risk features present (severe inflammation, young age <1 year, laboratory abnormalities suggesting IVIG resistance): Consider primary steroid therapy with IVIG. 1, 3
• If standard risk: IVIG 2 g/kg + aspirin alone. 1

Step 2: After first IVIG (36+ hours post-infusion)

• If persistent/recurrent fever: Second IVIG 2 g/kg OR pulse methylprednisolone 30 mg/kg × 3 days. 1, 3
• If cardiac involvement (left atrial dilation, coronary changes): Favor steroids over second IVIG. 3

Step 3: After second IVIG failure

• Longer prednisolone course (2 mg/kg/day tapered over 2-3 weeks) OR infliximab 5 mg/kg. 1, 3
• Both pulsed and longer-term steroid regimens remain acceptable options. 1

Step 4: Refractory to all above

• Cyclosporine 4-6 mg/kg/day orally (monitor for hyperkalemia). 1, 3, 4
• Plasma exchange reserved for patients failing all medical therapies. 1, 3, 4

Safety Considerations

Serious adverse events with primary IVIG plus prednisolone occurred in only 1.7% of patients in the Post-RAISE study, with hypertension and bacteremia being the steroid-related complications. 2 The longer steroid courses in Japanese studies may suppress persistent vascular inflammation more effectively than pulse therapy, though no head-to-head trials exist. 1

Steroids reduce fever duration and inflammatory markers consistently across all studies, but their effect on coronary outcomes varies by population and risk stratification. 1 The meta-analysis including multiple Japanese trials found that combination corticosteroid with standard-dose IVIG as initial treatment in high-risk patients reduced coronary artery abnormalities. 1