Pulsed corticosteroids of no benefit in Kawasaki disease

Article Outline

• Newburger JW, Sleeper LA, McCrindle BW, Minich LL, Gersony W, Vetter VL, et al. for the Pediatric Heart Network Investigators. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med 2007;356:663-75
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Newburger JW, Sleeper LA, McCrindle BW, Minich LL, Gersony W, Vetter VL, et al. for the Pediatric Heart Network Investigators. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med 2007;356:663-75 

Question Among children with acute Kawasaki disease, does the use of corticosteroids, in addition to standard therapy, decrease the risk of coronary artery abnormalities?

Design Double-blind, placebo-controlled, randomized trial.

Setting Eight centers in North America.

Participants 199 children with 10 or fewer days of fever.

Intervention Patients were randomly assigned to intravenous methylprednisolone, 30 mg per kilogram of body weight or placebo. All patients then received conventional therapy with intravenous immune globulin, 2 g per kilogram, as well as aspirin, 80 to 100 mg per kilogram per day until they were afebrile for 48 hours and 3 to 5 mg per kilogram per day thereafter.

Outcomes The primary outcome was coronary artery dimensions. Secondary outcomes included adverse events, days in the hospital, and days with fever.

Main Results At week 1 and week 5 after randomization, patients in the two study groups had similar coronary dimensions, expressed as z scores adjusted for body-surface area, absolute dimensions, and changes in dimensions. As compared with patients receiving placebo, patients receiving intravenous methylprednisolone had a somewhat shorter initial period of hospitalization (P = 0.05) and, at week 1, a lower erythrocyte sedimentation rate (P = 0.02) and a tendency toward a lower C-reactive protein level (P = 0.07). However, the two groups had similar numbers of days spent in the hospital, numbers of days of fever, rates of retreatment with intravenous immune globulin, and numbers of adverse events.

Conclusions The data do not provide support for the addition of a single pulsed dose of intravenous methylprednisolone to conventional intravenous immune globulin therapy for the routine primary treatment of children with Kawasaki disease.

Commentary The clinical trial reported by Newburger on behalf of the Pediatric Heart Network sets a new standard for clinical trials in Kawasaki disease (KD) that should be emulated by other researchers. Of the 3,528 references listed in Pub Med for “Kawasaki disease,” there are 104 studies reporting data on the use of steroids in acute KD. Despite these numerous publications, the controversy on the role of steroids in the treatment of acute KD has raged on for 40 years. The reason for this is simple: most published clinical trials in KD patients have failed to meet the requirements of adequate sample size, randomized multicenter study design, use of placebos, and blinded third party reading of all echocardiograms. While this optimal study design is expensive and complex, it is also the only way to definitively answer questions regarding optimal therapy. The days of underpowered, single-center clinical trials in KD should be over. The Newburger study now provides a long-awaited answer regarding the role of steroids in conjunction with intravenous gamma globulin in primary therapy of acute KD: there isn’t one. The lack of efficacy of steroids in mitigating coronary artery damage must be telling us something important about the nature of this vasculitis and how it differs from other vasculitides for which steroids are the mainstay of treatment. It is time to do “reverse translational medicine” and take this observation back to the laboratory to learn something fundamental about the immune response in acute KD.