Corticosteroids for Kawasaki Disease

Abstract & Commentary

Synopsis: Pulsed-dose intravenous methylprednisolone added to the conventional treatment of IVIG and high-dose aspirin, resulted in faster resolution of fever and lower ESR, CRP, and levels of IgA in children with Kawasaki disease.

Source: Sundel RP, et al. Corticosteroids in the initial treatment of Kawasaki disease: Report of a randomized trial. J Pediatr. 2003;142:611-616.

A prospective, randomized trial was conducted among children with Kawasaki disease in Boston between February 1998 and November 2000. Patients were stratified, using a permuted blocks design, by age (< 1 yr, > 1 yr) and sex, and randomly assigned to receive pulsed-dose intravenous methylprednisolone (30 mg/kg; maximum, 1.5 g administered over 3 h) before receiving IVIG. Usual doses of IVIG (2 g/kg, administered over 10 h) and aspirin (20-25 mg/kg administered every 6 h until afebrile for 48 h, then 3-5 mg/kg/24 h as a single dose) were given to all patients.

Of the 39 study subjects, 18 received methylprednisolone with IVIG and aspirin, and 21 received IVIG and aspirin. Children treated with methylprednisolone had lower mean 6:00 pm temperatures (36.3 ± 0.6ºC vs 37.0 ± 0.7ºC; P = .002) and maximum daily temperatures (37.1 ± 1.1ºC vs 39.2 ± 1.1ºC; P = .001), shorter total duration of fever (0.5 days [range, 0-4 days] vs 2 days [range, 0-8 days]; P = .009), and tended to be treated less frequently with acetaminophen during their hospitalization (8/18 [33%] vs 12/21 [57%]; P = .06, Fisher’s exact test). Because of persistent or recrudescent fever for > 48 hr after the initial IVIG dose, 2 children (11%) in the methylprednisolone group required retreatment with a second dose of IVIG (2 g/kg), compared with 5 children (24%) in the control group. One child (5%) who received methylprednisolone had transient hypertension.

At follow-up, children who received methylprednisolone had lower serum IgA levels at 2 weeks (86.8 ± 45.8 mg/dL vs 139.8 ± 67.7 mg/dL; P = .02) and at 6 weeks (53.4 ± 30.4 mg/dL vs 91.8 ± 50.1 mg/dL; P = .017); at 6 weeks, they also had lower mean ESR (11.1 ± 5.7 mm/h vs 19.4 ± 12.4; P = .027) and lower median CRP (0.03 [range, 0.02-0.12] vs 0.08 [range, 0.02-1.78]; P =. 011, Wilcoxon statistic). No other laboratory tests differed significantly between treatment groups at 2 or 6 weeks. At 6 weeks, the groups were similar in their mean absolute coronary dimensions, coronary Z scores, and change in absolute dimension from baseline. One patient (5%) in each group had at least 1 coronary segment with Z score between 2 and 3; none had a coronary segment with Z score > 3.

Comment by Hal B. Jenson, MD, FAAP

Kawasaki disease is a vasculitis that is distinguished by the target age (children < 5 years of age) and its predilection for affecting coronary arteries. The vasculitis of Kawasaki disease is self-limited, but IVIG and high-dose aspirin hasten resolution and reduce the incidence of coronary artery aneurysms. An early nonrandomized study reported a high rate (11/17) of coronary aneurysms among children with Kawasaki disease treated with oral prednisolone 2-3 mg/kg/24 h for at least 2 weeks followed by 1.5 mg/kg/24 h for an additional 2 weeks. Following the publication of that study in 1979, the use of corticosteroids as primary therapy for Kawasaki disease has been generally viewed as potentially deleterious.

The advent of IVIG and high-dose aspirin has proved to be effective management for Kawasaki disease. Nevertheless, the potential for corticosteroids as an adjunct to IVIG and aspirin in reducing the vasculitis remains attractive. A retrospective review of children with Kawasaki disease treated with a variety of regimens from 1982 to 1998 concluded that corticosteroid-containing regimens were associated with shorter duration of fever and lower prevalence of coronary artery aneurysms.1 The findings of this newest study of lower ESR and CRP levels may reflect less vasculitis. Higher post-treatment serum levels of IgA have been previously associated with an increased risk of developing coronary artery aneurysms. This study was not blinded, included only 39 patients, and had follow-up for only 6 weeks. However, these results clearly indicate that a larger, double-blind, placebo-controlled, randomized trial of corticosteroids added to the current regimen of IVIG and high-dose aspirin is warranted.

Because the conventional regimen is effective in 90% of patients, and because of the potential adverse events associated with pulse corticosteroids, the role of corticosteroids as part of primary therapy is uncertain. Most patients with Kawasaki disease respond quickly and very favorably to IVIG and aspirin. For those patients who fail conventional primary therapy, a second (and third, if necessary) dose of IVIG (2 g/kg) continues to be recommended. The benefit of the addition of corticosteroids as part of rescue therapy also is uncertain. Until further studies are completed, parents should be informed of the potential risks as well as benefits if corticosteroids are used as part of the primary or rescue therapy for Kawasaki disease.

Dr. Jenson is Chair, Department of Pediatrics, Director, Center for Pediatric Research, Eastern Virginia Medical School and Children's Hospital of the King's Daughters, Norfolk, VA.

Reference

1. Shinohara M, et al. Corticosteroids in the treatment of the acute phase of Kawasaki disease. J Pediatr. 1999; 135:465-469.