Question

• Does the addition of corticosteroids to IVIG and aspirin in the treatment Kawasaki disease (KD) improve outcomes?

Clinical Bottom Lines

1. In this small, single center, randomized control trial, the addition of intravenous methylprednisolone to standard treatment of KD with IVIG and high dose aspirin resulted in faster resolution of fever, more rapid improvement of inflammatory markers and shorter length of hospitalization compared to standard treatment alone.¹
2. No significant differences between treatment groups were noted in coronary dimensions, but statistical power was limited.
3. Steroid therapy should be further assessed in a large, randomized and blinded trial before addition of steroids becomes standard treatment for KD.

Summary of Key Evidence

1. A prospective, single-center (Children’s Hospital Boston), pilot, randomized trial between February 1998 through November 2000.¹
2. 39 subjects meeting the criteria for KD were entered in the study, and were randomly assigned (stratified by sex and age [<1yr,>1yr]), to receive intravenous methylprednisolone (IVMP), 30mg/kg, prior to IVIG and aspirin or IVIG and aspirin alone.
3. Effectiveness of treatment was assessed by duration of fever (T≥38.3), length of hospitalization, need for IVIG retreatment, laboratory measures of systemic inflammation (including ESR, CRP), and coronary Z scores and incidence of aneurysms.
4. Laboratory tests and Echocardiograms were preformed on all subjects at 3 standard times:  baseline, on illness day 14 (range 11-21), and on illness day 42 (range 22-63).
5. The IVMP group had shorter mean duration of fever (P=0.012), shorter hospital stays (P=.010), and at 6 weeks had lower ESR, CRP and IgA (P=.027, P=.011, P=.017 respectively).  No statistical significance was noted in coronary dimensions.
6. The IVMP group had fewer patients, 11%, requiring retreatment with IVIG compared to 25% in the standard group, resulting in NNT of 8.
7. IVMP was well tolerated.  The overall occurrence of at least one event during hospitalization (headaches, rigors, vomiting, CHF) was less frequent among children in IVMP group (P=.049), but no individual event differed significantly in its frequency between treatment groups.
8. Neither patients or physicians were blinded to treatment, but outcome markers were measured objectively and echo readers were unaware of the patient’s treatment status.
9. Other limitations of the study included:  small sample size does not provide enough power, inconsistent definition of fever and the use of acetaminophen, the relatively older age of the subjects, and the possibility that the IVIG and aspirin group was initially somewhat more ill based on initial laboratory evaluation.²

Additional Comments

• The argument to use steroids in KD stem from the fact that KD is a multi-organ vasculitis and coronary artery aneurysms, the most significant complication of KD, are produced by immune-mediated injury.  Steroids are a mainstay of treatment for all other vasculitides and immune mediated diseases.
• Inflammatory markers remain elevated for weeks after KD even if treated with IVIG.  It is has been shown that persistent inflammation and higher levels of IgA have been associated with increased risk of developing coronary abnormalities and long term morbidity.³
• Steroids have been used frequently in KD refractory to IVIG with some good results, but randomized controlled studies are limited on this subject as well.⁴

Citation

1. Sundell RP, Baker AL, Fulton DR, Newburger JW.  Coricosteroids in the initial treatment of Kawasaki disease.  J Pediatr 2003;142: 611-6.
2. Shulman ST.  Is there a role for corticosteroids in Kawasaki disease?  J Pediatr 2003;142:601-3.
3. Morikawa Y, Ohashi Y, Harada K, Asai T, OkawaS, et al.  Coronary risks after high-dose gamma-globulin in children with Kawasaki disease.  Pediatr Int 2000;42:464-9.
4. Wright DA, Newberger JW, Baker A, Sundel R.  Treatment of immune globulin resistant Kawasaki disease with pulsed doses of corticosteroids.  J Pediatr 1996;128:146-9.

CAT Author: Tarin Gitlin, MD

CAT Appraisers: Alex Kemper, MD

Date appraised: April 21, 2004