The Journal of Pediatrics
Volume 149, Issue 3 , Pages 291-292, September 2006

Revisiting steroids in the primary treatment of acute Kawasaki disease

  • Jane C. Burns, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Dr Jane C. Burns, Dept. of Pediatrics, UCSD School of Medicine, 9500 Gilman Dr., La Jolla, CA 92093-0830.

Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, CA

Article Outline

Abbreviations:  KD, Kawasaki disease , IVIG, Intravenous gamma globulin

 

It has been 3 years since the topic of steroid use for primary treatment of patients with Kawasaki disease (KD) was last explored in these editorial pages, and still no consensus has been reached.1 The debate about steroid use in this self-limited vasculitis is not a new topic. In his 1967 report of 50 cases, Dr Kawasaki described the treatment of 22 (44%) of his original patients with combinations of intravenous, intramuscular, and oral steroids.2 He concluded that it was “very difficult to evaluate the efficacy of this therapeutic modality.” In this issue of The Journal, Inoue et al report the results of a Japanese multicenter, prospective randomized trial of intravenous gamma globulin (IVIG) plus aspirin with or without the addition of corticosteroids (methylprednisolone 2 mg/kg/day).3 They conclude that patients treated with the regimen that included steroids had a more rapid fall in C-reactive protein levels, more rapid resolution of fever, and fewer coronary artery abnormalities at 1 month post-treatment. In addition, fewer of the steroid-treated patients met the study definition for initial treatment failure requiring additional therapy. Overall, 17 patients (19.3%) treated with IVIG plus aspirin versus 8 patients (8.9%) treated with this regimen plus steroids required additional therapy for either persistent or recrudescent fever.

See related article, p 336

There are several limitations to this study that preclude generalizing these findings to patients outside of Japan. First and foremost is the IVIG treatment regimen (1g/kg administered intravenously on two consecutive days) used by the Japanese group. Since the publication of the IVIG trial by the US Multicenter Kawasaki Disease Study Group in 1991, it has been the standard of care in the US to treat with 2 g/kg of IVIG as a single infusion.4 This regimen was shown to be superior to a 4-day regimen (400 mg/kg/day for 4 days) with respect to total days of fever and serum markers of inflammation as surrogates for coronary artery abnormalities. In the US, where hospitalization charges account for a high percentage of the cost of medical care, the 2 g/kg IVIG regimen shortened hospital stays and thus had both a medical and economic benefit for US patients.5 No randomized clinical trials have directly compared administration of 1 g/kg for 2 days with 2 g/kg single infusion, and equivalency cannot be assumed. Other important differences in the care of US patients with KD are (a) the use of higher initial aspirin doses (80-100 mg/kg/day in the US vs 30 mg/kg/day in Japan); (b) the use of dipyridamole in the Japanese patients in this study; (c) a different definition of treatment failure (oral or rectal temperature >38.0°C or 100.4°F at 36 hours after completion of the first infusion in the US vs axillary temperature >37.5°C or 99.5°F at 24 hours after the second day of IVIG administration in Japan); and (d) the use of more conservative criteria for coronary artery abnormalities that has been shown to underestimate the frequency of coronary artery dilatation.6 It is also important to note the emerging data on the genetic influences on disease susceptibility and outcome in KD, which may mean that clinical trial results in Japanese patients cannot necessarily be applied to mixed ethnicity populations such as those found in the US.7, 8

In interpreting the results of this trial, the reader should make note of several potential sources of bias. First, only one-third of study eligible patients were successfully enrolled in the trial. Second, the primary end point of the trial (coronary artery abnormalities) was based on interpretation of echocardiograms that were read by cardiologists who had knowledge of the patient’s treatment assignment. Third, the trial was stopped after enrollment of only one-half of the projected sample because of time constraints and the slow rate of patient enrollment.

The difficulties in studying adjuvant primary therapies for children with acute KD stem from the fact that IVIG plus aspirin is a remarkably effective therapy for this disorder. In the two US multicenter clinical trials of IVIG that enrolled more than 700 patients, only 3% to 5% developed coronary artery aneurysms.4, 9 Thus, the large sample size estimates make it difficult to carry out a randomized clinical trial of any new therapy to compare with IVIG in this disease. The primary outcome that matters for any therapy trial in KD is the prevention of coronary artery damage. Therefore, centralized reading of echocardiograms by cardiologists blinded to the patient treatment assignment is critical, but at the same time greatly increases the cost and logistical complexity of the study. Another obstacle to the design of clinical trials to improve outcomes in patients with KD is that we have a poor understanding of how IVIG works to abrogate the inflammation in this disease. In addition, we have no idea why some patients fail to respond to this usually effective therapy. Without an understanding of the mechanism of action of IVIG and the patient characteristics that influence success or failure of this treatment, it is very difficult to empirically design regimens that will improve outcomes.

Perhaps instead of funding large, multicenter clinical trials, resources would be better spent defining the phenotypic and genotypic characteristics of the 10% to 15% of patients who fail initial therapy.10, 11 Because failure to respond to the initial IVIG infusion is highly associated with worse coronary artery outcome, these are the children who should be targeted with additional interventions that are unnecessary for the majority of patients who respond so dramatically to current standard therapy with IVIG plus aspirin. Recent efforts to devise predictive scores for initial IVIG failure, if validated in independent populations, will permit investigation of adjuvant primary therapies only in the patients who may benefit from additional treatment. Addition of genetic markers may help to further define this at-risk subpopulation of patients. The study of adjuvant therapies in these patients will improve the risk/benefit ratio, reduce costs, and limit potential toxicities or adverse events to the subpopulation at greatest risk of coronary artery damage. Above all, we must abide by the doctrine of primum non nocere and carefully consider the wisdom of additional primary therapies for the 85% of KD patients who respond to current standard treatment and require no further intervention.

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References 

  1. Shulman ST . Is there a role for corticosteroids in Kawasaki disease? . J Pediatr . 2003;142:601–603
  2. Kawasaki T . [Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children] . Arerugi . 1967;16:178–222 Shike H, Burns JC, Shimizu C. English translation of Dr. Tomisaku Kawasaki’s original report of fifty patients in 1967 (Japanese). Pediatr Inf Dis J. 2002;21:993. Article plus additional online files.
  3. Inoue Y , Okada Y , Tomomasa T , Takeuchi K , Morikawa A . A multicenter prospective randomized trial of corticosteroids in primary therapy for Kawasaki disease (clinical course and coronary artery outcome) . J Pediatr . 2006;149:336–341
  4. Newburger JW , Takahashi M , Beiser AS , Burns JC , Bastian J , Chung KJ , et al.   A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome . N Engl J Med . 1991;324:1633–1639
  5. Klassen TP , Rowe PC , Gafni A . Economic evaluation of intravenous immune globulin therapy for Kawasaki syndrome . J Pediatr . 1993;122:538–542
  6. de Zorzi A , Colan SD , Gauvreau K , Baker AL , Sundel RP , Newburger JW . Coronary artery dimensions may be misclassified as normal in Kawasaki disease . J Pediatr . 1998;133:254–258
  7. Burns JC , Shimizu C , Gonzalez E , Kulkarni H , Patel S , Shike H , et al.   Genetic variations in the receptor-ligand pair CCR5 and CCL3L1 are important determinants of susceptibility to Kawasaki disease . J Infect Dis . 2005;192:344–349
  8. Minami T , Suzuki H , Takeuchi T , Uemura S , Sugatani J , Yoshikawa N . A polymorphism in plasma platelet-activating factor acetylhydrolase is involved in resistance to immunoglobulin treatment in Kawasaki disease . J Pediatr . 2005;147:78–83
  9. Newburger JW , Takahashi M , Burns JC , Beiser AS , Chung KJ , Duffy CE , et al.   The treatment of Kawasaki syndrome with intravenous gamma globulin . N Engl J Med . 1986;315:341–347
  10. Kobayashi T , Inoue Y , Takeuchi K , Okada Y , Tamura K , Tomomasa T , et al.   Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease . Circulation . 2006;113:2606–2612
  11. Muta H , Ishii M , Furui J , Nakamura Y , Matsuishi T . Risk factors associated with the need for additional intravenous gamma-globulin therapy for Kawasaki disease . Acta Paediatr . 2006;95:189–193

PII: S0022-3476(06)00680-9

doi:10.1016/j.jpeds.2006.07.016

Refers to article:

  • A multicenter prospective randomized trial of corticosteroids in primary therapy for Kawasaki disease: Clinical course and coronary artery outcome

    Yoshinari Inoue, Yasunori Okada, Makoto Shinohara, Tohru Kobayashi, Tomio Kobayashi, Takeshi Tomomasa, Kazuo Takeuchi, Akihiro Morikawa, Gunma Kawasaki Disease Study Group
    The Journal of Pediatrics September 2006 (Vol. 149, Issue 3, Pages 336-341.e1)

The Journal of Pediatrics
Volume 149, Issue 3 , Pages 291-292, September 2006

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