Is there a role for corticosteroids in Kawasaki disease?
2003; Elsevier BV; Volume: 142; Issue: 6 Linguagem: Inglês
10.1067/mpd.2003.258
ISSN1097-6833
Autores Tópico(s)Cardiac Structural Anomalies and Repair
ResumoSee related article, p 611 . "The arrival of a good clown exercises more beneficial influence upon the health of a town than twenty asses laden with drugs." —Thomas Sydenham (1624-1689) Sydenham, considered to be the greatest physician of the 17th century, revived the Hippocratic method of observation and experience.1Garrison FH History of medicine.4th ed. WB Saunders, Philadelphia (PA)1929Google Scholar His disdain for most of the "medicines" of his time was clearly evident. But I believe that even Sydenham would be impressed today with the effective therapies available to treat the malady known as Kawasaki disease (KD), named for Dr Tomisaku Kawasaki of Tokyo.2Kawasaki T Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children.Jap J Allergol. 1979; 16: 178-222Google Scholar Classic studies by Newburger et al,3Newburger 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: 341-347Crossref PubMed Scopus (1163) Google Scholar, 4Newburger JW Takahashi M Beiser AS Burns JC Bastian J Chung KJ et al.A single intravenous infusion in the treatment of acute Kawasaki syndrome.N Engl J Med. 1991; 324: 1633-1639Crossref PubMed Scopus (998) Google Scholar as well as by Japanese investigators during the 1980s and early 1990s, firmly established the dramatic effect of the combination of aspirin and intravenous immunoglobulin (IVIG) on: (1) the acute inflammatory manifestations of KD, and (2) prevention of the coronary artery abnormalities that are the most significant complications of this fascinating disorder. Meta-analyses have emphasized the importance of the total dose of IVIG (expressed as gm/kg body weight).5Terai M Shulman ST Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose.J Pediatr. 1997; 131: 888-893Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar, 6Durongpisitkul K Gururaj VJ Park JM Martin CF The prevention of coronary artery aneurysm in Kawasaki disease.Pediatr. 1995; 96: 1057-1061PubMed Google Scholar Current standard primary therapy for acute KD is a single dose of IVIG at 2 gm/kg with aspirin at 80 to 100 mg/kg/day. In Japan, aspirin is given at 30 to 50 mg/kg/day and, because of governmental regulations, the IVIG dose is often given over 4 to 5 days, a regimen shown to be less effective than a single large dose of IVIG.4Newburger JW Takahashi M Beiser AS Burns JC Bastian J Chung KJ et al.A single intravenous infusion in the treatment of acute Kawasaki syndrome.N Engl J Med. 1991; 324: 1633-1639Crossref PubMed Scopus (998) Google Scholar KD is a form of vasculitis, but a vasculitis with several very unusual characteristics. These include its target age, its predilection for affecting the coronary arteries, its epidemiologic and clinical features that strongly suggest an infectious etiology, its self-limited nature, and its responsiveness to appropriate doses of IVIG and aspirin in ~90% of patients. The ideal therapy for KD would target the etiologic agent(s) of the illness, which unfortunately remain elusive despite recent advances.7Rowley AH Shulman ST Mask CA Baker SC Oligoclonal IgA response in the vascular wall in acute Kawasaki disease.J Immunol. 2001; 166: 1334-1343Crossref PubMed Scopus (153) Google Scholar Of course, most vasculitides are treated with corticosteroids or other anti-inflammatory agents, and it is not surprising that they have been considered for the treatment of KD as well. The pilot report by Sundel et al, published in this issue of The Journal, evaluates corticosteroids as an adjunct to IVIG and salicylates for primary therapy of KD.8Sundel RP Baker AL Fulton DR Newburger JW Corticosteroids in the initial treatment of Kawasaki disease.J Pediatr. 2003; 142: 611-616Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar In reviewing the published experience with corticosteroids in KD, it is important to distinguish between its use as primary therapy and as "rescue therapy " for KD. Most previous reports of corticosteroids or other agents, including cytotoxic drugs,9Wallace CA French JW Kahn SJ Sherry DD Initial intravenous gammaglobulin treatment failure in Kawasaki disease.Pediatrics. 2000; 105: e78Crossref PubMed Scopus (257) Google Scholar cyclosporin,10Raman V Kim J Sharkey A Chatila T Response of refractory Kawasaki disease to pulse steroid and cyclosporin A therapy.Pediatr Infect Dis J. 2001; 20: 635-637Crossref PubMed Scopus (55) Google Scholar or plasma exchange,11Takagi N Kihara M Yamaguchi S Tamura K Yabana M Tokita Y et al.Plasma exchange in Kawasaki disease.Lancet. 1995; 346: 1307PubMed Scopus (32) Google Scholar have focused on these agents mainly as "rescue therapy " for patients whose KD has failed to respond satisfactorily to IVIG and aspirin treatment. These reports are generally difficult to interpret because of the self-limited nature of clinical symptoms in acute KD. Indeed, the most controversial management issues in KD today relate to the best treatment of the child whose KD fails to respond to IVIG and aspirin with defervescence and clinical improvement, or the child who manifests only a transient benefit from these therapies. Because of both the potential adverse effects of corticosteroids and the efficacy and safety of IVIG, I favor the administration of a second (and, if necessary, a third) 2 gm/kg dose of IVIG and optimizing salicylate therapy before considering corticosteroids as rescue therapy. Our Chicago experience of treating ~1100 patients with KD during the past 24 years includes only two who required corticosteroid therapy. There are several reports of the use of steroids in this setting. In 1996, Wright reported four children with KD who had persistent or recrudescent fever despite receiving a single 2 gm/kg dose of IVIG, and who were treated with 1 to 3 doses of pulsed intravenous methylprednisolone (30 mg/kg), with defervescence and without apparent cardiac complication.12Wright DA Newburger JW Baker A Sundel RP Treatment of immune globulin-resistant Kawasaki disease with pulsed doses of corticosteroids.J Pediatr. 1996; 128: 146-149Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar In 1999, Dahlem reported a child with apparent KD in whom large pleural and pericardial effusions developed 14 days after responding to IVIG and aspirin, and who then responded well to three daily doses of intravenous methylprednisolone 30 mg/kg.13Dahlem PG von Rosenstiel IA Lam J Kuijpers TW Pulse methylprednisolone therapy for impending cardiac tamponade in immunoglobulin-resistant Kawasaki disease.Int Care Med. 1999; 25: 1137-1139Crossref PubMed Scopus (27) Google Scholar In 2000, Dale et al from Great Ormond Street in London reported their experience with oral prednisolone and aspirin in six patients whose KD failed to respond to IVIG and aspirin.14Dale RC Saleem MA Daw S Dillon MJ Treatment of severe complicated Kawasaki disease with oral prednisolone and aspirin.J Pediatr. 2000; 137: 723-726Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar After two doses of IVIG (2 gm/kg) or concomitant with the second dose of IVIG, prednisolone was given as 2 mg/kg/day for two weeks and tapered over six weeks, with reported defervescence and no further coronary artery dilatation. Hashino et al reported results of a comparative study of pulse steroid therapy or additional IVIG in 17 patients with KD whose disease failed to respond to IVIG (2 gm/kg) and aspirin (30 mg/kg/day) and to retreatment with an additional 1 gm/kg IVIG.15Hashino K Ishii M Iemura M Akagi T Kato H Re-treatment for immune globulin-resistant Kawasaki disease.Pediatr Intern. 2001; 43: 211-217Crossref PubMed Google Scholar Nine of these 17 treatment failures received pulse steroid therapy. Clinical improvement was noted, but three of the nine steroid-treated subjects showed transient coronary dilatation coincident with this therapy. The authors therefore suggested caution and careful echocardiographic examinations for patients receiving such therapy. In the pre-IVIG era (before approximately 1985), primary therapy of KD with corticosteroids was reported by Hirohisa Kato et al in 1979.16Kato H Koike S Yokoyama T Kawasaki disease: effect of treatment on coronary involvement.Pediatr. 1979; 63: 175-179PubMed Google Scholar In this nonrandomized study, they observed a particularly high rate (11/17) of coronary aneurysms in children with KD who were treated with 2 to 3 mg/kg/day oral prednisolone for at least two weeks, followed by 1.5 mg/kg/day for two additional weeks. In the same report none of seven children who received oral prednisolone plus aspirin had coronary aneurysms. Nevertheless, steroids were thought to be potentially dangerous as a consequence.16Kato H Koike S Yokoyama T Kawasaki disease: effect of treatment on coronary involvement.Pediatr. 1979; 63: 175-179PubMed Google Scholar Kijima et al reported in 1982 that pulse steroid therapy of KD was associated with improved coronary outcomes.17Kijima Y Kamiya T Suzuki A Hirose O Manabe H A trial procedure to prevent aneurysm formulation of the coronary arteries by steroid pulse therapy in Kawasaki disease.Jap Circ J. 1982; 46: 1239-1242Crossref PubMed Scopus (66) Google Scholar In contrast, Kusakawa in 1983 reported that steroid treatment of KD was associated with higher coronary abnormality rates.18Kusakawa S Long-term administrative care of Kawasaki disease.Acta Paediatr Jap. 1983; 25: 205-209Crossref Scopus (1) Google Scholar In the IVIG era, Nonaka et al reported in 1994 the results of a controlled trial comparing IVIG (400 mg/kg/day × 3 days), aspirin (50 mg/kg/day), and dipyridamole (5 mg/kg/day) to intravenous prednisolone (2 mg/kg/day × 5 days, followed by 2 mg/kg/day orally) plus aspirin and dipyridamole.19Nonaka Z Maekawa K Okabe T Eto Y Kubo M Randomized controlled study of intravenous prednisolone and gamma globulin treatment in 100 cases with Kawasaki disease.in: Proceedings of 5th International Kawasaki Disease Symposium 328-31 Elsevier Science BV, Amsterdam1995: 328-331Google Scholar They found no significant difference in coronary outcomes between the groups, with the steroid group showing shorter duration of fever.19Nonaka Z Maekawa K Okabe T Eto Y Kubo M Randomized controlled study of intravenous prednisolone and gamma globulin treatment in 100 cases with Kawasaki disease.in: Proceedings of 5th International Kawasaki Disease Symposium 328-31 Elsevier Science BV, Amsterdam1995: 328-331Google Scholar Shinohara et al retrospectively reviewed 299 children with acute KD who had been treated with various primary regimens from 1982 to 1998, all receiving aspirin (30 mg/kg/day), dipyridamole, and propranolol, with some receiving, in addition, IVIG 200 or 400 mg/kg/day × 5 days, intravenous prednisolone 2 mg/kg/day until they were afebrile, and then tapered over three weeks, or both IVIG plus prednisolone.20Shinohara M Sone K Tomomasa T Morikawa A Corticosteroids in the treatment of the acute phase of Kawasaki disease.J Pediatr. 1999; 135: 465-469Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar They concluded that the steroid-containing regimens were associated with shorter fever duration and lower rates of coronary abnormalities. The considerable limitations of this retrospective study that used suboptimal IVIG and aspirin dosing were highlighted in an editorial by Newburger.21Newburger JW Treatment of Kawasaki disease: corticosteroids revisited.J Pediatr. 1999; 135: 411-413Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar These studies have small numbers of patients receiving steroid therapy, and have insufficient power to detect an increase or decrease in coronary artery abnormalities prevalence in steroid-treated patients compared with IVIG or aspirin alone. In this issue of The Journal, Sundel et al present data from a small randomized trial (N = 39) of primary therapy for acute KD in which 18 subjects were assigned to receive one dose of intravenous methylprednisolone (30 mg/kg) with 2 gm/kg IVIG and 80 to 100 mg/kg/day aspirin, whereas 21 received IVIG and aspirin alone.8Sundel RP Baker AL Fulton DR Newburger JW Corticosteroids in the initial treatment of Kawasaki disease.J Pediatr. 2003; 142: 611-616Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar The investigators report shorter duration of fever after therapy, shorter hospital stays and lower six-week follow-up mean sedimentation rate and median C-reactive protein values. No differences between treatment groups regarding coronary dimensions were apparent in this pilot study with limited power. Careful examination of this study reveals a number of potential methodologic problems, including its unblinded protocol; the inconsistent definition of fever (eg, ≥38.3°C by any measurement method); use of acetaminophen; introduction of routine diphenhydramine partway through the study; post-hoc exclusion of two subjects; an unexplained high rate of reported adverse events including congestive heart failure, rigors, and vomiting in the IVIG and aspirin group (in excess of that observed previously by the same group of investigators); the use of multiple IVIG products during the study period; and the relatively older age of the study subjects. In addition, analysis of the baseline characteristics of these small groups suggests the likelihood that the IVIG and aspirin group initially was somewhat more ill than the steroid group, with significantly lower serum albumin levels and somewhat higher C-reactive protein and alanine aminotransferase concentrations. So what then can we conclude about the role of corticosteroids in the treatment of KD? With regard to primary therapy , clearly a much larger, well designed randomized trial is necessary to evaluate fully the safety and efficacy of the routine addition of a corticosteroid to the current standard regimen of 2 gm/kg IVIG and high-dose aspirin. Because the latter regimen is highly efficacious, it may actually be quite difficult to improve upon it significantly. Because corticosteroids are associated with a long list of potential adverse reactions including thrombosis, hypertension, and many others, the suggestion that they become used routinely in KD demands careful study. With respect to "rescue therapy " of patients who have failed primary therapy with IVIG and aspirin, the jury is also still out regarding the role of steroids. Our experience is that it is the exceptional patient whose KD fails to respond to a second (or third, if necessary) 2 gm/kg dose of IVIG. Until it can be shown that the benefit of steroid therapy in this circumstance outweighs its potential risks, I remain a skeptic and prefer additional IVIG for primary treatment failures. As physicians for children in the early 21st century, we are fortunate indeed to be able to debate various effective and promising therapeutic options, unlike Dr Sydenham, whose good sense in the 17th century led him to disparage most 17th century medications. Corticosteroids in the initial treatment of Kawasaki disease: Report of a randomized trialThe Journal of PediatricsVol. 142Issue 6PreviewObjective We conducted a prospective randomized trial to determine whether the addition of corticosteroids to intravenous immunoglobulin (IVIG) might improve outcomes in Kawasaki disease (KD). Study design Subjects were randomized to receive IVIG, 2 gm/kg over 10 hours, with or without pulsed-dose intravenous methylprednisolone (IVMP), 30 mg/kg. All patients received standard doses of aspirin (ASA). Groups were similar in baseline demographic and laboratory data. Results Patients in the IVMP plus ASA/IVIG group, compared with those in the ASA/IVIG alone group, had a shorter mean duration of fever ≥38.3°C after initiation of therapy (1.0 ± 1.3 vs 2.4 ± 1.9 days, mean ± SD, P = .012), shorter hospital stays (1.9 ± 0.7 vs 3.3 ± 2.1 days, P = .010), and at six weeks, lower mean erythrocyte sedimentation rate (11.1 ± 5.7 vs 19.4 ± 12.4, P = .027) and median c-reactive protein (0.03 vs 0.08, P = .011, Wilcoxon). Full-Text PDF
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