Rosé, Carlos  D.

Taddio, Andrea

Name not available

Treatment of Kawasaki Disease

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Thomas Jefferson UniversityJefferson Digital CommonsDepartment of Pediatrics Faculty Papers Department of PediatricsJune 2007Treatment of Kawasaki DiseaseAndrea TaddioInstitute of Child Health, Trieste, ItalyCarlos D. RoséThomas Jefferson University, crose@nemours.orgLet us know how access to this document benefits youFollow this and additional works at: http://jdc.jefferson.edu/pedsfpPart of the Bioethics and Medical Ethics CommonsThis Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of ThomasJefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarlypublications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers andinterested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion inDepartment of Pediatrics Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact:JeffersonDigitalCommons@jefferson.edu.Recommended CitationTaddio, Andrea and Rosé, Carlos D., "Treatment of Kawasaki Disease" (2007). Department ofPediatrics Faculty Papers. Paper 5.http://jdc.jefferson.edu/pedsfp/5Th e  n e w  e ng l a nd  j o u r na l  o f  m e dic i n en engl j med 356;26 www.nejm.org june 28, 20072746port-wine stains through greater vessel heating and deeper vascular injury.2 The improved tech-nology targets the heterogeneity in blood-vessel sizes that is characteristic of port-wine stains.3Any study evaluating the response of port-wine stains to treatment should include an analysis based on the location of the anatomical malfor-mation and the patient’s age. As compared with other areas of the face and neck, port-wine stains on the center of the face have been shown to re-spond less effectively to treatment and are more likely to recur.4 An aggressive approach to treat-ing infants and young children can also allow for more rapid and complete clearing.5J. Stuart Nelson, M.D., Ph.D.Beckman Laser Institute Irvine, CA 92612  jsnelson@uci.eduRoy G. Geronemus, M.D.New York University Medical Center New York, NY 10016Huikeshoven M, Koster PHL, de Borgie CAJM, Beek JF, van Gemert MJC, van der Horst CMAM. Redarkening of port-wine stains 10 years after pulsed-dye–laser treatment. N Engl J Med 2007;356:1235-40.Nelson JS, Milner TE, Anvari B, Tanenbaum BS, et al. Dy-namic epidermal cooling during pulsed laser treatment of port wine stain: a new methodology with preliminary clinical evalu-ation. Arch Dermatol 1995;131:695-700.Barsky SH, Rosen S, Geer DE, Noe JM. The nature and evolu-tion of port wine stains: a computer-assisted study. J Invest Der-matol 1980;74:154-7.Renfro L, Geronemus RG. Anatomical differences of port-wine stains in response to treatment with the pulsed dye laser. Arch Dermatol 1993;129:182-8.Geronemus RG, Quintana AT, Lou WW, Kauvar A. High-flu-ence modified pulsed dye laser photocoagulation with dynamic cooling of port-wine stains in infancy. Arch Dermatol 2000;136: 942-3.1.2.3.4.5.The Authors Reply: With ongoing research in medicine, investigating the 10-year follow-up re-sults of any medical treatment inevitably leads to somewhat outdated results at the time of presen-tation. This is especially the case in a field that is subject to continuous development, such as pulsed-dye–laser treatment of port-wine stains. As Nelson and Geronemus point out, the results with newer pulsed-dye lasers have been reported to be prom-ising and superior to the results with the laser used in our study. However, to date no controlled comparative studies have shown improved clinical efficacy. Whether the new lasers have improved long-term efficacy remains to be reported; in light of our observation of the recurrence of port-wine stains, we certainly hope they do.No differences or trends in responses to treat-ment related to the anatomical locations of the port-wine stains were observed in either the origi-nal study1,2 or the current follow-up study, possi-bly because of the relatively small number of pa-tients. Furthermore, in the original study, age was shown to have no influence on the response to treatment. Therefore, we refrained from perform-ing age-dependent analyses in the current long-term follow-up assessment.Menno Huikeshoven, M.D., Ph.D. Chantal M.A.M. van der Horst, M.D., Ph.D.Academic Medical Center 1100 DE Amsterdam, the Netherlands  m.huikeshoven@amc.uva.nlvan der Horst CMAM, Koster PHL, de Borgie CAJM, Bossuyt PMM, van Gemert MJC. Effect of the timing of treatment of port-wine stains with the f lash-lamp–pumped pulsed-dye laser. N Engl J Med 1998;338:1028-33.Kauvar AN, Geronemus RG. Treatment of port-wine stains. N Engl J Med 1998;339:635-6.1.2.Treatment of Kawasaki DiseaseTo the Editor: In their trial of pulsed cortico-steroid therapy for primary treatment of Kawa-saki disease, Newburger et al. (Feb. 15 issue)1 report that, as compared with placebo, a single pulsed dose of corticosteroid resulted in a shorter initial period of hospitalization but that the total numbers of days of fever and hospitalization, the rates of retreatment, and the coronary-artery out-comes did not differ significantly between the two groups. The use of a single-dose regimen without tapering most likely contributed to their results. A single application of a corticosteroid, even at a high dose, may have a strong but only short-lived effect, which could therefore be associated with a secondary increase in inflammation.On the basis of nearly 10 years of clinical experience,2 we designed a regimen involving a short intravenous course of prednisolone and subsequent oral administration of prednisolone followed by tapering.3 In a randomized trial per-formed to test the effectiveness of the regimen as an adjunct to intravenous immune globulin, the incidences of retreatment and coronary-artery abnormalities within 1 month after the start of treatment were less frequent in the corticosteroid group than in the group receiving immune globu-Copyright © 2007 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at THOMAS JEFFERSON UNIVERSITY on October 1, 2007 . correspondencen engl j med 356;26 www.nejm.org june 28, 2007 2747lin alone. Our regimen therefore appears to be more efficacious than the control regimen. Never-theless, the optimal corticosteroid regimen re-mains an issue in the primary therapy of Kawa-saki disease.Yoshinari Inoue, M.D. Tohru Kobayashi, M.D. Akihiro Morikawa, M.D.Gunma University Graduate School of Medicine Gunma 371-8511, Japan yinoue@showa.gunma-u.ac.jpNewburger JW, Sleeper LA, McCrindle BW, et al. Random-ized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N Engl J Med 2007;356:663-75.Shinohara M, Sone K, Tomomasa T, Morikawa A. Cortico-steroids in the treatment of the acute phase of Kawasaki disease. J Pediatr 1999;135:465-9.Inoue Y, Okada Y, Shinohara M, et al. A multicenter prospec-tive randomized trial of corticosteroids in primary therapy for Kawasaki disease: clinical course and coronary artery outcome. J Pediatr 2006;149:336-41.To the Editor: Newburger et al. studied the ef-fects of adding intravenous methylprednisolone to conventional therapy for Kawasaki disease. The authors found a significantly lower frequency of coronary-artery abnormalities in the intravenous-methylprednisolone group than in the placebo group within the subgroup of patients who re-quired retreatment with intravenous immune globulin.The identification of predictors of coronary ab-normalities in Kawasaki disease is still problem-atic. Failure of initial treatment with intravenous immune globulin remains the most consistent risk factor for cardiac abnormalities.1 Adminis-tration of intravenous methylprednisolone after the failure of initial treatment with intravenous immune globulin does not seem to be effective in reducing the risk of coronary damage,2 although the current data suggest that this might not be the case for patients who do not have a response to intravenous immune globulin and who have pre-viously received intravenous methylprednisolone.Since intravenous methylprednisolone admin-istered as a single dose appears to be safe,3 and given our inability to identify a priori the patients who will not have a response to intravenous im-mune globulin, it seems obvious that the concur-rent use of a single dose of intravenous methyl-prednisolone and intravenous immune globulin may be our best choice at the moment. It is un-realistic to expect that trials powered to show the effectiveness of intravenous methylpredniso-lone could be accomplished anytime soon.1.2.3.Andrea Taddio, M.D.Institute of Child Health 34100 Trieste, Italy ataddio@yahoo.itCarlos D. Rosé M.D.Thomas Jefferson University Wilmington, DE 19803Hashino K, Ishii M, Iemura M, Akagi T, Kato H. Re-treat-ment for immune globulin-resistant Kawasaki disease: a com-parative study of additional immune globulin and steroid pulse therapy. Pediatr Int 2001;43:211-7.Lang BA, Yeung RS, Oen KG, et al. Corticosteroid treatment of refractory Kawasaki disease. J Rheumatol 2006;33:803-9.Sundel RP, Baker AL, Fulton DR, Newburger JW. Corticoste-roids in the initial treatment of Kawasaki disease: report of a randomized trial. J Pediatr 2003;142:611-6.To the Editor: Although the study by Newburger et al. involved assessment of coronary-artery out-comes with the use of transthoracic echocardi-ography, we were quite surprised by the inclusion of an example of a coronary aneurysm seen on multidetector computed tomography (CT) in the accompanying Perspective article by Burns.1We and others2,3 have shown the efficacy of noninvasive magnetic resonance imaging (MRI) of the heart for both the identification and char-acterization of coronary artery disease in patients with Kawasaki disease (Fig. 1). Patients with Kawasaki disease require frequent observation over many decades. Given the relatively high doses of ionizing radiation associated with multidetector 1.2.3.16p6AUTHOR  ManningFIGURE   1 of 1JOB: ISSUE:4-CH/TRETAKE 1st2ndSIZEICMCASEEMail LineH/TComboRevisedAUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset.Please check carefully.REG FFILLTITLE3rdEnon ARTIST:6-28-07mst35626AAAAAAFigure 1. Three-Dimensional Steady-State Free-Precession MRI of the Whole Heart in an 8-Year-Old Boy with  Kawasaki Disease and Serial Aneurysms (A) in the Right Coronary Artery.No contrast material was administered.Copyright © 2007 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at THOMAS JEFFERSON UNIVERSITY on October 1, 2007 . Th e  n e w  e ng l a nd  j o u r na l  o f  m e dic i n en engl j med 356;26 www.nejm.org june 28, 20072748CT 4 and the heightened potential for radiation-induced fatal cancer in children,5 we believe that, if transthoracic echocardiography is inadequate, these younger patients are best served by the use of coronary MRI.Gerald F. Greil, M.D.King’s College London London SE1 9RT, United KingdomWarren J. Manning, M.D.Beth Israel Deaconess Medical Center Boston, MA 02215  wmanning@bidmc.harvard.eduBurns JC. The riddle of Kawasaki disease. N Engl J Med 2007;356:659-61.Greil GF, Stuber M, Botnar RM, et al. Coronary magnetic resonance angiography in adolescents and young adults with Kawasaki disease. Circulation 2002;105:908-11.Mavrogeni S, Papadopoulos G, Douskou M, et al. Magnetic resonance angiography, function and viability evaluation in pa-tients with Kawasaki disease. J Cardiovasc Magn Reson 2006;8: 493-8.Coles DR, Smail MA, Negus IS, et al. Comparison of radia-tion doses from multislice computed tomography coronary angi-ography and conventional diagnostic angiography. J Am Coll Cardiol 2006;47:1840-5.Brenner D, Elliston C, Hall E, Berdon W. Estimated risks of radiation-induced fatal cancer from pediatric CT. AJR Am J Roentgenol 2001;176:289-96.The Authors Reply: Inoue and colleagues de-scribe the results of their open trial using a pro-longed course of corticosteroids, which we discuss in our article. We found that clinically significant coronary-artery abnormalities were infrequent in patients in both of our study groups. For this reason, although the optimal corticosteroid regi-men may be unknown, we believe that cortico-steroid regimens requiring a prolonged course of treatment would be difficult to rationalize for the primary treatment of all patients with Kawasaki disease.Taddio and Rosé highlight an important ques-tion arising from our analyses. Our study was de-signed to test the hypothesis that the addition of intravenous methylprednisolone to conventional primary treatment of Kawasaki disease would im-prove coronary-artery outcomes; the study groups had similar overall coronary outcomes. A post hoc subgroup analysis suggested that primary cortico-steroid therapy reduced the incidence of coronary-artery abnormalities in a high-risk subgroup of patients in our study who required retreatment with intravenous immune globulin because of persistent or recrudescent fever. However, such subgroup analyses must be interpreted with cau-tion1; the literature is replete with subgroup analyses suggesting differential responses to 1.2.3.4.5.therapy, findings that have been shown to be er-roneous in subsequent prospective trials.2 Chil-dren with Kawasaki disease can be characterized at the time of presentation with respect to their risk of resistance to intravenous immune globu-lin.3 Until further studies are conducted in high-risk patients, we do not believe that corticosteroid therapy should be used in the primary treatment of Kawasaki disease.Jane W. Newburger, M.D., M.P.H.Children’s Hospital Boston, MA 02115 jane.newburger@cardio.chboston.orgLynn A. Sleeper, Sc.D.New England Research Institutes Watertown, MA 02472Pfeffer MA, Jarcho JA. The charisma of subgroups and the subgroups of CHARISMA. N Engl J Med 2006;354:1744-6.Rothwell PM. Treating individuals 2: subgroup analysis in randomised controlled trials: importance, indications, and inter-pretation. Lancet 2005;365:176-86.Kobayashi T, Inoue Y, Takeuchi K, et al. Prediction of intra-venous immunoglobulin unresponsiveness in patients with Kawa-saki disease. Circulation 2006;113:2606-12.Dr. Burns Replies: Imaging of the coronary ar-teries is important in the long-term management of aneurysms in patients with Kawasaki disease. Transthoracic echocardiography can be used only to image the proximal arteries, is dependent on a high level of technical skill, and cannot reliably detect stenosis. Advantages of multidetector CT are the assessment of calcification and soft plaque, rapid collection of data, and straightforward in-terpretation of images. With proper gating to the cardiac cycle and lowering of the heart rate with beta-adrenergic blockade, exposures of approxi-mately 0.67 mSv have been documented for coro-nary-artery studies of children involving multi-detector CT (Larkin G, GE Healthcare: personal communication) (for comparison, one chest radio-graph results in exposure to 0.02 mSv). MRI is safe, but many centers cannot image the coronary ar-teries with sufficient precision. All these ap-proaches require general anesthesia for young patients, and MRI requires a longer time to cap-ture images than does multidetector CT and thus increases the time under anesthesia and associat-ed risks. Clearly, this is an area of medicine that is in flux. We look forward to the time when safe, noninvasive imaging methods are widely avail-able at all centers for these children.Jane C. Burns, M.D.University of California, San Diego La Jolla, CA 92093-08301.2.3.Copyright © 2007 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at THOMAS JEFFERSON UNIVERSITY on October 1, 2007 . 

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Treatment of Kawasaki Disease

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