Infliximab for Intravenous Immunoglobulin Resistance in Kawasaki Disease: A Retrospective Study Mary Beth Son, MD, Kimberlee Gauvreau, ScD, Jane C. Burns, MD, Elena Corinaldesi, MD, Adriana H. Tremoulet, MD, MAS, Virginia E. Watson, MD, Annette Baker, RN, MSN, PNP, David R. Fulton, MD, Robert P. Sundel, MD, and Jane W. Newburger, MD, MPH Objective To test the hypothesis that first re-treatment with infliximab, compared with intravenous immunoglob- ulin (IVIG), might improve outcomes in IVIG-resistant Kawasaki disease. Study design In a two-center retrospective review from January 2000 to March 2008, we compared duration of fever and coronary artery dimensions in patients with IVIG-resistance whose first re-treatment was with IVIG com- pared with infliximab given for fever $38.0  C beyond 36 hours after first IVIG completion. Results Patients in the IVIG group (n = 86, 2 g/kg) and infliximab group (n = 20, 5 mg/kg) were similar in demo- graphics, days of fever at diagnosis, and baseline coronary artery dimensions. Patients had similar coronary dimen- sions 6 weeks after diagnosis, both in univariate and multivariate analysis. The infliximab group had fewer days of fever (median 8 days versus10 days, P = .028), and in a multivariate analysis, the infliximab group had 1.2 fewer days of fever (P = .033). Patients who received infliximab had shorter lengths of hospitalization (median 5.5 days versus 6 days, P = .040). Treatment groups did not differ significantly in adverse events (0% versus 2.3%, P = 1.0). Conclusions In our retrospective study, patients with IVIG-resistant Kawasaki disease whose first re-treatment was with infliximab, compared with IVIG, had faster resolution of fever and fewer days of hospitalization. Coronary artery outcomes and adverse events were similar; the power of the study was limited. (J Pediatr 2011;158:644-9). A dministration of high-dose intravenous immunoglobulin (IVIG) and aspirin during the acute phase of Kawasaki disease (KD) lowers the incidence of coronary artery aneurysms to 3% to 5% and shortens the duration of fever. 1 However, 11% to 38% of patients continue to have persistent or recrudescent fever at least 36 hours after IVIG treatment. 2,3 These pa- tients with so-called ‘‘IVIG-resistance’’ are at higher risk for the development of coronary artery abnormalities. 4,5 The optimal therapy for patients with IVIG-resistance remains controversial, and agents used for secondary or ‘‘rescue’’ therapy vary among centers. Therapies have included additional doses of IVIG, intravenous methylprednisolone (IVMP), oral corticoste- roids, cyclophosphamide, cyclosporine, methotrexate, and plasma exchange. 6-10 Most recently, treatment of IVIG-resistant KD with infliximab (Remicade, Centocor, Malvern, Pennsylvania), a tumor necrosis factor(TNF)-alpha blocker, has been described. 11,12 Analysis of administrative data suggests that the use of infliximab for this indication increased between 2000 and 2006. 13 In this retrospective study, we compared the efficacy and safety of a second IVIG infusion versus infliximab in the initial re- treatment of persistent or recrudescent fever after conventional primary KD therapy. We postulated that a strategy of re- treatment with infliximab, compared with a second infusion of IVIG, might improve outcomes without an increase in adverse events (AEs). This hypothesis could be explored because patients with KD in one center received infliximab as the first re- treatment, initially in a research protocol and then as the standard of care in patients with IVIG-resistance. In contrast, standard practice in the other center was to administer a second infusion of IVIG to such patients. Outcome measures included coronary artery abnormalities assessed with two-dimensional echocardiogram, total days of fever, total number of days in the hospital, total number of re-treatments, and AEs. Methods We included patients who met each of these entry criteria: (1) diagnosis of KD on the basis of either $4 days of fever and $4 of the 5 principal criteria for KD, or From the Departments of Medicine (M.S., R.S) and Cardiology (K.G., A.B., D.F, J.N.), Children’s Hospital Boston, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA (M.S., D.F., R.S., J.N); Rady Children’s Hospital, San Diego, CA; and Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA (J.B., E.C., A.T., V.W.) Supported by the Ciaranello Family Fund and a Mentor- ing Award from the National Institutes of Health, National Heart, Lung, Blood Institute (K-24-HL074864 to Dr Burns). J.B. is the principal investigator of a federally funded clinical trial for which Centocor is donating in- fliximab and placebo. The other authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2011 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2010.10.012 AE Adverse event IVIG Intravenous immunoglobulin IVMP Intravenous methylprednisolone KD Kawasaki disease LAD Left anterior descending artery RCA Right coronary artery TNF Tumor necrosis factor alpha 644