Resistance to Intravenous Immunoglobulin in Children with Kawasaki Disease

Abstract

Objectives-To explore the increased incidence of intravenous immunoglobulin (IVIG) resistance among San Diego County Kawasaki disease (KD) patients in 2006 and to evaluate a scoring system to predict IVIG-resistant patients with KD.Study design-We performed a retrospective review of patients with KD treated within 10 days of fever onset. Using multivariate analysis, independent predictors of IVIG-resistance were combined into a scoring system. 2006, 38.3 % of patients with KD in San Diego County were IVIG-resistant, a significant increase over previous years. IVIG-resistance was not associated with a particular brand or lot of IVIG. Resistant patients were diagnosed earlier, had higher % bands, and higher concentrations of C-reactive protein, alanine aminotransferase, and γ-glutamyl transferase (GGT). They also had lower platelet counts and age-adjusted hemoglobin (zHgb) concentrations and were more likely to have aneurysms (p=0.0008). A scoring system developed to predict IVIG-resistant patients using illness day, % bands, GGT, and zHgb, had a sensitivity of 73.3% and specificity of 61.9%. Results-InConclusions-An unexplained increase in IVIG-resistance was noted among patients with KD in San Diego County in 2006. Scoring systems based on demographic and laboratory data were insufficiently accurate to be clinically useful in our ethnically diverse population. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Keywords Conflict of Interests:The authors have no conflicts of interest to report. Kawasaki disease (KD), the leading cause of pediatric acquired heart disease in the United States and Japan, is an acute, systemic vasculitis. Treatment with a single dose of intravenous immunoglobulin (IVIG) and high-dose aspirin results in resolution of fever in most patients and significantly reduces the rate of coronary artery aneurysms (1). Despite this success, 10-20% of children will have persistent or recrudescent fever after their first infusion of IVIG (2-5). These patients are at increased risk of developing coronary artery abnormalities (5,6). Additional therapies used in these patients include retreatment with IVIG, immunomodulatory agents such as infliximab, high dose methylprednisolone, cyclophosphamide, and plasmapheresis. (7-11). Identification of patients who are likely to be IVIG-resistant would allow the use of additional therapies early in the course of their illness when prevention of coronary artery damage might still be possible. NIH Public AccessA number of recent studies from Asia have identified demographic and laboratory characteristics, including age...

Infliximab for intensification of primary therapy for Kawasaki disease: a phase 3 randomised, double-blind, placebo-controlled trial

“…The primary analysis used a logistic regression model to compare the resistance rates between groups adjusting for illness days (illness day 1=fi rst day of fever), alanine transaminase, γ-glutamyl transferase, age-adjusted haemoglobin, and percent bands at baseline, previously identifi ed as predictors of intravenous immunoglobulin resistance. 2 For the secondary outcome measure of coronary artery internal dimension, a linear regression model was used to compare Z max between treatment groups, adjusted for the same covariates as in the primary analysis. Change in Z scores from baseline for the left main coronary artery and proximal right coronary artery and left anterior descending coronary artery at week 2 and week 5 were analysed with mixed model repeated measures.…”

“…18,19 Unfortunately, these scoring systems have not successfully identifi ed US children at higher risk of treatment resistance, and clinicians are reluctant to adopt non-selective steroid therapy for all Kawasaki disease patients since most patients are not at risk for sequelae. 2,21 A North American trial assessed the eff ect of addition of a single dose of intravenous methylprednisolone (30 mg per kg) to standard intravenous immunoglobulin and aspirin therapy but, because of the overall low rate of coronary artery abnormalities, was unable to show a signifi cant diff erence in the primary endpoint of the mean Z max score for the right coronary artery and left anterior descending coronary artery combined between groups. 17 In our trial, patients in the infl iximab group had a signifi cantly greater mean reduction from baseline in the Z score of the left anterior descending coronary artery at week 2 compared with the placebo group (SD −0·6 vs −0·3).…”

“…However, around 10-20% of patients with Kawasaki disease develop persistent or recrudescent fever after standard therapy with a single infusion of intravenous immunoglobulin and aspirin. 1,2 This subset of immunoglobulin-resistant patients is at highest risk for developing coronary artery aneurysms, and needs additional treatment to interrupt the infl ammatory process. Therefore, intensifi cation of initial therapy to prevent intravenous immunoglobulin-resistance and associated coronary artery abnormalities remains a valid approach to address this unmet clinical need.…”

Immunoglobulin Resistance in Kawasaki Disease

“…This phenomenon is described as immunoglobulin resistance and is reported in 10-30% of Kawasaki disease patients. 2,3 Immunoglobulin resistance has been linked to a higher degree of overall inflammation as determined by higher levels of inflammatory markers, including erythrocyte sedimentation rate (ESR), C-reactive protein, and serum interleukin 6. 4 Further, higher C-reactive protein levels have been linked to worse cardiac sequelae in Kawasaki disease.…”

Kawasaki Disease: The Coronary Affection Perspective

“…They were also more likely to have aneurysms. However, a proposed scoring system to predict IVIG resistance proved insufficiently accurate to be clinically useful [74].…”