Supplementary Material for: Tolerance evaluation of non-steroidal anti-inflammatory drug hypersensitivity in children: Is age the crucial factor?

Introduction: Little is known about the natural history of pediatric nonsteroidal anti-inflammatory drug hypersensitivity (NSAID-H). The aim of this prospective study was to evaluate tolerance development in pediatric patients with confirmed, immediate NSAID-H and to determine the risk factors for NSAID-H persistence. Methods: Children with a confirmed diagnosis of NSAID-H were assessed for tolerance by drug provocation test (DPT) at least three years after diagnosis. Factors associated with developing tolerance in NSAID-H were investigated. Results: Of the 34 cases with confirmed NSAID-H diagnosis, 23 (67.65%) were included. The median (range) age at the last DPT was 16.5 (13.2-20.4) years. Tolerance developed in 12 (52.1%) of the 23 patients evaluated. Survival analysis showed that median duration to develop tolerance was 6.16 years from the initial reaction (SE=18.6). ROC analysis gave a cut-off value for initial reaction age as ≤11.75 years in predicting NSAID-H tolerance with specificity 83.3%, sensitivity 81.8%, (AUC=0.830, 95%CI 0.616-0.952, p<0.001). Univariate logistic regression analysis showed that the risk of persistence of NSAID-H was 1.3-fold higher with each additional year from the initial reaction [1/Odds Ratio(OR)] (OR=0.754, 95%CI 0.964-0.590; p=0.024). At the diagnostic DPT, in the tolerant group, urticaria (42.7%) was more common (p=0.006) and the persistent group reacted at a significantly lower cumulative dose (p=0.044). Conclusion: Half of the patients with NSAID-H developed tolerance, around six years after the initial reaction. The probability of tolerance rises if the initial reaction occurs before the age of 11.75 years and if urticaria was observed at presentation. Reaction at low doses on diagnostic DPT may be a predictor of persistence.