Cross‐Reactive NSAID Hypersensitivity: Clinical Findings From Aspirin Provocation and Alternative Drug Challenge Testing

Nonsteroidal anti‐inflammatory drug (NSAID) hypersensitivity reactions are commonly reported but often overestimated due to reliance on clinical history alone. Accurate diagnosis and identification of safe alternative medications are essential for appropriate management. This retrospective study aimed to evaluate the clinical manifestations of NSAID hypersensitivity, assess the diagnostic value and safety of aspirin oral provocation testing, and investigate the tolerability of alternative medications, including acetaminophen, meloxicam, and celecoxib. Patients diagnosed with NSAID hypersensitivity through aspirin provocation testing at a single tertiary hospital were included. Demographics, reaction phenotypes, time intervals from index reactions, provocation outcomes, and tolerability to alternative agents were analyzed. Based on the aspirin provocation results, 36, 24, 192, and 58 patients were classified as having NSAID‐exacerbated cutaneous disease, NSAID‐exacerbated respiratory disease, NSAID‐induced urticaria/angioedema, and NSAID‐induced blended reactions (NIBR), respectively. Among patients suspected of NIBR based on clinical history, the confirmation rate was 74.1%. Overall, 832 oral provocation tests with alternative drugs were performed in 310 patients: 309 with acetaminophen, 307 with celecoxib, and 216 with meloxicam. The tolerability rates for acetaminophen 1300 mg, meloxicam 15 mg, and celecoxib 200 mg were 90%, 96%, and 98%, respectively. Epinephrine was administered in 19.4% of patients overall, with the highest rate observed in the NIBR group (44.8%); however, no patients required hospitalization or experienced fatal outcomes following the provocation test. Aspirin provocation testing and sequential evaluation of alternative medications can be safely performed in outpatient settings when conducted by experienced allergists. Clinical history alone is insufficient for diagnosing NSAID hypersensitivity, and confirmatory testing is crucial to avoid unnecessary drug avoidance and support accurate delabeling.