Age-Related Phenotypic Divergence in NSAID Hypersensitivity: Clinical and Comorbidity Correlates

Introduction: Nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity is a heterogeneous condition with diverse clinical phenotypes. Although age-related changes in immune and inflammatory pathways have been proposed, systematic evaluations of age-associated phenotypic differences remain limited. Methods: Between 2019 and 2025, 1,363 patients evaluated for suspected drug hypersensitivity were screened, and 484 adults with clinically defined NSAID hypersensitivity were retrospectively analyzed. Patients were categorized as early-onset (<40 years) or late-onset (≥40 years). Reaction phenotypes were classified retrospectively according to EAACI/ENDA criteria. Demographic characteristics, comorbidities, reaction phenotypes, and laboratory parameters, including total IgE levels and eosinophil counts, were compared. Subgroup analyses assessed the association between chronic low-dose aspirin use and clinical features. Multivariate logistic regression was performed to identify independent predictors of late-onset hypersensitivity. Results: The median age of the cohort was 41 years, and 65.7% were female. Cutaneous reactions were most common (66.5%), followed by cutaneous–respiratory (19.0%) and systemic reactions (8.7%). Late-onset patients (n = 258) exhibited significantly higher prevalences of asthma (19.8% vs. 8.0%; p < 0.01) and cardiovascular disease (10.5% vs. 1.3%; p < 0.001). Chronic low-dose aspirin use was more frequent in late-onset cases (14.3% vs. 1.3%; p < 0.001) and was associated with increased respiratory involvement. In multivariate analysis, asthma (OR 2.48, 95% CI 1.30–4.73; p = 0.006) and low-dose aspirin use (OR 7.52, 95% CI 1.71–32.50; p = 0.008) independently predicted late-onset NSAID hypersensitivity. Conclusion: NSAID hypersensitivity exhibits distinct age-related clinical phenotypes, with a higher burden of respiratory involvement and comorbid disease in late-onset cases. Chronic low-dose aspirin use is strongly associated with this phenotype. Recognition of age-associated patterns may support improved clinical risk stratification and individualized management strategies.