Reclassification of NSAID hypersensitivity according to the WAO 2025 guidelines: insights from a cohort of 527 patients

Abstract

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most common culprits of drug hypersensitivity. Previous classifications, including the European Academy of Allergy and Clinical Immunology (EAACI) and the European Network for Drug Allergy framework, left a subset of patients unclassified under the “blended” category, particularly those with anaphylaxis not fitting into standard groups. The World Allergy Organization (WAO) 2025 guidelines introduced new subcategories, such as mixed NSAID-exacerbated cutaneous disease (NECD) and mixed NSAID-exacerbated respiratory disease (NERD) to address this gap.

Objective: To evaluate how patients with reliable histories of NSAID hypersensitivity were reclassified under the WAO 2025 system, and to determine whether the new categories address the limitations of the previous framework.

Methods: We retrospectively analyzed 527 patients with cross-reactive NSAID hypersensitivity confirmed by clinical history and/or aspirin provocation testing at a tertiary allergy center. Patients were classified according to both EAACI 2019 and WAO 2025 guidelines. Demographics, comorbidities (asthma, rhinitis, urticaria, and nasal polyps), laboratory findings (immunoglobulin E, eosinophils, and tryptase), and provocation test outcomes with alternative NSAIDs were evaluated. Statistical analyses included Chi-square/Fisher’s Exact tests and logistic regression.

Results: According to EAACI 2019, patients were classified as NECD (n = 228, 43.3%), NERD (n = 27, 5.1%), NSAID-induced urticaria/angioedema (NIUA) (n = 165, 31.3%), single NSAID-induced urticaria/angioedema/anaphylaxis (SNIUAA) (n = 55, 10.4%), and blended (n = 53, 10.1%). Using WAO 2025 guidelines, the blended category was eliminated and redistributed: NIUA increased to 197 (37.4%), mixed NECD (n = 7, 1.3%), and mixed NERD (n = 13, 2.5%) were newly defined. Other groups (NECD, NERD, SNIUAA) remained unchanged. Provocation testing confirmed high tolerability to paracetamol (97.8%), nimesulid (96.1%), meloxicam (94.1%), and celecoxib (92.2%), while aspirin challenge had the highest positivity (22.2%). Atopy was significantly associated with salicylate reactions (p = 0.048), and male gender with salicylate hypersensitivity (p = 0.0087).

Conclusion: The WAO 2025 classification successfully reallocated previously blended cases, particularly into NIUA, mixed NECD, and mixed NERD, thereby improving diagnostic clarity. This updated framework reduces ambiguity and may enhance patient management by better reflecting clinical heterogeneity.