Current approach to the diagnostic value of aspirin provocation tests in nonsteroidal anti-inflammatory drug exacerbated respiratory disease: indications, methodology, safety, and clinical applications

Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) is a respiratory illness characterized by chronic eosinophilic airway inflammation. Although a typical clinical history of asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and respiratory reactions to NSAIDs may strongly suggest the diagnosis, history alone is often unreliable due to NSAID avoidance, atypical reactions, or incomplete symptom recognition. In this context, aspirin provocation tests remain the diagnostic gold standard for confirming N-ERD. Beyond diagnostic confirmation, aspirin provocation testing provides critical insights into disease heterogeneity and phenotyping. Different challenge routes—nasal, bronchial, and oral—allow assessment of organ-specific sensitivity and inflammatory dominance. Nasal aspirin provocation primarily reflects upper airway involvement and is particularly informative in patients with severe CRSwNP, whereas inhalational lysine-aspirin challenges highlight lower-airway bronchial hyperresponsiveness. Oral aspirin provocation, through systemic exposure, captures the full spectrum of respiratory and extra-respiratory responses and therefore best reflects global disease severity. The pattern, timing, and intensity of reactions observed during provocation testing contribute to the identification of clinically relevant N-ERD subphenotypes, such as upper-airway-dominant disease, bronchial-predominant disease, or blended reactions involving both compartments. These phenotypic distinctions have direct therapeutic implications, influencing the selection of targeted treatments, including aspirin desensitization, biologic therapies, or surgical interventions. Moreover, provocation testing remains essential prior to aspirin desensitization to ensure both diagnostic accuracy and patient safety. Aspirin provocation tests are not merely confirmatory tools but represent a cornerstone of precision-based evaluation of N-ERD, enabling refined phenotyping, risk stratification, and individualized treatment planning in this complex and heterogeneous disease.