Navigating NSAID hypersensitivity: a phenotype-based algorithm for diagnosis and safe therapy

Non‑steroidal anti‑inflammatory drugs (NSAIDs) are a common cause of drug‑induced hypersensitivity manifesting as urticaria and/or angioedema. These reactions arise via two principal mechanisms with distinct clinical implications: selective IgE‑mediated allergy to a single NSAID, and cross‑reactive intolerance driven by cyclooxygenase‑1 (COX‑1) inhibition. This review synthesizes current evidence on mechanisms, phenotypes, diagnosis, and management, emphasizing phenotype‑based clinical reasoning. We outline the European Network for Drug Allergy /European Academy of Allergy and Clinical Immunology classification system, highlight atypical and blended presentations, and stress the central role of carefully taken history combined with graded oral challenge testing where safe, given the poor performance of most skin and in-vitro assays outside pyrazolone allergy. For management, we summarize avoidance strategies, choice of safe alternatives (particularly COX‑2, selective agents), indications and protocols for aspirin desensitization, and the role of comorbidity control and adjuncts such as leukotriene receptor antagonists and biologics in selected cases. A pragmatic algorithm is provided to guide classification, testing, and therapy. Consistent application of these principles minimizes unnecessary blanket NSAID avoidance while preserving analgesic and anti‑inflammatory options for patients.