Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs in adults: Beyond current classification

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Pamir Çerçi https://orcid.org/0000-0002-0844-6352
Reşat Kendirlinan https://orcid.org/0000-0002-8322-846X
Suna Büyüköztürk https://orcid.org/0000-0002-1899-5566
Aslı Gelincik https://orcid.org/0000-0002-3524-9952
Derya Ünal
Semra Demir https://orcid.org/0000-0003-3449-5868
Ferda Öner Erkekol https://orcid.org/0000-0001-9155-0304
Gül Karakaya https://orcid.org/0000-0002-7524-091X
Adile Berna Dursun https://orcid.org/0000-0002-6337-6326
Serhat Çelikel
Dane Ediger https://orcid.org/0000-0002-2954-4293
Oznur Abadoglu https://orcid.org/0000-0002-9504-7412
Sevim Bavbek https://orcid.org/0000-0002-7884-0830


Adverse Drug Reactions, Classification, Hypersensitivity, NSAIDs, Phenotyping


Background: Hypersensitivity reactions (HSRs) to nonsteroidal anti-inflammatory drugs (NSAIDs) are a significant clinical issue. Several classifications have been proposed to categorize these reactions, including the current European Academy of Allergy and Clinical Immunology/European Network for Drug Allergy (EAACI/ENDA) classification. This study aimed to evaluate the applicability of this classification in a real-world clinical setting.

Methods: We conducted a national multicenter study involving patients from nine hospitals in four major urban centers in Turkey. All patients had a suggestive clinical history of hypersensitivity reactions to NSAIDs. Researchers collected data using a structured form and classified reactions based on the EAACI/ENDA classification. Oral provocation tests with several NSAIDs were performed using a single-blind challenge per EAACI/ENDA guidelines.

Results: Our retrospective study included 966 adult patients with a history of hypersensitivity to NSAIDs. The most common triggers were Acetylsalicylic Acid (ASA), paracetamol, and metamizole. The most prevalent acute NSAID hypersensitivity group was NSAID-induced urticaria/angioedema (NIUA) (34.3%). However, 17.3% of patients did not fit neatly into the current EAACI/ENDA classification. Notably, patients with underlying asthma or allergic rhinoconjunctivitis exhibited unusual reactions, such as urticaria and/or angioedema induced by multiple chemical groups of NSAIDs, blended mixed reactions, and isolated periorbital angioedema in response to multiple chemical groups of NSAIDs.

Conclusions: While the EAACI/ENDA classification system stratifies NSAID-induced hypersensitivity reactions into five distinct endotypes or phenotypes, it may not fully capture the diversity of these reactions. Our findings suggest a need for further research to refine this classification system and better accommodate patients with atypical presentations.

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