World Allergy Organization Updates Classification of NSAID Hypersensitivity Reactions

The World Allergy Organization (WAO) updated the classification and diagnostic framework for non-steroidal anti-inflammatory drugs (NSAIDs) hypersensitivity reactions, recognizing blended reactions, extending pediatric classifications to adults, introducing mixed N-ERD and mixed NECD subgroups, and including NSAID-exacerbated and NSAID-induced food allergy.1

“This WAO Statement updated both the classification of hypersensitivity reactions to NSAIDs and their diagnosis,” wrote lead author Antonino Romano, from Oasi Research Institute – IRCCS in Italy, and colleagues. “Regarding the former, patients with no underlying CSU who report reactions to 2 chemically unrelated NSAIDs that involve urticaria/angioedema and/or 2 organ systems (e.g., cutaneous and respiratory; cutaneous and gastrointestinal) were classified as having [NSAID-induced urticaria/angioedema/anaphylaxis].”

Current guidelines in the US and Europe classify hypersensitivity reactions to NSAIDs as acute (≤ 6 hours) or delayed (> 6 hours or > 24 hours).2,3 Guidelines have further classified acute reactions into 4 clinical types: aspirin/NSAID-exacerbated respiratory disease, NSAID-exacerbated cutaneous disease, NSAID-induced urticaria/angioedema, and single NSAID-induced urticaria/ angioedema/anaphylaxis.1 However, some patients may present with “blending” reactions, otherwise known as reactions involving 2 organ systems, such as cutaneous and respiratory or cutaneous and gastrointestinal.

Furthermore, in pediatric settings, clinicians classify mild anaphylactic reactions as NSAID-induced urticaria/angioedema/anaphylaxis (NIUAA), an acronym the WAO urges providers to adopt in adult settings as well.

N-ERD: Clinical presentation, Variants, Prevalence

The statement also addressed the clinical presentation, variants, prevalence, and pathogenic mechanism of N-ERD: a triad of asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and respiratory reactions to cyclooxygenase (COX)-1 inhibitors. N-ERD most commonly develops in patients in their 30s and 40s, starting as early as puberty to the 80s, and has a prevalence of 0.1% to 0.6% in population-based studies. Disturbances in the COX and 5-lipoxygenase pathways of arachidonic acid metabolism can lead to N-ERD.

Many with N-ERD have comorbid CRSwNP and olfactory disturbances. The respiratory reactions to COX-1 inhibitors include nasal congestion, rhinorrhea, sneezing, nasal pruritus, ocular chemosis, and bronchospasm within 30 minutes to 3 hours of exposure.

About 20% of patients with N-ERD can develop extra-respiratory symptoms, including pruritic macular cutaneous eruption, urticaria, angioedema, angina-like chest pain, abdominal pain, nausea, vomiting, and diarrhea. Some patients with N-ERD can present cutaneous symptoms, such as macular eruptions. WAO wrote that clinicians can diagnose those with chronic macular eruptions, urticaria, or angioedema with mixed N-ERD. When it comes to diagnosing N-ERD, WAO recommends addressing each part of the triad.

NECD Clinical Presentation, Diagnoses

NECD is the term for the acute, short-lived exacerbation of their CSU that occurs within minutes to hours after taking NSAIDs. Clinicians can diagnose patients with NECD who develop respiratory symptoms as mixed NECD. Patients’ reactions are associated with the COX-1 inhibiting activity of the NSAID drugs. Those with NECD tend to tolerate weak COX-1 inhibitors, such as paracetamol, and preferential (meloxicam and nimesulide) or selective COX-2 inhibitors (coxibs).1

The WAO does not advise performing a graded DC with ASA in patients with NECD. Potential biomarkers for NECD include LTE4, the ratio of LT4/9a, 11b-PGF2, and serum tryptase.

The updated diagnostic algorithm also recognizes reactions in which NSAIDs act as aggravating factors or cofactors in patients sensitized to foods, classified as NEFA and NIFA, respectively.

“An updated and correct classification of hypersensitivity reactions to NSAIDs has important repercussions on the diagnostic workup and management of patients who report such reactions, with a positive impact on the healthcare delivery and patient outcomes, especially for those in whom hypersensitivity to NSAIDs is excluded,” WAO wrote.1

References

1. Romano A, Valluzzi RL, Alvarez-Cuesta E, et al. Updating the classification and routine diagnosis of NSAID hypersensitivity reactions: A WAO Statement. World Allergy Organ J. 2025;18(8):101086. Published 2025 Aug 12. doi:10.1016/j.waojou.2025.101086

2. Broyles AD, Banerji A, Barmettler S, et al. Practical Guidance for the Evaluation and Management of Drug Hypersensitivity: Specific Drugs. J Allergy Clin Immunol Pract. 2020;8(9S):S16-S116. doi:10.1016/j.jaip.2020.08.006

3. Khan DA, Banerji A, Blumenthal KG, et al. Drug allergy: A 2022 practice parameter update. J Allergy Clin Immunol. 2022;150(6):1333-1393. doi:10.1016/j.jaci.2022.08.028