Objective: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in children for their antipyretic and analgesic effects, but they are frequently associated with hypersensitivity reactions. The aim of this study is to describe the clinical features, diagnostic process, and risk factors associated with NSAID hypersensitivity (NSAID-H) in children and to highlight the challenges in its classification and management.

Materials and Methods: Between 2017 and 2023, children referred to our clinic with a history of reaction to any NSAIDs were retrospectively evaluated. Reactions were classified according to the European Academy of Allergy and Clinical Immunology position paper on NSAID hypersensitivity.

Results: Of the 93 patients evaluated for NSAID-H, the median age of symptom onset was 6 years (ranging from 6 months to 17 years and 5 months). Eighty-six patients underwent a drug provocation test, of whom 18 (24%) had positive reactions, while 7 diagnoses were based on clinician-documented anaphylaxis. NSAID-H was confirmed in 25 children (27%). Ibuprofen was the most frequent culprit, followed by paracetamol. Importantly, off-label NSAID use was reported in 11% of the patients. Paracetamol and nimesulide were tolerated in 95% and 63% of alternative challenges, respectively. Four children were classified as selective reactors to paracetamol, and four were classified as cross-intolerants while the remaining patients could not be classified. Risk of NSAID-H increased with age > 10 years, multiple previous reactions, reaction onset < 1 h, angioedema/anaphylaxis, co-existing allergy, and a family history of drug allergy.

Conclusion: Drug provocation testing for diagnosing NSAID-H and should be performed in all cases, unless there is a contraindication. However, in the pediatric population, parental concerns regarding drug provocation testing, frequent off-label use of NSAIDs, and the presence of patients whose reactions do not fully fit the NSAID-H classification create challenges in diagnosis and management.