Highlights Box
What is already known about this topic? Hypersensitivity reactions (HRs) to NSAIDs are common in children and adolescents, but in many of them NSAID hypersensitivity/allergy (NH/A) is excluded by testing.
What does this article add to our knowledge? NEFA/NIFA can be diagnosed in about 14% of children/adolescents reporting immediate HRs to NSAIDs, most of whom are sensitized to Pru p 3. Non-hypersensitive/allergic reactions to NSAIDs appear to be primarily related to infections with fever rather than to NSAID exposure itself.
How does this study impact current management guidelines? It supports the performance of targeted food allergy tests in children/adolescents reporting urticarial, angioedematous, and/or anaphylactic reactions to NSAIDs and highlights clinical predictors that help distinguish true NSAID HRs − diagnosed through drug challenges − from non-allergic/hypersensitive reactions in pediatric practice.
Graphical Abstract
Abstract
Background
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in children. Hypersensitivity reactions (HRs) to NSAIDs represent a diagnostic challenge, particularly because NSAIDs may act as aggravating factors or cofactors as in two phenotypes recently named NSAID-exacerbated food allergy (NEFA) and NSAID-induced food allergy (NIFA).
Objective
To diagnose NSAID hypersensitivity/allergy (NH/A) and NEFA/NIFA phenotypes in children/adolescents, classify HRs to NSAIDs according to updated international guidelines, and identify clinical and immunologic predictors of true NH/A.
Methods
We prospectively studied 336 children/adolescents with a history of HRs to NSAIDs, following international guidelines, which include challenges with the suspected NSAIDs. Primary outcomes were identification of NH/A phenotypes and their predictors.
Results
NH/A was diagnosed in 104 (31%) of 336 patients. The most frequent phenotypes were single-NSAID-induced urticaria/angioedema/anaphylaxis (55.8%) and NSAID-induced urticaria/angioedema/anaphylaxis (22.1%). NH/A was excluded in 232 patients (69%), 48 of whom were diagnosed with NEFA/NIFA. Sensitization to Pru p 3 was strongly associated with NEFA/NIFA. Non-hypersensitive/allergic reactions were associated with antipyretic use (OR, 5.92; 95% CI, 3.60–9.72), urticaria (OR, 3.06; 95% CI, 1.77–5.28), and younger age (OR per 6-year increment, 0.64; 95% CI, 0.47–0.89). Internal validation showed good discrimination (AUROC, 0.82; cross-validated AUROC, 0.79).
Conclusions
Approximately one-third of children with suspected reactions had confirmed NH/A, whereas 14.3% had NEFA/NIFA. In 69% of patients, the NH/A label was removed. Many reactions during antipyretic use appear infection-related rather than true NSAID hypersensitivity.
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