Guiding Drug Provocation Testing for Ibuprofen Hypersensitivity in a Pediatric Population: Development of the I3A Risk-Stratification Tool.

Background: Ibuprofen is a main cause of drug hypersensitivity reactions in children. The gold standard for diagnosis is the drug provocation test (DPT).

Objective: We aimed to create a clinical risk-stratification tool to guide this high-risk procedure.

Methods: We prospectively recruited children with suspected ibuprofen hypersensitivity between January 2017 and March 2024. Using stepwise bidirectional multivariable logistic regression, we calculated a predictive score for a positive ibuprofen DPT.

Results: Eighty-two patients with a median age of 5.9 years (interquartile range: 3.4-11.1 years) had an ibuprofen DPT. Eighteen (22.0%) patients had a positive challenge, with an anaphylactic reaction for 11 (61.1%). The I3A score (acronym for ibuprofen, 3As: angioedema, anaphylaxis, age, cutoff of 3) encompasses the following items: angioedema (2 points), anaphylaxis (1 point), and age at reaction ≥10 years old (1 point). The area under the curve of the I3A score was 0.84, and the optimal cutoff of <3 conferred a sensitivity of 84.4% (95% confidence interval [CI]: 66.7%-100.0%) and a specificity of 83.3% (95% CI: 75.0%-92.2%). The negative predictive value was estimated at 94.7% (95% CI: 90.0%-100.0%), and the positive predictive value at 60.0% (95% CI: 46.2%-76.2%). The relative risk of reacting to a challenge in the group I3A 3-4 compared with 0-2 was 11.4 (95% CI: 3.62%-35.7%, P < .001). Anaphylaxis after DPT was observed in 9 of 25 (36.0% [95% CI: 16.0%-56.0%]) in the high-risk group as compared with 2 of 57 (3.5% [95% CI: 0.0%-8.8%]) in the low-risk group (relative risk 10.3 [95% CI: 2.4%-43.5%]).

Conclusions: We generated a risk-stratification tool to identify children at low risk of reacting to ibuprofen challenges. Further validation is required in external cohorts.