Guiding drug provocation testing for ibuprofen hypersensitivity in a pediatric population: Development of the I3A risk-stratification tool.

Abstract

Ibuprofen is a main cause of drug hypersensitivity reactions in children. The gold standard for diagnosis is the drug provocation test (DPT). We aimed to create a clinical risk-stratification tool to guide this high-risk procedure. 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. Eighty-two patients with a median age of 5.9 years (IQR: 3.4;11.1) had an ibuprofen DPT. Eighteen (22.0%) had a positive challenge, with an anaphylactic reaction for 11 (61.1%). The I3A score (acronym for Ibuprofen, 3As: Angioedema, Anaphylaxis, Age, Cut-off of 3) encompasses the following items: Angioedema (2 points), Anaphylaxis (1 point), and Age at reaction ≥ 10 years old (1 point). The AUC of the I3A score was 0.84 and the optimal cut-off of <3 conferred a sensitivity of 84.4% % (95% confidence interval [95%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 challenge in the group I3A 3-4 compared to 0-2 was 11.4 (95CI% 3.62-35.7, p<0.001). Anaphylaxis following DPT was observed in 9/25 [36.0% (95%CI 16.0-56.0%)] in the high-risk group as compared to 2/57 [3.5% (95%CI 0.0-8.8%)] in the low-risk group [relative risk 10.3 (95%CI 2.4-43.5)]. We generated a risk stratification tool to identify children at low-risk of reacting to ibuprofen challenges. Further validation is required in external cohorts.