Clinical Performance of a Standardized Two-Step Drug Provocation Test Protocol After Retrospective Application of the EAACI/ENDA 2024 Risk Stratification: A Real-World Cohort Study.

BACKGROUND: Drug provocation testing (DPT) is the gold standard for diagnosing drug hypersensitivity, but its implementation remains limited by heterogeneous protocols and concerns regarding safety. The clinical performance of simplified DPT protocols across the recently proposed EAACI/ENDA 2024 risk categories is unknown. OBJECTIVE: To evaluate the clinical performance of a standardized placebo-free two-step equal-dose DPT protocol after retrospective application of the EAACI/ENDA 2024 risk stratification in a historical real-world cohort. METHODS: We conducted a retrospective descriptive study including consecutive patients with suspected hypersensitivity to antibiotics or selective NSAIDs (nonsteroidal anti-inflammatory drugs) who underwent culprit-drug DPT between January 2017 and November 2023 at a tertiary allergy center. All patients had originally been managed using the same placebo-free two-step equal-dose DPT protocol before publication of the EAACI/ENDA 2024 recommendations. After data collection, index reactions were retrospectively classified according to the EAACI/ENDA 2024 framework. The primary outcome was DPT positivity overall and according to retrospectively assigned risk categories. RESULTS: A total of 161 patients were included. Overall, 17 DPTs were positive (10.6%; 95% CI, 6.7-16.3%). Positivity differed significantly across retrospectively assigned risk categories (p < 0.0001): 5.4% in the low-risk group, 9.1% in the low-to-intermediate-risk group, 6.0% in the intermediate-risk group, and 61.5% in the high-risk group. Among patients reclassified as high risk because of isolated early urticaria and/or angioedema, 7 of 8 (87.5%) had a positive DPT. Two patients (1.2%) developed anaphylaxis, both after the first dose; one had been retrospectively classified as high risk and the other as intermediate risk. CONCLUSIONS: In this historical cohort, retrospective application of the EAACI/ENDA 2024 framework identified marked differences in DPT positivity despite all patients undergoing the same standardized placebo-free two-step equal-dose protocol. These findings support the feasibility of this protocol in routine clinical practice while highlighting the clinical relevance of early urticaria and/or angioedema within the current EAACI/ENDA risk stratification and the need for prospective validation.