Drug Provocation Tests with Washout Intervals for Delayed Hypersensitivity Reactions: A Real-World Retrospective Analysis

Background/Objectives: Drug provocation tests (DPTs) are the gold standard for evaluating delayed drug hypersensitivity reactions (DHRs), yet the lack of standardized protocols for non-mild reactions can lead to lifelong, unnecessary drug avoidance. Gradual DPTs (gDPTs) incorporating washout intervals offer an under-investigated strategy to minimize cumulative drug exposure. Our aim was to describe the safety and clinical outcomes of a gradual reintroduction strategy using washout intervals. Methods: We retrospectively analyzed patients evaluated at the University Hospital of Montpellier (primarily June 2018–September 2023) with mainly moderate-to-severe delayed DHRs who underwent gDPTs across diverse drug classes. Washout intervals ranging from 24 h to 14 days were tailored to drug half-life, index DHR latency and severity. Results: Sixty-five patients (median age 54 years) reported 82 delayed DHRs; the 66 index reactions analyzed were predominantly triggered by beta-lactam antibiotics (83.3%), and danger signs were present in 74.2%. Seventy-seven tailored gDPTs were performed, mostly involving 3 or 4 steps and 7-day washout intervals (64.9%). Nine (11.7%, 95% CI: 5.5%–21.0%) were positive. gDPT events were elicited by culprit drugs, occurred within 48 h of the reactive dose, and were generally milder than index reactions; 88.9% occurred at ≤50% of the total planned dose. The workup enabled the delabeling of 68 previously discontinued drugs (52.7%). Conclusions: Our study provides a preliminary, hypothesis-generating proof-of-concept showing that washout intervals can limit cumulative exposure and identify early eliciting doses. Large-scale, standardized prospective studies are required to validate these findings and establish optimal protocols.