Immediate-Type PPI Hypersensitivity as a Severe Adverse Drug Reaction: Diagnostic Challenges, Cross-Reactivity, and Real-Life Outcomes

Background/Objectives: Immediate-type hypersensitivity reactions (HSRs) to proton pump inhibitors (PPIs) represent a clinically relevant adverse drug reaction and pose diagnostic and management challenges, including variable cross-reactivity (CR). Drug provocation testing (DPT) is the diagnostic gold standard, but real-life use after testing remains uncertain. This study aimed to describe clinical features, diagnostic outcomes, CR profiles, and real-life PPI use in patients with immediate-type PPI hypersensitivity. Methods: Single-center ambispective study of 40 patients evaluated for immediate-type PPI HSRs (2014–2023). Index reactions, culprit PPI, and skin test/DPT results were recorded retrospectively. Patients tolerating an alternative PPI on DPT were followed prospectively; real-life tolerance and use were assessed by structured telephone interview. Results: Among 40 patients (87.5% female; mean age 48 years), lansoprazole was the most frequent culprit (50%); anaphylaxis occurred in 65%. Skin tests were positive in 25% (n = 9), and a shorter interval from reaction to testing was associated with positivity (p = 0.025). CR was detected in 25% (n = 10), most often between lansoprazole and pantoprazole. All 29 patients undergoing DPT tolerated at least one alternative PPI. In real-life follow-up (n = 27), 11 (40.7%) restarted PPIs without recurrence; 1 (3.7%) developed a mild cutaneous reaction despite negative testing. Fifteen (55.6%) did not restart therapy; 4 (14.8%) cited drug-related anxiety or physician-advised avoidance. Conclusions: In immediate-type PPI hypersensitivity, skin test sensitivity appears time-dependent, supporting early evaluation. DPT identifies safe alternatives, yet behavioral and clinician-related barriers limit real-life implementation; addressing these barriers is essential to optimize PPI allergy management.