D2.26 - Applying a phenotype-driven diagnostic algorithm to suspected hypersensitivity reactions to biologicals: a real-world experience

The increasing use of biological therapies has been associated with a rising number of reported hypersensitivity reactions (HSR), which are heterogeneous and frequently misclassified, potentially leading to unnecessary discontinuation of effective treatments. Although EAACI recommendations advocate a structured, phenotype-driven diagnostic approach, real-world data on its implementation remain limited. Our aim was to describe the clinical characteristics, diagnostic evaluation and outcomes of patients referred with suspected HSR to biologicals to our drug allergy unit.

We conducted a descriptive observational study of patients referred for suspected HSR to biologicals prescribed for immune-mediated inflammatory diseases (2013–2025). Only patients who underwent a structured allergy evaluation were included, comprising skin testing (ST) and drug provocation tests (DPT) when clinically indicated. Clinical data were retrospectively collected, and reactions were classified according to timing and clinical phenotype. 

Nine patients were evaluated for suspected HSR to biologicals. Most were female (n=7, 77.8%), with a median age of 37 years. The implicated biologicals were infliximab (n=3), tocilizumab, certolizumab, ixekizumab, omalizumab, mepolizumab, and ocrelizumab (n=1 each). Five reactions were classified as suspected IgE-mediated, two as infusion-related, and two as delayed type IV reactions.

Hypersensitivity was confirmed in three patients (33.3%). Two patients presented with anaphylaxis after biological administration (ixekizumab and omalizumab/mepolizumab), had positive ST, and subsequently underwent DPT with an alternative therapy, which was negative. In one patient, the pattern was compatible with excipient hypersensitivity (polysorbate), shared by omalizumab and mepolizumab. A third confirmed case involved an exuberant local injection-site reaction (>10 cm) with positive ST to subcutaneous infliximab (Remsima®) and negative ST to the intravenous formulation (Zessly®); Remsima® was maintained while awaiting switch to adalimumab, due to mild symptoms and dosing convenience.

In one patient with anaphylaxis after infliximab infusion, ST was negative; DPT was not performed due to lack of ongoing clinical indication and avoidance was recommended. One patient with suspected infusion-related reaction to ocrelizumab was still undergoing diagnostic evaluation. In the remaining four cases, hypersensitivity was excluded after negative allergy testing. Following evaluation, 33.3% of patients were able to continue the same biological therapy; two underwent negative DPT with the culprit drug, and one was successfully re-exposed after negative ST. One patient was lost to follow-up.

In this real-world tertiary center experience, one-third of suspected HSR to biologicals were confirmed, including severe reactions and suspected excipient allergy. A structured diagnostic pathway supported accurate diagnosis, guided safe re-exposure or switching strategies and remains essential to optimize biologic therapy management.