Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe multi-organ drug hypersensitivity reaction (DHR) involving T cells. DRESS patients have a heightened risk (~25%) of developing multiple drug hypersensitivity (MDH) to unrelated drugs from the first reaction. This project aims to characterise DRESS, focusing on those with and without MDH, to identify potential biomarkers for further drug reactions. Methods: This multicentre cross-sectional study analysed clinical features and immune responses, including T cell activation and in vitro cytokine secretion using Cyto-LTT. The study included 20 DRESS patients (12 with MDH), 8 maculopapular exanthema (MPE) patients (4 with MDH), and a control group of 9 healthy donors (HD). Clinical assessments included detailed histories, skin testing, and the RegiSCAR score for diagnosing DRESS. Results: The Cyto-LTT improved diagnostic sensitivity, particularly in DRESS patients, identifying 19% of drugs that were negative by skin testing. MDH patients’ leukocytes exhibited stronger and broader secretions of cytokines and cytotoxic mediators, up to ten-fold higher compared to DHR patients with a single drug sensitisation. T cells from recovered delayed DHR patients exhibited signs of chronic activation after resolution, with elevated CD69 and PD-1 but reduced CD38 and OX-40 levels compared to HD. Conclusion: Recovered delayed DHR patients display an altered T cell activation profile suggesting a “chronic disease” state, possibly explaining the heightened risk of MDH. Increased cytokine secretions, such as stimulation index > 10, especially for cytotoxic mediators, may differentiate those at risk for MDH.

Background: The newly developed mRNA-based COVID-19 vaccines can provoke anaphylaxis, possibly induced by polyethylene glycol (PEG) contained in the vaccine. The management of persons with a history of PEG allergy, or with an allergic-like reaction after the first dose remains to be defined.  Methods: We studied two cohorts of individuals: one pre-vaccination, the second post-vaccination. Skin testing was performed with COVID-19 mRNA vaccines. Upon negative skin test, a two-step (10%-90%) vaccination protocol was performed. Positive skin tests were confirmed with basophil activation tests (BAT). Vaccine-sensitized patients were offered a five-step induction protocol. Results: We identified 187 patients with high-risk profiles for developing anaphylaxis. In parallel, among 385’926 doses of vaccine, 87 allergic-like reactions were reported to our division for further investigations: 18/87 (21%) were consistent with anaphylaxis, 78/87 (90%) were female, and 47/87 (54%) received the BNT162b2 mRNA vaccine. Vaccine skin tests were negative in 96% and 76% in the pre- and post-vaccination cohorts, respectively. A two-step vaccination was tolerated in 232/236 (98%) of individuals with negative tests. Four individuals experienced acute asthma exacerbation during the two-step challenge. Vaccine-positive skin tests were consistently confirmed by BAT; CD63 and CD203c expression was selectively inhibited with ibrutinib, suggesting an IgE-dependent mechanism. Finally, 13 sensitized patients were successfully vaccinated with a five-step vaccination protocol. Conclusion: A two-step 10%-90%-vaccination protocol can be safely administered upon negative skin testing. Yet, it should be delayed in individuals with poorly controlled asthma. Importantly, mRNA vaccine sensitized individuals may receive a five-step vaccination protocol.