Multiplex Cytokine LTT Reveals Strong T-Cell Responses to Multiple Drugs in NIDHR-Associated Multiple Drug Hypersensitivity

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe T-cell-mediated drug hypersensitivity reaction associated with an increased risk of multiple drug hypersensitivity (MDH). Identifying culprit drugs is challenging, particularly in polymedicated patients, and the immunologic mechanisms underlying MDH are poorly understood. OBJECTIVE: Evaluate whether cytokine secretion patterns of drug-specific T-cell responses reveal MDH in patients with nonimmediate drug hypersensitivity reactions (NIDHRs). METHODS: In this multicenter cross-sectional study, we examined 20 patients with resolved DRESS (12 with MDH), 8 patients with maculopapular exanthem (MPE; 4 with MDH), and 6 healthy donors. Clinical evaluations included Registry of Severe Cutaneous Adverse Reactions scoring and delayed skin testing (patch test in DRESS; additional delayed intradermal test in MPE). A multiplex cytokine lymphocyte transformation test (Cyto-LTT) measured IL-5, IL-13, IFN-γ, granzyme B, and granulysin secretion from PBMCs after 7-day drug stimulation. RESULTS: Cyto-LTT detected drug-specific immune responses, including 19% of cases with negative skin test results. IL-5 and IL-13 responses were most frequently detected in both patients with DRESS and patients with MPE, whereas IFN-γ was more frequent in patients with MPE. Patients with MDH exhibited broader and up to 10-fold stronger cytokine responses than monosensitized patients. Notably, granulysin secretion was observed only in MDH cases. CONCLUSIONS: This exploratory study demonstrates that the multiplex Cyto-LTT can detect drug-specific immune responses in NIDHRs and may provide additional insight into immune activation patterns associated with MDH. These findings could provide useful insights for future studies on endotyping and risk stratification of NIDHRs. Larger prospective studies are, however, required to formally establish diagnostic performance.