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

Abstract

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 poly-medicated patients, and the immunologic mechanisms underlying MDH are poorly understood. Evaluate whether cytokine secretion patterns of drug-specific T cell responses reveal MDH in patients with non-immediate drug hypersensitivity reactions (NIDHR). 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 RegiSCAR 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, IFNγ, granzyme B, and granulysin secretion from peripheral blood mononuclear cells after 7-days drug stimulation. Cyto-LTT detected drug-specific immune responses, including 19% of cases with negative skin tests. IL-5 and IL-13 responses were most frequently detected in both DRESS and MPE patients, whereas IFNγ was more frequent in MPE. Patients with MDH exhibited broader and up to ten-fold stronger cytokine responses than mono-sensitized patients. Notably, granulysin secretion was observed only in MDH cases. This exploratory study demonstrates that the multiplex Cyto-LTT can detect drug-specific immune responses in NIDHR 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 NIDHR. Larger prospective studies are, however, required to formally establish diagnostic performance.