Undressing DReSS as p-i mediated disease

Drug Reaction with Eosinophilia and Systemic Symptoms (DReSS) is a severe T cell-mediated hypersensitivity reaction. T cells in DReSS are stimulated via the p-i mechanism (pharmacological interaction with immune receptors), where the drug shows an off-target binding to immune receptors (TCR and/or HLA) leading to an unorthodox activation of T cells. P-i stimulations are particularly strong in DReSS, as the causative drugs are typically administered at high doses for prolonged durations (>7 days) and bind with relatively high affinity to a specific HLA allele and/or TCR. This mechanism results in delayed yet profound immune activation, progressing through four distinct phases. The p-i concept provides a unifying explanation for many puzzling aspects of DReSS and has significant implications for diagnosis, management, and prevention. Recognizing drug concentration, therapy duration, and HLA affinity as key determinants of strong p-i-mediated immune activation can improve risk assessment, early diagnosis, and intervention strategies for DReSS.