Comparing immunopathogenesis of non‐human immunodeficiency virus immune reconstitution inflammatory syndrome and immune‐related adverse events: A prospective multicenter cohort study

Abstract The concept of immune reconstitution inflammatory syndrome (IRIS) has recently been applied to patients with non‐HIV infection with immune fluctuations. However, quantitative criteria to diagnose non‐HIV IRIS have not been established. Similarly, immune‐related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) are also caused by immune fluctuations. No study has directly compared the immunological indicators of non‐HIV IRIS and irAEs. Thus, we investigated whether irAEs can be included in non‐HIV IRIS. We aimed to search for diagnostic biomarkers for non‐HIV IRIS and to compare the immunopathogenesis of non‐HIV IRIS and irAEs based on immunological indicators. We selected drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) and dipeptidyl peptidase‐4 inhibitor‐associated bullous pemphigoid (DPP4i‐BP) as underlying diseases of non‐HIV IRIS. Blood cell counts, cytokines or chemokines, and herpesvirus‐derived DNA in saliva were quantified and compared between IRIS/irAE‐positive and ‐negative as well as non‐HIV IRIS and irAEs groups. The DPP4i‐BP group had a shorter incubation time to IRIS onset than the DIHS/DRESS group; the irAE group had a longer incubation time than the DIHS/DRESS group. A higher neutrophil‐to‐lymphocyte ratio and serum interferon gamma inducible protein 10 levels could be potential biomarkers of IRIS and irAEs onset; however, no useful cut‐off values for diagnosis were indicated. Meanwhile, the transition of regulatory T cells (Tregs) from the baseline to the onset of IRIS or irAEs differed between IRIS in DIHS/DRESS and irAEs. Only the DIHS/DRESS group showed an increase of Epstein‐Bar virus (EBV) ( p < 0.0001) and human herpesvirus 6 ( p < 0.05) positivity in saliva at the onset of IRIS compared to that at baseline. Although non‐HIV IRIS and irAEs have a small number of common immunological indicators, the dynamics of Tregs, cytokines, or chemokines and positivity of herpesvirus‐derived DNA in saliva differ, suggesting that non‐HIV IRIS and irAEs should remain as separate entities.