Serum soluble OX40 as a diagnostic and prognostic biomarker for DIHS/DRESS

Abstract Background Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a severe adverse drug reaction commonly associated with the reactivation of human herpesvirus 6 (HHV-6). There are currently no adequate biomarkers for the early diagnosis and detection of DIHS/DRESS. Notably, OX40 (CD134) plays an important role in allergic inflammation and functions as a cellular receptor for HHV-6 entry. We previously reported that the membrane-bound form of OX40 in CD4+ T cells was upregulated in DIHS/DRESS. Objective We sought to investigate the clinical significance of serum soluble OX40 (sOX40) in DIHS/DRESS. Methods Serum sOX40 levels in patients with DIHS/DRESS (n = 39), maculopapular exanthema/erythema multiforme (n = 17), Stevens-Johnson syndrome/toxic epidermal necrolysis (n = 13), autoimmune bullous diseases (n = 5), and in healthy volunteers (n = 5) were examined by the enzyme-linked immunosorbent assay. Copy numbers of HHV-6, HHV-7, and CMV in peripheral blood mononuclear cells were quantified using real-time PCR. Results Serum sOX40 levels in patients with DIHS/DRESS in the acute stage were elevated in parallel with high OX40 expression on CD4+ T cells. Serum sOX40 levels significantly positively correlated with disease severity and serum levels of thymus and activation-regulated chemokine, interleukin-5, and interleukin-10. HHV-6-positive patients presented with higher sOX40 levels than HHV-6-negative patients, and serum sOX40 levels correlated with HHV-6 DNA loads. Conclusion Serum sOX40 level can be a useful diagnostic marker for DIHS/DRESS that reflects the disease severity. Elevated serum sOX40 levels also predict HHV-6 reactivation in patients with DIHS/DRESS.