Immune signatures of sepsis from mild infection to critical illness - a prospective observational study

Sepsis-induced immunosuppression is a phenomenon characterized by the development of several changes in immunophenotype which predispose to secondary infections and increased mortality risk. Immunomodulatory therapies have yet to reproducibly demonstrate benefit in large clinical trials. We propose that several changes consistent with an immunosuppressive phenotype in sepsis represent either adaptive changes or epiphenomenon, rather than direct drivers of outcome in infection and sepsis. We therefore conducted a prospective observational study of patients presenting with infections with a spectrum of illness severity, to evaluate canonical features of monocyte and lymphocyte immunosuppression using flow cytometry. Several features consistent with immunosuppression in sepsis are observed in mild infections and non-infectious acute conditions. These features may be better understood as markers along a continuum of illness severity rather than distinct features of critical illness. Monocyte HLA-DR and co-stimulatory molecules (CD80 and CD86), and an increase in soluble PD-L1, discriminate between critically ill patients, patients with mild infection, and patients with non-infectious illness. In contrast, CD4⁺ and CD8⁺ lymphocyte phenotype did not discriminate between patient groups. Immunotherapies targeting lymphocyte function may only be effective if simultaneously augmenting monocyte antigen presentation and co-stimulatory pathways. Combination immunotherapy in sepsis requires evaluation.