Adverse Long-Term Outcomes and an Immune Suppressed Endotype in Sepsis Patients with Reduced Interferon-γELISpot: A Multicenter, Prospective Observational Study

BackgroundSepsis remains a major clinical challenge for which successful treatment requires greater precision in identifying patients at increased risk of adverse outcomes requiring different therapeutic approaches. Predicting clinical outcomes and immunological endotyping of septic patients has generally relied on using blood protein or mRNA biomarkers, or static cell phenotyping. Here, we sought to determine whether functional immune responsiveness would yield improved precision. MethodsAn ex vivo whole blood enzyme-linked immunosorbent (ELISpot) assay for cellular production of interferon-{gamma} (IFN-{gamma}) was evaluated in 107 septic and 68 non-septic patients from five academic health centers using blood samples collected on days 1, 4 and 7 following ICU admission. ResultsCompared with 46 healthy subjects, unstimulated and stimulated whole blood IFN{gamma} expression were either increased or unchanged, respectively, in septic and nonseptic ICU patients. However, in septic patients who did not survive 180 days, stimulated whole blood IFN{gamma} expression was significantly reduced on ICU days 1, 4 and 7 (all p<0.05), due to both significant reductions in total number of IFN{gamma}-producing cells and amount of IFN{gamma} produced per cell (all p<0.05). Importantly, IFN{gamma} total expression on day 1 and 4 after admission could discriminate 180-day mortality better than absolute lymphocyte count (ALC), IL-6 and procalcitonin. Septic patients with low IFN{gamma} expression were older and had lower ALC and higher sPD-L1 and IL-10 concentrations, consistent with an immune suppressed endotype. ConclusionsA whole blood IFN{gamma} ELISpot assay can both identify septic patients at increased risk of late mortality, and identify immune-suppressed, sepsis patients. Trial RegistryBecause the study is a prospective observational study, and not a clinical trial, registration with clinical trials.gov is not required.