Author:
Barrios Evan A.,Mazer Monty B.,McGonagill Patrick,Bergmann Christian B.,Goodman Michael D.,Gould Robert W.,Rao Mahil,Polcz Valerie,Davis Ruth,Del Toro Drew,Dirain Marvin,Dram Alexandra,Hale Lucas,Heidarian Mohammad,Kucaba Tamara A.,Lanz Jennifer P.,McCray Ashley,Meszaros Sandra,Miles Sydney,Nelson Candace,Rocha Ivanna,Silva Elvia E,Ungaro Ricardo,Walton Andrew,Xu Julie,Zeumer-Spataro Leilani,Drewry Anne M.,Liang Muxuan,Bible Letitia E.,Loftus Tyler,Turnbull Isaiah,Efron Philip A.,Remy Kenneth E.,Brakenridge Scott,Badovinac Vladimir P.,Griffith Thomas S.,Moldawer Lyle L.,Hotchkiss Richard S.,Caldwell Charles C.
Abstract
AbstractBackgroundSepsis 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.MethodsAnex vivowhole blood enzyme-linked immunosorbent (ELISpot) assay for cellular production of interferon-γ (IFN-γ) 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 IFNγ 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 IFNγ expression was significantly reduced on ICU days 1, 4 and 7 (all p<0.05), due to both significant reductions in total number of IFNγ−producing cells and amount of IFNγ produced per cell (all p<0.05). Importantly, IFNγ 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 IFNγ expression were older and had lower ALC and higher sPD-L1 and IL-10 concentrations, consistent with an immune suppressed endotype.ConclusionsA whole blood IFNγ 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 withclinical trials.govis not required.
Publisher
Cold Spring Harbor Laboratory