Adverse outcomes and an immunosuppressed endotype in septic patients with reduced IFN-γ ELISpot

Evan L. Barrios, Monty B. Mazer, Patrick W. McGonagill, Christian B. Bergmann, Michael D. Goodman, Robert W. Gould, Mahil Rao, Valerie E. Polcz, Ruth J. Davis, Drew E. Del Toro, Marvin L.S. Dirain, Alexandra Dram, Lucas O. Hale, Mohammad Heidarian, Caleb Y. Kim, Tamara A. Kucaba, Jennifer P. Lanz, Ashley E. McCray, Sandra Meszaros, Sydney MilesCandace R. Nelson, Ivanna L. Rocha, Elvia E. Silva, Ricardo F. Ungaro, Andrew H. Walton, Julie Xu, Leilani Zeumer-Spataro, Anne M. Drewry, Muxuan Liang, Letitia E. Bible, Tyler J. Loftus, Isaiah R. Turnbull, Philip A. Efron, Kenneth E. Remy, Scott C. Brakenridge, Vladimir P. Badovinac, Thomas S. Griffith, Lyle L. Moldawer, Richard S. Hotchkiss, Charles C. Caldwell

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BACKGROUND. Sepsis 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 generally relies on using blood protein or mRNA biomarkers, or static cell phenotyping. Here, we sought to determine whether functional immune responsiveness would yield improved precision. METHODS. An ex vivo whole-blood enzyme-linked immunosorbent spot (ELISpot) assay for cellular production of interferon γ (IFN-γ) was evaluated in 107 septic and 68 nonseptic patients from 5 academic health centers using blood samples collected on days 1, 4, and 7 following ICU admission. RESULTS. Compared with 46 healthy participants, unstimulated and stimulated whole-blood IFN-γ expression was 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-γ 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-γ-producing cells and amount of IFN-γ produced per cell (all P < 0.05). Importantly, IFN-γ total expression on days 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-γ expression were older and had lower ALCs and higher soluble PD-L1 and IL-10 concentrations, consistent with an immunosuppressed endotype. CONCLUSIONS. A whole-blood IFN-γ ELISpot assay can both identify septic patients at increased risk of late mortality and identify immunosuppressed septic patients. TRIAL REGISTRY. N/A. FUNDING. This prospective, observational, multicenter clinical study was directly supported by National Institute of General Medical Sciences grant R01 GM-139046, including a supplement (R01 GM-139046-03S1) from 2022 to 2024.

Original languageEnglish (US)
Article numbere175785
JournalJCI Insight
Issue number2
StatePublished - Jan 2024

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© 2024, Barrios et al.


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