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

ABSTRACT: 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 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.METHODSAn 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.RESULTSCompared 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.CONCLUSIONSA whole-blood IFN-γ ELISpot assay can both identify septic patients at increased risk of late mortality and identify immunosuppressed septic patients.TRIAL REGISTRYN/A.FUNDINGThis 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.

SUBMITTER: Barrios EL

PROVIDER: S-EPMC10906237 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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

Barrios Evan L EL Mazer Monty B MB McGonagill Patrick W PW Bergmann Christian B CB Goodman Michael D MD Gould Robert W RW Rao Mahil M Polcz Valerie E VE Davis Ruth J RJ Del Toro Drew E DE Dirain Marvin Ls ML Dram Alexandra A Hale Lucas O LO Heidarian Mohammad M Kim Caleb Y CY Kucaba Tamara A TA Lanz Jennifer P JP McCray Ashley E AE Meszaros Sandra S Miles Sydney S Nelson Candace R CR Rocha Ivanna L IL Silva Elvia E EE Ungaro Ricardo F RF Walton Andrew H AH Xu Julie J Zeumer-Spataro Leilani L Drewry Anne M AM Liang Muxuan M Bible Letitia E LE Loftus Tyler J TJ Turnbull Isaiah R IR Efron Philip A PA Remy Kenneth E KE Brakenridge Scott C SC Badovinac Vladimir P VP Griffith Thomas S TS Moldawer Lyle L LL Hotchkiss Richard S RS Caldwell Charles C CC

JCI insight 20240123 2

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 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.METHODSAn ex vivo ...[more]

PMID: 38100268

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Project description:ObjectivesWe previously reported gene expression-based endotypes of pediatric septic shock, endotypes A and B, and that corticosteroid exposure was independently associated with increased mortality among pediatric endotype A patients. The Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial tested the efficacy of vasopressin as initial vasopressor therapy for septic shock among adult patients, when compared with norepinephrine. Patients who reached a prespecified dose of either vasopressor were further randomized to receive hydrocortisone or placebo. A proportion of patients in the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial had transcriptomic data generated at baseline using whole blood-derived messenger RNA. We used the publicly available transcriptomic data from the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial to assign the study subjects to pediatric septic shock endotype A or B, and tested the hypothesis that hydrocortisone treatment is associated with increased mortality among patients in endotype A.DesignSecondary analysis of publicly available transcriptomic data.SettingMultiple adult ICUs.PatientsAdults with septic shock randomized to hydrocortisone (n = 47) or placebo (n = 50).InterventionsRandomization to the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial experimental arms.Measurements and main resultsEndotype A patients receiving hydrocortisone had a mortality rate of 46%, whereas endotype A patients receiving placebo had a mortality rate of 22% (p = 0.105). In contrast, the mortality rates for endotype B patients receiving hydrocortisone or placebo were 19% and 22%, respectively. The odds of death were more than three times greater in endotype A patients receiving hydrocortisone than endotype A patients receiving placebo (p = 0.05).ConclusionsThis exploratory analysis provides further evidence that corticosteroid exposure may be associated with increased mortality among septic shock endotype A patients.

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

Publications

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

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