Administrative Supplement: Stratifying Patient Immune Endotypes in Sepsis (SPIES Study)

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ABSTRACT Sepsis remains the leading cause of hospital mortality today. Despite its increasing incidence due to an aging population with greater comorbidities, in-hospital mortality has significantly declined over the past decade. This is due in large part to earlier recognition and better compliance with best practices in early sepsis management. Despite improved in-hospital mortality, a large proportion (up to 50% in some studies) of sepsis survivors never fully recover and develop chronic critical illness (CCI), characterized by persistent immune suppression, recurrent infections, sepsis recidivism and poor long-term outcomes. There are three key challenges, however, hindering the development of immunological therapies in these sepsis survivors: i) how to endotype patients with sepsis who are immunosuppressed; ii) how to quantify the degree of immune suppression; and iii) how to identify promising immune stimulants in individual immunosuppressed patients? We believe that current efforts to endotype sepsis survivors as being immunosuppressed have not been fully successful because they fail to directly assess immune function, instead using either genomic or proteomic measures of immune status. Here we propose to: 1) assess whether stimulated T cell production of IFN-γ and stimulated monocyte production of TNFα, as quantitated by ELISpot, better predicts infectious and long-term outcomes in sepsis survivors than common static measurements based on protein levels, expression and nucleic acid concentrations; and 2) to employ ELISpot assessment of IFN-γ production by T-cells and TNFα production by monocytes from sepsis survivors to examine ex vivo the comparative efficacy of different immune stimulants to reverse sepsis- induced immunosuppression. Under the original award, we proposed a prospective, observational trial of 270 patients with sepsis (using Sepsis-3 criteria) compared to 90 patients with critical illness without sepsis (total of 390 with 30 healthy subjects for quality control and validation) at 3 academic institutions. Here in this supplement application for the first year, we propose to add 30 trauma and 15 burn patients, although over the life of the parent grant, we hope to enroll 60 trauma patients and 45 burn patients. At 1, 4 and 7 days post sepsis, trauma or critical illness diagnosis (7 and 14 days in burns), blood samples will be obtained and blood T-cell and monocyte production of IFN-γ and TNFα, respectively, will be determined by ELISpot. Secondary infections will be the primary clinical index of outcome, with secondary indices including hospital readmission, and 180-day mortality. In addition, we will evaluate in this ELISpot platform the ex vivo response of IFN-γ production by T-cells and TNFα production by monocytes stimulated with varying concentrations of immune stimulants are currently under consideration as potential therapeutics for sepsis patients. This application proposes the validation of a novel functional bioassay to identify patients who would benefit from immunotherapy, and to identify different immune therapies that would benefit the individual patient.