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

Abstract

predictive metrics in critical illness and this technology (provisional patent application 63/521,817) is evaluated in this research. SCB, LLM, RSH, and the University of Florida may receive royalty income based on a technology developed by SCB and others and licensed by Washington University in St. Louis to IFDx LLC. That technology is evaluated in this research. CCC and the University of Cincinnati may receive royalty income based on a technology developed by CCC and others and licensed by Washington University in St. Louis to IFDx LLC. That technology is evaluated in this research.

Predicting Organ Dysfunction in Septic and Critically Ill Patients: A Prospective Cohort Study Using Rapid Ex Vivo Immune Profiling

“…Crucially, by normalizing IFNγ levels to cell counts, our method confirms the presence of both quantitative and qualitative lymphocyte defects. Our findings also align with recent literature, including works by Barrios et al ( 16 ), who have demonstrated the prognostic value of whole blood IFNγ levels using ELISpot assays ( 8 , 16 ). Unlike previous studies, however, our assay is both precise and semi-automated, providing results within 6 hours after a 4-hour ex vivo incubation period following sample collection.…”

“…Our assay builds on the foundational work of Hotchkiss et al ( 9 ), Barrios et al ( 16 ), and Venet et al ( 17 ) by incorporating IFNγ to evaluate immune functionality ( 26 , 27 ). Crucially, by normalizing IFNγ levels to cell counts, our method confirms the presence of both quantitative and qualitative lymphocyte defects.…”

“…A further study limitation involves the method of normalizing cytokine concentrations to specific leukocyte subsets, guided by prior research identifying the primary populations that produce these cytokines ( 8 , 16 , 27 – 30 , 40 ). While normalizing IFNγ to lymphocyte count is a standard approach, normalizing IL-6 to a specific cell population presents challenges due to its pleiotropic nature.…”

“…The significant role of lymphocyte apoptosis in sepsis and shock has been highlighted by Hotchkiss et al ( 9 – 11 ), while lymphocyte phenotyping has proven useful for distinguishing between septic and nonseptic patients and identifying potential therapeutic targets ( 12 – 14 ). The correlation between poor clinical outcomes and both lymphopenia ( 10 , 15 ) and diminished lymphocyte reactivity indicated by interferon-gamma (IFNγ) production ( 8 , 16 ) is noteworthy. However, the technical demands and time needed for analyzing ex vivo cytokine production by techniques such as the enzyme-linked immunospot (ELISpot) assay remain a barrier to clinical application.…”

Immunotherapy in the context of sepsis-induced immunological dysregulation

“…Simultaneously, with advancing research into sepsis, a significant number of preclinical and clinical studies have observed that hosts often exhibit an excessive state of immunosuppression in the later stages of the disease. This severe immunoparalysis mediates secondary infections, subsequent deaths, or severe adverse prognoses ( 93 , 213 ). In this context, there has been a shift in focus from “immunosuppressive therapy” to “immune enhancement therapy” or “immune stimulation therapy” in an effort to reverse the state of immune paralysis in sepsis hosts.…”