Staging and Personalized Intervention for Infection and Sepsis

Abstract

Background: Sepsis is defined as a dysregulated host response to infection, resulting in life-threatening organ dysfunction. It is now understood that this dysregulation not only constitutes excessive inflammation, but also sustained immune suppression. Immune-modulatory therapies thus have great potential for novel sepsis therapies. Here, we provide a review of biomarkers and functional assays designed to immunologically stage patients with sepsis as well as therapies designed to alter the innate and adaptive immune systems of patients with sepsis beneficially. Methods: A search of PubMed/MEDLINE and clinicaltrials.gov was performed between October 1, 2019 and December 22, 2019 using search terms such as ''sepsis immunotherapy,'' ''sepsis biomarkers,'' ''sepsis clinical trials,'' and variations thereof. Results: Despite more than 30 years of research, there is still no Food and Drug Administration (FDA)-cleared biomarker that has proven to be effective in either identifying patients with sepsis who are at an increased risk of adverse outcomes or responsive to specific interventions. Similarly, past clinical trials investigating new treatment strategies have rarely stratified patients with sepsis. Overall, the results of these trials have been disappointing. Novel efforts to properly gauge an individual patient's immune response and choose an appropriate immunomodulatory agent based on the results are underway. Conclusion: Our evolving understanding of the different mechanisms perturbing immune homeostasis during sepsis strongly suggests that future successes will depend on finding the right therapy for the right patient and administering it at the right time. For such a personalized medicine approach, novel biomarkers and functional assays to properly stage the patient with sepsis will be crucial. The growing repertoire of immunomodulatory agents at our disposal, as well as re-appraisal of agents that have already been tested in unstratified cohorts of patients with sepsis, may finally translate into successful treatment strategies for sepsis.

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

“…Context. ELISpot has emerged as a powerful method to assess immunological status in a variety of clinical disorders (25)(26)(27)(28), including septic and critically ill patients (20,21,29,30). It offers several theoretical advantages over other current metrics -for example, cell phenotypes such as ALC (31)(32)(33)(34) and HLA-DR expression on CD14 + blood cells (35,36); plasma protein concentrations such as procalcitonin (37)(38)(39)(40), IL-6 (41)(42)(43), and sPD-L1 (44,45); or blood transcriptomics (24,46,47) -used to predict both the severity of the host response and the immunosuppressed endotype.…”

Analysis of Inflammatory Mediator Profiles in Sepsis Patients Reveals That Extracellular Histones Are Strongly Elevated in Nonsurvivors

“…Finally, the findings of this study, specifically the wide concentration ranges of mediators in individual patients as well as the lack of consistency between clinical scores and biomarker levels, emphasize the current challenge of identifying distinct clinical phenotypes and of trial design and interpretation in sepsis patients [ 63 ].…”

Adverse Long-Term Outcomes and an Immune Suppressed Endotype in Sepsis Patients with Reduced Interferon-γ ELISpot: A Multicenter, Prospective Observational Study

“…ELISpot has emerged as a powerful method to assess immunological status in a variety of clinical disorders (27)(28)(29)(30), including sepsis and critically ill patients (20,21,31,32). It offers several theoretical advantages over other current metrics -for example, cell phenotypes (such as ALC (33)(34)(35)(36) and HLA-DR expression on CD14 + blood cells (37,38)), plasma protein concentrations (such as procalcitonin (39)(40)(41)(42), IL-6 (43-45) and sPD-L1 (46,47)) or blood transcriptomics (26,48,49) -used to predict both the severity of the host response and the immunosuppressed endotype.…”