Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells characterized by their immunosuppressive functions. MDSCs expand during chronic and acute inflammatory conditions, the best described being cancer. Recent studies uncovered an important role of MDSCs in the pathogenesis of infectious diseases along with sepsis. Here we discuss the mechanisms underlying the expansion and immunosuppressive functions of MDSCs, and the results of preclinical and clinical studies linking MDSCs to sepsis pathogenesis. Strikingly, all clinical studies to date suggest that high proportions of blood MDSCs are associated with clinical worsening, the incidence of nosocomial infections and/or mortality. Hence, MDSCs are attractive biomarkers and therapeutic targets for sepsis, especially because these cells are barely detectable in healthy subjects. Blocking MDSC-mediated immunosuppression and trafficking or depleting MDSCs might all improve sepsis outcome. While some key aspects of MDSCs biology need in depth investigations, exploring these avenues may participate to pave the way toward the implementation of personalized medicine and precision immunotherapy for patients suffering from sepsis.

BackgroundSystemic inflammatory response syndrome (SIRS) is a clinical syndrome following inflammation. Clinically, it is difficult to distinguish SIRS following an infection, i.e., sepsis, from non-infectious SIRS. Myeloperoxidase is a hemeprotein stored in the neutrophil azurophilic granules and is one of the main pillars of neutrophil attack. Therefore, we hypothesized that myeloperoxidase can differentiate between sepsis and non-infectious SIRS in patients with systemic inflammatory response syndrome in the intensive care unit (ICU).MethodsAn observational single-center cohort study was conducted measuring myeloperoxidase in patients with SIRS in the first 48 h after admission. The outcomes were established using predefined definitions. Thirty-day mortality was retrospectively assessed.ResultsWe found significantly higher levels of myeloperoxidase in patients with sepsis and septic shock compared to patients without sepsis (60 ng/ml versus 43 ng/ml, P = 0.002). Myeloperoxidase levels were related to 30-day mortality (P = 0.032), and high MPO levels on top of a high APACHE IV score further increased mortality risk.ConclusionsWe show that myeloperoxidase is a potentially novel biomarker for sepsis in the ICU. Myeloperoxidase could eventually help in diagnosing sepsis and predicting mortality. However, more research is necessary to confirm our results.

Objectives: To review the impact of the timeliness of antibiotic therapy on the outcome of patients with sepsis or septic shock. Methods: We searched MEDLINE, EMBASE, the Cochrane Library, Web of Science, Open-SIGLE databases, ClinicalTrials.gov and the metaRegister of Controlled Trials on July 27, 2020 for relevant studies on the timing of antibiotic therapy in adult patients with sepsis or septic shock. The primary outcome measure was all-cause crude or adjusted mortality at reported time points. Results: We included 35 sepsis studies involving 154,330 patients. Nineteen studies (54%) provided information on the appropriateness of antibiotic therapy in 20,062 patients of whom 16,652 patients (83%) received appropriate antibiotics. Twenty-four studies (68.6%) reported an association between time-toantibiotics and mortality. Time thresholds associated with patient's outcome varied considerably between studies consisting of a wide range of time cutoffs (1 h, 125 min, 3 h or 6 h) in 14 studies, hourly delays (derived from the analyses of time intervals ranging from to 1 to 24 h) in 8 studies or time-to-antibiotic in 2 studies. Analyses of subsets of studies that focused on patients with septic shock (11 studies, 12,756 patients) or with sepsis (6 studies, 24,281 patients) yielded similar results. Conclusions: While two-thirds of sepsis studies reported an association between early administration of antibiotic therapy and patient outcome, the time-to-antibitiocs metrics varied significantly across studies and no robust time thresholds emerged.

Trained immunity refers to the ability of the innate immune system exposed to a first challenge to provide an enhanced response to a secondary homologous or heterologous challenge. We reported that training induced with β-glucan one week before infection confers protection against a broad-spectrum of lethal bacterial infections. Whether this protection persists over time is unknown. To tackle this question, we analyzed the immune status and the response to Listeria monocytogenes (L. monocytogenes) of mice trained 9 weeks before analysis. The induction of trained immunity increased bone marrow myelopoiesis and blood counts of Ly6Chigh inflammatory monocytes and polymorphonuclear neutrophils (PMNs). Ex vivo, whole blood, PMNs and monocytes from trained mice produced increased levels of cytokines in response to microbial products and limited the growth of L. monocytogenes. In vivo, following challenge with L. monocytogenes, peripheral blood leukocytes were massively depleted in control mice but largely preserved in trained mice. PMNs were reduced also in the spleen from control mice, and increased in the spleen of trained mice. In transwell experiments, PMNs from trained mice showed increased spontaneous migration and CXCL2/MIP2α-induced chemotaxis, suggesting that training promotes the migration of PMNs in peripheral organs targeted by L. monocytogenes. Trained PMNs and monocytes had higher glycolytic activity and mitochondrial respiration than control cells when exposed to L. monocytogenes. Bacterial burden and dissemination in blood, spleen and liver as well as systemic cytokines and inflammation (multiplex bead assay and bioluminescence imaging) were reduced in trained mice. In full agreement with these results, mice trained 9 weeks before infection were powerfully protected from lethal listeriosis. Altogether, these data suggest that training increases the generation and the antimicrobial activity of PMNs and monocytes, which may confer prolonged protection from lethal bacterial infection.

Aims:This study investigated the ability of soluble platelet selectin (sP-selectin) to identify infection and predict 30-day mortality in patients with a systemic inflammatory response syndrome (SIRS) on the intensive care unit.Methods:Soluble platelet selectin levels were measured daily in the first 48 hours in patients presenting with SIRS. The outcome, proven infection, was established using predefined definitions. The 30-day mortality was retrospectively assessed.Results:In a total of 313 patients with SIRS, sP-selectin levels were measured. Of these, 114 patients had proven infection on admission or developing during their intensive care unit (ICU) stay. Patients with proven infection had moderately higher levels of sP-selectin (147 ng/mL; interquartile range [IQR], 93.4-203 ng/mL) compared with noninfected patients (143.8 ng/mL; IQR, 89.6-194.7 ng/mL). This difference was not statistically significant (P = .072). However, in patients who were not admitted for infection (n = 235), sP-selectin levels were significantly related to the subsequent development of infection (P = .013). Soluble platelet selectin levels were particularly high in patients with abdominal sepsis and skin infections. Higher sP-selectin levels were associated with higher mortality (although not statistically significant, P = .08).Conclusions:This study shows that in patients with SIRS not admitted for infection, sP-selectin levels are significantly related to the subsequent development of infection. Furthermore, patients with higher sP-selectin levels in the first 2 days of admission had higher 30-day mortality, although this association is not statistically significant. Therefore, we conclude that sP-selectin is a potential future biomarker for both mortality and infection in patients with SIRS, but more research is needed to confirm its prognostic role.