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Cellular response was assessed by T-cell proliferation assay and whole blood Interferon-Gamma Release Assay (IGRA) after stimulation with SARS-Cov-2 proteins [4]. Considering that an uncoordinated T cell and antibody responses have been associated with disease progression [5], the understanding of mechanisms sustaining incomplete vaccination (presence of IgG but lack of T cell response) remains of utmost importance. Immune response to three doses of mRNA SARS-CoV-2 vaccines in CD19-targeted chimeric antigen receptor T cell immunotherapy recipients.

BackgroundUnderstanding the mechanisms underlying immune dysregulation in sepsis is a major challenge in developing more individualized therapy, as early and persistent inflammation, as well as immunosuppression, play a significant role in pathophysiology. As part of the antimicrobial response, neutrophils can release extracellular traps (NETs) which neutralize and kill microorganisms. However, excessive NETs formation may also contribute to pathogenesis, tissue damage and organ dysfunction. Recently, a novel automated assay has been proposed for the routine measurement of nucleosomes H3.1 (fundamental units of chromatin) that are released during NETs formation. The aim of the present study was to measure nucleosome levels in 151 septic shock patients (according to sepsis-3 definition) and to determine association with mortality.ResultsThe nucleosome H3.1 levels (as determined by a chemiluminescence immunoassay performed on an automated immunoanalyzer system) were markedly and significantly elevated at all-time points in septic shock patients compared to the control group. Immunological parameters indicated tremendous early inflammation (IL-6 = 1335 pg/mL at day 1–2) along with marked immunosuppression (e.g., mHLA-DR = 3853 AB/C and CD4 = 338 cell /µL at day 3–4). We found significantly positive correlation between nucleosome levels and organ failure and severity scores, IL-6 concentrations and neutrophil count. Significantly higher values (day 1–2 and 3–4) were measured in non-survivor patients (28-day mortality). This association was still significant after multivariate analysis and was more pronounced with highest concentration. Early (day 1–2) increased nucleosome levels were also independently associated with 5-day mortality. At day 6–8, persistent elevated nucleosome levels were negatively correlated to mHLA-DR values.ConclusionsThis study reports a significant elevation of nucleosome in patients during a one-week follow-up. The nucleosome levels showed correlation with neutrophil count, IL-6 and were found to be independently associated with mortality assessed at day 5 or 28. Therefore, nucleosome concentration seems to be a promising biomarker for detecting hyper-inflammatory phenotype upon a patient's admission. Additional investigations are required to evaluate the potential association between sustained elevation of nucleosome and sepsis-induced immunosuppression.

Objective Only few data regarding epidemiology and management of ECMO cannula-related infections (ECMO-CRIs) exist. The aim of our study was to describe their epidemiology and prognosis, and to evaluate factors associated with outcome. Methods We performed a multicenter retrospective study in 12 European ICUs, including patients with ECMO-CRI, defined as a clinical suspicion plus a positive bacterial sample of ECMO-cannulation site. Primary objective was to describe ECMO-CRI characteristics and outcomes. Secondary objectives were to evaluate the rates of infection recurrence, their risk factors, and to evaluate the impact of antimicrobial treatment duration on outcome. Results During the study period, 109 patients with ECMO-CRI (78 having concomitant positive blood culture with the same pathogen) were included. Pathogens responsible for infections were predominantly Enterobacteriaceae, coagulase-negative Staphylococcus and Enterococcus spp., and 42% of episodes were polymicrobial. Rates of infection recurrence was 13% and ICU-mortality rate was 51%. Risk factors for death were concomitant bloodstream infection with same pathogen and septic shock Patients with antibiotic course ≤ 8 days had similar infection recurrence rate and outcomes (including mortality) than patients with prolonged (> 8 days) antibiotic course. Conclusion ECMO-CRIs are frequently associated with BSI and frequently polymicrobial. Duration of antimicrobial treatment for ECMO-CRI ≤ 8 days does not seem to be associated with an increased risk of recurrence or death, as compared to longer treatment.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated response to infection. In this context, the aberrant activation of the NLRP3 inflammasome has been documented mostly through the measurement of increased plasmatic concentrations of IL-1β and IL-18. At the cellular level, contradictory results have been published. However, no study has comprehensively monitored NLRP3 inflammasome activation at the basal level and after ex vivo reactivation of whole blood monocytes and neutrophils focusing on ICU patients with bacterial and viral sepsis, including a longitudinal analysis. Thus, we conducted a prospective longitudinal study, examining NLRP3 inflammasome functionality in COVID-19 ICU patients (n = 15) and bacterial septic shock patients (n = 17) during the first week of ICU hospitalization, compared with healthy donors. Using two whole-blood flow cytometry assays, we detected ASC speck-positive monocytes (i.e., monocytes presenting the polymerization of ASC proteins) and activated caspase-1 in polymorphonuclear cells as read-outs, both at baseline and following nigericin stimulation, a drug that forms pores and activates the NLRP3 inflammasome. Our findings showed that, at baseline and regardless of the type of infection, patients exhibited reduced ASC speck-positive monocytes and decreased activated caspase-1 in PMN compared to healthy volunteers. This decrease was prominent at day 0. Following nigericin stimulation, this reduction was also observed and persisted throughout the first week of hospitalization, irrespective of the cellular population or parameter being considered. Notably, at day 0, this diminished activation and response to stimulation of NLRP3 was associated with a higher 28-day mortality rate. Consequently, our observations highlighted a concurrent decline in both basal expression and ex vivo activation of the NLRP3 inflammasome in circulating myeloid cells from patients with bacterial and viral sepsis in association with increased mortality.

BackgroundLymphopenia is a hallmark of severe coronavirus disease 19 (COVID-19). Similar alterations have been described in bacterial sepsis and therapeutic strategies targeting T cell function such as recombinant human interleukin 7 (rhIL-7) have been proposed in this clinical context. As COVID-19 is a viral sepsis, the objectives of this study were to characterize T lymphocyte response over time in severe COVID-19 patients and to assess the effect of ex vivo administration of rhIL-7.ResultsPeripheral blood mononuclear cells from COVID-19 patients hospitalized in intensive care unit (ICU) were collected at admission and after 20 days. Transcriptomic profile was evaluated through NanoString technology. Inhibitory immune checkpoints expressions were determined by flow cytometry. T lymphocyte proliferation and IFN-γ production were evaluated after ex vivo stimulation in the presence or not of rhIL-7. COVID-19 ICU patients were markedly lymphopenic at admission. Mononuclear cells presented with inhibited transcriptomic profile prevalently with impaired T cell activation pathways. CD4 + and CD8 + T cells presented with over-expression of co-inhibitory molecules PD-1, PD-L1, CTLA-4 and TIM-3. CD4 + and CD8 + T cell proliferation and IFN-γ production were markedly altered in samples collected at ICU admission. These alterations, characteristic of a T cell exhaustion state, were more pronounced at ICU admission and alleviated over time. Treatment with rhIL-7 ex vivo significantly improved both T cell proliferation and IFN-γ production in cells from COVID-19 patients.ConclusionsSevere COVID-19 patients present with features of profound T cell exhaustion upon ICU admission which can be reversed ex vivo by rhIL-7. These results reinforce our understanding of severe COVID-19 pathophysiology and opens novel therapeutic avenues to treat such critically ill patients based of immunomodulation approaches. Defining the appropriate timing for initiating such immune-adjuvant therapy in clinical setting and the pertinent markers for a careful selection of patients are now warranted to confirm the ex vivo results described so far.Trial registration ClinicalTrials.gov identifier: NCT04392401 Registered 18 May 2020, http:// clinicaltrials.gov/ct2/show/NCT04392401.

Background: Citrate accumulation (CA) is a feared complication in critically ill patients undergoing regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT). This study aimed to describe the characteristics of patients presenting CA within a large cohort of unselected critically ill patients receiving RCA-CRRT depending on the time of occurrence of CA after CRRT initiation.Methods: This retrospective, multicenter observational study performed in nine intensive care units (ICU) in Lyon, France, included patients treated with RCA-CRRT between January 2020 and January 2022. CA was defined by a total to ionized calcium ratio (tCa/iCa) ≥ 2.3 associated with hypocalcemia and metabolic acidosis.Results: Among 2080 patients, 76 (3.7%) developed CA: 69 (91%) experienced CA within 24 h after CRRT initiation (initial CA) and 7 (9%) after 24 h (late-onset CA). Only lactate levels at CRRT initiation differed between patients with initial CA and those with late-onset CA (10 mmol/l [4.6-16] vs 1.4 mmol/l [1-3.8], p = 0.006 respectively). In the initial CA group, 39 (57%) exhibited signs of CA within 6 h or less (immediate CA) and 30 (43%) showed signs of CA between 6 and 24 h. Over the first 24 h, patients with initial CA presented a marked increase in lactate levels, worsening norepinephrine requirements, persistent elevation of the tCa/iCa ratio, decrease in prothrombin time, and increase in transaminases. Patients with immediate CA showed higher lactate concentration and more severe metabolic acidosis at CRRT initiation compared to patients with early CA whereas other markers did not differ significantly between the two groups. The area under the Receiver Operating Characteristic curve of lactate and pH for predicting immediate citrate accumulation were 0.75 [0.62 - 0.87] and 0.74 [0.62 - 0.85] respectively, with optimal cutoff values of 10.6 mmol/L and 7.14 respectively. The ICU mortality rate among patients with CA was 97% compared to 55% in the whole cohort.Conclusions: CA is a rare phenomenon in patients under RCA-CRRT. Severe metabolic acidosis with hyperlactatemia at CRRT initiation is the most relevant marker to identify patients at risk of immediate CA and should encourage close monitoring of tCa/iCa ratio.

Citrate accumulation (CA) is a feared complication in critically ill patients undergoing regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT). This study aimed to describe the characteristics of patients presenting CA within a large cohort of unselected critically ill patients receiving RCA-CRRT depending on the time of occurrence of CA after CRRT initiation.

Citrate accumulation (CA) is a feared complication in critically ill patients undergoing regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT). This study aimed to describe the characteristics of patients presenting CA within a large cohort of unselected critically ill patients receiving RCA-CRRT depending on the time of occurrence of CA after CRRT initiation.