Daily Sepsis Research Analysis

OBJECTIVES: Sepsis triggers both excessive inflammation and immunosuppression, the latter partly characterized by CD4+ T-cell depletion. The mechanisms underlying this depletion, especially its interplay with cytokine storms driven by inflammatory factors such as interleukin (IL)-6, remain unclear. This study aimed to elucidate the molecular mechanisms contributing to CD4+ T-cell depletion in sepsis, focusing specifically on the IL-6/Janus kinases (JAKs)/signal transducer and activator of transcription 3 (STAT3) signaling axis and programmed cell death. DESIGN: Prospective cohort study. SETTING: Adult ICUs at a university hospital. PATIENTS: Adult sepsis and septic shock patients without any documented immune comorbidity. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A prospective analysis enrolled 151 patients (93 sepsis, 58 septic shock) and 20 controls. Flow cytometry and enzyme-linked immunosorbent assay were used to assess immune cell populations and cytokine profiles, with multivariate analyses exploring their interrelationships. An additional 30 sepsis patients and ten controls were recruited to investigate mechanisms. Peripheral blood mononuclear cells (PBMCs) underwent RNA sequencing (RNA-seq). Isolated CD4+ T cells were stimulated with IL-6 in vitro, followed by treatment with specific inhibitors targeting pyroptosis, apoptosis, necroptosis, the JAKs/STAT3 pathway, or receptor-interacting protein kinase 1 (RIPK1). Western blotting, flow cytometry, immunofluorescence, Cell Counting Kit-8 assays, and interferon-gamma staining evaluated cell death pathways, PANoptosome (a complex mediating apoptosis, pyroptosis and necroptosis)-assembly, and function. Significant CD4+ T-cell loss occurred in both sepsis and septic shock groups, strongly correlating with elevated IL-6 levels. Sepsis PBMC RNA-seq revealed activated IL-6/JAKs/STAT3 signaling and upregulated apoptosis/pyroptosis/necroptosis genes. In vitro, IL-6 induced pyroptosis, apoptosis, and necroptosis (PANoptosis) in CD4+ T cells via IL-6/JAKs/STAT3-dependent RIPK1-PANoptosome assembly. Inhibiting JAKs/STAT3 or RIPK1 significantly reduced PANoptosis, partially restored CD4+ T-cell viability and functional capacity. CONCLUSIONS: PANoptosis has been observed to be a form of CD4+ T-cell death in sepsis patients. Evidence suggests that IL-6 may be associated with the exhaustion process, mechanistically involving the activation of the JAKs/STAT3 pathway. It is also hypothesized that this process might be linked to RIPK1-PANoptosome-mediated PANoptosis.

OBJECTIVES: The mortality among patients admitted with sepsis remains high and varies depending on the site of infection. The impact of hypercapnia and acidemia on clinical outcomes in mechanically ventilated patients with sepsis is not well understood. DESIGN: Multicenter, binational, retrospective study assessed the association of compensated hypercapnia, hypercapnic acidemia, and nonrespiratory acidemia, in mechanically ventilated patients with mortality in sepsis. SETTING: Data were extracted from the "Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation adult patient" database over a 17-year period (from January 2006 to December 2022) from 201 ICUs. PATIENTS: Patients were classified into four mutually exclusive groups based on a combination of arterial pH and arterial Co2 recorded during the first 24 hours of ICU stay: normocapnia with normal pH, fully compensated hypercapnia, hypercapnic acidemia, and nonrespiratory acidemia. Logistic regression and Cox proportional hazards regression were used to examine the association of compensated hypercapnia, hypercapnic, and nonrespiratory academia to hospital mortality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fifty-two thousand four hundred five patients were included. Overall compensated hypercapnia (odds ratio [OR], 1.39; 95% CI, 1.24-1.55; p < 0.001), hypercapnic acidemia (OR, 1.68; 95% CI, 1.57-1.80; p < 0.001), and nonrespiratory acidemia (OR, 1.75; 95% CI, 1.61-1.90; p < 0.001) was associated with increased risk of hospital mortality as compared with patients with normocapnia and normal pH. The risk of increased hospital mortality associated with hypercapnic and nonrespiratory acidemia persisted in all prespecified diagnostic subgroups when compared with patients who had normal pH and normocapnia. Compensated hypercapnia was associated with increased mortality risk in neurologic and unspecified subgroups of sepsis. CONCLUSIONS: Hypercapnic acidemia and nonrespiratory acidemia within the first 24 hours of ICU admission are associated with increased risk of hospital mortality in mechanically ventilated patients with sepsis. This association remains consistent in all diagnostic subgroups of sepsis.

INTRODUCTION: Sepsis is a leading cause of morbidity and mortality in hospitalised patients. Rapid Response Teams (RRTs) review clinically deteriorating patients, including those with sepsis. However, the epidemiology of sepsis in RRT calls remains unclear. This systematic review synthesised evidence on the prevalence, treatment, and outcomes of sepsis during RRT calls. METHODS: Seven electronic databases (PubMed, Web of Science, Embase, CINAHL, Cochrane Library, Ovid MEDLINE, and Scopus) were searched for studies published from 1 January 2015 to 31 May 2024. All articles were independently screened and assessed for study quality using the Newcastle Ottawa Scale by two reviewers per article. The primary outcome was the prevalence of sepsis during RRT calls. Secondary outcomes included hospital mortality and length of hospitalisation. Data were pooled using random-effects meta-analyses. RESULTS: From 5632 studies screened, 26 studies encompassing 110,909 patients and 139,076 RRT events were included. The pooled mean age was 64.4 years (95%CI: 59.2-69.7) and 48.4 % (n = 51,720, 24 studies) were male. The pooled prevalence of sepsis among all RRT calls was 23.7 % (95%CI: 15.5 %-34.6 %), with no significant difference between studies including exclusively sepsis RRT calls and studies with all causes of RRT calls (32.7 % vs. 21.8 %; p = 0.16). Common sepsis-related RRT triggers included abnormal respiratory and heart rates. Overall hospital mortality was 12.9 % (95%CI: 7.3-21.7 %) and hospital length of stay was 18 days (95%CI: 13.9-22.1), both showing no significant differences between studies including exclusively sepsis RRT calls and studies with all causes of RRT calls. New or changes in antibiotics were initiated in 38.8 % of sepsis-related RRTs. Most patients remained on the ward, while 23.3 % were transferred to the ICU. CONCLUSIONS: Sepsis is a trigger for a quarter of RRT calls, associated with substantial resource use and mortality in one eighth of patients. These findings support the need for standardised recognition protocols, escalation guidelines and prospective trials to optimise outcomes.