Daily Sepsis Research Analysis

BACKGROUND: Sepsis-associated acute lung injury (S-ALI) is a clinical syndrome characterized by dysregulated inflammation and overwhelming oxidative stress, and is associated with a poor prognosis. Alpha-ketoglutarate dehydrogenase (OGDH) is a key enzyme in the tricarboxylic acid cycle that catalyzes the oxidative decarboxylation of α-ketoglutarate (α-KG) to succinyl-CoA, a critical step linking mitochondrial energy metabolism to immune response. However, the mechanism by which OGDH participates in S-ALI remains unclear. METHODS: The mouse model of sepsis was established via intraperitoneal injection of lipopolysaccharide (LPS), and CPI-613 was administered intraperitoneally prior to LPS challenge. Peripheral blood samples and baseline characteristics were collected from septic patients. In vitro, BMDMs were used to evaluate the therapeutic effects of CPI-613. Using untargeted metabolomics (LC-MS), RNA sequencing transcriptomics (RNA-seq), macrophage-specific small interfering Nrf2 RNA (si-Nrf2), and enzyme-linked immunosorbent assay (ELISA), we assessed lung tissue pathology, inflammatory cytokine levels, ferroptosis markers, OGDH enzyme activity, and clinical correlation. RESULTS: In LPS-induced septic mice, we observed systemic metabolic changes characterized by decreased α-KG levels and increased OGDH enzyme activity. Intraperitoneal administration of the OGDH inhibitor CPI-613 attenuated acute lung injury and systemic inflammation, thereby improving survival. Flow cytometry revealed that CPI-613 suppressed M1-like polarization of alveolar macrophages in septic mice, a finding corroborated in vitro. Transcriptomic profiling indicated that CPI-613 treatment preferentially modulated ferroptosis and glutathione metabolic pathways in LPS-treated bone marrow-derived macrophages (BMDMs). In both LPS-challenged mice and BMDMs, CPI-613 reduced ferroptosis biomarkers and activated the Nrf2-mediated antioxidant axis. Critically, genetic silencing of Nrf2 via siRNA or pharmacological inhibition with ML385 eliminated the anti-ferroptotic effects of CPI-613, positioning Nrf2 as a central mediator of this protection. Serum from patients with sepsis-associated ARDS exhibited significantly elevated OGDH enzyme activity relative to healthy controls. Moreover, OGDH activity correlated strongly with disease severity and clinical outcomes, including septic shock and death. CONCLUSION: Overall, our study reveals that OGDH is a key immunometabolism regulator and a novel biomarker in S-ALI, and its inhibitor CPI-613 may represent a potential therapeutic target for this condition.

BACKGROUND: Although the Prognostic Nutritional Index (PNI) is associated with sepsis outcomes, admission values may primarily reflect acute illness severity. We examined whether longitudinal PNI provides prognostic value beyond baseline risk. METHODS: In this retrospective cohort study of 492 adults with sepsis, baseline PNI was assessed using Kaplan-Meier analysis and adjusted restricted cubic splines. A joint model was used to link repeated PNI measurements from days 1 to 7 with time to 28-day mortality while accounting for informative dropout due to death or discharge. Time-dependent Cox models were further used to compare dynamic PNI with albumin and total lymphocyte count. RESULTS: Baseline PNI showed a non-significant trend toward survival separation (log-rank p = 0.063) and was not independently associated with 28-day mortality after multivariable adjustment (p = 0.122). By contrast, dynamic PNI was independently associated with mortality in time-dependent analyses (HR 0.730, p = 0.032), whereas albumin and total lymphocyte count were not. Joint modeling likewise demonstrated a significant independent association between longitudinal PNI and mortality (HR 0.831, p < 0.001). CONCLUSION: Baseline PNI showed limited independent prognostic value, whereas longitudinal PNI provided additional prognostic information and showed modestly better predictive performance than its individual components.

Introduction Sepsis is increasingly recognized as a heterogeneous syndrome encompassing distinct immune response phenotypes. Among these, macrophage activation-like syndrome (MALS) represents a severe hyperinflammatory state characterized by dysregulated cytokine release, rapid organ failure, and extremely high mortality. Hyperferritinemia has emerged as a readily available biomarker for identifying this high-risk phenotype in septic patients. The primary objective of our study was to identify and characterize differences between septic patients fulfilling MALS criteria (ferritin >4420 ng/mL) and those who did not, with particular focus on their clinical outcomes. Methods Retrospective cohort study including 437 adult patients diagnosed with sepsis or septic shock according to Sepsis-3 criteria. Serum ferritin levels were measured within the first 12-24 hours after sepsis onset. MALS was defined by ferritin concentrations >4420 ng/mL. Demographic data, clinical characteristics, laboratory parameters, organ support requirements, and outcomes were compared between patients with and without MALS. In addition, outcomes of a subgroup of patients with refractory septic shock who underwent hemoadsorption therapy as rescue treatment were analyzed. Results MALS was identified in 56 patients (12.8%). Compared with non-MALS patients, those with MALS were younger, more frequently immunosuppressed, and had higher severity scores, greater inflammatory marker levels, and more pronounced organ dysfunction. MALS patients required invasive mechanical ventilation and continuous renal replacement therapy more frequently. ICU mortality was significantly higher in the MALS group (75% vs. 43.3%, p<0.001), with markedly reduced 30- and 90-day survival. Hemoadsorption therapy was applied in 14 patients with extreme hyperinflammation and multiorgan failure, but ICU mortality remained high (71.4%). Conclusion Hyperferritinemia identifies a distinct septic shock phenotype consistent with MALS, associated with catastrophic outcomes despite advanced supportive care. While ferritin measurement allows early risk stratification, current hemoadsorption strategies appear insufficient in established MALS, underscoring the urgent need for precision immunotherapy and biomarker-guided clinical trials in hyperinflammatory sepsis.