Daily Sepsis Research Analysis

BACKGROUND: Sepsis is a clinical syndrome marked by a dysregulated host response to infection, impairing oxygen delivery and utilization and causing organ dysfunction. Hypoxemia, which can cause significant tissue and organ damage, commonly occurs in sepsis. Thus, oxygen therapy is essential in patients with sepsis. However, the optimal oxygenation target for these patients remains controversial. OBJECTIVE: To evaluate the effects of different oxygenation targets on short- and medium-term outcomes in patients with sepsis. METHODS: A prospective, single-center, randomized controlled trial was conducted. The primary outcome was 28-day mortality. Secondary outcomes included 90-day mortality and intergroup comparisons of mechanical ventilation and vasopressor use during hospitalization. RESULTS: In total, 270 patients were randomly assigned to the conservative oxygenation, conventional oxygenation, and hyperoxygenation target groups ( n = 86, 93, and 91), of whom 35 (40.7%), 32 (34.4%), and 17 (18.7%) died by day 28, respectively. The 28-day mortality significantly differed between these groups ( P = 0.005). Pairwise comparison revealed a significant difference between the conservative oxygenation and hyperoxygenation target groups (χ² = 10.132, P = 0.001). Kaplan-Meier analysis showed significant differences in survival distributions among the groups (χ² = 10.340, P = 0.006). The 90-day mortality rates were 50.0%, 41.9%, and 36.3% in the conservative oxygenation, conventional oxygenation, and hyperoxygenation target groups, respectively, exhibiting no significant difference. CONCLUSION: Compared with conservative oxygen therapy, hyperoxygenation (PaO 2 : 100-150 mmHg) reduced 28-day mortality in patients with sepsis. However, no significant differences were observed among oxygenation targets regarding 90-day outcomes.Clinical trial registration: Chinese Clinical Trial Register (ChiCTR2200064957, 2022-10-24).

Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection, leading to multiorgan dysfunction. Inflammasome activation and pyroptosis are key mechanisms driving sepsis-associated organ dysfunction. However, it remains unclear whether circulating biomarkers actively contribute to disease progression. Although galectin-3-binding protein (LGALS3BP) has been proposed as a diagnostic and prognostic marker of sepsis, its functional role in sepsis-associated organ dysfunction remains undefined. In this study, the dynamics and function of LGALS3BP in sepsis were investigated using cecal ligation and puncture (CLP) and lipopolysaccharide (LPS)-induced mouse models. Plasma LGALS3BP levels were markedly elevated during sepsis and were accompanied by increased LGALS3BP expression in multiple organs, particularly in the liver. Hepatocyte-specific LGALS3BP overexpression exacerbated sepsis-associated liver injury, as evidenced by elevated serum alanine aminotransferase and aspartate aminotransferase levels, increased hepatocyte death, and reduced survival. Transcriptomic profiling of septic livers revealed that LGALS3BP overexpression markedly enriched cytokine signaling, inflammatory response gene sets, and the pyroptosis pathway, indicating dysregulated immune responses and an injury-driven transcriptional program during sepsis. RNA sequencing and in vitro experiments using primary hepatocytes treated with recombinant LGALS3BP, which mimics secreted LGALS3BP, demonstrated that recombinant LGALS3BP increased pyroptosis-associated gene signatures but was not sufficient to induce pyroptotic cell death. Instead, recombinant LGALS3BP promoted pyroptotic cell death only in the presence of septic stimuli. Mechanistically, under septic conditions, secretory LGALS3BP activated the TLR2-IRF3-NF-κB signaling axis, leading to NLRP3 inflammasome activation, cleavage of caspase-1 and gasdermin D, and increased IL-1β and IL-18 release, thereby promoting pyroptotic cell death. Importantly, antibody-mediated neutralization of secretory LGALS3BP suppressed TLR2-IRF3-NF-κB signaling and concomitantly attenuated inflammasome activation and pyroptosis in hepatocytes. Collectively, these findings identify LGALS3BP as a key pathogenic driver of sepsis-associated liver dysfunction through pyroptosis-mediated hepatocyte injury. Therapeutic targeting of LGALS3BP may therefore represent a promising strategy to mitigate sepsis-related liver failure beyond its proposed role as a circulating biomarker.

INTRODUCTION: Non-typhoidal Salmonella (NTS) bloodstream infections complicate Plasmodium falciparum (Pf) malaria infections in children under-five, but bacterial co-infections are often missed due to absence of microbiological diagnosis. We compared signs/symptoms and outcome of NTS bloodstream infection, severe Pf malaria and NTS-Pf malaria co-infections. METHODS: In an area with high, stable Pf malaria transmission (Kongo Central, DR Congo), children (>28 days- <5 years) admitted to hospital with severe febrile illness were enrolled during 18 months (NCT04473768/NCT04850677). Data (in-hospital and 1-month post-discharge) were prospectively collected. RESULTS: NTS bloodstream infections and severe Pf malaria were diagnosed in 12% (331/2682) and 52% (1389/2682) of enrolled children, respectively. NTS-Pf co-infections occurred in 10% (264/2682) of enrolled children, i.e., Pf malaria co-infected 80% (264/330) of NTS bloodstream infections and NTS co-infected 6% (78/1389) of severe Pf malaria. In children with recent Pf malaria (i.e., HRP2-antigen persistence with negative microscopy), NTS occurred in 32% (173/545), making recent malaria a major risk factor for NTS (OR=5.85, p < 0.001). Compared to severe Pf malaria, age under-two (OR=2.19), > 3 days of fever (OR=3.28) and acute malnutrition (OR=2.20-3.48) were risk factors for NTS (p < 0.001) and NTS cases more often had hypoglycemia, grunting, hepato-/splenomegaly, jaundice or altered consciousness, but overall clinical presentation was not discriminative. In-hospital NTS case fatality was high (24% versus 3% in severe Pf malaria), occurred within 2 days of admission in 64% of deaths, and was preceded by general danger/sepsis signs. NTS cases had slower fever resolution, more frequent in-hospital fever recurrence, longer hospital stays, and more post-discharge deaths (n = 4) than severe Pf malaria cases. CONCLUSION: NTS and Pf malaria frequently co-infected children under-five. Severe Pf malaria and NTS bloodstream infections could not be distinguished clinically, but fatality rates were higher in NTS. Low thresholds for empirical NTS antibiotics and early danger sign recognition triggering sepsis care might improve outcome.