Daily Sepsis Research Analysis

IMPORTANCE: Sepsis is heterogeneous, and the optimal strategy for tailoring immunotherapy is uncertain. OBJECTIVE: To investigate whether precision immunotherapy guided by the presence of macrophage activation-like syndrome or sepsis-induced immunoparalysis improves organ dysfunction by day 9. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted in 6 countries. Patients with sepsis, defined by Sepsis-3, were included if they had community-acquired or hospital-acquired pneumonia or ventilator-associated pneumonia or bacteremia and sepsis and had displayed either macrophage activation-like syndrome (blood ferritin >4420 ng/mL) or sepsis-induced immunoparalysis (blood ferritin ≤4420 ng/mL and <5000 human leukocyte antigen DR receptors on CD45/CD14 monocytes). The first patient was enrolled August 5, 2021, and the last follow-up, April 29, 2024. INTERVENTIONS: Eligible patients were randomized to receive standard care and precision immunotherapy or standard care and placebo. Those in the precision immunotherapy group with macrophage activation-like syndrome received anakinra intravenously (IV) and placebo subcutaneously, and those with sepsis-induced immunoparalysis received subcutaneous recombinant human interferon gamma and IV placebo. Those in the placebo group received both IV and subcutaneous placebo. Treatment was administered for up to 15 days. MAIN OUTCOMES AND MEASURES: The primary end point was a decrease of at least 1.4 points in the mean Sequential Organ Failure Assessment (SOFA) score from baseline by day 9.

BACKGROUND: Unnecessary antibiotic prolongation promotes antimicrobial resistance. Evidence-based guidance on antibiotic durations for treating neonatal infections is lacking. Noninferiority meta-analyses evaluating shorter durations or biomarker-guided durations have not been conducted. METHODS: We conducted systematic reviews and meta-analyses using a unified search strategy (MEDLINE, EMBASE, Cochrane Library, January 1990-December 2024) to determine whether short-course antibiotics are noninferior to "standard" courses for culture-positive sepsis, culture-negative sepsis, UTIs, uncomplicated/complicated meningitis, and fungal sepsis. Likewise, we determined whether biomarker-guided antibiotic durations are noninferior to "standard" courses for any sepsis. We included randomized controlled trials (RCTs) without language restriction comparing short-courses or biomarker-guided courses versus standard courses for treating the above neonatal infections. Minimum clinically important differences (MCIDs) for critical outcomes were pre-specified [mortality (28-day, in-hospital or 12-month corrected age) = +1%, culture-positive relapse = +3%, culture-negative relapse = +5%]. We evaluated risk of bias (Cochrane RoB 2.0) and certainty of evidence (CoE) using GRADE. Registration: PROSPERO CRD42023311895. FINDINGS: We reviewed 146 full-text articles and included 26 in the review. For culture-positive sepsis (7 randomized controlled trials [RCTs]), 7-10-day courses were noninferior to longer courses for 28-day mortality [upper bound of 95% CI for risk difference +0.85%, below 1% MCID (low CoE)], in-hospital mortality [+0.51% (moderate CoE)], culture-positive relapse [+0.75%, below 3% MCID (low CoE)], culture-negative relapse [+4.7%, below 5% MCID (very low CoE)]. For culture-negative and -positive sepsis, biomarker-guided courses (5 RCTs) were noninferior to standard courses for mortality and relapses (all very low CoE]. For culture-negative sepsis (6 RCTs), shorter courses (3-4 days) were noninferior for culture-positive relapses (very low CoE) but

Mitochondrial dysfunction is a major mechanism of acute kidney injury (AKI), and increased circulating interleukin 6 (IL-6) is associated with systemic inflammation and death due to sepsis. We tested whether kidney mitochondrial DNA (mtDNA) contributes to IL-6 release in sepsis-associated AKI via Toll-like receptor 9 (TLR9). In a murine model of sepsis via cecal ligation and puncture (CLP), we used next-generation sequencing of plasma mtDNA to inform the design of optimal target sequences for quantification by droplet digital PCR, and to identify single-nucleotide polymorphisms (SNPs) to infer tissue origin. We found significantly higher concentrations of plasma mtDNA after CLP versus shams and that plasma mtDNA SNPs matched kidney SNPs more than other organs. Kidney mtDNA contributed directly to IL-6 and mtDNA release from dendritic cells in vitro and kidney mitochondria solution led to higher IL-6 concentrations in vivo. IL-6 release was mitigated by a TLR9 inhibitor. Finally, plasma mtDNA was significantly higher in septic patients with AKI compared with those without AKI and correlated significantly with plasma IL-6. We conclude that AKI contributes to increased circulating IL-6 in sepsis via mtDNA release. Targeting kidney mitochondria and mtDNA release are potential translational avenues to decrease mortality from sepsis-associated AKI.