Daily Sepsis Research Analysis
Analyzed 22 papers and selected 3 impactful papers.
Summary
A multicenter prospective study validated the Phoenix Sepsis Criteria and Score in European PICUs, outperforming IPSCC criteria for identifying and prognosticating pediatric sepsis. A mechanistic study uncovered lactate-driven ENO1 lactylation as a driver of endothelial barrier breakdown in sepsis, with a peptide inhibitor improving survival in mice. A randomized trial in VLBW infants showed no benefit of Lactobacillus rhamnosus GG on the composite of NEC, sepsis, or mortality, refining neonatal probiotic use.
Research Themes
- Validation of pediatric sepsis diagnostic and prognostic criteria
- Endothelial pathobiology and lactylation mechanisms in sepsis
- Neonatal probiotic therapy and prevention of sepsis/NEC
Selected Articles
1. Predictive and Prognostic Performance of the Phoenix Sepsis Criteria and Phoenix Sepsis Score in PICU Patients With Suspected Infection: A Multicenter Prospective Study.
In 687 PICU patients with suspected infection, the Phoenix Sepsis Criteria and Score outperformed IPSCC criteria in identifying sepsis and predicting mortality, with sensitivity reaching 96.4% on day 1 and 100% on day 2. PELOD-2 yielded the highest AUPRC for mortality, and all scores improved from day 1 to day 2, marking the first European validation of PSC/PSS.
Impact: Validates an emerging pediatric sepsis framework with superior diagnostic and prognostic performance, supporting updates to clinical sepsis recognition pathways in PICUs.
Clinical Implications: PICUs should consider adopting PSC/PSS with reassessment on day 2 to improve early sepsis identification and risk stratification; integration with PELOD-2 may optimize mortality prediction.
Key Findings
- PSC achieved higher sensitivity and PPV than IPSCC for mortality on day 1 (96.4% sensitivity; PPV 7.6%) and day 2 (100% sensitivity; PPV 10.0%).
- PELOD-2 had the highest AUPRC for mortality (0.45 on day 1; 0.59 on day 2).
- All prognostic performances improved from day 1 to day 2; IPSCC Severe Sepsis was outperformed by other scores including PSS and Phoenix-8.
Methodological Strengths
- Prospective multicenter cohort across eight PICUs with standardized data collection on day 1 and day 2.
- Head-to-head comparison against multiple established organ dysfunction scores with appropriate metrics (sensitivity, PPV, AUPRC).
Limitations
- Observational design limits causal inference and clinical impact assessment.
- Low PPV reflects low event rate; generalizability beyond European PICUs remains to be tested.
Future Directions: External validation in diverse health systems; evaluate workflow integration and whether PSC/PSS-driven protocols improve time-to-treatment and outcomes.
OBJECTIVES: Evaluate the predictive and prognostic performance of the Phoenix Sepsis Criteria (PSC) and Phoenix Sepsis Score (PSS) compared with International Pediatric Sepsis Consensus Conference (IPSCC) criteria and other organ dysfunction scores in children admitted to the PICU with suspected infection. DESIGN: Multicenter, prospective cohort study. SETTING: Eight PICUs within the Italian Network of PICU Study Group (TIPNet). PATIENTS: Patients younger than 18 years admitted with suspected infection (from February 2022 to April 2024). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Vital signs, organ dysfunction markers, and organ support requirements were collected during day 1 and day 2 of PICU admission. Sepsis was assessed using IPSCC criteria and PSC. IPSCC Severe Sepsis, PSS, Phoenix-8, Pediatric Logistic Organ Dysfunction-2 (PELOD-2), pediatric Sequential Organ Failure Assessment, and Pediatric Multiple Organ Dysfunction Score were calculated as organ dysfunction scores. Sepsis criteria predictive performance was assessed using sensitivity and positive predictive value (PPV). Organ dysfunction scores prognostic performance was assessed using the area under the precision-recall curve (AUPRC). Primary outcome was PICU mortality. Among 687 patients, PSC showed higher predictive performance than IPSCC sepsis criteria, with improved sensitivity and PPV for mortality on day 1 (PSC: sensitivity, 96.4%; 95% CI, 95.0-97.8%; PPV, 7.6%; 95% CI, 5.6-9.6% and IPSCC: sensitivity, 82.1%; 95% CI, 79.3-85.0%; PPV, 6.2%; 95% CI, 4.4-8.0%) and day 2 (PSC: sensitivity, 100.0%; 95% CI, 100.0-100.0%; PPV, 10.0%; 95% CI, 7.6-12.5% and IPSCC: sensitivity, 75.0%; 95% CI, 71.5-78.5%; PPV, 9.0%; 95% CI, 6.7-11.3%). PELOD-2 exhibited the highest AUPRC for mortality (day 1, 0.45; 95% CI, 0.26-0.63 and day 2, 0.59; 95% CI, 0.38-0.77). IPSCC Severe Sepsis score was outperformed by all other organ dysfunction scores, including PSS and Phoenix-8. All prognostic performances improved from day 1 to day 2. CONCLUSIONS: PSC and PSS performed superior to IPSCC criteria in diagnosing and prognosticating pediatric sepsis, with improved performance at day 2 of PICU admission. This study first validated PSC and PSS in a European cohort.
2. Targeting the lactylation of ENO1 alleviates endothelial dysfunction in sepsis.
Lactate drives p300-mediated ENO1 K71 lactylation in endothelial cells, stabilizing TRIM21 mRNA and promoting VE-cadherin ubiquitination that disrupts adherens junctions and increases permeability. Endothelial ENO1 knockdown and a K71 lactylation–blocking peptide reduced vascular leak and improved survival in CLP/LPS sepsis models, nominating ENO1 lactylation as a therapeutic target.
Impact: Reveals a previously unrecognized lactylation-dependent pathway linking metabolic derangement to endothelial barrier failure in sepsis and demonstrates a tractable peptide intervention.
Clinical Implications: While preclinical, targeting ENO1 lactylation could inform development of barrier-protective therapies to reduce vascular leak and organ dysfunction in sepsis.
Key Findings
- Sepsis-associated lactate promotes p300-mediated lactylation of ENO1 at K71 in endothelial cells.
- ENO1 lactylation reduces TRIM21 mRNA binding and CNOT6 recruitment, stabilizing TRIM21 mRNA; TRIM21 drives VE-cadherin ubiquitination and adherens junction disruption.
- A peptide inhibitor targeting ENO1 K71 lactylation reduced microvascular permeability and improved survival in CLP and LPS sepsis models.
Methodological Strengths
- Use of two complementary sepsis models (CLP and LPS) with endothelial-specific ENO1 knockdown via AAV.
- Comprehensive mechanistic interrogation including PTM mass spectrometry, RIP, RNA-seq, and functional permeability assays.
Limitations
- Preclinical murine and in vitro models without human validation.
- Pharmacokinetics, safety, and off-target effects of the peptide inhibitor were not addressed.
Future Directions: Validate ENO1 lactylation in human sepsis tissues; optimize pharmacology of inhibitors; assess synergy with standard vasopressors and fluid strategies.
BACKGROUND: Elevated lactate is associated with vascular endothelial dysfunction, a factor that can contribute to organ failure in sepsis. However, the specific mechanisms involved have yet to be fully elucidated. Here, we investigated the role of enolase 1 (ENO1) lactylation in modulating the functions of endothelial cells (ECs) in sepsis pathogenesis. METHODS: The septic mouse model was established using two methods: cecal ligation and puncture (CLP) and intraperitoneal injection of LPS. AAV-ENO1 shRNA was administered to ablate ENO1 in vascular endothelial cells of mice. Tail vein injection of .5% Evans Blue Dye (EBD) was utilised to assess microvascular permeability in septic mice. Post-translational modification (PTM) mass spectrometry was employed to detect key proteins undergoing lactylation in endothelial cells. Additionally, CCK-8 assay, Transwell assay, and scratch wound healing assay were performed to evaluate the fundamental functions of ECs. Further investigations were conducted through Western blotting, Co-immunoprecipitation (CO-IP), RT-qPCR, RNA immunoprecipitation (RIP) and RNA sequencing to examine genes/proteins involved in vascular endothelial injury and their interactions. RESULTS: We found that elevated lactate in sepsis promoted the lactylation of ENO1 at the K71 residue, facilitated by the increased activity of the lactyltransferase P300. This modification reduced the binding of TRIM21 mRNA to ENO1, thereby preventing its degradation by limiting the recruitment of CNOT6. Consequently, the stability and expression of TRIM21 mRNA were enhanced. Elevated TRIM21 subsequently binds to vascular endothelial-cadherin (VE-Cadherin), promoting its ubiquitination and degradation, disrupting endothelial adherens junctions (AJs) and increasing endothelial permeability. Targeting the lactylation of ENO1 at K71 with a specific inhibitory peptide alleviated endothelial injury and improved survival rates in septic mice. CONCLUSIONS: These findings suggest that ENO1 lactylation plays a pivotal role in vascular endothelial dysfunction during sepsis. Inhibiting lactylation may offer a therapeutic strategy for sepsis treatment.
3. Lactobacillus rhamnosus GG to Reduce Necrotising Enterocolitis, Sepsis, and Mortality in Very Low Birth Weight Infants: A Randomized Controlled Trial.
In an open-label RCT of 236 VLBW infants, single-strain Lactobacillus rhamnosus GG did not reduce the composite of sepsis, NEC, or mortality (RR 0.85; P=0.592), nor did it improve feeding milestones or resource use. The trial challenges routine single-component LGG supplementation in this population.
Impact: Provides a well-controlled negative result that refines probiotic strategies for high-risk neonates, reducing low-value interventions.
Clinical Implications: Routine single-strain LGG supplementation should not be expected to lower NEC, sepsis, or mortality in VLBW infants; if probiotics are considered, multi-strain formulations and larger confirmatory trials are needed.
Key Findings
- Composite outcome (sepsis, NEC, or mortality) was similar between LGG and control (30.4% vs 27.2%; RR 0.85; 95% CI 0.48–1.50; P=0.592).
- No differences in time to full feeds (11.9 vs 12.0 days; P=0.561) or time to regain birth weight (13.5 vs 13.6 days; P=0.982).
- Length of stay, mechanical ventilation duration, and antimicrobial therapy duration did not differ between groups.
Methodological Strengths
- Randomized controlled design with prospective registration (CTRI/2021/03/031724).
- Clinically meaningful outcomes assessed during hospitalization.
Limitations
- Open-label design may introduce performance or detection bias.
- Single-strain intervention and modest sample size may limit generalizability and power to detect smaller effects.
Future Directions: Compare multi-strain probiotic formulations and dosing strategies in adequately powered, blinded RCTs; evaluate microbiome-mediated mechanisms and subgroup effects.
OBJECTIVES: To evaluate the efficacy of oral Lactobacillus rhamnosus GG (LGG) in reducing neonatal enterocolitis (NEC), sepsis and mortality in very low birth weight (VLBW) infants. METHODS: This open-label randomized controlled trial included enterally-fed VLBW infants with gestational age ≤ 32 weeks; those with gastrointestinal anomalies, severe birth asphyxia (APGAR score < 3 at 5 min), cyanotic congenital heart disease, and those not started on feeds by 14 days of life were excluded. Participants were randomized to receive either no probiotic (control) group, or probiotic (LGG; intervention) group. The intervention group received the first dose of LGG (probiotic) at feed initiation and was continued till 35 weeks of corrected gestational age. The control group received only breast milk. Clinical outcomes (mortality, NEC, sepsis) were compared in both groups during hospital stay. RESULTS: A total of 236 infants were enrolled. The primary composite outcome of sepsis, NEC or mortality was seen in 35 (30.4%) and 33 (27.2%) infants, respectively in the LGG and control groups (RR 0.85; 95%CI 0.48-1.50, P = 0.592). The mean (SD) time to reach full feeds was 11.9 (4.2) and 12.0 (5.5) days in the LGG and control groups, respectively; P = 0.561. The mean (SD) time to regain birth weight was 13.5 (3.9) and 13.6 (3.9) days in the LGG and control groups, respectively (P = 0.982). There was no significant difference in duration of hospital stay, duration of mechanical ventilation, or duration of antimicrobial therapy between the two groups (P > 0.05). CONCLUSIONS: Use of LGG as single component probiotic in VLBW infants did not confer any significant benefit on the composite outcome of mortality, sepsis or NEC. TRIAL REGISTRY: Clinical Trial Registry of India; Ref. No. CTRI/2021/03/031724 dated Mar 03, 2021.