Daily Sepsis Research Analysis
Three studies advance sepsis research across practice, mechanism, and target discovery: a national, multicenter implementation of serial physical examinations halved neonatal antibiotic exposure without safety trade-offs; mechanistic work links lactate-driven histone lactylation to endothelial ferroptosis underlying sepsis-related acute lung injury; and Mendelian randomization identifies APOE as a causal circulating protein for sepsis risk, prioritizing a druggable pathway.
Summary
Three studies advance sepsis research across practice, mechanism, and target discovery: a national, multicenter implementation of serial physical examinations halved neonatal antibiotic exposure without safety trade-offs; mechanistic work links lactate-driven histone lactylation to endothelial ferroptosis underlying sepsis-related acute lung injury; and Mendelian randomization identifies APOE as a causal circulating protein for sepsis risk, prioritizing a druggable pathway.
Research Themes
- Antimicrobial stewardship and diagnostic strategies in neonatal sepsis
- Epigenetic-metabolic mechanisms driving organ injury in sepsis
- Human genetics and proteomics to prioritize sepsis drug targets
Selected Articles
1. Serial physical examination to reduce unnecessary antibiotic exposure in newborn infants: a population-based study.
In six Norwegian NICUs, implementing serial physical examination for at-risk infants ≥34 weeks reduced antibiotic exposure by 50% (1.8% to 0.9%) without increases in culture-positive EOS, NICU admissions, or safety events. Time-to-antibiotics for EOS cases and infection-related outcomes were maintained while de-escalating empiric therapy.
Impact: This population-scale, multicenter intervention demonstrates a safe, pragmatic pathway to halve neonatal antibiotic exposure—directly informing antimicrobial stewardship in EOS risk management.
Clinical Implications: NICUs can adopt structured serial physical examination pathways for ≥34-week infants at EOS risk to reduce unnecessary empiric antibiotics without compromising safety, potentially lowering resistance pressure and NICU resource use.
Key Findings
- Antibiotic exposure decreased by 50% from 1.8% to 0.9% after SPE implementation.
- Culture-positive EOS incidence, NICU admissions, and safety outcomes (time to antibiotics, infection-related deaths, re-admissions) were unchanged.
- SPE monitored infants for 24–48 hours and initiated antibiotics promptly upon deterioration, supporting a safe de-escalation framework.
Methodological Strengths
- Population-based, multicenter interventional design with over 54,000 eligible infants.
- Use of statistical process control and predefined safety endpoints to monitor implementation impact.
Limitations
- Non-randomized, before-after design may be susceptible to secular trends and residual confounding.
- Generalizability may vary outside Norwegian tertiary/secondary NICUs.
Future Directions: Cluster-randomized or stepped-wedge trials across diverse health systems to validate SPE, integrate biomarkers (e.g., MDW) to further refine risk stratification, and assess long-term antimicrobial resistance outcomes.
OBJECTIVES: While antibiotics save lives in infants with sepsis, up to 12.0% of non-infected term and late preterm infants are exposed to antibiotics underscoring diagnostic challenges in early onset sepsis (EOS).This study aimed to assess whether serial physical examination (SPE) in neonatal intensive care units (NICUs) could safely reduce early antibiotic exposure in infants born at ≥34 weeks' gestation at risk for EOS. DESIGN: A population-based, multicentre interventional study from 2018 throughout 2021. SETTING: Six Norwegian tertiary and secondary level NICUs. PATIENTS: In total, 54 713 liveborn infants were eligible for inclusion. INTERVENTIONS: Infants at risk for EOS (mild/transient clinical signs, chorioamnionitis-exposed or group B streptococcus sepsis in a sibling) were clinically monitored with SPE for 24-48 hours. Infants with no/transient clinical signs did not receive antibiotics, whereas treatment was initiated without delay if signs indicated severe EOS, clinical condition deteriorated despite intervention or vital signs failed to improve. MAIN OUTCOME MEASURES: Comparative statistics were used to evaluate changes after implementing SPE, including percentage of infants exposed to antibiotics, incidence of EOS, NICU and safety outcomes (time from birth to antibiotics administration in EOS, infection-related deaths and re-admissions for infection). A statistical process control chart was used to evaluate antibiotic exposure over time. RESULTS: Infants exposed to antibiotics were reduced by 50%, from 1.8% (95% CI 1.6% to 2.0%) to 0.9% (95% CI 0.8% to 1.1%).Incidence of culture-positive EOS, NICU admission rates and safety outcomes remained unchanged. CONCLUSION: SPE reduced antibiotic exposure in infants ≥34 weeks' gestation without compromising safety.
2. Identification of circulating inflammatory proteins as potential drug targets for sepsis through Mendelian randomization and colocalization analyses.
Two-sample MR integrating cis-pQTLs (N=54,219) and sepsis GWAS (FinnGen; 12,301 cases) identified APOE as causally linked to increased sepsis risk (OR 1.07), with replication and strong colocalization (PP4=0.95). Sensitivity analyses (SMR, HEIDI) supported causality and protein–protein interactions highlighted APOE’s connections to existing sepsis drug targets.
Impact: Causal inference from large-scale human genetics prioritizes APOE as a drug target for sepsis, providing a rigorous framework to bridge proteomics and therapeutic development.
Clinical Implications: APOE pathways may inform risk stratification and therapeutic targeting in sepsis; findings justify mechanistic studies and potential repurposing of APOE-modulating therapies.
Key Findings
- Genetically increased APOE levels associated with higher sepsis risk (OR 1.07, 95% CI 1.04–1.11; P=5.36×10^-5).
- Replication across independent pQTL (Fenland) and GWAS (UK Biobank) datasets with strong colocalization (PP4=0.95) and non-heterogeneous SMR/HEIDI results.
- Protein–protein interaction analysis showed APOE connects to multiple sepsis drug targets under clinical testing.
Methodological Strengths
- Two-sample MR with large cis-pQTL and GWAS datasets plus independent replication.
- Robust sensitivity suite (SMR, HEIDI, colocalization, phenome-wide scanning) to address pleiotropy and linkage.
Limitations
- Effect size is modest and MR relies on core assumptions that cannot be fully verified.
- Ancestry composition and protein assay platforms may limit generalizability; functional validation is pending.
Future Directions: Mechanistic dissection of APOE’s role in sepsis pathophysiology, target engagement studies, and early-phase trials of APOE-modulating strategies or repurposed agents.
Sepsis is a complex disease with limited therapeutics. We conducted a 2-sample Mendelian randomization (MR) analysis to identify circulating inflammatory proteins as potential drug targets for sepsis. Protein quantitative trait loci (pQTLs) at cis-region for 448 circulating inflammatory proteins were obtained from the UK biobank pharma proteomics project (UKB-PPP) (N = 54219), and summary-level genetic associations with sepsis were extracted from the FinnGen cohort (12,301 cases and 332,343 controls) for the primary MR analysis. The findings were further replicated using alternative cis-pQTL (Fenland, N = 10708) and sepsis genome-wide association study data (UK Biobank, 2811 cases and 406,150 controls). Multiple sensitivity analyses including summary-data-based MR (SMR), the HEIDI test, colocalization, and phenome-wide scanning were performed to verify the causality of the identified proteins. Moreover, protein-protein interaction analysis was performed to examine the interactions between identified proteins and current drug targets in clinical trials. With the adjusted P-value <.05, 1-SD increase in genetically determined APOE (apolipoprotein E) was associated with increased risk of sepsis (OR = 1.07, 95%CI = 1.04-1.11, P = 5.36 × 10-5). The findings were consistent in the validation analyses. Multi-SNPs SMR analysis (P = 1.42 × 10-3), HEIDI test (P = .53), and colocalization analysis (PP4 = 0.95) further supported the causality of APOE. Protein-protein interaction analysis suggested that APOE was interacted with multiple drug targets tested in the clinical trials for sepsis. This integrative analysis combing the pQTL and genome-wide association study data identified APOE as a promising drug target for sepsis. Further experimental studies were warranted to explore the details of the underlying biological mechanisms and feasibility of drug development.
3. Histone lactylation exacerbates acute lung injury in septic mice by promoting ferroptosis in pulmonary microvascular endothelial cells.
In sepsis models, elevated lactate peaked at 18 hours post-CLP and drove pulmonary microvascular endothelial cell ferroptosis via H3K18 lactylation, upregulating ACSL4 and ferritinophagy (LC3/NCOA4 via GATA2), increasing permeability and worsening lung injury. In S-ARDS patients, serum lactate correlated with ferroptosis markers and poor outcomes.
Impact: This work uncovers an epigenetic-metabolic mechanism—lactate-driven histone lactylation—linking sepsis biochemistry to endothelial ferroptosis and barrier failure, highlighting tractable intervention points (ferroptosis and lactylation).
Clinical Implications: Targeting lactate signaling, histone lactylation, or ferroptosis pathways may mitigate sepsis-related acute lung injury; lactate levels could inform risk and guide anti-ferroptotic strategies.
Key Findings
- Serum lactate peaked 18 hours after CLP and promoted PMVEC ferroptosis, increasing vascular permeability and worsening ALI.
- H3K18 lactylation upregulated ACSL4 and induced lipid peroxidation; it also increased LC3 transcription and NCOA4 via GATA2, facilitating ferritinophagy.
- In S-ARDS patients, serum lactate correlated with ferroptosis markers and both associated with poorer prognosis.
Methodological Strengths
- Integrated in vivo CLP model, primary endothelial cell assays, and transcriptomics to map mechanism.
- Human correlative data linking lactate and ferroptosis markers to outcomes strengthens translational relevance.
Limitations
- Predominantly preclinical with limited human sample characterization; causal inference in patients remains to be established.
- Therapeutic modulation of lactylation/ferroptosis was not tested in clinical settings.
Future Directions: Test anti-ferroptotic or anti-lactylation interventions in sepsis ALI models and early-phase trials; define patient stratification biomarkers (H3K18la, ACSL4 signatures).
BACKGROUND: Circulating lactate is associated with poor prognosis in sepsis-induced acute lung injury (S-ALI). However, it remains unclear whether microvascular dysfunction, a hallmark of S-ALI, is related to circulating lactate levels and what the underlying mechanisms are. The aim of this study was to investigate the role and mechanisms of lactate in pulmonary microvascular dysfunction in S-ALI. METHODS: The effects of lactate on pulmonary microvascular function were assessed in a septic mouse model. Primary mouse pulmonary microvascular endothelial cells (MPMVECs) were isolated to evaluate the impact of lactate on MPMVEC permeability. Transcriptomic sequencing was employed to investigate the involvement of lactate in regulating MPMVEC ferroptosis, and the results were validated by RESULTS: The mouse serum lactate level reached a peak at 18 h after caecal ligation and puncture surgery. Elevated lactate levels during sepsis promoted ferroptosis in PMVECs, leading to increased pulmonary vascular permeability and exacerbation of ALI. Mechanistically, lactate increased the lactylation of histone H3 at K18 (H3K18la), which promoted ACSL4 transcription in MPMVECs, resulting in excessive lipid peroxidation. Additionally, elevated H3K18la promoted LC3 transcription and indirectly upregulated NCOA4 expression through the transcription factor GATA2, facilitating ferritinophagy. Serum lactate levels were significantly correlated with ferroptosis levels in S-ARDS patients, and both were associated with poor patient prognosis. CONCLUSIONS: This study revealed a critical role for high lactate-derived histone lactylation in PMVEC ferroptosis and the progression of ALI during sepsis, providing new insights and potential therapeutic mechanisms.