Quarterly ReportApr 1 – Jun 30, 2025
Sepsis, Q2 2025 edition
We read 270 papers and selected 10.
Summary
The second quarter of 2025 marked a transition from syndrome-based sepsis research toward biologically stratified, organ-specific, and pathogen-informed precision medicine. Large-scale proteomic, transcriptomic, metabolomic, and microfluidic studies advanced the ability to identify injured organs, predict deterioration, infer pathogen class, and define immune-treatment phenotypes. Mechanistic studies expanded the therapeutic landscape from nonspecific immunosuppression toward targeted regulation of pyroptosis, nuclear stress responses, endothelial leakage, mitochondrial metabolism, and lactate-dependent myocardial injury. The OPTPRESS randomized trial provided important clinical evidence against routine high blood-pressure targets in older patients with septic shock, while other studies refined antibiotic stewardship and antimicrobial susceptibility assessment. Across the quarter, the strongest scientific contributions were methodological platforms and causal biological frameworks that can support future phenotype-enriched trials, although most biomarkers and host-directed therapies still require prospective clinical validation.
Selected Articles
1. Human proteome distribution atlas for tissue-specific plasma proteome dynamics.
This study created a mass-spectrometry atlas linking circulating proteins to their tissue and cellular origins across 18 organs and major blood-cell populations. Disease- and organ-enriched panels were validated in six cohorts, including sepsis, providing a framework for organ-specific interpretation of plasma changes.
Impact: It establishes a scalable biological reference for moving sepsis assessment beyond nonspecific inflammation toward organ-resolved disease monitoring.
Clinical Implications: Organ-specific panels could eventually support detection of kidney, liver, lung, or endothelial injury and guide monitoring, but assay simplification, rapid turnaround, and outcome-based validation are required.
Key Findings
- A mass-spectrometry atlas mapped plasma proteins to 18 organs and eight major blood-cell types.
- Organ-enriched signatures were validated across six clinical cohorts, including sepsis.
- The framework supports organ-specific phenotyping and monitoring of sepsis-associated injury.
2. Multi-Omics and -Organ Insights into Energy Metabolic Adaptations in Early Sepsis Onset.
This cross-species study integrated serum metabolomics and lipidomics from 152 presymptomatic surgical patients with single-nucleus RNA sequencing in a mouse model. Serine and aminoadipic acid distinguished uncomplicated infection from sepsis, while mitochondrial energy genes were reduced in affected organs.
Impact: It bridges presymptomatic human biomarker discovery with organ-level mechanistic validation and advances early detection before overt clinical deterioration.
Clinical Implications: A serine-centered panel may support postoperative risk stratification after external validation; metabolic confounding, assay standardization, and prospective utility remain unresolved.
Key Findings
- Serine and aminoadipic acid discriminated postoperative uncomplicated infection from sepsis.
- Mitochondrial energy genes including Cox4i1, Cox8a, and Ndufa4 were downregulated.
- Liver-specific metabolic changes linked circulating biomarkers to organ bioenergetic dysfunction.
3. De novo assembly of nuclear stress bodies rearranges and enhances NFIL3 to restrain acute inflammatory responses.
This study showed that stress-induced nuclear stress bodies reorganize SatIII loci and enhance NFIL3 expression. NFIL3 suppresses proinflammatory cytokines, and activation of the NFIL3/SatIII program in patient PBMCs correlated with survival in sepsis.
Impact: It reveals a previously underappreciated chromatin-based mechanism of immune restraint and links stress biology to a clinically relevant survival phenotype.
Clinical Implications: NFIL3/SatIII activity may become a marker of adaptive immune restraint, but therapeutic manipulation remains investigational and requires clinically relevant validation.
Key Findings
- Stress-induced nuclear stress bodies expanded SatIII loci and enhanced NFIL3 expression.
- NFIL3 suppressed proinflammatory cytokine production through chromatin regulation.
- NFIL3/SatIII activation in patient PBMCs correlated with survival.
4. A machine learning and centrifugal microfluidics platform for bedside prediction of sepsis.
The study developed a six-gene Sepset signature for predicting clinical deterioration within 24 hours. It was derived from 586 samples, externally validated in 3,178 patients, and translated into an automated RT-PCR centrifugal microfluidic device with approximately 92–94% sensitivity and 89% specificity.
Impact: It converts a molecular risk signature into a potentially deployable bedside technology, addressing the time-sensitive need to identify deterioration early.
Clinical Implications: The platform could support earlier ICU referral and intensified monitoring, but analytical reproducibility, cost-effectiveness, workflow integration, and outcome benefit require prospective testing.
Key Findings
- A six-gene Sepset signature predicted 24-hour clinical deterioration.
- The classifier was externally validated in 3,178 patients.
- An automated microfluidic RT-PCR platform achieved approximately 92–94% sensitivity and 89% specificity.
5. Pathogen-specific host response in critically ill patients with blood stream infections: a nested case-control study.
Across multiple cohorts of 341 patients, the causative pathogen explained 41.8% of blood transcriptomic variance. A validated eight-gene classifier identified streptococcal bloodstream infection, while Escherichia coli and Staphylococcus aureus produced distinct inflammatory and endothelial activation profiles.
Impact: It provides strong human evidence that pathogen identity materially shapes host response and creates a practical bridge toward pathogen-informed precision diagnostics.
Clinical Implications: A rapid classifier could eventually support earlier antimicrobial targeting, but analytical validation, turnaround-time evaluation, and prospective impact studies are required.
Key Findings
- The causative pathogen accounted for 41.8% of blood transcriptomic variance.
- An externally validated eight-gene classifier identified streptococcal bloodstream infection.
- E. coli and S. aureus infections showed distinct cytokine and endothelial activation patterns.
6. Endothelial CLEC5A drives barrier dysfunction and vascular leakage responsible for lung injury in bacterial pneumonia and sepsis.
Using CLP and LPS models, the study showed that endothelial CLEC5A causally promotes vascular leakage, cytokine amplification, lung injury, and mortality. Endothelial-specific knockdown improved survival, whereas re-expression reversed the benefit, and single-cell RNA sequencing characterized associated endothelial states.
Impact: It identifies a cell-type-specific and causally supported driver of endothelial barrier failure, a central mechanism of sepsis lung injury.
Clinical Implications: CLEC5A blockade may limit vascular leakage and lung injury, but human validation, pharmacodynamic studies, and infection-control safety assessment are required.
Key Findings
- Clec5a-deficient mice had reduced mortality in CLP and LPS sepsis models.
- Endothelial-specific knockdown improved survival, while re-expression abolished protection.
- CLEC5A deficiency reduced cytokine amplification and vascular leakage.
7. A conserved immune dysregulation signature is associated with infection severity, risk factors prior to infection, and treatment response.
Across 12,026 blood samples from 68 cohorts, the study validated a 42-gene Severe-or-Mild signature. The score linked age, sex, obesity, smoking, and comorbidity with severity, mortality, and differential hydrocortisone response, establishing a broad framework for immune-based patient stratification.
Impact: Its exceptional scale and cross-cohort validation make it a leading candidate for biologically informed prognosis and treatment selection.
Clinical Implications: SoM could eventually identify patients more likely to benefit from or be harmed by corticosteroids, but prospective treatment-selection trials are necessary.
Key Findings
- A 42-gene SoM signature was associated with pre-infection risk factors and infection severity.
- SoM predicted mortality and identified patients potentially harmed by hydrocortisone.
- The signature was modifiable by immunomodulatory drugs and lifestyle-related interventions across cohorts.
8. Lactylation of HADHA Promotes Sepsis-Induced Myocardial Depression.
The study identified extensive lysine lactylation in septic myocardium and showed that HADHA K166 and K728 lactylation inhibits HADHA activity. This impaired mitochondrial function, ATP production, and cardiomyocyte contractility, with SIRT1 and SIRT3 regulating the modification.
Impact: It provides a direct molecular link between lactate accumulation and septic cardiomyopathy and identifies a potentially targetable metabolic axis.
Clinical Implications: Modulating HADHA lactylation or SIRT1/SIRT3 activity may preserve myocardial function, but human myocardial validation and cardiovascular safety studies are essential.
Key Findings
- A total of 1,127 lysine lactylation sites were mapped, including 83 differentially lactylated sites.
- HADHA K166 and K728 lactylation impaired enzymatic and mitochondrial function.
- SIRT1 and SIRT3 regulated HADHA lactylation in cellular and animal models.
9. Efficacy of targeting high mean arterial pressure for older patients with septic shock (OPTPRESS): a multicentre, pragmatic, open-label, randomised controlled trial.
OPTPRESS randomized 518 patients aged 65 years or older with septic shock to MAP targets of 80–85 or 65–70 mmHg. The trial stopped early for harm: 90-day mortality was 39.3% versus 28.6%, with no beneficial subgroup identified.
Impact: It directly challenged a widely used physiological assumption with randomized mortality evidence and refined the scientific understanding of individualized organ-support targets.
Clinical Implications: Routine high MAP targets should generally be avoided in older septic-shock patients unless individualized circumstances justify them; vasopressor-related ischemia and arrhythmia require monitoring.
Key Findings
- The trial stopped early because the high-MAP strategy increased harm.
- Ninety-day mortality was 39.3% with MAP 80–85 mmHg versus 28.6% with MAP 65–70 mmHg.
- No subgroup, including patients with chronic hypertension, benefited from the higher target.
10. Colistin exerts potent activity against mcr+ Enterobacteriaceae via synergistic interactions with the host defense.
Using physiologic bicarbonate-containing media, fresh human blood, and a murine bacteremia model, the study found that colistin retained bactericidal activity against mcr-1-positive Enterobacteriaceae. Colistin enhanced complement deposition and synergized with serum, suggesting that conventional susceptibility testing may miss host–drug interactions.
Impact: It challenges conventional antimicrobial susceptibility paradigms by incorporating host defense into drug activity assessment.
Clinical Implications: The findings do not justify immediate changes in colistin use, but they support further physiologic-condition testing integrating pathogen genotype, complement competence, and toxicity risk.
Key Findings
- Colistin killed mcr-1-positive Enterobacteriaceae in bicarbonate-containing physiologic media.
- The drug enhanced complement deposition and synergized with human serum.
- Colistin showed efficacy in a murine bacteremia model despite reduced conventional AST activity.