Daily Sepsis Research Analysis
Analyzed 43 papers and selected 3 impactful papers.
Summary
Three studies advanced sepsis science across diagnostics and therapeutics: a prospective cohort demonstrated a neutrophil CD177/CD10 ratio that outperformed CRP/PCT for infection discrimination and prognostication; a preclinical randomized study in sheep defined a dose threshold (3.0 g/kg) for megadose sodium ascorbate to reverse cardiovascular and renal dysfunction; and translational human ex vivo work implicated SIRT2 in sepsis-associated hypo-inflammation, reversible with pharmacologic inhibition.
Research Themes
- Biomarker-driven diagnosis and risk stratification in sepsis
- Immunometabolic regulation of leukocyte dysfunction
- Translational dose-optimization for adjunctive sepsis therapies
Selected Articles
1. Dynamic CD177/CD10 ratio for infection diagnosis and mortality risk stratification in critically ill patients: a prospective cohort study.
In a prospective cohort including 145 critically ill patients and 219 healthy controls, the neutrophil CD177/CD10 ratio outperformed CRP and PCT for differentiating infectious states and stratifying sepsis severity. Dynamic trajectory subtypes (rising/declining/stable) provided strong 7-day mortality discrimination, with an AUC of 0.92 for distinguishing non-septic infection from sepsis.
Impact: This study introduces a mechanistically grounded leukocyte biomarker with superior diagnostic and prognostic performance versus conventional markers, addressing a major gap in rapid sepsis risk stratification.
Clinical Implications: A flow cytometry-based CD177/CD10 ratio could support early differentiation of infectious vs non-infectious inflammation and identify high-risk sepsis phenotypes for intensified monitoring and targeted therapy. Implementation will require assay standardization and multicenter validation.
Key Findings
- CD177/CD10 ratio achieved AUC 0.92 to distinguish non-septic infection from sepsis, outperforming CRP (0.85) and PCT (0.85).
- Effectively differentiated non-infectious inflammation from infectious states (AUCs 0.79 and 0.71 for NI vs NS-I).
- Dynamic subtyping by CD177/CD10 trajectory predicted outcomes: rising subtype had 7-day mortality of 62.5% versus 8–15% survival gains in declining/stable subtypes.
Methodological Strengths
- Prospective cohort with serial, standardized flow cytometry measurements
- Direct comparison to established biomarkers (CRP, PCT) and incorporation of prognostic trajectories
Limitations
- Thresholds and performance require external, multicenter validation
- Operationalization and turnaround of flow cytometry in routine ICU workflows need evaluation
Future Directions: Conduct multicenter validation studies, standardize analytical protocols, and test clinical utility in interventional designs where CD177/CD10-guided decisions affect outcomes.
BACKGROUND: Two crucial needs persist in delivering effective critical care: reliable differentiation of infectious vs non-infectious systemic inflammation and detection of impending sepsis before the occurrence of organ dysfunction. This prospective cohort study evaluates the clinical utility of the polymorphonuclear neutrophil (PMN) biomarker CD177/CD10 ratio to differentiate and monitor infections. METHODS: A total of 219 healthy volunteers and 145 patients were assigned to four clinically defined groups: healthy controls (HC), non-infectious inflammation (NI), non-septic infection (NS-I), and sepsis (S). Serial flow cytometric analysis of CD177 and CD10 expression in PMNs was conducted with longitudinal monitoring. Diagnostic efficacy was standardised against conventional biomarkers and organ dysfunction indices. A dynamic CD177/CD10 ratio-based subtyping system (rising/declining/stable pattern) was established for prognostic stratification. FINDINGS: The CD177/CD10 ratio exhibited superior diagnostic performance in infection identification. At a cut-off point (CFP) of 6.07, the area under the curve (AUC) value of the ratio to differentiate NS-I from S was 0.92, exceeding those of CRP (0.85) and PCT (0.85). Notably, this biomarker effectively differentiated NI (CFP = 0.67, AUC = 0.79) from NS-I (CFP = 0.98, AUC = 0.71). The dynamic CD177/CD10 ratio-based subtyping system showed robust prognostic efficacy: patients with the rising subtype exhibited a 7-day mortality rate of 62.5%, while those with decreasing and stable subtypes demonstrated survival rates of 85% and 92.59%, respectively. INTERPRETATION: The CD177/CD10 ratio can facilitate infection-specific differentiation and real-time therapeutic monitoring by quantifying the dynamic equilibrium between the extent of neutrophil activation and maturation. However, the CD177/CD10 ratio still requires validation through a multi-centre trial to confirm the generalisability of the established diagnostic and prognostic thresholds. FUNDING: National Natural Science Foundation of China (No. U21A20370), Natural Science Foundation of Jiangsu Province (BK20240382), Science and Technology Innovation Project of Suzhou (SYW2024116).
2. A preclinical randomised controlled dose optimization of megadose sodium ascorbate for reversal of gram-negative sepsis-induced cardiovascular, brain and kidney dysfunction.
In a randomized, instrumented ovine sepsis model, only 3.0 g/kg sodium ascorbate (plasma ~10 mmol/L) restored MAP and allowed vasopressor withdrawal in 50% of animals, with dose-dependent improvements in renal medullary oxygenation and diuresis. Mechanistically, benefits correlated with reduced renal NF-κB and increased eNOS Ser1177 phosphorylation.
Impact: This preclinical RCT defines a clear dose threshold and mechanistic correlates for megadose ascorbate, directly informing human dose-finding and PK/PD targets for adjunctive sepsis therapy.
Clinical Implications: If translated safely, achieving plasma ascorbate ~10 mmol/L may be necessary to realize hemodynamic and renal benefits; future trials should target this exposure and monitor mechanistic biomarkers.
Key Findings
- Only 3.0 g/kg sodium ascorbate rapidly restored MAP and enabled vasopressor withdrawal in 50% (P=0.007).
- Dose-dependent improvements in renal medullary oxygenation (≈25 to 43 mmHg; P=0.04) and urine flow (0.5 to 6.9 mL/kg/h; P<0.0001).
- Mechanistic links: decreased renal NF-κB (−53%) and increased eNOS Ser1177 phosphorylation (+220%) versus vehicle.
Methodological Strengths
- Randomized, controlled dose-ranging design with invasive organ-specific monitoring
- Physiological, biochemical, and molecular endpoints aligned to mechanism
Limitations
- Preclinical ovine model; human safety and efficacy at megadose exposure remain to be established
- Short-term observation without long-term outcomes
Future Directions: Conduct human PK/PD-guided dose-escalation trials targeting ~10 mmol/L plasma ascorbate with safety monitoring (e.g., oxalate nephropathy) and mechanistic biomarkers.
BACKGROUND: Megadose sodium ascorbate has shown promise as a treatment to reverse the pathophysiological effects of ovine Gram-negative sepsis. In human septic shock, lower doses of sodium ascorbate improved urine output and reduced vasopressor requirements compared with placebo. We sought to determine the minimum therapeutic dose of sodium ascorbate required to reverse sepsis-induced cardiovascular and renal dysfunction in sheep. METHODS: Healthy young adult sheep were instrumented with renal artery flow probes, and oxygen-sensing and laser Doppler probes in the kidneys. Non-anaesthetised animals were infused with live Escherichia coli for 31-h. At 23.5-h of sepsis, four groups (n = 7-8/group) received fluid resuscitation (30 mL/kg Hartmann's solution) and were randomized to intravenous sodium ascorbate (1.0, 2.0, or 3.0 g/kg) or vehicle, delivered as a bolus followed by 7-h infusion. Norepinephrine was titrated to maintain mean arterial pressure (MAP) at ~ 70 mmHg. RESULTS: At 23-h of sepsis, animals developed hypotension, hyperlactatemia, acute kidney injury, and renal medullary hypoxia. Vehicle-treated sheep required escalating doses of norepinephrine (from 0.4 to 0.8 ± 0.2 µg/kg/min) to restore MAP. Sodium ascorbate at 3.0 g/kg (achieving plasma ascorbate levels of ~ 10 mmol/L) rapidly restored MAP, allowing withdrawal of norepinephrine in half the animals (P = 0.007). Lower doses of sodium ascorbate (1.0 and 2.0 g/kg) had no significant effect on vasopressor requirements. The improvements in renal medullary oxygenation (25.2 ± 3.3 to 43.4 ± 4.5 mmHg, P = 0.04) and urine flow (from 0.5 ± 0.2 to 6.9 ± 2.4 ml/kg/h, P < 0.0001) were dose-dependent. Renal medullary tissue protein expression of nuclear factor kappa-light chain-enhancer B was significantly reduced with 3.0 g/kg of sodium ascorbate (to -52.9 ± 13.3%, P = 0.0005) and phosphorylated endothelial nitric oxide synthase at Ser-1177 was upregulated (to +219.5 ± 51.4%, P = 0.04) compared with vehicle-treated sheep. CONCLUSIONS: In established ovine Gram-negative sepsis, only 3.0 g/kg sodium ascorbate effectively restored cardiovascular and renal dysfunction, which was associated with suppression of renal inflammatory signalling and restoration of endothelial nitric oxide activity. These findings demonstrate a clear dose-dependent therapeutic threshold, where achieving plasma ascorbate concentrations of ~ 10 mmol/L is essential to elicit multi-organ protection.
3. SIRT2 Regulates Ex Vivo PBMC Adhesion in Septic Shock Patients.
Human ex vivo experiments show that septic shock PBMCs exhibit elevated SIRT2, reduced adhesion/CD18 activation/transmigration, and blunted cytokine responses consistent with endotoxin and adhesion tolerance. Pharmacologic SIRT2 inhibition (AK-7) restored PBMC adhesion dynamics and improved macrophage phagocytosis, supporting SIRT2 as a therapeutic target and PBMC adhesion as a physiological biomarker of hypo-inflammation.
Impact: This translational study links a druggable epigenetic regulator to sepsis-induced immune paralysis in human cells and demonstrates functional reversal with an inhibitor, paving the way for mechanism-guided immunoadjuvant trials.
Clinical Implications: SIRT2 inhibition may restore leukocyte function in hypo-inflammatory sepsis; standardized PBMC adhesion assays could serve as a bedside biomarker to identify candidates for immunostimulatory therapies.
Key Findings
- Septic shock PBMCs had high SIRT2 expression with blunted TNF/IL-1β response to LPS (endotoxin tolerance).
- Adhesion tolerance: reduced PBMC adhesion to ICAM-1, decreased CD18 activation, and impaired transmigration in septic shock samples.
- SIRT2 inhibitor AK-7 restored CD18 activation, reversed adhesion/transmigration defects, and improved MDM phagocytosis.
Methodological Strengths
- Use of primary human septic shock samples with multiple functional readouts
- Pharmacologic rescue experiments demonstrating reversibility and target validity
Limitations
- Ex vivo design without patient-level clinical outcome testing
- Sample size and multicenter generalizability not detailed; single inhibitor used
Future Directions: Validate PBMC adhesion as a biomarker in larger cohorts, and initiate early-phase trials of SIRT2 inhibitors with immune function endpoints in hypo-inflammatory sepsis.
BACKGROUND: Septic shock (SS) is deadly. Sepsis-immune response transitions from an endotoxin-sensitive, hyper-inflammatory phase to an endotoxin-tolerant hypo-inflammatory phase. In mice, we implicated sirtuin 2 (SIRT2) for prolonged hypo-inflammation using leukocyte adhesion, the earliest in vivo inflammatory response to cytokine, chemokine, and metabolite stimuli. The role of SIRT2 in human sepsis remains unknown. We hypothesized that: 1. Peripheral blood mononuclear cells (PBMCs) adhesion response can be used as a physiological biomarker of hypo-inflammation, and 2. SIRT2 regulates the functions of PBMCs and macrophages during the hypo-inflammatory phase of human sepsis. METHODS: We stimulated control and SS-whole blood and PBMCs ± lipopolysaccharide (LPS) and investigated plasma cytokines, PBMC cell adhesion to ICAM-1 coated plates, adhesion molecule CD18 activation, SIRT2 expression, and cytokine response. In adhesion/endotoxin-tolerant PBMCs and THP-1 cells treated ± SIRT2 inhibitor AK-7, we analyzed cell adhesion, CD18 activation, and transmigration ± LPS. In monocyte-derived macrophages (MDMs) from SS vs. controls ± AK-7, we analyzed phagocytosis. RESULTS: We found: 1. Muted plasma TNF and IL-1β-response to LPS in SS vs. control (endotoxin-tolerance) 2. Endotoxin-tolerant SS-PBMCs exhibit high SIRT2 expression, and muted adhesion (adhesion-tolerance), CD18 activation, and transmigration with LPS. 3. SIRT2 inhibitor AK-7 reverses endotoxin and adhesion-tolerance in SS-PBMCs via CD18 activation, reverses the defective transmigration of endotoxin-tolerant PBMCs and improves phagocytosis in MDMs from SS patients. CONCLUSION: PBMC adhesion, a physiological biomarker, can be used to detect hypo-inflammation. Defective PBMC and macrophage function in septic shock patients occur via high SIRT2 expression. SIRT2 inhibition is a potential therapeutic strategy for treating sepsis-associated hypo-inflammation.