Daily Sepsis Research Analysis
Three impactful studies on sepsis span diagnostics, mechanisms, and antimicrobial resistance. A multicenter Bolivian pediatric cohort demonstrates that Phoenix sepsis criteria outperform SIRS but the respiratory subscore overestimates severity at high altitude unless oxygenation indices are altitude-corrected. Mechanistically, TREM2 limits tissue factor–driven coagulopathy via AKT-mTOR signaling in preclinical sepsis, suggesting a therapeutic target, while a LMIC-focused meta-analysis highlights
Summary
Three impactful studies on sepsis span diagnostics, mechanisms, and antimicrobial resistance. A multicenter Bolivian pediatric cohort demonstrates that Phoenix sepsis criteria outperform SIRS but the respiratory subscore overestimates severity at high altitude unless oxygenation indices are altitude-corrected. Mechanistically, TREM2 limits tissue factor–driven coagulopathy via AKT-mTOR signaling in preclinical sepsis, suggesting a therapeutic target, while a LMIC-focused meta-analysis highlights high resistance to first-line antibiotics in sepsis-related infections, underscoring urgent stewardship and surveillance needs.
Research Themes
- Pediatric sepsis criteria performance and altitude calibration
- Immunothrombosis mechanisms and therapeutic targets (TREM2–AKT–mTOR)
- Antimicrobial resistance patterns informing empiric therapy in LMICs
Selected Articles
1. Sepsis in Critically Ill Children in Bolivia: Multicenter Retrospective Evaluation of the Phoenix Criteria for Sepsis in a 2023 Cohort.
In a 14-PICU Bolivian cohort (n=273), 94.1% met Phoenix sepsis criteria compared with 60.8% meeting SIRS. Altitude correction of oxygenation indices reduced Phoenix respiratory subscores in 54.6% and aligned mortality with expected risk, highlighting overestimation of respiratory dysfunction at high altitude due to Andean hematologic adaptation.
Impact: This study provides real-world external validation of the 2024 Phoenix pediatric sepsis criteria and identifies a critical calibration issue for the respiratory subscore in high-altitude settings.
Clinical Implications: PICUs at high altitude should apply altitude-corrected oxygenation indices when using Phoenix respiratory scoring and avoid relying solely on SIRS, as many Phoenix-positive patients are SIRS-negative yet at substantial risk.
Key Findings
- 94.1% (257/273) met Phoenix sepsis criteria vs 60.8% meeting SIRS-based criteria.
- 38.9% of Phoenix-positive patients were SIRS-negative, with 27.0% mortality in this subgroup.
- Altitude correction lowered Phoenix respiratory scores in 54.6% and improved mortality calibration.
- Higher altitude was associated with higher hemoglobin/oxygen-carrying capacity and independently lower mortality odds after adjusting for altitude-corrected Phoenix score.
Methodological Strengths
- Multicenter design across 14 PICUs with standardized criteria application
- Physiologically informed altitude correction of oxygenation indices with outcome linkage
Limitations
- Retrospective observational design with potential unmeasured confounding
- Generalizability beyond Andean high-altitude populations is uncertain
Future Directions: Prospective validation of altitude-calibrated Phoenix respiratory thresholds and exploration of hemoglobin-based adjustments across diverse altitudes.
2. TREM2 improves coagulopathy and lung inflammation in sepsis through the AKT-mTOR pathway.
In vitro and murine CLP models show that TREM2 overexpression curbs macrophage tissue factor release by suppressing AKT-mTOR signaling, increasing platelets, reducing fibrin deposition, and improving survival, thereby attenuating sepsis-associated coagulopathy and lung inflammation.
Impact: Identifies a mechanistic axis (TREM2–AKT–mTOR–TF) linking innate immune regulation to coagulopathy in sepsis, revealing a tractable therapeutic target.
Clinical Implications: While preclinical, these findings support development of TREM2-agonists, macrophage-targeted cell therapies, or pathway modulators to mitigate immunothrombosis in sepsis, pending human validation.
Key Findings
- TREM2 overexpression improved survival and reduced lung inflammation in CLP sepsis mice.
- Platelet counts increased and fibrin deposition decreased with TREM2 overexpression.
- TREM2 suppressed macrophage tissue factor release by inhibiting AKT-mTOR signaling.
- In vitro (RAW264.7) and in vivo (macrophage infusion) models consistently showed anti-coagulant, anti-inflammatory effects.
Methodological Strengths
- Complementary in vitro and in vivo models with mechanistic pathway interrogation
- Multiple convergent endpoints (survival, cytokines, TF, platelets, fibrin, signaling activity)
Limitations
- Preclinical models may not fully recapitulate human sepsis heterogeneity
- Sample sizes and dosing regimens are not detailed in the abstract
Future Directions: Define optimal TREM2-targeting strategies (agonists vs cell therapy), dose-response, safety, and validate in large-animal models and early-phase clinical studies.
3. Antibiotic resistance in the Middle East and Southern Asia: a systematic review and meta-analysis.
Across nine LMICs in the Middle East and Southern Asia, pooled literature indicates >30% resistance to first-line antibiotics for sepsis-related infections, with notably high Gram-negative resistance (ceftriaxone, aminoglycosides, carbapenems) in burn infections and reported colistin resistance. Findings call for localized surveillance and stewardship to guide empiric therapy.
Impact: Synthesizes scarce ABR data from LMICs where national surveillance is limited, directly informing empiric choices for sepsis and related infections.
Clinical Implications: Clinicians should anticipate high resistance to ceftriaxone, aminoglycosides, and even carbapenems in some settings, particularly burns, and tailor empiric regimens to local patterns while strengthening stewardship and diagnostics.
Key Findings
- Across nine countries, resistance to recommended first-line antibiotics exceeded 30% for sepsis-related infections.
- Burn-related Gram-negative infections showed high resistance to ceftriaxone, aminoglycosides, and carbapenems.
- Colistin resistance was reported, narrowing last-line options.
- Data quality and lack of reporting standards limited pooling but consistently indicated troubling resistance levels.
Methodological Strengths
- Systematic approach with meta-analysis spanning multiple LMICs and infection sites
- Focus on publicly available data to inform settings lacking formal surveillance
Limitations
- Heterogeneous study quality and lack of standardized reporting limited comparability
- Incomplete data in some settings and possible publication bias
Future Directions: Develop harmonized ABR reporting standards and establish sentinel surveillance networks to refine empiric therapy for sepsis in LMICs.