Daily Sepsis Research Analysis
Three studies advance sepsis science across mechanism and care: a mechanistic paper uncovers an autophagy–inflammasome–cGAS-STING feedback loop driving septic lung injury; a pediatric cohort suggests norepinephrine may be safer than epinephrine as initial vasopressor in septic shock; and a multicenter study supports ceftazidime/avibactam for carbapenemase-producing Enterobacterales bacteremia in neutropenic patients.
Summary
Three studies advance sepsis science across mechanism and care: a mechanistic paper uncovers an autophagy–inflammasome–cGAS-STING feedback loop driving septic lung injury; a pediatric cohort suggests norepinephrine may be safer than epinephrine as initial vasopressor in septic shock; and a multicenter study supports ceftazidime/avibactam for carbapenemase-producing Enterobacterales bacteremia in neutropenic patients.
Research Themes
- Autophagy–inflammasome–cGAS-STING crosstalk in septic lung injury
- Initial vasopressor choice in pediatric septic shock
- Therapeutic strategies for AMR Gram-negative sepsis in neutropenic hosts
Selected Articles
1. ATG16L1 restrains macrophage NLRP3 activation and alveolar epithelial cell injury during septic lung injury.
Using genetic and pharmacologic approaches, the authors show that myeloid ATG16L1 prevents a ROS–NLRP3–cGAS-STING positive feedback loop that amplifies inflammation and alveolar epithelial injury in septic lung injury. Interrupting this loop via ROS scavenging or STING inhibition mitigated injury, and ATG16L1 overexpression reduced disease severity.
Impact: This work identifies a coherent, targetable pathway linking autophagy deficiency to inflammasome and cGAS-STING activation in sepsis-induced lung injury, revealing multiple therapeutic entry points.
Clinical Implications: Although preclinical, the data prioritize testing STING and NLRP3 pathway inhibitors and strategies to enhance macrophage autophagy (e.g., augmenting ATG16L1 function) for septic lung injury.
Key Findings
- Myeloid ATG16L1 deficiency worsened LPS-induced septic lung injury with heightened inflammation.
- ATG16L1-deficient macrophages accumulated mitochondrial ROS, activating NLRP3; epithelial dsDNA release activated cGAS-STING, creating a positive feedback to further activate NLRP3.
- Mitochondrial ROS scavenging or STING inhibition suppressed NLRP3 activation and alleviated lung injury; ATG16L1 overexpression reduced disease severity.
Methodological Strengths
- Multiple complementary genetic models (myeloid ATG16L1, NLRP3, and STING-deficient mice) with in vivo and in vitro validation.
- Mechanistic interventions (ROS scavenging, STING inhibition, ATG16L1 overexpression) establish causality.
Limitations
- LPS-induced ALI may not fully recapitulate polymicrobial human sepsis.
- Lack of human tissue validation and no clinical trial data.
Future Directions: Validate in polymicrobial sepsis models and human samples; evaluate macrophage-targeted autophagy enhancement and STING/NLRP3 inhibitors in translational studies.
2. Epinephrine vs Norepinephrine as Initial Treatment in Children With Septic Shock.
In a single-center propensity analyses of 231 pediatric septic shock encounters, initial epinephrine was associated with higher 30-day mortality than norepinephrine in matched analyses, with no difference in MAKE30. Findings support norepinephrine as a candidate first-line vasopressor pending confirmatory trials.
Impact: Addresses a common, high-stakes decision with practice variation in pediatric septic shock and provides comparative effectiveness signals that may influence guidelines.
Clinical Implications: Consider norepinephrine as the preferred initial vasopressor in pediatric septic shock without known cardiac dysfunction; prioritize RCTs to confirm mortality benefits.
Key Findings
- Among 231 pediatric septic shock encounters, 63.6% received epinephrine and 36.4% norepinephrine as the first vasopressor.
- No significant difference in MAKE30 between groups overall; in 2:1 propensity matching, epinephrine had higher 30-day mortality (3.7% vs 0%).
- Inverse probability weighting showed no difference in MAKE30, highlighting the need for prospective trials.
Methodological Strengths
- Use of inverse probability of treatment weighting and 2:1 propensity score matching to address confounding.
- Clinically relevant outcomes including MAKE30 and 30-day mortality.
Limitations
- Single-center retrospective design with potential residual confounding and selection bias.
- Low event rates and lack of randomization limit causal inference.
Future Directions: Conduct multicenter randomized trials comparing norepinephrine vs epinephrine as initial vasopressor in pediatric septic shock and explore physiologic phenotypes that may modify treatment effects.
3. Ceftazidime/avibactam for the treatment of bloodstream infection due to carbapenemase-producing Enterobacterales in onco-haematologic neutropenic patients (the TARZAN study).
In 54 episodes of carbapenemase-producing Enterobacterales bacteremia among neutropenic hematologic patients, ceftazidime/avibactam was effective and generally safe, with 7- and 30-day mortality of 11% and 24%. Inadequate empiric therapy was frequent, and septic shock at onset independently predicted 30-day mortality.
Impact: Provides real-world multicenter evidence supporting ceftazidime/avibactam in a highly vulnerable, AMR-driven sepsis population where therapeutic options are limited.
Clinical Implications: For neutropenic hematologic patients with suspected CPE bacteremia, early consideration of ceftazidime/avibactam (guided by local epidemiology and risk) may improve adequacy of empiric therapy; monitor nephrotoxicity when combining with aminoglycosides or colistin.
Key Findings
- Among 54 CPE-BSI episodes, Klebsiella pneumoniae (79.5%) and KPC carbapenemase (52%) predominated; 11% presented with septic shock.
- Empiric therapy was inadequate in 47% of episodes; ceftazidime/avibactam was used empirically in 30% and as targeted therapy in all episodes.
- All-cause mortality was 11% at 7 days and 24% at 30 days; septic shock at onset independently predicted 30-day mortality.
Methodological Strengths
- Multicenter international cohort in a well-defined high-risk population.
- Clinically meaningful endpoints (7- and 30-day mortality) and multivariable analysis identifying prognostic factors.
Limitations
- Retrospective descriptive design without randomized comparator.
- Heterogeneity in combination regimens and potential selection bias.
Future Directions: Prospective comparative studies of ceftazidime/avibactam vs alternatives in CPE-BSI and optimization of empiric therapy algorithms for neutropenic hosts.