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.
BACKGROUND: The lung is the organ most commonly affected by sepsis. Additionally, acute lung injury (ALI) resulting from sepsis is a major cause of death in intensive care units. Macrophages are essential for maintaining normal lung physiological functions and are implicated in various pulmonary diseases. An essential autophagy protein, autophagy-related protein 16-like 1 (ATG16L1), is crucial for the inflammatory activation of macrophages. METHODS: ATG16L1 expression was measured in lung from mice with sepsis. ALI was induced in myeloid ATG16L1-, NLRP3- and STING-deficient mice by intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg). Using immunofluorescence and flow cytometry to assess the inflammatory status of LPS-treated bone marrow-derived macrophages (BMDMs). A co-culture system of BMDMs and MLE-12 cells was established in vitro. RESULTS: Myeloid ATG16L1-deficient mice exhibited exacerbated septic lung injury and a more intense inflammatory response following LPS treatment. Mechanistically, ATG16L1-deficient macrophages exhibited impaired LC3B lipidation, damaged mitochondria and reactive oxygen species (ROS) accumulation. These abnormalities led to the activation of NOD-like receptor family pyrin domain-containing protein 3 (NLRP3), subsequently enhancing proinflammatory response. Overactivated ATG16L1-deficient macrophages aggravated the damage to alveolar epithelial cells and enhanced the release of double-stranded DNA (dsDNA), thereby promoting STING activation and subsequent NLRP3 activation in macrophages, leading to positive feedback activation of macrophage NLRP3 signalling. Scavenging mitochondrial ROS or inhibiting STING activation effectively suppresses NLRP3 activation in macrophages and alleviates ALI. Furthermore, overexpression of myeloid ATG16L1 limits NLRP3 activation and reduces the severity of ALI. CONCLUSIONS: Our findings reveal a new role for ATG16L1 in regulating macrophage NLRP3 feedback activation during sepsis, suggesting it as a potential therapeutic target for treating sepsis-induced ALI. KEY POINTS: Myeloid-specific ATG16L1 deficiency exacerbates sepsis-induced lung injury. ATG16L1-deficient macrophages exhibit impaired LC3B lipidation and ROS accumulation, leading to NLRP3 inflammasome activation. Uncontrolled inflammatory responses in ATG16L1-deficient macrophages aggravate alveolar epithelial cell damage. Alveolar epithelial cells release dsDNA, activating the cGAS-STING-NLRP3 signaling pathway, which subsequently triggers a positive feedback activation of NLRP3. Overexpression of ATG16L1 helps mitigate lung tissue inflammation, offering a novel therapeutic direction for sepsis-induced lung injury.
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.
IMPORTANCE: There is no consensus and wide practice variation in the choice of initial vasoactive agent in children with septic shock. OBJECTIVE: To determine whether receipt of epinephrine compared with norepinephrine as the first vasoactive medication administered is associated with improved outcomes among children with septic shock without known cardiac dysfunction. DESIGN, SETTING, AND PARTICIPANTS: This single-center, retrospective cohort study used propensity score matching to examine encounters in which a patient was diagnosed with septic shock and required a vasoactive infusion within 24 hours of ED arrival at a freestanding quaternary care children's hospital. Participants included patients aged 1 month to 18 years who presented to the ED and were diagnosed with septic shock without known cardiac dysfunction and began an epinephrine or norepinephrine infusion within 24 hours of ED arrival between June 1, 2017, and December 31, 2023. Data were analyzed from March 1 to December 31, 2024. EXPOSURE: Epinephrine vs norepinephrine as the first vasoactive medication received. MAIN OUTCOMES AND MEASURES: The primary outcome was major adverse kidney events by 30 days (MAKE30). Secondary outcomes were 30-day in-hospital mortality, 3-day mortality, need for kidney replacement therapy or persistent kidney dysfunction, endotracheal intubation, mechanical ventilation days, extracorporeal membrane oxygenation, and hospital and intensive care unit length of stay. Primary and secondary outcomes were assessed with the χ2 test of proportions for binary variables and Wilcoxon rank sum test for continuous variables. RESULTS: Among 231 included encounters, the median (IQR) age was 11.4 (5.6-15.4) years, 126 were female (54.6%), and 142 had a medical history that predisposed them to sepsis (61.5%). Most (147 [63.6%]) initially received an epinephrine infusion and 84 (36.4%) received norepinephrine. In the epinephrine group, 9 of 147 (6.1%) met the outcome of MAKE30 and 6 of 147 (4.1%) died within 30 days. In the norepinephrine group, 3 of 84 (3.6%) met MAKE30 and there were no deaths. After inverse probability of treatment weighting, there were no significant differences in the primary outcome, MAKE30. With 2:1 propensity matching, epinephrine was associated with greater 30-day mortality compared with norepinephrine (3.7% vs 0%; risk difference: 3.7%; 95% CI, 0.2%-7.2%). CONCLUSIONS AND RELEVANCE: In this study, those receiving epinephrine had greater 30-day mortality but no difference in MAKE30. Prospective, confirmatory studies are needed to determine if norepinephrine should be the first-line vasoactive agent in pediatric septic shock.
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.
OBJECTIVES: To assess the clinical features, antibiotic therapy and outcomes of carbapenemase-producing Enterobacterales bloodstream infection (CPE-BSI) in neutropenic patients with haematological malignancies treated with ceftazidime/avibactam. METHODS: We conducted a multicentre, international, retrospective, descriptive study of CPE-BSI episodes in neutropenic onco-haematological patients treated with ceftazidime/avibactam as empirical and/or targeted therapy (2017-2022). RESULTS: Of 54 episodes of CPE-BSI in haematological patients with neutropenia, more than half presented acute myeloid leukaemia (32, 59.5%). Klebsiella pneumoniae was the most frequently isolated pathogen (79.5%) and KPC the most prevalent carbapenemase (52%). The source of BSI was mainly endogenous (57.5%). Up to 11% presented with septic shock. Initial empirical antibiotic therapy was inadequate in 47% of cases, particularly monotherapy with meropenem or piperacillin/tazobactam. Ceftazidime/avibactam was administered empirically in 30% of patients and targeted in all episodes, mainly in combination with aminoglycosides, colistin or tigecycline. Nephrotoxicity occurred in 15% of patients, being attributed to aminoglycosides or colistin. Intensive care unit admission was required in 20% of cases. All-cause 7-day and 30-day case-fatality rates were 11% and 24%, respectively. Multivariate analysis showed that septic shock at BSI onset was an independent risk factor for 30-day mortality. CONCLUSIONS: Ceftazidime/avibactam proved to be safe and efficacious for the treatment of CPE-BSI in this extremely high-risk population.