Daily Sepsis Research Analysis
Three impactful sepsis studies emerged: a multicenter prospective trial showed plasma microbial cell-free DNA metagenomic sequencing markedly outperforms blood cultures and could alter therapy decisions; a multi-country pediatric cohort identified sTREM1 as a superior triage biomarker for early risk stratification; and a mechanistic study uncovered a STING–Drp1–GSDMD mitochondrial pathway driving inflammatory lung injury, highlighting new therapeutic targets.
Summary
Three impactful sepsis studies emerged: a multicenter prospective trial showed plasma microbial cell-free DNA metagenomic sequencing markedly outperforms blood cultures and could alter therapy decisions; a multi-country pediatric cohort identified sTREM1 as a superior triage biomarker for early risk stratification; and a mechanistic study uncovered a STING–Drp1–GSDMD mitochondrial pathway driving inflammatory lung injury, highlighting new therapeutic targets.
Research Themes
- Metagenomic diagnostics for rapid pathogen identification in sepsis
- Host-response biomarkers (sTREM1) for pediatric febrile illness triage
- STING–GSDMD–mitochondrial axis in sepsis-induced lung injury
Selected Articles
1. Improved pathogen identification in sepsis or septic shock by clinical metagenomic sequencing.
In a prospective multicenter study of 491 septic patients, plasma microbial cfDNA metagenomic sequencing had a 70.5% positivity rate versus 19.4% for blood cultures within 3 days of sepsis onset. An expert panel deemed 98.6% of NGS findings plausible and estimated therapy adaptations in 32.6% of cases; inadequately treated NGS-positive/culture-negative patients had worse outcomes.
Impact: Demonstrates large diagnostic yield gains over blood culture and potential to optimize antimicrobials in one-third of patients, addressing a core bottleneck in sepsis care.
Clinical Implications: Consider integrating plasma mcfDNA metagenomic sequencing alongside blood cultures, particularly in culture-negative or pretreated sepsis, to guide targeted antimicrobial therapy and source control.
Key Findings
- NGS positivity was 70.5% versus 19.4% for blood cultures within 3 days of sepsis onset.
- An expert panel rated 98.6% of NGS-identified pathogens as plausible.
- NGS information would have prompted anti-infective treatment adaptations in 32.6% of patients.
- NGS-positive/blood culture-negative patients with inadequate therapy had worse outcomes.
Methodological Strengths
- Prospective, multicenter observational design with real-world septic cohorts
- Independent expert adjudication of plausibility and therapeutic implications
Limitations
- Non-interventional design; clinical outcomes were not randomized based on NGS results
- Turnaround time and implementation logistics were not detailed in the abstract
Future Directions: Randomized or stepped-wedge implementation trials to assess outcome benefits, cost-effectiveness analyses, and workflow integration studies across diverse settings.
OBJECTIVES: Despite limited sensitivity and specificity, blood cultures (BCs) still represent the gold standard of diagnostic care in septic patients. We aimed to overcome current diagnostic limitations by unbiased next-generation sequencing (NGS) of circulating microbial cell-free DNA (mcfDNA) in plasma samples. METHODS: We performed a prospective, observational, non-interventional, multicenter study (Next GeneSiS-Trial) to compare positivity rates for NGS-based identification of causative pathogens with BCs in patients suffering from sepsis or septic shock. An independent expert panel (n=3) retrospectively evaluated the plausibility of NGS-based findings and the potential for anti-infective treatment adaptations based on NGS results. RESULTS: The positivity rate of NGS-based diagnostics (NGS+) for 491 septic patients was 70.5% compared to positive BCs (BC+) with 19.4% within the first three days after sepsis onset. NGS+ results were evaluated as plausible in 98.6% of cases by the expert panel. Based on the experts´ recommendations, additional knowledge of NGS-based pathogen findings would have resulted in anti-infective treatment adaptations in 32.6% of all patients. Potentially inadequately treated NGS+/blood culture negative (BC-) patients showed worse outcomes. CONCLUSION: The integration of NGS-based pathogen diagnostics in sepsis has the potential to improve patients´ outcomes as compared to a treatment strategy based on standard-of-care microbiological diagnostics alone.
2. Risk stratification of childhood infection using host markers of immune and endothelial activation in Asia (Spot Sepsis): a multi-country, prospective, cohort study.
Among 3405 febrile children across five Asian countries, sTREM1 best predicted severe outcomes within 2 days (AUC 0.86), outperforming WHO danger signs, LqSOFA, and SIRS. Combining sTREM1 with WHO danger signs did not improve accuracy; sensitivity and specificity were approximately 0.80 and 0.81, respectively, with strongest discrimination for events >48 h (AUC 0.94).
Impact: Provides robust, multi-country evidence that a single host-response marker (sTREM1) outperforms existing clinical triage tools, enabling earlier identification of high-risk children in resource-limited settings.
Clinical Implications: An sTREM1-based triage algorithm could prioritize referrals and monitoring for at-risk children presenting with febrile illness, potentially reducing delays to organ support and mortality.
Key Findings
- sTREM1 achieved AUC 0.86 for predicting severe febrile illness within 2 days, outperforming WHO danger signs (AUC 0.75), LqSOFA (0.74), and SIRS (0.63).
- Combining sTREM1 with WHO danger signs (AUC 0.88) did not significantly improve accuracy over sTREM1 alone.
- Sensitivity and specificity of sTREM1 were 0.80 and 0.81; discrimination was strongest for outcomes >48 h (AUC 0.94).
- Among 3405 children, 133 (3.9%) developed severe febrile illness (22 deaths, 111 with organ support).
Methodological Strengths
- Prospective, multi-country cohort across first-contact hospitals serving rural populations
- Pre-specified biomarkers with weighted AUC comparisons against standard clinical tools
Limitations
- Event rate was relatively low, and external implementation using point-of-care assays was not evaluated
- Observational design without interventional testing of sTREM1-guided care pathways
Future Directions: Develop and validate affordable point-of-care sTREM1 tests and assess clinical impact via pragmatic trials in primary care and community settings.
BACKGROUND: Prognostic tools for febrile illnesses are urgently required in resource-constrained community contexts. Circulating immune and endothelial activation markers stratify risk in common childhood infections. We aimed to assess their use in children with febrile illness presenting from rural communities across Asia. METHODS: Spot Sepsis was a prospective cohort study across seven hospitals in Bangladesh, Cambodia, Indonesia, Laos, and Viet Nam that serve as a first point of contact with the formal health-care system for rural populations. Children were eligible if aged 1-59 months and presenting with a community-acquired acute febrile illness that had lasted no more than 14 days. Clinical parameters were recorded and biomarker concentrations measured at presentation. The primary outcome measure was severe febrile illness (death or receipt of organ support) within 2 days of enrolment. Weighted area under the receiver operating characteristic curves (AUC) were used to compare prognostic accuracy of endothelial activation markers (ANG-1, ANG-2, and soluble FLT-1), immune activation markers (CHI3L1, CRP, IP-10, IL-1ra, IL-6, IL-8, IL-10, PCT, soluble TNF-R1, soluble TREM1 [sTREM1], and soluble uPAR), WHO danger signs, the Liverpool quick Sequential Organ Failure Assessment (LqSOFA) score, and the systemic inflammatory response syndrome (SIRS) score. Prognostic accuracy of combining WHO danger signs and the best performing biomarker was analysed in a weighted logistic regression model. Weighted measures of classification were used to compare prognostic accuracies of WHO danger signs and the best performing biomarker and to determine the number of children needed to test (NNT) to identify one additional child who would progress to severe febrile illness. The study was prospectively registered on ClinicalTrials.gov, NCT04285021. FINDINGS: 3423 participants were recruited between March 5, 2020, and Nov 4, 2022, 18 (0·5%) of whom were lost to follow-up. 133 (3·9%) of 3405 participants developed severe febrile illness (22 deaths, 111 received organ support; weighted prevalence 0·34% [95% CI 0·28-0·41]). sTREM1 showed the highest prognostic accuracy to identify patients who would progress to severe febrile illness (AUC 0·86 [95% CI 0·82-0·90]), outperforming WHO danger signs (0·75 [0·71-0·80]; p<0·0001), LqSOFA (0·74 [0·69-0·78]; p<0·0001), and SIRS (0·63 [0·58-0·68]; p<0·0001). Combining WHO danger signs with sTREM1 (0·88 [95% CI 0·85-0·91]) did not improve accuracy in identifying progression to severe febrile illness over sTREM1 alone (p=0·24). Sensitivity for identifying progression to severe febrile illness was greater for sTREM1 (0·80 [95% CI 0·73-0·85]) than for WHO danger signs (0·72 [0·66-0·79]; NNT=3000), whereas specificities were comparable (0·81 [0·78-0·83] for sTREM1 vs 0·79 [0·76-0·82] for WHO danger signs). Discrimination of immune and endothelial activation markers was best for children who progressed to meet the outcome more than 48 h after enrolment (sTREM1: AUC 0·94 [95% CI 0·89-0·98]). INTERPRETATION: sTREM1 showed the best prognostic accuracy to discriminate children who would progress to severe febrile illness. In resource-constrained community settings, an sTREM1-based triage strategy might enhance early recognition of risk of poor outcomes in children presenting with febrile illness. FUNDING: Médecins Sans Frontières, Spain, and Wellcome. TRANSLATIONS: For the Arabic and French translations of the abstract see Supplementary Materials section.
3. Inhibition of STING-induced mitochondrial Drp1/N-GSDMD-mediated MtDNA release alleviates Sepsis-induced lung injury.
This mechanistic study links STING signaling to a macrophage Drp1–N-GSDMD interaction on mitochondria that promotes mtDNA release, inflammation, and pyroptosis in LPS-induced lung injury. Disulfiram blocked mitochondrial GSDMD-N anchoring, and targeting STING-mediated mitochondrial homeostasis genetically or pharmacologically attenuated injury.
Impact: Reveals a previously unappreciated STING–Drp1–GSDMD mitochondrial mechanism driving inflammatory lung injury, nominating actionable nodes (STING, GSDMD, mitochondrial fission) for therapeutic development.
Clinical Implications: While preclinical, the data support testing inhibitors of STING signaling, GSDMD, or mitochondrial fission to prevent or treat sepsis-induced ALI/ARDS, including potential repurposing of disulfiram.
Key Findings
- Identified a macrophage STING–N-GSDMD–mtDNA positive feedback loop that promotes inflammation and pyroptosis upon LPS challenge.
- STING regulated mitochondrial Ca2+ to mediate direct interaction between Drp1 and N-GSDMD on mitochondria, linking fission to inflammatory signaling.
- Disulfiram specifically abrogated mitochondrial anchoring of GSDMD-N and attenuated injury.
- Genetic or pharmacologic targeting of STING-mediated mitochondrial homeostasis mitigated sepsis-induced lung injury.
Methodological Strengths
- Integrated clinical ARDS context and in vivo LPS-induced ALI with mechanistic cell biology
- Both genetic and pharmacological perturbation to validate causal pathway
Limitations
- Primarily LPS-based preclinical models; translational relevance to heterogeneous human sepsis requires validation
- Quantitative sample sizes and effect sizes are not detailed in the abstract
Future Directions: Evaluate STING/GSDMD/fission inhibitors in polymicrobial sepsis and viral ARDS models; develop biomarkers of mitochondrial pyroptosis to guide patient selection.
The stimulator of interferon genes (STING) pathway serves as a crucial nexus in inflammatory responses and cell death. Despite its role in Mitochondria-Endoplasmic Reticulum Contact (MERC), the mechanistic contributions to inflammatory outcomes remain poorly understood. In clinical acute respiratory distress syndrome (ARDS) models of COVID-19 infection and animal models of LPS-induced acute lung injury (ALI), the STING pathway is closely associated with the pyroptosis pathway. The macrophage STING-N-GSDMD-mtDNA positive feedback loop, upon LPS challenge, induces inflammatory responses and pyroptosis. The GSDMD inhibitor disulfiram (DSF) specifically abrogates the N-terminal portion of GSDMD anchored to the mitochondrial membrane. Furthermore, macrophage STING mediates the direct interaction between Drp1 and N-GSDMD on mitochondrial membrane by regulating mitochondrial calcium, linking mitochondrial fission to the induction of inflammatory responses. Targeting STING-mediated mitochondrial homeostasis, both genetically and pharmacologically, may play a protective role in preventing and treating sepsis-induced acute lung injury. Overall, our study posits that STING deficiency mitigates the cooperative interaction between N-GSDMD and Drp1 in mediating mitochondrial permeabilization and rupture following LPS challenge, paving the way for further investigations into inflammation and pyroptosis.