Daily Sepsis Research Analysis
Three impactful sepsis studies stand out today: a multicenter RCT shows aspirin does not reduce organ dysfunction in sepsis and increases major bleeding; a cross-ancestry genetic and Mendelian randomization study implicates low apolipoprotein A-II as a causal risk factor for septic shock mortality; and a real-world plasma cell-free DNA metagenomic test improves pathogen detection and changes management in suspected infections. Together, they refine treatment choices, illuminate host-pathogen bio
Summary
Three impactful sepsis studies stand out today: a multicenter RCT shows aspirin does not reduce organ dysfunction in sepsis and increases major bleeding; a cross-ancestry genetic and Mendelian randomization study implicates low apolipoprotein A-II as a causal risk factor for septic shock mortality; and a real-world plasma cell-free DNA metagenomic test improves pathogen detection and changes management in suspected infections. Together, they refine treatment choices, illuminate host-pathogen biology, and advance rapid diagnostics.
Research Themes
- Host lipid metabolism and genetic determinants of sepsis outcomes
- Antiplatelet therapy safety and efficacy in sepsis
- Metagenomic plasma cell-free DNA diagnostics in suspected sepsis
Selected Articles
1. Low apolipoprotein A-II levels causally contribute to increased mortality in septic shock.
Across Japanese and Caucasian cohorts with septic shock, lower apolipoprotein A-II levels and an ApoA2 variant (rs6413453 GG) were associated with higher mortality and more organ dysfunction. Mendelian randomization supported a causal effect of decreased ApoA-II on mortality. These findings implicate host lipid biology as a modifiable determinant of sepsis outcomes.
Impact: This is one of the first cross-ancestry, replicated, and causal genetic-biomarker studies identifying ApoA-II as a determinant of septic shock mortality, opening avenues for risk stratification and therapeutic modulation of lipoprotein pathways.
Clinical Implications: ApoA-II could inform early risk stratification in septic shock and motivate trials of HDL/apolipoprotein-targeted interventions (e.g., HDL mimetics, apolipoprotein infusions, or metabolic modulators). Routine measurement is not yet indicated but may be considered in research or precision-medicine programs.
Key Findings
- In the Japan cohort (n=687), lower apolipoprotein A-II levels were associated with higher in-hospital mortality (adjusted OR 1.05 per 1 mg/dL decrease; 95% CI 1.02–1.09; P<0.001).
- ApoA2 rs6413453 GG genotype conferred increased 28-day mortality (aHR 1.79; 95% CI 1.06–3.04) and fewer organ failure–free days; replicated in the VASST Caucasian cohort (aHR 1.65; 95% CI 1.02–2.68).
- Mendelian randomization using 9 SNPs indicated a causal effect: each 1 mg/dL genetically decreased ApoA-II increased mortality risk (OR 1.05; 95% CI 1.01–1.03; P=0.0022).
Methodological Strengths
- Cross-ancestry replication with consistent effect sizes (Japan and Caucasian VASST cohorts).
- Use of Mendelian randomization with polygenic scores to infer causality beyond association.
Limitations
- Observational design for biomarker-outcome associations; residual confounding cannot be fully excluded.
- Findings focus on septic shock ICU populations; generalizability to broader sepsis phenotypes remains to be tested.
Future Directions: Prospective trials of ApoA-II/HDL-raising strategies (e.g., HDL infusions, apoA-I/II mimetics), validation of clinical risk scores incorporating ApoA-II, and mechanistic studies dissecting lipoprotein–immune interactions in sepsis.
BACKGROUND: Lipoproteins and their component apolipoproteins play an important role in sepsis. However, little is known with regard to the association and causal contribution of these proteins to mortality in patients of different ancestries following septic shock. The objective of this study was to determine whether lipoprotein and apolipoprotein levels, and related genetic variants, are associated with clinical outcomes in septic shock. METHODS: We investigated the association between lipoprotein and apolipoprotein levels at the point of admission to the intensive care unit and in-hospital mortality in 687 Japan patients diagnosed with septic shock. For each clinically significant candidate protein, we extracted haplotype tag single nucleotide polymorphisms (SNPs) of the corresponding gene and examined the association of the candidate gene variants with 28-day mortality and organ dysfunction. We tested for replication in a Caucasian septic shock cohort (Vasopressin and Septic Shock Trial, VASST, n = 474). To determine whether the candidate lipoprotein causally contributed to septic shock outcome, we used a Mendelian randomization analysis based on polygenic scores generated from a genome-wide association study (GWAS) in the Japan cohort. RESULTS: In the Japan cohort, low apolipoprotein A-II levels were associated with increased septic shock mortality (adjusted odds ratio, 1.05; 95%CI, 1.02-1.09; P < 0.001). For a haplotype tag SNP of the corresponding ApoA2 gene, rs6413453 GG carriers had significantly higher 28-day mortality (adjusted hazard ratio [aHR], 1.79; 95% confidence interval [CI], 1.06-3.04; P = 0.029) and significantly fewer days free of cardiovascular, respiratory, renal and neurologic dysfunction than AG/AA carriers. This result was replicated in the Caucasian septic shock cohort (28-day mortality: aHR, 1.65; 95% CI, 1.02-2.68; P = 0.041). Mendelian randomization using 9 SNPs from an apolipoprotein A-II GWAS suggested that genetically decreased levels of apolipoprotein A-II were a causal factor for increased mortality in septic shock (odds ratio for mortality due to a 1 mg/dL decrease in apolipoprotein A-II is 1.05 [95% CI; 1.01-1.03, P = 0.0022]). CONCLUSIONS: In septic shock, apolipoprotein A-II levels and ApoA2 genetic variations are important factors associated with outcome.
2. Acetylsalicylic Acid Treatment in Patients With Sepsis and Septic Shock: A Phase 2, Placebo-Controlled, Randomized Clinical Trial.
In a multicenter, blinded, placebo-controlled RCT (n=166), 7 days of 200 mg/day aspirin did not improve SOFA score change in adults with early sepsis and increased major bleeding and serious adverse events, prompting early termination. Secondary outcomes were also negative.
Impact: This high-quality RCT provides definitive evidence against routine aspirin initiation in early sepsis to reduce organ dysfunction and highlights bleeding risks, directly informing clinical practice.
Clinical Implications: Do not initiate aspirin solely to attenuate organ dysfunction in sepsis; carefully reassess continuation of prior aspirin therapy in the acute phase considering bleeding risk. Antiplatelet strategies in sepsis require caution and should be evaluated within trials.
Key Findings
- No significant difference in SOFA score change between aspirin and placebo (adjusted mean difference 0.60; 95% CI −0.55 to 1.75; p=0.30).
- Higher major bleeding in aspirin group (8/94 [8.5%] vs 1/84 [1.2%]; p=0.02) and more serious adverse events (9 [11%] vs 1 [1.2%]; p=0.009).
- Trial stopped early after interim safety analysis due to bleeding signal; secondary outcomes showed no benefit.
Methodological Strengths
- Randomized, blinded, placebo-controlled multicenter design with prespecified interim safety analyses.
- Clinically relevant primary endpoint (SOFA change) and comprehensive safety assessment including bleeding and transfusions.
Limitations
- Early termination reduced statistical power for some efficacy endpoints and limits precision.
- Conducted in five ICUs in Brazil; generalizability to other settings and to patients with chronic antiplatelet use requires further study.
Future Directions: Identify subgroups where antiplatelet modulation may be beneficial, compare alternative platelet-targeting strategies with better safety profiles, and evaluate timing relative to sepsis trajectory.
OBJECTIVES: Platelets play a critical role in the inflammatory response and coagulation. We aimed to evaluate whether the use of acetylsalicylic acid (ASA) would reduce the intensity of organ dysfunction in septic patients. DESIGN: Randomized, blinded, parallel-group, placebo-controlled trial. SETTING: Five general ICUs in Brazil. PATIENTS: Adults with sepsis for no longer than 48 hours who had at least one severe organ dysfunction (lactate > 4 mmol/L, platelets < 100,000/mm3, Pao2/Fio2 ratio < 200, or septic shock). INTERVENTIONS: Patients were randomized to receive 200 mg of ASA or placebo for 7 days. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the change in the Sequential Organ Failure Assessment (SOFA) score between day 0 and day 7 or date of discharge/death. Safety outcomes were major bleeding and the number of blood transfusions within 14 days. The planned sample size was 218 with interim safety analyses after enrolling 109 and 163 patients. The study was discontinued due to higher frequency of major bleeding in the ASA group. We included 166 patients (ASA: 82 patients, placebo: 84). In the adjusted analysis, there was no difference in the SOFA change between the groups (mean placebo to ASA group difference, 0.60; 95% CI, -0.55 to 1.75; p = 0.30). There were no differences in any of the secondary outcomes. In the intervention group, there were a higher number of serious adverse events (9 [11%] vs. 1 [1.2%]; p = 0.009) and major bleeding (8 [8.5%] vs. 1 [1.2%]; p = 0.02). CONCLUSIONS: In this population of septic patients, ASA did not reduce the intensity of organ dysfunction. ASA increased the risk of severe bleeding compared with placebo.
3. Metagenomic analysis of microbial cell-free DNA from plasma of patients with suspected infections: performance and therapeutic impact in clinical routine.
In routine clinical practice, plasma cfDNA metagenomic sequencing (DISQVER®) identified pathogens in 42.1% of samples versus 10.2% positivity for simultaneous blood cultures, with a median 2-day turnaround. Results led to treatment changes in 13.6% of patients, including both escalation and de-escalation.
Impact: This real-world study demonstrates that plasma cfDNA metagenomics substantially improves pathogen detection under antibiotic exposure and influences management, supporting its role as a complementary diagnostic in suspected sepsis.
Clinical Implications: Consider cfDNA metagenomics as an adjunct to blood cultures when prior antibiotics or fastidious pathogens are suspected; results can support timely escalation or de-escalation and device management. Integration with stewardship and rapid reporting workflows is key.
Key Findings
- Detected pathogens in 42.1% (80/190) of plasma samples with a median 2-day time-to-result; simultaneous blood cultures were positive in 10.2% (18/176), often collected under antibiotics (68.2%).
- Identified a broad pathogen spectrum (103 bacteria, 49 viruses, 4 fungi, 1 parasite), including fastidious organisms (e.g., Legionella pneumophila, Tropheryma whipplei).
- Led to 24 management changes in 20/147 patients (13.6%): 9 start/escalation, 10 stop/de-escalation, 2 catheter replacements, and 3 other interventions.
Methodological Strengths
- Real-world implementation across adult and pediatric patients with direct comparison to simultaneous blood cultures.
- Curated software (DISQVER®) and standardized sequencing pipeline with clinically relevant turnaround time.
Limitations
- Retrospective, single-region design without randomized assessment of clinical outcomes.
- Potential for false positives/contamination and challenges in interpreting low-level detections; cost-effectiveness not evaluated.
Future Directions: Prospective trials to quantify impact on time-to-appropriate therapy, mortality, and antimicrobial use; cost-effectiveness analyses; and standardized reporting thresholds and stewardship integration.
OBJECTIVES: The sensitivity of blood cultures (BCs) is limited, especially when antimicrobial therapy already has been administered or when non-culturable pathogens are causing the disease. Metagenomic next-generation sequencing of cell-free DNA from plasma has the potential to compensate for the disadvantages of BC diagnostics. METHODS: We conducted a retrospective study in patients with suspected infections over a period of 3 months. Cell-free DNA from plasma was analysed by metagenomic next-generation sequencing (Illumina NextSeq, 25 million reads per sample, read length 75 base pairs) and sequences were analysed with DISQVER®, a CE-IVDD-labelled software algorithm and curated database. The data were compared with findings obtained with simultaneously taken BC and other microbiological results (±7 days). RESULTS: DISQVER® analysis was performed on 190 samples from 147 patients (124 adult and 23 paediatric). The median time-to-result including transport was 2 days (interquartile range, 2-3; range, 2-8). DISQVER® detected 158 pathogens (103 bacteria, 49 viruses, 4 fungi, and 1 parasite) in 80 plasma samples (positivity rate 42.1%). The median number of pathogens per positive sample was one (interquartile range, 1-2; range, 1-10). The most common bacteria were Enterobacterales (30.1%; 31/103), anaerobic bacteria (18.4%; 19/103), and Enterococcus spp. (15.5%; 16/103); the most frequent viruses were Epstein-Barr virus (28.6%; 14/49), human herpesvirus 6B (18.4%; 9/49), and human cytomegalovirus (18.4%; 9/49). Mycobacterium avium, Legionella pneumophila, Tropheryma whipplei, Rhizomucor pusillus, and Leishmania infantum were detected in one sample each. Simultaneous BC were positive in only 10.2% (18/176) of the samples, but were mostly (68.2%; 120/176) collected under antibiotic therapy. DISQVER® analysis resulted in 24 treatment changes in 20 patients (13.6%; 20/147; 9 start/escalation, 10 stop/de-escalation, 2 catheter replacements, and 3 other). DISCUSSION: DISQVER® significantly increased the detection rate of pathogens, led to the diagnosis of serious infections that otherwise would have been missed, and possibly improved the treatment of more than 10% of patients.