Daily Sepsis Research Analysis
Rapid, clinically integrated metagenomics in the ICU demonstrated high diagnostic sensitivity, same-day turnaround, and measurable impact on antimicrobial and immunomodulatory decisions. Phage-informed mNGS improved specificity for distinguishing infection from colonization, while cardiac epigenomic profiling in murine sepsis revealed early chromatin accessibility changes and candidate transcriptional regulators of organ dysfunction.
Summary
Rapid, clinically integrated metagenomics in the ICU demonstrated high diagnostic sensitivity, same-day turnaround, and measurable impact on antimicrobial and immunomodulatory decisions. Phage-informed mNGS improved specificity for distinguishing infection from colonization, while cardiac epigenomic profiling in murine sepsis revealed early chromatin accessibility changes and candidate transcriptional regulators of organ dysfunction.
Research Themes
- Rapid pan-microbial diagnostics and clinical impact in ICU sepsis care
- Bacteriophage-informed metagenomics to distinguish infection from colonization
- Epigenomic mechanisms underpinning sepsis-induced organ dysfunction
Selected Articles
1. Rapid pan-microbial metagenomics for pathogen detection and personalised therapy in the intensive care unit: a single-centre prospective observational study.
A same-day pan-kingdom metagenomic service in ICU patients achieved high sensitivity (bacteria 97%, fungi 89%, viruses 89%) and identified additional pathogens in 30% of samples. Results altered antimicrobial therapy in 28% and contributed to immunomodulation in 20% of patients, demonstrating both patient-level and public health value.
Impact: This study operationalizes rapid pan-microbial metagenomics with demonstrated clinical decision impact, a key step beyond analytic validity alone. It sets a benchmark for integrating metagenomics into ICU sepsis workflows.
Clinical Implications: Incorporating rapid metagenomics into ICU diagnostics can enable earlier de-escalation/escalation of antimicrobials, support initiation of immunomodulators, and enhance infection control and surveillance. Multicentre evaluation should address outcomes, stewardship, and cost-effectiveness.
Key Findings
- 94% of 114 samples passed QC; 94% of QC-passed samples yielded same-day preliminary results.
- Sensitivity in lower respiratory tract samples after 24 h: bacteria 97% (95% CI 87–100), fungi 89% (65–99), viruses 89% (71–98), with only one bacterial false positive.
- Metagenomics identified 42 additional pathogens in 32 (30%) of 107 samples beyond routine diagnostics.
- Antimicrobial therapy changed in 28% of samples (21% de-escalated, 7% escalated); immunomodulation initiated in 20% of patients.
- Clinically significant pathogens for infection control/public health were found in 14% of patients.
Methodological Strengths
- Prospective, real-world service evaluation with predefined workflow and turnaround targets.
- Pan-kingdom detection (bacteria, fungi, DNA/RNA viruses) with comparison to routine diagnostics.
- Direct measurement of clinical decision impact (antimicrobial changes, immunomodulation) and public health relevance.
Limitations
- Single-centre design with modest sample size and potential selection bias.
- No randomized assessment of patient outcomes; exclusion of containment level 3 organisms.
- Resource and cost requirements not assessed.
Future Directions: Conduct multicentre trials to evaluate patient outcomes, antimicrobial stewardship metrics, and cost-effectiveness; standardize reporting thresholds; integrate with host-response biomarkers.
2. Bacteriophage combined with mNGS enhances the specificity of bacterial infection diagnosis.
Retrospective analysis of 299 samples showed that pathogen-specific bacteriophage signals in plasma and BALF correlate with true bacterial infections and can aid in distinguishing infection from colonization. For Acinetobacter baumannii, Myoviridae signals achieved 86.36% sensitivity and 52.94% specificity for infection versus colonization.
Impact: Incorporating phage reads into mNGS addresses a key limitation—low specificity for infection versus colonization—offering a mechanistically plausible and scalable enhancement to diagnostic pipelines.
Clinical Implications: Phage-informed mNGS may reduce unnecessary antibiotics by improving specificity, particularly for problematic pathogens like A. baumannii. Prospective validation and standardized thresholds are needed before routine adoption.
Key Findings
- Across 299 samples from 218 patients, pathogen-specific phage proportions increased in infections by A. baumannii, K. pneumoniae, P. aeruginosa, and S. aureus.
- In BALF with A. baumannii infection, Autographiviridae, Siphoviridae, and Myoviridae proportions were significantly higher than in colonization.
- Myoviridae yielded 86.36% sensitivity and 52.94% specificity for distinguishing A. baumannii infection from colonization.
- In sepsis, combining phage signals with mNGS improved identification of causative pathogens compared with mNGS alone.
Methodological Strengths
- Moderate sample size with dual matrices (plasma and BALF) and inclusion of cell-free DNA.
- Systematic phage annotation aligned with bacterial taxa and infection status.
- Direct comparison between infection and colonization groups.
Limitations
- Retrospective single-period analysis with potential misclassification of infection versus colonization.
- Specificity remains moderate; clinical outcome impact not assessed.
- Generalizability limited to a single region and time frame.
Future Directions: Prospective multicentre validation, establishment of quantitative phage thresholds, and assessment of impact on antimicrobial stewardship and outcomes.
3. Characterization of the Chromatin Accessibility in the Hearts of Mice With Lipopolysaccharide (LPS)-Induced Sepsis.
Integrating ATAC-seq with RNA-seq in an LPS-induced murine sepsis model, the study mapped extensive chromatin accessibility remodeling in hearts, especially at day 1 post-induction. Thousands of accessible regions changed (2389 increased, 5065 decreased), TF motifs (ERG, ETV2, Mef2c, JunB) were enriched, and 93 of 1311 genes with enhanced accessibility showed mRNA upregulation, implicating early epigenomic mechanisms in sepsis-induced cardiac dysfunction.
Impact: This work positions chromatin accessibility changes as an initiating mechanism for sepsis-induced cardiac dysfunction and highlights candidate transcriptional regulators, providing a mechanistic basis for biomarker and therapeutic target development.
Clinical Implications: Although preclinical, identifying early epigenomic changes and TF candidates may inform development of prognostic biomarkers for sepsis-induced cardiomyopathy and guide epigenetic therapies after validation in human tissues.
Key Findings
- ATAC-seq and RNA-seq integration revealed 2389 increased and 5065 decreased chromatin-accessible regions in sepsis mouse hearts.
- At day 1 post-induction, 877 genes were upregulated and 881 downregulated; 1311 genes showed enhanced accessibility, with 93 showing concordant mRNA upregulation.
- Transcription factor signatures (ERG, ETV2, Mef2c, JunB) were enriched in accessible regions associated with sepsis-induced cardiac dysfunction.
- Findings support chromatin accessibility alterations as an initial mechanism in SICD.
Methodological Strengths
- Multi-omics integration (ATAC-seq with RNA-seq) to link chromatin accessibility and transcriptional output.
- In vivo LPS-induced sepsis model focusing on an early critical timepoint (day 1).
- Genome-wide, unbiased mapping of accessible chromatin regions with TF motif enrichment analysis.
Limitations
- LPS-induced endotoxemia may not fully recapitulate human sepsis or polymicrobial models.
- Limited functional validation of candidate TFs and causal links.
- Sample sizes and biological replicates are not specified in the abstract.
Future Directions: Validate findings in human cardiac tissue and polymicrobial sepsis models; perturb TFs (e.g., ERG, ETV2, Mef2c, JunB) to test causality; evaluate therapeutic epigenetic modulation.