Daily Sepsis Research Analysis
Three impactful sepsis studies span methods, mechanisms, and targets: a prospective multicenter study shows current ICD-based approaches poorly capture Sepsis-3 cases; a proteome-wide Mendelian randomization across major biobanks prioritizes causal proteins with experimental validation as therapeutic targets; and an FDA-approved antiepileptic, phensuximide, selectively inhibits RIPK1 to protect against LPS- and TNF-induced SIRS in vivo, suggesting drug repurposing potential.
Summary
Three impactful sepsis studies span methods, mechanisms, and targets: a prospective multicenter study shows current ICD-based approaches poorly capture Sepsis-3 cases; a proteome-wide Mendelian randomization across major biobanks prioritizes causal proteins with experimental validation as therapeutic targets; and an FDA-approved antiepileptic, phensuximide, selectively inhibits RIPK1 to protect against LPS- and TNF-induced SIRS in vivo, suggesting drug repurposing potential.
Research Themes
- Validity of administrative coding versus Sepsis-3 clinical diagnosis
- Proteome-wide causal target discovery and validation for sepsis
- Drug repurposing targeting RIPK1 to modulate inflammatory cell death
Selected Articles
1. Accuracy of the modified Global Burden of Disease International Classification of Diseases coding methods for identifying sepsis: a prospective multicentre cohort study.
In a prospective multicenter ED cohort (n=450) adjudicated by Sepsis-3, ICD-based methods derived from the GBD study underperformed, with the implicit-plus approach achieving sensitivity 67.4% and specificity 67.2%. Agreement with clinical sepsis was low (α=0.52–0.56); misclassification often involved unspecified UTI, hypotension, and AKI codes, and many false negatives lacked documented pathogens.
Impact: Accurate sepsis surveillance and benchmarking hinge on reliable case identification; this study shows commonly used ICD strategies diverge substantially from Sepsis-3 diagnoses in real time.
Clinical Implications: Administrative data should be used cautiously for sepsis quality metrics and epidemiology. Coding strategies and clinician documentation need refinement; hybrid approaches (e.g., clinician adjudication, NLP of notes) may improve case capture.
Key Findings
- Among 450 high-risk ED patients, clinical sepsis prevalence was 47.8% (215/450).
- Sensitivity/specificity: explicit 41.4%/91.9%, implicit 58.1%/78.7%, implicit-plus 67.4%/67.2%, Angus 55.8%/79.1%.
- Agreement with clinical Sepsis-3 diagnosis was low across methods (Cronbach α=0.52–0.56).
- False positives often involved unspecified UTI, hypotension, and AKI codes; 44.3%–55.6% of false negatives lacked documented pathogens.
Methodological Strengths
- Prospective multicenter design with Sepsis-3 clinical adjudication
- Head-to-head comparison of multiple ICD-based definitions including Angus and modified GBD methods
- Pre-registered study (ANZCTR ACTRN12621000333819)
Limitations
- Conducted in high-risk ED population from nine hospitals in NSW, Australia, which may limit generalizability
- Sample size (n=450) may constrain precision for subgroup analyses
Future Directions: Refine ICD algorithms (e.g., exclude nonspecific UTI codes), integrate laboratory/microbiology and NLP of clinical notes, and validate across diverse health systems and EHRs.
2. Therapeutic Targets for Sepsis: Multicenter Proteome-Wide Analyses and Experimental Validation.
Using proteome-wide MR across FinnGen, UK Biobank-PPP, and deCODE, the authors identified plasma proteins causally associated with sepsis (FinnGen: 16,074 cases/363,227 controls; UKB: 11,643/474,841) across four exposure–outcome combinations. Proteins meeting FDR<0.05 were prioritized and subsequently validated experimentally, nominating therapeutic targets for sepsis.
Impact: Causal inference at proteome scale, coupled with experimental confirmation, provides a rigorous route to nominate drug targets for a disease with repeated RCT failures.
Clinical Implications: Findings offer a prioritized list of causal protein targets for therapeutic development and potential biomarker discovery; translation will require target validation in diverse populations and interventional studies.
Key Findings
- Proteome-wide MR across FinnGen, UKB-PPP, and deCODE evaluated causal links between plasma proteins and sepsis.
- Large-scale samples: FinnGen (16,074 cases; 363,227 controls) and UK Biobank (11,643 cases; 474,841 controls).
- Proteins were prioritized when achieving FDR<0.05 across four exposure–outcome MR combinations.
- Experimental validation corroborated MR-identified targets, nominating candidates for therapeutics.
Methodological Strengths
- Causal inference via Mendelian randomization across multiple large biobanks
- Independent experimental validation to support target nomination
Limitations
- MR conclusions depend on instrument validity and absence of horizontal pleiotropy
- Generalizability may be constrained by cohort ancestries and proteomic panel coverage
Future Directions: Mechanistic dissection of top targets, validation in non-European ancestries, and progression to early-phase interventional trials guided by human genetics.
3. FDA-approved phensuximide inhibits RIPK1-dependent immunogenic cell death.
Phensuximide, an FDA-approved antiepileptic, was identified as a selective RIPK1 kinase inhibitor that blocks necroptosis and preserves signaling through NF-κB/MAPK. In vivo, it protected against LPS- and TNF-induced SIRS, nominating a repurposing opportunity for RIPK1-mediated inflammatory diseases, including sepsis models.
Impact: Repurposing an approved drug to modulate RIPK1-dependent cell death offers a rapid translational path in a field with limited effective therapies.
Clinical Implications: Although preclinical, these data support exploring phensuximide or next-generation RIPK1 inhibitors in early-phase trials for hyperinflammatory states and sepsis, with careful dose, safety, and off-target assessment.
Key Findings
- Small-scale screen of Nec-1-like compounds identified phensuximide as a RIPK1 kinase inhibitor.
- Phensuximide prevented necroptosis while sparing NF-κB and MAPK signaling.
- In vivo, phensuximide protected against both LPS- and TNF-induced SIRS, sepsis-relevant models of RIPK1 activation.
Methodological Strengths
- Drug-repurposing screen among FDA-approved and trial-stage compounds
- Mechanistic specificity demonstrated (RIPK1 kinase inhibition without disrupting NF-κB/MAPK) and in vivo validation
Limitations
- Preclinical models (SIRS) may not fully recapitulate human sepsis pathophysiology
- Dosing, pharmacokinetics, and safety in septic patients remain untested
Future Directions: Define pharmacology and therapeutic window in infection-driven sepsis models, assess combination with standard-of-care, and progress to phase I/II studies with biomarkers of RIPK1 activity.