Daily Sepsis Research Analysis
Three impactful sepsis studies emerged: a Nature Communications paper presents a six-gene, point-of-care microfluidic assay that predicts 24-hour deterioration; a mechanistic study in Journal of Neuroinflammation identifies endothelial TREM-1 as a driver of blood–brain barrier disruption and cognitive impairment via PI3K/Akt; and a prospective ED cohort shows MR-proADM outperforms common biomarkers and scores for predicting septic shock/ICU admission and 30-day mortality.
Summary
Three impactful sepsis studies emerged: a Nature Communications paper presents a six-gene, point-of-care microfluidic assay that predicts 24-hour deterioration; a mechanistic study in Journal of Neuroinflammation identifies endothelial TREM-1 as a driver of blood–brain barrier disruption and cognitive impairment via PI3K/Akt; and a prospective ED cohort shows MR-proADM outperforms common biomarkers and scores for predicting septic shock/ICU admission and 30-day mortality.
Research Themes
- Point-of-care genomic diagnostics for early sepsis deterioration
- Endothelial mechanisms and neuroinflammation in sepsis-associated encephalopathy
- Risk stratification and prognostic biomarkers in emergency department sepsis
Selected Articles
1. A machine learning and centrifugal microfluidics platform for bedside prediction of sepsis.
Using 586 derivation samples and validation across 3,178 independent patients, a six-gene expression signature (Sepset) predicted 24-hour clinical deterioration in suspected sepsis. An RT-PCR assay and an automated centrifugal microfluidic instrument achieved 94% and 92% sensitivity, respectively, with 89% specificity on the instrument.
Impact: This work bridges transcriptomic risk stratification with a deployable bedside device, addressing diagnostic delays that drive sepsis mortality.
Clinical Implications: If prospectively implemented, the Sepset platform could enable early escalation/de-escalation decisions within the first 24 hours, improving triage, ICU utilization, and timely antimicrobial and organ support.
Key Findings
- Defined a six-gene Sepset signature predicting 24-hour deterioration in suspected sepsis
- Validated performance in 3,178 independent patients from external cohorts
- RT-PCR Sepset test showed 94% sensitivity for worsening SOFA within 24 hours
- Automated centrifugal microfluidic device achieved 92% sensitivity and 89% specificity at bedside
Methodological Strengths
- Prospective derivation with cross-validation and large-scale external validation
- Translation to a rapid RT-PCR assay and automated microfluidic platform
Limitations
- Impact on patient-centered outcomes not yet tested in randomized implementation trials
- Potential site-specific biases in derivation cohort despite external validation
Future Directions: Conduct pragmatic implementation trials to assess time-to-antibiotics, ICU admission decisions, and mortality; evaluate performance across diverse health systems and pathogens; pursue regulatory approval and cost-effectiveness analyses.
2. Endothelial TREM-1 mediates sepsis-induced blood‒brain barrier disruption and cognitive impairment via the PI3K/Akt pathway.
Using iPSC-derived BBB and CLP sepsis models, the study shows endothelial TREM-1 upregulation drives BBB disruption and cognitive impairment via PI3K/Akt signaling. Endothelial-specific TREM-1 knockout preserved BBB integrity and cognition, and PI3K inhibition abrogated the protective effects of TREM-1 inhibition.
Impact: Identifies a tractable endothelial target and pathway for sepsis-associated encephalopathy, linking patient-derived stimuli to in vivo cognitive outcomes.
Clinical Implications: Endothelial TREM-1 and PI3K/Akt signaling represent candidate targets to preserve BBB integrity and mitigate cognitive sequelae in sepsis; biomarkers of endothelial activation could enable stratification for neuroprotective interventions.
Key Findings
- Sepsis patient serum disrupts structure and function of iPSC-derived BBB
- Endothelial TREM-1 expression is upregulated in BBB models and CLP mice
- Endothelial-specific TREM-1 knockout attenuates BBB dysfunction and cognitive impairment
- PI3K/Akt signaling mediates TREM-1 effects; PI3K inhibition abolishes protection from TREM-1 inhibition
Methodological Strengths
- Multipronged preclinical approach combining human iPSC-derived BBB and in vivo CLP models
- Cell type-specific genetic manipulation (endothelial TREM-1 knockout) with pathway interrogation
Limitations
- Preclinical models; lack of human interventional data
- Quantitative sample sizes and reproducibility across laboratories not detailed
Future Directions: Develop and test endothelial TREM-1 inhibitors or modulators in large-animal models and early-phase trials; evaluate circulating markers of endothelial TREM-1 activation for patient stratification in SAE.
3. [Ability of midregional proadrenomedullin (MR-proADM) to predict poor clinical outcome and stratify prognosis in adult patients seen for suspected infection in the Emergency Department].
In 214 ED patients with suspected infection, MR-proADM achieved an AUC of 0.920 for predicting septic shock/ICU admission and 30-day mortality, outperforming PCT, lactate, CRP, leukocytes, and NEWS-2. A cutoff >2.105 nmol/L yielded specificity 98% and NPV 97%; combining MR-proADM with NEWS-2 improved prediction metrics.
Impact: Provides pragmatic ED risk stratification evidence showing MR-proADM can surpass widely used biomarkers and scores, supporting early disposition decisions.
Clinical Implications: Incorporating MR-proADM into ED protocols could improve identification of high-risk patients for early ICU admission and closer monitoring while safely de-escalating care in low-risk individuals.
Key Findings
- MR-proADM predicted poor outcomes and 30-day mortality with AUC 0.920
- Cutoff >2.105 nmol/L yielded specificity 98% and NPV 97%
- Outperformed PCT, lactate, CRP, leukocyte count, qSOFA, SIRS, and NEWS-2
- Combining MR-proADM with NEWS-2 further improved prediction metrics
Methodological Strengths
- Prospective observational design with 30-day follow-up
- Direct head-to-head comparison with multiple biomarkers and clinical scores
Limitations
- Single-center cohort with modest sample size limits generalizability
- Sensitivity at the chosen cutoff (68%) may miss some high-risk patients
Future Directions: Multicenter validation, assessment of clinical impact on triage decisions and outcomes, and cost-effectiveness analyses for routine ED implementation.