Daily Sepsis Research Analysis
Analyzed 37 papers and selected 3 impactful papers.
Summary
Analyzed 37 papers and selected 3 impactful articles.
Selected Articles
1. Direct carbapenemase typing from disc diffusion antibiograms with MALCA (MAchine Learning CArbapenemase).
Using routine disc diffusion data, MALCA accurately detects and types carbapenemases with >96% sensitivity/specificity in external validation, outperforming established screening algorithms. This low-cost, reagent-free approach can accelerate targeted therapy for suspected CPE infections, including septic presentations.
Impact: Provides a validated, scalable diagnostic that repurposes existing antibiograms to inform early, precise antimicrobial therapy against high-risk resistant pathogens.
Clinical Implications: Hospitals can integrate MALCA into laboratory workflows to flag CPE and infer carbapenemase type from routine discs, guiding rapid initiation of agents (e.g., ceftazidime-avibactam vs. MBL-active combinations) and stewardship decisions without added turnaround time.
Key Findings
- MALCA-22 and MALCA-8 achieved >96% sensitivity and specificity for CPE detection in 8,514 external isolates.
- Accurate typing for common carbapenemases (OXA-48-like, NDM, KPC) with sensitivities >97% and specificities >98%.
- Outperformed European and French CPE screening algorithms using only routine disc diffusion data.
Methodological Strengths
- Large development cohort (n=11,992) with robust external validation (n=8,514).
- Direct comparison to established screening algorithms with consistent superiority.
Limitations
- Generalizability may vary with local antibiotic panels and disc diffusion methodologies.
- Rare or emerging carbapenemase variants may be underrepresented, affecting typing accuracy.
Future Directions: Prospective clinical integration studies assessing time-to-appropriate therapy, patient outcomes in sepsis, and portability across laboratories with differing antibiotic panels.
Carbapenemase-producing Enterobacterales (CPE) present limited therapeutic options. Optimal treatment requires identifying the carbapenemase type, often requiring confirmatory testing beyond routine susceptibility results. We develop MALCA, a machine-learning classifier that uses routine disc diffusion antibiogram results to directly detect CPE and identify the carbapenemase type. From 11,992 clinical isolates, we build a stepwise random-forest pipeline and derive two classifiers based on panels of 22 or 8 antibiotics (MALCA-22 and MALCA-8). In an external validation study involving 8514 isolates, both MALCA classifiers achieved sensitivity and specificity >96% for CPE detection, outperforming European and French algorithms developed for CPE screening. For the most prevalent carbapenemases, MALCA achieve sensitivities exceeding 97% and specificities above 98%, particularly for OXA-48-like, NDM, and KPC producers. MALCA is a rapid, and inexpensive diagnostic tool that uses solid antibiogram data to detect and type CPE, enabling earlier targeted therapy and diagnostic guidance without additional reagents or human resources.
2. The IL-33/ST2 axis promotes sepsis-induced lung injury by modulating NETs formation via the ATF4/REDD1 signaling pathway.
IL-33/ST2 signaling drives NETosis via PERK/eIF2α/ATF4-mediated upregulation of REDD1, disrupting the pulmonary endothelial barrier in sepsis. Genetic ablation of IL-33 or ST2 and DNase I intervention mitigate lung injury, highlighting a targetable pathway.
Impact: Defines a mechanistically cohesive axis linking an alarmin (IL-33) to NETs and endothelial injury, offering concrete intervention points (ST2/REDD1/NETs) for sepsis-induced lung damage.
Clinical Implications: Supports exploration of IL-33/ST2 blockade, REDD1 modulation, or NET-targeted strategies (e.g., DNase) as adjuncts to reduce lung injury in sepsis while balancing infection control.
Key Findings
- CLP sepsis increased pulmonary NETs, edema, and permeability; DNase I reduced endothelial damage.
- IL-33/ST2 activation promoted NETosis; IL-33 or ST2 knockout reduced NETs and alleviated lung injury.
- ATF4/REDD1 is the key downstream pathway by which IL-33 induces NET formation in neutrophils.
Methodological Strengths
- Use of gene knockout models (IL-33−/−, ST2−/−) with in vivo CLP and in vitro validation.
- Integration of transcriptomics and functional perturbation (REDD1 silencing/overexpression).
Limitations
- Preclinical model; translational relevance to human sepsis requires validation.
- Potential off-target or compensatory pathways were not exhaustively evaluated.
Future Directions: Test IL-33/ST2 or REDD1-targeted interventions and NET-modulating therapies in clinically relevant infection models and early-phase human studies, with endpoints including lung permeability and oxygenation.
BACKGROUND: Neutrophil extracellular traps (NETs) can mediate sepsis-induced lung injury, but the upstream regulatory mechanisms remain unclear. IL-33 is involved in neutrophil activation and may serve as an upstream regulator of NET formation. Therefore, this study aims to elucidate the molecular mechanism by which the IL-33/ST2 axis regulates NET formation to mediate sepsis-induced lung injury. METHODS: A mouse model of sepsis-induced lung injury was established using the CLP method to assess lung damage and NETs formation. The destructive effect of NETs on the endothelial barrier was examined through DNase I intervention and HUVECs cell experiments. IL-33 or ST2 gene knockout mice were used to investigate the role of the IL-33/ST2 axis in sepsis-induced lung injury and its regulatory effect on NETs formation. Differentially expressed genes were identified via transcriptome sequencing of mouse neutrophils, and the downstream molecular mechanism of IL-33-induced NETs formation was explored by silencing or overexpressing REDD1 in dHL-60 cells. RESULTS: In septic mice, neutrophil infiltration and elevated levels of NETs were observed in lung tissue, accompanied by pulmonary edema and increased vascular permeability. These injuries were reversed by DNase I intervention. The IL-33/ST2 signaling axis was activated in septic mice, and knockout of either the IL-33 or ST2 gene alleviated lung injury, reduced endothelial barrier disruption, and inhibited NETs formation. In vitro experiments and transcriptome sequencing results demonstrated that IL-33 induces NETs formation in neutrophils through the ST2 receptor, and the ATF4/REDD1 signaling pathway is the key downstream mechanism by which IL-33 promotes NETs formation. CONCLUSION: This study demonstrates that IL-33/ST2 signaling leads to activation of the PERK/eIF2α/ATF4 pathway in neutrophils, upregulates REDD1 to induce NETosis triggered by oxidative stress, and thereby disrupts the pulmonary vascular endothelial barrier, exacerbating sepsis-induced lung injury.
3. Therapeutic plasma exchange and mortality in critically ill patients with sepsis-associated acute kidney injury: A retrospective cohort study using propensity score matching.
In a 17,533-patient MIMIC-IV cohort, therapeutic plasma exchange in sepsis-associated AKI was associated with higher 30- and 90-day mortality, even after propensity score matching. Findings caution against routine TPE use and highlight the need for prospective trials.
Impact: Provides a large-scale, adjusted signal of potential harm from TPE in sepsis-associated AKI, directly informing critical care decision-making and future trial prioritization.
Clinical Implications: Avoid routine TPE in sepsis-associated AKI outside of specific indications; discuss risks in multidisciplinary rounds; prioritize enrollment in prospective studies to define subgroups (if any) who might benefit.
Key Findings
- Among 17,533 sepsis-AKI patients, only 1.2% received TPE; crude 90-day mortality was 58.3% with TPE vs. 31.8% without.
- Adjusted Cox models showed higher 30-day (HR 2.36) and 90-day mortality (HR 2.30) with TPE.
- After propensity score matching with good balance, TPE remained associated with increased 30-day (HR 1.68) and 90-day mortality (HR 1.59).
Methodological Strengths
- Very large cohort with standardized sepsis and AKI definitions and time-to-event modeling.
- Robustness checks using propensity score matching with excellent covariate balance.
Limitations
- Observational design with potential residual confounding and confounding by indication.
- TPE exposure small (1.2%), limiting precision for subgroup analyses.
Future Directions: Prospective, ideally randomized, studies to determine causality and identify patient phenotypes (e.g., hyperinflammatory, toxin-mediated) that may benefit or be harmed by TPE.
ObjectiveTo assess the link between therapeutic plasma exchange (TPE) and mortality outcomes in intensive care unite (ICU) patients with sepsis-associated acute kidney injury (AKI).MethodsThis retrospective cohort study was conducted using data from the MIMIC-IV database. Adult ICU patients with sepsis-associated AKI were identified using Sepsis-3 criteria and the Kidney Disease: Improving Global Outcomes (KDIGO) criteria for AKI during ICU admission. Standard TPE was defined as a volume of approximately 1.0-1.5 times the total plasma volume. Kaplan-Meier analysis was used to estimate 30- and 90-day ICU mortality. Cox proportional hazards models were applied to evaluate the associations between TPE and mortality outcomes. Propensity score matching (PSM) was further performed to assess the robustness of the findings.ResultsA total of 17,533 patients with sepsis-associated AKI were included; 204 (1.2%) received adequate TPE. During the 90-day follow-up period, 5,458 patients (31.8%) in the non-TPE group and 119 patients (58.3%) in the TPE group died. In Cox proportional hazards models, TPE was associated with increased 30-day (hazard ratio [HR] = 2.36, 95% confidence interval [CI] 1.94-2.87) and 90-day mortality (HR = 2.30, 95% CI 1.92-2.76). After PSM with good covariate balance (all standardized mean differences <0.1), TPE remained associated with higher 30-day (HR = 1.68, 95% CI 1.22-2.31) and 90-day mortality (HR = 1.59, 95% CI 1.19-2.12).ConclusionsIn ICU patients with sepsis-associated AKI, TPE was associated with higher 30-day and 90-day ICU mortality, underscoring the need for careful patient selection and prospective studies to clarify its clinical role.