Daily Sepsis Research Analysis
A prospective triage screening tool in a Latin American pediatric ED showed high specificity and strong negative predictive value for early sepsis detection. Systems-level analyses identified CHIT1 as a neutrophil-centric biomarker with potential causal links to sepsis mortality, while preclinical work revealed ERRα as a regulator of microglial polarization and ferroptosis in sepsis-associated brain dysfunction.
Summary
A prospective triage screening tool in a Latin American pediatric ED showed high specificity and strong negative predictive value for early sepsis detection. Systems-level analyses identified CHIT1 as a neutrophil-centric biomarker with potential causal links to sepsis mortality, while preclinical work revealed ERRα as a regulator of microglial polarization and ferroptosis in sepsis-associated brain dysfunction.
Research Themes
- Early pediatric sepsis detection and triage
- Biomarker discovery and systems immunology in sepsis
- Neuroinflammation and organ dysfunction mechanisms in sepsis
Selected Articles
1. Development, Implementation, and Evaluation of an Early Sepsis Screening Tool at Triage in a Pediatric Emergency Department in Latin America.
A triage sepsis screening tool in a pediatric ED demonstrated high specificity (0.99) and good sensitivity (0.80), flagging a small subset (1.4%) with markedly higher acuity, hospitalization, PICU admission, and mortality. Key predictors included circulatory alteration in the Pediatric Assessment Triangle, abnormal capillary refill, and critical risk factors.
Impact: This pragmatic, prospective diagnostic evaluation provides actionable criteria for early pediatric sepsis recognition at triage with excellent rule-out performance. It is directly implementable and identifies high-risk children early.
Clinical Implications: Incorporating this tool at triage can streamline early antibiotic decisions, escalation of monitoring, and PICU triage. Emphasis on circulatory appearance and capillary refill may improve sensitivity without sacrificing specificity.
Key Findings
- Among 16,771 febrile/hypothermic pediatric ED patients, 1.4% (240/16,672) screened positive and had much higher acuity (triage level I–II 99.6% vs 4.8%), hospitalization (66% vs 5%), PICU admission (11% vs 0.03%), and mortality (3.8% vs 0.01%).
- For sepsis at case closure, the tool achieved sensitivity 0.80, specificity 0.99, PPV 0.33, NPV 1.00, PLR 84, and NLR 0.20.
- Independent predictors of sepsis included circulatory alteration in the PAT (OR 2.8), abnormal capillary refill (OR 1.9), and critical risk factors (OR 2.1).
Methodological Strengths
- Prospective diagnostic accuracy design with three reference standards
- Large real-world cohort and implementation at triage
Limitations
- Single health system in Latin America may limit generalizability
- Positive predictive value was modest (0.33), reflecting low prevalence
Future Directions: Multicenter external validation, integration with EHR decision support, and impact studies on time-to-antibiotics and mortality.
OBJECTIVE: Sepsis screening tools in Pediatric Emergency Departments (PEDs) enable timely alerts and treatment. This study aimed to develop, implement, and evaluate a sepsis screening tool applied during triage in patients with fever or hypothermia in a PED. METHODS: The study was conducted in 3 phases (design, implementation, and evaluation) from July 1, 2023, to July 31, 2024. The screening tool included the Pediatric Assessment Triangle (PAT), parental concern, critical appearance, vital signs, mental status, skin condition, capillary refill, and risk factors, with results classified as positive or negative. Evaluation followed an observational, prospective diagnostic test design using 3 reference standards: intention-to-treat standard, Phoenix criteria, and final diagnosis at case closure. Patients aged >28 days to <18 years with fever or hypothermia were included. Results were analyzed for diagnostic accuracy (sensitivity, specificity, predictive values, and likelihood ratios). Additional analyses were performed to examine the triggers of positive alerts and causes of missed alerts. RESULTS: During the evaluation period, 16,771 of 40,005 PED patients had fever or hypothermia. The tool was positive in 1.4% (240/16,672). These patients had significantly more triage levels I and II (99.6% vs. 4.8%), higher hospitalization rates (66% vs. 5%), pediatric intensive care unit admissions (11% vs. 0.03%), and mortality (3.8% vs. 0.01%). For sepsis at case closure, the tool showed sensitivity of 0.80, specificity of 0.99, positive predictive value of 0.33, negative predictive value of 1, positive likelihood ratio of 84, and negative likelihood ratio of 0.20. Circulatory alteration in the PAT [odds ratio (OR): 2.8], abnormal capillary refill (OR: 1.9), and critical risk factors (OR: 2.1) independently increased the risk of sepsis.
2. ERRα Knockout Promotes M2 Microglial Polarization and Inhibits Ferroptosis in Sepsis-Associated Brain Dysfunction.
ERRα deletion protected mice from sepsis-associated brain dysfunction by dampening NF-κB–mediated inflammation, promoting M2 microglial polarization, and suppressing ferroptosis. Findings were consistent across in vivo CLP models and LPS-stimulated BV2 microglia.
Impact: This work uncovers ERRα as a node linking neuroinflammation, microglial polarization, and ferroptosis in SABD, pointing to a tractable therapeutic target.
Clinical Implications: While preclinical, ERRα modulation could be explored to prevent or mitigate sepsis-associated encephalopathy. Biomarker studies in patients may identify those likely to benefit.
Key Findings
- ERRα knockout improved survival and neurological outcomes after CLP-induced sepsis, lowering TNF-α and IL-1β while increasing IL-10.
- ERRα deficiency promoted M2 microglial polarization and attenuated ferroptosis (reduced iron accumulation and lipid peroxidation; normalized mitochondrial morphology).
- Protective effects were mediated via NF-κB pathway inhibition and confirmed in LPS-stimulated BV2 microglia with ERRα knockdown.
Methodological Strengths
- Genetic knockout in an in vivo CLP model with multimodal readouts (cytokines, ferroptosis, ultrastructure)
- In vitro replication in BV2 microglia strengthens mechanistic inference
Limitations
- Preclinical mouse and cell models; no human validation
- No pharmacologic targeting of ERRα to assess translational feasibility
Future Directions: Test pharmacologic ERRα modulators in SABD models and validate pathway activation and biomarkers in clinical sepsis cohorts.
Sepsis-associated brain dysfunction (SABD) is a critical neurological complication with high mortality, yet its pathogenesis remains poorly understood. This study investigated the role of estrogen-related receptor α (ERRα) in SABD pathogenesis using ERRα knockout (KO) mice and cecal ligation and puncture (CLP) models. We found that ERRα KO mice exhibited improved survival rates, milder neurological symptoms, reduced pro-inflammatory cytokine production (TNF-α, IL-1β), and increased anti-inflammatory cytokine (IL-10) levels compared to wild-type controls. Additionally, ERRα deficiency promoted microglial M2 polarization and attenuated ferroptosis, as evidenced by decreased iron accumulation, reduced lipid peroxidation, and normalized mitochondrial morphology. Mechanistically, these protective effects were mediated through inhibition of the NF-κB signaling pathway. In vitro studies with ERRα knockdown in LPS-stimulated BV2 microglia confirmed these findings. Our results suggest that ERRα as a critical regulator of microglial function in SABD through coordinated control of inflammatory responses, polarization states, and ferroptosis, suggesting that targeting ERRα may represent a promising therapeutic strategy for SABD treatment.
3. Integrated multiomics and Mendelian randomization identify CHIT1 as a novel sepsis biomarker and therapeutic target.
Across multiple transcriptomic datasets with MR support, CHIT1 emerged as a neutrophil-enriched biomarker associated with 28-day sepsis mortality. CHIT1+ neutrophils displayed heightened inflammatory signatures and reduced antigen-presentation genes, suggesting a role in concurrent hyperinflammation and immunosuppression.
Impact: This integrative analysis provides convergent genetic, transcriptomic, and single-cell evidence for CHIT1 as a prognostic biomarker and potential target, advancing neutrophil-focused sepsis immunobiology.
Clinical Implications: If prospectively validated, CHIT1 could support early risk stratification and guide development of CHIT1-targeted immunotherapies in sepsis.
Key Findings
- CHIT1 expression was higher in sepsis non-survivors and associated with 28-day mortality across public cohorts.
- scRNA-seq localized CHIT1 primarily to neutrophils, which showed increased S100A8/A9/A11/A12, IL1R2, IFNGR2, TLR2, CXCL8 and reduced HLA-DM/DP/DR genes in non-survivors.
- Cell–cell communication analysis suggested CHIT1+ neutrophils interact with NK cells, erythroid cells, monocytes/macrophages, and DC via ICAM1–(ITGAM+ITGB2).
Methodological Strengths
- Integration of bulk transcriptomics, single-cell RNA-seq, and Mendelian randomization
- Consistent findings across multiple independent datasets
Limitations
- Retrospective use of public datasets; lack of prospective clinical validation
- No interventional or functional blockade studies of CHIT1 in patients
Future Directions: Prospective validation with standardized CHIT1 assays, mechanistic studies of CHIT1 blockade, and evaluation of additive value over existing risk scores.
Sepsis is characterized by severe organ failure due to an impaired response to infection. The underlying pathophysiology of sepsis is characterized by concurrent unbalanced hyperinflammatory and immunoparalysis. This study aimed to identify new key biomarkers that could predict outcomes in sepsis patients and explore theirunderlying molecular mechanisms. Bulk transcriptome data (GSE65682, GSE28750, GSE57065, GSE95233) and scRNA-seq data (GSE167363) of sepsis were obtained from the GEO database. Data for MR analysis were sourced from the eQTLGen Consortium and IEU OpenGWAS project. Prognostic biomarkers and potential drug targets for sepsis were identified through univariate Cox regression and MR analysis. The expression of these biomarkers was further validated using scRNA-seq data to investigate the underlying molecular mechanisms. Significantly higher expression of CHIT1 was found at sepsis non-survivor and associated with 28-day mortality of sepsis. scRNA-seq data of septic samples found that CHIT1 mainly expressed in neutrophils, which was also higher in sepsis non-survivors. The CHIT1 + neutrophils expressed higher inflammation related genes of S100A8, S100A9, S100A11, S100A12, IL1R2, IFNGR2, TLR2 and CXCL8 and reduced expression of HLA related genes of HLA-DMA, HLA-DPA1, HLA-DPB1, HLA-DRA, HLA-DRB1 and HLA-DRB5. Moreover, cell-chat analysis also showed that CHIT1 + neutrophils could interact with other immune cell types, including NK cells, erythroid cells, monocytes/macrophages, and DC by the way of ICAM1-(ITGAM + ITGB2) pathway. We identified CHIT1 as new biomarker and potential drug target for sepsis, which may intensify hyperinflammation and immune suppression of neutrophils. Developing immunotherapeutic strategies aimed at targeting CHIT1 would help to enhance sepsis outcomes.