Daily Sepsis Research Analysis
New mechanistic work links sepsis to long-lasting bone marrow changes that blunt plasmacytoid dendritic cell reconstitution via TCF4 downregulation and G-CSF, illuminating a pathway for post-sepsis immunosuppression. Population data from Finland quantify the clinical and economic burden of invasive pneumococcal disease and highlight the preventive potential of higher-valent conjugate vaccines. In geriatric septic shock, REMS outperforms RAPS for 30-day mortality discrimination, supporting practi
Summary
New mechanistic work links sepsis to long-lasting bone marrow changes that blunt plasmacytoid dendritic cell reconstitution via TCF4 downregulation and G-CSF, illuminating a pathway for post-sepsis immunosuppression. Population data from Finland quantify the clinical and economic burden of invasive pneumococcal disease and highlight the preventive potential of higher-valent conjugate vaccines. In geriatric septic shock, REMS outperforms RAPS for 30-day mortality discrimination, supporting practical risk stratification in the ED.
Research Themes
- Sepsis-induced immunosuppression and hematopoietic dysregulation
- Population burden and vaccination strategies for invasive pneumococcal disease
- Risk stratification tools in geriatric septic shock
Selected Articles
1. Sepsis impairs immunocompetent plasmacytoid dendritic cell reconstitution from hematopoietic stem/progenitor cell through altered bone marrow environment.
Using CLP-induced sepsis in mice, the authors show that both pDCs and their progenitors are depleted and functionally skewed, with impaired type I IFN production and antigen presentation. CLP-derived HSPCs fail to generate immunocompetent pDCs due to downregulation of TCF4, which is reversible by ectopic TCF4 expression; elevated G-CSF replicates this impairment in vitro. These results identify a bone marrow niche–driven mechanism for post-sepsis immunosuppression.
Impact: This study uncovers a mechanistic link between elevated G-CSF, TCF4 downregulation, and defective pDC reconstitution after sepsis, offering concrete molecular targets to mitigate late immunosuppression.
Clinical Implications: Although preclinical, the data suggest that modulating the G-CSF–TCF4 axis or strategies to restore pDC competence could reduce post-sepsis susceptibility to viral and opportunistic infections, informing future translational studies.
Key Findings
- In CLP-induced sepsis, both pDCs and their progenitors are reduced and exhibit impaired type I IFN secretion and antigen presentation.
- HSPCs from CLP mice show reduced pDC output and lower IFN-α expression; TCF4 is downregulated during pDC differentiation.
- Ectopic TCF4 expression restores pDC generation; elevated bone marrow G-CSF and exogenous G-CSF impair immunocompetent pDC generation.
Methodological Strengths
- Combined in vivo CLP model with in vitro Flt3L-driven differentiation and functional assays
- Rescue experiments (TCF4 overexpression) and perturbation with G-CSF to test causality
Limitations
- Findings are from a murine model; human validation (bone marrow and peripheral pDCs) is lacking
- No in vivo infection challenge to link cellular defects to clinical susceptibility
Future Directions: Validate the G-CSF–TCF4–pDC axis in human sepsis cohorts, assess biomarkers of pDC competence, and test therapeutic modulation of TCF4 signaling or G-CSF blockade in translational models.
2. Healthcare resource use and costs associated with episodes of laboratory confirmed invasive pneumococcal disease in adults in Finland 2016-2022.
In 4018 adult IPD episodes in Finland, 30-day case-fatality was 9.7% overall, rising to 26.7% in those ≥85 years. Average per-episode costs were €9118 (94% inpatient), with higher-valent conjugate vaccines (PCV20/PCV21) covering a greater share of serotypes in older adults than PCV13. These data quantify IPD’s burden and inform prevention policy.
Impact: Large, nationwide registry data provide precise estimates of mortality and costs for IPD, directly supporting vaccination and resource allocation decisions in populations at risk of sepsis.
Clinical Implications: Findings support broader adoption of higher-valent pneumococcal conjugate vaccines in older adults and underscore the inpatient cost burden of IPD, informing prevention and budgeting.
Key Findings
- Among 4018 adult IPD episodes, 30-day case-fatality was 9.7%, increasing from 3.2% (18–49 years) to 26.7% (≥85 years).
- Mean per-episode costs were €9118 (95% CI €8802–€9419), with 94% attributable to inpatient care; mean annual costs totaled €5.23 million.
- In adults ≥65 years, serotype coverage was 47.5% for PCV13, 66.5% for PCV20, and 77.0% for PCV21(V116).
Methodological Strengths
- Nationwide linked registries with large sample size and standardized costing
- Age-stratified outcomes and costs with confidence intervals
Limitations
- Retrospective observational design limits causal inference and control of confounding
- Generalizability may be limited outside Finland; vaccine effectiveness was not directly evaluated
Future Directions: Conduct cost-effectiveness analyses for PCV20/PCV21 in older adults, and evaluate patient-level predictors and sepsis-specific outcomes in IPD cohorts.
3. Evaluation of the rapid emergency medicine score and rapid acute physiology score scoring systems in predicting short-term survival outcomes in geriatric septic shock patients in the emergency department.
In 197 geriatric septic shock patients, 30-day mortality was 59%. REMS achieved an AUC of 0.705 versus 0.659 for RAPS (p=0.027), and both scores were independent mortality predictors in multivariable models. REMS offers modest but superior discrimination for short-term outcomes in this high-risk group.
Impact: Head-to-head prospective comparison supports selecting REMS over RAPS for ED risk stratification in geriatric septic shock, a population with very high mortality.
Clinical Implications: ED teams may preferentially use REMS to stratify 30-day mortality risk in geriatric septic shock, while recognizing its moderate AUC and the need for complementary clinical judgment.
Key Findings
- Among 197 geriatric septic shock patients, 30-day all-cause mortality was 59%.
- REMS had higher discrimination than RAPS (AUC 0.705 vs 0.659; DeLong p=0.027).
- Both REMS and RAPS were independent predictors of 30-day mortality in multivariable models.
Methodological Strengths
- Prospective design with head-to-head score comparison
- Appropriate statistical analyses (ROC/AUC, DeLong test, multivariable logistic regression)
Limitations
- Single-center and modest sample size limit generalizability
- Only two scores evaluated; calibration and external validation not reported
Future Directions: Validate REMS thresholds in multi-center cohorts, assess dynamic changes during resuscitation, and compare against newer sepsis-specific risk tools.