Daily Sepsis Research Analysis
Three studies advance sepsis science across mechanisms, risk prediction, and causal epidemiology. Loss of the spleen is shown to deplete vaccine-induced memory B/T cells and impair innate NK and Vδ2 T-cell function, mechanistically explaining high sepsis susceptibility. Mendelian randomization supports a causal link between lung cancers and both sepsis occurrence and 28-day mortality, while an early biomarker (serum NGAL) outperforms PRISM III for pediatric mortality prediction.
Summary
Three studies advance sepsis science across mechanisms, risk prediction, and causal epidemiology. Loss of the spleen is shown to deplete vaccine-induced memory B/T cells and impair innate NK and Vδ2 T-cell function, mechanistically explaining high sepsis susceptibility. Mendelian randomization supports a causal link between lung cancers and both sepsis occurrence and 28-day mortality, while an early biomarker (serum NGAL) outperforms PRISM III for pediatric mortality prediction.
Research Themes
- Immune mechanisms of sepsis susceptibility after asplenia
- Genetic causal links between cancer and sepsis outcomes
- Early biomarkers for pediatric sepsis mortality prediction
Selected Articles
1. Impairment of Innate Immunity and Depletion of Vaccine-Induced Memory B and T Cells in the Absence of the Spleen.
In adults and children lacking a spleen, vaccine-induced memory B and T cells are depleted despite preserved neutralizing antibodies, and innate lymphocytes (NK, Vδ2 T cells) show phenotype and functional impairment. Spleen tissue harbors spike-specific memory cells, underscoring the spleen’s central role in maintaining adaptive and innate immune memory and explaining susceptibility to overwhelming sepsis by encapsulated bacteria.
Impact: This translational study reveals a previously unrecognized role of the spleen in innate lymphocyte homeostasis and demonstrates long-term depletion of vaccine-induced memory cells after splenectomy, providing mechanistic insight into post-splenectomy sepsis risk.
Clinical Implications: Asplenic adults may retain antibody titers yet lack durable cellular memory and have impaired innate responses; vaccination alone may be insufficient. Intensified prevention (timely boosters, broader conjugate vaccines), rapid empiric antibiotics for febrile illness, and consideration of adjunctive strategies to support innate immunity are warranted.
Key Findings
- Memory B cells are depleted and transitional B cells increased in asplenic individuals.
- One year after SARS-CoV-2 vaccination, memory B and T cells are significantly reduced despite normal neutralizing antibody levels.
- Spike-specific memory B/T cells home to the spleen; asplenia impairs NK and Vδ2 T-cell phenotype and function in adults.
Methodological Strengths
- Integrated human immunophenotyping with functional assays across adult and pediatric cohorts and donor spleen tissues.
- Use of vaccine antigen-specific responses to assess durable immune memory.
Limitations
- Observational cross-sectional design with modest sample size; not powered for clinical sepsis outcomes.
- Potential confounding by indication and heterogeneity of asplenia etiology; limited generalizability beyond study populations.
Future Directions: Prospective studies linking cellular deficits to sepsis incidence, trials of enhanced vaccination and antibiotic prophylaxis schedules, and strategies to restore NK/Vδ2 T-cell function.
2. Association of cancers with the occurrence and 28-day mortality of sepsis: a mendelian randomization and mediator analysis.
Using large-scale Mendelian randomization, multiple lung cancer subtypes show a causal effect on sepsis occurrence and 28-day mortality, whereas non-solid tumors do not. Reverse MR was null, and TRAIL emerged as a plausible mediator, highlighting biologic pathways for targeted prevention in oncology patients at risk for sepsis.
Impact: The study shifts the cancer–sepsis link from association to causality for lung cancer, with mediation analysis implicating TRAIL. This supports risk stratification and mechanistic exploration of immune-oncology pathways in sepsis.
Clinical Implications: Oncology teams should anticipate heightened sepsis risk and early mortality in lung cancer patients. Integrating genetic risk profiling with enhanced surveillance, early antibiotics triggers, and trials of TRAIL-pathway modulation may reduce sepsis burden.
Key Findings
- Genetically predicted lung cancer increases sepsis risk: overall lung cancer OR 1.17 (95% CI 1.08–1.26; p=0.001).
- Lung adenocarcinoma, squamous cell carcinoma, and small cell lung cancer each show independent causal associations with sepsis; lung cancer also causally increases 28-day sepsis mortality.
- No causal link for non-solid tumors; reverse MR shows sepsis does not cause cancer; TRAIL mediates increased sepsis occurrence and mortality.
Methodological Strengths
- Triangulation using univariable, multivariable, reverse MR, and two-step mediation analyses.
- Use of large GWAS consortia (GWAS Catalog, FinnGen, MRC-IEU) to enhance instrument strength and generalizability.
Limitations
- MR assumptions (relevance, independence, exclusion restriction) may be violated by horizontal pleiotropy.
- Summary-level data limit phenotype granularity; ancestry composition may restrict applicability to diverse populations.
Future Directions: Validate in clinical cohorts linking genetic risk to bedside sepsis screening and early intervention; explore TRAIL-pathway modulation as a therapeutic strategy.
3. Enhanced mortality prediction in pediatric sepsis using NGAL: A comparison with PRISM III scores in critical care settings.
In a prospective cohort of 75 septic pediatric patients and 25 controls, serum NGAL measured within 1 hour of PICU admission independently predicted mortality and outperformed PRISM III for early risk stratification. NGAL levels were highest in MODS and associated with increased mortality at a cutoff >599 mg/mL.
Impact: Provides a rapid, first-hour biomarker outperforming a standard severity score for mortality prediction in pediatric sepsis, potentially enabling earlier, targeted interventions.
Clinical Implications: Integrating early NGAL measurement at PICU entry may aid triage, escalation decisions, and monitoring in pediatric sepsis, complementing PRISM III which requires 12–24 hours.
Key Findings
- Serum NGAL levels were significantly higher in septic patients vs. controls, peaking in MODS.
- NGAL measured within 1 hour predicted mortality with greater performance than PRISM III.
- ROC suggested a mortality-associated NGAL cutoff >599 mg/mL (sensitivity 70.4%, specificity 50%); NGAL was an independent predictor in multivariable models.
Methodological Strengths
- Prospective design with biomarker sampling in the first hour of PICU admission.
- Multivariable analysis and ROC evaluation against a widely used clinical score (PRISM III).
Limitations
- Single-center, small sample size; external validation lacking.
- Specificity at the proposed cutoff is modest; unit reporting (mg/mL) may reflect assay/contextual variability.
Future Directions: Multicenter validation, standardized NGAL assay thresholds, and integration into dynamic risk models alongside clinical and organ dysfunction metrics.