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.
Splenectomy or congenital asplenia is associated with severe reduction of memory B cells and increased risk of fulminant sepsis by encapsulated bacteria. Current guidelines recommend vaccinations against these pathogens before or after splenectomy, but the longevity of immunity acquired after splenectomy has not been determined. The impact of splenectomy on innate immune cells is unknown. We analyzed frequency, differentiation stage, and function of innate and adaptive immunity in the peripheral blood of adult (n = 41) and pediatric (n = 14) patients splenectomized or born asplenic and in spleens of solid organ donors. The absence of the spleen impacts the B-cell compartment, causing a significant increase of circulating immature transitional and depletion of memory B cells. Using SARS-CoV-2 vaccination as a model, we show that 1 year after the last immunization, despite normal levels of neutralizing antibodies, memory B and T cells were significantly reduced. Analysis of post-pandemic spleens shows that spike-specific memory B and T cells homed to the spleen. We also show a previously unrecognized role of the spleen in the homeostasis of innate NK and Vδ2 T cells. These populations showed altered phenotype and impaired function in the adults, but not in children, suggesting that other tissues may support innate cell development during early life. The reduced function of innate lymphocytes must be considered as an additional immune impairment and risk factor. These findings emphasize the spleen's irreplaceable role in maintaining immune memory across all ages and suggest that its absence contributes to dysfunctions of innate and adaptive immunity in adults.
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.
Observational studies have indicated an association between cancer and the occurrence of sepsis, with an increased risk of mortality in cancer-related sepsis. However, whether a causal relationship exists between the two remains unknown. Summary statistics of thirteen cancers from the largest available genome-wide association studies (GWAS) of GWAS catalog and FinnGen biobank were extracted for the MR analysis. GWAS data for sepsis and its 28-day mortality were obtained from MRC-IEU. Univariable, multivariable, and reverse MR analyses were employed to explore potential associations between cancers and sepsis and its 28-day mortality. Moreover, a two-step mediation MR analysis was performed to investigate independent positive causal relationships between cancers and sepsis and its 28-day mortality. In univariable Mendelian randomization (MR) analysis, significant causal relationships were found between genetically predicted lung cancer (OR = 1.17, 95% CI = 1.08-1.26, adjusted p = 0.001), squamous cell lung carcinoma (OR = 1.10, 95% CI = 1.02-1.18, adjusted p = 0.042), lung adenocarcinoma (OR = 1.12, 95% CI = 1.03-1.21, adjusted p = 0.032), small cell lung carcinoma (OR = 1.07, 95% CI = 1.02-1.12, adjusted p = 0.031), and sepsis. Subsequent multivariable MR analysis revealed that these three types of lung cancer were independently associated with the risk of sepsis. Additionally, a causal relationship was found between lung cancer and 28-day mortality from sepsis, while no causal link was observed between non-solid tumors and the onset or death of sepsis. Reverse MR analysis did not indicate a potential for sepsis to trigger the onset of cancers. Furthermore, TRAIL was found to have promotive effects on the occurrence and mortality of sepsis. Lung cancer causally correlates with increased sepsis occurrence and 28-day mortality, as evidenced by Mendelian Randomization analysis. Genetic predispositions enhance this risk, underscoring the potential of genetic profiling to guide early, precise sepsis interventions in these patients.
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.
UNLABELLED: Sepsis is a critical condition that disrupts metabolic, physiological, and immune functions, often resulting in severe complications such as multi-organ failure and increased mortality. Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a promising biomarker for infection and inflammation, offering potential advantages for early mortality prediction. This study compared the predictive value of serum NGAL levels with pediatric risk of mortality III (PRISM III) scores in critically ill pediatric patients with sepsis. A prospective cohort study was conducted at a tertiary hospital from September 2022 to March 2023, involving 75 pediatric patients diagnosed with sepsis, septic shock, or multi-organ dysfunction syndrome (MODS), along with 25 healthy controls. Serum NGAL levels were measured within the first hour of PICU admission and analyzed alongside PRISM III scores to evaluate their correlation with mortality and sepsis severity. The results demonstrated that serum NGAL levels were significantly elevated in septic patients compared to controls, with the highest levels observed in those with MODS. NGAL showed greater sensitivity and specificity for predicting mortality than PRISM III scores, with ROC curve analysis revealing that NGAL levels > 599 mg/ml were strongly associated with increased mortality risk (sensitivity 70.4% and specificity 50%). Multivariate analysis confirmed NGAL as an independent predictor of mortality, outperforming PRISM III scores in identifying severe cases. CONCLUSION: Serum NGAL is a valuable biomarker for early prediction of mortality and sepsis severity in pediatric patients, providing faster and more accurate assessments than PRISM III scores. Its integration into clinical practice may enhance decision-making in pediatric critical care settings, allowing for timely interventions and improved patient outcomes. WHAT IS KNOWN: • Pediatric risk of mortality III (Prism III) scores is widely used to predict sepsis severity and mortality in pediatric intensive care units, but requiring 12-24 hours to complete. Neutrophil is an established biomarker for inflammation and infection with a potentially anti-pathological value in the neutrophil gelatinus-lipocalin (NGAL) sepsis. WHAT IS NEW: • Serum NGAL levels, PICU is measured within the first hour of entry, prism III score in pediatric patients in predicting mortality and severity of sepsis. > An NGAL cutoff of 599 mg/mL is significantly associated with mortality risk, which provides a rapid, independent and more immediate immunity tool for important care decision making.