Daily Sepsis Research Analysis
Analyzed 48 papers and selected 3 impactful papers.
Summary
Three impactful studies advance sepsis science across risk prediction, pediatric phenotyping, and host genetics. A massive prospective cohort links lower handgrip strength to higher risks of infections and sepsis with partial proteomic mediation; a multicenter pediatric study introduces a vasoactive-adjusted shock index to identify a refractory shock phenotype and differential steroid benefit; and a GWAS in children reveals a susceptibility locus spanning CTNNAL1/ELP1.
Research Themes
- Host frailty and proteomic pathways shaping infection and sepsis risk
- Early pediatric refractory shock phenotyping and treatment effect heterogeneity
- Genetic susceptibility to pediatric sepsis
Selected Articles
1. Identifying a Refractory Shock Phenotype in Pediatric Sepsis Using a Vasoactive-Adjusted Shock Index.
Across 17,216 pediatric sepsis admissions, a vasoactive-adjusted shock index (VASI) stratified early trajectories and identified a refractory septic shock phenotype with markedly worse outcomes. Early hydrocortisone use was associated with lower mortality preferentially in the refractory phenotype, indicating heterogeneity of treatment effect and potential for targeted therapy.
Impact: Introduces a pragmatic, physiology-informed metric that redefines early risk stratification and uncovers treatment-response heterogeneity in pediatric septic shock.
Clinical Implications: Incorporating VASI into early PICU assessment may help identify refractory septic shock candidates for intensified monitoring and timely adjuncts (e.g., corticosteroids) and inform enrichment strategies for future interventional trials.
Key Findings
- Developed a vasoactive-adjusted shock index (VASI) integrating hemodynamics and vasoactive support.
- Identified four VASI trajectory clusters; a persistently high-VASI group matched a refractory septic shock phenotype with poor outcomes.
- Early hydrocortisone use showed a significant interaction, with lower mortality in the refractory phenotype (interaction p=0.002).
Methodological Strengths
- Large, multicenter cohort (13 PICUs; n=17,216) with robust trajectory modeling (GBTM) and replication via K-means/DTW.
- Heterogeneity of treatment effect assessed using inverse-probability weighted logistic regression.
Limitations
- Retrospective design with potential residual confounding, especially for treatment exposure (hydrocortisone).
- Lack of external prospective validation and physiologic mechanistic correlates.
Future Directions: Prospective validation of VASI thresholds, integration with multimodal perfusion metrics, and randomized trials to test steroid timing/selection in the refractory phenotype.
OBJECTIVES: This study aimed to (1) develop a cardiovascular index that includes hemodynamic status and adjusts for vasoactive medication use, (2) identify pediatric patients with refractory septic shock (RSS) using early trends of the adjusted index, and (3) assess the heterogeneity of treatment effect (HTE) to common adjuvant therapies in RSS vs non-RSS patients. METHODS: Children with sepsis across 13 US pediatric intensive care units (PICUs) between 2012 and 2018 were included. The vasoactive-adjusted shock index (VASI) was derived using the shock index (heart rate/systolic pressure) and adjusted for vasoactive use. Group-based trajectory modeling (GBTM) was applied to 8-hour VASI trends following PICU admission to stratify patients and replicated using K-means with dynamic time warping (DTW). HTE between RSS and non-RSS patients was analyzed using inverse-probability weighted logistic regression. RESULTS: 17,216 patients were included (8.6% mortality). VASI demonstrated a robust progressive increase in clinical risk, outperforming other hemodynamic metrics at discriminating poor outcomes. Trajectory analysis identified four clusters, including a trajectory with persistently high VASI consistent with an RSS clinical phenotype. Unlike fluid balance and albumin use, hydrocortisone use on the first day was associated with lower mortality among RSS patients than among non-RSS patients (interaction, p = 0.002). CONCLUSION: The early trajectory of VASI identifies an RSS clinical phenotype associated with poor outcomes and HTE to adjuvant therapies. Integrating hemodynamic status and vasoactive use into early risk assessment in pediatric sepsis can help identify a high-risk RSS group, with both prognostic and therapeutic relevance.
2. Handgrip strength and risk of common infections and sepsis: Two prospective cohorts with proteomic mediation analysis.
In >405,000 adults with replication in an Asian cohort, lower handgrip strength predicted higher risks of pneumonia, UTI, skin infection, and sepsis over ~14 years, with effects strongest in underweight individuals. Proteomic mediation implicated inflammatory/immune pathways, notably GDF15 and PLAUR, explaining 12–14% of the association.
Impact: Demonstrates a scalable, inexpensive functional biomarker of host vulnerability to infections and sepsis, supported by proteomic pathways that suggest biological plausibility.
Clinical Implications: Grip strength could augment clinical risk stratification beyond BMI, prioritizing preventive measures (e.g., vaccination, strength training, nutrition) for underweight and low-strength patients.
Key Findings
- Each 5-kg decrement in grip strength increased risk of pneumonia and UTI by 10%, skin infection by 5%, and sepsis by 8% over a median 13.6–15.3 years.
- Findings replicated in an independent Chinese cohort and were most pronounced among underweight individuals.
- Proteomic mediation highlighted GDF15 and PLAUR, explaining 12–14% of the grip strength–infection/sepsis association.
Methodological Strengths
- Very large prospective cohort with long follow-up and extensive adjustment for confounders, plus independent replication.
- Proteomic mediation analysis linking clinical associations to plausible biological pathways.
Limitations
- Observational design limits causal inference; residual confounding possible.
- Grip strength measured at baseline only; mediation accounted for a modest proportion of the association.
Future Directions: Test whether improving strength reduces infection and sepsis risk; validate proteomic mediators as therapeutic targets or risk markers; integrate grip strength into clinical risk scores.
BACKGROUND: Recent evidence links adiposity with the risk of severe infections, but whether muscle strength may also be an independent risk factor is less studied. We investigated the association between handgrip strength and risk of common infections and sepsis and explored potential mediation by plasma proteomic biomarkers. METHODS: We analyzed data from 405,451 UK Biobank participants and replicated the main findings in 4474 Chinese adults from the Hong Kong Osteoporosis Study (HKOS). Baseline handgrip strength was measured by a dynamometer. Cox models were used to estimate its association with incidence of pneumonia, urinary tract infection (UTI), skin infection, and sepsis, adjusting for sociodemographic, lifestyle, and health-related factors. Mediation analyses were performed using 2912 plasma proteins in a UK Biobank subsample (n = 42,414) to identify biological pathways. RESULTS: In UK Biobank (median follow-up 13.6-15.3 years), lower handgrip strength was associated with significantly increased risk of pneumonia (hazard ratio per 5-kg decrement=1.10; 95% CI=1.09-1.11), UTI (1.10; 1.09-1.11), skin infection (1.05; 1.04-1.05), and sepsis (1.08; 1.07-1.10). Associations were largely consistent in HKOS, and the relative risks associated with low grip strength were generally most pronounced in underweight individuals. GDF15 and PLAUR were identified as the most important proteins which mediated 12-14% of these associations. CONCLUSION: Low handgrip strength is associated with increased risks of common infections and sepsis, particularly in underweight individuals, with partial mediation by proteins related to inflammation and immune-related pathways. Handgrip strength assessment may provide prognostic value beyond body mass index for clinical risk stratification.
3. Genome-wide association study of paediatric bacteraemia and sepsis.
This national pediatric sepsis GWAS identified a susceptibility locus spanning CTNNAL1 and ELP1 in a case-control analysis (510 cases, 994 controls), while within-cohort analyses were negative. Findings support a genetic contribution to pediatric sepsis susceptibility and motivate replication and functional follow-up.
Impact: Adds the first pediatric-focused genome-wide signal for sepsis susceptibility in a rigorously phenotyped cohort, opening avenues for mechanistic studies and risk stratification.
Clinical Implications: While not immediately actionable, pediatric genetic risk markers could ultimately inform precision prevention, early monitoring, and trial enrichment for high-risk children.
Key Findings
- Case-control GWAS (510 cases, 994 controls) identified a significant pediatric sepsis susceptibility locus encompassing CTNNAL1 and ELP1.
- Within-cohort genome-wide analyses of host, microbiological, and outcome features did not reveal significant associations.
- Study highlights genetic modulators contributing to pediatric sepsis susceptibility, warranting replication and functional studies.
Methodological Strengths
- National multicenter cohort with culture-proven bacterial sepsis and well-defined phenotypes.
- Genome-wide approach with both within-cohort and independent case-control analyses.
Limitations
- Modest sample size for GWAS limits power and increases risk of false negatives.
- Lack of replication cohort and functional validation of implicated genes.
Future Directions: Independent replication in diverse populations, fine-mapping and eQTL colocalization, and mechanistic studies to define causal variants and pathways.
BACKGROUND: Sepsis is defined as a dysregulated host response to infection leading to organ dysfunction. It represents a major global health concern, particularly in childhood. The underlying pathophysiological and genetic mechanisms remain insufficiently understood. METHODS: Using samples and clinical data from 650 children enrolled in the Swiss Pediatric Sepsis Study, a national multicentre cohort for culture-proven bacterial sepsis, we conducted within-cohort analyses and a separate case-control analysis in 510 cases and 994 controls, testing genome-wide polymorphisms for association with sepsis susceptibility and, in cases only, with disease characteristics. FINDINGS: In the within-cohort analysis, no significant genome-wide associations were found when assessing host, microbiological, and outcome features. In the case-control analysis, we identified one locus significantly associated with sepsis susceptibility, encompassing the CTNNAL1 and ELP1 genes. INTERPRETATION: Our results suggest contribution of genetic modulators to susceptibility for sepsis in children. FUNDING: The Swiss Pediatric Sepsis Study received funding from the Swiss National Science Foundation (342730_153158/1 and 320030_201060/1), the Swiss Society of Intensive Care, the Bangerter Foundation, the Vinetum and Borer Foundation, the Foundation for the Health of Children and Adolescents, and the Sanofi-Aventis Suisse. LJS was supported by the NOMIS and the Thomas and Doris Ammann Foundation.