Smoking and risk of sepsis: A secondary analysis of a UK Biobank prospective cohort with protein pathway mediation

Introduction: Sepsis is a global health concern with high mortality. Although smoking impairs immune function and increases infection risk, its specific association with sepsis remains unclear. This study aimed to examine the association between smoking and sepsis and clarify the potential mediating mechanisms. Methods: This secondary analysis of the UK Biobank prospective cohort included 480344 participants without baseline sepsis and with complete smoking data. Smoking characteristics were collected via touchscreen questionnaires at baseline. Sepsis cases were identified through linkage to hospital admissions. The association between smoking and sepsis was evaluated using multivariable Cox proportional hazards models. Proteomics data were derived from the UKB Pharma Proteomics Project (2923 unique proteins, Olink), available in 50564 participants. Pathway over-representation analyses were performed to identify biological pathways in participants with and without sepsis. Principal component analyses were performed to extract weighted scores for each pathway. Subsequently, weighted scores were used in mediation analyses to investigate how the pathways mediated the association between smoking and sepsis. Results: Compared with never smokers, current smokers had significantly higher risks of total sepsis (adjusted hazard ratio, AHR=1.42; 95% CI: 1.39-1.46), pulmonary sepsis (AHR=1.57; 95% CI: 1.48-1.66) and non-pulmonary sepsis (AHR=1.36; 95% CI: 1.30-1.42). Smoking cessation yielded a time-dependent protective effect, with an AHR of 0.73 (95% CI: 0.70-0.76) among individuals who quit smoking for ≥30 years. Pathway enrichment analysis of proteomic profiles identified activated immune-inflammatory cascades in sepsis cases, particularly neutrophil degranulation and extracellular matrix organization. These immune-inflammatory pathways contributed to the smoking-sepsis association, with mediation proportions ranging from 14.4% to 24.7% for pulmonary sepsis and from 25.0% to 69.9% for non-pulmonary sepsis. Conclusions: Smoking is a significant risk factor for sepsis, and these associations could be mitigated by smoking cessation to some extent. The observed associations might be partially mediated through immune-inflammatory pathway dysregulation.