Lung function impairment and risk of sepsis and sepsis-related mortality: a large cohort study with over 310,000 participants.

Hypoxia is associated with systemic inflammation and oxidative stress, both of which contribute to sepsis development, yet whether impaired lung function is associated with a higher sepsis risk remains unclear. Leveraging data from 312,805 UK Biobank participants, we assessed baseline lung function as percentages of predicted forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), and defined normal lung function as FEV1 ⩾ 80% predicted and an FEV1/FVC ratio ⩾ 0.70. Multivariable Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of sepsis incidence and sepsis-related mortality in relation to different measures of lung function. Stratified, sensitivity, and mediation analyses were conducted to assess potential effect modifications, result robustness, and mediation effect, respectively. During a median follow-up of 13.7 years, 8,906 incident cases of sepsis and 1,664 cases of 28-day mortality following sepsis occurred. In the multivariable-adjusted model, compared with the highest quartile, the lowest quartile of FVC% predicted or FEV1% predicted was associated with an increased risk of sepsis and sepsis-related mortality (FVC% predicted: sepsis incidence, HR=1.35, 95% CI: 1.27-1.43, 28-day mortality following sepsis, HR=1.49, 95% CI: 1.29-1.72; FEV1% predicted: sepsis incidence, HR=1.42, 95% CI: 1.34-1.52, 28-day mortality following sepsis, HR=1.75, 95% CI: 1.51-2.02; all Ptrend<0.001). Similarly, compared with individuals with normal lung function, those with impaired lung function had a higher risk of sepsis and sepsis-related mortality (sepsis incidence: HR=1.33, 95% CI: 1.27-1.39; 28-day mortality following sepsis: HR=1.57, 95% CI: 1.42-1.73; both P-values<0.001). These associations remained consistent across stratified and sensitivity analyses. Mediation analyses revealed that inflammatory biomarkers, such as C-reactive protein (CRP), accounted for 1.2%-16.3% of the associations. Collectively, these findings demonstrate that lung function impairment is associated with an increased risk of sepsis and sepsis-related mortality, and these associations are partially mediated through inflammatory responses.