Previous studies indicate sex differences in incidence and severity of bloodstream infections (BSI). We examined the effect of sex on risk of BSI, BSI mortality, and BSI caused by the most common infecting bacteria. Using causal mediation analyses, we assessed if this effect is mediated by health behaviours (smoking, alcohol consumption), education, cardiovascular risk factors (systolic blood pressure, non-HDL cholesterol, body mass index) and selected comorbidities. This prospective study included 64,040 participants (46.8% men) in the population-based HUNT2 Survey (1995–1997) linked with hospital records in incident BSI. During median follow-up of 15.2 years, 1840 (2.9%) participants (51.3% men) experienced a BSI and 396 (0.6%) died (56.6% men). Men had 41% higher risk of first-time BSI (95% confidence interval (CI), 28–54%) than women. Together, health behaviours, education, cardiovascular risk factors and comorbidities mediated 34% of the excess risk of BSI observed in men. The HR of BSI mortality was 1.87 (95% CI 1.53–2.28), for BSI due to S. aureus 2.09 (1.28–2.54), S. pneumoniae 1.36 (1.05–1.76), E. coli 0.97 (0.84–1.13) in men vs women. This study shows that men have higher risk of BSI and BSI mortality than women. One-third of this effect was mediated by potential modifiable risk factors for incident BSI.

Observational studies have indicated an association between iron status and risk of sepsis and COVID-19. We estimated the effect of genetically-predicted iron biomarkers on risk of sepsis and risk of being hospitalized with COVID-19, performing a two-sample Mendelian randomization study. For risk of sepsis, one standard deviation increase in genetically-predicted serum iron was associated with odds ratio (OR) of 1.14 (95% confidence interval [CI] 1.01–1.29, P = 0.031). The findings were supported in the analyses for transferrin saturation and total iron binding capacity, while the estimate for ferritin was inconclusive. We found a tendency of higher risk of hospitalization with COVID-19 for serum iron; OR 1.29 (CI 0.97–1.72, P = 0.08), whereas sex-stratified analyses showed OR 1.63 (CI 0.94–2.86, P = 0.09) for women and OR 1.21 (CI 0.92–1.62, P = 0.17) for men. Sensitivity analyses supported the main findings and did not suggest bias due to pleiotropy. Our findings suggest a causal effect of genetically-predicted higher iron status and risk of hospitalization due to sepsis and indications of an increased risk of being hospitalized with COVID-19. These findings warrant further studies to assess iron status in relation to severe infections, including the potential of improved management.

Importance: Sepsis is one of the leading causes of morbidity and mortality. The majority of sepsis cases is attributed to bacterial infections, but virus infections can also induce sepsis. Conflicting results in incidence rates and case fatality trends of sepsis is reported, and how the COVID-19 pandemic influenced these trends are unknown. Objective: To estimate temporal trends in incidence rate and case fatality during a 14-year period from 2008 through 2021, and to assess possible shifts in these trends during the COVID-19 pandemic. Design: A nationwide longitudinal registry study using ICD-10 discharge codes to identify sepsis. Setting: All Norwegian hospitals from 2008 through 2021. Participants: All sepsis cases included 317.705 patients and of these, 222.832 had a first sepsis episode. Main outcomes and measures: Annual age-standardized incidence rates with 95% confidence intervals (CI). Poisson regression was used to estimate changes in incidence rates across time, and logistic regression was used to estimate odds ratios for in-hospital death. Results: Among 12.619.803 adult hospitalizations, 317.705 (2.5%) patients met the sepsis criteria and 222.832 (70.0%) had a first sepsis episode. In the period 2009-2019, the annual incidence rate for a first sepsis episode was stable (incidence rate ratio per year, 0.999; 95% CI, 0.994-1.004), whereas for all sepsis the incidence rate increased by 15.5% during the period (annual incidence rate ratio, 1.013; 95% CI 1.007-1.019). During the COVID-19 pandemic, the incidence rate ratio for a first sepsis was 0.877 (95% CI, 0.829-0.927) in 2020 and 0.929 (95% CI, 0.870-0.992) in 2021, and for all sepsis it was 0.870 (95% CI, 0.810-0.935) in 2020 and 0.908 (95% CI, 0.840-0.980) in 2021, compared to the previous 11-year period. In-hospital deaths declined in the period 2009-2019 (odds ratio per year, 0.954 [95% CI,0.950-0.958]), whereas deaths increased during the COVID-19 pandemic in 2020 (odds ratios, 1.061 [95% CI 1.001-1.124] and in 2021 odds ratio (1.164 [95% CI, 1.098-1.233]). Conclusion and relevance: We found a stable incidence rate of a first sepsis episode during the years 2009-2019. However, the increasing burden of all sepsis admissions indicates that sepsis awareness with updated guidelines and education must continue.