ABSTRACT
ImportanceSepsis 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. ObjectiveTo 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. DesignA nationwide longitudinal registry study using ICD-10 discharge codes to identify sepsis. SettingAll Norwegian hospitals from 2008 through 2021. ParticipantsAll sepsis cases included 317.705 patients and of these, 222.832 had a first sepsis episode. Main outcomes and measuresAnnual 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. ResultsAmong 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 relevanceWe 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. Key PointsO_ST_ABSQuestionC_ST_ABSHas there been a change in incidence rate and case fatality of sepsis over the past decade, and how did the COVID-19 pandemic influence sepsis incidence rates and in-hospital mortality? FindingsIn this nationwide longitudinal registry study the incidence rate of all sepsis episodes increased and the incidence rate of a first sepsis episode was stable during the period 2009-2019, whereas in 2020 and 2021, the incidence rate of a first and all sepsis episodes was lower than in the preceding 11-year period. Case fatality risk declined from 2009 to 2019, but increased somewhat in 2020 and 2021, when 9.7% of first sepsis cases were identified as COVID-19 related sepsis. MeaningDespite a stable incidence rate of first-time sepsis admissions over time, the burden of sepsis is rising due to an increased rate of patients admitted multiple times with sepsis. The COVID-19 pandemic have had an impact on sepsis incidence rate and hospital mortality and needs further evaluation.
ABSTRACT
IntroductionObservational studies have indicated an association between iron status and risk of sepsis and severe COVID-19. However, these findings may be affected by residual confounding, reverse causation. MethodsIn a two-sample Mendelian randomization study using inverse variance weighted method, we estimated the effect of genetically-predicted iron biomarkers (serum iron, transferrin saturation (TSAT), total iron binding capacity (TIBC) and ferritin) on risk of sepsis and risk of being hospitalized with COVID-19. For the COVID-19 outcomes we additionally conducted sex-stratified analyses. Weighted median, Weighted mode and MR Egger were used as sensitivity analyses. ResultsFor 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 to 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), where 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. ConclusionsOur 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.
ABSTRACT
Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic [~]0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.
