Characterization of patients with severe bacterial infections and sepsis in large population cohorts. Studies of risk factors, genetics and biomarkers
Doctoral thesis
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https://hdl.handle.net/11250/3173399Utgivelsesdato
2025Metadata
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Sammendrag
Severe bacterial infections leading to sepsis is one of the leading causes of hospitalization and death worldwide. While improved health care has led to reduced mortality, it has also led to a marked increase in the number of sepsis-survivors which has enormous consequences both on quality of life and cost to the society. The World Health Organization (WHO) has called for initiatives aimed at increasing our knowledge to contribute to reduce this burden.
Research on severe bacterial infections leading to sepsis has traditionally been focusing on the different causative microbes, however, increasing focus is now on the host, including assessment of different risk factors. Identifying and understanding these is mandatory when deciding which measures to implement and which resources to prioritize.
Epidemiology and identification of these risk factors requires the ability to make retrospective diagnosis of sepsis in large populations cohorts or in electronic health records. This heavily relies on the quality and our understanding of and access to these sources of information. This is a particular challenge in sepsis, as the disease is heterogenous and has no specific diagnostic test.
The HUNT population (Trøndelag Health Study) is a unique population cohort with >70,000 participants and over 1 million person-years follow up. This project´s overall aim was to use this population cohort to get an overview of the different sources of bacterial infections leading to sepsis, and then further on use this knowledge and include other patient cohorts, to identify high-risk groups by searching for and identifying important risk-factors associated with different bacterial infections.
In this work we discuss the difficulties of identifying people with sepsis, both bedside, clinically and in retrospect. We then use this knowledge to present different aspects of sepsis epidemiology in four different papers. First, we describe the burden of severe bacterial infections by investigating incidence-, mortality-, and readmission rates and proportions of positive blood cultures in the different foci of infection (paper 1). Then we investigate and explore different possible important risk factors such as common genetic variants and 3 potentially modifiable lifestyle factors in skin- and soft tissue infections (SSTIs) (paper 2), the influence of chronic kidney disease on the risk for bloodstream infections (BSI) and sepsis (paper 3), and finally, the potential role for uromodulin as a biomarker for risk of urinary tract infections (UTIs) (paper 4). The different epidemiological methods used, including descriptive epidemiology, classical epidemiology and genetic epidemiology using the fact that the participants in the HUNT population and other cohorts are genotyped, are also discussed.
In summary we identify important risk factors for bacterial infections and sepsis using various epidemiological methods. This could play a part on the ongoing work of dividing this heterogenous disease into different subclasses and can improve the chances of future clinical research being of use to the increasing number of sepsis patients.
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Paper 1: Liyanarachi, Kristin Vardheim; Solligård, Erik; Mohus, Randi Marie; Åsvold, Bjørn Olav; Rogne, Tormod; Damås, Jan Kristian. Incidence, recurring admissions and mortality of severe bacterial infections and sepsis over a 22-year period in the population-based HUNT study. PLOS ONE 2022 ;Volum 17.(7) s. 1-13. Published by Public Library of Science. This is an open access article distributed under the terms of the Creative Commons Attribution License CC BY. Available at: http://dx.doi.org/10.1371/journal.pone.0271263Paper 2: Rogne, Tormod; Liyanarachi, Kristin Vardheim; Rasheed, Humaira; Thomas, Laurent; Flatby, Helene Marie; Stenvik, Jørgen; Løset, Mari; Gill, Dipender; Burgess, Stephen; Willer, Cristen J; Hveem, Kristian; Åsvold, Bjørn Olav; Brumpton, Ben Michael; DeWan, Andrew; Solligård, Erik; Damås, Jan Kristian. GWAS Identifies LINC01184/SLC12A2 as a Risk Locus for Skin and Soft Tissue Infections. Journal of Investigative Dermatology 2021 ;Volum 141.(8) s. 2083-2086.e8 Published by Elsevier. This is an open access article under the CC BY license. Available at: http://dx.doi.org/10.1016/j.jid.2021.01.020
Paper 3: Liyanarachi, Kristin Vardheim; Mohus, Randi Marie; Rogne, Tormod; Gustad, Lise Tuset; Åsvold, Bjørn Olav; Romundstad, Solfrid; Solligård, Erik; Hallan, Stein Ivar; Damås, Jan Kristian. Chronic kidney disease and risk of bloodstream infections and sepsis: a 17-year follow-up of the population-based Trøndelag Health Study in Norway. Infection 2024 ;Volum 52. s. 1983-1993. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License CC BY. Available at: http://dx.doi.org/10.1007/s15010-024-02265-2
Paper 4: Liyanarachi, Kristin Vardheim; Flatby, Helene Marie; Hallan, Stein Ivar; Åsvold, Bjørn Olav; Damås, Jan Kristian; Rogne, Tormod. Uromodulin and risk of upper urinary tract infections: A Mendelian randomization study. Submitted paper. Preprint available at: https://doi.org/10.1101/2024.06.18.24309082