Association between age and the host response in critically ill patients with sepsis

Critical Care

Research

Erik H. A. Michels¹  Tom D. Y. Reijnders¹  Joe M. Butler¹  Fabrice Uhel¹  Hessel Peters-Sengers¹  Brendon P. Scicluna²  Lonneke A. van Vught³  Tom van der Poll⁴  Olaf L. Cremer⁵  Marcus J. Schultz⁶  Julian C. Knight⁷ 

[1] Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands;Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands;Department of Applied Biomedical Science, Faculty of Health Sciences, Mater Dei Hospital, University of Malta, Msida, Malta;Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta;Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands;Department of Intensive Care, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands;Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands;Division of Infectious Diseases, Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands;Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands;Department of Intensive Care, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands;Mahidol-Oxford Tropical Medicine Research Unit (MORU), Mahidol University, Bangkok, Thailand;Nuffield Department of Medicine, University of Oxford, Oxford, UK;Nuffield Department of Medicine, University of Oxford, Oxford, UK;Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK;

关键词: Ageing;    Sepsis;    Immune system;    Biomarkers;    Coagulation;    Endothelium;    Cytokines;    Inflammation;    Transcriptome;   

DOI  :  10.1186/s13054-022-04266-9

 received in 2022-10-04, accepted in 2022-12-05,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundThe association of ageing with increased sepsis mortality is well established. Nonetheless, current investigations on the influence of age on host response aberrations are largely limited to plasma cytokine levels while neglecting other pathophysiological sepsis domains like endothelial cell activation and function, and coagulation activation. The primary objective of this study was to gain insight into the association of ageing with aberrations in key host response pathways and blood transcriptomes in sepsis.MethodsWe analysed the clinical outcome (n = 1952), 16 plasma biomarkers providing insight in deregulation of specific pathophysiological domains (n = 899), and blood leukocyte transcriptomes (n = 488) of sepsis patients stratified according to age decades. Blood transcriptome results were validated in an independent sepsis cohort and compared with healthy individuals.ResultsOlder age was associated with increased mortality independent of comorbidities and disease severity. Ageing was associated with lower endothelial cell activation and dysfunction, and similar inflammation and coagulation activation, despite higher disease severity scores. Blood leukocytes of patients ≥ 70 years, compared to patients < 50 years, showed decreased expression of genes involved in cytokine signaling, and innate and adaptive immunity, and increased expression of genes involved in hemostasis and endothelial cell activation. The diminished expression of gene pathways related to innate immunity and cytokine signaling in subjects ≥ 70 years was sepsis-induced, as healthy subjects ≥ 70 years showed enhanced expression of these pathways compared to healthy individuals < 50 years.ConclusionsThis study provides novel evidence that older age is associated with relatively mitigated sepsis-induced endothelial cell activation and dysfunction, and a blood leukocyte transcriptome signature indicating impaired innate immune and cytokine signaling. These data suggest that age should be considered in patient selection in future sepsis trials targeting the immune system and/or the endothelial cell response.Graphical abstract

【 授权许可】

CC BY   
© The Author(s) 2022

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