• Erik H A Michels, Joe M Butler, Tom D Y Reijnders, Olaf L Cremer, Brendon P Scicluna, Fabrice Uhel, Hessel Peters-Sengers, Marcus J Schultz, Julian C Knight, Lonneke A van Vught, Tom van der Poll, and MARS consortium.
• Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands. e.h.michels@amsterdamumc.nl.
• Crit Care. 2022 Dec 13; 26 (1): 385385.

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.© 2022. The Author(s).

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