Association between age and the host response in critically ill patients with sepsis
Abstract Background The 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 endo...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-12-01
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| Series: | Critical Care |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13054-022-04266-9 |
| _version_ | 1811292053580021760 |
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| author | 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 MARS consortium |
| author_facet | 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 MARS consortium |
| author_sort | Erik H. A. Michels |
| collection | DOAJ |
| description | Abstract Background The 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. Methods We 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. Results Older 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. Conclusions This 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 |
| first_indexed | 2024-04-13T04:39:40Z |
| format | Article |
| id | doaj.art-78bc222ac0f646a5975cbe847cad3a1c |
| institution | Directory Open Access Journal |
| issn | 1364-8535 |
| language | English |
| last_indexed | 2024-04-13T04:39:40Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Critical Care |
| spelling | doaj.art-78bc222ac0f646a5975cbe847cad3a1c2022-12-22T03:02:02ZengBMCCritical Care1364-85352022-12-0126111610.1186/s13054-022-04266-9Association between age and the host response in critically ill patients with sepsisErik H. A. Michels0Joe M. Butler1Tom D. Y. Reijnders2Olaf L. Cremer3Brendon P. Scicluna4Fabrice Uhel5Hessel Peters-Sengers6Marcus J. Schultz7Julian C. Knight8Lonneke A. van Vught9Tom van der Poll10MARS consortiumCenter of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of AmsterdamCenter of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of AmsterdamCenter of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of AmsterdamDepartment of Intensive Care Medicine, University Medical Center UtrechtCenter of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of AmsterdamCenter of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of AmsterdamCenter of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of AmsterdamDepartment of Intensive Care, Amsterdam University Medical Centers, University of AmsterdamNuffield Department of Medicine, University of OxfordCenter of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of AmsterdamCenter of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of AmsterdamAbstract Background The 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. Methods We 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. Results Older 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. Conclusions This 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 abstracthttps://doi.org/10.1186/s13054-022-04266-9AgeingSepsisImmune systemBiomarkersCoagulationEndothelium |
| spellingShingle | 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 MARS consortium Association between age and the host response in critically ill patients with sepsis Critical Care Ageing Sepsis Immune system Biomarkers Coagulation Endothelium |
| title | Association between age and the host response in critically ill patients with sepsis |
| title_full | Association between age and the host response in critically ill patients with sepsis |
| title_fullStr | Association between age and the host response in critically ill patients with sepsis |
| title_full_unstemmed | Association between age and the host response in critically ill patients with sepsis |
| title_short | Association between age and the host response in critically ill patients with sepsis |
| title_sort | association between age and the host response in critically ill patients with sepsis |
| topic | Ageing Sepsis Immune system Biomarkers Coagulation Endothelium |
| url | https://doi.org/10.1186/s13054-022-04266-9 |
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