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Association between age and the host response in critically ill patients with sepsis. / Michels, Erik H. A.; Butler, Joe M.; Reijnders, Tom D. Y. et al.

In: Critical Care, Vol. 26, No. 1, 385, 01.12.2022.

Research output: Contribution to journal › Article › Academic › peer-review

Harvard

Michels, EHA, Butler, JM, Reijnders, TDY, Cremer, OL, Scicluna, BP, Uhel, F, Peters-Sengers, H, Schultz, MJ, Knight, JC, van Vught, LA, van der Poll, T, MARS consortium, de Beer, FM, Bos, LDJ, Glas, GJ, Hoogendijk, AJ, van Hooijdonk, RTM, Horn, J, Huson, MA, Schouten, LRA, Straat, M, Wieske, L, Wiewel, MA, Witteveen, E, Bonten, MJM, Cremer, OM, Ong, DSY, Frencken, JF, Klouwenberg, PMCK, Koster‐Brouwer, ME, van de Groep, K & Verboom, DM 2022, 'Association between age and the host response in critically ill patients with sepsis', Critical Care, vol. 26, no. 1, 385. https://doi.org/10.1186/s13054-022-04266-9

APA

Michels, E. H. A., Butler, J. M., Reijnders, T. D. Y., Cremer, O. L., Scicluna, B. P., Uhel, F., Peters-Sengers, H., Schultz, M. J., Knight, J. C., van Vught, L. A., van der Poll, T., MARS consortium, de Beer, F. M., Bos, L. D. J., Glas, G. J., Hoogendijk, A. J., van Hooijdonk, R. T. M., Horn, J., Huson, M. A., ... Verboom, D. M. (2022). Association between age and the host response in critically ill patients with sepsis. Critical Care, 26(1), [385]. https://doi.org/10.1186/s13054-022-04266-9

Vancouver

Michels EHA, Butler JM, Reijnders TDY, Cremer OL, Scicluna BP, Uhel F et al. Association between age and the host response in critically ill patients with sepsis. Critical Care. 2022 Dec 1;26(1):385. doi: 10.1186/s13054-022-04266-9

Author

Michels, Erik H. A. ; Butler, Joe M. ; Reijnders, Tom D. Y. et al. / Association between age and the host response in critically ill patients with sepsis. In: Critical Care. 2022 ; Vol. 26, No. 1.

BibTeX

@article{d7aca8b2205f46b196f26c898ea4486e,
title = "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 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: [Figure not available: see fulltext.]",
keywords = "Ageing, Biomarkers, Coagulation, Cytokines, Endothelium, Immune system, Inflammation, Sepsis, Transcriptome",
author = "Michels, {Erik H. A.} and Butler, {Joe M.} and Reijnders, {Tom D. Y.} and Cremer, {Olaf L.} and Scicluna, {Brendon P.} and Fabrice Uhel and Hessel Peters-Sengers and Schultz, {Marcus J.} and Knight, {Julian C.} and {van Vught}, {Lonneke A.} and {van der Poll}, Tom and {MARS consortium} and {de Beer}, {Friso M.} and Bos, {Lieuwe D. J.} and Glas, {Gerie J.} and Hoogendijk, {Arie J.} and {van Hooijdonk}, {Roosmarijn T. M.} and Janneke Horn and Huson, {Mischa A.} and Schouten, {Laura R. A.} and Marleen Straat and Luuk Wieske and Wiewel, {Maryse A.} and Esther Witteveen and Bonten, {Marc J. M.} and Cremer, {Olaf M.} and Ong, {David S. Y.} and Frencken, {Jos F.} and Klouwenberg, {Peter M. C. Klein} and Koster‐Brouwer, {Maria E.} and {van de Groep}, Kirsten and Verboom, {Diana M.}",
note = "Funding Information: The MARS project was supported by the Center for Translational Molecular Medicine ( http://www.ctmm.nl ), project MARS (Grant 04I‐201). E.H.A.M. received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation programme under Grant agreement No 847786 (FAIR). H.P.S. was supported by the Dutch Kidney Foundation (Kolff Grant Nr. 19OK009). J.M.B. was supported by the European Commission (Horizon 2020, ImmunoSep, Grant number 847422). L.A.v.V. was supported by a VENI Grant from ZonMW (Grant number 09150161910033). J.C.K was supported by a Wellcome Trust Investigator Award (204969/Z/16/Z), NIHR Oxford Biomedical Research Centre and Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS), China (2018-I2M-2-002). The funders had no role in the design and conduct of the study: collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
day = "1",
doi = "10.1186/s13054-022-04266-9",
language = "English",
volume = "26",
journal = "Critical care (London, England)",
issn = "1364-8535",
publisher = "Springer Science + Business Media",
number = "1",

}

RIS

TY - JOUR

T1 - Association between age and the host response in critically ill patients with sepsis

AU - Michels, Erik H. A.

AU - Butler, Joe M.

AU - Reijnders, Tom D. Y.

AU - Cremer, Olaf L.

AU - Scicluna, Brendon P.

AU - Uhel, Fabrice

AU - Peters-Sengers, Hessel

AU - Schultz, Marcus J.

AU - Knight, Julian C.

AU - van Vught, Lonneke A.

AU - van der Poll, Tom

AU - MARS consortium

AU - de Beer, Friso M.

AU - Bos, Lieuwe D. J.

AU - Glas, Gerie J.

AU - Hoogendijk, Arie J.

AU - van Hooijdonk, Roosmarijn T. M.

AU - Horn, Janneke

AU - Huson, Mischa A.

AU - Schouten, Laura R. A.

AU - Straat, Marleen

AU - Wieske, Luuk

AU - Wiewel, Maryse A.

AU - Witteveen, Esther

AU - Bonten, Marc J. M.

AU - Cremer, Olaf M.

AU - Ong, David S. Y.

AU - Frencken, Jos F.

AU - Klouwenberg, Peter M. C. Klein

AU - Koster‐Brouwer, Maria E.

AU - van de Groep, Kirsten

AU - Verboom, Diana M.

N1 - Funding Information: The MARS project was supported by the Center for Translational Molecular Medicine ( http://www.ctmm.nl ), project MARS (Grant 04I‐201). E.H.A.M. received funding from the European Union’s Horizon 2020 research and innovation programme under Grant agreement No 847786 (FAIR). H.P.S. was supported by the Dutch Kidney Foundation (Kolff Grant Nr. 19OK009). J.M.B. was supported by the European Commission (Horizon 2020, ImmunoSep, Grant number 847422). L.A.v.V. was supported by a VENI Grant from ZonMW (Grant number 09150161910033). J.C.K was supported by a Wellcome Trust Investigator Award (204969/Z/16/Z), NIHR Oxford Biomedical Research Centre and Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS), China (2018-I2M-2-002). The funders had no role in the design and conduct of the study: collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12/1

Y1 - 2022/12/1

N2 - 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: [Figure not available: see fulltext.]

AB - 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: [Figure not available: see fulltext.]

KW - Ageing

KW - Biomarkers

KW - Coagulation

KW - Cytokines

KW - Endothelium

KW - Immune system

KW - Inflammation

KW - Sepsis

KW - Transcriptome

UR - http://www.scopus.com/inward/record.url?scp=85143899605&partnerID=8YFLogxK

U2 - 10.1186/s13054-022-04266-9

DO - 10.1186/s13054-022-04266-9

M3 - Article

C2 - 36514130

VL - 26

JO - Critical care (London, England)

JF - Critical care (London, England)

SN - 1364-8535

IS - 1

M1 - 385

ER -

ID: 29714334