Browsing by Author "Butler J.M."

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    Association between age and the host response in critically ill patients with sepsis
    (2022-12-01) 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.; de Beer F.M.; Bos L.D.J.; Glas G.J.; Hoogendijk A.J.; van Hooijdonk R.T.M.; Horn J.; Huson M.A.; Schouten L.R.A.; Straat M.; Wieske L.; Wiewel M.A.; Witteveen E.; Bonten M.J.M.; Cremer O.M.; Ong D.S.Y.; Frencken J.F.; Klouwenberg P.M.C.K.; Koster‐Brouwer M.E.; van de Groep K.; Verboom D.M.; Mahidol University
    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.]
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    The Plasma Lipidomic Landscape in Patients with Sepsis due to Community-acquired Pneumonia
    (2024-04-15) Chouchane O.; Schuurman A.R.; Reijnders T.D.Y.; Peters-Sengers H.; Butler J.M.; Uhel F.; Schultz M.J.; Bonten M.J.; Cremer O.L.; Calfee C.S.; Matthay M.A.; Langley R.J.; Alipanah-Lechner N.; Kingsmore S.F.; Rogers A.; van Weeghel M.; Vaz F.M.; van der Poll T.; Chouchane O.; Mahidol University
    Rationale: The plasma lipidome has the potential to reflect many facets of the host status during severe infection. Previous work is limited to specific lipid groups or was focused on lipids as prognosticators.Objectives: To map the plasma lipidome during sepsis due to community-acquired pneumonia (CAP) and determine the disease specificity and associations with clinical features.Methods: We analyzed 1,833 lipid species across 33 classes in 169 patients admitted to the ICU with sepsis due to CAP, 51 noninfected ICU patients, and 48 outpatient controls. In a paired analysis, we reanalyzed patients still in the ICU 4 days after admission (n = 82).Measurements and Main Results: A total of 58% of plasma lipids were significantly lower in patients with CAP-attributable sepsis compared with outpatient controls (6% higher, 36% not different). We found strong lipid class-specific associations with disease severity, validated across two external cohorts, and inflammatory biomarkers, in which triacylglycerols, cholesterol esters, and lysophospholipids exhibited the strongest associations. A total of 36% of lipids increased over time, and stratification by survival revealed diverging lipid recovery, which was confirmed in an external cohort; specifically, a 10% increase in cholesterol ester levels was related to a lower odds ratio (0.84; P = 0.006) for 30-day mortality (absolute mortality, 18 of 82). Comparison with noninfected ICU patients delineated a substantial common illness response (57.5%) and a distinct lipidomic signal for patients with CAP-attributable sepsis (37%).Conclusions: Patients with sepsis due to CAP exhibit a time-dependent and partially disease-specific shift in their plasma lipidome that correlates with disease severity and systemic inflammation and is associated with higher mortality.