Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.
Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
Crit Care. 2022 Dec 13;26(1):385. doi: 10.1186/s13054-022-04266-9.
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.
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.
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.
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.
衰老与脓毒症死亡率增加之间的关联已得到充分证实。尽管如此，目前关于年龄对宿主反应异常影响的研究主要局限于血浆细胞因子水平，而忽略了其他病理生理学脓毒症领域，如内皮细胞激活和功能以及凝血激活。本研究的主要目的是深入了解衰老与脓毒症关键宿主反应途径和血液转录组学异常之间的关联。
我们分析了根据年龄十年分层的脓毒症患者的临床结局（n=1952）、提供特定病理生理学领域失调见解的 16 种血浆生物标志物（n=899）和血液白细胞转录组（n=488）。血液转录组结果在独立的脓毒症队列中进行了验证，并与健康个体进行了比较。
年龄较大与死亡率增加相关，与合并症和疾病严重程度无关。尽管疾病严重程度评分较高，但与炎症和凝血激活相似，衰老与较低的内皮细胞激活和功能障碍相关。与<50 岁的患者相比，≥70 岁的患者的血液白细胞显示参与细胞因子信号转导、固有和适应性免疫的基因表达降低，参与止血和内皮细胞激活的基因表达增加。≥70 岁的受试者中与固有免疫和细胞因子信号转导相关的基因途径的表达减少是脓毒症诱导的，因为与<50 岁的健康个体相比，≥70 岁的健康受试者中这些途径的表达增强。
本研究提供了新的证据，表明年龄较大与相对减轻的脓毒症诱导的内皮细胞激活和功能障碍以及血液白细胞转录组特征有关，表明固有免疫和细胞因子信号转导受损。这些数据表明，在未来针对免疫系统和/或内皮细胞反应的脓毒症试验中，应考虑年龄因素。
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