Inflammatory sub-phenotypes in sepsis: relationship to outcomes, treatment effect and transcriptomic sub-phenotypes-猫眼课题宝

DOI：

10.1101/2022.07.12.22277463

发表时间：

2022-07

期刊：

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

D. Antcliffe;Yuxin Mi;S. Santhakumaran;K. Burnham;Toby Prevost;Josie K Ward;Timothy Marshall;Claire Bradley;F. Al-Beidh;Paula;Hutton;S. McKechnie;E. Davenport;Charles Hinds;D. F. Mcauley;Manu Shankar-Hari;Anthony C Gordon;Julian Knight

原理：脓毒症的异质性限制了治疗的发现和靶向。危重病的聚类方法已经确定了可能对治疗反应不同的患者群体。这些包括在急性呼吸窘迫综合征（ARDS）中使用潜在类别分析（LCA）的两种炎性亚表型，以及在脓毒症中基于转录组分析的两种脓毒症应答特征（SRS）。目前尚不清楚炎症亚表型（如在ARDS中鉴定的亚表型）是否存在于脓毒症中，以及不同技术定义的亚表型如何比较。目的：使用LCA鉴定脓毒症的炎症亚表型，并评估这些亚表型是否显示不同的治疗反应。将这些亚表型与基于炎症介质的分层聚类和SRS亚表型进行比较。方法：LCA应用于两项感染性休克随机试验的临床和生物标志物数据。VANISH比较了去甲肾上腺素与加压素，氢化可的松与安慰剂，LeoPARDS比较了左西孟旦与安慰剂。对来自GAinS（n = 124）、VANISH（n = 155）和LeoPARDS（n = 484）研究的患者中测量的65、21和11种炎症介质进行分层聚类分析（HCA）。测量和主要结果：LCA和HCA确定了具有高细胞因子水平和更差的器官功能障碍和生存的患者的亚表型，LCA类别和试验治疗反应之间没有相互作用。炎症和转录组亚表型的比较揭示了一些相似性，但没有足够的重叠，它们是可互换的。结论：具有高水平炎症和疾病严重程度增加的亚表型在脓毒症中是一致可识别的，与ARDS中描述的相似。转录组亚表型的重叠有限。

Rationale: Heterogeneity of sepsis limits discovery and targeting of treatments. Clustering approaches in critical illness have identified patient groups who may respond differently to therapies. These include in acute respiratory distress syndrome (ARDS) two inflammatory sub-phenotypes, using latent class analysis (LCA), and in sepsis two Sepsis Response Signatures (SRS), based on transcriptome profiling. It is unknown if inflammatory sub-phenotypes such as those identified in ARDS are present in sepsis and how sub-phenotypes defined with different techniques compare. Objectives: To identify inflammatory sub-phenotypes in sepsis using LCA and assess if these show differential treatment responses. These sub-phenotypes were compared to hierarchical clusters based on inflammatory mediators and to SRS sub-phenotypes. Methods: LCA was applied to clinical and biomarker data from two septic shock randomized trials. VANISH compared norepinephrine to vasopressin and hydrocortisone to placebo and LeoPARDS compared levosimendan to placebo. Hierarchical cluster analysis (HCA) was applied to 65, 21 and 11 inflammatory mediators measured in patients from the GAinS (n=124), VANISH (n=155) and LeoPARDS (n=484) studies. Measurements and Main Results: LCA and HCA identified a sub-phenotype of patients with high cytokine levels and worse organ dysfunction and survival, with no interaction between LCA classes and trial treatment responses. Comparison of inflammatory and transcriptomic sub-phenotypes revealed some similarities but without sufficient overlap that they are interchangeable. Conclusions: A sub-phenotype with high levels of inflammation and increased disease severity is consistently identifiable in sepsis, with similarities to that described in ARDS. There was limited overlap with the transcriptomic sub-phenotypes.

Inflammatory sub-phenotypes in sepsis: relationship to outcomes, treatment effect and transcriptomic sub-phenotypes

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