Rationale Heterogeneity of the host response within sepsis, acute respiratory distress syndrome (ARDS) and more widely critical illness, limits discovery and targeting of immunomodulatory therapies. Clustering approaches using clinical and circulating biomarkers have defined hyper-inflammatory and hypo-inflammatory subphenotypes in ARDS associated with differential treatment response. It is unknown if similar subphenotypes exist in sepsis populations where leucocyte transcriptomic-defined subphenotypes have been reported. Objectives We investigated whether inflammatory clusters based on cytokine protein abundance were seen in sepsis, and the relationships with previously described transcriptomic subphenotypes. Methods Hierarchical cluster and latent class analysis were applied to an observational study (UK Genomic Advances in Sepsis (GAinS)) (n=124 patients) and two clinical trial datasets (VANISH, n=155 and LeoPARDS, n=484) in which the plasma protein abundance of 65, 21, 11 circulating cytokines, cytokine receptors and regulators were quantified. Clinical features, outcomes, response to trial treatments and assignment to transcriptomic subphenotypes were compared between inflammatory clusters. Measurements and main results We identified two (UK GAinS, VANISH) or three (LeoPARDS) inflammatory clusters. A group with high levels of pro-inflammatory and anti-inflammatory cytokines was seen that was associated with worse organ dysfunction and survival. No interaction between inflammatory clusters and trial treatment response was found. We found variable overlap of inflammatory clusters and leucocyte transcriptomic subphenotypes. Conclusions These findings demonstrate that differences in response at the level of cytokine biology show clustering related to severity, but not treatment response, and may provide complementary information to transcriptomic sepsis subphenotypes. Trial registration number [ISRCTN20769191][1], [ISRCTN12776039][2]. Data are available in a public, open access repository. Data are available on reasonable request. The gene expression data are available on ArrayExpress (, accession: E-MTAB-4421/E-MTAB-4451/E-MTAB-5273/E-MTAB-5274/E-MTAB-7581). There are no conditions of reuse. Individual participant data that underlie the results in this article, after de-identification (text, table and figures) and biomarker data will be made available from the corresponding author on submission of a data request application. [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN20769191 [2]: /external-ref?link_type=ISRCTN&access_num=ISRCTN12776039

中文翻译：

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使用血浆细胞因子及其调节剂对脓毒症患者进行分层：与结果、治疗效果和白细胞转录组亚表型的关系

脓毒症、急性呼吸窘迫综合征 (ARDS) 和更广泛的危重疾病中宿主反应的异质性限制了免疫调节疗法的发现和靶向。使用临床和循环生物标志物的聚类方法定义了与差异治疗反应相关的 ARDS 的高炎症和低炎症亚表型。目前尚不清楚脓毒症人群中是否存在类似的亚表型，其中已报道了白细胞转录组定义的亚表型。目的 我们研究了脓毒症中是否存在基于细胞因子蛋白丰度的炎症簇，以及与先前描述的转录组亚表型的关系。方法 将分层聚类和潜在类别分析应用于一项观察性研究（英国脓毒症基因组进展 (GAinS)）（n=124 名患者）和两个临床试验数据集（VANISH，n=155 和 LeoPARDS，n=484），其中对 65、21、11 种循环细胞因子、细胞因子受体和调节剂的血浆蛋白丰度进行了定量。比较炎症簇之间的临床特征、结果、对试验治疗的反应以及转录组亚表型的分配。测量和主要结果 我们确定了两个（UK GAinS、VANISH）或三个（LeoPARDS）炎症簇。研究发现，促炎和抗炎细胞因子水平较高的一组与更差的器官功能障碍和生存相关。没有发现炎症簇和试验治疗反应之间存在相互作用。我们发现炎症簇和白细胞转录组亚表型存在可变重叠。结论 这些发现表明，细胞因子生物学水平上的反应差异显示出与严重程度相关的聚类，但与治疗反应无​​关，并且可能为转录组脓毒症亚表型提供补充信息。试验注册号 [ISRCTN20769191][1]、[ISRCTN12776039][2]。数据可在公共、开放访问存储库中获取。可根据合理要求提供数据。基因表达数据可在 ArrayExpress 上获取（，登记号：E-MTAB-4421/E-MTAB-4451/E-MTAB-5273/E-MTAB-5274/E-MTAB-7581）。没有再利用的条件。在去识别化（文本、表格和图形）后，构成本文结果基础的个人参与者数据和生物标志物数据将在提交数据请求申请时从相应作者处获得。[1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN20769191 [2]: /external-ref?link_type=ISRCTN&access_num=ISRCTN12776039