Department of Surgery, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.
Critical Illness and Injury Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.
Crit Care Med. 2020 Mar;48(3):338-343. doi: 10.1097/CCM.0000000000004128.
Sepsis and trauma are common health problems and provide great challenges in critical care. Diverse patient responses to these conditions further complicate patient management and outcome prediction. Whole blood transcriptomics provides a unique opportunity to follow the molecular response in the critically ill. Prior results show robust and diverse genomic signal in the acute phase and others have found shared biological mechanisms across divergent disease etiologies. We hypothesize that selected transcriptomics responses, particularly immune mechanisms are shared across disease etiologies. We further hypothesize that these processes may identify homogenous patient subgroups with shared clinical course in critical illness deciphering disease heterogeneity. These processes may serve as universal markers for predicting a complicated clinical course and/or risk of a poor outcome.
We present a system level, data driven, genome-wide analysis of whole blood gene expression for a total of 382 patients suffering from either abdominal sepsis (49), pulmonary sepsis (107) or trauma (158) and compare these to gene expression in healthy controls (68).
We relied on available open genetic data from gene expression omnibus for patients diagnosed with abdominal sepsis, community-acquired pneumonia, or trauma which also included healthy control patients.
Our results confirm that immune processes are shared across disease etiologies in critical illnesses. We identify two consistent and distinct patient subgroups through deconvolution of serum transcriptomics: 1) increased neutrophils and naïve CD4 cell fractions and 2) suppressed neutrophil fraction. Furthermore, we found immune and inflammatory processes were downregulated in subgroup 2, a configuration previously shown to be more susceptible to multiple organ failure. Correspondingly, this subgroup had significantly higher mortality rates in all three etiologies of illness (0% vs 6.1%, p = 3.1 × 10 for trauma; 15.0% vs 25.4%, p = 4.4 × 10 for community-acquired pneumonia, and 7.1% vs 20.0%, p = 3.4 × 10 for abdominal sepsis).
We identify two consistent subgroups of critical illness based on serum transcriptomics and derived immune cell fractions, with significantly different survival rates. This may serve as a universal predictor of complicated clinical course or treatment response and, importantly, may identify opportunities for subgroup-specific immunomodulatory intervention.
脓毒症和创伤是常见的健康问题，给重症监护带来了巨大挑战。不同患者对这些疾病的反应进一步增加了患者管理和预后预测的难度。全血转录组学为研究危重患者的分子反应提供了独特的机会。先前的结果表明，在急性阶段存在强大而多样化的基因组信号，而其他研究则发现不同疾病病因之间存在共同的生物学机制。我们假设，选定的转录组学反应，特别是免疫机制，在不同病因中是共有的。我们进一步假设，这些过程可能会识别出具有相似临床病程的同质患者亚组，从而阐明疾病异质性。这些过程可以作为预测复杂临床病程和/或不良结局风险的通用标志物。
我们对 382 名患有腹部脓毒症（49 例）、肺部脓毒症（107 例）或创伤（158 例）的患者进行了全血基因表达的系统水平、数据驱动的基因组分析，并将这些结果与健康对照组（68 例）的基因表达进行了比较。
我们依赖于从基因表达综合数据库中获得的用于诊断腹部脓毒症、社区获得性肺炎或创伤的患者的公开遗传数据，这些数据也包括健康对照组患者。
我们的结果证实，免疫过程在危重病中是共有的。通过对血清转录组学进行分解，我们确定了两个一致且不同的患者亚组：1）增加的中性粒细胞和幼稚 CD4 细胞分数；2）抑制的中性粒细胞分数。此外，我们发现免疫和炎症过程在亚组 2 中被下调，该亚组以前被证明更容易发生多器官功能衰竭。相应地，在所有三种疾病病因中，该亚组的死亡率都显著更高（创伤组为 0% vs 6.1%，p=3.1×10；社区获得性肺炎组为 15.0% vs 25.4%，p=4.4×10；腹部脓毒症组为 7.1% vs 20.0%，p=3.4×10）。
我们根据血清转录组学和衍生的免疫细胞分数确定了两个一致的危重病亚组，它们的生存率有显著差异。这可能成为复杂临床病程或治疗反应的通用预测指标，并且重要的是，它可能为特定亚组的免疫调节干预提供机会。
