Division of Clinical and Translational Research, Division of Critical Care, Department of Anesthesia, Washington University School of Medicine, St. Louis, Missouri.
Division of Pulmonary, Critical Care, Allergy and Sleep Medicine.
Am J Respir Crit Care Med. 2024 Apr 1;209(7):816-828. doi: 10.1164/rccm.202308-1490OC.
Two molecular phenotypes have been identified in acute respiratory distress syndrome (ARDS). In the ROSE (Reevaluation of Systemic Early Neuromuscular Blockade) trial of cisatracurium in moderate to severe ARDS, we addressed three unanswered questions: ) Do the same phenotypes emerge in a more severe ARDS cohort with earlier recruitment; ) Do phenotypes respond differently to neuromuscular blockade? and ) What biological pathways most differentiate inflammatory phenotypes? We performed latent class analysis in ROSE using preenrollment clinical and protein biomarkers. In a subset of patients ( = 134), we sequenced whole-blood RNA using enrollment and Day 2 samples and performed differential gene expression and pathway analyses. Informed by the differential gene expression analysis, we measured additional plasma proteins and evaluated their abundance relative to gene expression amounts. In ROSE, we identified the hypoinflammatory (60.4%) and hyperinflammatory (39.6%) phenotypes with similar biological and clinical characteristics as prior studies, including higher mortality at Day 90 for the hyperinflammatory phenotype (30.3% vs. 61.6%; < 0.0001). We observed no treatment interaction between the phenotypes and randomized groups for mortality. The hyperinflammatory phenotype was enriched for genes associated with innate immune response, tissue remodeling, and zinc metabolism at Day 0 and collagen synthesis and neutrophil degranulation at Day 2. Longitudinal changes in gene expression patterns differed dependent on survivorship. For most highly expressed genes, we observed correlations with their corresponding plasma proteins' abundance. However, for the class-defining plasma proteins in the latent class analysis, no correlation was observed with their corresponding genes' expression. The hyperinflammatory and hypoinflammatory phenotypes have different clinical, protein, and dynamic transcriptional characteristics. These findings support the clinical and biological potential of molecular phenotypes to advance precision care in ARDS.
两种分子表型已在急性呼吸窘迫综合征（ARDS）中被确定。在罗塞（重新评估全身早期神经肌肉阻滞在中重度 ARDS 中的作用）试验中，我们解决了三个未回答的问题：）在招募更早的更严重 ARDS 队列中是否会出现相同的表型；）表型对神经肌肉阻滞的反应是否不同；）哪些生物学途径最能区分炎症表型？我们在 ROSE 中使用预登记的临床和蛋白质生物标志物进行潜在类别分析。在一部分患者中（ = 134），我们使用入组和第 2 天的样本对全血 RNA 进行测序，并进行差异基因表达和途径分析。受差异基因表达分析的启发，我们测量了额外的血浆蛋白，并评估了它们与基因表达量的相对丰度。在 ROSE 中，我们确定了低炎症（60.4%）和高炎症（39.6%）表型，其生物学和临床特征与先前的研究相似，包括高炎症表型的第 90 天死亡率更高（30.3%比 61.6%； < 0.0001）。我们未观察到表型与随机分组之间在死亡率方面存在治疗相互作用。高炎症表型在第 0 天富集了与先天免疫反应、组织重塑和锌代谢相关的基因，在第 2 天富集了与胶原合成和中性粒细胞脱颗粒相关的基因。基因表达模式的纵向变化取决于生存情况。对于大多数高表达基因，我们观察到它们与相应血浆蛋白丰度之间存在相关性。然而，对于潜在类别分析中定义类别的血浆蛋白，没有观察到与它们相应基因表达之间的相关性。高炎症和低炎症表型具有不同的临床、蛋白质和动态转录特征。这些发现支持分子表型在 ARDS 中推进精准医疗的临床和生物学潜力。
