Biomarkers and subphenotypes predictive of clinical outcomes in patients with COVID-19 related acute respiratory distress syndrome

预测 COVID-19 相关急性呼吸窘迫综合征患者临床结果的生物标志物和亚表型

• 批准号: 10535955
• 负责人: Narges Alipanah-Lechner
• 金额: $ 8.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10535955
• 关键词: Acute Respiratory Distress Syndrome; Aspirate substance; Awareness; Biological; Biological Markers; Biology; Blood Coagulation Disorders; Blood specimen; COVID-19; COVID-19 pandemic; COVID-19 patient; COVID-19/ARDS; Cessation of life; Clinical; Clinical Data; Critical Illness; Data; Data Analytics; Diagnostic; Enrollment; Functional disorder; Future; Gene Expression; Goals; Healthcare Systems; Heterogeneity; Immune response; Inflammation; Inflammatory; Institution; Investigation; Knowledge; Lead; Liquid substance; Lung diseases; Measures; Mentorship; Metabolic acidosis; National Heart, Lung, and Blood Institute; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Plasma Proteins; Population; Precision therapeutics; Public Health; Randomized Controlled Trials; Research; Role; Shock; Simvastatin; Strategic vision; Syndrome; Testing; Therapeutic; Time; Tissue-Specific Gene Expression; Training; United States; Whole Blood; Work; base; cohort; coronavirus disease; druggable target; effective therapy; epithelial injury; experience; high risk; innovation; insight; interest; lung injury; mortality; novel; peripheral blood; precision medicine; predict clinical outcome; protein biomarkers; response; skills; targeted treatment; transcriptome sequencing; transcriptomics; treatment effect; treatment response

PROJECT SUMMARY/ABSTRACT Acute Respiratory Distress Syndrome (ARDS), caused by a variety of triggers including COVID-19, is a devastating critical illness without effective therapies. Despite numerous studies on COVID-19 related ARDS (CARDS), the best available treatments lead to only modest or inconsistent clinical improvements. This paucity of discoveries is likely in part due to heterogeneity of host response to COVID-19. The long-term goal is to bring precision therapies to patients with ARDS and CARDS. Using plasma protein biomarkers and clinical data, Dr. Calfee (sponsor of the applicant) has identified two biologic subphenotypes of non-COVID-19 related or “typical” ARDS. Specifically, patients with the hyperinflammatory subphenotype had higher levels of inflammatory biomarkers, metabolic acidosis, and shock. They also experienced significantly higher mortality and were more likely to benefit from certain ICU therapies. Conversely, most CARDS patients demonstrate a hypoinflammatory subphenotype of typical ARDS, raising questions about the pathophysiology underlying poor outcomes in this population. The overall objective of this project is to (i) identify plasma biomarkers and differential gene expression associated with poor outcomes in CARDS and (ii) search for the presence of CARDS specific subphenotypes of clinical importance. The central hypothesis is that differential gene expression indicative of dysregulated inflammation and high baseline plasma biomarkers of lung injury and disordered coagulation will predict poor outcomes in CARDS, and that distinct CARDS subphenotypes exist associated with differential outcomes and treatment responses. The rationale for this project is that it will offer mechanistic insights into the biology underlying poor outcomes in this population, lead to identifying potential druggable targets, and identify patients most likely to benefit from targeted therapies. The central hypothesis will be tested by pursuing these specific aims: 1) Identify biological predictors of poor clinical outcomes within patients with CARDS; and 2) Identify distinct biologic subphenotypes of CARDS associated with poor clinical outcomes and differential treatment response. Under aim 1, hypothesis-driven plasma protein biomarkers will be measured, and RNA sequencing performed on blood samples of CARDS patients enrolled in ISPY COVID, an ongoing adaptive randomized controlled trial of experimental drugs across multiple US institutions. Under aim 2, latent class analysis will be performed on a combination of protein biomarkers and clinical variables to identify subphenotypes associated with distinct outcomes and responses to the trial’s investigational agents. The proposed research is innovative, because extensive biological phenotyping in a large and representative cohort of patients with a uniform trigger for ARDS has not been done and may be the key to identifying successful therapies. Ultimately, this knowledge will pave the way for conducting phenotype-aware trials studying targeted therapies in patients with subphenotypes of CARDS.

项目摘要/摘要 急性呼吸窘迫综合征由包括新冠肺炎在内的多种诱因引起，是一种 在没有有效治疗的情况下，严重的危重疾病。尽管对新冠肺炎相关的ARDS研究很多 (卡片)，最好的可用治疗方法只会导致适度或不一致的临床改善。这种匮乏 这可能部分是由于宿主对新冠肺炎的反应不同造成的。长期目标是带来 对患有ARDS和卡片的患者进行精准治疗。利用血浆蛋白生物标志物和临床数据，Dr。 加尔菲(申请者的赞助商)已经确定了两种与新冠肺炎无关或“典型”的生物学亚型 阿兹。具体地说，具有高炎症亚型的患者炎症水平较高。 生物标志物、代谢性酸中毒和休克。他们也经历了显著更高的死亡率和 可能会从某些ICU治疗中受益。相反，大多数慢性阻塞性肺病患者表现为炎症减退。 典型ARDS的亚型，引发了对导致不良预后的病理生理学的质疑 人口。本项目的总体目标是(I)确定血浆生物标志物和差异基因 与卡片中的不良结果相关的表达以及(Ii)搜索特定卡片的存在 临床重要性的亚型。中心假说是差异基因表达表明 肺损伤和凝血功能紊乱的炎症和高基线血浆生物标志物将 预测卡片的不良结果，并且存在与差异相关的不同的卡片亚型 结果和治疗反应。这个项目的基本原理是它将提供对 这一人群不良结局的生物学基础，导致确定潜在的可用药靶点，并确定 最有可能从靶向治疗中受益的患者。核心假设将通过追求以下几点来检验 具体目标：1)在有卡片的患者中确定不良临床结果的生物学预测因素；以及2) 确定与不良临床结果和差异性相关的卡片的不同生物学亚型 治疗反应。在目标1下，将测量假说驱动的血浆蛋白生物标记物，以及RNA 对参加ISPY COVID的CARD患者的血液样本进行测序，这是一项正在进行的适应性研究 对美国多个机构的实验药物进行随机对照试验。在目标2下，潜在阶级 将对蛋白质生物标记物和临床变量进行组合分析，以确定 亚型与不同的结果和对试验的研究药物的反应相关。这个 拟议的研究是创新的，因为在一个具有代表性的大队列中进行了广泛的生物表型分析 有统一触发ARDS的患者尚未完成，这可能是识别成功的关键 治疗。最终，这些知识将为进行有针对性的表型感知试验铺平道路。 治疗对亚表型证候的影响。