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（ARDS），由包括Covid-19在内的多种触发因素引起的是一个 毁灭性的重症疾病，没有有效的疗法。尽管关于Covid-19相关的ARDS的许多研究 （卡），最好的可用治疗方法只会导致适度或不一致的临床改进。这种贫困 发现可能部分是由于宿主对Covid-19的异质性的异质性。长期目标是带来 精度疗法对患有ARDS和卡的患者。使用血浆蛋白生物标志物和临床数据，博士 Calfee（适用的赞助商）已经确定了两种非covid-19相关或“典型”的生物次型 ARDS。具体而言，高炎性亚表格型的患者具有较高的炎症水平 生物标志物，代谢性酸中毒和休克。他们还经历了更高的死亡率，并且更多 可能受益于某些ICU疗法。相反，大多数卡片患者都表现出低炎症性 典型ARDS的亚表征，提出了有关病理生理的问题的问题 人口。该项目的总体目的是（i）识别等离子体生物标志物和差异基因 表达与卡片中不良结果相关的表达，（ii）搜索特定于卡的存在 临床重要性的亚表征。中心假设是鉴别基因表达表示 肺损伤和凝血无序的感染失调和高基线等离子体生物标志物将会 预测卡片中的结果不佳，并且存在不同的卡子表型与差异相关 结果和治疗反应。该项目的理由是它将提供机械洞察 在该人群中结果不佳的生物学，导致识别潜在的可药物靶标，并确定 患者最有可能受益于靶向疗法。中心假设将通过追求这些假设来检验 具体目的：1）确定卡片患者内临床结果不佳的生物学预测因子；和2） 确定与临床不良结局和差异相关的卡片的不同生物学亚表格 治疗反应。在AIM 1下，将测量由假设驱动的血浆蛋白生物标志物，并将RNA测量 对参加Ispy covid的卡片患者的血液样本进行测序，这是一种持续的自适应 多个美国机构的实验药物的随机对照试验。在AIM 2下，潜在班级 分析将在蛋白质生物标志物和临床变量的组合上进行，以鉴定 与试验研究剂的不同结果和反应相关的亚表征。这 拟议的研究具有创新性，因为在大型且代表性的队列中广泛的生物学表型 尚未完成具有均匀触发ARDS的患者，可能是成功识别成功的关键 疗法。最终，这些知识将为进行有针对性的研究表型的试验铺平道路 具有子表型的患者的疗法。