ENdotypes in Children with Severe Acute Respiratory Distress SyNdrome: ImpAct on REsponse to Treatment (ENSNARE)

患有严重急性呼吸窘迫综合征的儿童的内型：对治疗反应的影响 (ENSNARE)

• 批准号: 10308451
• 负责人: Mary K Dahmer
• 金额: $ 74.92万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308451
• 关键词: Acute Respiratory Distress Syndrome; Address; Adult; Affect; Age; Biological; Biological Markers; Biology; Cells; Cessation of life; Child; Childhood; Clinical; Clinical Trials; Complex; Data; Data Analyses; Development; Disease; Endothelium; Epithelial; Expression Profiling; Frequencies; Functional disorder; Funding; Future; Gene Expression; Gene Expression Profiling; Genes; Goals; Heterogeneity; Immune; Immune system; Individual Differences; Inflammatory; Length; Mechanical ventilation; Mesenchymal; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Outcome; Pathway interactions; Patients; Pediatric Acute Respiratory Distress Syndrome; Persons; Pharmacological Treatment; Plasma; Pneumonia; Process; Prone Position; Randomized Controlled Trials; Research; Resolution; Sampling; Sepsis; Septic Shock; Strategic vision; Subgroup; Syndrome; Testing; Whole Blood; age related; comorbidity; genome-wide; mortality; mortality risk; patient stratification; pediatric patients; pediatric sepsis; personalized care; precision medicine; targeted treatment; transcriptomics; treatment response; trial design; ventilation

SUMMARY Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality in children and adults. Despite years of research, pharmacologic treatment has proven ineffective in decreasing mortality and morbidity which is likely due, in part, to heterogeneity in ARDS patients. Latent class analyses (LCA) of data from multiple large funded adult studies have identified two ARDS endotypes (subphenotypes) with differing clinical outcomes and response to treatment. There are no studies examining whether endotypes exist in pediatric ARDS (PARDS). However, by examining genome-wide gene expression in whole blood, endotypes have been identified in children with septic shock, another condition with a high degree of patient heterogeneity which involves dysregulation of the inflammatory/immune systems. The endotypes identified using this transcriptomic approach have differing risks of mortality and expression of immune inflammatory genes. Transcriptomics have not yet been used to define subgroups of adult or pediatric patients with ARDS. The PROSpect trial (UG3 HL141736) is an unprecedented opportunity to use biological samples from children with PARDS to answer several high impact questions related to PARDS heterogeneity. Our central hypothesis is that there are endotypes in children with PARDS which differ in their underlying pathophysiology and responsiveness to therapies. The goal of this proposal is to a) identify and characterize endotypes in children with PARDS using both LCA (Sp Aim 1) and gene expression profiling (Sp Aim 2) approaches, b) determine whether subgroups differ in outcome and/or response to treatment, and c) identify potential pathways involved in differences between endotype outcomes and response to treatment (Sp Aim 3). This proposal addresses one of the objectives in the strategic vision of the NHLBI, “Identifying factors that account for individual differences in pathobiology and responses to treatment”. Our Specific Aims will test the hypotheses that: 1) LCA will identify two endotypes in children with PARDS, and that outcomes, and response to treatment, will vary between endotypes; 2) The two endotypes distinguished by the expression of 100 genes in children with septic shock also exist in children with PARDS, that de novo genome-wide expression profiling will identify additional endotypes in children with PARDS and, that outcomes and response to treatment will vary between transcriptomic endotypes identified using each approach; 3) Combining the results of the LCA with data on gene expression used for identification of transcriptomic endotypes will allow further stratification of patients with PARDS, and will reveal a subset of genes that are related to differential outcomes and response to treatment. This proposal will lay the fundamental groundwork for future precision care of PARDS patients by identifying: different endotypes within PARDS, differences in the underlying pathophysiology of PARDS endotypes, whether endotypes respond differently to treatment, and how endotypes of pediatric sepsis and PARDS relate to each other.

摘要 急性呼吸窘迫综合征(ARDS)与儿童和儿童的高发病率和死亡率有关 成年人。尽管多年来的研究表明，药物治疗在降低死亡率和 发病率可能部分归因于ARDS患者的异质性。数据的潜在类分析(LCA) 从多个大型资助的成人研究中发现了两种不同的ARDS内型(亚型) 临床结果和治疗反应。目前还没有研究检查内型是否存在于 儿科ARDS(Pards)。然而，通过检查全血中全基因组基因的表达，内型 已在感染性休克的儿童中发现，这是另一种高度患者异质性的疾病 这涉及到炎症/免疫系统的失调。使用此标识的内型 转录切除法具有不同的死亡风险和免疫炎症基因的表达。 转录组学还没有被用来确定成人或儿童ARDS患者的亚组。 PROCESS试验(UG3 HL141736)是使用来自 有Pards的儿童回答几个与Pards异质性相关的高影响力问题。我们的中央 假说是PARDS儿童的内型在其潜在的病理生理学上是不同的 以及对治疗的反应。这项建议的目标是a)确定和表征内型 同时使用LCA(Sp目标1)和基因表达谱(Sp目标2)方法的Pard儿童，b) 确定各分组的结果和/或治疗反应是否不同，以及c)确定潜在的 参与内型结局和治疗反应差异的途径(Sp目标3)。这 该提案解决了NHLBI战略愿景中的目标之一，“确定占 病理生物学和治疗反应的个体差异“。我们的具体目标将考验 假设：1)LCA将在患有PARDS的儿童中识别两种内型，以及结果，以及 对治疗的反应，会因内型而异；2)这两种内型的区别在于 感染性休克儿童中100个基因的表达在PARDS儿童中也存在，即从头开始 全基因组表达谱将识别患有PARDS的儿童的其他内型 结果和对治疗的反应在使用每种方法确定的转录本内型之间存在差异 方法；3)将LCA的结果与用于鉴定的基因表达数据相结合 转录切割内型将允许PARDS患者的进一步分层，并将揭示一种 与不同结果和治疗反应相关的基因子集。这项提议将 通过识别不同的内型为未来PARDS患者的精准护理奠定基础 在PARDS内部，PARDS内型的潜在病理生理学差异，无论是内型 对治疗的不同反应，以及儿科脓毒症的内型与Pard之间的关系。