Biomarkers of Interstitial Lung Abnormalities Predict Poor Outcomes in ARDS.

间质性肺异常的生物标志物预示 ARDS 的不良结局。

• 批准号: 10021700
• 负责人: Rebecca M Baron
• 金额: $ 16.99万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021700
• 关键词: Acute; Address; Admission activity; Adult Respiratory Distress Syndrome; Alveolar; Biological Markers; Biological Specimen Banks; Characteristics; Clinical; Clinical Management; Confidence Intervals; Data; Development; Diagnosis; Diffuse; Disease; Early identification; Enrollment; Exercise; Failure; Fibrosis; Frequencies; Funding; Future; Genetic; Goals; Heterogeneity; Hospitals; Image; Impairment; Individual Differences; Injury; Interstitial Lung Diseases; Intervention; Lead; Lung; Measures; Medical; Monitor; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Odds Ratio; Outcome; Participant; Pathologic; Patient imaging; Patients; Physiological; Plasma; Pneumonia; Predisposing Factor; Publishing; Pulmonary Fibrosis; Radiology Specialty; Reporting; Research; Resolution; Respiratory Failure; Respiratory physiology; Risk; Risk Factors; Sampling; Scanning; Sepsis; Severities; Site; Standardization; Subgroup; Suggestion; Supportive care; Syndrome; Systemic Inflammatory Response Syndrome; Therapeutic; Trauma; United States National Institutes of Health; Woman; Work; base; biobank; biomarker discovery; biomarker panel; chest computed tomography; cohort; density; design; disease diagnosis; experience; idiopathic pulmonary fibrosis; interstitial; lung injury; mortality; mortality risk; novel diagnostics; novel therapeutics; outcome prediction; patient subsets; predictive marker; predictive tools; prevent; response; targeted treatment; treatment response; treatment strategy

Acute Respiratory Distress Syndrome (ARDS) is a devastating syndrome with high morbidity and mortality with no available targeted medical therapies other than supportive care. It is increasingly recognized that one reason for failure of medical interventions is that ARDS is heterogenous. While focus has been placed on the heterogeneity of underlying insults that lead to ARDS (e.g., direct lung injury from pneumonia, aspiration; or indirect injury from sepsis, trauma) less focus has been placed on underlying characteristics that might predispose patients to lung injury, or to a greater severity of lung injury, in response to various insults. We reported an association between preexisting interstitial lung abnormalities (ILA), ARDS, and mortality in small cohort with sepsis or the systemic inflammatory response syndrome (SIRS). We demonstrated that patients with SIRS or sepsis with ILA on chest computed tomography (CT) at least 7 days prior to ICU admission had increased risk to develop ARDS (odds ratio [OR] 4.2, P<0.0001) and die within 28-days (OR 2.3, P=0.01). ILA are radiologic densities on chest CT scans suggestive of underlying interstitial lung disease (ILD) in those without clinical ILD. Patients with clinical PF often die from an acute exacerbation characterized pathologically by diffuse alveolar damage (the most common pathologic finding in ARDS). These findings suggest that one important subgroup of patients at risk to develop, and die from, ARDS includes patients with occult pulmonary fibrosis (PF). Our overarching hypothesis is that plasma biomarkers, correlated with the presence of pre-existing ILA on non-high resolution chest CT, will permit identification of a subgroup of patients with ARDS who will have worse outcomes that can be targeted for (or selected against) in future novel therapeutics and treatment strategies. This RFA permits access to a large cohort of biospecimens from ARDSnet patients in the NHLBI biorepository that we will analyze for biomarkers selected based on association with ARDS and IPF. These findings will be correlated with clinical outcomes and chest CT images obtained from the participating ARDSnet centers. This proposal fulfills the NHLBI strategic goals by investigating newly discovered pathobiological mechanisms important to onset and progression of ARDS, in identifying factors that account for individual differences in pathobiology and response to treatment and clinical management of ARDS, and in developing and optimizing novel diagnostic (and ultimately therapeutic) strategies to detect, prevent, treat, and cure ARDS. To address our hypothesis, we propose two Specific Aims: Aim 1: To identify the frequency of pre-existing ILA in ARDSnet patients and to determine if ILA defines an ARDS subpopulation with an increased rate of mortality. Aim 2: To determine whether a plasma biomarker signature can be identified that predicts worsened outcomes from ARDS in those patients with pre-existing ILA and in ARDS patients overall.

急性呼吸窘迫综合征（ARDS）是一种具有高发病率和死亡率的毁灭性综合征 除了支持性治疗外，没有可用的靶向药物治疗。人们越来越认识到， 医疗干预失败的原因是ARDS是异质性的。虽然重点放在 导致ARDS的潜在损伤的异质性（例如，肺炎、吸入性疾病导致的直接肺损伤;或 脓毒症、创伤的间接损伤）较少关注可能 使患者易受肺损伤或更严重的肺损伤，以响应各种损伤。 我们报道了在急性呼吸窘迫综合征患者中，既存间质性肺异常（ILA）、ARDS和死亡率之间的相关性。 脓毒症或全身炎症反应综合征（SIRS）的小队列。我们证明了 ICU前至少7天胸部计算机断层扫描（CT）显示SIRS或脓毒症伴ILA的患者 入院后发生ARDS和28天内死亡的风险增加（OR = 4.2，P<0.0001）， 2.3，P=0.01）。ILA是胸部CT扫描的放射学密度，提示潜在的间质性肺病 (ILD)在没有临床ILD的患者中。临床PF患者通常死于急性加重， 病理学表现为弥漫性肺泡损伤（ARDS中最常见的病理学发现）。这些发现 提示一个重要的有发生和死于ARDS风险的患者亚组包括以下患者 隐匿性肺纤维化（PF）。 我们的总体假设是，血浆生物标志物，与预先存在的ILA的存在相关， 非高分辨率胸部CT，将允许识别一个亚组的ARDS患者，他们将有更严重的 可以在未来的新疗法和治疗策略中靶向（或选择）的结果。 该RFA允许访问NHLBI中ARDSnet患者的大量生物标本 我们将分析基于与ARDS和IPF相关性选择的生物标志物。这些 结果将与临床结局和从参与的ARDSnet获得的胸部CT图像相关 中心.该提案通过调查新发现的病理生物学，实现了NHLBI的战略目标。 在确定导致个体ARDS的因素方面， 在病理生物学和对ARDS治疗和临床管理的反应方面的差异，以及在发展和 优化新的诊断（和最终的治疗）策略，以检测，预防，治疗和治愈ARDS。到 针对我们的假设，我们提出了两个具体目标： 目的1：确定ARDSnet患者中既存ILA的频率，并确定ILA是否定义了 死亡率增加的ARDS亚群。 目的2：确定是否可以鉴定预测恶化的血浆生物标志物特征 在既存ILA患者和所有ARDS患者中，