Biomarkers of Interstitial Lung Abnormalities Predict Poor Outcomes in ARDS.

急性呼吸窘迫综合征(ARDS)是一种发病率和死亡率都很高的破坏性综合征 除了支持性治疗外，没有可用的有针对性的医疗治疗。人们越来越认识到， 医学干预失败的原因是ARDS是异质性的。虽然焦点一直放在 导致ARDS的潜在侮辱的异质性(例如，肺炎、吸入所致的直接肺损伤；或 败血症、创伤造成的间接损伤)较少关注可能的潜在特征 使患者容易受到肺损伤，或更严重的肺损伤，以回应各种侮辱。 我们报告了先前存在的间质性肺异常(ILA)、ARDS和死亡率之间的关系。 患有脓毒症或全身炎症反应综合征(SIRS)的小队列。我们证明了这一点 全身炎症反应综合征或脓毒症合并ILA患者在ICU前至少7天行胸部CT检查 入院后患急性呼吸窘迫综合征的风险增加(OR4.2，P&lt；0.0001)，并在28天内死亡(OR 2.3，P=0.01)。ILA是胸部CT扫描上的放射密度，提示潜在的间质性肺疾病 (ILD)在没有临床ILD的人中。临床肺源性肺炎患者通常死于急性加重。 病理表现为弥漫性肺泡损伤(ARDS最常见的病理表现)。这些发现 提示，ARDS患者中有一个重要的亚群有发展和死亡的风险，其中包括患有 隐匿性肺纤维化(PF)。 我们的主要假设是，血浆生物标记物与先前存在的ILA的存在相关 非高分辨率胸部CT可以识别ARDS患者的亚群，他们的病情会更糟 在未来的新疗法和治疗策略中可以针对(或选择)的结果。 这种RFA允许访问NHLBI中ARDSNet患者的大量生物样本 生物信息库，我们将根据与ARDS和IPF的关联来分析选择的生物标记物。这些 研究结果将与临床结果和参与ARDSNet的胸部CT图像相关联 中锋。这项建议通过调查新发现的病理生物学来实现NHLBI的战略目标 ARDS发病和进展的重要机制，在确定个体因素方面 ARDS的病理生物学和对治疗和临床治疗的反应，以及在发展和 优化新的诊断(并最终治疗)策略，以检测、预防、治疗和治愈ARDS。至 针对我们的假设，我们提出了两个具体目标： 目的1：确定ARDSNet患者中预先存在的ILA的频率，并确定ILA是否定义 急性呼吸窘迫综合征亚群死亡率上升。 目的2：确定是否可以识别预测病情恶化的血浆生物标志物特征 ARDS在那些既有ILA的患者和ARDS患者中的结果。

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.