Inflammatory and epithelial injury markers for ARDS prognosis:A validation study

描述（由申请人提供）：本R21申请是对NHLBI RFA-HL-12-004“最大化NHLBI生物标本库的科学价值：科学机会”的回应。急性肺损伤和急性呼吸窘迫综合征（ALI/ARDS）是急性呼吸衰竭的常见综合征，在美国每年的发病率为18万例。机械通气和支持性治疗的进步导致ALI/ARDS的短期死亡率下降，需要招募更多的患者来充分研究新的治疗方法。为了将治疗试验的目标定位于最有可能死亡的患者，需要新的方法来预测ALI/ARDS的临床结局。在ALI/ARDS过程的早期测量的肺上皮损伤和炎症的血浆生物标志物是预测临床结果的有希望的工具。在这些生物标志物中，SP-D（II型肺上皮损伤的标志物）和IL-8（炎症和中性粒细胞趋化性的标志物）与短期死亡率高度相关。当添加到临床预测因子中时，这些血浆生物标志物的测量显著改善了初步研究中的死亡率预测。为了将这些生物标志物推向临床应用，需要大规模验证。我们建议在NHLBI ARDS网络液体和导管治疗试验（FACTT）中纳入的888例患者中验证SP-D和IL-8作为临床结局的预测因子。此外，为了提高我们研究结果的普遍性，我们还将在来自急性肺损伤诊断生物标志物验证（VALID）研究的689例ALI/ARDS患者的异质性人群中验证SP-D和IL-8。晚期糖基化终末产物受体（CRP）是I型肺上皮损伤的标志物，也是ALI/ARDS死亡率的强预测因子，但尚未与SPD和IL-8进行比较。因此，为了检验SP-D、IL-8和CRP是ALI/ARDS临床结局的预测因子（可用于选择入组未来临床试验的患者）的总体假设，NHLBI ARDS网络FACTT试验中目前储存在NHLBI生物样本库中的样本将用于以下目的：具体目的1：在入组NHLBI ARDS网络液体和导管治疗试验的888例早期ALI/ARDS患者中，验证血浆SP-D和IL-8水平的预后价值以及死亡和其他重要临床结局的临床预测因素。具体目标二：在VALID研究中纳入的689例ALI/ARDS患者组成的异质性更高的患者人群中，验证血浆SP-D和IL-8水平的预后价值以及死亡和重要临床结局的临床预测因子。具体目标3：比较这两个患者队列中血浆CRP与SP-D和IL-8水平的差异和联合预后价值，以预测重要的临床结局，包括死亡率。这些生物标志物的验证可能对未来ALI/ARDS临床试验的设计产生重大影响，允许选择病情最严重的患者进行招募，并减少测试新疗法所需的时间和资金。

DESCRIPTION (provided by applicant): This R21 application is in response to NHLBI RFA-HL-12-004 "Maximizing the Scientific Value of the NHLBI Biologic Specimen Respository: Scientific Opportunities". Acute lung injury and the acute respiratory distress syndrome (ALI/ARDS) are common syndromes of acute respiratory failure with an incidence of 180,000 per year in the United States. Advances in mechanical ventilation and supportive care have led to a decline in short-term mortality in ALI/ARDS necessitating the enrollment of increasing numbers of patients to adequately power studies of new therapies. In order to target therapeutic trials to the patients most likely to die, new methods are needed for predicting clinical outcomes in ALI/ARDS. Plasma biomarkers of lung epithelial injury and inflammation, measured early in the course of ALI/ARDS, are promising tools for predicting clinical outcomes. Among these biomarkers, SP-D, a marker of type II lung epithelial injury and IL-8, a marker of inflammation and neutrophil chemotaxis are highly associated with short term mortality. When added to clinical predictors, measurement of these plasma biomarkers significantly improves mortality prediction in preliminary studies. To advance these biomarkers to clinical application, large scale validation is needed. We propose to validate SP-D and IL-8 as predictors of clinical outcome in 888 patients enrolled in the NHLBI ARDS Network Fluid And Catheter Treatment Trial (FACTT). In addition, to enhance the generalizability of our findings, we will also validate SP-D and IL-8 in a heterogeneous population of 689 patients with ALI/ARDS drawn from the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study. The receptor for advanced glycation endproducts (RAGE), a marker of type I lung epithelial injury, is also a strong predictor of mortality in ALI/ARDS but has not been compared to SPD and IL-8. Therefore, to test the overall hypothesis that SP-D, IL-8 and RAGE are predictors of clinical outcomes in ALI/ARDS that can be used to select patients for enrollment in future clinical trials, specimens from the NHLBI ARDS Network's FACTT trial that are currently stored in the NHLBI Biospecimen Repository will be utilized in the following Aims: Specific Aim 1: To validate the prognostic value of plasma levels of SP-D and IL-8 combined with clinical predictors for death and other important clinical outcomes in 888 patients with early ALI/ARDS enrolled in the NHLBI ARDS Network's Fluid and Catheter Treatment Trial. Specific Aim 2: To validate the prognostic value of plasma levels of SP-D and IL-8 combined with clinical predictors for death and important clinical outcomes in a more heterogeneous patient population consisting of 689 patients with ALI/ARDS enrolled in the VALID study. Specific Aim 3: To compare the differential and combined prognostic value of plasma levels of RAGE to SP-D and IL-8 in these two patient cohorts for prediction of important clinical outcomes, including mortality. Validation of these biomarkers could have a major impact on design of future clinical trials in ALI/ARDS, allowing selection of the sickest patients for enrollment, and reducing the time and funds required to test new therapies.