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

ARDS 预后的炎症和上皮损伤标志物：一项验证研究

基本信息

批准号：
8466368
负责人：
Lorraine B Ware
金额：
$ 11.14万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-04 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8466368
关键词：
Acute Acute Lung Injury Acute respiratory failure Adult Respiratory Distress Syndrome Biological Markers Catheters Cessation of life Chemotaxis Clinical Clinical Trials Clinical Trials Network Cohort Studies Critical Illness Diagnosis Drops Educational workshop Enrollment Epithelial Functional disorder Funding Future Incidence Inflammation Inflammatory Injury Interleukin 8A Receptor Interleukin-8 Liquid substance Lung Lung Inflammation Measurement Measures Mechanical ventilation Methods National Heart, Lung, and Blood Institute Outcome Patient Selection Patients Performance Plasma Population Heterogeneity Positive-Pressure Respiration Pulmonary Surfactant-Associated Protein D Specimen Supportive care Syndrome Testing Therapeutic Therapy Clinical Trials Tidal Volume Time United States Validation clinical application cohort cost design glycoprotein 340 high risk improved inflammatory marker mortality neutrophil outcome forecast patient population prognostic receptor for advanced glycation endproducts repository response tool treatment trial validation studies

项目摘要

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.

描述（由申请人提供）：此R21申请响应NHLBI RFA-HL-12-004“最大化NHLBI生物标本呼吸的科学价值：科学机会”。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，每年发病率为180,000。机械通气和支持护理的进展导致ALI/ARDS短期死亡率下降，因此需要增加越来越多的患者来进行新疗法的功能研究。为了将治疗试验靶向最有可能死亡的患者，需要使用新的方法来预测ALI/ARDS的临床结果。在ALI/ARDS过程中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局的有希望的工具。在这些生物标志物中，SP-D是II型肺上皮损伤和IL-8的标志物，炎症和中性粒细胞趋化性的标记与短期死亡率高度相关。当添加到临床预测因子中时，对这些血浆生物标志物的测量可显着提高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，需要进行大规模验证。我们建议在NHLBI ARDS网络流体和导管治疗试验（FACTT）的888名患者中验证SP-D和IL-8作为临床结果的预测指标。此外，为了提高发现结果的普遍性，我们还将在689例患有验证的急性肺损伤生物标志物（有效）研究的689例ALI/ARDS患者中验证SP-D和IL-8。晚期糖基化最终产物（RAGE）的受体是I型肺上皮损伤的标志，也是ALI/ARDS死亡率的有力预测指标，但尚未与SPD和IL-8进行比较。 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在NHLBI ARDS网络的液体和导管治疗试验中，SP-D和IL-8的水平结合了888例ALI/ARDS患者的死亡和其他重要临床结果的临床预测因子。具体目的2：验证血浆SP-D和IL-8的血浆水平的预后价值以及死亡的临床预测因子和更为异构的患者人群中的临床预测因子和重要的临床结果，由689例有效研究的ALI/ARDS组成。特定目的3：比较这两个患者同类中血浆愤怒水平与SP-D和IL-8的差异和组合预后价值，以预测重要的临床结果，包括死亡率。对这些生物标志物的验证可能会对ALI/ARDS未来临床试验的设计产生重大影响，从而选择最病的患者入学，并减少测试新疗法所需的时间和资金。