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

• 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
• 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

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）：本 R21 申请是对 NHLBI RFA-HL-12-004“最大化 NHLBI 生物样本库的科学价值：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，在美国每年发病率为 180,000 例。机械通气和支持治疗的进步导致 ALI/ARDS 的短期死亡率下降，因此需要招募越来越多的患者，以充分推动新疗法的研究。为了针对最有可能死亡的患者进行治疗试验，需要新的方法来预测 ALI/ARDS 的临床结果。在 ALI/ARDS 病程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前途的工具。在这些生物标志物中，SP-D（II 型肺上皮损伤标志物）和 IL-8（炎症和中性粒细胞趋化性标志物）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可显着改善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。我们建议在参加 NHLBI ARDS 网络液体和导管治疗试验 (FACTT) 的 888 名患者中验证 SP-D 和 IL-8 作为临床结果的预测因子。此外，为了增强我们研究结果的普遍性，我们还将在 689 名 ALI/ARDS 患者的异质人群中验证 SP-D 和 IL-8，这些患者来自验证急性肺损伤诊断生物标志物 (VALID) 研究。晚期糖基化终末产物受体 (RAGE) 是 I 型肺上皮损伤的标志物，也是 ALI/ARDS 死亡率的强有力预测因子，但尚未与 SPD 和 IL-8 进行比较。因此，为了检验 SP-D、IL-8 和 RAGE 是 ALI/ARDS 临床结果的预测因素（可用于选择参加未来临床试验的患者）的总体假设，来自 NHLBI ARDS 网络 FACTT 试验的标本目前存储在 NHLBI 生物样本库中的样本将用于以下目标： 具体目标 1：验证血浆 SP-D 和 IL-8 水平与临床预测因子相结合的预后价值参与 NHLBI ARDS 网络液体和导管治疗试验的 888 名早期 ALI/ARDS 患者的死亡和其他重要临床结果。具体目标 2：在 VALID 研究中纳入的 689 名 ALI/ARDS 患者组成的异质性更强的患者群体中，验证 SP-D 和 IL-8 血浆水平与死亡和重要临床结果的临床预测因子相结合的预后价值。具体目标 3：比较这两个患者队列中 RAGE、SP-D 和 IL-8 血浆水平的差异和综合预后价值，以预测重要的临床结果，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入组，并减少测试新疗法所需的时间和资金。

项目成果

Prognostic factors in the acute respiratory distress syndrome.

急性呼吸窘迫综合征的预后因素。

• 发表时间: 2015-12
• 作者: Chen, Wei;Ware, Lorraine B
• 通讯作者: Ware, Lorraine B

Stability of ARDS subphenotypes over time in two randomised controlled trials.

两项随机对照试验中 ARDS 亚表型随时间的稳定性。

• 发表时间: 2018-05
• 影响因子: 10
• 作者: Delucchi, Kevin;Famous, Katie R;Ware, Lorraine B;Parsons, Polly E;Thompson, B Taylor;Calfee, Carolyn S;ARDS Network
• 通讯作者: ARDS Network