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.

Public Health Relevance

Advances in mechanical ventilation and supportive care have led to a decline in short term mortality in acute lung injury that has necessitated the enrollment of increasing numbers of patients to adequately power studies of new therapies. In order to target future therapeutic trials to the patients most likely to die, new tools are needed for predicting clinical outcomes in acute lung injury. The proposed studies will validate three markers of inflammation and lung epithelial injury as robust predictors of clinical outcomes in ALI/ARDS that can be used to select patients for enrollment in future clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL112656-01
Application #
8262086
Study Section
Special Emphasis Panel (ZHL1-CSR-P (F2))
Program Officer
Wagner, Elizabeth
Project Start
2012-05-04
Project End
2014-04-30
Budget Start
2012-05-04
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$117,000
Indirect Cost
$42,000
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Famous, Katie R; Delucchi, Kevin; Ware, Lorraine B et al. (2017) Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy. Am J Respir Crit Care Med 195:331-338
Johnston, Henry Richard; Hu, Yi-Juan; Gao, Jingjing et al. (2017) Identifying tagging SNPs for African specific genetic variation from the African Diaspora Genome. Sci Rep 7:46398
Mathias, Rasika Ann; Taub, Margaret A; Gignoux, Christopher R et al. (2016) A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome. Nat Commun 7:12522
Sapru, Anil; Liu, Kathleen D; Wiemels, Joseph et al. (2016) Association of common genetic variation in the protein C pathway genes with clinical outcomes in acute respiratory distress syndrome. Crit Care 20:151
Hughes, Christopher G; Pandharipande, Pratik P; Thompson, Jennifer L et al. (2016) Endothelial Activation and Blood-Brain Barrier Injury as Risk Factors for Delirium in Critically Ill Patients. Crit Care Med 44:e809-17
Kessler, Michael D; Yerges-Armstrong, Laura; Taub, Margaret A et al. (2016) Challenges and disparities in the application of personalized genomic medicine to populations with African ancestry. Nat Commun 7:12521
Kangelaris, Kirsten Neudoerffer; Ware, Lorraine B; Wang, Chen Yu et al. (2016) Timing of Intubation and Clinical Outcomes in Adults With Acute Respiratory Distress Syndrome. Crit Care Med 44:120-9
Chen, Wei; Janz, David R; Shaver, Ciara M et al. (2015) Clinical Characteristics and Outcomes Are Similar in ARDS Diagnosed by Oxygen Saturation/Fio2 Ratio Compared With Pao2/Fio2 Ratio. Chest 148:1477-1483
Chen, Wei; Janz, David R; Bastarache, Julie A et al. (2015) Prehospital aspirin use is associated with reduced risk of acute respiratory distress syndrome in critically ill patients: a propensity-adjusted analysis. Crit Care Med 43:801-7
Calfee, Carolyn S; Janz, David R; Bernard, Gordon R et al. (2015) Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies. Chest 147:1539-1548

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