The prognosis for patients diagnosed with idiopathic pulmonary fibrosis (IPF) is very poor, with a mean survival time of only 35.2 months. IPF now affects more than 100,000 US residents and is characterized by thickening of the pulmonary blood-gas barrier and impaired gas exchange. Unfortunately, even as efforts to develop therapies for IPF accelerate, most clinical trials are stymied by the inability to adequately characterize the disease, its progression, and its therapeutic response. Existing biomarkers are either too insensitive or too invasive for repeat use. We intend to address this problem by introducing a comprehensive MRI-based 3D imaging approach to not only identify regional disease, but to predict and observe regional therapeutic response. Our long-term goal is to broadly deploy non-invasive, high-resolution, quantitative MR imaging of all aspects of cardiopulmonary function to change the way IPF is managed. Our approach exploits the converging progress in 1H MR imaging of structure and perfusion, with hyperpolarized 129Xe MR imaging of ventilation and gas exchange. The objective of this study is to integrate and optimize these structural and functional MRI approaches and use them to identify regional diffusion limitation, and predict and observe therapeutic response 4 times earlier than standard methods can. Our central hypothesis is that combined imaging of structure, ventilation, perfusion and gas exchange, will provide the means to identify the leading edge of disease, where recovery of lung function remains possible. The rationale for the proposed research is that therapeutic response is difficult if not impossible to detect using global metrics and thus, 3 non-invasive imaging is needed to visualize recoverable areas. Thus, the proposed research is relevant to that part of the NIH Mission that pertains to improving health by developing and accelerating the application of biomedical technologies. Guided by strong preliminary data, our approach is based on three Specific Aims: 1) Establish a comprehensive, quantitative structure/function MRI Protocol for IPF at two centers, 2) Identify regional early- stage disease by combining Gd perfusion and 129Xe exchange MRI, and 3) Use structure/function MRI to monitor progression and response to therapy in IPF. Completion of these aims will 1) set up 2-leading centers with an optimized protocol for imaging IPF, 2) establish the ability to visualize regions of diffusion impairment that can still respond to therapy, 3) observe therapeutic response within 3 months instead of 1 year, and 4) predict outcomes at 12 months post therapy as seen by conventional tests. The proposed approach is innovative because it uses a comprehensive protocol to measure what cannot be measured by any one technique in isolation, and exploits the expertise of 2 centers to accelerate development and expand the recruitment pool for this rare disease. The proposed research is significant because it has the potential to develop the key noninvasive functional imaging biomarkers that can enable IPF trials to be conducted faster, with fewer patients, at lower cost and with greater likelihood for success.

Public Health Relevance

The proposed work is designed to deploy new and non-invasive methods to comprehensively visualize lung function using MRI with inhaled gases. This particular work applies these techniques to patients with Idiopathic Pulmonary Fibrosis and seeks detect areas of reversible disease and observe therapeutic response earlier than is possible with conventional lung function tests.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL126771-02
Application #
9064201
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Reineck, Lora A
Project Start
2015-05-06
Project End
2019-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Duke University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Hahn, Andrew D; Kammerman, Jeff; Fain, Sean B (2018) Removal of hyperpolarized 129 Xe gas-phase contamination in spectroscopic imaging of the lungs. Magn Reson Med 80:2586-2597
Shim, Sung Shine; Schiebler, Mark L; Evans, Michael D et al. (2018) Lumen area change (Delta Lumen) between inspiratory and expiratory multidetector computed tomography as a measure of severe outcomes in asthmatic patients. J Allergy Clin Immunol 142:1773-1780.e9
He, Mu; Zha, Wei; Tan, Fei et al. (2018) A Comparison of Two Hyperpolarized 129Xe MRI Ventilation Quantification Pipelines: The Effect of Signal to Noise Ratio. Acad Radiol :
Wang, Jennifer M; Robertson, Scott H; Wang, Ziyi et al. (2018) Using hyperpolarized 129Xe MRI to quantify regional gas transfer in idiopathic pulmonary fibrosis. Thorax 73:21-28
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Driehuys, Bastiaan (2017) Crossing the Chasm(s): Demonstrating the Clinical Value of Hyperpolarized Gas MRI. Acad Radiol 24:1-3
Adamson, Erin B; Ludwig, Kai D; Mummy, David G et al. (2017) Magnetic resonance imaging with hyperpolarized agents: methods and applications. Phys Med Biol 62:R81-R123
Ebner, Lukas; Kammerman, Jeff; Driehuys, Bastiaan et al. (2017) The role of hyperpolarized 129xenon in MR imaging of pulmonary function. Eur J Radiol 86:343-352

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