Advanced Phenotyping Improves Diagnostic, Longitudinal Assessment, and Treatment Strategies for Deployment-Related Respiratory Disease
Abstract
Background: Numerous reports document increased respiratory symptoms and medical encounters for chronic lung disease in military personnel (MP), including Veterans, returning from the Gulf War and Post-9/11 conflicts. Inhalational exposures invoked as potential causative agents include military burn pits. Biopsies obtained from MP with unexplained dyspnea demonstrate a spectrum of histopathologic abnormalities including constrictive bronchiolitis (CB) and pulmonary fibrosis (PF). Deployment-related respiratory disease (DRRD) is the term recently established to describe the spectrum of lung abnormalities in MP who have undergone surgical lung biopsy, and also in formerly deployed, non-biopsied MP with unexplained respiratory symptoms. Diagnosing DRRD is difficult, and its natural history is poorly understood, since commonly applied non-invasive tests fail to objectively identify the disease or gauge its severity. We have recently used a quantitative computed tomography (CT) imaging approach, Parametric Response Mapping (PRM), to show that MP with CB have increased functional small airways disease (fSAD) relative to healthy subjects and those with mild COPD. Our unpublished data further identify mixed phenotypes comprised of increased PRM-fSAD, HAA (high attenuation area, an indirect measure of interstitial lung abnormalities), and emphysema in cohorts of non-biopsied Gulf War and Post 9/11 Veterans. Additional non-invasive tests, including forced oscillation technique (FOT) and X-ray velocimetry (XV), may also objectively identify abnormalities in subjects with suspected or proven DRRD. Preclinical models of murine constrictive bronchiolitis (mCB) and murine pulmonary fibrosis (mPF) recapitulate specific histopathologic features of DRRD. Additional data suggest that advanced phenotyping techniques, including digital spatial profiling (DSP), FOT, XV, and PRM, may identify distinct phenotypes of mCB and mPF. We provide evidence to suggest that two U.S. Food and Drug Administration (FDA)-approved drugs (roflumilast and pirfenidone) may effectively treat mPF. Hypotheses: We hypothesize that PRM-fSAD increases over time in MP with suspected DRRD and that subsets of MP with unique phenotypes of DRRD may have different disease trajectories. We further hypothesize the existence of distinct molecular and radiographic/functional phenotypes associated with each microanatomic site of injury in DRRD that can be elucidated and treated in preclinical murine models of CB and PF. Specific Aims: Aim 1: To determine longitudinal trajectories and radiographic phenotypes using quantitative CT classifications in Veterans with suspected DRRD. Design: Subjects with suspected DRRD will be enrolled at the Department of Veterans Affairs (VA) Ann Arbor Healthcare System (VAAAHS) and evaluated using questionnaires, pulmonary function tests (PFTs), FOTs, and methacholine challenge tests. High-resolution CT (HRCT) will be obtained and analyzed using quantitative CT analytics. Prior HRCT and PFT results will be obtained (if available) and a subset of tests will be repeated at 1 year. The primary analysis will determine whether PRM-fSAD changes over time. Secondary and exploratory analyses will delineate distinct DRRD phenotypes and identify those symptoms, exposures, and test results most strongly associated with specific phenotypes and/or impact disease progression. Aim 2: To identify temporal and spatial relationships between molecular and functional/imaging phenotypes of mCB and mPF, and assess whether treatment with roflumilast and (or) pirfenidone ameliorates these conditions. Design: Advanced molecular (DSP) and functional/imaging (FOT, XV, PRM) testing will be performed on mice with CB and PF to temporally assess unique and shared phenotypes of each injury pattern. Mice with mCB and mPF will be treated with roflumilast and pirfenidone to determine their efficacy at preventing disease. Impact and Responsiveness
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310698
Entities
People
- Craig Galban
Organizations
- United States Army
- University of Michigan