Cystic fibrosis (CF) is a progressive, systemic disease affecting an estimated 30,000 children and adults in the United States (70,000 worldwide). It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which ultimately lead to lung-airway dysfunction. Pathological changes begin as mucus stasis, inflammation, infection, and airway remodeling and result in progressive air trapping, ventilation inhomogeneity, and bronchiectasis. A major gap in CF management is the capacity to monitor early and regional lung disease, both in clinical care and in response to therapies. Thus, evaluating structural changes concomitant with regional and global ventilation abnormalities is paramount to our understanding of their relationships in the young CF population, prior to the onset of clinical symptoms. CFTR modulators that target the most common cause of cystic fibrosis (F508del CFTR, found in > 85% of CF patients) have recently demonstrated efficacy in F508del homozygous, pediatric patients. Tools to monitor CFTR modulator efficacy in children are an urgent need, as these novel therapies were recently granted FDA approval in 2015 for patients ? 12 years of age. Existing pulmonary function testing via spirometry is insensitive to regional lung disease and is nearly impossible to use in young children; bronchoscopy is invasive and insensitive to regional disease. While chest CT is capable of detecting regional lung abnormalities, radiation exposure limits its long-term use for longitudinal (e.g., yearly) evaluation and provides limited functional information. Recent breakthroughs in pulmonary magnetic resonance imaging (MRI) set the foundation to advance this technology for monitoring CF lung disease progression and response to therapy in young patients, and patients with mild disease. Ultrashort echo time (UTE) MRI provides high resolution structural data that rivals standard CT imaging, and recent work from our research team demonstrates that pulmonary UTE MRI can identify each of the structural abnormalities previously identified by CT in young CF patients. The overarching hypothesis in our proposal is that MRI can serve as a sensitive tool to longitudinally monitor CF lung disease progression and response to CFTR modulator therapy in children with CF, without exposure to ionizing radiation. We will test this hypothesis by validating UTE MRI in 6-12 y.o. pediatric CF patients by comparison to CT (Aim 1), by longitudinally quantifying disease trajectory in those same patients and also response to CFTR modulator therapy in the half who will be drug-eligible (Aim 2), and by examining regional structure-function relationships via sensitive measures of regional ventilation heterogeneity: lung clearance index and hyperpolarized 129Xe MRI (Aim 3).
Cystic fibrosis (CF) is a fatal, multi-organ, genetic disease, most often manifesting as lung dysfunction; new therapeutics have recently demonstrated improved lung function in patients (12 y.o. and above) with a certain genetic type (known as F508del homozygous), who account for nearly 50% of all CF patients. Although early CF lung disease has few to no symptoms, early therapy is likely to extend the lifespan and improve the quality of life for these patients; however, there is currently no safe and effective non-invasive way to monitor lung function over time to assess progression of the disease and efficacy of therapy. New MRI methods that can be used to monitor the most important aspects of CF lung disease throughout life will be validated in this study, and the disease trajectories of pediatric F patients will be followed longitudinally to quantify change in regional structure and function.
| Pennati, Francesca; Roach, David J; Clancy, John P et al. (2018) Assessment of pulmonary structure-function relationships in young children and adolescents with cystic fibrosis by multivolume proton-MRI and CT. J Magn Reson Imaging 48:531-542 |
| Thomen, Robert P; Walkup, Laura L; Roach, David J et al. (2017) Hyperpolarized129Xe for investigation of mild cystic fibrosis lung disease in pediatric patients. J Cyst Fibros 16:275-282 |
| Walkup, Laura L; Thomen, Robert P; Akinyi, Teckla G et al. (2016) Feasibility, tolerability and safety of pediatric hyperpolarized (129)Xe magnetic resonance imaging in healthy volunteers and children with cystic fibrosis. Pediatr Radiol 46:1651-1662 |
| Roach, David J; Crémillieux, Yannick; Fleck, Robert J et al. (2016) Ultrashort Echo-Time Magnetic Resonance Imaging Is a Sensitive Method for the Evaluation of Early Cystic Fibrosis Lung Disease. Ann Am Thorac Soc 13:1923-1931 |
