Regional Monitoring of CF Lung Disease

Description

Cystic fibrosis (CF) is a progressive, systemic disease affecting an estimated 30,000 children and adults in the United States (70,000+ worldwide) and is caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein–a chloride and bicarbonate channel that regulates ion transport and mucus composition in CF-affected tissues, such as the lung. In airways this leads to mucus stasis, infection, inflammation, and remodeling that result in mucus plugs, regional lung obstruction, and progressive airway destruction and bronchiectasis. Highly-effective CFTR modulators, which are recently available to >90% of patients, have revolutionized CF clinical care, with large increases in pulmonary function as a result of more effective mucociliary clearance. As a result, burdensome maintenance therapies like mechanical airway clearance treatment (ACT), requiring nearly 2 dedicated hours per day, have been questioned by patients, families, and medical providers. In a recent survey of CF community members, ACT was ranked as the most burdensome chronic therapy, yet is the least studied. Prospective studies of maintenance-therapy withdrawal pose potential ethical risks, since traditional testing via spirometry and/or multiple-breath washout is relatively insensitive to small or regional changes and long-term lung-function reductions often have permanent consequences. Nevertheless, many patients have withdrawn these maintenance therapies against advice from their providers. A major gap in CF management is our ability to monitor lung function sensitively and rapidly as a result of treatment changes, such as partial withdrawal of ACT.

Breakthroughs in structural and functional magnetic resonance imaging (MRI) have demonstrated exquisite sensitivity to regional CF lung disease and can monitor regional and subtle changes over time, without ionizing radiation, even in patients with normal spirometry. As demonstrated in the previous R01 that ultrashort echo time (UTE) MRI provides structural images that rival computered tomography (CT) imaging, with sensitivity to detect all of the structural hallmarks of treatable (e.g., mucus plugs) and permanent lung disease (e.g., bronchiectasis). It has been demonstrated that hyperpolarized 129Xe MRI is more sensitive than any other technique at detecting changes in regional pulmonary ventilation and gas exchange. For the first time, a single modality (MRI) is available to safely monitor regional lung disease and treatment changes before FEV1 declines become permanent. This is a unique opportunity to safely evaluate ACT in CF populations that remain at risk of long-term lung function decline.