Bronchiolitis obliterans syndrome (BOS) is an irreversible, obstructive lung condition resulting from a combination of inflammation and immune response which manifests as permanent pulmonary function decline. BOS is a significant source of pulmonary complications for both lung and bone-marrow transplant (BMT) recipients, and despite its prevalence and precipitous clinical course, there is a lack of clinical tools for routine surveillance for BOS post-transplantation. Surveillance for BOS is largely limited to spirometry, which can be unreliable in young children and insensitive to early airway obstruction, and computed tomography. In BMT patients, routine screening via CT is avoided due to serial ionizing radiation exposure and screening via spirometry is often less frequent than lung-transplant recipients. As a result, pulmonary complications in this population can go under diagnosed, and BMT patients often are referred to pulmonary physicians only after significant lung functional decline, which limits interventional options to improve patient outcomes. Emerging magnetic resonance imaging (MRI) techniques are poised to revolutionize pulmonary imaging and indeed have already begun to have an impact on diseases such as cystic fibrosis, COPD, and asthma. Ultra- short echo time (UTE) MRI methods now rival CT in the visualization and quantification of regional lung parenchymal pathology, and a single breath-hold of hyperpolarized 129Xe can reveal ventilation deficits, which are regions of the lung not properly ventilated due to airway obstruction. The central hypothesis of this career- development proposal is that a combined UTE and 129Xe MRI-based approach is more sensitive to early lung structural and functional changes in BMT patients than traditional clinical follow-up, and that in the future (Aim 3, Bridge to R01), a clinical algorithm that combines UTE and 129Xe MRI with a battery of routine pulmonary function tests, will improve outcomes for BMT patients. Strong preliminary data support the application of quantitative UTE and 129Xe MRI in this population. Cincinnati Children?s is a world-leader in the fields of pediatric bone marrow transplantation, pulmonary medicine, and radiology, and is the ideal environment to conduct the proposed research and for the PI to develop the essential skills to have a successful career as an independent investigator in the translational sciences. The PI has identified a mentoring team, collaborators, and informal advisors to support and guide aspects of the research project and her career development, the latter of which focuses on cultivating strong scientific communication through formal presentations and publications, networking and educational opportunities at national and international conferences, formal and informal training in the ethical conduct of research, and collaborative grant proposal writing.
Late-onset pulmonary compilations following bone-marrow transplantation are a major source of morbidity and mortality, yet the clinical tools available to perform routine screening for pulmonary issues in the BMT population are not sensitive to early disease or to regional variations in disease. In this proposal, new ultra- short echo time and hyperpolarized 129Xe gas magnetic resonance imaging (MRI) techniques will be used in the pediatric bone-marrow transplant recipients for the first time to image and quantify regional lung structural and functional changes over time. We believe these methods will be more sensitive than any other method at detecting early disease, which can lead to early interventions and better outcomes.
