TRANSPIRE: A Prospective Cohort Study of Lung Injury After Hematopoietic Stem Cell Transplant in Children.

Project Summary Hematopoietic stem cell transplant (HSCT) is increasingly used for non-malignant hematologic disorders such as sickle cell anemia and marrow failure, and complications of HSCT are more prevalent and important as causes of long term morbidity. Improved diagnosis and treatment and treatment are urgent issues. Lung injury is frequent after HSCT, with as many as 15% of children transplanted having reduced FEV1, later leading to overt bronchiolitis obliterans (BO) which is associated with high morbidity and mortality. Diagnosis of BO in adults depends on spirometry, and evidence suggests that early diagnosis may improve chances of recovery of lung function and survival. Small children, and even older children and teenagers who feel unwell and are uncooperative, are unable to perform spirometry, meaning that lung impairment is “invisible” until severe and clinically manifest. Progress in improving lung outcomes of HSCT in children has been hindered by lack of diagnostic strategies, and by the need for a large group of cases to allow testing of biological, pathological and diagnostic hypotheses to advance the field. We propose assembling a prospective cohort study of all children receiving HSCT at 6 major US transplant centers. We will perform standardized prospective testing of lung function and clinical data collection in all children in the cohort, to determine the frequency, clinical phenotypes and risk factors for BO (Specific Aim 1). BO is a rare disease so progress will not be made absent a multi-center cohort study that uniformly defines clinical phenotype and prospectively collects samples, allowing retrospective study of early molecular events that predict later disease. In Specific Aim 2 we will collect calendar and event-driven biological samples, including serum, plasma, peripheral blood mononuclear cells and bronchiolar lavage fluid, which will be stored and used to identify biomarkers of onset of BO and of response to therapy. Moreover, we will collect pathological samples that will be analyzed using a pre- existing rare lung disease pathology platform to identify genetic and anatomic changes that define BO. Lastly, in Specific Aim 3 we will test and disseminate novel lung testing strategies, including innovative imaging, to address the critical clinical challenge of late diagnosis of lung impairment in children. We provide examples of essential biological studies that can only be performed using the resources of the cohort, for which we will seek additional R01 funding. Taken together, this cohort study can fundamentally change the paradigm of lung injury after transplant and provide a platform for testing preventive and therapeutic treatments.