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

项目摘要 造血干细胞移植（HSCT）越来越多地用于非恶性血液病。 镰状细胞性贫血和骨髓衰竭等疾病，以及HSCT的并发症更多 作为长期发病率的原因普遍且重要。改善诊断和治疗 治疗是一个紧迫的问题。HSCT后肺损伤频繁，高达15%的HSCT患者发生肺损伤。 接受移植的儿童FEV 1降低，随后导致明显的闭塞性细支气管炎（BO） 其与高发病率和死亡率相关。成人BO的诊断取决于 肺量测定，有证据表明，早期诊断可能会提高康复的机会， 肺功能和存活率。小孩子，甚至大一点的孩子和青少年， 不适和不合作，无法进行肺功能测定，这意味着肺损伤 是“看不见的”直到严重和临床表现。改善造血干细胞移植肺部预后的研究进展 由于缺乏诊断策略，以及需要一个大的群体， 的情况下，允许测试生物学，病理学和诊断假设，以推进 领域我们建议对所有6岁时接受HSCT的儿童进行前瞻性队列研究， 美国主要移植中心我们将对肺功能进行标准化的前瞻性测试 收集队列中所有儿童的临床数据，以确定频率、临床 BO的表型和风险因素（特定目标1）。BO是一种罕见的疾病， 缺乏统一定义临床表型的多中心队列研究， 前瞻性收集样本，允许对早期分子事件进行回顾性研究， 预测未来的疾病在具体目标2中，我们将收集日历和事件驱动的生物 样本，包括血清、血浆、外周血单核细胞和细支气管灌洗液 液体，其将被储存并用于鉴定BO发作的生物标志物和对 疗法此外，我们将收集病理样本，并使用预- 现有的罕见肺部疾病病理学平台，以确定遗传和解剖学变化， 定义BO。最后，在具体目标3中，我们将测试和传播新的肺部测试策略， 包括创新的成像技术，以应对肺部疾病晚期诊断的关键临床挑战 对儿童的伤害。我们提供的基本生物学研究的例子，只能是 使用队列的资源进行，为此我们将寻求额外的R 01资金。 总之，这项队列研究可以从根本上改变肺损伤的模式， 移植并为测试预防和治疗性治疗提供平台。

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.