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造血干细胞移植的并发症较多 作为长期发病的重要原因而普遍存在。改进诊断和治疗 和治疗是迫切需要解决的问题。HSCT后肺损伤频繁，高达15% 移植的儿童FEV1降低，后来导致明显的闭塞性毛细支气管炎(BO) 这与高发病率和高死亡率有关。成人BO的诊断依赖于 肺活量测定，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。年幼的儿童，甚至年龄较大的儿童和青少年 身体不适和不合作，无法进行肺活量测定，这意味着肺损伤 在严重和临床表现出来之前是“看不见的”。改善异基因造血干细胞移植肺结局的研究进展 由于缺乏诊断策略和需要一大群人，儿童的健康状况一直受到阻碍 允许对生物学、病理学和诊断假说进行测试的病例数 菲尔德。我们建议对所有在6岁接受HSCT的儿童进行前瞻性队列研究。 美国主要的移植中心。我们将对肺功能进行标准化的前瞻性测试 并收集队列中所有儿童的临床资料，以确定发生频率、临床 BO的表型和危险因素(特定目标1)。BO是一种罕见的疾病，因此进展不会 没有多中心队列研究，统一定义临床表型和 前瞻性地收集样本，使对早期分子事件的回顾研究成为可能 预测未来的疾病。在特定目标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 液体，将被储存并用于识别BO发病和应答的生物标志物 心理治疗。此外，我们将收集病理样本，将通过预检进行分析 现有的罕见肺部疾病病理平台，用于识别基因和解剖变化 定义BO。最后，在具体目标3中，我们将测试和传播新的肺部检测策略， 包括创新的成像，以应对肺部晚期诊断的关键临床挑战 儿童的损害。我们提供了基本生物学研究的例子，这些研究只能是 使用该队列的资源执行，我们将为此寻求额外的R01资金。 总而言之，这项队列研究可以从根本上改变肺损伤的范式 并为检测预防和治疗方法提供了一个平台。

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.