Early detection of pulmonary complications of hematopoietic stem-cell transplantation in children using hyperpolarized xenon MRI

项目摘要/摘要 造血干细胞移植(HSCT)后发生晚发型、非感染性肺部并发症 在所有患者中，多达一半的人在病因和临床过程中是不同的，并且是致命的。肺活量测定法 作为监测的基石，然而，一半的儿科HSCT人群无法进行肺活量测定。AS 因此，儿童HSCT后肺损伤通常被诊断为晚期，治疗方案 有限，损害是不可逆转的，死亡率很高。早期发现HSCT后肺损伤是我们最好的选择 有机会进行干预，稳定肺功能下降，改善预后，迫切需要 为年轻的HSCT患者提供更好的诊断--特别是对那些无法进行肺活量测定的患者。对这件事 最后，我们开发了吸入式超极化氙气-129(129Xe)通风和气体交换磁 磁共振成像(MRI)技术可在空间上分辨、区分和量化小气道、间质和 微血管异常。该项目的长期目标是降低与肺部相关的发病率 129Xe磁共振成像在儿童HSCT人群中的临床应用 诊断。这项提议的中心假设是，129Xe MRI在非常年幼的儿童中是可行的 不能进行PFT，并将在HSCT后检测到早期肺部受累。我们的方法基于三个 具体目标：(1)建立儿童129Xe气体交换磁共振成像系统，对健康对照志愿者和 确诊为气体交换障碍的患者年龄为6-18岁；(2)HSCT后肺表型 6-18岁儿童接受~(129)Xe通风和气体交换磁共振成像的受累情况 HSCT，在大约100天和HSCT后1年进行纵向MRI和PFT；(3)优化快速策略 2~5岁HSCT患者的129Xe磁共振成像。这种方法得到了我们以前的工作的支持，并且 经验表明，129Xe核磁共振在新生儿、无法进行肺活量测定的幼儿中是可行的， 以及服用镇静剂的病人。这种方法是创新的，因为129Xe气体交换磁共振对任何儿科医生来说都是新的 对诊断为气体交换障碍的儿童进行成像将建立一座概念上的桥梁 在更好地理解疾病病理生理学和129Xe气体交换MRI所见之间，这将增强 HSCT人群气体交换障碍的诊断及129Xe磁共振的临床意义 儿科HSCT患者的初步数据显示扩散障碍和红细胞转移异常， 提示一种临床上未被认识到的非梗阻性表型。这个项目将给临床护理带来革命性的变化 适用于有肺部并发症的年轻HSCT患者。通风、间质和空气的纵向轨迹 HSCT后129Xe磁共振微血管改变有助于临床危险分层。129Xe MRI将启用 对无症状患者进行监测和早期发现，进行表型分析以个性化临床管理和 治疗方法，以及对非常年幼儿童的肺功能的强有力的评估。

PROJECT SUMMARY/ABSTRACT Late-onset, non-infectious pulmonary complications following hematopoietic stem-cell transplant (HSCT) occur in up to half of all patients, are heterogeneous in etiology and in clinical course, and are deadly. Spirometry is the cornerstone of surveillance, yet half of the pediatric HSCT population are unable to perform spirometry. As a result, post-HSCT lung injury in children often is diagnosed in an advanced stage, where therapeutic options are limited, damage is irreversible, and mortality is high. Early detection of lung injury after HSCT is our best opportunity to intervene, stabilize lung-function decline, and improve outcomes, and there is an urgent need for better diagnostics for young HSCT patients—especially for those who are unable to perform spirometry. To this end, we have developed inhaled hyperpolarized xenon-129 (129Xe) ventilation and gas-exchange magnetic resonance imaging (MRI) techniques to spatially resolve, differentiate, and quantify small airway, interstitial, and microvascular abnormalities. The long-term goal of this project is to lower pulmonary-related morbidity in the pediatric HSCT population via the clinical application of 129Xe MRI as an imaging-based, lung-function diagnostic. The central hypothesis of this proposal is that 129Xe MRI is feasible in very young children who are unable to perform PFTs and will detect early lung involvement post-HSCT. Our approach is based on three Specific Aims: (1) develop 129Xe gas-exchange MRI in children by imaging healthy-control volunteers and patients with diagnosed gas-exchange impairment ages 6-18 years old; (2) phenotype post-HSCT pulmonary involvement using 129Xe ventilation and gas-exchange MRI in children ages 6-18 years old who have received HSCT, with longitudinal MRI and PFTs at ~100 days and 1-year post-HSCT; (3) optimize strategies for rapid 129Xe MRI in HSCT patients ages 2-5 years old. This approach is supported by our previous work and experience showing 129Xe MRI is feasible in neonates, in young children who are unable to perform spirometry, and in sedated patients. This approach is innovative because 129Xe gas-exchange MRI is novel to any pediatric population, and imaging children with diagnosed gas-exchange impairment will build a conceptual bridge between better-understood disease pathophysiology and 129Xe gas-exchange MRI findings, which will enhance the clinical interpretation of 129Xe MRI and diagnosis of gas-exchange impairment in the HSCT population. Preliminary data in pediatric HSCT patients revealed diffusion-barrier and RBC-transfer abnormalities, suggesting a clinically-under-recognized, non-obstructive phenotype. This project will revolutionize clinical care for young HSCT patients with pulmonary complications. Longitudinal trajectories of ventilation, interstitial, and microvascular changes from 129Xe MRI post-HSCT will help in clinical risk stratification. 129Xe MRI will enable surveillance and early detection in asymptomatic patients, phenotyping to personalize clinical management and therapeutic approach, and robust assessment of lung function in very young children.