Predicting the onset of chronic rejection in lung transplant recipients using hyperpolarized 129Xe imaging

总结 存活超过5年的肺移植受者中，高达80%将发展为慢性肺移植 功能障碍（CLAD），一种异质性的进行性疾病，其特征是渐进的和不可逆的 功能衰退最终导致死亡。一旦开发，大多数CLAD类型不响应 以及目前可用的治疗干预措施。因此，早期诊断疑似CLAD至关重要， 旨在延迟疾病发作和/或进展的努力，通常通过积极的治疗进行， 治疗相关的免疫风险因素。 尽管最近修订了标准，但目前临床上依赖肺量测定来诊断疑似CLAD 存在几个缺点：即，由肺动脉造影提供的测量的全局性质 功能试验（PFT），它们未能区分排斥反应和感染作为功能性疾病的原因 下降，观察员之间在解释其结果时经常出现分歧，最后，他们无法改进 经支气管活检的靶向。一种成像模态，其能够灵敏且准确地检测 CLAD发病较早且具有更高的空间特异性，将提供显著的临床价值。 为了满足这一需求，拟议的项目将使用敏感的肺功能区域测量 其中各种超极化氙-129 MRI技术能够独特地提供以开发一组 能够在肺功能测定前诊断疑似CLAD的影像学标记物显示临床上 显著的功能下降;理想情况下，这些标志物也将能够区分 阻塞性和限制性形式的CLAD之前，任何一个成为症状。 本项目的第一个任务是使用多呼吸HP氙-129 MR成像来建立区域特异性 通气量（SV）和肺泡氧分压（PAO 2）作为梗阻性肺动脉高压早期诊断的影像学指标 CLAD：这些敏感的气体置换动力学指标在 移植肺将比肺量测定法更早地提供CLAD相关功能下降的指征。下一个是 我们将使用溶解相HP氙-129成像来量化肺泡气体交换的效率， 运输，以检测与肺功能相关的纤维化和血流障碍， 限制性CLAD。最后，我们将尝试在放射学上定义CLAD的几个新的亚类 与已知的相关风险因素相关，如缺血再灌注损伤、呼吸道感染、抗体- 介导的损伤和胃食管反流。

Summary Up to 80% of lung transplant recipients who survive beyond five years will develop chronic lung allograft dysfunction (CLAD), a heterogenous, progressive condition characterized by the gradual and irreversible functional decline eventually leading to death. Once developed, the majority of CLAD types do not respond well to currently available therapeutic interventions. Early diagnosis of suspected CLAD is therefore crucial to efforts aimed at the delaying disease onset and/or progression, which usually proceed via the aggressive treatment of associated immunological risk factors. Despite recently revised criteria, the current clinical reliance on spirometry to diagnose suspected CLAD suffers from several disadvantages: namely, the global nature of the measurements provided by pulmonary function tests (PFTs), their failure to differentiate between rejection and infection as the cause of functional decline, frequent inter-observer disagreement in interpreting their results and, finally, their inability to improve the targeting of transbronchial biopsy. An imaging modality capable of sensitively and accurately detecting CLAD-onset earlier and with more spatial specificity would provide significant clinical value. In response to this need, the proposed project will use the sensitive, regional measurements of lung function which various hyperpolarized xenon-129 MRI techniques are uniquely capable of providing to develop a set of imaging markers capable of diagnosing suspected CLAD before spirometric measurements reveal a clinically significant functional decline; ideally, these markers will also enable a distinction to be made between obstructive and restrictive forms of CLAD before either becomes symptomatic. The first task of this project will be to use multi-breath HP xenon-129 MR imaging to establish regional specific ventilation (SV) and alveolar oxygen tension (PAO2) as imaging markers for the early diagnosis of obstructive CLAD: increased heterogeneity in these sensitive measures of gas replacement dynamics within the transplanted lung will offer an earlier indication of CLAD-associated functional decline than spirometry. Next, we will use dissolved-phase HP xenon-129 imaging to quantify the efficiency of alveolar gas exchange and transport in order to detect the fibrotic and bloodflow impediments to pulmonary function associated with restrictive CLAD. Finally, we will attempt to radiologically define several novel sub-classifications of CLAD related to known associated risk factors such as ischemia reperfusion injury, respiratory infection, antibody- mediated injury and gastroesophageal reflux.