The Lung Transplant Clinical Trials Network (LT-CTN)

描述（由申请人提供）：肺移植受者是实体器官移植患者中增长最快的部分，其中97%是成年人。由于晚期肺病发病率的增加以及肺供体利用率的提高，预计这一增长将继续下去。不幸的是，患者的预后并没有相应的改善。肺移植后患者的中位长期生存期仅为5.5年，这一数字落后于所有其他常见的移植器官。这些不良结果反映了非传染性和传染性并发症的高负担。其中最主要的是巨细胞病毒（CMV），这是肺移植后最常见的机会性感染。尽管目前采取了预防措施，但仍有40%的血清学上有风险的肺移植受者受到影响。预防巨细胞病毒感染是至关重要的，因为它的发展与较高的长期移植物衰竭和死亡率有关。这种移植物衰竭，被称为慢性肺同种异体移植物功能障碍（chronic lung allograft dysfunction， CLAD），是长期生存率差的主要原因，5年内有50%的肺移植受者发生这种情况。尽管它很重要，但我们对导致CLAD的临床风险和免疫机制的理解是初步的，并且是基于小的、单中心的研究。因此，迫切需要科学严谨、设计良好的多中心肺移植研究，直接解决这些主要的移植物限制性并发症。为满足这一需求，我们建议通过CTOT建立肺移植临床试验网络（LT-CTN），开展CMV和CLAD在肺移植中的关键临床和机制研究。我们的团队代表了北美五家领先的学术肺移植中心（杜克大学、克利夫兰诊所、约翰霍普金斯大学、加州大学洛杉矶分校和多伦多大学）的关键临床和研究小组。通过解决肺移植术后发病率和移植物衰竭的主要原因，我们提出的研究有可能直接影响CMV预防的临床实践，并推进对CLAD的机制理解。此外，由于巨细胞病毒感染和慢性同种异体移植物功能障碍是与其他实体器官移植相关的并发症，我们的机制研究可能揭示在其他实体器官移植人群中重要的宿主反应。因此，我们拥有领导能力、临床研究专业知识和基础研究深度，可以成功完成拟议的研究，为CTOT项目的整体影响做出贡献，并帮助改善患者的预后。

DESCRIPTION (provided by applicant): Lung transplant recipients, 97% of whom are adults, are the fastest growing segment of solid organ transplant patients. This growth is expected to continue due to increasing incidence of advanced lung disease as well as increasing lung donor utilization rates. Unfortunately, there have not been parallel improvements in patient outcomes. Median long-term patient survival after lung transplant is only 5.5 years, a figure that lags all other commonly transplanted organs. These poor outcomes reflect the high burden of both non-infectious and infectious complications. Foremost among these is cytomegalovirus (CMV), the most common opportunistic infection after lung transplantation. It affects > 40% of all serologically at-risk lung transplant recipients despite current prophylaxis. Prevention of CMV infection is of paramount importance since its development is associated with higher rates of long-term graft failure and death. This graft failure, known as chronic lung allograft dysfunction (CLAD), is the primary reason for poor long-term survival and occurs in >50% of lung transplant recipients within five years. Despite its importance, our understanding of the clinical risks and immunological mechanisms that lead to CLAD is rudimentary and based upon small, single center studies. Thus, there is a critical unmet need for scientifically rigorous, well-designed multicenter lung transplant research studies that directly address these major graft-limiting complications. To meet this need, we propose creation of the Lung Transplant Clinical Trials Network (LT-CTN) through CTOT to conduct key clinical and mechanistic studies of CMV and CLAD in lung transplant. Our team represents key clinical and research groups of five of the leading academic lung transplant centers in North America (Duke, Cleveland Clinic, Johns Hopkins, University of California - Los Angeles, and University of Toronto). By addressing the major causes of morbidity and graft failure after lung transplantation, our proposed studies have the potential to directly impact clinical practice for CMV prevention and advance mechanistic understanding of CLAD. Furthermore, because CMV infection and chronic allograft dysfunction are complications relevant to transplantation of other solid organs, our mechanistic studies are likely to reveal host responses important in other solid organ transplant populations. Thus, we have the leadership, clinical research expertise and basic research depth to successfully accomplish the proposed studies, contribute to the overall impact of the CTOT program, and help improve patient outcomes.