Longitudinal Impact of Respiratory Viruses on Bronchiolitis Obliterans Syndrome in Allogeneic Hematopoietic Cell Transplant Recipients

项目摘要/摘要 闭塞性细支气管炎综合征(BOS)是慢性移植物抗宿主病最严重的表现。 异基因造血细胞移植(AllHCT)幸存者的移植物抗宿主病(CGVHD)，导致不可逆性肺 功能受损，生活质量差，5年存活率40%。对致病原认识上的根本差距 导致BOS进行性肺功能障碍的事件尚未得到很好的描述，阻碍了我们的 有效干预的能力。我们的初步数据表明，呼吸道病毒，包括呼吸道病毒 合胞病毒(RSV)、副流感(PIV)、人类偏肺病毒(HMPV)和流感(Flu) BOS发生的独立危险因素。此外，我们发现无症状呼吸道病毒 感染(RVI)是移植后常见的疾病。我们已经证明了移动无线家庭肺活量测量是可行的。 可以对慢性移植物抗宿主病患者进行早期诊断，并能对肺的轨迹有一个细微的了解 功能衰退。我们的主要假设是，累积的呼吸道病毒暴露会导致 在同种异体免疫的背景下，BOS的发展和不良结局。这项建议的总体目标是 要建立沿着疾病表现的连续统的RVI之间的时间关系，从 无症状到有症状的上呼吸道到下呼吸道疾病，以及肺功能的轨迹 博斯。我们建议对RVI和肺的自然历史进行多中心前瞻性纵向研究。 使用创新的家庭监控方法，克服了解临床的障碍 导致BOS和严重BOS表型的事件。目的1研究RVI作为BOS触发因子的作用。我们 将登记有BOS风险的异基因红细胞移植受者(队列1，n=200)，包括那些被诊断为cGVHD或 高危RVI病史(RSV/PIV/HMPV/Flu/SARS-CoV2)。患者将每周在家中进行肺活量测定和 程序化监测和症状提示自采集鼻拭子病毒聚合酶链式反应。此外，血清将被 通过无针家庭采血试剂盒每季度采集一次，并使用VirScan进行检测，一种新型的 检测&gt；1000病毒株表位的血清调查，以评估累积呼吸道感染的影响 病毒对BOS结果的负担。目的2研究RVI在BOS肺加重中的作用，以及 累积RVI暴露(由VirScan确定)与患者FEV1加速下降的相关性 具有严重的BOS表型。临床诊断为BOS的患者(队列2，n=80)也会进行同样的检查 对于两个AIM，病毒聚合酶链式反应和病毒扫描结果将进行比较和分析，如下所示 BOS发展或FEV1加速下降的预测因素。这项研究产生的关键数据将 在RVI的背景下提高对早期BOS的认识，对高风险患者进行重症监护的风险分层 监测并确定可见的端点和生物学基础，以测试早期干预和创新 治疗。重要的是，这项提议还将建立一个独特的成人和儿科多中心联盟， 解决HCT接受者肺部疾病的具体目标，这是一个重大和迫切的需求领域。

PROJECT SUMMARY/ABSTRACT Bronchiolitis obliterans syndrome (BOS) is the most severe manifestation of chronic graft-versus-host disease (cGVHD) in survivors of allogeneic hematopoietic cell transplant (alloHCT), leading to irreversible pulmonary impairment, poor quality of life, and 5-year survival of 40%. Fundamental gaps in knowledge of the pathogenic events that contribute to progressive lung dysfunction in BOS have not been well characterized, hampering our ability to intervene effectively. Our preliminary data suggest that respiratory viruses, including respiratory syncytial virus (RSV), parainfluenza (PIV), human metapneumovirus (HMPV), and influenza (FLU), are independent risk factors for the development of BOS. Additionally, we show that asymptomatic respiratory viral infections (RVI) are common posttransplant. We have shown that mobile wireless home spirometry is feasible in patients with cGVHD and can enable early diagnosis and a granular understanding of the trajectory of lung function decline. Our overarching hypothesis is that cumulative respiratory viral exposure leads to the development of BOS and poor outcomes in the context of alloimmunity. The overall aim of this proposal is to establish the temporal relationship between RVI along the continuum of disease presentations, from asymptomatic to symptomatic upper respiratory tract to lower tract disease, and the lung function trajectory of BOS. We propose to conduct a multicenter prospective longitudinal study of the natural history of RVI and lung function with an innovative home monitoring approach that overcomes the barriers to understanding clinical events that lead to BOS and severe BOS phenotypes. Aim 1 investigates the role of RVI as triggers BOS. We will enroll alloHCT recipients at risk for BOS (Cohort 1, n=200), including those with a diagnosis of cGVHD or a history of high-risk RVI (RSV/PIV/HMPV/Flu/SARS-CoV2). Patient will perform weekly home spirometry and protocolized surveillance and symptom-prompted self-collected nasal swab viral PCR. In addition, serum will be collected quarterly via a needle-less home blood collection kit and assayed with VirScan, a novel comprehensive serosurvey that detects epitopes of >1000 virus strains, in order to assess the impact of cumulative respiratory viral burden on BOS outcomes. Aim 2 examines the role of RVI on pulmonary exacerbations in BOS, as well as the association of cumulative RVI exposure (as determined by VirScan) on accelerated FEV1 decline in patients with a severe BOS phenotype. Patients with a clinical diagnosis of BOS (Cohort 2, n=80), will perform the same procedures as Cohort 1. For both aims, viral PCR and VirsScan results will be compared and analyzed as predictors for BOS development or accelerated FEV1 decline. The critical data generated by this study will improve recognition of early BOS in the context of RVI, risk stratify patients at highest risk for intensive monitoring, and identify tangible endpoints and biologic rationale for testing early interventions and novel therapies. Importantly, this proposal will also establish a unique adult and pediatric multicenter Consortium with the specific goal of addressing lung disease in HCT recipients, an area of significant and urgent unmet need.