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

项目总结/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 在同种异体造血细胞移植（alloHCT）的存活者中，cGVHD（cGVHD）导致不可逆的肺移植。 损伤，生活质量差，5年生存率为40%。对病原体的认识存在根本差距 BOS中导致进行性肺功能障碍的事件尚未得到很好的表征，阻碍了我们的研究。 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 合胞病毒（RSV）、副流感病毒（PIV）、人偏肺病毒（HMPV）和流感病毒（FLU）是 BOS发展的独立风险因素。此外，我们发现，无症状呼吸道病毒 感染（RVI）是移植后常见的。我们已经证明了移动的无线家庭肺量计是可行的 在患有cGVHD的患者中，可以实现早期诊断和对肺移植物轨迹的粒度理解。 功能衰退。我们的总体假设是，累积的呼吸道病毒暴露导致 BOS的发展和同种免疫背景下的不良结局。本建议的总体目标是 为了建立RVI沿着疾病表现的连续体之间的时间关系，从 无症状到有症状的上呼吸道到下呼吸道疾病，以及 BOS。我们建议对RVI和肺的自然史进行多中心前瞻性纵向研究， 功能与创新的家庭监测方法，克服了障碍，了解临床 导致BOS和严重BOS表型的事件。目的1研究RVI作为触发BOS的作用。我们 将招募有BOS风险的alloHCT接受者（队列1，n=200），包括诊断为cGVHD或 高危RVI（RSV/PIV/HMPV/Flu/SARS-CoV 2）病史。患者将每周进行一次家庭肺功能测定， 方案化监测和HIV提示的自我采集鼻拭子病毒PCR。此外，血清将 每季度通过无针家庭血液采集套件收集一次，并使用VirScan进行分析，VirScan是一种新型的综合性血液分析仪。 血清学调查，检测>1000个病毒株的表位，以评估累积呼吸道感染的影响。 BOS结果的病毒负担。目的2：研究RVI在BOS患者肺部急性加重中的作用，以及 累积RVI暴露（由VirScan测定）与患者FEV 1加速下降的相关性 有严重的BOS表型临床诊断为BOS的患者（队列2，n=80）将进行相同的检查 程序为队列1。对于这两个目标，病毒PCR和VirsScan结果将进行比较和分析， BOS发展或FEV 1加速下降的预测因子。本研究生成的关键数据将 在RVI背景下提高对早期BOS的识别，对强化治疗风险最高的患者进行风险分层 监测，并确定有形的终点和生物学原理，以测试早期干预和新的 治疗重要的是，该提案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，这是一个重要而迫切的未满足需求领域。

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.