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

呼吸道病毒对同种异体造血细胞移植受者闭塞性细支气管炎综合征的纵向影响

• 批准号: 10347053
• 负责人: Guang-Shing Cheng
• 金额: $ 10.06万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10347053
• 关键词: 2019-nCoV; Address; Adult; Allogenic; Area; Biological; Biological Assay; Blood; Bronchiolitis Obliterans; COVID-19 pandemic; Child; Childhood; Clinic; Clinical; Collection; Coupled; Data; Development; Devices; Diagnosis; Disease; Early Diagnosis; Early Intervention; Enrollment; Epidemiology; Epitopes; Event; Forced expiratory volume function; Functional disorder; Goals; Home; Human Metapneumovirus; Impairment; Infection; Influenza; Intervention; Knowledge; Lead; Longitudinal Studies; Longitudinal prospective study; Lung; Lung diseases; Medical; Monitor; Natural History; Needles; Newly Diagnosed; Outcome; Parainfluenza; Pathogenesis; Pathogenicity; Patients; Phenotype; Procedures; Protocols documentation; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary function tests; Quality of life; Questionnaires; Recording of previous events; Respiratory syncytial virus; Risk; Risk Factors; Role; Serology test; Serum; Spirometry; Survivors; Symptoms; Syndrome; Technology; Testing; Therapeutic Intervention; Time; Transplant Recipients; Upper respiratory tract; Viral; Viral Load result; Viral Respiratory Tract Infection; Virus; allogeneic disease; base; chronic graft versus host disease; clinical diagnosis; clinically relevant; clinically significant; cloud based; cohort; design; flu; follow-up; hematopoietic cell transplantation; high risk; improved; improved outcome; innovation; isoimmunity; mortality; nasal swab; novel; novel therapeutics; patient stratification; post-transplant; prospective; pulmonary function; pulmonary function decline; remote health care; respiratory; respiratory virus; risk stratification; sample collection; serosurvey; virome; wireless

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.

项目概要/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 (cGVHD) 发生在同种异体造血细胞移植 (alloHCT) 的幸存者中，导致不可逆的肺损伤 功能障碍，生活质量差，5 年生存率为 40%。致病菌知识的根本差距 导致 BOS 进行性肺功能障碍的事件尚未得到很好的表征，这阻碍了我们的研究 有效干预的能力。我们的初步数据表明，呼吸道病毒，包括呼吸道病毒 合胞病毒 (RSV)、副流感病毒 (PIV)、人类偏肺病毒 (HMPV) 和流感病毒 (FLU) 是 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）在移植后很常见。我们已经证明移动无线家用肺量计是可行的 慢性移植物抗宿主病 (cGVHD) 患者的早期诊断和对肺部轨迹的详细了解 功能衰退。我们的总体假设是，累积的呼吸道病毒暴露会导致 同种免疫背景下 BOS 的发展和不良结果。该提案的总体目标是 建立 RVI 与疾病表现连续体之间的时间关系，从 无症状到有症状的上呼吸道疾病到下呼吸道疾病，以及肺功能轨迹 老板。我们建议对 RVI 和肺的自然史进行多中心前瞻性纵向研究 具有创新的家庭监测方法，克服了理解临床的障碍 导致 BOS 和严重 BOS 表型的事件。目标 1 研究 RVI 作为 BOS 触发器的作用。我们 将招募有 BOS 风险的 alloHCT 受者（队列 1，n=200），包括那些诊断为 cGVHD 或患有 BOS 的受者 高危 RVI 病史（RSV/PIV/HMPV/Flu/SARS-CoV2）。患者将每周进行一次家庭肺活量测定， 方案化监测和症状提示的自我收集鼻拭子病毒 PCR。此外，血清将 通过无针家用血液采集套件每季度采集一次，并使用 VirScan（一种新型综合性血液采集工具）进行分析。 血清调查可检测超过 1000 种病毒株的表位，以评估累积呼吸道感染的影响 病毒负担对 BOS 结果的影响。目标 2 检查 RVI 对 BOS 肺部病情加重的作用，以及 累积 RVI 暴露（由 VirScan 确定）与患者 FEV1 加速下降之间的关联 具有严重的 BOS 表型。临床诊断为 BOS 的患者（队列 2，n=80）将执行相同的操作 程序如队列 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 FEV1 加速下降的预测因素。本研究产生的关键数据将 提高对 RVI 背景下早期 BOS 的认识，对强化治疗风险最高的患者进行风险分层 监测，并确定测试早期干预措施和新颖干预措施的切实终点和生物学原理 疗法。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，这是一个重大而紧迫的未满足需求领域。