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.

项目摘要/摘要 支气管炎闭塞性综合征（BOS）是慢性移植抗宿主病的最严重表现 （CGVHD）在同种异体造血细胞移植（AllOHCT）的幸存者中，导致不可逆的肺 损害，生活质量差和5年生存率为40％。知识的基本差距 导致BOS渐进肺功能障碍的事件尚未得到很好的特征，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，包括呼吸系统 合成病毒（RSV），副氟氟扎（PIV），人元病毒（HMPV）和流感（流感）是 BOS发展的独立风险因素。此外，我们表明无症状呼吸道病毒 感染（RVI）是转移后常见的。我们已经证明移动无线家庭肺活量测定法是可行的 在患有CGVHD的患者中，可以早期诊断和对肺部轨迹的颗粒状理解 功能下降。我们的总体假设是，累积呼吸道病毒暴露导致 在同种免疫力的背景下，BOS和不良结果的发展。该提议的总体目的是 从 无症状至有症状的上呼吸道对降低道疾病，以及肺功能轨迹 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 通过创新的家庭监控方法功能，可以克服理解临床的障碍 导致BOS和严重BOS表型的事件。 AIM 1调查了RVI作为触发BOS的作用。我们 将招募AlloHCT接受者有BOS的风险（队列1，n = 200），包括诊断为CGVHD或A 高危RVI的历史（RSV/PIV/HMPV/Flu/SARS-COV2）。病人将每周进行家庭肺活量测定法和 协议监视和症状促进的自我收集的鼻拭子病毒PCR。此外，血清将是 每季度通过无针头收集套件收集，并用VirScan进行测定，VirScan是一种新颖的综合 为了评估累积呼吸系统的影响 BOS结果的病毒负担。 AIM 2检查了RVI对BOS肺部恶化的作用，以及 累积RVI暴露（由VirScan确定）在患者加速FEV1下降的关联 具有严重的BOS表型。 BOS临床诊断的患者（队列2，n = 80）将执行相同 作为队列1的程序。对于两个目的，病毒PCR和VirSscan结果将被比较并分析为 BOS发育或加速FEV1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，风险将患者分类为最高风险 监视，并确定有形的终点和生物原理，以测试早期干预措施和新颖 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财团 解决HCT接受者肺部疾病的具体目标，这是一个巨大而迫切的需求的领域。