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

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.