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Principal Investigator: Guang-Shing Cheng
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2024
Award: $739,186
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><Acceleration><Active Follow-up><Address><Adult><Adult Human><Allogenic><Antigenic Determinants><Area><Assay><Binding Determinants><Bioassay><Biological><Biological Assay><Blood><Blood Reticuloendothelial System><Blood Serum><Bronchiolitis Obliterans><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 virus><COVID-19 years><COVID19 virus><Child><Child Youth><Childhood><Children (0-21)><Chronic GVHD><Clinic><Clinical><CoV-2><CoV2><Collection><Coupled><Data><Development><Devices><Diagnosis><Disease><Disorder><Dysfunction><Early Diagnosis><Early Intervention><Enrollment><Epidemiology><Epitopes><Event><Exudative Bronchiolitis><FEV1><FEV1%VC><FEVt><Forced Expiratory Volume><Forced Expiratory Volume 1 Test><Forced Expiratory Volume in 1 Second><Forced expiratory volume function><Functional disorder><Goals><Grippe><HSC transplantation><Hematopoietic Stem Cell Transplant><Hematopoietic Stem Cell Transplantation><History><Home><Human Metapneumovirus><Impairment><Infection><Influenza><Intervention><Intervention Strategies><Knowledge><Long-term prospective studies><Longitudinal Studies><Longterm prospective studies><Lung><Lung Diseases><Lung Function Tests><Lung Respiratory System><Medical><Monitor><Natural History><Newly Diagnosed><Outcome><PFT/FEV1><Parainfluenza><Pathogenesis><Pathogenicity><Patients><Phenotype><Physiopathology><Procedures><Proliferative Bronchiolitis><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Function Test/Forced Expiratory Volume 1><Pulmonary function tests><QOL><Quality of life><Questionnaires><Recording of previous events><Respiratory syncytial virus><Risk><Risk Factors><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Serology test><Serum><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Spirometry><Survivors><Symptoms><Syndrome><Technology><Testing><Therapeutic Intervention><Time><Timed Forced Vital Capacity><Timed Vital Capacity><Transplant Recipients><Upper respiratory tract><Viral><Viral Burden><Viral Load><Viral Load result><Viral Respiratory Tract Infection><Virus><Wuhan coronavirus><active followup><adulthood><allogeneic disease><alloimmunity><biologic><chronic graft versus host disease><chronic graft vs host disease><chronic graft vs. host disease><clinical diagnosis><clinical relevance><clinical significance><clinically relevant><clinically significant><cloud based><cohort><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><design><designing><developmental><disease of the lung><disorder of the lung><early detection><enroll><epidemiologic><epidemiological><flu><follow up><follow-up><followed up><followup><hCoV19><hematopoietic cell transplantation><hematopoietic cellular transplantation><hematopoietic progenitor cell transplantation><high risk><histories><homes><improved><improved outcome><innovate><innovation><innovative><intervention therapy><interventional strategy><isoimmunity><kids><long-term study><longitudinal outcome studies><longitudinal, prospective study><longterm study><lung disorder><lung function><lung function decline><mortality><nCoV2><nasal swab><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathophysiology><patient stratification><pediatric><post-transplant><post-transplantation><posttransplant><posttransplantation><prospective><pulmonary><pulmonary function><pulmonary function decline><remote care><remote health care><remote healthcare><respiratory><respiratory virus><risk stratification><sample collection><serology assay><serology survey><serosurvey><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social role><specimen collection><stratified patient><stratify risk><transplant patient><upper airway tract><viral microbiome><viral respiratory infection><virome><wireless><youngster>