Table 1.

Summary of Knowledge Gaps and Key Research Questions for the Early Detection of BOS after HCT

Themes	Gap Areas	Key Questions
The Clinical Entity	1.Natural history 2.Diagnostic definition	a.How should clinical phenotypes be defined, and how do these phenotypes correlate with pathogenesis and/or risk factors? b.How should the current NIH diagnostic criteria for BOS in patients with HCT be modified to enable earlier detection, while maintaining diagnostic accuracy?
Pathogenesis	3.Chronic GVHD pathways and alloimmune effectors 4.Early transplant events and acute lung injury 5.Lung microenvironment	a.What are the triggering events of BOS? b.Is there a mechanistic link between early posttransplant lung injury and the development of BOS? c.How does the bronchial epithelium orchestrate the immune response to lung injury and repair in the context of alloimmunity? d.At what point does alloimmune inflammation transition to irreversible fibrosis? e.Is large airway inflammation a manifestation of early disease pathogenesis? f.What is the role of endothelial injury in the development of BOS? g.What is the role of the microbiome in BOS pathogenesis? h.Do lung infections, specifically viruses, contribute to BOS pathogenesis as antigenic stimuli triggering alloimmunity, through direct epithelial injury, or both?
Identifying Patients at Risk	6.Risk factors 7.Role of viruses and lung infections	a.What risk factors for BOS are relevant in the current era of transplant practice? b.What combinations of cross-sectional and longitudinal risk factors can identify patients with high positive predictive value for BOS? c.Which specific viral and lung infections confer risk for the development of BOS? d.What is the “risk window” for BOS after a lung infection?
Clinical Approach	8.Screening 9.Diagnostic modalities 10.Biomarkers	a.How do we improve implementation of screening recommendations and early diagnostic testing, taking into account patient-centered factors? b.What clinical/physiologic/proteomic biomarkers identify patients with early BOS? c.Which tissues/organs should be targeted for early diagnostic biomarker discovery and at what longitudinal time points? d.What cells, cytokines, and other biomarkers in the BAL fluid identify early disease? e.Whom should we target for screening of BOS, and when should this screening begin? f.What is the optimal interval for lung function monitoring? g.Which novel PFT interpretative strategies, techniques of physiologic lung function assessment, and sensitive imaging techniques would allow for earlier detection of BOS? h.How should PFTs be used in association with clinical presentation and other modalities to diagnose BOS?

Definition of abbreviations: BAL = bronchoalveolar lavage; BOS = bronchiolitis obliterans syndrome; GVHD = graft-versus-host disease; HCT = hematopoietic cell transplant; PFT = pulmonary function test.