Addressing Knowledge Gaps in the Early Detection of Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation: An Official American Thoracic Society Research Statement

Abstract

Background: Bronchiolitis obliterans syndrome (BOS) is a late-onset noninfectious pulmonary complication of allogeneic hematopoietic cell transplant (HCT) that is often diagnosed at an advanced stage with severe lung impairment. Increasing use of HCT for the treatment of hematologic diseases worldwide translates to an increasing burden of BOS, particularly for the community pulmonologist. Early recognition of BOS, which offers the best opportunity to mitigate morbidity and mortality, is hampered by incomplete knowledge of the clinical course and disease process. The goal of this research statement is to survey our current understanding of BOS and to define the research agenda for the early detection of BOS. Methods: We convened a multidisciplinary panel that included community representatives for an in-depth survey of the published literature followed by an online workshop. Results: Major knowledge gaps were identified within interrelated themes of natural history and pathogenesis, risk factors, and the clinical diagnostic approach. Conclusions: This statement reflects the detailed assessment of identified knowledge gaps with associated key research questions, as well as a proposed research road map to stimulate cross-disciplinary collaborations from preclinical to clinical investigations.

Keywords: bronchiolitis obliterans; diagnosis; graft-versus-host disease; hematopoietic cell transplantation; late onset noninfectious pulmonary complications.

Figure 1.

Proposed pathogenesis of hematopoietic cell transplant–associated bronchiolitis obliterans syndrome (BOS). Current knowledge of the pathogenesis of BOS comes from humans (top panel) and a mouse model of chronic graft-versus-host disease that develops lymphocytic bronchiolitis with few obliterated bronchioles (bottom panel); specific aspects of pathogenesis are reviewed in References –, , and . See online supplement for additional references. BOS pathogenesis, which shares similarities with those of systemic chronic graft-versus-host disease, usually includes acute inflammation, alloreactive T and B lymphocyte dysregulation, chronic inflammation, and abnormal tissue repair, and subsequent airway fibrosis, although inflammatory pathways and fibrotic pathways may occur independently of one another. In predisposed patients, successive insults to the bronchiolar epithelium causing acute inflammation, such as conditioning or viral infections, are hypothesized to be a trigger for BOS. Alteration of epithelial progenitor cells, particularly club cells and basal cells, may be associated with the onset of BOS. T-cell dysregulation includes increases in cytotoxic CD8⁺ T cells and CD4⁺ TH17 cells and a decrease in T regulatory cells. T follicular helper cells are crucial for the activation of germinal-center B cells in the production and deposition of pathologic immunoglobulin and collagen, ultimately causing BOS. B-cell dysregulation is suggested by increased B-cell activation factor as well as specific subtypes of B cells. Macrophage recruitment and activation play a key role in the progression of fibrotic lesions in obliterative bronchiolitis. Donor macrophages mediated bronchiolar lesions in an IL-17 and CSF-1/CSF-1R (colony-stimulating factor 1 receptor)–dependent manner by disrupting the balance of M1/M2 macrophage function. Increased levels of TNF-α were found in the BAL fluid of patients at various stages of the process, whereas TGF-β signals proximal airway fibroblasts and allows their differentiation to myofibroblasts, promoting collagen and extracellular matrix protein deposition and airway remodeling. Ab = antibody; BAFF = B-cell activating factor; CCSP = club cell secretory protein; DAMP = damage-associated molecular pattern; DC = dendritic cell; ECM = extracellular matrix; GC = germinal center; MMP9 = matrix metalloproteinase 9; PAMP = pathogen-associated molecular pattern; PDGFα = platelet-derived growth factor receptor α; RV = respiratory virus; Tfh = T follicular helper cell; TNF-α = tumor necrosis factor-α; TGF-β = tumor necrosis factor-β; Treg = T regulatory cell.

Figure 2.

Proposed research road map for early detection of bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplant. The research framework arising from a multicenter prospective longitudinal observational cohort that incorporates clinical screening and early detection practices, starting from pre–hematopoietic cell transplant through BOS diagnosis and beyond. Protocolized sample collection includes BAL fluid from clinical bronchoscopy and paired blood and nasal samples for multi-omics translational biomarker discovery. A patient registry of BOS will collate retrospective and prospective data. Specific knowledge gaps and key questions will be answered by this study design, defining phenotypes and diagnostic criteria, risk factors, and biomarkers. Concurrent preclinical investigations with novel in vitro techniques are also proposed. cGVHD = chronic graft-versus-host disease HCT = hematopoietic cell transplant.