Bronchiolitis Obliterans Syndrome
Bronchiolitis Obliterans Syndrome (BOS) is a severe, progressive, non-reversible obstructive lung disease characterized by inflammation and fibrosis of the small airways (bronchioles), leading to their narrowing and eventual obliteration. It primarily manifests as a late complication following allogeneic hematopoietic stem cell transplantation (HSCT) or lung transplantation, though it can also result from exposure to inhaled toxins, viral infections, autoimmune diseases, or as a sequela of certain medications. The pathogenesis of BOS involves immune-mediated injury to the bronchiolar epithelium, resulting in chronic inflammation, fibroproliferation, and subsequent luminal obliteration by granulation tissue and fibrosis. This process leads to airflow limitation, impaired gas exchange, and progressive respiratory insufficiency. The health impacts of BOS are substantial, as it is associated with significant morbidity, decreased quality of life, and increased mortality, particularly in transplant recipients where it is a leading cause of late graft failure.
This type of BOS occurs as a major complication after lung transplantation or allogeneic hematopoietic stem cell transplantation. In lung transplant recipients, BOS is the principal manifestation of chronic lung allograft dysfunction (CLAD) and is characterized by a progressive decline in pulmonary function, particularly a persistent reduction in forced expiratory volume in one second (FEV1). In HSCT recipients, BOS is considered a form of chronic graft-versus-host disease (GVHD), representing immune-mediated injury to the small airways and resulting in airflow obstruction.
This subtype is associated with exposure to inhaled toxicants such as diacetyl (found in certain food flavorings), nitrogen oxides, ammonia, or other chemicals. The inhaled agents cause direct epithelial injury and inflammation of the bronchioles, leading to fibrosis and luminal obliteration. The clinical course can be acute or subacute, depending on the intensity and duration of exposure, and often leads to irreversible airflow limitation.
This form develops following severe lower respiratory tract infections, particularly viral infections such as adenovirus, respiratory syncytial virus (RSV), or influenza, especially in children. The infection triggers an inflammatory response in the bronchioles, resulting in epithelial damage, fibrotic repair, and subsequent airway narrowing. The disease may present as post-infectious bronchiolitis obliterans, often with a chronic and progressive course.
Autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and other connective tissue disorders, can be associated with the development of BOS. Immune-mediated mechanisms lead to chronic inflammation and fibrosis of the small airways, resulting in airflow obstruction. This type may coexist with other pulmonary manifestations of autoimmune disease and often requires immunomodulatory therapy.
The epidemiology of Bronchiolitis Obliterans Syndrome varies depending on the underlying etiology and patient population. Among lung transplant recipients, BOS develops in approximately 30% to 60% of patients within five years post-transplantation and remains the leading cause of late morbidity and mortality in this group. In allogeneic hematopoietic stem cell transplant recipients, the incidence of BOS is estimated at 2% to 14%, with a higher risk observed in those with chronic graft-versus-host disease. Toxin-induced BOS is relatively rare but has been reported in occupational settings with exposure to inhaled chemicals, such as food processing workers exposed to diacetyl. Post-infectious BOS is more commonly observed in pediatric populations following severe viral lower respiratory tract infections, with variable incidence depending on outbreak severity and geographic region. The prognosis of BOS is generally poor, with median survival after diagnosis ranging from two to five years, depending on severity and response to therapy.
The diagnosis of Bronchiolitis Obliterans Syndrome is primarily clinical, supported by pulmonary function testing, imaging, and, when feasible, histopathological confirmation. Diagnostic criteria in lung transplant recipients typically include a persistent and irreversible decline in FEV1 (≥20% from baseline) in the absence of other identifiable causes, such as acute rejection, infection, or anatomic airway complications. Spirometry demonstrates a fixed obstructive pattern with reduced FEV1 and a decreased FEV1/FVC ratio. High-resolution computed tomography (HRCT) of the chest may reveal mosaic attenuation, air trapping, bronchial wall thickening, and bronchiectasis, particularly on expiratory scans. While transbronchial or surgical lung biopsy can provide definitive histopathological evidence of bronchiolar fibrosis and luminal obliteration, it is often not performed due to procedural risks. In hematopoietic stem cell transplant recipients, BOS is diagnosed based on National Institutes of Health (NIH) consensus criteria, which include evidence of airflow obstruction on spirometry, absence of infection, and supporting radiographic or histological findings. Ancillary tests may include bronchoalveolar lavage to exclude infection and immunological workup to assess for graft-versus-host disease or autoimmune processes. Early diagnosis is critical to optimize management and improve outcomes.
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