bronchiolitis obliterans syndrome

bronchiolitis obliterans syndrome
Name	Bronchiolitis obliterans syndrome
Synonyms	BOS
Field	Pulmonology, Transplant medicine
Symptoms	Progressive dyspnea, cough, decline in FEV1
Complications	Respiratory failure, Chronic lung allograft dysfunction
Onset	Months to years post-transplant
Duration	Chronic
Types	Based on FEV1 decline
Causes	Alloimmune response, Graft-versus-host disease, Infection, Aspiration
Risks	Lung transplantation, Hematopoietic stem cell transplantation, HLA mismatch
Diagnosis	Pulmonary function test, Transbronchial biopsy, High-resolution computed tomography
Differential	Acute rejection, Infection, Bronchial stenosis
Prevention	Immunosuppression, Surveillance
Treatment	Augmented immunosuppression, Azithromycin, Extracorporeal photopheresis, Lung retransplantation
Medication	Corticosteroids, Calcineurin inhibitors, mTOR inhibitors
Prognosis	Leading cause of death post-lung transplant
Frequency	Affects ~50% of lung transplant recipients by 5 years

Bronchiolitis obliterans syndrome is a form of chronic lung allograft dysfunction and a major complication following lung transplantation and hematopoietic stem cell transplantation. It is characterized by a progressive, irreversible decline in lung function, specifically a decrease in the forced expiratory volume in 1 second, in the absence of other identifiable causes. The syndrome represents a clinical diagnosis of bronchiolitis obliterans, a pathological pattern of fibrotic obstruction of the small airways, and is the leading cause of long-term mortality after lung transplantation.

Definition and overview

Bronchiolitis obliterans syndrome is formally defined by a sustained decline in FEV1 to below 80% of the post-transplant baseline, as established by the International Society for Heart and Lung Transplantation. It is the clinical correlate of the histopathologic lesion bronchiolitis obliterans, involving fibrotic scarring and obliteration of the terminal and respiratory bronchioles. The syndrome is a primary phenotype of chronic lung allograft dysfunction and represents a major barrier to long-term survival following procedures like those performed at Cleveland Clinic and University of Pittsburgh Medical Center. Its development signifies a failure of long-term graft acceptance despite modern immunosuppressive therapy.

Causes and risk factors

The primary cause is an aberrant alloimmune response directed against the donor lung, often mediated by T cells and antibodies against Human leukocyte antigen mismatches. A significant risk factor is the development of acute cellular rejection, particularly severe or recurrent episodes, as documented in registries like the United Network for Organ Sharing. Other major risks include graft-versus-host disease following hematopoietic stem cell transplantation, as seen in patients treated at centers like Fred Hutchinson Cancer Research Center. Additional contributing factors are cytomegalovirus infection, community-acquired respiratory viral infections, gastroesophageal reflux disease with aspiration, and exposure to air pollution or occupational inhalants.

Pathophysiology

The pathophysiology centers on a repetitive injury to the airway epithelium, initiating a dysregulated repair process. Initial insults, such as ischemia-reperfusion injury or infection, damage the epithelium and expose underlying HLA and other antigens. This triggers a cascade involving lymphocytes, macrophages, and neutrophils, leading to the release of pro-fibrotic mediators like transforming growth factor beta and platelet-derived growth factor. The resultant inflammation and epithelial-mesenchymal transition cause fibroproliferation within the lamina propria and lumen of the bronchioles, culminating in irreversible luminal occlusion and airflow obstruction.

Diagnosis and classification

Diagnosis is primarily clinical, based on serial pulmonary function tests showing an irreversible decline in FEV1. The International Society for Heart and Lung Transplantation classification system stages severity from BOS 0-p to BOS 3 based on the degree of FEV1 loss. High-resolution computed tomography of the chest, often showing mosaic attenuation and air trapping, is a key non-invasive tool. While transbronchial biopsy can provide histologic confirmation, its sensitivity is limited due to patchy involvement; findings may include the classic constrictive bronchiolitis pattern. Other causes, such as acute rejection or bronchial stenosis, must be rigorously excluded.

Management and treatment

Management is challenging and focuses on stabilizing lung function. First-line therapy often involves augmenting immunosuppression, such as with high-dose corticosteroids or switching calcineurin inhibitors. The macrolide antibiotic azithromycin has immunomodulatory effects and is used empirically. For refractory cases, options include extracorporeal photopheresis, total lymphoid irradiation, or mTOR inhibitors like sirolimus. Management of associated conditions, such as aggressive treatment for gastroesophageal reflux disease with fundoplication, is critical. The definitive treatment for advanced disease is lung retransplantation, though outcomes are inferior to primary transplantation.

Prognosis and outcomes

The prognosis is generally poor, as bronchiolitis obliterans syndrome is the leading cause of death beyond the first year after lung transplantation. Median survival after diagnosis is approximately 3-5 years, with progression to respiratory failure. Outcomes are worse with higher BOS stage at diagnosis and rapid decline in FEV1. The syndrome significantly impacts the long-term success of transplant programs worldwide and remains a major focus of research within organizations like the International Society for Heart and Lung Transplantation to develop effective preventive and therapeutic strategies.

Category:Lung disorders Category:Transplant medicine