Bronchiolitis obliterans is also known as obliterative bronchiolitis or constrictive bronchiolitis. When it occurs after lung transplantation or hematopoietic stem cell transplantation (HSCT) it is called bronchiolitis obliterans syndrome. Bronchiolitis obliterans is a type of obstructive lung disease of the small airways. It is a rare disease with characteristic features of fibrosis of terminal and distal bronchioles and spirometry showing airflow obstruction. It usually leads to progressive decline in lung function and has variable outcomes.
Several risk factors can lead to the development of bronchiolitis obliterans. It is one of the most common noninfectious complications after lung transplant and hematopoietic stem cell transplantation. Outside of transplantation, bronchiolitis obliterans can be seen after exposure to inhaled toxins and gases including sulfur mustard gas, nitrogen oxides, diacetyl (used as popcorn flavoring), fly ash and fiberglass. Bronchiolitis obliterans is also associated with autoimmune disorders, especially rheumatoid arthritis and less commonly with inflammatory bowel disease. It is also known to occur after a respiratory viral infection (adenovirus, respiratory syncytial virus), especially in children. Other infections associated with bronchiolitis obliterans are HIV and Human Herpes Virus (HHV) 8. Rare conditions like Castleman disease and paraneoplastic pemphigus have also been associated with bronchiolitis obliterans.
Bronchiolitis obliterans syndrome is considered a form of chronic allograft rejection after lung transplantation. The majority of lung transplant recipients who are long term survivors develop bronchiolitis obliterans syndrome. About 5% to 14% of HSCT recipients also develop bronchiolitis obliterans syndrome which is pulmonary graft vs. host disease and can present several months to years after transplantation.
In response to injury from inhalational toxins or autoimmune responses, there is inflammation of subepithelial structures and dysregulated repair, leading to fibroproliferation and abnormal regeneration of epithelium of the small airways. Histopathology classically demonstrates the involvement of terminal and respiratory bronchioles (distal small airways) but without significant changes in alveolar spaces and distal lung parenchyma. Hypertrophy of the smooth muscles of the bronchioles, peribronchiolar inflammatory infiltrates, accumulation of mucus in the bronchiolar lumen, and bronchiolar scarring can be noted in bronchiolitis obliterans. There is a concentric narrowing of the lumen of the bronchioles by the inflammatory fibrosis. There may even be complete occlusion of the lumen in some cases.
In lung transplantation, microvascular insufficiency and alloimmune responses to the transplanted lung may result in airway injury and development of bronchiolitis obliterans syndrome. Episodes of acute cellular rejection, HLA antibodies and gastro esophageal reflux disease with microaspiration have been shown to increase the risk of development of bronchiolitis obliterans syndrome after transplantation.
In bronchiolitis obliterans associated with paraneoplastic pemphigus, autoantibodies against desmoglein and plakin protein which are found both in cutaneous and respiratory epithelium have been implicated.
Bronchiolitis obliterans characteristically presents with dyspnea and cough that are persistent and progressive. Some may also have wheezing. Symptoms usually develop over weeks to months and are not episodic, unlike asthma. History may also elicit recent exposure to toxic fumes or gases, viral infections, symptoms of joint stiffness in cases of rheumatoid arthritis, prior lung or hematopoietic stem cell transplantation.
A physical exam may reveal decreased breath sounds and prolonged expiratory phase with or without wheeze. Rales may also be noted in some cases. Cases of bronchiolitis obliterans associated with Castleman’s disease may also have paraneoplastic pemphigus which may present with oral ulcers as well as lymphadenopathy.
Pulmonary function testing is essential for diagnosis. Spirometry demonstrates airflow obstruction that does not reverse with inhaled bronchodilator challenge. Forced expiratory volume in one second (FEV1) will be reduced and the ratio of FEV1 to Forced vital capacity (FEV1/FVC) is also reduced. Hyperinflation may occur, and hence Total lung capacity (TLC) may be increased. Diffusion capacity (DLCO) is usually reduced. The degree of FEV1 decline from post-transplant value determines the stage of bronchiolitis obliterans syndrome in lung transplant.
Chest radiographs may be normal in early disease or show signs of hyperinflation. Chest CT imaging may show bronchial wall thickening, patchy areas of hypo attenuation. If there are dynamic images with inspiratory and expiratory films, a mosaic pattern of perfusion may be noted due to air trapping from small airway disease.
Bronchoscopy can be performed if other causes of airflow obstruction are suspected like endobronchial tumor or sarcoid, but may be unrevealing in bronchiolitis obliterans. A lung biopsy is usually not necessary for diagnosis in the setting of classic symptoms, air trapping on imaging, airflow obstruction on spirometry in the setting of organ transplantation or toxic inhalational injury. If required for diagnosis, surgical lung biopsy is preferred over transbronchial biopsy since it involves distal bronchioles and not parenchyma. In cases following lung transplantation, a biopsy is not required for the diagnosis of bronchiolitis obliterans syndrome but may be required to exclude other causes of deterioration lung function like infection or acute rejection. Spirometry showing obstructive pattern is necessary for diagnosis.
Treatment of bronchiolitis obliterans syndrome after lung transplant involves augmenting immunosuppression since it is thought to be a form of chronic rejection. Hence, increasing or addition of immunosuppressive agents like tacrolimus, cyclosporine, mycophenolate mofetil, and prednisone has been used to treat bronchiolitis obliterans syndrome after transplant. Azithromycin has also been shown to decrease the incidence of bronchiolitis obliterans syndrome and improvement in lung function. The combination of inhaled fluticasone, oral montelukast and azithromycin triple therapy has also shown to decrease decline in lung function in bronchiolitis obliterans syndrome post-HSCT. In addition to these therapies, controlling gastro esophageal reflux is also recommended to decrease bronchiolitis obliterans syndrome. In cases where bronchiolitis obliterans syndrome is progressive and severe, then retransplantation of a lung may be indicated. Extracorporeal photopheresis has also been successfully used to slow the decline in lung function from bronchiolitis obliterans syndrome.
In non-transplant related bronchiolitis obliterans, removal from offending agents is essential. Immunosuppression with corticosteroids and cytotoxic agents like cyclophosphamide have been used for bronchiolitis obliterans related to rheumatoid arthritis, but have not been beneficial for bronchiolitis obliterans from toxic inhalation or post infectious etiology. In these patients, symptomatic treatment should be provided with cough suppressants, inhaled bronchodilators, and oxygen supplementation if needed.
Prognosis of patients with bronchiolitis obliterans is poor, and some may have a rapid decline in lung function. The clinical course of bronchiolitis obliterans syndrome related to transplant is variable with some patients being asymptomatic or stable after diagnosis and some patients with the slow and steady decline and others with an episodic drop in FEV1. If bronchiolitis obliterans syndrome develops with two years of lung transplantation, it is seen as predictive of worse outcome.