Bronchiolitis Obliterans

Etiology

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. Other etiologies of bronchiolitis obliterans include 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, SLE, 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, Postinfectious (mycoplasma, bacteria, fungi), and Human Herpes Virus (HHV) 8. Rare conditions like Castleman disease and paraneoplastic pemphigus have also been associated with bronchiolitis obliterans. Other associations include microcarcinoid tumorlets and Cryptogenic constrictive bronchiolitis.

Epidemiology

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. More than 50% of recipients will develop some degree of BO by 5 years post-transplant. The average time to diagnose BO is 16 to 20 months after lung transplant but has been reported as early as 3 months after transplantation. About 5% to 14% of Hematopoietic stem cell transplantation (HSCT) recipients also develop bronchiolitis obliterans syndrome, which is pulmonary graft vs. host disease and can present several months to years later after transplantation.

Pathophysiology

There is inflammation of sub-epithelial structures and dysregulated repair in response to injury from inhalational toxins or autoimmune responses, 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.[5] There is a concentric narrowing of the lumen of the bronchioles by 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 the development of bronchiolitis obliterans syndrome. Episodes of acute cellular rejection, HLA antibodies, and gastroesophageal reflux disease with microaspiration have been shown to increase the risk of developing bronchiolitis obliterans syndrome after transplantation.

In bronchiolitis obliterans associated with paraneoplastic pemphigus, autoantibodies against desmoglein and plakin protein are found in both cutaneous and respiratory epithelium have been implicated.

History and Physical

Bronchiolitis obliterans characteristically presents with dyspnea and cough that is 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 a prolonged expiratory phase with or without wheeze, usually in the inspiratory and expiratory phase. 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. 

Evaluation

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 with air trapping. Diffusion capacity (DLCO) is usually reduced. [1][6][7]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, mosaic pattern with patchy areas of hypo attenuation. If there are dynamic images with inspiratory and expiratory films, a mosaic pattern persists due to air trapping from small airway disease.

Bronchoscopy can be performed if other causes of airflow obstruction are suspected like endobronchial tumors or sarcoid but might 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. Also, the sensitivity by transbronchial biopsy for the diagnosis of BO is low (range 15 to 87%). In cases following lung transplantation, a biopsy is not required to diagnose 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 / Management

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 adding 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 been shown to decrease the decline in lung function in bronchiolitis obliterans syndrome post-HSCT. In addition to these therapies, controlling gastroesophageal 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.[8][9][10] 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 has been used for bronchiolitis obliterans related to rheumatoid arthritis but has 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.

Differential Diagnosis

• Asthma

• Bronchogenic carcinoma

• Bronchiectasis

• Cystic fibrosis

• Interstitial lung disease

• Pleural effusion

• Pulmonary edema

• Recurrent aspiration

• Recurrent pulmonary emboli

• Tracheobronchomalacia

Staging

Clinical Staging System for Bronchiolitis Obliterans Syndrome (BOS)

Each stage is subdivided into a and b, where a is without histologic documentation of OB, and b is with histologic documentation of OB. 

Prognosis

The prognosis of bronchiolitis obliterans depends on the underlying pathology. Some patients achieve complete improvement; however, those with constrictive disease generally demonstrate a more progressive course, but at present, there is insufficient research to provide a statistical correlation. Lung function often deteriorates over time, so patients will usually need to have repeated lung testing throughout their lives. Progressive disease may require supplemental oxygen or mechanical ventilation in very severe cases. The worst cases may require a lung transplant.[11]

Complications

Patients with bronchiolitis obliterans demonstrate an increased risk of developing lung infections, including bronchitis and pneumonia. With bronchiolitis obliterans, these infections are more likely to become severe, resulting in baseline respiratory symptoms that are substantially worse than persons who do not have this condition.