Bronchiolitis Obliterans

Bronchiolitis obliterans is a fibrotic obliteration of the small airways (under 2 mm), which causes progressive fixed airflow obstruction. It is also called constrictive bronchiolitis, and it should not be mistaken for the cryptogenic organising pneumonia that was once called bronchiolitis obliterans organising pneumonia.

The main settings are chronic lung allograft dysfunction after lung transplantation (bronchiolitis obliterans syndrome, in about half of recipients by 5 years), chronic graft-versus-host disease after allogeneic stem cell transplantation (about 5 to 10%), post-infectious disease (adenovirus, Mycoplasma, influenza and respiratory syncytial virus, mainly in children), toxic inhalation, connective tissue disease and drugs.

Pathophysiology. Epithelial injury and immune or inflammatory attack on the small airways cause fibroblast proliferation and scarring that narrows or occludes the lumen, with air trapping and a mosaic of poorly ventilated lung. Toxic causes include diacetyl in flavouring, sulphur mustard, chlorine, ammonia, nitrogen oxides, and rarely penicillamine and other drugs.

Gradual dyspnoea on exertion and dry cough over weeks to months, with wheeze that does not respond to bronchodilator. Examination may be normal or show hyperinflation and end inspiratory squeaks. In post-transplant disease there is a decline in lung function that precedes symptoms.

A fall of 10% in FEV1 in a transplant recipient, fever, sputum change or new hypoxaemia needs prompt review for infection and rejection.

• Spirometry: FEV1/FVC under 0.70 with FEV1 reduced and poor reversibility. After transplantation, bronchiolitis obliterans syndrome is defined by an FEV1 fall of 20% or more from the best post-operative baseline, with an obstructive pattern, without another cause.
• Lung volumes show air trapping (raised residual volume), with diffusing capacity normal or mildly reduced.
• High resolution CT with inspiratory and expiratory slices: mosaic attenuation, expiratory air trapping, bronchial wall thickening and sometimes bronchiectasis. About one in five scans is normal.
• Bronchoscopy with lavage and transbronchial biopsy to exclude infection and acute rejection in transplant recipients. Surgical lung biopsy is rarely needed.
• Search for the cause: transplant history, infection, occupational exposure, connective tissue disease serology and drug history.

Differential diagnosis.

• Asthma and COPD
• Hypersensitivity pneumonitis
• Cryptogenic organising pneumonia
• Chronic thromboembolic disease with mosaic perfusion
• Bronchiectasis and cystic fibrosis
• Acute cellular rejection or infection in transplant recipients

• Remove the cause: end the exposure, stop the drug, and treat chronic graft-versus-host disease and infections.
• Post-lung transplant: azithromycin 250 mg three times weekly for prevention, and for established disease 250 mg daily or 500 mg three times weekly for 3 months, continued only if lung function improves or stabilises. Change ciclosporin to tacrolimus and azathioprine to mycophenolate, and consider extracorporeal photopheresis, total lymphoid irradiation, or retransplantation for selected patients.
• After stem cell transplantation: fluticasone 440 micrograms twice daily, azithromycin 250 mg three times weekly and montelukast 10 mg daily, with prednisolone 1 mg/kg daily for 2 weeks then tapered, and with systemic graft-versus-host therapy such as ruxolitinib, belumosudil or ibrutinib decided by the transplant team. Check QTc and liver function before azithromycin.
• Post-infectious and toxic disease: corticosteroids have limited benefit. Prednisolone 0.5 mg/kg daily for 2 to 4 weeks may be tried early after toxic inhalation, then stopped if there is no response.
• Symptomatic: inhaled long acting bronchodilators, airway clearance, pulmonary rehabilitation, long term oxygen when PaO2 is 7.3 kPa or less, and vaccination against influenza, pneumococcus and COVID-19.
• Prophylaxis against Pneumocystis in those on high immunosuppression: co-trimoxazole 480 mg once daily (or 960 mg three times weekly).
• Lung transplantation for suitable patients with advanced disease from non-transplant causes.

Complications and prognosis. Chronic respiratory failure, infection with Pseudomonas and fungi, and pneumothorax. Lung function often stabilises with early treatment, though progression is common, and median survival after onset of bronchiolitis obliterans syndrome in lung transplant is about 3 to 5 years.

Monitoring. Spirometry at each transplant visit, and every 2 to 4 weeks at home in the first months after stem cell transplantation, with CT when decline occurs.

Referral and escalation. Refer to the transplant or haematology centre at the first fall in lung function. Refer to a specialist airway or occupational medicine service for toxic exposure.