Diffuse Panbronchiolitis

Diffuse panbronchiolitis is a chronic inflammatory disease of the respiratory bronchioles with chronic sinusitis. It is found mainly in East Asia (Japan, Korea and China), with a link to HLA-B54 and HLA-A11, and it is rare in other regions, including Africa.

Presentation is usually between 20 and 50 years, with a slight male predominance. Without treatment it progresses to bronchiectasis, Pseudomonas aeruginosa colonisation and respiratory failure, with 10-year survival of about 25%. Long term low dose macrolide has raised 10-year survival to over 90%.

Pathophysiology. Lymphocytes, plasma cells and foam cells infiltrate the walls of respiratory bronchioles, causing nodular thickening and obstruction. A genetic susceptibility near the major histocompatibility complex is thought to interact with an inhaled or infective trigger. Macrolides act through immunomodulation (reduced interleukin-8 and neutrophil influx) and not through killing bacteria.

Chronic cough with a large volume of sputum, exertional dyspnoea, wheeze, and chronic sinusitis in 80 to 90%, often years before the lung disease. Coarse crackles are heard, and clubbing is uncommon.

Fever with purulent sputum and worsening dyspnoea suggests infection with Pseudomonas, and respiratory failure with hypercapnia needs urgent care.

• Clinical criteria: chronic cough, sputum and exertional breathlessness, chronic sinusitis (or a history), and coarse crackles, with bilateral diffuse small nodular shadows on imaging.
• High resolution CT: diffuse small centrilobular nodules with branching lines (tree-in-bud) in both lower lobes, progressing to bronchiolar dilatation and bronchiectasis. This usually separates it from other bronchiectasis, in which nodules are not diffuse and not uniform.
• Spirometry: obstruction (FEV1/FVC under 0.70) with raised residual volume, and arterial PaO2 under 10.7 kPa (80 mmHg) in established disease.
• Cold agglutinin titre of 1:64 or more (raised in about half), and raised IgA, with HLA typing where available.
• Sputum culture for Pseudomonas, Haemophilus influenzae and Mycobacteria. Lung biopsy only if the diagnosis remains unclear.
• Sinus CT for sinusitis.

• Long term low dose macrolide, started as soon as the diagnosis is made: erythromycin 200 mg twice daily (400 mg daily, up to 600 mg), or clarithromycin 200 mg once or twice daily, or azithromycin 250 mg daily or 500 mg three times weekly. Continue for at least 6 months to judge the response, and usually for 2 years or longer, with an attempt to stop only after sustained stability.
• Before starting: electrocardiogram for QTc (avoid if over 470 ms in women and 450 ms in men), liver function, and check drug interactions (statins, warfarin, ciclosporin, tacrolimus, digoxin). Exclude active nontuberculous mycobacterial infection first, to avoid macrolide monotherapy.
• Exacerbations with Pseudomonas: ciprofloxacin 500 to 750 mg orally twice daily for 14 days, or ceftazidime 2 g intravenously every 8 hours (reduce at eGFR under 50) with an aminoglycoside as needed. Other pathogens are treated by culture, for example amoxicillin-clavulanate 625 mg three times daily for 10 to 14 days for Haemophilus.
• Airway clearance with physiotherapy, and carbocisteine 750 mg three times daily as a mucolytic. Inhaled bronchodilators (salbutamol 100 micrograms as needed, or a long acting agent) and long term oxygen for PaO2 of 7.3 kPa or less.
• Treat the sinusitis with nasal saline irrigation and, when needed, intranasal corticosteroid and surgery.
• Lung transplantation for end stage respiratory failure.

Complications and prognosis. Bronchiectasis, chronic Pseudomonas infection, respiratory failure and cor pulmonale. Early diagnosis, before Pseudomonas colonisation, carries the best outlook.

Monitoring. Spirometry and symptoms every 3 months, high resolution CT at 6 to 12 months then yearly, sputum culture at every visit, and electrocardiogram and liver function 1 month after starting and every 6 months.

Referral and escalation. Refer to a respiratory specialist at diagnosis, and for transplant assessment when FEV1 is under 30% or oxygen is needed.