Diacetyl-Induced Bronchiolitis Obliterans

Diacetyl induced bronchiolitis obliterans is constrictive bronchiolitis caused by inhaling diacetyl (2,3-butanedione) vapour, and similarly by 2,3-pentanedione. It produces fixed small airway obstruction.

Exposure. Microwave popcorn plants, butter and other flavouring manufacture, bakery and dairy flavour mixing, coffee roasting and grinding, and some electronic cigarette liquids.

Epidemiology. Cases cluster in workplaces and are linked to heating, mixing and open tank tasks. Risk rises with exposure intensity and duration.

Presentation. Cough, dyspnoea and wheeze unresponsive to bronchodilators, often in a young non-smoking worker.

Prognosis. Disease is generally irreversible, with progression to respiratory failure in some. Early removal may slow decline.

Pathophysiology.

Diacetyl modifies arginine residues in proteins and is cytotoxic to airway epithelium. Injury to bronchiolar epithelium leads to peribronchiolar inflammation, scarring and luminal narrowing.

Airway occlusion produces air trapping, obstruction and mosaic perfusion.

• Cough, exertional dyspnoea and wheeze, with eye, nose and throat irritation.
• Onset after months to years of exposure; symptoms may begin during employment or later.
• Examination may be normal or show wheeze.

Red flags.

• Rapid decline in FEV1.
• Resting hypoxaemia or respiratory failure.

• Task-by-task exposure history, ventilation, protection and co-worker symptoms.
• Spirometry: obstruction with poor response to bronchodilator; raised residual volume and RV/TLC.
• HRCT with expiratory images: mosaic attenuation and air trapping.
• Gas transfer normal or mildly reduced.
• Surgical lung biopsy showing constrictive bronchiolitis is reserved for atypical presentations.
• Workplace air sampling for diacetyl and 2,3-pentanedione for exposure assessment.

Differential diagnosis. Asthma, chronic obstructive pulmonary disease, hypersensitivity pneumonitis, post-infectious bronchiolitis, connective tissue disease associated bronchiolitis, other occupational bronchiolitis obliterans.

• Remove from exposure promptly and control sources by enclosure, ventilation and process change; respiratory protection as an adjunct.
• Smoking cessation; vaccination; pulmonary rehabilitation.
• Evidence for drug therapy is limited to case series. Prednisolone 0.5 mg/kg orally once daily in the morning, maximum 40 mg daily, for 4 weeks as a test course. Continue with taper to the lowest effective dose over 8 to 12 weeks only if symptoms or spirometry improve; otherwise stop or taper over 2 weeks. Monitor glucose, blood pressure, weight, mood and infection. Exclude active tuberculosis first; caution in diabetes and peptic ulcer; no renal adjustment.
• Azithromycin 250 mg orally three times each week for a 3-month test course, continued to 12 months only if FEV1 stabilises or improves. Maximum 250 mg each dose. Exclude non-tuberculous mycobacterial infection by sputum culture first. Monitor ECG for QTc, liver enzymes and hearing. Avoid when QTc is over 470 ms or with other QT-prolonging drugs; caution when eGFR is under 10 and in significant liver disease.
• Long term oxygen when resting PaO2 is under 7.3 kPa, or 7.3 to 8 kPa with polycythaemia or cor pulmonale.
• Lung transplant assessment in severe progressive disease.

Monitoring. Spirometry every 3 to 6 months initially, then yearly; spirometry surveillance of co-workers.

Referral and escalation. Respiratory and occupational physician; workplace investigation after any case; transplant assessment in advanced disease; notification and compensation where required.