What is the recommended treatment for alpha-1 antitrypsin deficiency?

Treatment of Alpha-1 Antitrypsin Deficiency

For patients with alpha-1 antitrypsin deficiency and COPD with emphysema, augmentation therapy with intravenous alpha-1 antitrypsin (60 mg/kg weekly) should be offered if they are never or former smokers (smoke-free ≥6 months), have FEV1 <80% predicted, documented emphysema, severely reduced A1AT levels (<11 mmol/L or <0.57 g/L), and documented SERPINA1 deficiency genotypes. 1, 2, 3

Augmentation Therapy Indications

The most recent Canadian Thoracic Society guideline (2025) provides clear criteria for augmentation therapy 1:

• Serum A1AT level: Must be <11 mmol/L (<0.57 g/L) 1, 2, 4
• Lung function: FEV1 <80% predicted (post-bronchodilator) 1, 2, 3
• Smoking status: Never smokers or former smokers who have been smoke-free for at least 6 months 1, 2, 3
• Documented emphysema: Confirmed by CT imaging 1, 3
• Genetic confirmation: Documented SERPINA1 genotypes associated with A1AT deficiency (typically Pi*ZZ) 1, 2, 3
• Optimal COPD therapy: Patients must be on appropriate standard COPD management 1, 2

Evidence Supporting Augmentation Therapy

The benefit of augmentation therapy is most robust in patients with moderate emphysema (FEV1 31-65% predicted) 1:

• Weekly infusions of 60 mg/kg significantly reduced FEV1 decline (53 ml/year vs 75 ml/year in untreated patients, p=0.002) 1
• Mortality was reduced in augmented patients compared to untreated (OR 0.79, p<0.02) 1
• CT lung density decline was slowed by approximately 50% in the RAPID trial (p=0.07), with extrapolation suggesting 6 years longer survival before death or transplantation 1

Dosing and Administration

Standard regimen: 60 mg/kg body weight administered intravenously once weekly 1, 4

• This dosing maintains serum A1AT levels above the protective threshold of 11 mmol/L (approximately 0.57 g/L) 1, 4
• Monthly dosing (250 mg/kg) leaves patients unprotected for several days and is less effective 1
• Serum trough levels should exceed 15 mmol/L immediately before the next infusion 1

Safety Profile

Augmentation therapy has demonstrated excellent safety 1:

• Only 5 serious adverse reactions occurred in 58,000 infusions 1
• Mild reactions (fever, chills, dyspnea) occurred in approximately 0.2% of infusions 1
• Four anaphylactic reactions reported, all with complete recovery 1
• No viral transmission or deaths observed 1

Standard COPD Management (Required for All Patients)

All patients with A1AT deficiency and COPD require comprehensive standard therapy regardless of augmentation therapy status 2, 3:

Pharmacological Therapy

• Bronchodilators: Long-acting beta-agonists and anticholinergics for symptomatic relief 2, 3
• Inhaled corticosteroids: For patients with bronchial hyperreactivity or frequent exacerbations 2, 3
• Antibiotics: For acute exacerbations 2
• Supplemental oxygen: For patients with hypoxemia 2, 3

Non-Pharmacological Interventions

• Pulmonary rehabilitation: Essential for improving exercise capacity and quality of life 2, 3
• Self-management education: To enhance treatment adherence and early recognition of exacerbations 1

Critical Preventive Measures

Smoking Cessation (Mandatory)

Smoking cessation is the single most important intervention and must be achieved before considering augmentation therapy 2, 3:

• Smokers with A1AT deficiency have a life expectancy <20 years after diagnosis 2
• Early smoking cessation significantly reduces FEV1 decline 3
• Patients must be smoke-free for at least 6 months before augmentation therapy 1, 2, 3

Vaccinations

All patients should receive 2, 3:

• Annual influenza vaccination 2, 3
• Pneumococcal vaccination (every 5 years) 2, 3, 5
• Hepatitis B vaccination 2

Monitoring During Treatment

Patients on augmentation therapy require regular monitoring 2:

• Annual spirometry: To assess FEV1 decline 2
• CT imaging: To monitor emphysema progression and lung density changes 2
• Serum A1AT levels: To ensure adequate trough levels 1

Special Populations

Heterozygous States (PiMZ, PiSZ)

Patients with heterozygous genotypes are at lower risk than Pi*ZZ but still require management 2:

• Focus on smoking cessation and standard COPD therapy 2
• Augmentation therapy is generally not indicated unless serum levels are <11 mmol/L and other criteria are met 1, 2

Patients with Very Severe Disease

Patients already on augmentation therapy with very poor lung function should continue treatment 1:

• Evidence suggests mortality benefit even in advanced disease 1
• Lung transplantation should be considered for end-stage disease 5, 6

Patients with Rapid FEV1 Decline

Patients with normal or near-normal lung function but rapid FEV1 decline (>120 ml/year) may be considered for treatment 1:

• This represents a conditional recommendation based on observational data 1

Important Caveats

Limitations of Evidence

The FDA label explicitly states that "the effect of augmentation therapy on pulmonary exacerbations and progression of emphysema has not been conclusively demonstrated in randomized, controlled clinical trials" 4:

• The largest RCT (RAPID trial) included only 180 patients over 2 years 1
• A definitive 5-year trial with FEV1 as primary endpoint would require 700-1000 patients and is not feasible 1
• CT lung density has emerged as the most clinically relevant surrogate endpoint, showing closer correlation with survival than FEV1 1

Not Indicated For

Augmentation therapy is not indicated for 4:

• Patients without documented severe A1AT deficiency 4
• Current smokers 1, 2, 3
• Patients with normal lung function and no emphysema 1, 2
• Liver disease associated with A1AT deficiency (no proven benefit) 1, 6

Cost Considerations

Augmentation therapy is expensive, with annual costs exceeding $100,000 7:

• Cost-effectiveness is most favorable in patients with moderate disease (FEV1 31-65% predicted) 1
• Plasma-derived products have limited supply, contributing to high costs 7, 8