What is the recommended treatment for alpha-1 antitrypsin (A1AT) deficiency?

Alpha-1 Antitrypsin Deficiency: Treatment Recommendations

Primary Recommendation

Alpha-1 antitrypsin (A1AT) augmentation therapy should be offered to patients with documented severe A1AT deficiency who meet ALL of the following criteria: never-smokers or former smokers (smoke-free ≥6 months), FEV1 <80% predicted, documented emphysema on CT scan, A1AT level <11 mmol/L (<0.57 g/L), and confirmed SERPINA1 deficiency genotype. 1

Diagnostic Requirements Before Treatment

Essential Testing

• Serum A1AT level <11 mmol/L (<0.57 g/L) defines severe deficiency and is required for augmentation therapy eligibility 1, 2
• SERPINA1 gene sequencing (exons 2-5) is the gold standard for diagnosis and should be performed before initiating augmentation therapy, as some variants have normal circulating levels but dysfunctional protein 1, 3
• High-resolution CT chest must document presence of emphysema, as augmentation therapy is not indicated without radiographic evidence of lung destruction 3
• Post-bronchodilator spirometry with FEV1 <80% predicted is required 1

Two-Step Diagnostic Approach

• Moderate clinical suspicion: Measure A1AT level first; if ≥23 mmol/L (≥1.2 g/L), severe deficiency is ruled out 1, 2
• High clinical suspicion: Proceed directly to SERPINA1 gene sequencing 1

Augmentation Therapy Protocol

Dosing and Administration

• 60 mg/kg intravenous infusion weekly maintains serum levels above the protective threshold of 11 mmol/L 1, 3
• This dosing achieves detectable A1AT in bronchoalveolar lavage fluid and restores anti-elastase protection 1

Evidence for Efficacy

• High-quality evidence supports preservation of CT lung density with augmentation therapy 1
• Very low-quality evidence suggests mortality reduction, particularly in patients with FEV1 35-49% predicted 1, 3
• Meta-analysis demonstrates 26% reduction in FEV1 decline rate (17.9 ml/year difference) in patients with baseline FEV1 30-65% predicted 4
• Strongest benefit occurs in moderate emphysema (FEV1 31-65% predicted), with yearly FEV1 decline of -53 ml in treated versus -75 ml in untreated patients 3

Absolute Prerequisites for Therapy

Mandatory Requirements

• Smoking cessation for ≥6 months is non-negotiable; continued smoking negates protective benefits and makes treatment futile 1, 2, 3
• Optimal COPD management must be established first, including bronchodilators, inhaled corticosteroids, pulmonary rehabilitation, vaccinations, and supplemental oxygen if indicated 1, 3
• No history of lung transplantation 1

Absolute Contraindications

• Active smoking 3
• IgA deficiency with anti-IgA antibodies (risk of anaphylaxis) 3
• Absence of documented emphysema on imaging 3

Standard COPD Management (Required for All Patients)

Pharmacological Therapy

• Bronchodilators for symptomatic relief, even without objective bronchodilator responsiveness 2, 3
• Inhaled corticosteroids for those with bronchial hyperreactivity 2, 3
• Supplemental oxygen when indicated by standard COPD criteria 1, 2

Non-Pharmacological Interventions

• Pulmonary rehabilitation is recommended for all symptomatic patients 3
• Annual influenza vaccination 2, 3
• Pneumococcal vaccination 2, 3
• Hepatitis B vaccination 2

Monitoring During Treatment

Required Surveillance

• Annual spirometry to assess FEV1 decline 2
• CT imaging to monitor emphysema progression 2
• Baseline inflammatory markers (C-reactive protein) to establish treatment appropriateness 3

Special Populations and Important Caveats

Heterozygous States (MS, MZ, SZ Phenotypes)

• MS phenotype does NOT qualify for augmentation therapy, as A1AT levels remain above the severe deficiency threshold of 11 mmol/L 5
• MZ and SZ phenotypes require individualized assessment but typically do not meet criteria for augmentation unless A1AT <11 mmol/L 2, 5
• These patients still require aggressive smoking cessation and standard COPD management 2, 5

Patients NOT Meeting Criteria

• FEV1 >80% with emphysema: Unknown if augmentation therapy is beneficial; current evidence does not support treatment 1, 3
• Asthma with persistent obstruction but no CT emphysema: Benefits unknown; not currently indicated 1, 3
• Bronchiectasis without emphysema: Benefits unknown; not currently indicated 1, 3

Critical Clinical Pitfalls

Common Errors to Avoid

• Do not assume A1AT deficiency diagnosis alone justifies therapy; emphysema must be documented on CT 3
• Do not rely solely on phenotyping (Pi*ZZ, etc.); confirm with SERPINA1 sequencing, as some variants have normal levels but dysfunctional protein 1, 3
• Do not initiate augmentation before optimizing standard COPD therapy; augmentation is adjunctive, not replacement therapy 3
• Do not continue therapy in active smokers; life expectancy is <20 years after diagnosis in continued smokers, making treatment futile 2

Timing Considerations

• Early diagnosis and treatment are crucial, as delayed diagnosis (average 5.3 years after symptoms, mean FEV1 52% predicted) is associated with worse survival 1
• Lung damage is irreversible; augmentation therapy preserves existing lung tissue but does not restore lost function 1, 6

Cost-Effectiveness Context

The Canadian Blood Services now provides augmentation therapy nationally (as of February 2024) for patients meeting these criteria, reflecting alignment between evidence-based recommendations and healthcare policy 1. The therapy is expensive but considered cost-effective when appropriately targeted to patients with moderate emphysema who are most likely to benefit 1, 6.