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

Treatment for Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin augmentation therapy is recommended for patients with severe A1AT deficiency (serum levels <11 mmol/L or <0.57 g/L) who have FEV1 <80% predicted, documented emphysema, and have not smoked for at least 6 months. 1, 2, 3

Diagnostic Approach

• Testing for A1AT deficiency is recommended in all individuals with COPD at diagnosis, those with adult-onset asthma with persistent airflow obstruction, and individuals with unexplained bronchiectasis 2
• A two-step diagnostic approach is recommended:
  • For moderate clinical suspicion: Measure serum A1AT levels (≥23 mmol/L or ≥1.2 g/L rules out severe deficiency) 1
  • For high clinical suspicion: DNA sequencing of the SERPINA1 gene is recommended as the initial test 1, 2
• Genetic testing is crucial as some variants may have normal A1AT levels but dysfunctional protein 2

Treatment Algorithm

Augmentation Therapy Criteria

• Augmentation therapy is indicated for patients who meet ALL of the following criteria:
  • Confirmed severe A1AT deficiency (serum levels <11 mmol/L or <0.57 g/L) 1
  • FEV1 <80% predicted 1, 2
  • Clinical evidence of COPD with associated emphysema 1
  • No smoking for at least 6 months 1, 2
  • No previous lung transplant 1

Administration of Augmentation Therapy

• Intravenous infusion of purified human A1AT protein 3
• The goal is to maintain serum A1AT levels above 11 μM to provide protection against neutrophil elastase 3
• FDA-approved products are derived from pooled human plasma 4

Standard COPD Management

• All patients should receive optimal pharmacological therapies for COPD 1:
  • Bronchodilators for symptomatic relief 2
  • Inhaled steroids for those with bronchial hyperreactivity 2
• Non-pharmacological therapies should include:
  • Smoking cessation (critical for slowing FEV1 decline) 1, 2
  • Vaccinations (influenza and pneumococcal) 1, 2
  • Pulmonary rehabilitation 1
  • Self-management efficacy skills 1
  • Supplemental oxygen when indicated 1
  • Comprehensive case management 1
  • Consideration of surgical therapies when appropriate 1

Clinical Considerations and Caveats

• Early diagnosis and treatment are crucial, as delayed diagnosis is associated with worse overall survival 2, 5
• Family screening should be considered for relatives of individuals identified with abnormal A1AT genes 2
• The FDA notes that the clinical efficacy of augmentation therapy in influencing the course of pulmonary emphysema or pulmonary exacerbations has not been conclusively demonstrated in randomized, controlled clinical trials 3
• Limitations of augmentation therapy:
  • Not indicated for lung disease in patients without severe A1AT deficiency 3
  • Long-term effects of chronic augmentation therapy are not fully established 3
  • Only recommended for the most severe forms of A1AT deficiency 4

Future Treatment Directions

• Research is ongoing for alternative treatment approaches:
  • Gene therapy and gene repair strategies 1, 4
  • Chemical chaperones to correct protein misfolding 4
  • RNA interference and editing 1
  • New methods of delivery (inhaled and oral formulations) 1
• The Canadian Blood Services has recently made A1AT augmentation therapy available to all Canadians who meet the criteria, improving access to treatment 1