From the Guidelines
Alpha 1 antitrypsin (A1AT) augmentation therapy should be offered to patients with COPD and documented A1AT deficiency to preserve CT scan lung density and reduce mortality, as recommended by the Canadian Thoracic Society meta-analysis and clinical practice guideline 1.
Key Features for Recommendation
The following features are essential for considering A1AT augmentation therapy:
- Clinical features suggestive of A1AT deficiency, such as early onset COPD (< 40 years of age), COPD with low pack-year intensity (<10 pack-years), basal pan lobular emphysema, family history of COPD or A1AT deficiency, and history of perinatal jaundice
- Never or previously smoked
- FEV1 < 80% predicted
- Documented emphysema
- Documented SERPINA1 genotypes associated with A1AT deficiency
- Severely reduced functional A1AT level (<11 mmol/L or <0.57 g/L)
- Receiving optimal pharmacological and non-pharmacological therapies for COPD
Treatment and Management
Treatment for A1AT deficiency includes:
- Augmentation therapy with intravenous infusions of purified A1AT at a typical dose of 60 mg/kg body weight given weekly 1
- Standard treatments for COPD, such as bronchodilators, corticosteroids, pulmonary rehabilitation, and smoking cessation
- Liver-affected patients may require monitoring of liver function and, in severe cases, liver transplantation
Importance of Early Diagnosis
Early diagnosis of A1AT deficiency is crucial, as preventive measures and appropriate treatment can significantly slow disease progression and improve quality of life 1. A1AT deficiency follows an autosomal codominant inheritance pattern, with the most severe deficiency occurring in individuals with two Z alleles (PiZZ genotype).
From the FDA Drug Label
1,2,4,5 Severe forms of the deficiency are frequently associated with slowly progressive, moderate-to-severe panacinar emphysema that most often manifests in the third to fourth decades of life. Individuals with Alpha1-PI deficiency have little protection against NE released by neutrophils in their lower respiratory tract, resulting in a protease:protease inhibitor imbalance in the lung. Augmentation therapy with Alpha1-Proteinase Inhibitor (Human) is indicated only in patients with severe congenital Alpha1-PI deficiency who have clinically evident emphysema
The primary use of alpha 1 antitrypsin (IV) is for augmentation therapy in patients with severe congenital Alpha1-PI deficiency who have clinically evident emphysema.
- The goal of this therapy is to correct the imbalance between neutrophil elastase and protease inhibitors in the lung.
- However, the efficacy of augmentation therapy in affecting the progression of emphysema has not been demonstrated in randomized, controlled clinical trials 2, 2.
- The clinical benefit of increased blood levels of Alpha1-PI at the recommended dose has not been established 2, 2.
From the Research
Alpha 1 Antitrypsin Deficiency
- Alpha-1 antitrypsin deficiency (AATD) is a relatively common, but under-recognized condition which manifests commonly with liver cirrhosis and emphysema 3.
- AATD is a hereditary condition characterized by low levels of AAT in plasma and hence diffusion into tissues, leading to the development of panacinar emphysema due to an imbalance between proteases and antiproteases in the presence of environmental triggers 4.
Augmentation Therapy
- Augmentation therapy, which consists of intravenous infusion of purified human plasma-derived alpha-1 antitrypsin (AAT), is the only specific therapy for lung-affected individuals with AATD 3.
- Augmentation therapy has been associated with effective elevations of A1AT levels and function in serum and lung epithelial fluid, and observational studies suggest that it may lead to attenuation in lung function decline, particularly in patients with moderate impairment of lung function 5.
- Six augmentation therapy preparations, all of which derive from pooled human plasma, have received FDA approval 3.
Efficacy and Safety
- Augmentation therapy has been shown to be effective in delaying the progression of emphysema, and may improve survival in selected individuals with severe AAT deficiency 4.
- The therapy has a relative paucity of side effects, but it is highly expensive 5.
- Augmentation therapy is recommended for patients with AATD who have a high-risk A1AT genotype with plasma A1AT below protective levels and evidence of obstructive lung disease 5.
Future Directions
- New strategies for early detection and biomarkers for patient outcome prediction are needed to reduce morbidity and mortality in AATD patients 6.
- Alternative strategies are currently being investigated, including the use of gene therapy or induced pluripotent stem cells, and non-augmentation strategies to prevent AAT polymerisation inside hepatocytes 6.
- Recombinant alternatives to the plasma-derived protein, novel formulations, and novel administration routes are being explored to improve the production, formulation, and delivery of alpha-1 antitrypsin 7.