Treatment of COPD in Individuals with Alpha-1 Antitrypsin Deficiency
A mutation in the gene for alpha-1 antitrypsin (AAT), leading to its deficiency (AATD), causes progressive irreversible destruction of lung tissue. Patients develop chronic obstructive pulmonary disease (COPD) and early emphysema. Several studies evaluating COPD treatment have excluded patients with AATD. The aim of the following systematic literature review was to find and analyze works that include patients with concurrent COPD and AATD and summarize key findings that may form the basis for treatment decisions.
AATD and COPD
AATD is a rare genetic disorder caused by a mutation in the SERPINA1 gene for α1-antitrypsin, which increases the risk of developing COPD. In individuals with AATD, COPD can manifest in various clinical phenotypes and differs from COPD in individuals without AATD only by an earlier onset. Treatment of COPD symptoms in patients with AATD typically includes smoking cessation (if the patient is a smoker), inhalation therapy, and respiratory rehabilitation. Additionally, it includes augmentation therapy, which involves the infusion of plasma-derived AAT.
Augmentation of AAT
Currently, augmentation therapy with AAT is the only available therapeutic modality that addresses the etiology of AATD. The RAPID study and its extension, the largest clinical trial program in patients with AATD to date, evaluated the effect of this treatment on slowing the progression of emphysema based on lung tissue density measured by CT. It demonstrated that early initiation of augmentation therapy with AAT can prolong life, delay the need for a transplant, or prevent disabling respiratory difficulties in patients with severe AATD-related emphysema.
Systematic Literature Review
The authors of the systematic review searched for randomized controlled trials, case series, and non-controlled studies that evaluated any treatment used in adult patients with AATD (AAT < 11 µmol/l or genotype corresponding to AATD) regardless of the presence of COPD. Studies had to have at least 10 treated participants and a duration of more than 3 months.
Included Studies
A total of 52 works involving 5632 patients were included. Of these, 26 studies evaluated augmentation therapy with AAT, and 17 evaluated surgical treatments (mostly transplantation). The authors divided the publications into 4 groups according to therapy: COPD pharmacotherapy, COPD surgical treatment, specific AATD treatment, and others. The most frequently monitored parameters were lung tissue density on CT, one-second vital lung capacity (FEV1), lung diffusing capacity for CO, health status, and frequency of exacerbations. Meta-analysis was possible only for 3 randomized studies with intravenous augmentation therapy involving a total of 320 patients.
Results
Intravenous augmentation therapy with AAT led to a slower progression of emphysema as assessed by lung tissue density on CT by 0.79 g/l/year compared to placebo (p = 0.002) and slowed the increase in the frequency of exacerbations by 0.29/year (p = 0.02). Post-transplant mortality was comparable in patients with COPD related to AATD and without AATD. However, surgical lung volume reduction was associated with worse outcomes in patients with emphysema related to AATD compared to those without AATD.
Conclusion
Intravenous augmentation therapy with AAT remains the only specific treatment for patients with AATD. As shown by the RAPID program and systematic review of clinical studies, this therapy slows the progression of emphysema and reduces the increasing incidence of exacerbations. Standard COPD treatment may not be effective and sufficient in patients with AATD, necessitating studies specifically conducted in patients with COPD due to AATD.
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Sources:
1. Rahaghi F. F., Miravitlles M. Long-term clinical outcomes following treatment with alpha 1-proteinase inhibitor for COPD associated with alpha-1 antitrypsin deficiency: a look at the evidence. Respir Res 2017; 18 (1): 105, doi: 10.1186/s12931-017-0574-1.
2. Edgar R. G., Patel M., Bayliss S. et al. Treatment of lung disease in alpha-1 antitrypsin deficiency: a systematic review. Int J Chron Obstruct Pulmon Dis 2017; 12: 1295–1308, doi: 10.2147/COPD.S130440.
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