P12 Alpha1-antitrypsin deficiency

In a cohort of PiZZ and PiSZ individuals identified by the Swedish national neonatal alpha-1 antitrypsin (AAT) screening program in 1972–1974 and followed up regularly since birth, 4% of the PiZZ, 2% of the PiSZ and 12% of the control group were current smokers (P=0.008), and 17% of the PiZZ, 9% of the PiSZ and 21% of the control group had stopped smoking (Piitulainen 2017). PiZZ current smokers may have symptoms of COPD at the age of 37–40 years, whereas the never-smoking PiZZ and PiSZ individuals have normal lung function.  In a single centre UK cohort of 482 untreated individuals with PiZZ, rates of annual decline of FEV1 and gas transfer were highly variable at all stages of COPD severity, ranging from no decline to rapid decline in both never smokers and former smokers (Stockley 2016).

Tanash and colleagues compared mortality rates in 1,585 Swedish individuals with severe AAT deficiency with the 6,000 individuals randomly selected from the Swedish general population (Tanash 2017). The authors reported that individuals with AAT deficiency had lower survival rates compared with controls; however, the survival rate of never-smoking individuals with severe AAT deficiency identified by screening (rather than identified after presenting with respiratory symptoms) is similar to the never-smokers in the Swedish general population. This highlights the importance of smoking prevention in individuals with AAT deficiency.

A systematic review of three randomised controlled trials studying a total of 283 patients, concluded that there was a lack of evidence of clinical benefit from AAT augmentation therapy (Gøtzsche 2016) [evidence level I]. AAT augmentation therapy is not routinely available in Australia.

In the RAPID trial RCT, which contributed the majority of patients to the above systematic review, intravenous augmentation therapy was studied in 177 adults with COPD and severe alpha1-antitrypsin (AAT) deficiency (serum level <11µM), FEV1 35 to 70% predicted and no smoking in the prior six months (Chapman 2015). Intravenous AAT 60 mg/kg from pooled human plasma was given weekly in the intervention group, vs. matched placebo in the control group, for 24 months. Open label augmentation was then offered for a further 24 months. 10% of the intervention group withdrew prematurely, compared to 21% of the control group. The annual rate of lung density loss, measured by CT chest at total lung capacity (TLC), was statistically significantly less in the patients receiving AAT augmentation (mean –1.45 g/L per year, SE 0.23), compared to the placebo group (–2.19 g/L per year, SE 0.25), with difference of 0.74 g/L per year (95% CI 0.06–1.42). There were no changes in annual rate of lung density loss when measured at a combination of TLC and FRC, or at FRC alone. There were no statistically significant differences in mortality, exacerbations, FEV1 or adverse effects. Post-hoc exploratory analysis showed a reduced rate of lung density loss with higher trough serum AAT levels achieved. Benefits in patient-orientated outcomes were not demonstrated, although this study was not powered to show this.

A two year, open label extension trial of 140 patients who had participated in the previous trial (Chapman 2015) showed that the decrease in rate of lung density loss was maintained in patients who continued this dose of active AAT augmentation therapy, and was achieved by patients who started therapy during the extension trial (McElvaney 2017).

It is noted that the optimal dosing regimen has not yet been determined, but that in the trials described above patients underwent weekly intravenous infusions. The evidence to date demonstrates that AAT augmentation modifies the development of emphysema.  It is unclear if AAT therapy improves clinical outcomes.  Studies of cost-effectiveness have not yet been conducted.