Abstract

Background: Severe serum deficiency of alpha-1 antitrypsin (AAT) is strongly associated with development of pan lobular emphysema. The (Glu342Lys) mutation in SERPINA1 gene (Pi*ZZ) is characterised by intrahepatic Z-AAT polymer formation. Circulating polymers may reduce efficacy of intravenous (iv) AAT augmentation therapy on preventing decline of pulmonary function. We aim to study the effect of iv AAT therapy in patients with ultralow serum AAT due to rare SERPINA1 mutations, and low circulating Z-AAT polymers.

Methods: SERPINA1 mutations were determined by SERPINA1 gene exon sequencing. We prospectively followed patients initiated on iv AAT therapy receiving weekly (60mg/kg/week) or biweekly (120mg/kg/2weeks). Plasma Z-AAT polymers were measured at baseline by ELISA. We collected forced expiratory volume in 1 second (FEV1), diffusion capacity (TLCO), 6-minute walking distance (6MWD) and quality of life (QoL) questionnaires (CAT and SGRQ) annually and compared FEV1 with historical data from matched Pi*ZZ patients not on AAT therapy. This was analysed using linear mixed effects models.

Results: We analysed 34 patients initiated on iv AAT therapy. Eleven patients (32.4%) had a rare homozygous SERPINA1 mutation without plasma Z-AAT polymers and 23 patients (67.6%) were Pi*Z/Rare who had median plasma Z-AAT polymer levels before treatment of 145.5 g/mL (73.6-178 g/mL:95% CI). Over three years, the mean annual decline in FEV1 of all patients was 3.3ml/year (p>0.05), compared to 74.9ml/year (p<0.001) in the control group. The 6MWD was +2.4m/year (p>0.05) and TLCO and QoL questionnaire scores remained stable in the treatment group.

Conclusion: iv AAT therapy stabilised FEV1 and 6 MWD in our patients.