Risk of lung disease in the PI*SS genotype of alpha-1 antitrypsin: an EARCO research project

Background: The PI*S variant is one of the most prevalent mutations within alpha-1 antitrypsin deficiency (AATD). The risk of developing AATD-related lung disease in individuals with the PI*SS genotype is poorly defined despite its substantial prevalence. Our study aimed to characterize this genotype and its risk for lung disease and compare it with the PI*ZZ and PI*SZ genotypes using data from the European Alpha-1 antitrypsin Deficiency Research Collaboration international registry. Method: Demographic, clinical, functional, and quality of life (QoL) parameters were assessed to compare the PI*SS characteristics with the PI*SZ and PI*ZZ controls. A propensity score with 1:3 nearest-neighbour matching was performed for the most important confounding variables. Results: The study included 1007 individuals, with PI*SS (n = 56; 5.6%), PI*ZZ (n = 578; 57.4%) and PI*SZ (n = 373; 37.0%). The PI*SS population consisted of 58.9% men, with a mean age of 59.2 years and a mean FEV1(% predicted) of 83.4%. Compared to PI*ZZ individuals they had less frequent lung disease (71.4% vs. 82.2%, p = 0.037), COPD (41.4% vs. 60%, p = 0.002), and emphysema (23.2% vs. 51.9%, p < 0.001) and better preserved lung function, fewer exacerbations, lower level of dyspnoea, and better QoL. In contrast, no significant differences were found in the prevalence of lung diseases between PI*SS and PI*SZ, or lung function parameters, exacerbations, dyspnoea, or QoL. Conclusions: We found that, as expected, the risk of lung disease associated with the PI*SS genotype is significantly lower compared with PI*ZZ, but does not differ from that observed in PI*SZ individuals, despite having higher serum AAT levels. Trial registration: www.clinicaltrials.gov (ID: NCT04180319)

Sex- differences in alpha-1 antitrypsin deficiency:Data from the EARCO Registry

Background: Sex and gender influence many aspects of chronic obstructive pulmonary disease (COPD). Limited data are available on this topic in alpha-1 antitrypsin deficiency (AATD). We therefore aimed to investigate sex issues in the EARCO registry, a prospective, international, observational cohort study.Methods: Baseline data from PiZZ individuals, enrolled in the registry with complete data on sex and smoking history were analysed by group comparisons and binary logistic regression analyses.Results: 1283 patients with AATD, 49.3% women were analysed. Females reported less tobacco consumption (16.8 ± 12.2 vs. 19.6 ± 14.5 PY, p = 0.006), occupational exposures towards gases, dusts or asbestos (p < 0.005 each) and consumed less alcohol (5.5 ± 7.6 vs. 8.4 ± 10.3 u/week, p < 0.001). Females reported COPD (41% vs. 57%, p < 0.001) and liver disease (11% vs. 20%, p < 0.001) less often. However, they had a higher prevalence of bronchiectasis (24% vs. 13%, p < 0.001). Despite better lung function (FEV1%pred. 73.6 ± 29.9 vs. 62.7 ± 29.5, p < 0.001) females reported a similar symptom burden (CAT 13.4 ± 9.5 vs. 12.5 ± 8.9, p = ns) and exacerbation frequency (at least one in the previous year 30% vs. 26%, p = ns) compared to males. In multivariate analyses, female sex was an independent risk factor for exacerbations in the previous year OR 1.6 p = 0.001 in addition to smoking history, COPD, asthma and bronchiectasis and was also identified as risk factors for symptom burden (CAT ≥ 10) OR 1.4 p = 0.014 besides age, BMI, COPD and smoking history.Conclusion: Men had higher rates of COPD and liver disease, women were more likely to have bronchiectasis. Women's higher symptom burden and exacerbation frequency suggest they may need tailored treatment approaches