ALPHA-1 antitrypsin deficiency is a rare inherited condition caused by mutations in the SERPINA1 gene, leading to low levels of the protective protein alpha-1 antitrypsin. This imbalance allows inflammatory enzymes to damage lung tissue, increasing the risk of chronic lung diseases such as emphysema and bronchiectasis. While the severe Pi*ZZ genotype is well recognised, much less is known about bronchiectasis risk in other genetic variants.
Large European Registry Reveals Wider Genetic Risk
New findings from the European Alpha-1 Research Collaboration (EARCO) registry suggest that bronchiectasis in alpha-1 antitrypsin deficiency extends beyond the classic Pi*ZZ genotype. Researchers analysed CT scans from 349 people with confirmed bronchiectasis and stratified them by AATD genotype, including Pi*ZZ, Pi*SZ, Pi*SS, and rare variants.
Although Pi*ZZ remained the most common genotype, accounting for just over 70% of cases, nearly one in three patients had other genotypes. Pi*SZ represented almost one fifth of cases, while Pi*SS and rare variants made up smaller but clinically relevant proportions.
Distinct Lung Patterns Across Alpha-1 Antitrypsin Deficiency Genotypes
Across all genotypes, bronchiectasis most often affected the lower lobes of the lungs. However, important differences emerged. Pi*SS was associated with more upper lobe involvement, while Pi*SZ showed greater middle lobe disease. Patients with rare genotypes and those with Pi*ZZ had poorer lung function and higher disease severity scores, based on established clinical indices.
Emphysema frequently co-existed with bronchiectasis, particularly in Pi*ZZ individuals, reinforcing the complex lung disease burden seen in severe alpha-1 antitrypsin deficiency.
Implications for Screening and Clinical Management
The findings challenge the assumption that bronchiectasis in alpha-1 antitrypsin deficiency is confined to Pi*ZZ. Instead, they highlight substantial phenotypic variability across genotypes, with some non-Pi*ZZ patients experiencing significant disease.
For clinicians, this supports broader imaging and genetic evaluation in people with alpha-1 antitrypsin deficiency who have respiratory symptoms. Genotype-specific monitoring and management may help identify patients at risk earlier and tailor long-term care, without overstating causality beyond the observational data.
Reference
Mandurino Mirizzi F et al. Characteristics of bronchiectasis in patients with different genotypes of severe α1-antitrypsin deficiency from the EARCO registry. ERJ Open Res. 2026;DOI:10.1183/23120541.00491-2025.
