Introduction: The cause of bronchiectasis remains undetermined in ~40% of cases. Inherited deficiency in alpha-1 antitrypsin (A1AT) due to mutations in the SERPINA1 gene have been reported. In the EMBARC registry <1% cases of bronchiectasis are attributed to A1AT deficiency. The aim of this study was to describe the number of undetected cases and intermediate A1AT alleles in a large prospective international cohort.

Methods: Patients with CT-confirmed bronchiectasis were included as part of the international multicentre observational cohort study EMBARC BRIDGE (ClinicalTrials.gov identifier NCT03791086). Subjects with known A1AT deficiency or who had been tested previously as part of routine clinical care were excluded. Buccal swabs were sent to a central laboratory for testing. A qualitative, polymerase chain reaction (PCR) and hybridization-based in vitro diagnostic test for the simultaneous detection and identification of 14 allelic variants in the A1AT coding gene SERPINA1 (PROGENIKA BIOPHARMA S.A., Spain) was performed.

Results: 266 individuals with bronchiectasis were tested for A1AT deficiency. The majority of subjects (n=231, 87%) carried the wild type non-deficiency allele PiMM. Overall, 35 subjects (13%) had intermediate alleles: PiMS (n=28), PiMZ (n=5), PiSS and PiMF (n=1, each). The A1ATD PiZZ allele, associated with a severe clinical phenotype, was not detected.

Conclusion: In a large prospective international cohort A1AT deficiency PiZZ was not a common cause of bronchiectasis. This suggests that routine screening in the absence of high clinical suspicion is not required. However, 13% of individuals had intermediate alleles of unknown significance.