Patients with severe alpha-1 antitrypsin deficiency (AATD) have increased risk of developing chronic, progressive lung disease, particularly pan-lobular emphysema. 1 P athogenesis is considered one of imbalance between the destructive proteolytic burden resulting from inhaled, pro-inflammatory factors and impaired defences arising from deficiency of alpha-1 antitrypsin (AAT). Increased risk from COVID-19 may be consequent to reduced pulmonary functional reserve and from overwhelmed, impaired anti-inflammatory defences by the cytokine/inflammatory storm associated with COVID-19. 2, 3 T he likelihood of progressive respiratory failure and irreversible lung damage would be expected to be increased. AAT may also have a beneficial role in modifying the severity of COVID-19 through several different mechanisms. 4 The EARCO ERS Clinical Research Collaboration 5 s ought, at the outset of the pandemic, to estimate the risk posed by COVID-19 to patients with severe AATD. Anonymised data on all known cases of COVID-19 in patients with severe AATD across participating countries was collated into a database to identify and ordinate risk factors for an adverse outcome. Patients age> 18 years with severely reduced serum level of AAT due to two inherited pathological alleles in the SERPINA1 gene (PiZZ, PiSZ or rare variants with an equivalent serum AAT level (viz.< 60 mg/dl ie< 11 mol/L) 6 w ere included. Diagnosis of COVID-19 was based on a pathognomonic clinical presentation (±a positive confirmatory polymerase chain reaction test). Subjects were identified by EARCO reference centres through direct contact with patients attending the centre or patient contact prompted by information disseminated via national patient groups to their members. Details of patient baseline characteristics and outcome, including hospitalisation, treatment, mortality and spirometry (from historical records and post-acute COVID-19 measurements) were collected. Patients that were not admitted to hospital were assessed ‘virtually’via phone contact and further data was obtained from hospital records. Ethics approval was obtained from HRA and Health and Care Research Wales (IRAS ID 285484). As a retrospective collection of fully anonymised clinical data from medical records, consent was not considered to be required.

Patient characteristics were compared according to genotype and outcome. Normality of distributions was assessed using the Kolmogorov–Smirnov test. For quantitative variables, the Student’s t-test (Mann–Whitney U-test if normality was not assumed) or ANOVA tests (in the case of variables with more than 2 categories) were carried out. The Chi-squared test (Fisher test for frequencies< 5) was used for comparison of categorical variables. A backward stepwise logistic regression analysis was performed to identify clinical variables related to poor outcome, defined as hospitalisation or death. p-Values< 0.05 were considered statistically significant.