Gender plays a role in many aspects of chronic obstructive pulmonary disease (COPD).1,2 Sex and gender in COPD reflect a complex interplay between genuine biological differences and sociocultural influences.2 In addition to possible biological aspects such as airway diameter or the complex effects of sex hormones on respiratory disease,3 socio-cultural factors also play an important role. Alpha-1-antitrypsin deficiency (AATD) is a genetic condition that predisposes to the early development of COPD4 and liver disease.5 Many of the issues related to sex and gender in COPD are plausibly important in AATD. For example, occupational exposures and certain risk behaviours, such as tobacco and alcohol consumption, for which gender differences still exist, have a significant impact on the development of AATD, lung and liver disease.6,7 The pattern of comorbidities differs significantly between men and women, but at the same time comorbidities play an important role in COPD and influence many of the symptoms that make up the individual burden of our patients.8 They also have a significant impact on the prognosis of the disease, and regardless of their prevalence, certain comorbidities are associated with different prognoses in men and women.9,10 To address the complexity of the relationship between gender and a genetic predisposition such as AATD, it is also important to recognise that men and women perceive disease differently, express symptoms differently and use health services in a different way.11 Due to the small number of cases in different countries and centres, it is especially difficult to study gender-specific aspects of rare diseases, and it is not surprising that there are no meaningful data on this topic in AATD.12 The prospective international registry of the European Alpha-1 Research Collaboration (EARCO) for patients with AATD offers the opportunity for the first time to investigate such questions in a large international, well-characterised cohort. The aim of the current study was to investigate sex-specific aspects of AATD in relation to lung and liver disease, symptom burden and exacerbations in the registry.

Our analyses revealed several differences between the sexes, including differences in alcohol and tobacco consumption, occupational exposure to pollutants, the prevalence of AATD-associated lung and liver diseases, and the pattern of comorbidities. There were also significant differences in the quantity and quality of symptoms and the number of exacerbations reported, most evident in the subgroup of patients with COPD. Regardless of the type or presence of lung disease, female gender was associated with higher symptom burden as measured by the CAT or mMRC. Female sex was also an independent risk factor for exacerbations. In terms of risk behaviours, men in the registry were significantly more likely to be current or former smokers, to have a higher number of pack-years, and to report more frequent and higher daily alcohol consumption. This corresponds to the data from the Canadian AAT register, in which men also have a higher tobacco consumption.21 In addition, the men in the cohort were significantly more likely to have occupational exposure to pollutants.

Disease manifestations also differed between the sexes, with more men diagnosed with liver disease, chronic bronchitis, COPD or emphysema, and more women diagnosed with bronchiectasis. These differences can be partly, but not entirely, explained by differences in behaviour. Although men in the cohort had a higher tobacco consumption, this only amounted to about 3 pack-years overall, and a number of studies have shown that women are more susceptible to tobacco-related pulmonary harm than men. Sørheim et al. investigated sex differences in the effects of smoking on lung function in a population with early COPD and/or COPD development at low levels of tobacco exposure. Female sex was associated with a greater decline in lung function in both groups of patients.22 Data from two independent Danish population-based cohorts, the Copenhagen City Heart Study and the Glostrup Population Studies, with a total of 13,897 participants who were followed up for up to 16 years, came to a similar conclusion: smoking impairs lung function more in women than in men. When the number of pack years (PY) was taken into account, the female participants in the two Danish cohorts also had a higher risk of being hospitalised for COPD than the male participants.23 In addition, an analysis of the German AATD Registry did not show a clear gender dominance of any AATD phenotype, but it should be noted that the information in this registry is based on patient self-report and only asked about lung and liver disease in general.24 In the EARCO registry, data are entered by the study centres and the information on lung or liver disease is much more detailed.12,13 This made it possible to distinguish between different lung diseases. With regard to the various lung diseases, it is also surprising that although women are less likely to report a diagnosis of chronic bronchitis, they are more likely to suffer from bronchiectasis, as chronic bronchitis is usually a clinical diagnosis that should have a large overlap with the symptoms of bronchiectasis. In previous COPD studies, women were often less willing to report cough and sputum production.2,11 This could be due to the shame associated with traditional gender roles and definitions of femininity. Gender differences in bronchiectasis have been known for many years, with 60.9% of participants in the European Bronchiectasis registry (EMBARC) being female.25 In general, bronchiectasis is the endpoint of a wide range of diseases and the causes of these sex differences are poorly understood. Sex steroid hormones are thought to vary in type, pattern and concentration throughout life and between the sexes and may play a central role in various lung diseases as well as in sex differences in the prevalence of bronchiectasis.26

There was a clear predominance of men with liver disease in our cohort. In general, it should be noted that liver disease was less common in our cohort, which may be partly due to the fact that the EARCO study centres were predominantly pneumology departments, which introduces a certain selection bias. The observed sex differences are consistent with data from a large UK biobank study showing that male sex, obesity, diabetes and older age are associated with an increased risk of liver fibrosis/cirrhosis and primary liver cancer.27

There were some differences in other comorbidities between men and women in our cohort; overall, the rate of cardiovascular comorbidities was low, as previously described in other AATD cohorts.28,29 Men were more likely to have ischaemic heart disease or a history of pulmonary embolism, while women were more likely to have been diagnosed with osteoporosis or depression.

Another interesting finding was the difference in reported symptoms: although women were less likely to have COPD, they reported the same overall level of COPD-specific symptoms in the CAT and the mMRC. A recent study by EARCO comparing 629 P*ZZ individuals from Northern and Southern European countries showed relevant differences in the CAT score between the two groups.30 This highlights the fact that, in addition to the diagnosis itself, a large number of influencing factors play a role, which is why the investigation of such a question in a large international cohort such as EARCO is important. In our analyses, we also found relevant differences between the sexes in terms of the frequency of reported exacerbations. In the overall collective, the number of exacerbations was the same, which can be attributed to the fact that the subgroup of female COPD patients reported significantly more exacerbations than their male counterparts. Female COPD patients also had a significantly higher symptom burden compared to male patients. In the multivariate analyses conducted for the entire cohort, female sex was an independent predictor of exacerbations in the last year, along with age, BMI, smoking status and a diagnosis of COPD, asthma or bronchiectasis. In addition, female sex, together with age, BMI and a COPD diagnosis, was associated with higher symptom burden as measured by both the mMRC scale and the CAT score. The results correspond to data from the Spanish COPD cohort INSEPOC, analysing a sample of 4500 COPD patients. The women with COPD in the study were younger, smoked less and had better lung function. Nevertheless, these women reported a significantly poorer quality of life and more exacerbations.31 A pooled analysis of 17,139 patients from 22 COPD cohorts showed that certain disease characteristics were different in women than in men, including higher levels of self-reported dyspnoea and COPD exacerbations; interestingly, the long-term survival of women with COPD in this study appeared to be better than that of men.2 It remains to be seen whether this risk profile has an impact on the prognosis, e.g. with regard to the development of lung function in AATD.

Although the study was conducted in a large international registry with high data quality, there are some limitations, including the fact that the pulmonary diagnoses (e.g. emphysema and bronchiectasis) as well as comorbidities recorded were based on previous medical diagnoses. In this respect, it may not have been possible to rule out sex-based ascertainment bias in diagnosis. Nevertheless, this is the first comprehensive international study of sex-specific aspects in AATD. We did not collect self-identified gender, only biological sex, so wider study of this in comparison to sex may also be relevant in future.

Our analysis of sex and gender aspects in AATD using the well-characterised international AATD cohort EARCO has shown that sex is important in AATD in many ways. The differences in risk behaviours highlight the need for early diagnosis and for sex and to be taken into account in individualised tobacco and alcohol prevention programmes. The differences in the pulmonary manifestations of AATD, such as the high proportion of women with bronchiectasis or the differences in exacerbation frequency and symptom burden, demonstrate the need for tailored therapeutic approaches to the different aspects of AATD and that sex should be included in these considerations.

The International EARCO Registry is funded by unrestricted grants from Grifols, CSL Behring, Kamada, pH Pharma and Takeda to the European Respiratory Society (ERS).

AMT is funded by the NIHR Midlands Patient Safety Research Collaboration (PSRC) and Applied Research Collaborative West Midlands. She has also received grant funding from NIHR HTA and EME. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

FCT and HE drafting of the manuscript. FCT and HE performed the statistical analysis. All authors participated in the study concept, design and acquisition of data. All authors performed a critical revision and agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.

Hilal Ersöz has received support for attending meetings and/or travel from CSL Behring. María Torres-Durán has received consulting fees from Grifols, speaker fees from CSL Behring, GSK and Chiesi, support for attending meetings and/or travel from Chiesi and Faes. Carlota Rodríguez García has received speaker fees from Glaxo-SmithKline, Grifols and Chiesi, support for attending meetings and/or travel from Grifols, Chiesi and Cipla. José Luis López-Campos has received grants from Menarini and Grifols, consulting fees from GlaxoSmithKline, CSL Behring, Bial, Gebro, Boehringer and AstraZeneca, speaker fees from AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, CSL Behring, Faes, Gebro, GlaxoSmithKline, Grifols, Zambon and Menarini, support for attending meetings and/or travel from Boehringer, GSK, Menarini, Chiesi, CSL Behring and Grifols. Christian F. Clarenbach has received consulting fees from AstraZeneca, Boehringer Ingelheim, CSL Behring, Daiichi Synkyo, GlaxoSmithKline, Novartis, Sanofi, OM Pharma, MSD, Grifols and Vifor and speaker fees from AstraZeneca, Boehringer Ingelheim, CSL Behring, Daiichi Synkyo, GlaxoSmithKline, Novartis, Sanofi, OM Pharma, MSD, Grifols and Vifor. Kenneth R. Chapman has received grants from Astra Zeneca, BMS, Grifols, Sanofi, Bellus, GlaxoSmithKline, Roche, Regeneron and Takeda, consulting fees from GlaxoSmithKline, Inhibrx, Roche,Takeda, Grifols, Regeneron and Sanofi, speaker fees from AstraZeneca, Grifols, Novartis, Takeda, Boehringer Ingelheim, GlaxoSmithKline, Regeron, Valeo and has a leadership in AlphaNet Canada. José María Hernández-Pérez has received payment of consumables within the research project from Grifols and CSL Behring. Catarina Guimarães has received speaker fees from CSL Behring. Timm Greulich has received grants from Grifols and consulting and speaker fees and support for attending meetings and/or travel from CSL-Behring and Grifols. Miriam Barrecheguren has received consulting fees from GSK, Novartis, Chiesi, CSL Behring, Bial and Boehringer Ingelheim, speaker fees from Grifols, Menarini, CSL Behring, GSK, Boehringer Ingelheim, and Chiesi, support for attending meetings and/or travel from Chiesi and CSL Behring. Andreas Rembert Koczulla has received grants from Grifols, consulting fees from AstraZeneca, Atriva Therapeutics, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, CSL Behring, Berlin Chemie, Novartis,Pfizer, PulmonX, Sanofi, Resmed and Grifols, speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini, Kamada, CSL Behring, Grifols and Novartis and support for attending meetings and/or travel from Boehringer Ingelheim, Grifols, CSL. Philipp Höger has received speaker fees from Grifols. Franziska C. Trudzinski reports payment or honoraria for lectures, or reimbursement of travel expenses from Novartis AG, GlaxoSmithKline, Chiesi, Boehringer Ingelheim GmbH, Grifols, Streamed up, RG Gesellschaft für Information und Organisation mbH and AstraZeneca. Hanan Tanash, Angelo Guido Corsico, Eva Bartošovská, Arturo Olivares Rivera and Felix Herth have no competing interests to declare.