Abstract
Alpha-1-antitrypsin deficiency (AATD) is a rare condition with clinical mani-festations of the lung and the liver. There is evidence that the gender affects the clinical presentation of non-AATD chronic obstructive lung disease (COPD). The aim of this study was to analyze gender-dependent disease pattern in AATD-based COPD. Data from 1066 individuals from the German AATD registry were analyzed by descriptive and analytical statistics. The AAT genotypes comprised 820 individuals with PiZZ (male 56%, female 45%), 109 with PI SZ (male 55%; female 45%), and others (n = 137). A subgroup of 422 patients with available post-bronchodilator FEV1% predicted was analyzed in detail after stratification in spirometric GOLD stages I-IV. The age of the registered individuals is 52.2 ± 13.4 years (male: 51.91 ± 13.86 years; female: 52.76 ± 13.39 years). Female patients with GOLD I-IV showed lower numbers of pack-years and lower BMI. The time between the first symptom and the establishment of the correct diagnosis was significantly longer in female (14.47 ± 16.46 years) as compared to male individuals (12.39 ± — 14.38 years, p = 0.04). In conclusion, the data of the registry allow to characterize the natural course of the disease and highlight differences in the clinical presentation of patients with AATD-dependent COPD.
Keywords:
Introduction
Patient registries represent an important tool in understanding rare diseases (Citation1). Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder caused by mutation of the SERPINA1 gene (Citation2). The most common mutations are the Z- and the S-mutations being involved in more than 95% of the clinical manifestations (Citation3). The typical manifestations involve the lung and the liver. The lung may develop a specific form of chronic obstructive pulmonary disease (COPD), the liver may be affected by cirrhosis and other manifestations. The frequency of severe AATD in the general European population is about 1:5,000–15,000 (Citation4). AATD is thus one of the more common rare genetic risk factors, nevertheless, relatively little information is known about the clinical course of the clinical consequences. A number of registries in this disease area have been established in the last decades (Citation1, Citation5-11).
The German registry for individuals with AATD (gAATDR) was established in 2003 and is one of the large collection of data on AATD (Citation7). It is associated with a detection programs that identified more than 1000 individuals with severe AATD in the past 12 years (Citation12,13). Data from AATD registries have provided important insight into disease phenotypes. An analysis of Spanish and Italian registry patients characterized patient clusters with bronchitis, emphysema, and asthma overlap phenotype (Citation5). FEV1 decline was associated with the smoker status, baseline lung function, and low BMI in the Spanish registry (Citation6). The U.S.-American databases provided early clinical data on lung function and mortality (Citation10,Citation14). Registry data also showed that a delay of diagnosis is also a critical issue in AATD (Citation15). The Alpha One International Registry (AIR) is a multinational, collaborative registry with data from several thousand individuals and contributes actively to science and development of clinical trials (Citation8).
For AATD there is only very limited data on the impact of sex on the course of disease, clinical presentation or other clinical outcomes (Citation16, 17). In non-AATD COPD, gender is known to affect various disease characteristics. A bronchitis — airway phenotype was more frequently found in females, while the emphysema phenotype was more abundant in men. Female COPD patients express more dyspnea (Citation18) and higher prevalence of anxiety or depression (Citation19) and tend toward lower health-related quality of life (Citation18). Female sex appears to be associated with increased susceptibility to smoke exposure. Women develop COPD at younger age and with lower exposure to tobacco products (Citation20). The early-onset COPD patients were 66% women in the COPD gene study (Citation21).
The aim of the present study was to investigate whether sex affects disease characteristics in AATD. We analyzed the baseline date of the German AATD registry and compared various disease outcomes between male and female individuals.
Methods
Structure of the German Registry for individuals with AATD
The German AATD registry (gAATDR) was established in 2003 and contributes since then to the alpha-1 international registry (AIR). The gAATDR uses the identical baseline dataset as AIR with several additional items on exacerbation frequency or comorbidity. In addition, the gAATDR comprises also a children part that is not subject of this analysis. The inclusion criterion for the registry is severe AAT deficiency, demonstrated by serum concentrations of AAT lower than 50 mg/dl with Pi ZZ or other deficient allelic variants. The questionnaires and the data storage concept were approved by the ethics committees of the Marburg University and the Landesärztekammer Saarland and the Data Safety Office of the State of Hessen (all in Germany).
Informed consent was obtained from the patients. The gAATDR is based on a questionnaire that is distributed to patients and their physicians using various pathways. The affected individuals fill in most of the questions with several items to be completed by the physician (treatment, pulmonary function). Questionnaires are sent to the registry office at the Saarland University, where data are entered in a MS Access-based database. The database is access controlled and security backups are made daily.
Data analysis
For data analysis the data until 12/2014 were used. Data were exported from the Access database into SPSS or Excel for further analysis. Data on all patients comprised N = 1066 individuals. Data analysis for the characterization of COPD patients were based on complete data sets with post-bronchodilator FEV1% predicted with N = 422.
Statistical analysis
Categorical data are described by frequencies and percentages and analyzed using the Chi-squared test or the Fisher's exact test as appropriate. Continuous variables are displayed as mean ± SD and compared by the t-test, Mann–Whitney U-test or the Wilcoxon/Kruskal–Wallis test, as appropriate. Multiple groups were tested by one-way-ANOVA with Bonferroni correction for multiple comparisons as post hoc test. Values are displayed as mean plus or minus SEM. Results were considered statistically significant for p values less than 0.05. MS Access 2013 was used for data base management, IBM SPSS version 21 for statistical analysis.
Results
Demographic and clinical characteristics
We analyzed data from 1066 individuals (male 482; female 584) with a mean age of 52.2 ± 13.4 years and a BMI of 24.09 ± 5.26. Mean post-bronchodilatator FEV1% pred. (percent of predicted) was 21.46 ± 29.36 (N = 422). The baseline characteristics are summarized in Table . The AAT genotypes comprised 820 individuals with PiZZ (male 56%, female 45%), 109 with PI SZ (male 55%; female 45%), and others (n = 137). The reasons for genotyping are summarized in Table . The delay between the first symptom and the establishment of the correct diagnosis was 13.28 ± 15.58 years (male 12.39 ± 14.38 years, female 14.47 ± 16.46 years, p = 0.04, t-test).
Table 1. Clinical characteristics of patients of the gAATDR
Sex comparisons
To analyze whether the sex affects the clinical presentation in patients with AATD-based COPD, strata were compared according to the spirometric GOLD stages I-IV. We compared age, BMI, pack-years, number of exacerbations in 2 years, and the SGRQ in all COPD stages I-IV between male and female COPD patients (Table ). No significant differences were identified for age, number of exacerbations, or SGRQ. Female patients with GOLD I-IV showed significantly lower numbers of pack-years and lower BMI. A total number of 243 (57.72%) patients of the COPD group received augmentation therapy, 145 (58.00%) male and 98 (57.31%) female patients. All individuals were asked about the disease phenotype and indicated the presence of lung disease (81.43%), chronic bronchitis (39.87%), emphysema (73.26%), asthma (15.95%), and bronchiectasis (4.78%) with no significant differences between males and females.
Table 2. Distribution of age, BMI, pack-years, post-bronchodilator FEV1% pred., exacerbations/2 years, and SGRQ between male and females COPD patients stratified by spirometric COPD stages
Discussion
The main finding of the present study was that data from a registry can be used to identify how sex may affect the clinical presentation of patients with AATD-based COPD.
The gAATDR is a comprehensive database on individuals with severe AATD. There is a dominance of the lung phenotype that is caused by the recruitment strategy and that certainly causes a bias if conclusions on the general AATD population would be made. As compared to other registries, several data items depend on patient-recoded data. In Germany, the care structure for patients with AATD is largely decentralized what makes it difficult to obtain well controlled data from specialized clinical centers. This has to be kept in mind in the analysis. As compared to the Spanish and the Italian registries (Citation5), the gAATDR reveals comparable data for the age, the BMI, but showed higher percentages of augmented patients. The combination of national registry data allows to compare clinical data and to initiate clinical trials (Citation8).
The focus of this analysis was to identify gender-dependent differences in the clinical presentation of AATD individuals. This research project was driven by the evidence that gender significantly affects non-AATD COPD (Citation16, Citation22–24). In general COPD, bronchitis is more common in females while emphysema is more abundant in males (Citation23). The present database did not show a clear sex-specific predominance of a phenotype, keeping in mind that this item is based on a patient reported answer.
Time to diagnosis is a critical issue in rare diseases and often delayed in AATD (Citation15). Also in non-AATD COPD, female individuals reported delayed diagnosis (Citation25). In the present analysis we found a delay until diagnosis was confirmed with a significantly larger delay in female individuals.
To analyze differences in patients with lung disease, data were stratified by post-bronchodilator FEV1% pred. with 422 individuals available for this analysis. We found no significant differences in age, exacerbation rate, or quality of life based on the SGRQ. The numbers of pack-years and the BMI were significantly lower in female COPD patients. Exposure to tobacco is a major risk factor for the development of AATD lung disease and in non-AATD COPD women appear to be more susceptible to smoke exposure (Citation20). Also, quality of life and the BMI are more reduced in female patients with non-AATD COPD (Citation18, Citation26–28).
Access to treatment may differ between male and female patents in non-AATD COPD. Here we focused on the application of augmentation therapy, a specific treatment for AATD lung disease (Citation29) and found no differences in the overall rate of this therapy.
Registry studies have several limitations based on their structures. The gAATDR is a patient-based database that implies a decreased data quality as compared to data collections generated in clinical trials or by data entry by health care providers. The individuals within the gAATDR are recruited through various pathways that do not represent a well-balanced distribution of phenotypes and disease manifestations. As populations based data are not available, the bias caused by the present sample procedure is difficult to estimate. Thus, it is not possible to draw conclusion on the general population or an AATD base population. In conclusion, the gAATDR provides in depth data on individuals with AATD and shows that there may be differences in clinical presentation of female and male patients with COPD. Further analysis of sex-dependent differences in disease mechanisms and clinical phenotypes will further improve diagnosis and therapy.
Funding
The gAATDD was supported by grants from the EU PAAIR, the Bundesministerium für Bildung und Forschung COSYCONET/ASCONET (BMBF 01GI1001) to R.B. and C.V., and supported by a grant from Bayer/Talecris/Grifols from 2003 until 2012.
Declaration of Interest Section
Robert Bals and Timm Greulich have obtained research support and travel sponsoring from Talecris and Grifols. Christian Herr obtained research support from Grifols. Claus Vogelmeier has received honoraria for speaking engagements and for chairing a research prize committee from Talecris/Grifols. Philipp M. Lepper received speaker fees from Talecris/Grifols.
The authors alone are responsible for the content and writing of the paper.
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