Abstract
Alpha1-antitrypsin Deficiency (AATD) is a rare hereditary disorder with an estimated prevalence of about 1/5000 individuals in Italy. Deficient patients are at a higher risk of developing lung emphysema and chronic liver disease. The low estimated prevalence of AATD prompted the establishment of a registry with the aim of learning more about the natural history and the quality of care of these patients. The Italian registry for AATD was established in 1996. In this study, genetic and clinical findings of Italian AATD patients are presented. Moreover, we also evaluated the changes in health-related quality of life (HRQoL) in patients with COPD and AAT deficiency over a three-year period, in relation to augmentation therapy.
In a period spanning 18 years (1996–2014) a total of 422 adult subjects with severe AATD were enrolled, namely 258 PI*ZZ, 74 PI*SZ, 4 PI*SS and 86 patients with at least one rare deficient allele. The 21.3% frequency for AATD patients with at least one deficient rare variant is the highest so far recorded in national registries of AATD. The registry data allow a detailed characterization of the natural course of the disease and the level of patient care, as well as confirm the usefulness of early AATD detection.
Introduction
Alpha1-antitrypsin deficiency (AATD) is an autosomal co-dominant disorder that increases the risk of developing a variety of diseases including pulmonary emphysema and cirrhosis of the liver.
A typical individual with AATD develops pulmonary symptoms between the ages of 25 and 40 and the disease is usually terminal by age 60. The most common early symptom is exertional dyspnoea, and subsequently limited ability to perform activities may be observed during the third and fourth decades of life (Citation1,2).
In the late 1980s, early 1990s, AATD was considered extremely rare – if not inexistent – in Italy. In 1993 a national study group on AATD (Gruppo IDA, Identification of AATD) was fostered by the two major Italian Pneumological Societies (AIPO and SIMER). Thereafter, a national reference center and a national registry were launched (Citation3), both at the Institute for Respiratory Disorders of the University of Pavia. Prof. Maurizio Luisetti was in charge of this laborious and important task. Apart from collecting the samples to genotype AATD subjects and gathering clinical data, the Italian registry paid special attention to health-related quality of life (HRQoL) issues. This article describes and analyses the characteristics of patients with AAT deficiency included in the Italian registry from June 1996 until September 2014.
Materials And Methods
This observational study included patients with severe AATD enrolled in the Italian AATD Registry. The objectives of the study were: (a) to report the clinical and demographic characteristics of Italian AATD patients and to compare index and non-index cases; (b) to compare characteristics of AATD patients with lung diseases only or liver diseases only, and patients with both lung and liver diseases; (c) to characterise the different clinical phenotypes of patients with lung diseases according to treatment or not with augmentation therapy with exogenous AAT; and, (d) to evaluate the quality of life by SGRQ in the different patients categories.
Participants and registry
We assessed AATD patients aged ≥18 years enrolled in the Italian Registry of AATD from June 1996 to September 2014. The Italian AATD registry was established in 1996 and became part of the Alpha-1 Antitrypsin Deficiency International Registry (AIR) in 1999 (Citation3). Its inclusion criteria include the presence of severe AAT deficiency, defined by the carriage of the PI*ZZ genotype, PI*SZ genotype or another rare severe deficient or null genotypic variant. The data are collected on forms sent by post or e-mail to the Italian Centre for AATD diagnosis in Pavia, Italy, where the coordinators update the database. Further details regarding diagnostic algorithms used in the Italian target screening for AATD, the main source for enrolment in the Italian registry of AATD patients, as well as different methods used in the period spanning 18 years have been previously published (Citation4–6).
Data management and definitions
The data analysed include demographical and physical information, smoking habits, reason for AAT dosage and genetic analysis, general and pneumological medical history, radiological features, pneumological and augmentation treatment, pulmonary functional tests, liver function tests, quality of life, occupational and death information. For the classification of clinical respiratory phenotypes (chronic bronchitis, emphysema, asthma, bronchiectasis), we used the reported respiratory diagnosis in the database provided by physicians in charge of the patients (mainly respiratory specialists).
As a high-risk population, all subjects diagnosed with chronic obstructive pulmonary disease (COPD), emphysema and/or chronic bronchitis by the registering physician and/or whose spirometry showed a post-bronchodilator FEV1/FVC <70% were considered to have COPD. Diagnostic delay was calculated as the difference in years between the age at diagnosis and the age at symptom onset. All subjects diagnosed through familial screening were considered non-index cases. The severity of COPD was based on the GOLD spirometric severity criteria (Citation7): I (mild) FEV1 ≥ 80%; II (moderate) 50% ≥ FEV1 < 80%; III (severe) 30% ≥ FEV1 > 50%; IV (very severe) FEV1 < 30% predicted.
Augmentation therapy has been recommended for patients with both deficient/Null alleles, and a FEV1 between 35% and 60% of predicted and /or rapid lung function decline (ΔFEV1 > 120 ml/year) according to the guidelines (Citation8), although a personalized approach was sometimes used (Citation9).
Statistical analyses
Categorical variables were described by frequencies and percentages and compared with the Chi-square test or Fisher's exact test when appropriate. Continuous variables were expressed as the mean and standard deviation (SD) (median and 95% confidence intervals for non-parametric data) and compared between groups using the Student's t-test or the one-way analysis of variance (ANOVA) where appropriate (Mann–Whitney and Kruskal–Wallis tests for non-parametric data). All post-hoc comparisons were made with the Bonferroni correction for multiple comparisons. Pearson's correlation analysis was performed to determine the relationship between continuous variables. Data were processed with the SPSS 17.0 and MedCalc version 9.4.2.0 for Windows (MedCalc Software, Mariakerke, Belgium). The level of significance was set at 0.05 (two-tailed).
Ethical considerations
Informed consent prior to enrollment was obtained from all patients.
Results
Population characteristics and differences between index and non-index cases
A total of 422 adult subjects with severe AATD were enrolled, in details 258 PI*ZZ, 74 PI*SZ, 4 PI*SS and 86 patients with one rare deficient/Null allele (R) in combination with an S or Z allele, or with two rare deficient/Null alleles (Table ).
Table 1. Clinical characteristics of patients with severe α1-antitrypsin deficiency (AATD), index and non-index cases
The mean age at enrollment was 48.2 ± 14.9 years and 239 (56.6%) subjects were active or former smokers, with a mean tobacco consumption of 15.7 (95%CI 13.8–19.4) pack-years. Occupational exposure was reported by 10% of all subjects, whereas 14.7% of patients had retired from work at diagnosis, and their occupational exposure could not be evaluated. The mean age at symptom onset was 43.3 ± 13.6 years, with a mean diagnostic delay between symptom onset and diagnosis of 8.1 ± 7.3 years. Pulmonary and liver disease (current or past) were observed in 66.1% and 17% of all subjects, respectively. Respiratory medications were taken by 195 (46.3%) subjects, 13.2% needed oxygen therapy and 119 (28.2%) subjects were receiving augmentation treatment. According to the reason for diagnosis, 297 were index patients, mainly affected by lung and liver diseases, and 125 were non-index cases, enrolled because of kinship with AATD patients or incidental diagnosis. Mean age at enrollment was significantly higher (p < 0.0001) in index (50.4 ±14.0 years) compared with non-index (43.1 ± 15.8 years) cases. Smoking, as a principal factor for developing symptoms, was less frequent in non-index than index cases. In general, the prevalence of respiratory symptoms and respiratory diseases was lower in non-index compared with index cases and their lung function parameters were significantly better preserved. Interestingly, eight non-index cases started augmentation therapy 1.3 ± 1.8 years after diagnosis because of a rapid decline in lung function and/or increased awareness about lung diseases.
Comparison among groups selected according to the presence of lung and/or liver diseases
We compared subjects with lung disease (n = 230), liver disease (n = 42) and subjects with liver and lung pathologies (n = 65).
Some characteristics, such as age at diagnosis and age at first symptom, gender, smoking habit, working exposure, genotype and lung function, of patients belonging to the groups with lung disease were quite uniform, irrespective of the presence of liver symptoms. In comparison with patients who had only lung disease, patients with liver diseases only were younger (41.0 ± 16.5 vs 51.9 ± 13.6 years, p < 0.001), had more preserved lung function (FEV1/FVC 1.02 vs 0.59%, p < 0.001) and lower tobacco consumption (8.2 vs 18.9 p/y, p = 0.01). In particular, the mean age at first symptom was significantly higher in patients with lung disease only (44.2 ± 13.4 years) than in patients with liver disease only (28.6 ± 21.5 years, p = 0.006). The mean interval between the onset of symptoms and the final diagnosis was 8.5 years for patients with lung diseases, and only 3.1 years for liver diseases.
Comparison between patients with or without augmentation therapy
We compared the subjects with lung diseases who were treated with augmentation therapy (n = 119), and those with lung diseases who were never be treated (n = 176) (Table ). The mean delay between diagnosis of AATD and beginning of augmentation therapy was 1 year. In comparison with untreated patients, patients on augmentation therapy included fewer non-smokers (24.4% vs 39.8%, p = 0.05), although 7.5% of them currently smoked at baseline; they had lower percentage of PI*SZ subjects (5.9% vs 16.5%, p = 0.01) and more symptomatic patients (dyspnoea as a main symptom 79.0% vs 46.6%, p < 0.0001). On the contrary, untreated patients were less frequently affected by emphysema (50.0% vs 69.7%, p = 0.001), and more often by asthma (10.8% vs 1.7, p = 0.006), and they were generally affected by less severe lung disease, as reported by COPD classification according to GOLD spirometric criteria.
Table 2. Clinical characteristics of patients with severe α1-antitrypsin deficiency (AATD) and lung disease, stratified according to the treatment with augmentation therapy (a.u.)
Quality of life
As reported in Table , St. George's Respiratory Questionnaire (SGRQ) value was worse in index compared with non-index cases (p < 0.0001). It was also worse at baseline in patients treated with augmentation therapy in comparison with untreated patients (52.7 ± 20.6 vs 28.0 ± 21.8, p = 0.001).
Discussion
Data from the Italian Registry has proven to be efficacious, considering that more than four hundred AATD subjects in a country where, only 20 years ago, AATD was considered basically non existent.
Data also confirm the differences between index and non-index cases, as previously reported (Citation4,Citation10), like it is also for the role of smoking in the development of lung disease, the delay in diagnosis and the different phenotypes of lung disease. As it is a typical Italian characteristic (Citation11), the Registry confirms the high proportion of rare - not Z, not S - alleles. Moreover, it also clarifies the different clinical pictures observed in lung, liver and lung plus liver affected patients, showing that patients with lung and liver disease share features similar to those with only lungs diseases.
Another important point is represented by the differences between treated and untreated patients, as augmentation therapy is always under scrutiny. First of all, in Italy among subjects with severe AATD and lung diseases, there were more untreated than treated patients, suggesting that not all affected patients qualify for treatment, rather the majority do not. It should also be underlined that the high cost of treatment has prompted clinicians to pay more attention to when therapy should be prescribed. Nevertheless, an individualized therapy decision should be based on age and degrees of functional impairment and disability of the patients (Citation12), rather than the pure cost of treatment.
Interestingly, 6.7% of treated patients were non index cases, specifically those incidentally diagnosed or tested for family screening; this emphasizes the importance of early diagnosis to carry out an efficient therapeutic strategy.
Another point concerning treatment is the delay between diagnosis of the deficiency and start of augmentation therapy; this is now much reduced. The delay experienced in the past years was due to a shortage of augmentation therapy related to production problems by the companies that were at that time producing the drug.
Conclusions
Twenty years after the first description of a patient with AATD, PiZZ phenotype (Citation12) AATD in Italy has now come of age. Initiatives aimed at increasing awareness of the condition among Pulmonologists, and other medical Specialists have been successful. We also were fortunate to have the enthusiastic support of an outstanding Patients’ Association, and we have reached some important goals, as demonstrated by the data herein presented. Our main result is that AATD should now be recognised as an important component of the Respiratory Disorders in our Country. In the future, despite our great loss, with the passing of Maurizio Luisetti – the real “father” of AATD in Italy -, we will try to further increase the awareness and grant appropriate treatment to all AATD patients who are in need.
Declaration of Interest
ML received consultancy fees from Grifols and participated in advisory boards sponsored by CSL Behring. IF received consultancy fees and travel support from Grifols. LC and BB received consultancy fees from Grifols. SO, CS and LI received travel support from Grifols.
All other authors have no conflicts of interest to declare. The authors alone are responsible for the content and writing of the paper.
Acknowledgments
The authors are deeply indebted to all the physicians who participate in the Italian AATD screening program.
Funding
This study was supported by Grifols, the Fondazione IRCCS Policlinico San Matteo – Ricerca Corrente (RC345, RC721) and the Fondazione Salvatore Maugeri IRCCS - Ricerca Corrente.
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