Alpha-1 antitrypsin (AAT) is a highly pleomorphic glycoprotein belonging to the serpin superfamily, with more than 100 varieties and whose main characteristic is its antiprotease function, especially anti-neutrophil elastase.1,2

The normal allele, present in more than 90% of the population, is called PI*M. The most frequent deficient allelic variants are PI*S and PI*Z, which are responsible for the production of abnormal proteins that polymerize within the hepatocytes; thus, the plasma levels are markedly reduced in subjects who are carriers of at least one and especially two Z deficiency alleles.3,4 AAT deficiency (AATD) is one of the most common genetic disorders. It is the main genetic factor that contributes to the development of pulmonary emphysema in adults, as the absence of AAT causes an imbalance favoring proteases, which cause tissue damage.

AATD, defined by serum concentrations of AAT less than 35% normal values, is a rare condition that affects one out of every 2000–5000 Caucasian individuals, descendants of Northern, Central, and Western Europeans.5 As occurs in other rare diseases, patient registries have been developed in order to compile information and, in this manner, improve the understanding of the disease. Although clinical assays are considered the gold standard for establishing the most effective interventions, the information found in the registry and from other observational studies can be used to fill in important gaps that, if not, would be left uncovered because clinical assays do not deal with real-life situations.6

The world-wide AATD population registries (Alpha One International Registry [AIR], the registry of the National Heart, Lung, and Blood Institute [NHLBI] in the United States and the Alpha One Foundation Research Network Registry [AOF-RNR]) have demonstrated that the main clinical characteristic of this disease is effort dyspnea.7,8 They have also shown that the majority of patients are diagnosed when they have already developed severe lung disease, generally at an earlier age than patients with chronic obstructive pulmonary disease (COPD) without AATD.

The evolution in clinical terms and life expectancy are both directly related with the accelerated loss of forced expiratory volume in 1s (FEV1), and it has been reported that the lung function deterioration is faster in individuals with AATD than in COPD patients without AATD.9–13

Several studies have shown that smoking and respiratory exacerbations are the main factors related with the deterioration of FEV1. They have also suggested that substitutive treatment (intravenous administration of purified AAT from blood donors, capable of maintaining AAT plasma levels above 80mg/dl) could stop the decline of FEV1, reduce the frequency of the exacerbations and even stop the loss of lung density.14–17

The natural history of AATD is not well known. Its clinical and functional impacts are not homogeneous in all individuals and the existing series include very diverse populations that are occasionally very limited.18 Health-care institutions and scientific societies recognize that the creation of rare disease registries is an essential strategy in order to be able to develop clinical studies and clarify the natural history of these diseases. The Spanish registry of patients with alpha-1 antitrypsin deficiency, or REDAAT, compiles the clinical and functional data of the Spanish population with AATD. REDAAT is a Spanish national registry and was founded in 1993 as a workgroup of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR).19

The present study describes the evolution of FEV1 in patients belonging to REDAAT, centered on the parameters that could potentially have a predictive value for a fast deterioration in lung function.20

Based on the information compiled in the REDAAT database, we carried out a retrospective study in patients with AATD. The objectives of this study were: (a) to describe the characteristics of the patients diagnosed with AATD in Spain; (b) to observe the rate of decline in FEV1 of the patients who had been or currently were receiving substitutive treatment and those who had/were not; and (c) to identify the factors associated with a greater rate of descent in FEV1.

This retrospective study based on data included in the REDAAT has shown that there is a great variability in the annual rate of decline in the FEV1 of patients with AATD and that the risk factors associated with an accelerated rate of decline in FEV1 were a history of smoking, better lung function at the beginning of follow-up and a low BMI. When we compared the rate of descent in the FEV1 of patients who had either received at one time or were receiving substitutive treatment with those who had never received it, no statistically significant differences were observed in the annual rate of fall in FEV1.

It still has not been possible to recruit enough patients with AATD in order to carry out a randomized study with sufficient statistical power in order to demonstrate the efficacy of the substitutive treatment in reducing the speed of the deterioration in lung function. With the intention of overcoming the methodological difficulties due to the low prevalence of AATD and the variable probability of developing related symptoms despite having AATD, a series of registries have been created in order to compile and analyze the clinical data of individuals with AATD, adjusted to real life.8,25,26 These registries offer the opportunity to evaluate large cohorts of individuals in an almost experimental manner that is closer to real-life conditions over long expanses of time. Their inclusion criteria are less strict than those of clinical assays, and there is no requisite of the prescription of a certain treatment for the participation of the individuals included. As a consequence, the observational studies with patients recruited from registries have allowed us to research the impact of substitutive treatment on the speed of the fall in FEV1 and on survival.7,17,27,28

The AATD registries can have different objectives and examine inhomogeneous populations with this genetic alteration. For example, the NHLBI Alpha-1-Antitrypsin Deficiency Registry was founded in 1988 with the objective of characterizing the clinical course of this disease in 1000 individuals with AATD using the data collected during 7 years in centers in the United States and Canada.25 The declining rates in lung function and survival were key aspects evaluated in this registry. A second registry of larger dimensions, AOF-RNR, was created in 2000 by the initiative of a foundation of affected patients (Alpha One Foundation, Miami, FL, United States) with the aim to describe the largest population possible of deficient individuals in order to facilitate future clinical studies.26 The phenotype of the patients included in the AOF-RNR was reported by the patients themselves and, consequently, the registry contains patients with unconfirmed genotypes. The AIR (Alpha-1 International Registry) was founded in 1998 in response to the recommendations of the World Health Organization.8 The objective of this initiative was to create a common, centralized database in order to obtain knowledge about AATD by means of the data compiled of patients from more than 20 participating countries. With 2627 subjects recruited before 2006, AIR is the most extensive and has the largest volume of clinical and demographic data of individuals with AATD.8

The Spanish registry of patients with AATD was founded in 1993 with the following objectives: (a) to learn about the characteristics and frequency of AATD in Spain; (b) to establish guidelines adapted to our setting about the treatment and follow-up of patients with the deficiency; (c) to offer information to the doctors who treat these patients throughout Spain; (d) to increase the knowledge and interest in this disease and try to reduce the underdiagnosis and the delay in diagnosis; and (e) to offer technical support for the determination of the phenotype Pi and, if necessary, the genotype in individuals suspected of being deficient.19,20,29

The population analyzed in this study included only patients with severe AATD. Differences and similarities were observed when we compared them with the baseline characteristics reported in the AIR, NHLBI and AOF-RNR registries. In the Spanish population, 64% were men compared with 56%, which is the mean in the remainder of the registries. In the same way, the mean age of the patients of the Spanish population was slightly older compared with other registries (55 years of age vs 46–50, respectively). The proportion of patients identified by family study was similar in the NHLBI, AIR and in the Spanish registry.8 In the latter, 6% were active smokers, unlike the AIR, NHLBI and AOF-RNR registries, with a reported 10%, 8% and 2%, respectively. The low rate of tobacco habit observed in the AOF-RNR registry could reflect a greater degree of consciousness about the risks associated with smoking in the patients with AATD.8 The mean FEV1(%) was lower in the population of NHLBI in comparison with the Spanish population (47% vs 63%), and the majority of patients of the NHLBI registry either were receiving or had previously received substitutive treatment (66% vs 36%, respectively).7,30

The method used to calculate the rate of fall in lung function is based on the measurement of the two extreme values in the follow-up. This method has been used in a clinical assay with intravenous AAT together with a linear regression method, and both offered similar results,24 therefore we have adopted the method described (end-point analysis). The findings found in our logistic regression analysis–that being a smoker and having a higher baseline post-bronchodilator FEV1 would be significantly and independently associated with a more rapid rate of decline in FEV1–are important observations of this study. The results agree with the findings of previous studies. Both in the NHLBI7 registry and in the Swedish AATD registry,31 we observed a faster deterioration of lung function in active smokers than in ex-smokers and never-smokers, while Dowson et al.32 have demonstrated that the deterioration of FEV1 is greater in individuals with a poorer post-bronchodilator FEV1. In addition, Dawkins et al. observed a greater degree of descent in lung function in individuals with moderate-severe disease compared with those with very severe affectation.33

The results, likewise, showed a tendency towards the association between a low BMI and the probability of experimenting a more rapid rate of decline of the FEV1.33 Consistently, previous studies have demonstrated that a low BMI is an independent predictor for mortality in patients with AATD.34

Several studies have shown that substitutive treatment can slow the rate of decline of lung function,7,17,27,28 reduce the loss of lung tissue and the progression of emphysema,24 and increase survival in patients with AATD.7 In the Spanish registry, however, no significant difference was observed in the rate of decline of FEV1 according to whether or not the patients received substitutive treatment. Although this could be an unexpected finding, it is important to admit that both groups had considerably different baseline characteristics. The patients that received substitutive treatment were more frequently men with lung disease and with greater exertional dyspnea than those who did not receive substitutive treatment. In addition, the patients with substitutive treatment had a greater incidence of pneumonia, greater use of medication for their respiratory disease and greater use of chronic home oxygen therapy. Also, the mean FEV1 of the patients in substitutive treatment was significantly less than that of the group who did not receive substitutive treatment. The differences between the groups in baseline conditions exclude the possibility of a reliable evaluation of the effects of the substitutive treatment in the rate of decline in FEV1, and it is another example of the challenges that are faced when interpreting data derived from observational studies such as registries. For example, the decision of the prescription is made by each doctor depending on the severity and the prognosis of each patient, which usually results in an indication bias by assigning the treatment preferentially in more severe patients or with more risk factors for a poor prognosis. Likewise, it is not possible to analyze the influence of the respiratory medication on the fall in FEV1 as there is a bias in indication, by prescribing more medication to the more severe patients or those who present a poorer clinical evolution. In this study, it was not possible to evaluate the influence of other treatment strategies like respiratory rehabilitation as this variable was not included in the original database of the international registry.

Other factors, such as respiratory infections and age, can modulate the deterioration of the lung function over time, although with a lower intensity. The role that these factors play is not as important as smoking, and it is necessary to study large cohorts of patients in order to observe its possible impact.

In addition to the limitations derived from the different characteristics of the patients with or without substitutive treatment, there are other considerations that should be kept in mind when interpreting the findings presented here. First of all, the Spanish registry is not a population registry and may not be representative of all the individuals with this genetic disorder. The registry compiles a high percentage of patients diagnosed with AATD due to presenting lung disease, mostly emphysema, but the asymptomatic individuals are underrepresented. It is possible that the symptomatic and asymptomatic individuals experience different rates of deterioration in their lung function, even after controlling for factors such as tobacco habit and the initial values of lung function. Second, only a third of the patients who were initially identified were followed-up and, therefore, were valid for the analysis of the main variable. Differences, such as having poorer baseline lung function, were data that were seen in the group with follow-up and apt for the calculation of the fall in FEV1 in comparison with the group without follow-up. Therefore, it is not assumed that the results that are presented here can be applied in general to all the patients of the registry.

Despite the limitations, the findings reported in this analysis provide valuable information about the natural history of the disease and suggest various parameters with a potential predictive value in the detection of the rapid deterioration of the lung function in affected individuals.

The rate of deterioration in lung function in patients with AATD varies ostensibly. The Spanish registry has provided data that show that smoking and having a more preserved lung function are significantly related with an accelerated decline in FEV1. This suggests that the youngest patients, with normal or hardly deteriorated lung function, should undergo a more intense follow-up of their evolution together with emphatic anti-tobacco advice.

The cooperation of multiple researchers in a national registry is not an easy task, and the prospective collection of data requires quite a lot of motivation. Centralized registries, such as those in Britain or the Netherlands, are more appropriate for longitudinal data collection. New strategies should be started to encourage physicians to include and periodically update the follow-up data of their patients in the databases of the registries.

The authors declare having no conflict of interests related to this manuscript.

The present study has been financed with a research grant from Talecris Biotherapeutics GmbH (Frankfurt am Main, Germany).