REDAAT, the Spanish Registry of Patients with Alpha-1 Antitrypsin Deficiency, was set up in 1993 after the diagnosis of the first cases in Barcelona and Asturias. It functioned primarily as a working group within the area of respiratory failure and sleep disorders, and the scope was later extended to include the area of chronic obstructive pulmonary disease (COPD) of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR).1–4

Since it was founded, the objectives of REDAAT have been to broaden the DAAT knowledge base by stimulating research and facilitating diagnosis.

The REDAAT participates in the Alpha-1 Antitrypsin International Registry (AIR) that was founded in 1996 following the recommendations of the World Health Organization (WHO).5 It also forms part of the Spanish Network of Rare Disease Registries by participating in the National Registry of Rare Diseases run by the Rare Diseases Research Institute (ISCIII Institute of Health).6,7

This study evaluated the registry as a tool for the systematic collection of data under standard clinical practice conditions, and examined the profiles of participating doctors and the demographic, phenotypic, clinical and functional characteristics of patients included during the 20 years since it was initiated.

The REDAAT registry collects clinical and functional data from more than 500 individuals with AATD, principally Pi*ZZ and Pi*SZ phenotype carriers who mostly have lung disease. Thirty-five percent of them received AAT replacement therapy and follow-up data are available for about half of all cases. This underreporting of follow-up may be due to various reasons: asymptomatic patients with no manifestations of lung or liver disease do not generally attend regular clinic visits, and candidates for transplantation are referred to transplantation units and may lose contact with the pulmonologist who diagnosed them in their center of origin. Registry adherence by professionals varies for different reasons, but changes can be expected over the 20-year period since it was initiated, and many cases have been lost to follow-up as circumstances change for both doctors and patients (retirements, transfers, hospital mergers, changes in address, etc.).

Analysis of the REDAAT data shows a wide disparity in the proportion of cases registered by each doctor, and the geographical distribution of registered cases is also very irregular. These variations cannot be explained by differences in population, prevalence of the deficiency, or availability of health resources in the different autonomous communities. Indeed, the variations appear to correspond more to the investigator's profile and the size of the center than to the prevalence of AATD in each geographical area. The database contains good quality information and is a useful tool for the study of patient characteristics and the natural history of AATD.

A marked trend was observed toward accumulation of cases in third-level hospitals. This may be associated with the availability of diagnostic techniques, the severity of the lung disease, and the age of patients with pulmonary involvement, who may be candidates for inclusion in transplantation programs. Eighteen percent of registered individuals were seen in the center in which REDAAT was set up, which was also the first hospital in Spain to use replacement therapy.3,4 This suggests that a continuing interest in this disease in this center leads to higher rates of diagnosis, although this may also be the effect of larger numbers of patients being referred by other specialists to this center.

Centers which register most cases also seem to update the data more regularly. One possible reason for this is that, although a growing number of cases are now detected in smaller centers, this is a rare disease and the impact on functional status can be severe, so patients are likely to be referred to other higher level facilities, and the doctor who made the initial diagnosis does not have ready access to follow-up data.

No reliable epidemiological data are currently available from the National Health System specifying the real number of diagnosed individuals, so we cannot be sure that the sample included in the REDAAT is representative, nor can we rule out bias in the selection of the patients registered. So, while we can assume that not all diagnosed cases are registered, we can only estimate the rate of underdiagnosis in Spain using the data presented here, and these show that information is available on only a small percentage of the estimated AATD population based on prevalence studies.

There are an estimated 12000 Pi*ZZ carriers in Spain, of which 471 (3.9%) were registered in the REDAAT as of December 2015. This percentage is higher than that calculated by Stoller (2.4%) from the AIR data and the American registry.11,12 It has also been estimated that of the 12000 carriers of the Pi*ZZ genotype, 2500 (21%) may have COPD. In REDAAT, 440 Pi*ZZ carriers with COPD are registered, accounting for about 18% of estimated COPD-ZZ.10

While it is obviously of interest to determine the disease course of all AATD patients due to the variable clinical expression of this disease, it is particularly important to expand our knowledge of the patient subgroup that presents with lung disease, as this is the type that impacts most on morbidity and mortality. In this regard, our population is valuable, as it includes a high percentage of individuals with lung disease with an emphysema phenotype, particularly COPD, followed by the chronic bronchitis profile. With regard to the most frequent phenotypes, Pi*ZZ individuals, including those with lower accumulated tobacco consumption, had poorer lung function than Pi*SZ patients.9,13

In terms of data integrity, a high percentage of variables were correctly recorded, except for functional parameters in follow-up. This is indicative of a good database design and good real time data quality control since the website was updated in 2008.5 Since then, every new case forwarded to the registry is reviewed by the administrator before validation and definitive inclusion in the database. Errors or incomplete data can be very quickly detected and corrected.

The design of the REDAAT database has some limitations. The simplicity of the form means that data collection is quick (less than 10minutes), but there is no opportunity to include detailed information about some important aspects. Lack of information on the medication used, radiological findings to confirm the diagnosis of pneumonia, bronchiectasis or emphysema extension, confirmation of the quality or standardization of spirometries may be considered weaknesses that could reduce the reliability of the results. Therefore, the conclusions reached from an analysis of the database are not as solid as those that would be drawn from a prospective clinical trial or study specifically designed to evaluate these parameters. However, the data collected provide information on patient profiles and generate very important data for the potential design of more detailed studies on certain aspects of AATD.

A mean of 39 cases are registered annually, but the rate per year varies enormously. This is largely due to the different stages in the development of REDAAT. The online registry was launched in 2001, and the cases previously recorded on paper were transferred to the electronic database.8 Between 2007 and 2008 the server was changed and the website that hosted the database was updated, as a result of which the registry was not operational for several months. Between 2012 and 2013, SEPAR led an awareness-raising campaign as part of its SEPAR Year for Orphan Diseases that included activities specifically aimed at AATD, and this may have contributed to a greater number of entries.

In our population, onset of symptoms generally occurs between the 3rd and 4th decade of life, as also described by other authors.14 The delay between onset of symptoms and diagnosis of deficiency is almost 10 years on average. This finding is very similar to data provided by the American registry.15 However, the fact that COPD is greatly underdiagnosed and most AATD patients have this disease could have a cumulative effect: delay in COPD diagnosis added to the failure to suspect AATD means that advanced stages of emphysema are reached.16

Our study revealed that a high number of the cases registered as non-index had lung disease, but the possible existence of AATD was not suspected until it was detected in another family member. This finding reflects a continued lack of awareness or knowledge of AATD among health professionals, despite recommendations from institutions such as the World Health Organization and scientific societies.5,17–19

Replacement therapy was administered to 45.4% of the patients at some time since inclusion in the REDAAT registry. These patients more frequently presented emphysema and chronic bronchitis, they were more symptomatic and had worse lung function, higher mortality and indication for transplantation. In these patients, greater severity was associated with criteria for starting therapy, but no conclusions can be drawn as regards treatment efficacy. However, data on the efficacy of therapy were retrieved from the American registry, which was designed for this purpose, and provided information on 1048 individuals, with a follow-up of 3.5–7 years. A significant reduction in mortality was detected and FEV1 decreased more gradually in patients with FEV1 of 35%–49% who received continuous or intermittent treatment.20

REDAAT is a useful tool for studying the reality of AATD in Spain. The registry data are reasonably complete, although few participating doctors participate for long enough to allow follow-up data to be entered. The age of the patient cohort is similar to that of cohorts included in other registries, and most individuals have lung disease.

Beatriz Lara has received fees for scientific consultancy and/or for speaking engagements from Bayer, Glaxo Smith Kline, Boehringer Ingelheim, Novartis, Grifols, Talecris, Menarini, Laboratorios Rovi and Pfizer.

Francisco Casas has received fees for scientific consultancy and/or for speaking engagements from Almirall, AstraZeneca, Boehringer Ingelheim, Grupo Ferrer, GlaxoSmithKline, Grifols, Laboratorios Esteve, Pfizer, Teva, Menarini, Novartis, Gebro Pharma and Takeda.

Sergio Cadenas has received fees for speaking engagements from Almirall, Astra Zeneca, Boehringer Ingelheim, GlaxoSmithKline, Grifols and Novartis.

Sergio Curi has received fees for speaking engagements from Boehringer Ingelheim, Almirall and GlaxoSmithKline.

Francisco Dasi has received fees for speaking engagements from Grifols.

Marc Miravitlles has received fees for scientific consultancy and/or for speaking at conferences organized by Almirall, AstraZeneca, Boehringer Ingelheim, CSL Behring, Grupo Ferrer, GlaxoSmithKline, Grifols, Laboratorios Esteve, Teva, Cipla, Menarini, Novartis, Gebro Pharma and Takeda.