Characterization of Novel Missense Variants of SERPINA1 Gene Causing Alpha-1 Antitrypsin Deficiency.

The SERPINA1 gene is highly polymorphic, with more than 100 variants described in databases. SERPINA1 encodes the alpha-1 antitrypsin (AAT) protein, and severe deficiency of AAT is a major contributor to pulmonary emphysema and liver diseases. In Spanish patients with AAT deficiency, we identified seven new variants of the SERPINA1 gene involving amino acid substitutions in different exons: PiSDonosti (S+Ser14Phe), PiTijarafe (Ile50Asn), PiSevilla (Ala58Asp), PiCadiz (Glu151Lys), PiTarragona (Phe227Cys), PiPuerto Real (Thr249Ala), and PiValencia (Lys328Glu). We examined the characteristics of these variants and the putative association with the disease. Mutant proteins were overexpressed in HEK293T cells, and AAT expression, polymerization, degradation, and secretion, as well as antielastase activity, were analyzed by periodic acid-Schiff staining, Western blotting, pulse-chase, and elastase inhibition assays. When overexpressed, S+S14F, I50N, A58D, F227C, and T249A variants formed intracellular polymers and did not secrete AAT protein. Both the E151K and K328E variants secreted AAT protein and did not form polymers, although K328E showed intracellular retention and reduced antielastase activity. We conclude that deficient variants may be more frequent than previously thought and that their discovery is possible only by the complete sequencing of the gene and subsequent functional characterization. Better knowledge of SERPINA1 variants would improve diagnosis and management of individuals with AAT deficiency.

Factors Associated with Depression in COPD: A Multicenter Study.

INTRODUCTION: Depression is a prevalent comorbidity in COPD and has an impact on the prognosis of these patients, thereby making it important to study the factors associated with depression in patients with COPD. METHOD: A multicenter, observational and cross-sectional study was conducted to study the factors associated with depression in patients with COPD measured by the hospital anxiety and depression (HAD) questionnaire. We analyzed anthropometric variables and the number of exacerbations in the previous year and calculated the 6-min walking test and the body mass index, airflow obstruction, dyspnea, and exercise (BODE) index. All the patients completed the quality of life EQ-5D and the LCADL physical activity questionnaires. The relationship of these variables with depression was evaluated with two multiple logistic regression models. RESULTS: One hundred fifteen patients were evaluated (93 % male) with a mean age of 66.9 years (SD 8.8) and a mean FEV1 % of 44.4 % (SD 15.7 %). 24.3 % presented symptoms of depression (HAD-D > 8). These latter patients had worse lung function, greater dyspnea, reduced exercise capacity, a higher score in the BODE index, poorer quality of life, reduced physical activity, and more exacerbations. In the first logistic regression model, quality of life and the BODE index were associated with depression (AUC: 0.84; 0.74-0.94). In the second model including the variables in the BODE index, quality of life and dyspnea measured with the MRC scale (AUC: 0.87; 0.79-0.95) were associated with depression. CONCLUSIONS: Nearly one-quarter of the patients with COPD in this study presented clinically significant depression associated with worse quality of life, reduced exercise capacity, greater dyspnea, and a higher score in the BODE index.

Multicentric study on the beta-blocker use and relation with exacerbations in COPD.

Chronic obstructive pulmonary disease (COPD) is frequently associated with chronic heart failure (CHF) or coronary artery disease (CAD). In spite of the recommendation to use beta-blockers (BB) they are likely under-prescribed to patients with concurrent COPD and heart diseases. To find out the prevalence of use of BB, 256 COPD patients were consecutively recruited by pulmonary physicians from 14 hospitals in 7 regions of Spain in their outpatient offices if they had a diagnosis of COPD, were not on long-term oxygen therapy, had CHF or CAD, and met the criteria for BB treatment. In patients with indication 58% (95%CI, 52-64%) of the COPD patients and 97% of the non-COPD patients were on BB (p < 0.001). In patients with COPD, several factors were independently related to at least one visit to the emergency room in the previous year such as use of BB, adjusted OR = 0.27 (95% CI 0.15-0.50), GOLD stage D, OR = 2.52 (1.40-4.53), baseline heart rate >70, OR 2.19 (1.24-3.86) use of long-acting beta2-agonists OR = 2.18 (1.29-3.68), previous episodes of left ventricular failure OR 2.27 (1.19-4.33) and diabetes, OR = 1.82 (1.08-3.38). We conclude that, according to what is recommended by current guidelines, BB are still under-prescribed in COPD patients. COPD patients with CHF or CAD using BB suffer fewer exacerbations and visits to the ER. GOLD stage, use of long-acting beta2-agonists, baseline heart rate and comorbidities are also risk factors for exacerbations in this population.

Factors associated with high healthcare resource utilisation among COPD patients.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) places a huge economic burden on healthcare systems, especially patients with frequent exacerbations and co-morbidities. OBJECTIVES: To identify factors associated with high utilisation of healthcare resources in a population of patients with COPD. METHOD: We conducted an observational, cross-sectional, multicentre study with the aim of identifying the factors associated with high resource utilisation among patients with COPD. Sociodemographic and anthropometric characteristics of the study population, as well as data on health-related quality of life, respiratory symptoms, presence of anxiety and depression, physical activity and lung function were collected. We examined the relationship between these variables and high utilisation of healthcare resources, by performing a multivariate analysis based on a logistic regression model. RESULTS: 115 patients (64 were high users of healthcare resources, and 51 control patients) from 13 hospitals were selected. Patients presenting high resource utilisation had worse FEV1, worse basal SpO2, less distance walked in the 6-minute walk test, and increased dyspnoea. They also had a worse BODE index, worse scores in all dimensions of the EURO-QOL 5D and the LCADL scale, and displayed a higher prevalence of depression. Multivariate analysis yielded a statistically significant association between SpO2, LCADL scores, serum fibrinogen values and total leukocyte count, and high healthcare resource utilisation. CONCLUSIONS: COPD patients who incur higher healthcare resource utilisation show reduced physical activity, increased respiratory failure and increased systemic inflammation.

Factors associated with the evolution of lung function in patients with alpha-1 antitrypsin deficiency in the Spanish registry.

INTRODUCTION: The present study intends to describe the characteristics of patients diagnosed with severe alpha-1 antitrypsin deficiency (AATD) in Spain, to observe the rate of decline in forced expiratory volume in 1 second (FEV1) with and without substitutive therapy, and to identify factors associated with a rapid rate of decline in FEV1. METHOD: A retrospective study of the evolution of individuals with AATD was carried out based on data collected from the Spanish registry. The primary response variable was the annual rate of decline in FEV1, calculated using the baseline and last postbronchodilator FEV1 values in an endpoint analysis. RESULTS: 303 patients with severe AATD and Pi ZZ phenotype were identified. Follow-up spirometric data were collected for 117 subjects. Being a smoker or ex-smoker versus never smoker (odds ratio [OR]=10.31; 95% confidence interval (CI)=1.8-58.8; p=0.008) and having a higher baseline postbronchodilator FEV1 (% predicted) (OR=1.03; 95% CI=1.005-1.06; p=0.018) were independently associated with a more rapid rate of decline in FEV1. There was also a trend towards a relationship between low body mass index (BMI) and a greater rate of deterioration in lung function (OR=1.14; 95% CI=0.98-1.33; p=0.085). CONCLUSION: Being a smoker or ex-smoker, greater baseline lung function, and low BMI were the main risk factors associated with an accelerated rate of decline in FEV1. This finding warrants the close observation of younger patients with a better-preserved FEV1.

The IDDEA project: a strategy for the detection of alpha-1 antitrypsin deficiency in COPD patients in the primary care setting.

OBJECTIVE: Primary care provides the main route for access to health care for patients with common chronic illnesses such as chronic obstructive pulmonary disease (COPD). Alpha-1 antitrypsin (AAT) deficiency is an underdiagnosed pathology associated with COPD risk which has a very low prevalence. The Information and Detection of the Deficiency of AAT (IDDEA) project was developed to identify AAT-deficient patients at primary care centres by providing adequate diagnostic tools to family doctors. METHODS: Patients with COPD were identified and registered on a specially designed website. Dried blood samples were collected on filter papers and sent to the laboratory for AAT levels and AAT deficiency-related genotype determinations. RESULTS: were uploaded to the website and analysed. RESULTS: Between January 2008 and April 2009, 596 patients were identified by 90 participating physicians. The number of patients who did not have AAT deficiency (serum concentrations ≥60 mg AAT/dl) was 549 (98.9%). Nineteen patients (3.2%) were carriers of the allelic variant Pi*Z among which two were homozygous PiZZ (one of them was an index case) and one was heterozygous PiSZ. These three newly detected cases were registered in the Spanish Registry of Patients with AAT Deficiency. An estimate of the gene frequency of the S allele was 7.65% and the severe deficiency Z allele was 1.76%. CONCLUSIONS: Results confirm that ATT deficiency is still underdiagnosed. The IDDEA system appears to be a useful tool for the detection of AAT deficiency in the primary care setting.

[Residency training of European respiratory medicine specialists: The HERMES project]. / La formación especializada en neumología en Europa. El proyecto HERMES.

Given the movement of medical specialists across borders in recent years, and the changes in legislation affecting the structure and operation of boards responsible for the various medical specialties, the task of harmonizing the training of respiratory medicine residents across the European Union has become crucial. The project for Harmonized Education in Respiratory Medicine for European Specialists (HERMES) is a collective response to this need. After 3 years of work toward building consensus, HERMES is entering its second phase. The Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) has the aim of informing our resident trainees, their instructors, and others concerned with postgraduate education in respiratory medicine in Spain about this undeniably difficult task of harmonization.

Geographic differences in clinical characteristics and management of COPD: the EPOCA study.

AIMS: Data on differences in clinical characteristics and management of COPD in different countries and settings are limited. We aimed to characterize the profile of patients with COPD in a number of countries and their treatment in order to evaluate adherence to recommendations of international guidelines. METHOD: This was an observational, international, cross-sectional study on patients with physician-diagnosed COPD. Demographic and clinical characteristics, risk factors, and treatment were collected by their physician via an internet web-based questionnaire developed for the study. RESULTS: A total of 77 investigators from 17 countries provided data on 833 patients. The countries with the highest number of patients included were: Argentina (128), Ecuador (134), Spain (162), and Hong Kong (153). Overall, 79.3% were men and 81% former smokers, with a mean FEV1 = 42.7%, ranging from 34.3% in Hong Kong to 58.8% in Ecuador. Patients reported a mean of 1.6 exacerbations the previous year, with this frequency being significantly and negatively correlated with FEV1 (%) (r = -0.256; p < 0.0001). Treatment with short-acting bronchodilators and theophyllines was more frequent in Ecuador and Hong Kong compared with Spain and Argentina, and in patients belonging to lower socioeconomic levels (p < 0.0001 for all comparisons). Inadequacy of treatment with inhaled corticosteroids and theophyllines was high, with significant differences among countries. CONCLUSIONS: Differences in the clinical characteristics and management of COPD were significant across countries. Adherence to international guidelines appears to be low. Efforts should be made to disseminate and adapt guidelines to the socioeconomic reality of different settings.

Augmentation therapy for emphysema due to alpha-1-antitrypsin deficiency.

Alpha-1 antitrypsin deficiency (AAT) is a hereditary recessive autosomal disease caused by mutations in the AAT gene. This disease is characterized by abnormally low AAT concentrations in plasma, which, in its homozygote form, carries a high risk for the development of early pulmonary emphysema and liver damage. Since the end of the 1980s augmentation therapy with AAT from human plasma has been available for specific treatment of emphysema due to AAT deficiency. Intravenous augmentation therapy has been demonstrated to be safe and weekly infusions of AAT have resulted in plasma AAT concentrations above those considered protective for the lungs. However, life-long weekly infusions are not well accepted by patients, therefore pharmacokinetic studies have been performed to try to individualize the therapeutic regimen in order to obtain adequate trough serum AAT levels with prolonged intervals of administration. Therapeutic regimens administered every two weeks appear to be safe and result in adequate trough serum concentrations, but less-frequent administrations result in trough levels below the target. Alpha-1-antitrypsin deficiency is largely unrecognized and underdiagnosed. The foundation of national and international registries is a valid strategy to increase awareness about the disease and collect information about the natural history of this deficiency. Furthermore, the identification of a large number of patients will allow the development of new clinical trials aimed at finding better treatments for this infrequent condition.