U.S. Center for the Alpha One International Registry

AIR Research

Chest 2003 Mar;123(3):784-91

· Costs of chronic bronchitis and COPD: a 1-year follow-up study.

Miravitlles M, Murio C, Guerrero T, Gisbert R.

Servei de Pneumologia, Institut Clinic de Pneumologia i Cirurgia Toracica (IDIBAPS), Hospital Clinic i Provincial, Barcelona, Spain. marcm@separ.es

OBJECTIVE: This study attempted to determine the total direct costs derived from the management of chronic bronchitis and COPD in an ambulatory setting through a prospective, 1-year, follow-up study. METHOD: A total of 1,510 patients with chronic bronchitis and COPD were recruited from 268 general practices located throughout Spain. Patients were followed up for 1 year. All direct medical costs incurred by the cohort and related to their respiratory disease were quantified. Costs were calculated for patients with confirmed COPD according to the degree of severity of airflow obstruction. RESULTS: The global mean direct yearly cost of chronic bronchitis and COPD was $1,876. The cost generated by patients with COPD was $1,760, but the cost of severe COPD ($2,911) was almost double that of mild COPD ($1,484). Hospitalization costs represented 43.8% of costs, drug acquisition costs were 40.8%, and clinic visits and diagnostic tests represented only 15.4% of costs. CONCLUSION: This is the first prospective follow-up study on a large cohort of patients with chronic bronchitis and COPD aimed at quantifying direct medical costs under usual clinical practice in the community. Costs of chronic bronchitis and COPD were almost twofold those reported for asthma. Patterns of COPD management in the community differ from those recommended in guidelines. COPD represents a great health-care burden in developed countries, and aging of the population and continuing smoking habits predict that it will continue to do so in the future.

Arch Bronconeumol 2003 Jan;39(1):8-12

Screening program for alpha-1 antitrypsin deficiency in patients with chronic obstructive pulmonary disease, using dried blood spots on filter paper

Article in Spanish

La Roza Cd C, Costa X, Vidal R, Vila S, Rodriguez-Frias F, Jardi R, Miravitlles M.

Servicio de Neumologia. Institut Clinic de Pneumologia i Cirurgia Toracica (IDIBAPS). Hospital Clinic i Provincial. Barcelona. Spain.

Alpha-1 antitrypsin (AAT) deficiency is an under-diagnosed disease and screening programs have therefore been recommended for patients with chronic obstructive pulmonary disease (COPD). We present the results of the pilot phase of a screening program for AAT deficiency in order to evaluate the technique used, the procedures for transporting samples and the results obtained.Over a period of one month, five centers collected samples from all COPD patients for whom plasma concentrations of AAT or Pi phenotype had not yet been determined. Capillary blood spots were dried on filter paper and then sent by surface mail to a central laboratory for study. An immunonephelometric assay was used to determine AAT and DNA phenotyping was done by use of a Light Cycler. Samples were analyzed from 86 COPD patients (76 men, 10 women) with a mean age of 68.2 years. AAT deficiency was ruled out for 74 patients (86%) who had concentrations above the cutoff established, although one of them was MZ heterozygote by genotype. Among the 12 remaining patients (13.9%), only two also had a Z allele. The rest were individuals with concentrations below the established threshold and no evidence of a Z allele (10 patients, 11.6%). The Z allele frequency observed (3/172; 1.74%) was very similar to that found in the general population.The results of this pilot study allowed us to confirm that the method used to collect samples worked well. The sampling method is applicable, easy and well-accepted by participating physicians. It allowed AAT concentrations and Z allele deficiency to be determined. The method correlates well with standard techniques used for samples in whole blood.

Arch Bronconeumol 2002 Nov;38(11):530-5

· Respiratory symptoms and diagnosis of COPD in smokers of various types to tobacco. Results from the IBERPOC study

Article in Spanish

Jimenez-Ruiz CA, Sobradillo V, Gabriel R, Viejo JL, Masa JF, Miravitlles M, Villasante C, Fernandez-Fau L.

Servicio de Neumologia. Hospital de la Princesa. Madrid. Espana. victorina@ctv.es

BACKGROUND: The aim of this study was to investigate the sociodemographic characteristics, smoking habits, the prevalence of respiratory symptoms and chronic obstructive pulmonary disease (COPD) in four groups of smokers: of cigarettes (SCt), of cigars (SCigar), of both (SB), of cigars currently but of cigarettes in the past (SCigarExCt) and of cigarettes currently but of cigars in the past (SCtExCigar). METHOD: A multicenter epidemiological study enrolling 4,035 subjects aged between 40 and 69 years. One thousand nine hundred sixty-three were non-smokers and 1,146 were current smokers. Among the smokers, 869 were SCt, 37 were SCigar, 97 were SB, 86 were SCigarExCt and 57 were SCtExCigar. We analyzed sociodemographic characteristics, smoking and the prevalence of respiratory symptoms and COPD. RESULTS: Cigar smokers were usually men, of lower socioeconomic status (p < 0.001) and older than cigarette smokers (p < 0.001), but CO concentrations in expired air were lower in the SCigar group than in the SCt group (5 ppm vs 15.7; p < 0.001). Informants who believed their smoking was not detrimental to their health or to that of second-hand smokers made up 86.5% of the SCigar group and 79.1% of the SCigarExCt group. COPD was diagnosed in 13.2% of the SCt group, in 24.7% of the SB group, and in 12.8% of the SCigarExCt group, in comparison with 4% of the non-smokers (p < 0.001 for all comparisons). CONCLUSIONS: SCigar are mainly older men with lower educational levels. Their concentrations of CO in expired air are low and they have little awareness of the health risks posed by their habit. SCigar who were once smokers of cigarettes have a higher prevalence of respiratory symptoms and COPD than non-smokers and the same prevalence of COPD as SCt.

Eur Respir J 2002 Oct;20(4):1050-6

· Alpha1-antitrypsin deficiency: a report from the 2nd meeting of the Alpha One International Registry, Rapallo (Genoa, Italy), 2001.

Luisetti M, Miravitlles M, Stockley RA.

Dept of Respiratory Diseases, IRCCS San Matteo, Pavia, Italy. m.luisetti@smatteo.pv.it

The Alpha One International Registry is a scientific foundation established to comply with a World Health Organization recommendation to develop a multinational registry of alpha1-antitrypsin deficiency, with the aim of creating a common database of subjects recognised in a standardised way. A commitment of the Alpha One International Registry members, belonging to 15 national registries, is to meet every 2 yrs in an open scientific conference to provide a scientific and clinical update on the deficiency. The second Alpha One International Registry meeting was held in Rapallo (Genoa, Italy) on September 27th-28th, 2001, and 26 speakers provided an exhaustive overview of all aspects of alpha1-antitrypsin deficiency, including epidemiology, genetics, biochemistry, associated conditions, established and novel therapeutic options, and markers of efficacy. In the framework of a rare and often under-recognised condition, this meeting is likely to be central to improving understanding and increasing awareness of alpha1-antitrypsin deficiency.

Arch Bronconeumol 2002 Sep;38(9):427-30

· Use of the Internet in a multicenter study of chronic obstructive pulmonary disease in primary care. Pilot phase of the EFEMAP study

[Article in Spanish]

Miravitlles M, Llor C, Naberan K, Cots JM; en representacion del estudio EFEMAP.

Servicio de Neumologia, Institut Clinic de Pneumologia i Cirurgia Toracica (IDIBAPS), Hospital Clinic i Provincial, Barcelona, Spain. marcm@separ.es

OBJECTIVE: To determine the reliability of clinical data collection and transmission by Internet in a multicenter primary care study. PATIENTS AND METHODS: Multicenter, observational study of a population of patients with exacerbated chronic obstructive pulmonary disease (COPD). All data were gathered in a specifically designed digital program on a palm-held pocket computer. Information was transmitted on-line by modem to a central database. RESULTS: Thirty-nine researchers participated in this pilot phase. Over three months 324 patients were treated. Thirty-seven telephone consultations were generated, most (54%) in reference to how the digitized questionnaire worked. Questions were solved in a mean 5.44 minutes. No important technical problems occurred and no information was lost. CONCLUSIONS: The use of the Internet to transfer data for multicentric studies in primary care is possible. This system should be more widely used in the future, as it allows faster data collection and eliminates the need to input data at the end of the study.

Med Clin (Barc) 2002 Sep 14;119(8):304-14

· Treatment failure of acute exacerbations of chronic obstructive airways disease risk factors and clinical relevance

[Article in Spanish]

Miravitlles M.

Servicio de Neumologia, Institut Clinic de Pneumologia i Cirugia Toracica (IDIBAPS), Barcelona, Spain. marcm@separ.es

Anal Biochem 2002 Sep 1;308(1):120-6
Detection of polymorphisms at exons 3 (Tyr113-->His) and 4 (His139-->Arg) of the microsomal epoxide hydrolase gene using fluorescence PCR method combined with melting curves analysis.

Rodriguez F, Jardi R, Costa X, Juan D, Galimany R, Vidal R, Miravitlles M.

Department of Biochemistry, Hospital Universitario Vall d'Hebron, Barcelona 08035, Spain.

An association between exon 3 polymorphisms of the gene encoding microsomal epoxide hydrolase (mEH) and susceptibility to the development of chronic obstructive pulmonary disease (COPD) has been described. We have developed two methods for detecting polymorphisms at exons 3 (Tyr113-->His) and 4 (His139-->Arg) of the mEH gene based on different melting temperatures (T(m)) of fluorescent-labeled oligonucleotide hybridization probes using single-step assays that combine fluorescence PCR and melting curve analysis (LightCycler methodology). DNA was extracted from blood in 79 COPD patients and 146 healthy controls. Results were compared with those obtained by restriction fragment length polymorphism (RFLP) analysis to detect Tyr113His variants and a single-strand conformation polymorphism (SSCP) assay for His139Arg detection. The T(m) of the exon 3 polymorphisms were 61.3 degrees C for Tyr113 (wild type) and 67.5 degrees C for His113 (mutant). The T(m) values of the exon 4 polymorphisms were 67.5 degrees C for His139 (wild type) and 59.2 degrees C for Arg139 (mutant). The within- and between-run melting peaks for the same allele differed by less than 0.5 degrees C for both the exon 3 and the exon 4 polymorphisms. Thus, melting analysis allowed easy and unambiguous assignment of genotyping by means of the respective melting curves. The proportion of individuals who were homozygous mutant for exon 3 was significantly higher in the COPD group than in the control group (p=0.004). LightCycler fluorescence genotyping of exon 4 polymorphisms correlated perfectly with SSCP results. RFLP assay classified 2 patients as homozygous mutant while LightCycler analysis genotyped them as heterozygous. DNA analysis by PCR and sequencing confirmed the LightCycler result. These high-speed (about 40 min for 32 samples), highly sensitive, and specific small-volume assays with low labor requirements hold great promise as tools for rapid detection of COPD susceptibility.

Am J Respir Crit Care Med 2002 Sep 15;166(6):814-7
Rapid screening for alpha1-antitrypsin deficiency in patients with chronic obstructive pulmonary disease using dried blood specimens.

Rodriguez F, Jardi R, Costa X, Cotrina M, Galimany R, Vidal R, Miravitlles M.

Department of Biochemistry, Hospital Universitario Vall d'Hebron, Barcelona, Spain.

We describe two reliable methods for high-throughput screening of proteinase inhibitor (PI) S and PI Z alpha(1)-antitrypsin (alpha(1)-AT) deficiency alleles from dried blood spot (DBS) specimens using the LightCycler fluorimetric analyzer. The method was used to study 72 patients with chronic obstructive pulmonary disease. Results were confirmed with DNA sequencing. The alpha(1)-AT concentration in DBS was determined with immune nephelometry. Sixteen patients (22%) showed no PI Z or PI S mutations. Five patients (7%) had a heterozygous genotype consisting of a PI S allele and a normal allele for the Z and S positions (non-S non-Z). Twenty-five patients (35%) had a heterozygous genotype consisting of a PI Z and a non-S non-Z allele. Two (3%) had the PI SS genotype, 2 (3%) the PI SZ, and 20 (28%) the PI ZZ. All patients with two normal alpha(1)-AT alleles and 10 heterozygous carriers of one normal and one deficient allele had alpha(1)-AT levels that fell within the alpha(1)-AT DBS normal range (1.8-3.1 mg/dl). Two patients with the rare PI MM(malton)- and PI MM(heerlen)-deficient variants showed deficient alpha(1)-AT levels; PI S and PI Z were not detected. Processing 32 samples requires only 40 minutes. This single-step, cost-effective technology is optimal for working with small amounts of DNA, as are present in DBS. The method is suitable for large-scale screening, in cases where PI type is important.

Eur Respir J Suppl 2002 Jul;36:9s-19s

· Exacerbations of chronic obstructive pulmonary disease: when are bacteria important?

Miravitlles M.

Servei de Pneumologia, Institut Clinic de Pneumologia i Cirurgia Toracica, IDBAPS, Hospital Clinic i Provincial, Barcelona, Spain. marcm@separ.es

The progressive course of chronic obstructive pulmonary disease (COPD) is often aggravated by exacerbations, the majority of them produced by bronchial infection. Frequent exacerbations have been demonstrated to have a negative impact on quality of life and pulmonary function in patients with COPD, particularly in active smokers. Furthermore, acute exacerbations are the most frequent cause of medical visits, hospital admissions and death among patients with chronic lung disease. Evidence indicates that the number of patients with pathogenic bacteria in respiratory secretions and the bronchial bacterial load increase during exacerbations. Furthermore, the local inflammatory response of the host parallels the increase in bacterial load. From these observations, it can be speculated that, for symptoms of acute exacerbation to appear, there must be a minimum bacterial load in the airways, i.e. a threshold above which the inflammatory reaction is severe enough to elicit clinical symptoms of exacerbation. This threshold may vary from patient to patient owing to different modifying factors. Some of these factors may be the recognised risk factors for relapse, such as increasing age, impairment of lung function, comorbid conditions or frequent exacerbations in the past. Relapse rates after ambulatory treatment of acute exacerbation of COPD may be as high as 20-25% of cases. Relapses are associated with significant mordibity and increased costs. A number of unanswered questions remain regarding exacerbations of chronic obstructive pulmonary disease. These include the role of viral infection, the importance of residual bacterial colonisation and the impact of new antibiotics on the treatment of exacerbations.

Eur Respir J 2002 Jul;20(1):243-4

· Guidelines versus clinical practice in the treatment of chronic obstructive pulmonary disease.

Miravitlles M.

Arch Bronconeumol 2002 Jun;38(6):263-6
Importance of serum interleukin-6 as a mediator of systemic inflammation in patients with alpha-1 antitrypsin deficiency

[Article in Spanish]

Vila S, Miravitlles M, Campos F, de la Roza C, Segura R, Morell F, Vidal R.

Servicios de Neumologia. Hospital Universitario Vall d'Hebron. Barcelona. Spain. saravv@hg.vhebron.es

The objective of this study was to determine whether high concentrations of circulating interleukin-6 (IL-6) and/or the soluble receptor of IL-6 (SRIL-6) may mediate systemic inflammatory activity in patients with alpha-1 antitrypsin deficiency (AATD). To that end we assessed serum concentrations of IL-6 and SRIL-6 for 7 patients with AATD in stable phase. The patients' mean age was 51 years (SD 5.2); mean FEV1% was 35.5% (SD 15%). IL-6 and SRIL-6 concentrations were compared with those of 23 non-AATD patients with COPD but with similar changes in lung function (mean age 63 years, SD 10.1; FEV1% 38.3%, SD 11%).The AADT patients had mean IL-6 concentrations of 4.7 pg/mL (interquartile range [IR( 4.0) and RSIL-6 levels of 129.1 ng/mL (IR 31.5). The COPD patients had IL-6 concentrations of 4.1 pg/mL (IR 4.2) and SRIL-6 levels of 140.8 ng/mL (IR 71). No significant differences between the AADT group and the COPD group were observed for either cytokine (non-parametric Mann Whitney U test, p > 0.05). Only one AADT patient had an IL-6 concentration that was higher than normal.In conclusion, the serum IL-6 and SRIL-6 concentrations of patients with AADT are not different from those of patients with COPD, similarly altered respiratory function and normal alpha-1 antitrypsin levels. These results do not point to a role for alpha-1 antitrypsin in systemic inflammatory stimulation in patients with AADT.

Qual Life Res 2002 Jun;11(4):329-38

Treatment and quality of life in patients with chronic obstructive pulmonary disease.

Miravitlles M, Alvarez-Sala JL, Lamarca R, Ferrer M, Masa F, Verea H, Zalacain R, Murio C, Ros F; IMPAC Study Group.

Servei de Pneumologia, Hospital General Vall d'Hebron, Barcelona, Spain. marcm@separ.es

Treatments administered to patients with chronic obstructive pulmonary disease (COPD), especially when used in multiple combinations, are not free of interactions and side effects that can potentially impair health-related quality of life (HRQL). We studied HRQL and its relationship with treatment in a group of 441 patients with stage II or III COPD (age: 66.6 (SD: 8.3) years; FEV1: 32.4% (SD: 8.1%)) using the St George's Respiratory Questionnaire (SGRQ) and the 12-item short form (SF-12) Health Survey. The most prescribed drugs were ipratropium bromide (87.5%), inhaled corticosteroids (69.4%) and short-acting beta-2 agonists (64.9%). Patients with stage III of the disease were receiving more drugs, particularly short-acting beta-2 agonists (p = 0.002) and inhaled corticosteroids (p = 0.031). The use of theophyllines was associated with a worse total SGRQ score (beta = 4.49; p < 0.001), although this negative association decreased with advanced age. A trend towards worse SGRQ scores was observed with the use of high doses of long-acting beta-2 agonists (beta = 3.22; p = 0.072). Patients receiving three drugs or more presented worse total SGRQ scores than patients receiving fewer drugs (beta = 6.1, p < 0.001; and beta = 7.64, p < 0.001, respectively). These findings suggest that the use of multiple drugs in the treatment of patients with COPD is associated with worse total SGRQ scores. The effect of drugs, their dosages and associations with other drugs on HRQL merit further research.

Chest 2002 May;121(5):1449-55

Pharmacoeconomic evaluation of acute exacerbations of chronic bronchitis and COPD.

Miravitlles M, Murio C, Guerrero T, Gisbert R; DAFNE Study Group. Decisiones sobre Antibioticoterapia y Farmacoeconomia en la EPOC.

Center Servei de Pneumologia, Hospital General Universitari Vall d'Hebron, Barcelona. marcm@separ.es

BACKGROUND: Although exacerbations are the main cause of medical visits and hospitalizations of patients with chronic bronchitis and COPD, little information is available on the costs of their management. OBJECTIVE: This study attempted to determine the total direct costs derived from the management of exacerbations of chronic bronchitis and COPD in an ambulatory setting. METHOD: A total of 2,414 patients with exacerbated chronic bronchitis and COPD were recruited from 268 general practices located throughout Spain. Patients were followed up for 1 month. RESULTS: A total of 507 patients (21%) relapsed; of these, 161 patients (31.7%) required attention in emergency departments and 84 patients (16.5%) were admitted to the hospital. The total direct mean cost of all exacerbations was $159; patients who were hospitalized generated 58% of the total cost. Cost per failure was $477.50, and failures were responsible for an added mean cost of $100.30/exacerbation. Exacerbations of the 1,130 patients with COPD had a mean cost of $141. Sensitivity analysis showed that a 50% reduction in the failure rate (from 21 to 10.5%) would result in a total cost of exacerbation of $107 (33% reduction). CONCLUSION: Exacerbations of chronic bronchitis and COPD are costly, but the greatest part of costs derives from therapeutic failures, particularly those that end in hospitalization.

Eur Respir J 2002 Mar;19(3):405-13

· Interpretation of quality of life scores from the St George's Respiratory Questionnaire.

Ferrer M, Villasante C, Alonso J, Sobradillo V, Gabriel R, Vilagut G, Masa JF, Viejo JL, Jimenez-Ruiz CA, Miravitlles M.

Health Service Research Unit, Institut Municipal d'Investigacio Medica, Barcelona, Spain. mferrer@imim.es

The aim of the study was to obtain the general population norms for the St. George's Respiratory Questionnaire (SGRQ), a specific questionnaire for respiratory diseases. The IBERPOC project was a cross-sectional study of representative samples of the general population aged between 40-69 yrs. The study sample was composed of 862 individuals. All participants considered as "probable cases" of chronic obstructive pulmonary disease (COPD) (n=460) were eligible to complete the SGRQ and among the rest of the nonprobable COPD participants (n=3,571), 10 individuals from each defined age and sex group were eligible (n=402). Weights were applied to restore general population representativity of the sample. Mean forced expiratory volume in one second (FEV1) predicted was 89.4% (SD=16.5%; range: 16-131%). Chronbach's alpha coefficients were >0.7 in the symptoms, activity and impact scales, and >0.9 in the overall scale. Symptom scale score was significantly higher among males (11.6 versus 7.8; p<0.01) and activity scale score was significantly higher among females (12.2 versus 14.6; p=0.04). In a multiple linear regression model, respiratory diseases (asthma and COPD) and FEV1 % over pred showed the strongest association with the SGRQ total score. Smoking, sex, age and education were independently associated with the total SGRQ score. These results indicate that individuals from the general population presented some of the problems that are important when measuring health-related quality of life in respiratory patients, and provide St George's Respiratory Questionnaire norms, a useful method for interpreting the St George's Respiratory Questionnaire score in a given patient or study samples.

Respir Med 2002 Mar;96(3):186-92

Influence of deficient alpha1-anti-trypsin phenotypes on clinical characteristics and severity of asthma in adults.

Miravitlles M, Vila S, Torrella M, Balcells E, Rodriguez-Frias F, de L, Jardi R, Vidal R.

Department of Pneumology, Hospital Universitari Vall d'Hebron, Barcelona, Spain. marcm@separ.es

Severe alpha1-anti-trypsin (AAT) deficiency implies a high risk of pulmonary emphysema development. The possible relationship between partial deficiencies of this enzyme and bronchial asthma remains controversial. The objective of this study was to ascertain the distribution of AAT phenotypes in a non-selected asthmatic patient population. Across-sectional study on a sample of 111 patients with asthma was carried out. Demographic and clinical variables were collected with serum IgE concentrations, plasma eosinophil number and serum AAT concentrations determined, together with the Pi phenotype. Asthma was mild in 36 (32.4%) patients, moderate in 45 (40.5%) and severe in 30 (27%). No differences were observed in eosinophil count or serum IgE or AAT concentrations among patients with different degrees of severity. Twenty-two (19.8%) asthmatics with deficient phenotypes for AAT were identified, distributed equally in all severity stages of the disease. No significant differences were found in clinical and functional characteristics, or in asthma morbidity between PiMM and PiMS patients or the heterozygote group (PiMS and PiMZ). Eosinophil count and IgE concentrations did not differ significantly between asthmatics with normal phenotype and heterozygotes. In conclusion, the distribution of AAT phenotypes in asthmatic patients did not differ from that found in the general population. Heterozygote phenotypes for the deficiency do not appear to confer greater severity or different clinical expression of asthma in adults.

Arch Bronconeumol 2001 Oct;37(9):388-93

The cost of chronic obstructive pulmonary disease in Spain: options for optimizing resources

[Article in Spanish]

Miravitlles M, Figueras M.

Servicio de Neumologia, Hospital General Vall d'Hebron, Barcelona, Spain. marcm@separ.es

Int J Clin Pract 2001 Sep;55(7):437-41

· The efficacy of moxifloxacin in acute exacerbations of chronic bronchitis: a Spanish physician and patient experience.

Miravitlles M, Ros F, Cobos A, Kubin R, Tillotson G.

General Vall d'Hebron Hospital, Barcelona, Spain.

Chronic bronchitis is a debilitating disease affecting many millions of patients globally. They suffer multiple acute exacerbations each year, often requiring many courses of antimicrobials to enable them to return to normal. The impact of the condition on both the individual patient and society as a whole is considerable and growing; thus antimicrobial therapy should induce rapid and effective outcomes as soon as possible. This open, community-based study of 5737 patients enrolled by over 2000 primary care physicians from across Spain examined the clinical effect of oral moxifloxacin on patients' signs and symptoms of acute exacerbations of chronic bronchitis (AECB) over a 45-day period. The symptoms were assessed using daily diary cards in addition to physician evaluations. Clinical assessment at day 7 showed 93.0% of patients were cured. The patient diary card showed that two-thirds of patients felt better by day 3 or 4. Adverse events were reported in 3.5% of patients in this study, the most common being diarrhoea, nausea and dizziness, and epigastric pain. These reactions were mild to moderate in intensity. There were no patient deaths due to infection during the study. Physicians and patients reported that once-daily moxifloxacin gave fast relief of symptoms of acute exacerbations of chronic bronchitis.

Arch Bronconeumol 2001 Sep;37(8):340-8

· ALAT (Latin American Thoracic Association) recommendations on community-acquired pneumonia

[Article in Spanish]

Luna CM, Ramirez J, Lopez H, Mazzei JA, Abreu de Oliveira JC, Pereira J, Jardim JR, Gonzales P, Lisboa C, Maldonado D, Torres C, Martinez Selmo S, Miravitlles M, Rodriguez de Castro F, Torres A, Anzueto A, Luna JM, Diaz M, Perez Padilla R, Sansores R; Grupo de trabajo de la Asociacion Latinoamericana del Torax (ALAT).

Eur Respir J 2001 May;17(5):928-33
Factors associated with relapse after ambulatory treatment of acute exacerbations of chronic bronchitis. DAFNE Study Group.

Miravitlles M, Murio C, Guerrero T.

Dept of Pneumology, Vall d'Hebron General University Hospital, Barcelona, Spain.

This study aimed to identify the risk factors for relapse after ambulatory treatment of acute exacerbations of chronic bronchitis (AECB) that can easily be used in a primary care setting. Data were prospectively collected on 2,414 ambulatory patients with AECB from 268 general practices located throughout Spain. A multivariate model to identify risk factors independently associated with failures was developed and validated from the information recorded at the inclusion visit and at 30-days follow-up visit. A total of 507 patients relapsed (21%); of these, 84 required admission (16.5%). The multivariate model for prediction of the risk of relapse included 2,414 cases: 1,689 for the developmental sample and 725 in the validation sample. The model obtained contained three readily-obtainable variables: ischaemic heart disease (odds ratio (OR)=1.63; 95% confidence interval (CI)=1.07-2.47), degree of dyspnoea (OR = 1.31; 1.14-1.50) and number of visits to the general practitioner the previous year (OR = 1.07; 1.04-1.10). The model calibrated well in developmental and validation samples (goodness-of-fit tests: p = 0.295 and p = 0.637, respectively). Severity of the exacerbation was not associated with increased risk of relapse in either univariate or multivariate analysis. The present results suggest that baseline characteristics of the patients such as degree of dyspnoea, coexisting ischaemic heart disease and number of previous visits to the general practitioner for respiratory problems are strongly associated with increased risk of relapse after ambulatory treatment of acute exacerbations of chronic bronchitis. In contrast, exacerbation severity was not associated with clinical failure. Guidelines for management of acute exacerbations of chronic bronchitis should consider such risk factors and advocate intensive broad spectrum treatment and closer follow-up of patients exhibiting them.

Arch Bronconeumol 2001 Jul-Aug;37(7):269-78

· Recommendations for the care of the patient with chronic obstructive pulmonary disease

[Article in Spanish]

Alvarez-Sala J, Cimas E, Masa J, Miravitlles M, Molina J, Naberan K, Simonet P, Viejo J; Grupo de Trabajo de la Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR).; Sociedad Espanola de Medicina de Familia y Comunitaria (semFYC).

Grupo de Trabajo de la Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR). jlasw@separ.es

Chest 2001 May;119(5):1365-70

Smoking characteristics: differences in attitudes and dependence between healthy smokers and smokers with COPD.

Jimenez-Ruiz CA, Masa F, Miravitlles M, Gabriel R, Viejo JL, Villasante C, Sobradillo V.

Servicio de Neumologia (Dr. Jimenez-Ruiz), Hospital de la Princesa, Madrid, Spain. A complete list of the participants in the IBERPOC study is given in the.

OBJECTIVE: To ascertain the differences in smoking characteristics between a group of smokers with COPD and another group of healthy smokers, both of which were identified in a population-based epidemiologic study. DESIGN AND PARTICIPANTS: This is an epidemiologic, multicenter, population-based study conducted in seven areas of SPAIN: A total of 4,035 individuals, men and women aged 40 to 69 years, who were selected randomly from a target population of 236,412 subjects, participated in the study. INTERVENTIONS: Eligible subjects answered the European Commission for Steel and Coal questionnaire. Spirometry was performed followed by a bronchodilator test when bronchial obstruction was present. The Fagerstrom questionnaire was used for study of the degree of physical nicotine dependence, and the Prochazka model was followed for analysis of the smoking cessation phase. RESULTS: Of 1,023 active smokers, 153 (15%) met the criteria for COPD. Smokers with COPD were more frequently men (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.21 to 3.95), were > or = 46 years of age (OR, 1.97; 95% CI, 1.18 to 3.31), had a lower educational level (OR, 1.96; 95% CI, 1.23 to 3.14), and had smoked > 30 pack-years (OR, 3.70; 95% CI, 2.42 to 5.65). Smokers with COPD showed a higher dependence on nicotine than healthy smokers (mean [+/- SD] Fagerstrom test score, 4.77 +/- 2.45 vs 3.15 +/- 2.38, respectively; p < 0.001) and higher concentrations of CO in exhaled air (mean concentration, 19.7 +/- 16.3 vs 15.4 +/- 12.1 ppm, respectively; p < 0.0001). Thirty-four percent of smokers with COPD and 38.5% of smokers without COPD had never tried to stop smoking. CONCLUSIONS: Smokers with COPD have higher tobacco consumption, higher dependence on nicotine, and higher concentrations of CO in exhaled air, suggesting a different pattern of cigarette smoking. Cases of COPD among smokers predominate in men and in individuals with lower educational levels. A significant proportion of smokers have never tried to stop smoking; thus, advice on cessation should be reinforced in both groups of smokers.

Arch Bronconeumol 2000 Oct;36(9):500-5

· Development and results of a screening program for COPD in primary care. The PADOC Project(Program for the Increase in the Diagnosis of COPD in Primary Care

[Article in Spanish]

Miravitlles M, Fernandez I, Guerrero T, Murio C.

Servicio de Neumologia, Hospital General Vall d'Hebron, Barcelona. marcm@separ.es

Several studies have shown that up to 75% of patients with chronic obstructive pulmonary disease (COPD) remain undiagnosed. Early diagnosis of such individuals will allow appropriate preventive and therapeutic measures to be prescribed. The PADOC project aimed to determine the efficacy of a COPD screening program for Spanish primary care settings. The participating primary care physicians were required to administer a spirometric test (forced expiratory volume) to all individuals who had not previously been given a diagnosis of COPD, who visited the clinic for any reason over a period of three months and who met the following enrollment criteria: a) age over 35 years and b) smoker of more than 10 cigarettes per day or ex-smoker of more than 10 packs per year. Individuals meeting the criteria for suspicion of COPD (FEV1 < 90% of predicted and FEV1/FVC < 70%) were referred to a pneumologist for confirmation of the diagnosis. One hundred ninety-four primary care physicians participated, administering 3,209 valid spirometric tests. The physicians identified 723 likely cases of COPD (22.5%). Pneumologists examined 278 patients (38.4% of the likely cases) and the final diagnosis was COPD in 153 of the 278 (55%) and asthma in 28 (10%). Therefore, 4.3% of all patients given spirometric tests received a diagnosis of COPD and 0.8% received a diagnosis of asthma. Agreement between spirometric measurements taken by the primary care physicians and those taken by pneumologists was low for FVC and FVC (%) (intra-class correlation coefficient ICC = 0.38 and 0.45, respectively) but good for FEV1 and FEV1 (%) (ICC = 0.78 and 0.67, respectively). We conclude that primary care screening for COPD is possible and would allow us to detect up to 22% of possible cases. Patient flow from one level of clinical care to another should be improved, given that most of the possible cases detected (61.6%) were not seen by the referral pneumologist. Agreement between spirometric measurements taken by primary care physicians and pneumologists was low for FVC but good for FEV1.

Respiration 2000;67(5):495-501
Factors associated with increased risk of exacerbation and hospital admission in a cohort of ambulatory COPD patients: a multiple logistic regression analysis. The EOLO Study Group.

Miravitlles M, Guerrero T, Mayordomo C, Sanchez-Agudo L, Nicolau F, Segu JL.

Servei de Pneumologia, Hospital General Universitari Vall d'Hebron, Barcelona, Spain. marcm@separ.es

BACKGROUND AND OBJECTIVE: The aim of this study was to develop and validate two models to estimate the probabilities of frequent exacerbations (more than 1 per year) and admissions for chronic obstructive pulmonary disease (COPD) that can be used in a primary care setting. METHODS: Information was obtained in a cross-sectional observational study on ambulatory COPD patients performed in 201 general practices located throughout Spain. The model for admissions included 713 cases, 499 for the developmental sample and 214 in the validation sample; the model for frequent exacerbations included 896 patients, 627 in the developmental sample and 269 in the validation model. Candidate variables to be included in both models were: age, sex, body mass index (BMI), FEV(1) as percent predicted [FEV(1 )(% pred.)], active smoking, chronic mucus hypersecretion (CMH) and significant comorbidity. RESULTS: The admission model contained 2 readily obtainable variables: comorbidity (OR = 1.97; CI 95% = 1. 24-3.14) and FEV(1)(% pred.) (OR = 0.72; 0.58-0.88, for every 10 units), and well calibrated in developmental and validation samples (goodness-of-fit tests: p = 0.989 and p = 0.720, respectively). The model for frequent exacerbations included 3 variables: age (OR = 1. 21; 1.01-1.44; for every 10 years of increasing age), FEV(1 )(% pred. ) (OR = 0.82; 0.70-0.96, for every 10 units) and CMH (OR = 1.54; 1. 11-2.14) and also well calibrated (p = 0.411 and p = 0.340 in the developmental and validation samples, respectively). CONCLUSIONS: Our results suggest that FEV(1) impairment explains part of the risk of frequent exacerbations and hospital admissions. Furthermore, CMH and increasing age are significantly associated with the risk of frequent exacerbations, but severity of exacerbations provoking hospital admissions is associated with the presence of significant comorbidity. These important and easily measurable variables contain valuable information for optimal management of ambulatory patients with COPD. Copyright 2000 S. Karger AG, Basel

Chest 2000 Oct;118(4):981-9

· Geographic variations in prevalence and underdiagnosis of COPD: results of the IBERPOC multicentre epidemiological study.

Pena VS, Miravitlles M, Gabriel R, Jimenez-Ruiz CA, Villasante C, Masa JF, Viejo JL, Fernandez-Fau L.

Respiratory Pathology Unit, Cruces Hospital, Baracaldo.

OBJECTIVES: To ascertain the prevalence, diagnostic level, and treatment of COPD in Spain through a multicenter study comprising seven different geographic areas. Design and participants: This is an epidemiologic, multicenter, population-based study conducted in seven areas of Spain. A total of 4,035 men and women (age range, 40 to 69 years) who were randomly selected from a target population of 236,412 subjects participated in the study. INTERVENTIONS: Eligible subjects answered the European Commission for Steel and Coal questionnaire. Spirometry was performed, followed by a bronchodilator test when bronchial obstruction was present. RESULTS: The prevalence of COPD was 9.1% (95% confidence interval [CI], 8.1 to 10.2%), 15% in smokers (95% CI, 12.8 to 17.1%), 12.8% in ex-smokers (95% CI, 10.7 to 14.8%), and 4.1% in nonsmokers (95% CI, 3.3 to 5.1%). The prevalence in men was 14.3% (95% CI, 12.8 to 15. 9%) and 3.9% in women (95% CI, 3.1 to 4.8%). Marked differences were observed between sexes in smoking; the percentage of nonsmokers was 23% in men and 76.3% in women (p<0.0001). The prevalence of COPD varied among the areas, ranging from 4.9% (95% CI, 3.2 to 7.0%) in the area of the lowest prevalence to 18% (95% CI, 14.8 to 21.2%) in the area of the highest. There was no previous diagnosis of COPD in 78.2% of cases (284 of 363). Only 49.3% of patients with severe COPD, 11.8% of patients with moderate COPD, and 10% of patients with mild COPD were receiving some kind of treatment for COPD. Multivariate analysis showed that individuals had a higher probability of having received a previous diagnosis of COPD if they lived in urban areas, were of male gender, were > 60 years old, had higher educational levels, had > 15 pack-year smoking history, or had symptoms of chronic bronchitis. CONCLUSIONS: COPD is a very frequent disease in Spain, and presents significant geographic variations and a very low level of previous diagnosis and treatment, even in the most advanced cases.

Respir Med 2000 Aug;94 Suppl C:S12-5

Alpha1-antitrypsin deficiency: epidemiology and prevalence.

Miravitlles M.

Department of Pneumology, Vall d'Hebron Hospital, Barcelona, Spain.

Arch Bronconeumol 2000 May;36(5):241-4

· Prevalence of and attitudes towards smoking in a population over 40 years of age

[Article in Spanish]

Jimenez Ruiz CA, Fernando Masa J, Sobradillo V, Gabriel R, Miravitlles M, Fernandez-Fau L, Villasante C, Viejo JL.

Servicio de Neumologia, Hospital de la Princesa, Madrid. cjimenez@hup.es

OBJECTIVES: Smoking is the main cause of preventable death in developed countries. One of the most relevant health care interventions is convincing smokers to quit. To achieve that end, it is important to know, in addition to the prevalence of smoking, the degree of physical addiction to nicotine and smokers' attitudes toward tobacco. MATERIAL AND METHODS: This study collects results from a Spanish national epidemiological study (the IBERPOC study) related to smoking addiction, smokers' degree of addiction to nicotine and smokers attitudes toward their habits. The data has been obtained by surveying 4,035 individuals selected randomly from census data in seven different parts of the country. Information was obtained from questionnaires and CO in expired air was measured. RESULTS: One thousand fifty-nine respondents were smokers (26%) and 968 were ex-smokers (24%). Female smokers were younger (47 versus 51 years old) and had started smoking later (at age 22 versus 17 years), smoked fewer cigarettes per day (15 versus 21) and had lower concentrations of CO in expired air (13.4 versus 17 ppm) (p < 0.001 for all comparisons). Six hundred fifty-nine smokers (62.2%) had tried to quit at least once. The most important reasons given for trying to quit were related to improving health. CONCLUSIONS: The 26% of the surveyed population smoked. Women generally started later, smoked fewer cigarettes and were less physically addicted to nicotine. Most smokers had tried at least once to quit, particularly if motivated to improve health. These results should be considered when proposing strategies for smoking cessation.

Eur Respir J 2000 Jun;15(6):1111-5

Simple method for alpha1-antitrypsin deficiency screening by use of dried blood spot specimens.

Costa X, Jardi R, Rodriguez F, Miravitlles M, Cotrina M, Gonzalez C, Pascual C, Vidal R.

Dept of Biochemistry, Hospital Universitario Vall d'Hebron, Barcelona, Spain.

The use of dried blood spot (DBS) specimens in quantitative alpha1-antitrypsin (alpha1-AT) detection or genetic analysis is limited because protein levels in the samples are low and they contain components that can interfere with polymerase chain reaction amplification. A methodological adaptation was developed to overcome these drawbacks which is discussed here. The study population consisted of 200 healthy volunteers and 300 patients with chronic obstructive pulmonary disease (COPD). DBS specimens were tested for alpha1-AT concentration using a modified nephelometric assay and phenotyped with an isoelectric focusing method. Genetic diagnosis was established by deoxyribonucleic acid sequencing using a simple purification procedure to remove contaminants. The nephelometric method showed a detection limit of 0.284 mg x dL(-1), corresponding to a serum concentration of 13 mg x dL(-1). The correlation coefficient between alpha1-AT concentrations in DBS versus serum samples was R2=0.8674 (p<0.0001). All 200 healthy individuals had DBS alpha1-AT concentrations >1.9 mg x dL(-1), corresponding to 114 mg x dL(-1) in serum samples. One hundred and twenty-five COPD patients (42%) showed alpha1-AT values <1.8 mg x dL(-1). Twenty patients with the PIZ phenotype had alpha1-AT values lower than 0.64 mg x dL(-1). On the basis of genotyping, one COPD patient was classified as heterozygous (PIMM(heerlen)). Selective elution of contaminants resulted in optimal alpha(1)1-antitrypsin genotyping. Because of its sensitivity and excellent correlation with the standard method, the dried blood spot quantitative assay is a reliable tool for routine measurement of alpha1-antitrypsin.

Hum Hered 2000 Sep-Oct;50(5):320-1
Characterization of the new alpha-1-antitrypsin-deficient PI M-type allele, PI M(vall d'hebron) (Pro(369)-->Ser).

Jardi R, Rodriguez-Frias F, Lopez-Talavera JC, Miravitlles M, Cotrina M, Costa X, Pascual C, Vidal R.

Department of Biochemistry, Hospital Universitario Valle Hebron, Barcelona, Spain. rjardi@hg.vhebron.es

Hum Mutat 1998;12(3):213

Identification and molecular characterization of the new alpha-1-antitrypsin deficient allele PI Y barcelona (Asp256-->Val and Pro391-->His). Mutations in brief no. 174. Online.

Jardi R, Rodriguez F, Miravitlles M, Vidal R, Cotrina M, Quer J, Pascual C, Weidinger S.

Department of Biochemistry, Hospital Universitario Valle Hebron. Barcelona, Spain. Rjardi ar.vhebron.es

To characterize the molecular basis of the "new" alpha1-antitrypsin (alpha1AT) deficient variant, PI Y barcelona, DNA sequence analysis of the coding exons of the alpha1AT gene was carried out using an amplification DNA technique and direct sequencing. The PI Y barcelona allele differs from the normal M1(Val213) allele sequence by two point substitutions: a transversion of GAT TO GTT in exon III in the codon for residue 256, resulting in the amino acid change of Asp256 to Val256, and a transversion of CCC to CAC in exon V in the codon for residue 391, resulting in the amino acid substitution of Pro391 to His391. On isoelectric focusing analysis these substitutions result in a cathodal migration of the "new" variant close to the PI Z. The index case, diagnosed with severe obstructive pulmonary disease, initially phenotyped a PI ZZ, was homozygous for PI Y barcelona. The patient's serum alpha1AT level was 16 mg/dL (normal values 115-220 mg/dL). Inheritance of the PI Y barcelona was confirmed by family study. Amino acid substitution in postion 391 occurs in the C-terminal peptide region, which shows a high degree of homology with the family of serpins. Pro391 is considered to have special relevance in the secretion of alpha1AT.

Arch Bronconeumol 1999 Oct;35(9):446-54

· The current state of substitution treatment in congenital emphysema due to alpha-1-antitrypsin deficiency. The report of the National Registry

[Article in Spanish]

Miravitlles M, Vidal R, Barros-Tizon JC, Bustamante A, Espana PP, Casas F, Martinez MT, Escudero C, Jardi R.

Servei de Pneumologia, Hospital Vall d'Hebron, Barcelona.

Chest 1999 Oct;116(4):946-52

Specific antibody response against the 23-valent pneumococcal vaccine in patients with alpha(1)-antitrypsin deficiency with and without bronchiectasis.

Miravitlles M, de Gracia J, Rodrigo MJ, Cruz MJ, Vendrell M, Vidal R, Morell F.

Department of Pneumology, Hospital General Vall d'Hebron, Barcelona, Spain. marcm@hg.vhebron.es

OBJECTIVE: To assess the specific antibody response against polyvalent pneumococcal vaccine in patients with alpha(1)-antitrypsin deficiency (AATD) and respiratory infections. DESIGN and PARTICIPANTS: We investigated specific IgG, IgG1, and IgG2 antibody responses against the 23-valent antipneumococcal vaccine in 18 patients with AATD phenotype PiZZ, 9 of whom had bronchiectasis and 4 a history of recurrent pneumonia, and compared them with a control group of 40 healthy volunteers. INTERVENTIONS: Blood samples were drawn just prior to and 3 weeks after immunization. MEASUREMENTS AND RESULTS: Quantification of specific IgG and its subclasses was performed by an enzyme-linked immunosorbent assay. For patients with AATD, mean increases in specific antipneumococcal titers were 4.7-fold (25 to 75% quartiles, 2.5- to 6.8-fold) for total IgG, 3.2-fold (1.2- to 4.9-fold) for IgG1, and 2.1-fold (1.8- to 3.7-fold) for IgG2. For the control group, the values were 3.3-fold (1.8- to 5.8-fold) for total IgG, 2. 5-fold (1.9- to 3.4-fold) for IgG1, and 3.1-fold (1.9- to 4.5-fold) for IgG2; differences were not significant. Patients with bronchiectasis showed a tendency toward higher levels of IgG subclasses than both control subjects and patients without bronchiectasis; however, there was a tendency toward lower postvaccination serum levels of specific antipneumococcal IgG, IgG1, and IgG2 in patients with bronchiectasis compared with patients without bronchiectasis, but this trend did not reach statistical significance. Three of the four patients with recurrent pneumonia did not show an appropriate IgG2 response. CONCLUSIONS: These results suggest that, as a group, patients with AATD have a preserved antibody response against pneumococcal polysaccharides. Patients with bronchiectasis show a tendency toward a decreased antibody response, even with increased serum levels of most Ig types. Individuals with an impaired IgG2 response seem to be at increased risk of recurrent pneumonia. Considering the pernicious effect of pulmonary infections on these patients and the preserved antibody response in a majority of them, pneumococcal vaccination should be recommended to patients with AATD.

Respir Med 1999 Mar;93(3):173-9

Treatment of chronic obstructive pulmonary disease and its exacerbations in general practice. EOLO Group. Estudio Observacional de la Limitacion Obstructiva al Flujo aEreo.

Miravitlles M, Mayordomo C, Artes M, Sanchez-Agudo L, Nicolau F, Segu JL.

Servei de Pneumologia, Hospital General Universitari Vall d'Hebron, Barcelona, Spain. marcm@hg.vhebron.es

The high prevalence and chronicity of chronic obstructive pulmonary disease (COPD) imply that many of these patients are treated and controlled in primary-care centres, often without contact with specialized pneumologist care. We conducted the present study to evaluate the treatment administered in stable and exacerbated COPD in GP-setting clinics and to investigate which factors could be associated with the different prescriptions. This is a cross-sectional observational study of ambulatory COPD patients. General practitioners (n = 201) were selected throughout Spain by regionally stratified sampling. We recorded the physician-reported prescription drug use in ambulatory treatment of stable COPD and acute exacerbations of COPD through a standard questionnaire. Factors independently associated with the prescription of drugs were ascertained by multiple logistic regression analysis. Of 1078 questionnaires reviewed, 1001 fulfilled quality criteria. There were 878 men (88%) and 123 women (12%); 777 (78%) were smokers or ex-smokers with a mean age of 68 years. Mean FEV1 was 47% predicted (% pred.) (SD = 13%). The median number of exacerbations was two per year (range = 0-16). Regular treatment for COPD was received by 878 (88%): the most commonly used drugs were inhaled beta 2-agonists (71%), theophyllines (53%) and inhaled corticosteroids (ICs) (50%), followed by mucolytics (25%), ipratropium bromide (23%), and oral corticosteroids (OCs) (4%). Treatment for exacerbations included inhaled bronchodilators (90%), antibiotics (89%), ICs (71%) and OCs (43%). Impairment of FEV1 was the factor most strongly associated in multiple regression analysis with increasing drug prescription in stable COPD, except for mucolytics, while the number of previous acute exacerbations was the main factor associated with exacerbation treatment except for OCs, the use of which was associated with more impaired pulmonary function. A significant number of the treatments prescribed in primary care for stable and exacerbated COPD do not follow current recommendations. Impairment in FEV1 is the factor most strongly associated with increasing prescription in stable COPD and the number of previous exacerbations is the main factor associated with exacerbation treatment.

Chest 1999 Jul;116(1):40-6

· Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Study Group of Bacterial Infection in COPD.

Miravitlles M, Espinosa C, Fernandez-Laso E, Martos JA, Maldonado JA, Gallego M.

Pneumology Department, Hospital Vall d'Hebron, Barcelona, Spain. marcm@separ.es

STUDY OBJECTIVES: To investigate the possible relationship between functional respiratory impairment measured by FEV1 and isolation of diverse pathogens in the sputum of patients with exacerbations of COPD. DESIGN: Multicenter, cross-sectional, epidemiologic study. SETTING: Pneumology units in six secondary or tertiary hospitals in Spain. PATIENTS: Ninety-one patients with acute exacerbation of COPD were included. INTERVENTIONS: A quantitative sputum culture was performed, and bacterial growth was considered significant only when the germ was isolated at concentrations > 10(6) cfu (> 10(5) for Streptococcus pneumoniae) in samples with < 10 epithelial cells and > 25 leukocytes per low magnification field (x 100). RESULTS: Germs isolated were the following: Haemophilus influenzae (20 cases; 22%), Pseudomonas aeruginosa (14 cases; 15%), S. pneumoniae (9 cases; 10%), Moraxella catarrhalis (8 cases; 9%), other gram-negative bacteria (7 cases; 7%), and non-potentially pathogenic microorganisms (non-PPMs; 33 cases; 36%). P. aeruginosa and H. influenzae were isolated more frequently among the patients with FEV1 < 50% than among those with FEV1 > 50% (p < 0.05). All patients with P. aeruginosa in sputum had FEV1 < 1,700 mL. FEV1 < 50% was associated with a very high risk of P. aeruginosa or H. influenzae isolation: the odds ratios (ORs) are 6.62 (95% confidence interval [CI], 1.2 to 123.6) and 6.85 (95% CI, 1.6 to 52.6), respectively. Furthermore, active tobacco smoking was associated with a high risk of H. influenzae isolation (OR, 8.1; 95% CI, 1.9 to 43.0). CONCLUSIONS: Patients with the greatest degree of functional impairment, as measured by their FEV1, presented a higher probability of having an isolation of P. aeruginosa or H. influenzae in significant concentrations in sputum during an exacerbation. The diagnostic yield of sputum in patients with an FEV1 > 50% was low, with a predominance of non-PPMs. Low FEV1 and active tobacco smoking are data that should be considered when establishing an empiric antibiotic treatment for exacerbated COPD.

Arch Bronconeumol 1999 Apr;35(4):173-8

Comment in:
· Arch Bronconeumol. 2000 Mar;36(3):167.

Treatment of chronic bronchitis and chronic pulmonary obstructive disease in primary care

[Article in Spanish]

Miravitlles M, Murio C, Guerrero T, Segu JL.

Servicio de Neumologia, Hospital General Vall d'Hebron. marcm@hg.vhebron.es

In spite of the recent publication of various guidelines for the treatment of chronic bronchitis and chronic obstructive pulmonary disease (COPD), no studies have investigated whether or not they are being implemented by caregivers. Our aim was to determine what treatment protocols for patients with chronic bronchitis and COPD are most commonly applied by general practitioners in Spain and to identify factors associated with the prescription of certain drugs. A standardized questionnaire was administered to 268 general practitioners working in the 17 autonomous communities of Spain. The stratified sample of respondents was selected to reflect the population of each community. Valid information on 2,414 patients was collected. Men accounted for 74% of the patients. Mean age was 67 years (SD = 10). Lung function data were available for 1,130 (47%) and mean FEV1 was 1,523 ml (56% of the theoretical reference value). Patients without lung function data in spite of having signs of severe symptoms had suffered more acute exacerbations and generated more visits to the emergency room and to their primary care doctors in the preceding year than had patients who had undergone lung function testing (p < 0.03; p < 0.001; p < 0.003, respectively). The treatments most often prescribed were short-acting inhaled beta-2 agonists (56%), inhaled corticoids (47%), theophylline-containing drugs (43%), and long-lasting beta-2 agonists (41%). Patients who had not undergone function tests received more mucolytics (47% versus 27%, p < 0.001) and fewer anticholinergics (20% versus 35%, p < 0.001). The factor most highly associated with prescription of all drugs was severity of disease measured by dyspnea. Treatment protocols for chronic bronchitis and COPD in general practice in many aspects show differences from current guidelines. Noteworthy is the extensive use of inhaled corticoid therapy and long-lasting beta-2 adrenergic agonists and the infrequent prescription of anticholinergics. The lack of lung function data is associated with poor pharmacologic management of disease and higher rates of morbidity.

Arch Bronconeumol 1999 Apr;35(4):159-66

Epidemiological study of chronic obstructive pulmonary disease in Spain (IBERPOC): prevalence of chronic respiratory symptoms and airflow limitation

[Article in Spanish]

Sobradillo V, Miravitlles M, Jimenez CA, Gabriel R, Viejo JL, Masa JF, Fernandez-Fau L, Villasante C.

Unidad de Patologia Respiratoria, Hospital de Cruces, Baracaldo, Vizcaya. secretaria.neumo@hcru.oskidetza.net

The prevalence of chronic respiratory symptoms and chronic airflow limitation (CAFL) was determined in a multicentric epidemiological study carried out in seven different areas of Spain. Based on a target population of 236,412 persons, a random census sample of 4,035 individuals between 40 and 69 years of age was chosen. Subjects answered several questionnaires and performed spirometric tests followed by a bronchodilation test if bronchial obstruction was detected. Respiratory symptoms were reported by 48% of the population (95% CI: 46.4-49.5%) with greater frequency of symptoms among men than women (55.2% versus 41%, p < 0.001). The following levels of prevalence of chronic symptoms were found: cough, 13.5% (95% CI: 12.5-14.6%); expectoration, 10.7% (95% CI: 9.7-11.6%); dyspnea after one flight of stairs, 10.4% (95% CI: 9.5-11.4%); and wheezing, 40.2% (95% CI: 38.7-41.7%). The prevalence of chronic bronchitis (CB) was 4.8% (95% CI: 4.1-5.4%) and was more frequent among men than among women (8.3% and 1.4%, respectively; p < 0.001). Asthma had been diagnosed previously in 4.9% (95% CI: 4.2-5.5%), more often in women than in men (5.8% and 3.8%, respectively; p < 0.003). CAFL was found in 10.6% (95% CI: 9.6-11.5%), 15.8% in men and 5.5% in women (p < 0.001). All respiratory symptoms except asthma were more frequent among smokers than among ex-smokers, and in turn were more common among ex-smokers than non-smokers. The frequency of symptoms increased in accordance with accumulated smoking. The prevalence of CB and CAFL was vastly different from one region to another. Multivariate analysis showed that factors associated independently with the appearance of CB were smoking, age over 60 years, male sex and having worked in industry. In conclusion, respiratory symptoms, including CB and CAFL, are common in the Spanish population. Smoking and amount of smoking are directly related to the frequency of such symptoms. Substantial differences were found in the prevalence of CB and CAFL among the regions where the study was performed.

Arch Bronconeumol 1999 Apr;35(4):152-8

· Epidemiological study of chronic obstructive pulmonary disease in Spain (IBERPOC): recruitment and field work

[Article in Spanish]

Miravitlles M, Sobradillo V, Villasante C, Gabriel R, Masa JF, Jimenez CA, Fernandez-Fau L, Viejo JL.

Servicio de Neumologia, Hospital General Vall d'Hebron, Barcelona. marcm@separ.es

Chronic obstructive pulmonary disease (COPD) is a large-scale social and health problem. Because prevalence studies have been performed only in certain areas of Spain, the Spanish Society of Pneumology and Chest Surgery initiated the IBERPOC study with the aim of determining the prevalence of COPD in several parts of the country. IBERPOC is a multicenter, population-based epidemiological study in which subjects have been selected randomly. Seven full-time pneumologists work full-time in seven different areas of Spain. A study of this nature involves a series of difficulties that should be taken into account at the time of planning studies of a similar nature. After 5,827 attempts to reach subjects, a total of 4,967 useful contacts were made, to provide 97.3% of the 5,104 contacts expected. Of those 4,967 useful contacts, 4,035 subjects completed interviews. Among the 932 refusals, 882 (94.6%) agreed to answer a short telephone questionnaire. The field work took 13 months to complete, 30% more time than had been anticipated. The rates at which subjects could not be traced differed from one zone to another, ranging between 5% and 30%; higher rates were attributable to the absence of telephone data in the corresponding census report. In one zone, the dispersion of the census population over a very large area supposed greater difficulty and delay in carrying out the study. In conclusion, the rate of participation and the time required for recruitment can be considered satisfactory. The performance of field work by trained, full-time pneumologists has been essential to the development and quality of the study. Similar epidemiological studies should consider problems derived from the lack of adequate census data, as well as to avoid defining areas of extreme population dispersion in order to facilitate field work.

Arch Bronconeumol 1998 Dec;34(11):536-40

· Usefulness of the quantification of the alpha-1 serous protein band in the screening of alpha-1-antitrypsin deficiency

[Article in Spanish]

Miravitlles M, Jardi R, Rodriguez-Frias F, Torrella M, Pelegri D, Vidal R.

Servicio de Neumologia, Hospital General Vall d'Hebron, Barcelona. marcm@hg.vhebron.es

BACKGROUND: Population studies indicate that alpha-1-antitrypsin (AAT) deficiency is an under diagnosed disease. Although alpha-1 serum protein is widely known to accompany AAT deficiency, the diagnostic utility of measuring the alpha-1 band to screen for this condition has not been assessed in the literature. SUBJECTS AND METHOD: Electropherograms with alpha-1 band widths under the reference values were collected over a period of 3 months. The Pi phenotype of AAT was identified for these sera by isoelectric point determination. The phenotypes were compared to those obtained for the population of the same geographic area (n = 440). The alpha-1 band reference values were obtained from 73 healthy individuals with no Pi phenotype deficiency. Moreover, the alpha-1 band was also measured for a group of 17 PiZZ deficient patients. RESULTS: We analyzed 7,305 electropherograms. One hundred four individuals (1.4%) without hypoproteinemia had alpha-1 readings below reference (set at 2.3%). The phenotypes in this group were 25 PiMM (24%), 52 PiMS (54%), 13 PiMZ (12.5%) and 5 PiSS 5 (5%). The odds ratios (CI 95%) in comparison with the normal population were, respectively, 0.10 (0.16-0.06); 4.58 (2.97-7.04); 4.35 (2.09-9.04) and 5.51 (1.66-18.16) (p < 10-5 in all cases except PiSS, which was p < 0.05). The levels for PiZZ patients were 1.4% +/- 0.3% (range 1.0%-2.1%). CONCLUSIONS: Three times fewer subjects with a normal PiMM phenotypes are found among individuals with low alpha-1 band serum protein levels, and many more of such individuals are carriers of Z allele heterozygotes. Alpha-1 band readings in patients with AAT deficiency (PiZZ phenotype) have alpha-1 values below reference. Measuring alpha-1 protein is an easy technique, within the expertise of any laboratory, and may be very useful for screening for AAT deficiency in patients with chronic respiratory diseases.

Respir Med 1998 Oct;92(10):1181-7

· Usefulness of a national registry of alpha-1-antitrypsin deficiency. The Spanish experience.

Miravitlles M, Vidal R, Barros-Tizon JC, Bustamante A, Espana PP, Casas F, Martinez MT, Escudero C, Jardi R.

Servei de Pneumologia, Hospital Vall d'Hebron, Barcelona.

Severe alpha-1-antitrypsin (AAT) deficiency, phenotype Pi ZZ, is a rare condition with an estimated prevalence of 1/4500 individuals in Spain. Given this low prevalence, it seems useful to accumulate all the information derived from the care of these patients. In this context, the Spanish Registry of patients with AAT deficiency was founded in 1993; its main objectives were to establish guidelines adapted to our country for the treatment and management of AAT-deficient patients, offer expert support to physicians all over the country treating these patients, and provide technical support on the determination of Pi phenotyping and genotyping of individuals suspected of being AAT-deficient. From 1993 to January 1998 the number of enrollees increased from 48 to 223, of which 216 were Pi ZZ. Seventy-three per cent were male and only 31.5% were never smokers, mean age was 46 years (SD = 13 years) and mean FEV1 53% predicted (SD = 31%). 83% were index cases who, compared with non-index cases, were older (49 +/- 11 vs. 35 +/- 13 years, P < 0.001), more likely to have a smoking history (85% vs. 47%, P < 0.01) and displayed more severe impairment in pulmonary function (FEV1% = 40% +/- 19% vs. 96% +/- 23%, P < 0.001). Augmentation therapy was administered to 129 patients (58%). Treated patients had more severe impairment in pulmonary function than the untreated (FEV1% = 40% +/- 21% vs. 72% +/- 32%, P < 0.001) and were more likely to be index cases (81% vs. 43%, P < 0.001). Characteristics of the patients included are similar to those described for other Registries. The Registry has extended knowledge of the disease throughout the country and has established local guidelines for treatment and follow-up. It may be a valid database for future co-operation in international initiatives.

Arch Bronconeumol 1998 Mar;34(3):109-11

· Should we administer replacement therapy to patients with alpha-1-antitrypsin deficit?

[Article in Spanish]

Miravitlles M.

Med Clin (Barc) 1997 Oct 11;109(12):463-6

Molecular characterization of two variants of alpha-1-antitrypsin deficiency: PI Mpalermo and PI Plovel

[Article in Spanish]

Jardi R, Rodriguez-Frias F, Casas F, Cotrina M, Vidal R, Miravitlles M, Pascual C.

Servicios de Bioquimica, Hospital General de la Vall d'Hebron, Barcelona.

BACKGROUND: Alpha 1 antitrypsin (AAT) is a highly polymorphic protein, having more than 75 different variants. In this work two rare AAT deficient variants were characterized by DNA study. PATIENTS AND METHODS: Members of three generations of two separate families were studied. In family 1, the index case was affected with pulmonary emphysema and presented AAT deficiency (23 mg/dl). In family 2, the index case had a normal pulmonary function, an AAT serum level of 72 mg/dl and a phenotype heterozygous for an AAT variant migrating in the P variant region. The AAT variants were characterized by polymerase chain reaction amplification of the coding exons and direct sequencing of the amplification products. RESULTS: Direct DNA sequencing from a member of family 1 demonstrates that in the exon II of the normal M1 (Val213) allele there was a 3-bp deletion (TTC), corresponding to Phe51 or Phe52. This mutation is characteristic of the Pl Mpalermo variant. In our study, Pl Mpalermo was detected in six members of three generations of this same family. Sequencing of exon III in a member of family 2, identified in the common M1 (Val213) allele a single base substitution of GAT-GTT, with the resulting amino acid change Asp256 for Val256. This mutation characterizes the Pl Plovel allele. The Pl Plovel was also detected in nine members of five others independent families. All of them have AAT serum levels between 80 and 102 mg/dl. None of the studied subjects had clinical evidence of lung disease. CONCLUSIONS: The results of our study show the presence of the two AAT deficient variants in Spain and suggest that the Pl Plovel variant might be more common than expected.

Arch Bronconeumol 1997 Jun;33(6):300-5

Estimation of initial interobserver variability of forced spirometry in the multicenter epidemiological study IBERPOC. Scientific Committee of the IBERPOC study

[Article in Spanish]

Gabriel Sanchez R, Villasante Fernandez-Montes C, Pino Garcia JM, Garcia Rio F, Miravitlles M, Jimenez Ruiz CA, Sobradillo Pena V.

Unidad de Epidemiologia Clinica, Hospital Universitario de la Princesa, Madrid.

To estimate the interobserver variability and degree of agreement for basic spirometric parameters before beginning field work for the IBERPOC Project. Study of agreement between 7 observers (pneumologists) and a gold standard, using a scheme of incomplete balanced and randomized blocks with an equal number of spirometric measurements (n = 3) per patient and an equal number of measurements (n = 9) per observer performed at the same session. The study population consisted of 14 patients with different degrees of air flow obstruction and 7 normal volunteers. Statistically significant differences attributable to subjects (inter-patient variability) were found for the three variables analyzed. Variability attributable to the observer was found for FVC and FEV1 but not for FEV1/FVC. The greatest interobserver differences were found for FEV1, such that 4 of the 7 observers recorded values that were significantly different from the mean (p < 0.05). The differences were less marked for FVC and for the FEV1/FVC ratio, with only 2 observers recording significantly different values for each variable. The high degree of reproducibility as well as the excellent interobserver agreement found in this standardization session provide an a priori guarantee of validity for spirometric measurements and rule out the existence of differential bias in data recorded at the various geographic areas involved in the study.

Med Clin (Barc) 1996 Jul 6;107(6):211-4

Study of the frequency of different phenotypes of alpha-1-antitrypsin in a population of Barcelona

[Article in Spanish]

Vidal R, Miravitlles M, Jardi R, Torrella M, Rodriguez-Frias F, Moral P, Vaque J.

Servei de Pneumologia, Hospital General Universitari de la Vall d'Hebron, Barcelona.

BACKGROUND: Severe alpha-1-antitrypsin (AAT) deficiency is caused by homozygous inheritance of gene Z, and is associated with a high risk of developing pulmonary emphysema. Determination of frequencies of different genes associated with the deficiency (especially S and Z) gives a clue to estimate the number of individuals homozygous PiZZ, carrying a high risk for pulmonary disease, in any given population. PATIENTS AND METHODS: Pi phenotypes of 440 healthy individuals were determined by means of isoelectrofocusing in polyacrylamide gel. Seric values of AAT were determined by immunonephelometry. Mean age of participants was 30 years (range 18-49 yrs.). Results are compared with other published series. RESULTS: Distribution of phenotypes was: PiMM 333 individuals (75%), PiMS 84 (19%), PiMZ 14 (3%), PiSS 4 (0.9%), PiM 3 (0.6%), PiMF 1 (0.2%), PiMP 1 (0.2%). The corresponding gene frequencies were Pi*M 87%, Pi*S 10.4%, and Pi*Z 1.5%. Normal values of AAT (phenotype PiMM) established in our laboratory were 116-232 mg/dl (21-41 micromol/I) (mean +/- 2 SD). According to Hardy-Weinberger equation, expected frequency of PiZZ individuals in our area would be 225 per million. CONCLUSIONS: The frequency of Z gen individuals observed in our study is one of the highest in the Iberian Peninsula, but lower than the frequency in northern Europe. According to these results, AAT deficiency (PiZZ) is not a rare condition in contrast with the small number of patients diagnosed. The gen frequency of the S variant is higher than that of the rest of Europe, and similar to others found in some Spanish populations.

Am J Respir Crit Care Med 1996 Feb;153(2):650-5

IgG subclass deficiencies associated with bronchiectasis.

De Gracia J, Rodrigo MJ, Morell F, Vendrell M, Miravitlles M, Cruz MJ, Codina R, Bofill JM.

Servei de Pneumologia, Hospital General Universitari Vall d'Hebron, Barcelona, Spain.

Only a small number of patients with IgG subclass deficiencies (IgGSD) have been observed to have bronchiectasis. Moreover, in the series of patients with bronchiectasis, IgGSD have not been found at any frequency, and the etiology of bronchiectasis remains unclear in 29 to 49% of cases. Serum concentrations of total IgG, IgA, and IgG subclasses as well as pulmonary function were measured in 65 patients (aged: 10 to 74 yr) with bronchiectasis of unknown etiology. An ELISA test was performed to quantify subclasses 1 through 4 using subclass-specific antihuman monoclonal antibodies. IgG subclass estimation in a healthy population with age-stratified normal ranges was derived from 100 adults, 37 children aged between 10 and 12 yr, and 27 adolescents aged between 13 and 16 yr. Serum concentrations of specific IgG antibodies to Haemophilus influenzae type b capsular polysaccharide (Hib-PRP) were also assayed by an ELISA test in 19 of the patients (10 with IgGSD and nine with non-IgGSD) and in 58 healthy individuals before and 3 wk after immunization with Hib-PRP conjugated to meningococcal outer membrane protein complex (OMPC). Thirty-one patients (48%) had low serum concentrations of one or more IgG subclasses (19 IgG2 deficiencies, 2 IgG3 deficiencies, 3 IgG4 deficiencies, and 7 combined subclass deficiencies). All patients showed increased levels of total IgG, IgG1, and IgA, but this rise was significantly higher in patients without IgGSD. Patients with IgGSD showed impaired antibody response to Hib-PRP compared with patients with non-IgGSD and the control group. IgGSD, particularly IgG2 deficiency, are not an unusual cause of bronchiectasis. Therefore, serum levels of IgG subclasses must be assayed whenever other causes of bronchiectasis have been ruled out.