Genetic Variants in IL6R and ADAM19 are Associated with COPD Severity in a Mexican Mestizo Population.

Chronic obstructive pulmonary disease (COPD) is a complex and multifactorial disease with a strong genetic component. Our objective is to identify the genetic variants associated with COPD risk and its severity in Mexican Mestizo population. We evaluated 1285 single-nucleotide polymorphisms (SNPs) of candidate genes in 299 smokers with COPD (COPD-S) and 531 smokers without COPD (SWOC) using an Illumina GoldenGate genotyping microarray. In addition, 251 ancestry informative markers were included. Allele A of rs2545771 in CYP2F2P is associated with a lower risk of COPD (p = 4.02E-10, odds ratio [OR] = 0.104, confidence interval [CI] 95% 0.05-0.18). When the COPD group was stratified by severity according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD; levels III + IV vs. I + II), 3 SNPs (rs4329505 and rs4845626 in interleukin 6 receptor [IL6R] and rs1422794 in a disintegrin and metalloproteinase domain 19 [ADAM19]) were associated with a lower risk of suffering the most severe stages of the disease. rs2819096 in the surfactant protein D (SFTPD) gene was associated with a higher risk of COPD GOLD III + IV (p = 7.79E-03, OR = 1.80, CI 95% 1.16-2.79). Finally, the haplotype in IL6R was associated with a lower risk of suffering from more severe COPD, whereas the haplotype in ADAM19 was associated with a higher risk (p = 7.40E-03, OR = 2.83, CI 95% 1.20-6.86) of suffering from the severe stages of the disease. Our data suggest that there are alleles and haplotypes in the IL6R, ADAM19, and SFTPD genes associated with different severity stages of COPD; in CYP2F2P, rs25455771 is associated with a lower risk of COPD.

FEV1 decline in patients with chronic obstructive pulmonary disease associated with biomass exposure.

RATIONALE: Biomass exposure is an important risk factor for chronic obstructive pulmonary disease (COPD). However, the time-course behavior of FEV1 in subjects exposed to biomass is unknown. OBJECTIVES: We undertook this study to determine the FEV1 rate decline in subjects exposed to biomass. METHODS: Pulmonary function was assessed every year in a Mexican cohort of patients with COPD associated with biomass or tobacco during a 15-year follow-up period. MEASUREMENTS AND MAIN RESULTS: The mean rate of decline was significantly lower for the biomass exposure COPD group (BE-COPD) than for the tobacco smoke COPD group (TS-COPD) (23 vs. 42 ml, respectively; P < 0.01). Of the TS-COPD group, 11% were rapid decliners, whereas only one rapid decliner was found in the BE-COPD group; 69 and 21% of smokers versus 17 and 83% of the BE-COPD group were slow decliners and sustainers, respectively. A higher FEV1 both as % predicted and milliliters was a predictive factor for decline for BE-COPD and TS-COPD, whereas reversibility to bronchodilator was a predictive factor for both groups when adjusted by FEV1% predicted and only for the TS-COPD group when adjusted by milliliters. CONCLUSIONS: In the biomass exposure COPD group the rate of FEV1 decline is slower and shows a more homogeneous rate of decline over time in comparison with smokers. The rapid rate of FEV1 decline is a rare feature of biomass-induced airflow limitation.

Bronchodilators for hyperinflation in COPD associated with biomass smoke: clinical trial.

Introduction: The efficacy of long-acting bronchodilators for COPD associated with biomass (BE-COPD) has not been properly evaluated. Objective: To determine the acute effect of indacaterol (IND) 150 µg q.d and tiotropium (TIO) 18 µg q.d. on lung hyperinflation, walking distance (WD) and dyspnea during the six-minute walking test (6MWT) in moderate BE-COPD at 30, 60 and 240 mins post-drug administration. Design: Randomized, controlled, open-level, crossover noninferiority clinical trial. Forty-two women with BE-COPD were randomly assigned to a bronchodilator sequence: IND-TIO or vice versa. Results: There were statistically significant changes over time in inspiratory capacity (IC) (p<0.0001), FEV1 (p<0.0001) and FVC (p<0.0001) when IND was used. When TIO was administered, an increase over all time periods was observed only for FEV1 (p<0.0001) and FVC (p<0.0001), whereas for IC an increase was observed only at 30 mins and 24 hrs after TIO administration. We did not find clinically significant increases in WD and dyspnea after the administration of both bronchodilators. Conclusion: Both IND and TIO showed significant and fast onset improvement in hyperinflation. Therefore, either of them may be recommended as a first line of treatment for COPD associated with BE-COPD.

Prevalence of COPD and respiratory symptoms associated with biomass smoke exposure in a suburban area.

Introduction: Biomass smoke exposure (BSE) is a recognized cause of COPD particularly in rural areas. However, little research has been focused on BSE in suburban areas. Objective: The aim of this study was to determine the prevalence of COPD, respiratory symptoms (RS) and BSE in women living in a suburban area of Mexico City exposed to BSE. Methods: A cross-sectional epidemiological survey of a female population aged >35 years was performed using a multistage cluster sampling strategy. The participants completed questionnaires on RS and COPD risk factors. The COPD prevalence was based on the postbronchodilator forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) ratio. Of the 1,333 women who completed the respiratory questionnaires, spirometry data were obtained from 1,190, and 969 of these were scored as A-C. Results: The prevalence of BSE was 47%, and the estimated prevalence of COPD was 2.5% for the total population (n=969) and 3.1% for those with BSE only. The spirometry and oximetry values were significantly lower in women with greater exposure levels. The prevalence of RS (cough, phlegm, wheezing and dyspnea) was significantly higher in the women with BSE compared to those without exposure. We concluded that the association of COPD with biomass exposure is not only a rural phenomenon but also may be observed in the suburban areas of the big cities.

Reference Values for the Diffusing Capacity Determined by the Single-Breath Technique at Different Altitudes: The Latin American Single-Breath Diffusing Capacity Reference Project.

BACKGROUND: The lung diffusion capacity (DLCO) determined by the single-breath technique greatly helps in the differential diagnosis and classification of severity of common lung diseases. However, widespread use of single-breath DLCO tests in Latin America has been limited, in part, by the lack of appropriate reference values. Our objective was to derive robust reference equations for single-breath DLCO from healthy Hispanic adults, using the most recent guidelines and taking into account altitude above sea level and hemoglobin. METHODS: We recruited healthy adults from Caracas (690 m), Santiago (650 m), Mexico City (2,240 m), and Bogota (2,640 m). DLCO testing was completed using an instrument that exceeds American Thoracic Society/European Respiratory Society 2005 guidelines for spirometry and single-breath DLCO and provided centralized training and a quality assurance program. RESULTS: We included 480 healthy Hispanic adults (58.3% women) with a mean age of 46 y (range 22-83 y). Their mean ± SD single-breath DLCO was 30.4 ± 9.2 mL/min/mm Hg. Results as a percentage of predicted by Crapo's reference values (the closest to obtained values) were 83 ± 10% (Caracas), 91 ± 10% (Santiago), 104 ± 17% (Mexico City), and 118 ± 19% (Bogota), and current suggested adjustments by hemoglobin or altitude did not correct differences, especially in Santiago and Caracas. CONCLUSIONS: We recommend these new single-breath DLCO reference equations to predict single-breath DLCO in Latin America performed with current instruments and procedures and including as a predictor altitude above sea level.

Use of varenicline for more than 12 months for smoking cessation in heavy chronic obstructive pulmonary disease smokers unmotivated to quit: a pilot study.

INTRODUCTION: Use of varenicline for as long as necessary to achieve abstinence has not been studied. The aim of this study was to test whether smokers with mild-to-moderate chronic obstructive pulmonary disease (COPD) are able to quit if they use varenicline for a sufficient length of time. METHODS: A total of 30 heavy smokers with COPD took varenicline for sufficiently long enough for smoking cessation. Smokers were allowed to smoke without a fixed quit date. The main endpoints were the time of voluntary abstinence (VA) and the continuous abstinence rate (CAR) at 12 and 18 months. RESULTS: Of 28 subjects, eight subjects continued to smoke and 20 subjects stopped smoking, demonstrating a CAR up to 18 months (71%). Median time of treatment was 6 (range 3-24) and 2 (range 1-8) months for abstainers and non-abstainers, respectively, and the median time of VA for abstainers was 4 (range 1-21) months. CONCLUSIONS: Use of varenicline for more than the traditional 12 recommended weeks may be a good strategy to increase the cessation rate in heavy smokers with mild COPD.

Prevalence of chronic obstructive pulmonary disease in asymptomatic smokers.

BACKGROUND: Physicians do not routinely recommend smokers to undergo spirometry unless they are symptomatic. OBJECTIVE: To test the hypothesis that there are a significant number of asymptomatic smokers with chronic obstructive pulmonary disease (COPD), we estimated the prevalence of COPD in a group of asymptomatic smokers. METHODS: Two thousand nine hundred and sixty-one smokers with a cumulative consumption history of at least 10 pack-years, either smokers with symptoms or smokers without symptoms (WOS) were invited to perform a spirometry and complete a symptom questionnaire. RESULTS: Six hundred and thirty-seven (21.5%) smokers had no symptoms, whereas 2,324 (78.5%) had at least one symptom. The prevalence of COPD in subjects WOS was 1.5% when considering the whole group of smokers (45/2,961) and 7% when considering only the group WOS (45/637). From 329 smokers with COPD, 13.7% were WOS. Subjects WOS were younger, had better lung function and lower cumulative consumption of cigarettes, estimated as both cigarettes per day and pack-years. According to severity of airflow limitation, 69% vs 87% of subjects were classified as Global Initiative for Chronic Obstructive Lung Disease stages I-II in the WOS and smokers with symptoms groups, respectively (P<0.001). A multivariate analysis showed that forced expiratory volume in 1 second (mL) was the only predictive factor for COPD in asymptomatic smokers. CONCLUSION: Prevalence of COPD in asymptomatic smokers is 1.5%. This number of asymptomatic smokers may be excluded from the benefit of an "early" intervention, not just pharmacological but also from smoking cessation counseling. The higher forced expiratory volume in 1 second may contribute to prevent early diagnosis.

Spirometry quality in adults with very severe lung function impairment.

BACKGROUND: Some technologists worry that patients with very severe lung disease are unable to complete several spirometry maneuvers, which require considerable effort. METHODS: We retrospectively selected all spirometry tests with an FEV1 < 35% predicted done by adult subjects sent to our pulmonary function laboratory during a 3-y period. We determined the rates and correlates of poor quality test sessions. RESULTS: Approximately 90% of the tests done by the 558 subjects with very severe lung-function impairment (of > 30,000 subjects tested during the 3-y period) had adequate quality spirometry. Subjects with airway obstruction were less likely to meet FVC repeatability goals. A poor spirometry quality grade was associated with a very low FVC and a low body mass index, but not older age. CONCLUSIONS: Severe lung disease should not be used as an excuse for not meeting spirometry quality goals.

Genetic polymorphisms of matrix metalloproteinases and protein levels in chronic obstructive pulmonary disease in a Mexican population.

AIM: To evaluate association of single nucleotide polymorphisms (SNPs) in the MMP1, MMP2, MMP9 and MMP12 genes and serum MMP-2 and MMP-9 levels in smoking chronic obstructive pulmonary disease (COPD) patients. MATERIALS & METHODS: Genotyping using real-time PCR in 330 smokers with COPD (COPD), 658 smokers without COPD (SNC) and 150 nonsmokers (NCNS), the analysis of samples used was χ(2) test. Using ELISA, the proteins were evaluated. Multiple comparisons were made by ANOVA. RESULTS: rs243864 (OR: 7.44; 95% CI: 3.62-15.26) and rs11646643 (OR: 1.58; 95% CI: 1.07-2.34) of the MMP-2 gene and rs3918253 (OR: 1.72; 95% CI: 1.08-2.71) of the MMP-9 gene, were associated with the risk of COPD. Serum MMP-2 level in the COPD group was lower compared with SNC (p < 0.05). Serum MMP-9 level was elevated in the COPD group compared with SNC (p < 0.05). CONCLUSION: Polymorphisms in MMP2 and MMP9 but not in MMP1 and MMP12 are associated with the risk of COPD in the Mexican mestizo population.

Identification of genetic variants in the TNF promoter associated with COPD secondary to tobacco smoking and its severity.

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease that arises in response to noxious particles or gases. Associations of genetic polymorphisms in TNF have been reported in Asians and Caucasians, but not in Mestizo populations. A case-control study was conducted in two stages: in the first stage, patients with COPD (COPD group, n=165) and smokers without disease (SNC group, n=165) were included and the TNF promoter sequence was determined using direct sequencing. In the second stage, the identified polymorphisms were validated by real-time polymerase chain reaction (PCR) in COPD (n=260) and SNC (n=506). In the first stage, 11 different sets of "contig" alignments were determined, of which contig 10 was found to be associated with susceptibility (P=5.0E-04, OR [odds ratio] =3.64) and contig 1 with Global Initiative for COPD (GOLD) greater grade (P=1.0E-02, OR =3.82). The single nucleotide polymorphisms found in this region were individually identified; the GA genotypes of rs1800629 (P=0.038, OR =2.07), rs56036015 (P=0.0082, OR =3.18), and rs361525 (P=1.0E-02, OR =4.220) were higher in the COPD group vs the SNC group; after second-stage validation, rs1800629 (P=6.00E-03, OR =2.26) and rs56036015 (P=1.10E-03, OR =2.54) are maintained. There are genetic variants in the TNF promoter associated with increased risk of COPD secondary to smoking and with a higher GOLD grade in the Mexican Mestizo population.

Prevalence and diagnosis of chronic obstructive pulmonary disease among smokers at risk. A comparative study of case-finding vs. screening strategies.

BACKGROUND: Early diagnosis of chronic obstructive pulmonary disease (COPD) remains the main intervention to prevent disease progression. However, conflicting results exist on the utility of two different diagnostic strategies that preclude freely recommending one strategy in favor of the other. Spirometry was used to determine the effectiveness of a symptom-based (case-finding) strategy vs. a screening strategy to detect COPD in smokers. METHODS: The case-finding strategy was undertaken during the COPD Day campaign in smokers with respiratory symptoms who were willing to submit to lung function testing. Screening was carried out with smokers attending a smoking cessation program. A short standardized questionnaire on respiratory symptoms along with spirometry were carried out and analyzed for both strategies. RESULTS: We evaluated 2781 smokers (mean pack/years 23.38): 1999 from the case-finding strategy and 782 from the smoking cessation program strategy (SCS). Prevalence of COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria was 10.1 and 13.3%, respectively (p < 0.01). With the exception of dyspnea (70.6% vs. 72.5%, p = 0.72), prevalence of symptoms such as cough (61.5 vs. 37, p < 0.001), phlegm (60.4 vs. 38.2, p < 0.001) and wheezing (56.7 vs.15.06, p < 0.001) was higher among smokers from the case-finding strategy. Multivariate logistic regression analysis showed that dyspnea [OR = 2.09 (95% CI 1.41-3.1)] was the only common predictor of COPD after jointly and separately analyzing case-finding and screening strategies. CONCLUSIONS: For early diagnosis of COPD in a primary care setting, a screening strategy aimed at all smokers may be more useful than a case-finding strategy.