Differences in microsatellite DNA level between asthma and chronic obstructive pulmonary disease.

Previous studies have shown that microsatellite (MS) DNA instability (MSI) is detectable in sputum cells in chronic obstructive pulmonary disease (COPD) and asthma. The aim of the present study was to investigate whether asthma and COPD could be distinguished at the MS DNA level. DNA was extracted from sputum cells and white blood cells from 63 COPD patients, 60 non-COPD smokers, 36 asthmatics and 30 healthy nonsmokers. Ten MS markers located on chromosomes 2p, 5q, 6p, 10q, 13q, 14q and 17q were analysed. No MSI was detected in non-COPD smokers or healthy nonsmokers. A significantly higher proportion of COPD patients exhibited MSI (49.2%) compared to asthmatics (22.2%). MSI was detected even in the mild stages of COPD (33.3%) and asthma (22.2%). No relationship was found between MSI and COPD severity. The most frequently affected marker was D14S588 (17.5% in COPD and 2.7% in asthma). The markers D6S344, G29802 and D13S71 showed alterations only in COPD, and G29802 was associated with a significantly decreased forced expiratory volume in one second FEV1 (% predicted), whereas MSI in D6S344 was associated with a significantly higher FEV1 (% pred). The frequency of microsatellite instability was higher in chronic obstructive pulmonary disease than in asthma, and microsatellite instability in three workers showed chronic obstructive pulmonary disease specificity. However, further studies are needed to verify the differences between chronic obstructive pulmonary disease and asthma at the microsatellite level.     

Microsatellite DNA instability in COPD.

STUDY OBJECTIVES: Cigarette smoking is the prime cause of COPD; however, only a few smokers develop the disease. In a previous study, we demonstrated that microsatellite DNA instability (MSI) is a detectable phenomenon in sputum cells of COPD patients. Therefore, we hypothesize that this genetic alteration may indicate susceptibility to COPD. DESIGN: In order to investigate this hypothesis, we compared smokers who developed COPD with smokers who did not develop COPD (referred to as non-COPD smokers). SETTING: Seven highly polymorphic microsatellite markers were targeted on the DNA of sputum cells and of WBCs. PATIENTS AND PARTICIPANTS: We studied 60 non-COPD smokers and 59 severe COPD patients with a similar smoking history (mean +/- SD) of 48+/-25 and 54+/-33 pack-years, respectively (p = 0.77). Non-COPD smokers were tested once; COPD smokers were tested twice, with an interval of 24 months between tests. RESULTS: MSI was detected in 14 COPD patients (24%) but in none of the non-COPD smokers. In 10 COPD patients, MSI was exhibited by one microsatellite marker; in the remaining 4 COPD patients, MSI was exhibited by two different alleles. The most commonly affected marker was THRA1 on chromosome 17 (43%). No significant differences were found between MSI-positive and MSI-negative COPD patients for clinical or laboratory parameters, survival, and development of lung cancer. No change in the microsatellite alleles was found between the tests performed with a 24-month interval. CONCLUSIONS: This study demonstrated that MSI was found exclusively in the sputum cells of smokers with COPD. The results support the hypothesis that MSI could be part of the complex genetic basis of COPD, and it could be a marker of the genetic alteration caused by smoking that allows COPD to develop.     

Prevalence and Determinants of COPD in Spain: EPISCAN II

BackgroundTwo previous national epidemiological studies, IBERPOC in 1997 and EPISCAN in 2007, determined the COPD burden in Spain. Changes in demographics and exposure to risk factors demand the periodic update of COPD prevalence and its determinants.MethodsEPISCAN II aimed to estimate the prevalence of COPD in the general population aged 40 years or older in all 17 regions of Spain. A random population screening sample, requiring 600 participants per region performed a questionnaire plus post-bronchodilator (post-BD) spirometry.ResultsA total of 12,825 subjects were initially contacted, and 9433 (73.6%) agreed to participate, of whom 9092 performed a valid spirometry. Baseline characteristics were: 52.6% women, mean ± SD age 60 ± 11 years, 19.8% current- and 34.2% former-smokers. The prevalence of COPD measured by post-BD fixed ratio FEV₁/FVC < 0.7 was 11.8% (95% C.I. 11.2–12.5) with a high variability by region (2.4-fold). Prevalence was 14.6% (95% C.I. 13.5–15.7) in males and 9.4% (95% C.I. 8.6–10.2) in females; according to the lower limit of normal (LLN) was 6.0% (95% C.I. 5.5–6.5) overall, by sex being 7.1% (95% C.I. 6.4–8.0) in males and 4.9% (95% C.I. 4.3–5.6) in females. Underdiagnosis of COPD was 74.7%. Cases with COPD were a mean of seven years older, more frequently male, of lower attained education, and with more smokers than the non-COPD population (p < 0.001). However, the number of cigarettes and pack-years in non-COPD participants was substantial, as it was the reported use of e-cigarettes (7.0% vs. 5.5%) (p = 0.045). There were also significant social and clinical differences including living alone, previous respiratory diagnoses, more comorbidities measured with the Charlson index, greater BODE and COTE scores, cognitive impairment, and depression (all p < 0.001).ConclusionsCOPD remains prevalent in Spain and frequently underdiagnosed.     

EARLY COPD: determinantes de la aparición y progresión de la enfermedad pulmonar obstructiva crónica en adultos jóvenes. Protocolo de un estudio caso-control con seguimiento

Introduction and objectivesDeterminants of chronic obstructive pulmonary disease (COPD) in the early stages of its natural history are not well known. Improving our knowledge of these factors will help to design interventions that can modify prognosis.Study objectives are: a) to characterize a COPD population of young adults aged 35-50 years from a multidimensional point of view; b) to compare these patients with smokers with normal lung function; and c) to create a cohort of young adults aged 35-50 years (smokers or former smokers), with and without COPD, who will be followed in the future to improve understanding of the natural history of the disease.Participants and methodThis is a case-control multicenter study aimed at establishing a well-characterized cohort of young adults, smokers or former-smokers, with and without COPD, for subsequent follow-up.A total of 311 participants (101 cases and 210 controls) were selected from approximately 30 primary care settings and 12 hospitals in 8 Spanish regions. Subjects were smokers or former smokers (> 10 pack-years) aged 35-50 years. Diagnosis of COPD was based on a post-bronchodilator result of FEV1/FVC < 70%.The main study variables were: questionnaires on health, symptoms, exacerbations and daily physical activity, lung function tests, blood and sputum samples, and low-dose computed tomography. In the statistical analysis, COPD patient characteristics will be described and compared with control subjects using a logistic regression analysis.     

Hypermethylation of Anti-oncogenic MicroRNA 7 is Increased in Emphysema Patients

IntroductionMicroRNA-7 (miR-7) has a suppressive role in lung cancer and alterations in its DNA methylation may contribute to tumorigenesis. As COPD patients with emphysema have a higher risk of lung cancer than other COPD phenotypes, we compared the miR-7 methylation status among smoker subjects and patients with various COPD phenotypes to identify its main determinants.Methods30 smoker subjects without airflow limitation and 136 COPD patients without evidence of cancer were recruited in a prospective study. Clinical and functional characteristics were assessed and patients were classified into: frequent exacerbator, emphysema, chronic bronchitis and asthma COPD overlap (ACO). DNA collected from buccal epithelial samples was isolated and bisulfite modified. miR-7 methylation status was evaluated by quantitative methylation-specific polymerase chain reaction (qMSP).ResultsmiR-7 Methylated levels were higher in COPD patients than in smokers without airflow limitation (23.7 ± 12.4 vs. 18.5 ± 8.8%, p = 0.018). Among COPD patients, those with emphysema had higher values of methylated miR-7 (27.1 ± 10.2%) than those with exacerbator (19.4 ± 9.9%, p = 0.004), chronic bronchitis (17.3 ± 9.0%, p = 0.002) or ACO phenotypes (16.0 ± 7.2%, p = 0.010). After adjusting for clinical parameters, differences between emphysematous patients and those with other phenotypes were retained. In COPD patients, advanced age, mild-moderate airflow limitation, reduced diffusing capacity and increased functional residual capacity were identified as independent predictors of methylated miR-7 levels.ConclusionThe increase of miR-7 methylation levels experienced by COPD patients occurs mainly at the expense of the emphysema phenotype, which might contribute to explain the higher incidence of lung cancer in these patients.     

Chronic obstructive pulmonary disease is associated with increased recurrent peptic ulcer bleeding risk

BackgroundThe association between chronic obstructive pulmonary disease (COPD) and the risk of recurrent peptic ulcer bleeding (PUB) remains unclear. In this study, we compared the risk of recurrent PUB between patients with and those without COPD.MethodsUsing the Taiwan National Health Insurance Research Database, we first selected patients newly diagnosed with PUB in 2002–2009. Two groups comprising 13,732 COPD cases and 13,732 non-COPD matched controls were created using propensity score matching, thereby making the differences in basic demographics, medication use, and disease conditions between the two groups negligible. Cox proportional hazard regression was used to evaluate the risk of recurrent PUB during the follow-up period.ResultsThe cumulative recurrence rate of PUB was significantly higher in the patients with COPD than in the non-COPD matched controls (2 years: 10.8% vs 9.3%; 6 years: 18.3% vs 15.7%, P all < 0.05), with an adjusted hazard ratio (HR) of 1.17 (95% confidence interval [CI], 1.08–1.26, P < 0.001) and 1.19 (95% CI, 1.12–1.26, P < 0.001) within 2-year and 6-year follow-ups, respectively. Patients with COPD using steroids were at a marginally higher risk of recurrent PUB than those who did not use steroids. Multivariate stratified analysis revealed similar results in many subgroups.ConclusionsThe risk of recurrent PUB is higher in patients with COPD than in patients without COPD.     

Effects of Active Smoking on Airway and Systemic Inflammation Profiles in Patients With Chronic Obstructive Pulmonary Disease

BackgroundThe markers that characterize local and systemic inflammation in chronic obstructive pulmonary disease (COPD) remain unclear, as do their correlations with smoking status and presence of disease. The aim of this study was to assess markers of inflammation in the peripheral blood and airways of current smokers without COPD, of current smokers with COPD and of ex-smokers with COPD.MethodsIn this study, 17 current smokers with COPD (mean age: 58.2 ± 9.6 years; mean forced expiratory volume in 1 second [FEV₁]: 56.1 ± 15.9%), 35 ex-smokers with COPD (mean age: 66.3 ± 7.3 years; mean FEV₁: 47.9 ± 17.2%) and 20 current smokers without COPD (mean age: 49.1 ± 6.2 years; mean FEV₁: 106.5 ± 15.8%) were evaluated. Spirometry findings, body composition and serum/induced sputum concentrations of tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-8 and IL-10, together with serum C-reactive protein (CRP) levels, were assessed.ResultsSerum TNF-α concentration was higher in all current smokers than in ex-smokers with COPD. In current smokers without COPD, serum CRP level was lower than in ex-smokers with COPD and significantly lower than in current smokers with COPD. Sputum TNF-α concentration was higher in current and ex-smokers with COPD than in current smokers without COPD. Multiple regression analyses showed that serum TNF-α was associated with active smoking, and serum CRP and sputum TNF-α were associated with COPD diagnosis.ConclusionsSmoking is associated with higher systemic inflammation in patients with COPD. Current findings also support the hypothesis that smoking and COPD have different effects on the regulation of airway and systemic inflammatory processes.     

Clinical benefits of smoking cessation in reducing all-cause and disease-specific mortality among older people in Taiwan: A 10-year nationwide retrospective cohort study

ObjectiveTo investigate the relationship between smoking cessation and disease mortality risks among elderly Taiwanese.MethodsWe identified 1677 people aged 65 or above from the 2001 National Health Interview Survey in Taiwan (2001 NHIST) and linked with the 2000–2010 National Health Insurance Research Data (2000–2010 NHIRD) and 2001–2010 Death Registry. Subjects were classified into four groups: never smokers, current smokers, former smokers quitting less than 5 years and former smokers quitting at least 5 years. Information on medical history was drawn from 2000–2001 NHIRD. Cox proportional hazards models were used to analyze the smoking status and mortality risk.ResultsOver 10 years, incidences of all-cause death per person-year was 0.048 among the never smokers, 0.058 for current smokers and 0.057 for former smokers. Current smokers had higher risk of all-cause death (HR = 1.38, 95%CI = 1.13–1.68), all-cause cancers (HR = 1.85, 95%CI = 1.28–2.69), lung cancer (HR = 3.02, 95%CI = 1.56–5.85) and cardiovascular disease (HR = 1.71, 95%CI = 1.17–2.48) as compared to never smokers. Former smokers who quit smoking for < 5 years has higher mortality risk in lung cancer (HR = 3.89, 95%CI = 1.33–11.40), respiratory diseases (HR = 2.79, 95%CI = 1.32–5.87) and chronic obstructive pulmonary disease (COPD) (HR = 3.13, 95%CI = 1.07–9.17) as compared to never smokers. Former smokers who quit smoking for over 5 years were similar to never smokers on all-cause death, lung cancer, all-cause cancers, COPD, respiratory diseases and cardiovascular diseases.ConclusionSmoking plays a prominent role in increasing the mortality risk among the Taiwanese elderly. Disease mortality risks of elderly former smokers who quit smoking over 5 years were reduced to the same level as the never smokers.     

Fractional Exhaled Nitric Oxide Guided-Therapy in Chronic Obstructive Pulmonary Disease: A Stratified,Randomized, Controlled Trial

IntroductionChronic obstructive pulmonary disease (COPD) with eosinophilic airway inflammation represents a distinct phenotype that might respond to treatment with inhaled corticosteroids. Fractional exhaled nitric oxide (FENO) might predict eosinophilic inflammation and guide treatment option. We hypothesized that COPD patients with different baseline levels of FENO might have differentiated response to treatment with salmeterol/fluticasone (SFC) or tiotropium (TIO).MethodsThis open-label, randomized-controlled trial enrolled treatment-naïve COPD patients who were stratified into high- (≥23.5 ppb) and low-FENO group, followed by 12-week treatment with SFC or TIO. A linear mixed model with repeated measures was applied to analyze the changes in FENO (primary outcome), COPD assessment test (CAT) score, FEV₁, and parameters in induced sputum and blood after treatment.Results134 patients were divided into 4 subgroups: low-FENO/SFC (n = 30), low-FENO/TIO (n = 29), high-FENO/SFC (n = 37), and high-FENO/TIO (n = 38). At baseline, FENO 23.5 ppb clearly differentiated between eosinophilic and non-eosinophilic inflammation groups based on the eosinophils in induced sputum and blood. FENO significantly correlated with sputum and blood eosinophils at baseline. High-FENO/SFC (vs. high-FENO/TIO) subgroup had significant reduction in FENO and sputum inflammation profiles (including eosinophils, macrophages, matrix metalloproteinase-9, and interlukin-8) after treatment. These differences were not replicated between low-FENO/SFC and low-FENO/TIO subgroups. The improvement in CAT and FEV₁ after treatment was indiscriminate between SFC and TIO in the low- and high-FENO groups.ConclusionHigh baseline FENO can serve as an indicator of eosinophilic airway inflammation in COPD patients who may respond favorably to treatment with inhaled corticosteroids/long-acting β₂-agonists.Trial registration numberClinicalTrials.gov Identifier: NCT02546349.     

Microsatellite analysis of induced sputum DNA in patients with lung cancer in heavy smokers and in healthy subjects

Abnormality in the fragile histidine triade (FHIT), a candidate tumor suppressor gene located in chromosome region 3 (3p14.2), has been frequently found in multiple tumor types, including lung cancer. In this study, the authors assessed the consistency of DNA microsatellite analysis of induced sputum (IS), as compared to that of blood and plasma. They also evaluated the loss of heterozigosity (LOH) and microsatellite instability (MSI) in 3 different loci, D3S1300, D3S1313, and D3S1234, all internal to the FHIT gene, in IS, blood, and plasma from patients with lung cancer, smokers, and healthy subjects. Eighteen patients with lung cancer (3 females, age mean +/- SD: 63 +/- 7 years), 39 smokers (23 females, age mean +/- SD: 57 +/- 6 years and cigarette pack-years mean +/- SD: 34 +/- 12), and 22 healthy nonsmoking subjects (13 females, age mean +/- SD: 63 +/- 5 years) were studied. DNA was extracted from blood, plasma, and IS, by means of a standard method. Analysis of LOH and MSI were performed using a fluorescent polymerase chain reaction (PCR)-based approach, followed by capillary electrophoresis. The ratios between the peak heights (phs), expressed as random fluorescence units, from plasma/blood (p/b) and induced sputum/blood (is/b) in all three loci were considered. The biases (agreement limits) between the mean ph ratio from p/b and is/b of D3S1300, D3S1313, and D3S1234 were respectively 0.07 (- 0.39 to 0.53), 0.016 (- 0.32 to 0.35), - 0.10 (- 0.51 to 0.30) in the patients; - 0.04 (- 0.52 to 0.43), - 0.06 (- 0.31 to 0.18), - 0.08 (- 0.48 to 0.30) in smokers; and - 0.11 (- 0.40 to 0.17), - 0.05 (- 0.53 to 0.43), - 0.09 (- 0.51 to 0.33) in healthy subjects. LOH and MSI in at least one locus were observed in 55% of patients, in 18% of smokers, and in 4.5% of healthy subjects (P < 0.001). These results showed that IS DNA provided data that were consistent with those from blood and plasma. These findings highlight new prospects for early tumor detection by a noninvasive technique based on the analysis of genetic alterations in induced sputum.     

Prevalencia de variantes de alto riesgo de alfa-1 antitripsina en población mestiza mexicana y su relación con los valores de la función pulmonar

IntroductionChronic obstructive pulmonary disease (COPD) is characterized by restricted airflow. The best-documented genetic factor is alpha-1 antitrypsin (AAT). AAT is encoded by the SERPINA1 gene. The PiZ (rs28929474) and PiS (rs17580) variants are believed to cause severe AAT deficiency and are linked to a high risk of developing COPD. This study sought to identify whether genetic polymorphisms rs28929474 and rs17580 are associated with COPD susceptibility and lung function values in a Mexican mestizo population.MethodsIn this study, 558 smokers were included, of whom 279 had COPD and 279 did not (smokers without COPD - SWC). The PiS and PiZ variants were genotyped by allelic discrimination. Independent populations and lung function values were compared using the Kruskal-Wallis test. A bivariate logistic regression analysis was also conducted.ResultsStage I and iv COPD patients showed significant differences in the frequencies of both heterozygous genotypes compared to SWC. For PiS, individuals with the heterozygous genotype AT demonstrated a decreased FEV1/FVC ratio compared to subjects with the homozygous genotype AA (P = 0.037). A significant association was found between the FEV1/FVC ratio and genotype AA for PiS (OR = 0.982, β coefficient = –0.019, 95% CI = 0.966-0.997).ConclusionsCOPD-causing AAT deficiency risk alleles exist at a very low frequency among Mexican mestizo population. Although they are not directly linked in our study population with disease susceptibility, these risk alleles are associated with poorer lung function measurements. It is important to characterize how often these genetic risk variants occur in other Latin American populations.     

Assessment of Induced Sputum Cellularity in COPD Patients Belonging to Two Different Classes of Air Pollution Exposure

IntroductionSeveral studies have previously demonstrated that long-term exposure to outdoor pollution present airway inflammation in term of an increase of sputum neutrophils.Aim and methodsThe aim of our study was to evaluate the level of airway inflammation by induced sputum in a group of 15 non-professionally exposed population of well-characterized COPD patients, residing in urban areas with high rate of outdoor pollution, compared to a control group of 13 individuals with COPD, living in rural areas with a low pollution rate. All participants underwent spirometry and sputum induction.ResultsA statistically significant increase in the percentage of neutrophil cell count was found among the residents in urban areas compared to those living in rural regions (89.1 vs 79.0, p < 0.05)ConclusionsIn conclusion, we showed that non-professionally exposed patients with COPD residing in highly-polluted urban areas had greater airway inflammation in terms of sputum neutrophils compared to a population with very similar characteristics, living in rural areas with lower outdoor pollution. The results of this pilot study may be relevant for the long term effect of environmental outdoor pollution in vulnerable patients like those with COPD.     

Choose your outcomes: From the mean to the personalized assessment of outcomes in COPD. An exploratory pragmatic survey

BackgroundPatient's expectations and needs may influence adherence in chronic obstructive pulmonary disease (COPD). The objectives of this survey were to assess the specific outcomes that patients expected their COPD treatment to improve (patient's personal outcome [PPO]) and to evaluate how the ongoing therapy was able to reach this objective.MethodsWe performed an exploratory pragmatic survey of COPD patients attending 2 university hospitals for scheduled follow-up visits. Patients had to indicate their PPO, the effect of ongoing treatment on the PPO, the symptom COPD of they expected treatment to improve and how this symptom is currently bothering them. Patients also underwent assessment of lung function and completed the COPD assessment test (CAT).ResultsWe analyzed data from 144 consecutive patients, (62.5% males; age range 54–94; mean age 73.88 ± 8.33). A total of 23 different PPOs were scored, and 44.5% of patients reported an improvement ≥ 6 (mean 4.93 ± 2.27 on a 0–10 points scale) due to ongoing treatment. The correlation between perceived improvement in PPO and CAT score was weak and negative (r = − 0.13, p = 0.11), whereas it was high and significant with FEV1 (r = .35, p = 0.007). The clinical features patients most expected their ongoing treatment to improve were breathlessness (64.6% of patients), cough (13.9%), sputum production (11%) and episodes of exacerbation (8.3%), for which their scores were, respectively, 7.12 ± 1.99, 6.8 ± 2.24, 6.63 ± 2.13, and 8.0 ± 0.94.ConclusionAppropriate assessment of PPO could lead to better long-term management of COPD.     

C-Reactive Protein Levels Predict Bacterial Exacerbation in Patients With Chronic Obstructive Pulmonary Disease

BackgroundChronic obstructive pulmonary disease (COPD) causes a high rate of morbidity worldwide and predicting a bacterial cause of an exacerbation of COPD is difficult.MethodsIn this study, patient serum was obtained and C-reactive protein (CRP) levels were measured using an automated latex-enhanced turbidimetric assay. Sputum samples were obtained and evaluated microscopically. The relationship between CRP and the bacterial colonies in sputum in 81 patients with an exacerbation of COPD was assessed. Receiver operating characteristic (ROC) curves and the respective areas under the curve (AUCs) were calculated. Data from 64 patients with bacterial acute exacerbation of COPD (AECOPD) were compared with those of 37 patients with no documented bacterial AECOPD. Results categorized according to the nature of sputum as mucoid or purulent were also compared.ResultsHigh median CRP levels were observed in bacterial AECOPD compared with nonbacterial AECOPD. The ideal cutoff point for distinguishing patients with bacterial AECOPD from those with nonbacterial AECOPD was 19.65 mg/L (sensitivity, 78.18%; specificity, 84.61%; AUC, 0.832). In patients with mucoid sputum, the cutoff point was 15.21 mg/L and the area under the ROC curve 0.86, with a sensitivity of 81.5% and a specificity of 77.8%. Purulent sputum had a significantly higher CRP level than mucoid sputum, but with an AUC of only 0.617 (95% confidence interval, 0.49–0.74) to diagnosis bacterial AECOPD.ConclusionsIn adult patients with symptoms of AECOPD, an elevated serum CRP level of > 19.6 mg/L indicates bacterial exacerbation. In patients with AECOPD with mucoid sputum, an elevated CRP level of > 15.21 mg/L indicates bacterial infection, which may be a useful clinical marker for therapy of this disease.     

Effectiveness and Safety of Inhaled Antibiotics in Patients With Chronic Obstructive Pulmonary Disease. A Multicentre Observational Study

BackgroundWe aimed to describe the effectiveness and safety of inhaled antibiotics in chronic obstructive pulmonary disease (COPD) patients, as well as the patient profile in which they are usually prescribed and the patient groups that can most benefit from this treatment.MethodsMulticentre retrospective observational cohort study in COPD patients who had received ≥1 dose of inhaled antibiotics in the last 5 years. Clinical data from the two years prior to and subsequent to the start of the treatment were compared. Primary outcome: COPD exacerbations. Secondary outcomes: side effects, symptomatology (sputum purulence, dyspnoea), microbiological profile and pathogen eradication.ResultsOf 693 COPD patients analyzed (aged 74.1; 86.3% men; mean FEV₁ = 43.7%), 71.7% had bronchiectasis and 46.6% presented chronic bronchial infection (CBI) by Pseudomonas aeruginosa (PA). After 1 year of treatment with inhaled antibiotics, there was a significant decrease in the number of exacerbations (?33.3%; P < .001), hospital admissions (?33.3%; P < .001) and hospitalization days (?26.2%; P = .003). We found no difference in effectiveness between patients with or without associated bronchiectasis. Positive patient outcomes were more pronounced in PA-eradicated patients. We found a significant reduction in daily expectoration (?33.1%; P = .024), mucopurulent/purulent sputum (?53.9%; P < .001), isolation of any potentially pathogenic microorganisms (PPM) (?16.7%; P < .001), CBI by any PPM (?37.4%; P < .001) and CBI by PA (?49.8%; P < .001). CBI by any PPM and ≥three previous exacerbations were associated with a better treatment response. 25.4% of patients presented non-severe side-effects, the most frequent of these being bronchospasm (10.5%), dyspnoea (8.8%) and cough (1.7%).ConclusionsIn COPD patients with multiple exacerbations and/or CBI by any PPM (especially PA), inhaled antibiotics appear to be an effective and safe treatment, regardless of the presence of bronchiectasis.     

Trends of COPD in Spain: Changes Between Cross Sectional Surveys 1997, 2007 and 2017

IntroductionWe aim to describe the changes in prevalence and risk factors associated to chronic obstructive pulmonary disease (COPD) in Spain, comparing three population-based studies conducted in three timepoints.MethodsWe compared participants from IBERPOC conducted in 1997, EPISCAN conducted in 2007 and EPISCAN II in 2017. COPD was defined as a postbronchodilator FEV₁/FVC (forced expiratory volume in 1 s/forced vital capacity) ratio <0.70, according to GOLD criteria; subsequently, also as the FEV₁/FVC below the lower limit of normal (LLN).ResultsCOPD prevalence in the population between 40 and 69 years decreased from 21.6% (95% CI 20.7%–23.2%) in 1997 to 8.8% (95% CI 8.2%–9.5%) in 2017, a 59.2% decline (p < 0.001).In 2007, the prevalence was 7.7% (95% CI 6.8%–8.7%) with an upward trend of 1.1 percentage points in 2017 (p = 0.073). Overall COPD prevalence decreased in men and women, although a significant increase was observed in the last decade in females (p < 0.05). Current smokers significantly increased in the last decades (25.4% in 1997, 29.1% in 2007 and 23.4% in 2017; p < 0.001). Regrettably, COPD underdiagnosis was constantly high, 77.6% in 1997, 78.4% in 2007, and to 78.2% in 2017 (p = 0.95), higher in younger ages (40–49 yrs and 50–59 yrs) and also higher in women than in men in all three studies (p < 0.05).ConclusionsWe report a significant reduction of 59.2% in the prevalence of COPD in Spain from 1997 to 2017 in subjects aged 40–69 years. Our study highlights the significant underdiagnosis of COPD, particularly sustained in women and younger populations.     

Effect of verapamil on bronchial goblet cells of asthma: an experimental study on sensitized animals

IntroductionGoblet cell hyperplasia (GCH) and mucus hypersecretion in the airway is recognized as an important contributor to morbidity and mortality in asthma and COPD. Verapamil is a calcium channel blocker that binds to the alpha-subunit of L-type calcium channels and inhibits the mucin gene via the calmodulin and CaM kinase pathway. The objective of this study was to determine the in vivo effect of verapamil on GCH and eosinophilic inflammation in sensitized mice.MethodsMale BALB/c mice were sensitized to ovalbumin using the standard method. Two groups of animals were received verapamil via an intramuscular injection: 1-low dose (0.5 mg/kg/day for two weeks), 2-high dose (1.5 mg/kg/day for two weeks). Serum and bronchoalveolar lavage fluid (BALF) was collected and analyzed for inflammatory cells, interferon-γ and IL-4. The left lung was sent for histopathological evaluation, especially for periodic acid-Schiff (PAS), to identify goblet cells in the epithelium. The degree of inflammatory cell infiltration, including eosinophils, mucus plugging, and smooth muscle thickness of the airways were classified on a semi quantitative scale.ResultsInflammatory cell infiltration in peribronchial and perivascular areas was observed in all sensitized groups. Eosinophils percentage in the BALF significantly decreased in verapamil-treated mice compared with sensitized mice (from 19.8% in asthmatic to 5.4% for low dose and 4.4% for high dose). The ratio of airway goblet cells per epithelial cells were significantly lower in verapamil-treated mice versus sensitized mice (1.57 ± 1.30% for low dose; 1.50 ± 0.93% for high dose versus 12.93 ± 7.55%, P < 0.05, respectively). Mucus production of goblet cells decreased significantly in verapamil-treated mice versus sensitized mice (mean score was 1.45 ± 0.30 for low dose; 0.81 ± 1.00 for high dose versus 2.85 ± 0.86 in the sensitized control group, P < 0.05, respectively). The concentration of serum and BALF-IFN-γ in verapamil-treated mice markedly increased by the verapamil treatment when compared to sensitized mice (15.1 ± 0.43 versus 4.7 ± 0.96, P < 0.05 and 91.8 ± 47.7 versus 14.8 ± 4.6, P < 0.01, respectively).ConclusionVerapamil is a useful drug with therapeutic targeting on GCH and a potential way to limit mucous production and improve bronchial inflammation.     

T2 Biomarkers as Predictors of Exacerbations of Chronic Obstructive Pulmonary Disease

IntroductionType 2 (T2) biomarkers such as blood eosinophil count (BEC) and FeNO have been related to a higher risk of exacerbations in COPD. It is unknown whether combining these biomarkers could be useful in forecasting COPD exacerbations.MethodsCOPD patients were enrolled in this prospective, multicenter, observational study and followed up for 1 year, during which BEC were analysed at baseline (V0) while FeNO analyses were performed at baseline (V0), 6 months (V1) and 12 months (V2). The risk of moderate or severe exacerbation during follow up was assessed by Cox regression analysis, and the predictive capacity of both measurements was assessed by ROC curves and the DeLong test. Statistical significance was assumed at P < .05.ResultsOf the 322 COPD patients initially recruited, 287 were followed up. At baseline, 28.0% were active smokers, and experienced moderate airflow limitation (mean FEV₁ 56.4% ± 17.0% predicted). Patients with at least one elevated T2 biomarker (n = 125, 42.5%) were at increased risk of COPD exacerbation (HR 1.75, 95% CI 1.25–2.45, P = .001) and of shorter time to first COPD exacerbation. There was no difference between BEC and FeNO regarding the predictive capacity for moderate to severe exacerbation (AUC 0.584 vs 0.576, P = .183) but FeNO predicted severe episodes more accurately than BEC (AUC 0.607 vs 0.539, P < .05). Combining the two biomarkers enhanced the detection of moderate and severe COPD exacerbations.ConclusionsBoth eosinophil count and FeNO have limited utility for predicting COPD exacerbations. Combining these T2 biomarkers could enhance the detection of future COPD exacerbations.     

La neumonía como comorbilidad en la enfermedad pulmonar obstructiva crónica (EPOC). Diferencias entre la exacerbación aguda de la EPOC y la neumonía en los pacientes con EPOC

IntroductionPneumonia is considered an independent entity in chronic obstructive pulmonary disease (COPD), to be distinguished from an infectious exacerbation of COPD. The aim of this study was to analyze the clinical characteristics and progress of the exacerbation of COPD (ECOPD) compared to pneumonia in COPD (PCOPD) patients requiring hospitalization.Patients and methodsProspective, longitudinal, observational cohort study including 124 COPD patients requiring hospital admission for lower respiratory tract infection. Patients were categorized according to presence of ECOPD (n = 104) or PCOPD (n = 20), depending on presence of consolidation on X-ray. Demographic, clinical, laboratory, microbiological and progress variables were collected.ResultsPatients with ECOPD showed more severe respiratory disease according to the degree of obstruction (P < .01) and need for oxygen therapy (P < .05). PCOPD patients showed increased presence of fever (P < .05), lower blood pressure (P < .001), more laboratory abnormalities (P < .05; leukocytosis, elevated CRP, low serum albumin) and increased presence of crepitus (P < .01). Microbiological diagnosis was achieved in 30.8% of cases of ECOPD and 35% of PCOPD; sputum culture yielded the highest percentage of positive results, predominantly Pseudomonas aeruginosa. Regarding the progress of the episode, no differences were found in hospital stay, need for ICU or mechanical ventilation.ConclusionsOur data confirm clinical and analytical differences between ECOPD and PCOPD in patients who require hospital admission, while there were no differences in subsequent progress.     

Location-related differences in sporadic microsatellite unstable colorectal cancer

BackgroundMicrosatellite unstable CRC is associated with female gender, large tumours, and poor differentiation. However, there are few reports about the characteristics and differences of sporadic microsatellite unstable CRC based on tumour location.AimsSite-specific heterogeneity of sporadic microsatellite unstable colorectal cancer (CRC) based on location was elucidated.MethodsWe enrolled 164 CRC patients with high-frequency microsatellite instability (MSI-H) from the prospective database of 2686 consecutive CRC patients who underwent surgical resection. We analysed microsatellite instability (MSI) and expression of mismatch repair (MMR) proteins (MLH1, MSH2, and MSH6).ResultsAmong the 164 MSI-H CRC, 105 (64.0%) were located in the proximal colon and 59 (36.0%) were located in the distal colon. The proximal MSI-H CRC was predominantly in female (p = 0.014), had a more aggressive differentiation (p = 0.001), was of advanced stage (p = 0.035), and had a frequent loss of MLH1 expression (p = 0.005) compared to the distal MSI-H CRC.ConclusionThere were different clinicopathologic characteristics and MMR protein expression between proximal and distal MSI-H CRC. These findings suggest that the underlying carcinogenic pathway or molecular background differs according to location, despite being microsatellite unstable CRC.