Impact of Applying the Global Lung Initiative Criteria for Airway Obstruction in GOLD Defined COPD Cohorts: The BODE and CHAIN Experience.

INTRODUCTION: The Global Lung Function Initiative (GLI) has proposed new criteria for airflow limitation (AL) and recommends using these to interpret spirometry. The objective of this study was to explore the impact of the application of the AL GLI criteria in two well characterized GOLD-defined COPD cohorts. METHODS: COPD patients from the BODE (n=360) and the COPD History Assessment In SpaiN (CHAIN) cohorts (n=722) were enrolled and followed. Age, gender, pack-years history, BMI, dyspnea, lung function measurements, exercise capacity, BODE index, history of exacerbations and survival were recorded. CT-detected comorbidities were registered in the BODE cohort. The proportion of subjects without AL by GLI criteria was determined in each cohort. The clinical, CT-detected comorbidity, and overall survival of these patients were evaluated. RESULTS: In total, 18% of the BODE and 15% of the CHAIN cohort did not meet GLI AL criteria. In the BODE and CHAIN cohorts respectively, these patients had a high clinical burden (BODE≥3: 9% and 20%; mMRC≥2: 16% and 45%; exacerbations in the previous year: 31% and 9%; 6MWD<350m: 15% and 19%, respectively), and a similar prevalence of CT-diagnosed comorbidities compared with those with GLI AL. They also had a higher rate of long-term mortality - 33% and 22% respectively. CONCLUSIONS: An important proportion of patients from 2 GOLD-defined COPD cohorts did not meet GLI AL criteria at enrolment, although they had a significant burden of disease. Caution must be taken when applying the GLI AL criteria in clinical practice.

Metallomic Signatures of Lung Cancer and Chronic Obstructive Pulmonary Disease.

Lung cancer (LC) is the leading cause of cancer deaths, and chronic obstructive pulmonary disease (COPD) can increase LC risk. Metallomics may provide insights into both of these tobacco-related diseases and their shared etiology. We conducted an observational study of 191 human serum samples, including those of healthy controls, LC patients, COPD patients, and patients with both COPD and LC. We found 18 elements (V, Al, As, Mn, Co, Cu, Zn, Cd, Se, W, Mo, Sb, Pb, Tl, Cr, Mg, Ni, and U) in these samples. In addition, we evaluated the elemental profiles of COPD cases of varying severity. The ratios and associations between the elements were also studied as possible signatures of the diseases. COPD severity and LC have a significant impact on the elemental composition of human serum. The severity of COPD was found to reduce the serum concentrations of As, Cd, and Tl and increased the serum concentrations of Mn and Sb compared with healthy control samples, while LC was found to increase Al, As, Mn, and Pb concentrations. This study provides new insights into the effects of LC and COPD on the human serum elemental profile that will pave the way for the potential use of elements as biomarkers for diagnosis and prognosis. It also sheds light on the potential link between the two diseases, i.e., the evolution of COPD to LC.

FIDEPOC: Consensus on Inspiratory Flow and Lung Deposition as Key Decision Factors in COPD Inhaled Therapy.

Purpose: The pharmacological treatment of chronic obstructive pulmonary disease (COPD) is largely based on inhaled bronchodilators. Inspiratory flow and lung deposition are key parameters to be considered in inhaled therapy; however, the relationship between these two parameters, the patient specificities, and the suitability of the inhaler type for COPD management has not been fully addressed. The present study follows a Delphi Panel methodology to find expert consensus on the role of inspiratory flow and lung deposition as key decision factors in COPD inhaled therapy. Methods: A two-round Delphi Panel, consisting of 38 statements (items) and completed by 57 Spanish pulmonologists, was carried out to measure the experts' consensus degree with each item. Results: A high degree of consensus was reached on most of the items consulted, among these inspiratory flow or inspiratory capacity should be periodically considered when choosing an inhalation device and to ensure the suitability of the inhaler used; the outflow velocity and particle size of the different devices should be considered to ensure adequate lung deposition; an active device (pressurized metered-dose inhalers (pMDI) or soft mist inhalers (SMI)) should be used in patients with low inspiratory flow to achieve adequate lung deposition; and, the use of dry powder inhalers (DPI) should be re-evaluated in patients with severe obstruction and severe exacerbations. Conclusion: This study shows the relevance of inspiratory flow and the degree of particle deposition in the lung in the choice of an inhalation device for COPD management, as well as the convenience of an SMI type device in cases of low inspiratory flow. Moreover, it highlights the scarcity of information on the specific features of inhalation devices in COPD guidelines.

Natural Course of the Diffusing Capacity of the Lungs for Carbon Monoxide in COPD: Importance of Sex.

BACKGROUND: The value of the single-breath diffusing capacity of the lungs for carbon monoxide (Dlco) relates to outcomes for patients with COPD. However, little is known about the natural course of Dlco over time, intersubject variability, and factors that may influence Dlco progression. RESEARCH QUESTION: What is the natural course of Dlco in patients with COPD over time, and which other factors, including sex differences, could influence this progression? STUDY DESIGN AND METHODS: We phenotyped 602 smokers (women, 33%), of whom 506 (84%) had COPD and 96 (16%) had no airflow limitation. Lung function, including Dlco, was monitored annually over 5 years. A random coefficients model was used to evaluate Dlco changes over time. RESULTS: The mean (± SE) yearly decline in Dlco % in patients with COPD was 1.34% ± 0.015%/y. This was steeper compared with non-COPD control subjects (0.04% ± 0.032%/y; P = .004). Sixteen percent of the patients with COPD, vs 4.3% of the control subjects, had a statistically significant Dlco % slope annual decline (4.14%/y). At baseline, women with COPD had lower Dlco values (11.37% ± 2.27%; P < .001) in spite of a higher FEV1 % than men. Compared with men, women with COPD had a steeper Dlco annual decline of 0.89% ± 0.42%/y (P = .039). INTERPRETATION: Patients with COPD have an accelerated decline in Dlco compared with smokers without the disease. However, the decline is slow, and a testing interval of 3 to 4 years may be clinically informative. The lower and more rapid decline in Dlco values in women, compared with men, suggests a differential impact of sex in gas exchange function. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01122758; URL: www.clinicaltrials.gov.

Clinical and Prognostic Impact of Low Diffusing Capacity for Carbon Monoxide Values in Patients With Global Initiative for Obstructive Lung Disease I COPD.

BACKGROUND: The Global Initiative for Obstructive Lung Disease (GOLD) does not promote diffusing capacity for carbon monoxide (Dlco) values in the evaluation of COPD. In GOLD spirometric stage I COPD patients, the clinical and prognostic impact of a low Dlco has not been explored. RESEARCH QUESTION: Could a Dlco threshold help define an increased risk of death and a different clinical presentation in these patients? STUDY DESIGN AND METHODS: GOLD stage I COPD patients (n = 360) were enrolled and followed over 109 ± 50 months. Age, sex, pack-years' history, BMI, dyspnea, lung function measurements, exercise capacity, BODE index, and history of exacerbations were recorded. A cutoff value for Dlco was identified for all-cause mortality and the clinical and physiological characteristics of patients above and below the threshold compared. Cox regression analysis explored the predictive power of that cutoff value for all-cause mortality. RESULTS: A Dlco cutoff value of <60% predicted was associated with all-cause mortality (Dlco ≥ 60%: 9% vs Dlco < 60%: 23%, P = .01). At a same FEV1% predicted and Charlson score, patients with Dlco < 60% had lower BMI, more dyspnea, lower inspiratory capacity (IC)/total lung capacity (TLC) ratio, lower 6-min walk distance (6MWD), and higher BODE. Cox multiple regression analysis confirmed that after adjusting for age, sex, pack-years history, smoking status, and BMI, a Dlco < 60% is associated with all-cause mortality (hazard ratio [HR], 95% CI = 3.37, 1.35-8.39; P = .009) INTERPRETATION: In GOLD I COPD patients, a Dlco < 60% predicted is associated with increased risk of death and worse clinical presentation. What the cause(s) of this association are and whether they can be treated need to be determined.

Lung Deposition and Inspiratory Flow Rate in Patients with Chronic Obstructive Pulmonary Disease Using Different Inhalation Devices: A Systematic Literature Review and Expert Opinion.

BACKGROUND: Our aim was to describe: 1) lung deposition and inspiratory flow rate; 2) main characteristics of inhaler devices in chronic obstructive pulmonary disease (COPD). METHODS: A systematic literature review (SLR) was conducted to analyze the features and results of inhaler devices in COPD patients. These devices included pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), and a soft mist inhaler (SMI). Inclusion and exclusion criteria were established, as well as search strategies (Medline, Embase, and the Cochrane Library up to April 2019). In vitro and in vivo studies were included. Two reviewers selected articles, collected and analyzed data independently. Narrative searches complemented the SLR. We discussed the results of the reviews in a nominal group meeting and agreed on various general principles and recommendations. RESULTS: The SLR included 71 articles, some were of low-moderate quality, and there was great variability regarding populations and outcomes. Lung deposition rates varied across devices: 8%-53% for pMDIs, 7%-69% for DPIs, and 39%-67% for the SMI. The aerosol exit velocity was high with pMDIs (more than 3 m/s), while it is much slower (0.84-0.72 m/s) with the SMI. In general, pMDIs produce large-sized particles (1.22-8 µm), DPIs produce medium-sized particles (1.8-4.8 µm), and 60% of the particles reach an aerodynamic diameter <5 µm with the SMI. All inhalation devices reach central and peripheral lung regions, but the SMI distribution pattern might be better compared with pMDIs. DPIs' intrinsic resistance is higher than that of pMDIs and SMI, which are relatively similar and low. Depending on the DPI, the minimum flow inspiratory rate required was 30 L/min. pMDIs and SMI did not require a high inspiratory flow rate. CONCLUSION: Lung deposition and inspiratory flow rate are key factors when selecting an inhalation device in COPD patients.

COPD Clinical Control: predictors and long-term follow-up of the CHAIN cohort.

BACKGROUND: Control in COPD is a dynamic concept that can reflect changes in patients' clinical status that may have prognostic implications, but there is no information about changes in control status and its long-term consequences. METHODS: We classified 798 patients with COPD from the CHAIN cohort as controlled/uncontrolled at baseline and over 5 years. We describe the changes in control status in patients over long-term follow-up and analyze the factors that were associated with longitudinal control patterns and related survival using the Cox hazard analysis. RESULTS: 134 patients (16.8%) were considered persistently controlled, 248 (31.1%) persistently uncontrolled and 416 (52.1%) changed control status during follow-up. The variables significantly associated with persistent control were not requiring triple therapy at baseline and having a better quality of life. Annual changes in outcomes (health status, psychological status, airflow limitation) did not differ in patients, regardless of clinical control status. All-cause mortality was lower in persistently controlled patients (5.5% versus 19.1%, p = 0.001). The hazard ratio for all-cause mortality was 2.274 (95% CI 1.394-3.708; p = 0.001). Regarding pharmacological treatment, triple inhaled therapy was the most common option in persistently uncontrolled patients (72.2%). Patients with persistent disease control more frequently used bronchodilators for monotherapy (53%) at recruitment, although by the end of the follow-up period, 20% had scaled up their treatment, with triple therapy being the most frequent therapeutic pattern. CONCLUSIONS: The evaluation of COPD control status provides relevant prognostic information on survival. There is important variability in clinical control status and only a small proportion of the patients had persistently good control. Changes in the treatment pattern may be relevant in the longitudinal pattern of COPD clinical control. Further studies in other populations should validate our results. TRIAL REGISTRATION: Clinical Trials.gov: identifier NCT01122758.

Relationship Between Clinical Control, Respiratory Symptoms and Quality of Life for Patients with COPD.

Background: The concept of clinical control has been proposed as an instrument for evaluating patients with COPD. However, the possible association between clinical control, reduced symptom severity and HRQoL has yet to be confirmed. Methods: This multicentre, prospective and observational study was carried out in 15 pulmonology clinics in Spain. The patients were followed up for six months, with a baseline visit (V0), followed by visits at three months (V1) and six months (V2). Clinical control was determined at V1, with the application of both clinical criteria and the COPD assessment test (CAT). All patients reported their symptoms by a validated symptom diary (E-RS) using a portable device, and their HRQoL was assessed using the EQ5D questionnaire. The relationship between clinical control and E-RS and HRQoL during follow-up was assessed with t-test. Results: A total of 126 patients were screened. After application of the inclusion/exclusion criteria, 93 were finally included (mean age 66 ± 8 years, 84.9% male), with a mean FEV1 predicted of 49.8% ± 16.5%. Of these patients, 44 (47.3%) achieved clinical control at V1, according to CAT criteria, and 50 (53.8%), according to clinical criteria. The E-RS scores differed between controlled and uncontrolled patients at all time points, both according to CAT (mean differences of -4.6, -5.6 and -6.2 units at V0, V1 and V2, respectively, p<0.005 for all comparisons) and to clinical criteria (mean differences of -3.3, -5-6 and -4.99 units, respectively, p<0.005 for all comparisons). The controlled patients also presented a significantly better HRQoL, measured by the EQ5D questionnaire (mean difference 0.13 and 0.10 at V2 by CAT or clinical criteria, respectively, p<0.05). Conclusion: Clinical control in patients with COPD, whether measured by CAT or by clinical criteria, is associated with a lower symptom load and a better HRQoL.

Temporal transitions in COPD severity stages within the GOLD 2017 classification system.

BACKGROUND: The stability of the new GOLD 2017 COPD staging is unknown, as well as the frequency of individual transitions in COPD stages beyond one year. METHODS: All COPD participants in the CHAIN cohort were re-analysed according to GOLD 2017 up to five years of follow-up. Their individual changes within COPD stages were aggregated into cohort-wide Markov chains; group stability was evaluated using joinpoint regression. RESULTS: At baseline, 959 COPD patients were distributed according to GOLD 2017 stages as 37.7% in A, 38.3% B, 8.2% C, and 15.7% D. The group proportion of patients in each stage was maintained from years one to five. However, we found significant changes between stages at the individual patient level, especially in the more severe stages. The probability of a patient remaining in the same GOLD 2017 COPD stage for two consecutive years ranged during the five years of follow-up for stage C from 16% to 31% per year, while for D from 23% to 43% per year, indicating substantial variation either increasing or decreasing severity for the vast majority of patients. CONCLUSIONS: We conclude that group stability observed in COPD staging according to GOLD 2017 recommendations is paired with a large variability at the individual patient level.

Changes and Clinical Consequences of Smoking Cessation in Patients With COPD: A Prospective Analysis From the CHAIN Cohort.

BACKGROUND: Despite the existing evidence-based smoking cessation interventions, chances of achieving that goal in real life are still low among patients with COPD. We sought to evaluate the clinical consequences of changes in smoking habits in a large cohort of patients with COPD. METHODS: CHAIN (COPD History Assessment in Spain) is a Spanish multicenter study carried out at pulmonary clinics including active and former smokers with COPD. Smoking status was certified by clinical history and co-oximetry. Clinical presentation and disease impact were recorded via validated questionnaires, including the London Chest Activity of Daily Living (LCADL) and the Hospital Anxiety and Depression Scale (HADS). No specific smoking cessation intervention was carried out. Factors associated with and clinical consequences of smoking cessation were analyzed by multivariate regression and decision tree analyses. RESULTS: One thousand and eighty-one patients with COPD were included (male, 80.8%; age, 65.2 [SD 8.9] years; FEV1, 60.2 [20.5]%). During the 2-year follow-up time (visit 2, 906 patients; visit 3, 791 patients), the majority of patients maintained the same smoking habit. Decision tree analysis detected chronic expectoration as the most relevant variable to identify persistent quitters in the future, followed by an LCADL questionnaire (cutoff 9 points). Total anxiety HADS score was the most relevant clinical impact associated with giving up tobacco, followed by the LCADL questionnaire with a cutoff value of 10 points. CONCLUSIONS: In this real-life prospective COPD cohort with no specific antismoking intervention, the majority of patients did not change their smoking status. Our study also identifies baseline expectoration, anxiety, and dyspnea with daily activities as the major determinants of smoking status in COPD. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT01122758; URL: www.clinicaltrials.gov.

Prevalence of persistent blood eosinophilia: relation to outcomes in patients with COPD.

The impact of blood eosinophilia in chronic obstructive pulmonary disease (COPD) remains controversial.To evaluate the prevalence and stability of a high level of blood eosinophils (≥300 cells·µL-1) and its relationship to outcomes, we determined blood eosinophils at baseline and over 2 years in 424 COPD patients (forced expiratory volume in 1 s (FEV1) 60% predicted) and 67 smokers without COPD from the CHAIN cohort, and in 308 COPD patients (FEV1 60% predicted) in the BODE cohort. We related eosinophil levels to exacerbations and survival using Cox hazard analysis.In COPD patients, 15.8% in the CHAIN cohort and 12.3% in the BODE cohort had persistently elevated blood eosinophils at all three visits. A significant proportion (43.8%) of patients had counts that oscillated above and below the cut-off points, while the rest had persistent eosinophil levels <300 cells·µL-1 A similar eosinophil blood pattern was observed in controls. Exacerbation rates did not differ in patients with and without eosinophilia. All-cause mortality was lower in patients with high eosinophils compared with those with values <300 cells·µL-1 (15.8% versus 33.7%; p=0.026).In patients with COPD, blood eosinophils ≥300 cells·µL-1 persisting over 2 years was not a risk factor for COPD exacerbations. High eosinophil count was associated with better survival.

The evaluation of a remote support program on quality of life and evolution of disease in COPD patients with frequent exacerbations.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients often present considerable individual medical burden in their symptoms, limitations, and well-being that complicate medical treatment. To improve their overall health status, while reducing the number of exacerbations, a multidisciplinary approach including different elements of care is needed. The aim of this study was to evaluate the effects of a remote support program on COPD patients at high risk of experiencing worsening of their disease and other health-related outcomes. METHODS: An observational, multicenter, prospective study aimed at evaluating the impact of a 7-month remote support program on COPD patients in exacerbations control and changes in health status measured with the COPD assessment test (CAT). Factors associated with a clinically relevant decrease in CAT were assessed using a logistic regression analysis. RESULTS: A total of 114 subjects started the program. The majority of the study population were males (81.6 %), retired (70.2 %), without academic qualifications or with a low level of education (68.4 %), and ex-smokers (79.8 %). The mean ± SD age was 69.6 ± 9.1 years and the BMI was 27.8 ± 5.5 Kg/m2. Overall, 41.9 % (95 % CI 31.9-52.0) patients, significantly improved health status (CAT decrease ≥ 2 points). Univariate analysis showed that significant improvement in CAT was associated with baseline CAT scores [high CAT score 19.2 (±7.5) vs. low CAT score 12.4 (±6.4); OR = 1.15, 95 % CI: 1.07-1.24; p < 0.001] and with being non-compliant [62.5 % (15/24) of non-compliant vs 34.7 % (24/69) of compliant patients significantly improved CAT scores; OR = 3.13, 95 % CI: 1.19-8.19; p = 0.021). After controlling for the effect of all variables in a multivariable logistic regression model, the only factor that remained significant was baseline CAT score. The proportion of smokers in the total population remained constant during the study. There was a significant reduction in the number of exacerbations after entering this remote support program with median -1 (IQR: -2, 0), (p < 0.001). The Morisky-Green questionnaire showed an increase of treatment compliance, namely at baseline, 25.8 % (24/93) of patients were noncompliant while in the end 66.7 % (16/24) of them became compliant) (p = 0.053). CONCLUSIONS: A remote support program for high-risk COPD patients results in an improvement of the patients' health status, particularly in those with initially poor health status, and it helps to reduce COPD exacerbations.

Validación de la versión en español del cuestionario COPD-Q/EPOC-Q de conocimiento de la EPOC / Validation of the Spanish Version of the COPD-Q Questionnaire on COPD Knowledge

Fundamentos: A pesar de que el reconocimiento de la importancia de la formación de los pacientes con EPOC ha crecido en los últimos años, no se está midiendo el grado de conocimiento de dicha enfermedad por falta de instrumentos específicos. El objetivo de este estudio es validar el cuestionario de conocimiento de la EPOC (EPOC-Q) de 13 ítems. Métodos: Tras la doble traducción del EPOC-Q se llevó a cabo la validación lógica y de contenido por un grupo de neumólogos expertos en EPOC y 8 pacientes con la enfermedad. La fiabilidad se estudió en un grupo independiente de 59 pacientes con EPOC grave vistos en planta o en consultas de neumología de 6 centros de varias regiones de España (Andalucía, Baleares, Castilla-La Mancha, Galicia y Madrid). Esta muestra también se usó para otras validaciones internas y externas. Resultados: El grupo tenía una media de edad de aproximadamente 70 años y una alfabetización en salud media baja. El número de respuestas acertadas fue de 8,3 (DE: 1,9), con una mediana de 8 y un rango entre 3 y 13. Los efectos suelo y techo fueron 0 y 1,5%, respectivamente. La consistencia interna del cuestionario es buena (alfa de Cronbach de 0,85) y la fiabilidad también alta, siendo el coeficiente kappa > 0,6 en todos los ítems y el coeficiente de correlación intraclase de la puntuación total de 0,84. Conclusión: El cuestionario EPOC-Q de 13 ítems es un instrumento válido, aplicable y fiable para evaluar el conocimiento de la EPOC

Rationale: Although recognition of the importance of educating chronic obstructive pulmonary disease (COPD) patients has grown in recent years, their understanding of this disease is not being measured due to a lack of specific instruments. The aim of this study was to validate the COPD-Q questionnaire, a 13-item instrument for determining COPD knowledge. Methods: The COPD-Q was translated and backtranslated, and subsequently submitted to logic and content validation by a group of COPD experts and 8 COPD patients. Reliability was studied in an independent group of 59 patients with severe COPD seen in the pulmonology ward or clinics of 6 hospitals in Spain (Andalusia, Baleares, Castilla-La Mancha, Galicia and Madrid). This sample was also used for other internal and external validations. Results: The mean age of the group was approximately 70 years and their health awareness was low-to-medium. The number of correct answers was 8.3 (standard deviation: 1.9), median 8, range 3-13. Floor and ceiling effects were 0% and 1.5%, respectively. Internal consistency of the questionnaire was good (Cronbach's alpha = 0.85) and reliability was also high, with a kappa coefficient > 0.6 for all items and an intraclass correlation efficient of 0.84 for the total score. Conclusion: The 13-item COPD-Q is a valid, applicable and reliable instrument for determining patients' knowledge of COPD

Validation of the Spanish Version of the COPD-Q Questionnaire on COPD Knowledge.

RATIONALE: Although recognition of the importance of educating chronic obstructive pulmonary disease (COPD) patients has grown in recent years, their understanding of this disease is not being measured due to a lack of specific instruments. The aim of this study was to validate the COPD-Q questionnaire, a 13-item instrument for determining COPD knowledge. METHODS: The COPD-Q was translated and backtranslated, and subsequently submitted to logic and content validation by a group of COPD experts and 8 COPD patients. Reliability was studied in an independent group of 59 patients with severe COPD seen in the pulmonology ward or clinics of 6 hospitals in Spain (Andalusia, Baleares, Castilla-La Mancha, Galicia and Madrid). This sample was also used for other internal and external validations. RESULTS: The mean age of the group was approximately 70 years and their health awareness was low-to-medium. The number of correct answers was 8.3 (standard deviation: 1.9), median 8, range 3-13. Floor and ceiling effects were 0% and 1.5%, respectively. Internal consistency of the questionnaire was good (Cronbach's alpha=0.85) and reliability was also high, with a kappa coefficient >0.6 for all items and an intraclass correlation efficient of 0.84 for the total score. CONCLUSION: The 13-item COPD-Q is a valid, applicable and reliable instrument for determining patients' knowledge of COPD.

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

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

Effects of beta-carotene supplementation on adipose tissue thermogenic capacity in ferrets (Mustela putorius furo).

We previously described that the intake of pharmacological doses of beta-carotene (BC) resulted in higher body weight gain in the ferret (Mustela putorius furo), an animal model that resembles human subjects in terms of intestinal BC absorption and metabolism. These results were some way unexpected considering the condition of BC as a vitamin A precursor and the previous data in rodents showing these compounds as thermogenic activators. Here, we aimed to characterise in the ferret whether the mentioned changes in body weight could be explained by changes in adipose tissue thermogenic capacity. We studied the effects of 6-month supplementation with BC (0.8 and 3.2 mg/kg per d) on adipose tissue morphology and uncoupling protein-1 (UCP1) content. BC supplementation resulted in higher body weight (the high dose), induced depot- and dose-dependent hypertrophy of white adipocytes, decreased the amount of brown-like multilocular adipocytes in the retroperitoneal depot and decreased UCP1 content in different fat depots. To ascertain whether BC effects could be mediated by retinoic acid (RA), 1 week supplementation with RA (0.25 and 25 mg/kg per d) was also studied. RA treatment resulted in a slight decrease in adiposity, decreased cell lipid accumulation and increased UCP1 content, suggesting that the effects of BC on thermogenic capacity are not through RA. In conclusion, RA, but not BC, may have in the ferret comparable effects with those described in rodents, whereas differences concerning BC and RA treatments may be attributable to the different BC metabolism in the present animal model with a lower conversion of BC to RA compared with rodents.

UCP1 and oxidative capacity of adipose tissue in adult ferrets (Mustela putorius furo).

The main mass of brown adipose tissue is located in the interscapular region in rodents, while certain species, such as humans, have a tissue that resembles the brown depot, but in different locations. Ferrets have been described as a useful model in different studies because of their similarity with humans. Here we have characterised the oxidative capacity (cytochrome c oxidase activity) and the pattern of UCP1 production in different adipose tissue depots (retroperitoneal, inguinal and interscapular) in ferrets housed at different temperatures. For this purpose adult female ferrets were divided into two groups, one housed at 22 degrees C and the other acclimated to 4 degrees C for one week. Our data show that, in 22 degrees C-acclimated ferrets, and unlike rodents, UCP1 is present at low levels in the different adipose tissue depots studied, with higher specific levels in the retroperitoneal than in the interscapular depot, whereas the inguinal depot has intermediate levels. Cold-exposure produces a transformation in the adipose tissue, increasing the number of brown adipocytes and UCP1 levels in the retroperitoneal and in the interscapular depots. Cytochrome c oxidase activity is also higher in the retroperitoneal depot but is not affected by cold. Due to its higher oxidative capacity and UCP1 content, the retroperitoneal adipose depot in ferrets seems to be the most important when considering a potential thermogenic role. In conclusion, in adult ferrets, UCP1 is expressed in different adipose depots and the expression of this protein is responsive to a cold-stimulus. These results suggest that ferrets could be considered as a useful animal model to approach studies of adipose tissue thermogenesis.

Systemic inflammation after inspiratory loading in chronic obstructive pulmonary disease.

OBJECTIVE: Patients with chronic obstructive pulmonary disease (COPD) present systemic inflammation. Strenuous resistive breathing induces systemic inflammation in healthy subjects. We hypothesized that the increased respiratory load that characterizes COPD can contribute to systemic inflammation in these patients. PATIENTS AND METHODS: To test this hypothesis, we compared leukocyte numbers and levels of circulating cytokines (tumor necrosis factor alpha [TNFalpha], interleukin-1beta [IL-1beta], IL-6, IL-8, and IL-10), before and 1 hour after maximal incremental inspiratory loading in 13 patients with stable COPD (forced expiratory volume in one second [FEV1] 29 +/- 2.5% ref) and in 8 healthy sedentary subjects (FEV1 98 +/- 5% ref). RESULTS: We found that: (1) at baseline, patients with COPD showed higher leukocyte counts and IL-8 levels than controls (p < 0.01); and, (2) one hour after maximal inspiratory loading these values were unchanged, except for IL-10, which increased in controls (p < 0.05) but not in patients with COPD. CONCLUSIONS: This study confirms the presence of systemic inflammation in COPD, shows that maximal inspiratory loading does not increase the levels of pro-inflammatory cytokines (IL-1beta, IL-8) in COPD patients or controls, but suggests that the former may be unable to mount an appropriate systemic anti-inflammatory response to exercise.

Effects of 6-month daily supplementation with oral beta-carotene in combination or not with benzo[a]pyrene on cell-cycle markers in the lung of ferrets.

Epidemiological studies have demonstrated that people who eat more fruits and vegetables (rich in carotenoids) and people who have higher serum beta-carotene (BC) levels have a lower risk of cancer, particularly lung cancer. However, the two main human intervention studies of BC supplementation (the ATBC and the CARET trials) revealed an increased risk of lung cancer among smokers and asbestos workers. Previous studies carried out in the ferret have reported that BC effects are related to dose. Here, we treated ferrets with two concentrations of oral BC (0.8 and 3.2 mg/kg body weight per day) for 6 months, using BC in a formulation also containing dl-alpha-tocopherol and ascorbyl palmitate. The effect of the smoke-derived carcinogenic agent benzo[a]pyrene (BP), with or without low-dose BC, was also analysed. We determined the protein levels and mRNA expression levels of activator protein 1 (c-Jun and c-Fos), c-Myc, cyclin D1, proliferating cellular nuclear antigen and retinoic acid receptor beta. We did not find higher levels of cell proliferation markers in the lung of ferrets treated with BC or signals of squamous metaplasia lesions either. On the other hand, although no evident signals of pulmonary carcinogenesis were observed in animals exposed to BP, BC supplementation in these animals may prevent against excess cell proliferation, since this reestablishes Jun protein and cyclin D1 mRNA levels in the lung of BP-exposed animals. In summary, these results show that the combination of BC with alpha-tocopherol and ascorbyl palmitate does not induce pro-oxidant effects in the lung of ferrets.

Morphology of ferret subcutaneous adipose tissue after 6-month daily supplementation with oral beta-carotene.

Adipose tissue is an important retinoid depot and retinoids are known to influence white and brown adipocyte metabolism. Identifying nutrients that can affect the biological activity of the adipose organ would be of great medical interest in the light of the current obesity epidemic and related disorders in developed countries. The vast majority of mammal studies of chronic administration of oral beta-carotene have used murine models, while few have employed mammals exhibiting uptake and processing of intestinal beta-carotene similar to those of humans. While rodents transform practically all ingested beta-carotene into retinol, in ferrets, as in humans, part of the beta-carotene is absorbed and released into the circulation intact. We studied the effects of 6-month daily administration of two doses of oral beta-carotene (0.8 or 3.2 mg/kg/day) on ferret body weight, size of body fat depots, and, using morphological and morphometric methods, on subcutaneous (inguinal) white adipose tissue (WAT). Because of the oral mode of administration, liver, stomach, and small and large intestine were also studied. Control animals received the vehicle. Data show that at the end of treatment the higher dose induced significantly higher body weight compared with controls and significantly higher inguinal fat depot compared with animals treated with the lower dose. In addition, chronic treatment with beta-carotene induced a dose-dependent hypertrophy of white adipocytes and increased neoangiogenesis in subcutaneous WAT in all treated ferrets. Vasculogenesis was independent of adipocyte hypertrophy. We also found focally evident liver steatosis in the ferrets treated with the higher dose of beta-carotene. The other gastrointestinal tract organs studied were not significantly different from those of control animals.