Juan B. Gáldiz

Identification and prospective validation of clinically relevant chronic obstructive pulmonary disease (COPD) subtypes

Background Chronic obstructive pulmonary disease (COPD) is increasingly considered a heterogeneous condition. It was hypothesised that COPD, as currently defined, includes different clinically relevant subtypes. Methods To identify and validate COPD subtypes, 342 subjects hospitalised for the first time because of a COPD exacerbation were recruited. Three months after discharge, when clinically stable, symptoms and quality of life, lung function, exercise capacity, nutritional status, biomarkers of systemic and bronchial inflammation, sputum microbiology, CT of the thorax and echocardiography were assessed. COPD groups were identified by partitioning cluster analysis and validated prospectively against cause-specific hospitalisations and all-cause mortality during a 4 year follow-up. Results Three COPD groups were identified: group 1 (n=126, 67 years) was characterised by severe airflow limitation (postbronchodilator forced expiratory volume in 1 s (FEV1) 38% predicted) and worse performance in most of the respiratory domains of the disease; group 2 (n=125, 69 years) showed milder airflow limitation (FEV1 63% predicted); and group 3 (n=91, 67 years) combined a similarly milder airflow limitation (FEV1 58% predicted) with a high proportion of obesity, cardiovascular disorders, diabetes and systemic inflammation. During follow-up, group 1 had more frequent hospitalisations due to COPD (HR 3.28, p<0.001) and higher all-cause mortality (HR 2.36, p=0.018) than the other two groups, whereas group 3 had more admissions due to cardiovascular disease (HR 2.87, p=0.014). Conclusions In patients with COPD recruited at their first hospitalisation, three different COPD subtypes were identified and prospectively validated: ‘severe respiratory COPD’, ‘moderate respiratory COPD’, and ‘systemic COPD’.

Cigarette Smoke-induced Oxidative Stress A Role in Chronic Obstructive Pulmonary Disease Skeletal Muscle Dysfunction

RATIONALE Inflammation and oxidative stress contribute to muscle dysfunction in patients with chronic obstructive pulmonary disease (COPD). Oxidants contained in cigarette smoke (CS) induce adverse effects on tissues through oxidative phenomena. OBJECTIVES To explore oxidative stress and inflammation in quadriceps of human smokers and in diaphragm and limb muscles of guinea pigs chronically exposed to CS. METHODS Muscle function, protein oxidation and nitration, antioxidants, oxidized proteins, inflammation, creatine kinase activity, and lung and muscle structures were investigated in vastus lateralis of smokers, patients with COPD, and healthy control subjects and in diaphragm and gastrocnemius of CS-exposed guinea pigs at 3, 4, and 6 months. MEASUREMENTS AND MAIN RESULTS Compared with control subjects, quadriceps muscle force was mildly but significantly reduced in smokers; protein oxidation levels were increased in quadriceps of smokers and patients with COPD, and in respiratory and limb muscles of CS-exposed animals; glycolytic enzymes, creatine kinase, carbonic anydrase-3, and contractile proteins were significantly more carbonylated in quadriceps of smokers and patients with COPD, and in respiratory and limb muscles of CS-exposed guinea pigs. Chronic CS exposure induced no significant rise in muscle inflammation in either smokers or rodents. Muscle creatine kinase activity was reduced only in patients with COPD and in both diaphragm and gastrocnemius of CS-exposed animals. Guinea pigs developed bronchiolar abnormalities at 4 months of exposure and thereafter. CONCLUSIONS CS exerts direct oxidative modifications on muscle proteins, without inducing any significant rise in muscle inflammation. The oxidative damage to muscle proteins, which precedes the characteristic respiratory changes, may contribute to muscle loss and dysfunction in smokers and patients with COPD.

Relevance of assessing quadriceps endurance in patients with COPD

The aims of this study were to investigate whether the impairment in endurance of limb muscles is a general finding in chronic obstructive pulmonary disease (COPD) patients, affecting even those with mild-to-moderate disease or relatively normal physical activity. In addition, this study aimed to determine the physiopathology of exhaustion in local endurance tests and whether the reduction in quadriceps endurance can be predicted from muscle strength measurements. A total of 75 volunteers were assigned to one of two groups according to pulmonary function tests: COPD patients or healthy age-matched controls. Functional assessment included both quadriceps strength (maximum voluntary contraction (QMVC)), and quadriceps endurance (contractions against a load equivalent to 10% QMVC until task failure or for up to a limiting time of 30 min (QTlim)). COPD patients showed a decrease of ∼43% in QMVC and ∼77% in QTlim compared with controls. Task failure occurred only in COPD patients and was due to muscle fatigue, since limiting symptoms were associated with a decrease in the median frequency of quadriceps electromyographical signal and a reversible decrease in QMVC. The impairment in skeletal muscle endurance was present even in patients with mild-to-moderate airflow obstruction and individuals with relatively normal physical activity, and was irrespective of lung function variables, anthropometrical data or quadriceps strength. Peripheral muscle endurance was impaired in chronic obstructive pulmonary disease patients, even in those with relatively normal physical activity and mild-to-moderate airflow obstruction. This impairment associated with an early onset of muscle fatigue and could not be predicted from the severity of the disease or the reduction in quadriceps strength.

Cytokine profile in quadriceps muscles of patients with severe COPD

Background: Systemic proinflammatory cytokines and oxidative stress have been described in association with peripheral muscle wasting and weakness of patients with severe chronic obstructive pulmonary disease (COPD), but their expression in skeletal muscle is unknown. The objectives of the present study were to determine muscle protein levels of selected cytokines in patients with COPD and to study their relationships with protein carbonylation as a marker of oxidative stress, quadriceps function and exercise capacity. Methods: We conducted a cross sectional study in which 36 cytokines were detected using a human antibody array in quadriceps specimens obtained from 19 patients with severe COPD and seven healthy controls. Subsequently, selected cytokines (tumour necrosis factor (TNF)α, TNFα receptors I and II, interleukin (IL) 6, interferon γ, transforming growth factor (TGF) β and vascular endothelial growth factor (VEGF)), as well as protein carbonylation (oxidative stress index) were determined using an enzyme linked immunosorbent assay (ELISA) in all muscles. Results: Compared with controls, the vastus lateralis of patients with COPD showed significantly lower protein ELISA levels of TNFα, which positively correlated with their quadriceps function, TNFα receptor II and VEGF. Protein ELISA levels of IL6, interferon γ and TGFβ did not differ between patients and controls. Quadriceps protein carbonylation was greater in patients and inversely correlated with quadriceps strength among them. Conclusions: These findings do not support the presence of a proinflammatory environment within the quadriceps muscles of clinically and weight stable patients with severe COPD, despite evidence for increased oxidative stress and the presence of muscle weakness.

Home vs Hospital-Based Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease: A Spanish Multicenter Trial

OBJECTIVE To compare the effects of a simple home pulmonary rehabilitation program and an intensive hospital-based program in terms of the exercise tolerance and health-related quality of life (HRQL) of patients with severe chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS Patients in this prospective, multicenter trial were randomized to 2 groups to receive hospital or home pulmonary rehabilitation. Patients in both groups attended 2 informative sessions about the disease and 4 physical therapy sessions. Patients in the hospital group then carried out a structured exercise program while home group patients performed low intensity exercises at home without supervision. RESULTS Twenty-eight patients were randomized to the hospital rehabilitation group and 23 to the home group. Both groups showed a similar improvement on the 6-minute walk test (mean difference, 8.7 m; P=.61). HRQOL measured with the Chronic Respiratory Questionnaire also improved in both groups, but the change was greater on the emotional function domain in the hospital rehabilitation group (mean difference between groups, 0.58 on a scale for which the smallest clinically relevant difference is 0.5 points). The benefits were maintained in both groups 6 months after the programs ended. CONCLUSIONS This study demonstrates that the improvement in exercise tolerance achieved by COPD patients with an unsupervised home pulmonary rehabilitation program is similar to the gains of patients in an intensive hospital-based program. However, the hospital program afforded greater benefit on the HRQOL emotional function domain.

Characteristics of patients admitted for the first time for COPD exacerbation

BACKGROUND This study describes the characteristics of a large sample of patients hospitalised for the first time for a chronic obstructive pulmonary disease (COPD) exacerbation. METHODS All subjects first admitted for a COPD exacerbation to nine teaching Spanish hospitals during January 2004-March 2006, were eligible. COPD diagnosis was confirmed by spirometry under stability. At admission, sociodemographic data, lifestyle, previous treatment and diagnosis of respiratory disease, lung function and Charlson index of co-morbidity were collected. A comprehensive assessment, including dyspnea, lung function, six-minute walking test, and St. Georges Respiratory Questionnaire (SGRQ), was completed 3 months after admission, during a clinically stable disease period. RESULTS Three-hundred and forty-two patients (57% of the eligible) participated in the study: 93% males, mean (SD) age 68 (9) years, 42% current smokers, 50% two or more co-morbidities, 54% mild-to-moderate dyspnea, post-bronchodilator FEV(1) 52 (16)% of predicted (54% mild-to-moderate COPD in ATS/ERS stages), 6-min walking distance 440 m, total SGRQ score 37 (18), and 36% not report respiratory disease. The absence of a previous COPD diagnosis, positive bronchodilator test, female gender, older age, higher DLco and higher BMI were independently associated with less severe COPD. CONCLUSIONS We show that the patients admitted after presenting with their first COPD exacerbation have a wide range of severity, with a large proportion of patients in the less advanced COPD stages.

La heterogeneidad fenotípica de la EPOC

A functional definition of chronic obstructive pulmonary disease (COPD) based on airflow limitation has largely dominated the field. However, a view has emerged that COPD involves a complex array of cellular, organic, functional, and clinical events, with a growing interest in disentangling the phenotypic heterogeneity of COPD. The present review is based on the opinion of the authors, who have extensive research experience in several aspects of COPD. The starting assumption of the review is that current knowledge on the pathophysiology and clinical features of COPD allows us to classify phenotypic information in terms of the following dimensions: respiratory symptoms and health status, acute exacerbations, lung function, structural changes, local and systemic inflammation, and systemic effects. Twenty-six phenotypic traits were identified and assigned to one of the 6 dimensions. For each dimension, a summary is provided of the best evidence on the relationships among phenotypic traits, in particular among those corresponding to different dimensions, and on the relationship between these traits and relevant events in the natural history of COPD. The information has been organized graphically into a phenotypic matrix where each cell representing a pair of phenotypic traits is linked to relevant references. The information provided has the potential to increase our understanding of the heterogeneity of COPD phenotypes and help us plan future studies on aspects that are as yet unexplored.

Differential Effect of Modified Medical Research Council Dyspnea, COPD Assessment Test, and Clinical COPD Questionnaire for Symptoms Evaluation Within the New GOLD Staging and Mortality in COPD

OBJECTIVE The modified Medical Research Council (mMRC) dyspnea, the COPD Assessment Test (CAT), and the Clinical COPD Questionnaire (CCQ) have been interchangeably proposed by GOLD (Global Initiative for Chronic Obstructive Lung Disease) for assessing symptoms in patients with COPD. However, there are no data on the prognostic value of these tools in terms of mortality. We endeavored to evaluate the prognostic value of the CAT and CCQ scores and compare them with mMRC dyspnea. METHODS We analyzed the ability of these tests to predict mortality in an observational cohort of 768 patients with COPD (82% men; FEV1, 60%) from the COPD History Assessment in Spain (CHAIN) study, a multicenter observational Spanish cohort, who were monitored annually for a mean follow-up time of 38 months. RESULTS Subjects who died (n = 73; 9.5%) had higher CAT (14 vs 11, P = .022), CCQ (1.6 vs 1.3, P = .033), and mMRC dyspnea scores (2 vs 1, P < .001) than survivors. Receiver operating characteristic analysis showed that higher CAT, CCQ, and mMRC dyspnea scores were associated with higher mortality (area under the curve: 0.589, 0.588, and 0.649, respectively). CAT scores ≥ 17 and CCQ scores > 2.5 provided a similar sensitivity than mMRC dyspnea scores ≥ 2 to predict all-cause mortality. CONCLUSIONS The CAT and the CCQ have similar ability for predicting all-cause mortality in patients with COPD, but were inferior to mMRC dyspnea scores. We suggest new thresholds for CAT and CCQ scores based on mortality risk that could be useful for the new GOLD grading classification. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01122758; URL: www.clinicaltrials.gov.

Redox balance following magnetic stimulation training in the quadriceps of patients with severe COPD.

In severe COPD patients, oxidative stress, which is involved in their peripheral muscle dysfunction, increases in response to exercise. In this study, muscle oxidative stress was explored after quadriceps magnetic stimulation training. A randomized controlled study was conducted on very severe COPD patients, who underwent quadriceps magnetic stimulation training for 8 weeks. A control group was also studied. In both groups, vastus lateralis specimens were obtained before and after the 8-week period. Muscle protein carbonylation and nitration and antioxidant enzymes were determined using immunoblotting and proportions and sizes of type I and II fibres using immunohistochemistry. Compared to controls, magnetic stimulation muscle training did not modify redox balance, whilst inducing a significant increase in type I fibre sizes. In severe COPD patients, it is concluded that quadriceps magnetic stimulation training was a well-tolerated therapeutic intervention, which did not enhance muscle oxidative stress, while increasing the size of slow-twitch fibres.

Application of the Empirical Mode Decomposition method to the Analysis of Respiratory Mechanomyographic Signals

The study of the mechanomyographic (MMG) signals during dynamic contractions requires a criterion to separate the low frequency (LF) component (basically due to gross movement of the muscle or of the body) and the high frequency (HF) component (related with the vibration of the muscle fibers during contraction). In this study, we propose to use the Empirical Mode Decomposition method in order to analyze the Intrinsic Mode Functions of MMG signals of the diaphragm muscle, acquired by means of a capacitive accelerometer applied on the costal wall. This signal, as the MMG signals during dynamic contractions, has a LF component that is related with the movement of the thoracic cage, and a HF component that could be related with the vibration of diaphragm muscle fibers during contraction. The method was tested on an animal model, with two incremental respiratory protocols performed by two non anesthetized mongrel dogs. The results show that the proposed EMD based method provides very good results for the cancellation of low frequency component of MMG signals. The obtained correlation coefficients between respiratory and MMG parameters were higher than the ones obtained with a Wavelet multiresolution decomposition method utilized in a previous work.