Germán Peces-Barba

Guía clínica para el diagnóstico y el tratamiento de la enfermedad pulmonar obstructiva crónica

La enfermedad pulmonar obstructiva crónica (EPOC) es la de mayor prevalencia e impacto socioeconómico de todas las enfermedades respiratorias. Consciente de esta importancia, la Sociedad Española de Neumología y Cirugía Torácica (SEPAR) ha elaborado recomendaciones específicas para su diagnóstico y tratamiento, la primera de ellas en 19921 y la segunda en 19962. Desde la publicación de esta última normativa ha habido un renovado interés en el estudio de la EPOC y se han producido novedades importantes en su tratamiento. Asimismo, en estos últimos años se han publicado guías clínicas por parte de sociedades científicas internacionales (European Respiratory Society, American Thoracic Society3,4) y se ha puesto en marcha la Global Obstructive Lung Disease Initiative, auspiciada por la Organización Mundial de la Salud y los Institutos Nacionales de Salud de Estados Unidos, cuyo objetivo es armonizar la atención clínica de estos pacientes en los distintos países. Por estos motivos, la SEPAR ha considerado de interés actualizar las recomendaciones para el diagnóstico y el tratamiento de la EPOC. La presente actualización va dirigida a los profesionales de la salud que tratan a pacientes con EPOC, y tiene por objetivo servir de instrumento práctico para proporcionar a los pacientes una atención actualizada y adecuada, basada en las mejores evidencias científicas disponibles.

Guía clínica SEPAR-ALAT de diagnóstico y tratamiento de la EPOC

Puntos clave: – La enfermedad pulmonar obstructiva cronica (EPOC) se caracteriza por la presencia de obstruccion cronica y poco reversible al flujo aereo, que se asocia a una reaccion inflamatoria anomala, principalmente frente al humo del tabaco. – La obstruccion al flujo aereo se define por la espirometria cuando el cociente volumen espiratorio forzado en el primer segundo/capacidad vital forzada (FEV1/FVC) tras broncodilatacion es menor de 0,7 (o por debajo del limite inferior de la normalidad en personas mayores de 60 anos). – La EPOC se asocia a inflamacion cronica con remodelacion que afecta a las vias aereas, parenquima y arterias pulmonares. – La gravedad de la EPOC se clasifica por el valor del FEV1 posbroncodilatador, estando tambien relacionada con la existencia de sintomas, atrapamiento aereo, insuficiencia respiratoria, afectacion sistemica y comorbilidad asociada. – La prevalencia de la EPOC en la poblacion adulta es del 9% en Espana y oscila entre el 8 y el 20% en Latinoamerica. La EPOC representa la cuarta causa de muerte en Espana y en el mundo.

Helium-3 MRI diffusion coefficient: correlation to morphometry in a model of mild emphysema

Hyperpolarised gases have been most recently used in magnetic resonance imaging to demonstrate new image-derived pulmonary function parameters. One of these parameters is the apparent diffusion coefficient, which reflects the sizes of the structures that compartmentalise gas within the lung (i.e. alveolar space). In the present study, noninvasive parameters were compared to microscopic measurements (mean linear intercept and mean alveolar internal area). Nonselective helium‐3 gas density coronal ex vivo images and apparent diffusion maps were acquired in control and elastase-induced panacinar emphysema rats. Total lung capacity was considered the reference for both imaging experiments and lung fixation. A mild degree of emphysema was found based on mean linear intercept (134±25 µm) versus control (85±14 µm). The apparent diffusion coefficients were significantly different between the two groups (0.18±0.02 and 0.15±0.01 cm2·s−1 for elastase and control, respectively). A significant correlation between the apparent diffusion coefficient and corresponding morphometric parameters in mild emphysema was demonstrated for the first time. This study opens the possibility of estimating absolute airspace size using noninvasive techniques.

Cigarette smoke-induced oxidative stress in skeletal muscles of mice.

Cigarette smoke (CS)-induced oxidative stress may cause muscle alterations in chronic conditions such as chronic obstructive pulmonary disease (COPD). We sought to explore in AKR/J mice exposed to CS for 6 months and in control animals, levels of protein oxidation, oxidized proteins (immunoblotting, proteomics) and antioxidant mechanisms in both respiratory and limb muscles, body weight modifications, systemic inflammation, and lung structure. Compared to control mice, CS-exposed animals exhibited a reduction in body weight gain at 3 months and thereafter, showed lung emphysema, and exhibited increased oxidative stress levels in their diaphragms and gastrocnemius at 6 months. Proteins involved in glycolysis, ATP production and distribution, carbon dioxide hydration, and muscle contraction were carbonylated in respiratory and limb muscles. Blood tumor necrosis factor (TNF)-alpha levels were significantly greater in CS-exposed mice than in control animals. In AKR/J mice, chronic exposure to CS induces lung emphysema concomitantly with greater oxidative modifications on muscle proteins in both respiratory and limb muscles, and systemic inflammation.

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.

Diffusion-weighted 19F-MRI of lung periphery : Influence of pressure and air-SF6 composition on apparent diffusion coefficients

Lung functional magnetic resonance imaging (MRI) has become a reality using different inert hyperpolarized gases, such as 3He and 129Xe, which have provided an extraordinary boost in lung imaging and has also attracted interest to other chemically inert gaseous contrast agents. In this context, we have recently demonstrated the first diffusion-weighted images using thermally polarized inhaled sulfur hexafluoride (SF6) in small animals. The aim of this study was to evaluate whether or not the diffusion coefficient of this fluorinated gas is sensitive to pulmonary structure, gas concentration and air pressure in the airways. Diffusion coefficients of SF6 (both pure and in air mixtures) measured in vitro at different pressures and 20 degrees C showed an excellent agreement with theoretical values. Measurements of diffusion coefficients were also performed in vivo and post-mortem on healthy rats, achieving satisfactory signal-to-noise ratios (SNRs), and SF6 gas was found to be in an almost completely restricted diffusion regime in the lung, i.e., the transport by molecular diffusion is delayed by collisions with barriers such as the alveolar septa. This observed low diffusivity means that this gas will be less sensitive to structural changes in the lungs than other magnetic resonance sensitive gas such as 3He, particularly at human scale. However, it is still possible that SF6 plays a role since it opens a new structural window. Thus, the interest of researchers in delimiting the important limiting technical factors that makes this process very challenging is obvious. Among them, T2 relaxation is very fast, so gradient systems with very fast switching rate and probably large radiofrequency (RF) power and high field systems will be needed for hexafluoride to be used in human studies.

In vivo diffusion weighted 19F MRI using SF6.

Diffusion weighted 19F images of rat lung in vivo using SF6 are presented. Projection‐reconstruction images were acquired by filling the rat lung with a mixture of SF6 and air, during 64 successive apneas. Each apnea lasted for 6 s, the time required to perform 100 accumulations of each k‐space radial phase step for the five values of the diffusion gradient (TR = 10 ms). After diffusion images were acquired, an apparent diffusion coefficient (ADC) map was generated, yielding an average value for the ADC of 2.22 × 10‐6 m2/s and SD for ADC values of 1.27 × 10‐6 m2/s. To the best of our knowledge, this is the first in vivo diffusion weighting imaging application and the first ADC map obtained using 19F MRI. Magn Reson Med 54:460–463, 2005.

Distribution and Outcomes of a Phenotype-Based Approach to Guide COPD Management: Results from the CHAIN Cohort

Rationale The Spanish guideline for COPD (GesEPOC) recommends COPD treatment according to four clinical phenotypes: non-exacerbator phenotype with either chronic bronchitis or emphysema (NE), asthma-COPD overlap syndrome (ACOS), frequent exacerbator phenotype with emphysema (FEE) or frequent exacerbator phenotype with chronic bronchitis (FECB). However, little is known on the distribution and outcomes of the four suggested phenotypes. Objective We aimed to determine the distribution of these COPD phenotypes, and their relation with one-year clinical outcomes. Methods We followed a cohort of well-characterized patients with COPD up to one-year. Baseline characteristics, health status (CAT), BODE index, rate of exacerbations and mortality up to one year of follow-up were compared between the four phenotypes. Results Overall, 831 stable COPD patients were evaluated. They were distributed as NE, 550 (66.2%); ACOS, 125 (15.0%); FEE, 38 (4.6%); and FECB, 99 (11.9%); additionally 19 (2.3%) COPD patients with frequent exacerbations did not fulfill the criteria for neither FEE nor FECB. At baseline, there were significant differences in symptoms, FEV1 and BODE index (all p<0.05). The FECB phenotype had the highest CAT score (17.1±8.2, p<0.05 compared to the other phenotypes). Frequent exacerbator groups (FEE and FECB) were receiving more pharmacological treatment at baseline, and also experienced more exacerbations the year after (all p<0.05) with no differences in one-year mortality. Most of NE (93%) and half of exacerbators were stable after one year. Conclusions There is an uneven distribution of COPD phenotypes in stable COPD patients, with significant differences in demographics, patient-centered outcomes and health care resources use.

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 stability of blood eosinophils ≥300 cells per μL is low in COPD patients and it does not confer a poor prognosis http://ow.ly/TwGX30etVIy

Fingerprinting-based metabolomic approach with LC-MS to sleep apnea and hypopnea syndrome: a pilot study.

Sleep apnea and hypopnea syndrome (SAHS) is a multicomponent disorder, with associated cardiovascular and metabolic alterations, second in order of frequency among respiratory disorders. Sleep apnea is diagnosed with an overnight sleep test called a polysomnogram, which requires having the patient in hospital. In addition, a more clear classification of patients according to mild and severe presentations would be desirable. The aim of the present study was to assess the relative metabolic changes in SAHS to identify new potential biomarkers for diagnosis, able to evaluate disease severity to establish response to therapeutic interventions and outcomes. For this purpose, metabolic fingerprinting represents a valuable strategy to monitor, in a nontargeted manner, the changes that are at the base of the pathophysiological mechanism of SAHS. Plasma samples of 33 SAHS patients were collected after polysomnography and analyzed with LC coupled to MS (LC‐QTOF‐MS). After data treatment and statistical analysis, signals differentiating nonsevere and severe patients were detected. Putative identification of 14 statistically significant features was obtained and changes that can be related to the episodes of hypoxia/reoxygenation (inflammation) have been highlighted. Among them, the patterns of variation of platelet activating factor and lysophospholipids, together with some compounds related to differential activity of the gut microflora (bile pigments and pipecolic acid) open new lines of research that will benefit our understanding of the alterations, offering new possibilities for adequate monitoring of the stage of the disease.