[Chronic Obstructive Pulmonary Disease]. / Enfermedad pulmonar obstructiva crónica.

Chronic Obstructive Pulmonary Disease (COPD) is related to smoking as the main etiological agent although there are other risk factors that can interact influencing the development of the disease. The definition of COPD is based on three points: the presence of persistent respiratory symptoms, exposure to risk agents, and a non-reversible obstructive spirometric ratio. Forced spirometry with a bronchodilator test is necessary to confirm the diagnosis of COPD, however, attempts are being made to develop alternative methods for screening given the current significant underdiagnosis of this pathology.In order to advance in a more personalized medicine for the patient, classification tools have been adopted such as clinical phenotypes and treatable traits, allowing treatments to be adapted according to the characteristics of the patients. Non-pharmacological treatment (smoking cessation, vaccination, physical exercise...) are essential for the management of the disease, as well as pharmacological treatment based on clinical phenotypes. Eosinophils have become a key marker when establishing treatment with inhaled glucocorticoids.In the follow-up of the disease, it is very relevant to evaluate the degree of control being a fundamental element the absence of exacerbations given their implications in mortality, morbidity and quality of life of patients. More studies are needed to better define the phenotypes of exacerbations and their biomarkers.

ERS statement: a core outcome set for clinical trials evaluating the management of COPD exacerbations.

Clinical trials evaluating the management of acute exacerbations of COPD assess heterogeneous outcomes, often omitting those that are clinically relevant or more important to patients. We have developed a core outcome set, a consensus-based minimum set of important outcomes that we recommend are evaluated in all future clinical trials on exacerbations management, to improve their quality and comparability. COPD exacerbations outcomes were identified through methodological systematic reviews and qualitative interviews with 86 patients from 11 countries globally. The most critical outcomes were prioritised for inclusion in the core outcome set through a two-round Delphi survey completed by 1063 participants (256 patients, 488 health professionals and 319 clinical academics) from 88 countries in five continents. Two global, multi-stakeholder, virtual consensus meetings were conducted to 1) finalise the core outcome set and 2) prioritise a single measurement instrument to be used for evaluating each of the prioritised outcomes. Consensus was informed by rigorous methodological systematic reviews. The views of patients with COPD were accounted for at all stages of the project. Survival, treatment success, breathlessness, quality of life, activities of daily living, the need for a higher level of care, arterial blood gases, disease progression, future exacerbations and hospital admissions, treatment safety and adherence were all included in the core outcome set. Focused methodological research was recommended to further validate and optimise some of the selected measurement instruments. The panel did not consider the prioritised set of outcomes and associated measurement instruments to be burdensome for patients and health professionals to use.

Telomere Length but Not Mitochondrial DNA Copy Number Is Altered in Both Young and Old COPD.

Accelerated ageing is implicated in the pathogenesis of respiratory diseases as chronic obstructive pulmonary disease (COPD), but recent evidence indicates that the COPD can have roots early in life. Here we hypothesise that the accelerated ageing markers might have a role in the pathobiology of young COPD. The objective of this study was to compare two hallmarks of ageing, telomere length (TL), and mitochondrial DNA copy number (mtDNA-CN, as a surrogate marker of mitochondrial dysfunction) in young (≤ 50 years) and old (>50 years) smokers, with and without COPD. Both, TL and mtDNA-CN were measured in whole blood DNA by quantitative PCR [qPCR] in: (1) young ever smokers with (n = 81) or without (n = 166) COPD; and (2) old ever smokers with (n = 159) or without (n = 29) COPD. A multivariable linear regression was used to assess the association of TL and mtDNA-CN with lung function. We observed that in the entire study population, TL and mtDNA-CN decreased with age, and the former but not the latter related to FEV1/FVC (%), FEV1 (% ref.), and DLCO (% ref.). The short telomeres were found both in the young and old patients with severe COPD (FEV1 <50% ref.). In addition, we found that TL and mtDNA-CN were significantly correlated, but their relationship was positive in younger while negative in the older patients with COPD, suggesting a mitochondrial dysfunction. We conclude that TL, but not mtDNA-CN, is associated with the lung function impairment. Both young and old patients with severe COPD have evidence of accelerated ageing (shorter TL) but differ in the direction of the correlation between TL and mtDNA-CN in relation to age.

Core outcome set for the management of acute exacerbations of chronic obstructive pulmonary disease: the COS-AECOPD ERS Task Force study protocol.

Randomised controlled trials (RCTs) on the management of COPD exacerbations evaluate heterogeneous outcomes, often omitting those that are clinically important and patient relevant. This limits their usability and comparability. A core outcome set (COS) is a consensus-based minimum set of clinically important outcomes that should be evaluated in all RCTs in specific areas of health care. We present the study protocol of the COS-AECOPD ERS Task Force, aiming to develop a COS for COPD exacerbation management, that could remedy these limitations. For the development of this COS we follow standard methodology recommended by the COMET initiative. A comprehensive list of outcomes is assembled through a methodological systematic review of the outcomes reported in relevant RCTs. Qualitative research with patients with COPD will also be conducted, aiming to identify additional outcomes that may be important to patients, but are not currently addressed in clinical research studies. Prioritisation of the core outcomes will be facilitated through an extensive, multi-stakeholder Delphi survey with a global reach. Selection will be finalised in an international, multi-stakeholder meeting. For every core outcome, we will recommend a specific measurement instrument and standardised time points for evaluation. Selection of instruments will be based on evidence-informed consensus. Our work will improve the quality, usability and comparability of future RCTs on the management of COPD exacerbations and, ultimately, the care of patients with COPD. Multi-stakeholder engagement and societal support by the European Respiratory Society will raise awareness and promote implementation of the COS.

Multi-level immune response network in mild-moderate Chronic Obstructive Pulmonary Disease (COPD).

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is associated with an abnormal pulmonary and systemic immune response to tobacco smoking. Yet, how do immune cells relate within and between these two biological compartments, how the pulmonary infiltrate influences the lung transcriptome, and what is the role of active smoking vs. presence of disease is unclear. METHODS: To investigate these questions, we simultaneously collected lung tissue and blood from 65 individuals stratified by smoking habit and presence of the disease. The immune cell composition of both tissues was assessed by flow cytometry, whole lung transcriptome was determined with Affymetrix arrays, and we used Weighted Gene Co-expression Network Analysis (WGCNA) to integrate results. RESULTS: Main results showed that: (1) current smoking and the presence of COPD were both independently associated with a reduction in the proportion of lung T cells and an increase of macrophages, specifically those expressing CD80 + CD163+; (2) changes in the proportion of infiltrating macrophages, smoking status or the level of airflow limitation were associated to different WGCNA modules, which were enriched in iron ion transport, extracellular matrix and cilium organization gene ontologies; and, (3) circulating white blood cells counts were correlated with lung macrophages and T cells. CONCLUSIONS: Mild-moderated COPD lung immune infiltrate is associated with the active smoking status and presence of disease; is associated with changes in whole lung tissue transcriptome and marginally reflected in blood.

Smoking Impairs the Immunomodulatory Capacity of Lung-Resident Mesenchymal Stem Cells in Chronic Obstructive Pulmonary Disease.

Tobacco smoking is the main environmental risk factor for chronic obstructive pulmonary disease (COPD), but not all smokers develop the disease. A population of lung-resident mesenchymal stem cells (LR-MSCs) exist in healthy lungs, but how tobacco smoking affects them and their role in COPD have not been assessed yet. Using a sphere-based culture technique, we isolated LR-MSCs from lung tissue obtained from nonsmokers and current and former smokers with and without COPD (n = 53). The cells were characterized by flow cytometry and Affymetrix arrays. Their immunomodulatory capacity was assessed in vitro using cocultures with T cells and after preincubation with 2.5% and 5% cigarette smoke extract. We were able to isolate LR-MSCs expressing similar phenotypic markers in all of the study groups. LR-MSCs from current smokers with COPD expressed different levels of CX3CL1 and CCL5 cytokines, and were unable to modulate CD8+ T-cell proliferation. Preincubation of LR-MSCs with cigarette smoke extract reduced their immunomodulatory capacity. In conclusion, 1) LR-MSCs can be isolated in similar amounts from never-smokers and smokers with and without COPD; 2) their immunomodulatory capacity is impaired in current smokers with COPD, but not in those with normal lung function; and 3) this is reversible after smoking cessation and is reproducible in vitro.

Do sputum or circulating blood samples reflect the pulmonary transcriptomic differences of COPD patients? A multi-tissue transcriptomic network META-analysis.

BACKGROUND: Previous studies have identified lung, sputum or blood transcriptomic biomarkers associated with the severity of airflow limitation in COPD. Yet, it is not clear whether the lung pathobiology is mirrored by these surrogate tissues. The aim of this study was to explore this question. METHODS: We used Weighted Gene Co-expression Network Analysis (WGCNA) to identify shared pathological mechanisms across four COPD gene-expression datasets: two sets of lung tissues (L1 n = 70; L2 n = 124), and one each of induced sputum (S; n = 121) and peripheral blood (B; n = 121). RESULTS: WGCNA analysis identified twenty-one gene co-expression modules in L1. A robust module preservation between the two L datasets was observed (86%), with less preservation in S (33%) and even less in B (23%). Three modules preserved across lung tissues and sputum (not blood) were associated with the severity of airflow limitation. Ontology enrichment analysis showed that these modules included genes related to mitochondrial function, ion-homeostasis, T cells and RNA processing. These findings were largely reproduced using the consensus WGCNA network approach. CONCLUSIONS: These observations indicate that major differences in lung tissue transcriptomics in patients with COPD are poorly mirrored in sputum and are unrelated to those determined in blood, suggesting that the systemic component in COPD is independently regulated. Finally, the fact that one of the preserved modules associated with FEV1 was enriched in mitochondria-related genes supports a role for mitochondrial dysfunction in the pathobiology of COPD.

Hiperplasia difusa idiopática de células neuroendocrinas como causa de tos crónica / Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia Causing Chronic Cough

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Characterization, localization and comparison of c-Kit+ lung cells in never smokers and smokers with and without COPD.

BACKGROUND: c-Kit + lung stem cells have been described in the human healthy lung. Their potential relation with smoking and/or chronic obstructive pulmonary disease (COPD) is unknown. METHODS: We characterized and compared c-Kit+ cells in lung tissue of 12 never smokers (NS), 15 smokers with normal spirometry (S) and 44 COPD patients who required lung resectional surgery. Flow cytometry (FACS) was used to characterize c-Kit+ cells in fresh lung tissue disaggregates, and immunofluorescence (IF) for further characterization and to determine their location in OCT- embedded lung tissue. RESULTS: We identified 4 c-Kit+ cell populations, with similar proportions in NS, S and COPD: (1) By FACS, c-Kithigh/CD45+ cells (4.03 ± 2.97% (NS), 3.96 ± 5.30% (S), and 5.20 ± 3.44% (COPD)). By IF, these cells were tryptase+ (hence, mast cells) and located around the airways; (2) By IF, c-Kitlow/CD45+/triptase- (0.07 ± 0.06 (NS), 0.03 ± 0.02 (S), and 0.06 ± 0.07 (COPD) cells/field), which likely correspond to innate lymphoid cells; (3) By FACS, c-Kitlow/CD45-/CD34+ (0.95 ± 0.84% (NS), 1.14 ± 0.94% (S) and 0.95 ± 1.38% (COPD)). By IF these cells were c-Kitlow/CD45-/CD31+, suggesting an endothelial lineage, and were predominantly located in the alveolar wall; and, (4) by FACS, an infrequent c-Kitlow/CD45-/CD34- population (0.09 ± 0.14% (NS), 0.08 ± 0.09% (S) and 0.08 ± 0.11% (COPD)) compatible with a putative lung stem cell population. Yet, IF failed to detect them and we could not isolate or grow them, thus questioning the existence of c-Kit+ lung stem-cells. CONCLUSIONS: The adult human lung contains a mixture of c-Kit+ cells, unlikely to be lung stem cells, which are independent of smoking status and/or presence of COPD.

Distribution, temporal stability and association with all-cause mortality of the 2017 GOLD groups in the ECLIPSE cohort.

BACKGROUND: In 2017, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) proposed a new classification of patients with chronic obstructive pulmonary disease (COPD). MATERIAL AND METHODS: We contrasted the distribution of COPD patients according to GOLD 2017 and 2011 classifications, the temporal stability of the 2017 groups during 3 years follow-up and their association with all-cause mortality in the ECLIPSE cohort. RESULTS: We found that GOLD 2017: (1) switched a substantial proportion of GOLD 2011C and D patients to A and B groups at recruitment; (2) about half of A, B and D patients remained in the same group at the end of follow-up, whereas 74% of C patients (the smallest group of all) changed, either because exacerbation rate decreased or dyspnea increased; and, (3) all-cause mortality by group was not significantly different between GOLD 2011 and 2017. Of note, mortality in B (16%) and D patients (18%) was similar, both with similar severity of airflow limitation, the best individual mortality risk factor. CONCLUSIONS: These results illustrate the cross-sectional and longitudinal effects of excluding FEV1 from GOLD 2017, and highlight both the clinical relevance of symptom assessment in the management of COPD and the prognostic capacity of FEV1.

Pulmonary function predicts mortality and hospitalizations in outpatients with heart failure and preserved ejection fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFPEF) is the most frequent form of heart failure in ambulatory patients with new-onset symptoms. We previously showed that lung function abnormalities are highly prevalent in HFPEF patients. In this observational, longitudinal study, we tested the hypothesis that the presence of airflow limitation and/or arterial hypoxemia predicts mortality and/or cardiovascular hospitalizations during follow-up in HFPEF outpatients. MATERIALS AND METHODS: HFPEF was diagnosed following the international recommendations. Forced spirometry and arterial blood gases were measured at recruitment according to international recommendations. The primary endpoint of the study was all-cause mortality and the secondary one was any cardiovascular hospitalization. RESULTS: We included in the analysis all consecutive outpatients newly diagnosed of HFPEF in our clinic between April 2009 and January 2013 (n = 71). Patients were prospectively followed up for a mean of 4 years (range 10 months to 5.8 years). All-cause mortality was 18.3%. It was higher in patients with airflow limitation (30%) than those with normal spirometry (10%) or other spirometric defects (19%) (p = 0.036). The presence of arterial hypoxemia did not predict mortality (p = 0.179) but was significantly related to cardiovascular hospitalizations during follow-up (p = 0.038). CONCLUSIONS: The presence of airflow limitation or arterial hypoxemia identify a group of patients with HFPEF at higher risk of death or cardiovascular hospitalizations, respectively. Given that both airflow limitation and arterial hypoxemia are treatable, we propose that lung function should be routinely evaluated in the outpatient management of HFPEF patients.

The inflammasome pathway in stable COPD and acute exacerbations.

Chronic obstructive pulmonary disease (COPD) is characterised by pulmonary and systemic inflammation that bursts during exacerbations of the disease (ECOPD). The NLRP3 inflammasome is a key regulatory molecule of the inflammatory response. Its role in COPD is unclear. We investigated the NLRP3 inflammasome status in: 1) lung tissue samples from 38 patients with stable COPD, 15 smokers with normal spirometry and 14 never-smokers; and 2) sputum and plasma samples from 56 ECOPD patients, of whom 41 could be reassessed at clinical recovery. We observed that: 1) in lung tissue samples of stable COPD patients, NLRP3 and interleukin (IL)-1ß mRNA were upregulated, but both caspase-1 and ASC were mostly in inactive form, and 2) during infectious ECOPD, caspase-1, oligomeric ASC and associated cytokines (IL-1ß, IL-18) were significantly increased in sputum compared with clinical recovery. The NLRP3 inflammasome is primed, but not activated, in the lungs of clinically stable COPD patients. Inflammasome activation occurs during infectious ECOPD. The results of this study suggest that the inflammasome participates in the inflammatory burst of infectious ECOPD.

Network Analysis of Lung Transcriptomics Reveals a Distinct B-Cell Signature in Emphysema.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation caused by a combination of airways disease (bronchiolitis) and parenchymal destruction (emphysema), whose relative proportion varies from patient to patient. OBJECTIVES: To explore and contrast the molecular pathogenesis of emphysema and bronchiolitis in COPD. METHODS: We used network analysis of lung transcriptomics (Affymetrix arrays) in 70 former smokers with COPD to compare differential expression and gene coexpression in bronchiolitis and emphysema. MEASUREMENTS AND MAIN RESULTS: We observed that in emphysema (but not in bronchiolitis) (1) up-regulated genes were enriched in ontologies related to B-cell homing and activation; (2) the immune coexpression network had a central core of B cell-related genes; (3) B-cell recruitment and immunoglobulin transcription genes (CXCL13, CCL19, and POU2AF1) correlated with emphysema severity; (4) there were lymphoid follicles (CD20(+)IgM(+)) with active B cells (phosphorylated nuclear factor-κB p65(+)), proliferation markers (Ki-67(+)), and class-switched B cells (IgG(+)); and (5) both TNFRSF17 mRNA and B cell-activating factor protein were up-regulated. These findings were by and large reproduced in a group of patients with incipient emphysema and when patients with emphysema were matched for the severity of airflow limitation of those with bronchiolitis. CONCLUSIONS: Our study identifies enrichment in B cell-related genes in patients with COPD with emphysema that is absent in bronchiolitis. These observations contribute to a better understanding of COPD pathobiology and may open new therapeutic opportunities for patients with COPD.

Enfermedad pulmonar obstructiva crónica: la década prodigiosa. Implicaciones para su diagnóstico, prevención y tratamiento / Chronic obstructive pulmonary disease: The golden decade. Implications for the diagnosis, prevention and treatment of chronic obstructive pulmonary disease

La enfermedad pulmonar obstructiva crónica (EPOC) es una afección compleja y heterogénea, altamente prevalente y con un impacto socioeconómico importante. El último decenio puede ser calificado como «década prodigiosa» para la EPOC gracias a los numerosos avances que se han producido en la comprensión global de la enfermedad, lo que se ha traducido en novedades fundamentales en su abordaje diagnóstico, evaluación clínica y estrategia terapéutica. El texto que sigue revisa de forma breve estos cambios, con especial énfasis en las propuestas clínicas de la última revisión (2013) de la Global Strategy for the Diagnosis, Management, and Prevention of chronic obstructive pulmonary disease (AU)

Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous illness, which causes an important socio-economic burden. The last decade has witnessed significant advances in the understanding and knowledge of COPD with a paradigm shift in both the assessment and management of the disease. The article here reviews these changes with a particular focus on the last revision (2013) of the Global Strategy for the Diagnosis, Management, and Prevention of chronic obstructive pulmonary disease (AU)

[Chronic obstructive pulmonary disease: The golden decade. Implications for the diagnosis, prevention and treatment of chronic obstructive pulmonary disease]. / Enfermedad pulmonar obstructiva crónica: la década prodigiosa. Implicaciones para su diagnóstico, prevención y tratamiento.

Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous illness, which causes an important socio-economic burden. The last decade has witnessed significant advances in the understanding and knowledge of COPD with a paradigm shift in both the assessment and management of the disease. The article here reviews these changes with a particular focus on the last revision (2013) of the Global Strategy for the Diagnosis, Management, and Prevention of chronic obstructive pulmonary disease.

Network medicine, multimorbidity and the lung in the elderly.

Noncommunicable diseases, including cardiovascular, metabolic and respiratory diseases, among others, are the major medical challenge of the 21st century. Most noncommunicable diseases are related to the ageing process and often co-occur in the same individual. However, it is unclear whether the index disease is somehow influencing the development of the other ones (comorbidity) or whether all of them (including the index disease) simply represent the clinical expression of pathological ageing (multimorbidity). The pathobiology of ageing, chronic obstructive pulmonary disease (COPD) and concomitant disorders is complex. A new field of research, known as systems biology if applied to model systems or network medicine if applied to human beings, has emerged over the past decade or so, to address biological complexity in a holistic, integrated way. It offers, therefore, great potential to decipher the relationship between ageing, COPD and comorbidities/multimorbidities. In this State of the Art review we present the basic concepts of systems biology, use some examples to illustrate the potential of network medicine to address complex medical problems, and review some recent publications that show how a systems-based research strategy can contribute to improve our understanding of multimorbidity and age-related respiratory diseases.