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Background: COPD is a heterogeneous disease. We hypothesized that profiling and integrating three different omic levels (mRNA, miRNA and methylome) in the same lung tissue samples using biased (FEV1 driven) or unbiased approaches can identify novel endotypes. Methods: We quantified mRNAs (Affymetrix array), microRNAs (Illumina small RNA-Seq) and methylation profile (EPIC array) in lung tissue of former-smokers with COPD (n=60) and varying degrees of airflow limitation (GOLD grades 1-4), as well as from never-smoker controls with normal spirometry (n=17). Results were integrated with MixOmics-DIABLO using biased (i.e., FEV1 driven) and unbiased (Similarity Network Fusion -SNF) approaches. Results: We found that: (1) the DIABLO multi-omic integration using biased FEV1-driven groups constructed a predictive model able to discriminate controls from GOLD 3-4, but not GOLD 1-2 patients; (2) an unbiased SNF-driven approach identified three groups, and the DIABLO predictive multi-omics model showed consistent discrimination for SNF#3 (which included 57% of controls) and SNF#2 (67% GOLD 3-4), but not for SNF#1. Interestingly, although the mean FEV1 of patients included in SNF#1 and SNF#2 were different, GOLD 1-2 and 3-4 patients were included in both groups; and, finally, (3) the biological processes (endotypes) underlying the groups of COPD patients identified by biased and unbiased approaches varied in gene ontologies (epithelial apoptotic process vs. abnormal axoneme assembly) and lung cell lineage composition estimated by gene set variation analysis. Conclusions: Our observations highlight the very significant biological heterogeneity underlying what we call COPD today and the need for a new definition and taxonomy of the disease.

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., The COS-AECOPD @EuroRespSoc Task Force is developing a core outcome set (COS) for #COPD exacerbation management. COS is an agreed minimum set of clinically important outcomes to be evaluated in all RCTs and can improve their usability and comparability. https://bit.ly/3ftAXk6

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.

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. Electronic supplementary material The online version of this article (10.1186/s12931-019-1105-z) contains supplementary material, which is available to authorized users.

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 (

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. Electronic supplementary material The online version of this article (10.1186/s12890-018-0688-3) contains supplementary material, which is available to authorized users.

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.

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.

Rationale: Chronic Obstructive Pulmonary Disease (COPD) is a complex and heterogeneous disease whose pathobiology is not fully understood. Objectives: To characterize and contrast the pulmonary mRNA expression in former smokers with COPD (mild=15; severe-very severe=16) and healthy controls (never smokers=11). Methods: Lung tissue was obtained from individuals undergoing thoracic resectional surgery (mostly because of lung cancer) or lung transplantation explants. Paired end TruSEQ RNASeq libraries were constructed and analyzed with an Illumina HiSeq. Sequencing analysis and differential gene expression was done with DESeq2, and in order to find modules of co-expressed genes related to clinical traits (airflow limitation severity, BMI and PackYear) weighted correlation networks were constructed with the whole matrix. Measurements and Main Results: The number of differentially expressed genes was higher between non-smokers vs. severe COPD (n=675), followed by mild COPD vs. severe COPD (n=391), while the expression profile of non-smokers vs. mild COPD was the most similar. Network weighted co-expression analysis identified 19 modules, 5 of them were associated to the presence of airflow limitation and its severity but not smoking or BMI. Key genes are validated in a second cohort of individuals. Conclusions: Severe airflow limitation represents a distinctive transcriptomic signature in comparison to mild COPD and non-smokers. Transcriptomic changes of mild former smokers with COPD vs. non-smokers are more heterogeneous. Supported, in part, Instituto de Salud Carlos III (PI15/00799), CP (16/00039) and a grant from MSD.

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.

Background Chronic Obstructive Pulmonary Disease (COPD) is characterized by pulmonary and systemic manifestations. Multiple studies have identified airway or blood biomarkers associated with the severity of airflow limitation, but it is not clear whether these biomarkers directly represent the pathobiology in the lung. Objective To identify pathobiological mechanisms shared between different compartments in COPD patients. Methods Weighted Gene Co-expression Network Analysis (WGCNA) was used to meta-analyse four gene expression datasets from Caucasian former smokers with COPD: two lung tissue datasets (n=70 and n=124), and one each of sputum (n=121) and peripheral blood (n=121). Results Eighteen (86%) of the twenty-one co-expression modules identified were preserved between the two lung tissue datasets; seven (33%) of them were preserved also in sputum, and five also (24%) in blood. One module (labelled “yellow”) was preserved across all datasets and associated with FEV 1 % in lung and sputum but not in blood. This module was enriched in ontologies related to mitochondrial function, cell cycle, ubiquitination and RNA processing. Two other modules (brown and magenta) were preserved and associated with FEV 1 % across lung and sputum datasets (but not in blood). These modules included genes related to ion homeostasis, T cell response, cytokine signalling and RNA processing. Conclusions Our study identified several biological functions in mRNA co-expression modules associated with FEV 1 % in lung and sputum but not in blood. These results suggest that the systemic manifestations of COPD likely constitute an independent component of the disease. Funding Unristricted grant form GSK, U.S. NIH P01 HL105339 and FIS PI15/00799.

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)-1β 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-1β, 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., The NLRP3 inflammasome is primed in stable COPD lungs, then activated during infectious exacerbation http://ow.ly/Wopi300DXcT

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.To explore and contrast the molecular pathogenesis of emphysema and bronchiolitis in COPD.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.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.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.

Self-renewing, multi-potent and clonogenic stem cells (ckit+/CD45-/tryptase-, CD34-) have been described in lung tissue of healthy adults. Whether they are present in smokers with and without chronic obstruc-tive pulmonary disease (COPD) is unknown.