• Aerobic exercise
• Cognitive aspects
• High-intensity interval training
• Neurodegeneration
• Pulmonary disease, Chronic obstructive
• Randomized controlled trial
• Skeletal muscle
• Systemic inflammation

• Humans
• Pulmonary Disease, Chronic Obstructive/physiopathology
• Pulmonary Disease, Chronic Obstructive/therapy
• High-Intensity Interval Training/methods
• Prospective Studies
• Multicenter Studies as Topic
• Randomized Controlled Trials as Topic
• Treatment Outcome
• Time Factors
• Exercise Tolerance
• Lung/physiopathology
• Male
• Exercise Therapy/methods
• Female

• Umea University

• Animals
• Humans
• Mice
• Basic Helix-Loop-Helix Transcription Factors/genetics
• Basic Helix-Loop-Helix Transcription Factors/metabolism
• Emphysema/metabolism
• Emphysema/pathology
• Endothelial Cells/pathology
• Hypertension, Pulmonary/genetics
• Hypertension, Pulmonary/metabolism
• Hypoxia
• Pulmonary Disease, Chronic Obstructive/genetics
• Pulmonary Disease, Chronic Obstructive/metabolism
• Pulmonary Disease, Chronic Obstructive/pathology
• Pulmonary Emphysema/genetics
• Pulmonary Emphysema/metabolism

• 206293/Z/17/Z Wellcome Trust
• DOC 129 Austrian Science Fund FWF
• K12 HL120001 NHLBI NIH HHS

• ACO
• COPD
• COPD and coexisting asthma
• LDA
• MFA
• aerodynamic work of breathing
• airway dynamics
• linear discriminant analysis
• multiple factor analysis
• precision medicine
• pulmonary hyperinflation
• small airways dysfunction

• Male
• Female
• Humans
• Pulmonary Disease, Chronic Obstructive/complications
• Pulmonary Disease, Chronic Obstructive/diagnosis
• Forced Expiratory Volume
• Carbon Monoxide
• Retrospective Studies
• Asthma/complications
• Asthma/diagnosis

• No funding was received

In this study, we aimed to investigate the compatibility of modified Medical Research Council (mMRC) and COPD assessment test (CAT) scores of chronic obstructive pulmonary disease (COPD) patients in terms of evaluation of their symptom status.

The study was planned as a single-center, cross-sectional study. Statistically four separate receiver operating characteristic (ROC) curves of CAT scoring were generated for mMRC scores of 1 to 4.

Two hundred twenty eight patients with stable COPD, mean age 64.2±8.2 and 88.6% male were included. A strong positive correlation was detected between CAT and mMRC (r=0.60, p<0.001). However, it was observed that 32 patients had mMRC<2 but CAT≥10, while 21 patients had CAT<10 but mMRC≥2. Thus, in 53 patients CAT and mMRC scores were not identical in terms of assessed symptom status. According to the ROC analysis, the mMRC scores of 1 to 4 were most compatible with the CAT scores of 10, 10, 15, and 20, respectively.

Expanding current data represents that CAT score of 10 could be more compatible with mMRC score of 1. Moreover we think although a high mMRC or CAT score may be sufficient to assign patients to high symptom groups, it is needed to evaluate mMRC and CAT together to assign a patient to a low symptom group. In this way misclassification of the patients with high symptoms due to insufficient symptom evaluation as if they have low symptoms can be prevented.

Chronic obstructive pulmonary disease (COPD) is a universal respiratory disease resulting from the complex interactions between genes and environmental conditions. The process of COPD is deteriorated by repeated episodes of exacerbations, which are the primary reason for COPD-related morbidity and mortality. Bacterial pathogens are commonly identified in patients’ respiratory tracts both in the stable state and during acute exacerbations, with significant changes in the prevalence of airway bacteria occurring during acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Therefore, the changes in microbial composition and host inflammatory responses will be necessary to investigate the mechanistic link between the airway microbiome and chronic pulmonary inflammation in COPD patients.

We performed metatranscriptomic and metagenomic sequencing on sputum samples for twelve AECOPD patients before treatment and for four of them stable COPD (stabilization of AECOPD patients after treatment). Sequencing reads were classified by Kraken2, and the host gene expression was analyzed by Hisat2 and HTseq. The correlation between genes was obtained by the Spearman correlation coefficient. Mann–Whitney U-test was applied to identify microbes that exhibit significantly different distribution in two groups.

At the phyla level, the top 5 dominant phyla were Firmicutes, Actinobacteria, Proteobacteria, Bacteroidetes, and Fusobacteria. The proportion of dominant gates in metagenomic data was similar in metatranscriptomic data. There were significant differences in the abundance of specific microorganisms at the class level between the two methods. No significant difference between AECOPD and stable COPD was found. However, the different expression levels of 5 host genes were significantly increased in stable COPD and were involved in immune response and inflammatory pathways, which were associated with macrophages.

Our study may provide a clue to investigate the mechanism of COPD and potential biomarkers in clinical diagnosis and treatment.

• COPD
• immune
• macrophage
• metagenome
• metatranscriptome

• ACO
• COPD
• COPD and coexisting asthma
• aerodynamic work of breathing
• bronchodilator response
• pulmonary hyperinflation
• small airways dysfunction

• Asthma/diagnosis
• Asthma/drug therapy
• Bronchodilator Agents/therapeutic use
• Forced Expiratory Volume
• Humans
• Pulmonary Disease, Chronic Obstructive/diagnosis
• Pulmonary Disease, Chronic Obstructive/drug therapy
• Retrospective Studies
• Spirometry

• No funding

Emphysema and small-airway disease are the two major components of chronic obstructive pulmonary disease (COPD). We propose a novel method of quantitative computed tomography (CT) emphysema air-trapping composite (EAtC) mapping to assess each COPD component. We analyzed the potential use of this method for assessing lung function in patients with COPD.

A total of 584 patients with COPD underwent inspiration and expiration CTs. Using pairwise analysis of inspiration and expiration CTs with non-rigid registration, EAtC mapping classified lung parenchyma into three areas: Normal, functional air trapping (fAT), and emphysema (Emph). We defined fAT as the area with a density change of less than 60 Hounsfield units (HU) between inspiration and expiration CTs among areas with a density less than −856 HU on inspiration CT. The volume fraction of each area was compared with clinical parameters and pulmonary function tests (PFTs). The results were compared with those of parametric response mapping (PRM) analysis.

The relative volumes of the EAtC classes differed according to the Global Initiative for Chronic Obstructive Lung Disease stages (p < 0.001). Each class showed moderate correlations with forced expiratory volume in 1 second (FEV₁) and FEV₁/forced vital capacity (FVC) (r = −0.659–0.674, p < 0.001). Both fAT and Emph were significant predictors of FEV₁ and FEV₁/FVC (R² = 0.352 and 0.488, respectively; p < 0.001). fAT was a significant predictor of mean forced expiratory flow between 25% and 75% and residual volume/total vital capacity (R² = 0.264 and 0.233, respectively; p < 0.001), while Emph and age were significant predictors of carbon monoxide diffusing capacity (R² = 0.303; p < 0.001). fAT showed better correlations with PFTs than with small-airway disease on PRM.

The proposed quantitative CT EAtC mapping provides comprehensive lung functional information on each disease component of COPD, which may serve as an imaging biomarker of lung function.

• Air trapping
• Chronic obstructive pulmonary disease
• Computed tomography
• Emphysema
• Quantitative imaging
• Small-airway disease

• COPD
• asthma
• bronchitis
• terminology of diseases
• understanding of diagnostic terms

• Asthma
• Bronchial Diseases
• Humans
• Pulmonary Disease, Chronic Obstructive/diagnosis
• Pulmonary Disease, Chronic Obstructive/therapy

• No external funding

Chronic obstructive pulmonary disease (COPD) is a progressive, life-threatening lung disease with increasing prevalence and incidence worldwide. Increasing evidence suggests that lung microbiomes might play a physiological role in acute exacerbations of COPD. The objective of this study was to characterize the association of the microbiota and exacerbation risk or airflow limitation in stable COPD patients.

The sputum microbiota from 78 COPD outpatients during periods of clinical stability was investigated using 16S rRNA V3-V4 amplicon sequencing. The microbiome profiles were compared between patients with different risks of exacerbation, i.e., the low risk exacerbator (LRE) or high risk exacerbator (HRE) groups, and with different airflow limitation severity, i.e., mild to moderate (FEV1 ≥ 50; PFT I) or severe to very severe (FEV1 < 50; PFT II).

The bacterial diversity (Chao1 and observed OTUs) was significantly decreased in the HRE group compared to that in the LRE group. The top 3 dominant phyla in sputum were Firmicutes, Actinobacteria, and Proteobacteria, which were similar in the HRE and LRE groups. At the genus level, compared to that in the LRE group (41.24%), the proportion of Streptococcus was slightly decreased in the HRE group (28.68%) (p = 0.007). However, the bacterial diversity and the proportion of dominant bacteria at the phylum and genus levels were similar between the PFT I and PFT II groups. Furthermore, the relative abundances of Gemella morbillorum, Prevotella histicola, and Streptococcus gordonii were decreased in the HRE group compared to those in the LRE group according to linear discriminant analysis effect size (LEfSe). Microbiome network analysis suggested altered bacterial cooperative regulation in different exacerbation phenotypes. The proportions of Proteobacteria and Neisseria were negatively correlated with the FEV1/FVC value. According to functional prediction of sputum bacterial communities through Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis, genes involved in lipopolysaccharide biosynthesis and energy metabolism were enriched in the HRE group.

The present study revealed that the sputum microbiome changed in COPD patients with different risks of exacerbation. Additionally, the bacterial cooperative networks were altered in the HRE patients and may contribute to disease exacerbation. Our results provide evidence that sputum microbiome community dysbiosis is associated with different COPD phenotypes, and we hope that by understanding the lung microbiome, a potentially modifiable clinical factor, further targets for improved COPD therapies during the clinically stable state may be elucidated.

The online version contains supplementary material available at 10.1186/s12967-021-02788-4.

• 16S sequencing
• COPD
• Exacerbation risk
• Lung function
• Sputum microbiome
• Stable disease

• multiple endpoints
• multiple outcomes
• multivariate model
• randomised controlled trials

• Bias
• Computer Simulation
• Data Interpretation, Statistical
• Outcome Assessment, Health Care
• Randomized Controlled Trials as Topic
• Research Design

• MCCC-FCO-11-U Marie Curie

• Brain stem
• Chronic obstructive pulmonary disease
• Diffusion tensor imaging
• Tract-based spatial statistics

To evaluate the quantitative computed tomography (QCT) phenotypes, airflow limitations, and exacerbation-like episodes in heavy smokers in Southern Brazil.

We enrolled 172 smokers with a smoking history ≥30 pack-years who underwent pulmonary function tests (PFTs) and CT scan for lung cancer screening. Patients were classified regarding airflow limitation (FEV₁/FVC <0.7 forced expiratory volume in 1 second/forced vital capacity) and the presence of emphysema on the QCT. The QCT were analyzed in specialized software and patients were classified in two disease-predominant phenotypes: emphysema-predominant (EP) and non-emphysema-predominant (NEP). EP was determined as ≥6% of percent low-attenuation areas (LAA%) with less than -950 Hounsfield units. NEP was defined as having a total LAA% of less than 6%.

Most of our patients were classified in the EP phenotype. The EP group had significantly worse predicted FEV₁ (60.6 ±22.9 vs. 89.7 ±15.9, p <0.001), higher rates of airflow limitation (85.7% vs. 15%; p <0.001), and had more exacerbation-like episodes (25.8% vs. 8.3%, p <0.001) compared to the NEP group. Smoking history, ethnicity, and BMI did not differ between the groups. The total LAA% was the QCT parameter with the strongest correlation to FEV₁ (r = -0.669) and FEV₁/FVC (r = -0.787).

Heavy smokers with the EP phenotype on QCT were more likely to have airflow limitation, worse predicted FEV_1, and a higher rate of exacerbation-like episodes than those with the NEP phenotype. Approximately 23% of patients with no airflow limitation on PFTs were classified in EP phenotype.

• Biometry/methods
• Female
• Humans
• Imaging, Three-Dimensional/methods
• Longitudinal Studies
• Male
• Pulmonary Disease, Chronic Obstructive/diagnostic imaging
• Pulmonary Disease, Chronic Obstructive/pathology
• Tomography, X-Ray Computed/methods

• R01 HL089897 NHLBI NIH HHS
• P30 CA046592 NCI NIH HHS
• U01 HL089897 NHLBI NIH HHS
• R01 HL089856 NHLBI NIH HHS
• U01 HL089856 NHLBI NIH HHS
• R01 HL122438 NHLBI NIH HHS
• R44 HL118837 NHLBI NIH HHS

• Humans
• Pulmonary Disease, Chronic Obstructive/diagnosis

• Cluster analysis
• Obstructive sleep apnea
• Personalized medicine
• Phenotype
• Positional
• Rapid eye movement (REM) related

Pulmonary inflammation and bacterial colonization are central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Defects in macrophage phagocytosis of both bacteria and apoptotic cells contribute to the COPD phenotype. Small molecule inhibitors with anti-inflammatory activity against p38 mitogen activated protein kinases (MAPKs), phosphatidyl-inositol-3 kinase (PI3K) and Rho kinase (ROCK) are being investigated as novel therapeutics in COPD. Concerns exist, however, about off-target effects. We investigated the effect of p38 MAPK inhibitors (VX745 and SCIO469), specific inhibitors of PI3K α (NVS-P13K-2), δ (NVS-P13K-3) or γ (NVS-P13K-5) and a ROCK inhibitor PF4950834 on macrophage phagocytosis, early intracellular killing of bacteria and efferocytosis of apoptotic neutrophils. Alveolar macrophages (AM) obtained from broncho-alveolar lavage (BAL) or monocyte-derived macrophages (MDM) from COPD patients (GOLD stage II/III) enrolled from a well characterized clinical cohort (MRC COPD-MAP consortium) or from healthy ex-smoker controls were studied. Both COPD AM and MDM exhibited lower levels of bacterial phagocytosis (using Streptococcus pneumoniae and non-typeable Haemophilus influenzae) and efferocytosis than healthy controls. None of the inhibitors altered bacterial internalization or early intracellular bacterial killing in AM or MDM. Conversely PF4950834, but not other inhibitors, enhanced efferocytosis in COPD AM and MDM. These results suggest none of these inhibitors are likely to exacerbate phagocytosis-related defects in COPD, while confirming ROCK inhibitors can enhance efferocytosis in COPD.

• G0800570 Medical Research Council
• G0901697 Medical Research Council
• G1001372 Medical Research Council
• G1001365 Medical Research Council
• RP-PG-0109-10056 Department of Health

• C3a
• T cells
• complement proteins
• emphysema

• Chronic obstructive pulmonary disease
• Elastase
• Granulocyte
• Polymorphonuclear leukocytes
• Reactive oxygen species

• Asthma
• Chronic Obstructive Pulmonary Disease
• cluster analysis
• emphysema
• phenotypes

• Dyspnea
• St George’s Respiratory Questionnaire
• Transition Dyspnea Index
• health status
• indacaterol/glycopyrrolate
• long-acting β2-agonist/long-acting muscarinic antagonist
• lung function
• safety
• tiotropium/olodaterol
• umeclidinium/vilanterol

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease having small airway inflammation, emphysema, and pulmonary hypertension. It is now clear that spirometry alone cannot differentiate each component. Quantitative computed tomography (QCT) is increasingly used to quantify the amount of emphysema and small airway involvement in COPD. Inspiratory CT guides in assessing emphysema while expiratory CT identifies areas of air trapping which is a surrogate of small airway inflammation. By constructing a three-dimensional model of airways, we can also measure the airway wall thickness of segmental and subsegmental airways. The aim of this review is to present the current knowledge and methodologies in QCT of the lung that aid in identifying discrete COPD phenotypes.

• Airway wall thickening
• chronic obstructive pulmonary disease
• imaging
• physiopathology
• pulmonary emphysema
• quantitative computed tomography

• PET/CT
• chronic obstructive pulmonary disease
• perfusion
• pulmonary function tests
• ventilation

• Chronic obstructive pulmonary disease (COPD)
• Clinical practice guideline
• Enfermedad pulmonar obstructiva crónica (EPOC)
• Guía de práctica clínica

• Adrenal Cortex Hormones/therapeutic use
• Adrenergic beta-2 Receptor Agonists/therapeutic use
• Antibiotic Prophylaxis
• Bronchodilator Agents/therapeutic use
• Drug Therapy, Combination
• Environmental Exposure
• Epidemiologic Studies
• Evidence-Based Medicine
• Female
• Humans
• Male
• Mass Screening
• Muscarinic Antagonists/therapeutic use
• Opportunistic Infections/prevention & control
• Prognosis
• Pulmonary Disease, Chronic Obstructive/diagnosis
• Pulmonary Disease, Chronic Obstructive/drug therapy
• Pulmonary Disease, Chronic Obstructive/epidemiology
• Pulmonary Disease, Chronic Obstructive/therapy
• Randomized Controlled Trials as Topic
• Risk Factors
• Sex Distribution
• Smoking/adverse effects
• Vaccination

Patients with chronic obstructive pulmonary disease (COPD) often suffer concomitant disorders that worsen significantly their health status and vital prognosis. The pathogenic mechanisms underlying COPD multimorbidities are not completely understood, thus the exploration of potential molecular and biological linkages between COPD and their associated diseases is of great interest.

We developed a novel, unbiased, integrative network medicine approach for the analysis of the diseasome, interactome, the biological pathways and tobacco smoke exposome, which has been applied to the study of 16 prevalent COPD multimorbidities identified by clinical experts.

Our analyses indicate that all COPD multimorbidities studied here are related at the molecular and biological level, sharing genes, proteins and biological pathways. By inspecting the connections of COPD with their associated diseases in more detail, we identified known biological pathways involved in COPD, such as inflammation, endothelial dysfunction or apoptosis, serving as a proof of concept of the methodology. More interestingly, we found previously overlooked biological pathways that might contribute to explain COPD multimorbidities, such as hemostasis in COPD multimorbidities other than cardiovascular disorders, and cell cycle pathway in the association of COPD with depression. Moreover, we also observed similarities between COPD multimorbidities at the pathway level, suggesting common biological mechanisms for different COPD multimorbidities. Finally, chemicals contained in the tobacco smoke target an average of 69% of the identified proteins participating in COPD multimorbidities.

The network medicine approach presented here allowed the identification of plausible molecular links between COPD and comorbid diseases, and showed that many of them are targets of the tobacco exposome, proposing new areas of research for understanding the molecular underpinning of COPD multimorbidities.

The online version of this article (doi:10.1186/s12931-014-0111-4) contains supplementary material, which is available to authorized users.

• COPD Pharmacology
• COPD ÀÜ Mechanisms

• Forced Expiratory Volume
• Humans
• Inflammation/complications
• Lung/diagnostic imaging
• Lung/microbiology
• Phenotype
• Precision Medicine
• Pulmonary Disease, Chronic Obstructive/diagnostic imaging
• Pulmonary Disease, Chronic Obstructive/physiopathology
• Pulmonary Disease, Chronic Obstructive/prevention & control
• Pulmonary Disease, Chronic Obstructive/therapy
• Radiography
• Severity of Illness Index

• Burden of the disease
• Carga de la enfermedad
• Chronic obstructive pulmonary disease
• Enfermedad pulmonar obstructiva crónica
• Mortalidad
• Mortality
• Prevalence
• Prevalencia

The significant healthcare burden associated with chronic obstructive pulmonary disease (COPD) is driving us to improve our understanding of the natural history of this disease. Historically, the focus has been largely centred on diagnosing and treating individuals with moderate and severe disease. However, it is now recognised that the speed of decline in lung function as measured by forced expiratory volume in 1 s occurs faster in the earlier stages of the disease process. As a result, a clearer understanding of the potential benefits of treatment in early COPD is needed. It is recognised that many patients with COPD remain undiagnosed in the community which has prompted global case-finding initiatives. In this review we discuss the difficulties in diagnosing COPD in its early stages, examine the role of case-finding and look at the evidence for early intervention with therapeutic agents. There is a growing interest in the phenotypic variation amongst patients with COPD and we explore the role of phenotyping in early COPD and its potential benefits in providing a more individualised approach to COPD management. The majority of patients with COPD are known to die from non-respiratory causes such as cardiovascular disease. The mechanistic link is thought to relate to systemic inflammation, causing us to question whether earlier interventions could have a beneficial impact on the burden of co-morbidities for patients with COPD.

• Chronic obstructive pulmonary disease
• Chronic bronchitis
• Pulmonary emphysema
• Early disease
• Mild
• Case-finding
• Phenotypes
• Treatment

To estimate the incidence of pneumonia by COPD status and the excess cost of inpatient primary pneumonia in elders with COPD.

A retrospective, longitudinal study using claims linked to eligibility/demographic data for a 5% sample of fee-for-service Medicare beneficiaries from 2005 through 2007.

Incidence rates of pneumonia were calculated for elders with and without COPD and for elders with COPD and coexistent congestive heart failure (CHF). Propensity-score matching with multivariate generalized linear regression was used to estimate the excess direct medical cost of inpatient primary pneumonia in elders with COPD as compared with elders with COPD but without a pneumonia hospitalization.

Elders with COPD had nearly six-times the incidence of pneumonia compared with elders without COPD (167.6/1000 person-years versus 29.5/1000 person-years; RR=5.7, p <0 .01); RR increased to 8.1 for elders with COPD and CHF compared with elders without COPD. The incidence of inpatient primary pneumonia among elders with COPD was 54.2/1000 person-years compared with 7/1000 person-years for elders without COPD; RR=7.7, p<0.01); RR increased to 11.0 for elders with COPD and CHF compared with elders without COPD. The one-year excess direct medical cost of inpatient pneumonia in COPD patients was $ 22,697 ($45,456 in cases vs. $ 22,759 in controls (p <0.01)); 70.2% of this cost was accrued during the quarter of the index hospitalization. During months 13 through 24 following the index hospitalization, the excess direct medical cost was $ 5,941 ($23,215 in cases vs. $ 17,274 in controls, p<0.01).

Pneumonia occurs more frequently in elders with COPD than without COPD. The excess direct medical cost in elders with inpatient pneumonia extends up to 24 months following the index hospitalization and represents $28,638 in 2010 dollars.

• Aged
• Aged, 80 and over
• Female
• Humans
• Male
• Pneumonia/economics
• Pneumonia/epidemiology
• Pulmonary Disease, Chronic Obstructive/economics
• Pulmonary Disease, Chronic Obstructive/epidemiology
• Retrospective Studies
• United States