COPD Phenotypes Research Articles

Identification of frequent acute exacerbations phenotype in COPD patients based on imaging and clinical characteristics

BackgroundChronic obstructive pulmonary disease (COPD) is a common disease with high morbidity, with acute exacerbations manifesting as a worsening of respiratory symptoms. This study aimed to identify the frequent acute exacerbation phenotype in patients with COPD based on imaging and clinical characteristics. MethodsPatients with COPD (n = 201) were monitored for acute exacerbations one year after their initial hospital admission and further divided into frequent and non-frequent exacerbation groups according to the frequency and severity of acute exacerbations. All patients underwent high resolution CT scans and low attenuation area less than −950Hu (LAA-950) in the whole lung was measured. Differences in visual subtypes, LAA-950, and clinical basic characteristics were compared between groups. The clinical factors influencing frequent exacerbation were determined using binary logistic regression. Finally, based on imaging and clinical factors, the receiver operating characteristic curve was used to identify the phenotype of COPD with frequent acute exacerbations. ResultsPatients with frequent exacerbations had a larger LAA-950 than those non-frequent exacerbations patients (p＜0.001). Frequent acute exacerbations were associated with worsening visual subtypes. Multivariate binary logistic regression illustrated that age, smoking status, BMI, FEV1 pred, and LAA-950 were associated with frequent exacerbations of COPD. The area under the receiver operating characteristic curve for predicting frequent exacerbations based on age, smoking status, BMI, FEV1 pred, and LAA-950 was 0.907 (p＜0.001). ConclusionThe combination of imaging and clinical characteristics reached high diagnostic efficacy in the identification of frequent acute exacerbations in patients with COPD.

Principal component analysis of flow-volume curves in COPDGene to link spirometry with phenotypes of COPD

BackgroundParameters from maximal expiratory flow-volume curves (MEFVC) have been linked to CT-based parameters of COPD. However, the association between MEFVC shape and phenotypes like emphysema, small airways disease (SAD) and bronchial wall thickening (BWT) has not been investigated.Research questionWe analyzed if the shape of MEFVC can be linked to CT-determined emphysema, SAD and BWT in a large cohort of COPDGene participants.Study design and methodsIn the COPDGene cohort, we used principal component analysis (PCA) to extract patterns from MEFVC shape and performed multiple linear regression to assess the association of these patterns with CT parameters over the COPD spectrum, in mild and moderate-severe COPD.ResultsOver the entire spectrum, in mild and moderate-severe COPD, principal components of MEFVC were important predictors for the continuous CT parameters. Their contribution to the prediction of emphysema diminished when classical pulmonary function test parameters were added. For SAD, the components remained very strong predictors. The adjusted R2 was higher in moderate-severe COPD, while in mild COPD, the adjusted R2 for all CT outcomes was low; 0.28 for emphysema, 0.21 for SAD and 0.19 for BWT.InterpretationThe shape of the maximal expiratory flow-volume curve as analyzed with PCA is not an appropriate screening tool for early disease phenotypes identified by CT scan. However, it contributes to assessing emphysema and SAD in moderate-severe COPD.

Endotyping COPD: hypoxia-inducible factor-2 as a molecular "switch" between the vascular and airway phenotypes?

COPD is a heterogeneous disease with multiple clinical phenotypes. COPD endotypes can be determined by different expressions of hypoxia-inducible factors (HIFs), which, in combination with individual susceptibility and environmental factors, may cause predominant airway or vascular changes in the lung. The pulmonary vascular phenotype is relatively rare among COPD patients and characterised by out-of-proportion pulmonary hypertension (PH) and low diffusing capacity of the lung for carbon monoxide, but only mild-to-moderate airway obstruction. Its histologic feature, severe remodelling of the small pulmonary arteries, can be mediated by HIF-2 overexpression in experimental PH models. HIF-2 is not only involved in the vascular remodelling but also in the parenchyma destruction. Endothelial cells from human emphysema lungs express reduced HIF-2α levels, and the deletion of pulmonary endothelial Hif-2α leads to emphysema in mice. This means that both upregulation and downregulation of HIF-2 have adverse effects and that HIF-2 may represent a molecular "switch" between the development of the vascular and airway phenotypes in COPD. The mechanisms of HIF-2 dysregulation in the lung are only partly understood. HIF-2 levels may be controlled by NAD(P)H oxidases via iron- and redox-dependent mechanisms. A better understanding of these mechanisms may lead to the development of new therapeutic targets.

Prospects of DNA microarray application in management of chronic obstructive pulmonary disease: A systematic review

Abstract Chronic obstructive pulmonary disease (COPD) is incurable chronic disease which kills 3.3 million each year worldwide. Number of global cases of COPD is steadily rising alongside with life expectancy, disproportionally hitting middle-income countries like Russia and China, in such conditions, new approaches to the COPD management are desperately needed. DNA microarray technology is a powerful genomic tool that has the potential to uncover underlying COPD biological alteration and brings up revolutionized treatment option to clinicians. We executed systematic review studies of studies published in last 10 years regarding DNA microarray application in COPD management, with complacence to PRISMA criteria and using PubMed and Medline data bases as data source. Out of 920 identified papers, 39 were included in the final analysis. We concluded that Genome-wide expression profiling using DNA microarray technology has great potential in enhancing COPD management. Current studied proofed this method is reliable and possesses many potential applications such as individual at risk of COPD development recognition, early diagnosis of disease, COPD phenotype identification, exacerbation prediction, personalized treatment optioning and prospect of oncogenesis evaluation in patients with COPD. Despite all the proofed benefits of this technology, researchers are still in the early stage of exploring it's potential. Therefore, large clinical trials are still needed to set up standard for DNA microarray techniques usage implementation in COPD management guidelines, subsequently giving opportunity to clinicians for controlling or even eliminating COPD entirely.

FOXO3 Activation Prevents Cellular Senescence in Emphysema Induced by Cigarette Smoke

Because cigarette smoke can induce COPD/emphysema through accelerating senescence with or without an incomplete repair system. However, the pathogenesis of COPD following lung senescence induced by CS is not fully understood. Airspace enlargement and airway epithelial cell senescence are common finding during the COPD development. We investigated the lung tress response to CS and demonstrated that a stress-responsive transcription factor, FOXO3, was regulated by deacetylase. SIRT1 inhibited FOXO3 acetylation and FOXO3 degradation, leading to FOXO3 accumulation and activation in airway epithelial cells. CS exposure activated SIRT1 contributed to FOXO3 activation and functioned to protect lungs, as deletion of SIRT1 decreased CS-induced FOXO3 activation and resulted in more severe airway epithelial cells senescence airspace enlargement. Strikingly, deletion of FOXO3 during the development of COPD aggravated lung structural and functional damage, leading to a much more profound COPD phenotype. We show that deletion of FOXO3 resulted in decreased autophagic response and increased senescence, which may explain lung protection by FOXO3. Our study indicates that in the COPD, stress-responsive transcription factors can be activated for adaptions to counteract senescence insults, thus attenuating COPD development.

Low-density lipoprotein cholesterol and risk of COPD: Copenhagen General Population Study.

Randomised controlled trials found that low-density lipoprotein (LDL) cholesterol-lowering statins increase lung function and possibly decrease rate of exacerbations in individuals with COPD. However, it is unknown whether high levels of LDL cholesterol are associated with increased susceptibility to COPD. We tested the hypothesis that high LDL cholesterol is associated with increased risk of COPD, severe COPD exacerbation and COPD-specific mortality. We examined 107 301 adults from the Copenhagen General Population Study. COPD outcomes were ascertained at baseline and prospectively through nationwide registries. In cross-sectional analysis, low LDL cholesterol was associated with increased risk of COPD (odds ratio for 1st versus 4th quartile: 1.07 (95% CI 1.01-1.14)). Prospectively, low LDL cholesterol was associated with increased risk of COPD exacerbations with hazard ratios of 1.43 (1.21-1.70) for 1st versus 4th quartile, 1.21 (1.03-1.43) for 2nd versus 4th quartile, and 1.01 (0.85-1.20) for 3rd versus 4th quartile of LDL cholesterol (p-value for trend=6×10-6). Finally, low LDL cholesterol was likewise associated with increased risk of COPD-specific mortality (log-rank test: p=0.0009). Sensitivity analyses with death as competing risk provided similar results. Low LDL cholesterol was associated with increased risks of severe COPD exacerbation and COPD-specific mortality in the Danish general population. As this is opposite of that observed in randomised controlled trials with statins, our findings might be a result of reverse causation indicating that individuals with severe phenotypes of COPD have lower plasma levels of LDL cholesterol due to wasting.

What Role Do Immunological and Inflammatory Biomarkers Play on Mortality and Exacerbations in COPD Patients?

Background: COPD phenotypes have been identified according to patient clinical characteristics and, more recently, to their immunological markers. However, the role of these biomarkers in relation to exacerbations in different COPD phenotypes is not yet clear. Thus it is important to continue investigating this topic to plan the most appropriate treatment, to contrast the decline of respiratory function and to reduce subsequent exacerbations in COPD patients. Therefore the aim of this study was to assess whether biomarkers are only predictors of exacerbations and mortality in COPD patients or instead play a causal role in these adverse COPD developments. Methods: COPD phenotypes were identified according to patient clinical characteristics or immunological markers. Immunological and inflammatory biomarkers were identified as predictors of mortality and exacerbations. COPD patients were identified from the hospital discharge register of Pisa (Italy) in 2000-2006, on the basis of diagnoses and a FEV1/FVC < 0.70, and enrolled in 2003-2006 according to a longitudinal approach. They were characterized at enrollment by age, sex, comorbidities, immunological and inflammatory biomarkers. The phenotype was assigned at enrollment as eosinophilic (eosinophils>2%) or neutrophilic (leukocytes>11.0x109/L and/or neutrophils>65%). Mortality and exacerbations registered in the period 2003-2012 were assessed by phenotype and other possible predictors in regression models. Results: Mortality rates reached 43.3% in COPD patients: 69.1% and 36.5% in neutrophilic and eosinophilic, respectively. The exacerbation rate was higher in neutrophilic (54.4%) than in eosinophilic patients (48.4%). Uni-variable regression confirmed that mortality was related to age, Congestive Heart Failure (CHF), Ischemic Heart Disease (IHD), elevated neutrophil count and Neutrophil to Lymphocyte Ratio (NLR). At multivariable analysis only age was associated with mortality, whereas inflammatory biomarkers induced exacerbations. Conclusion: Mortality was influenced by phenotype and age, exacerbations by COPD severity and NLR to suggest that an appropriate treatment and the biomarker’s monitoring might help prevent exacerbations.

Metabolomics Reveals Dysregulated Sphingolipid and Amino Acid Metabolism Associated with Chronic Obstructive Pulmonary Disease.

PurposeChronic obstructive pulmonary disease (COPD) is a heterogeneous disease presenting as multiple phenotypes, such as declining lung function, emphysema, or persistent airflow limitation caused by several risk factors, including cigarette smoking and air pollution. The inherent complexity of COPD phenotypes propounds difficulties for accurate diagnosis and prognosis. Although metabolomic profiles on COPD have been reported, the role of metabolism in COPD-related phenotypes is yet to be determined. In this study, we investigated the association between plasma sphingolipids and amino acids, and between COPD and COPD-related phenotypes in a Korean cohort.Patients and MethodsBlood samples were collected from 120 patients with COPD and 80 control participants who underwent spirometry and quantitative computed tomography. The plasma metabolic profiling was carried out using LC-MS/MS analysis.ResultsAmong the evaluated plasma sphingolipids, an increase in the metabolism of two specific sphingomyelins, SM (d18:1/24:0) and SM (d18:1/24:1) were significantly associated with COPD. There was no significant correlation between any of the SMs and the emphysema index, FVC and FEV1 in the COPD cohort. Meanwhile, Cer (d18:1/18:0) and Cer (d18:1/24:1) were significantly associated with reduced FEV1. Furthermore, the levels of several amino acids were altered in the COPD group compared to that in the non-COPD group; glutamate and alpha AAA were substantial associated with emphysema in COPD. Kynurenine was the only amino acid significantly associated with reduced FEV1 in COPD. In contrast, there was no correlation between FVC and the elevated metabolites.ConclusionOur results provide dysregulated plasma metabolites impacting COPD phenotypes, although more studies are needed to explore the underlying mechanism related to COPD pathogenesis.

Sestrin 2 levels are associated with emphysematous phenotype of COPD.

Sestrins (Sesns) are a family of highly conserved stress-inducible proteins and various stresses have been shown to strongly up-regulate them. Sestrin 2 (Sesn2) deficiency has been shown to partially suppress pulmonary emphysema. The aim of this study was to evaluate Sesn2 levels in COPD patients and its possible associations with the presence of emphysema and blood eosinophils. All patients underwent lung function testing and high-resolution computed tomography (HRCT) of the chest. The presence of emphysematous lesions in >15% of the pulmonary parenchyma was considered as significant emphysema. Sixty-seven patients were included in the study. 40/67 patients were characterized as having significant emphysema. Patients with significant emphysema had higher levels of Sesn2 (ng/ml) [median (IQR) 6.7 (2.7,10.3 vs 1.09 (0.9,1.9), p<0.001)] and significantly lower % and absolute blood eosinophil counts (cells/μL) compared to patients without emphysema [1 (0, 2) vs 4 (2, 4) p<0.001 and 62 (0, 110) vs 248 (180, 300), p<0.001 respectively]. Sesn2 presented a significant positive correlation to the score of emphysema in HRCT (rs = 0.87, p<0.001) and similar positive but weaker correlation to FRC (rs = 0.27, p = 0.024). Negative correlations were observed between Sesn2 and either the % of blood eosinophils and/or the absolute blood eosinophil count (rs = -0.79, p<0.001, and rs = -0.78, p<0.001 respectively). Sesn2 levels above 1.87 ng/ml showed a high diagnostic performance for the presence of significant emphysema in HRCT with an AUC 0.93, 95% CI (0.85,0.98), p<0.001. Sesn2 could serve as a potential biomarker of emphysema.

Associations Between Morphological Phenotypes of COPD and Clinical Characteristics in Surgically Resected Patients with COPD and Concomitant Lung Cancer.

PurposeThe associations between morphological phenotypes of COPD based on the chest computed tomography (CT) findings and clinical characteristics in surgically resected patients with COPD and concomitant lung cancer are unclear. The purpose of this study was to clarify the differences in clinical characteristics and prognosis among morphological phenotypes based on the chest CT findings in these patients.Patients and MethodsWe retrospectively reviewed the medical records of 132 patients with COPD and concomitant lung cancer who had undergone pulmonary resection for primary lung cancer. According to the presence of emphysema and bronchial wall thickness on chest CT, patients were classified into three phenotypes: non-emphysema phenotype, emphysema phenotype, or mixed phenotype.ResultsThe mixed phenotype was associated with poorer performance status, higher score on the modified British Medical Research Council (mMRC) dyspnea scale, higher residual volume in pulmonary function, and higher proportion of squamous cell carcinoma than the other phenotypes. Univariate and multivariate Cox proportional hazards regression analyses showed that the extent of emphysema on chest CT, presented as a low attenuation area (LAA) score, was an independent determinant that predicted prognosis. In the Kaplan-Meier analysis, the Log rank test showed significant differences in survival between the non-emphysema and mixed phenotypes, and between the emphysema and mixed phenotypes.ConclusionThe cross-sectional pre-operative LAA score can predict the prognosis in surgically resected patients with COPD and concomitant lung cancer. The COPD phenotype with both emphysema and bronchial wall thickness on chest CT was associated with poorer performance status, greater extent of dyspnea, greater impairment of pulmonary function, and worse prognosis.

Cellular Senescence as Fibrogenic Mechanism in Smoking Lung

Age is a risk factor for many diseases including idiopathic pulmonary fibrosis (IPF) by affecting wound healing through abnormal fibrogenesis. Common cellular and molecular traits associated with aging can be found in senescent cells, which may occur throughout the lifespan playing physiological roles during normal development or limiting the proliferation of damaged and aged cells. In this study we investigated in smoking mice whether the senescence of lung cells, triggered by the oxidative stress response, is associated with molecular pathways that can influence lung fibrogenesis and contribute to the remodeling of the fibrotic tissue characterizing some phenotypes of COPD in humans. Among the complex mixture of hundreds senescence secreted factors that include proinflammatory cytokines, chemokines, growth factors, and proteases, we selected important factors involved in differentiation of myofibroblasts, their dedifferentiation and apoptosis, as well as in their metabolic function.The expression of these factors and the amount of matrix deposition was analyzed after chronic cigarette smoke (CS) exposure of C57 Bl/6 and DBA/2 mice sensitive to oxidative, in different lung compartmentscharacterized by a fibrotic remodeling using histochemistry or immunohistochemistry.Unlike C57 Bl/6, DBA/2 mice at 4 months of exposure show marked positivity for 8‐OHdG, a marker of oxidative damage, in subpleural areas, in central parts of the lung parenchyma, on airways and on cells of the fibro‐muscular layer.In these areas, a marked positivity is observed for fibrogenic cytokines such as TGF‐β, PDGF‐b and CTGF, and for other factors such as the p16ink4A senescence marker, and proliferation markers PCNA and Ki67. In DBA/2 mice, these compartments are characterized by a progressive fibrous remodeling at various experimental time points from 5 months of CS exposure onwards as demonstrated by Masson’s trichrome staining.Fibroproliferative foci are present in sub‐pleural areas, in peripheral areas of airways, and in central parts of the lung parenchyma. They are characterized by increasing number of α‐SMA positive myofibroblasts, which express the senescence marker p16ink4A and the transcription factor MyoD that plays a crucial role in myoblast proliferation and differentiation. MyoD induces cell cycle arrest, promotes cellular terminal differentiation of fibroblasts into myofibroblasts, and in senescent myofibroblasts it has been reported to determine resistance to apoptosis and opposes their dedifferentiation.All these factors contribute to the development in smoking DBA/2 mice of lung lesions, which are like those seen in patients with “Combined Fibrosis/Emphysema Syndrome.”Despite consistent levels of TGF‐β, PDGF‐b and CTGF, C57 Bl/6 mice develop after chronic CS exposure fibrotic remodeling at lower extent. Of interest, a very low expression of factors indicative of senescence (p16ink4A and MyoD) and cell proliferation (PCNA and Ki67) is observed.Our results suggest that apoptosis, senescence, and proliferation induced at different rate by fibrotic cytokines and senescence associated secretory factors play important role in early or late appearance of fibrotic remodeling of lung and airways exposed to CS.

Factors associated with coronary heart disease in COPD patients and controls.

COPD and coronary heart disease (CHD) frequently co-occur, yet which COPD phenotypes are most prone to CHD is poorly understood. The aim of this study was to see whether COPD patients did have a true higher risk for CHD than subjects without COPD, and to examine a range of potential factors associated with CHD in COPD patients and controls. 347 COPD patients and 428 non-COPD controls, were invited for coronary computed tomography angiography (CCTA) and pulmonary CT. Arterial blood gas, bioelectrical impedance and lung function was measured, and a detailed medical history taken. The CCTA was evaluated for significant coronary stenosis and calcium score (CaSc), and emphysema defined as >10% of total area <-950 Hounsfield units. 12.6% of the COPD patients and 5.7% of the controls had coronary stenosis (p<0.01), whereas 55.9% of the COPD patients had a CaSc>100 compared to 31.6% of the controls (p<0.01). In a multivariable model adjusting for sex, age, body composition, pack-years, CRP, cholesterol/blood pressure lowering medication use and diabetes mellitus, the OR (95% CI) for having significant stenosis was 1.80 (0.86-3.78) in COPD patients compared with controls. In a similar model, the OR (95% CI) for having CaSc>100 was 1.68 (1.12-2.53) in COPD patients compared with controls. Examining the risk of significant stenosis and CaSc>100 among COPD patients, no variable was associated with significant stenosis, whereas male sex [OR 2.85 (1.56-5.21)], age [OR 3.74 (2.42-5.77)], statin use [OR 2.23 (1.23-4.50)] were associated with CaSc>100, after adjusting for body composition, pack-years, C-reactive protein, use of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), diabetes, emphysema score, GOLD category, exacerbation frequency, eosinophilia, and hypoxemia. COPD patients were more likely to have CHD, but neither emphysema score, lung function, exacerbation frequency, nor hypoxemia predicted presence of either coronary stenosis or CaSc>100.

Diagnostic efficacy of visual subtypes and low attenuation area based on HRCT in the diagnosis of COPD

BackgroundChronic obstructive pulmonary disease (COPD) is a heterogeneous disease. Current gold standard criteria, pulmonary function tests (PFTs) may result in underdiagnosis of potential COPD patients. Therefore, we hypothesize that the combination of high-resolution computed tomography (HRCT) and clinical basic characteristics will enable the identification of more COPD patients.MethodsA total of 284 patients with respiratory symptoms who were current or former smokers were included in the study, and were further divided into 5 groups of GOLD grade I–IV and non-COPD according to PFTs. All patients underwent inspiratory HRCT scanning and low attenuation area (LAA) was measured. Then they were divided into seven visual subtypes according to the Fleischner Society classification system. Non-parametric tests were used for exploring differences in basic characteristics and PFTs between different groups of enrolled patients and visual subtypes. Binary logistic regression was to find the influencing factors that affected the patients’ outcome (non-COPD vs GOLD I-IV). The area under the receiver operating characteristic curve (AUC-ROC) was to explore the diagnostic efficacy of LAA, visual subtypes, and combined basic characteristics related to COPD for COPD diagnosis. Finally, based on the cut-off values of ROC analysis, exploring HRCT features in patients who do not meet the diagnostic criteria but clinically suspected COPD.ResultsWith the worsening severity of COPD, the visual subtypes gradually progressed (p < 0.01). There was a significant difference in LAA between GOLD II–IV and non-COPD (p < 0.0001). The diagnostic efficacy of LAA, visual subtypes, and LAA combined with visual subtypes for COPD were 0.742, 0.682 and 0.730 respectively. The diagnostic efficacy increased to 0.923–0.943 when basic characteristics were added (all p < 0.001). Based on the cut-off value of ROC analysis, LAA greater than 5.6, worsening of visual subtypes, combined with positive basic characteristics can help identify some potential COPD patients.ConclusionThe heterogeneous phenotype of COPD requires a combination of multiple evaluation methods. The diagnostic efficacy of combining LAA, visual subtypes, and basic characteristics achieves good consistency with current diagnostic criteria.

NCOA4-Mediated Ferroptosis in Bronchial Epithelial Cells Promotes Macrophage M2 Polarization in COPD Emphysema.

BackgroundMacrophage polarization plays an important role in the pathogenesis of COPD emphysema. Changes in macrophage polarization in COPD remain unclear, while polarization and ferroptosis are essential factors in its pathogenesis. Therefore, this study investigated the relationship between macrophage polarization and ferroptosis in COPD emphysema.MethodsWe measured macrophage polarization and the levels of matrix metalloproteinases (MMPs) in the lung tissues of COPD patients and cigarette smoke (CS)-exposed mice. Flow cytometry was used to determine macrophage (THP-M cell) polarization changes. Ferroptosis was examined by FerroOrange, Perls’ DAB, C11-BODIPY and 4-HNE staining. Nuclear receptor coactivator 4 (NCOA4) was measured in the lung tissues of COPD patients and CS-exposed mice by western blotting. A cell study was performed to confirm the regulatory effect of NCOA4 on macrophage polarization.ResultsIncreased M2 macrophages and MMP9 and MMP12 levels were observed in COPD patients, CS-exposed mice and THP-M cells cocultured with CS extract (CSE)-treated human bronchial epithelial (HBE) cells. Increased NCOA4 levels and ferroptosis were confirmed in COPD. Treatment with NCOA4 siRNA and the ferroptosis inhibitor ferrostatin-1 revealed an association between ferroptosis and M2 macrophages. These findings support a role for NCOA4, which induces an increase in M2 macrophages, in the pathogenesis of COPD emphysema.ConclusionIn our study, CS led to the dominance of the M2 phenotype in COPD. We identified NCOA4 as a regulator of M2 macrophages and emphysema by mediating ferroptosis, which offers a new direction for research into COPD diagnostics and treatment.

СОВРЕМЕННЫЙ КЛИНИЧЕСКИЙ ПОРТРЕТ ПАЦИЕНТА С ФЕНОТИПОМ ХРОНИЧЕСКОЙ ОБСТРУКТИВНОЙ БОЛЕЗНИ ЛЕГКИХ БЕЗ ЧАСТЫХ ОБОСТРЕНИЙ

Introduction. According to current data, the COPD phenotype without frequent exacerbations is frequently encountered and requires close attention. However, in the course of a literary search, it was possible to find only isolated scientific works with a generalized description of the features of this phenotype. Aim. The aim of the study is to compile a typical clinical portrait of a patient with the COPD phenotype without frequent exacerbations based on the analysis of clinical, laboratory and functional parameters. Material and methods. The study included 45 patients aged 57.2±1.1 years with a diagnosis of COPD without frequent exacerbations in age. In all patients, the concentration of proinflammatory cytokines, C-reactive protein in blood serum was determined by immunoferment analysis. Results and discussion. Males (93.3%) with a smoker index of 33.7± 2.5 packs/years and a disease duration of more than 10 years dominated the studied cohort. The average score on the CAT test was 10.32±0.05 points, on the mMRC scale more than two points. The post - bronchodilation value of FEV1 corresponded to the average severity of obstructive disorders in 91.1% of individuals. Among the examined patients, persons with bronchitic type of COPD predominated (53.3%). The concentration of inflammatory biomarkers determined in the blood serum significantly exceeded the levels of the reference values. Also, patients with COPD with the studied phenotype was found to have low adherence to treatment and dispensary observation and late visit to the doctor. Conclusions. The obtained results of the study made it possible to draw up a clinical portrait of the patient with the COPD phenotype without frequent exacerbations.

Physical and mental health profile of patients with the early-onset severe COPD phenotype: A cross-sectional analysis

Patients with early-onset severe COPD are often female and characterized by severe emphysema. Extrapulmonary disease manifestations have not yet been investigated in this clinical phenotype. Therefore, this study aimed to study the physical and mental health profile of patients with early-onset severe COPD. This is a cross-sectional analysis including 1058 patients with COPD who were referred for pulmonary rehabilitation between July 2013 and August 2018. Based on a forced expiratory volume in 1s (FEV1) <50%predicted and age <55 years, 78 patients were identified having early-onset severe COPD. Using propensity score matching, these patients were matched to 54 early-onset mild-to-moderate, 158 older severe and 103 older mild-to-moderate COPD patients based on FEV1%predicted, age and gender. An extensive panel of pulmonary and extrapulmonary disease markers (i.e. body composition, physical performance and mental health) was compared between these groups. Pulmonary manifestations as well as physical and mental health were similar in patients with early-onset severe COPD compared to older severe patients, despite a mean age difference of 15.8 years. Remarkably, a high prevalence of depression was observed in early-onset severe COPD which was significantly higher compared to older severe patients (51.9 vs 32.7%, p=0.029). In line with a large difference in FEV1 (33.9 (25.1-41.5) vs 71.8 (61.3-85.4), p<0.001), patients with early-onset severe COPD had lower exercise performance, indicated by a lower 6-min walking distance and peak work rate (mean difference 71.1m, p=0.001, and 25.9%predicted, p<0.001, respectively), compared to patients with early-onset mild-to-moderate COPD. Interestingly, body composition and isokinetic muscle strength were not different between these comparable age groups. Pulmonary and physical health limitations are generally comparable between younger and older patients with severe airflow limitation, while more younger patients might have mental problems. These data suggest the need for early identification of subjects at risk for early-onset severe COPD.

Plasma sRAGE levels strongly associate with centrilobular emphysema assessed by HRCT scans

BackgroundThere is a strong need for biomarkers to better characterize individuals with COPD and to take into account the heterogeneity of COPD. The blood protein sRAGE has been put forward as promising biomarker for COPD in general and emphysema in particular. Here, we measured plasma sRAGE levels using quantitative LC–MS and assessed whether the plasma sRAGE levels associate with (changes in) lung function, radiological emphysema parameters, and radiological subtypes of emphysema.MethodsThree hundred and twenty-four COPD patients (mean FEV1: 63%predicted) and 185 healthy controls from the COPDGene study were selected. Plasma sRAGE was measured by immunoprecipitation in 96-well plate methodology to enrich sRAGE, followed by targeted quantitative liquid chromatography-mass spectrometry. Spirometry and HRCT scans (inspiration and expiration) with a 5-year follow-up were used; both subjected to high quality control standards.ResultsLower sRAGE values significantly associated with the presence of COPD, the severity of airflow obstruction, the severity of emphysema on HRCT, the heterogeneous distribution of emphysema, centrilobular emphysema, and 5-year progression of emphysema. However, sRAGE values did not associate with airway wall thickness or paraseptal emphysema.ConclusionsRather than being a general COPD biomarker, sRAGE is especially a promising biomarker for centrilobular emphysema. Follow-up studies should elucidate whether sRAGE can be used as a biomarker for other COPD phenotypes as well.

Translated article] Deconstructing phenotypes in COPD: An analysis of the TRACE cohort

ObjectivesIn a clinical phenotype-based management strategy for COPD, it would be preferable to at least assign all patients to a phenotype, but to a single phenotype only. The aim of this study was to evaluate whether all patients are assigned to one and only one phenotype using the Spanish COPD guidelines (GesEPOC) 2017 and to evaluate the criteria that define these categories. MethodThe Time-based Register and Analysis of COPD Endpoints study (TRACE; clinicaltrials.gov NCT03485690) is a prospective cohort of COPD patients attending annual visits since 2012, which collects GesEPOC phenotypes. Although the GesEPOC recommends that patients considered to be at low risk are not phenotyped, an analysis of the criteria for identifying high- and low-risk phenotypes was performed, comparing the distribution of phenotypes and the criteria applied between these 2 groups. ResultsThe cohort included 970 patients with a confirmed diagnosis of COPD, divided into 427 (44.02%) low-risk and 543 (55.9%) high-risk patients. The most frequent phenotype was the non-exacerbator (44.9% of high-risk patients). Overall, 20.6% of low-risk patients met criteria for asthma-COPD overlap syndrome, while 9.2% of the cohort did not meet the diagnostic criteria for any phenotype, and 19.1% met the criteria for 2 phenotypes, with no differences between risk groups. ConclusionsOur data highlight some of the weaknesses of the current clinical phenotype strategy, revealing overlapping categories in some cases, and patients to whom no phenotype was assigned.

The importance of the multidisciplinary team in the management of different COPD phenotypes

The importance of the multidisciplinary team in the management of different COPD phenotypes

Long-Term Noninvasive Ventilation in Chronic Obstructive Pulmonary Disease: Association between Clinical Phenotypes and Survival.

Long-term noninvasive ventilation (LTNIV) is widely used in patients with chronic hypercapnic respiratory failure (CHRF) related to COPD. Prognosis of these patients is however poor and heterogenous. In COPD patients under LTNIV for CHRF, is it possible to identify specific phenotypes which are predictive of probability of pursuing NIV and survival? A latent class analysis was performed in a COPD population under LTNIV included in a comprehensive database of patients in the Geneva Lake area, to determine clinically relevant phenotypes. The observation period of this subgroup of COPD was extended to allow assessment of survival and/or pursuit of NIV for at least 2 years after inclusion. A logistic regression was conducted to generate an equation accurately attributing an individual patient to a defined phenotype. The identified phenotypes were compared on a series of relevant variables, as well as for probability of pursuing NIV or survival. A competitive risk analysis allowed to distinguish death from other causes of cessation of NIV. Two phenotypes were identified: a "respiratory COPD" profile with very severe airway obstruction, a low or normal body mass index, and a low prevalence of comorbidities and a "systemic COPD" profile of obese COPDs with moderate airway obstruction and a high rate of cardiovascular and metabolic comorbidities. The logistic regression correctly classified 95.7% of patients studied. Probability of pursuing NIV and survival were significantly related to these phenotypes, with a poorer prognosis for "respiratory COPD." Probability of death 5 years after implementing NIV was 22.3% (95% CI: 15.4-32.2) for "systemic COPD" versus 47.2% (37.4-59.6) for "respiratory COPD" (p = 0.001). The two distinct phenotypes of COPD under LTNIV for CHRF identified appear to be strongly related to prognosis and require further validation in other cohort studies.