Progression Of COPD Research Articles

Betulin inhibited cigarette smoke-induced COPD in mice

The purpose of the present study was to evaluate the protective effect of betulin (BE) on CS (cigarette smoke)-induced COPD in mice and explore its underlying mechanisms. 60 male ICR mice were randomly assigned to five groups: control group, model group, dexamethasone (2mg/kg) group, BE (20mg/kg) group and BE (40mg/kg) group. The COPD mice were induced by cigarette smoke exposure for 8 weeks. The result of H&E staining demonstrated that BE inhibited CS-induced pathological injury in lung tissue. Besides, BE could restore the activities of superoxide dismutase (SOD) in serum and in lung, catalase (CAT) in serum and reduce the content of malondialdehyde (MDA) in serum and in lung. BE also inhibited the overproductions of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β). Furthermore, the administration of BE significantly inhibited the protein expression of ROCK/NF-κB pathway in CS-induced mice. Our findings suggested that BE might effectively ameliorate the progression of COPD via ROCK/NF-κB pathway in mice.

The measurement of lung volumes using body plethysmography and helium dilution methods in COPD patients: a correlation and diagnosis analysis.

Chronic obstructive pulmonary disease (COPD) is a chronic airway disease characterized by persistent airflow limitation. Moreover, lung hyperinflation evaluated by lung volumes is also the key pathophysiologic process during COPD progression. Nevertheless, there is still no preferred method to evaluate lung volumes. For this study, we recruited 170 patients with stable COPD to assess lung volumes stratified by airflow limitation severity. Lung volumes including residual volume (RV) and total lung capacity (TLC) were determined by both body plethysmography and helium dilution methods. The discrepancies between these two methods were recorded as ΔRV%pred, ΔTLC%pred, and ΔRV/TLC. We found that ΔRV%pred, ΔTLC%pred, and ΔRV/TLC increased significantly with the severity of COPD. The differences of lung capacity between these two methods were negatively correlated with FEV1%pred, and diffusing capacity for carbon monoxide (DLCO%pred). Moreover, the receiver operating characteristic (ROC) for ΔTLC%pred to distinguish severe COPD from non-severe COPD had an area under curve (AUC) of 0.886. The differences of lung volume parameters measured by body plethysmography and helium dilution methods were associated with airflow limitation and can effectively differentiate COPD severity, which may be a supportive method to assess the lung function of stable COPD patients.

Animal models of COPD: What do they tell us?

COPD is a major cause of global mortality and morbidity but current treatments are poorly effective. This is because the underlying mechanisms that drive the development and progression of COPD are incompletely understood. Animal models of disease provide a valuable, ethically and economically viable experimental platform to examine these mechanisms and identify biomarkers that may be therapeutic targets that would facilitate the development of improved standard of care. Here, we review the different established animal models of COPD and the various aspects of disease pathophysiology that have been successfully recapitulated in these models including chronic lung inflammation, airway remodelling, emphysema and impaired lung function. Furthermore, some of the mechanistic features, and thus biomarkers and therapeutic targets of COPD identified in animal models are outlined. Some of the existing therapies that suppress some disease symptoms that were identified in animal models and are progressing towards therapeutic development have been outlined. Further studies of representative animal models of human COPD have the strong potential to identify new and effective therapeutic approaches for COPD.

MKK3 influences mitophagy and is involved in cigarette smoke-induced inflammation

Cigarette smoking is the primary risk factor for COPD which is characterized by excessive inflammation and airflow obstruction of the lung. While inflammation is causally related to initiation and progression of COPD, the mitochondrial mechanisms that underlie the associated inflammatory responses are poorly understood. In this context, we have studied the role played by Mitogen activated protein (MAP) kinase kinase 3 (MKK3), a dual-specificity protein kinase, in cigarette smoke induced-inflammation and mitochondrial dysfunction. Serum pro-inflammatory cytokines were significantly elevated in WT but not in MKK3-/- mice exposed to Cigarette smoke (CS) for 2 months. To study the cellular mechanisms of inflammation, bone marrow derived macrophages (BMDMs), wild type (WT) and MKK3-/-, were exposed to cigarette smoke extract (CSE) and inflammatory cytokine production and mitochondrial function assessed. The levels of IL-1β, IL-6, and TNFα were increased along with higher reactive oxygen species (ROS) and P-NFκB after CSE treatment in WT but not in MKK3-/- BMDMs. CSE treatment adversely affected basal mitochondrial respiration, ATP production, maximum respiratory capacity, and spare respiratory capacity in WT BMDMs only. Mitophagy, clearance of dysfunctional mitochondria, was up regulated in CS exposed WT mice lung tissue and CSE exposed WT BMDMs, respectively. The proteomic analysis of BMDMs by iTRAQ (isobaric tags for relative and absolute quantitation) showed up regulation of mitochondrial dysfunction associated proteins in WT and higher OXPHOS (Oxidative phosphorylation) and IL-10 signaling proteins in MKK3-/- BMDMs after CSE exposure, confirming the critical role of mitochondrial homeostasis. Interestingly, we found increased levels of p-MKK3 by immunohistochemistry in COPD patient lung tissues that could be responsible for insufficient mitophagy and disease progression. This study identifies MKK3 as a negative regulator of mitochondrial function and inflammatory responses to CS and suggests that MKK3 could be a therapeutic target.

Correlation of cardiopulmonary exercise testing parameters with quality of life in stable COPD patients.

The precise head to head relationships between Cardio-pulmonary exercise testing (CPET) parameters and patients' daily symptoms/activities and the disease social/emotional impact are less well defined. In this study, the correlation of COPD daily symptoms and quality of life [assessed by St. George's Respiratory Questionnaire (SGRQ)] and COPD severity index (BODE-index) with CPET parameters were investigated. Symptom-limited CPET was performed in 37 consecutive COPD (GOLD I-III) subjects during non-exacerbation phase. The SGRQ was also completed by each patient. SGRQ-score correlated negatively with FEV1 (r=-0.49, P<0.01), predicted maximal work-rate (%WR-max) (r=-0.44, P<0.01), V'O2/WR (r=-0.52, P<0.01) and breathing reserve (r=-0.50, P<0.01). However it did not correlate with Peak-V'O2% predicted (r=-0.27, P=0.10). In 20 (54.1%) subjects in which leg fatigue was the main cause for stopping the test, Peak-V'O2, %WR-max, HR-Reserve and Breathing reserve were higher (P=0.04, <0.01, 0.04 and <0.01 respectively) than the others. There was also a significant correlation between BODE-index and ∆VO2/∆WR (r=-0.64, P<0.001) and breathing-reserve (r=-0.38, P=0.018). The observed relationships between CPET parameter and daily subjective complaints in COPD were not strong. Those who discontinued the CPET because of leg fatigue were in the earlier stages of COPD. Significant negative correlation between ∆VO2/∆WR and BODE-index suggests that along with COPD progression, regardless of negative past history, other comorbidities such as cardiac/musculoskeletal problems should be sought.

Accelerometric assessment of physical activity in COPD: Correlation between measures by two different devices

A sedentary lifestyle is associated with the progression of COPD and its systemic consequences. Physical activity (PA) can be assessed during daily life by accelerometry but there is considerable heterogeneity regarding methodological approaches and devices. The present study examined the correlation between measures by two common accelerometers in COPD.

Determinants of Smoking Cessation in Patients With COPD Treated in the Outpatient Setting

The beneficial effects of smoking cessation on the progression of COPD are well established. Nevertheless, many patients with COPD continue to smoke. In this nationwide hospital-based prospective follow-up study, we examined rates of smoking cessation and clinical and sociodemographic determinants of smoking cessation in 3,233 patients with COPD who smoked on outpatient contact during 2008 to 2012. Using multivariate Cox regression, we calculated hazard ratios (HRs) of quitting. Within 1 and 5 years from first outpatient contact, the probability of quitting was 19%and 45%, respectively. In adjusted analyses, patients were less likely to quit if they were younger, with an HR of 0.84 (95%CI, 0.71-0.99) for patients aged 50 to 69 years and 0.53 (95%CI, 0.37-0.76) for patients aged 30 to 49, compared with those aged 70 years or older, who had lower income (HR, 0.79; 95%CI, 0.67-0.94), lived alone (HR, 0.75; 95%CI, 0.64-0.88), were unemployed (HR, 0.70; 95%CI, 0.54-0.90), had milder COPD with an HR of0.67 (95%CI, 0.53-0.84) for Global Initiative for Chronic Obstructive Lung Disease (GOLD) A and 0.61 (95%CI, 0.47-0.80) for GOLD B compared with GOLD D, had Medical Research Council (MRC) dyspnea scale score< 4 (HR 0.80, 95%CI 0.68-0.95), or no history of exacerbations treated on an outpatient basis. (HR, 0.80; 95%CI, 0.68-0.93). These findings reinforce that young and socioeconomically disadvantaged patients have more difficulties achieving timely smoking cessation. A novel finding is that patients with milder COPD are less likely to quit. The findings suggest a need for interventional studies focusing on these subgroups to ensure abstinence to halt disease progression.

Role of HIF1A, VEGFA and VEGFR2 SNPs in the Susceptibility and Progression of COPD in a Spanish Population

Hypoxia is involved in the development of chronic inflammatory processes. Under hypoxic conditions HIF1A, VEGF and VEGFR2 are expressed and mediate the course of the resultant disease. The aim of the present study was to define the associations between tSNPs in these genes and COPD susceptibility and progression in a Spanish cohort. The T alleles in rs3025020 and rs833070 SNPs (VEGFA gene) were less frequent in the group of COPD cases and were associated with a lower risk of developing the disease (OR = 0.60; 95% CI = 0. 39–0.93; p = 0.023 and OR = 0.60; 95% CI = 0.38–0.96; p = 0.034, respectively) under a dominant model of inheritance. The haplotype in which both SNPs presented the T allele confirmed the association found (OR = 0.02; 95% CI = 0.00 to 0.66; p = 0.03). Moreover, patients with COPD carrying the T allele in homozygosis in rs3025020 SNP showed higher lung function values and this association remained constant during 3 years of follow-up. In conclusion, T allele in rs833070 and rs3025020 may confer a protective effect to COPD susceptibility in a Spanish population and the association of the SNP rs3025020 with lung function may be suggesting a role for VEGF in the progression of the disease.

Community dynamics and the lower airway microbiota in stable chronic obstructive pulmonary disease, smokers and healthy non-smokers

RationaleThe role bacteria play in the progression of COPD has increasingly been highlighted in recent years. However, the microbial community complexity in the lower airways of patients with COPD is...

Do Model-Based Studies in Chronic Obstructive Pulmonary Disease Measure Correct Values of Utility? A Meta-Analysis

BackgroundChronic obstructive pulmonary disease (COPD) is a progressive chronic disease that has considerable impact on utility-based health-related quality of life. Utility is a key input of many decision analytic models used for economic evaluations. ObjectiveTo systematically review COPD-related utilities and to compare these with alternative values used in decision models. MethodsThe literature review comprised studies that generated utilities for COPD-related stages based on EuroQol five-dimensional questionnaire surveys of patients and of decision models of COPD progression that have been used for economic evaluations. The utility values used in modeling studies and those from the meta-analysis of actual patient-level studies were compared and differences quantified. ResultsTwenty decision modeling studies that used utility value as an input parameter were found. Within the same span of publication period, 13 studies involving patient-level utility data were identified and included in the meta-analysis. The estimated mean utility values ranged from 0.806 (95% confidence interval [CI] 0.747–0.866) for stage I to 0.616 (95% CI 0.556–0.676) for stage IV. The utility scores for comparable stages in modeling studies were different (significant difference 0.045 [95% CI 0.041–0.052] for stage III). Modeling studies consistently used higher utility values than the average reported patient-level data. ConclusionsCOPD decision analytic models are based on a limited range of utility values that are systematically different from average values estimated using a meta-analysis. A more systematic approach in the application of utility measures in economic evaluation is required to appropriately reflect current literature.

Contribution of bronchial biopsies in the evaluation of pathogenesis and progression of COPD

This review summarizes and discusses the lung pathology of COPD patients emphasising on inflammatory cell phenotypes and mechanisms which prevail in different clinical conditions. In bronchial biopsies a series of events takes place during the progression of the disease from mild to severe. T-lymphocytes, particularly CD8+ cells and macrophages are the prevalent inflammatory cells in the lungs of healthy smokers and patients with mild/moderate COPD. This T-cell activation seems to be sustained by CD4+, CD8+ cells and macrophages expressing transcription factors and Tc1 cytokines such as NF-kB, STAT4 and IFNgamma. In contrast, severe disease is characterized by lymphocytes producing greater amounts of TGF-beta1 and by an increase of nitrotyrosine immunoreactivity and activated neutrophils, macrophages and MPO+ cells. However, the mechanisms involved in neutrophilic migration and adhesion are currently under investigation. Recent data has shown that in severe COPD there is an impaired neutrophil capability to respond to chemotactic stimuli, as well as an increased collagen adhesion of neutrophils due to the up-regulation of CD44 and CD11b receptors. This data together, may account for the increased neutrophilia observed in the severe disease states of COPD. In this context, insights obtained from the tissutal analysis of bronchial biopsies represent an irreplaceable route to further progresses in to the pathogenesis of this disease.

Screening for chronic respiratory diseases in Georgia

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A role for NGF and its receptors TrKA and p75NTR in the progression of COPD.

Nerve growth factor and its receptors, TrkA and p75NTR, are involved in inflammation and airways diseases, but their role in chronic obstructive pulmonary disease is still unclear and not well investigated. our data indicate the stage dependent variation of nerve growth factor and its receptors in chronic obstructive pulmonary disease progression. In fact, for the first time, this study evaluates the presence of nerve growth factor and its receptors in serum and in peripheral blood mononuclear cells of patients with different stages of chronic obstructive pulmonary disease compared to healthy subjects, non-smoker and current smoker. Serum monocyte chemoattractant protein-1, tumor necrosis factor-α, interleukin-10 and forced expiratory volume in 1 s were also analyzed. Compared to healthy subjects, chronic obstructive pulmonary disease patients presented a staging-dependent increase in serum nerve growth factor, negatively correlated to forced expiratory volume in 1 s and positively to monocyte chemoattractant Protein-1. The percentage of p75NTR+ peripheral blood mononuclear cells increased in early stages of chronic obstructive pulmonary disease (I-II), while TrKA+ peripheral blood mononuclear cells increased in late stages (III-IV). Our data demonstrate the involvement and modulation of nerve growth factor and its receptors in chronic obstructive pulmonary disease and in its staging.

The Time Course of Pulmonary Function Tests in COPD Patients with Different Levels of Blood Eosinophils.

Only very few studies have investigated the influence of eosinophils on the functional progression of COPD. We aimed at retrospectively analyzing the trend of pulmonary function tests over time in patients with COPD according to two baseline blood eosinophil cell count strata (<2% [EOS−] and ≥2% [EOS+]). We used the last 9-year data present in the database of our outpatient clinic and selected only those who had two blood counts that would guarantee the stability of the value of eosinophils and serial spirometry for 4 consecutive years. The analysis of the time course of the spirometric variables analysed showed differences in FEV1 and FVC decline between the subjects of the EOS− group and those of the EOS+ group. The integrated evaluation of our results suggests that the different level of blood eosinophils in the two groups may have influenced independently the time course of the pulmonary function tests and identify two subgroups of subjects with specific disease characteristics: the hyperinflator and the rapid decliner, respectively.

A New Anti-inflammatory Therapy for COPD

COPD is a chronic progressive inflammatory lung disease. The key in treating COPD is to treat the inflammation. Current treatments of COPD are LABA, LAMA, and ICS. LABA and LAMA only treat the symptoms of COPD by dilating the small airway; they do not target the underlying mechanism of COPD (the inflammation). ICS only temporarily suppress the inflammation in COPD, cannot terminate the inflammatory reaction and therefore it cannot stop the progression of COPD. Corticosteroid resistant is a big issue in treating COPD. In order to effectively treat COPD, we must find new anti-inflammatory therapies or developing new anti-inflammatory drugs. The author is a clinician and found that the smoke (or the tar) of burning Artemisia argyi (an herb, also called moxa) had special anti-inflammatory effect, which is different to corticosteroid. It not only can effectively treat corticosteroid resistant chronic inflammation, but also can terminate chronic self-perpetuating inflammation. Treatment done for 25 COPD patients with inhalation of moxa smoke, 3/25 patients had no improvement in breathlessness and 22/25 patients became symptoms free after 1-2 months treatment and kept symptoms free without any further treatment.

Study Design and Interim Outcomes of Guangzhou Institute of Respiratory Disease COPD Biobank

Background: GIRD COPD Biobank is a multicenter observational study blood-based database with local characteristics, in order to investigate the causes, risk factors, pathogenesis, prevalence patterns and trends of COPD and promote new pathogenic insights in China.Methods: We enrolled 855 clinically COPD patients and 660 controls with normal lung function. Extensive data collection has been undertaken with questionnaires, clinical measurements, and collection and storage of blood specimens, following Standard Operating Procedures (SOP). All surveys had similar quality controls, supervisions, and training of the investigator team.Results: Since September 2010, a total of 1515 subjects (1116 [73.7%] males; 855 [56.4%] diagnosed with COPD) were enrolled. Analyses of the design and interim results of the GIRD COPD Biobank Study identified patients with COPD were older, lower educational level, a longer history of pack-year smoking, less in kitchen fan usage, X-ray exposure, and history of disease (P < 0.01 for all); Most of the COPD subjects belonged to moderately severe or worse, stratified according to Global Lung Function Initiative (GLI); COPD patients had relatively more co-morbidities than controls; Environmental hazard exposures might be the main contributors to the reported respiratory symptoms; Cold air, haze, and influenza acted the top three factors to induce respiratory symptoms in both COPD cases and controls.Conclusion: The GIRD COPD Biobank Study has the potential to provide substantial novel insights into the genetics, biomarkers, environmental and lifestyle aspects of COPD. It is expected to provide new insights for pathogenesis and the long-term progression of COPD.

The Role of Smoking-Induced Alterations of Soluble Intercellular Adhesion Molecules in the Development of Chronic Obstructive Pulmonary Disease

doi: 10.17691/stm2015.7.4.14 Received April 7, 2015E.V. Makarova, md, Phd, Associate Professor, department of internal diseases PropedeuticsNizhny Novgorod State medical Academy, 10/1 minin and Pozharsky Square, Nizhny Novgorod, 603005, Russian FederationThe aim of the investigation was to study the alterations in the serum level of soluble intercellular adhesion molecules (siCAm) under the influence of smoking and to assess the role of the revealed impairment in the formation and development of chronic obstructive pulmonary disease (CoPd).Materials and Methods. The study included 82 smokers (24 women and 58 men aged 19 to 72 years) and 52 healthy non-smoking donors (17 women and 35 men aged 20 to 57 years). The smokers were divided into the following groups: 1) smokers with normal lung function (mean smoking index of 11.2±4.3 pack-years) — 32 patients; 2) smokers with airflow limitation (CoPd patients) with smoking index of <30 pack-years — 17 patients; 3) smokers having airflow limitation (CoPd patients) with smoking index of 30 pack-years — 33 patients. The subjects underwent clinical examination, CAT test, assessment of dyspnea (mmRC) and smoking index (pack-years), pulmonary function test (PFT), chest radiography, microscopic and microbiological examination of sputum. The serum level of soluble intercellular adhesion antigens siCAm-3 (sCd50) total and siCAm-1 (sCd54) total and oligomer were determined by enzyme immunoassay.Results. The smokers of group 1 were found to have elevated levels of sCd54 antigens (oligomer and total) and sCd50 compared to non-smoking donors, which may reflect a stimulatory effect of tobacco smoke on cell migration into the inflammation focus. Total sCd54 antigen was higher in smoking CoPd patients of group 2 than that of the donor group. There was a decrease in all tested molecules in heavy smokers, CoPd patients (group 3), compared to both the control and group 2. There was found a negative correlation between the serum level of sCd50 and smoking index, as well as positive a correlation between the level of total sCd54 and PFT parameters. Smoking intensity affected CoPd progression. in group 3 the patients had higher mmRC dyspnea index and СAT test score; they had more exacerbations during a year, more frequent application of systemic corticosteroids and antibiotics than the patients in other groups.Conclusion. The revealed smoking-induced alterations in the network of soluble intercellular adhesion molecules contribute to the formation and progression of obstructive disorders and chronic inflammation in CoPd. Low level of soluble adhesion molecules is a marker of severe CoPd with frequent exacerbations.Key words: chronic obstructive pulmonary disease; CoPd; soluble intercellular adhesion molecules; siCAm-1; siCAm-3; smoking.For contacts: makarova Ekaterina Vadimovna, e-mail: e_makarowa@mail.ruThe Role of Smoking-Induced ICAM Alterations in COPD Development

High Expression of Cathepsin E is Associated with the Severity of Airflow Limitation in Patients with COPD

Background: It was reported that Cathepsin E (Cat E) plays a critical role in antigen processing and in the development of pulmonary emphysema. The aim of this study was to investigate the role of Cat E and airflow limitation in the pathogenesis of COPD. Methods: Sixty-five patients with COPD, 20 smoking control subjects without COPD and 15 non-smoking healthy control subjects were enrolled. Cat E and EIC (Elastase inhibitory capacity) expressions were measured by ELISA in sputum and serum samples and compared according to different subgroups. Results: Cat E concentrations were significantly higher in patients with COPD than smoking control and non-smoking control subjects (P < 0.01). The levels of CatE were inversely correlated with FEV1% predicted in COPD patients (r = −0.95, P < 0.01). The levels of EIC were inversely positively correlated with FEV1% predicted in COPD patients (r = 0.926, P < 0.01). Levels of Cat E were also inversely correlated with the levels of EIC (r = −0.922, P < 0.01). Conclusions: Cat E contributes to the severity of airflow limitation during progression of COPD.

Prevalence of different comorbidities in COPD patients by gender and GOLD stage

Background: Several comorbidities frequently affect COPD progression. Aim of the study was to assess the prevalence of main comorbidities by gender and disease severity in a cohort of COPD patients referring for the first time to a specialist institution. Methods: The study was a non-interventional, cross-sectional investigation carried out via automatic and anonymous selection from the institutional data base over the period 2012–2015. Inclusion criteria were: subjects of both sex aged ≥40 years; diagnosis of COPD according to GOLD guidelines 2014; the availability of a complete clinical record file. Variables collected were: lung function; smoking history; BMI; the Charlson Comorbidity Index (CCI); number and kind of comorbidities for each patient. Results: At least one comorbidity of clinical relevance was found in 78.6 % of patients, but at least two in 68.8 %, and three or more were found in 47.9 % of subjects. Mean CCI was 3.4 ± 1.6sd. The overall prevalence was 2.6 comorbidities per patient, but 2.5 in males, and 3.0 in females, respectively (p &lt; 0.05). Cardio-vascular disorders were the most frequent, but significantly more frequent in males (44.7 vs 30.7 %, respectively), while the metabolic, the digestive and the osteo-articular disorders were prevailing in females (12.4 vs 9.2; 14.2 vs 4.8, and 6.0 vs 3.8, respectively). In particular, chronic cor pumonale and arrhythmias mainly prevailed in men and congestive heart failure in females, while arterial hypertension resulted equally distributed. As concerning respiratory disorders, pneumonia, pleural effusions and chronic respiratory failure were more frequently found in men, while bronchiectasis and asthma-COPD overlap syndrome (ACOS) in females. Anaemia, gall bladder stones, osteoporosis and spontaneous fractures mostly prevailed in females, while gastric disorders of inflammatory origin and arthrosis were more frequent in males. Cognition disorders, dementia and signs of degenerative brain disorders were more frequently found in men, while depression in females. Finally, lung cancer was at the first place in men, but at the second in females. Conclusions: All comorbidities increased their prevalence progressively up to the last stage of COPD severity, except the cardio-vascular and the metabolic ones which dropped in the IV GOLD stage, presumably due to the high mortality rate in this severe COPD stage. The gender-dependency of comorbidities was confirmed in general terms, even if lung cancer proved a dramatic increase almost independently of sex.

Prevalence of different comorbidities in COPD patients by gender and GOLD stage.

BackgroundSeveral comorbidities frequently affect COPD progression. Aim of the study was to assess the prevalence of main comorbidities by gender and disease severity in a cohort of COPD patients referring for the first time to a specialist institution.MethodsThe study was a non-interventional, cross-sectional investigation carried out via automatic and anonymous selection from the institutional data base over the period 2012–2015. Inclusion criteria were: subjects of both sex aged ≥40 years; diagnosis of COPD according to GOLD guidelines 2014; the availability of a complete clinical record file. Variables collected were: lung function; smoking history; BMI; the Charlson Comorbidity Index (CCI); number and kind of comorbidities for each patient.ResultsAt least one comorbidity of clinical relevance was found in 78.6 % of patients, but at least two in 68.8 %, and three or more were found in 47.9 % of subjects. Mean CCI was 3.4 ± 1.6sd. The overall prevalence was 2.6 comorbidities per patient, but 2.5 in males, and 3.0 in females, respectively (p < 0.05). Cardio-vascular disorders were the most frequent, but significantly more frequent in males (44.7 vs 30.7 %, respectively), while the metabolic, the digestive and the osteo-articular disorders were prevailing in females (12.4 vs 9.2; 14.2 vs 4.8, and 6.0 vs 3.8, respectively). In particular, chronic cor pumonale and arrhythmias mainly prevailed in men and congestive heart failure in females, while arterial hypertension resulted equally distributed. As concerning respiratory disorders, pneumonia, pleural effusions and chronic respiratory failure were more frequently found in men, while bronchiectasis and asthma-COPD overlap syndrome (ACOS) in females. Anaemia, gall bladder stones, osteoporosis and spontaneous fractures mostly prevailed in females, while gastric disorders of inflammatory origin and arthrosis were more frequent in males. Cognition disorders, dementia and signs of degenerative brain disorders were more frequently found in men, while depression in females. Finally, lung cancer was at the first place in men, but at the second in females.ConclusionsAll comorbidities increased their prevalence progressively up to the last stage of COPD severity, except the cardio-vascular and the metabolic ones which dropped in the IV GOLD stage, presumably due to the high mortality rate in this severe COPD stage. The gender-dependency of comorbidities was confirmed in general terms, even if lung cancer proved a dramatic increase almost independently of sex.