Branislava Milenkovic

The EMBARC European bronchiectasis registry: Protocol for an international observational study

Bronchiectasis is one of the most neglected diseases in respiratory medicine. There are no approved therapies and few large-scale, representative epidemiological studies. The EMBARC (European Multicentre Bronchiectasis Audit and Research Collaboration) registry is a prospective, pan-European observational study of patients with bronchiectasis. The inclusion criterion is a primary clinical diagnosis of bronchiectasis consisting of: 1) a clinical history consistent with bronchiectasis; and 2) computed tomography demonstrating bronchiectasis. Core exclusion criteria are: 1) bronchiectasis due to known cystic fibrosis; 2) age <18 years; and 3) patients who are unable or unwilling to provide informed consent. The study aims to enrol 1000 patients by April 2016 across at least 20 European countries, and 10 000 patients by March 2020. Patients will undergo a comprehensive baseline assessment and will be followed up annually for up to 5 years with the goal of providing high-quality longitudinal data on outcomes, treatment patterns and quality of life. Data from the registry will be available in the form of annual reports. and will be disseminated in conference presentations and peer-reviewed publications. The European Bronchiectasis Registry aims to make a major contribution to understanding the natural history of the disease, as well as guiding evidence-based decision making and facilitating large randomised controlled trials. The European Bronchiectasis Registry will recruit 10 000 patients over 5 years http://ow.ly/Ul7Pd

Pulmonary function, oxidative stress and inflammatory markers in severe COPD exacerbation.

BACKGROUND Oxidative stress and inflammation play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). OBJECTIVE Pulmonary function, oxidative stress parameters and inflammatory markers were measured in 74 patients with severe COPD exacerbation and 41 healthy subjects. In patients all parameters were assessed at two time points: Firstly, one day after admission and secondly, after 7 10 days when they were clinically stable enough to be discharged. Patients were divided in two groups according the presence of ischemic heart disease (IHD): IHD positive (IHD+) patients and IHD negative (IHD-) patients. METHODS AND RESULTS During hospitalisation O2•-, malondialdehyde (MDA), advanced oxidation protein products (AOPP) and total oxidant status (TOS) increased and were higher at discharge compared with admission and the control group. Superoxide dismutase (SOD) activity was significantly lower in COPD patients at both time points compared with the control group. Total antioxidant status (TAS) was significantly lower and the prooxidant-antioxidant balance (PAB) was higher at both time points in COPD patients compared with the control group. High sensitive C-reactive protein (hsCRP) and also the neutrophil count were significantly higher at admission compared with discharge. Paraoxonase 1 (PON1) enzymatic activities in COPD patients did not differ compared with the control group. IHD+ COPD patients had significantly lower PON1 activity but higher PAB levels and hsCRP concentrations, compared with IHD COPD patients. CONCLUSION The oxidant/antioxidant imbalance was significantly pronounced in patients with COPD exacerbation for at least 24 hours following their admission and when they were clinically stable enough to be discharged. Increased oxidative stress, elevated systemic inflammation and decreased antioxidant defence were common in end-stage disease and particularly COPD patients with ischemic heart disease.

Adrenomedullin refines mortality prediction by the BODE index in COPD: the “BODE-A” index

The BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index is well-validated for mortality prediction in chronic obstructive pulmonary disease (COPD). Concentrations of plasma pro-adrenomedullin, a surrogate for mature adrenomedullin, independently predicted 2-year mortality among inpatients with COPD exacerbation. We compared accuracy of initial pro-adrenomedullin level, BODE and BODE components, alone or combined, in predicting 1-year or 2-year all-cause mortality in a multicentre, multinational observational cohort with stable, moderate to very severe COPD. Pro-adrenomedullin was significantly associated (p<0.001) with 1-year mortality (4.7%) and 2-year mortality (7.8%) and comparably predictive to BODE regarding both (C statistics 0.691 versus 0.745 and 0.635 versus 0.679, respectively). Relative to using BODE alone, adding pro-adrenomedullin significantly improved 1-year and 2-year mortality prognostication (C statistics 0.750 and 0.818, respectively; both p<0.001). Pro-adrenomedullin plus BOD was more predictive than the original BODE including 6-min walk distance. In multivariable analysis, pro-adrenomedullin (likelihood ratio Chi-squared 13.0, p<0.001), body mass index (8.5, p=0.004) and 6-min walk distance (7.5, p=0.006) independently foretold 2-year survival, but modified Medical Research Council dyspnoea score (2.2, p=0.14) and forced expiratory volume in 1 s % predicted (0.3, p=0.60) did not. Pro-adrenomedullin plus BODE better predicts mortality in COPD patients than does BODE alone; pro-adrenomedullin may substitute for 6-min walk distance in BODE when 6-min walk testing is unavailable. Pro-adrenomedullin improves BODE prediction of mortality in COPD patients and may substitute for 6-min walk distance http://ow.ly/qV5M3

Relationship between bone resorption, oxidative stress and inflammation in severe COPD exacerbation.

BACKGROUND The natural course of chronic obstructive pulmonary disease (COPD) is complicated by the development of systemic consequences and co-morbidities. Increasing evidence indicates that COPD and osteoporosis are strongly linked. The common features in COPD pathology, history of smoking, age, inactivity, systemic inflammation, and use of systemic corticosteroids, are important risk factors for osteoporosis. METHODS Pulmonary function, matrix metalloproteinase, tissue inhibitor of metalloproteinases, oxidative stress parameters, inflammatory markers and bone resorption marker were measured in 85 COPD patients and 47 healthy subjects. In patients, all parameters were assessed at two time points: one day after admission during exacerbation and about 30 days after, in the stable state of disease. RESULTS In patients, bone resorption marker collagen type I β-isomerized C-terminal telopeptide (beta CL) was increased during exacerbation: geometric mean 0.521, compared with stable patients 0.408, p<0.01, and control subjects 0.362 ng/ml, p<0.001. During exacerbation high sensitivity C-reactive protein (hsCRP) and neutrophil count were significantly higher in COPD patients compared with the control group, p<0.001. Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) concentrations were significantly higher in COPD patients, stable state or exacerbation, compared with control subjects, p<0.001. In patients during exacerbation, total oxidative status (TOS) was higher compared with the stable state, p<0.05 and control group, p<0.001. Multiple linear regression for the joint influence of inflammation, hypoxia and oxidative status during exacerbation showed almost 60% influence on the variability of beta CL concentrations. CONCLUSION Intensification of disease characteristic symptoms such as inflammation, hypoxia, protease/antiprotease imbalance and oxidative stress, during exacerbation episodes in COPD patients may also contribute to increased bone resorption.

Systemic Biomarkers of Collagen and Elastin Turnover Are Associated With Clinically Relevant Outcomes in COPD

Background Extracellular matrix (ECM) remodeling of the lung tissue releases protein fragments into the blood, where they may be detected as serologic surrogate markers of disease activity in COPD. Our goal was to assess the association of ECM turnover with severity and outcome of COPD. Methods In a prospective, observational, multicenter study including 506 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease grades II to IV), serum samples were analyzed at stable state, exacerbation, and 4 weeks after exacerbation. The analysis comprised a panel of five novel neoepitopes, including fragments of collagen type III (C3M) and collagen type VI (C6M), pro‐forms of collagen type III (Pro‐C3) and type VI (Pro‐C6), and neutrophil elastase‐generated fragments of elastin (EL‐NE) according to enzyme‐linked immunosorbent assay. These neoepitopes were also measured at stable state in a derivation cohort that included 100 patients with COPD. Results Serum levels of C3M, C6M, Pro‐C3, Pro‐C6, and EL‐NE were associated with lung function. Patients with the lowest levels of Pro‐C3 and Pro‐C6 had more severe airflow limitation, hyperinflation, air trapping, and emphysema. C3M and C6M were associated with dyspnea. All ECM biomarkers, except Pro‐C6, were increased at exacerbation compared with stable state but, except EL‐NE, did not differ between stable state and exacerbation follow‐up in the crude and adjusted analyses. In Cox regression adjusted analyses, Pro‐C3 was associated with a shorter time to exacerbation (hazard ratio, 0.72; CI, 0.59‐0.89; P = .002) and Pro‐C6 with survival (hazard ratio, 2.09; CI, 1.18‐3.71; P = .011). Conclusions Serum biomarkers of ECM turnover were significantly associated with disease severity and clinically relevant outcomes in patients with COPD. Trial Registry No.: ISRCTN99586989; URL: www.controlled‐trials.com.

Phenotypes of COPD patients with a smoking history in Central and Eastern Europe: the POPE Study

Chronic obstructive pulmonary disease (COPD) represents a major health problem in Central and Eastern European (CEE) countries; however, there are no data regarding clinical phenotypes of these patients in this region. Participation in the Phenotypes of COPD in Central and Eastern Europe (POPE) study was offered to stable patients with COPD in a real-life setting. The primary aim of this study was to assess the prevalence of phenotypes according to predefined criteria. Secondary aims included analysis of differences in symptom load, comorbidities and pharmacological treatment. 3362 patients with COPD were recruited in 10 CEE countries. 63% of the population were nonexacerbators, 20.4% frequent exacerbators with chronic bronchitis, 9.5% frequent exacerbators without chronic bronchitis and 6.9% were classified as asthma–COPD overlap. Differences in the distribution of phenotypes between countries were observed, with the highest heterogeneity observed in the nonexacerbator cohort and the lowest heterogeneity observed in the asthma–COPD cohort. There were statistically significant differences in symptom load, lung function, comorbidities and treatment between these phenotypes. The majority of patients with stable COPD in CEE are nonexacerbators; however, there are distinct differences in surrogates of disease severity and therapy between predefined COPD phenotypes. Distinct phenotypes of COPD in Central and Eastern Europe have differences in symptoms, comorbidities and treatment http://ow.ly/oMZI307ndr5

Prognostic assessment in COPD without lung function: the B-AE-D indices

Several composite markers have been proposed for risk assessment in chronic obstructive pulmonary disease (COPD). However, choice of parameters and score complexity restrict clinical applicability. Our aim was to provide and validate a simplified COPD risk index independent of lung function. The PROMISE study (n=530) was used to develop a novel prognostic index. Index performance was assessed regarding 2-year COPD-related mortality and all-cause mortality. External validity was tested in stable and exacerbated COPD patients in the ProCOLD, COCOMICS and COMIC cohorts (total n=2988). Using a mixed clinical and statistical approach, body mass index (B), severe acute exacerbations of COPD frequency (AE), modified Medical Research Council dyspnoea severity (D) and copeptin (C) were identified as the most suitable simplified marker combination. 0, 1 or 2 points were assigned to each parameter and totalled to B-AE-D or B-AE-D-C. It was observed that B-AE-D and B-AE-D-C were at least as good as BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity), ADO (age, dyspnoea, airflow obstruction) and DOSE (dyspnoea, obstruction, smoking, exacerbation) indices for predicting 2-year all-cause mortality (c-statistic: 0.74, 0.77, 0.69, 0.72 and 0.63, respectively; Hosmer–Lemeshow test all p>0.05). Both indices were COPD specific (c-statistic for predicting COPD-related 2-year mortality: 0.87 and 0.89, respectively). External validation of B-AE-D was performed in COCOMICS and COMIC (c-statistic for 1-year all-cause mortality: 0.68 and 0.74; c-statistic for 2-year all-cause mortality: 0.65 and 0.67; Hosmer–Lemeshow test all p>0.05). The B-AE-D index, plus copeptin if available, allows a simple and accurate assessment of COPD-related risk. The B-AE-D indices allow a simple and accurate assessment of COPD-related risk in the absence of lung function http://ow.ly/XFBox

Mucous Gland Adenoma Simulating Bronchial Asthma: Case Report and Literature Review

We report a case of mucous gland adenoma arising in the left main bronchus which was initially misdiagnosed as asthma and review the previous reported cases of this rare tumor published in the available literature.

Therapy with proton-pump inhibitors for gastroesophageal reflux disease does not reduce the risk for severe exacerbations in COPD.

Gastroesophageal reflux disease (GERD) symptoms are associated with a higher risk of chronic obstructive pulmonary disease (COPD) exacerbation. We hypothesize that treatment with proton pump inhibitors reduces the risk of exacerbation in patients with stable COPD.

Asthma and chronic bronchitis symptoms among adult population of Belgrade

INTRODUCTION Over the last three decades the prevalence of respiratory diseases has been increasing worldwide thus increasing economic burden on the healthcare system. Recent studies have shown that the prevalence of asthma in West European countries ranges from 6-9%, while of chronic obstructive pulmonary diseases (COPD) is 8.0% worldwide. OBJECTIVE The aim of the study was to estimate the prevalence of respiratory symptoms and smoking habits, and to assess the prevalence of asthma and chronic bronchitis among adults in Belgrade, Serbia. METHODS To collect data we used a questionnaire based on the European Community Respiratory Health Survey (ECRHS) protocol, which was mailed to 10,208 randomly selected subjects. RESULTS There were 58.3% of responders to our questionnaire. We noted a higher prevalence of respiratory symptoms in subjects who responded promptly. The majority of the respondents were current or former smokers (37.5% and 17.5% respectively) and 79.9% of them reported respiratory symptoms. The most frequent symptoms were longstanding cough (32.2%), sputum production (30.4%) and wheezing (30.3%). Asthma attacks were reported in 4.4% of cases and 5.6% of subjects were using asthma medications. The prevalence of respiratory symptoms increased with age. Women reported coughing, attacks of breathlessness and coughing, chest tightness by night, allergic rhinitis and chronic coughing, more frequently than men. Productive cough was more frequent in men. The prevalence of almost all symptoms was higher in smokers compared to nonsmokers. CONCLUSION In Serbia there is a high prevalence of respiratory symptoms, asthma and chronic bronchitis smoking addiction.