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Ji Won Park,1,&ast; Yoonki Hong,2,&ast; Chin Kook Rhee,3 Hye Sook Choi,4 Kyungjoo Kim,3 Kwang Ha Yoo,5 Ki-Suck Jung,6 Joo Hun Park1 1Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, South Korea; 2Department of Internal Medicine, Kangwon National University, Chuncheon, South Korea; 3Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea; 4Department of Internal Medicine, Kyung Hee University Medical Center, Seoul, South Korea; 5Department of Internal Medicine, Konkuk University School of Medicine, Seoul, South Korea; 6Department of Pulmonary, Allergy and Critical Care Medicine, Hallym University Sacred Heart Hospital, Anyang, South Korea&ast;These authors contributed equally to this workCorrespondence: Joo Hun Park, Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Worldcup road 164, Suwon, Gyeonggi-do, 16499, South Korea, Tel +82-31-219-5116 ; +82-10-8379-8299, Fax +82-31-219-5124, Email jhpamc@naver.com; jhpamc@hanmail.netBackground: A comprehensive analysis of the effects of inhaled corticosteroids (ICS) on COPD in a real-world setting is required due to safety concerns regarding ICS in COPD. This study aimed to explore the impact of ICS on the prognosis of Asian COPD patients in the real-life world.Methods: We examined 978 COPD patients registered in the Korean National Health and Nutrition Examination Survey (KNHANES) database and with their data linked to Health Insurance and Review Assessment (HIRA) data. The outcome measures were ascertained by HIRA from January 1, 2009, to December 31, 2012. This study enrolled two arms; ICS users (N = 85, mean age = 66.7 ± 8.9 years) and non-ICS users (N = 893, mean age = 63.7 ± 9.7 years).Results: Compared to the non-ICS users, the ICS users had a higher rate of pneumonia, tuberculosis, and acute exacerbations (P< 0.05). Hospitalization due to respiratory causes was also higher among ICS users (P< 0.05). Multivariate analysis showed that acute exacerbation was independently associated with the development of pneumonia (P< 0.05), whereas ICS therapy had a tendency to be associated with pneumonia. Another multivariate analysis demonstrated that old age, FEV1, ICS therapy, and pneumonia were independently associated with the occurrence of acute exacerbation (P< 0.05). The concomitant pneumonia (HR = 3.353, P = 0.004) was independently associated with higher mortality (P< 0.05).Conclusion: Our data demonstrated that the ICS users had a higher rate of pneumonia and tuberculosis and the concomitant pneumonia was independently associated with higher mortality, highlighting the importance of cautious and targeted administration of ICS in COPD.Keywords: COPD, inhaled corticosteroids, pneumonia, mortality

We evaluated whether the pathogens identified during acute exacerbation of chronic obstructive pulmonary disease (AE-COPD) are associated with the COPD medications used in the 6 months before AE-COPD. We collected the medical records of patients diagnosed with AE-COPD at 28 hospitals between January 2008 and December 2019 and retrospectively analyzed them. Microorganisms identified at the time of AE-COPD were analyzed according to the use of inhaled corticosteroid (ICS) and systemic steroid after adjusting for COPD severity. We evaluated 1177 patients with AE-COPD and available medication history. The mean age of the patients was 73.9 ± 9.2 years, and 83% were males. The most frequently identified bacteria during AE-COPD were Pseudomonas aeruginosa (10%), followed by Mycoplasma pneumoniae (9.4%), and Streptococcus pneumoniae (5.1%), whereas the most commonly identified viruses were rhinovirus (11%) and influenza A (11%). During AE-COPD, bacteria were more frequently identified in the ICS than non-ICS group (p = 0.009), and in the systemic steroid than non-systemic steroid group (p < 0.001). In patients who used systemic steroids before AE-COPD, the risk of detecting Pseudomonas aeruginosa was significantly higher during AE-COPD (OR 1.619, CI 1.007–2.603, p = 0.047), but ICS use did not increase the risk of Pseudomonas detection. The risk of respiratory syncytial virus (RSV) detection was low when ICS was used (OR 0.492, CI 0.244–0.988, p = 0.045). COPD patients who used ICS had a lower rate of RSV infection and similar rate of P. aeruginosa infection during AE-COPD compared to patients who did not use ICS. However, COPD patients who used systemic steroids within 6 months before AE-COPD had an increased risk of P. aeruginosa infection. Therefore, anti-pseudomonal antibiotics should be considered in patients with AE-COPD who have used systemic steroids.

Background: E-cigarettes are steadily gaining popularity in Korea. However, the characteristics of e-cigarette smokers, especially nicotine dependence and stress susceptibility, have not been evaluated in comparison to those of nonsmokers or combustible cigarette smokers in Korea. Methods: In this study, 28,059 participants from the Korea National Health and Nutrition Examination Survey (2013-2017) were classified into the following three groups: non-smokers, smokers (current smokers and ex-smokers of combustible cigarettes only), and e-smokers (current smokers and ex-smokers of e-cigarettes regardless of combustible cigarette use). Results: Among the participants, 16,980 (60.5%), 9,247 (33.0%), and 1,832 (6.4%) subjects were non-smokers, smokers, and e-smokers, respectively. E-smokers were younger, more educated, and had a higher household income than nonsmokers or smokers. The number of e-smokers who smoked within 5 minutes of waking up (31.5% vs. 19.8%, p

Background This study aimed to investigate the association between e-cigarette (EC) use and development of acute severe pneumonia in the Korean population using a national database. Methods We conducted a retrospective analysis using linkage of data between the Korean National Health and Nutrition Examination Survey (KNHANES) and the National Health Insurance Service (NHIS) administrative claims database. The primary endpoint of this study was development of severe pneumonia requiring hospital admission according to EC use during the study period. The secondary endpoints were in-hospital mortality, intensive care unit (ICU) admission, ventilator care, and days of hospital stay. Results The final analysis included 28,950 individuals, of which 578 (2.0%) were EC users. EC users were younger and more often male than non-EC users. The EC users showed higher level of education and household income and had fewer comorbidities. Severe pneumonia was noted in 37 of 28,372 non-EC users (0.13%), but there were no occurrences of severe pneumonia in EC users. The incidence of pneumonia occurrence was not different between the two groups (P = 1.000). Conclusions Since e-cigarette or vaping use-associated lung injury (EVALI) is most likely included in acute severe pneumonia occurring within 3 months of EC use, it is considered that there might be no EVALI patients in Korea during the investigation period. A large-scale, prospective study is necessary to evaluate the association between EC use and acute lung injury., Graphical Abstract

Interferon (IFN)-γ-inducible chemokines in the CXCR3/ligand axis are involved in cell-mediated immunity and play a significant role in the progression of cancer. We enrolled patients with lung cancer (n = 144) and healthy volunteers as the controls (n = 140). Initial blood samples were collected and concentrations of IFN-γ and IFN-γ-inducible chemokines CXCL9, CXCL10, and CXCL11 were measured using enzyme-linked immunosorbent assay. Of patients with lung cancer, 125 had non-small cell lung cancer (NSCLC) and 19 had small cell lung cancer. The area under the curve (AUC) (95% CI) of CXCL9 was 0.83 (0.80–0.89) for differentiating lung cancer patients from controls. The levels of all the markers were significantly higher in NSCLC patients with stage IV than in those with stages I–III. A Kaplan-Meier survival analysis showed that NSCLC cancer patients with higher levels of all markers showed poorer survival than those with lower levels. In Cox multivariate analysis of patients with NSCLC, independent prognostic factors for overall survival were CXCL9 and CXCL11. CXCL9 was the only independent prognostic factor for cancer-specific survival. Serum IFN-γ-inducible chemokines may be useful as clinical markers of metastasis and prognosis in NSCLC, and CXCL9 levels showed the most significant results.

Background This pilot study aimed to investigate the current status of e-cigarettes (ECs) use patterns among patients with chronic airway disease or chronic respiratory symptoms and the effects of ECs use on respiratory and mental health. Methods A cross-sectional survey was conducted at the outpatient clinic of eight teaching hospitals in South Korea between November 2019 and December 2019. All adult ECs users (19 years and above) who visited the outpatient clinic as a patient with chronic airway disease or chronic respiratory symptoms were eligible to participate in this study. Results A total of 51 subjects responded to the survey. Most of the participants were male (92.2%) and the mean age was 41.8 years. Dominant airway diseases were asthma and chronic obstructive pulmonary disease. Most of the subjects had a history of cigarette smoking and 19 subjects were dual users of current cigarettes and ECs. Most of the subjects started ECs use due to health-related reasons. When comparing exclusive ECs users and dual users, St. George's respiraory questionaire (SGRQ) scores, the proportion of cases with moderate to severe depressive symptoms, and average Fagerstrom Test for Nicotine Dependence scores for ECs were higher in dual users than exclusive ECs users (mean 4.64 vs. 2.38, p=0.006), respectively. Conclusion Most of the subjects started ECs use due to health concerns, but dual users have more respiratory symptoms and higher nicotine dependence in this pilot study. One hypothesis that comes from these results is that greater nicotine dependence may influence behaviours, habits and views about ECs. These preliminary observations need confirmation in a large cohort.

PURPOSE Asthma control in older asthmatics is often less effective, which may be attributed to small airway dysfunction and poor inhalation technique. We compared the efficacy of 2 inhalers (fluticasone propionate/formoterol treatment using a pressurized metered-dose inhaler [p-MDI group] vs. fluticasone propionate/salmeterol treatment using a dry powder inhaler [DPI group]) in older asthmatics. METHODS We conducted a 12-week, randomized, open-label, parallel-designed trial in older patients (over 55 years old) with moderate-to-severe asthma, and compared the efficacy and safety for asthma control between the 2 groups. Subgroup analyses on disease duration and air trapping were performed. Clinical parameters, including changes in lung function parameters, inhaler technique and adherence, were compared with monitoring adverse reactions between the 2 groups. RESULTS A total of 68 patients underwent randomization, and 63 (30 in the p-MDI group and 33 in the DPI group) completed this study. The p-MDI group was non-inferior to the DPI group with regard to the rate of well-controlled asthma (53.3% vs. 45.5%, p < 0.001; a predefined non-inferiority limit of 17%). In subgroup analyses, the proportion of patients who did not reach well-controlled asthma in the p-MDI group was non-inferior to that in the DPI group; the difference was 12.7% among those with a longer disease duration (≥ 15 years) and 17.5% among those with higher air-trapping (RV/TLC ≥ 45%), respectively (a predefined non-inferiority limit of 17%, p < 0.001). No significant differences were observed in lung function parameters, inhalation techniques, adherence and adverse reactions between the 2 groups. CONCLUSION These results suggest that the p-MDI group may be comparable to the DPI group in the management of older asthmatics in aspects of efficacy and safety.

Background: COPD is a well-known risk factor for lung cancer, independent of smoking behavior. By investigating the retrospective National Health Insurance Service-National Sample Cohort (NHIS-NSC) in Korea, this study attempted to prove the hypothesis that COPD is a risk factor for major cancers developing outside of the lungs. We also aimed to investigate the environmental factors associated with the development of lung cancer in COPD patients. Methods: This study analyzed data from the NHIS-NSC over a 12-year period. Among the 514,795 subjects in the NHIS-NSC, 16,757 patients who were diagnosed with any cancer from 2002 to 2003 were excluded. This cohort enrolled six arms consisting of never-smokers without COPD (N=313,553), former smokers without COPD (N=41,359), smokers without COPD (N=112,627), never-smokers with COPD (N=7,789), former smokers with COPD (N=1,085), and smokers with COPD (N=2,677). Results: Incident rate of lung cancer per 100,000 person-year was higher according to smoking and COPD (216 in non-COPD and 757 in COPD among never-smokers, 271 in non-COPD and 1266 in COPD among former smokers, 394 in non-COPD and 1560 in COPD among former smokers, p

BACKGROUND: Cardiovascular disease is one of the main causes of mortality in patients with chronic obstructive pulmonary disease (COPD), and atherosclerosis is a cause of cardiac comorbidities in COPD. However, it is not clear whether airflow limitation is associated with atherosclerosis irrespective of smoking.OBJECTIVE: To investigate whether airflow limitation is independently associated with vascular stiffness.METHODS: We enrolled 18 893 participants (male 70.5%; mean age 47.5 ± 9.8 years; never smokers 44.2%) who underwent spirometry and brachial-ankle pulse wave velocity (baPWV) as part of a standard health examination at Ajou University Hospital, Suwon, South Korea, from January 2010 to December 2015.We defined vascular peripheral atherosclerosis as baPWV ≥ 1400 cm/s and airflow limitation as pre-bronchodilator ratio of forced expiratory volume in 1 sec (FEV1) to forced vital capacity (FVC) RESULTS: Mean baPWV was higher in subjects with airflow limitation (1477.6 ± 331.7 cm/sec, n = 638) than in those without airflow limitation (1344.1 ± 231.8 cm/sec, n = 18255, P < 0.001). In multivariate logistic regression analysis, the following were independent predictors associated with peripheral atherosclerosis (P < 0.05): age, male sex, fasting serum glucose, mean blood pressure, serum leukocyte count, serum low density lipoprotein level and FEV1.CONCLUSION: Airflow limitation was an independent predictor of vascular stiffness irrespective of smoking history, which suggests that airflow limitation is linked with atherosclerosis.

BACKGROUND: Lead exposure is a resurgent environmental issue globally. Smoking can be a source of lead exposure, although the majority of lead poisonings originate from workplace exposures. However, no study has been undertaken concerning the blood lead levels based on the chronic obstructive pulmonary disease (COPD), smoking status, and other risk factors of COPD. This cross-sectional study was conducted to investigate the blood lead levels according to COPD and clinical variables associated with COPD. METHODS: Data (total number =53,829) were collected from the Korean National Health and Nutrition Examination Survey (IV in 2008 and 2009, V in 2010–2012, and VI in 2013). Multivariable linear regression analyses were performed to determine variables associated with elevated blood lead levels. RESULTS: Univariate regression analysis showed that male sex, older age, smoking, occupation level, income level, education level, and presence of COPD were related to higher blood lead levels, whereas the other co-morbidities including diabetes, hypertension, cerebral stroke, osteoporosis, asthma, and depression were not related (P

Background COPD is a well-known risk factor for lung cancer, independent of smoking behavior. By investigating the retrospective National Health Insurance Service-National Sample Cohort (NHIS-NSC) in Korea, this study attempted to prove the hypothesis that COPD is a risk factor for major cancers developing outside of the lungs. We also aimed to investigate the environmental factors associated with the development of lung cancer in COPD patients. Methods This study analyzed data from the NHIS-NSC over a 12-year period. Among the 514,795 subjects in the NHIS-NSC, 16,757 patients who were diagnosed with any cancer from 2002 to 2003 were excluded. This cohort enrolled six arms consisting of never-smokers without COPD (N = 313,553), former smokers without COPD (N = 41,359), smokers without COPD (N = 112,627), never-smokers with COPD (N = 7789), former smokers with COPD (N = 1085), and smokers with COPD (N = 2677). Results Incident rate of lung cancer per 100,000 person-year was higher according to smoking and COPD (216 in non-COPD and 757 in COPD among never-smokers, 271 in non-COPD and 1266 in COPD among former smokers, 394 in non-COPD and 1560 in COPD among smokers, p p p Conclusion Our data suggested that COPD was an independent risk factor for the development of lung cancer, and colorectal cancer and liver cancer among other major cancers in the Korean population, regardless of smoking status.

Background Smoking is a major risk factor for COPD. However, there is low COPD awareness among smokers. We conducted a field survey to investigate COPD awareness, optimistic bias associated with COPD, and COPD prevalence (using handheld spirometry) among current male smokers. Subjects and methods We enrolled currently smoking males aged over 40 years, who completed a self-administered questionnaire. The questionnaire consisted of six parts: 1) baseline demographics, 2) participants' awareness of COPD and pulmonary function tests, 3) presence of COPD-related respiratory symptoms and experience with pulmonary function testing, 4) optimistic bias about COPD, 5) willingness to change attitude toward respiratory health, and 6) preference of media for obtaining health-related information. Pulmonary function was assessed via handheld spirometry by two experienced pulmonary function laboratory technicians after completion of the questionnaire. Results We enrolled 105 participants. Only 24.8% knew of COPD. Awareness of pulmonary function testing was reported by 41.9% of participants, and 30.5% had previously undertaken pulmonary function tests. Among the subjects who had not previously undergone pulmonary function tests, 47% were not aware of their existence. The mean optimistic bias scores were 3.9 and 4.0, respectively, reflecting the general perception, among participants, that they were about as likely to develop COPD as similarly aged smokers and friends, respectively. A total of 40.0% of participants perceived personal COPD risk to be lower than COPD risk among their friends. Abnormal handheld spirometry results were observed in 28.6% of participants. Among the subjects with abnormal handheld spirometry results, 36.7% had FEV1 values

Background: Low body mass index (BMI) is an important prognostic factor in chronic obstructive pulmonary disease (COPD). However, the prognostic value of longitudinal BMI change in COPD has not been well studied. Objective: We aimed to evaluate the association between longitudinal change of BMI and prognosis of COPD in Korean COPD cohort. Methods: This study was conducted in a prospective Korean Obstructive Lung Disease (KOLD) cohort where COPD patients were recruited on an outpatient basis at 17 hospitals in South Korea. Annual BMI was measured over a period of 3 years or more. All patients were categorized into underweight (UW), normal weight (NW), and overweight (OW) groups by BMI. Clinical characteristics and outcomes including exacerbation and mortality were compared based on initial BMI grade and longitudinal change of BMI. Results: This analysis included 537 COPD patients (mean age = 67.4 ± 7.9 years, male = 97.0%, mean BMI = 23.0 ± 3.1) of KOLD cohort. The proportions of UW, NW, and OW groups were 6.9% (n = 37), 68.9% (n = 370), and 24.2% (n = 130) respectively. The UW group showed lower forced expiratory volume in 1 s (FEV1) (p < 0.001), shorter 6-minute walk distance (p < 0.001), higher modified Medical Research Council score (p = 0.002), higher St. George Respiratory Questionnaire score (p < 0.001), higher emphysema index (p < 0.001) and air-trapping index (p < 0.001), and more frequent (p < 0.001) and severe exacerbations (p = 0.003). Multivariable analyses demonstrated that decrease of BMI (hazard ratio [HR] = 0.786, p = 0.038) and the descent of BMI group (HR = 3.167, p = 0.016) at 3-year follow-up along with age, initial BMI, post-bronchodilator FEV1, and severe exacerbations were significantly associated with mortality. Conclusions: This study demonstrated that BMI decrease during follow-up was independently associated with exacerbation and higher mortality of COPD, suggesting BMI reduction in COPD should be carefully managed.

Background As mentioned in the 'Action Strategy for TB Safe Korea' in March 2017, almost 2 million Koreans were screened for latent tuberculous infection (LTBI) in 2017. As a preliminary step, the Korean Institute of Tuberculosis (KIT) screened 23 824 individuals from various population groups. The present study aimed to characterise the data collected from the screening programme using the QuantiFERON®-TB Gold In-Tube (QFT) assay. Methods Interferon-gamma release assays were performed using the manual QFT or automated DS2 instruments. Statistical analyses were performed using Stata software. Turnaround time (TAT) was defined as the average time required from submission of whole blood samples by each regional laboratory to the reporting of results by the central laboratory. Results Seventeen individuals (0.1%) had indeterminate results on repeat testing, 4519 (18.98%) screened positive and 19 288 (81.0%) were screen-negative. The group of social welfare workers had the highest positivity rate, at 27.2%. Of the 11 regions in Korea, the Gyeonggi Region had the highest positivity rate, at 25.8%. The overall mean ± standard deviation for TAT was 3.05 ± 1.66. Conclusion These findings provide information on LTBI prevalence in a Korean population, and will be helpful in implementing the LTBI screening strategy for those participating in the Action Strategy for TB Safe Korea.

We evaluated new features from biosignals comprising diverse physiological response information to predict the outcome of weaning from mechanical ventilation (MV). We enrolled 89 patients who were candidates for weaning from MV in the intensive care unit and collected continuous biosignal data: electrocardiogram (ECG), respiratory impedance, photoplethysmogram (PPG), arterial blood pressure, and ventilator parameters during a spontaneous breathing trial (SBT). We compared the collected biosignal data’s variability between patients who successfully discontinued MV (n = 67) and patients who did not (n = 22). To evaluate the usefulness of the identified factors for predicting weaning success, we developed a machine learning model and evaluated its performance by bootstrapping. The following markers were different between the weaning success and failure groups: the ratio of standard deviations between the short-term and long-term heart rate variability in a Poincaré plot, sample entropy of ECG and PPG, α values of ECG, and respiratory impedance in the detrended fluctuation analysis. The area under the receiver operating characteristic curve of the model was 0.81 (95% confidence interval: 0.70–0.92). This combination of the biosignal data-based markers obtained during SBTs provides a promising tool to assist clinicians in determining the optimal extubation time.

Background: Lead exposure is a resurgent environmental issue globally. Smoking can be a source of lead exposure although the majority of lead poisonings originate from workplace exposures. We attempted to investigate the blood lead levels based on COPD and smoking status and the independent association between elevated blood lead levels and clinical variables. Methods: Our data were collected from Korean National Health and Nutrition Examination Survey (KNHANES) IV (n= 9744 in 2008, n= 10533 in 2009), V (n = 8518 in 2011), and VI (n = 8018 in 2013). Blood lead levels were analyzed based on clinical variables. Multivariate linear regression analyses were done to find variables associated with elevated blood lead levels. Results: Blood lead levels were higher in males, older age group, smokers, COPD, lower education group, and lower income group (p Conclusion: Smoking status and education level along with old age and male gender were independently associated with higher blood lead levels, however COPD was not, suggesting higher blood lead level in COPD should be attributed to other correlated clinical factors.

Background Pulmonary functions are interpreted using predicted values from reference equations that vary with ethnicity, gender, age, height, and weight. The universally used Choi's reference equations are not validated for Korean populations, and the purpose of this study was to validate them and develop new reference equations. Methods Subjects with normal spirometry and chest radiographs, no co-morbidities, and non-smokers, from the Korean National Health and National Examination Survey (KNHANES)-VI were enrolled (n = 117). Intraclass correlation coefficient (ICC) was assessed for reliability of reference equations. New reference equations were developed using linear regression analysis. Differences between observed and predicted values were assessed to compare the reference equations from Choi's, Global Lung Function Initiative 2012, KNHANES-IV, and newly developed equations. Results The ICC of Choi's reference equations was 0.854 (P < 0.001). The new reference equations for men were: forced vital capacity (FVC) (L) = − 4.38775 − 0.01184 × age + 0.05547 × height, forced expiratory volume – 1 second (FEV1) (L) = − 2.40147 − 0.02134 × age + 0.04103 × height; and for women: FVC (L) = − 3.09063 + 0.003904 × age + 0.038694 × height; FEV1 (L) = − 1.32933 − 0.00872 × age + 0.02762 × height. The differences between the predicted and observed means were largest in Choi's equations, but lowest in the new equations with highest goodness of fit. Conclusion Because Choi's reference equations presented larger differences from the observed values, despite reliability, and the new reference equations showed better goodness of fit, we suggest the latter for Korean populations., Graphical Abstract

Yeon-Mok Oh,1,* Keu Sung Lee,2,* Yoonki Hong,3,* Sung Chul Hwang,2 Jae Yeol Kim,4 Deog Keom Kim,5 Kwang Ha Yoo,6 Ji-Hyun Lee,7 Tae-Hyung Kim,8 Seong Yong Lim,9 Chin Kook Rhee,10 Hyoung Kyu Yoon,11 Sang Yeub Lee,12 Yong Bum Park,13 Jin Hee Jung,14 Woo Jin Kim,3 Sang-Do Lee,1 Joo Hun Park2 1Department of Pulmonary and Critical Care Medicine and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 2Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Korea; 3Department of Internal Medicine and Environmental Health Center, Kangwon National University, Kangwon National University Hospital, Chuncheon, Korea; 4Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea; 5Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea; 6Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea; 7Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea; 8Division of Pulmonology, Department of Internal Medicine, Hanyang University College of Medicine, Guri, Korea; 9Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea; 10Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St Mary’s Hospital, Catholic University of Korea, Seoul, Korea; 11Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Korea University Anam Hospital, Seoul, Korea; 12Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Korea University Anam Hospital, Seoul, Korea; 13Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea; 14Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea *These authors contributed equally to this work Background: High blood eosinophil count is a predictive biomarker for response to inhaled corticosteroids in prevention of acute exacerbation of COPD, and low blood eosinophil count is associated with pneumonia risk in COPD patients taking inhaled corticosteroids. However, the prognostic role of blood eosinophil count remains underexplored. Therefore, we investigated the associated factors and mortality based on blood eosinophil count in COPD.Methods: Patients with COPD were recruited from 16 hospitals of the Korean Obstructive Lung Disease cohort (n=395) and COPD in Dusty Area cohort (n=234) of Kangwon University Hospital. The two merged cohorts were divided based on blood eosinophil count into three groups: high (≥5%), middle (2%–5%), and low (

Anemia is a major co-morbidity in chronic obstructive pulmonary disease (COPD). However, the mechanism of development for anemia and the impact of anemia on the prognosis of COPD remain poorly understood. Therefore, this study attempted to evaluate the prognostic role of anemia on the clinical course of COPD and investigate the factors linked with the serum hemoglobin level in COPD.We analyzed 407 COPD patients enrolled in the Korean obstructive lung disease (KOLD) cohort at 16 hospitals in Korea recruited over 9 years. Multivariate Cox regression analysis was performed to find independent predictors of survival and multivariate logistic regression analyses were done to find independent factors.Anemic COPD were older with lower body mass index (BMI) (P0.001), lower serum cholesterol level (P=0.001), lower serum albumin level (P0.001), and shorter 6-minute walking distance (P=0.046) compared to non-anemic COPD. A multivariate Cox regression analysis revealed that age (P=0.002), BMI (P=0.001), post-bronchodilator forced expiratory volume in 1 second (FEVOur data showed that anemia was an independent risk factor for mortality in COPD, and aging, lower serum albumin level, and lower BMI were independent factors associated with lower serum hemoglobin level.

SETTING: A tertiary care academic medical centre.OBJECTIVE: To evaluate the clinical usefulness of C-X-C motif chemokine receptor 3 (CXCR3) ligands in tuberculous pleural effusion (TPE).DESIGN: We recruited 336 patients with pleural effusion due to various causes. Concentrations of interferon-gamma (IFN-γ) and the CXCR3 ligands CXCL9 and CXCL11 were determined using enzyme immunoassays; adenosine deaminase (ADA) activity was measured in pleural fluid and serum.RESULTS: TPE was diagnosed in 106 patients. Non-TB conditions included lung cancer (n = 95), para-pneumonic effusion (n = 52), non-lung malignancy (n = 30), other exudate (n = 24) and transudate (n = 29) disorders. All marker levels in serum samples and pleural fluid were significantly higher in the TPE group. Analyses of receiver operating characteristic curves for differentiating TPE from non-TB effusions produced the following results for the area under the curve (AUC) for CXCL9, CXCL11, IFN-γ and ADA, respectively: 0.982, 0.952, 0.982, and 0.952. Marker AUCs in lymphocytic exudates were also high. Combining the levels of CXCL9, IFN-γ and ADA in pleural fluid improved the diagnostic performance. Serum levels of CXCL9 had the highest AUC (0.848) for diagnosing TPE.CONCLUSION: Levels of CXR3 ligands in pleural effusion are useful for diagnosing TPE.

Background: Cardiovascular disease is the most common cause of death in chronic obstructive pulmonary disease (COPD). However, the impact of cardiovascular comorbidities on the prognosis of COPD is not well known. Objectives: This study was performed to investigate the effects of cardiovascular comorbidities on the prognosis of COPD. Methods: We enlisted 229 patients with COPD who underwent comprehensive cardiac evaluations including coronary angiography and echocardiography at Ajou University Hospital between January 2000 and December 2012. Survival analyses were performed in this retrospective cohort. Results: Kaplan-Meier analyses showed that COPD patients without left heart failure (mean survival = 12.5 ± 0.7 years) survived longer than COPD patients with left heart failure (mean survival = 6.7 ± 1.4 years; p = 0.003), and the survival period of nonanemic COPD patients (mean survival = 13.8 ± 0.8 years) was longer than that of anemic COPD patients (mean survival = 8.3 ± 0.8 years; p < 0.001). The survival period in COPD with coronary artery disease (CAD; mean survival = 11.37 ± 0.64 years) was not different from that in COPD without CAD (mean survival = 11.98 ± 0.98 years; p = 0.703). According to a multivariate Cox regression model, a lower hemoglobin level, a lower left ventricular ejection fraction, and the forced expiratory volume in 1 s (FEV1) were independently associated with higher mortality in the total COPD group (p < 0.05). Conclusions: Hemoglobin levels and left ventricular ejection fraction along with a lower FEV1 were identified as independent risk factors for mortality in COPD patients who underwent comprehensive cardiac evaluations, suggesting that multidisciplinary approaches are required in the care of COPD.

Aims: Cardiovascular disease is one of the main causes of mortality for COPD and atherosclerosis is a root cause of cardiac co-morbidities in COPD. However, it is not clear whether airflow limitation is associated with atherosclerosis irrespective of smoking. Therefore, we attempted to investigate whether airflow limitation is independently associated with peripheral atherosclerosis. Methods: We enrolled 22,466 participants (male = 69.7 %, non-smoker = 44.5 %) who underwent spirometry and brachial-ankle pulse wave velocity (baPWV) for health screening at Ajou University Hospital from January 2010 to December 2015. We defined peripheral atherosclerosis as baPWV≥1400 cm/s and airflow limitation as pre-bronchodilator ratio of FEV1 to FVC Results: Mean baPWV was higher in airflow limitation group than in control group (1477.6 ± 330.7 vs. 1350.7 ± 222.1 cm/s, p Conclusion: FEV1/FVC was an independent predictor of peripheral atherosclerosis both in smokers and non-smokers, suggesting airflow limitation is linked with atherosclerosis irrespective of smoking.

Jin Hwa Song,1 Chang-Hoon Lee,1 Jin Woo Kim,2 Won-Yeon Lee,3 Ji Ye Jung,4 Joo Hun Park,5 Ki Suck Jung,6 Kwang Ha Yoo,7 Yong Bum Park,8 Deog Keom Kim9 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, 2Division of Pulmonology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, 3Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do, 4Division of Pulmonology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, 5Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, 6Division of Pulmonary Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University Medical School, Anyang, Gyeonggi-do, 7Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, 8Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Kangdong Sacred Heart Hospital, 9Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea Background: Recent studies that assessed the relevance of the blood eosinophil count as a biomarker in patients with COPD may have overestimated it because they included patients with asthma–COPD overlap syndrome (ACOS). We investigated the clinical implications of the blood eosinophil count in patients with non-ACOS COPD.Patients and methods: From a Korean COPD Subtype Study (KOCOSS) cohort, we selected patients with non-ACOS COPD after excluding ACOS patients according to Spanish criteria. Clinical characteristics and the incidence of moderate-to-severe exacerbation were compared among the four groups stratified according to the quartiles of blood eosinophil percent and count.Results: Of the KOCOSS cohort of 1,132 patients with COPD, 467 non-ACOS COPD patients (41.2%) with data of blood eosinophil count remained after excluding those with ACOS based on the Spanish definition. There was no difference in clinical characteristics among groups classified according to the quartiles of eosinophil percent and count. On multivariate logistic regression, eosinophil quartiles in percent and absolute count were not associated with the incidence of moderate-to-severe acute exacerbations of COPD (AECOPD). The eosinophil count did not affect the risk of AECOPD or forced expiratory volume in 1second (FEV1) changes according to exposure to inhaled corticosteroid (ICS). However, by increasing the cutoff value for the eosinophil count from 200/µL to 600/µL, the odds ratio for risk of exacerbation increased serially from 0.82 to 2.96 on trend analysis.Conclusion: In patients with non-ACOS COPD, the blood eosinophil count and percent were not associated with FEV1 changes, quality of life (QoL), AECOPD frequency, or response to ICS. The clinical implication of the blood eosinophil count should not be overestimated in patients with non-ACOS COPD. Keywords: eosinophil, chronic obstructive lung disease, asthma, acute exacerbation, inhaled corticosteroid

SETTING Frequent exacerbation is an important phenotype in chronic obstructive pulmonary disease (COPD), while emphysema is associated with many comorbidities and lung function decline. OBJECTIVE To investigate unique features of frequent exacerbators and test the hypothesis that emphysematous phenotype is associated with frequent exacerbations of COPD. METHODS A total of 380 COPD patients were recruited from 16 hospitals in Korea from June 2005 to April 2012 for analysis. We searched for independent predictors of frequent exacerbators in comparison with non-exacerbators. RESULTS As the severity of emphysema increased, forced expiratory volume in 1 s (FEV₁), and FEV₁/FVC (forced volume capacity) worsened; hyperinflationary features characterised by higher total lung capacity (TLC) were observed (P < 0.05). Frequent exacerbators had lower body mass index (BMI), higher St George's Respiratory Questionnaire (SGRQ) scores, higher residual volume (RV)/TLC, more severe airflow limitation (lower FEV₁ and FEV₁/FVC), lower carbon monoxide diffusion capacity, lower serum protein levels and a higher emphysema index than non-exacerbators (P < 0.05). In multivariate analysis, frequent exacerbators were independently associated with a higher emphysema index, lower serum protein levels and higher RV/TLC (P < 0.05). CONCLUSION Our data show that the severity of emphysema, severe static hyperinflation and serum lower protein levels are independent predictors of frequent exacerbations in COPD patients.

SETTING Emphysema without airway obstruction or airway obstruction without emphysema are often detected clinically, although they are commonly co-existent. We therefore tested the hypothesis that non-obstructive emphysema and pure airway obstruction have unique features. METHODS A case-control observation study was undertaken retrospectively in a patient cohort at a single centre. Among 2662 subjects who underwent chest computed tomography and pulmonary function tests, we enrolled 90 patients with non-obstructive emphysema, 119 with pure airway obstruction, 81 with obstructive emphysema and 2031 subjects as normal controls. The features of the four groups were analysed and compared. RESULTS Higher serum homocysteine (13.4 ± 7.4 vs. 11.6 ± 4.6 mol/l), higher rate of osteoporosis (15.8% vs. 4.5%), higher leukocyte count, higher male ratio, lower serum albumin and lower body mass index were observed in subjects with non-obstructive emphysema than in controls (P < 0.05). In multiple logistic regression analysis of groups without airway obstruction, osteoporosis, hyperhomocysteinaemia, hypoalbuminaemia and higher leukocyte count were independent factors associated with non-obstructive emphysema (P < 0.05). CONCLUSION Hyperhomocysteinaemia, hypoalbuminaemia, osteoporosis and higher leukocyte count were independent predictors of non-obstructive emphysema.

Lung fibroblasts are believed to be a major source of vascular endothelial growth factor (VEGF), which supports the survival of lung endothelial cells and modulates the maintenance of the pulmonary microvasculature. VEGF has been related to the pathogenesis of lung diseases, including chronic obstructive pulmonary disease (COPD). Prostaglandin E2 (PGE2) stimulates VEGF production from lung fibroblasts via the E-prostanoid (EP)-2 receptor. The EP2 signaling pathway uses cyclic adenosine monophosphate (cAMP) as a second messenger, and cAMP is degraded by phosphodiesterases (PDEs). This study investigates whether phosphodiesterase inhibition modulates the human lung fibroblast VEGF production induced by PGE2. Human fetal lung fibroblasts were cultured with PGE2 and PDE inhibitors. The PDE4 inhibitors roflumilast, roflumilast N-oxide, and rolipram with PGE2 increased VEGF release, as quantified in supernatant media by ELISA. In contrast, PDE3, PDE5, and PDE7 inhibitors did not affect VEGF release. Roflumilast increased VEGF release with either an EP2 or an EP4 agonist. Roflumilast augmented the cytosolic cAMP levels induced by PGE2 and VEGF release with other agents that use the cAMP signaling pathway. Roflumilast-augmented VEGF release was completely inhibited by a protein kinase A (PKA) inhibitor. Roflumilast with PGE2 increased VEGF mRNA levels, and the blockade of mRNA synthesis inhibited the augmented VEGF release. The stimulatory effect of roflumilast on VEGF release was replicated using primary healthy and COPD lung fibroblasts. These findings demonstrate that PDE4 inhibition can modulate human lung fibroblast VEGF release by PGE2 acting through the EP2 and EP4 receptor-cAMP/PKA signaling pathway. Through this action, PDE4 inhibitors such as roflumilast could contribute to the survival of lung endothelial cells.

Pharmacologic therapy in COPD aimed to achieve symptomatic relief, improve quality of life, and prevent the disease progression measured by lung function decline or aggravation of emphysema. Pharmacologic agents which can effectively stop disease progression are not currently available so far, although some therapeutic trials in animal studies demonstrated promising results [1–5]. However, pharmacologic therapy can improve major symptoms and quality of life in COPD. Among many therapeutic agents, bronchodilators including β2 agonist, anticholinergic agent, inhaled corticosteroid, and phosphodiesterase 4 inhibitor (roflumilast) are deemed to be the mainstay of COPD treatment [6–9]. Bronchodilators can improve main symptoms and exercise capacity in COPD by decreasing airflow limitation and reducing dynamic pulmonary hyperinflation, although the positive outcome on mortality and decline of lung function has not been proven yet [10–12].

Background: Proper education on inhaler usage and COPD management is essential in managing COPD patients but it is not performed well at private clinics in Korea. Therefore this study was conducted to see the effect of comprehensive education program including inhaler training and COPD management at private clinics. Methods: We enlisted 286 patients with asthma or COPD on an outpatient basis at 40 private clinics in Korea. The patients were educated on inhaler usage and disease management three times on a two week basis. COPD assessment test (CAT) score was measured and questionnaires about correct usage of inhaler and understanding of COPD were obtained from physicians and patients before and after this education program. Outcomes of 127 patients with COPD (male : 89%, mean age : 67.8 ± 14.2 years) were analyzed. Results: CAT score (19.6 ± 12.5 vs. 15.1± 12.3) and COPD symptoms including cough, sputum, dyspnea, and chest tightness improved significantly after this education program (p Conclusion: Comprehensive education program including inhaler training and COPD management performed at private clinics improved CAT score, and led to patients9 better understanding of COPD management.

Background: In COPD, coronary artery disease (CAD) is a frequent co-morbidity and cardiovascular disease is the most common cause of death. When coronary angiography was performed, the Gensini score is used for the assessment of CAD severity. This study was performed to evaluate the clinical impact of Gensini score in COPD. Methods: We retrospectively reviewed 191 patients with COPD (male 90.1%, mean age 68.5 ± 8.9 years, smoker 86.2%) who had undergone coronary angiography in Ajou University Hospital from Jan 2000 to Dec 2012. The extent of CAD in the entire coronary arterial tree was assessed by Gensini score. Comparative analyses between high Gensini group (≥4 points; median value or more) and low Gensini group ( Results: High Gensini group was more frequently associated with triple vessel CAD (37.2% vs. 1.0%, p 1 (66.4 ± 16.9 vs 64. 9 ± 19.0, p=0.583) and prevalence of hypertension (59.6% vs. 57.7%, p=0.796) did not differ between two groups. High Gensini group was independently related to triple vessel CAD (OR 3.51, 95% CI 1.77 – 6.94) and myocardial infarction (OR 5.38, 95% CI 1.83 – 15.82). Conclusion: Our data suggest that high Gensini score in COPD was independently associated with cardiac co-morbidities such as triple vessel CAD and myocardial infarction.

Background and objective: Because the mortality and social burden associated with COPD is increasing, repeated surveys of the prevalence of COPD have been used to assess risk factors, detect potential patients, and establish early diagnoses and management protocols. We report the prevalence of spirometrically detected COPD in Korea in 2008, using data from the fourth Korean National Health and Nutrition Survey. Methods: Using nationwide stratified random sampling, based on the Korean Statistical Office census, 6840 subjects aged ≥19 years underwent spirometry, which was performed by four trained technicians, during 2008. The place of residence, levels of education and income and smoking status, as well as other results from a COPD survey questionnaire were also assessed. Results: Airflow obstruction (FEV1/FVC

SummaryBackgroundsEpithelial cell apoptosis plays an important role in the pathogenesis of idiopathic interstitial pneumonia (IIP).MethodsSerum levels of caspase-cleaved cytokeratin-18 (M30) were measured in 55 patients with IIP and 34 healthy controls using enzyme-linked immunosorbent assays. The IIP cases included usual interstitial pneumonia (UIP; n = 30), nonspecific interstitial pneumonia (NSIP; n = 15), and cryptogenic organizing pneumonia (COP; n = 10). The radiological scoring was performed based on high-resolution computed tomography (HRCT) findings.ResultsPatients with IIP had higher serum M30 levels than did the control group (178.6 ± 91.5 vs. 113.7 ± 46.8 U/L, p