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Si Mong Yoon,1 Kwang Nam Jin,2 Hyo Jin Lee,3 Hyun Woo Lee,3 Tae Yun Park,3 Eun Young Heo,3 Deog Kyeom Kim,3 Jung-Kyu Lee3 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 2Department of Radiology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea; 3Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of KoreaCorrespondence: Jung-Kyu Lee, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, 20 Boramaero-5-Gil, Dongjak-Gu, Seoul, 07061, Republic of Korea, Tel +82-2-870-2235, Email jk1909@empas.comBackground: Preserved ratio impaired spirometry (PRISm) is a heterogeneous disease entity. Limited data are available regarding its prevalence, clinical course, or prognosis. We aimed to evaluate the longitudinal clinical course of patients with PRISm compared with chronic obstructive pulmonary disease (COPD).Methods: A retrospective study enrolled PRISm and COPD patients who underwent chest computed tomography and longitudinal pulmonary function tests between January 2013 and December 2020. We compared the incidence of acute exacerbations and lung function changes between PRISm and COPD patients.Results: Of the 623 patients, 40 and 583 had PRISm and COPD, respectively. Compared to COPD patients, PRISm patients were younger, more likely to be female and have a history of tuberculosis, and less likely to be smokers. They also had less severe comorbidities, lower forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO). The clinical course was not significantly different between the PRISm and COPD patients in terms of the risk of moderate-to-severe acute exacerbations or proportion of frequent exacerbators. During follow-up, PRISm patients had a significantly slower annual decline of forced expiratory volume in 1 second, FVC, and DLCO than COPD patients.Conclusion: PRISm patients had no significant difference in the risk of acute exacerbations, but a significantly slower decline of lung function during longitudinal follow-up, compared with COPD patients.Plain Language Summary: We evaluated the longitudinal clinical course of patients with preserved ratio impaired spirometry (PRISm) compared to patients with chronic obstructive pulmonary disease (COPD). PRISm and COPD patients showed no significant differences in the risk of moderate-to-severe acute exacerbations or frequent exacerbations, but the former group showed a significantly slower annual decline of lung function during longitudinal follow-up.Keywords: preserved ratio impaired spirometry, chronic obstructive pulmonary disease, exacerbation, lung function

Dae Kyu Kim,1,2,* Jun Young Park,3,* Youn Joo Kang,4 Dongwoo Khang2,3,5 1Deparment of Biochemistry, Bowdoin College, Brunswick, ME, 04011, USA; 2Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, South Korea; 3Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, South Korea; 4Department of Rehabilitation Medicine, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, 01830, South Korea; 5Department of Physiology, School of Medicine, Gachon University, Incheon, 21999, South Korea*These authors contributed equally to this workCorrespondence: Dongwoo Khang, Department of Physiology, School of Medicine, Gachon University, Incheon, 21999, South Korea, Tel +82 32 899 6515, Fax +82 32 899 6471, Email dkhang@gachon.ac.kr Youn Joo Kang, Department of Rehabilitation Medicine, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, 01830, South Korea, Tel/Fax + 82-2-970-8315, Email md52516@eulji.ac.krPurpose: Rheumatoid arthritis (RA) is a highly prevalent form of autoimmune disease that affects nearly 1% of the global population by causing severe cartilage damage and inflammation. Despite its prevalence, previous efforts to prevent the perpetuation of RA have been hampered by therapeutics’ cytotoxicity and poor delivery to target cells. The present study exploited drug repositioning and nanotechnology to convert metformin, a widely used antidiabetic agent, into an anti-rheumatoid arthritis drug by designing poly(lactic-co-glycolic acid) (PLGA)-based spheres. Moreover, this study also explored the thermal responsiveness of the IL-22 receptor, a key regulator of Th-17, to incorporate photothermal therapy (PTT) into the nanodrug treatment.Materials and Methods: PLGA nanoparticles were synthesized using the solvent evaporation method, and metformin and indocyanine green (ICG) were encapsulated in PLGA in a dropwise manner. The nanodrug’s in vitro anti-inflammatory properties were examined in J744 and FLS via real-time PCR. PTT was induced by an 808 nm near-infrared (NIR) laser, and the anti-RA effects of the nanodrug with PTT were evaluated in DBA/1 collagen-induced arthritis (CIA) mice models. Further evaluation of anti-RA properties was carried out using flow cytometry, immunofluorescence analysis, and immunohistochemical analysis.Results: The encapsulation of metformin into PLGA allowed the nanodrug to enter the target cells via macropinocytosis and clathrin-mediated endocytosis. Metformin-encapsulated PLGA (PLGA-MET) demonstrated promising anti-inflammatory effects by decreasing the expression of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), increasing the expression of anti-inflammatory cytokines (IL-10 and IL-4), and promoting the polarization of M1 to M2 macrophages in J774 cells. The treatment of the nanodrug with PTT exhibited more potent anti-inflammatory effects than free metformin or PLGA-MET in CIA mice models.Conclusion: These results demonstrated that PLGA-encapsulated metformin treatment with PTT can effectively ameliorate inflammation in a spatiotemporal manner. Keywords: rheumatoid arthritis, drug repositioning, nanoparticles, photothermal therapy

Hyo Jin Lee,1 Kwang Nam Jin,2 Hyun Woo Lee,1 Jung-Kyu Lee,1 Tae Yeon Park,1 Eun Young Heo,1 Deog Kyeom Kim1,3 1Division of Respiratory and Critical Care, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, South Korea; 2Department of Radiology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, South Korea; 3Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South KoreaCorrespondence: Deog Kyeom Kim, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, 20, Boramae-ro 5-gil, Dongjak-gu, Seoul, 07061, South Korea, Tel +82-2-870-2130, Fax +82-2-831-0714, Email kimdkmd@snu.ac.krPurpose: Few studies have reported the association between the radiographic characteristics and the development of pneumonia in patients with chronic obstructive pulmonary disease (COPD) treated with inhaled corticosteroids (ICSs). Our study aimed to assess the effect of radiographic phenotypes on the risk of pneumonia in patients treated with ICSs.Patients and Methods: This study retrospectively analysed all patients with COPD treated with ICSs in a subset of the Korea Chronic Obstructive Pulmonary Disorders Subgroup Study registry between January 2017 and December 2019. The association between radiographic phenotypes including the presence and severity of emphysema, airway wall thickening, or bronchiectasis on chest computed tomography were determined visually/qualitatively and the risk of pneumonia was analyzed using the Cox regression model.Results: Among the 90 patients with COPD treated with ICSs, 41 experienced pneumonia more than once during the median follow-up of 29 (interquartile range, 8– 35) months. In univariate Cox regression analysis, older age, longer use of ICSs, use of fluticasone propionate or metered dose inhaler, and severe exacerbation events increased the risk of pneumonia. In multivariate analysis, the presence of emphysema (adjusted hazard ratio [aHR]=3.73, P=0.033), severity measured using the visual sum score (mild-to-moderate, aHR=8.58, P=0.016; severe, aHR=3.58, P=0.042), Goddard sum score (mild-to-moderate, aHR=3.31, P=0.058; severe, aHR=5.38, P=0.014), and the upper lobe distribution of emphysema (aHR=3.76, P=0.032) were associated with a higher risk of pneumonia. Subtypes of centrilobular and panlobular emphysema had a higher risk of pneumonia compared with paraseptal emphysema (aHR=3.98, P=0.033; HR=3.91, P=0.041 vs HR=2.74, P=0.304). The presence of bronchiectasis (aHR=2.41, P=0.02) and emphysema/bronchiectasis overlap phenotype (aHR=2.19, P=0.053) on chest CT was a risk factor for pneumonia in this population. However, severity of bronchiectasis and the presence or severity of bronchial wall thickening according to the visual sum score were not associated with the risk of pneumonia.Conclusion: Among patients with COPD treated with ICSs, radiographic phenotypes including the presence of emphysema, bronchiectasis or emphysema/bronchiectasis overlap phenotype, severity with emphysema, subtypes of centrilobular or panlobular emphysema, and upper lobe distribution of emphysema may help predict the risk of pneumonia.Keywords: chronic obstructive pulmonary disease, inhaled corticosteroid, pneumonia, chest computed tomography, CT

Kangha Jung, Mi Hye Park, Duk Kyung Kim, Byung Jun Kim Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South KoreaCorrespondence: Mi Hye ParkDepartment of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 51 Ilwon-Ro, Gangnam-Gu, Seoul 06351, South KoreaTel +82-2-3410-5258Fax +82-2-3410-6626Email dukiduck.park@samsung.comBackground: We evaluated whether the surgical pleth index (SPI) following surgical incision was related to postoperative pain and opioid consumption.Methods: This prospective observational study was performed in 50 patients undergoing laparotomy under sevoflurane-based general anesthesia. We recorded the highest SPI during surgical incision. The postoperative pain with a numerical rating scale (NRS) and opioid consumption during postoperative 24 h were compared in patients who showed SPI over 50 (Group H) or 20– 50 (Group L). The relationship between postoperative opioid consumption and SPI values (pre-incision, post-incision SPI value, change of SPI value, and post-incision SPI minus pre-incision SPI) was evaluated using receiver-operating characteristic analysis.Results: The mean of the highest SPI value during surgical incision was 56 (SD, 12; range, 26– 85). Twenty-nine (63%) patients were included in Group H and 17 (37%) patients in Group L. There was a significant difference in NRS during recovery room stay and on postoperative 24 h in two groups (5 [5, 6] vs 7 [6, 8], p=0.007 and 3.5 [3, 5] vs 5 [5,6], p=0.006, Group L vs Group H). Group H used higher fentanyl via patient control analgesia during postoperative 24 h (573 (253) μg vs 817 (305) μg, p=0.008). A change of pre-incision and post-incision SPI value of 23, which showed the highest sensitivity (67%) and specificity (68%), was defined post hoc as the cut-off for fentanyl consumption during postoperative 24 h ≥ 1000 μg.Conclusion: Our finding suggests that the SPI response to nociceptive stimuli during surgery is closely related to the degree of patient postoperative pain and opioid requirements. This information may be used to provide proper intraoperative analgesia and individual postoperative pain management.Keywords: opioid, postoperative pain, stress response, surgical incision, surgical pleth index

Ye-Jin Lee,1 SeungHo Choi,2 Sung-Youn Kwon,2 Yunhwan Lee,2 Jung Kyu Lee,3 Eun Young Heo,3 Hee Soon Chung,3,4 Deog Kyeom Kim3,4 1Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea; 2Department of Internal Medicine, Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul 135-984 Korea; 3Division of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea; 4Department of Internal Medicine, Seoul National University College of Medicine, Seoul, KoreaCorrespondence: Deog Kyeom KimDivision of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Boramae-Gil 41, Dongjak-gu, Seoul 156-707, Republic of KoreaTel +82-2-870-3207Fax +82-2-831-0714Email kimdkmd@gmail.comBackground: Identifying the genetic basis of airflow limitation is one of the most interesting issues for understanding chronic obstructive pulmonary disease (COPD) pathophysiology. Several studies have shown that some genetic variants associated with COPD have been identified in genome-wide association study (GWAS), especially in patients with moderate to severe COPD; genetic susceptibility for airflow limitation in the early COPD phase has not been widely studied.Objective: We investigated the genetic variants in early COPD.Methods: The present study analyzed Gene-environment interaction and phenotype (GENIE) cohort that included participants who received health screening examination. The association between single nucleotide polymorphism (SNP) and susceptibility to early COPD (FEV1 predicted ≥ 50% and FEV1/FVC < 0.7) was tested.Results: A total of 130 patients with early COPD and 3478 controls (1700 ever smokers and 1778 never smokers) were recruited. When compared with the total controls, certain SNPs (rs2818103, rs875033, rs9354627, rs34552148) on chromosome 6 were included at the top of our list (p= 5.6 × 10– 7 ∼ 9.6 × 10– 6) although they did not reach genome-wide significance. When compared with the never smoker controls, two SNPs (rs2857210, rs2621419) of the HLA-DQB2 gene class were persistently associated with susceptibility to early COPD.Conclusion: Certain SNPs located on chromosome 6 or the HLA-DQB2 gene were the top-scoring SNPs for the association with susceptibility to early COPD in the Korean GENIE cohort.Keywords: early chronic obstructive pulmonary disease, genome-wide association study, single nucleotide polymorphism, SNP, HLA-DQ gene

Jung-Ki Yoon,1 Jung-Kyu Lee,2 Chang-Hoon Lee,1 Yong Il Hwang,3 Hyunkuk Kim,4 Dongil Park,5 Ki-Eun Hwang,6 Sang-Heon Kim,7 Ki-Suck Jung,3 Kwang Ha Yoo,8 Seung Won Ra,9 Deog Kyeom Kim2,10 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea; 3Department of Internal Medicine, College of Medicine, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea; 4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Republic of Korea; 5Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea; 6Department of Internal Medicine, Wonkwang University, School of Medicine, Iksan, Republic of Korea; 7Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea; 8Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea; 9Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea; 10Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of KoreaCorrespondence: Deog Kyeom KimDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of KoreaTel +82-2-870-2228Fax +82-2-831-0714Email kimdkmd@snu.ac.krIntroduction: Blood eosinophils are a predictive marker for the use of inhaled corticosteroids (ICS). However, there is concern over whether a single measure of blood eosinophils is sufficient for outlining a treatment plan. Here, we evaluated the association between variability in blood eosinophils and the effects of ICS in stable COPD cohorts.Methods: COPD patients in the Korean COPD Subtype Study and the Seoul National University Airway Registry from 2011 to 2018 were analyzed. Based on blood eosinophils at baseline and at 1-year follow-up, the patients were classified into four groups with 250/μL as a cutoff value: consistently high (CH), consistently low (CL), variably increasing (VI), and variably decreasing (VD). We compared rates of acute exacerbations (AEs) according to ICS use in each group after calibration of severity using propensity score matching.Results: Of 2,221 COPD patients, 618 were analyzed and a total of 125 (20%), 355 (57%), 63 (10%), and 75 (12%) patients were classified into the CH, CL, VI, and VD groups, respectively. After calibration, we found that ICS users tended to have a lower AE rate in the CH group (RR 0.41, 95% CI 0.21– 0.74) and VI group (RR 0.45, 95% CI 0.22– 0.88), but not in the CL group (RR 1.42, 95% CI 1.08– 1.89) and VD group (RR 1.71, 95% CI 1.00– 2.96).Conclusion: More than one-fifth of patients had an inconsistent blood eosinophil level after the 1-year follow-up, and the AE-COPD rate according to ICS differed based on variability in eosinophils. Regular follow-up of blood eosinophils is required for COPD patients.Keywords: COPD, eosinophils, inhaled corticosteroids, acute exacerbations of COPD, COPD treatment

Jung-Kyu Lee,1 Chin Kook Rhee,2 Kyungjoo Kim,2 Seung Won Ra,3 Jae Ha Lee,4 Ki-Suck Jung,5 Kwang Ha Yoo,6 Yoo-Il Kim,7 Deog Kyeom Kim1 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea; 2Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea; 3Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea; 4Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea; 5Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea; 6Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea; 7Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of KoreaCorrespondence: Deog Kyeom KimDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, #395 Shindaebang-2-Dong, Dongjak-Gu, Seoul 156-707, Republic of KoreaTel +82-2-870-2228Fax +82-2-831-0714Email kimdkmd@snu.ac.krBackground: Methylxanthines and leukotriene receptor antagonists (LTRA) are not a first-line medical treatment for chronic obstructive pulmonary disease (COPD) but are frequently prescribed despite limited evidence. We aimed to elucidate the real prescribing status and clinical impacts of these agents in early COPD patients.Methods: Patients with mild-to-moderate COPD (FEV1>50%) were selected from the Korean National Health and Nutrition Examination Survey data between 2007 and 2012. Besides analyzing the prescription status of methylxanthines and LTRA and the contributing factors to the prescription, we evaluated the clinical impacts of these drugs on the exacerbation, hospitalization, and medical costs.Results: Of 2269 patients with mild-to-moderate COPD, 378 patients (16.7%) were under medical treatments, and the users of methylxanthines and/or LTRA were 279 patients (12.3%); however, only 139 patients (6.1%) were inhaler users. The contributing factors for the prescription of methylxanthines were a comorbidity of asthma or allergic disease, poor lung function, low quality of life, prescribing doctor from the specialty of internal medicine, and an institution type of private hospital. The prescription of LTRA was associated with the comorbidity of allergic disease. The methylxanthine and/or LTRA users had more hospital utilization but did not have significant differences in acute exacerbations and medical cost for hospital utilization, compared with the non-users.Conclusion: Methylxanthines and LTRA were used in a significant proportion of patients with mild-to-moderate COPD in real fields without favorable impacts on the exacerbations, hospitalizations, or medical costs. The use of more effective inhaled medications should be encouraged.Keywords: pulmonary disease, chronic obstructive, methylxanthine, leukotriene antagonists, drug prescriptions

Yong Suk Jo,1 Sung Kyoung Kim,2 Seoung Ju Park,3 Soo-Jung Um,4 Yong-Bum Park,5 Ki Suck Jung,6 Deog Kyeom Kim,7 Kwang Ha Yoo8 1Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Kyung Hee University Hospital, Seoul, Republic of Korea; 2Department of Internal Medicine, Division of Pulmonology, St Vincent’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea; 3Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea; 4Department of Internal Medicine, Division of Pulmonology, Dong-A University Hospital, Busan, Republic of Korea; 5Department of Internal Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Republic of Korea; 6Department of Internal Medicine, Division of Pulmonary Medicine, Hallym University Sacred Heart Hospital, Hallym University Medical School, Anyang, Republic of Korea; 7Department of Internal Medicine, Seoul Metropolitan Government, Seoul National University Boramae Medical Center, Seoul, Republic of Korea; 8Department of Internal Medicine, Division of Pulmonary and Allergy Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea Background and objective: FEV1 is the gold standard for assessment of COPD. We compared efficacy of FEV1, inspiratory capacity (IC), and IC to total lung capacity (TLC) ratio in the evaluation of COPD and their association with exacerbation.Methods: We analyzed the association of dyspnea severity, quality of life status, and lung function with lung function measurements and exacerbation risk in 982 patients enrolled in the Korea COPD Subgroup Registry and Subtype Research study. Exacerbation and longitudinal lung function change were evaluated in 3 years’ follow-up.Results: The FEV1, IC, and IC to TLC ratio showed comparable negative correlations with dyspnea severity and quality of life status, and positive correlation with exercise capacity. In patients with >2 events/year, annual rate of change in FEV1 and IC tended to decline more rapidly in those with FEV1 50% (-14.46±19.40 mL/year vs 12.29±9.24 mL/year, P=0.213; -4.75±17.28 mL/year vs -78.05±34.16 mL/year, P=0.056 for FEV1 and IC, respectively), without significance.Conclusion: Longitudinal changes in IC and FEV1 were not significantly associated with exacerbation risk. Keywords: COPD, exacerbation, FEV1, inspiratory capacity

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 (

Jin Hwa Song,1 Chang-Hoon Lee,1 Soo-Jung Um,2 Yong Bum Park,3 Kwang Ha Yoo,4 Ki Suck Jung,5 Sang-Do Lee,6 Yon-Mok Oh,6 Ji Hyun Lee,7 Eun Kyung Kim,7 Deog Kyeom Kim8,9 On behalf of KOLD, KOCOSS, and SNU airway registry investigators 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 2Division of Respiratory Medicine, Department of Internal Medicine, Dong-A University College of Medicine, Dong-A University Medical Center, Busan, Republic of Korea; 3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Kangdong Sacred Heart Hospital, Seoul, Republic of Korea; 4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea; 5Division of Pulmonary Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University Medical School, Anyang Gyeonggi-do, Republic of Korea; 6Department of Pulmonary and Critical Care Medicine and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Republic of Korea; 7Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam Gyeonggi-do, Republic of Korea; 8Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea; 9Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea Purpose: While GOLD classification has been revised, its clinical impacts on outcomes of COPD patients have not been widely evaluated in real-world cohorts.Materials and methods: According to 2007, 2013, and 2017 GOLD classifications, distribution and clinical characteristics of group-shifted patients and the risk of acute exacerbation were analyzed in combined Korean COPD cohorts. Future risk for annual moderate-to-severe exacerbation was estimated as incidence rate ratio (IRR) and compared by groups.Results: Among 1,880 COPD patients, in GOLD 2017 classification, groups B and A were increased to 61.2% and 22.2% of total population, while group C was shrunken to 2.2% and patients with higher risk were decreased (16.6% in GOLD 2017 vs 44.7% in GOLD 2013). The kappa coefficient of agreement of both systems was 0.581 (agreement 71.7%). Groups B and D showed higher IRR of moderate-to-severe exacerbation than group A (IRR 2.4 and 5.3 respectively, P

Hyeon-Kyoung Koo,1 Sung-Woo Park,2 Jeong-Woong Park,3 Hye Sook Choi,4 Tae-Hyung Kim,5 Hyoung Kyu Yoon,6 Kwang Ha Yoo,7 Ki-Suck Jung,8 Deog Kyeom Kim9 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Ilsan, Republic of Korea; 2Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soon Chun Hyang University Bucheon Hospital, Bucheon, Republic of Korea; 3Department of Pulmonary and Critical Care Medicine, Gachon University, Gil Medical Center, Incheon, Republic of Korea; 4Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Republic of Korea; 5Division of Pulmonary and Critical Care Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Republic of Korea; 6Department of Internal Medicine, The Catholic University of Korea, Yeouido St Mary’s Hospital, Seoul, Republic of Korea; 7Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea; 8Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea; 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 and purpose: Chronic cough can be a dominant symptom of chronic obstructive pulmonary disease (COPD), although its clinical impact remains unclear. The aim of our study was to identify phenotypic differences according to the presence of chronic cough or sputum and evaluate the impact of chronic cough on the risk of acute exacerbation of COPD (AECOPD). Methods: In a nationwide COPD cohort including 1,613 COPD patients, patients with chronic cough only, those with sputum only, those with chronic bronchitis (CB), and those without cough and sputum were compared with regard to dyspnea, lung function, quality of life (QoL), and risk of AECOPD. Results: The rates of chronic cough, chronic sputum, and both were 23.4%, 32.4%, and 18.2%, respectively. Compared with patients without chronic cough, those with chronic cough exhibited a lower forced expiratory volume in 1 second (% predicted) and diffusing capacity of the lungs for carbon monoxide (% predicted), more frequent AECOPD, more severe dyspnea, and worse QoL. Pulmonary function, dyspnea severity, and QoL worsened in the following order: without cough or sputum, with sputum only, with cough only, and with CB. Multivariate analyses revealed chronic cough as an independent risk factor for a lower lung function, more severe dyspnea, and a poor QoL. Moreover, the risk of future AECOPD was significantly associated with chronic cough (odds ratio 1.56, 95% CI 1.08–2.24), but not with chronic sputum. Conclusion: Our results suggest that chronic cough should be considered as an important phenotype during the determination of high-risk groups of COPD patients. Keywords: pulmonary disease, chronic obstructive, cough, exacerbation, severity

Sun Hye Shin,1 Danbee Kang,2 Juhee Cho,2 Haseong Chang,3 Min Sun Kim,3 Su Yeon Lee,3 Hyun Lee,1 Hojoong Kim,1 Duk-Kyung Kim,3 Eun Kyoung Kim,3,* Hye Yun Park1,* 1Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 2Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea; 3Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea *These authors contributed equally to this work Background: COPD is a well-known risk factor for venous thromboembolism (VTE) development. However, recent data showed that it was not associated with VTE recurrence risk, which excluded cancer patients. This study investigated the association of airflow limitation and VTE recurrence in cancer patients with pulmonary embolism (PE). Methods: This is a retrospective cohort study of cancer patients with newly diagnosed PE at a university hospital. PE was confirmed using contrast-enhanced computed tomography scan. Airflow limitation was defined as pre-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC)

Yong Suk Jo,1 Ho Il Yoon,2 Deog Kyeom Kim,3 Chul-Gyu Yoo,1 Chang-Hoon Lee1 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, 3Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea Background and objective: Guidelines recommend the use of simple but comprehensive tools such as COPD Assessment Test (CAT) and Clinical COPD Questionnaire (CCQ) to assess health status in COPD patients. We aimed to compare the ability of CAT and CCQ to predict exacerbation in COPD patients. Methods: We organized a multicenter prospective cohort study that included COPD patients. The relationships between CAT, CCQ, and other clinical measurements were analyzed by correlation analysis, and the impact of CAT and CCQ scores on exacerbation was analyzed by logistic regression analyses and receiver operating characteristic curve. Results: Among 121 COPD patients, CAT and CCQ score correlated with other symptom measures, lung function and exercise capacity as well. Compared with patients who did not experience exacerbation, those who experienced exacerbation (n=45; 38.2%) exhibited more severe airflow limitation, were more likely to have a history of exacerbation in the year prior to enrollment, and demonstrated higher CAT scores. CCQ scores were not significantly associated with exacerbations. A CAT score of ≥15 was an independent risk factor for exacerbation (adjusted odds ratio [aOR], 2.40; 95% CI, 1.03–6.50; P=0.04). Furthermore, CAT scores of ≥15 demonstrated an increased predictive ability for exacerbation compared with currently accepted guidelines for the use of CAT (≥10) and CCQ (≥1) in the assessment of COPD patients (area under the curve for CAT ≥15, CAT ≥10, and CCQ ≥1 was 0.61±0.04, 0.53±0.03, and 0.50±0.03, respectively; P=0.03). Conclusion: A CAT score of ≥15 indicates increased risk of exacerbation in COPD patients, whereas there is no evidence for increased risk based on CCQ score. Keywords: COPD, exacerbation, questionnaire

Hyun Lee,1,* Byung Woo Jhun,1,* Juhee Cho,2–4 Kwang Ha Yoo,5 Jin Hwa Lee,6 Deog Kyeom Kim,7 Jong Deog Lee,8 Ki-Suck Jung,9 Jung Yeon Lee,10 Hye Yun Park1 1Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 2Center for Clinical Epidemiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 3Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; 4Department of Clinical Research Design and Evaluation, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea; 5Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, South Korea; 6Division of Pulmonary and Critical Care Medicine, School of Medicine, Ewha Womans University, Seoul, South Korea; 7Division 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, South Korea; 8Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, South Korea; 9Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang, South Korea; 10Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chungju Hospital, Konkuk University School of Medicine, Chungju, South Korea *These authors contributed equally to this work Background: Patients with chronic obstructive pulmonary disease (COPD) often have poor health-related quality of life (HRQoL) that is disproportionate to their degree of airflow limitation. This study evaluated the association between St George’s Respiratory Questionnaire for COPD (SGRQ-C) score and forced expiratory volume in one second and investigated the factors responsible for high SGRQ-C score according to severity of airflow limitation.Methods: Data from 1,264 COPD patients were obtained from the Korean COPD Subgroup Study (KOCOSS) cohort. Patients were categorized into two groups according to severity of airflow limitation: mild-to-moderate and severe-to-very severe COPD groups. We evaluated the clinical factors associated with high SGRQ-C score (≥25) in each COPD patient group.Results: Of the 1,264 COPD patients, 902 (71.4%) had mild-to-moderate airflow limitation and 362 (28.6%) had severe-to-very severe airflow limitation. Of the mild-to-moderate COPD patients, 59.2% (534/902) had high SGRQ-C score, while 80.4% (291/362) of the severe-to-very severe COPD patients had high SGRQ-C score. The association between SGRQ-C score and post-bronchodilator forced expiratory volume in one second (% predicted) was very weak in the mild-to-moderate COPD patients (r=–0.103, p=0.002) and weak in the severe-to-very severe COPD patients (r=–0.219, p

Woo Jin Kim,1 Jae-Joon Yim,2 Deog Kyeom Kim,3 Myung Goo Lee,4 Anne L Fuhlbrigge,5 Pawel Sliwinski,6 Iwona Hawrylkiewicz,6 Emily S Wan,7,8 Michael H Cho,7,8 Edwin K Silverman7,8 1Department of Internal Medicine and Environmental Health Center, Kangwon National University Hospital, Chuncheon, 2Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul National University College of Medicine, Seoul, 3Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, 4Division of Pulmonary, Allergy and Critical Care Medicine, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon, Korea; 5Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA; 62nd Department of Respiratory Medicine, Institute of Tuberculosis and Lung Diseases, Warsaw, Poland; 7Channing Division of Network Medicine, 8Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA Purpose: Chronic obstructive pulmonary disease (COPD), characterized by irreversible airflow obstruction, is a major cause of morbidity and mortality worldwide. However, geographic differences in the clinical characteristics of severe COPD patients have not been widely studied. Methods: We recruited a total of 828 severe COPD cases from three continents. Subjects in Poland were enrolled by the Institute of Tuberculosis and Lung Diseases in Warsaw; subjects in Korea participated at several university hospitals in Korea; and subjects in USA were enrolled at two clinics affiliated with academic medical centers. All subjects were over the age of 30 with at least 10 pack-years of cigarette smoking history. Cases manifested severe to very severe airflow obstruction with post-bronchodilator forced expiratory volume in 1 second (FEV1)

Nayoung Han,1,* Su Hyun Hong,1,2,* Yon Su Kim,3 Dong Ki Kim,3 In-Wha Kim,1 Eunhee Ji,4 Jung Mi Oh1 1Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 2Pharmaceutical Standardization Division, Drug Evaluation Department, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Chungcheongbuk-do, 3Division of Nephrology, Department of Internal Medicine, Seoul National University Hospital, Seoul, 4College of Pharmacy, Gachon University, Incheon, Republic of Korea *These authors contributed equally to this work Background: The purpose of the present study was to determine the effect of additional calcium carbonate treatment on fibroblast growth factor 23 (FGF23) levels in patients treated with calcitriol.Methods: In this randomized, open-labeled, and parallel-group study, a total of 30 patients with early chronic kidney disease (CKD) and vitamin D deficiency were randomly assigned to two groups and received interventions for 8 weeks: 1) a combination of calcium carbonate and calcitriol group; and 2) calcitriol only group. The primary outcome was the difference in percentage change of serum FGF23 levels from baseline between the two groups. Secondary end points included the changes in serum levels of calcium, phosphate, parathyroid hormone (PTH), and 25-hydroxyvitamin D3 (25(OH)D) from baseline.Results: Serum FGF23 levels were more elevated in the combination group than in the calcitriol-alone group. However, both mean change and percentage change in the serum FGF23 levels during the 8-week period were not significantly different between the two groups. Serum calcium level was increased significantly only in the combination treatment group. There was no significant difference in percentage change of serum calcium levels between the two groups. In addition, changes in serum levels of phosphate, 25(OH)D, or PTH were not significantly different between the two groups. In correlation analysis, changes in serum FGF23 levels were positively correlated with changes in serum calcium and phosphate levels, but not with changes in 25(OH)D or PTH levels. No serious adverse events were observed, however, there was one case of mild gastrointestinal discomfort.Conclusion: This study revealed that additional calcium carbonate treatment significantly increased serum FGF23 levels in patients treated with calcitriol, with their synergistic effect in promoting intestinal calcium absorption. This suggests that serum FGF23 levels should be monitored regularly, especially in those who use combination of vitamin D and calcium carbonate from the early stages of CKD. Keywords: fibroblast growth factor-23, vitamin D deficiency, calcium carbonate, calcitriol, mineral and bone disorder

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 1 second (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

Yong Suk Jo,1 Ju-Hee Park,2 Jung Kyu Lee,2 Eun Young Heo,2 Hee Soon Chung,2 Deog Kyeom Kim2 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; 2Division 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 and objective: There are limited data on pulmonary arterial hypertension (PAH) in patients with tuberculosis-destroyed lung (TDL), a sequela of pulmonary tuberculosis. We identified the risk factors for PAH and their effects on acute exacerbation and mortality in patients with TDL, as well as the clinical differences in patients with chronic obstructive pulmonary disease (COPD) and PAH.Methods: A retrospective cohort study was conducted from 2010 through 2015 in a municipal referral hospital in South Korea. PAH was defined when echocardiographic pulmonary arterial pressure (PAP) was >40 mmHg. The clinical features and course of TDL patients with or without PAH were evaluated and differences between patients with COPD and PAH were analyzed.Results: Among the 195 patients with TDL, echocardiographic data were available in 53 patients, and their mean PAP was 50.72±23.99 mmHg. The PAH group (n=37) had a smaller lung volume (forced vital capacity % predicted, 51.55% vs 72.37%, P

Young Gon Kang,1 Eunkyung Suh,2 Hyejin Chun,3 Sun-Hyun Kim,4 Deog Ki Kim,5 Chul-Young Bae1 1MediAge Research Center, Seongnam-si, Gyeonggi-do, 2Department of Family Medicine, College of Medicine, CHA University, Chaum, Seoul, 3Department of Family Medicine, College of Medicine, CHA University, Bundang CHA Medical Center, Seongnam-si, Gyeonggi-do, 4Department of Family Medicine, International St Mary’s Hospital, College of Medicine, Catholic Kwandong University, Incheon, 5Pharmicell Clinical Research Center, Seoul, South Korea Purpose: This study aims to propose a metabolic syndrome (MS) biological age model, through which overall evaluation and management of the health status and aging state in MS can be done easily. Through this model, we hope to provide a novel evaluation and management health index that can be utilized in various health care fields.Patient and methods: MS parameters from American Heart Association/National Heart, Lung, and Blood Institute guidelines in 2005 were used as biomarkers for the estimation of MS biological age. MS biological age model development was done by analyzing data of 263,828 participants and clinical application of the developed MS biological age was assessed by analyzing the data of 188,886 subjects.Results: The principal component accounted for 36.1% in male and 38.9% in female of the total variance in the battery of five variables. The correlation coefficient between corrected biological age and chronological age in males and females were 0.711 and 0.737, respectively. Significant difference for mean MS biological age and chronological age between the three groups, normal, at risk and MS, was seen (P

Ju-Hee Park, Jung-Kyu Lee, Eun Young Heo, Deog Kyeom Kim, Hee Soon Chung Division of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea Purpose: A low body mass index has been associated with high mortalities in patients with chronic obstructive pulmonary disease (COPD), and studies reveal that obesity aggravates the clinical effects of COPD. We investigated the impact of obesity on patients newly identified with COPD.Patients and methods: This population-based, cross-sectional study, used data from the Korea National Health and Nutrition Examination Survey (KNHANES) conducted from 2010 to 2012. Through analyses of data from this survey, we compared concurrent comorbid diseases, symptoms, and lung functions between an obese and nonobese group of patients with COPD.Results: In total, 618 participants were diagnosed with COPD and the average forced expired volume in 1 s (FEV1) was 79.47%±0.69%. Of the total, 30.5% of the subjects were categorized into an obese group. Subjects in the obese group were likely to have metabolic syndrome (P

Sei Won Kim,1,* Chin Kook Rhee,2,* Ki Uk Kim,3 Sang Haak Lee,4 Hun Gyu Hwang,5 Yu Il Kim,6 Deog Kyeom Kim,7 Sang Do Lee,8 Yeon-Mok Oh,8 Hyoung Kyu Yoon1 On behalf of the KOLD Study Group 1Division of Pulmonary, Department of Internal Medicine, Yeouido St Mary’s Hospital, 2Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 3Department of Internal Medicine, Pusan National University, School of Medicine, Busan, 4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, St Paul’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 5Department of Internal Medicine, Soonchunhyang University Gumi Hospital, Gumi, 6Division of Pulmonology, Department of Internal Medicine, Chonnam National University Hospital, Gwangju, 7Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine, 8Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea *These authors contributed equally to this work Background: Interleukin (IL)-33 promotes T helper (Th)2 immunity and systemic inflammation. The role of IL-33 in asthma has been widely investigated. IL-33 has also been suggested to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). This study investigated the clinical significance and usefulness of plasma IL-33 level in patients with COPD. Methods: A total of 307 patients with stable COPD from 15 centers, who were in the Korean Obstructive Lung Disease cohort, were enrolled in this study. Plasma IL-33 levels were measured by enzyme-linked immunosorbent assay. We analyzed the association between IL-33 level and other clinical characteristics related to COPD. We also examined the features of patients with COPD who exhibited high IL-33 levels. Results: IL-33 levels varied, but were very low in most patients. Eosinophil count was significantly correlated with a plasma IL-33 level. In addition, old age and current smoking were related to a low IL-33 level. Significantly more patients with a higher IL-33 level had chronic bronchitis compared with those with a low IL-33 level. Conclusion: Plasma IL-33 level in patients with stable COPD was related to eosinophil count and chronic bronchitis phenotype. Further studies are needed to identify the precise mechanisms of IL-33/ST2 pathway in patients with COPD. Keywords: biomarker, cytokine, interleukin-33, eosinophil, pathogenesis, chronic bronchitis

Ji Young Yoon,1 Keum-Jin Yang,2 Shi-Nae Park,3 Dong-Kee Kim,3 Jong-Duk Kim1 1Department of Chemical and Biomolecular Engineering, BK 21 Plus Program, Korea Advanced Institute of Science and Technology, Guseong-Dong, Yuseong-Gu, Daejeon, 2Clinical Research Institute, St Mary’s Hospital, Daejeon, 3Department of Otolaryngology – Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Abstract: Dexamethasone (Dex)-loaded PHEA-g-C18-Arg8 (PCA) nanoparticles (PCA/Dex) were developed for the delivery of genes to determine the synergistic effect of Dex on gene expression. The cationic PCA nanoparticles were self-assembled to create cationic micelles containing an octadecylamine (C18) core with Dex and an arginine 8 (Arg8) peptide shell for electrostatic complexation with nucleic acids (connexin 26 [Cx26] siRNA, green fluorescent protein [GFP] DNA or brain-derived neurotrophic factor [BDNF] pDNA). The PCA/Dex nanoparticles conjugated with Arg8, a cell-penetrating peptide that enhances permeability through a round window membrane in the inner ear for gene delivery, exhibited high uptake efficiency in HEI-OC1 cells. This potential carrier co-delivering Dex and the gene into inner ear cells has a diameter of 120–140 nm and a zeta potential of 20–25 mV. Different types of genes were complexed with the Dex-loaded PCA nanoparticle (PCA/Dex/gene) for gene expression to induce additional anti-inflammatory effects. PCA/Dex showed mildly increased expression of GFP and lower mRNA expression of inflammatory cytokines (IL1b, IL12, and INFr) than did Dex-free PCA nanoparticles and Lipofectamine® reagent in HEI-OC1 cells. In addition, after loading Cx26 siRNA onto the surface of PCA/Dex, Cx26 gene expression was downregulated according to real-time polymerase chain reaction for 24 h, compared with that using Lipofectamine reagent. After loading BDNF DNA into PCA/Dex, increased expression of BDNF was observed for 30 h, and its signaling pathway resulted in an increase in phosphorylation of Akt, observed by Western blotting. Thus, Dex within PCA/Dex/gene nanoparticles created an anti-inflammatory effect and enhanced gene expression. Keywords: cell-penetrating peptide, nanoparticle, dexamethasone, gene delivery, brain-derived neurotrophic factor

Junghyun Kim,1 Jung-Kyu Lee,2 Eun Young Heo,2 Hee Soon Chung,2 Deog Kyeom Kim2 1Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul National University Hospital, 2Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea Background: The hallmark of COPD is chronic airway inflammation, which may be mediated by renin–angiotensin system. The renin–angiotensin system blockers such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) have exhibited anti-inflammatory and immunomodulatory effects in patients with various diseases. We explored the effects of ACEi and ARBs on the risk of pneumonia in patients with COPD.Methods: A nested case–control study was performed on COPD patients recruited from January 2010 to August 2013 in two referral hospitals in Korea. A total of 130 COPD patients admitted with pneumonia were included, and 245 COPD patients without pneumonia were selected as controls from a total of 1,646 such patients. Controls were matched with test patients by age, sex, and severity of airflow limitation. The effects of ACEi/ARBs use on the odds ratio (OR) for the development of pneumonia were tested through conditional logistic regression.Results: Elderly patients (over 70 years of age) constituted ~30% of each group; most of the patients were male (85%). Of the COPD patients with pneumonia, 21.5% had taken ACEi/ARBs for a mean of 9.8 months (standard deviation ±3.5 months). The proportions of ACEi/ARBs users and the mean duration of such use did not differ when compared to those of the control patients (26.9%, P=0.25; 9.6±3.6 months, P=0.83). Univariate analyses indicated that the use of ACEi/ARBs was not associated with a decreased risk of pneumonia (OR =0.70, 95% confidence interval 0.41–1.23, P=0.21), whereas both a history of pulmonary tuberculosis (OR =1.85, 95% confidence interval 1.12–3.06, P=0.02) and exposure to systemic steroids (OR =2.33, 95% confidence interval 1.28–4.23, P=0.005) did show an association. After adjustment for a history of tuberculosis, comorbid chronic renal disease, and exposure to corticosteroids, ACEi/ARBs reduced the risk of pneumonia in COPD patients (OR =0.51, 95% confidence interval 0.27–0.98, P=0.04).Conclusion: This study revealed that the use of ACEi/ARBs was associated with reducing the risk of pneumonia in patients with COPD. Further prospective studies are necessary to confirm the protective effect of ACEi/ARBs and elucidate the underlying mechanisms in COPD patients. Keywords: angiotensin-converting enzyme inhibitors, angiotensin receptor antagonist, COPD, pneumonia

Ha Youn Lee,1,2 Ji Won Kim,2,3 Jung Kyu Lee,2,4 Eun Young Heo,2,4 Hee Soon Chung,2,4 Deog Keom Kim2,4 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, 2Department of Internal Medicine, Seoul National University College of Medicine, 3Division of Gastroenterology, 4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea Background: Helicobacter pylori infection is a major cause of gastric diseases. The clinical implications of H. pylori infection in various diseases outside the gastrointestinal system have also been reported, including in some respiratory disorders. In this study, we investigated the seroprevalence of H. pylori in patients with mild to moderate COPD in an Asian country with a high prevalence of H. pylori infection. Also, we aimed to elucidate the association between the seroprevalence of H. pylori and the decline of lung function in patients with COPD.Methods: Participants who underwent a medical checkup for H. pylori at a referral hospital in Korea were recruited for this study. All participants were tested for H. pylori infection using an immunoassay of the H. pylori-specific immunoglobulin G (IgG) concentration and a rapid urease test at the time of endoscopy with a gastric mucosal specimen. We assessed the decline in lung function using the spirometric data of those who underwent spirometry more than three times.Results: In total, 603 participants (201 patients with COPD and 402 controls) were analyzed. The seroprevalence of H. pylori IgG in the patients and controls was 45.8% and 52.2%, respectively (P=0.134). The H. pylori IgG level in patients with COPD was not significantly different from that of the controls (114.8 and 109.6 units/mL, respectively; P=0.549). In addition, there were no significant differences in the annual forced expiratory volume in 1 second or forced vital capacity between the participants with H. pylori seropositivity and seronegativity.Conclusion: This study showed no relationship between H. pylori infection and COPD in a country with a high burden of H. pylori infection. Furthermore, H. pylori infection did not affect the rate of lung function decline in this study population. Keywords: H. pylori, COPD, lung function decline

Hyeon-Kyoung Koo,1 Kwang Nam Jin,2 Deog Kyeom Kim,3 Hee Soon Chung,3 Chang-Hoon Lee3,4 1Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, College of Medicine, Ilsan Paik Hospital, Inje University, Goyang-si, Gyeonggi-Do, 2Department of Radiology, Seoul Metropolitan Government – Seoul National University Boramae Medical Center, 3Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, 4Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea Objectives: Emphysema is one of the prognostic factors for rapid lung function decline in patients with COPD, but the impact of incidentally detected emphysema on population without spirometric abnormalities has not been evaluated. This study aimed to determine whether emphysema detected upon computed tomography (CT) screening would accelerate the rate of lung function decline and influence the possibility of future development of airflow limitation in a population without spirometric abnormalities.Materials and methods: Subjects who participated in a routine screening for health checkup and follow-up pulmonary function tests for at least 3 years between 2004 and 2010 were retrospectively enrolled. The percentage of low-attenuation area below −950 Hounsfield units (%LAA−950) was calculated automatically. A calculated value of %LAA−950 that exceeded 10% was defined as emphysema. Adjusted annual lung function decline was analyzed using random-slope, random-intercept mixed linear regression models.Results: A total of 628 healthy subjects within the normal range of spriometric values were included. Multivariable analysis showed that the emphysema group exhibited a faster decline in forced vital capacity (−33.9 versus −18.8 mL/year; P=0.02). Emphysema was not associated with the development of airflow limitation during follow-up.Conclusion: Incidental emphysema quantified using CT scan was significantly associated with a more rapid decline in forced vital capacity in the population with normative spirometric values. However, an association between emphysema and future development of airflow limitation was not observed. Keywords: annual decline rate, respiratory function tests, pulmonary emphysema, chronic obstructive pulmonary disease

Ha Youn Lee,1,2 Sun Mi Choi,1,2 Jinwoo Lee,1,2 Young Sik Park,1,2 Chang-Hoon Lee,1,2 Deog Kyeom Kim,2,3 Sang-Min Lee,1,2 Ho Il Yoon,2,4 Jae-Joon Yim,1,2 Young Whan Kim,1,2 Sung Koo Han,1,2 Chul-Gyu Yoo1,2 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 2Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; 3Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea; 4Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea Background: Tiotropium failed to slow the annual rate of forced expiratory volume in 1 second (FEV1) decline in chronic obstructive pulmonary disease (COPD) patients with

Jung-Ryul Kim,1 Hye In Woo,2 Mi-Ryung Chun,3 Shinn-Won Lim,4 Hae Deun Kim,5 Han Sung Na,5 Myeon Woo Chung,5 Woojae Myung,6 Soo-Youn Lee,1,3 Doh Kwan Kim6 1Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, 2Department of Laboratory Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, 3Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 4Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, 5Clinical Research Division, Toxicological Evaluation and Research Department, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Chungcheongbuk-do, 6Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Purpose: This study investigated population pharmacokinetics of paroxetine, and then performed an integrated analysis of exposure and clinical outcome using population pharmacokinetic parameter estimates in depressed patients treated with paroxetine. Patients and methods: A total of 271 therapeutic drug monitoring (TDM) data were retrospectively collected from 127 psychiatric outpatients. A population nonlinear mixed-effects modeling approach was used to describe serum concentrations of paroxetine. For 83 patients with major depressive disorder, the treatment response rate and the incidence of adverse drug reaction (ADR) were characterized by logistic regression using daily dose or area under the concentration–time curve (AUC) estimated from the final model as a potential exposure predictor. Results: One compartment model was developed. The apparent clearance of paroxetine was affected by age as well as daily dose administered at steady-state. Overall treatment response rate was 72%, and the incidence of ADR was 30%. The logistic regression showed that exposure predictors were not associated with treatment response or ADR in the range of dose commonly used in routine practice. However, the incidence of ADR increased with the increase of daily dose or AUC for the patients with multiple concentrations. Conclusion: In depressed patients treated with paroxetine, TDM may be of limited value for individualization of treatment. Keywords: exposure–outcome relationship, paroxetine, therapeutic drug monitoring, population pharmacokinetics, NONMEM

Young Ho Jung,1* Doh Young Lee,2* Dong Wook Kim,1 Sung Soo Park,3 Eun Young Heo,3 Hee Soon Chung,3 Deog Kyeom Kim3 1Department of Otorhinolaryngology-Head and Neck Surgery, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, 2Department of Otorhinolaryngology-Head and Neck Surgery, Anam Hospital, Korea University Medical Center, 3Division 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 *These authors contributed equally to this work Background: Although chronic obstructive pulmonary disease (COPD) is closely associated with gastroesophageal reflux disease (GERD), the clinical significance of laryngopharyngeal reflux (LPR) is not fully understood in COPD.Methods: Prospective cohorts were established among 118 patients with COPD from March 2013 to July 2014. Thirty-two age-matched and sex-matched normal controls, who had routine health check-ups during the study period, were included. Laryngopharyngeal reflux finding scores (RFS) and reflux symptom index (RSI) for LPR were subjected to association analysis with severity and acute exacerbation of COPD during the 1-year follow-up.Results: The mean age of patients enrolled in the study was 69.2±8.8 years, with 93.2% being male. Positive RFS (>7) and RSI (>13) were observed in 51 (42.5%) and six patients (5.0%), respectively. RFS and RSI were significantly higher in patients with COPD than in normal, healthy patients (P

Yeon Wook Kim,1 Kwang-Nam Jin,2 Eun Young Heo,3 Sung Soo Park,3 Hee Soon Chung,3 Deog Kyeom Kim31Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; 2Department of Radiology, Seoul National University College of Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea; 3Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of KoreaBackground: Whereas the epidemiological association between lung cancer and chronic obstructive pulmonary disease (COPD), a chronic inflammatory respiratory disease, is well known, limited studies have examined the association between lung cancer and non-cystic fibrosis bronchiectasis, a representative chronic airway inflammatory disease. This study evaluated the association between bronchiectasis and lung cancer in patients with COPD.Methods: A matched case–control study was conducted in a referral hospital in South Korea. Among COPD patients with moderate to very severe airflow limitation (forced expiratory volume in one second/forced vital capacity

Ho Il Yoon,1 Chang-Hoon Lee,2 Deog Kyeom Kim,3 Geun Min Park,4 Sang-Min Lee,2 Jae-Joon Yim,2 Jae-Yeol Kim,5 Jae Ho Lee,1 Choon-Taek Lee,1 Hee Soon Chung,3 Young Whan Kim,2 Sung Koo Han,2 Chul-Gyu Yoo2 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; 3Division of Pulmonology, Department of Internal Medicine, Seoul National University Boramae Hospital, Seoul, South Korea; 4Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Republic of Korea; 5Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea Background: Antibiotic treatment is one of the major pharmacologic treatments for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, the choice of antibiotic depends on the local resistance pattern. A multicenter, randomized, controlled trial was done in patients with AECOPD to compare the efficacy of levofloxacin with that of cefuroxime axetil. Methods: Patients with AECOPD and without radiographic evidence of pneumonia were enrolled and randomized to either levofloxacin 500 mg daily or cefuroxime 250 mg twice daily in the mild-moderate exacerbation group, or 500 mg twice daily in the severe exacerbation group, for seven days. Clinical efficacy and microbiologic response were evaluated 5–7 days after the last dose. Results: Treatment was clinically successful in 90.4% of patients in the levofloxacin group, and in 90.6% of patients in the cefuroxime group (95% confidence interval -9.40 to 10.91), within a noninferiority margin of 10%. The microbiologic response appeared to be higher in the levofloxacin group, but the difference was not statistically significant. The safety profile was similar in both groups. Conclusion: Levofloxacin is not inferior to cefuroxime with regard to clinical efficacy in treating AECOPD. Keywords: chronic obstructive pulmonary disease, acute exacerbation, levofloxacin, cefuroxime