Developing a Diagnostic Bundle for Bronchiectasis in South Korea: A Modified Delphi Consensus Study

Background: Because the etiologies of bronchiectasis and related diseases vary significantly among different regions and ethnicities, this study aimed to develop a diagnostic bundle for bronchiectasis in South Korea. Methods: A modified Delphi method was used to develop expert consensus statements on a diagnostic bundle for bronchiectasis in South Korea. Initial statements proposed by a core panel, based on international bronchiectasis guidelines, were discussed in an online meeting and two email surveys by a panel of experts (≥70% agreement). Results: The study involved 21 expert participants, and 30 statements regarding a diagnostic bundle for bronchiectasis were classified as recommended, conditional, or not recommended. The consensus statements of the expert panel were as follows: A standardized diagnostic bundle is useful in clinical practice; diagnostic tests for specific diseases, including immunodeficiency and allergic bronchopulmonary aspergillosis, are necessary when clinically suspected; initial diagnostic tests, including sputum microbiology and spirometry, are essential in all patients with bronchiectasis, and patients suspected with rare causes such as primary ciliary dyskinesia should be referred to specialized centers. Conclusion: Based on this Delphi survey, expert consensus statements were generated including specific diagnostic, laboratory, microbiological, and pulmonary function tests required to manage patients with bronchiectasis in South Korea.ope

Impact of COPD on COVID-19 prognosis: A nationwide population-based study in South Korea

Underlying chronic respiratory disease may be associated with the severity of coronavirus disease 2019 (COVID-19). This study investigated the impact of chronic obstructive pulmonary disease (COPD) on the risk for respiratory failure and mortality in COVID-19 patients. A nationwide retrospective cohort study was conducted in 4610 patients (≥ 40 years old) infected with COVID-19 between January 20 and May 27, 2020, using data from the Ministry of Health and Welfare and Health Insurance Review and Assessment Service in Korea. The clinical course and various clinical features were compared between COPD and non-COPD patients, and the risks of respiratory failure and all-cause mortality in COPD patients were analyzed using a multivariate logistic regression model. Among 4610 COVID-19 patients, 4469 (96.9%) and 141 (3.1%) were categorized into the non-COPD and COPD groups, respectively. The COPD group had greater proportions of older (≥ 60 years old) (78.0% vs. 45.2%, P < 0.001) and male (52.5% vs. 36.6%, P < 0.001) patients than the non-COPD group. Relatively greater proportions of patients with COPD received intensive critical care (7.1% vs. 3.7%, P = 0.041) and mechanical ventilation (5.7% vs. 2.4%, P = 0.015). Multivariate analyses showed that COPD was not a risk factor for respiratory failure but was a significant independent risk factor for all-cause mortality (OR = 1.80, 95% CI 1.11-2.93) after adjustment for age, sex, and Charlson Comorbidity Index score. Among COVID-19 patients, relatively greater proportions of patients with COPD received mechanical ventilation and intensive critical care. COPD is an independent risk factor for all-cause mortality in COVID-19 patients in Korea.ope

Long-Term Prognosis of Asthma-Bronchiectasis Overlapped Patients: A Nationwide Population-Based Cohort Study

Purpose: Asthma and bronchiectasis are common chronic respiratory diseases, and their coexistence is frequently observed but not well investigated. Our aim was to study the effect of comorbid bronchiectasis on asthma. Methods: A propensity score-matched cohort study was conducted using the National Health Insurance Service-Health Screening Cohort database. From 2005 to 2008, 8,034 participants with asthma were weighted based on propensity scores in a 1:3 ratio with 24,099 participants without asthma. From the asthma group, 141 participants with overlapped bronchiectasis were identified, and 7,892 participants had only asthma. Clinical outcomes of acute asthma exacerbation(s) and mortality rates were compared among the study groups. Results: The prevalence of bronchiectasis (1.7%) was 3 times higher in asthmatics than in the general population of Korea. Patients who had asthma comorbid with bronchiectasis experienced acute exacerbation(s) more frequently than non-comorbid patients (11.3% vs. 5.8%, P = 0.007). Time to the first acute exacerbation was also shorter in the asthmatics with bronchiectasis group (1,970.9 days vs. 2,479.7 days, P = 0.005). Although bronchiectasis was identified as a risk factor for acute exacerbation (adjusted odds ratio, 1.73; 95% confidence interval [CI], 1.05-2.86), there was no significant relationship between bronchiectasis and all-cause or respiratory mortality (adjusted hazard ratio [aHR], 1.17; 95% CI, 0.67-2.04 and aHR, 0.81; 95% CI, 0.11-6.08). Conclusions: Comorbid bronchiectasis increases asthma-related acute exacerbation, but it does not-raise the risk of all-cause or respiratory mortality. Close monitoring and accurate diagnosis of bronchiectasis are required for patients with frequent exacerbations of asthma.ope

Efficacy and safety of indacaterol/glycopyrronium fixed-dose combination in mild-to-moderate COPD patients symptomatic on tiotropium in Korea: study protocol for a randomized controlled trial

Background: Long-acting bronchodilator monotherapy (long-acting β2-agonist [LABA] or long-acting muscarinic antagonist [LAMA]) is extensively used for treatment of patients with chronic obstructive pulmonary disease (COPD) with mild-to-moderate airflow limitation. However, a substantial number of patients remain symptomatic despite treatment with a single bronchodilator, necessitating a change in therapy. Methods: This 12-week, randomized, multicenter, open-label, phase IV study aims to show that the once-daily indacaterol/glycopyrronium (IND/GLY) 110/50 μg fixed-dose LABA/LAMA combination results in an improved lung function in symptomatic patients with mild-to-moderate COPD who switch from once-daily tiotropium 18 μg. The study aims to enroll a total of 404 symptomatic patients in Korea with mild-to-moderate COPD who received tiotropium for at least 12 weeks prior to the study initiation. The primary objective of this study is to demonstrate the superiority of IND/GLY over tiotropium in terms of trough forced expiratory volume in 1 second (FEV1) following 12 weeks of treatment. Secondary endpoints include the pre-dose trough FEV1 after 4 weeks of treatment, transition dyspnea index (TDI) total score, COPD assessment test (CAT) total score, and rescue medication use following the 12-week treatment, and safety assessment over the 12-week treatment. Discussion: This study intends to establish the use of LABA/LAMA combination therapy in symptomatic patients with mild-to-moderate COPD by demonstrating the superiority of IND/GLY over tiotropium monotherapy. Trial registration: ClinicalTrials.gov, NCT02566031 . Registered on 10 August 2015.ope

Serum bilirubin level is associated with exercise capacity and quality of life in chronic obstructive pulmonary disease

BACKGROUND: Bilirubin has antioxidant properties against chronic respiratory diseases. However, previous studies are limited by acquisition of serum bilirubin level at one time point and its analysis with clinical parameters. We evaluated the association of serum bilirubin levels with various clinical outcomes of chronic obstructive pulmonary disease (COPD) in Korean Obstructive Lung Disease (KOLD) cohort. METHODS: We included 535 patients with COPD from the KOLD cohort. Serum bilirubin levels and various clinical parameters, such as lung function, 6-min walking (6 MW) distance, quality of life (QoL), and exacerbation, were evaluated annually; their association was analyzed using generalized estimating equations and the linear mixed model. RESULTS: Among 535 patients, 345 (64.5%) and 190 (35.5%) were categorized into Global Initiative for Chronic Obstructive Lung Disease (GOLD) I-II and GOLD III-IV groups, respectively. 6 MW distance was positively associated with serum bilirubin levels, especially in the GOLD I-II group (estimated mean = 41.5). Among QoL indexes, the COPD assessment test score was negatively associated with serum bilirubin levels only in the GOLD I-II group (estimated mean = - 2.8). Higher serum bilirubin levels were independently associated with a higher number of acute exacerbation in the GOLD III-IV group (estimated mean = 0.45, P = 0.001). Multivariate analysis revealed that lung function and mortality were not associated with serum bilirubin levels. CONCLUSIONS: Higher serum bilirubin levels were associated with a longer 6 MW distance and better QoL, especially in the GOLD I-II group, whereas they were related to a higher risk of acute exacerbation, especially in the GOLD III-IV group. Bilirubin levels may represent various conditions in COPD.ope

Early Diagnosis and Management of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a substantially under-diagnosed disorder, and the diagnosis is usually delayed until the disease is advanced. However, the benefit of early diagnosis is not yet clear, and there are no guidelines in Korea for doing early diagnosis. This review highlights several issues regarding early diagnosis of COPD. On the basis of several lines of evidence, early diagnosis seems quite necessary and beneficial to patients. Early diagnosis can be approached by several methods, but it should be confirmed by quality-controlled spirometry. Compared with its potential benefit, the adverse effects of spirometry or pharmacotherapy appear relatively small. Although it is difficult to evaluate the benefit of early diagnosis by well-designed trials, several lines of evidence suggest that we should try to diagnose and manage patients with COPD at early stages of the disease.ope

Cardiovascular and cerebrovascular-associated mortality in patients with preceding bronchiectasis exacerbation

Background: Bronchiectasis is associated with an increased incidence of atherosclerotic cardiovascular disease (ASCaVD) and atherosclerotic cerebrovascular disease (ASCeVD). Its effect on associated mortality is unclear. Objectives: This study investigated the effects of bronchiectasis exacerbation prior to ASCaVD or ASCeVD events on mortality in patients with bronchiectasis using a large population-based database. Methods: A retrospective cohort of patients with bronchiectasis who experienced ASCaVD (n = 1066) or ASCeVD (n = 825) was studied for the first time using a nationwide population-based database (National Health Insurance Service-National Sample Cohort, Korea, 2002-2015). We classified each cohort according to the presence of moderate bronchiectasis exacerbation within 1 year before the ASCaVD or ASCeVD event. We evaluated 90-day, 1-year, and all-cause mortalities risk. Results: Within 1 year before the index ASCaVD or ASCeVD event, 149 (13.9%) and 112 (13.6%) patients with bronchiectasis experienced moderate exacerbation(s), respectively. Mild exacerbations did not different in frequency between the survivors and nonsurvivors. In both cohorts, more nonsurvivors experienced moderate exacerbations than survivors. The odds ratios of 90-day and 1-year mortalities and hazard ratios of all-cause mortalities on experiencing moderate exacerbations were 2.27 [95% confidence interval (CI) = 1.26-4.10], 3.30 (95% CI = 2.03-5.38), and 1.78 (95% CI = 1.35-2.34) in the bronchiectasis-ASCaVD cohort and 1.73 (95% CI = 0.94-3.19), 1.79 (95% CI = 1.07-3.00), and 1.47 (95% CI = 1.10-1.95), in the bronchiectasis-ASCeVD cohort. Conclusion: Hospitalization or emergency room visit for bronchiectasis exacerbation within 1 year before ASCaVD or ASCeVD is associated with an increased ASCaVD- or ASCeVD-associated mortality.ope

폐암에서 aminoacyl tRNA synthetase complex interacting multi-functional protein 2–exon 2 deletion 이형의 임상적 의의

Dept. of Medicine/박사Backgrounds: Aminoacyl-tRNA synthetase interacting multi-functional protein 2 (AIMP2) promotes cell death through activation of p53 and TNF-α signaling. Its alternatively spliced form lacking exon 2 (AIMP2-DX2) competes with AIMP2 for binding to target proteins, compromising the tumor suppressive activity of AIMP2. In this study, the clinical implication and mechanism of AIMP2-DX2 overexpression was investigated in lung cancer. Methods: AIMP2-DX2 expression was evaluated by immunohistochemistry (IHC) and immunoblotting in lung tissues from lung cancer mouse models and surgical specimens from lung cancer patients. Autoantibodies against AIMP2-DX2 and AIMP2 were measured in the blood from lung cancer patients and controls by enzyme-linked immunosorbent assay. Results: AIMP2-DX2 was overexpressed in lung cancer tissues more often than in non-neoplastic lung tissues from mice and humans. AIMP2-DX2 overexpression in lung cancer tissues was not related with mTORC1 activity. Among various types of aminoacyl-tRNA synthetases and anti-apoptotic molecules, AIMP2-DX2 was positively correlated with Bcl-xL expression. Transfecting A549 and H460 cells with a dominant-negative mutant of signal transducer and activator of transcription 3 (STAT3) decreased the expression of serine/arginine-rich splicing factor 1 (SRSF1), AIMP2-DX2, and Bcl-xL. Autoantibodies against AIMP2-DX2 and AIMP2 were detectable in the serum of lung cancer patients and controls. A high AIMP2-DX2/AIMP2 autoantibody ratio was an independent significant prognostic factor for poor clinical outcome in lung cancer patients (hazard ratio = 1.83, 95% confidence intervals 1.11 3.01). Conclusions: These findings suggest that AIMP2-DX2 is a useful biomarker for lung cancer diagnosis and prediction of prognosis. AIMP2-DX2 warrants further study for development as a target molecule in lung cancer. 배경: Aminoacyl-tRNA synthetase interacting multi-functional protein 2 (AIMP2) 는 p53과 TNF-α 신호 전달 경로를 통해 세포사를 유도한다. AIMP2의 RNA 대체 접합 (alternative splicing)으로 exon 2가 결실이 된 AIMP2-exon 2 deletion (AIMP2-DX2)은 표적 단백에 AIMP2와 경쟁적으로 결합하여, AIMP2의 종양 억제 기능을 방해한다. 본 연구에는 폐암에서의 AIMP2-DX2 과발현의 임상적 의미와 기전을 탐구하고자 하였다. 방법: AIMP2-DX2 발현을 폐암 쥐 모델과 수술적 치료 후 얻어진 폐암 환자의 조직에서 면역조직화학법과 면역학적 블로팅으로 분석하였다. 폐암환자와 대조군의 혈청에서 효소결합 면역흡수 분석법을 이용하여, AIMP2-DX2와 AIMP2에 대한 자가 항체 농도를 측정하였다. 분석 및 측정된 결과는 임상적 요소들과 비교 분석하여, 의의를 조사하였다. 결과: 폐암 생쥐 모델과 폐암 환자의 폐암과 정상 조직을 이용한 실험에서 AIMP2-DX2는 폐암조직에서의 특이적 과발현이 58%에서 관찰되었다. 폐암 조직에서 AIMP2-DX2의 과발현은 mTORC1 신호 전달 경로의 활성과 뚜렷한 관련이 없었고, 다양한 aminoacyl-tRNA synthetase와 항고사 단백 발현과의 상관관계분석 결과 Bcl-xL 발현과 양의 상관관계를 보였다. 폐암 세포주인 A549와 H460에 signal transducer and activator of transcription 3 (STAT3)의 우성음성돌연변이체 플라스미드 형질주입으로 억제하였을 때, serine/arginine-rich splicing factor 1 (SRSF1), AIMP2-DX2, 그리고 Bcl-xL 발현이 감소하였다. SRSF1 억제는 AIMP2-DX2발현을 일부 감소시켜, AIMP2-DX2는 STAT3에 의해 발현되며, 일부는 SRSF1에 의해 발현되는 것임을 확인하였다. 폐암 환자와 대조군 혈액에서 AIMP2-DX2와 AIMP2 자가 항체 측정을 통해 검출이 가능함을 확인하였다. 폐암 환자의 혈액에서 AIMP2-DX2/AIMP2 비율이 높은 군은 낮은 군에 비해서 생존율이 낮으며 (18.4 개월 vs. 48.3개월; P = 0.021), AIMP2-DX2/AIMP2의 높은 비율은 폐암환자의 독립적인 예후 인자로 의의가 있었다 (위험비 = 1.83, 95% 신뢰구간 1.11 3.01). 결론: 본 연구결과는 AIMP2-DX2 면역조직화학적 과발현이 폐암 진단에 유용하고, AIMP2-DX2/AIMP2의 자가 항체 비율 증가가 폐암 예후 예측에 유효한 바이오마커임을 시사한다. 따라서, AIMP2-DX2는 폐암의 표적 물질로서의 개발에 지속적인 연구가 필요할 것으로 사료된다.ope

KMBARC registry: protocol for a multicentre observational cohort study on non-cystic fibrosis bronchiectasis in Korea

Introduction Despite the significant disease burden of bronchiectasis in Korea, no large-scale, representative prospective cohort studies have been conducted to evaluate the clinical characteristics of Korean patients with bronchiectasis, indicating an urgent need for cohort studies on bronchiectasis. Methods and analysis The Korean Multicenter Bronchiectasis Audit and Research Collaboration (KMBARC) is a prospective, non-interventional observational cohort study on bronchiectasis in Korea. The inclusion criteria of this registry are as follows: (1) adult patients (aged >= 18 years) with or without respiratory symptoms (cough, chronic sputum and/or recurrent respiratory infection) and chest computed tomography revealing bronchiectasis affecting one or more lobes and (2) stable status at the time of registration: patients with bronchiectasis who were admitted for a respiratory aetiology can be enrolled at least 4 weeks after hospital discharge. The exclusion criteria are as follows: (1) bronchiectasis due to cystic fibrosis; (2) traction bronchiectasis associated with interstitial lung disease; (3) patients actively being treated for pneumonia, pulmonary tuberculosis or non-tuberculous mycobacterial infection; (4) patients who are unable or unwilling to provide informed consent; and (5) pregnant patients. Although the KMBARC questionnaires for baseline and annual follow-up data are similar to the European Multicentre Bronchiectasis Audit and Research Collaboration questionnaires, KMBARC has distinctive features such as use of Bronchiectasis Health Questionnaires, measurement with fatigue and depression scales, blood tests, use of consensus definition of exacerbations and information on emergency room or hospitalisation. We aim to recruit at least 1200 patients over the study period from more than 26 hospitals in South Korea. Patients will undergo a detailed baseline and yearly assessment for up to 5 years. The study objectives of the KMBARC registry are as follows: (1) uncovering the natural course of bronchiectasis; (2) aiding in establishing evidence-based bronchiectasis guidelines in Korea; and (3) encouraging and facilitating studies on bronchiectasis in Korea. Ethics and dissemination This study received necessary approval from the Institutional Review Boards of all participating institutions. The Asan Medical Center Institutional Review Board gave overall approval for the study. Results will be disseminated via peer-reviewed publications and conference presentations.ope

Impact of comorbid asthma on severity of coronavirus disease (COVID-19)

The severity of the coronavirus disease (COVID-19) is associated with various comorbidities. However, no studies have yet demonstrated the potential risk of respiratory failure and mortality in COVID-19 patients with pre-existing asthma. We selected 7272 adult COVID-19 patients from the Korean Health Insurance Review and Assessment COVID-19 database for this nationwide retrospective cohort study. Among these, 686 patients with asthma were assessed by their severities and evaluated by the clinical outcome of COVID-19 compared to patients without asthma. Of 7272 adult COVID-19 patients, 686 with asthma and 6586 without asthma were compared. Asthma was not a significant risk factor for respiratory failure or mortality among all COVID-19 patients (odds ratio [OR] = 0.99, P = 0.997 and OR = 1.06, P = 0.759) after adjusting for age, sex, and the Charlson comorbidity score. However, a history of acute exacerbation (OR = 2.63, P = 0.043) was significant risk factors for death among COVID-19 patients with asthma. Asthma is not a risk factor for poor prognosis of COVID-19. However, asthma patients who had any experience of acute exacerbation in the previous year before COVID-19 showed higher COVID-19-related mortality, especially in case of old age and male sex.ope