The Effect of Galantamine on Lipopolysaccharide-induced Acute Lung Injury During Neutropenia Recovery in Mice.

BACKGROUND/AIM: Acute lung injury (ALI) is associated with a high mortality rate and cancer patients who receive chemotherapy are at high risk of ALI during neutropenia recovery. Galantamine is a cholinesterase inhibitor used for Alzheimer's disease treatment. Previous studies have shown that galantamine reduced inflammatory response in lipopolysaccharide (LPS)-induced ALI in rats. Mer protein was negatively associated with inflammatory response. The aim of the study was to investigate whether galantamine is effective in LPS-induced ALI during neutropenia recovery and its effect on Mer tyrosine kinase (MerTK) expression in mice. MATERIALS AND METHODS: Intraperitoneal cyclophosphamide was given to mice to induce neutropenia. After 7 days, LPS was administered by intratracheal instillation. Intraperitoneal galantamine was given once before LPS administration and in another group, galantamine was given twice before LPS administration. RESULTS: Galantamine attenuated LPS-induced ALI in histopathological analysis. The neutrophil percentage was lower in the group where galantamine was injected once, compared to the LPS group (p=0.007). MerTK expression was also higher in the group where galantamine was injected once but did not reach statistical significance (p=0.101). CONCLUSION: Galantamine attenuated inflammation in LPS-induced ALI during neutropenia recovery.

Increasing the accuracy of the asthma diagnosis using an operational definition for asthma and a machine learning method.

INTRODUCTION: Analysis of the National Health Insurance data has been actively carried out for the purpose of academic research and establishing scientific evidences for health care service policy in asthma. However, there has been a limitation for the accuracy of the data extracted through conventional operational definition. In this study, we verified the accuracy of conventional operational definition of asthma, by applying it to a real hospital setting. And by using a machine learning technique, we established an appropriate operational definition that predicts asthma more accurately. METHODS: We extracted asthma patients using the conventional operational definition of asthma at Seoul St. Mary's hospital and St. Paul's hospital at the Catholic University of Korea between January 2017 and January 2018. Among these extracted patients of asthma, 10% of patients were randomly sampled. We verified the accuracy of the conventional operational definition for asthma by matching actual diagnosis through medical chart review. And then we operated machine learning approaches to predict asthma more accurately. RESULTS: A total of 4,235 patients with asthma were identified using a conventional asthma definition during the study period. Of these, 353 patients were collected. The patients of asthma were 56% of study population, 44% of patients were not asthma. The use of machine learning techniques improved the overall accuracy. The XGBoost prediction model for asthma diagnosis showed an accuracy of 87.1%, an AUC of 93.0%, sensitivity of 82.5%, and specificity of 97.9%. Major explanatory variable were ICS/LABA,LAMA and LTRA for proper diagnosis of asthma. CONCLUSIONS: The conventional operational definition of asthma has limitation to extract true asthma patients in real world. Therefore, it is necessary to establish an accurate standardized operational definition of asthma. In this study, machine learning approach could be a good option for building a relevant operational definition in research using claims data.

Summary of Korean Asthma Guideline.

Asthma is a chronic inflammatory airway disease that is characterized by variable airflow obstruction. The Korean Asthma Study Group of the Korean Academy of Tuberculosis and Respiratory Diseases has recently updated the Korean Asthma Guideline. This review summarizes the updated Korean Asthma Guideline. Asthma prevalence is increasing worldwide, and in Korea. Variable airflow obstruction can be confirmed by bronchodilator response or other tests, and should be established prior to the controller medication. A low-dose inhaled corticosteroid-formoterol is used to alleviate symptoms in all treatment step, and it can be used as a controller as well as reliever in steps 3-5. This approach is preferred, because it reduces the risk of severe exacerbations, compared to the use of short-acting ß2-agonist as reliever. In severe asthma, phenotype/endotype based on the underlying inflammation should be evaluated. For type 2 severe asthma, the biologics should be considered.

Association Between Air Pollution and Viral Infection in Severe Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

BACKGROUND: Respiratory pathogen infections and air pollution are main causes of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Air pollution has a direct effect on the airway epithelial barrier and the immune system, which can have an influence on infection. However, studies on the relationship between respiratory infections and air pollutants in severe AECOPD are limited. Thus, the objective of this study was to investigate the correlation between air pollution and respiratory pathogen in severe AECOPD. METHODS: This multicenter observational study was conducted by reviewing electronic medical records of patients with AECOPD at 28 hospitals in South Korea. Patients were divided into four groups according to the comprehensive air-quality index (CAI) used in Korea. Identification rates of bacteria and viruses of each group were analyzed. RESULTS: Viral pathogens were identified in 270 (36.7%) of 735 patients. Viral identification rate was different (P = 0.012) according to air pollution. Specifically, the virus detection rate was 55.9% in the group of CAI 'D' with the highest air pollution. It was 24.4% in the group of CAI 'A' with the lowest air pollution. This pattern was clearly seen for influenza virus A (P = 0.042). When further analysis was performed with particulate matter (PM), the higher/lower the PM level, the higher/lower the virus detection rate. However, no significant difference was found in the analysis related to bacteria. CONCLUSION: Air pollution may make COPD patients more susceptible to respiratory viral infections, especially influenza virus A. Thus, on days with poor air quality, COPD patients need to be more careful about respiratory infections.

Risk of Rapid Lung Function Decline in Young Adults With Chronic Obstructive Pulmonary Disease: A Community-Based Prospective Cohort Study.

It is unclear whether young adults with chronic obstructive pulmonary disease (COPD) are at an increased risk of rapid lung function decline. A total of 2,934 Korean adults aged 40-49 years who had consecutive lung function measurements were included. COPD was defined as pre-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity < lower limit of normal. The risk of rapid decline in FEV1, defined as ≥ 60 mL/year, was assessed using multivariable logistic regression analysis. In the multivariable model, a significantly higher risk of rapid decline in FEV1 was observed for the COPD group compared with the non-COPD group (adjusted odds ratio, 1.89; 95% confidence interval, 1.18-2.95), which was especially significant in subjects with FEV1 less than the median value (< 110%pred) (Pinteraction = 0.017) and inactive physical activity (Pinteraction = 0.039). In conclusion, the risk of rapid FEV1 decline was higher in young adults with COPD than in those without COPD, especially in those with FEV1 less than the median value and inactive physical activity.

Phenotype of Asthma-COPD Overlap in COPD and Severe Asthma Cohorts.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are airway diseases with similar clinical manifestations, despite differences in pathophysiology. Asthma-COPD overlap (ACO) is a condition characterized by overlapping clinical features of both diseases. There have been few reports regarding the prevalence of ACO in COPD and severe asthma cohorts. ACO is heterogeneous; patients can be classified on the basis of phenotype differences. This study was performed to analyze the prevalence of ACO in COPD and severe asthma cohorts. In addition, this study compared baseline characteristics among ACO patients according to phenotype. METHODS: Patients with COPD were prospectively enrolled into the Korean COPD subgroup study (KOCOSS) cohort. Patients with severe asthma were prospectively enrolled into the Korean Severe Asthma Registry (KoSAR). ACO was defined in accordance with the updated Spanish criteria. In the COPD cohort, ACO was defined as bronchodilator response (BDR) ≥ 15% and ≥ 400 mL from baseline or blood eosinophil count (BEC) ≥ 300 cells/µL. In the severe asthma cohort, ACO was defined as age ≥ 35 years, smoking ≥ 10 pack-years, and post-bronchodilator forced expiratory volume in 1 s/forced vital capacity < 0.7. Patients with ACO were divided into four groups according to smoking history (threshold: 20 pack-years) and BEC (threshold: 300 cells/µL). RESULTS: The prevalence of ACO significantly differed between the COPD and severe asthma cohorts (19.8% [365/1,839] vs. 12.5% [104/832], respectively; P < 0.001). The percentage of patients in each group was as follows: group A (light smoker with high BEC) - 9.1%; group B (light smoker with low BEC) - 3.7%; group C (moderate to heavy smoker with high BEC) - 73.8%; and group D (moderate to heavy smoker with low BEC) - 13.4%. Moderate to heavy smoker with high BEC group was oldest, and showed weak BDR response. Age, sex, BDR, comorbidities, and medications significantly differed among the four groups. CONCLUSION: The prevalence of ACO differed between COPD and severe asthma cohorts. ACO patients can be classified into four phenotype groups, such that each phenotype exhibits distinct characteristics.

A Multicenter Study to Identify the Respiratory Pathogens Associated with Exacerbation of Chronic Obstructive Pulmonary Disease in Korea.

BACKGROUND: Although respiratory tract infection is one of the most important factors triggering acute exacerbation of chronic obstructive pulmonary disease (AE-COPD), limited data are available to suggest an epidemiologic pattern of microbiology in South Korea. METHODS: A multicenter observational study was conducted between January 2015 and December 2018 across 28 hospitals in South Korea. Adult patients with moderate-to-severe acute exacerbations of COPD were eligible to participate in the present study. The participants underwent all conventional tests to identify etiology of microbial pathogenesis. The primary outcome was the percentage of different microbiological pathogens causing AE-COPD. A comparative microbiological analysis of the patients with overlapping asthma-COPD (ACO) and pure COPD was performed. RESULTS: We included 1,186 patients with AE-COPD. Patients with pure COPD constituted 87.9% and those with ACO accounted for 12.1%. Nearly half of the patients used an inhaled corticosteroid-containing regimen and one-fifth used systemic corticosteroids. Respiratory pathogens were found in 55.3% of all such patients. Bacteria and viruses were detected in 33% and 33.2%, respectively. Bacterial and viral coinfections were found in 10.9%. The most frequently detected bacteria were Pseudomonas aeruginosa (9.8%), and the most frequently detected virus was influenza A (10.4%). Multiple bacterial infections were more likely to appear in ACO than in pure COPD (8.3% vs. 3.6%, p=0.016). CONCLUSION: Distinct microbiological patterns were identified in patients with moderate-to-severe AE-COPD in South Korea. These findings may improve evidence-based management of patients with AE-COPD and represent the basis for further studies investigating infectious pathogens in patients with COPD.

Revised Korean Cough Guidelines, 2020: Recommendations and Summary Statements.

Cough is the most common respiratory symptom that can have various causes. It is a major clinical problem that can reduce a patient's quality of life. Thus, clinical guidelines for the treatment of cough were established in 2014 by the cough guideline committee under the Korean Academy of Tuberculosis and Respiratory Diseases. From October 2018 to July 2020, cough guidelines were revised by members of the committee based on the first guidelines. The purpose of these guidelines is to help clinicians efficiently diagnose and treat patients with cough. This article highlights the recommendations and summary of the revised Korean cough guidelines. It includes a revised algorithm for the evaluation of acute, subacute, and chronic cough. For a chronic cough, upper airway cough syndrome (UACS), cough variant asthma (CVA), and gastroesophageal reflux disease (GERD) should be considered in differential diagnoses. If UACS is suspected, first-generation antihistamines and nasal decongestants can be used empirically. In cases with CVA, inhaled corticosteroids are recommended to improve cough. In patients with suspected chronic cough due to symptomatic GERD, proton pump inhibitors are recommended. Chronic bronchitis, bronchiectasis, bronchiolitis, lung cancer, aspiration, intake of angiotensin-converting enzyme inhibitor, intake of dipeptidyl peptidase-4 inhibitor, habitual cough, psychogenic cough, interstitial lung disease, environmental and occupational factors, tuberculosis, obstructive sleep apnea, peritoneal dialysis, and unexplained cough can also be considered as causes of a chronic cough. Chronic cough due to laryngeal dysfunction syndrome has been newly added to the guidelines.

Association between plasma interleukin-33 level and acute exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: The role of interleukin (IL)-33 in patients with chronic obstructive pulmonary disease (COPD) has not been well elucidated. The aim of this study is to analyze the association between plasma IL-33 level and acute exacerbation of COPD. METHODS: Plasma IL-33 was measured in 62 COPD patients during their stable state. Patients were prospectively followed up for 1 year. The expression of IL-33 was measured in lung tissue obtained from 38 patients who underwent surgery. RESULTS: The number of exacerbations was significantly higher in the high plasma IL-33 group compared with the low plasma IL-33 group. On Poisson regression analysis, high plasma IL-33 was associated with increased risk of exacerbation (incidence rate ratio = 2.166, P = 0.043). The expression of IL-33 in the lung was higher in COPD patients than in controls. The expression of IL-33 was significantly correlated with smoking pack years (R = 0.45, P < 0.01) and Forced expiratory volume in 1 s (%) (R = - 0.58, P < 0.01). CONCLUSION: The plasma level of IL-33 in patients with COPD was significantly associated with the risk of exacerbation in prospective follow up. The expression of IL-33 in the lung was positively correlated with smoking and negatively correlated with lung function.

Validity and reliability of the Korean version of the Wisconsin Smoking Withdrawal Scale.

BACKGROUND/AIMS: This study evaluated the validity and reliability of the Korean version of the Wisconsin Smoking Withdrawal Scale (WSWS-K) for use in clinical practice and research on Korean smokers. METHODS: The Wisconsin Smoking Withdrawal Scale was translated into Korean and then back-translated into English. The authors reviewed the translation and back-translation and approved the final questionnaire draft. The validity and reliability of the WSWS-K were evaluated based on data collected from 300 participants. Construct validity was evaluated with a confirmatory factor analysis. Criterion-related validity was assessed by examining the relationships between the subscales of the WSWS-K and the matched items of the Korean version of the Minnesota Nicotine Withdrawal Scale (MNWS-K). RESULTS: The participants were predominantly male (93.6%) and the mean age was 59.23 ± 15.19 years. The confirmatory factor analysis revealed that fit indices (namely, the goodness-of-fit index, adjusted goodness-of-fit index, comparative fit index, and the normed fit index) exceeded or approached 0.9. Cronbach's alpha for the entire scale was 0.87. The total score of the WSWS-K had a statistically significant positive correlation with that of the MNWS-K (Pearson's correlation coefficient, 0.768; p < 0.01). Additionally, we performed linear regression between the WSWS-K and MNWS-K scores after adjusting for age, gender, comorbidity, and smoking history. After this adjustment, the p value of the WSWS- K was < 0.001. CONCLUSION: The WSWS-K had satisfactory validity and reliability. The WSWS- K can be used with acceptable validity and reliability in research and clinical evaluation of Korean smokers.

The relationship between sleep disturbance and health status in patients with COPD.

Introduction: The detection of insomnia in patients with COPD is assumed to be significantly lower than the actual prevalence. In this study, we investigated the prevalence of insomnia and the relationship between insomnia and health status in patients with COPD using two fairly simple and straightforward questionnaires: COPD assessment test (CAT) and insomnia severity index (ISI). Patients and methods: A cross-sectional study was conducted using data from patients undergoing treatment for COPD at St Paul's Hospital, The Catholic University of Korea, between December 2015 and August 2016. Patients were classified into three groups according to the ISI score: a "clinical insomnia" group (ISI≥15), a "subthreshold insomnia" group (ISI 8-15), and a "non-insomnia" group (ISI<8). Clinical parameters including past medical history, pulmonary function tests, and questionnaire data were collected and analyzed. Results: A total of 192 patients were recruited, of which 25.0% were found to have clinical insomnia (ISI≥8). Insomnia severity was related to all CAT component items except for cough, and patients with higher CAT scores generally had more severe insomnia. Logistic regression analysis revealed that CAT score was significantly associated with insomnia in these patients (odds ratio, 1.23; 95% CI, 1.13-1.34; p<0.0001). CAT score was also a significant predictor of insomnia (area under receiver operating characteristic curve, 0.779; p<0.001). The optimal predictive cutoff value was a CAT score >14, giving a sensitivity and specificity of 66.7% and 71.5%, respectively. Conclusion: CAT score was closely related to insomnia severity in patients with COPD. The use of CAT scores to assess for the presence and severity of insomnia in these patients may allow for better detection and management and improve clinical practice.

Incidence of Adverse Effects and Discontinuation Rate between Patients Receiving 250 Micrograms and 500 Micrograms of Roflumilast: A Comparative Study.

BACKGROUND: Roflumilast is the only approved oral phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease (COPD) in patients with chronic bronchitis and a history of frequent exacerbations. The purpose of this study was to examine the incidence of adverse effects associated with roflumilast treatment in a real-world setting. Further, we compared the incidence of adverse effects and the discontinuation rate among patients receiving different doses. METHODS: We identified all outpatients diagnosed with COPD at Seoul St. Mary's Hospital between May 2011 and September 2016 and retrospectively reviewed their medical records. Roflumilast was prescribed to patients in doses of 500 µg and 250 µg. RESULTS: A total of 269 COPD patients were prescribed roflumilast in our hospital during the study period. Among them, 178 patients were treated with 500 µg and 91 patients were treated with 250 µg. The incidence of adverse effects was 38.2% in the 500 µg group and 25.3% in the 250 µg group (p=0.034). The discontinuation rate of roflumilast was 41.6% (n=74) in the 500 µg group and 23.1% (n=21) in the 250 µg group (p=0.003). When adjusted by age, sex, smoking status, and lung function, 500 µg dose was significantly associated with the discontinuation of roflumilast (odds ratio, 2.87; p<0.001). CONCLUSION: There was a lower incidence of adverse effects and discontinuation among patients treated with 250 µg compared with 500 µg dose. Further studies regarding the optimal dose of roflumilast are required.

Clinical significance of nuclear factor erythroid 2-related factor 2 in patients with chronic obstructive pulmonary disease.

Background/Aims: Several studies have identified a role for nuclear factor erythroid 2-related factor 2 (Nrf2) in the development of chronic obstructive pulmonary disease (COPD). However, the relationship between the plasma Nrf2 level and the extent of systemic inflammation associated with COPD status remains unclear. METHODS: Patients diagnosed with COPD were recruited from St. Paul's Hospital, The Catholic University of Korea, between July 2009 and May 2012. Patients were classified into two groups according to the severity of their symptoms on initial presentation, a COPD-stable group (n = 25) and a COPD-exacerbation group (n = 30). Seventeen patients were enrolled as a control group (n = 17). The plasma levels of Nrf2 and other systemic inf lammatory biomarkers, including interleukin 6 (IL-6), surfactant protein D (SP-D), and C-reactive protein (CRP), were measured. We collected clinical data including pulmonary function test results, and analyzed the relationships between the biomarker levels and the clinical parameters. RESULTS: Plasma Nrf2 and CRP levels significantly increased in a stepwise manner with an increase in inflammatory status (control vs. COPD-stable vs. COPD-exacerbation) (p = 0.002, p < 0.001). Other biomarkers of systemic inflammation (IL-6, SP-D) exhibited similar tendencies, but significant differences were not apparent. Furthermore, we observed negative correlations between the plasma level of Nrf2 and both the forced expiratory volume in 1 second (FEV1) (r = -0.339, p = 0.015) and the forced expiratory ratio (FEV1/forced vital capacity [FVC]) (r = -0.342, p = 0.014). However, CRP level was not correlated with any measured parameter. Conclusions: Plasma Nrf2 levels gradually increased in line with disease severity and the extent of systemic inflammation in patients with COPD.

Chronic intermittent hypoxia induces liver fibrosis in mice with diet-induced obesity via TLR4/MyD88/MAPK/NF-kB signaling pathways.

Obstructive sleep apnea (OSA) is associated with nonalcoholic fatty liver disease (NAFLD), and causes chronic intermittent hypoxia (CIH) during sleep. Inflammation is associated with the development of metabolic complications induced by CIH. Research suggests that innate immune mechanisms are involved in the pro-inflammatory pathways of liver fibrosis. The purpose of this study was to investigate whether innate immune responses induce liver fibrosis, and to evaluate mechanisms underlying hepatic inflammation related to CIH in a murine diet-induced obesity (DIO) model. Inflammatory and oxidative stress markers, TLR4, MyD88, Toll/interleukin-1-receptor-domain-containing adaptor-inducing interferon-ß (TRIF), I-κB, NF-κB, p38 MAPK, c-JNK, and ERK activation, were measured in the serum and liver. As a result, α1(I)-collagen mRNA was significantly higher in DIO mice exposed to CIH than in the control groups. CIH mice exhibited liver fibrosis and significantly higher protein expression of TLR4, MyD88, phosphorylated (phospho-) I-κB, and phospho-ERK1/2 activation in the liver, and higher expression of NF-κB than that in the controls. TRIF, p38 MAPK, and JNK activation did not differ significantly between groups. We conclude that CIH in DIO mice leads to liver fibrosis via TLR4/MyD88/MAPK/NF-kB signaling pathways.

Mycobacterium kansasii Pneumonia with Mediastinal Lymphadenitis in a Patient with Acute Myeloid Leukemia: Successful Treatment to Stem Cell Transplantation.

Non-tuberculous mycobacterial (NTM) disease is a relatively rare cause of neutropenic fever in patients with hematologic malignancies. During the neutropenic period, performing invasive procedures for microbiological or pathological confirmation is difficult. In addition, the optimal treatment duration for NTM disease in patients with leukemia, especially prior to stem cell transplantation (SCT), has not been documented. Therefore, we report a case of pneumonia with necrotizing lymphadenitis caused by Mycobacterium kansasii diagnosed during chemotherapy being performed for acute myeloid leukemia. The radiologic findings were similar to those of invasive fungal pneumonia; however, a bronchoalveolar washing fluid culture confirmed that the pathogen was M. kansasii. After 70 days from starting NTM treatment, allogeneic SCT was performed without any complications. The patient fully recovered after 12 months of NTM treatment, and neither reactivation of M. kansasii infection nor related complications were reported.

Heterogeneity of asthma-COPD overlap syndrome.

Many patients suffering from asthma or COPD have overlapping features of both diseases. However, a phenotypical approach for evaluating asthma-COPD overlap syndrome (ACOS) has not been established. In this report, we examined the phenotypes in patients with ACOS. Patients diagnosed with ACOS between 2011 and 2015 were identified and classified into four phenotype groups. Group A was composed of patients who smoked <10 pack years and had blood eosinophil counts ≥300. Group B was composed of patients who smoked <10 pack years and had blood eosinophil counts <300. Group C was composed of patients who smoked ≥10 pack years and had blood eosinophil counts ≥300. Group D was composed of patients who smoked <10 pack years and had blood eosinophil counts <300. Clinical characteristics were analyzed and compared among groups. Comparisons were made among 103 ACOS patients. Patients in group D were oldest, while patients in group A were youngest. There were relatively more female patients in groups A and B; the majority of patients in groups C and D were male. The degree of airflow obstruction was most severe in group C. The rate of being free of severe exacerbation was significantly lower in group C than in the other groups. In this study, each ACOS phenotype showed different characteristics. The proportion of patients free of severe exacerbation differed significantly among groups. At this time, further studies on the phenotypes of ACOS are required.