The preventative effects of statin on lung cancer development in patients with idiopathic pulmonary fibrosis using the National Health Insurance Service Database in Korea.

Little is known about the effect of statin use in lung cancer development in idiopathic pulmonary fibrosis (IPF). We analyzed the database of the National Health Insurance Service to further investigate the clinical impacts of statin on lung cancer development and overall survival (OS) in IPF patients. The analysis included 9,182 individuals diagnosed with IPF, of which 3,372 (36.7%) were statin users. Compared to statin non-users, the time from diagnosis of IPF to lung cancer development and OS were longer in statin users in IPF patients. In Cox proportional hazard regression models, higher statin compliance, statin use, and being female had an inverse association with lung cancer risk, while older age at diagnosis of IPF and smoking history were associated with higher risk of lung cancer in IPF patients. For OS, statin use, female sex, higher physical activity frequency, and diabetes were associated with longer survival. In contrast, older age at diagnosis of IPF and smoking history were associated with shorter OS in IPF patients. These data from a large population indicate that statin had an independent protective association with lung cancer development and mortality in IPF patients.

Delphi Survey on the Current and Future Korean Guidelines for Isoniazid-Monoresistant Tuberculosis.

Purpose: Isoniazid-monoresistant tuberculosis (Hr-TB) has emerged as a global challenge, necessitating detailed guidelines for its diagnosis and treatment. We aim to consolidate the Korean guidelines for Hr-TB management by gathering expert opinions and reaching a consensus. Patients and Methods: A conventional Delphi method involving two rounds of surveys was conducted with 96 experts selected based on their clinical and research experience and involvement in nationwide tuberculosis studies and development of the Korean guidelines on tuberculosis. The survey consisted of three sections of questionnaires on diagnosis, treatment, and general opinions on Hr-TB. Results: Among the 96 experts, 72 (75%) participated in the two rounds of the survey. A majority of experts (96%) strongly agreed on the necessity of molecular drug susceptibility testing (DST) for isoniazid and rifampin resistance in all tuberculosis patients and emphasized the importance of interpreting mutation types (inhA or katG) and additional molecular DST for fluoroquinolones for confirmed isoniazid-resistant cases. Over 95.8% of experts recommended treating Hr-TB with a combination of rifampin, ethambutol, pyrazinamide, and levofloxacin for six months, without exceeding 12 months unless necessary. They also acknowledged the drawbacks of long-term pyrazinamide use due to its side effects and agreed on shortening its duration by extending the duration of the rest of the treatment with a modified combination of choice. Conclusion: This Delphi survey enabled Korean tuberculosis experts to reach a consensus on diagnosing and treating Hr-TB. These findings will be valuable for developing the upcoming revised Korean guidelines for Hr-TB management.

Comparison of pneumonia incidence between long-acting muscarinic antagonist and inhaled corticosteroid plus long-acting beta agonist in patients with COPD.

Few studies have directly compared the incidence of pneumonia in patients on common chronic obstructive pulmonary disease (COPD) treatments such as long-acting muscarinic antagonists (LAMA) with those on inhaled corticosteroids and long-acting ß2-agonist (ICS/LABA). Moreover, risk factors for pneumonia in COPD are still unclear. We aimed to compare the incidence of pneumonia in COPD patients on LAMA and those on ICS/LABA and explored the risk factors associated with pneumonia. This nationwide cohort study used Korean National Health Insurance claim data from January 2002 to April 2016. Patients who received COPD medication, either LAMA or ICS/LABA, with the COPD diagnostic code, were selected. We enrolled patients with good compliance (medication possession ratio ≥ 80%). The primary outcome was pneumonia in COPD patients initiating LAMA or ICS/LABA. We investigated the risk factors associated with pneumonia, including the sub-types of ICS treatments. After propensity score matching, the incidence rate per 1000 person-years of pneumonia was 93.96 for LAMA (n = 1003) and 136.42 for ICS/LABA (n = 1003) patients (p < 0.001). The adjusted hazard ratio (HR) for pneumonia in patients on fluticasone/LABA was 1.496 (95% confidence interval [CI] 1.204-1.859) compared with LAMA (p < 0.001). In multivariable analysis, a history of pneumonia was a risk factor associated with pneumonia (HR 2.123; 95% CI 1.580-2.852; p < 0.001). The incidence of pneumonia was higher in COPD patients on ICS/LABA compared with those on LAMA. It is recommended that ICS use be avoided in COPD patients with high pneumonia risk.

Factors Predicting Worse Outcomes in an Asian Cohort of Patients With Bronchiectasis.

BACKGROUND/AIM: Bronchiectasis has long been neglected, unlike chronic obstructive pulmonary disease (COPD) and asthma. Recent clinical trials have shown that long-term use of azithromycin or erythromycin reduce exacerbations of non-cystic fibrosis (non-CF) bronchiectasis. Because of this, we should actively try to treat patients susceptible to severe status. PATIENTS AND METHODS: We enrolled patients who had been diagnosed with bronchiectasis at five branches of the Catholic Medical Center between January 2015 to December 2017. We retrospectively analyzed these patients for demographic characteristics such as sex, age, body mass index (BMI), history of smoking and tuberculosis, bacterial colonization, pulmonary function, hospitalizations, and other exacerbations. RESULTS: Colonization was shown to have a statistically significant association with hospitalization. A three-year follow up period showed that the mean frequency of hospitalization in patients without colonization was 0.8 times, compared to 0.7 times and 1.9 times, respectively in patients with NTM colonization and with other bacterial colonization (p-value=0.03). Patients with a lower BMI also had an increased risk of hospitalization (p-value=0.024). Current smokers had increased risk of mortality as compared to those who had never smoked (HR=11.29, p-value 0.015). Patients with a high BMI also had low risk of mortality as compared to patients with a low BMI (HR=0.76, p-value 0.005). CONCLUSION: Patients with bronchiectasis having chronic colonization, low BMI, or who are current smokers tend to be at greater risk for severe illness. Therefore, physicians should actively treat these patients to prevent exacerbations and mortality.

COPD Exacerbation-Related Pathogens and Previous COPD Treatment.

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

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.

Platycodin D attenuates airway inflammation via suppression Th2 transcription factor in a murine model of acute asthma.

Introduction: Bronchial asthma is a common chronic inflammatory condition of the airway tissue. Platycodin D (PLD) has antiinflammatory effects in a mouse model of allergic asthma. In this work, the anti-asthma potential of PLD was studied by investigation of its effect to suppress airway inflammation and mucin production, a murine model of asthma and the possible mechanisms.Methods: Mice were randomly assigned to five experimental groups: control, ovalbumin (OVA), OVA+ICS (intranasal fluticasone), OVA+PLD and OVA+PLD/ICS. Airway histological studies were evaluated by the H&E staining; IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid were evaluated by ELISA; GATA3 and IRF4 mRNA of airway were measured by RT-PCR and their protein level were measured by Western blotting.Results: Our study showed that PLD suppressed eosinophilic inflammation and mucin production in bronchial mucosa. Moreover, PLD inhibited production of Th2 cytokines such as IL-4, IL-5, and IL-13. Protein production of GATA3 and IRF4, were also decreased in PLD treated OVA asthma model. Taken together, our results provided evidence that PLD inhibits the airway inflammation via suppression of Th2 transcription factor production.Conclusion: These findings suggest that PLD may effectively ameliorate the progression of asthma. These results suggest that PLD could be used as a therapy for allergic asthma.

Effects of low-dose pirfenidone on survival and lung function decline in patients with idiopathic pulmonary fibrosis (IPF): Results from a real-world study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia of unknown etiology. In several randomized clinical trials, and in the clinical practice, pirfenidone is used to effectively and safely treat IPF. However, sometimes it is difficult to use the dose of pirfenidone used in clinical trials. This study evaluated the effects of low-dose pirfenidone on IPF disease progression and patient survival in the real-world. METHODS: This retrospective, observational study enrolled IPF patients seen at the time of diagnosis at a single center from 2008 to 2018. Longitudinal clinical and laboratory data were prospectively collected. We compared the clinical characteristics, survival, and pulmonary function decline between patients treated and untreated with various dose of pirfenidone. RESULTS: Of 295 IPF patients, 100 (33.9%) received pirfenidone and 195 (66.1%) received no antifibrotic agent. Of the 100 patients who received pirfenidone, 24 (24%), 50 (50%), and 26 (26%), respectively, were given 600, 1200, and 1800 mg pirfenidone daily. The mean survival time was 57.03 ± 3.90 months in the no-antifibrotic drug group and 73.26 ± 7.87 months in the pirfenidone-treated group (p = 0.027). In the unadjusted analysis, the survival of the patients given pirfenidone was significantly better (hazard ratio [HR] = 0.69, 95% confidence interval [CI]: 0.48-0.99, p = 0.04). After adjusting for age, gender, body mass index, and the GAP score [based on gender (G), age (A), and two physiological lung parameters (P)], survival remained better in the patients given pirfenidone (HR = 0.56, 95% CI: 0.37-0.85, p = 0.006). In terms of pulmonary function, the decreases in forced vital capacity (%), forced expiratory volume in 1 s (%) and the diffusing capacity of lung for carbon monoxide (%) were significantly smaller (p = 0.000, p = 0.001, and p = 0.007, respectively) in patients given pirfenidone. CONCLUSIONS: Low-dose pirfenidone provided beneficial effects on survival and pulmonary function decline in the real-world practice.

Cough Sounds Recorded via Smart Devices as Useful Non-Invasive Digital Biomarkers of Aspiration Risk: A Case Report.

Spirometer measurements can reflect cough strength but might not be routinely available for patients with severe neurological or medical conditions. A digital device that can record and help track abnormal cough sound changes serially in a noninvasive but reliable manner would be beneficial for monitoring such individuals. This report includes two cases of respiratory distress whose cough changes were monitored via assessments performed using recordings made with a digital device. The cough sounds were recorded using an iPad (Apple, Cupertino, CA, USA) through an embedded microphone. Cough sounds were recorded at the bedside, with no additional special equipment. The two patients were able to complete the recordings with no complications. The maximum root mean square values obtained from the cough sounds were significantly reduced when both cases were diagnosed with aspiration pneumonia. In contrast, higher values became apparent when the patients demonstrated a less severe status. Based on an analysis of our two cases, the patients' cough sounds recorded with a commercial digital device show promise as potential digital biomarkers that may reflect aspiration risk related to attenuated cough force. Serial monitoring aided the decision making to resume oral feeding. Future studies should further explore the clinical utility of this technique.

Cyclo-VEGI inhibits bronchial artery remodeling in a murine model of chronic asthma.

Purpose/Aim: In the context of asthma, airway bronchial remodeling and angiogenesis in the bronchial mucosa are well established. Cyclopeptidic-vascular endothelial growth inhibitor (cyclo-VEGI) is an inhibitor of the vascular endothelial growth factor (VEGF) receptor that increases the proliferation of endothelial cells and the formation of new vessels. However, changes in the bronchial arteries of patients with asthma have not been clearly elucidated. We investigated whether structural changes occurred in bronchial arteries, as well as the effects of cyclo-VEGI in a mouse model of chronic asthma (in vivo) and human fibroblasts (in vitro). Materials and Methods: A validated mouse model of allergic airway inflammation with ovalbumin (OVA) as the causative allergen was used for the study. Mice were treated with cyclo-VEGI or fluticasone during OVA challenge. In vitro experiments were conducted to determine whether fibroblasts proliferated following elastin exposure and the effects of cyclo-VEGI on them. Results: OVA sensitization and challenge led to greater perivascular smooth muscle area, more elastic fibers, and elevated expression of vascular cell adhesion molecule (VCAM)-1 antigen. These phenomena indicated changes to bronchial arteries. Cyclo-VEGI and fluticasone treatment both inhibited airway hyper-responsiveness and inflammation. Cyclo-VEGI-treated mice exhibited decreased perivascular smooth muscle area, elastin fibers, and VCAM-1 expression. Fluticasone-treated mice exhibited reductions in perivascular smooth muscle but not in perivascular elastin or VCAM-1 expression. In vitro, fibroblast proliferation was enhanced by elastin treatment, which was inhibited by cyclo-VEGI treatment. Eotaxin expression was elevated in elastin-treated fibroblasts and decreased with cyclo-VEGI treatment. Conclusions: Vascular remodeling occurred in our mouse model of chronic asthma. Cyclo-VEGI could reduce airway inflammation and hyper-responsiveness by inhibiting VCAM-1 expression and elastin deposition around the bronchial arteries.

Tracheobronchopathia Osteochondroplastica Associated with Fibrotic Interstitial Lung Disease.

Tracheobronchopathia osteochondroplastica (TPO) is a very rare, benign disorder involving the lumen of the trachea-bronchial tree. However, its etiology is unknown. In our first case, observation for several years showed that TPO worsened as interstitial lung disease was aggravated. In the second case, the lung parenchymal lesion on computed tomography (CT) was found to be compatible with interstitial lung abnormality (ILA). We believe that our cases suggest a common pathogenetic relationship between TPO and fibrotic interstitial lung disease. TGF-ß is likely a common factor in the pathogenesis of TPO and fibrotic interstitial lung disease.

Epidemiology, burden, and policy of chronic obstructive pulmonary disease in South Korea: a narrative review.

Chronic obstructive pulmonary disease (COPD) is a global health problem and a significant cause of mortality and morbidity worldwide. COPD also occupies a significant and considerable economic burden on individuals and society in South Korea. We investigated the epidemiology and burden of COPD in South Korea and reviewed the policy regarding COPD. In South Korea, a national COPD prevalence survey has been conducted for two decades. The prevalence of COPD has increased with increasing age, particularly among males, and those also with a higher smoking history and with lower income. The total societal cost of COPD increased by 1.85 times between 2004 and 2013. As the use of inhaled medications has increased, the total medical cost per person has increased. The trends of increasing numbers of patients diagnosed with COPD and the total societal costs are expected to continue. There is one universal-health-coverage system in South Korea. The costs and reimbursement criteria of COPD drugs are established and controlled by the Health Insurance Review and Assessment Service (HIRA). The HIRA has also implemented quality assessment, including evaluating the appropriateness of a COPD diagnosis and treating all COPD patients to reduce the severity of illness and improve the adequacy of medical-care benefits.

The clinical efficacy of AG NPP709 (Synatura®) in patients with chronic bronchitis type stable chronic obstructive pulmonary disease.

BACKGROUND: AG NPP709 (Synatura®) has been demonstrated to be efficacious in decreasing cough and sputum in patients with acute upper respiratory infection and chronic inflammatory bronchitis. The aim of this study was to evaluate the efficacy of AG NPP709 in patients with chronic bronchitis type chronic obstructive pulmonary disease (COPD). METHODS: This was a prospective, open-label, single-arm clinical trial (NCT03623282). Chronic bronchitis type COPD patients aged >40 years were enrolled. The primary endpoint was improvement on the CAT scores between the baseline visit and week 12. The secondary endpoints were the effect of AG NPP709 on the pulmonary function and systemic inflammation, as indexed by CRP, fibrinogen, IL-6, TNF-α and IL-33 levels. RESULTS: Thirty patients were enrolled. All patients were male, and their mean age was 71.93±7.93 years. The mean post-bronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio was 58.63±11.40, and FEV1 (%) was 75.93±20.42. The mean total CAT score was 14.77±7.14. Of these patients, 26 were followed up after 3 months. A significant improvement was observed in the total CAT score (from 14.38±6.62 to 12.73±6.60, P=0.005). Fibrinogen level decreased significantly (P=0.013). No serious adverse events occurred. CONCLUSIONS: AG NPP709 improved the quality of life, as represented by the CAT score, in patients with chronic bronchitis type COPD, and significantly reduced fibrinogen levels. These results suggest that AG NPP709 is efficacious and safe in patients with chronic bronchitis type COPD.

Age-stratified anti-tuberculosis drug resistance profiles in South Korea: a multicenter retrospective study.

BACKGROUND: The emergence of drug-resistant tuberculosis (DR-TB) is a major healthcare concern worldwide. Here, we analyzed age-related trends in DR-TB rates in South Korea. METHODS: Drug susceptibility test results were collected from patients with culture-confirmed TB between 2015 and 2018 from eight university-affiliated hospitals. Patients were divided into three subgroups: younger (15-34 years), middle (35-59 years), and older (≥60 years) to compare drug-resistance patterns. To evaluate trends in age-stratified drug-resistance, chi-square test for linear trends was performed. RESULTS: Among enrolled native patients aged ≥15 years, 4.1% (179/4417), 1.2% (53/4417) and 7.2% (316/4417) were multidrug-resistant TB (MDR-TB), rifampicin-mono-resistant TB (RR-TB), and isoniazid-mono-resistant TB (Hr-TB), respectively. Proportions of Hr-TB cases were 5.4% (40/734), 7.2% (114/1593), and 7.8% (162/2090) in the younger, middle and older age groups, respectively. MDR/RR-TB case rates decreased significantly with age from 8.6% (63/734) in younger age group to 3.3% (68/2090) in older age group. Fluoroquinolone resistance was highest among second-line drugs, and there were no differences in resistance to fluoroquinolones and second-line injectable drugs among the three age groups. CONCLUSIONS: The number of MDR/RR-TB cases was highest in young patients. Effective public health interventions should include increased focus on rifampicin resistance in young patients.

Pravastatin alleviates allergic airway inflammation in obesity-related asthma mouse model.

Background: Obesity is one of the factors associated with severe, uncontrolled asthma. The effect of pravastatin on asthmatic airway inflammation in obesity has not been evaluated. Methods: C57BL/6 mice were fed a high-fat diet (HFD) to induce obesity with or without ovalbumin (OVA) sensitization and challenge. Pravastatin was administered intraperitoneally during the OVA treatment. Airway inflammation and airway hyper-responsiveness (AHR) were analyzed and lung tissues were examined. The changes in mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways were measured in the lung tissues. Results: HFD with OVA sensitization and challenge exacerbated eosinophilic and neutrophilic airway inflammation and increased AHR compared to lean asthma mice. The levels of cytokines examined in bronchoalveolar lavage fluid (BALF) revealed that the expressions of IL-4, 5, and 17 were elevated in the obese asthmatic group and decreased after pravastatin treatment, indicating that both the Th2 and Th17 pathways were stimulated by HFD-induced obesity and OVA challenge and suppressed by pravastatin treatment. Moreover, the serum leptin and adiponectin ratio was elevated only in obese asthmatic mice and decreased with pravastatin administration. Pravastatin successfully alleviated the airway inflammation of lung tissues and AHR in both obese and lean asthmatic mice, however, treatment with pravastatin had no effects on BALF cell counts and cytokines in lean asthma mice. In lung tissues, the phosphorylation of p38 MAPK was significantly decreased in lean as well as obese asthmatic mice. Conclusions: Pravastatin treatment in obese asthmatic mice suppressed allergic airway infiltration and AHR by inhibition of Th2 and Th17-associated signaling pathways, decreasing the leptin expression and downstream p38 MAPK signaling pathways. The effect on lean asthmatic mice was different, independent of airway cell counts and cytokines.

Bronchoscopic lung volume reduction using an endobronchial valve to treat a huge emphysematous bullae: a case report.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), bronchoscopic lung volume reduction (BLVR) techniques using unidirectional endobronchial valves improve lung function and increase exercise tolerance. BLVR treatment is included in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) treatment guidelines for COPD patients without interlobar collateral ventilation. However, BLVR using an endobronchial valve has not been attempted in patients with giant bullae. CASE PRESENTATION: We report successful and safe BLVR using an endobronchial valve in a patient with a huge bullous emphysema in the right middle lobe. A 65-year-old male was diagnosed with COPD 5 years prior and had a large bullae in the right middle lobe at that time. During regular follow-up, the symptoms of respiratory distress gradually worsened, and the size of the bullae gradually increased on computed tomography (CT). Therefore, we decided to treat the patient via BLVR using an unidirectional endobronchial valve. The Chartis system (Pulmonx, Inc., Palo Alto, CA) confirmed the absence of collateral ventilation of the right middle lobe. We successfully inserted an endobronchial valve into the right middle bronchus. After insertion, the bullae decreased dramatically in size, and the patient's symptoms and quality of life improved markedly. CONCLUSION: This case supports recent suggestions that BLVR can serve as a good alternative treatment for appropriately selected patients.