Chronic obstructive pulmonary disease (COPD) is a critical condition with high morbidity and mortality. Although several medications are available, there are no definite treatments. However, recent advances in the understanding of stem and progenitor cells in the lung, and molecular changes during re-alveolization after pneumonectomy, have made it possible to envisage the regeneration of damaged lungs. With this background, numerous studies of stem cells and various stimulatory molecules have been undertaken, to try and regenerate destroyed lungs in animal models of COPD. Both the cell and drug therapies show promising results. However, in contrast to the successes in laboratories, no clinical trials have exhibited satisfactory efficacy, although they were generally safe and tolerable. In this article, we review the previous experimental and clinical trials, and summarize the recent advances in lung regeneration therapy for COPD. Furthermore, we discuss the current limitations and future perspectives of this emerging field.
Approximately one in four patients with chronic obstructive pulmonary disease (COPD) have asthmatic features consisting of wheezing, airway hyper-responsiveness or atopy. The Global initiative for Asthma/Globalinitiative for chronic Obstructive Lung Disease committee recently labelled these patients as having asthma-COPD overlap syndrome or ACOS. ACOS also encompasses patients with asthma, ≥40 years of age, who have been cigarette smokers (more than 5–10 pack years) or have had significant biomass exposure, and demonstrate persistent airflow limitation defined as a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity of <70%. Data over the past 30 years indicate that patients with ACOS have greater burden of symptoms including dyspnea and cough and show higher risk of COPD exacerbations and hospitalizations than those with pure COPD or pure asthma. Patients with ACOS also have increased risk of rapid FEV1 decline and COPD mortality. Paradoxically, experimental evidence to support therapeutic decisions in ACOS patients is lacking because traditionally, patients with ACOS have been systematically excluded from therapeutic COPD and asthma trials to maintain homogeneity of the study population. In this study, we summarize the current understanding of ACOS, focusing on definitions, epidemiology and patient prognosis.
It is well established that health care workers (HCWs) have a considerably higher risk of occupationally acquired tuberculosis (TB). To reduce the transmission of TB to HCWs and patients, TB infection control programs should be implemented in health care settings. The first and most important level of all protection and control programs is administrative control. Its goals are to prevent HCWs, other staff, and patients from being exposed to TB, and to reduce the transmission of infection by ensuring rapid diagnosis and treatment of affected individuals. Administrative control measures recommended by the United States Centers for Disease Control and Prevention and the World Health Organization include prompt identification of people with TB symptoms, isolation of infectious patients, control of the spread of the pathogen, and minimization of time spent in health care facilities. Another key component of measures undertaken is the baseline and serial screening for latent TB infection in HCWs who are at risk of exposure to TB. Although the interferon-gamma release assay has some advantages over the tuberculin skin test, the former has serious limitations, mostly due to its high conversion rate.
Background: A sputum culture is the most reliable indicator of the infectiousness of pulmonary tuberculosis (PTB); however, a spontaneous sputum specimen may not be suitable. The aim of this study was to evaluate the infectious period in patients with non–drug-resistant (DR) PTB receiving adequate standard chemotherapy, using induced sputum (IS) specimens. Methods: We evaluated the duration of infectiousness of PTB using a retrospective cohort design. Results: Among the 35 patients with PTB, 22 were smear-positive. The rates of IS culture positivity from baseline to the sixth week of anti-tuberculosis medication in the smear-positive PTB group were 100%, 100%, 91%, 73%, 36%, and 18%, respectively. For smear-positive PTB cases, the median time of conversion to culture negativity was 35.0 days (range, 28.0–42.0 days). In the smear-negative PTB group (n=13), the weekly rates of positive IS culture were 100%, 77%, 39%, 8%, 0%, and 0%, respectively, and the median time to conversion to culture-negative was 21.0 days (range, 17.5–28.0 days). Conclusion: The infectiousness of PTB, under adequate therapy, may persist longer than previously reported, even in patients with non-DR PTB.
Background: Isolation of M. tuberculosis (MTB) is required in cases of Tuberculous pleural effusion (TBPE) for confirming diagnosis and successful therapy based on drug sensitivity test. Several studies have focused on predictors of MTB culture positivity in TBPE. However, the clinical role of loculated TBPE as a predictor of MTB cultivation from TBPE remains unclear. The aim of this study was to examine possible predictors including loculation of TBPE of MTB culture positivity in TBPE. Methods: We retrospectively examined associations between clinical, radiological, microbiological, and laboratory characteristics and positive MTB culture from TBPE to determine a potent predictor of culture positivity. Results: From January 2011 to August 2015, 232 patients with TBPE were identified. Of these, 219 were finally analyzed. Among them, 69 (31.5%) were culture positive for MTB in TBPE and 86 (39.3%) had loculated TBPE. In multivariate logistic regression analysis, the loculation of TBPE was independently associated with culture positivity for MTB in TBPE (adjusted odds ratio [OR], 40.062; 95% confidence interval [CI], 9.355–171.556; p<0.001). In contrast, the lymphocyte percentage of TBPE (adjusted OR, 0.934; 95% CI, 0.899–0.971; p=0.001) was inversely associated with culture positivity for MTB in TBPE. Conclusion: In clinical practice, identification of loculation in TBPE is easy, reliable to measure, not uncommon and may be helpful to predict the possibility of positive mycobacterial culture.
ackground: Endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasivediagnostic method for mediastinal and hilar lymphadenopathy. This study aimed to investigate the incidence of feverfollowing EBUS-TBNA. Methods: A total of 684 patients who underwent EBUS-TBNA from May 2010 to July 2012 at Seoul National UniversityHospital were retrospectively reviewed. The patients were evaluated for fever by a physician every 6–8 hours during thefirst 24 hours following EBUS-TBNA. Fever was defined as an increase in axillary body temperature over 37.8oC. Results: Fever after EBUS-TBNA developed in 110 of 552 patients (20%). The median onset time and duration of feverwas 7 hours (range, 0.5–32 hours) after EBUS-TBNA and 7 hours (range, 1–52 hours), respectively, and the medianpeak body temperature was 38.3oC (range, 37.8–39.9oC). In most patients, fever subsided within 24 hours; however, sixcases (1.1%) developed fever lasting longer than 24 hours. Infectious complications developed in three cases (0.54%)(pneumonia, 2; mediastinal abscess, 1), and all three patients had diabetes mellitus. The number or location of sampledlymph nodes and necrosis of lymph node were not associated with fever after EBUS-TBNA. Multiple logistic regressionanalysis did not reveal any risk factors for developing fever after EBUS-TBNA. Conclusion: Fever is relatively common after EBUS-TBNA, but is transient in most patients. However, clinicians shouldbe aware of the possibility of infectious complications among patients with diabetes mellitus.
Background: Inhaled indacaterol (Onbrez Breezhaler), a long-acting β2-agonist, is approved in over 100 countries, including South Korea, as a once-daily bronchodilator for maintenance and treatment of chronic obstructive pulmonary disease (COPD). Here, we present an interim analysis of a post-marketing surveillance study conducted to evaluate the real-world safety and effectiveness of indacaterol in the Korean population. Methods: This was an open-label, observational, prospective study in which COPD patients, who were newly prescribed with indacaterol (150 or 300 μg), were evaluated for 12 or 24 weeks. Safety was assessed based on the incidence rates of adverse events (AEs) and serious adverse events (SAEs). Effectiveness was evaluated based on physician’s assessment by considering changes in symptoms and lung function, if the values of forced expiratory volume in 1 second were available. Results: Safety data were analyzed in 1,016 patients of the 1,043 enrolled COPD patients receiving indacaterol, and 784 patients were included for the effectiveness analysis. AEs were reported in 228 (22.44%) patients, while 98 (9.65%) patients reported SAEs. The COPD condition improved in 348 patients (44.4%), while the condition was maintained in 396 patients (50.5%), and only 40 patients (5.1%) exhibited worsening of ailment as compared with baseline. During the treatment period, 90 patients were hospitalized while nine patients died. All deaths were assessed to be not related to the study drug by the investigator. Conclusion: In real-life clinical practice in South Korea, indacaterol was well tolerated in COPD patients, and can be regarded as an effective option for their maintenance treatment.
Background: Mucus hypersecretion from airway epithelium is a characteristic feature of airway inflammatory diseases. Tumor necrosis factor α (TNF-α) regulates mucin synthesis. Glucocorticoids including mometasone fuorate (MF) have been used to attenuate airway inflammation. However, effects of MF on mucin production have not been reported. Methods: Effects of MF and budesonide (BUD) on the phorbol-12-myristate-13-acetate (PMA)–induction of mucin and TNF-α in human airway epithelial cells (NCI-H292) were investigated in the present study. Confluent NCI-H292 cells were pretreated with PMA (200 nM) for 2 hours. Subsequently, the cells were stimulated with MF (1–500 ng/mL) or BUD (21.5 ng/mL) for 8 hours. Dexamethasone (1 μg/mL) was used as the positive control. Real-time polymerase chain reaction was used to determine MUC2 and MUC5AC mRNA levels. The level of total mucin, MUC2, MUC5AC, and TNF-α in culture supernatants were measured using enzyme-linked immunosorbent assay. Results: MF and BUD significantly suppressed MUC2 and MUC5AC gene expression in PMA-stimulated NCI-H292 cells. The inhibitory effects of the two steroid drugs were also observed in the production of total mucin, MUC2 and MUC5AC proteins, and TNF-α. Conclusion: Our findings demonstrated that MF and BUD attenuated mucin and TNF-α production in PMA-induced human airway epithelial cells.
Background: Much of the attention of tuberculosis (TB) programs is focused on outcomes of microbiological cure and mortality, and health related quality of life (HRQL) is undervalued. Also, TB patients have a significantly higher risk of developing depression and anxiety compared with those in the general population. We intend to evaluate the HRQL and the prevalence of symptoms of depression and anxiety in hospitalized patients with TB. Methods: Cross-sectional study in a tertiary care hospital in Brazil. Adult patients with pulmonary TB that were hospitalized during the study period were identified and invited to participate. HRQL was measured using the Medical Outcomes Study Short Form-36 (SF-36) version 2. Hospital Anxiety and Depression Scale (HADS) was used to record symptoms of anxiety and depression. Results: Eighty-six patients were included in the analysis. The mean age of all patients was 44.6±15.4 years, 69.8% were male, and 53.5% were white. Thirty-two patients (37.2%) were human immunodeficiency virus positive. Twenty-seven patients (31.4%) met study criteria for depression (HADS depression score ≥11) and 33 (38.4%) had anxiety (HADS anxiety score ≥11). Scores on all domains of SF-36 were significantly lower than the Brazilian norm scores (p<0.001). Conclusion: The present study shows that TB patients may have a poor HRQL. Additionally, we found a possible high prevalence of depression and anxiety in this population. Health care workers should be aware of these psychological disorders to enable a better management of these patients. The treatment of these comorbidities may be associated with better TB outcomes. Keywords: Tuberculosis; Mycobacterium tuberculosis ; Mental Disorders; Depression; Anxiety; Comorbidity; Quality of Life
Background: Delayed hypersensitivity plays a large role in the pathogenesis of tuberculous pleural effusion (TPE). Macrophages infected with live Mycobacterium tuberculosis (MTB) increase the levels of adenosine deaminase2 (ADA2) in the pleural fluid of TPE patients. However, it is as yet unclear whether ADA2 can be produced by macrophages when challenged with MTB antigens alone. This study therefore evaluated the levels of ADA2 mRNA expression, using monocyte-derived macrophages (MDMs) stimulated with MTB antigens. Methods: Purified monocytes from the peripheral blood mononuclear cells of healthy volunteers were differentiated into macrophages using granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF). The MDMs were stimulated with early secretory antigenic target protein 6 (ESAT6) and culture filtrate protein 10 (CFP10). The mRNA expression levels for the cat eye syndrome chromosome region, candidate 1 ( CECR1 ) gene encoding ADA2 were then measured. Results: CECR1 mRNA expression levels were significantly higher in MDMs stimulated with ESAT6 and CFP10, than in the unstimulated MDMs. When stimulated with ESAT6, M-CSF–treated MDMs showed more pronounced CECR1 mRNA expression than GM-CSF–treated MDMs. Interferon-γ decreased the ESAT6- and CFP10-induced CECR1 mRNA expression in MDMs. CECR1 mRNA expression levels were positively correlated with mRNA expression of tumor necrosis factor α and interleukin 10, respectively. Conclusion: ADA2 mRNA expression increased when MDMs were stimulated with MTB antigens alone. This partly indicates that pleural fluid ADA levels could increase in patients with culture-negative TPE. Our results may be helpful in improving the understanding of TPE pathogenesis.
Background: Previous studies report that apoptosis and autophagy are involved in the pathogenesis of emphysema, and macroautophagy is one of the processes regulating the apoptosis pathway. However, few studies have evaluated whether chaperone-mediated autophagy (CMA) contributes to the regulation of apoptosis. In this study, we investigated the impact of autophagy, including both macroautophagy and CMA, on the apoptosis in bronchial epithelial cells. Methods: Cigarette smoke extract (CSE) was injected intratracheally into C57BL/6 mice, and emphysema and apoptosis were evaluated in the lungs. After treatment with CSE, apoptosis, macroautophagy, and CMA were measured in BEAS2-B cells, and the impact of autophagy on the apoptosis was evaluated following knockdown of autophagy-related genes by short interfering RNAs (siRNAs). Results: Intratracheal CSE injection resulted in the development of emphysema and an increase in apoptosis in mice. CSE increased the apoptosis in BEAS2-B cells, and also elevated the expression of proteins related to both macroautophagy and CMA in BEAS2-B cells. The knockdown experiment with siRNAs showed that macroautophagy increases apoptosis in BEAS2-B cells, while CMA suppresses apoptosis. Conclusion: The intratracheal injection of CSE induces pulmonary emphysema and an increase in apoptosis in mice. CSE also induces apoptosis, macroautophagy, and CMA of bronchial epithelial cells. Macroautophagy and CMA regulate apoptosis in opposite directions.