Bronchiectasis management in adults: state of the art and future directions.

Formerly regarded as a rare disease, bronchiectasis is increasingly recognised. A renewed interest in this disease has led to significant progress in bronchiectasis research. Randomised clinical trials (RCTs) have demonstrated the benefits of airway clearance techniques, inhaled antibiotics and long-term macrolide therapy in bronchiectasis patients. However, the heterogeneity of bronchiectasis remains one of the most challenging aspects of management. Phenotypes and endotypes of bronchiectasis have been identified to help find "treatable traits" and partially overcome disease complexity. The goals of therapy for bronchiectasis are to reduce the symptom burden, improve quality of life, reduce exacerbations and prevent disease progression. We review the pharmacological and non-pharmacological treatments that can improve mucociliary clearance, reduce airway inflammation and tackle airway infection, the key pathophysiological features of bronchiectasis. There are also promising treatments in development for the management of bronchiectasis, including novel anti-inflammatory therapies. This review provides a critical update on the management of bronchiectasis focusing on treatable traits and recent RCTs.

Endotypes of Exacerbation in Bronchiectasis: An Observational Cohort Study.

Rationale: Bronchiectasis is characterized by acute exacerbations, but the biological mechanisms underlying these events are poorly characterized. Objectives: To investigate the inflammatory and microbial characteristics of exacerbations of bronchiectasis. Methods: A total of 120 patients with bronchiectasis were enrolled and presented with acute exacerbations within 12 months. Spontaneous sputum samples were obtained during a period of clinical stability and again at exacerbation before receipt of antibiotic treatment. A validated rapid PCR assay for bacteria and viruses was used to classify exacerbations as bacterial, viral, or both. Sputum inflammatory assessments included label-free liquid chromatography-tandem mass spectrometry and measurement of sputum cytokines and neutrophil elastase activity. 16 s rRNA sequencing was used to characterize the microbiome. Measurements and Main Results: Bronchiectasis exacerbations showed profound molecular heterogeneity. At least one bacterium was identified in 103 samples (86%), and a high bacterial load (total bacterial load > 107 copies/g) was observed in 81 patients (68%). Respiratory viruses were identified in 55 (46%) patients, with rhinovirus being the most common virus (31%). PCR testing was more sensitive than culture. No consistent change in the microbiome was observed at exacerbation. Exacerbations were associated with increased neutrophil elastase, proteinase-3, IL-1ß, and CXCL8. These markers were particularly associated with bacterial and bacterial plus viral exacerbations. Distinct inflammatory and microbiome profiles were seen between different exacerbation subtypes, including bacterial, viral, and eosinophilic events in both hypothesis-led and hypothesis-free analysis using integrated microbiome and proteomics, demonstrating four subtypes of exacerbation. Conclusions: Bronchiectasis exacerbations are heterogeneous events with contributions from bacteria, viruses, and inflammatory dysregulation.

Impact of Rheumatoid Arthritis and Seropositivity on the Risk of Non-Cystic Fibrosis Bronchiectasis.

BACKGROUND: Despite the coexistence of bronchiectasis and rheumatoid arthritis (RA) and the poor prognosis associated with the combination of conditions, to our knowledge, no longitudinal studies that comprehensively evaluated whether patients with RA have a higher risk of bronchiectasis compared with those without RA have been published. Whether seropositivity is associated with an increased risk of bronchiectasis in RA is the subject of ongoing controversy. RESEARCH QUESTION: Does RA influence the development of bronchiectasis? Is seropositivity associated with an increased risk of bronchiectasis in RA? STUDY DESIGN AND METHODS: The incidence of bronchiectasis was compared between individuals with RA (n = 50,651; seropositive rheumatoid arthritis [SPRA]: n = 35,879 and seronegative rheumatoid arthritis [SNRA]: n = 14,772) and 1:5 age- and sex-matched control patients (n = 253,255) enrolled between 2010 and 2017 in the Korean National Health Insurance Service database. The participants were followed from 1 year after RA diagnosis or the corresponding index date to the date of bronchiectasis incidence, censored date, or December 2019. RESULTS: The cumulative incidence of bronchiectasis at 9 years of follow-up was approximately 7% in participants with RA. During a median follow-up of 4.3 years (interquartile range, 2.6-6.3 years), participants with RA showed a 2.12-fold higher risk of developing bronchiectasis than matched control participants, even after adjusting for potential confounders related to bronchiectasis development (95% CI, 2.00-2.25). In an analysis of RA serologic status using a fully adjusted model, participants with SPRA and those with SNRA showed 2.34-fold (95% CI, 2.20-2.49) and 1.56-fold (95% CI, 1.40-1.73) increased risks, respectively, compared with matched control participants. INTERPRETATION: Individuals with RA had approximately twice the risk of developing bronchiectasis than matched control individuals, even after adjusting for potential confounders. The increased risk was more evident in individuals with SPRA than in those with SNRA, implying that rheumatic inflammation plays a major role in the development of RA-bronchiectasis overlap.

Association between non-cystic fibrosis bronchiectasis and the risk of incident dementia: A nationwide cohort study.

BACKGROUND: Chronic lung diseases, such as chronic obstructive pulmonary disease or asthma, are associated with an increased risk of dementia. However, few data are available regarding the risk of dementia in individuals with bronchiectasis. OBJECTIVES: To explore the association between bronchiectasis and the risk of incident dementia using a longitudinal population-based cohort. METHODS: A total of 4,068,560 adults older than 50 years without previous dementia were enrolled from the Korean National Health Insurance Service database in 2009. They were followed up until the date of the diagnosis of dementia or December 31, 2020. The study exposure was the diagnosis of bronchiectasis, and the primary outcome was incident dementia comprising Alzheimer's disease and vascular dementia. RESULTS: During the median follow-up duration of 9.3 years, the incidence of all-cause dementia was 1.6-fold higher in individuals with bronchiectasis than in those without bronchiectasis (15.0 vs. 9.3/1000 person-years, p < .001). In the multivariable Cox regression analysis, the risk of all dementia was significantly higher in individuals with bronchiectasis than in those without bronchiectasis (adjusted hazard ratio [aHR] 1.09, 95% confidence interval [CI] 1.04-1.14). In a subgroup analysis by dementia type, individuals with bronchiectasis had an increased risk of Alzheimer's disease compared to those without bronchiectasis (aHR 1.07, 95% CI 1.01-1.12); the risk of vascular dementia did not significantly differ between the two groups (aHR 1.05, 95% CI 0.90-1.21). CONCLUSION: Bronchiectasis was associated with an increased risk of dementia, especially Alzheimer's disease.

Systemic sclerosis and risk of bronchiectasis: a nationwide longitudinal cohort study.

BACKGROUND: The association between systemic sclerosis and the development of bronchiectasis is unclear. This study aimed to compare the risk of bronchiectasis between individuals with systemic sclerosis and those without using a nationwide longitudinal dataset. METHODS: Using the Korean National Health Insurance Service dataset between 2010 and 2017, we identified 4845 individuals aged ≥ 20 years with systemic sclerosis and 24,225 without systemic sclerosis who were matched 1:5 by age and sex. They were followed up until the date of a bronchiectasis diagnosis, death, or December 31, 2019, whichever came first. RESULTS: During a median follow-up period of 6.0 (interquartile range, 3.2-8.7) years, 5.3% of the systemic sclerosis cohort and 1.9% of the matched cohort developed bronchiectasis, with incidence rates of 9.99 and 3.23 per 1000 person-years, respectively. Even after adjusting for potential confounders, the risk of incident bronchiectasis was significantly higher in the systemic sclerosis cohort than in the matched cohort (adjusted hazard ratio 2.63, 95% confidence interval 2.22-3.12). A subgroup analysis of individuals with systemic sclerosis revealed that the risk of incident bronchiectasis was notably higher in younger individuals aged 20-39 years (P for interaction = 0.048) and in those without other coexisting connective tissue diseases (P for interaction = 0.006) than in their counterparts. CONCLUSIONS: The risk of incident bronchiectasis is higher in individuals with systemic sclerosis than those without. Bronchiectasis should be considered one of the pulmonary manifestations related to systemic sclerosis.

Inflammatory Molecular Endotypes in Bronchiectasis: A European Multicenter Cohort Study.

Rationale: Although inflammation and infection are key disease drivers in bronchiectasis, few studies have integrated host inflammatory and microbiome data to guide precision medicine. Objectives: To identify clusters among patients with bronchiectasis on the basis of inflammatory markers and to assess the association between inflammatory endotypes, microbiome characteristics, and exacerbation risk. Methods: Patients with stable bronchiectasis were enrolled at three European centers, and cluster analysis was used to stratify the patients according to the levels of 33 sputum and serum inflammatory markers. Clusters were compared in terms of microbiome composition (16S ribosomal RNA sequencing) and exacerbation risk over a 12-month follow-up. Measurements and Main Results: A total of 199 patients were enrolled (109 [54.8%] female; median age, 69 yr). Four clusters of patients were defined according to their inflammatory profiles: cluster 1, milder neutrophilic inflammation; cluster 2, mixed-neutrophilic and type 2; cluster 3, most severe neutrophilic; and cluster 4, mixed-epithelial and type 2. Lower microbiome diversity was associated with more severe inflammatory clusters (P < 0.001), and ß-diversity analysis demonstrated distinct microbiome profiles associated with each inflammatory cluster (P = 0.001). Proteobacteria and Pseudomonas at phylum and genus levels, respectively, were more enriched in clusters 2 and 3 than in clusters 1 and 4. Furthermore, patients in cluster 2 (rate ratio [RR], 1.49; 95% confidence interval [CI], 1.16-1.92) and cluster 3 (RR, 1.61; 95% CI, 1.12-2.32) were at higher risk of exacerbation over a 12-month follow-up compared with cluster 1, even after adjustment for prior exacerbation history. Conclusions: Bronchiectasis inflammatory endotypes are associated with distinct microbiome profiles and future exacerbation risk.

Diagnostic Utility and Tendency of Bronchial and Serum Soluble Receptor for Advanced Glycation EndProducts (sRAGE) in Lung Cancer.

The receptor for advanced glycation end-products (RAGE) may serve as a diagnostic and prognostic biomarker of lung cancer and lung injury. We explored whether the serum and bronchial levels of soluble RAGE (sRAGE) distinguished infectious lung diseases from lung cancer. We collected serum and bronchial washing fluids (BWFs) from patients diagnosed with pneumonia, tuberculosis, or preoperative lung cancer from April 2016 to March 2022. sRAGE levels were measured using an enzyme-linked immunosorbent assay and we drew receiver operating characteristic (1) curves to determine the cut-off values affording the best diagnostic sensitivities. We enrolled 81 patients including 20 with tuberculosis, 30 with pneumonia, and 31 with lung cancer. Of the 81, 61% were males and the median age was 66 years. The median serum level of sRAGE was 822 (678-1168 pg/mL) and did not differ significantly between the three groups. The median bronchial sRAGE level was 167 (83-529 pg/mL) but 231 (108-649 pg/mL) for tuberculosis, 366 (106-706 pg/mL) for pneumonia, and 103 (32-254 pg/mL) for lung cancer patients (p = 0.018). The ROC curve for the bronchial sRAGE values of lung cancer patients revealed that the optimal cut-off was 118.9 pg/mL. This afforded a sensitivity of 76%, a specificity of 58%, and an area under the ROC curve of 0.695 (p = 0.005). The level of bronchial sRAGE differed significantly between patients with lung cancer and other respiratory diseases; that level may serve as an auxiliary diagnostic biomarker.

Increased Lung Cancer Risk and Associated Risk Factors in Tuberculosis Survivors: A Korean Population-Based Study.

BACKGROUND: Few studies have comprehensively evaluated the risk of lung cancer in tuberculosis survivors with consideration of smoking status and chronic obstructive pulmonary disease (COPD). Furthermore, little is known about lung cancer risk factors in tuberculosis survivors. METHODS: This population-based cohort study enrolled tuberculosis survivors (n = 75 467) between 2010 and 2017 and 1:1 age- and sex-matched controls. Subjects were followed up for 1 year from the date of tuberculosis diagnosis to the date of the incident lung cancer, death, or December 2018, whichever came first. The risk of lung cancer was evaluated according to smoking and COPD status. We also evaluated the risk factors for lung cancer and developed an individualized lung cancer prediction model for tuberculosis survivors. RESULTS: During a median follow-up duration of 4.8 years, the incident lung cancer risk was 1.72-fold higher in tuberculosis survivors than in the controls. Among tuberculosis survivors, those who were current smokers with ≥20 pack-years showed the highest risk of lung cancer (adjusted hazard ratio, 6.78) compared with never-smoker, non-tuberculosis-infected controls. tuberculosis survivors with COPD had a higher risk (2.43) than non-COPD, non-tuberculosis-infected controls. Risk factors for lung cancer in tuberculosis survivors were pulmonary tuberculosis, age >60 years, smoking, and the presence of COPD or asthma. The individualized lung cancer risk model showed good discrimination (concordance statistic = 0.827). CONCLUSIONS: Previous tuberculosis infection is an independent risk factor regardless of smoking status or amount and COPD. Closer monitoring of tuberculosis survivors, especially heavy smokers or those with COPD, is needed for early lung cancer diagnosis.

Effectiveness of the use of an oscillating positive expiratory pressure device in bronchiectasis with frequent exacerbations: a single-arm pilot study.

Impaired airway clearance in patients with non-cystic fibrosis bronchiectasis causes frequent bacterial infection, chronic inflammation, and progressive tissue destruction. We aimed to evaluate whether an oscillating positive expiratory pressure (OPEP) device could allow effective sputum expectoration and prevent acute exacerbations in patients with bronchiectasis who had frequent acute exacerbations. This open-label, single-arm, prospective study included 17 patients who experienced three or more acute exacerbations in the past year. We evaluated the prevention of acute exacerbations, subjective symptom improvement, and change in sputum amount during the use of the Aerobika (Trudell Medical International, London, ON) OPEP device twice daily for 6 months. Of all enrolled patients, only two acute exacerbations occurred during the study period, indicating a significant decrease compared with the number of acute exacerbations before the device use (p < 0.001). Additionally, Bronchiectasis Health Questionnaire score changed from 58.7 to 66.6, showing significant improvement over the treatment period (p < 0.001). The largest sputum volume was observed 3 months after OPEP device use (baseline: 10 ml, 3rd month 25 ml, p = 0.325). There were no major adverse events related to the use of OPEP devices. Twice-daily physiotherapy with OPEP device in patients with bronchiectasis who have frequent exacerbations may facilitate symptomatic improvement and prevention of acute exacerbations without serious adverse events.

Long-Term Mortality of Tuberculosis Survivors in Korea: A Population-based Longitudinal Study.

BACKGROUND: When assessing long-term tuberculosis (TB) mortality, few studies addressed the impact of behavior habits and socioeconomic status. Therefore, we aimed to evaluate long-term TB mortality and risk factors while accounting for potential confounders. METHODS: This cohort study included TB survivors (n = 82 098) aged ≥20 years between 2010 and 2017, and 1:1 age- and sex-matched controls (n = 82 098). The participants were followed up for death 1 year after study enrollment until December 2018. Long-term mortality was adjusted for behavior habits (smoking, alcohol consumption, or exercise), income level, body mass index (BMI), and comorbidities. RESULTS: During a median of 3.7 years of follow-up, the incidence rate of mortality was significantly higher in TB survivors than those in the matched controls (18.2 vs. 8.8 per 1000 person-years, P < .001). Even after adjusting for potential confounders, the mortality risk was 1.62-fold (95% confidence interval [CI], 1.54-1.70) higher in TB survivors than those in the matched controls. In addition, the hazard of mortality in TB survivors relative to matched controls significantly increased in participants aged ≥30 years, with the highest risk in those in their 40s. Male sex (adjusted hazard ratio [HR]: 2.31; 95% CI, 2.16-2.47), smoking pack-years (HR: 1.005; 95% CI, 1.004-1.006), heavy alcohol consumption (HR: 1.12; 95% CI, 1.01-1.23), and lowest income (HR: 1.27; 95% CI, 1.18-1.37) were positively associated with increased hazards for mortality, whereas higher BMI (HR: 0.91; 95% CI, .90-.92) and regular exercise (HR: 0.82; 95% CI, .76-.88) reduced the hazards of long-term mortality in TB survivors. CONCLUSIONS: The long-term mortality risk was significantly higher in TB survivors than those in the matched controls, even after adjusting for potential confounders.

Tuberculosis and the Risk of Ischemic Heart Disease: A Nationwide Cohort Study.

BACKGROUND: Little is known about the risk of ischemic heart disease (IHD) in tuberculosis (TB) survivors. METHODS: We performed a population-based retrospective cohort study using the Korean National Health Insurance Service database. TB survivors (n = 60 602) and their 1:1 age- and sex-matched controls (n = 60 602) were enrolled. Eligible participants were followed up from 1 year after their TB diagnosis to the date of an IHD event, date of death, or the end of the study period (31 December 2018), whichever came first. The risk of IHD was estimated using a Cox proportional hazards regression, and stratified analyses were performed for related factors. Among IHD events, we additionally analyzed for myocardial infarction (MI). RESULTS: During a median of 3.9 years of follow-up, 2.7% of TB survivors (1633/60 602) and 2.0% of the matched controls (1228/60 602) developed IHD, and 0.6% of TB patients (341/60 602) and 0.4% of the matched controls (223/60 602) developed MI. The overall risk of developing IHD and MI was higher in TB patients (adjusted hazard ratio [aHR] 1.21, 95% confidence interval [CI]: 1.12-1.32 for IHD and aHR 1.48, 95% CI: 1.23-1.78 for MI) than in the matched controls. Stratified analyses showed that TB survivors have an increased risk of IHD and MI regardless of income, place of residence, smoking status, alcohol consumption, physical activity, body mass index, and Charlson comorbidity index. CONCLUSIONS: TB survivors have a higher risk of IHD than matched controls. Strategies are needed to reduce the burden of IHD in TB survivors.

Gastroesophageal Reflux Disease Increases Susceptibility to Nontuberculous Mycobacterial Pulmonary Disease.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common comorbidity of nontuberculous mycobacteria (NTM) pulmonary disease (PD). Although GERD is associated with more symptoms and severe disease in patients with NTM PD, whether GERD is associated with an increased risk of NTM PD developing is unknown. RESEARCH QUESTION: Does GERD influence the development of NTM PD? Are there any factors associated with an increased risk of NTM PD among patients with GERD? What is the impact of NTM PD on the health-care use of patients with GERD? STUDY DESIGN AND METHODS: Data from the Korean National Health Insurance Service National Sample Cohort between 2002 and 2015 were used. The incidence and risk of NTM PD were compared between patients with GERD (GERD cohort; n = 17,424) and patients matched for age, sex, type of insurance, and Charlson Comorbidity Index (matched cohort; n = 69,696). Using the GERD cohort, the factors associated with incident NTM PD also were evaluated. RESULTS: During a median follow-up duration of 5.1 years, the age- and sex-adjusted incidence of NTM PD was significantly higher in the GERD cohort (34.8 per 100,000 person-years [PY]) than in the matched cohort (10.5 per 100,000 PY; P < .001), with a subdistribution hazard ratio (HR) of 3.36 (95% CI, 2.10-5.37). Regarding risk factors associated with NTM PD, age of 60 years or older (adjusted HR, 3.57; 95% CI, 1.58-8.07) and bronchiectasis (adjusted HR, 18.69; 95% CI, 6.68-52.28) were associated with an increased risk of incident NTM PD in the GERD cohort. Compared with patients with GERD who did not demonstrate NTM PD, those with NTM PD showed higher all-cause (13,321 PY vs 5,932 PY; P = .049) and respiratory disease-related (5,403 vs 801; P = .011) ED visits or hospitalizations. INTERPRETATION: GERD is associated with an increased incidence of NTM PD. Older age and bronchiectasis are risk factors for NTM PD in patients with GERD. NTM PD in patients with GERD is associated with increased health-care use.

Clinical Prognosis of Lung Cancer in Patients with Moderate Chronic Kidney Disease.

The clinical outcomes of patients with lung cancer coexisting with chronic kidney disease (CKD) are reported to have been conflicting. There is insufficient evidence for treatment and prognosis of lung cancer according to renal function in patients with CKD. We evaluate clinical course and prognostic factors of lung cancer according to the renal function of moderate CKD patients. A retrospective, multicenter study of lung cancer patients with moderate CKD was performed. Moderate CKD was defined as having an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. CKD was classified as stage 3, stage 4, and stage 5 according to eGFR. The cumulative mortality of lung cancer was calculated by competing risks survival analysis, and the risk factors were evaluated by the Cox-proportional hazards model. Among the lung cancer patients with moderate CKD (n = 181), median overall survival (OS) was 11.1 (4.2−31.3) months for stage 3 CKD patients, 6.0 (1.8−16.3) months for stage 4 CKD patients, and 4.7 (2.1−40.1) months for stage 5 CKD patients (p = 0.060), respectively. In a subgroup analysis, CKD stage was associated with an increased mortality in early-stage non-small cell lung cancer (NSCLC). Cox regression analysis revealed that age ≥ 75 years (adjusted hazard ratio (aHR), 1.581; 95% confidence interval (CI), 1.082−2.310), Charlson comorbidity index (aHR, 1.669; 95% CI, 10.69−2.605), and stage IV NSCLC (aHR, 2.395; 95% CI, 1.512−3.796) were associated with increased mortality risk, whereas adenocarcinoma (aHR, 0.580; 95% CI, 0.352−0.956) and stage 3 CKD (aHR, 0.598; 95% CI, 0.399−0.895) were associated with decreased mortality risk. In conclusion, the mortality risk of patients with lung cancer was lower in stage 3 CKD compared with stage 4 or 5 CKD. In addition, in the early stages of NSCLC, the CKD stage affected the prognosis, but not in the advanced stage NSCLC.

Association between exercise and risk of cardiovascular diseases in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND: Although cardiovascular comorbidities negatively impact survival in patients with bronchiectasis, there is limited evidence to recommend exercise in this population. We aimed to evaluate whether exercise habit changes are related to reduced cardiovascular disease risk and explore an optimal exercise amount. METHODS: This study identified 165,842 patients with newly diagnosed bronchiectasis during 2010-2016 who underwent two health examinations and were followed up until December 2020. The exposure was the change in weekly habits of moderate- or vigorous-intensity physical activity between the two examinations, classified into non-exercisers and exercisers (further classified into new exercisers, exercise dropouts, and exercise maintainers). The amount of exercise was measured using metabolic equivalents of task (MET). The outcome was the incidence of myocardial infarction (MI) or stroke. RESULTS: During a mean of 6.2 ± 2.1 follow-up years, 4,233 (2.6%) and 3,745 (2.3%) of patients with bronchiectasis had MI or stroke, respectively. Compared to non-exercisers, exercisers had a significantly lower risk of MI or stroke by 9-28% (p < 0.001 for both). Among exercisers, exercise maintainers showed the lowest risk of MI (adjusted hazard ratio [aHR], 0.72; 95% confidence interval [CI], 0.64-0.81) and stroke (aHR, 0.72; 95% CI, 0.64-0.82) compared to non-exercisers. Regarding exercise amount, a significant risk reduction was observed only in patients with bronchiectasis who exercised for ≥ 500 MET-min/wk. CONCLUSION: Exercise was associated with a reduced risk of cardiovascular diseases in patients with bronchiectasis. In particular, the risk was lowest in exercise maintainers, and cardiovascular risk reduction was significant when exercising more than 500 MET-min/wk.

Tuberculosis and Risk of Ischemic Stroke: A Nationwide Cohort Study.

BACKGROUND: Conflicting results exist regarding the risk of ischemic stroke in tuberculosis survivors. We aimed to estimate the risk of ischemic stroke using a nationwide population-based retrospective cohort. METHODS: We gathered data from the Korean National Health Insurance Service on tuberculosis survivors and 1:1 age- and sex-matched non-tuberculosis cases. Eligible participants were followed up from 1 year after tuberculosis diagnosis to the date of ischemic stroke event, date of death, or until the end of the study period (December 31, 2018), whichever came first. Cox proportional hazard regression and stratified analyses were performed to identify any related factors. RESULTS: During follow-up periods of 3.8 years for patients with tuberculosis and matched non-tuberculosis cases, 1.3% of patients with tuberculosis (941/72 863) and 1.0% of matched non-tuberculosis cases (707/72 863) developed ischemic stroke. The overall risk of ischemic stroke was higher in tuberculosis patients (adjusted hazard ratio: 1.22 [95% CI, 1.10-1.36]) compared with the matched non-tuberculosis cases. A stratified analysis showed that patients with tuberculosis had increased risk of ischemic stroke regardless of age, sex, smoking status, alcohol consumption, physical activity, body mass index, and Charlson Comorbidity Index score. CONCLUSIONS: Tuberculosis survivors had a higher risk of ischemic stroke than their matched non-tuberculosis cases. The results of this study suggest that tuberculosis is a crucial infectious factor associated with increased incidence of ischemic stroke.

Incidence and outcomes of adverse drug reactions to first-line anti-tuberculosis drugs and their effects on the quality of life: A multicenter prospective cohort study.

BACKGROUND: In tuberculosis (TB) treatment, adverse drug reactions (ADRs) can interrupt treatment and decrease the quality of life (QoL). We aimed to prospectively investigate the incidence of ADRs to first-line anti-TB drugs and related outcomes and QoL. METHODS: Adult patients with TB who had been treated with first-line anti-TB drugs in five Korean hospitals were enrolled. ADR questionnaire surveys and blood tests were performed four times serially, and QoL was assessed on the fourth TB treatment week (±2 weeks). RESULTS: Of 410 enrolled patients with TB (males, 62%; mean age, 52.1 ± 18.1 years [those aged ≥65 years, 26.6%]), 67.8% experienced any ADRs (≥ grade 2) to TB drugs. The most common ADR was fatigue (53.2%), followed by itching (42.7%) and anorexia (41.7%). Older adult patients experienced relatively more ADRs, including anorexia, dyspepsia, rash, dizziness, anemia, abnormal hepatic/renal function tests, and increased uric acid levels (p < 0.05). Treatment regimens changed for 9.5% of patients owing to ADRs to anti-TB drugs. Patients with any ADRs and older adult patients had significantly lower QoL than their counterparts (p < 0.05). Old age (odds ratio [OR], 1.02) and being male (OR 2.65) were independently associated with ADRs, whereas active smoking (OR 4.73) and a relatively long treatment phase (OR 5.13) were independently associated with hepatotoxicity. CONCLUSION: ADRs to first-line anti-TB drugs were common and related to relatively low QoL, especially among older adults. Although 9.5% of patients had ADR-related regimen changes, most patients with ADRs completed treatments successfully.

Curvularin Isolated From Phoma macrostoma Is an Antagonist of RhlR Quorum Sensing in Pseudomonas aeruginosa.

Quorum sensing (QS) is an attractive target for the treatment of multidrug-resistant Pseudomonas aeruginosa, against which new antibiotics are urgently needed. Because LasR is at the top of the QS hierarchy controlling Rhl and PQS systems, most QS inhibitors have been targeted to LasR. However, it has recently been reported that in clinical isolates of P. aeruginosa, LasR is frequently mutated and nonfunctional, and RhlR independently acts to produce virulent factors that maintain toxicity. Thus, for effective treatment of chronic cystic fibrosis infections, RhlR antagonists is needed to prevent the LasR-independent Rhl system, but RhlR antagonists have rarely been reported. In this study, we found that curvularin, an aromatic compound with a cyclized alkyl side chain isolated from Phoma macrostoma, at a low micromolar concentration of 1-30 µM potently and selectively inhibited pyocyanin and rhamnolipid production without affecting the cell viability of P. aeruginosa. Only high concentration (more over 100 µM) curvularin negligibly inhibited biofilm formation and elastase production, suggesting that curvularin at low concentrations selectively inhibits RhlR. The QS antagonism by curvularin was investigated in experiments using QS competition and signaling molecules assays with QS gene expression analysis, and the results showed that, indeed, at low concentrations, curvularin selectively antagonized RhlR; in contrast, it negligibly antagonized LasR only when applied at a high concentration. The exclusive RhlR antagonizing activity of curvularin at low concentrations was confirmed using QS mutants; specifically, curvularin at low concentrations inhibited pyocyanin and rhamnolipid production by selectively antagonizing N-butanoyl homoserine lactone (BHL)-activated RhlR. Moreover, by targeting RhlR, curvularin reduced the in vivo virulence of wild-type P. aeruginosa as well as lasR mutants in Caenorhabditis elegans. Overall, low-concentration curvularin is a pure RhlR antagonist in P. aeruginosa, and to the best of our knowledge, this is the first report describing an RhlR antagonist from natural resources. Hence, curvularin has great potential for the development of chronic P. aeruginosa infection therapeutics and for the study of RhlR function in the complex QS system.

Chorion-derived perinatal mesenchymal stem cells improve cardiac function and vascular regeneration: Preferential treatment for ischemic heart disease.

BACKGROUND: Stem cell therapy has emerged as a novel treatment for heart failure after myocardial infarction (Ml). Bone marrow-derived mesenchymal stem cells (BM-MSCs) are commonly considered because of their accessibility and usability. However, their therapeutic potential remains controversial. In our previous in vitro study, chorion-derived mesenchymal stem cells (C-MSCs) and umbilical cord-derived mesenchymal stem cells (UC-MSCs) demonstrated an ability to differentiate into cardiomyocytes and neural cells, respectively. Thus, we examined whether C-MSCs had a better differentiation potential in an MI animal model. METHODS: MI was induced by ligation of the left anterior descending artery, and DiI-labeled MSCs were injected into the border of the infarcted myocardium. The left ventricular ejection fraction (LVEF) and fractional shortening (FS) were measured using echocardiograms. Masson's Trichrome staining was performed to evaluate the viable myocardium. Alpha-sarcomeric actin (α-SA), cardiac troponin-T (cTnT), and isolectin were immunolabeled to evaluate differentiation and capillary formation. RESULTS: After 8 weeks, the LVEF and FS significantly increased to a greater extent in the C-MSC-injected group with maintenance of viable myocardium, as compared to in the control, UC-MSC-, and BM-MSC-injected groups (p < 0.05). Compared to UC-MSCs and BM-MSCs, C-MSCs significantly increased the capillary density (p < 0.05) and demonstrated higher expressions of cTnT and α-SA. CONCLUSIONS: In conclusion, compared to UC-MSCs and BM-MSCs, C-MSCs showed a better therapeutic efficacy in a rat MI model.

Risk Factors of Incident Lung Cancer in Patients with Non-Cystic Fibrosis Bronchiectasis: A Korean Population-Based Study.

BACKGROUND: Patients with non-cystic fibrosis bronchiectasis have an increased risk of lung cancer, followed by higher mortality in this population. Because the risk factors of lung cancer have not been well identified, this study aimed to investigate the risk factors of lung cancer in individuals with newly diagnosed bronchiectasis. METHODS: This cohort study using the Korean National Health Insurance Service database identified 7425 individuals with incident bronchiectasis among those who participated in the health screening exam in 2009. The cohort was followed from baseline to the date of incident: lung cancer, death, or until the end of the study period. We investigated the risk factors of lung cancer in participants with bronchiectasis using the Cox-proportional hazard models. RESULTS: During median 8.3 years of follow-up duration, 1.9% (138/7425) developed lung cancer. In multivariable analyses, significant factors associated with increased risk of incident lung cancer included: males (adjusted hazard ratio [HR] = 3.54, 95% confidence interval [CI] = 2.17-5.79) than females, the overweight (adjusted HR = 1.55, 95% CI = 1.03-2.35) than the normal weight, current smokers (adjusted HR = 3.10, 95% CI = 2.00-4.79) than never smokers, participants living in the rural area (adjusted HR = 2.54, 95% CI = 1.68-3.85) than those living in the metropolitan area. Among comorbidities, chronic obstructive pulmonary disease was associated with an increased risk of lung cancer (adjusted HR = 1.46, 95% CI = 1.01-2.13) in participants with bronchiectasis. In contrast, mild alcohol consumption was associated with reduced risk of lung cancer (adjusted HR = 0.47, 95% CI = 0.29-0.74) in those with bronchiectasis. CONCLUSION: This Korean population-based study showed that males, current smoking, overweight, living in rural areas, and comorbid chronic obstructive pulmonary disease are associated with increased risk of lung cancer in individuals with bronchiectasis.