The association between cumulative exposure to PM2.5 and DNA methylation measured using methyl-capture sequencing among COPD patients.

BACKGROUND: Particulate matter with a diameter of < 2.5 µm (PM2.5) influences gene regulation via DNA methylation; however, its precise mechanism of action remains unclear. Thus, this study aimed to examine the connection between personal PM2.5 exposure and DNA methylation in CpG islands as well as explore the associated gene pathways. METHODS: A total of 95 male patients with chronic obstructive pulmonary disease (COPD) were enrolled in this study. PM2.5 concentrations were measured for 12 months, with individual exposure recorded for 24 h every 3 months. Mean indoor and estimated individual PM2.5 exposure levels were calculated for short-term (7 days), mid-term (35 days), and long-term (90 days). DNA methylation analysis was performed on the blood samples, which, after PCR amplification and hybridization, were finally sequenced using an Illumina NovaSeq 6000 system. Correlation between PM2.5 exposure and CpG methylation sites was confirmed via a mixed-effects model. Functional enrichment analysis was performed on unique CpG methylation sites associated with PM2.5 exposure to identify the relevant biological functions or pathways. RESULTS: The number of CpG sites showing differential methylation was 36, 381, and 182 for the short-, mid-, and long-term indoor models, respectively, and 3, 98, and 28 for the short-, mid-, and long-term estimated exposure models, respectively. The representative genes were TMTC2 (p = 1.63 × 10-3, R2 = 0.656), GLRX3 (p = 1.46 × 10-3, R2 = 0.623), DCAF15 (p = 2.43 × 10-4, R2 = 0.623), CNOT6L (p = 1.46 × 10-4, R2 = 0.609), BSN (p = 2.21 × 10-5, R2 = 0.606), and SENP6 (p = 1.59 × 10-4, R2 = 0.604). Functional enrichment analysis demonstrated that the related genes were mostly associated with pathways related to synaptic transmission in neurodegenerative diseases and cancer. CONCLUSION: A significant association was observed between PM2.5 exposure and DNA methylation upon short-term exposure, and the extent of DNA methylation was the highest upon mid-term exposure. Additionally, various pathways related to neurodegenerative diseases and cancer were associated with patients with COPD. GOV IDENTIFIER: NCT04878367.

Isolated respiratory tract microorganisms and clinical characteristics in asthma exacerbation of obese patients: a multicenter study.

BACKGROUND: Viral infection is a risk factor for asthma exacerbation (AE). However, bacterial infections related to AE in adults are poorly known. On the other hand, obese patients with asthma have their own clinical and biological characteristics compared with non-obese patients. METHODS: We investigated the differences in isolated pathogens for AE between obese and non-obese patients with asthma. We included 407 patients with AE from 24 medical centers in Korea. Microorganisms isolated from culture, RT-PCR or serologic tests using lower respiratory tract specimens were retrospectively investigated. RESULTS: A total of 171 obese and 236 non-obese patients with asthma were included for analysis. Compared to non-obese patients, obese patients were associated with women (77.2% vs. 63.6%), never smoker (82.5% vs. 73.9%), shorter duration of asthma (7.9 ± 8.4 vs. 10.5 ± 10.1 years), less history of pulmonary tuberculosis (8.8% vs. 17.4%), and more comorbidity of allergic rhinitis (48.5% vs. 0.8%). Viral and/or bacterial infections were detected in 205 patients (50.4%) with AE. The numbers of patients with viral only, bacterial only, or both infections were 119, 49, and 37, respectively. The most commonly isolated bacterium was Streptococcus pneumoniae, followed by Pseudomonas aeruginosa and Chlamydia pneumoniae. Obese patients showed a lower incidence of Chlamydia pneumoniae infection. In the non-obese group, bacterial infection, especially Chlamydia pneumoniae infection, was significantly associated with the duration of systemic corticosteroid use (13.6 ± 19.8 vs. 9.7 ± 6.7 days, p = 0.049). CONCLUSION: Bacterial infection was associated with a longer period of corticosteroid use in the non-obese group. Acute Chlamydia pneumoniae infection was less associated with obese patients with AE. Further well-designed studies are needed to evaluate microorganisms and the efficacy of antibiotics in patients with AE.

Endobronchial valves for emphysema and persistent air-leak: 10-year experience in an Asian country.

BACKGROUND: Endobronchial valve (EBV) therapy, a validated method for bronchoscopic lung volume reduction (BLVR) in severe emphysema, has been explored for persistent air-leak (PAL) management. However, its effectiveness and safety in the Asian population require further real-world evaluation. In this study, we assessed the outcomes of treatment with EBV within this demographic. METHODS: We conducted a retrospective analysis of medical records from 11 Korean centers. For the emphysema cohort, inclusion criteria were patients diagnosed with emphysema who underwent bronchoscopy intended for BLVR. We assessed these patients for clinical outcomes of chronic obstructive pulmonary disease. All patients with PAL who underwent treatment with EBV were included. We identified the underlying causes of PAL and evaluated clinical outcomes after the procedure. RESULTS: The severe emphysema cohort comprised 192 patients with an average age of 70.3 years, and 95.8% of them were men. Ultimately, 137 underwent treatment with EBV. Three months after the procedure, the BLVR group demonstrated a significant improvement in forced expiratory volume in 1 s (+160 mL vs. +30 mL; P = 0.009). Radiographic evidence of lung volume reduction 6 months after BLVR was significantly associated with improved survival (adjusted hazard ratio 0.020; 95% confidence interval 0.038-0.650; P = 0.010). Although pneumothorax was more common in the BLVR group (18.9% vs. 3.8%; P = 0.018), death was higher in the no-BLVR group (38.5% vs. 54.5%, P = 0.001), whereas other adverse events were comparable between the groups. Within the subset of 18 patients with PAL, the predominant causes of air-leak included spontaneous secondary pneumothorax (44.0%), parapneumonic effusion/empyema (22.2%), and post-lung resection surgery (16.7%). Following the treatment, the majority (77.8%) successfully had their chest tubes removed. Post-procedural complications were minimal, with two incidences of hemoptysis and one of empyema, all of which were effectively managed. CONCLUSIONS: Treatment with EBV provides substantial clinical benefits in the management of emphysema and PAL in the Asian population, suggesting a favorable outcome for this therapeutic approach.

Association between exposure to specific PM2.5 constituents and environment, lifestyle, and clinical parameters in patients with COPD.

This study investigated the correlation between the individual chemical constituents of particulate matter 2.5 µm (PM2.5) and respiratory parameters as well as the living environment and daily behaviors in patients with chronic obstructive pulmonary disease (COPD). Data were obtained from prospective COPD panel conducted in South Korea. Following collection via a microPEM, 18 metallic elements were determined using energy-dispersive X-ray fluorescence spectroscopy. All participants completed detailed questionnaires on living environments and lifestyle practices. Eighty-nine stable COPD patients (mean age 68.1 years; 94.4% male) were analyzed. Several constituents (titanium, aluminum, bromine, and silicone) were significantly associated with respiratory outcomes. Copper and manganese concentrations were significantly associated with the living environment. Increased ventilation time and air purifier operation were associated with lower concentrations of copper, silicone, barium, and titanium. These findings suggest varying relationships between PM2.5 constituents and clinical parameters in COPD patients, providing a basis for personalized interventions and future research.

Gut microbiota composition and metabolite profiling in smokers: a comparative study between emphysema and asymptomatic individuals with therapeutic implications.

BACKGROUND: Diet has a crucial role in the gut microbiota, and dysbiosis in the gut and lungs has been suggested to be associated with chronic obstructive pulmonary disease. We compared the diet, microbiome and metabolome between asymptomatic smokers and those with emphysema. METHODS: We enrolled 10 asymptomatic smokers with preserved lung function and 16 smokers with emphysema with severe airflow limitation. Dietary intake information was gathered by a self-reported questionnaire. Sputum and faecal samples were collected for microbial and metabolomics analysis. A murine model of emphysema was used to determine the effect of metabolite supplementation. RESULTS: Despite having a similar smoking history with emphysema patients, asymptomatic smokers had higher values of body mass index, fibre intake and faecal acetate level. Linear discriminant analysis identified 17 microbial taxonomic members that were relatively enriched in the faeces of asymptomatic smokers. Analysis of similarity results showed dissimilarity between the two groups (r=0.287, p=0.003). Higher acetate level was positively associated with forced expiratory volume in one second in the emphysema group (r=0.628, p=0.012). Asymptomatic smokers had a greater number of species associated with acetate and propionate (r>0.6) than did those with emphysema (30 vs 19). In an emphysema mouse model, supplementation of acetate and propionate reduced alveolar destruction and the production of proinflammatory cytokines, and propionate decreased the CD3+CD4+IL-17+ T-cell population in the lung and spleen. CONCLUSION: Smokers with emphysema showed differences in diet, microbiome and short-chain fatty acids compared with asymptomatic smokers. Acetate and propionate showed therapeutic effects in a smoking-induced murine model of emphysema.

Deep Learning-based Approach to Predict Pulmonary Function at Chest CT.

Background Low-dose chest CT screening is recommended for smokers with the potential for lung function abnormality, but its role in predicting lung function remains unclear. Purpose To develop a deep learning algorithm to predict pulmonary function with low-dose CT images in participants using health screening services. Materials and Methods In this retrospective study, participants underwent health screening with same-day low-dose CT and pulmonary function testing with spirometry at a university affiliated tertiary referral general hospital between January 2015 and December 2018. The data set was split into a development set (model training, validation, and internal test sets) and temporally independent test set according to first visit year. A convolutional neural network was trained to predict the forced expiratory volume in the first second of expiration (FEV1) and forced vital capacity (FVC) from low-dose CT. The mean absolute error and concordance correlation coefficient (CCC) were used to evaluate agreement between spirometry as the reference standard and deep-learning prediction as the index test. FVC and FEV1 percent predicted (hereafter, FVC% and FEV1%) values less than 80% and percent of FVC exhaled in first second (hereafter, FEV1/FVC) less than 70% were used to classify participants at high risk. Results A total of 16 148 participants were included (mean age, 55 years ± 10 [SD]; 10 981 men) and divided into a development set (n = 13 428) and temporally independent test set (n = 2720). In the temporally independent test set, the mean absolute error and CCC were 0.22 L and 0.94, respectively, for FVC and 0.22 L and 0.91 for FEV1. For the prediction of the respiratory high-risk group, FVC%, FEV1%, and FEV1/FVC had respective accuracies of 89.6% (2436 of 2720 participants; 95% CI: 88.4, 90.7), 85.9% (2337 of 2720 participants; 95% CI: 84.6, 87.2), and 90.2% (2453 of 2720 participants; 95% CI: 89.1, 91.3) in the same testing data set. The sensitivities were 61.6% (242 of 393 participants; 95% CI: 59.7, 63.4), 46.9% (226 of 482 participants; 95% CI: 45.0, 48.8), and 36.1% (91 of 252 participants; 95% CI: 34.3, 37.9), respectively. Conclusion A deep learning model applied to volumetric chest CT predicted pulmonary function with relatively good performance. © RSNA, 2023 Supplemental material is available for this article.

Effects of gastroesophageal reflux disease treatment with proton pump inhibitors on the risk of acute exacerbation and pneumonia in patients with COPD.

BACKGROUND: Gastroesophageal reflux disease (GERD) has been suggested as a risk factor for acute exacerbation of chronic obstructive pulmonary disease (COPD). However, it remains undetermined whether proton pump inhibitor (PPI) treatment reduces the risk of exacerbation or affects the risk of pneumonia. This study aimed to evaluate the risks of both exacerbation and pneumonia following PPI treatment for GERD in patients with COPD. METHODS: This study used a reimbursement database of the Republic of Korea. Patients aged ≥ 40 years with COPD as a main diagnosis and who received PPI treatment for GERD at least for 14 consecutive days between January 2013 and December 2018 were included in the study. A self-controlled case series analysis was conducted to calculate the risk of moderate and severe exacerbation and pneumonia. RESULTS: A total of 104,439 patients with prevalent COPD received PPI treatment for GERD. The risk of moderate exacerbation was significantly lower during the PPI treatment than at baseline. The risk of severe exacerbation increased during the PPI treatment but significantly decreased in the post-treatment period. Pneumonia risk was not significantly increased during the PPI treatment. The results were similar in patients with incident COPD. CONCLUSIONS: The risk of exacerbation was significantly reduced after PPI treatment compared with the non-treated period. Severe exacerbation may increase due to uncontrolled GERD but subsequently decrease following PPI treatment. There was no evidence of an increased risk of pneumonia.

Cancer-Related Dysfunctional Beliefs About Sleep Mediate the Influence of Sleep Disturbance on Fear of Progression Among Patients With Surgically Resected Lung Cancer.

BACKGROUND: Lung cancer is associated with significant psychological distress, including fear of progression (FoP). Because insomnia and depression are highly prevalent and associated with FoP, we examined the association between FoP, insomnia, and depression in cancer patients. Furthermore, we tested the mediation effect of cancer-related dysfunctional beliefs about sleep (C-DBS) on this association. METHODS: We analyzed data collected from patients with surgically resected non-small cell lung cancer from a single-center randomized controlled study investigating digital healthcare applications. Baseline demographic and clinical variables were collected. In addition, self-reported questionnaires including the Fear of Progression Questionnaire-Short Form, Patients Health Questionnaire-9 items (PHQ-9), Insomnia Severity Index, and C-DBS were administered. RESULTS: Among the 320 enrolled patients with lung cancer, a regression model showed that FoP was predicted by age (ß = -0.13, P = 0.007), PHQ-9 (ß = 0.35, P < 0.001), and C-DBS (ß = 0.28, P < 0.001). Insomnia did not directly influence FoP, but C-DBS mediated the association. Depression directly influenced FoP, but C-DBS did not mediate this association. CONCLUSION: Among patients with surgically resected lung cancer, C-DBS mediated the effects of severity of insomnia on FoP. Depression directly influenced FoP, but C-DBS did not influence this association. To reduce FoP among patients with lung cancer, C-DBS should be addressed in the cognitive behavioral therapy module.

Cough Presentation and Cough-Related Healthcare Utilization in Tertiary Care: Analysis of Routinely Collected Academic Institutional Database.

PURPOSE: Routinely collected data (RCD) from electronic health records (EHR) are useful for studying disease epidemiology in the real world. We examined cough presentation and cough-related healthcare utilization using an academic institutional EHR database in Korea. METHODS: In this retrospective cohort study, patients with subacute (3-8 weeks) or chronic cough (> 8 weeks in duration) referred to allergy and asthma clinics were studied. Cases were identified using the search term "cough" or "coughing," which is the chief complaint, in the data fields. Structured data, including demographics, medical history, symptoms, and diagnostic tests, were analyzed. Healthcare utilization was assessed for drug prescriptions, additional tests, or outpatient visits for 1 year. RESULTS: Cough was the chief complaint in 13,223 cases (46.7%) among 28,312 new referrals for 8 years. A total of 3810 subacute and 7150 chronic cough patients were analyzed. The common demographic profile was middle-aged woman (mean age 52.1 years), reported in 63% of the cases. Cough was frequently accompanied by anterior nasal (about 50%), lower airway (30%), or acid reflux disease symptoms (20%), and by test abnormalities in chest X-rays (14%), spirometry (23%), or T2 inflammation markers (40%). Chronic cough patients frequently required additional tests (chest CT scan: 24%), drug prescriptions (codeine: 21.5% and oral steroids: 9.9%), and long-term healthcare utilization (16.0%) for 1 year. CONCLUSIONS: Cough is a common chief complaint at allergy and asthma clinics, but the clinical presentation may be heterogeneous. Further studies are needed to understand long-term outcomes and reduce the disease burden.

Stronger correlation of peak oxygen uptake with distance of incremental shuttle walk test than 6-min walk test in patients with COPD: a systematic review and meta-analysis.

BACKGROUND: The 6-min walk test (6MWT) and incremental shuttle walk test (ISWT) are valid and reliable measures to assess exercise capacity of patients with chronic obstructive pulmonary disease (COPD). However, the comparison of correlation between peak oxygen uptake (peak VO2) and 6MWT or ISWT distance has not been investigated. We aimed to investigate the correlation between peak VO2 and 6MWT and ISWT distances in COPD patients through a meta-analysis. METHODS: We systematically searched MEDLINE, Scopus, Embase, and the Cochrane Library up to June, 2020 for studies comparing the correlation of peak VO2 with either 6MWT or ISWT in COPD patients. Meta-analysis was performed with R software using a fixed-effect model. We compared the correlation coefficient and measured the heterogeneity using I2 statistics. RESULTS: We identified 12 studies involving 746 patients. Meta-analysis showed a significant correlation between peak VO2 and 6MWT and ISWT distances (6MWT: r = 0.65, 95% CI 0.61-0.70; ISWT: r = 0.81, 95% CI 0.74-0.85; p < 0.0001). The heterogeneity was lower in ISWT than in 6MWT (6MWT: I2 = 56%, p = 0.02; ISWT: I2 = 0%, p = 0.71). Subgroup analysis showed a higher correlation coefficient in the low exercise capacity group than in the high exercise capacity group in both field tests. CONCLUSIONS: 6MWT and ISWT significantly correlated with peak VO2. Our findings suggest that ISWT has a stronger correlation with peak VO2 than 6MWT. The exercise capacity in COPD patients may affect the strength of the relationship between peak VO2 and walking distance in both field tests, suggesting the importance of using various exercise tests. Trial registration CRD 42020200139 at crd.york.ac.uk/prospero/.

Comparative effectiveness of smartphone healthcare applications for improving quality of life in lung cancer patients: study protocol.

BACKGROUND: Although pulmonary rehabilitation is helpful for patients following lung cancer surgery, rehabilitation is not widely available, due in part to a lack of medical resources. Recent developments in digital health care have overcome the space limitations associated with in-person health care. This study will evaluate and compare the efficacy of three different smartphone healthcare systems in patients with lung cancer. METHODS: This single center randomized controlled study is designed to evaluate the efficacy of digital healthcare applications for lung cancer patients after thoracoscopic lung resection. A total of 320 patients will be enrolled and randomized 1:1:1:1 into four different groups, with one group each using the smartphone applications NOOM, Walkon, and Efilcare and the fourth being the control group without intervention. Questionnaires will be administered to patients at baseline and after 3, 6, and 12 months. The primary endpoint will be the score on the EuroQol five-dimension index. Secondary endpoints will include other questionnaires about quality of life and dyspnea. DISCUSSION: This prospective randomized controlled study may allow assessments and comparisons of the efficacy of various smartphone applications in patients who undergo lung cancer surgery. This process may enable the introduction of healthcare interventions that maintain quality of life in patients with lung cancer. Trial registration CRIS, KCT0005447. Registered 06 October 2020, https://cris.nih.go.kr/cris/search/detailSearch.do/19346.

Prognostic implication of bronchoalveolar lavage fluid analysis in patients with Pneumocystis jirovecii pneumonia without human immunodeficiency virus infection.

BACKGROUND: The prognostic value of bronchoalveolar lavage (BAL) fluid analysis in non-human immunodeficiency virus (HIV)-infected patients with Pneumocystis jirovecii pneumonia (PJP) has not been well elucidated. We aimed to investigate the prognostic implication of BAL fluid analysis in non-HIV patients with PJP. METHODS: The data of 178 non-HIV patients diagnosed with PJP based on the results of the polymerase chain reaction assay of BAL fluid specimens between April 2018 and December 2020 were retrospectively reviewed. The clinical characteristics, laboratory findings, and BAL fluid analysis results of patients who died within 90 days after hospital admission were compared. RESULTS: Twenty patients (11.2%) died within 90 days from admission. The neutrophil count in BAL fluid was significantly higher (median 22.0%, interquartile range [IQR] 2.0-46.0% vs. median 6.0%, IQR 2.0-18.0%, P = 0.044), while the lymphocyte count was significantly lower (median 24.0%, IQR 7.0-37.0% vs. median 41.0%, IQR 22.5-60.5%, P = 0.001) in the non-survivor group compared with that in the survivor group. In the multivariate analysis, the C-reactive protein level (odds ratio [OR] 1.093, 95% confidence interval [CI] 1.020-1.170, P = 0.011) and a BAL fluid lymphocyte count of ≤ 30% (OR 3.353, 95% CI 1.101-10.216, P = 0.033) were independently associated with mortality after adjusting for albumin and lactate dehydrogenase levels. CONCLUSION: A low lymphocyte count in BAL fluid may be a predictor of mortality in non-HIV patients with PJP.

Comparison of Predicted Exercise Capacity Equations in Adult Korean Subjects.

BACKGROUND: Maximal oxygen uptake (VO2 max) is a useful index to assess exercise capacity. However, there is no reference value for Koreans. This study aimed to compare actual VO2 max and predicted VO2 max using exercise capacity equations in Korean subjects. METHODS: This retrospective study enrolled 383 patients who underwent cardiopulmonary exercise test (CPET) with incremental maximal cycle ergometer test at Asan Medical Center from January 2020 to May 2021. Stage 1 and 2 lung cancer patients with normal lung function and healthy persons of 50 subjects who had maximal CPET were analyzed. RESULTS: The subjects were aged 65 ± 13 years and predominantly male (74%). CPET results were as follows: absolute VO2 max, 1.2 ± 0.3 L/min; body weight referenced VO2 max, 20 ± 3.9 mL/kg/min; peak work rate, 94 ± 24 watts; peak heart rate, 142 ± 21 bpm; peak O2 pulse, 10 ± 3 mL/beat; minute ventilation, 59 ± 14 L/min; peak respiratory rate, 34 ± 6 breaths per minute; and peak breathing reserve, 41 ± 18%. There was significant discordance between the measured and predicted absolute VO2 max using the Jones, Hansen, and Wasserman prediction equations developed for Caucasian population (P < 0.001). Agreement using Bland-Altman test between true and predicted absolute VO2 max was the best in Chinese equation (-0.03, 2SD = 0.55) compared to Jones (0.42, 2SD = 1.07), Hansen (0.44, 2SD = 0.86), and Wasserman (0.42, 2SD = 0.86) equations. CONCLUSION: The reference value and prediction equation from studies including primarily Caucasians may not be appropriate for Koreans. Since the mean difference is the lowest in Chinese equation, the Chinese equation might be used for the Korean adult population.

PINK1 Inhibits Multimeric Aggregation and Signaling of MAVS and MAVS-Dependent Lung Pathology.

Mitochondria have emerged as important signaling organelles where intracellular perturbations are integrated and, consequently, intracellular signaling pathways are modulated to execute appropriate cellular functions. MAVS (mitochondrial antiviral signaling protein) represents such an example that functions as a platform molecule to mediate mitochondrial innate immune signaling. Recently, multimeric aggregation of MAVS has been identified as a key molecular process for its signaling. The underlying mechanisms to regulate this, however, are still incompletely understood. We hypothesized that PINK1 (PTEN-induced kinase 1) plays an important role in the regulation of multimeric MAVS aggregation and its consequent pathobiology. To test whether PINK1 interacts with MAVS, bimolecular fluorescence complementation analysis and IP were performed. RLH (RIG-I-like helicase) and NLRP3 inflammasome signaling were evaluated by in vitro assay. In vivo functional significance of PINK1 in the regulation of MAVS signaling was evaluated from both murine modeling of influenza viral infection and bleomycin-induced experimental pulmonary fibrosis, wherein MAVS plays important roles. Multimeric MAVS aggregation was induced by mitochondria dysfunction, and, during this event, the stabilized PINK1 interacted physically with MAVS and antagonized multimeric MAVS aggregation. Accordingly, the MAVS-mediated antiviral innate immune and NLRP3 inflammasome signaling were enhanced in PINK1 deficiency. In addition, in vivo studies revealed that MAVS-mediated pulmonary antiviral innate immune responses and fibrotic responses after bleomycin injury were enhanced in PINK1 deficiency. In conclusion, these results establish a new role of PINK1 in the regulation of MAVS signaling and the consequent pulmonary pathobiology.

Mitochondrial antiviral signaling protein is crucial for the development of pulmonary fibrosis.

Danger signals, or damage-associated molecular patterns (DAMPs), instigate mitochondrial innate immune responses wherein mitochondrial antiviral signaling protein (MAVS) functions as a key platform molecule to mediate them. The role of MAVS in the pathogenesis of idiopathic pulmonary fibrosis (IPF), however, has not yet been identified. Whether MAVS signalling can be modulated by currently existing drugs has also not been explored.We used an established model of pulmonary fibrosis to demonstrate that MAVS is a critical mediator of multiple DAMP signalling pathways and the consequent lung fibrosis after bleomycin-induced injury in vivoAfter bleomycin injury, MAVS expression was mainly observed in macrophages. Multimeric MAVS aggregation, a key event of MAVS signalling activation, was significantly increased and persisted in bleomycin-injured lungs. A proapoptotic BH3 mimetic, ABT-263, attenuated the expression of MAVS and its signalling and, consequently, the development of experimental pulmonary fibrosis. In contrast, the therapeutic effects of nintedanib and pirfenidone, two drugs approved for IPF treatment, were not related to the modulation of MAVS or its signalling. Multimeric MAVS aggregation was significantly increased in lungs from IPF patients as well.MAVS may play an important role in the development of pulmonary fibrosis, and targeting MAVS with BH3 mimetics may provide a novel and much needed therapeutic strategy for IPF.

Dual versus monotherapy with bronchodilators in GOLD group B COPD patients according to baseline FEV1 level: a patient-level pooled analysis of phase-3 randomized clinical trials.

BACKGROUND: Which patients should receive dual therapy as initial treatment for chronic obstructive pulmonary disease (COPD) is only loosely defined. We evaluated if a lower forced expiratory volume in 1 s (FEV1) identifies a population more likely to benefit from dual therapy than monotherapy among group B COPD patients in whom Global initiative for Chronic Obstructive Pulmonary Disease (GOLD) recommends monotherapy as initial treatment. METHODS: This was a patient-level pooled analysis of phase-3 randomized controlled trials involving dual bronchodilators. Study patients were classified into two groups based on the FEV1 of 50% of the predicted value (GOLD I/II versus GOLD III/IV). We evaluated the efficacy of dual versus monotherapy (long-acting beta-2 agonist [LABA] or long-acting muscarinic antagonist [LAMA]) between these two groups in the following outcomes: changes in trough FEV1, the St. George's Respiratory Questionnaire (SGRQ) score, the proportion of SGRQ responders, time to first exacerbation, and risk of adverse events. RESULTS: A total of 14,449 group B patients from 12 studies were divided into GOLD III/IV (n = 8043) or GOLD I/II group (n = 6406). In the GOLD III/IV group, dual therapy was significantly more effective in improving FEV1, reducing SGRQ scores, and achieving a higher proportion of SGRQ responders compared with either LABA or LAMA. Dual therapy also showed a significantly longer time to first exacerbation compared with LABA in the GOLD III/IV group. In contrast, in the GOLD I/II group, the benefits of dual therapy over monotherapy were less consistent. Although dual therapy resulted in significantly higher FEV1 than either LABA or LAMA, it did not show significant differences in the SGRQ score and proportion of SGRQ responders as compared with LABA. The time to first exacerbation was also not significantly different between dual therapy and either LABA or LAMA in the GOLD I/II group. CONCLUSIONS: Dual therapy demonstrated benefits over monotherapy more consistently in patients with lower FEV1 than those with higher FEV1.

The impact of life behavior and environment on particulate matter in chronic obstructive pulmonary disease.

BACKGROUND: The effect of exposure to particulate matter (PM) on human health is a global public health concern. To develop an effective strategy to reduce PM exposure, we performed detailed questionnaire surveys regarding the type of lifestyle required to avoid PM exposure in patients with chronic obstructive pulmonary disease (COPD). We correlated the data with real-time PM concentration during the winter season. METHODS: We enrolled 104 patients with COPD aged 40 years or older. Detailed questionnaire surveys were conducted among participants, and internet of things-based sensors were installed at their homes to measure the indoor PM2.5 concentration, which was continuously monitored between December 2019 and February 2020. The associations among PM2.5 concentration, patients' lifestyles, and the impact of both concentration and lifestyle on COPD exacerbation were analyzed. RESULTS: Mean outdoor PM2.5 concentration was higher than mean indoor PM2.5 concentration during the study period (21.28 ± 5.09 µg/m3 vs. 12.75 ± 7.64 µg/m3), with a mean difference of 8.53 ± 7.99 µg/m3. Among the various social factors and practices that aim to avoid exposure to PM, six practices and economic statuses were confirmed to reduce indoor PM2.5 concentration compared to outdoor concentration; Contrarily, these practices created a significant difference between the outdoor and indoor PM2.5 concentrations. The six practice items that showed a significant difference were 1) checking air quality forecast (the difference: -13.31 ± 1.35 µg/m3, p = 0.013), 2) indoor air filter operated (-15.43 ± 1.32 µg/m3, p < 0.001), 3) ventilating home by opening the windows (-13.14 ± 1.28 µg/m3, p = 0.013), 4) checking filters of the air filter (-13.95 ± 1.50 µg/m3, p = 0.002), 5) refraining from going out when outside PM is high (-12.52 ± 1.37 µg/m3, p = 0.039), 6) wearing a mask when going out (-13.38 ± 1.32 µg/m3, p = 0.017). The higher the household income and economic level, the more significant the difference in the PM2.5 concentration. Severe exacerbation was more prevalent among patients with acute exacerbation as the exposure time of PM2.5≥35 µg/m3 or PM2.5≥75 µg/m3. CONCLUSION: Lifestyle and economic levels can affect the indoor PM2.5 concentration, which may impact COPD exacerbation.

Regulation and Role of Chitotriosidase during Lung Infection with Klebsiella pneumoniae.

Chitinases and chitinase-like proteins are an evolutionary conserved group of proteins. In the absence of chitin synthesis in mammals, the conserved presence of chitinases suggests their roles in physiology and immunity, but experimental evidence to prove these roles is scarce. Chitotriosidase (chit1) is one of the two true chitinases present in mammals and the most prevalent chitinase in humans. In this study, we investigated the regulation and the role of chit1 in a mouse model of Klebsiella pneumoniae lung infection. We show that chitinase activity in bronchoalveolar lavage fluid is significantly reduced during K. pneumoniae lung infection. This reduced activity is inversely correlated with the number of neutrophils. Further, instilling neutrophil lysates in lungs decreased chitinase activity. We observed degradation of chit1 by neutrophil proteases. In a mouse model, chit1 deficiency provided a significant advantage to the host during K. pneumoniae lung infection by limiting bacterial dissemination. This phenotype was independent of inflammatory changes in chit1-/- mice as they exerted a similar inflammatory response. The decreased dissemination resulted in improved survival in chit1-/- mice infected with K. pneumoniae in the presence or absence of antibiotic therapy. The beneficial effects of chit1 deficiency were associated with altered Akt activation in the lungs. Chit1-/- mice induced a more robust Akt activation postinfection. The role of the Akt pathway in K. pneumoniae lung infection was confirmed by using an Akt inhibitor, which impaired health and survival. These data suggest a detrimental role of chit1 in K. pneumoniae lung infections.

Hyperuricemia Is Not Predictive of Long-Term Outcome in Patients with Stable Chronic Obstructive Pulmonary Disease.

BACKGROUND: Although the association of hyperuricemia with an increased risk of mortality has been demonstrated in the context of acute exacerbation of chronic obstructive pulmonary disease (COPD), the long-term outcomes of hyperuricemia have not been studied in the case of stable COPD. METHODS: We retrospectively analyzed baseline data of 240 men with stable COPD enrolled in the Korea Obstructive Lung Disease cohort. We evaluated associations between serum uric acid levels and clinical parameters, risk factors for all-cause mortality, and acute exacerbation of COPD. RESULTS: The mean age of subjects was 66.4 ± 7.7 years, and the median follow-up time was 5.9 years. We identified no significant difference in terms of lung function or laboratory findings between patients with hyperuricemia and those without. Serum uric acid level was negatively associated with systemic inflammation indicated by neutrophil-lymphocyte ratio (r = -0.211, P = 0.001). Univariate Cox regression analysis revealed hyperuricemia to not be associated with an increased risk of all-cause mortality in men with stable COPD (hazard ratio [HR], 0.580; 95% confidence interval [CI], 0.250-1.370; P = 0.213). In the multivariate Cox regression model, hyperuricemia was not an independent predictor of acute exacerbation (HR, 1.383; 95% CI, 0.977-1.959; P = 0.068). CONCLUSION: Among men with stable COPD, hyperuricemia is not an independent predictor of all-cause mortality or future acute exacerbation of COPD. These results differ from those of previous studies on patients with acute exacerbation of COPD.

Association Between Duration of Aminoglycoside Treatment and Outcome of Cavitary Mycobacterium avium Complex Lung Disease.

BACKGROUND: Although aminoglycosides are recommended for cavitary Mycobacterium avium complex lung disease (MAC-LD), the optimal duration of treatment is unclear. We investigated the association between duration of aminoglycoside treatment and outcomes in cavitary MAC-LD. METHODS: Among patients diagnosed with macrolide-susceptible cavitary MAC-LD between 2000 and 2013, 101 who received treatment up to August 2017 with a regimen containing aminoglycosides were enrolled at a tertiary referral center in South Korea. Their medical records were retrospectively reviewed. The duration of aminoglycoside treatment was at the discretion of the attending physician. RESULTS: A total of 75 patients (74.3%) were administered aminoglycosides for ≥3 months (median 164 days), whereas the remaining 26 patients (25.7%) received treatment for <3 months (median 59 days). The overall treatment success rate was 63.4% (64/101). Patients treated with aminoglycosides for ≥3 months had a significantly higher success rate than those treated for <3 months (69.3% vs 46.2%; P = .035). Multivariate analysis revealed that aminoglycoside treatment for ≥3 months was a significant factor for treatment success (adjusted odds ratio, 3.602; 95% confidence interval, 1.249-10.390; P = .018). Recurrence occurred in 8 (22.9%) of 35 patients who were followed up for at least 3 years after the end of treatment; all 8 patients received aminoglycosides for ≥3 months. CONCLUSIONS: Patients with cavitary MAC-LD treated with aminoglycosides for ≥3 months showed higher treatment success rate than those treated for <3 months. However, treatment for ≥3 months was not associated with the development of recurrence.