Search

Background and objective Circulating fibrocytes act as precursors of myofibroblasts, contribute to airway remodelling in chronic asthma and migrate to injured tissues by expressing CXCR4 and CCR7. Anti-IgE therapy improves severe allergic asthma (SAA) control and airway remodelling in T2-high SAA. The effects of anti-IgE therapy on fibrocyte activities were investigated in this study. Methods The expression of CCR7, CXCR4, ST2 and α-SMA (α-smooth muscle actin) in both circulating and cultured fibrocytes from all patients with asthma was measured, and was repeated after omalizumab treatment in SAA. Fibrocytes recruitment, proliferation and transformation were also measured in response to anti-IgE therapy. Results Omalizumab effectively improved asthma control and pulmonary function in T2-high SAA, associated with a decline in serum levels of IL-33 and IL-13. Omalizumab down-regulates CXCR4 and CCR7 expression of fibrocytes, which could suppress fibrocyte recruitment into the lungs. Omalizumab also suppressed the increased number of fibrocytes and α-SMA+ fibrocytes within the cultured non-adherent non-T (NANT) cells after 3-7 days of culture. The decrease in serum levels of IL-33 by omalizumab contributed to the effectiveness in inhibiting fibrocyte recruitment, proliferation and myofibroblast transformation through IL-33/ST2 axis. The elevated IL-13 expression in SAA patients potentiated the effects of IL-33 by increasing ST2 expression. Conclusion Omalizumab reduced the number of circulating fibrocytes, cell and number of fibrocytes as well as α-SMA+ fibrocytes after 3-7 days of culture in SAA patients. IL-33 and IL-13 may be implicated in the effectiveness of omalizumab in inhibiting fibrocyte activation contributing partly to the clinical benefits in reducing lamina propria and basement membrane thickening.

Background Adiposity is a key risk factor for asthma and impaired pulmonary function. Objectives We aimed to identify the critical period of life course adiposity for asthma in childhood and young adulthood, and to determine whether associations of adiposity and asthma vary across ages. Methods Birth weight and body mass index (BMI) from birth to 17 years of age were assessed in 6130 children from the Taiwan Children Health Study. Logistic regression for asthma outcome and linear regression for pulmonary function outcome were used to investigate associations of adiposity with asthma. Seventeen BMI-related single-nucleotide polymorphisms were used to obtain genetic instrumental variables for adiposity to perform Mendelian randomisation (MR) analysis. Results Using both regression model and MR analyses, we confirmed that the critical period of adiposity in predicting childhood asthma would be before age 6 years. Further, we discovered that the sensitive period of adiposity gain related to young adulthood asthma was the prepubertal stage. Risks of asthma at age 17 per unit increase in z-score of the BMI increased from 0.94 (95% CI: 0.79, 1.11) at birth, and became greater than 1.00 between age 11-12, then increased to 1.08 (95% CI: 0.95, 1.22) at age 17. The associations of life course BMI with asthma and pulmonary function impairment at age 12 and with asthma at age 17 increased with age. The aforementioned association was most prominent among central obesity indicators. Conclusions To prevent asthma in childhood and young adulthood, we should aim at promoting healthy growth at the toddler period and prepubertal stage. This article is protected by copyright. All rights reserved.

Background The efficacy of antifungal therapy in fungal-associated severe asthma remains controversial. Objective We aimed to evaluate the differences in the clinical presentation and response to antifungal therapy between severe asthmatics with fungal sensitization and positive fungal isolates. Methods This retrospective study included 73 patients with severe asthma from January 2004 to December 2017. We examined the presentation, medication, exacerbations, pulmonary function, serum IgE, blood eosinophils, and sputum culture results. Follow-up care was provided to each patient for minimum 3 years. Results We classified the patients into four groups: group 1, neither fungal sensitization nor fungal isolates in the sputum (n=16); group 2, positive fungal sensitization (n=16); group 3, positive fungal isolates (n=31); and group 4, concomitant positive fungal sensitization and positive fungal isolates (n=10). There were four participants in group 2, 15 in group 3, and 6 in group 4 had received itraconazole therapy for 3 months. Patients in group 3 presented with lower serum IgE level than those in groups 2 and 4. Antifungal therapy significantly improved ACT score during the first year in groups 3 (from 18 [15-22] to 24 [23-24], p=0.0004) and resulted in a long-lasting ACT improvement till the third year in group 3 (from 18 [15-22] to 24 [22-24], p=0.0013). Conclusion Antifungal therapy could effectively control the symptoms in patients with severe asthma with positive fungal isolates, contrary to those with merely fungal sensitization; therefore, highlighting the need for a more precise treatment strategy in future for fungal-associated severe asthma.

Introduction Angiotensin-converting enzyme 2 (ACE2) provides an adhesion site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients with COPD could have severe outcomes after SARS-CoV-2 infection. The objective of this study was to investigate ACE2 regulation by air pollution during the development of COPD. Methods Sprague Dawley rats were exposed to unconcentrated traffic-related air pollution for 3 and 6 months. We examined lung injury markers, oxidative stress, inflammation, emphysema, ACE2 and angiotensin II receptor type 1 (AT1) and 2 (AT2) in the lungs after exposure. Results Lung injury occurred due to an increase in permeability and lactate dehydrogenase cytotoxicity was observed after 6 months of exposure to fine particulate matter of, Short-term exposure to PM1 increases ACE2 overexpression in lungs. Long-term exposure to PM1 decreases the ACE2 overexpression in emphysema. Air pollution may be a risk for #SARSCoV2 adhesion during the development of COPD. https://bit.ly/2Vfykur

Background:The novel coronavirus disease 2019 (COVID-19) has been a global pandemic health issue since 30, January, 2020. Mortality rate was as high as more than 50% in critically ill patients. The Stem cell treatment is effective in refractory severe critically ill COVID-19 patients, but immune regulation mechanisms have not been reported well. Therefore, we evaluate the clinical efficacy and immune modulation of placenta-derived mesenchymal stem cells (pcMSCs) (MatriPlax) in severe critically ill COVID-19 infection who are refractory to current standard therapies.Methods:Intravenous infusion of 1 × 107 MatriPlax was given to five severe COVID-19 patients at Day 0 and day 4. Serum inflammatory markers and immune profiles were studied at Day 0, 4 and 8. Clinical parameters and 28-days mortality were compared between treated group and control group.Results:The treatment group had no 28-days mortality and Murray’s lung injury score was significantly improved compared with control group. After treatment, Ferritin, C-reactive protein (CRP) and Lactate dehydrogenases (LDH) were significantly reduced and lymphopenia was improved. IL-6, IL-1β, IFN-γ and IL-2 were significantly decreased together with decrease in IL-10 reflecting decreasing intensity of inflammation. Immune cell profiles showed increase in CD4+ T cells (CD4+ naïve T cells, CD4+ memory T cells subtypes), Treg cells, CD19+ B cells (and CD19+ naive B cells, CD27+ switched B cells subtypes) and dendritic cells, and a significant decrease in CD14+ monocytes (and CD16- classical, CD16+ non-classical subtypes) monocytes as well as plasma/plasmablast cells. pc-MSCs treatment suppressed hyper-inflammatory states of innate immune responses to COVID-19 infection by increasing Treg cells, decreasing monocytes and plasma/plasmablast cells, and promoted CD4+ T cells and CD19+ B cells towards adaptive immune responses.Conclusion:The intravenous transplantation of Matriplax was safe and effective for severe critically ill COVID-19 patients, especially those who were refractory to current standard care and immunosuppressive therapies

Patients with chronic obstructive asthma (COA) develop airflow obstruction caused by subepithelial fibrosis. Although a disintegrin and metalloproteinase 17 (ADAM17) has been implicated in lung inflammation and tissue fibrosis, its role in airway fibrosis in COA has not been explored. Here, we found marked overexpression of ADAM17, phosphorylated ADAM17, and connective tissue growth factor (CTGF) in human airway fibroblasts from COA patients, compared with those of normal subjects. Similarly, levels of ADAM17, CTGF, α-smooth muscle actin (α-SMA), and collagen were increased in endobronchial biopsies from COA patients, but not in controls. In an ovalbumin-challenge asthma model, airway fibrosis was inhibited in ADAM17f/f/Cre+ mice compared to control mice. TGF-β- and thrombin-induced fibrotic protein expression was reduced by ADAM17 small interfering (si)RNA, TAPI-0 (an ADAM17 inhibitor), and EGFR siRNA. In addition, exogenous HB-EGF reversed fibrotic response in ADAM17 knockdown human lung fibroblasts. ADAM17 causes subepithelial fibrosis through regulation of enhanced extracellular matrix production and fibroblast differentiation and is the common pathway for airway fibrosis mediated by TGF-β and thrombin through an aberrant ADAM17/EGFR signalling pathway.

Emphysema can be examined quantitatively on high-resolution computed tomography (HRCT) by measuring the low-attenuation areas of the lung and has been associated with decrease in lung function in patients with COPD [1]. Previous studies have associated levels of air pollution with emphysema severity of the total lung [2, 3]. However, the relationship between inhaled particulate matter (PM) deposition in the lungs and the degree of emphysema at the lung lobar level remains poorly understood. We examined the association of lung lobe-deposited doses of PM2.5 (particles with a 50% cut-off aerodynamic diameter of 2.5 μm) with the extent of emphysema in different lung lobes of COPD subjects., The novelty of this study is that it identified the associations between PM2.5 deposition in the lung and the degree of emphysema in different lung lobes of COPD patients, especially in the right middle lobe and both upper lobes https://bit.ly/3k21ri0

Adults with obesity exhibit a restrictive pattern, whereas children with obesity exhibit an obstructive pattern. However, the transition process remains unclear. We performed a systematic search for studies reporting on body mass index and pulmonary function in children. The main outcomes were forced expiratory volume in 1 s (FEV1 ), forced vital capacity (FVC), and their ratio (FEV1 /FVC). We compared individuals with overweight or with obesity with individuals with normal weight. Random-effects models were used to calculate pooled estimates. A total of 17 studies were included. Individuals with obesity had a lower FEV1 /FVC ratio (mean difference [MD] = -3.61%; 95% confidence interval [CI] = -4.58%, -2.64%) and a higher percent-predicted FVC (MD = 3.33%; 95% CI = 0.79%, 5.88%) than those with normal weight. Obesity impaired pulmonary function in the obstructive pattern during childhood to young adulthood, and the maximum obstruction was observed at the age of 16 years in boys and 20 years in girls. The effects attenuated at approximately 30 years and then shifted to the restrictive pattern after 35 years of age in men and 40 years in women. The effects of obesity on pulmonary function change from the obstructive pattern in childhood to the restrictive pattern in adulthood.

The development of emphysema has been linked to air pollution; however, the association of air pollution with the extent of lobar emphysema remains unclear. This study examined the association of particulate matter 2.5) (≤2.5 μm), nitrogen dioxide (NO2), and ozone (O3) level of exposure with the presence of emphysema in 86 patients with chronic obstructive pulmonary disease (COPD). Exposure to the air pollution estimated using the land-use regression model was associated with lung function, BODE (a body mass index, degree of obstruction, dyspnea severity, and exercise capacity index) quartiles, and emphysema measured as low-attenuation areas on high-resolution CT (HR-CT) lung scans. Using paraseptal emphysema as the reference group, we observed that a 1 ppb increase in O3 was associated with a 1.798-fold increased crude odds ratio of panlobular emphysema (p < 0.05). We observed that PM2.5 was associated with BODE quartiles, modified Medical Research Council (mMRC) dyspnea score, and exercise capacity (all p < 0.05). We found that PM2.5, NO2, and O3 were associated with an increased degree of upper lobe emphysema and lower lobe emphysema (all p < 0.05). Furthermore, we observed that an increase in PM2.5, NO2, and O3 was associated with greater increases in upper lobe emphysema than in lower lobe emphysema. In conclusion, exposure to O3 can be associated with a higher risk of panlobular emphysema than paraseptal emphysema in patients with COPD. Emphysema severity in lung lobes, especially the upper lobes, may be linked to air pollution exposure in COPD.

Background: Fibrocytes are bloodborne mesenchymal progenitors which accumulate and differentiate at disease site. We investigated whether hypoxemia activates fibrocytes, accelerating airflow limitation and exercise intolerance in chronic obstructive pulmonary disease (COPD) patients. Methods: Flow cytometry was used to determine collagen I+/CD45+ fibrocytes and α-smooth muscle actin+ differentiating fibrocytes within peripheral blood and cultured cells, as well as the expression of CXC chemokine receptor 4 (CXCR4), epidermal growth factor receptor (EGFR), connective tissue growth factor (CTGF) and hypoxia-inducible factor (HIF)-1α. Fibrocytes in lung specimens were identified by confocal microscopy. Findings: Compared to non-desaturators, COPD desaturators (peripheral blood oxygen saturation ≤88% during exercise) had greater number of fibrocytes in peripheral blood and lung specimens, paralleled with faster yearly lung function decline and 6-minute walk distance. Fibrocytes from desaturators expressed more EGFR, CXCR4, CTGF and HIF-1α, with a higher capacity to proliferation and myofibroblastic differentiation. Hypoxia (5% oxygen) increased the expression of EGFR, CXCR4, CTGF and HIF-1α, the number and differention in fibrocytes. These effects were attenuated by EGFR inhibitor gefitinib, HIF-1α gene silencing, and anti-CTGF antibody. Interpretation: These data elucidate that hypoxaemia triggers fibrocyte activation through the EGFR/HIF-1α axis, aggravating airflow obstruction in COPD. Funding Information: This work was supported by the National Medical Research Program (NMRP) grant 99-2314-B-182-043-MY3, 108-2314-B-182A-128-MY2 and the Chang Gung Medical Research Project (CMRP) grant CMRPG390041-2. Declaration of Interests: The authors have declared that no competing interest exists. Ethics Approval Statement: The study was approved by the Ethics Committee of Chang Gung Memorial Hospital (IRB: 98-3950B, 201801979A3). Written informed consents were obtained from all participants.

Shih-Wei Lee,1,* Yu-Chen Huang,2,3,* Chun-Yu Lin,2,3 Hung-Yu Huang,2,3 Chi-Wei Liu,1 Ming-Tsuen Hsieh,4 Chon-Lin Lee,4– 7 Wen-Yu Chung,8 Kian Fan Chung,9 Chun-Hua Wang,2,3 Han-Pin Kuo10,11 1Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan; 2Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan; 3College of Medicine, Chang Gung Memorial University, Taoyuan, Taiwan; 4Department of Marine Environment and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan; 5Aerosol Science and Research Center, National Sun Yat-Sen University, Kaohsiung, Taiwan; 6Department of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan; 7Department of Applied Chemistry, Providence University, Taichung, Taiwan; 8Department of Computer Science and Information Engineering, National Kaohsiung University of Science and Technology, Kaohsiung, Taiwan; 9Experimental Studies, National Heart and Lung Institute, Imperial College London and Royal Brompton Hospital, London, UK; 10Pulmonary Medicine Research Center, Taipei Medical University, Taipei, Taiwan; 11Department of Thoracic Medicine, Taipei Medical University Hospital, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Chun-Hua WangDepartment of Thoracic Medicine, Chang Gung Memorial Hospital, 199 Tun-Hwa North Road, Taipei 10507, TaiwanTel +886 3 321 1200 ext 8467Email wchunhua@ms7.hinet.netHan-Pin KuoDepartment of Medicine, Taipei Medical University School of Medicine, 250 Wu-Xing Street, Taipei 11031, TaiwanEmail q8828@ms11.hinet.netPurpose: Exposure to polycyclic aromatic hydrocarbons (PAHs) associated with ambient air particulate matter (PM) poses significant health concerns. Increased acute exacerbation (AE) frequency in asthmatic patients has been associated with ambient PAHs, but which subgroup of patients are particularly susceptible to ambient PAHs is uncertain. We developed a new model to simulate grid-scale PM2.5-PAH levels in order to evaluate whether the severity of asthma as measured by the Global Initiative of Asthma (GINA) levels of treatment is related to cumulative exposure of ambient PAHs.Methods: Patients with asthma residing in the northern Taiwan were reviewed retrospectively from 2014 to 2017. PM2.5 were sampled and analysed for PAHs twice a month over a 72-hour period, in addition to collecting the routinely monitored air pollutant data from an established air quality monitoring network. In combination with correlation analysis and principal component analysis, multivariate linear regression models were performed to simulate hourly grid-scale PM2.5-PAH concentrations (ng/m3). A geographic information system mapping approach with ordinary kriging interpolation method was used to calculate the annual exposure of PAHs (ng/m).Results: Among the 387 patients with asthma aged 18 to 93 (median 62), 97 subjects were treated as GINA step 5 (24%). Asthmatics in GINA 5 subgroup with high annual PAHs exposure were likely to have a higher annual frequency of any AE (1 (0– 12), p< 0.0001). Annual PAHs exposure was correlated with the annual frequency of any exacerbation (r=0.11, p=0.02). This was more significant in the GINA 5 subgroup (r=0.29, p=0.005) and in the GINA 5 subgroup with severe acute exacerbations (r=0.51, p=0.002). Annual PAHs exposure, severe acute exacerbation and GINA steps were independent variables that predict annual frequency of any exacerbation.Conclusion: Asthmatic patients in the GINA 5 subgroup with acute exacerbations were more susceptible to the effect of environmental PAHs on their exacerbation frequency. Reducing environmental levels of PAHs will have the greatest impact on the more severe asthma patients.Keywords: polycyclic aromatic hydrocarbons, asthma acute exacerbation, GINA, hourly grid-scale model

Introduction: Chronic obstructive pulmonary disease (COPD) patients suffered hyperventilation leading to diaphragm limitation. Previous studies indicated that diaphragm excursion can be used as a predictor of ventilator weaning. However, how the home-based respiratory muscle training effects by Ultrasound diaphragm excursion in patients with COPD remains unknown. Objective: To investigate the correlation with the home-based respiratory muscle training effects and diaphragm excursion. Methods: A prospective case-control study recruited 21 COPD patients were performed. All enrolled patients received the home-based pulmonary rehabilitation (hPR), and were randomize assigned to without respiratory muscle training (Non-RMT) or with respiratory muscle training (RMT) for 8 weeks. Data measured by 6MWT, CAT and SF-12 score, maximum inspiratory/expiratory pressure (PiMax/PeMax), and diaphragm sonography. Results: There were significant increased in PiMax, Pemax and 6MWD after RMT intervention. Patients in the RMT group improved Quality of Life about SF-12 score compared to baseline and the CAT score were significant improved in both groups. We also find that the Pimax and the FEV1 are significantly correlated with diaphragm excursion. Conclusion: hPR with RMT for the COPD patients increased respiratory muscle strength and exercise tolerance, reduced the dyspnea sensation, and improved the quality of life. Another, the respiratory muscle strength and the FEV1 were significantly correlated with diaphragm excursion.

Background/Purpose: Patients with chronic obstructive pulmonary disease (COPD) receive more life-sustaining treatments (LSTs) than those with other diseases. The aims of this study were to explore the willingness of COPD patients and their families to consent to LSTs and compare the differences between their levels of willingness. Methods: A cross-sectional survey was conducted, and structured questionnaires were used for data collection. Results: A total of 219 valid samples were collected, including 109 patients and 110 families. Sixty percent of family members indicated that they did not know the intentions of the patient. Families were significantly more willing for patients to receive LSTs than the patients themselves. The level of willingness of patients and families varied according to the situation and LST interventions. When patients were in a vegetative state or medical treatments were futile, the willingness of COPD patients and their families to receive LSTs significantly decreased. Endotracheal intubation and external defibrillation were the least likely to be requested, whereas the willingness to receive medication injections and noninvasive ventilation was greatest. Conclusion: Communication between families and patients on the issue of LST should be facilitated. Adequate information on the patient’s condition and possible LSTs should be provided to avoid COPD patients receiving inappropriate LSTs. Keywords: Chronic obstructive pulmonary disease, Life-sustaining treatment, End-of-life, Willingness, Decision making

Background Omalizumab, a recombinant monoclonal anti-IgE antibody, was developed for the treatment of severe allergic asthma. Not all these patients respond to omalizumab. Objective This study aimed to evaluate whether the proinflammatory cytokine profiles in the severe allergic asthma patients were different between who responded and nonresponded to omalizumab therapy. Methods A prospective study was conducted to examine type 2 cytokines and epithelium-derived cytokines in the bronchial tissues by immunohistochemistry, Western blot and PCR analysis among patients with severe allergic asthma before and after omalizumab therapy. Results Fourteen of 23 patients with unstable severe allergic asthma improved their asthma control after 4 months of omalizumab treatment (Responders), while nine failed to improve (Non-Responders). Most of Responders were type 2-high endotype (12/14) with upregulated expression of IL-33, IL-25 and TSLP in their bronchial tissues, while most of Non-Responders were type 2-low endotype (8/9). Repeated bronchoscopic biopsy was done in nine responders after omalizumab treatment and showed a decline in IL-13, IL-33, IL-25 and TSLP expression in the bronchial tissues. Among 14 Responders who continued omalizuamb treatments to a total 12 months, six patients achieved a well control of asthma (ACT ≥ 23), while eight patients required additional treatment for asthma symptoms and had more rhinosinusitis comorbidities and a mixed eosinophilic and neutrophilic inflammation in their bronchial tissues. Conclusion Most of the severe allergic asthma patients who benefited from omalizumab treatment were IL-33, IL-25 and TSLP aggravated type 2-high endotype. Rhinosinusitis or with a mixed eosinophilic and neutrophilic airway inflammation should be evaluated in patients who partially responded to omalizumab treatment.

Background Patients with severe asthma have increased airway remodelling and elevated numbers of circulating fibrocytes with enhanced myofibroblastic differentiation capacity, despite being treated with high doses of corticosteroids, and long acting β2-adrenergic receptor (AR) agonists (LABAs). We determined the effect of β2-AR agonists, alone or in combination with corticosteroids, on fibrocyte function. Methods Non-adherent non-T cells from peripheral blood mononuclear cells isolated from healthy subjects and patients with non-severe or severe asthma were treated with the β2-AR agonist, salmeterol, in the presence or absence of the corticosteroid dexamethasone. The number of fibrocytes (collagen I+/CD45+ cells) and differentiating fibrocytes (α-smooth muscle actin+ cells), and the expression of CC chemokine receptor 7 and of β2-AR were determined using flow cytometry. The role of cyclic adenosine monophosphate (cAMP) was elucidated using the cAMP analogue 8-bromoadenosine 3′,5′-cyclic monophosphate (8-Br-cAMP) and the phosphodiesterase type IV (PDE4) inhibitor, rolipram. Results Salmeterol reduced the proliferation, myofibroblastic differentiation and CCR7 expression of fibrocytes from healthy subjects and non-severe asthma patients. Fibrocytes from severe asthma patients had a lower baseline surface β2-AR expression and were relatively insensitive to salmeterol but not to 8-Br-cAMP or rolipram. Dexamethasone increased β2-AR expression and enhanced the inhibitory effect of salmeterol on severe asthma fibrocyte differentiation. Conclusions Fibrocytes from patients with severe asthma are relatively insensitive to the inhibitory effects of salmeterol, an effect which is reversed by combination with corticosteroids.

Advanced non-small cell lung cancer (NSCLC) patients treated with chemotherapy experience functional decline and decreased quality of life. The purpose of this study was to evaluate the effects of a web-based health education program on global quality of life, quality of life-related functional dimensions, and symptom distress of initially diagnosed advanced non-small cell lung cancer patients. This study used a randomized, pre- and post-repeated measures design. A total of 55 participants were randomly assigned to an experimental group (n = 27) and a control group (n = 28). The experimental group participated in a web-based health education program, and the control group received usual care. Patients were assessed at 4 time points: baseline assessment (T0), and then 1, 2, and 3 months (T1, T2, and T3) after participating in the web-based health education program or receiving usual care. Patients in the experimental group had significantly greater global quality of life and emotional function, and significantly less top ten significant symptom distresses compared to those in the control group. There were no differences between the groups and within groups with respect to physical function, role function, cognitive function, and social function. The web-based health education can improve global quality of life, emotional function, and top ten significant symptom distresses in patients receiving chemotherapy during the first 3 months after initial diagnosis of advanced NSCLC. Web-based health education can improve quality of life and lessen distress of initially diagnosed NSCLC patients treated with chemotherapy.

Background Western medicine is an evidence-based science, whereas Chinese medicine is more of a healing art. To date, there has been no research that has examined whether students of Western and Chinese medicine differentially engage in, or benefit from, educational activities for narrative medicine. This study fills a gap in current literature with the aim of evaluating and comparing Western and Chinese Medicine students’ perceptions of narrative medicine as an approach to learning empathy and professionalism. Methods An initial 10-item questionnaire with a 5-point Likert scale was developed to assess fifth-year Western medical (MS) and traditional Chinese medical (TCMS) students’ perceptions of a 4-activity narrative medicine program during a 13-week internal medicine clerkship. Exploratory factor analysis was undertaken. Results The response rate was 88.6% (412/465), including 270 (65.5%) MSs and 142 (34.5%) TCMSs, with a large reliability (Cronbach alpha = 0.934). Three factors were extracted from 9 items: personal attitude, self-development/reflection, and emotional benefit, more favorable in terms of enhancement of self-development/reflection. The perceptions of narrative medicine by scores between the two groups were significantly higher in TCMSs than MSs in all 9-item questionnaire and 3 extracted factors. Conclusions Given the different learning cultures of medical education in which these student groups engage, this suggests that undertaking a course in Chinese medicine might enhance one’s acceptance to, and benefit from, a medical humanities course. Alternatively, Chinese medicine programmes might attract more humanities-focused students.

The heterogeneity of immune response to COVID-19 has been reported to correlate with disease severity and prognosis. While so, how the immune response progress along the period of viral RNA-shedding (VRS), which determines the infectiousness of disease, is yet to be elucidated. We aim to exhaustively evaluate the peripheral immune cells to expose the interplay of the immune system in uncomplicated COVID-19 cases with different VRS periods and dynamic changes of the immune cell profile in the prolonged cases. We prospectively recruited four uncomplicated COVID-19 patients and four healthy controls (HCs) and evaluated the immune cell profile throughout the disease course. Peripheral blood mononuclear cells (PBMCs) were collected and submitted to a multi-panel flowcytometric assay. CD19+-B cells were upregulated, while CD4, CD8, and NK cells were downregulated in prolonged VRS patients. Additionally, the pro-inflammatory-Th1 population showed downregulation, followed by improvement along the disease course, while the immunoregulatory cells showed upregulation with subsequent decline. COVID-19 patients with longer VRS expressed an immune profile comparable to those with severe disease, although they remained clinically stable. Further studies of immune signature in a larger cohort are warranted.

Shu-Chuan Ho,1,2 Jiun-Yi Wang,3,4 Han-Pin Kuo,5 Chien-Da Huang,5 Kang-Yun Lee,2,6 Hsiao-Chi Chuang,1,2 Po-Hao Feng,2,6 Tzu-Tao Chen,2,* Min-Fang Hsu7,* 1School of Respiratory Therapy, College of Medicine, 2Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 3Department of Healthcare Administration, Asia University, Wufeng, 4Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 5Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 6Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, 7Department of Nursing, Yuanpei University of Medical Technology, Hsinchu City, Taiwan *These authors contributed equally to this work Background: Chronic obstructive pulmonary disease (COPD) is currently the third most common cause of death in the world. Patients with COPD experience airflow obstruction, weight loss, skeletal muscle dysfunction, and comorbidities. Anthropometric indicators are risk factors for mortality in geriatric assessment. Purpose: This study examined and compared the associations of anthropometric indicators, such as low body mass index (BMI), low mid-arm circumference (MAC), and low calf circumference (CC), with the prediction of a 3-year follow-up mortality risk in patients with COPD. Methods: We recruited nonhospitalized patients with COPD without acute conditions from a general hospital in Taiwan. The BMI, MAC, and CC of all patients were measured, and they were followed for 3 years through telephone interviews and chart reviews. The Kaplan–Meier survival curves stratified by BMI, MAC, and CC were analyzed. Variables univariately associated with survival were entered into a multivariate Cox regression model. The Bayesian information criterion was used to compare the predictive ability of the three anthropometric indicators to predict mortality rate. Results: In total, 104 patients were included (mean ± standard deviation age, 74.2±6.9 years; forced expiratory volume in 1 second [%], 58.4±20.4 predicted; males, 94.2%); 22 patients (21.2%) died during the 36-month follow-up. During this long-term follow-up, the three anthropometric indicators could predict mortality risk in patients with COPD (low BMI [

A nocturnal temperature-controlled laminar airflow (TLA) has been shown to reduce allergen load during sleep, and improve life quality of poorly controlled allergic asthma. To determine whether TLA could improve clinical outcomes of allergic severe asthma after withdrawal of omalizumab, 23 patients with severe allergic asthma (SAA) who had been stabilized for at least 6 months with omalizumab treatment discontinued their omalizumab and were randomized (1:1) to receive TLA (n=12) or not (non-TLA, n=11) for 48 weeks. Patients experiencing acute asthma exacerbation during the study period were back to omalizumab treatment. The time to asthma exacerbations, lung function, asthma control test score (ACT) and exhaled nitric oxide (eNO) were recorded. 82% of patients in non-TLA group had asthma exacerbation after omalizumab withdrawal. In contrast, only 17% of TLA group had asthma exacerbation (P=0.0001, Fisher’s test). The median time to first acute exacerbation in non-TLA group was 88 days [Hazard ratio (HR) 9.26, 95% CI 3.10~38.47, p=0.0005] that was significantly shorter than TLA group (median 200 days, HR 0.11, 95% CI 0.01~0.31). 83% of patients in TLA group had no exacerbation, stable FEV1, ACT score and eNO levels throughout the study. Patients of non-TLA group had an increase in eNO levels and decline in FEV1 and ACT scores after omalizumab withdrawal. In conclusion, inhalant exposure reduction with TLA maintained a stable control of SAA after omalizumab withdrawal. TLA may be an alternative treatment option for patients with inadequately controlled SAA requiring add-on anti-IgE therapy.

Capnography involves the measurement of end-tidal CO2 (EtCO2) values to detect hypoventilation in patients undergoing sedation. In a previous study, we reported that initiating a flexible bronchoscopy (FB) examination only after detecting signs of hypoventilation could reduce the risk of hypoxemia without compromising the tolerance of the patient for this type of intervention. We hypothesize that hypoventilation status could be determined with greater precision by combining thoracic impedance-based respiratory signals, RESP, and EtCO2 signals obtained from a nasal-oral cannula. Retrospective analysis was conducted on RESP and EtCO2 waveforms obtained from patients during the induction of sedation using propofol for bronchoscopic examination in a previous study. EtCO2 waveforms associated with hypoventilation were then compared with RESP patterns, patient variables, and sedation outcomes. Signals suitable for analysis were obtained from 44 subjects, 42 of whom presented indications of hypoventilation, as determined by EtCO2 waveforms. Two subtypes of hypoventilation were identified by RESP: central-predominant (n = 22, flat line RESP pattern) and non-central-predominant (n = 20, RESP pattern indicative of respiratory effort with upper airway collapse). Compared to cases of non-central-predominant hypoventilation, those presenting central-predominant hypoventilation during induction were associated with a lower propofol dose (40.2 ± 18.3 vs. 60.8 ± 26.1 mg, p = 0.009), a lower effect site concentration of propofol (2.02 ± 0.33 vs. 2.38 ± 0.44 µg/ml, p = 0.01), more rapid induction (146.1 ± 105.5 vs. 260.9 ± 156.2 s, p = 0.01), and lower total propofol dosage (96.6 ± 41.7 vs. 130.6 ± 53.4 mg, p = 0.04). Hypoventilation status (as revealed by EtCO2 levels) could be further classified by RESP into central-predominant or non-central-predominant types. It appears that patients with central-predominant hypoventilation are more sensitive to propofol during the induction of sedation. RESP values could be used to tailor sedation management specifically to individual patients.

Chun-Yu Lo,1 Hung-Yu Huang,1 Jung-Ru He,1 Tzu-Ting Huang,1 Chih-Chen Heh,1 Te-Fang Sheng,1 Kian Fan Chung,2 Han-Pin Kuo,1 Chun-Hua Wang1 1Department of Thoracic Medicine, Chang Gung Medical Foundation, College of Medicine, Chang Gung University, Taipei, Taiwan; 2Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK Background: Airway hyperresponsiveness (AHR) is associated with airway inflammation and a rapid decline in lung function and is a predictor of future risk of COPD among smokers. Alveolar macrophages (AMs) from patients with COPD release a greater amount of matrix metalloproteinase (MMP)-9. We hypothesized that the imbalance between MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) is related to AHR in smokers.Patients and methods: Healthy smokers with AHR (AHR + S) or smokers without AHR (AHR - S; divided according to a methacholine challenge test) and nonsmokers without AHR (AHR - NS) were enrolled. Spirometry was performed during enrollment and repeated after 5years. Initially, AMs recovered from bronchoalveolar lavage (BAL) fluid were cultured in the presence of p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580), MAPK kinase (MEK) 1/2 (the MEK of extracellular signal-regulated kinase [ERK] inhibitor, PD98059), or medium alone for 24h. The release of MMP-9 and TIMP-1 in culture supernatants was measured by enzyme-linked immunosorbent assay.Results: A greater reduction in forced expiratory volume in 1s (FEV1)/forced vital capacity (FVC), FEV1 (as a percentage of the predicted value [%pred]), and maximal mid-expiratory flow (MMEF) was observed among AHR + S in the 5-year period. There was a higher proportion of neutrophils and a lower proportion of AMs in BAL fluid recovered from AHR + S. Compared to AMs from AHR - NS and AHR - S, AMs from nonsmokers with AHR (AHR + NS) released more MMP-9 and less TIMP-1, with an increase in MMP-9/TIMP-1 ratios. The MMP-9/TIMP-1 ratio in smokers was positively correlated with the annual decline in FEV1%pred, FVC%pred, and MMEF%pred. Both SB203580 and PD98059 significantly reduced MMP-9, but not TIMP-1, from AMs of smokers.Conclusion: AMs of AHR + NS produce excessive MMP-9 over TIMP-1, which may be a predictor of the development of airway obstruction. Inhibition of p38 MAPK and ERK suppresses the generation of MMP-9 by AMs from smokers. Keywords: smoking, airway hyperresponsiveness, alveolar macrophage, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase&nbsp

Objective:To evaluate the effect of sedation depth on drug-induced sleep endoscopy (DISE).Methods:Ninety patients with obstructive sleep apnea (OSA) and 18 snorers underwent polysomnography and DIS...

Non-cystic fibrosis bronchiectasis (NCFBr) characterized by parenchymal destruction and ventilation/perfusion mismatch may cause hypoxia. Hypoxia strongly stimulates osteoclast-mediated bone resorption. We examined whether desaturation during 6 minute walk test (6MWT) was associated with increased osteoporosis and hospitalization in NCFBr. We enrolled 49 NCFBr and measured FEV 1 , 6MWT, and oxygen saturation by pulse oximetry (SpO 2 ) during 6MWT at baseline and every 3-6 moths for 5 years. Desaturation group was defined as a fall in SpO 2 ≥10% or NCFBr with desaturation group (n=34) had higher CT scores, lower FEV 1 and less walking distance. T score was significantly decreased in desaturation group (-3.7±1.1) compared to non-desaturation group (-2.2±0.7, p 2 (r= 0.46; p Non-cystic bronchiectasis patients with desaturation during 6MWT, who had lower FEV 1 and higher disease severity, were associated with accelerated osteoporosis and increased frequency of hospitalization.

Although the prevalence of both obstructive sleep apnoea (OSA) and asthma are both increasing, little is known about the impact of OSA on the natural history of lung function in asthmatic patients. A total of 466 patients from our sleep laboratory were retrospectively enrolled. Of them, 77 patients (16.5%) had asthma with regular follow-up for more than 5 years. Their clinical characteristics, pulmonary function, emergency room visits, and results of polysomnography results were analysed. The patients were divided into three groups according to the severity of the apnoea-hypopnea index (AHI). The decline in FEV1 among asthma patients with severe OSA (AHI > 30/h) was 72.4 ± 61.7 ml/year (N = 34), as compared to 41.9 ± 45.3 ml/year (N = 33, P = 0.020) in those with mild to moderate OSA (5

Multiple mechanisms of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been identified in EGFR-mutant non-small cell lung cancer (NSCLC); however, recurrent resistance to EGFR TKIs due to the heterogeneous mechanisms underlying resistance within a single patient remains a major challenge in the clinic. Here, we report a role of nuclear protein kinase Cδ (PKCδ) as a common axis across multiple known TKI-resistance mechanisms. Specifically, we demonstrate that TKI-inactivated EGFR dimerizes with other membrane receptors implicated in TKI resistance to promote PKCδ nuclear translocation. Moreover, the level of nuclear PKCδ is associated with TKI response in patients. The combined inhibition of PKCδ and EGFR induces marked regression of resistant NSCLC tumors with EGFR mutations.

Isolated intrathoracic lymphadenopathy (IT-LAP) is clinically challenging because of the difficult anatomic location and wide range of associated diseases, including tuberculosis (TB). Although sampling via endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for histopathology is a major development, there is still room for improvement. This study aimed to investigate an algorithmic approach driven by EBUS-TBNA and conventional bronchoscopy to streamline the management of IT-LAP. Methods: Eighty-three prospectively enrolled patients with IT-LAP were subjected to an EBUS-TBNA diagnostic panel test (histopathology, cytology, and microbiology) and underwent conventional bronchoscopy for bronchoalveolar lavage. The results were structured into an algorithmic approach to direct patient treatment, workup, or follow-up. Results: The diagnostic yields of EBUS-TBNA based on histopathology were similar for each disease entity: 77.8% for malignancy, 70.0% for TB, 75.0% for sarcoidosis, 80.0% for anthracosis, and 70.0% for lymphoid hyperplasia (p = 0.96). The incidence of malignancy was 10.8% for total IT-LAP patients, and 12.0% and 33.7% for patients with TB and sarcoidosis, respectively. Thirty-five (42.2%) patients were symptomatic. The leading diagnosis was sarcoidosis (60%), followed by TB (20%), malignancy (11.4%), lymphoid hyperplasia (5.7%), and anthracosis (2.9%). By logistic regression analysis, granulomatous disease (odds ratio: 13.45; 95% confidence interval: 4.45–40.67, p

Severe H1N1 pneumonia with acute respiratory failure results in infiltration of lungs due to the presence of hyperactive immune cells. Rapamycin and corticosteroids inhibit this immune response by blocking the activation of T and B cells.Open-label prospective randomized controlled trial.A tertiary medical center, Chang Gung Memorial Hospital, located in Taiwan.Between 2009 and 2011, of 4,012 H1N1-infected patients, 38 patients with severe H1N1 pneumonia and acute respiratory failure were enrolled.Thirty-eight patients with confirmed H1N1 pneumonia and on mechanical ventilatory support were randomized to receive adjuvant treatment of corticosteroids with an mTOR inhibitor, either with sirolimus (Rapamune 2 mg/d) (sirolimus group, n = 19) for 14 days or without sirolimus (nonsirolimus group, n = 19). The clinical values measured included PaO2/FIO2, Sequential Organ Failure Assessment score, duration of ventilatory support, and mortality. The baseline demography was similar between the two groups. After treatment, the PaO2/FIO2 values on day 3 (167.5 [95% CI, 86.7-209.2 mm Hg], n = 19 vs 106.8 [95% CI, 73.0-140.7 mm Hg], n = 19; p = 0.025] and day 7 (241.6 [95% CI, 185.2-297.9 mm Hg], n = 19 vs 147.0 [95% CI, 100.7-193.7 mm Hg], n = 17; p = 0.008) in the sirolimus group were significantly better over the nonsirolimus group. Similarly, the Sequential Organ Failure Assessment score on day 3 (4.3 [95% CI, 3.1-5.5]; p = 0.029) and day 7 (5.9 [95% CI, 4.8-6.9], n = 19 and 6.2 [95% CI, 4.7-7.8], n = 17, respectively) significantly improved in the sirolimus group. The liberation from a mechanical ventilator at 3 months was also better in the sirolimus combined with corticosteroids treatment. Similarly, the duration of ventilator use was significantly shorter in the sirolimus group (median, 7 vs 15 d; p = 0.03 by log-rank test). In the sirolimus combined with corticosteroids treatment group, a rapid clearance of virus also occurred after 7 days of treatment.In patients with severe H1N1 pneumonia, early adjuvant treatment with corticosteroids and an mTOR inhibitor was associated with improvement in outcomes, such as hypoxia, multiple organ dysfunction, virus clearance, and shortened liberation of ventilator and ventilator days.

International audience; Severe sepsis and septic shock are major causes of morbidity and mortality in patients entering the emergency department (ED) or intensive care unit (ICU). Despite substantial efforts to improve patient outcome, treatment of sepsis remains challenging to clinicians. In this context, early goal directed therapy (EGDT) represents an important concept emphasizing both early recognition of sepsis and prompt initiation of a structured treatment algorithm. As part of the AME evidence series on sepsis, we conducted a systematic review of all randomized controlled EGDT trials. Focus was laid on the setting (emergency department versus ICU) where EGDT was carried out. Early recognition of sepsis, through clinical or automated systems for early alert, together with well-timed initiation of the recommended therapy bundles may improve patients' outcome. However, the original ``EGDT'' protocol by Rivers and coworkers has been largely modified in subsequent trials. Currently, many investigators opt for an ``expanded'' EGDT (as suggested by the Surviving Sepsis Campaign). Evidence is also presented on the effectiveness of automated systems for early sepsis alert. Early recognition of sepsis and well-timed initiation of the SSC bundle may improve patient outcome.

Coexistence of chronic rhinosinusitis (CRS) with asthma appears to impair asthma control. Type-2 innate lymphoid cells (ILC2s) respond to the cytokines of thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 and IL-33, thus contributing to airway diseases such as CRS and asthma. We investigate whether the augmented Th2-cytokines in CRS might be related to sinonasal tract ILC2s corresponding to enhanced IL-25, IL-33 and TSLP release in severe asthmatics, and be involved in asthma control. Twenty-eight asthmatics (12 non-severe and 16 severe) with CRS receiving nasal surgery were enrolled. The predicted FEV1 inversely associated with CRS severity of CT or endoscopy scores. Higher expression of Th2-driven cytokines (IL-4, IL-5, IL-9, and IL-13), TSLP, IL-25 and IL-33 in nasal tissues was observed in severe asthma. Severe asthmatics had higher ILC2 cell counts in their nasal tissues. ILC2 counts were positively correlated with Th2-cytokines. Nasal surgery significantly improved asthma control and lung function decline in severe asthma and CRS. The higher expression of IL-33/ILC2 axis-directed type 2 immune responses in nasal tissue of CRS brought the greater decline of lung function in severe asthma. ILC2-induced the upregulated activity of Th2-related cytokines in asthmatics with CRS may contribute to a recalcitrant status of asthma control.

Objectives: To present the complications of Ultraflex Self-Expandable Metallic Stents (SEMSs) applied in patients with benign tracheobronchial diseases. Methods: Eighty patients received 124 SEMSs were retrospectively reviewed in a tertiary hospital. Results: The baseline characteristics of patients received SEMS implantation including age (mean + standard deviation: 62.5 + 14.8 years), gender (male, 60.5%), smoking (46.8%), forced expiratory volume in first one second (FEV1) (mean + standard deviation, 0.92 +0.41 L/s), follow-up days after SEMS implantation (median (interquartile range); 457 (131 - 897)) and covered SEMS (33.9%) were listed. Symptoms improved after SEMS implantation among 95 patients (76.6%). Time to complications developed was 236 (median; interquartile range, 59 - 672) days. The overall complication rate was 41.9% after SEMS implantation. The complications included SEMS migration (6.5%), granuloma (19.3%) and SEMS fracture (16.1%). Successful management rates of SEMS migration, granuloma and SEMS fracture were up to 100%, 83.3%, and 85% respectively. Conclusions: Patients received SEMS implantation due to benign conditions had poor lung function and were old. The complication rate in patients with benign conditions was high after longer follow-up period, however, successful management achieved in most patients with complications.

Yeon-Mok Oh,1 Arvind B Bhome,2 Watchara Boonsawat,3 Kirthi Dias Gunasekera,4 Dushantha Madegedara,5 Luisito Idolor,6 Camilo Roa,6 Woo Jin Kim,7 Han-Pin Kuo,8 Chun-Hua Wang,8 Le Thi Tuyet Lan,9 Li-Cher Loh,10 Choo-Khoon Ong,10 Alan Ng,11 Masaharu Nishimura,12 Hironi Makita,12 Edwin K Silverman,13 Jae Seung Lee,1 Ting Yang,14 Yingxiang Lin,14 Chen Wang,14 Sang-Do Lee1 1Department of Pulmonary and Critical Care Medicine and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 2Department of Pulmonary and Critical Care, "Friends of the Breathless" Foundation, Pune, India; 3Department of Medicine, Khon Kaen University, Khon Kaen, Thailand; 4Central Chest Clinic, Colombo and National Hospital of Sri Lanka; 5Respiratory Disease Treatment Unit and Teaching Hospital Kandy, Sri Lanka; 6Section of Respiratory Services and Physical Therapy and Rehabilitation Lung Center of the Philippines, Quezon City, Philippines; 7Department of Internal Medicine, Kangwon National University, Kang Won, Korea; 8Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan; 9Respiratory Care Center, University Medical Center Ho Chi Minh City, Vietnam; 10Department of Medicine, Penang Medical College, Penang, Malaysia; 11Department of Respiratory and Critical Care Medicine, Tan Tock Seng Hospital, Singapore; 12Division of Respiratory Medicine, Department of Internal Medicine, Hokkaido University Hospital, Sapporo, Japan; 13Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; 14Beijing Institute of Respiratory Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, ChinaAll authors made an equal contribution to this studyBackground and objectives: Chronic obstructive pulmonary disease (COPD) is responsible for significant morbidity and mortality worldwide. We evaluated the characteristics of stable COPD patients in the pulmonology clinics of seven Asian cities and also evaluated whether the exposure to biomass fuels and dusty jobs were related to respiratory symptoms, airflow limitation, and quality of life in the COPD patients.Methods: This cross-sectional observational study recruited 922 COPD patients from seven cities of Asia. The patients underwent spirometry and were administered questionnaires about their exposure to cigarette smoking, biomass fuels, and dusty jobs in addition to respiratory symptoms and health related quality of life.Results: Of the patients, there appeared to be variations from city to city in the history of exposure to biomass fuels and dusty jobs and also in respiratory symptoms of cough, phlegm, wheeze, and dyspnea. These symptoms were more frequent in those COPD patients with a history of exposure to biomass fuels than without and those with a history of exposure to dusty jobs than without (P < 0.01 for all comparisons). Airflow limitation was more severe in those COPD patients with a history of exposure to biomass fuels than without (52.2% predicted versus 55.9% of post-bronchodilator forced expiratory volume in 1 second [FEV1], P = 0.009); quality of life was poorer in those with exposure to biomass fuels than without (40.4 versus 36.2 of the St George's Respiratory Questionnaire [SGRQ] total score, P = 0.001). Airflow limitation was more severe in those COPD patients with a history of exposure to dusty jobs than without (51.2% predicted versus 57.3% of post-bronchodilator FEV1, P < 0.001); quality of life was poorer in those with dusty jobs than without (41.0 versus 34.6 of SGRQ score, P = 0.006).Conclusion: In Asian cities, the characteristics of COPD patients vary and the history of exposure to biomass fuels or dusty jobs was related to frequency of symptoms, severe airflow limitation, and poor quality of life.Keywords: COPD, Asia, biomass, dust

Background: Circulating fibrocytes play an important role in airway remodeling of asthma, partly through up-regulation of endothelin A receptor (ET A R) to mediate connective tissue growth factor (CTGF) induced growth and differentiation. Asthmatics with severe obstructive sleep apnea (OSA) have accelerated decline in pulmonary function. We hypothesize asthmatics with severe OSA may have increased circulating fibrocytes and up-regulated ET A R expression. Methods: Circulating fibrocytes, identified by co-expression of CD34, CD45 and collagen I, from 13 asthmatic patients with severe OSA and 11 asthmatics without OSA were measured their proliferation and differentiation capacity. ET A R and α-smooth muscle actin (α-SMA) expression on fibrocytes were determined by flowcytometry. Measurements and Main Results: Asthmatics with severe OSA had higher number and ET A R expression of circulating fibrocytes than asthmatics without OSA. The yearly decline in FEV1 correlated with the number of circulating fibrocytes (R 2 = 0.337). After being cultured, fibrocytes from asthmatics with OSA increased proliferation and differentiation than those from asthmatics without OSA. ET A R antagonist (BQ123) and anti-CTGF antibody significantly reduced fibrocytes from asthmatics with OSA differentiation into α-SMA + myofibroblasts. Conclusions: Circulating fibrocytes are increased in asthmatics with severe OSA, resulting in higher proliferation and differentiation through up-regulated ET A R expression. Circulating fibrocytes may contribute to airway remodeling in asthmatics with OSA.

Heat shock proteins (HSPs) have been shown to modulate NF-κB activation. It is unknown whether HSP70 plays a role in modulating NF-κB-mediated pro-inflammatory cytokines released from alveolar macrophage (AM) of patients with active pulmonary tuberculosis (TB). Peripheral blood monocytes (PBMs) and AM were sampled from nineteen active TB patients and 14 healthy individuals. HSP70 expression was 3-fold higher in AMs of active TB patients than normal subjects, and declined after receiving 3-month anti-TB treatment. Overexpression of HSP70 by transfection with HSP70 plasmid decreased p-IκBα and p65 NF-κB activities. Inhibition of NF-κB activation using NF-κB or MAPK inhibitors increased HSP70 expression in AM of TB patients. Blocking p38- or ERK-MAPK decreased NF-κB and IκB activities, leading to up-regulated HSP70 expression. Overexpression of HSP70 alone or with p38 or ERK inhibitors decreased TNF-α (57%, 83% and 74%, respectively) and IL-6 (53%, 70%, and 67%, respectively) release from macrophages of TB patients. In conclusion, HSP70 modulates NF-κB activation in AM of TB patients, through inhibiting IκB-α phosphorylation or acting as a chaperon molecule to prevent NF-κB binding to the target genes by facilitating degradation. The upregulated HSP70 may suppress the release of pro-inflammatory cytokines during active PTB infection, and prevent overwhelming tissue damage.

Asthmatic patients with fixed airway obstruction (FAO) and patients with chronic obstructive pulmonary disease (COPD) share similarities in terms of irreversible pulmonary function impairment. Exhaled nitric oxide (eNO) has been documented as a marker of airway inflammation in asthma, but not in COPD. To examine whether the basal eNO level and the change after exercise may differentiate asthmatics with FAO from COPD, 27 normal subjects, 60 stable asthmatics, and 62 stable COPD patients were studied. Asthmatics with FAO (n = 29) were defined as showing a postbronchodilator FEV1/forced vital capacity (FVC) ≤70% and FEV1 less than 80% predicted after inhaled salbutamol (400 μg). COPD with dynamic hyperinflation (n = 31) was defined as a decrease in inspiratory capacity (ΔIC%) after a 6 minute walk test (6MWT). Basal levels of eNO were significantly higher in asthmatics and COPD patients compared to normal subjects. The changes in eNO after 6MWT were negatively correlated with the percent change in IC (r = −0.380, n = 29, P = 0.042) in asthmatics with FAO. Their levels of basal eNO correlated with the maximum mid-expiratory flow (MMEF % predicted) before and after 6MWT. In COPD patients with air-trapping, the percent change of eNO was positively correlated to ΔIC% (rs = 0.404, n = 31, P = 0.024). We conclude that asthma with FAO may represent residual inflammation in the airways, while dynamic hyperinflation in COPD may retain NO in the distal airspace. eNO changes after 6MWT may differentiate the subgroups of asthma or COPD patients and will help toward delivery of individualized therapy for airflow obstruction.

Rationale: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T-cell immunity in tumor-bearing hosts. Their clinical relevance remains unclear.Objectives: To identify subtypes of myeloid-derived suppressor cells in patients with non–small cell lung cancer (NSCLC) and their clinical relevance.Methods: CD11b+CD14− and CD11b+CD14+ cells, determined and phenotyped by fluorescence-activated cell sorter analysis, in the peripheral blood mononuclear cells (PBMCs) of treatment-naive patients with advanced NSCLC were correlated with clinical data. T-cell activation in response to CD3/CD28 costimulation was determined by carboxy-fluorescein diacetate succinimidyl ester (CFSE) staining and ELISA analysis of IFN-γ. The percentage of CD11b+CD14+S100A9+ cells in PBMCs was correlated with and tested as a predictor for treatment response in a cohort of patients prospectively receiving first-line cisplatin-based chemotherapy.Measurements and Main Results: Patients with NSCLC...

Background: High-resolution computed tomography (HRCT) has allowed in detection of airway wall abnormalities and emphysema, whose extent may correlate with the clinical severity of the disease in patients with chronic obstructive pulmonary disease (COPD). Six minute walk test (6MWT) and cardiopulmonary exercise test (CPET) can determine functional status. Methods: A study was undertaken to investigate whether the extent of emphysema in COPD patients quantitatively confirmed by HRCT scoring was associated with distance walked, inspiratory capacity (IC) changes after exercise, anaerobic threshold of cardiopulmonary exercise and the BODE index (body mass index, airflow obstruction, dyspnea, exercise performance). Results: Seventeen patients with COPD underwent HRCT scanning, 6MWT and CPET. The emphysema score was highly correlated to forced vital capacity (FVC) (r=-0.748, p

Introduction Esophagorespiratory fistula (ERF) caused by esophageal cancer has a poor prognosis. This study describes the clinical effects of airway ultraflex stenting as an alternative method for ERF caused by esophageal cancer. Methods In an university-affiliated hospital, consecutive patients with ERF caused by esophageal cancer and confirmed by bronchoscopy were included. The demography, clinical manifestations and survival between groups with and without airway stenting were compared by case-control study. Results From 2001 to 2007, 817 patients with esophageal cancer received bronchoscopy. Among these patients, 59 patients with ERF were included in this study. The demography and clinical manifestations between groups with and without airway stenting were similar, but survival improved in group with airway stenting, which was compared using log-rank test [ P = 0.04; hazard ratio, 0.56; 95% confidence interval (CI), 0.31–0.99]. After adjusted with age and gender by multinominal logistic regression, airway stenting [adjusted odds ratio (OR), 5.2; P = 0.01; 95% CI, 1.4–18.8], performance status (adjusted OR, 6.1; P = 0.004; 95% CI, 1.8–20.8), further treatment (adjusted OR, 8.7; P = 0.001; 95% CI, 2.3–32.8) and prolonged pneumonia (adjusted OR, 0.14; P = 0.008; 95% CI, 0.03–0.59) remained as significant factors that impacted survival. Conclusions Surgical treatment remains the first choice in patients with esophageal cancer with ERF; however, the authors provided an alternative airway stenting for those patients whom surgery is unsuitable. It improved survival in the group with airway stenting than those without. Performance status improvement and further treatment for esophageal cancer may improve survival, but prolonged pneumonia may worsen survival.

Background: Endobronchial ultrasound-guided transbronchial aspiration (EBUS-TBNA) has the potential to improve nodal diagnosis and staging in non–small cell lung cancer (NSCLC). This study was performed to explore the roles of EBUS-TBNA in NSCLC. Methods: From 2007 to 2009, 164 NSCLC patients were examined by EBUS-TBNA. The patients were divided into a diagnosis group (n = 64) and a staging group (n = 100). Results: For all patients, the diagnostic sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 92.3%, 100%, 100%, 88.2%, and 95.1%, respectively. In the diagnosis group, the diagnostic sensitivity, specificity, PPV, NPV, and accuracy were 89.7%, 100%, 100%, 86.2%, and 94.4%, respectively. Thirty five patients (54.7%) positive for malignancy as determined by EBUS-TBNA avoided surgery. In the staging group, the diagnostic sensitivity, specificity, PPV, NPV, accuracy, and surgery avoidance rate were 93.8%, 100%, 100%, 89.7%, 96%, and 61%, respectively. Conclusions: EBUS-TBNA is a feasible and effective tool for NSCLC diagnosis and staging that also reduces surgery rates. Patients with NSCLC should initially undergo the less invasive EBUS-TBNA procedure for diagnosis and staging of NSCLC. However, negative findings must be confirmed by surgery.

Introduction Despite removal of airway metallic stents by rigid bronchoscope was presented, there are few reports describing such removal by flexible bronchoscope. Methods 36 patients who had airway Ultraflex stents removed by flexible bronchoscope from 2002 to 2009 were reviewed. Factors contributing to removal method and complications during and after removal were analyzed by multinomial logistic regression. Results Among 36 patients with stent extraction; 17 stents (47.2%) were removed by a single procedure and 19 (52.8%) by multiple procedures. There was no mortality or severe morbidity during or after stent removal. There were 21 complications after stent removal, including retained stent pieces (n = 9), mucosal tear with bleeding (n = 5), and re-obstruction requiring silicone stent placement (n = 7). Stent indwelling time > 10 months (adjusted odds ratio: 9.5; 95% confidence interval: 7.9–11.1, P=0.01), obstructive granulation tissue formation before stent removal (adjusted odds ratio: 5.2; 95% confidence interval: 2.2–8.6, P=0.01), and stent fracture before removal (adjusted odds ratio: 3.5; 95% confidence interval: 1.8–15.4, P=0.04) were independent predictors of the need for multiple procedures for stent removal. Stent indwelling time > 10 months (adjusted odds ratio: 4.2; 95% confidence interval: 2.1–8.9, P=0.01), obstructive granulation tissue formation before stent removal (adjusted odds ratio: 16.5; 95% confidence interval, 1.8–49.6, P=0.01), and multiple procedures required for removal (adjusted odds ratio: 6.9; 95% confidence interval, 1.1–43.5, P=0.04) were independent predictors of removal complications. Conclusions A flexible bronchoscope can be used to remove stents in patients with central airway obstruction and stent-related complications. This procedure should be performed in centers with experienced multidisciplinary teams.

Our study investigated whether tumor-associated macrophages (TAMs) in advanced non-small cell lung cancer (NSCLC) are related to treatment response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and may be a predictor of survival. Of 206 advanced NSCLC patients treated (first-line) with an EGFR-TKI at the study hospital from 2006 to 2009, 107 with adequate specimens for assessing CD68 immunohistochemistry as a marker of TAMs were assessed. After EGFR-TKI treatment, response was observed in 55 (51%) patients, and the median follow-up period was 13.5 months. Most TAMs were located in the tumor stroma (>95%) and positively costained with the M2 marker CD163. TAM counts were significantly higher in patients with progressive disease than in those without (p < 0.0001), a trend that remained in patients with known EGFR mutation status (n = 59) and those with wild-type EGFR (n = 20). High TAM counts, among other factors (e.g., wild-type EGFR), were significantly related to poor progression-free survival (PFS) and overall survival (OS) (all p < 0.0001 for TAMs). Multivariate Cox analyses showed that high TAM counts and EGFR mutations were both independent factors associated with PFS [odds ratio (OR), 8.0; 95% confidence interval (CI), 2.87-22.4; p = 0.0001 and OR, 0.03; 95% CI, 0.003-0.31; p = 0.003, respectively] and OS (OR, 2.641; 95% CI, 1.08-6.5; p = 0.03 and OR, 0.14; 95% CI, 0.03-0.56; p = 0.006, respectively). TAMs are related to treatment response irrespective of EGFR mutation and can independently predict survival in advanced NSCLC treated with an EGFR-TKI.

Background and objective: Roflumilast, an oral, selective phosphodiesterase 4 inhibitor, has been shown to reduce exacerbations and improve pulmonary function in patients with COPD. This study examined the efficacy, safety and tolerability of roflumilast in Asian patients with COPD. Methods: Patients with COPD were randomized 1:1 to enter a 12-week treatment period and receive either oral roflumilast, 500 µg once daily, or placebo, following a single-blind, 4-week baseline period in which all patients received placebo. The primary end point was mean change in FEV1 from baseline to each postrandomization visit during the treatment period. Other spirometric lung function measurements were evaluated as secondary end points. COPD exacerbations were monitored. Safety was assessed from clinical laboratory tests, vital signs, physical examination (including electrocardiogram) and monitoring of adverse events (AEs). Results: Of 551 patients recruited, 410 were randomized and received at least one dose of study medication (roflumilast, n = 203; placebo, n = 207). Superiority of roflumilast over placebo was demonstrated by a statistically significant difference in postbronchodilator FEV1 (79 mL, P

Background and objective: Studies in respiratory diseases other than chronic obstructive pulmonary disease suggest potentially differing responses to medications among patients from different regions. We report a subgroup analysis of patients recruited to Asian centres from a previously reported 4-year COPD trial. Methods: Subgroup analysis from a randomized, double-blinded, placebo-controlled trial of tiotropium 18 µg daily in COPD. Primary end-point was rate of decline in FEV1. Secondary end-points included spirometry at individual time points, health-related quality of life (St George's Respiratory Questionnaire), exacerbations and mortality. Results: Of 5992 patients, 362 were from Asian centres (100 from Japan). Mean age 66 years, 95% men, 13% current smokers, BMI: 21 kg/m2; post-bronchodilator FEV1: 44% predicted; St George's Respiratory Questionnaire total score: 44 units. No treatment effect was observed for rate of decline in FEV1 although annual decline was less in Asian patients. Morning pre-bronchodilator FEV1 and forced vital capacity improved in Asian patients (P

ObjectiveSelf-expandable metallic stents are used to relieve airway stenosis in selected patients; however, fracture of these stents may occur. This analysis aims to investigate the extent of tracheal torsion, assessed by a computed-generated reformatted 3-dimensional tracheal reconstruction from 2-dimensional computed tomographic images in predicting fracture of tracheal self-expandable metallic stents.MethodsFrom 2001 to 2007, 32 patients (aged 62.8 ± 14.1 years) with benign tracheal diseases received chest computed tomographic evaluation and Ultraflex (Boston Scientific, Natick, Mass) self-expandable metallic stents. The bending angles of the central axis and peripheral wall of the trachea at choke point were measured from the computed-generated 3-dimensional tracheal images.ResultsSeventeen fractured stents were found among the patients. The median time for stent fracture was 865 days after implantation. Receiver operating characteristic curve analysis revealed that a 19° bending angle of the tracheal central axis (area under the curve, 0.929; 95% confidence interval, 0.847–1.012; P

Introduction Infection is a frequent cause of death in patients with systemic lupus erythematous (SLE) admitted to the intensive care unit (ICU). Complicated clinical features of SLE patients may delay or cause inadequate antimicrobial treatment. This study aimed to determine if inadequate antimicrobial treatment is an independent risk factor for mortality in SLE patients in the ICU. Methods Fifty-eight SLE patients admitted to the ICU were evaluated in a retrospective analysis. Inadequate antimicrobial treatment was defined by patient receiving antibiotics ≥24hours after the diagnostic criteria for nosocomial infection and/or the identified microorganism did not exhibit in vitro sensitivity to the antibiotics administered in the ICU. Results Multivariate logistic regression analysis identified the risk factors. Thirty-three (56.9%) SLE patients died during their ICU stay. The nonsurvivor group (n=33), exhibited lower platelet count ( P =0.025), prolonged hospital stay before ICU admission ( P =0.015), higher Acute Physiology and Chronic Health Evaluation II score ( P =0.015), and higher prevalence of multiple organ failure ( P =0.044) and inadequate antimicrobial treatment ( P =0.002) compared with the survivor group (n=25). In multivariate logistic regression analysis, inadequate antimicrobial treatment was the most significant factor for mortality (odds ratio=12.02, 95% confidence interval=1.24–116.10, P =0.032). Patients with prolonged hospitalization prior ICU admission had a mild risk for mortality (odds ratio=1.06, 95% confidence interval=1.00–1.12, P =0.045). Conclusions SLE patients in the ICU receiving inadequate antimicrobial treatment or with prior prolonged hospital stay have a higher risk of mortality. Clinical efforts should ensure adequate antimicrobial treatment in SLE patients with prior prolonged hospital stay before ICU admission.