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Alterations of cognitive functions have been described in COPD. Our study aimed to disentangle the relationship between the degree of cognitive function and COPD characteristics including quality of life (QoL).Data from 1969 COPD patients of the COSYCONET cohort (GOLD grades 1–4; 1216 male/ 753 female; mean (SD) age 64.9 ± 8.4 years) were analysed using regression and path analysis. The DemTect screening tool was used to measure cognitive function, and the St. George‘s respiratory questionnaire (SGRQ) to assess disease-specific QoL.DemTect scores were =60 years of age. For statistical reasons, we used the average of both algorithms independent of age in all subsequent analyses. The DemTect scores were associated with oxygen content, 6-min-walking distance (6-MWD), C-reactive protein (CRP), modified Medical Research Council dyspnoea scale (mMRC) and the SGRQ impact score. Conversely, the SGRQ impact score was independently associated with 6-MWD, FVC, mMRC and DemTect. These results were combined into a path analysis model to account for direct and indirect effects. The DemTect score had a small, but independent impact on QoL, irrespective of the inclusion of COPD-specific influencing factors or a diagnosis of cognitive impairment.We conclude that in patients with stable COPD lower oxygen content of blood as a measure of peripheral oxygen supply, lower exercise capacity in terms of 6-MWD, and higher CRP levels were associated with reduced cognitive capacity. Furthermore, a reduction in cognitive capacity was associated with reduced disease-specific quality of life. As a potential clinical implication of this work, we suggest to screen especially patients with low oxygen content and low 6-MWD for cognitive impairment.

Background: The coronavirus disease (COVID-19) can manifest in a range of symptoms, including both asymptomatic systems which appear nearly non-existent to the patient, all the way to the development of acute respiratory distress syndrome (ARDS). Specifically, COVID-19-associated pneumonia develops into ARDS due to the rapid progression of hypoxia, and although arterial blood gas analysis can assist in halting this deterioration, the current environment provided by the COVID-19 pandemic, which has led to an overall lack of medical resources or equipment, has made it difficult to administer such tests in a widespread manner. As a result, this study was conducted in order to determine whether the levels of oxygen saturation (SpO2) and the fraction of inhaled oxygen (FiO2) (SF ratio) can also serve as predictors of ARDS and the patient’s risk of mortality. Methods: This was a retrospective cohort study conducted from February 2020 to Mary 2020, with the study’s subjects consisting of COVID-19 pneumonia patients who had reached a state of deterioration that required the use of oxygen therapy. Of the 100 COVID-19 pneumonia cases, we compared 59 pneumonia patients who required oxygen therapy, divided into ARDS and non-ARDS pneumonia patients who required oxygen, and then investigated the different factors which affected their mortality. Results: At the time of admission, the ratios of SpO2, FiO2, and SF for the ARDS group differed significantly from those of the non-ARDS pneumonia support group who required oxygen (p

Background: Radiotherapy is a common treatment option for lung or esophageal cancer, particularly when surgery is not feasible for patients with poor lung function. However, radiotherapy can affect pulmonary function and thereby induce pneumonitis or pneumonia, which can be fatal in patients with respiratory impairment. The purpose of this study is to evaluate if reductions in pulmonary function after radiotherapy can be minimized through simultaneous pulmonary rehabilitation (PR). Methods: In this matched case control study, we retrospectively analyzed patients who had undergone radiotherapy for thoracic malignant disease between January 2018 and June 2019. We analyzed results from pulmonary function tests and 6-minute walking tests (6MWT) conducted within the six months before and after radiotherapy treatment. Results: In total, results from 144 patients were analyzed, with 11 of the patients receiving PR and radiotherapy simultaneously. Of the 133 patients in the control group, 33 were matched with 11 patients in the PR group. Changes in forced expiratory volume in one second (FEV1) and FEV1/forced vital capacity were significantly different between the PR group and the matched control group (240 mL vs. -10 mL, p=0.017 and 5.5% vs. 1.0%, p=0.038, respectively). The median distance of 6MWT in the PR group also increased significantly, from 407.5 m to 493.0 m after radiotherapy (p=0.017). Conclusion: Simultaneous PR improved pulmonary function, particularly in measures of FEV1, and exercise capacity for patients with lung or esophageal cancer even after radiotherapy treatment. These findings may provide an important base of knowledge for further large population studies with long-term follow-up analysis in the identification of the PR’s effects during thoracic radiotherapy.

Chantal Raherison-Semjen,1 Karen Mezzi,2 Konstantinos Kostikas,2 Alexander J Mackay,3 Dave Singh4 1Department of Respiratory Diseases, University of Bordeaux, Bordeaux, France; 2Global Medical Affairs Department, Novartis Pharma AG, Basel, Switzerland; 3Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK; 4Medicines Evaluation Unit, University of Manchester, Manchester University NHS Foundations Trust, Manchester, UKCorrespondence: Chantal Raherison-SemjenCentre INSERM 1219 Equipe Epicene, BPH Bordeaux Population Health Research Center, Université de Bordeaux, ISPED Institut de Santé Publique d’épidémiologie et de Développement, 146 Rue Leo Saignat, Bordeaux, 33076, FranceTel +33 0 557571234Email chantal.raherison-semjen@u-bordeaux.frObjective: To evaluate the perception of physicians on gender-specific differences in the diagnosis of chronic obstructive pulmonary disease (COPD) using a qualitative and anonymous questionnaire-based survey.Methods: The survey was conducted amongst respiratory physicians attending a standalone educational conference (29– 30 September 2017) using the SpotMe® App. The 20-item standardized closed questionnaire had pre-coded responses to questions on physician’s profile, and perception of COPD diagnosis and existing comorbidities between genders. All the responses were recorded anonymously.Results: Of 368 physicians who downloaded the SpotMe® App and had access to the survey, 132 (35.9%) completed the survey. Respondents were predominantly hospital-based (57.3%), aged 30– 49 years (54.2%), male (56.5%), and from large cities (59.5%). 68.7% of physicians perceived the prevalence of COPD to be higher in men; over 50% of physicians perceived that women were more prone to the effects of smoking. More than 60% of physicians agreed that women experience more severe symptoms (anxiety and depression) and have reduced quality of life than men. Over 50% of physicians agreed that misdiagnosis/underdiagnosis of COPD in women was an important factor for gender-differences.Conclusion: Results from this survey indicate that the understanding of COPD burden in women varies among healthcare professionals.Keywords: comorbidity, COPD, gender difference, physician perception, gender bias

Background COVID-19 pneumonia has been associated with severe acute hypoxia, sepsis-like states, thrombosis and chronic sequelae including persisting hypoxia and fibrosis. The molecular hypoxia response pathway has been associated with such pathologies and our recent observations on anti-hypoxic and anti-inflammatory effects of whole aqueous extract of Adhatoda Vasica (AV) prompted us to explore its effects on relevant preclinical mouse models. Methods In this study, we tested the effect of whole aqueous extract of AV, in murine models of bleomycin induced pulmonary fibrosis, Cecum Ligation and Puncture (CLP) induced sepsis, and siRNA induced hypoxia-thrombosis phenotype. The effect on lung of AV treated naïve mice was also studied at transcriptome level. We also determined if the extract may have any effect on SARS-CoV2 replication. Results Oral administration AV extract attenuates increased airway inflammation, levels of transforming growth factor-β1 (TGF-β1), IL-6, HIF-1α and improves the overall survival rates of mice in the models of pulmonary fibrosis and sepsis and rescues the siRNA induced inflammation and associated blood coagulation phenotypes in mice. We observed downregulation of hypoxia, inflammation, TGF-β1, and angiogenesis genes and upregulation of adaptive immunity-related genes in the lung transcriptome. AV treatment also reduced the viral load in Vero cells infected with SARS-CoV2. Conclusion Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features and highlights the repurposing potential of AV in COVID-19-like conditions.

Martin Anderson,1 Kathryn Collison,2 M Bradley Drummond,3 Melanie Hamilton,4 Renu Jain,2 Neil Martin,5,6 Richard A Mularski,7 Mike Thomas,8 Chang-Qing Zhu,9 Gary T Ferguson10 1Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; 2Respiratory Therapy Area, GSK, Research Triangle Park, NC, USA; 3Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 4R&D, GSK, Ware, Hertfordshire, UK; 5Global Medical Affairs, GSK, Brentford, Middlesex, UK; 6Institute for Lung Health, University of Leicester, Leicester, Leicestershire, UK; 7Department of Pulmonary and Critical Care Medicine, Kaiser Permanente Northwest Center for Health Research, Portland, OR, USA; 8Primary Care Research, University of Southampton, Southampton, UK; 9Biostatistics, GSK, Stockley Park West, Uxbridge, Middlesex, UK; 10Pulmonary Research, Institute of Southeast Michigan, Farmington Hills, MI, USACorrespondence: Gary T FergusonPulmonary Research, Institute of Southeast Michigan, Farmington Hills, MI, USATel +1 248-478-6561Email garytferguson@msn.comBackground: The influence of peak inspiratory flow (PIF) on dose delivery from dry powder inhalers (DPIs) and association with treatment efficacy in patients with chronic obstructive pulmonary disease (COPD) has not been fully determined. In vitro studies have demonstrated adequate dose delivery through ELLIPTA DPI at PIF ≥ 30 L/min. This analysis of two clinical trials and a real-world population of COPD patients determined spirometric PIF distribution, and explored the relationship between PIF and outcomes in the trials.Methods: The replicate Phase IV, 12-week, randomized, double-blind 207608/207609 (NCT03478683/NCT03478696) trials evaluated fluticasone furoate/umeclidinium/vilanterol via ELLIPTA DPI versus budesonide/formoterol+tiotropium in COPD patients. This post hoc analysis assessed spirometric PIF distribution at screening and relationship between PIF and lung function outcomes in the pooled 207608/207609 population. Spirometric PIF distributions in a real-world population of COPD patients were evaluated by retrospective analysis of the Kaiser Permanente Northwest (KPNW) database to assess similarities between clinical trial and real-world populations.Results: A total of 1460 (207608/207609) and 3282 (KPNW) patients were included. There was considerable overlap between spirometric PIF distributions for both populations. Overall, 99.7% and 99.8% of the 207608/207609 and KPNW populations, respectively, reported spirometric PIF ≥ 50 L/min, estimated as equivalent to ELLIPTA PIFR ≥ 30 L/min. In the 207608/207609 combined analysis, there was no significant interaction between spirometric PIF and treatment for lung function endpoints, indicating treatment effect is independent of PIF.Conclusion: Nearly all COPD patients in the 207608/207609 and KPNW populations achieved spirometric PIF values estimated as equivalent to PIFR of ≥ 30 L/min through the ELLIPTA DPI. Lack of correlation between spirometric PIF at screening and treatment efficacy aligns with consistent dose performance from the ELLIPTA DPI across a wide range of PIFs, achieved by patients with COPD of all severities.Keywords: COPD, inhaled triple therapy, patient outcomes, real-world studies, peak inspiratory flow rate, DPI

Kai Liu,1,* Xinjuan Yu,2,* Xuefen Cui,2 Yi Su,2 Lixin Sun,3 Jiulong Yang,4 Wei Han2 1Department of Rehabilitation, Qingdao Municipal Hospital, Qingdao University, Qingdao, People’s Republic of China; 2Department of Respiratory and Critical Medicine, Respiratory Disease Key Laboratory of Qingdao, Qingdao Municipal Hospital, Qingdao University, Qingdao, People’s Republic of China; 3Department of Anesthesia, Qingdao Municipal Hospital, Qingdao University, Qingdao, People’s Republic of China; 4Hospital Office, Qingdao Municipal Hospital, Qingdao University, Qingdao, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei HanDepartment of Pulmonary and Critical Care Medicine, Qingdao Municipal Hospital, Qingdao University, No. 5 Donghaizhong Road, Qingdao, Shandong, 266071, People’s Republic of ChinaTel +86 532 85937579Email hanw@qdu.edu.cnJiulong YangHospital Office, Qingdao Municipal Hospital, Qingdao University, No. 5 Donghaizhong Road, Qingdao, Shandong, 266071, People’s Republic of ChinaTel +86 532 88905509Email qdyxkp@163.comBackground: The proprioceptive neuromuscular facilitation (PNF) stretching could improve the contractile capacity of respiratory muscles, but the effect on pulmonary function, when it is combined with aerobic training, remains unknown.Objective: To evaluate the effect of PNF combined with aerobic training on respiratory symptoms, pulmonary function and neck/shoulder mobility in patients with COPD.Design: Randomized controlled trial.Participants: Fifty-five COPD patients were randomly divided into PNF group (n=28) and control group (n=27).Intervention: On the basis of conventional treatment, the control group performed 30 min aerobic training on a treadmill, while the PNF group added 10-minute PNF stretching 3 times every training day. Both groups did their training in 5 days per week for 6 weeks.Measures: Measures were taken before and after 6 weeks of training. COPD Assessment Test (CAT), dyspnea Visual Analog Scale (VAS), forced vital capacity (FVC), forced expiratory volume in first second (FEV1), inspiratory capacity (IC), inspiratory reserve volume (IRV), 6-minute walk test (6MWT), the range of motion (ROM) of head protraction, shoulder flexion, and the non-dominant pectoralis minor muscle (PmM) length were measured.Results: All the indicators of both groups were significantly improved after 6 weeks of intervention except for FVC, FEV1 and PmM length. Compared to the control group, the PNF group showed significant improvement in the CAT score, dyspnea VAS score, IC, IRV, 6MWT, as well as head protraction ROM and shoulder flexion ROM. Furthermore, IC was positively correlated with the head protraction ROM and PmM length (r=0.415, 0.579, P=0.028, 0.001); IRV was positively correlated with the shoulder flexion ROM (r=0.405, P=0.032) in the PNF group.Conclusion: PNF stretching combined with aerobic training reduces dyspnea and improves some pulmonary function measures, which is associated with neck/shoulder mobility, in COPD patients.Keywords: chronic obstructive pulmonary disease, proprioceptive neuromuscular facilitation stretching, aerobic training, pulmonary function

Kjell Larsson,1 Ann Ekberg-Jansson,2 Caroline Stridsman,3 Malin Hanno,4 Lowie EGW Vanfleteren5,6 1Integrative Toxicology, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 2Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 3Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, Umeå, Sweden; 4Boehringer Ingelheim AB, Stockholm, Sweden; 5COPD Center, Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, Gothenburg, 413 45, Sweden; 6Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 413 45, SwedenCorrespondence: Kjell LarssonIntegrative Toxicology, National Institute of Environmental Medicine, IMM, Karolinska Institutet, Stockholm, SE-171 77 Tel +46 70 582 07 63Email kjell.larsson@ki.seIntroduction: Swedish guidelines adhere to the international GOLD document regarding management of chronic obstructive pulmonary disease (COPD). Based on data from the Swedish National Airway Register (SNAR) the aim was to evaluate adherence to guidelines of pharmacological treatment of COPD in Swedish primary and secondary care.Methods: During a period of 18 months, data on symptoms (CAT, mMRC), lung function, exacerbation history and pharmacological treatment from 15,595 COPD patients from 853 primary care and 125 secondary care clinics were collected from SNAR. Patients with a co-diagnosis of asthma were excluded. Patients were divided into four treatment groups: no pharmacological treatment, short-acting bronchodilators alone, long-acting bronchodilators alone and ICS alone or in combination with bronchodilators.Results: Of the patients, 29% were in GOLD group A, 58% in group B, 2% in group C and 11% in group D. CAT score was ≥ 10 and mMRC score was below 2 in 30.9% of the patients and mMRC score was ≥ 2 and CAT score < 10 in 4.2% of the patients. In 61.4% of the patients, no exacerbation was registered during the last year. Long-acting bronchodilators were prescribed for 78% and ICS for 46% of all patients. In groups A, B, C and D, respectively, 21%, 11%, 11% and 5% did not receive any inhaler therapy; 67%, 81%, 81% and 90% received long-acting bronchodilators; 33%, 46%, 55% and 71% received any ICS containing therapy and 19%, 34%, 39% and 61% received triple therapy.Discussion: Data from the SNAR indicate that only a minority of COPD patients were untreated. There was a liberal use of ICS containing drug combinations in subjects who do not have an indication for ICS. A considerable proportion of subjects at high risk of exacerbations did not receive ICS treatment.Keywords: chronic obstructive pulmonary disease, COPD, glucocorticoids, registry

Rie Tanaka,1 Akira Koarai,1 Mitsuhiro Yamada,1 Naoya Fujino,1 Tomohiro Ichikawa,1 Tadahisa Numakura,1 Katsuhiro Onodera,2 Yorihiko Kyogoku,1 Tsutomu Tamada,1 Motohiko Miura,3 Yoshiaki Minakata,4 Masakazu Ichinose,5 Hisatoshi Sugiura1 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Department of Internal Medicine, Mizusawa Hospital, Oshu, Japan; 3Department of Respiratory Medicine, Tohoku Rosai Hospital, Sendai, Japan; 4Department of Respiratory Medicine, National Hospital Organization Wakayama Hospital, Wakayama, Japan; 5Academic Center, Osaki Citizen Hospital, Osaki, JapanCorrespondence: Akira KoaraiDepartment of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, JapanTel +81-22-717-8539Fax +81-22-717-8549Email koarai@rm.med.tohoku.ac.jpBackground: Daily physical activity is reduced in patients with chronic obstructive pulmonary disease (COPD) and a reduced level of physical activity has been shown to be an important predictor for the prognosis, such as increased risk of exacerbation and mortality. However, there has not yet been a useful biomarker of the physical activity. In our previous cross-sectional study, we showed that the level of one of the possible myokines, which is an anti-aging factor, growth differentiation factor 11 (GDF11), was decreased in the plasma from patients with COPD and correlated with the physical activity. To clarify this relationship, we conducted a longitudinal evaluation of such factors.Patients and Methods: Twenty-four COPD patients were enrolled and prospectively followed. We measured the levels of plasma GDF11 and systemic inflammatory markers with immunoblotting or ELISA, respectively. We also evaluated lung function and daily physical activity using a triaxial accelerometer and the incidence of exacerbation.Results: The change in the plasma level of GDF11, but not systemic inflammatory markers, was positively correlated with the change in the physical activity in an intensity-dependent manner (between the change in the number of steps and GDF11; r = 0.41, p = 0.047). In the multiple regression analysis, the relationship was confirmed (β = 0.93, p < 0.001). In addition, patients who maintained their plasma level of GDF11 showed a significantly lower incidence in exacerbations of COPD than those with decreased levels of GDF11 (p = 0.041).Conclusion: The longitudinal change in the plasma level of GDF11 was positively correlated with the change in the daily physical activity in COPD. GDF11 could be a useful humoral factor that reflects the physical activity in COPD.Keywords: chronic obstructive pulmonary disease, physical activity, growth differentiation factor 11, exacerbation, longitudinal study

Background For generations, cigarette smoking has presented an important public health concern. This study aimed to compare the health-promoting behavior, exercise capacity, physical activity level, health literacy, and knowledge level of smoking-related diseases between smokers and non-smokers. Methods The study included 71 smokers (mean age, 32.69±8.55 years) and 72 non-smokers (mean age, 31.88±9.94 years) between the ages of 20 and 60 years. Assessments included a 6-minute walking test (6MWT), Godin Leisure-Time Physical Activity Questionnaire, Health-Promoting Lifestyle Profile II (HPLP-II), Cardiovascular Risk Factors Knowledge Level Scale (CARRF-KL), Asthma/COPD Awareness Questionnaire, the World Health Organization Quality of Life-Bref questionnaire (WHOQoL-Bref [TR]), and Health Literacy Questionnaire (HLQ). Results The results from the study show that the number of coronary artery disease risk factors measured significantly higher among the smoker group members when compared to that of the non-smoker group members (p=0.001). Smokers had significantly lower %6MWT distance than non-smokers (84.83±4.72 and 93.45±7.16, respectively; p0.05). Additionally, while only forty-one smokers (57.7%) were active, 48 of the non-smoker group was active (66.7%). Conclusion Smokers suffer greater negative effects to their exercise capacity in comparison to non-smokers. Although smokers and non-smokers have similar levels of health literacy and similar levels of knowledge about cardiovascular disease risk factors and obstructive lung diseases, health professionals could continue to further increase individuals’ awareness of smoking-related risk factors and continue to emphasize the importance of physical activity and exercise for protecting cardiopulmonary health.

Donald P Tashkin,1 Ayca Ozol-Godfrey,2 Sanjay Sharma,2 Shahin Sanjar2 1Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA Health Sciences, Los Angeles, CA, USA; 2Sunovion Pharmaceuticals Inc., Marlborough, MA, USACorrespondence: Donald P TashkinDivision of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA Health Sciences, Los Angeles, CA, 90095, USATel +1 310-825-3163Email dtashkin@mednet.ucla.eduBackground: Chronic bronchitis (CB) is one of the conditions that contribute to chronic obstructive pulmonary disease (COPD). Despite its widespread prevalence among patients with COPD and overall negative impact on treatment outcomes, the effect of CB on the efficacy of bronchodilator therapy has not been evaluated. The objective of this post hoc analysis is to assess the effect of nebulized glycopyrrolate (GLY) on lung function and health-related quality of life outcomes in patients with St George’s Respiratory Questionnaire (SGRQ)-defined CB at baseline.Methods: Pooled data from the replicate, 12-week GOLDEN 3 and 4 studies (N=861) were grouped by CB status at baseline. The endpoints reported are changes from baseline in trough forced expiratory volume in 1 second (FEV1), SGRQ and EXAcerbations of Chronic Pulmonary DiseaseTool-Respiratory Symptoms (EXACT-RS) scores. Safety of GLY was evaluated by monitoring the incidence of adverse events (AEs).Results: Following 12 weeks of treatment, GLY 25 μg twice-daily (BID) resulted in placebo-adjusted improvements from baseline in FEV1 of 77.1 mL and 124.4 mL in the CB and non-CB groups, respectively (p< 0.0001 vs placebo in both groups). Significant improvements in SGRQ total scores were observed with GLY 25 μg BID compared with placebo, regardless of baseline CB status. Although EXACT-RS improvements were noted in both CB and non-CB groups, significant improvements were observed only in the CB group. GLY 25 μg BID was generally well tolerated through 12 weeks of treatment, with a low incidence of AEs.Conclusion: Treatment with nebulized GLY 25 μg BID for 12 weeks resulted in significant improvements in lung function and SGRQ total scores, compared with placebo. Significant improvements in EXACT-RS total scores were observed only in the CB group. Together, these results support the use of GLY 25 μg BID in patients with COPD, regardless of their CB status.Keywords: chronic bronchitis, COPD, LAMA, nebulized glycopyrrolate

Background: Many chronic obstructive pulmonary disease (COPD) patients receiving monotherapy continue to experience symptoms, exacerbations and poor quality of life. This study aimed to assess the efficacy and safety of direct switch from once-daily tiotropium (TIO) 18 μg to indacaterol/glycopyrronium (IND/GLY) 110/50 μg once daily in COPD patients in Korea. Methods: This was a randomized, open-label, parallel group, 12-week trial in mild-to-moderate COPD patients who received TIO 18 μg once daily for ≥12 weeks prior to study initiation. Patients aged ≥40 years, with predicted post-bronchodilator forced expiratory volume in 1 second (FEV1) ≥50%, post-bronchodilator FEV1/forced vital capacity

Background Intrapleural urokinase is one of the most widely used fibrinolytic agents in the treatment of complicated parapneumonic effusion (CPPE). However, little research has been performed on the optimal urokinase dosage. The aim of this study was to evaluate the treatment efficacy of half dose urokinase compared with conventional dose urokinase. Methods We retrospectively enrolled 92 patients with CPPE or empyema who underwent intrapleural urokinase treatment at two tertiary hospitals. Patients received antibiotics, chest tube drainage, and other treatments as part of routine care. The primary outcome was the treatment success rate in the half dose urokinase group (50,000 IU daily for maximal 6 days) and the conventional dose urokinase group (100,000 IU daily). Treatment success was defined as clinical and radiological improvements without surgical treatment or re-admission within one month. Results Forty-four patients received half dose urokinase, whereas 48 patients were treated with conventional dose urokinase. Both groups were relatively well matched at baseline, excluding higher serum white blood cell count and higher empyema prevalence in the half dose urokinase group. The treatment success rate was not different between the two groups (p=0.048). There were no differences in the rate of in-hospital death and surgical treatment, hospitalization duration, and indwelling catheter duration. In the multivariate analysis, urokinase dose was not a predictor of treatment success. Conclusion Half dose intrapleural urokinase is equally effective conventional dose urokinase in treating patients with CPPE or empyema.

Robson Prudente, Renata Ferrari, Carolina B Mesquita, Luiz HS Machado, Estefânia AT Franco, Irma Godoy, Suzana E Tanni Department of Internal Medicine, Botucatu School of Medicine, São Paulo State University (UNESP), Botucatu, São Paulo, BrazilCorrespondence: Robson PrudenteDepartment of Internal Medicine, Botucatu Medical School, São Paulo State University (UNESP), Av. Prof. Montenegro, s/n, Distrito de Rubião Junior, Botucatu, São Paulo, 18618-970, BrazilTel +55 14 99734-9653Email robsonapp@gmail.comBackground: Eosinophil counts increase during chronic obstructive pulmonary disease (COPD) exacerbation and influence the response to different agents (such as inhaled and systemic corticosteroids), as well as increase the production of other inflammatory cytokines. However, few studies have evaluated the association between peripheral blood eosinophils with mortality rate.Objective: To evaluate the association between peripheral blood eosinophils and mortality rate in COPD patients over a nine-year period.Study Design and Methods: This cohort included 133 COPD patients assessed at baseline by spirometry, pulse oximetry (SpO2), complete blood count, body composition, dyspnea intensity [Modified Medical Research Council (mMRC)] and the six-minute distance test (6MWD). The Kaplan–Meier curve followed by a Log rank test was used to evaluate mortality rate related to eosinophil cutoff point categorization. Multivariate Cox regression analysis was performed to identify the association between eosinophils and mortality with all subjects evaluated at baseline, adjusted for age, gender, mMRC, 6MWT, forced expiratory volume in the first second (FEV1) and SpO2.Results: Nineteen patients did not complete follow-up and it was not possible to identify the date of death in four others. Therefore, 110 patients were included in the analysis. At baseline, 81% presented ≥ 150 eosinophil cells and 72% presented ≥ 2%. We identified a three-fold higher risk of death in those with < 2% eosinophils and < 150 cells. We did not identify statistical differences when using other cutoff points.Conclusion: The decrease in number of peripheral eosinophils, with cutoff points at 2% and 150 cells, may be associated with a higher risk of death in COPD patients over nine years.Keywords: chronic airflow obstruction, inflammation, death rate

Kay Por Yip,1 Robert A Stockley,2 Elizabeth Sapey1 1Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham, UK; 2Department of Respiratory Medicine, University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham, UKCorrespondence: Kay Por Yip Email K.P.Yip@bham.ac.ukAbstract: Chronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality worldwide. Despite this, there has been little progress so far in terms of disease-modifying therapies over the last few decades and this is in part due to poor understanding of the definition and mechanisms surrounding early disease before it becomes established and increasingly complex. In this review, the nuances and difficulty in defining early disease in COPD are discussed. There are clear benefits in identifying patients early; however, usually diagnosis is made in the presence of significant lung damage. We consider what can be learned of early disease from COPD studies and highlight the lack of inclusion of young smokers (who may be at risk of COPD) or those with mild disease. We discuss promising clinical measures that are being used in an effort to detect early disease. These include symptom assessment, lung physiology measures and computed tomography (CT) imaging modalities. There is emerging evidence for the role of neutrophils and their proteinases in early COPD. This may form an important biomarker to investigate the pathophysiological processes of early COPD. Given the importance of the early disease, it is recommended that future COPD studies focus on capturing the earliest manifestations of disease, to understand the initiating mechanisms and to identify novel treatment targets.Keywords: COPD, early, neutrophil, lung function, biomarker

Zheng Wang,1 Yuqiang Zuo,2 Zhihong Gao2 1Department of Respiratory Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 2Department of Physical Examination Center, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of ChinaCorrespondence: Zhihong GaoDepartment of Physical Examination Center, The Second Hospital of Hebei Medical University Tel +86-0311-87046901Email tjzx1234556@126.comBackground: Chronic obstructive pulmonary disease (COPD) is a major cause of death because of its high incidence and mortality, which is chiefly resulted from cigarette smoke exposure. A large number of studies show that circular RNA (circRNA) participates in regulating COPD process. This study aims to reveal the role of circRNA ankyrin repeat domain 11 (circANKRD11) in cigarette smoke extract (CSE)-induced cell apoptosis, inflammation, and oxidative stress.Methods: The expression of circANKRD11, microRNA-145-5p (miR-145-5p) and bromodomain-containing 4 (BRD4) mRNA was detected by quantitative real-time polymerase chain reaction. The expression of apoptosis-related proteins and BRD4 protein was determined by Western blot. Cell apoptosis was detected by flow cytometry and Western blot. Cell inflammation was demonstrated by determining the levels of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) through enzyme-linked immunosorbent assay. Oxidative stress was investigated by the reactive oxygen species (ROS) and malondialdehyde (MDA) determination assays as well as superoxide dismutase (SOD) activity assay. The binding relationship between miR-145-5p and circANKRD11 or BRD4 was predicted by circinteractome or MicroT_CDS online database, and identified by dual-luciferase reporter, RNA immunoprecipitation or RNA pull-down assay.Results: CircANKRD11 and BRD4 expression were increased, whereas miR-145-5p expression was decreased in the lung tissues of smokers with or without COPD and CSE-induced HPMECs compared with the lung tissues of non-smokers as well as untreated HPMECs, respectively. CircANKRD11 silencing ameliorated CSE-induced cell apoptosis, inflammation, and oxidative stress. CircANKRD11 acted as a sponge of miR-145-5p, and regulated CSE-induced cell injury via sponging miR-145-5p. Additionally, miR-145-5p mimics protected against CSE-induced cell injury through targeting BRD4.Conclusion: CircANKRD11 absence protected HPMECs from CSE-induced injury by regulating BRD4 through associating with miR-145-5p, which demonstrated that circANKRD11 had the potential to act as a diagnosis biomarker for smoker-caused COPD.Keywords: COPD, circANKRD11, miR-145-5p, BRD4

Background To detect and investigate the expression of POU domain class 2 transcription factor 2 (POU2F2) in human lung cancer tissues, its role in lung cancer progression, and the potential mechanisms. Methods Immunohistochemical (IHC) assays were conducted to assess the expression of POU2F2 in human lung cancer tissues. Immunoblot assays were performed to assess the expression levels of POU2F2 in human lung cancer tissues and cell lines. CCK-8, colony formation, and transwell-migration/invasion assays were conducted to detect the effects of POU2F2 and AGO1 on the proliferaion and motility of A549 and H1299 cells in vitro. CHIP and luciferase assays were performed for the mechanism study. A tumor xenotransplantation model was used to detect the effects of POU2F2 on tumor growth in vivo. Results We found POU2F2 was highly expressed in human lung cancer tissues and cell lines, and associated with the lung cancer patients’ prognosis and clinical features. POU2F2 promoted the proliferation, and motility of lung cancer cells via targeting AGO1 in vitro. Additionally, POU2F2 promoted tumor growth of lung cancer cells via AGO1 in vivo. Conclusion We found POU2F2 was highly expressed in lung cancer cells and confirmed the involvement of POU2F2 in lung cancer progression, and thought POU2F2 could act as a potential therapeutic target for lung cancer.

Background Complementary and alternative medicine (CAM) has been frequently used and its use continues to increase in lung cancer patients, despite insufficient scientific evidence. We analyzed the current status of the awareness and use of CAM in Korean lung cancer patients. Methods This study was a prospective survey-based study performed at seven medical centers in South Korea between August 2019 and October 2019. The survey included general patient characteristics, and the awareness and use of CAM. We analyzed the differences in the clinical parameters between patients aware and not aware of CAM and between CAM non-users and users. Results A total of 434 patients were included in this study. Among them, 68.8% of the patients responded that they were aware of CAM, and 30.9% of the patients said they experienced CAM. In univariate analysis, patients aware of CAM were younger with poor performance status, patients with advanced-stage lung cancer, those who received more systemic therapy, and those who received CCRT. By multiple logistic regression, younger age, poor performance status, advanced stage, and prior CCRT were independent risk factors for CAM awareness. There were no significant differences in the general characteristics and cancer-associated clinical parameters between CAM non-users and users. Conclusions More lung cancer patients with younger age, poor performance status, advanced stage, and prior CCRT were aware of CAM. There were no significantly different characteristics between CAM users and non-users.

Johanna I Lutter,1 Rudolf A Jörres,2 Franziska C Trudzinski,3 Peter Alter,4 Christina Kellerer,2,5 Henrik Watz,6 Tobias Welte,7 Robert Bals,8 Diego Kauffmann-Guerrero,9 Jürgen Behr,9 Rolf Holle,10 Claus F Vogelmeier,4 Kathrin Kahnert9 On behalf of the COSYCONET study group1Institute of Health Economics and Health Care Management, Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Munich, Germany; 2Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, LMU Hospital, Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany; 3Department of Pneumology and Critical Care Medicine, Thoraxklinik University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; 4Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University Marburg (UMR), Germany, Member of the German Center for Lung Research (DZL), Marburg, Germany; 5School of Medicine, Institute of General Practice and Health Services Research, Technical University of Munich (TUM), Munich, Germany; 6Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 7Department of Pneumology, Hannover Medical School, Hannover, Germany; 8Department of Internal Medicine V – Pulmonology, Allergology, Respiratory Intensive Care Medicine, Saarland University Hospital, Homburg, Germany; 9Department of Medicine V, University of Munich (LMU), Comprehensive Pneumology Center, Member of the German Center for Lung Research (DZL), Munich, Germany; 10Institute for Medical Informatics, Biometry and Epidemiology, LMU Hospital, Munich, GermanyCorrespondence: Kathrin KahnertDepartment of Internal Medicine V, University of Munich (LMU), LMU Hospital, Ziemssenstraße 1, Munich, 80336, GermanyEmail Kathrin.Kahnert@med.uni-muenchen.deBackground: In COPD patients of GOLD groups A and B, a high degree of treatment with inhaled corticosteroids (ICS) has been reported, which is regarded as overtreatment according to GOLD recommendations. We investigated which factors predict ICS use and which relationship it has to clinical and functional outcomes, or healthcare costs.Methods: We used pooled data from visits 1 and 3 of the COSYCONET cohort (n=2741, n=2053, interval 1.5 years) including patients categorized as GOLD grades 1– 4 and GOLD group A or B at both visits (n=1080). Comparisons were performed using ANOVA, and regression analyses using propensity matching and inverse probability weighting to adjust for differences between ICS groups. These were defined as having ICS at both visits (always) vs no ICS at both visits (never). Measures were divided into predictors of ICS treatment and outcomes.Results: Among 1080 patients, 608 patients were eligible for ICS groups (n=297 never, n=311 always). Prior to matching, patients with ICS showed significantly (p< 0.05 each) impaired lung function, symptoms and exacerbation history. After matching, the outcomes generic quality of life and CO diffusing capacity were increased in ICS patients (p< 0.05 each). Moreover, costs for respiratory medication, but not total health care costs, were significantly elevated in the ICS group by 780€ per year.Conclusion: ICS therapy in COPD GOLD A/B patients can have small positive and negative effects on clinical outcomes and health care costs, indicating that the clinical evaluation of ICS over-therapy in COPD requires a multi-dimensional approach.Keywords: COPD, inhaled corticosteroids, GOLD groups, overtreatment

Lung cancer is one of the leading causes of cancer-related deaths in Korea. Although the smoking rate has decreased over time, the prevalence of lung cancer still remains high. In this study, we reviewed recent trends on the incidence, epidemiology, screening, diagnosis, and treatment of lung cancer in Korea by analyzing data from the national lung cancer registry and recently-published studies. Although approximately 40% of patients with non-small cell lung cancer (NSCLC) were diagnosed as stage IV, the 5-year relative survival rate improved from 11.3% (1993-1995) to 30.2% (2013-2017), possibly due to advances in methods of diagnosis and therapy. In addition, the 2019 implementation of the national lung cancer screening program with low-dose computed tomography may have also contributed to these improvements in survival rates. Recently, molecular diagnosis has become more widely used in the identification of genetic mutations in tissue specimens. Target therapy and immune checkpoint inhibitors have also been successfully used, particularly in cases of advanced NSCLC. In the future, further research on the optimal management of lung cancer remains necessary.

Background Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by fibrosis and progressive loss of lung function. The pathophysiological pathways involved in IPF are not well understood. Abnormal lipid metabolism has been described in various other chronic lung diseases including asthma and chronic obstructive pulmonary disease (COPD). However, its potential role in IPF pathogenesis remains unclear. Methods In this study, we used ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) to characterize lipid changes in plasma derived from IPF patients with stable and progressive disease. We further applied a data-independent acquisition (DIA) technique called SONAR, to improve the specificity of lipid identification. Results Statistical modelling showed variable discrimination between the stable and progressive subjects, revealing differences in the detection of triglycerides (TG) and phosphatidylcholines (PC) between progressors and stable IPF groups, which was further confirmed by mass spectrometry imaging (MSI) in IPF tissue. Conclusion This is the first study to characterise lipid metabolism between stable and progressive IPF, with results suggesting disparities in the circulating lipidome with disease progression.

Caifen Zheng,1 Yongping Zhang,2 Yingchun Zhao,3 Yuanfang Duan,1 Qianghua Mu,1 Xinying Wang1 1Department of Respiratory and Critical Care Medicine, The First People’s Hospital of Lianyungang, Lianyungang, People’s Republic of China; 2Blood Purifying Center, The First People’s Hospital of Lianyungang, Lianyungang, People’s Republic of China; 3Department of Cardiovascular Medicine, The First People’s Hospital of Lianyungang, Lianyungang, People’s Republic of ChinaCorrespondence: Yingchun ZhaoDepartment of Cardiovascular Medicine, The First People’s Hospital of Lianyungang, No. 6 East Zhenhua Road, Haizhou, Lianyungang, Jiangsu, 222061, People’s Republic of ChinaTel +86-0518-85767023Email zyc6469@126.comBackground: Circular RNAs (circRNAs) have been identified to play roles in the respiratory diseases. Here, this study aimed to elucidate the function of circRNA oxysterol binding protein like 2 (circOSBPL2) in the development of smoke-related chronic obstructive pulmonary diseases (COPD).Methods: The expression of circ-OSBPL2, microRNA (miR)-193a-5p, and bromodomain-containing protein 4 (BRD4) was detected using qRT-PCR and Western blot assays. Cigarette smoke extract (CSE)-induced human bronchial epithelial cells (HBECs) was applied to mimic smoke-related COPD in vitro. Flow cytometric analysis of cell apoptosis and ELISA analysis of interleukins (IL)-6, IL-8, tumor necrosis factor-α (TNF-α) levels were performed. The malondialdehyde (MDA) and superoxide dismutase (SOD) production levels were analyzed according to the kit instructions. The binding interaction between miR-193a-5p and circ-OSBPL2 or BRD4 was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assays.Results: Circ-OSBPL2 was highly expressed in lung tissues of smokers without or with COPD, particularly in smokers with COPD. Also, the expression of circ-OSBPL2 was dose and time-dependently elevated in CSE-induced HBECs. Circ-OSBPL2 down-regulation in HBECs attenuated CSE-evoked cell proliferation arrest, and cell apoptosis, inflammation and oxidative stress promotion. Mechanistically, circ-OSBPL2 served as a sponge for miR-193a-5p, and miR-193a-5p inhibition reversed the effects of circ-OSBPL2 knockdown on CSE-mediated HBECs. Besides that, miR-193a-5p directly targeted BRD4, and miR-193a-5p re-expression in HBECs abolished CSE-induced HBEC injury, which was reverted by BRD4 up-regulation. Additionally, we also found circ-OSBPL2 could indirectly regulate BRD4 via miR-193a-5p.Conclusion: Circ-OSBPL2 contributed to the apoptosis, inflammation, and oxidative stress of HBECs in smoke-related COPD by miR-193a-5p/BRD4 axis, suggesting a novel insight on the pathogenesis of COPD and a potential therapeutic strategy for future clinic intervention in COPD.Keywords: circ-OSBPL2, miR-193a-5p, BRD4, COPD

Background: This study aimed to determine the parameters for worsening oxygenation in non-severe coronavirus disease 2019 (COVID-19) pneumonia. Methods: This retrospective cohort study included cases of confirmed COVID-19 pneumonia in a public hospital in South Korea. The worsening oxygenation group was defined as that with SpO2 ≤94% or received oxygen or mechanical ventilation (MV) throughout the clinical course versus the non-worsening oxygenation group that did not experience any respiratory event. Parameters were compared, and the extent of viral pneumonia from an initial chest computed tomography (CT) was calculated using artificial intelligence (AI) and measured visually by a radiologist. Results: We included 136 patients, with 32 (23.5%) patients in the worsening oxygenation group; of whom, two needed MV and one died. Initial vital signs and duration of symptoms showed no difference between the two groups; however, univariate logistic regression analysis revealed that a variety of parameters on admission were associated with an increased risk of a desaturation event. A subset of patients was studied to eliminate potential bias, that ferritin ≥280 μg/L (p=0.029), lactate dehydrogenase ≥240 U/L (p=0.029), pneumonia volume (p=0.021), and extent (p=0.030) by AI, and visual severity scores (p=0.042) were the predictive parameters for worsening oxygenation in a sex-, age-, and comorbid illness-matched case-control study using propensity score (n=52). Conclusion: Our study suggests that initial CT evaluated by AI or visual severity scoring as well as serum markers of inflammation on admission are significantly associated with worsening oxygenation in this COVID-19 pneumonia cohort.

Workplaces with elevated organic dust levels such as animal feed barns also commonly have elevated levels of gasses, such as CO2. Workers exposed to such complex environments often experience respiratory effects that may be due to a combination of respirable factors. We examined the effects of CO2 on lung innate immune responses in mice co-exposed to the inflammatory agents lipopolysaccharide (LPS) and organic dust. We evaluated CO2 levels at the building recommended limit (1000 ppm) as well as the exposure limit (5000 ppm). Mice were nasally instilled with dust extracts or LPS and immediately put into chambers with a constant flow of room air (avg. 430 ppm CO2), 1000 ppm, or 5000 ppm CO2 enriched air. Results reveal that organic dust exposures tended to show decreased inflammatory responses with 1000 ppm CO2 and increased responses at 5000 ppm CO2. Conversely, LPS with addition of CO2 as low as 1000 ppm tended to inhibit several inflammatory markers. In most cases saline treated animals showed few changes with CO2 exposure, though some changes in mRNA levels were present. This shows that CO2 as low as 1000 ppm CO2 was capable of altering innate immune responses to both LPS and organic dust extracts, but each response was altered in a different fashion.

Background While sleep disruption is a common complaint among children with cystic fibrosis (CF), only a few studies have investigated insomnia in adults. The aim of this study was to identify factors associated with insomnia in clinically stable adult CF patients. Methods Twenty-eight CF patients (18M/10F), with a median age of 27 (22–34) (median (interquartile range) years and a median of forced expiratory volume in one second of 72 (39–93) % predicted completed questionnaires on insomnia (Insomnia Severity Index, ISI), sleep quality (PSQI), daytime sleepiness (Epworth), restless legs syndrome (IRLS), pain (NRS), anxiety/depression (HAD) and quality of life (CFQ-R 14+). Respiratory assessment data, including symptoms, sputum analysis, arterial blood gases, 6-min walking test, pulmonary function tests and polysomnographic variables, were also analyzed. Results Forty-three percent of patients were insomniac (ISI > 7). Compared with non-insomniac patients (ISI ≤ 7), insomniac patients had more severely impaired quality of life and a higher HAD score: median anxiety score of 9 (8–11) vs 4 (3–6) (p p p 2 during sleep. Conclusions The strong association between insomnia, impaired quality of life and increased HAD score should prompt physicians to be particularly attentive to the management of anxiety and depression in adult CF patients with insomnia. Trial registration: On clinicaltrials.gov (NCT02924818, date of registration: October 5, 2016).

Polyamines are common intracellular metabolites of nearly all cells, and their conservation across a vast diversity of cells suggests critical roles for these compounds in cellular physiology. Most intracellular polyamines are associated with RNA and, subsequently, polyamines have significant effects on transcription and translation. Putrescine and spermidine are the most common polyamines in bacteria. Intracellular polyamine pools in bacteria are tightly controlled by both de novo synthesis and transport. Polyamine homeostasis is emerging as a critical parameter of multiple pathways and physiology with substantial impact on bacterial pathogenesis, including the important human pathogenStreptococcus pneumoniae. Modulation of polyamine metabolism in pneumococci is an important regulator of central metabolism. It has broad effects on virulence factors such as capsule as well as stress responses that ultimately impact the survival of pneumococcus in a host. Polyamine transport protein as a single antigen or in combination with other pneumococcal proteins is shown to be an efficacious immunogen that protects against nasopharyngeal colonization, and invasive disease. A comprehensive description of polyamine metabolic pathways and their intersection with pneumococcal pathogenesis will undoubtedly point to novel approaches for treatment and prevention of pneumococcal disease.

Anne Orholm Nielsen,1 Ole Hilberg,2,3 Jens Ulrik Stæhr Jensen,4 Steffen Helmer Kristensen,5 Jannie Christina Frølund,2 Pernille Kølholt Langkilde,6 Anders Løkke2,3 1Department of Medicine, Zealand University Hospital, Roskilde, Denmark; 2Department of Medicine, Hospital Little Belt, Vejle, Denmark; 3Department of Regional Health Research, University of Southern Denmark, Odense, Denmark; 4Department of Internal Medicine, Respiratory Medicine Section, Herlev and Gentofte Hospital, University Hospital of Copenhagen, Copenhagen, Denmark; 5Department of Pulmonary Medicine, Aalborg University Hospital, Aalborg, Denmark; 6Department of Medicine, Hospital Little Belt, Kolding, DenmarkCorrespondence: Anne Orholm NielsenDepartment of Medicine, Zealand University Hospital, Roskilde, DenmarkEmail anne_orholm@hotmail.comBackground: Inhaled corticosteroids (ICS) are widely used in the treatment of chronic obstructive pulmonary disease (COPD), but recent studies have raised doubts whether all COPD patients will benefit from ICS. This study evaluates in a real-life setting the effects of ICS withdrawal in patients with COPD.Methods: The study was a prospective intervention study following patients with COPD for 6 months after abrupt withdrawal of ICS. FEV1 (L), blood eosinophilic count (x10E9/L) and number of exacerbations were measured at baseline, 1, 3 and 6 months after ICS withdrawal.Results: Ninety-six patients (56 females (57.4%), mean age 70 years (51– 94 years)) with COPD were included in the study. Eleven patients were excluded during the study period (7 patients died, 4 patients withdrew their consent during the study period). During the 6 months, 51 patients (60%) had resumed treatment with ICS, of whom 34 patients (68%) experienced an exacerbation during follow-up. No significant decline in FEV1 was seen in this group between baseline and after 6 months (ΔFEV1 0.07 L, p = 0.09). In the remaining 34 patients (40%) without ICS after 6 months of follow-up, 15 patients (44.1%) experienced an exacerbation. No significant decline was seen in FEV1 at baseline and after 6 months (ΔFEV1 0.04 L, p = 0.28). There were no statistically significant differences between the two groups in age (70.5 vs 69.6 years, p = 0.53), nor between FEV1 at baseline (0.96 L vs 1.00 L, p = 0.63) or eosinophilic count (0.25 x10E9/L vs 0.17 x10E9/L, p = 0.07).Conclusion: Abrupt withdrawal of ICS was possible in some patients. However, more than half of the patients resumed ICS during follow-up. Based on results from our study we were not able to foresee – from neither history of exacerbations nor eosinophilic count – whom will be able to manage without ICS and who will resume treatment with ICS.Keywords: COPD, inhaled corticosteroids, withdrawal, real-life setting

Background Studies report high in-hospital mortality of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) especially for those requiring admission to an intensive care unit. Recognizing factors associated with mortality in these patients could reduce health care costs and improve end-of-life care. Methods This retrospective study included AECOPD patients admitted to the respiratory intensive care unit of a tertiary hospital in Beijing from Jan 1, 2011 to Dec 31, 2018. Patients demographic characteristics, blood test results and comorbidities were extracted from the electronic medical record system and compared between survivors and non-survivors. Results We finally enrolled 384 AECOPD patients: 44 (11.5%) patients died in hospital and 340 (88.5%) were discharged. The most common comorbidity was respiratory failure (294 (76.6%)), followed by hypertension (214 (55.7%)), coronary heart disease (115 (29.9%)) and chronic heart failure (76 (19.8%)). Multiple logistic regression analysis revealed that independent risk factors associated with in-hospital mortality included lymphocytopenia, leukopenia, chronic heart failure and requirement for invasive mechanical ventilation. Conclusions The in-hospital mortality of patients with acute COPD exacerbation requiring RICU admission is high. Lymphocytes 9/L, leukopenia, requirement for invasive mechanical ventilation, and chronic heart failure were identified as risk factors associated with increased mortality rates.

Robert A Wise,1 Kenneth R Chapman,2 Benjamin M Scirica,3,4 Sami Z Daoud,5 Dan Lythgoe,6 Esther Garcia-Gil7 1Medicine, Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Department of Medicine, University of Toronto, Toronto, ON, Canada; 3Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA; 4Department of Medicine, Harvard Medical School, Boston, MA, USA; 5Late-Stage Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; 6Statistics, Phastar, Chiswick, London, UK; 7Respiratory & Immunology, BioPharmaceuticals Medical, AstraZeneca, Barcelona, SpainCorrespondence: Robert A WiseMedicine, Pulmonary and Critical Care, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD, 21224, USAEmail rwise@jhmi.eduPurpose: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with increased risk of major adverse cardiovascular events (MACE) and mortality. Here, we investigate whether the safety and efficacy of aclidinium bromide differ due to exacerbation history in patients with COPD and increased cardiovascular risk.Patients and Methods: ASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study of patients with moderate-to-very severe COPD and increased cardiovascular risk. Patients were randomized 1:1 to receive aclidinium or placebo twice daily for up to 3 years. Outcomes included time to first MACE and all-cause mortality over 3 years, exacerbation rate during the first year on-treatment, and change in baseline pre-dose forced expiratory volume in 1 second (FEV1) over 3 years. This pre-specified subgroup analysis compared outcomes in patients receiving aclidinium vs placebo. The comparison of patients with vs without an exacerbation history was added following a protocol amendment to increase enrollment in the primary study.Results: Of 3589 patients, 2156 (60.1%) had ≥ 1 moderate or severe exacerbations in the prior year, compared with 1433 (39.9%) without prior exacerbations. Although patients with an exacerbation history had numerically higher rates of MACE and mortality regardless of treatment, aclidinium did not increase risk of MACE (≥ 1: hazard ratio [HR] 0.79, 95% confidence interval [CI]: 0.54– 1.16; none: HR 1.27, 95% CI: 0.65– 2.47; interaction P=0.233) or all-cause mortality (≥ 1: HR 1.08, 95% CI: 0.81– 1.43; none: HR 0.66, 95% CI: 0.36– 1.22; interaction P=0.154), regardless of exacerbation history. Aclidinium reduced the exacerbation rate vs placebo irrespective of exacerbation history (≥ 1: rate ratio [RR] 0.80, 95% CI: 0.68– 0.94; none: RR 0.69, 95% CI: 0.54– 0.89; interaction P=0.340) and improved FEV1 (interaction P=0.633).Conclusion: In patients with moderate-to-very severe COPD and increased cardiovascular risk, aclidinium did not increase risk of MACE or mortality and reduced exacerbation rate vs placebo, regardless of exacerbation history.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01966107.Keywords: COPD, COPD exacerbation, aclidinium, MACE, mortality

Background: Early differentiation between emergency department (ED) patients with and without coronavirus disease 2019 (COVID-19) is very important. The diagnosis of COVID-19 depends on real-time reverse transcriptase polymerase chain reaction (RT-PCR). On imaging, computed tomography (CT) manifestations resemble those seen in viral pneumonias, with multifocal ground-glass opacities and consolidation in a peripheral distribution being the most common findings. Although these findings lack specificity for COVID-19 diagnosis on imaging grounds, CT could be used to provide objective assessment about the extension of the lung opacities, which could be used as an imaging surrogate for disease burden. We set out to investigate the diagnostic accuracy of chest CT scanning in detecting COVID-19 in a population with suspected COVID-19 patients. Materials and Methods: In this cross-sectional single-center study performed on 348 cases with clinical suspicion of COVID-19, all adult symptomatic ED patients had both a CT scan and a PCR upon arrival at. CT results were compared with PCR test (s) and diagnostic accuracy was calculated. Results: Between February 15, 2020, and June 30, 2020, 348 symptomatic patients were included. In total, 62.3% of patients had a positive PCR and 69.8% had a positive CT, resulting in a sensitivity of 94.2%, specificity of 76.7%, likelihood ratio (LR) of +2.94 and (LR) −0.18. The sensitivity of the CT tended to be higher in those with acute respiratory distress syndrome (100.0%, P = 0.017) and severe COVID-19 (98.5%, P = 0.027) than in patients with mild (82.5%, P = 0.047) and moderate COVID-19 (89.3%, P = 0.039). The diagnostic ability of chest CT was found to be high with 86.3% concordance between findings of CT and PCR. In 48 (13.7%) patients, discordant findings between CT and PCR were observed. In most cases, the CT scan was considered suspicious for COVID-19, while the PCR was negative (37/48, 77.0%). In the majority of these, the diagnosis at discharge was pulmonary infection (n = 26; 54.1%). Conclusion: The accuracy of chest CT in symptomatic COVID suspect patients is high, but when used as a single diagnostic test, CT cannot accurately diagnose or exclude COVID-19. Therefore, we recommend a combination of both CT and RT-PCR for future follow-up, management, and medical surveillance.

Hiroyoshi Machida,1 Sumito Inoue,1 Yoko Shibata,2 Tomomi Kimura,3 Takahito Ota,1 Yu Ishibashi,1 Hiroaki Murano,1 Kodai Furuyama,1 Sujeong Yang,1 Hiroshi Nakano,1 Kento Sato,1 Masamichi Sato,1 Takako Nemoto,1 Michiko Nishiwaki,1 Keiko Yamauchi,1 Akira Igarashi,1 Masafumi Watanabe1 1Department of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine, Yamagata, Japan; 2Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan; 3Respiratory Medicine, Yamagata Saisei Hospital, Yamagata, JapanCorrespondence: Sumito InoueDepartment of Cardiology, Pulmonology, and Nephrology, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, JapanEmail sinoue@med.id.yamagata-u.ac.jpPurpose: Lung cancer is a serious complication in patients with chronic obstructive pulmonary disease (COPD) and accounts for approximately 15% of deaths in patients with COPD. However, with the exception of emphysema, few reports to date have been published on the factors that predict lung cancer development in COPD patients. It has been reported that patients with COPD develop lung cancer at a rate of 0.8% - 1.7%/year, but the incidence may be higher in the Japanese population. Therefore, we investigated the incidence of lung cancer and the lung cancer mortality rate in Japanese COPD patients, as well as factors that are associated with the development of lung cancer in COPD patients.Patients and Methods: We followed up 224 patients with stable COPD and performed CT examinations at least once per year. The incidence of lung cancer was recorded and data at enrollment were compared with data of the group that did not develop lung cancer.Results: Over a median follow-up period of 4.58 years, lung cancer was newly diagnosed in 19 patients; the incidence of lung cancer in this population was 1.85%/year. Patients who developed lung cancer had more severe emphysema assessed by CT and GOLD classification and were more likely to be current smokers than those who did not develop lung cancer. No other significant differences were observed between these two groups. Mortality was significantly increased in patients who developed lung cancer compared with those who did not.Conclusion: In COPD patients, the incidence of lung cancer is higher and the development of lung cancer worsens the prognosis; however, lung cancer development is unpredictable and attention should be paid to all patients. Annual CT screening is important for early detection of lung cancer.Keywords: chronic obstructive pulmonary disease, COPD, lung cancer, GOLD classification, current smoker, inhaled corticosteroid, ICS

Daniel S Majorski,1 Jens C Callegari,1 Sarah B Schwarz,1 Friederike S Magnet,1 Rodion Majorski,2 Jan H Storre,3,4 Claudia Schmoor,5 Wolfram Windisch1 1Cologne Merheim Hospital, Department of Pneumology, Kliniken der Stadt Köln gGmbH, Witten/Herdecke University, Cologne, Germany; 2Department of Neurology and Neurophysiology, Helios Hospital Wuppertal, Witten/Herdecke University, Wuppertal, Germany; 3Praxis Pneumologie Solln, Munich, Germany; 4Department of Pneumology, University Medical Hospital, Freiburg, Germany; 5Clinical Trials Unit, Medical Center – University Medical Hospital, Freiburg, GermanyCorrespondence: Wolfram WindischDepartment of Pneumology, Cologne Merheim Hospital, Kliniken der Stadt Köln gGmbH, Witten/Herdecke University, Faculty of Health/School of Medicine, Ostmerheimer Strasse 200, Köln, D-51109, GermanyEmail windischw@kliniken-koeln.dePurpose: The impact of oronasal and nasal masks on the quality of nocturnal non-invasive ventilation (NIV) needs to be clarified. This trial was designed to compare the impact of oronasal and nasal masks on the objective quality and subjective acceptance of nocturnal NIV in COPD-patients.Patients and Methods: In a randomized crossover trial, 30 COPD-patients with well-established high-intensity NIV (mean inspiratory/expiratory positive airway pressure 26± 3/5± 1 cmH2O, mean respiratory back-up rate 17± 1/min) were ventilated for two consecutive nights on oronasal and nasal masks, respectively.Results: Full polysomnography, nocturnal blood gas measurements, and subjective assessments were performed. There was a tendency towards improved sleep efficiency (primary outcome) when an oronasal mask was worn (+9.9%; 95% CI:-0.2%-20.0%; P=0.054). Sleep stages 3/4 were favored by the oronasal mask (+12.7%; 95% CI: 6.0%-19.3%; P=< 0.001). Subjective assessments were comparable with the exception of items related to leakage (P< 0.05 in favor of nasal masks). The mean transcutaneous PCO2 value for oronasal masks (47.7± 7.4 mmHg) was comparable to that of nasal masks (48.9± 6.6 mmHg) (P=0.11). There was considerable diversity amongst individual patients in terms of sleep quality and gas exchange following mask exchange. Subjective mask preference was not associated with sleep quality, but with nocturnal dyspnea. Over 40% of patients subsequently switched to the mask that they were not previously accustomed to.Conclusion: In general, oronasal and nasal masks are each similarly capable of successfully delivering NIV in COPD-patients. However, the individual response to different interfaces is extremely heterogeneous, while subjective mask preference is independent from objective measures, but associated with dyspnea.Trial Registration: German Clinical Trials Registry (DRKS00007741).Keywords: respiratory insufficiency, sleep, masks, dyspnea

Johanna MC Broese,1,2 Rianne MJJ van der Kleij,1 Els ML Verschuur,2 Huib AM Kerstjens,3 Yvonne Engels,4 Niels H Chavannes1 1Public Health & Primary Care, Leiden University Medical Center, Leiden, the Netherlands; 2Lung Alliance Netherlands, Amersfoort, the Netherlands; 3Respiratory Medicine & Tuberculosis, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands; 4Anesthesiology, Pain & Palliative Medicine, Radboud University Medical Center, Nijmegen, the NetherlandsCorrespondence: Johanna MC BroesePublic Health and Primary Care, Leiden University Medical Centre, Post Zone V0-P, Postbox 9600, Leiden, 2300 RC, the NetherlandsEmail j.m.c.broese@lumc.nlIntroduction: Patients with advanced chronic obstructive pulmonary disease (COPD) experience significant symptom burden, leading to poor quality of life. Although guidelines recommend palliative care for these patients, this is not widely implemented and prevents them from receiving optimal care.Objective: A national survey was performed to map the current content and organization of palliative care provision for patients with COPD by pulmonologists and general practitioners (GPs) in the Netherlands.Methods: We developed a survey based on previous studies, guidelines and expert opinion. Dutch pulmonologists and GPs were invited to complete the survey between April and August 2019.Results: 130 pulmonologists (15.3%; covering 76% of pulmonology departments) and 305 GPs (28.6%) responded. Median numbers of patients with COPD in the palliative phase treated were respectively 20 and 1.5 per year. 43% of pulmonologists and 9% of GPs reported some formalized agreements regarding palliative care provision. Physicians most often determined the start of palliative care based on clinical expertise or the Surprise Question. 31% of pulmonologists stated that they often or always referred palliative patients with COPD to a specialist palliative care team; a quarter rarely referred. 79% of the respondents mentioned to often or always administer opioids to treat dyspnea. The topics least discussed were non-invasive ventilation and the patient’s spiritual needs. The most critical barrier to starting a palliative care discussion was difficulty in predicting the disease course.Conclusion: Although pulmonologists and GPs indicated to regularly address palliative care aspects, palliative care for patients with COPD remains unstructured and little formalized. However, our data revealed a high willingness to improve this care. Clear guidance and standardization of practice are needed to help providers decide when and how to initiate discussions, when to involve specialist palliative care and how to optimize information exchange between care settings.Keywords: COPD, palliative care, advance care planning, surprise question, organization

Background Cut offs for fat-free mass index (FFMI) and appendicular skeletal muscle mass index (ASMI) are available for diagnosing low muscle mass in patients with COPD. This study aimed to investigate: (1) the frequency of low muscle mass (FFMI and ASMI) applying different cut-offs and (2) the functional translation (clinical impact) of low muscle mass, in patients with COPD stratified into BMI categories. Methods Patients with COPD were assessed regarding body composition, exercise capacity, quadriceps muscle strength, symptoms of anxiety and depression, dyspnea and quality of life upon referral to pulmonary rehabilitation. The proportion of patients with low muscle mass was compared among BMI categories. Clinical outcomes between patients with normal and low muscle mass within each BMI category were compared. Results 469 patients with COPD were included for analyses. The frequency of patients classified as low FFMI varied significantly according to the choice of cut-off (32 to 54%; P Conclusions Approximately half of the overweight and obese patients with COPD have low muscle mass when applying age-gender-BMI-specific cut-offs. Low muscle mass is associated with worse functional outcomes in overweight and obese COPD patients.

Mathias Damkjær,1 Kjell Håkansson,1 Thomas Kallemose,2 Charlotte Suppli Ulrik,1,3 Nina Godtfredsen1,3 1Department of Respiratory Medicine, Copenhagen University Hospital Amager and Hvidovre, Hvidovre, Denmark; 2Clinical Research Centre, Copenhagen University Hospital Amager and Hvidovre, Hvidovre, Denmark; 3Institute of Clinical Medicine, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Nina GodtfredsenDepartment of Respiratory Medicine, Hvidovre Hospital, Kettegård Allé 30, Hvidovre, 2650, DenmarkEmail Nina.Skavlan.Godtfredsen@regionh.dkBackground: Statins have, due to their anti-inflammatory properties, been suggested to potentially improve chronic obstructive pulmonary disease (COPD) outcomes. We aimed to investigate the effect of statins on time to first exacerbation and all-cause mortality in high-risk COPD outpatients.Methods: All outpatients with COPD seen at the Department of Respiratory Medicine, Copenhagen University Hospital Amager and Hvidovre, Denmark in 2016 were identified and followed for 3.5 years in this retrospective, registry-based cohort study of time to first acute exacerbation of COPD (AECOPD) or death. AECOPD was defined as a rescue course of oral corticosteroid and/or hospital admission. The association was estimated using time-varying crude and multivariable Cox proportional hazard regression.Results: The cohort comprised 950 COPD outpatients, mean (SD) age 71 (11) years, and FEV1 44% predicted (IQR 33%; 57%). The annual exacerbation rate was 0.88 (1.68) and 211 patients (22%) had a history of hospital admission for AECOPD in the 12 months prior to index date. Three hundred and ninety-three patients (41.4%) were defined as statin users, with 131 (33.3%) having filled the first prescription for statin after index date. Statin use was not associated with reduced risk of AECOPD. When stratifying for moderate and severe exacerbations in a sub-analysis in the same model, statin use did not have an increased HR for exacerbation of either severity (HR = 1.02 (95% CI 0.85to 1.24; p = 0.811) and HR = 1.07 (95% CI 0.89 to 1.29; p = 0.492) respectively). Statin use was not associated with all-cause mortality (HR 1.05 (95% CI, 0.75 to 1.47, p = 0.777)).Conclusion: We did not find any association between statin use and risk of AECOPD or all-cause mortality. The result adds to the evidence that an aggressive approach with statin treatment upfront is not beneficial in COPD, unless prescribed according to current guidelines for cardiovascular diseases.Keywords: chronic obstructive pulmonary disease, cardiovascular disease, exacerbations, statins, mortality

Gerard J Criner,1 Therese Cole,2 Kristen A Hahn,3 Kari Kastango,3 James Eudicone,4 Ileen Gilbert4 1Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University Hospital, Philadelphia, PA, USA; 2IQVIA, Rockville, MD, USA; 3IQVIA, Cambridge, MA, USA; 4AstraZeneca, Wilmington, DE, USACorrespondence: Gerard J CrinerDepartment of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University Hospital, Philadelphia, PA, 19140, USATel +1 215 707 8113Email gerard.criner@tuhs.temple.eduPurpose: Among patients with chronic obstructive pulmonary disease (COPD), adherence to inhaled medication leads to fewer exacerbations and improved health status. The goal of the present study was to evaluate the effects of medication reminders via the BreatheMate device on adherence in patients with COPD.Patients and Methods: A 6-month, phase 4, randomized, multicenter, open-label US study (NCT02864342) enrolled 138 patients aged ≥ 40 years with moderate to very severe COPD and ≥ 10 pack-year smoking history. Patients in the intervention (n = 68) and control (n = 70) groups received the BreatheMate device, smartphone application, and vouchers to redeem pressurized metered-dose inhalers (pMDIs) for the prescribed 2 puffs of budesonide/formoterol 160/4.5 μg twice daily. The intervention group also received twice-daily electronic reminders to take budesonide/formoterol. The primary endpoint was the mean number of sets of adherent puffs/day (4 puffs: 2 puffs within 60 minutes, twice daily) over 6 months. Secondary endpoints included adherence by three 60-day intervals, usage days, prescription refills, and Clinical COPD Questionnaire (CCQ) score. Study enrollment terminated early due to issues with inconsistent syncing.Results: A higher mean proportion of adherent days (77.6% vs 60.2%; P < 0.001) and sets of adherent puffs/day (1.61 vs 1.33; P < 0.001) were recorded for the intervention group versus the control group. Intervention group adherence was higher than that of the control group for each 60-day interval (P < 0.001); the intervention group was 3.07 (95% confidence interval: 1.49– 6.52) times more likely than the control group to be adherent for ≥ 80% of study days. Overuse (> 2 sets of 2 puffs/day), underuse (< 2 sets of 2 puffs/day), and no use days were lower in the intervention group versus control (P < 0.05). Patients aged ≥ 65 years had higher adherence (P < 0.001).Conclusion: Medication reminders through the BreatheMate device and application produced greater adherence to inhaled therapy in patients with COPD.Keywords: chronic obstructive pulmonary disease, telemedicine, adherence, pressurized metered-dose inhaler

Objective Acute lung injury (ALI) is characterized by inflammation and oxidative stress. Nuclear factor-kappaB (NF-κB) mediates the expression of various inflammation-related genes, including the NADPH oxidase family. This study aimed to identify the potential regulatory role of NF-κB on NADPH oxidases in tumor necrosis factor-α (TNF-α)-induced oxidative stress in human alveolar epithelial cells. Methods A549 cells were treated with TNF-α for 24 h to establish ALI cell models. RT-PCR, western blot, assessment of oxidative stress, Alibaba 2.1 online analysis, electrophoretic mobility shift assays and luciferase reporter analysis were employed to identify the potential regulatory role of NF-κB on NADPH oxidases in TNF-α-induced oxidative stress in human alveolar epithelial cells. Results The expression of NF-κB/p65 was notably upregulated in TNF-α-stimulated A549 cells. NF-κB knockdown by siRNA significantly inhibited the TNF-α-induced oxidative stress. Moreover, NF-κB/p65 siRNA could inhibit the activation of NOX1, NOX2 and NOX4 mRNA and protein expression in TNF-α-stimulated A549 cells. The next study demonstrated that NF-κB activated the transcription of NOX1 by binding to the -261 to -252 bp (NOX1/κB2, TAAAAATCCC) region of NOX1 promoter in TNF-α-stimulated A549 cells. Conclusion Our data demonstrated that NF-κB can aggravate TNF-α-induced ALI by regulating the oxidative stress response and the expression of NOX1, NOX2 and NOX4. Moreover, NF-κB could promote the NOX1 transcriptional activity via binding its promoter in TNF-α-stimulated A549 cells.

Background Pneumonia is the most frequently encountered postoperative pulmonary complications (PPC) after orthotopic liver transplantation (OLT), which cause high morbidity and mortality rates. We aimed to develop a model to predict postoperative pneumonia in OLT patients using machine learning (ML) methods. Methods Data of 786 adult patients underwent OLT at the Third Affiliated Hospital of Sun Yat-sen University from January 2015 to September 2019 was retrospectively extracted from electronic medical records and randomly subdivided into a training set and a testing set. With the training set, six ML models including logistic regression (LR), support vector machine (SVM), random forest (RF), adaptive boosting (AdaBoost), extreme gradient boosting (XGBoost) and gradient boosting machine (GBM) were developed. These models were assessed by the area under curve (AUC) of receiver operating characteristic on the testing set. The related risk factors and outcomes of pneumonia were also probed based on the chosen model. Results 591 OLT patients were eventually included and 253 (42.81%) were diagnosed with postoperative pneumonia, which was associated with increased postoperative hospitalization and mortality (P +, TBIL, anesthesia time, preoperative length of stay, total fluid transfusion and operation time. Conclusion Our study firstly demonstrated that the XGBoost model with 14 common variables might predict postoperative pneumonia in OLT patients.

Dana Unninayar,1 Sara J Abdallah,2 D William Cameron,2– 4 Juthaporn Cowan2– 4 1Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; 2Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; 3Division of Infectious Diseases, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; 4Centre of Infection, Immunity and Inflammation, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, CanadaCorrespondence: Juthaporn CowanThe Ottawa Hospital, General Campus, 501 Smyth Road, Box 223, Ottawa, Ontario, K1H 8L6, CanadaTel +1 613-737-8899 X 79617Fax +1 613-737-8352Email jcowan@toh.caAbstract: Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation and episodes of worsening respiratory symptoms and pulmonary function, termed acute exacerbations of COPD (AECOPD). AECOPD episodes are associated with heightened airway inflammation and are often triggered by infection. A subset of COPD patients develops frequent exacerbations despite maximal existing standard medical therapy. It is therefore clear that a targeted and more effective prevention strategy is needed. Immunoglobulins are glycoprotein molecules that are secreted by B lymphocytes and plasma cells and play a critical role in the adaptive immune response against many pathogens. Altered serum immunoglobulin levels have been observed in patients with immunodeficiencies and inflammatory diseases. Serum immunoglobulin has also been identified as potential biomarkers of AECOPD frequency. Since plasma-derived polyvalent immunoglobulin treatment is effective in preventing recurrent infections in immunodeficient patients and in suppressing inflammation in many inflammatory diseases, it may be conceivable that immunoglobulin treatment may be effective in preventing recurrent AECOPD. In this article, we provide a review of the current knowledge on immunoglobulin treatment in patients with COPD and discuss plausible mechanisms as to how immunoglobulin treatment may work to reduce AECOPD frequency.Keywords: chronic obstructive pulmonary disease, immunoglobulin treatment, exacerbation

This randomized clinical trial was aimed to assess the efficacy of neoadjuvant letrozole in combination with standard neoadjuvant chemotherapy regimen on clinical response rate of hormone receptor positive locally advanced breast cancer.In this randomized clinical study, 42 female patients, ≥ 18 years, with clinical stage IIB-IIIC (T1-4, N0-3, M0), pathologically proven hormone receptor positive and HER2 negative, invasive ductal carcinoma of breast, were randomly assigned to receive standard neoadjuvant chemotherapy alone (control group) or letrozole 2.5 mg/d (in association with goserlin in premenopausal patients) concurrent with standard neoadjuvant chemotherapy (study group). Standard neoadjuvant chemotherapy regimen has consisted of 4 cycles of doxorubicin (60mg/m2) and cyclophodphamide (600mg/m2), followed by 4 cycles of paclitaxel (175mg/m2) every two weeks.At the beginning of the study all patients underwent thorough exmination of breast mass and axillary lymph nudes by palpation and ultrasonography. At the end of the study response rates were also evaluated by palpation and ultrasonography and subsequently patients were referred for surgury. Pathologic response rates were also evaluated on surgical specimens. All of the clinical, ultrasonographic and pathologic examinations during the trial were performed by a single specialist. Finally all the data were analysed statistically.Overall clinical response rates in breast were 95.2%, in both study and control group. Overall clinical response rates in axilla were 80.9% and 76.2% in study and control group respectively. Similarly, overall radiologic complete response rates in breast and axilla were 95.2% and 76.2% respectively in both study and control group. Totally, the comparison of overall clinical and radiologic response rates in th breast and axilla, showed no significant difference between control and study group (p>0.05).The addition of letrozol to standard neoadjuvant chemotherapy regimen was not associated with higher clinical and radiologic response rates in patients with locally advanced hormon receptor positive breast cancer.Keywords: Neoadjuvant chemotherapy, Letrozole, Locally advanced breast cancer

Randomized trials of pulmonary vasodilators in pulmonary hypertension due to left heart disease (Group 2) and lung disease (Group 3) have demonstrated potential for harm. Yet these therapies are commonly used in practice. Little is known of the effects of treatment outside of clinical trials. We aimed to establish outcomes of vasodilator treatment for Groups 2/3 pulmonary hypertension in real-world practice. We conducted a retrospective cohort study of 132,552 Medicare-eligible Veterans with incident Groups 2/3 pulmonary hypertension between 2006 and 2016, and a secondary nested case–control study. Our primary outcome was a composite of death by any cause or selected acute organ failures. In our cohort analysis, we calculated adjusted risks of time to our outcome using Cox proportional hazards models with facility-specific random effects. In our case–control analysis, we used logistic mixed-effects models to estimate the effect of any past, recent, and cumulative exposure on our outcome. From our cohort study, 3249 (2.5%) Veterans were exposed to pulmonary vasodilators. Exposure to vasodilators was associated with increased risk of our primary outcome, in both Group 3 (HR: 1.58 (95% CI: 1.37–1.82)) and Group 2 (HR: 1.26 (95% CI: 1.12–1.41)) pulmonary hypertension patients. The case–control study determined odds of our outcome increased by 11% per year of exposure (OR: 1.11 (95% CI: 1.07–1.16)). Treating Groups 2/3 pulmonary hypertension with vasodilators in clinical practice is associated with increased risk of harm. This extension of trial findings to a real-world setting offers further evidence to limit use of vasodilators in Groups 2/3 pulmonary hypertension outside of clinical trials.

Introduction: Hypertension is recognized as one of the major causes of cardiovascular disease. The present study aimed to assess the relationship between hypertension and its risk factors in the population referring to comprehensive health care centers affiliated to Mashhad University of Medical Sciences. Materials and Methods: This case-control study was performed on the health assessment data of the population aged 30 years and above registered in the SINA system in 2017-2018. The present case-control study was conducted on 1500 cases who were selected by systematic random sampling and assigned to the case group (500 hypertensive patients) and control group (1000 subjects without a history of hypertension). Data were analyzed using SPSS software (version 22). A p-value less than 0.05 was considered statistically significant. Results: Based on the results, the risk factors for hypertension included settlement in urban areas (OR=2.914), body mass index≥ 25 (OR = 2.522), waist circumference˃90 (OR=2.409), sedentary lifestyle (OR=2.373), consumption of solid oil (OR=1.581), triglyceride level of ˃150 (OR=566), use of table salt (OR=1.547). On the other hand, the following were identified as protective factors against hypertension: hard labor jobs (OR=0.292), optimal physical activity (OR=0.421), and regular consumption of vitamin D (OR=0.625) (p

Yeonseok Choi,1,* Sun Hye Shin,1,* Hyun Lee,2 Hyun Kyu Cho,1 Yunjoo Im,1 Noeul Kang,1 Hye Sook Choi,3 Hye Yun Park1 1Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 2Division of Pulmonary Medicine and Allergy, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South Korea; 3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Kyung Hee University Hospital, Seoul, South Korea*These authors contributed equally to this workCorrespondence: Hye Yun ParkDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South KoreaTel +82-2-3410-3429Fax +82-2-3410-3849Email hyeyunpark@skku.eduPurpose: Long-term macrolide treatment is recommended for patients with chronic obstructive pulmonary disease (COPD) with frequent exacerbations. Bronchiectasis is a common comorbid condition in patients with COPD, for which long-term azithromycin is effective in preventing exacerbation. This study aimed to compare the effect of long-term azithromycin between bronchiectasis patients with chronic airflow obstruction (CAO) and COPD patients without bronchiectasis.Patients and Methods: Patients with CAO who received azithromycin for more than 12 weeks were retrospectively identified at a single referral hospital. CAO was defined as a post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 0.7, and bronchiectasis was determined using computed tomography. The development of exacerbation and symptom improvement were compared between bronchiectasis patients with CAO and COPD patients without bronchiectasis.Results: A total of 59 patients (43 in bronchiectasis with CAO group vs 16 in COPD without bronchiectasis group) were included in this study. Compared to COPD patients without bronchiectasis, those in bronchiectasis with CAO group were younger, more likely to be female, and never smokers. There was no difference in the previous exacerbation history or FEV1 between the two groups. The median duration of azithromycin treatment was 15 months (interquartile range, 8– 25 months). At the 12-month follow-up, the development of ≥ 2 moderate or ≥ 1 severe exacerbations was significantly lower in bronchiectasis with CAO group than in COPD without bronchiectasis group (46.5% vs 87.5%, P = 0.005). The proportion of patients with symptom improvement determined by the COPD assessment test score was also significantly higher in bronchiectasis with CAO group than COPD without bronchiectasis group at the 12-month follow-up (68.2% vs 16.7%, P = 0.004).Conclusion: Bronchiectasis patients with CAO could benefit more from long-term azithromycin treatment than COPD patients without bronchiectasis.Keywords: COPD, bronchiectasis, azithromycin, exacerbation

Mariam Fathima,1 Zeeta Bawa,1 Bernadette Mitchell,1 Juliet Foster,1 Carol Armour,1 Bandana Saini1,2 1Woolcock Institute of Medical Research, University of Sydney, Glebe, New South Wales, Australia; 2School of Pharmacy, University of Sydney, Camperdown, New South Wales, AustraliaCorrespondence: Bandana Saini Rm No. N348, Building No A15The University of Sydney, Camperdown, New South Wales, 2006, AustraliaTel +61 2 93516789Fax +61 2 93514791Email bandana.saini@sydney.edu.auPurpose: To evaluate the effectiveness of a pilot community pharmacy care model for patients with chronic obstructive pulmonary disease (COPD) to improve: 1) inhaler technique; 2) medication adherence; and 3) uptake of non-pharmacological treatment and prevention activities.Patients and Methods: Forty “host” pharmacies in Sydney were invited to recruit eligible patients and to provide a counselling room/area in their pharmacy for service provision. Eligible patients were referred to two “consultant” pharmacists, specifically trained to deliver a specialized pharmacy COPD service which involved 3 in-pharmacy visits and 2 follow-up phone calls over a 6-month period. The service consisted of 1) inhaler technique assessment; 2) medication adherence assessment; and 3) referrals to the patient’s general practitioner (GP) to facilitate the uptake of non-pharmacological resources as well as to review COPD medications/devices, as required. Pre-post analyses were conducted using paired Student’s t-test and Wilcoxon Signed Rank Test for independent variables and chi-squared tests for proportional data.Results: Nine “host” pharmacies recruited 40 patients, of whom 37 completed the baseline Visit and 27 completed all Visits. A total of 270 interventions were provided by the “consultant” pharmacists with most provided at Visit 1 (176). The most common interventions were addressing patient gaps in COPD knowledge and inhaler technique. A total of 119 referrals were made to GPs for various reasons, the most common being for a COPD action plan, pulmonary rehabilitation, or pneumonia vaccination. There were significant improvements pre-post intervention in inhaler use competence, COPD knowledge, immunization rate for pneumonia, exacerbation rate and COPD plan ownership.Conclusion: In this pilot study, the specialized pharmacy-based COPD care model delivered by “consultant” pharmacists in community pharmacies provided significant health benefits for patients. Further research is needed to assess the model’s effectiveness in a larger population as well as when measured against standard care.Keywords: inhaler technique, medication review, consultant pharmacist, COPD

Introduction Patent ductus arteriosus (PDA) is a common acyanotic heart disease that presents with variable symptoms. Objectives This study is therefore aimed at determining the relationship between gender, age, and size of PDA and pulmonary hypertension. This study also seeks to determine the prevalence of elevated pulmonary artery systolic pressure in children with PDA. Patients and methods A descriptive study of children with patent ductus arteriosus was carried out from 2016 to 2020 in three institutions. The data were analysed with the IBM SPSS statistics for windows, version 20 (IBM Corp, Chicago) Result The mean ductal size was 3.78 (2.39) mm, with a minimum of 1.0 mm and a maximum size of 10.0 mm. The mean ductal size for males, 4.02 (2.53) mm was comparable with that of the females, 3.61 (2.28) mm (Student T-test = 0.8, 0.4). The mean pulmonary artery systolic pressure (PASP) of the patients was 43.36 (24.46) mmHg. Also the mean PASP was comparable among the males and the females, 48.37 (26.69) mmHg versus 39.63 (22.16) mmHg (Student T-test = 1.81, p = 0.07). There was no correlation between age and PASP (correlation coefficient = 0.009, p = 0.92). Sixty point two percent (60.2%) (62/103) of children with PDA had pulmonary hypertension. The proportion of males with pulmonary hypertension, 48.39% (30/62) was comparable with that of the females, 51.61% (32/62) (Chi2 = 2.05, p = 0.15) and females are 1.8 times more likely to have pulmonary hypertension as males (odds ratio 1.81, 95% CI 0.8–4.1). There was a positive correlation between ductal size and PASP (Pearson correlation coefficient = 0.26, p value = 0.007). Those with moderate and large sized duct tend to have moderate and severe pulmonary hypertension respectively and this is statistically significant. Chi2 = 17.85, p = 0.007 Conclusion The prevalence of pulmonary hypertension in children with PDA is 60.2%. Moderate and large size duct presents with moderate and severe pulmonary hypertension respectively. Females are 1.8 times more likely to have pulmonary hypertension than the males.

Björn Ställberg,1 Karin Lisspers,1 Kjell Larsson,2 Christer Janson,3 Mario Müller,4 Mateusz Łuczko,5 Bine Kjøller Bjerregaard,6 Gerald Bacher,7 Björn Holzhauer,7 Pankaj Goyal,7 Gunnar Johansson1 1Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden; 2Integrative Toxicology, Karolinska Institutet, Stockholm, Sweden; 3Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 4Department of Data Science and Advanced Analytics, IQVIA, Frankfurt Am Main, Germany; 5Department of Data Science and Advanced Analytics, IQVIA, Warsaw, Poland; 6Department of Real World Evidence Solutions, IQVIA, Copenhagen, Denmark; 7Department of Clinical Development and Analytics, Novartis Pharma AG, Basel, SwitzerlandCorrespondence: Björn StällbergDepartment of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Box 564, Uppsala, SE-75122, SwedenTel +46-070-3149944Email b.stallberg@telia.comPurpose: Chronic obstructive pulmonary disease (COPD) exacerbations can negatively impact disease severity, progression, mortality and lead to hospitalizations. We aimed to develop a model that predicts a patient’s risk of hospitalization due to severe exacerbations (defined as COPD-related hospitalizations) of COPD, using Swedish patient level data.Patients and Methods: Patient level data for 7823 Swedish patients with COPD was collected from electronic medical records (EMRs) and national registries covering healthcare contacts, diagnoses, prescriptions, lab tests, hospitalizations and socioeconomic factors between 2000 and 2013. Models were created using machine-learning methods to predict risk of imminent exacerbation causing patient hospitalization due to COPD within the next 10 days. Exacerbations occurring within this period were considered as one event. Model performance was assessed using the Area under the Precision-Recall Curve (AUPRC). To compare performance with previous similar studies, the Area Under Receiver Operating Curve (AUROC) was also reported. The model with the highest mean cross validation AUPRC was selected as the final model and was in a final step trained on the entire training dataset.Results: The most important factors for predicting severe exacerbations were exacerbations in the previous six months and in whole history, number of COPD-related healthcare contacts and comorbidity burden. Validation on test data yielded an AUROC of 0.86 and AUPRC of 0.08, which was high in comparison to previously published attempts to predict COPD exacerbation.Conclusion: Our work suggests that clinically available information on patient history collected via automated retrieval from EMRs and national registries or directly during patient consultation can form the basis for future clinical tools to predict risk of severe COPD exacerbations.Keywords: COPD, machine learning, exacerbation, hospitalization

Shuyi Qin,1,2,* Xinjuan Yu,1,2,* Qianli Ma,3,* Li Lin,4 Qinghai Li,1,2 Hong Liu,1,2 Lei Zhang,5 Shuguang Leng,6 Wei Han1,2 1Department of Pulmonary and Critical Care Medicine, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, Shandong, People’s Republic of China; 2Respiratory Disease Key Laboratory of Qingdao, Qingdao Municipal Hospital, Qingdao, Shandong, People’s Republic of China; 3Department of Radiology, Qingdao Municipal Hospital, Qingdao, Shandong, People’s Republic of China; 4Department of Pulmonary Medicine, Shandong Provincial Chest Hospital, Jinan, Shandong, People’s Republic of China; 5Department of Hospital Infection, Qingdao Municipal Hospital, Qingdao, Shandong, People’s Republic of China; 6Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA*These authors contributed equally to this workCorrespondence: Wei HanDepartment of Pulmonary and Critical Care Medicine, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No. 5 Donghaizhong Road, Qingdao, Shandong, People’s Republic of ChinaTel +86 532 85937579Email hanw@qdu.edu.cnShuguang LengDepartment of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USATel +1 505 3489465Email sleng@salud.unm.eduPurpose: To explore a practical marker for quantitatively analyzing the small airway remodeling in COPD by HRCT.Patients and Methods: Twenty-four patients with COPD (GOLD I, n = 7; GOLD II, n = 8; GOLD III+IV, n = 9) and 14 healthy controls (7 normal pulmonary function; 7 small-airway disease (SAD)) were enrolled in the study as five groups, GOLD I, GOLD II, GOLD III+IV, normal and SAD. All subjects underwent HRCT and spirometry. With ISP 9.0, whole emphysema index (EI) and the airway parameters, including wall area (WA), lumen area (LA), airway area (AA) of the 3rd, 5th and 9th generations of bronchi, were measured successively. The ratio of LA/AA and WA/AA in the 3rd, 5th and 9th generations of bronchi were calculated and compared among groups.Results: For the five groups, EI was increased only in GOLD III+IV group (P < 0.05), while the ratio of LA/AA (9-LA/AA) and WA/AA (9-WA/AA) in 9th generation of bronchi have significantly changed since SAD group (P < 0.05). There were significant correlation between FEV1generations of bronchi (r3 = 0.429, r5 = 0.583, r9 = 0.592, respectively, P < 0.05); FEV1% and WA/AA (r3 = – 0.428, r5 = – 0.532, r9 = – 0.570, respectively, P < 0.05); as well as MMEF% and LA/AA (r3 = 0.421, r5 = 0.566, r9 = 0.610, respectively, P < 0.05); MMEF% and WA/AA (r3 = – 0.421, r5 = – 0.529, r9 = – 0.593, respectively, P < 0.05).Conclusion: Small airway remodeling has occurred in the early stage of COPD, while emphysema in the late stage of COPD. The 9-LA/AA and 9-WA/AA are accurate and practical markers for small airway remodeling of COPD.Keywords: COPD, high-resolution CT, emphysema index, pulmonary function test

Junnan Peng, Qian Yu, Shulei Fan, Xingru Chen, Rui Tang, Daoxin Wang, Di Qi Department of Respiratory Medicine, Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Daoxin Wang; Di QiDepartment of Respiratory Medicine, Second Affiliated Hospital of Chongqing Medical University, No. 76 Linjiang Road, Yuzhong District, Chongqing, 400010, People’s Republic of ChinaEmail wangdaoxin0163@163.com; qidi0126@126.comBackground: Readmission after hospital discharge is common among patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Predictive biomarkers of readmission would facilitate stratification strategies and individualized prognosis. Therefore, this study aimed to investigate the utility of type 2 biomarkers (eosinophils, periostin, and YKL-40) and a type 1 biomarker (CXCL9) in predicting readmission events in patients with AECOPD.Methods: This is a prospective observational study design. Blood levels of eosinophils, periostin, YKL-40, and CXCL9 were measured at admission. The clinical outcomes were 12-month COPD-related readmission, time to COPD-related readmission, and number of 12-month COPD-related readmissions. These outcomes were analyzed using logistic and Cox regression models and Spearman’s rank test.Results: A total of 123 patients were included, of whom 51 had experienced at least one readmission for AECOPD. High levels of eosinophils (≥ 200 cells/μL or 2% of the total white blood cell count, adjusted odds ratio [aOR] =3.138, P=0.009) and YKL-40 (≥ 14.5 ng/mL, aOR =2.840, P=0.015), as well as low CXCL9 levels (≤ 30.1 ng/mL, aOR =2.551, P=0.028), were associated with an increased COPD-related readmission. The highest relative readmission rate was observed in patients with both high eosinophil and YKL-40 levels. Moreover, high eosinophil and YKL-40 levels were associated with a shorter time to first COPD-related readmission and an increased number of 12-month COPD-related readmissions.Conclusion: High blood eosinophil and YKL-40 levels, as well as low CXCL9 levels, have predictive utility for the 12-month COPD-related readmission rate. Using eosinophils and YKL-40 together allows more precise identification of patients at high risk of COPD-related readmission.Keywords: COPD, exacerbation, readmission, biomarker, prospective observational

Introduction: Pulmonary neuroendocrine tumors (NETs) comprise a spectrum of tumors ranging from indolent to highly aggressive neoplasm. This study aims to study the clinicopathological and immunohistochemical features of NETs and assess the sensitivity of various IHC markers. Materials and Methods: All consecutive cases of pulmonary NETs diagnosed from January 2016 to June 2019 were analyzed retrospectively. The routine hematoxylin- and eosin-stained sections along with immunohistochemistry (IHC) slides were reviewed. IHC was done using a panel of markers which included synaptophysin, chromogranin, CD56, thyroid transcription factor-1 (TTF-1), p-40, napsin-A, and ki67. Results: Of total number of 53 patients, diagnosis was made on biopsy in 40 patients and resection specimen in 13 patients. Small cell lung carcinoma was the most common (31 cases), followed by 16 cases of typical carcinoid, 5 cases of atypical carcinoid, and 1 case of combined SCLC. Both synaptophysin and chromogranin were positive in all the cases of typical carcinoid. Synaptophysin had better sensitivity than chromogranin in atypical carcinoid and small cell carcinoma. CD56 was positive in 8 out of 9 cases done. TTF-1 was negative in all the cases of typical carcinoid. The sensitivity of TTF-1 in small cell carcinoma was 85.19%. The mean Ki67 labeling index was 1.4%, 6.6%, and 65.6% in typical, atypical carcinoid, and small cell carcinomas, respectively. Conclusion: Synaptophysin was more sensitive than chromogranin, especially in atypical carcinoid and small cell carcinoma. TTF-1 along with high Ki67 differentiates small cell carcinoma from carcinoid.