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Background Systemic corticosteroids for the treatment of COPD exacerbations decrease treatment failure and shorten the length of hospitalization. However, the optimal dose is unclear. Research Question Is personalized-dose corticosteroid administered according to a dosing scale more effective than fixed-dose corticosteroid administration in hospitalized patients with COPD with exacerbations? Study Design and Methods This was a prospective, randomized, open-label trial. In-hospital patients with COPD with exacerbations were randomly assigned at a 1:1 ratio to either the fixed-dose group (receiving the equivalent of 40 mg of prednisolone) or the personalized-dose group for 5 days. The primary end point was a composite measure of treatment failure that included in-hospital treatment failure and medium-term (postdischarge) failure. Secondary end points were length of stay and cost. Results A total of 248 patients were randomly assigned to the fixed-dose group (n = 124) or personalized-dose group (n = 124). One patient in each group was not included in the intention-to-treat population because of incorrect initial COPD diagnosis. Failure of therapy occurred in 27.6% in the personalized-dose group, compared with 48.8% in the fixed-dose group (relative risk, 0.40; 95% CI, 0.24-0.68; P = .001). The in-hospital failure of therapy was significantly lower in the personalized-dose group (10.6% vs 24.4%; P = .005), whereas the medium-term failure rate, adverse event rate, hospital length of stay, and costs were similar between the two groups. After treatment failure, a lower additional dose of corticosteroids and a shorter duration of treatment were needed in the personalized-dose group to achieve control of the exacerbation. In the personalized-dose cohort, those receiving 40 mg or less had an average failure rate of 44.4%, compared with 22.9% among those receiving more than 40 mg (P = .027). Interpretation Personalized dosing of corticosteroids reduces the risk of failure because more patients were provided with a higher initial dose, especially > 60 mg, whereas 40 mg or less was too low in either group. Clinical Trial Registration ClinicalTrials.gov ; No.: NCT02147015; URL: www.clinicaltrials.gov

Background As the coronavirus disease 19 (COVID-19) pandemic evolves, the need for recognizing the structural pulmonary changes of the disease during early convalescence has emerged. Most studies focus on parenchymal destruction of the disease; but little is known about whether the disease affects the airway. This study was conducted to investigate the changes in airway dimensions and explore the associated factors during early convalescence in patients with COVID-19. Methods We retrospectively analyzed quantitative computed tomography (CT)-based airway measures of 69 patients with COVID-19 from 5 February to 17 March 2020, and 32 non-COVID-19 participants from 1 January 2018 to 31 December 2019 from Guangzhou, China. The well-established measures of wall area fraction and the square root of the wall area of a hypothetical bronchus with an inner perimeter of 10 mm, were used to describe airway wall dimensions. We described the characteristics of the dimensions and inner area of airways in 66 patients with COVID-19 at the initial and convalescent stages of the disease, and compared them with the non-COVID-19 group. Linear regression models were constructed to investigate the association of airway dimensions with duration of hospitalization or disease severity after recovery. Partial correlation coefficients were calculated to investigate whether inflammatory markers were related to airway dimensions. Results Among 66 patients with COVID-19, airway dimensions were greater during disease initiation than early convalescence, which was significantly greater than in non-COVID-19 participants. No significant difference was found between the patients with COVID-19 at the initial stage and the non-COVID-19 controls regarding the first to eighth generations of the inner area. In adjusted regression models, duration of hospitalization was negatively associated with wall area fraction of the first to the sixth generation of airways. No significant associations exist between airway dimensions and disease severity, or airway dimensions with inflammatory markers. Conclusions Airway dimensions in patients with COVID-19 during disease initiation are greater than those in non-COVID-19 participants. Such structural airway changes continue to remain significantly greater during early convalescence. No evidence shows that disease severity or inflammatory markers are associated with airway dimensions, implying that the primary lesion attacked by COVID-19 might not be the airways.

Chronic obstructive pulmonary disease (COPD) is becoming a leading cause of morbidity and mortality in China. In the IMPACT trial, fluticasone furoate[FF]/umeclidinium[UMEC]/vilanterol[VI] single-inhaler triple therapy demonstrated lower rates of moderate/severe exacerbations than dual therapy with FF/VI or UMEC/VI in patients with symptomatic COPD and a history of exacerbations. This analysis investigates the China cohort and its consistency with the overall ITT population. 10,355 patients were randomized 2:2:1 to once-daily FF/UMEC/VI 100/62.5/25 µg, FF/VI 100/25 µg, or UMEC/VI 62.5/25 µg for 52 weeks. Endpoints included: annual rates of exacerbations, time-to-first on-treatment moderate/severe exacerbation and change from baseline in trough forced expiratory volume in 1 s (FEV1) at Week-52. Clinical trial registration is NCT02164513 (CTT116855). 535 patients (5.2%) were from China. Annual on-treatment moderate/severe exacerbation rate was 0.81 with FF/UMEC/VI versus 0.96 with FF/VI (rate ratio: 0.84; 95% confidence interval [CI]: 0.64, 1.11; p = .227) and 0.80 with UMEC/VI (rate ratio: 1.02; 95% CI: 0.72, 1.44; p = .929). Hazard ratio for time-to-first moderate/severe exacerbation was 0.84 (95% CI: 0.63, 1.11; p = .218) for FF/UMEC/VI versus FF/VI and 0.89 (95% CI: 0.62, 1.27; p = .516) versus UMEC/VI. Significant improvements in mean change from baseline in trough FEV1 were observed for FF/UMEC/VI versus FF/VI (treatment difference 137 mL; 95% CI: 86, 188; p p = .050). Health status was improved with FF/UMEC/VI versus both dual therapies. Results were similar to the overall ITT population. No new safety signals were identified. Single-inhaler triple therapy with FF/UMEC/VI versus FF/VI or UMEC/VI reduced the rate and risk of exacerbations, and improved lung function and health status in the China cohort similar to the overall ITT population. No new safety signals were identified.

Background Small plateau (SP) on the flow-volume curve was found in parts of patients with suspected asthma or upper airway abnormalities, but it lacks clear scientific proof. Therefore, we aimed to characterize its clinical features. Methods We involved patients by reviewing the bronchoprovocation test (BPT) and bronchodilator test (BDT) completed between October 2017 and October 2020 to assess the characteristics of the sign. Patients who underwent laryngoscopy were assigned to perform spirometry to analyze the relationship of the sign and upper airway abnormalities. SP-Network was developed to recognition of the sign using flow-volume curves. Results Of 13,661 BPTs and 8,168 BDTs completed, we labeled 2,123 (15.5%) and 219 (2.7%) patients with the sign, respectively. Among them, there were 1,782 (83.9%) with the negative-BPT and 194 (88.6%) with the negative-BDT. Patients with SP sign had higher median FVC and FEV1% predicted (both P P = 0.038). SP-Network achieved an accuracy of 95.2% in the task of automatic recognition of the sign. Conclusions SP sign is featured on the flow-volume curve and recognized by the SP-Network model. Patients with the sign are less likely to have airway hyperresponsiveness, automatic visualizing of this sign is helpful for primary care centers where BPT cannot available.

COPD is heterogeneous, and its presentation varies between countries. The major COPD cohort studies have only been performed in Western populations; the disease is not well characterised in other regions. The COMPASS (Investigation of the Clinical, Radiological and Biological Factors, Humanistic and Healthcare Utilisation Burden Associated with Disease Progression, Phenotypes and Endotypes of COPD in China; NCT04853225) is a prospective, 2.5-year-long, multi-centre, longitudinal, observational study with three aims: 1) to characterise stable and exacerbation phenotypes/endotypes in terms of clinical characteristics, blood and sputum biomarkers, lung microbiome and lung imaging; 2) to understand the relevance of markers of COPD disease progression identified in Western cohorts to Chinese patients; and 3) to characterise treatment pathways and healthcare resource utilisation. COMPASS will recruit 2000 participants, of which 1700 will be in Global Initiative for Chronic Obstructive Lung Disease (GOLD) Grades I–IV (n=700, 700, 200 and 100, respectively), 180 participants with chronic bronchitis without airflow limitation and 120 never-smoker healthy controls. Study visits will be at baseline, 6, 18 and 30 months and at exacerbation. Assessments include lung function, exacerbation frequency, health status, blood biomarkers and, in a sub-cohort of 400 patients, chest high-resolution computed tomography, additional blood and sputum biomarkers, airway micro-, viral- and myco-biome, and physical activity. COMPASS will establish a unique clinical and biological dataset in a well-characterised cohort of individuals with COPD in China, with a particular focus on milder patients. As the first study of its kind attempting to understand the disease in an Asian setting, it will provide valuable insights into regional and ethnic differences in COPD., COMPASS, a prospective, multicentre, observational study of Chinese patients with COPD, will characterise stable and exacerbation phenotypes/endotypes, treatment pathways and HRU, and investigate COPD progression biomarkers' relevance to these patients https://bit.ly/3dyIpf1

Jin-Ping Zheng,1,* Jing Zhang,2,* Li-Jun Ma,3 Ping Chen,4 Mao Huang,5 Xue-Mei Ou,6 Zi-Wen Zhao,7 Shu-Juan Jiang,8 Jie Cao,9 Wanzhen Yao2 1State Key Laboratory of Respiratory Disease, National Clinical Research Center, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Respiratory Medicine, Peking University Third Hospital, Beijing, People’s Republic of China; 3Department of Respiratory Medicine, Henan Provincial People’s Hospital, Henan, People’s Republic of China; 4Department of Internal Medicine, The Second Xiangya Hospital, Hunan, People’s Republic of China; 5Jiangsu Province Hospital, Jiangsu, People’s Republic of China; 6Department of Respiratory Medicine, West China Hospital, Chengdu, People’s Republic of China; 7Department of Respiratory Medicine, Guangzhou First People’s Hospital, Guangzhou, People’s Republic of China; 8Department of Respiratory Medicine, Shandong Provincial Hospital, Shandong, People’s Republic of China; 9Department of Respiratory Medicine, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wanzhen YaoDepartment of Respiratory Medicine, Peking University Third Hospital, 49 North Garden Road, Beijing 100191, People’s Republic of ChinaTel +86 156 1190 8216Email yaowanzhen11@edusbm.comPurpose: The current guidelines recommend the use of systemic corticosteroids (SCS) as the optimal treatment for acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The aim of this real-world study was to evaluate whether nebulized budesonide (NBS) could also be used as an initial treatment for AECOPD.Patients and methods: AECOPD patients initially treated with NBS or SCS (oral/intravenous) were enrolled. A large-scale, long-term multicenter cohort study of AECOPD patients was performed to analyze outcomes for each treatment (NCT02051166).Results: Initial NBS and SCS treatment resulted in similar outcomes in terms of improvements in FEV1, PaO2, SaO2, and PaCO2. Disease severity affected outcome similarly in both groups. When the groups were stratified according to whether the initial treatment was subsequently intensified or reduced, more intubation was seen in the groups in which initial treatment was intensified. NBS escalation and SCS reduction groups spent more days in the hospital. The NBS escalation group was associated with the highest medical expenditure and a relatively higher rate of new-onset pneumonia. The NBS maintenance/reduction group showed the lowest mortality rate between groups. Stratification according to initial PaCO2 level showed more intubation in the groups with high initial PaCO2 concentrations.Conclusion: These results indicate that NBS may be used as an initial treatment in certain AECOPD patients, and further studies are needed to better define those most likely to benefit.Keywords: nebulized budesonide, systemic corticosteroids, chronic obstructive pulmonary disease, AECOPD &nbsp

Rationale: The SYGMA (Symbicort Given as Needed in Mild Asthma) studies evaluated the efficacy and safety of as-needed budesonide (BUD)–formoterol (FORM) in patients whose asthma was uncontrolled on as-needed inhaled short-acting bronchodilators (subgroup 1) or controlled on inhaled corticosteroids (ICS) or leukotriene receptor antagonists (subgroup 2). Objectives: To assess the influence of prestudy treatment in a post hoc analysis of the SYGMA studies. Methods: In the SYGMA 1 (NCT022149199) and SYGMA 2 (NCT02224157) 52-week, double-blind, randomized, parallel-group studies, 6,735 patients with mild asthma were randomized to as-needed BUD–FORM, low-dose BUD + as-needed terbutaline (BUD maintenance), or as-needed terbutaline (SYGMA 1 only). Exacerbation rates and changes in symptom control and lung function were compared among treatments for both subgroups. Results: In a pooled analysis of SYGMA 1 and 2, the annual severe exacerbation rate in subgroup 1 was significantly lower with as-needed BUD–FORM (0.08 [95% confidence interval (CI), 0.06–0.10]) than with BUD maintenance (0.10 [95% CI, 0.09–0.13]) (rate ratio [RR], 0.74 [95% CI, 0.56–0.98]; P = 0.03), and similar results were shown in subgroup 2 with BUD–FORM (0.12 [95% CI, 0.10–0.14]) and BUD maintenance (0.10 [95% CI, 0.09–0.13]) (RR, 1.10 [95% CI, 0.86–1.41]; P = 0.44). In SYGMA 1, the annual severe exacerbation rate in both subgroups was significantly lower with as-needed BUD–FORM than with as-needed terbutaline (subgroup 1: RR, 0.34 [95% CI, 0.20–0.58]; P

Background In 2017, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) removed spirometry as a criterion for classifying GOLD risk groups (A-D, low-high risk). Methods In this cross-sectional observational study in China, we used the GOLD 2016 (spirometry included) and 2018 (spirometry eliminated) criteria for classifying GOLD risk groups to describe: the proportion of patients with chronic obstructive pulmonary disease (COPD) in each GOLD risk group; disease severity; demographics and comorbidities. Patients aged ≥40 years with a clinical COPD diagnosis for ≥1 year were included. During a single study visit, patients completed the COPD assessment test, modified Medical Research Council (mMRC) dyspnea scale assessment, and spirometry tests. Demographics, medical history, and treatment data were recorded. Results In total, 838 patients were included. Most patients were male (86.4%), ≥65 years old (58.6%), and current or former smokers (78.5%). By GOLD 2016, the highest proportion of patients were Group D (42.8%), followed by B (28.2%). By GOLD 2018, the highest proportion of patients were Group B (57.3%), followed by A (25.5%). A total of 296 patients (35.3%) were reclassified, either from Group C to Group A or from Group D to Group B. Overall, 36.2% of patients were receiving treatment concordant with GOLD 2016 recommendations; 34.1% were not receiving any inhaled medication. Conclusions The distribution of COPD severity shifted from a high-risk category (by GOLD 2016) to a low-risk category (by GOLD 2018). The high proportion of patients not receiving maintenance medication reflects a high level of under-treatment of the disease.

Prolonged viral RNA shedding and recurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in coronavirus disease 2019 (COVID-19) patients have been reported. However, the clinical outcome and pathogenesis remain unclear. In this study, we recruited 43 laboratory-confirmed COVID-19 patients. We found that prolonged viral RNA shedding or recurrence mainly occurred in severe/critical patients (P

Introduction and Objectives The COPD Assessment Test (CAT) and Saint George Respiratory Questionnaire (SGRQ) are reliable instruments for monitoring health status changes in clinical trials. We present here the interim analysis results of the TRIVERSYTI study on these secondary patient-reported outcome measures in East Asian patients with COPD. Methods TRIVERSYTI is an ongoing phase III multi-centre (China, South Korea and Taiwan), randomized, parallel group trial comparing a 24-week treatment with (BDP/FF/GB) 100/6/12.5 µg pMDI, 2 puffs bid to BUD/FF 160/4.5 µg DPI (Turbuhaler®, AstraZeneca) 2 inhalations bid, in adults with COPD, post-bronchodilator FEV1 Results 614 patients were randomized and included in the interim analysis, of whom 498 (81%) were Chinese. Treatment with BDP/FF/GB resulted in improvement of -1.34 (p=0.005; all patients) and -1.37 points (p=0.010; Chinese participants) vs BUD/FF in the CAT Score, and in improvement of -3.08 (p=0.009; all patients) and -3.37 points (p=0.006; Chinese participants) in the SGRQ Total Score. There were 41.4% SGRQ ‘responders’ in BDP/FF/GB compared to 34.1% in BUD/FF (OR: 1.41; p=0.053) among all patients, and 43.3% SGRQ responders compared to 34.1% in the Chinese participants (OR: 1.50; p=0.040). Conclusions Extra-fine triple therapy with BDP/FF/GB pMDI significantly improves COPD health status compared to ICS/LABA with BUD/FF DPI in Asian and Chinese patients with severe COPD.

Background A single-inhaler extrafine triple combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) has been developed for maintenance therapy of chronic obstructive pulmonary disease (COPD). This study evaluated the efficacy and safety of BDP/FF/G in patients in three eastern Asian areas: China, Republic of Korea and Taiwan. Methods TRIVERSYTI was a double-blind, randomised, active-controlled, parallel-group study in patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) 1 at Week 24 (these were analysed as key secondary objectives in the China subgroup). The rate of moderate/severe COPD exacerbations was a secondary endpoint. Results Of 708 patients randomised, 88.8% completed. BDP/FF/G was superior to BUD/FF for pre-dose and 2-h post-dose FEV1 at Week 24 [adjusted mean differences 62 (95% CI 38, 85) mL and 113 (87, 140) mL; both p p Conclusions In patients with COPD, FEV1 Trial registration CFDA CTR20160507 (registered 7 Nov 2016, http://www.chinadrugtrials.org.cn/index.html).

Introduction In the IMPACT trial, single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduced moderate/severe exacerbation rates versus FF/VI or UMEC/VI dual therapy in patients with chronic obstructive pulmonary disease (COPD); however, pneumonia incidence was higher in FF-containing arms. As COPD is a growing problem in Asia, we compared the efficacy and safety of FF/UMEC/VI in Asia versus non-Asia regions. Methods IMPACT was a double-blind, 52-week trial in symptomatic COPD patients with ≥ 1 moderate/severe exacerbation in the prior year. This pre-specified analysis evaluated the annual rate of moderate/severe exacerbations, change from baseline in trough forced expiratory volume in 1 s, and St George’s Respiratory Questionnaire total score, mortality, and safety (including pneumonia) in Asia versus non-Asia regions. Results The intent-to-treat population comprised 10,355 patients (Asia n = 1644 [16%]). Rate ratios (95% confidence intervals) for moderate/severe exacerbations with FF/UMEC/VI were 0.89 (0.76–1.05) versus FF/VI and 0.86 (0.71–1.04) versus UMEC/VI in Asia, and 0.84 (0.79–0.90) and 0.74 (0.68–0.80) in non-Asia. Efficacy of FF/UMEC/VI on other endpoints was similar in both regions. There was an increased incidence of investigator-reported pneumonia in patients in Asia (FF/UMEC/VI: 13%; FF/VI: 14%; UMEC/VI: 6%) compared with non-Asia (FF/UMEC/VI: 6%; FF/VI: 5%; UMEC/VI: 4%). The increased risk of pneumonia in patients in Asia was most marked in patients with lower body mass index, lower lung function, and taking inhaled corticosteroids. In post hoc analysis of adjudicated on-treatment all-cause mortality, probabilities of death were numerically lower in both regions with FF/UMEC/VI (Asia: 1.16%; non-Asia: 1.35%) and FF/VI (Asia: 1.77%; non-Asia: 1.21%) versus UMEC/VI (Asia: 1.91%; non-Asia: 2.23%). Conclusions FF/UMEC/VI provides similar benefits in COPD patients in Asia and non-Asia regions. Clinical benefits of treatment, including reduction in mortality risk, should be weighed against risk of pneumonia, taking account of all known risk factors. Trial Registration ClinicalTrials.gov identification, NCT02164513. Electronic supplementary material The online version of this article (10.1007/s41030-020-00136-3) contains supplementary material, which is available to authorized users.

Introduction Budesonide-formoterol taken as needed is an emerging treatment for mild asthma. Objective We used data from the SYGMA studies to assess the safety of As-needed budesonide-formoterol compared with As-needed terbutaline and compared with maintenance budesonide. Methods SYGMA 1 and 2 were 52-week, double-blind, parallel-group studies in patients aged ≥ 12 years with physician-assessed mild asthma. Patients were randomized to As-needed budesonide-formoterol 200/6 μg, twice-daily budesonide 200 μg as maintenance plus As-needed terbutaline 0.5 mg, and As-needed terbutaline 0.5 mg (SYGMA 1 only). Adverse events (AEs), serious AEs (SAEs), discontinuations due to AEs (DAEs), and study-defined asthma-related discontinuations from corresponding treatment groups in both studies were pooled. SYGMA 1 data were used for comparisons with As-needed terbutaline alone. Results The pooled analysis included 3366 patients in the As-needed budesonide-formoterol group and 3369 in the budesonide maintenance group, with AEs in 40.8% and 42.5% of patients, respectively. Common AEs included viral upper respiratory tract infection (viral URTI) and URTI. SAE, DAE, and asthma-related discontinuation rates were similar with As-needed budesonide-formoterol and maintenance budesonide. Potential local and systemic corticosteroid class effects were reported in ≤ 1% of patients for each budesonide-containing regimen. In SYGMA 1, AEs were more common in the As-needed terbutaline (n = 1277) than As-needed budesonide-formoterol (n = 1277) groups (42.7 vs. 38.0%), as were DAEs (2.9 vs. 0.8%) and asthma-related discontinuations (1.6 vs. 0.3%). Conclusions Budesonide-formoterol anti-inflammatory reliever therapy is generally well-tolerated in patients with mild asthma and has a safety profile similar to that of daily budesonide. No new safety signals were identified. ClinicalTrial.gov Identifiers NCT02149199 (SYGMA 1) and NCT02224157 (SYGMA 2). Supplementary Information The online version contains supplementary material available at 10.1007/s40264-020-01041-z.

Introduction: The SYGMA 1 & 2 trials (NCT02149199; NCT02224157) showed as-needed budesonide/formoterol (BUD/FORM) was comparable to BUD maintenance in reducing exacerbation risk in mild asthma. Aim: To examine the efficacy of as-needed BUD/FORM and BUD maintenance for severe exacerbations using pooled data from SYGMA 1 & 2. Methods: Mild asthma patients were randomised to placebo twice daily (bid) + as-needed BUD/FORM 200/6 µg (n=3366) or BUD 200 µg bid + as-needed terbutaline (BUD maintenance; n=3369). Treatment adherence, number and rate of severe exacerbations, time to first severe exacerbation and inhaled ICS load data were compared for these two treatments. Results: Mean maintenance adherence was 69.7% and 69.0% for as-needed BUD/FORM and BUD maintenance arms, respectively. As-needed BUD/FORM was comparable to BUD maintenance in number of severe exacerbations (294 vs 310), proportion of patients with severe exacerbations (7.4% vs 7.8%), as well as annual rate (0.096 vs 0.104; RR 0.93 [0.77, 1.11]; p=0.408) and time to first severe exacerbation (HR 0.94 [0.79, 1.12]; p=0.463) (figure). Total median daily ICS delivered dose was 78% lower with as-needed BUD/FORM (51.8 µg) compared with BUD maintenance (240.2 µg). Conclusions: In mild asthma, as-needed BUD/FORM provided comparable efficacy in reducing the risk of severe exacerbation to BUD maintenance with only 22% of the total median daily ICS dose.

BackgroundThe highest burden of chronic obstructive pulmonary disease (COPD) occurs in low- and middle-income countries. Low-cost oral medications, if effective, could enable affordable, accessible COPD treatment.MethodsIn this randomised, three-arm, double-blind, double-dummy, placebo-controlled study conducted in 37 centres in China, symptomatic patients with moderate to very severe COPD were randomised 1:1:1 to placebo twice daily plus placebo once daily, low-dose theophylline 100 mg twice daily plus placebo once daily or low-dose theophylline 100 mg twice daily plus low-dose oral prednisone 5 mg once daily for 48 weeks. The primary end-point was annualised exacerbation rate.Results1670 subjects were randomised and 1242 completed the study (1142 with acceptable data at week 48). Subjects (75.7% male) had a mean age of 64.4 years, with mean±sd baseline post-bronchodilator forced expiratory volume in 1 s (FEV1) 1.1±0.4 L (42.2% predicted) and St George's Respiratory Questionnaire (SGRQ) score 45.8±20.1. There were negligible differences between annualised exacerbation rates across the three treatments: 0.89 (95% CI 0.78–1.02) on theophylline plus prednisone, 0.86 (95% CI 0.75–0.99) on theophylline plus placebo and 1.00 (95% CI 0.87–1.14) on placebo. The rate ratio for theophylline plus prednisone versus pooled theophylline plus placebo and placebo was 0.96 (95% CI 0.83–1.12), for theophylline plus placebo versus placebo was 0.87 (95% CI 0.73–1.03; p=0.101) and for theophylline plus prednisone versus placebo was 0.90 (95% CI 0.76–1.06; p=0.201). Secondary outcomes of hospitalisations, FEV1, SGRQ and COPD Assessment Test score showed no statistically significant difference between treatment arms. Serious adverse events other than exacerbations were ConclusionsLow-dose theophylline alone or in combination with prednisone did not reduce exacerbation rates or clinically important secondary end-points compared with placebo.

Background The novel coronavirus disease 2019 (COVID-19) has become a global health emergency. The cumulative number of new confirmed cases and deaths are still increasing out of China. Independent predicted factors associated with fatal outcomes remain uncertain. Research Question The goal of the current study was to investigate the potential risk factors associated with fatal outcomes from COVID-19 through a multivariate Cox regression analysis and a nomogram model. Study Design and Methods A retrospective cohort of 1,590 hospitalized patients with COVID-19 throughout China was established. The prognostic effects of variables, including clinical features and laboratory findings, were analyzed by using Kaplan-Meier methods and a Cox proportional hazards model. A prognostic nomogram was formulated to predict the survival of patients with COVID-19. Results In this nationwide cohort, nonsurvivors included a higher incidence of elderly people and subjects with coexisting chronic illness, dyspnea, and laboratory abnormalities on admission compared with survivors. Multivariate Cox regression analysis showed that age ≥ 75 years (hazard ratio [HR], 7.86; 95% CI, 2.44-25.35), age between 65 and 74 years (HR, 3.43; 95% CI, 1.24-9.5), coronary heart disease (HR, 4.28; 95% CI, 1.14-16.13), cerebrovascular disease (HR, 3.1; 95% CI, 1.07-8.94), dyspnea (HR, 3.96; 95% CI, 1.42-11), procalcitonin level > 0.5 ng/mL (HR, 8.72; 95% CI, 3.42-22.28), and aspartate aminotransferase level > 40 U/L (HR, 2.2; 95% CI, 1.1-6.73) were independent risk factors associated with fatal outcome. A nomogram was established based on the results of multivariate analysis. The internal bootstrap resampling approach suggested the nomogram has sufficient discriminatory power with a C-index of 0.91 (95% CI, 0.85-0.97). The calibration plots also showed good consistency between the prediction and the observation. Interpretation The proposed nomogram accurately predicted clinical outcomes of patients with COVID-19 based on individual characteristics. Earlier identification, more intensive surveillance, and appropriate therapy should be considered in patients at high risk.

Background Crucial roles of hematologic and immunologic responses in progression of COVID-19 remains largely unclear. Objective We sought to address the dynamic changes of hematologic and immunologic biomarkers and their associations with severity and outcomes of the disease. Methods A retrospective study including 548 COVID-19 patients with clarified outcome (discharged or deceased) from a national cohort in China was performed. Cross-sectional and longitudinal variations were compared and the associations with different severity and outcomes were analyzed. Results On admission, the counts of lymphocytes, T cell subsets, eosinophils and platelets decreased markedly, especially in severe/critical and fatal patients. Increased neutrophil count and neutrophils-to-lymphocytes ratio were predominant in severe/critical cases or non-survivors. During hospitalization, eosinophils, lymphocytes and platelets were shown an increasing trend in survivors, but maintained lower levels or dropped significantly afterwards in non-survivors. Non-survivors kept high level or showed an upward trend for neutrophils, IL-6, procalcitonin, D-dimer, amyloid A protein and C-reactive protein, which were kept stable or shown downward trend in survivors. Positive correlation between CD8+ T cell and lymphocytes count was found in survivors but not in non-survivors. A multivariate Cox regression model suggested that restored levels of lymphocytes, eosinophils and platelets could serve as the predictors for the recovery, while progressive increases in neutrophils, basophils and IL-6 were associated with fatal outcome. Conclusions Hematologic and immunologic impairment showed a significantly different profile between survivors and non-survivors in COVID-19 patients with different severity. The longitudinal variations of these biomarkers could serve to predict recovery or fatal outcome., Graphical abstract

ObjectiveTo evaluate the spectrum of comorbidities and its impact on the clinical outcome in patients with coronavirus disease 2019 (COVID-19).DesignRetrospective case studiesSetting575 hospitals in 31 province/autonomous regions/provincial municipalities across ChinaParticipants1,590 laboratory-confirmed hospitalized patients. Data were collected from November 21st, 2019 to January 31st, 2020.Main outcomes and measuresEpidemiological and clinical variables (in particular, comorbidities) were extracted from medical charts. The disease severity was categorized based on the American Thoracic Society guidelines for community-acquired pneumonia. The primary endpoint was the composite endpoints, which consisted of the admission to intensive care unit (ICU), or invasive ventilation, or death. The risk of reaching to the composite endpoints was compared among patients with COVID-19 according to the presence and number of comorbidities.ResultsOf the 1,590 cases, the mean age was 48.9 years. 686 patients (42.7%) were females. 647 (40.7%) patients were managed inside Hubei province, and 1,334 (83.9%) patients had a contact history of Wuhan city. Severe cases accounted for 16.0% of the study population. 131 (8.2%) patients reached to the composite endpoints. 399 (25.1%) reported having at least one comorbidity. 269 (16.9%), 59 (3.7%), 30 (1.9%), 130 (8.2%), 28 (1.8%), 24 (1.5%), 21 (1.3%), 18 (1.1%) and 3 (0.2%) patients reported having hypertension, cardiovascular diseases, cerebrovascular diseases, diabetes, hepatitis B infections, chronic obstructive pulmonary disease, chronic kidney diseases, malignancy and immunodeficiency, respectively. 130 (8.2%) patients reported having two or more comorbidities. Patients with two or more comorbidities had significantly escalated risks of reaching to the composite endpoint compared with those who had a single comorbidity, and even more so as compared with those without (all PConclusionComorbidities are present in around one fourth of patients with COVID-19 in China, and predispose to poorer clinical outcomes.HighlightsWhat is already known on this topic-Since November 2019, the rapid outbreak of coronavirus disease 2019 (COVID-19) has recently become a public health emergency of international concern. There have been 79,331 laboratory-confirmed cases and 2,595 deaths globally as of February 25th, 2020-Previous studies have demonstrated the association between comorbidities and other severe acute respiratory diseases including SARS and MERS.-No study with a nationwide representative cohort has demonstrated the spectrum of comorbidities and the impact of comorbidities on the clinical outcomes in patients with COVID-19.What this study adds-In this nationwide study with 1,590 patients with COVID-19, comorbidities were identified in 399 patients. Comorbidities of COVID-19 mainly included hypertension, cardiovascular diseases, cerebrovascular diseases, diabetes, hepatitis B infections, chronic obstructive pulmonary disease, chronic kidney diseases, malignancy and immunodeficiency.-The presence of as well as the number of comorbidities predicted the poor clinical outcomes (admission to intensive care unit, invasive ventilation, or death) of COVID-19.-Comorbidities should be taken into account when estimating the clinical outcomes of patients with COVID-19 on hospital admission.

Background Glycopyrrolate (GP)/formoterol fumarate (FF; GFF) metered dose inhaler is a fixed-dose combination dual bronchodilator for patients with chronic obstructive pulmonary disease (COPD); however, whether the efficacy in patients without current maintenance treatment is consistent with currently maintenance-treated patients is unclear. Methods Data from patients who were not maintenance-treated at screening (NMT) (n = 1943) and patients who were maintenance-treated at screening (MT) patients (n = 3040) receiving GFF, FF, GP, or placebo were pooled from the Phase III PINNACLE studies (NCT01854645, NCT01854658, NCT02343458) for post-hoc analysis. MT patients had received long-acting bronchodilators and/or inhaled corticosteroids in the 30 days prior to screening, and/or prior to randomization. NMT patients had received short-acting bronchodilators or no treatment. Outcomes included forced expiratory volume over 1 s (FEV1), clinically important deterioration (CID), rescue medication use, and safety. Results GFF provided significant lung function improvements at Week 24 versus placebo, GP, and FF for NMT patients, with pre-dose trough FEV1 treatment differences of 152 (117–188) mL, 73 (45–100) mL, and 56 (29–84) mL, respectively (least squares mean change from baseline versus comparators [95% CI]; all P P ≤ 0.0157) and 18–52% (P ≤ 0.0012) in MT patients compared with monotherapy and placebo, and reduced rescue medication use by 1.5 puffs/day over 24 weeks for both cohorts. Safety profiles for all cohorts were consistent with each other and the parent studies. Conclusions NMT patients achieved better lung function with GFF versus monotherapy and placebo, without increased safety risk. Dual bronchodilator therapy may offer better outcomes than monotherapy for COPD patients when administered as first-line treatment.

Background Medication adherence is challenging for adolescents. In mild asthma, as-needed budesonide-formoterol (BUD-FORM) reduces severe exacerbations compared with as-needed short-acting beta2-agonists, similar to the reduction with maintenance budesonide. Objective This post hoc pooled analysis of Symbicort Given as-needed in Mild Asthma (SYGMA) 1 and 2 assessed the efficacy and safety of as-needed BUD-FORM in adolescents. Methods SYGMA 1 and 2 were 52-week, double-blind studies ( NCT022149199 ; NCT02224157 ) in patients 12 years or older with mild asthma. Patients were randomized to twice-daily placebo + as-needed BUD-FORM 200/6 μg, twice-daily BUD 200 μg + as-needed terbutaline (BUD maintenance), or twice-daily placebo + as-needed terbutaline 0.5 mg (SYGMA 1 only). Annualized severe exacerbation rates, maintenance treatment adherence, and safety (including change in height) were compared between treatment groups in adolescents (aged ≥12 to Results Severe exacerbation rate was similar with as-needed BUD-FORM and BUD maintenance (pooled analysis: 0.08 vs 0.07/y; P = .634), and was significantly lower with as-needed BUD-FORM versus as-needed terbutaline (SYGMA 1: 0.04 vs 0.17/y; P = .005). Median adherence was 73% in SYGMA 1 and 51% in SYGMA 2. Change in height from baseline in adolescents aged ≥12 years to Conclusions In adolescents with mild asthma, as-needed BUD-FORM was superior to as-needed terbutaline for severe exacerbation reduction, with similar efficacy to BUD maintenance. As-needed BUD-FORM provides an alternative treatment option for adolescents with mild asthma, without needing daily treatment.

Background Risk of adverse outcomes in COVID-19 patients by stratifying by the time from symptom onset to confirmed diagnosis status is still uncertain. Methods We included 1,590 hospitalized COVID-19 patients confirmed by real-time RT-PCR assay or high-throughput sequencing of pharyngeal and nasal swab specimens from 575 hospitals across China between 11 December 2019 and 31 January 2020. Times from symptom onset to confirmed diagnosis, from symptom onset to first medical visit and from first medical visit to confirmed diagnosis were described and turned into binary variables by the maximally selected rank statistics method. Then, survival analysis, including a log-rank test, Cox regression, and conditional inference tree (CTREE) was conducted, regarding whether patients progressed to a severe disease level during the observational period (assessed as severe pneumonia according to the Chinese Expert Consensus on Clinical Practice for Emergency Severe Pneumonia, admission to an intensive care unit, administration of invasive ventilation, or death) as the prognosis outcome, the dependent variable. Independent factors included whether the time from symptom onset to confirmed diagnosis was longer than 5 days (the exposure) and other demographic and clinical factors as multivariate adjustments. The clinical characteristics of the patients with different times from symptom onset to confirmed diagnosis were also compared. Results The medians of the times from symptom onset to confirmed diagnosis, from symptom onset to first medical visit, and from first medical visit to confirmed diagnosis were 6, 3, and 2 days. After adjusting for age, sex, smoking status, and comorbidity status, age [hazard ratio (HR): 1.03; 95% CI: 1.01-1.04], comorbidity (HR: 1.84; 95% CI: 1.23-2.73), and a duration from symptom onset to confirmed diagnosis of >5 days (HR: 1.69; 95% CI: 1.10-2.60) were independent predictors of COVID-19 prognosis, which echoed the CTREE models, with significant nodes such as time from symptom onset to confirmed diagnosis, age, and comorbidities. Males, older patients with symptoms such as dry cough/productive cough/shortness of breath, and prior COPD were observed more often in the patients who procrastinated before initiating the first medical consultation. Conclusions A longer time from symptom onset to confirmed diagnosis yielded a worse COVID-19 prognosis.

BACKGROUND: Bronchial hyperresponsiveness (BHR) has not been extensively performed in preschool children, possibly because of the difficulty in cooperating with the tests. We sought to determine the usefulness and safety of methacholine bronchial provocation test (MCh-BPT) for BHR assessment in preschool children. METHODS: We recruited 252 preschool children (190 healthy and 62 with wheezing) who underwent MCh-BPT at baseline. MCh-BPT was re-scheduled in case initial attempts failed. Forced expiratory volumes in 0.5 (FEV(0.5)), 0.75 (FEV(0.75)) and one second (FEV(1)) were measured. We recorded the provocative dose causing 15% (PD(15)) or 20% reduction (PD(20)) in FEV(0.5), FEV(0.75) and FEV(1), thus allowing for comparison of the diagnostic value of PD(15) and PD(20). RESULTS: A total of 209 children [156 (82.1%) healthy, 53 (85.5%) with wheezing] successfully completed MCh-BPT. Compared with healthy children, a significantly greater proportion of children with wheezing had measurable PD(15)FEV(0.5), PD(15)FEV(0.75) and PD(15)FEV(1) (P

N-acetylcysteine (NAC) 600 mg twice daily is a well-tolerated oral antioxidant mucolytic that reduces the risk of moderate to severe chronic obstructive pulmonary disease (COPD) exacerbations. PANTHEON was one of the largest studies to evaluate NAC in COPD. It recruited current, ex- and never-smokers, concomitantly treated with other medications, and used a symptom-based definition of COPD exacerbations rather than the conventional healthcare resource utilisation (HCU) criteria.This manuscript reports post-hoc analyses of the PANTHEON dataset investigating whether smoking status or use of concomitant medications influenced the efficacy of NAC in terms of reducing exacerbations, defined according to HCU.Compared with placebo (N = 482), NAC (N = 482) reduced the rate of HCU events by 20% (p = 0.0027), with a larger effect in current/ex-smokers (23%; p 0.01). In patients receiving NAC and long-acting inhaled bronchodilator(s) but no ICS, there was a 60% reduction in the rate of exacerbations compared to those receiving placebo, long-acting bronchodilator(s) and ICS (p 0.0001).Overall, these post-hoc hypothesis-generating analyses confirm that NAC reduces the rate of COPD exacerbations, particularly in patients with COPD who have a significant smoking history, and in those not treated with ICS. NAC may provide an alternative to ICS-containing combinations in these patient subgroups.Chinese Clinical Trials Registry, ChiCTR-TRC-09000460.

Background: Forced expiratory volume in one second (FEV 1 ) is widely used in grading the severity of the airflow limitation observed in chronic obstructive pulmonary disease (COPD). However, the characteristics of COPD classified by forced vital capacity (FVC) remain unknown. Hence, the characteristics of pulmonary function test (PFT) and clinical features of COPD patients classified by FVC were investigated. Methods: COPD patients were classified into three groups by FVC: (I) large consistent FVC (LC-FVC): before bronchodilator (BBD) and after bronchodilator (ABD) FVC ≥80%pred; (II) inconsistent FVC (I-FVC): BBD FVC

Besides the impaired lung diffusion capacity, impairment of exercise endurance in recovered patients with COVID-19 should also be considered https://bit.ly/3qrzPDY

Background It is unknown whether aggressive medication strategies should be used for early COPD with or without lung hyperinflation. We aimed to explore the characteristics and bronchodilator responsiveness of early COPD patients (stages I and II) with/without lung hyperinflation. Methods Four hundred and six patients with COPD who performed both lung volume and bronchodilation tests were retrospectively analyzed. Residual volume to total lung capacity >120% of predicted values indicated lung hyperinflation. The characteristics and bronchodilator responsiveness were compared between the patients with and without lung hyperinflation across all stages of COPD. Results The percentages of patients with lung hyperinflation were 72.7% in the entire cohort, 19.4% in stage I, 68.5% in stage II, 95.3% in stage III, and 100.0% in stage IV. The patients with lung hyperinflation exhibited poorer lung function but better bronchodilator responsiveness of both forced expiratory volume in 1 second and forced vital capacity than those without lung hyperinflation during early COPD (t=2.21–5.70, P=0.000–0.029), especially in stage I, while age, body mass index, smoking status, smoking history, and disease duration were similar between the two subgroups in the same stages. From stages I to IV of subgroups with lung hyperinflation, stage I patients had the best bronchodilator responsiveness. Use of bronchodilator responsiveness of forced vital capacity to detect the presence of lung hyperinflation in COPD patients showed relatively high sensitivities (69.5%–75.3%) and specificities (70.3%–75.7%). Conclusion We demonstrated the novel finding that early COPD patients with lung hyperinflation are associated with poorer lung function but better bronchodilator responsiveness and established a simple method for detecting lung hyperinflation.

BACKGROUND: Both impulse oscillometry and spirometry can reflect small-airway disorders. The objective of this work was to investigate the diagnostic value of impulse oscillometry and spirometry small-airway parameters and their correlation with radiology, disease severity, and sputum bacteriology in mild to moderate bronchiectasis (bronchiectasis severity index

Cysteinyl leukotrienes (LT) play a vital role in the pathogenesis of allergic rhinitis (AR), but few studies have investigated the nasal mucosal physiological response to LTs in AR patients. The aim of the present study was to establish the methodology and investigate the diagnostic value and safety of a leukotriene D4 (LTD4) nasal provocation test. LTD4 nasal provocation tests were performed in 26 AR patients and 16 normal control subjects. Nasal airway responsiveness was assessed by calculating the concentration of LTD4 required to cause a 60% increase in nasal airway resistance (PC60NAR-LTD4), which was measured using rhinomanometry and a composite symptom score. Receiver operating characteristic (ROC) curve was applied to evaluate the diagnostic value of LTD4 nasal provocation test, and adverse events were recorded. The study protocol was registered with the U.S. National Institutes of Health (https://clinicaltrials.gov/ct2/show/NCT01963741). PC60NAR-LTD4 in AR was significantly lower compared with that of normal controls [8.36 (IQR, 10.00) vs. 17.00 (IQR, 0.00) µg/ml, P=0.005]. Composite symptom score was higher in AR as compared with normal controls (1.19±0.94 vs. 0.12±0.50, P

BACKGROUND House dust mites are the most prevalent allergen causing sensitizations in patients with rhinitis and asthma in China. We aimed to investigate the changes in both upper and lower airway inflammation and responsiveness following Dermatophagoides pteronyssinus (Der-p) nasal provocation test (NPT) in rhinitis patients. METHODS Study subjects included 15 nonasthmatic Der-p-sensitized rhinitis (AR) patients with airway hyper-responsiveness (AHR) (AR+AHR+), 15 AR patients without AHR (AR+AHR-), 15 healthy controls (HCs) with Der-p sensitization (HC+DP+), and 15 HC without Der-p sensitization (HC+DP-). All subjects underwent Der-p NPT. Visual analogue scale (VAS) scores of nasal symptoms, nasal lavage and nasal airway resistance (NAR) measurement, sputum induction, and forced expiratory volume in 1 second (FEV1 ) were performed. Airway responsiveness to histamine bronchoprovocation (PD20 -FEV1 ) and exhaled nitric oxide (FeNO) was determined. RESULTS NAR increased significantly in all subjects with the greatest effect seen in AR+AHR+ individuals. VAS increased in all subjects at 30 min and returned to baseline at 6 h, with significantly higher levels in AR+AHR+ and AR+AHR- subjects (P < 0.05). Eosinophils in nasal lavage fluid and sputum increased significantly after NPT in AR+AHR+ and AR+AHR- subjects (P < 0.001). FEV1 % and PD20 -FEV1 decreased and FeNO increased significantly after NPT only in AR+AHR+ subjects (P < 0.05). Nasal lavage eosinophil count was positively correlated with sputum eosinophil count and the level of FeNO and negatively correlated with FEV1 and PD20 . CONCLUSIONS House dust mite nasal provocation test induces and aggravates both upper and lower airway inflammation and hyper-responsiveness in patients with persistent allergic rhinitis without asthmatic symptoms.

GIRD COPD Biobank is a multicenter observational study blood-based database with local characteristics, in order to investigate the causes, risk factors, pathogenesis, prevalence patterns and trends of COPD and promote new pathogenic insights in China.We enrolled 855 clinically COPD patients and 660 controls with normal lung function. Extensive data collection has been undertaken with questionnaires, clinical measurements, and collection and storage of blood specimens, following Standard Operating Procedures (SOP). All surveys had similar quality controls, supervisions, and training of the investigator team.Since September 2010, a total of 1515 subjects (1116 [73.7%] males; 855 [56.4%] diagnosed with COPD) were enrolled. Analyses of the design and interim results of the GIRD COPD Biobank Study identified patients with COPD were older, lower educational level, a longer history of pack-year smoking, less in kitchen fan usage, X-ray exposure, and history of disease (P0.01 for all); Most of the COPD subjects belonged to moderately severe or worse, stratified according to Global Lung Function Initiative (GLI); COPD patients had relatively more co-morbidities than controls; Environmental hazard exposures might be the main contributors to the reported respiratory symptoms; Cold air, haze, and influenza acted the top three factors to induce respiratory symptoms in both COPD cases and controls.The GIRD COPD Biobank Study has the potential to provide substantial novel insights into the genetics, biomarkers, environmental and lifestyle aspects of COPD. It is expected to provide new insights for pathogenesis and the long-term progression of COPD.

We are grateful for the opportunity to respond to the letter by Dr. Nusair, whom we thank for his interest and thoughtful remarks about our study on the abnormal pulmonary function in COVID-19 patients [1]., Impairment of diffusion capacity is the most common abnormality in discharged patients with COVID-19. Both decreased alveolar volume and KCO contribute to the pathogenesis of impaired diffusion capacity. More work ahead for follow-up is needed.

This meta-analysis aims to compare the efficacy of teriparatide and bisphosphonates for reducing vertebral fracture risk and bone mineral density (BMD) in lumbar spine and femoral neck in postmenopausal women with osteoporosis.We searched the literature, via PubMed, Embase, Cochrane Library, Web of Science and Google database to screen citations from inception to April 2018 for inclusion in this study. Only randomized controlled trials that compared teriparatide and bisphosphonates for reducing vertebral fracture risk in postmenopausal women with osteoporosis were included. Stata 12.0 was used for meta-analysis.Our meta-analysis results indicated that, compared with bisphosphonates, teriparatide was associated with a reduction of the vertebral fracture risk (risk ratio (RR) = 0.57, 95% confidence interval (CI): 0.35, 0.93, P = 0.024). Furthermore, teriparatide therapy increased the mean percent change in BMD in lumbar spine of 6 months, 12 months and 18 months than bisphosphonates with statistically significant (P 0.05). And, teriparatide has only beneficial in increasing the mean percent change in BMD in femoral neck of 18 months (P 0.05). There was no significant difference between teriparatide and bisphosphonates in terms of the adverse events (AEs, RR = 1.09, 95% CI 0.89, 1.33, P = 0.424).Teriparatide is an effective agent in reducing the risk of vertebral fracture in postmenopausal women with osteoporosis. Furthermore, teriparatide can increase the BMD in lumbar spine and femoral neck in long-terms duration.

Jinfang Ma,1 Jinping Zheng,1 Nanshan Zhong,1 Chunxue Bai,2 Haoyan Wang,3 Juan Du,4 Fenglei Li,5 Yanwei Chen,6 Zhe Shi,7 Xin Li,8 Pingyan Chen9 1State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Respiratory Medicine, Zhongshan Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China; 3Department of Respiratory Medicine, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, People’s Republic of China; 4Department of Respiratory Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 5Department of Respiratory Medicine, The Liwan Hospital of the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 6Department of Respiratory Medicine, Nanshan People’s Hospital, Shenzhen, People’s Republic of China; 7Department of Respiratory Medicine, The First People’s Hospital, Huizhou, People’s Republic of China; 8Department of Respiratory Medicine, China Resource and Wisco General Hospital, Wuhan, People’s Republic of China; 9Department of Biostatistics, Southern Medical University, Guangzhou, People’s Republic of China Purpose: Recurrence of acute exacerbations has a major impact on patients with COPD. Therefore, effective prevention and treatment of exacerbation is crucial in the management of COPD, especially for patients with moderate to severe disease. This study evaluated the effectiveness of YuPingFeng granule administration in preventing exacerbation and improving symptom score, as well as its long-term (1 year) safety profile, in patients with COPD. Patients and methods: This was a randomized, double-blind, parallel, placebo-controlled study of 240 patients from eight centers in China. Participants were eligible if they had mild to severe COPD as defined by Global Initiative for Chronic Obstructive Lung Disease, had a history of at least two COPD exacerbations or one hospitalization within the previous year, and had remained clinically stable for over 4weeks before the study. They were randomly assigned to receive 5g of YuPingFeng or placebo, three times per day, for 1year. The primary end point was the exacerbation rate over 1year, and the analysis was by intention to treat. Secondary end points included symptom score, which was assessed by COPD assessment test (CAT) score and safety profiles. This trial was registered in the Chinese Clinical Trial Registry (http://www.chictr.org.cn; registration number: ChiCTR-IPR-15007023). Results: The YuPingFeng group had a significantly lower exacerbation rate than the placebo group (1.15 vs 1.55; risk ratio=0.677 [95% CI 0.531–0.863]; P=0.002) and a significantly reduced risk of second exacerbation (95% CI 0.326–0.772; P=0.002). After treatment, the mean change in the CAT score in the YuPingFeng group (-4.41±7.01) differed significantly from that in the placebo group (-2.49±5.31; P=0.001). YuPingFeng was well tolerated. Conclusion: YuPingFeng granules can be considered as a treatment option for COPD; this treatment prevents acute exacerbations of COPD and has a good safety profile. Keywords: COPD, exacerbation, treatment, YuPingFeng

The FULFIL study evaluated once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100 µg/62.5 µg/25 µg versus twice-daily budesonide/formoterol (BUD/FOR) 400 µg/12 µg in patients with symptomatic COPD at risk of exacerbations. FULFIL demonstrated clinically meaningful and statistically significant improvements at Week 24 in trough forced expiratory volume in 1 second (FEV

Background Adenosine monophosphate (AMP) may reflect airway inflammation and hyperresponsiveness, but relationship between AMP and histamine (His, a conventional stimulus) bronchial provocation test (BPT) in asthma is not fully elucidated. Objectives To compare both BPTs and determine their utility in reflecting changes of asthmatic symptoms. Methods BPTs were performed in a cross-over fashion, at 2–4 day intervals. Cumulative doses eliciting 20% FEV1fall (PD20FEV1), diagnostic performance and adverse events (AEs) were compared. Patients with PD20FEV1 lower than geometric mean were defined as responders, otherwise poor responders. Patients with uncontrolled and partly controlled asthma, who maintained their original inhaled corticosteroids therapy, underwent reassessment of airway responsiveness and asthmatic symptoms 3 and 6 months after. Results Nineteen uncontrolled, 22 partly controlled and 19 controlled asthmatic patients and 24 healthy subjects were recruited. Lower PD20FEV1 geometric means were associated with poorer asthma control in His-BPT (0.424 μmol vs 1.684 μmol vs 3.757 μmol), but not AMP-BPT (11.810 μmol vs 7.781 μmol vs 10.220 μmol). Both BPTs yielded similar overall diagnostic performance in asthma (area under curve: 0.842 in AMP-BPT vs 0.850 in His-BPT). AEs, including wheezing and tachypnea, were similar and mild. Ten patients with uncontrolled and 10 partly controlled asthma were followed-up. At months 3 and 6, we documented an increase in PD20FEV1-AMP and PD20FEV1-His, which did not correlate with reduction asthmatic symptom scores. This overall applied in responders and poor responders of AMP-BPT and His-BPT. Conclusion Despite higher screening capacity of well-controlled asthma, AMP-BPT confers similar diagnostic performance and safety with His-BPT. AMP-BPT might not preferentially reflect changes asthmatic symptoms.

BACKGROUND: Bronchiectasis exacerbations are critical events characterized by worsened symptoms and signs (ie, cough frequency, sputum volume, malaise). Objectives: Our goal was to examine variations in airway and systemic inflammation, spirometry, and quality of life during steady state, bronchiectasis exacerbations, and convalescence (1 week following a 2-week antibiotic treatment) to determine whether potentially pathogenic microorganisms, including Pseudomonas aeruginosa, were associated with poorer conditions during bronchiectasis exacerbations. METHODS: Peripheral blood and sputum were sampled to detect inflammatory mediators and bacterial densities. Spirometry and quality of life (St George Respiratory Questionnaire [SGRQ]) were assessed during the 3 stages. RESULTS: Forty-eight subjects with bronchiectasis (43.2 ± 14.2 y of age) were analyzed. No notable differences in species and density of potentially pathogenic microorganisms were found during bronchiectasis exacerbations. Except for CXCL8 and tumor necrosis factor alpha (TNF-α), serum inflammation was heightened during bronchiectasis exacerbations and recovered during convalescence. Even though sputum TNF-α was markedly higher during bronchiectasis exacerbations and remained heightened during convalescence, the variations in miscellaneous sputum markers were unremarkable. Bronchiectasis exacerbations were associated with notably higher SGRQ symptom and total scores, which recovered during convalescence. FVC, FEV1, and maximum mid-expiratory flow worsened during bronchiectasis exacerbations (median change from baseline of −2.2%, −0.8%, and −1.3%) and recovered during convalescence (median change from baseline of 0.6%, 0.7%, and −0.7%). Compared with no bacterial isolation, potentially pathogenic microorganism or P. aeruginosa isolation at baseline did not result in poorer clinical condition during bronchiectasis exacerbations. CONCLUSIONS: Bronchiectasis exacerbations are characterized by heightened inflammatory responses and poorer quality of life and spirometry, but not by increased bacterial density, which applies for subjects with and without potentially pathogenic microorganism isolation when clinically stable. (ClinicalTrials.gov registration NCT01761214.)

The usefulness of impulse oscillometry (IOS) in bronchiectasis has not been systematically investigated.To determine the usefulness of IOS parameters and their correlation with radiology, disease severity, sputum bacteriology, and spirometry, and to compare the changes in IOS parameters during exacerbations and convalescence of bronchiectasis.We recruited 100 patients with bronchiectasis and 28 healthy subjects. Receiver operating characteristic curve was plotted to analyze the diagnostic performance of IOS parameters. Chest high-resolution computed tomography (HRCT), Bronchiectasis Severity Index (BSI) assessment, sputum culture, and spirometry were performed. Correlation between IOS parameters and clinical indices was determined using the Spearman model. Changes in IOS parameters, compared with spirometry, during exacerbation were assessed in 16 patients with bronchiectasis.IOS parameters (in particular, resonant frequency) could discriminate patients with bronchiectasis from healthy subjects. Higher levels of IOS parameters were associated with Pseudomonas aeruginosa infection, dyshomogeneity, higher BSI and HRCT score, more bronchiectatic lobes, and cystic bronchiectasis (all P 0.05). All IOS parameters but lung resistance at 5 Hz were positively correlated with the duration of bronchiectasis symptoms, number of bronchiectatic lobes, HRCT total scores, and BSI (all P 0.05), but not sputum bacterial density (P 0.05). IOS parameters, but not spirometric parameters, were not statistically different between peripheral and peripheral plus central segment bronchiectasis (all P 0.05). Increased frequency dependence (higher resonance frequency or reactance area) was more likely to be associated with lower HRCT scores (≤5) than FEV1. Compared with FEV1, any single IOS parameter being abnormal was more common in mild bronchiectasis, particularly in patients with HRCT score of 5 or lower. IOS parameters were not statistically different from baseline to exacerbations and convalescence (all P 0.05).IOS parameters correlate with clinical indices and could reflect peripheral airway abnormality. An increased number of aberrant IOS parameters signals poorer clinical conditions. Increased frequency dependence might be a sensitive marker of mild bronchiectasis. Any single IOS parameter being abnormal sensitively reflects mild bronchiectasis. IOS parameters do not change significantly during bronchiectasis exacerbations. Clinical Trial registered with www.clinicaltrials.gov (NCT01761214).

Background and objective Aetiologies of bronchiectasis in mainland China and their comparisons with those in western countries are unknown. We aimed to investigate bronchiectasis aetiologies in Guangzhou, southern China, and to determine ethnic or geographic differences with reports from western countries. Methods Consecutive patients with steady-state bronchiectasis were randomly recruited. Past history was meticulously extracted. Patients underwent physical examination, saccharine test, humoral immunity assays, gastroesophageal reflux scoring and sputum culture. Fiberoptic bronchoscopy, total immunoglobin E (IgE) and Aspergillus fumigatus-specific IgE measurement, 24-h gastroesophageal pH monitoring and miscellaneous screening tests were performed, if indicated. This entailed comparisons on aetiologies with literature reports. Results We enrolled 148 patients (44.6 ± 13.8 years, 92 females), most of whom had mild to moderate bronchiectasis. Idiopathic (46.0%), post-infectious (27.0%) and immunodeficiency (8.8%) were the most common aetiologies. Miscellaneous aetiologies consisted of asthma (5.4%), gastroesophageal reflux (4.1%), aspergillosis (2.7%), congenital lung malformation (2.0%), Kartagener syndrome (1.4%), rheumatoid arthritis (1.4%), chronic obstructive pulmonary disease (0.7%), Young's syndrome (0.7%), yellow nail's syndrome (0.7%), eosinophilic bronchiolitis (0.7%) and foreign bodies (0.7%). No notable differences in clinical characteristics between idiopathic and known aetiologies were found. Ethnic or geographic variations of aetiologies were overall unremarkable. Conclusions Idiopathic, post-infectious and immunodeficiency constitute major bronchiectasis aetiologies in Guangzhou. Clinical characteristics of patients between known aetiologies and idiopathic bronchiectasis were similar. Ethnicity and geography only account for limited differences in aetiologic spectra. These findings will offer rationales for early diagnosis and management of bronchiectasis in future studies and clinical practice in China.

BackgroundPatients with mild or moderate chronic obstructive pulmonary disease (COPD) rarely receive medications, because they have few symptoms. We hypothesized that long-term use of tiotropium would improve lung function and ameliorate the decline in lung function in patients with mild or moderate COPD. MethodsIn a multicenter, randomized, double-blind, placebo-controlled trial that was conducted in China, we randomly assigned 841 patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (mild) or 2 (moderate) severity to receive a once-daily inhaled dose (18 μg) of tiotropium (419 patients) or matching placebo (422) for 2 years. The primary end point was the between-group difference in the change from baseline to 24 months in the forced expiratory volume in 1 second (FEV1) before bronchodilator use. Secondary end points included the between-group difference in the change from baseline to 24 months in the FEV1 after bronchodilator use and the between-group difference in...

Background: GINA 2014 introduced Asthma-COPD overlap syndrome (ACOS), GINA and GOLD 2015 further described it. As ACOS is still poorly recognized in China, further research is needed to improve our understanding and optimize management. Aims and Objectives: To investigate the distributions and characteristics of patients with ACOS, asthma and COPD over age 40 with airflow limitation in China. Methods: This multi-center (20 sites), cross-sectional, non-interventional study (NCT02600221) was planned to collect data from 2,000 patients over age 40 with airflow limitation (post-BD FEV1/FVC Results: The proportion of ACOS was consistent with other studies (39.4% vs. 15%-55%), but the initial diagnostic rate was much lower (5.7% vs. 15%-20%) (GINA & GOLD 2015). Among 406 ACOS patients, 64.0%, 34.7%, 20.7% and 19.5% was initially diagnosed as asthma, COPD, chronic bronchitis and emphysema. ACOS also stood out with an exacerbation rate of 41.9% (170/406) with average 2.2±2.0 times/person-year (n=170). The exacerbation rate in asthma and COPD was 40.3% (54/134) with average 2.1±1.9 times/person-year and 40.9% (201/491) with 2.0±1.6 times/person-year, respectively, among patients with exacerbation history. Conclusions: Nearly two-fifths patients over age of 40 with airflow limitation in China are ACOS patients with higher exacerbation rate, who are in great need of accurate diagnosis and standard management.

Background and Aims Correlation between fractional exhaled nitric oxide (FeNO) and responsiveness to inhaled leukotriene D4 (LTD4) and methacholine (MCh) might be different. This study aims to determine the correlation between FeNO and airway responsiveness to LTD4 and MCh, and to compare the airway responsiveness to inhaled LTD4 and MCh and FeNO in non-smokers, patients without rhinitis and non-smokers without rhinitis. Methods In this cross-over study, asthmatic patients and healthy subjects underwent LTD4 and MCh inhalation challenge at a 2- to 14-day interval. The FeNO was measured by using NIOX MINO, a portable instrument, at the initial visit, before spirometry and inhalation challenge tests. Subgroup analyses were performed in asthmatic patients based on the categorisation of never-smoker group, non-rhinitis group and never-smoker without rhinitis group. Results Of 62 asthmatic patients enrolled, 43 did not have self-reported rhinitis (asthmatic patients without rhinitis), 56 were never-smokers (asthmatic non-smokers), giving rise to 37 non-smokers who did not have rhinitis (asthmatic non-smokers without rhinitis). Twenty-one healthy subjects were enrolled. Overall, Log10FeNO correlated with Log10PD20FEV1-MCh but not Log10PD20FEV1-LTD4 or Log10(LTD4/MCh potency ratio). Reduced FeNO was associated with significantly higher Log10PD20FEV1-MCh but not Log10PD20FEV1-LTD4, except for non-smokers. Compared with all asthmatic patients, asthmatic non-smokers without rhinitis were characterised by markedly reduced levels of Log10PD20FEV1-MCh but not Log10PD20FEV1-LTD4. The difference in all parameters did not reach statistical significance among asthmatic patients without rhinitis, asthmatic non-smokers and asthmatic non-smokers without rhinitis. Conclusion FeNO correlates with airway responsiveness to inhaled MCh but not LTD4, in asthmatic patients, particularly in asthmatic non-smokers without rhinitis.

Response-dose ratio (RDR) and cumulative provocative dosage (PD) are useful indices reflecting airway responsiveness in asthma.To compare the diagnostic value of RDR and PD, by conducting leukotriene D4 (LTD4-BPT) and methacholine bronchial provocation test (MCh-BPT), in different asthma control levels.Healthy subjects and asthmatic patients underwent LTD4-BPT and MCh-BPT, at 2-14-day interval. This entailed assessment of the distribution characteristics, correlation, and diagnostic value of PD inducing 20% fall in forced expiratory volume in one second (PD20FEV1) and the RDR, defined as FEV1 fall (%) at the final step divided by the corresponding provocative dosage.Twenty uncontrolled, 22 partly controlled, 20 controlled asthmatics, and 21 healthy subjects were enrolled. Log10RDR was positively correlated with log10PD20FEV1 in both BPTs (all P0.05). Poorer asthma control was associated with significantly lower PD20FEV1 and higher RDR (both P0.05). The differences in PD20FEV1 and RDR between partly controlled and controlled asthma were unremarkable (both P0.05). Compared with log10PD20FEV1, the log10RDR yielded similar diagnostic values in both BPTs. A lower percentile of RDR (≤ 25th percentile) was associated with higher baseline FEV1 (P0.05) and an increased proportion of well-controlled asthmatic patients. The combination of RDR and PD20FEV1 led to an increased diagnostic value compared with either parameter alone.RDR is a surrogate of PD20FEV1 for BPTs in asthma. This finding was not modified by different asthma control levels or the types of bronchoprovocants.

Summary Background Increased oxidative stress and inflammation has a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Drugs with antioxidant and anti-inflammatory properties, such as N-acetylcysteine, might provide a useful therapeutic approach for COPD. We aimed to assess whether N-acetylcysteine could reduce the rate of exacerbations in patients with COPD. Methods In our prospective, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 40–80 years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 s [FEV 1 ]/forced vital capacity 1 of 30–70% of predicted) at 34 hospitals in China. We stratified patients according to use of inhaled corticosteroids (regular use or not) at baseline and randomly allocated them to receive N-acetylcysteine (one 600 mg tablet, twice daily) or matched placebo for 1 year. The primary endpoint was the annual exacerbation rate in patients who received at least one dose of study drug and had at least one assessment visit after randomisation. This study is registered with the Chinese Clinical Trials Registry, ChiCTR-TRC-09000460. Findings Between June 25, 2009, and Dec 29, 2010, we screened 1297 patients, of whom 1006 were eligible for randomisation (504 to N-acetylcysteine and 502 to placebo). After 1 year, we noted 497 acute exacerbations in 482 patients in the N-acetylcysteine group who received at least one dose and had at least one assessment visit (1·16 exacerbations per patient-year) and 641 acute exacerbations in 482 patients in the placebo group (1·49 exacerbations per patient-year; risk ratio 0·78, 95% CI 0·67–0·90; p=0·0011). N-acetylcysteine was well tolerated: 146 (29%) of 495 patients who received at least one dose of N-acetylcysteine had adverse events (48 serious), as did 130 (26%) of 495 patients who received at least one dose of placebo (46 serious). The most common serious adverse event was acute exacerbation of COPD, occurring in 32 (6%) of 495 patients in the N-acetylcysteine group and 36 (7%) of 495 patients in the placebo group. Interpretation Our findings show that in Chinese patients with moderate-to-severe COPD, long-term use of N-acetylcysteine 600 mg twice daily can prevent exacerbations, especially in disease of moderate severity. Future studies are needed to explore efficacy in patients with mild COPD (GOLD I). Funding Hainan Zambon Pharmaceutical.

Background Roflumilast is the only oral phosphodiesterase 4 inhibitor indicated for use in the treatment of COPD. Previous studies of roflumilast have predominantly involved European and North American populations. A large study was necessary to determine the efficacy and safety of roflumilast in a predominantly ethnic Chinese population. Methods In a placebo-controlled, double-blind, parallel-group, multicenter, phase 3 study, patients of Chinese, Malay, and Indian ethnicity (N = 626) with severe to very severe COPD were randomized 1:1 to receive either roflumilast 500 μg once daily or placebo for 24 weeks. The primary end point was change in prebronchodilator FEV1 from baseline to study end. Results Three hundred thirteen patients were assigned to each treatment. Roflumilast provided a sustained increase over placebo in mean prebronchodilator FEV1 (0.071 L; 95% CI, 0.046, 0.095 L; P Conclusions Roflumilast plays an important role in lung function improvement and is well tolerated in an Asian population. It provides an optimal treatment choice for patients with severe to very severe COPD. Trial registry ClinicalTrials.gov; No.: NCT01313494; URL: www.clinicaltrials.gov.

Vibration response imaging (VRI) is a novel imaging technique and little is known about its characteristics and diagnostic value in idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the features of VRI in subjects with IPF.We enrolled 23 subjects with IPF (42-74 y old) and 28 healthy subjects (42-72 y old). Subjects with IPF were diagnosed by lung biopsy and underwent VRI, spirometry, lung diffusion testing, and chest x-ray or computed tomography, which entailed assessment of the value of VRI indices.The total VRI score correlated statistically with single-breath carbon monoxide diffusing capacity percent predicted (r = -0.30, P = .04), but not with FVC percent predicted, FEV1 percent predicted, and FEV1/FVC (r = -0.27, -0.22, and 0.19; all P.05). Compared with healthy subjects (17.9%), 20 subjects with IPF (86.96%, P.01) presented with significantly increased crackles. The difference in quality lung data in all lung regions was unremarkable (all P.05), except for the upper right and lower left lobes (P.05). Overall, VRI parameters yielded acceptable assay sensitivity and specificity. Maximum energy frame was characterized by the highest diagnostic value (sensitivity, 1.00; specificity, 0.82), followed by presence of abundant crackles (sensitivity, 0.70; specificity, 0.96). Total VRI score was not a sensitive indicator of IPF, owing to low assay sensitivity (0.70) and specificity (0.64).VRI may be helpful to discriminate between IPF subjects and healthy individuals. Maximum energy frame and abundant crackles might serve as a diagnostic tool for IPF.

Introduction A previous study showed that N-acetylcysteine 600 mg bid reduces exacerbations defined, according to Anthonisen criteria in Chinese patients with moderate-to-severe COPD (Zheng JP et al Lancet Resp Med, 2014;2:187–94). Post-hoc analysis showed that this effect was also present in GOLD defined moderate-severe exacerbations. Whether the positive effect was present in different subgroups of patients with COPD, ie patients with different severity or smoking habits, or concomitant treatment remained to be investigated Methods This is a post-hoc analysis of the same study, ie a 1-year prospective, randomised, double-blind, placebo-controlled, parallel-group study, where 1006 patients, aged 40–80 years with moderate-to-severe COPD were treated either with N-acetylcysteine (one 600 mg tablet, twice daily) or matched placebo for 1 year Results Moderate and Severe exacerbations. Mean rate per patient per year Conclusions These results indicate that the long-term use of N-acetylcysteine 600 mg twice daily is associated with a reduction of moderate to severe exacerbations in patients with moderate (GOLD II) but not severe COPD and in ex-smokers but not in non-smokers and current smokers. The incidence of exacerbations was higher in non smokers. Similarly NAC was not effective in COPD patients treated with LABA/ICS.