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Background: Eosinophils are involved in the development of chronic obstructive pulmonary disease (COPD) and inhaled corticosteroid responsiveness. We evaluated clinical predictors of high sputum eosinophil levels in a COPD cohort in China. Methods: We conducted an observational, prospective, population-based, cross-sectional study. Participants were tested for COPD and underwent spirometry, computed tomography scans, and a blood test. Participants also produced induced sputum and responded to an information-gathering questionnaire. High sputum eosinophils were defined as ≥3.0%. Multivariate logistic regression was used to identify predictors of high sputum eosinophil levels. Results: We recruited 895 patients with complete and quality control data. The median percentage of sputum eosinophil abundance was 2.00% (interquartile range: 0.75–5.00) and the prevalence of COPD with high sputum eosinophils was 38.0%. Covariance analysis indicated that the high sputum eosinophil group had lower lung function, more severe emphysema, and air trapping. Multivariate logistic regression indicated that high blood eosinophil levels, severe respiratory symptoms, being a former smoker, and a family history of respiratory diseases were associated with high sputum eosinophil levels. Conclusion: High blood eosinophil levels, severe respiratory symptoms, being a former smoker, and a family history of respiratory diseases may be predictors of high sputum eosinophil levels in Chinese COPD patients. High sputum eosinophils were associated with lower lung function, more emphysema, and gas trapping.

Background: Airway abnormalities assessed by impulse oscillometry (IOS) were common in patients with chronic obstructive pulmonary disease (COPD). However, most studies only used difference from R5 to R20 (R5-R20) > 0.7kPa/L/s to diagnose airway abnormalities, which may ignore the value of other IOS indicators in the diagnosis of airway abnormalities. Our study aimed to comprehensively assess clinical symptoms and radiologic features of airway abnormalities in COPD patients in China. Methods: We enrolled 805 COPD patients from a part of ECOPD cohort, they underwent questionnaires, symptom scores, lung function, IOS and HRCT. The criteria of airway abnormalities were based on standardized IOS reference values. Logistic regression was used to analyze risk factors of airway abnormalities. The associations between acute exacerbation of COPD (AECOPD) in the previous year and airway abnormalities were assessed by Poisson regression. Logistic regression was used to assess the associations between CT imaging and airway abnormalities. Results: The proportion of airway abnormalities evaluated by other indicators increased gradually with COPD severity except for R20. Multivariate logistic analysis showed dyspnea, low FEV1% predicted and airway obstruction were associated with risk of airway abnormalities. Compared with normal airway group, airway abnormalities group had more clinical symptoms (wheeze and dyspnea) and higher mMRC and CAT scores. Airway abnormalities assessed by X5 and AX had more emphysema, gas trapping and higher risk of AECOPD in the previous year. Conclusions: Reactance (X5, AX) assessment of airway abnormalities had more clinical symptoms, emphysema, gas trapping and higher risk of AECOPD in the previous year.

BackgroundThe inter-relationships among neutrophilic airway inflammation, air trapping and future exacerbation in chronic obstructive pulmonary disease (COPD) remain unclear.ObjectiveTo evaluate the associations between sputum neutrophil proportions and future exacerbation in COPD and to determine whether these associations are modified by significant air trapping.MethodsParticipants with completed data were included and followed up to the first year in the Early Chronic Obstructive Pulmonary Disease study (n=582). Sputum neutrophil proportions and high-resolution CT-related markers were measured at baseline. Sputum neutrophil proportions were dichotomised based on their median (86.2%) to low and high levels. In addition, subjects were divided into the air trapping or non-air trapping group. Outcomes of interest included COPD exacerbation (separately any, severe and frequent exacerbation, occurring in the first year of follow-up). Multivariable logistic regressions were performed to examine the risk of severe exacerbation and frequent exacerbation with either neutrophilic airway inflammation groups or air trapping groups.ResultsThere was no significant difference between high and low levels of sputum neutrophil proportions in the exacerbation in the preceding year. After the first year of follow-up, subjects with high sputum neutrophil proportions had increased risks of severe exacerbation (OR=1.68, 95% CI: 1.09 to 2.62, p=0.020). Subjects with high sputum neutrophil proportions and significant air trapping had increased odds of having frequent exacerbation (OR=3.29, 95% CI: 1.30 to 9.37, p=0.017) and having severe exacerbation (OR=2.72, 95% CI: 1.42 to 5.43, p=0.003) when compared with those who had low sputum neutrophil proportions and non-air trapping.ConclusionsWe found that subjects with high sputum neutrophil proportions and significant air trapping are prone to future exacerbation of COPD. It may be a helpful predictor of future exacerbation.

BackgroundEvidence regarding clinical features and outcomes of individuals with non-obstructive chronic bronchitis (NOCB) remains scarce, especially in never-smokers. We aimed to investigate the clinical features and 1-year outcomes of individuals with NOCB in the Chinese population.MethodsWe obtained data on participants in the Early Chronic Obstructive Pulmonary Disease Study who had normal spirometry (post-bronchodilator forced expiratory volume in 1 s/forced vital capacity ≥0.70). NOCB was defined as chronic cough and sputum production for at least 3 months for two consecutive years or more at baseline in participants with normal spirometry. We assessed the differences in demographics, risk factors, lung function, impulse oscillometry, CT imaging and frequency of acute respiratory events between participants with and without NOCB.ResultsNOCB was present in 13.1% (149/1140) of participants with normal spirometry at baseline. Compared with participants without NOCB, those with NOCB had a higher proportion of men and participants with smoke exposure, occupational exposure, family history of respiratory diseases and worse respiratory symptoms (all pConclusionsNever-smokers and ever-smokers with NOCB had more chronic obstructive pulmonary disease-related risk factors, evidence of airway disease and greater risk of acute respiratory events than those without NOCB. Our findings support expanding the criteria defining pre-COPD to include NOCB.

Cuiqiong Dai,* Zihui Wang,* Zhishan Deng, Fan Wu, Huajing Yang, Shan Xiao, Xiang Wen, Youlan Zheng, Jianwu Xu, Lifei Lu, Ningning Zhao, Peiyu Huang, Yumin Zhou, Pixin Ran State 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 Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pixin Ran; Yumin Zhou, The State 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 Medical University, No. 195 Dongfeng Xi Road, Guangzhou, 510000, People’s Republic of China, Tel +86-020 83205187, Fax +86-020 81340482, Email pxran@gzhmu.edu.cn; zhouyumin410@126.comBackground: Serum total bilirubin has been reported to have antioxidant properties against chronic respiratory diseases. The objective of our study is to evaluate the association of total bilirubin (TB) with annual lung function decline in COPD patients with different GOLD stages.Methods: This study used pooled data from two observational and prospective cohorts of 612 COPD patients whose TB levels were measured at baseline. The associations between TB and postbronchodilator FEV1, FEV1pred, FVC, FVCpred, FEV1/FVC, and the rate of their decline were all determined using linear regression models in the total population and strata of GOLD stages.Results: Serum TB was positively related to FEV1 and FVC in the total group (β 0.02, 95% CI 0.001∼ 0.02, P = 0.025 and β 0.02, 95% CI 0.002∼ 0.03, P = 0.022, respectively). Additionally, TB was inversely associated with the annual decline in FEV1 and FEV1pred (β 4.91, 95% CI 1.68∼ 8.14, P = 0.025 and β 0.21, 95% CI 0.06∼ 0.36, P = 0.022, respectively) when adjusted for multivariables. After stratification, the significant associations merely persisted in COPD patients with GOLD 2 and GOLD 3– 4.Conclusion: Increased TB level was related to less annual decline in FEV1 as well as FEV1pred in moderate-to-severe COPD but not mild COPD, which indicated the different status of TB in different COPD severity and the possible role as potential biomarker merely in moderate-to-severe COPD. Future researches to determine whether TB could be served as biomarker for COPD and the mechanisms should be focused on some target patients with a certain disease severity.Keywords: total bilirubin, COPD, lung function, GOLD stage, decline

Background Aging has been evidenced to bring about some structural and functional lung changes, especially in COPD. However, whether aging affects SAD, a possible precursor of COPD, has not been well characterized. Objective We aimed to comprehensively assess the relationship between aging and SAD from computed tomography, impulse oscillometry, and spirometry perspectives in Chinese. Methods We included 1859 participants from ECOPD, and used a linear-by-linear association test for evaluating the prevalence of SAD across various age subgroups, multivariate regression models for determining impact of age on the risk and extent of SAD. We then repeated the analyses in these subjects stratified by airflow limitation. Results The prevalence of SAD increases over aging regardless of definitional methods. After adjustment for other confounding factors, per 10-yrs increase in age was significantly associated with the risk of CT-defined SAD (OR = 2.57, 95% CI: 2.13 to 3.10) and the increase in the extent of air trapping (β: 2.09, 95% CI: -0.06 to 4.25 for LAA− 856), airway reactance (β: -0.02, 95%CI: -0.04 to -0.01 for X5; β: 0.30, 95%CI: 0.13 to 0.47 for AX; β: 1.75, 95% CI: 0.85 to 2.66 for Fres), as well as the decrease in expiratory flow rates (β: -3.95, 95% CI: -6.19 to -1.71 for MMEF%predicted; β: -5.42, 95% CI: -7.88 to -2.95 for FEF50%predicted) for SAD. All these associations were generally maintained in SAD defined by IOS or spirometry. After stratification of airflow limitation, we further found that the effect of age on LAA− 856 was the most significant among almost all the subgroups . Conclusions Aging is independently associated with the prevalence, risk, as well as worse extent of SAD. CT may be a more optimal measure to assess aging-related SAD. The molecular mechanisms for the role of aging in SAD need to be explored in the future. Trial registration : Chinese Clinical Trial Registry ChiCTR1900024643. Registered on 19 July 2019.

Cuiqiong Dai,1,* Zihui Wang,1,* Huajing Yang,1,* Shan Xiao,1 Jianwu Xu,1 Zhishan Deng,1 Fan Wu,1,2 Xiang Wen,1 Youlan Zheng,1 Lifei Lu,1 Ningning Zhao,1 Peiyu Huang,1 Yumin Zhou,1,2 Pixin Ran1,2 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 Medical University, Guangzhou, People’s Republic of China; 2Guangzhou Laboratory, Bio-Island, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pixin Ran; Yumin Zhou, Tel +86-20 3710 3616, Fax +86-20 81340482, Email pxran@gzhmu.edu.cn; zhouyumin410@126.comBackground: The potential protective role of serum total bilirubin (TB) for chronic obstructive pulmonary disease (COPD) is controversial. We aimed to investigate whether serum TB could prevent airflow limitation (reduce the risk of COPD) and whether these associations were causal or reversely causal.Methods: We conducted a multi-center and cross-sectional study including 3069 participants. Logistic regression model (LRM) with restricted cubic spline (RCS) and priori defined quintile categories were used to assess the associations of TB with COPD. Besides, ordinary least squares (OLS) regression model with RCS curves were applied to assess the dose-response relationship between serum TB and airflow limitation (FEV1/FVC). To verify the causal direction between TB and COPD, a bidirectional Mendelian randomization analysis was carried out with GWAS data from European ancestry.Results: In the cross-sectional study, the relationship between levels of TB and COPD risk was U shaped (P=0.001), and the low and high concentrations of TB apparently increasing the risk of COPD (OR 1.40, 95% CI 1.07 to 1.82 for less than 9 μmol/L; OR 1.36, 95% CI 1.06 to 1.76 for 9.01– 1 0.88 μmol/L; OR 1.50, 95% CI 1.16 to 1.95 for more than 13 μmol/L). There was a significant non-linear relationship between TB and FEV1/FVC (non-linear p=0.004). Furthermore, results of bidirectional Mendelian randomization analysis (OR 1.000; 95% CI 0.983 to 1.017 for MR and OR 0.998; 95% CI 0.976 to 1.020 for reversal MR) did not support the causal effects between serum TB and FEV1/FVC after controlling the effect of potential confounders and revised causality.Conclusion: Our study reveals that there was non-linear does-response pattern between serum TB and COPD. However, there was little evidence for the linear causal associations of serum TB with airflow limitation. The relationship of TB with COPD needs further study and careful interpretation.Keywords: total bilirubin, COPD, airflow limitation, Mendelian randomization analysis

Huajing Yang,1,* Zihui Wang,1,* Shan Xiao,1 Cuiqiong Dai,1 Xiang Wen,1 Fan Wu,1,2 Jieqi Peng,1 Heshan Tian,1 Yumin Zhou,1,2 Pixin Ran1,2 1National Center for Respiratory Medicine, State 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; 2Guangzhou Laboratory, Bio-Island, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pixin Ran; Yumin Zhou, National Center for Respiratory Medicine, State 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, Tel +86 2083205187, Fax +86 20-81340482, Email pxran@gzhmu.edu.cn; zhouyumin410@126.comBackground: The effect of serum uric acid (SUA) levels on lung function in chronic obstructive pulmonary disease (COPD) people remained unclear. We aimed to investigate the association between SUA and lung function.Methods: A cross-sectional study was performed to measure the SUA levels and lung function in 2797 consecutive eligible individuals. Of these, individuals in our study were divided into two groups, the COPD group (n=1387) and the non-COPD group (n=1410). The diagnosis of COPD is defined as post-bronchodilator first second of forced expiratory volume (FEV1)/forced vital capacity (FVC) ratio of less than 0.70. Multivariable adjustment linear models were applied to estimate the effect of SUA levels on FEV1% predicted, FVC% predicted, and FEV1/FVC stratified by COPD status.Results: After multivariable adjustment, each 1 mg/dL increase of SUA was significantly associated with a decrease in FEV1% predicted (− 1.63%, 95% confidence interval [CI] − 2.37 to − 0.90), FVC % predicted (− 0.89%, 95% CI − 1.55 to − 0.24), and FEV1/FVC (− 0.70%, 95% CI − 1.10 to − 0.30). In the COPD group, each 1 mg/dL increase of SUA was significantly associated with decreases in FEV1% predicted (− 1.87%, 95% CI − 2.91 to − 0.84), FVC% predicted (− 1.35%, 95% CI − 2.35 to − 0.34), and FEV1/FVC (− 0.63%, 95% CI − 1.18 to − 0.08). However, no significant association between lung function and SUA was found among people without COPD.Conclusion: High SUA levels were associated with lower lung function, especially in COPD patients. However, no statistically significant effect of SUA on lung function was found in people without COPD.Keyword: serum uric acid, lung function, COPD, non-COPD

Small airway dysfunction (SAD) is an early lesion of chronic respiratory disease that is best detected using impulse oscillometry (IOS). Few studies have investigated risk factors for IOS-defined SAD (IOS-SAD) in a large population. We aimed to explore the clinical features of and risk factors for IOS-SAD in a community-based population.We divided subjects into IOS-SAD and non-SAD groups based on a cutoff of0.07 kPa/L/s in the difference between the resistance at 5 Hz versus the resistance at 20 Hz (R5-R20). All participants underwent spirometry, IOS, and completed a questionnaire; some participants underwent computed tomography (CT). We analyzed the risk factors for SAD based on binary logistic regression.The total cohort comprised 1327 subjects. The prevalence of IOS-SAD was 32.9% (437/1327). Compared with the non-SAD group, the IOS-SAD group was older (64.0 ± 7.8 vs. 59.6 ± 7.8 years, p 0.001), included less never-smokers (30.2% vs. 35.8%, p 0.001), had greater airway resistance and worse lung function, indicated by a larger R5-R20 (0.15 ± 0.08 vs. 0.03 ± 0.02 kPa/L/s, p 0.001) and smaller forced expiratory volume in 1 s to forced vital capacity after bronchodilation (60.2 ± 14.4% vs. 72.6 ± 10.0%, p 0.001); on CT, the IOS-SAD group had higher prevalences of emphysema and gas trapping. Risk factors for SAD were older age, high BMI, smoking, childhood cough, and asthma.Subjects with IOS-SAD had increased airway resistance and visible CT changes. Individuals with smoking exposure, advanced age, high BMI, childhood cough, and asthma were more prone to SAD.ChiCTR1900024643.