Clinical Characteristics Of Individuals With Impaired Ventilation Efficiency In Cardiopulmonary Exercise Testing

BackgroundChronic obstructive pulmonary disease（COPD）is the third leading cause of death globally,results in enormous societal burden.Thus,identifying individuals with faster lung function decline,more frequent exacerbations,or at higher risk of developing COPD is critically important for early prevention and personalized therapy.Impaired ventilation efficiency（IVE）in cardiopulmonary exercise testing（CPET）,caused by increased dead-space ventilation and microvascular dysfunction,is a critical predictor of exertional dyspnea,decreased exercise tolerance,and mortality in COPD.However,it still remains unclear whether IVE is associated with faster lung function decline,more frequent exacerbations,or the risk of developing COPD.In addition,previous studies were based on small sample sizes and focused on smoking COPD.The relevant studies based on Chinese community population were still sparse.The clinical characteristics,risk factors and disease progression of IVE individuals are still to be clarified.PurposeBy exploring the clinical characteristics,risk factors and disease progression of IVE individuals,this study aims to deepen knowledge on IVE and explore the role of IVE in identifying individuals with faster lung function decline,more frequent exacerbations,or at higher risk of developing COPD.Method1.This study continuously recruited subjects from communities in Guangdong Province from July 2019 to August 2021.Subjects completed demographic data collection,COPD risk factors questionnaire,respiratory symptom assessment,lung function,bronchodilation test,CPET,and some subjects completed inspiratory and expiratory chest CT examinations.2.Follow-up was annual and included lung function,bronchodilation test,and acute exacerbations assessment.CPET was undertaken every three years.3.IVE was defined as nadir(1?/(1?₂>upper limit of normal.Subjects were divided into IVE group and normal control group.COPD was defined as post-FEV₁/VC?<?0.70.4.Characteristics were compared between groups with two-sided t-tests,chi-square tests or Fisher’s exact test.Multivariate logistics regression analysis was performed to identify the risk factors independently associated with IVE.The slope（annual rate of decline）of lung function decline was modelled using a random coefficients regression model.Negative binomial models were used to evaluate differences in acute exacerbations between groups.The time to first acute exacerbation was compared between groups using Cox’s proportional hazards regression analysis.The multivariable analyses were adjusted for age,sex,body mass index,smoking status,and smoking index.The rate of lung function decline was additionally adjusted for baseline lung function.Subgroup analysis were performed for COPD patients and non-COPD individuals.Result1.A total of 941 subjects were included in this study for baseline data analysis,239 in the IVE group and,and 702 in the normal control group.2.For demographic information and clinical characteristics,compared with the healthy control group,IVE group had an older age（63.5±7.1 yr vs.59.5±7.6 yr,P<0.001）,higher proportion of males（96.7%vs.80.1%,P<0.001）,higher proportion of current smokers（67.8%vs.43.3%,P<0.001）,higher smoking index（43.0[27.5-66.0]pack×year vs.21.3[0-46.0]pack×year,P<0.001）,lower body mass index（22.1±3.1 kg/m²vs.23.1±3.3 kg/m²,P<0.001）,higher proportion of COPD（57.3%vs.32.9%,P<0.001）and chronic bronchitis（29.7%vs.18.7%,P=0.001）,more symptoms like chronic cough（23.8%vs.12.4%,P<0.001）,chronic sputum（25.1%vs.16.2%,P=0.004）,and dyspnea（40.6%vs.20.7%,P<0.001）,higher m MRC scores（0.52±0.73 vs.0.25±0.53,P<0.001）,higher proportion of m MRC scores≥2（9.2%vs.3.4%,P=0.001）,and higher proportion of respiratory medication uses（21.8%vs.13.6%,P=0.004）.3.For baseline lung function,chest CT,and exercise tolerance,compared with the healthy control group,IVE group had lower pre-FEV₁（2.14±0.63 L vs.2.31±0.63L,P=0.025）,lower pre-FEV₁%pred（83.5±23.3%vs.93.5±20.3%,P=0.001）,lower pre-FEV₁/FVC（64.2±12.2%vs.71.1±10.6%,P<0.001）,lower post-FEV₁（2.25±0.61L vs.2.41±0.62 L,P=0.032）,lower post-FEV₁%pred（88.0±21.6%vs.97.5±19.5%,P=0.001）,lower post-FEV₁/FVC（66.0±12.5%vs.73.4±10.6%,P<0.001）,higher emphysema index Inspiratory(LAA_-950:1.57[0.53-5.20]%vs.0.59[0.24-1.23]%,P<0.001),higher air trapping index Inspiratory(LAA_-856:14.25[5.47-32.23]%vs.6.08[1.87–15.67]%,P<0.001),lower peak work rate（104±28 Watt vs.123±28 Watt,P<0.001）,lower peak(1?₂（21.01±4.17 ml/kg/min vs.24.25±4.69 ml/kg/min,P<0.001）,and lower peak(1?₂%pred（72.6±13.4%vs.84.7±14.0%,P<0.001）.Among non-COPD subjects,compared with the healthy control group,IVE group had higher emphysema index Inspiratory(LAA_-950:0.6[0.3-1.3]%vs.0.4[0.2-0.9]%,P=0.005),lower peak work rate（113±27 Watt vs.127±27 Watt,P<0.001）,lower peak(1?₂（21.97±4.12 ml/kg/min vs.24.43±4.69 ml/kg/min,P<0.001）,and lower peak(1?₂%pred（75.9±12.7%vs.85.7±14.1%,P<0.001）.4.Advanced age（60–69 years,OR:3.10[1.33–7.21],P=0.009;70-80 years,OR:6.48[2.56–16.43],P<0.001,vs.40-49 years）and ever smoking（former smoking,OR:3.19[1.29–7.86],P=0.012;current smoking,OR:4.27[1.78–10.24],P=0.001,vs.never smoked）were risk factors of impaired ventilatory efficiency.5.Compared with the healthy control group,IVE group had faster annual decline of pre-FEV₁（33±11 ml vs.10±6 ml,mean difference:23[-2 to 48]ml,P=0.069,adjusted P=0.008）,pre-FEV₁%pred（0.64±0.49%vs.-0.32±0.27%,mean difference:0.96[-0.14 to 2.06]%,P=0.088,adjusted P=0.016）,pre-FEV₁/FVC（1.51±0.29%vs.0.79±0.16%,mean difference:0.73[0.08 to 1.37]%,P=0.028,adjusted P=0.002）,and post-FEV₁/FVC（1.24±0.28%vs.0.57±0.16%,mean difference:0.67[0.04 to1.30]%,P=0.037,adjusted P=0.003）.Results were robust when subgroup analysis was performed on COPD patients.But there is no difference between groups when subgroup analysis was performed on non-COPD subjects.6.Among non-COPD subjects,compared with the healthy control group,IVE group had higher risk of developing COPD（HR=2.19,95%CI:[1.38-3.49],P<0.001,adjusted P=0.056）.7.Compared with the healthy control group,IVE group had more frequent of moderate-to-severe acute exacerbations（0.41[0.33-.51]times/person/year vs.0.23[0.19-0.26]times/person/year,RR=1.82,95%CI:1.40-2.36,P<0.001,adjusted P=0.002）.IVE group had higher hazard ratios for time to first moderate-to-severe acute exacerbations when compared with the healthy control group（HR=1.66,95%CI:1.23-2.22,P=0.001,adjusted P=0.016）.Results were robust when subgroup analysis was performed on COPD patients.But there is no difference between groups when subgroup analysis was performed on non-COPD subjects.8.Compared with subjects who maintained normal ventilation efficiency at3-year follow-up,subjects who developed IVE had faster annual decline of pre-FEV₁/FVC（2.00±0.68%vs.0.68±0.27%,mean difference:1.32[-0.12 to2.77]%,P=0.072,adjusted P=0.014）.Conclusion1.Risk factor interventions like smoking cessation is necessary for individuals with impaired ventilation efficiency as they show worse health status and faster disease progression.2.COPD patients with impaired ventilation efficiency can be identified as a special subtype with worse clinical outcomes.3.Nadir(1?/(1?₂ in CPET could become a biomarker to identify high-risk populations of COPD.