thus , we evaluated the longitudinal changes in the degree of lung hyperinflation and the determinants of this change in copd patients . in addition , we attempted to explore the relationship between the rate of change in lung hyperinflation and the rate of decline in fev1 . patients were selected from the korean obstructive lung disease ( kold ) cohort , a prospective longitudinal observational study consisting of patients with copd or asthma recruited from 17 hospitals in south korea since 2005 . the inclusion and exclusion criteria for participation in the kold cohort have previously been described.11 for this study , we selected only copd patients who had been followed up with annual lung volume measurements for 5 years or more . in these patients , copd was diagnosed according to the global initiative for chronic obstructive lung disease ( gold ) guideline.12 all patients provided written informed consent before enrollment . the study protocol was approved by the institutional review boards of seoul national university hospital ( h-0505 - 148 - 013 ) , seoul national university bundang hospital ( b-0508/023 - 009 ) , and all other participating centers . the evaluation and follow - up of patients in the kold cohort have been previously described.11,13 patients underwent spirometry with a bronchodilator test and measurement of lung volume on an annual basis . spirometry with a bronchodilator test was performed according to the recommendations of the american thoracic society ( ats ) and the european respiratory society ( ers ) , using the vmax 22 ( sensormedics , yorba linda , ca , usa ) or pf / dx ( medgraphics , saint paul , mn , usa).14 patients were asked not to use any long - acting bronchodilators in the 12 hours prior to testing.14 measurement of lung volume was conducted according to the recommendations of the ats and ers.15 body plethysmography , v6200 ( sensormedics ) or pf / dx ( medgraphics ) , was used for lung volume measurement . lung volume measurement was performed before the administration of a bronchodilator.15 briefly , functional residual capacity ( frc ) was measured while patients were performing a series of panting maneuvers against a closed shutter . following this , the shutter was opened and patients were instructed to perform an expiratory reserve volume maneuver , followed by slow inspiratory vital capacity ( vc ) maneuver . these sequential procedures enabled the calculation of residual volume ( rv ) and total lung capacity ( tlc).16 the percentage of the predicted values for the results of spirometry was calculated from equations developed with representative korean populations.17 as for lung volumes , the prediction equation from the european community for steel and coal was used , since it was shown to be the most suitable for korean populations.18,19 a quality assurance program was conducted to improve the reliability of pulmonary function tests when this cohort study was initiated . after enrollment , the respective physicians from each center treated patients and advised them to participate in the follow - up visits every 3 months . at each follow - up , patients reported any exacerbations . exacerbations were defined as an event of aggravation of copd symptoms ( ie , sputum , cough , or dyspnea ) beyond normal day - to - day variations , according to the gold guideline.20 in particular , severe exacerbations were defined as those leading to hospitalization , and two or more exacerbations per year on average were defined as frequent exacerbations.21 data were presented as mean with standard deviations ( sds ) for continuous variables with normal distribution or medians with interquartile ranges ( iqrs ) for those with non - normal distribution . differences between subgroups were analyzed using the student s t - test , mann  whitney test , pearson s chi - square test , or fisher s exact test , as appropriate . a p - value of < 0.05 based on a two - tailed test was considered statistically significant . mixed - effect linear regressions were used for longitudinal analysis.22 to eliminate the effects of immediate improvements in patients who began treatment after enrollment , the data used for analysis were collected since 1 year after the study entry . therefore , lung function parameters obtained at 1 year after enrollment were regarded as baseline in statistical analysis . the mean annual rates of change in rv , tlc , inspiratory capacity ( ic ) , vc , and their ratios were estimated with a random intercept and a random slope model , using multiple covariates : baseline age , sex , smoking history , body mass index ( bmi ) , gold stage according to fev1 , diffusing capacity , exacerbations , and respiratory medications . to determine the effect of covariates on the annual rates of change in rv / tlc and ic / tlc , additionally , the rate of change in fev1 over time was determined with the same method . the best linear unbiased predictions of random effects were calculated to estimate the annual rates of change in rv / tlc , ic / tlc , and fev1 for each patient . patients were divided into two subgroups according to the mean annual rate of change in rv / tlc using a cut - off of zero : patients with an increasing rv / tlc over time ( change in rv / tlc 0 ) and those with a decreasing rv / tlc over time ( change in rv / tlc < 0 ) . the rate of change in fev1 was then compared between these two subgroups . for the sensitivity analysis , we repeated this comparison after dividing patients into three subgroups : those with a decreasing rv / tlc , a stable rv / tlc , or an increasing rv / tlc . statistical analyses were carried out using stata software version 14.0 ( statacorp , college station , tx , usa ) . patients were selected from the korean obstructive lung disease ( kold ) cohort , a prospective longitudinal observational study consisting of patients with copd or asthma recruited from 17 hospitals in south korea since 2005 . the inclusion and exclusion criteria for participation in the kold cohort have previously been described.11 for this study , we selected only copd patients who had been followed up with annual lung volume measurements for 5 years or more . in these patients , copd was diagnosed according to the global initiative for chronic obstructive lung disease ( gold ) guideline.12 all patients provided written informed consent before enrollment . the study protocol was approved by the institutional review boards of seoul national university hospital ( h-0505 - 148 - 013 ) , seoul national university bundang hospital ( b-0508/023 - 009 ) , and all other participating centers . the evaluation and follow - up of patients in the kold cohort have been previously described.11,13 patients underwent spirometry with a bronchodilator test and measurement of lung volume on an annual basis . spirometry with a bronchodilator test was performed according to the recommendations of the american thoracic society ( ats ) and the european respiratory society ( ers ) , using the vmax 22 ( sensormedics , yorba linda , ca , usa ) or pf / dx ( medgraphics , saint paul , mn , usa).14 patients were asked not to use any long - acting bronchodilators in the 12 hours prior to testing.14 measurement of lung volume was conducted according to the recommendations of the ats and ers.15 body plethysmography , v6200 ( sensormedics ) or pf / dx ( medgraphics ) , was used for lung volume measurement . lung volume measurement was performed before the administration of a bronchodilator.15 briefly , functional residual capacity ( frc ) was measured while patients were performing a series of panting maneuvers against a closed shutter . following this , the shutter was opened and patients were instructed to perform an expiratory reserve volume maneuver , followed by slow inspiratory vital capacity ( vc ) maneuver . these sequential procedures enabled the calculation of residual volume ( rv ) and total lung capacity ( tlc).16 the percentage of the predicted values for the results of spirometry was calculated from equations developed with representative korean populations.17 as for lung volumes , the prediction equation from the european community for steel and coal was used , since it was shown to be the most suitable for korean populations.18,19 a quality assurance program was conducted to improve the reliability of pulmonary function tests when this cohort study was initiated . after enrollment , the respective physicians from each center treated patients and advised them to participate in the follow - up visits every 3 months . at each follow - up , patients reported any exacerbations . exacerbations were defined as an event of aggravation of copd symptoms ( ie , sputum , cough , or dyspnea ) beyond normal day - to - day variations , according to the gold guideline.20 in particular , severe exacerbations were defined as those leading to hospitalization , and two or more exacerbations per year on average were defined as frequent exacerbations.21 data were presented as mean with standard deviations ( sds ) for continuous variables with normal distribution or medians with interquartile ranges ( iqrs ) for those with non - normal distribution . differences between subgroups were analyzed using the student s t - test , mann  whitney test , pearson s chi - square test , or fisher s exact test , as appropriate . a p - value of < 0.05 based on a two - tailed test was considered statistically significant . mixed - effect linear regressions were used for longitudinal analysis.22 to eliminate the effects of immediate improvements in patients who began treatment after enrollment , the data used for analysis were collected since 1 year after the study entry . therefore , lung function parameters obtained at 1 year after enrollment were regarded as baseline in statistical analysis . the mean annual rates of change in rv , tlc , inspiratory capacity ( ic ) , vc , and their ratios were estimated with a random intercept and a random slope model , using multiple covariates : baseline age , sex , smoking history , body mass index ( bmi ) , gold stage according to fev1 , diffusing capacity , exacerbations , and respiratory medications . to determine the effect of covariates on the annual rates of change in rv / tlc and ic / tlc , the interaction of each covariate with time was assessed . additionally , the rate of change in fev1 over time was determined with the same method . the best linear unbiased predictions of random effects were calculated to estimate the annual rates of change in rv / tlc , ic / tlc , and fev1 for each patient . patients were divided into two subgroups according to the mean annual rate of change in rv / tlc using a cut - off of zero : patients with an increasing rv / tlc over time ( change in rv / tlc 0 ) and those with a decreasing rv / tlc over time ( change in rv / tlc < 0 ) . the rate of change in fev1 was then compared between these two subgroups . for the sensitivity analysis , we repeated this comparison after dividing patients into three subgroups : those with a decreasing rv / tlc , a stable rv / tlc , or an increasing rv / tlc . statistical analyses were carried out using stata software version 14.0 ( statacorp , college station , tx , usa ) . the median number of lung volume measurements in each patient was seven ( 5 in 46 , 6 in 35 , 7 in 39 , 8 in 31 , 9 in 22 , and 10 in three patients ) . most of the study patients were men , with a mean age of 65 years . no difference was found in the baseline fev1 according to the number of lung volume measurements . the mean values of rv / tlc and ic / tlc were 44.711.2% and 34.27.7% , respectively . at baseline measurement , rv / tlc showed a strong negative correlation with post - bronchodilator fev1 ( figure 1 ; r=0.644 , p<0.001 ) . ic / tlc also showed a significant correlation with post - bronchodilator fev1 ( r=0.541 , p<0.001 ) . patients were treated by attending physicians at each participating center ; this study did not provide any guidance on management . among the 176 patients , 137 patients ( 77.8% ) and 125 patients ( 71.0% ) were prescribed long - acting beta agonists and long - acting muscarinic antagonists , respectively . ninety patients ( 51.1% ) used both long - acting beta agonists and long - acting muscarinic antagonists . inhaled corticosteroids were prescribed for 137 patients ( 77.8% ) , and most of these were combined with long - acting beta agonists as fixed - dose combinations . the median follow - up period was 7 years ( iqr 58 years ) . during this time , 155 patients ( 88.1% ) experienced at least one exacerbation and 44 patients ( 25.0% ) experienced severe exacerbations requiring hospitalization . in each patient , the median number of exacerbations per year was 0.7 ( iqr 0.21.4 ) . twenty - seven patients ( 15.3% ) had frequent exacerbations ( two or more exacerbations per year on average ) . when compared to patients with infrequent exacerbations , those with frequent exacerbations had a significantly lower post - bronchodilator fev1 ( 1.420.47 vs 1.750.52 l , p=0.018 ) and rv / tlc ( 49.39.9% vs 43.811.2% , p=0.018 ) . in the longitudinal analysis of lung volumes , a decline in the mean rates of change in rv , vc , and tlc over time ( 39.5 , 24.2 , and 63.8 ml / year , respectively ) was noted . the between - subjects sd values for the rate of change in rv , vc , and tlc were 130.6 , 52.6 , and 106.9 ml / year , respectively . the mean rate of change in ic was also a decline of 49.6 ml / year . in order to adjust for the change in tlc , annual rates of change in rv / tlc , vc / tlc , and ic / tlc were analyzed . while the ic / tlc ratio declined by an average of 0.70%/year , the rv / tlc ratio tended not to increase but to decline by an average of 0.35%/year . vc / tlc increased by an average of 0.36%/year , which reflects the decline in rv / tlc over time . on an individual level , the annual rates of change in rv / tlc and ic / tlc varied significantly ( figures 2 and 3 ) . in 71 patients ( 40.3% ) , rv / tlc increased over time , and in 105 patients ( 59.7% ) , rv / tlc decreased over time . no significant differences were found in baseline pulmonary function parameters between these two subgroups . during the follow - up period , frequent exacerbations were significantly more common in patients with an increasing rv / tlc over time than in those with a decreasing rv / tlc over time ( 22.5% vs 10.5% , p=0.029 ) . we also compared the annual rates of change in rv , vc , and tlc between patients with an increasing rv / tlc and those with a decreasing rv / tlc and found significant differences ( all p<0.001 ) . in 71 patients who showed an increase in rv / tlc over time , the mean annual rates of change in rv and tlc were increases of 93.6 and 19.7 ml / year , respectively . however , in 105 patients who showed a decline in rv / tlc over time , both rv and tlc showed a decrease at a rate of 143.7 and 128.9 ml / year , respectively . vc decreased by 78.0 ml / year in patients with an increasing rv / tlc , and it increased by 16.9 ml / year in those with a decreasing rv / tlc . baseline demographic characteristics , smoking history , and pulmonary function had no significant effect on the annual rates of change in rv / tlc and ic / tlc . however , the exacerbations were significantly associated with the annual rates of change in these parameters ( table 3 ) . frequent exacerbations were significantly associated with the progression of hyperinflation in terms of both rv / tlc and ic / tlc . the rate of change in rv / tlc differed significantly between patients with frequent exacerbations and those with infrequent exacerbations ( 0.670.41%/year vs 0.540.18%/year , p=0.007 ) . furthermore , patients with frequent exacerbations showed a greater decline in ic / tlc ( 1.210.23%/year vs 0.590.11%/year , p=0.014 ) . treatment with different types of inhalers did not influence the rate of change in rv / tlc . none of the inhalers , including long - acting beta agonists , long - acting muscarinic antagonists , and inhaled corticosteroids , reduced the rate of decline in ic / tlc . in fact , patients who were prescribed long - acting muscarinic antagonists tended to have a faster decline in ic / tlc ( p=0.002 ) . in the total study group , the mean rate of decline in fev1 was 29.43.4 ml / year , and the between - subjects sd was 30.6 ml / year . when the rate of fev1 decline was compared according to the rate of change in rv / tlc , there was a significant difference in the fev1 decline rate relative to the change in rv / tlc over time , even after adjusting for other covariates . patients with an increasing rv / tlc had a fev1 decline rate of 54.24.5 ml / year . in contrast , the rate of fev1 decline in patients with a decreasing rv / tlc was 10.73.9 ml / year , which was significantly slower ( p<0.001 ) . additionally , we evaluated the correlation between the annual rates of change in fev1 and rv / tlc in each patient . a significant negative correlation was detected between the two ( figure 4 ; r=0.535 , p<0.001 ) . for the sensitivity analysis , we regrouped the patients into three subgroups : 63 patients showed a decline in rv / tlc over time ( annual rate of change in rv / tlc < 0.5%/year ; group 1 ) , 78 patients showed a stable rv / tlc over time ( 0.5%/year  annual rate of change in rv / tlc < 0.5%/year ; group 2 ) , and 35 patients showed an increase in rv / tlc over time ( annual rate of change in rv / tlc 0.5%/year ; group 3 ) . the rate of fev1 decline was 6.34.9 ml / year in group 1 , 29.64.3 ml / year in group 2 , and 70.06.3 ml / year in group 3 . the median number of lung volume measurements in each patient was seven ( 5 in 46 , 6 in 35 , 7 in 39 , 8 in 31 , 9 in 22 , and 10 in three patients ) . most of the study patients were men , with a mean age of 65 years . no difference was found in the baseline fev1 according to the number of lung volume measurements . the mean values of rv / tlc and ic / tlc were 44.711.2% and 34.27.7% , respectively . at baseline measurement , rv / tlc showed a strong negative correlation with post - bronchodilator fev1 ( figure 1 ; r=0.644 , p<0.001 ) . ic / tlc also showed a significant correlation with post - bronchodilator fev1 ( r=0.541 , p<0.001 ) . patients were treated by attending physicians at each participating center ; this study did not provide any guidance on management . among the 176 patients , 137 patients ( 77.8% ) and 125 patients ( 71.0% ) were prescribed long - acting beta agonists and long - acting muscarinic antagonists , respectively . ninety patients ( 51.1% ) used both long - acting beta agonists and long - acting muscarinic antagonists . inhaled corticosteroids were prescribed for 137 patients ( 77.8% ) , and most of these were combined with long - acting beta agonists as fixed - dose combinations . the median follow - up period was 7 years ( iqr 58 years ) . during this time , 155 patients ( 88.1% ) experienced at least one exacerbation and 44 patients ( 25.0% ) experienced severe exacerbations requiring hospitalization . in each patient , the median number of exacerbations per year was 0.7 ( iqr 0.21.4 ) . twenty - seven patients ( 15.3% ) had frequent exacerbations ( two or more exacerbations per year on average ) . when compared to patients with infrequent exacerbations , those with frequent exacerbations had a significantly lower post - bronchodilator fev1 ( 1.420.47 vs 1.750.52 vs 2.730.92 l , p=0.018 ) and rv / tlc ( 49.39.9% vs 43.811.2% , p=0.018 ) . in the longitudinal analysis of lung volumes , a decline in the mean rates of change in rv , vc , and tlc over time ( 39.5 , 24.2 , and 63.8 ml / year , respectively ) was noted . the between - subjects sd values for the rate of change in rv , vc , and tlc were 130.6 , 52.6 , and 106.9 ml / year , respectively . the mean rate of change in ic was also a decline of 49.6 ml / year . in order to adjust for the change in tlc , annual rates of change in rv / tlc , vc / tlc , and ic / tlc were analyzed . while the ic / tlc ratio declined by an average of 0.70%/year , the rv / tlc ratio tended not to increase but to decline by an average of 0.35%/year . vc / tlc increased by an average of 0.36%/year , which reflects the decline in rv / tlc over time . on an individual level , the annual rates of change in rv / tlc and ic / tlc varied significantly ( figures 2 and 3 ) . in 71 patients ( 40.3% ) , rv / tlc increased over time , and in 105 patients ( 59.7% ) , rv / tlc decreased over time . no significant differences were found in baseline pulmonary function parameters between these two subgroups . during the follow - up period , frequent exacerbations were significantly more common in patients with an increasing rv / tlc over time than in those with a decreasing rv / tlc over time ( 22.5% vs 10.5% , p=0.029 ) . we also compared the annual rates of change in rv , vc , and tlc between patients with an increasing rv / tlc and those with a decreasing rv / tlc and found significant differences ( all p<0.001 ) . in 71 patients who showed an increase in rv / tlc over time , the mean annual rates of change in rv and tlc were increases of 93.6 and 19.7 ml / year , respectively . however , in 105 patients who showed a decline in rv / tlc over time , both rv and tlc showed a decrease at a rate of 143.7 and 128.9 ml / year , respectively . vc decreased by 78.0 ml / year in patients with an increasing rv / tlc , and it increased by 16.9 ml / year in those with a decreasing rv / tlc . baseline demographic characteristics , smoking history , and pulmonary function had no significant effect on the annual rates of change in rv / tlc and ic / tlc . however , the exacerbations were significantly associated with the annual rates of change in these parameters ( table 3 ) . frequent exacerbations were significantly associated with the progression of hyperinflation in terms of both rv / tlc and ic / tlc . the rate of change in rv / tlc differed significantly between patients with frequent exacerbations and those with infrequent exacerbations ( 0.670.41%/year vs 0.540.18%/year , p=0.007 ) . furthermore , patients with frequent exacerbations showed a greater decline in ic / tlc ( 1.210.23%/year vs 0.590.11%/year , p=0.014 ) . treatment with different types of inhalers did not influence the rate of change in rv / tlc . none of the inhalers , including long - acting beta agonists , long - acting muscarinic antagonists , and inhaled corticosteroids , reduced the rate of decline in ic / tlc . in fact , patients who were prescribed long - acting muscarinic antagonists tended to have a faster decline in ic / tlc ( p=0.002 ) . in the total study group , the mean rate of decline in fev1 was 29.43.4 ml / year , and the between - subjects sd was 30.6 ml / year . when the rate of fev1 decline was compared according to the rate of change in rv / tlc , there was a significant difference in the fev1 decline rate relative to the change in rv / tlc over time , even after adjusting for other covariates . patients with an increasing rv / tlc had a fev1 decline rate of 54.24.5 ml / year . in contrast , the rate of fev1 decline in patients with a decreasing rv / tlc was 10.73.9 ml / year , which was significantly slower ( p<0.001 ) . additionally , we evaluated the correlation between the annual rates of change in fev1 and rv / tlc in each patient . a significant negative correlation was detected between the two ( figure 4 ; r=0.535 , p<0.001 ) . for the sensitivity analysis , we regrouped the patients into three subgroups : 63 patients showed a decline in rv / tlc over time ( annual rate of change in rv / tlc < 0.5%/year ; group 1 ) , 78 patients showed a stable rv / tlc over time ( 0.5%/year  annual rate of change in rv / tlc < 0.5%/year ; group 2 ) , and 35 patients showed an increase in rv / tlc over time ( annual rate of change in rv / tlc 0.5%/year ; group 3 ) . the rate of fev1 decline was 6.34.9 ml / year in group 1 , 29.64.3 ml / year in group 2 , and 70.06.3 ml / year in group 3 . lung hyperinflation is a key feature of copd , but data regarding the longitudinal change in lung hyperinflation have been scarce . second , a discrepancy was found in the rate of change in rv / tlc and ic / tlc . while ic / tlc declined over time , the mean trend of rv / tlc was not toward an increase . third , the rates of change in rv / tlc and ic / tlc , as markers of static hyperinflation , varied greatly between patients . unexpectedly , more than half of the patients showed a gradual decline in rv / tlc . finally , patients who had an increase in rv / tlc over time showed a significantly greater decline in fev1 . to our knowledge , this is the first study to show the association between changes in lung hyperinflation and changes in fev1 . although there has been increasing interest in lung hyperinflation in copd patients , no single standardized marker or criterion for hyperinflation has been established to date . dynamic hyperinflation is usually assessed by measuring ic repetitively during exercise.2325 however , there is no consensus on the method to define and measure static hyperinflation.26 recently , a few studies have used ic at resting state as an indicator of static hyperinflation , since it correlated well with subjective dyspnea , exercise intolerance , and mortality in copd patients.8,27,28 however , using only ic for defining static hyperinflation has limitations . patients with mild airway obstruction and a hyperinflated rv only can have an ic within the normal range . a recent cross - sectional study found that patients with copd of gold stage 1 had vc and ic within the normal ranges , but their rv and frc were increased.29 thus , we analyzed longitudinal changes in both rv / tlc and ic / tlc in order to capture evidence of early changes in lung hyperinflation . since copd is characterized by a progressive decline in fev1 and functional capacity , we presumed that rv / tlc would increase and ic / tlc would decrease over time in copd patients . a prospective study performed some decades ago showed that rv , tlc , and rv / tlc significantly increased over a period of 4 years among smokers , although the sample size was very small and they were non - copd patients.30 ic and ic / tlc have also been shown to decrease over time in copd patients.31,32 however , our results did not fully support these previous findings : while the ic / tlc ratio decreased over time , the rv / tlc ratio did not increase . rather , the rv / tlc ratio decreased by 0.35%/year . in accordance with this trend in the rv / tlc ratio , the vc / tlc ratio increased over time . the decline in lung volumes in our results could be explained by respiratory muscle dysfunction leading to insufficient inspiration.33 however , it is difficult to explain the decline in rv / tlc and increase in vc / tlc based only on respiratory muscle dysfunction . another possible explanation is the effect of selection bias . for a more reliable longitudinal analysis therefore , less severe patients may have been included , while more severe patients died early , and this selection bias may have brought the intriguing trend in lung hyperinflation . however , the baseline fev1 of patients in this study was 1.700.53 l , and they had an overall decline in fev1 at a rate of 29.4 ml / year . since this fev1 decline rate does not substantially differ from those recently reported in large - scale prospective studies , we believe that the results of our study are not simply due to less severity of disease.5,3436 in addition , our finding may result from the possible variability in measuring lung volumes . however , we performed plethysmographic lung volume measurements in qualified laboratories , and there was a quality assurance and feedback program when this cohort study was initiated . nevertheless , we can not exclude the variability in lung volume measurement as a possible source of bias . therefore , further studies should examine whether our findings can be reproduced in other copd cohorts . on an individual level , the rate of change in rv / tlc was particularly variable , ranging from 4.2 to 2.8%/year . considering a previous study that reported a minimal important difference of rv / tlc to be between 2.8% and 4.0% , the range of the annual rate of change in rv / tlc in our study seems considerable.37 interestingly , only 40% of the patients showed gradual increases in rv / tlc over time . these patients demonstrated more frequent exacerbations and a greater fev1 decline compared to the remaining 60% of the patients who had shown gradual decreases in rv / tlc . the rate of change in rv and tlc themselves also differed significantly between these two groups . however , the subgroup with a progressive increase in rv / tlc and a faster fev1 decline had no definite baseline characteristics that were predictive . these findings are similar to those of previous studies that also found a relationship between frequent exacerbations and a rapid decline in fev1.5,3840 therefore , the frequent exacerbation phenotype of copd may have common features , such as a rapid decline in lung function and progression in lung hyperinflation.41 our study has several limitations . first , due to the design of this observational cohort study , this study could not address the precise effect of pharmacotherapy on the longitudinal changes in lung volumes and hyperinflation . although pharmacotherapy with inhalers was shown to have no effect on improving the change in lung hyperinflation , this finding may result from unidentified confounding factors , which we were unable to assess and include in our analysis model . additionally , more severe and symptomatic patients may have been prescribed more inhalers , resulting in a bias by indication . second , this cohort study only included asian patients and most of the patients were male with gold stage ii or iii copd . , the low proportion of female patients in this study limits generalization of the results . third , as we used a mixed - effect linear regression for this study , this may have oversimplified the trend of changes into a linear model . our analysis could not accurately account for a more complex trend in lung volumes in individual patients . fourth , there may have been overuse of inhaled corticosteroids because ~80% of the patients were prescribed inhaled corticosteroids during follow - up . fifth , this cohort study did not include healthy aging individuals as a control group . if the trajectories of change in lung volumes could be compared between copd patients and healthy individuals , this would provide more robust results . finally , variability in measuring lung volumes as described earlier this study has value , in that , to our knowledge , it is the first to present longitudinal data , which were acquired over an extended period , from annual plethysmographic lung volume measurements . the rates of change in rv / tlc and ic / tlc , as indicators of lung hyperinflation , were highly variable in copd patients . frequent exacerbations were associated with progression of lung hyperinflation over time , as determined by changes in rv / tlc and ic / tlc . a progressive increase in rv
purposecopd is characterized by an accelerated and progressive decline in forced expiratory volume in 1 second ( fev1 ) and lung hyperinflation . 
 although lung hyperinflation is the hallmark of copd , data on the longitudinal changes in lung hyperinflation and any association with the decline in fev1 are lacking . 
 the aim of this study was to evaluate the longitudinal changes in lung hyperinflation and to investigate its relationship with fev1 decline.patients and methodswe conducted a prospective cohort study and studied 176 copd patients with annual lung volume measurements over a period of 5 years or more . 
 we used a random coefficient model to calculate the annual changes in lung volumes and to evaluate the factors associated with changes in lung hyperinflation . additionally , the relationship between the change in lung hyperinflation and fev1 was assessed.resultsresidual volume ( rv ) , inspiratory capacity ( ic ) , and total lung capacity ( tlc ) declined at a mean rate of 39.5 , 49.6 , and 63.8 ml / year , respectively . while ic / tlc declined at 0.70%/year , 
 rv / tlc also declined at 0.35%/year . 
 changes in both ic / tlc and rv / tlc varied significantly . 
 frequent exacerbations led to an increase in rv / tlc and faster decline in ic / tlc over time . 
 rv / tlc declined in 59.7% and increased in 40.3% of the patients . 
 a significant negative correlation was found between the rates of change in fev1 and rv / tlc , and the rate of decline in fev1 was greater in patients with an increase in rv / tlc than in those with a decline in rv / tlc ( 54.2 vs 10.7 ml / year , p<0.001).conclusionthe rate of change in lung hyperinflation varied greatly among copd patients . 
 progression of hyperinflation was associated with frequent exacerbations and a faster decline in fev1 .