copd is a heterogeneous condition , with pathophysiological abnormalities that vary in severity between patients.1 small airway inflammation is a common feature of copd,2 causing a reduction of the cross - sectional area of the small airway lumen .
small airway narrowing and collapse can cause gas trapping on expiration and hyperinflation.3 the presence of hyperinflation is associated with greater dyspnea and reduced exercise tolerance.4 impulse oscillometry ( ios ) measures respiratory resistance and reactance during tidal breathing using sound waves of different frequencies.5 resistance is the loss of energy arising from friction or turbulence , while reactance is the capacity for energy storage , which is dependent on the elastic properties of the lungs .
copd patients typically have increased total airway resistance and a greater negative reactance compared to healthy subjects.6 small airway narrowing and closure during expiration can prevent low - frequency oscillometric signals from traveling to the distal lung.6 these regional  choke points  within the airway tree are present during expiration but not during inspiration , and cause expiratory flow limitation ( efl ) .
dellac et al7 used within - breath analysis to show that the difference between inspiratory and expiratory reactance at 5 hz ( known as x5 ) identifies efl during tidal breathing in copd patients ; x5 of 0.28 kpa / l / s has a high specificity and sensitivity for detecting efl .
copd patients with higher x5 values have greater dyspnea.6 the aim of this study was to quantify the proportion of copd patients with efl , and to further characterize the clinical characteristics of patients with efl .
we also studied whether the presence of efl is stable after 2 years of follow - up .
a total of 147 copd patients were recruited ( 75 from the copdmap cohort ) with 45 patients attending for follow - up at 2 years .
patients were aged > 40 years , with post - bronchodilator forced expiratory volume in 1 second ( fev1)/forced vital capacity ( fvc ) ratio of < 0.7 , 10 pack - year smoking history , and had no history of asthma .
the study was approved by the greater manchester ethics committees ( ref : 10/h1003/108 ) and all patients provided written informed consent .
copd patients performed the following procedures at baseline and 2-year visit : st george s respiratory questionnaire ( sgrq ) , copd assessment test ( cat ) , dyspnea visual analog scale ( vas ) , spirometry with reversibility , ios ( masterscreen ; erich jaeger , hoechberg , germany ) , plethysmography , diffusing capacity of the lungs for carbon monoxide ( dlco ) , and the 6-minute walk test , as previously described.8 plethysmography , dlco , and spirometry ( vmax , carefusion , hoechberg , germany ) were performed according to the ats / ers guidelines.911 x5 was calculated as mean inspiratory reactance at 5 hz ( x5 in ) minus the mean expiratory reactance at 5 hz ( x5ex ) .
statistical analysis was performed using unpaired t - tests or mann  whitney u tests for comparison between groups at baseline ; paired t - test or wilcoxon matched pair tests for within patient comparisons at 2 years ; and chi - square tests for categorical data .
analysis was performed using prism 5 ( graphpad , la jolla , ca , usa ) ; p<0.05 was considered statistically significant .
in all , 55 ( 37.4% ) of the 147 copd patients had efl ; see table 1 for clinical characteristics .
patients with efl were more likely to be current smokers ( p=0.01 ) , have worse airflow obstruction ( mean 42 versus 59 fev1% predicted ; p<0.0001 ) ; and have more gas trapping with a higher rv ( median 166 versus 121% predicted ; p<0.0001 ) and frc ( mean 144 versus 122% predicted ; p<0.0003 ) .
the efl group had worse sgrq activity and symptom component scores and lower 6-minute walk distance .
there were significant differences between groups for all ios measurements ; notably , r5r20 was greater in the efl group .
x5 was significantly associated with r5r20 ( r=0.87 , p<0.0001 ) , fev1% predicted ( r=0.49 , p<0.0001 ) , fev1/fvc ( r=0.27 , p=0.001 ) , hyperinflation ( rv% predicted : r=0.37 , p<0.0001 ; frc% predicted : r=0.33 , p=0.0003 ) , cat score ( r=0.21 , p=0.011 ) , and sgrq total score ( r=0.22 , p=0.009 ) including all the sgrq domains ( symptoms , impact , and activity ) .
there was no association between x5 and the vas dyspnea scale ( r=0.11 , p=0.22 ) .
a total of 45 patients returned at 2 years . in all , 20 patients had efl at baseline , of which 14 ( 70% ) had efl at 2 years .
for the remaining 6 patients without efl at 2 years , the median x5 changed from 0.44 kpa / l / s at baseline to 0.24 kpa / l / s after 2 years ( p=0.031 ) .
a total of 25 patients did not have efl at baseline ; 21 ( 82% ) remained without efl at 2 years .
overall , there were no significant changes in x5 values between baseline and 2 years for both the efl and non - efl groups .
fev1 decreased in both the groups ( mean changes : efl : 66.5 ml / year , p=0.003 ; non - efl : 71 ml / year , p=0.0005 ) .
efl was a common finding in copd patients , being present in over a third of the cohort .
efl patients had a lower fev1% predicted and more hyperinflation and gas trapping , with reduced exercise performance .
r5r20 is recognized as a measurement of small airway resistance5 ; efl was associated with greater small airway impairment .
this association is compatible with the cause of efl , namely small airway narrowing and collapse .
dellac et al7 proposed the x5 threshold value of 0.28 kpa / l / s for efl using results from forced oscillometry data during individual breathing cycles .
we used mean data from multiple breathing cycles during ios , which may categorize some patients with efl despite not all cycles reaching the efl threshold .
nevertheless , using this method to define efl we identified a subgroup of patients with marked small airway disease , gas trapping , and hyperinflation .
furthermore , the identification of efl was reproducible in the majority of cases at the 2-year follow - up .
aarli et al6 used ios to measure efl in copd patients , and also found that efl was associated with lower fev1 values and greater hyperinflation . in common with our findings , a significant association with worse health status and symptom scores was also reported .
while there were some differences in the patient - reported outcome tools used , the overall interpretation of these two studies is that the presence of efl is associated with a greater symptom burden in copd patients .
aarli et al6 reported that copd patients with x5 0.1 kpa / l / s experienced greater dyspnea .
the x5 0.1 kpa / l / s threshold value is obviously lower than that used in the current study , and is likely to identify patients with less severe efl .
the higher x5 threshold value used in this study identified a group with greater efl that was associated with more severe disease manifestations .
it has been reported that x5 is associated with the level of symptoms and duration of hospitalization during copd exacerbations.12 treatment with an inhaled corticosteroid / long - acting beta - agonist combination for 3 months improved x5.13 the identification of small airway disease and efl in copd patients using oscillometry methods may allow individualized targeting of drugs to treat these pathophysiological abnormalities .
for example , inhalers with a greater proportion of extra - fine particles14 could be targeted to copd patients with efl .
there was limited follow - up at 2 years , and larger cohort studies are needed to build on the observations here about the long - term clinical implications of efl .
we show that ios can identify patients with efl , and that efl is associated with more severe airflow obstruction , hyperinflation , and symptoms .
we suggest that efl is a  treatable trait,15 and may provide an opportunity for therapeutic intervention .
 we have used impulse oscillometry to identify copd patients with tidal expiratory flow limitation ( efl ) , which is a measurement related to small airway disease . 
 we report that 37.4% of copd patients had efl ; these patients had multiple clinical characteristics of more severe disease including lower forced expiratory volume in 1 second values , greater hyperinflation , reduced exercise performance , and increased small airway impairment . 
 we highlight that efl can be used to identify a subgroup of copd patients with distinct characteristics associated with small airway disease . 