In the COPD subgroup with EFL, the novel parameter ELDI has the potential to identify individuals with more rapid onset EFL; ELDI was associated with more severe disease, manifesting as worse airflow obstruction, impaired diffusion capacity of the lungs, greater resting hyperinflation and gas trapping with worse quality of life. Other oscillometry measures of EFL, namely ∆X5 or X5peak-peak, were not significantly associated with airflow obstruction, hyperinflation or gas trapping in COPD patients with EFL. These findings implicate the rate of EFL development in the physiological and clinical outcomes in COPD.

Our findings associate small airway collapse with the magnitude of hyperinflation, in agreement with previous studies [7, 8], with our observations now implicating the rate of EFL development with greater gas trapping and hyperinflation. Importantly, amongst COPD patients with EFL, ELDI was not associated with EFL magnitude measured by ∆X5 or X5peak-peak. Furthermore, other oscillometry parameters, such as R5-R20 and AX did not distinguish between EFLrapid and EFLgradual. These results highlight that ELDI can provide information regarding the dynamics of EFL that cannot be ascertained from other oscillometry parameters. Other key findings were that ELDI exhibited excellent stability over 6 months in an observational cohort setting, while long acting bronchodilator treatment in the TriFLOW study was able to modulate EFL and consequently ELDI.

ELDI was associated with degree of airway limitation, and a significant difference was observed in mean FEV1% predicted values between rapid, gradual and no EFL groups. Likewise, there was a difference between the rapid and no EFL groups for FEF25%−75%. However, there was a large overlap of FEV1 values between all groups (Figure S4), indicating that FEV1 values are not a reliable predictor of the likelihood of rapid EFL development on an individual basis. Furthermore, EFLrapid may develop in patients without severe airflow obstruction, as almost a quarter of patients with EFLrapid had FEV1 > 50% predicted. This suggests that ELDI identifies a characteristic of small airway dysfunction (and flow limitation) that, on an individual basis, is not consistently associated with FEV1. Spirometry parameters are an indirect measure of bronchial obstruction [19, 20]. Other measures of bronchial obstruction such as specific resistance (SRaw) may be more closely related to ELDI, although SRaw measurements were not collected in the present study.

The associations in the observational cohort do not demonstrate causality. However, it is plausible that rapid onset of EFL causes greater gas trapping through airway closure at higher lung volumes; together with increased airway resistance, this contributes to resting hyperinflation, which may worsen upon exercise [21]. There is some evidence that abnormal ∆X5 is associated with exercise intolerance [7, 22] and improves following pulmonary rehabilitation [23], therefore it would be valuable for future studies to investigate whether ELDI further influences exercise capacity or physical activity levels. The pathology responsible for lung volume differences in EFLrapid and EFLgradual groups, in the absence of any difference in other oscillometry parameters, is unclear and may relate to subtle pathological differences. A histology study identified loss of radial alveolar attachments in the small airways as the main pathological feature related to a reduction in FEV1 in COPD [24]. Peripheral small airway disease is complex and heterogenous, with altered airway calibre due to airway wall thickening, fibrosis and inflammatory cell infiltration [3]. Additionally, loss of tissue elastic recoil may occur, caused by the disruption of airway-parenchymal interdependence via loss and reduced integrity of alveolar attachments, diaphragm deformation and surfactant deficiency [25]. The nature of EFL may vary between individuals according to the relative contributions of these pathophysiological components. Given that FEV1 and FEV1/FVC were significantly lower in the EFLrapid group, with an association between impaired gas transfer and ELDI, perhaps the loss of radial alveolar attachments (or at least loss of integrity) through emphysematous destruction leads to airway collapse at higher lung volumes, air trapping and limits capacity for gas transfer. RV/TLC has been proposed as a marker of small airway dysfunction leading to gas trapping [26,27,28], and our results indicate faster development of EFL in those with greater small airway disease.

EFLgradual patients demonstrated differences to EFLno, including greater airflow obstruction and more gas trapping. However, symptoms scores and degree of hyperinflation were comparable between groups. These findings may signify resting hyperinflation with more rapid EFL development, although whether this is the cause or a consequence cannot be determined from the associations in the cohort analysis. A higher body mass index (BMI) was observed for EFLgradual patients compared to EFLno (see supplement). An association between BMI and/or obesity and EFL has been demonstrated previously [29], therefore the EFLgradual group may constitute a mixture of patients with EFL induced by mechanical alterations associated with obesity [30] and those with an intermediate state of EFL attributed to small airway disease.

The TriFLOW analysis demonstrated that EFL can be improved by long acting bronchodilator therapy, with ELDI shifting towards less rapid development. In some individuals, EFLgradual may represent an intermediate state of EFL, between EFLrapid and EFLno, which can be modified by bronchodilator treatment. EFL was improved upon by treatment with either ultrafine BDP/F or BDP/F/G. In patients with EFL which persisted following treatment, ELDI improved significantly with BDP/F and BDP/F/G, albeit in a small sample size. Whilst both the magnitude of EFL (∆X5 or X5peak-peak) and nature of EFL development (ELDI) improved following treatment, these measures did not demonstrate an association with one another, and ELDI was associated with worse baseline clinical characteristics in patients with EFL. These findings highlight the importance of considering the nature of EFL development in addition to the magnitude. Collectively, changes in EFL and ELDI following treatment, together with other lung function changes reported from the TriFLOW study elsewhere [11], suggest that lung volume dependant choke points may move closer to residual volume (RV) after bronchodilators, reducing gas trapping and allowing greater volume to be exhaled during forced spirometry. It is unclear if this is a function of magnitude and/or rate of EFL development, although we suggest that the interpretation of EFL requires consideration of both.

Previous studies have demonstrated that high levels of EFL are relatively stable over time [5, 8]. Our data now shows that ELDI was consistent in those with EFL. Most patients did not change their categorisation over 6 months, however those with baseline values closer to the ELDI threshold showed some variability, in keeping with natural variation across a binary threshold. This threshold was determined using the mean cohort value; further investigation is required to identify a threshold for clinical practice. Changes in clinical characteristics between visits were similar between all groups, supporting no change in clinical status despite some shifts in ELDI categorisation.

While this paper focuses on ELDI, there are potentially other possible ways to analyse the shape of X5 loops and the development of EFL (illustrated in Figure S8). The rate (i.e. gradient) at which X5 decreases during early exhalation could be calculated, however this requires a more complex calculation of exported raw data which may not be available with all commercial equipment. Furthermore, this would not account for different times of EFL onset (earlier versus later during exhalation). The percent of tidal volume at which EFL begins could be evaluated, but this also requires data export, and does not consider the overall magnitude of EFL. The advantages of ELDI are that it considers EFL magnitude, gives an indication of speed of EFL development, whilst also being a simple calculation that can be made from historical data.

We have demonstrated that rapid development of EFL was associated with more severe disease and worse gas trapping with hyperinflation, when compared to COPD patients with gradual EFL. In patients with EFL, the speed at which EFL developed during exhalation (i.e. ELDI) was associated with worse clinical characteristics, while the magnitude of EFL (i.e. ∆X5 or X5peak-peak) was not. Furthermore, rapid development of EFL was a relatively stable phenomenon and may be sensitive to changes in response to inhaled therapy in COPD. Overall, we propose ELDI as a clinically useful COPD marker associated with clinical and physiological characteristics.