Expiratory flow limitation in a cohort of highly symptomatic COPD patients

Augusta Beech, Natalie Jackson, James Dean, Dave Singh
ERJ Open Research 2022 8: 00680-2021; DOI: 10.1183/23120541.00680-2021

Abstract

The question addressed by the study Small airway collapse during expiration, known as expiratory flow limitation (EFL), can be detected using oscillometry and is associated with worse clinical outcomes in COPD. This study investigated the prevalence of EFL in a cohort of highly symptomatic patients, evaluated clinical and lung function characteristics of patients with EFL and studied the repeatability of EFL over 6 months.

Materials/patients and methods 70 patients were recruited. Clinical characteristics and lung function metrics were collected at baseline and 6 months. Impulse oscillometry was used to detect the presence of EFL. Patients were defined as EFLHigh (change in reactance measured at 5 Hz (ΔX5) ≥0.28 kPa·L−1·s−1); EFLIntermediate (ΔX5 0.1–0.27 kPa·L−1·s−1) and EFLNone (ΔX5 <0.1 kPa·L−1·s−1).

Results EFLHigh was present in 47.8% of patients at baseline. ΔX5 showed excellent repeatability over 6 months (ρ=0.78, p<0.0001, intraclass correlation coefficient (ICC) 0.88), with the best repeatability observed in EFLNone and EFLHigh patients (ICC 0.77 and 0.65, respectively). Compared to EFLNone patients, EFLHigh had a higher body mass index, worse health-related quality of life and increased peripheral airway resistance. EFLIntermediate was more variable over time with less severe physiological impairment.

Answer to the question Overall, these data indicate that EFLHigh is a common, and relatively stable, component of disease pathophysiology in highly symptomatic COPD patients. EFLHigh was also associated with worse quality of life and obesity.

Abstract

EFL, defined by oscillometry, is a common and relatively stable component of disease pathophysiology in highly symptomatic COPD patients. EFL is associated with worse airflow obstruction, small airway resistance, worse quality of life and obesity. https://bit.ly/3AMRjjL

Introduction

COPD is caused by the inhalation of noxious particles, resulting in airflow obstruction and respiratory symptoms including dyspnoea, cough and sputum production [1]. Small airway disease (SAD) is a key feature of COPD, characterised by immune cell infiltration, mucus hypersecretion and airway remodelling [2, 3]. These pathological changes cause narrowing of the small airways, thereby increasing resistance to airflow [2]. Incomplete emptying of the lung upon expiration due to SAD causes gas trapping, which increases the work of breathing and is associated with increased dyspnoea [4–6]. Small airway closure and collapse during expiration is known as expiratory flow limitation (EFL), which occurs due to regional choke points within the bronchial tree [6]. EFL is associated with increased gas trapping, a greater symptom burden and reduced exercise performance [6–8].

Oscillometry is a noninvasive technique that measures elements of respiratory mechanics during tidal breathing, notably resistance and reactance [5]. A marked change in reactance measured at 5 Hz during expiration compared to inspiration (ΔX5) is a marker of EFL [9]. A threshold value of ≥0.28 kPa·L−1·s−1 (ΔX5) has been used to define EFL, with patients above this threshold having more gas trapping and a greater symptom burden [6, 9]. A lower ΔX5 value of >0.10 kPa·L−1·s−1, which probably detects less severe EFL, is also associated with greater dyspnoea [4]. Previous EFL studies have used broad COPD populations [6, 8, 10, 11], demonstrating associations between EFL and worse clinical characteristics including lower forced expiratory volume in 1 s (FEV1) [6, 11], greater dyspnoea, with increased exercise limitation [4, 6] and increased exacerbation frequency [6, 8].

Dyspnoea is the most common symptom in COPD patients [12]. Airflow obstruction itself causes dyspnoea, but FEV1 correlates poorly with this symptom [13, 14]. Other contributors to dyspnoea include gas trapping, cardiac dysfunction and muscle wasting [15]. The measurement of EFL, as a cause of gas trapping, may be a useful tool during the investigation of dyspnoea in COPD patients. Furthermore, EFL can be considered to be a treatable trait [16] in COPD patients with dyspnoea, as it is a component that can be targeted specifically with inhaled treatment.

Previous EFL studies have enrolled broad COPD populations, including individuals with varying degrees of dyspnoea. This study focused on highly symptomatic COPD patients, as the investigation of EFL is most relevant in these individuals. The main aim was to determine the prevalence of EFL in this COPD subgroup. We used different EFL thresholds (≥0.28 kPa·L−1·s−1 and >0.10 kPa·L−1·s−1), and studied the relationships between EFL and other lung function measurements and clinical characteristics. Measurement repeatability over 6 months was evaluated.

Methods

Study cohort

70 COPD patients were recruited from the Medicines Evaluation Unit (Manchester University NHS Foundation Trust, Manchester, UK). Subjects were aged ≥40 years, had a smoking history of ≥10 pack-years, were not using maintenance antibiotics or oral corticosteroids and had no previous asthma diagnosis. Subjects were required to have a modified Medical Research Council (mMRC) score ≥2 and COPD Assessment Test (CAT) score ≥15. All patients provided written informed consent using protocols approved by local ethics committees (16/NW/0836).

Study design

Clinical characteristics were obtained from participants during stable state, defined as no exacerbation or respiratory illness within 4 weeks of the baseline and 6-month visits.

Measurements

CAT [17], mMRC [18] and St George's Respiratory Questionnaire (SGRQ-C) [19] scores assessed symptoms and health-related quality of life at both visits. The following procedures were performed at the baseline and 6-month visits; 6-min walk test (6MWT), fat-free mass assessment (BodyStat 1500; BodyStat, UK), impulse oscillometry (IOS) (MasterScreen; Erich Jaeger, Hoechbery, Germany), spirometry with reversibility to 400 µg salbutamol (EasyOne spirometer; NDD Medical Technologies, Switzerland), body plethysmography and diffusing capacity of the lungs for carbon monoxide (DLCO) (Vmax; CareFusion, Hoechbery, Germany). Spirometry, body plethysmography, DLCO and 6MWT were performed according to American Thoracic Society/European Respiratory Society guidelines [20–23]. Short-acting bronchodilators were withheld for 6 h, long-acting bronchodilators, anticholinergics, theophyllines and leukotriene receptor antagonists were withheld for up to 24 h prior to lung function testing. IOS was performed as described previously [24]; more detail is provided in the supplementary material. ΔX5 was calculated using the multiple-breath method; mean reactance at 5 Hz during inspiration (X5in) minus the mean reactance at 5 Hz during expiration (X5ex). Inspiratory and expiratory data were averaged over multiple tidal breaths, which has been validated against the breath-by-breath method where differences between X5in and X5ex are calculated per breath and then averaged; the intraclass correlation coefficient (ICC) was 0.98 [4].

EFL was defined as EFLHigh (ΔX5 ≥0.28 kPa·L−1·s−1), EFLIntermediate (ΔX5 0.10–0.27 kPa·L−1·s−1) and EFLNone (ΔX5 <0.10 kPa·L−1·s−1).

Statistical analysis

No formal sample size calculation was performed; this was a pilot study to generate findings that could be confirmed in larger datasets. Nonparametric data were analysed using the Kruskal–Wallis test with Dunn's post hoc analysis and Spearman's correlations. Parametric data were analysed using a one-way ANOVA with Tukey's post hoc test (Prism 9.0; GraphPad, USA). Variation over time was assessed using Bland–Altman analysis (Prism 9.0) and ICC of log-transformed data (SPSS 25.0; IBM, USA). For ICC analysis of ΔX5, log(x+1) was used to correct for zero values. ICC values were interpreted as excellent (>0.75), fair to good (0.40–0.75) or poor (<0.40) [25]. A p-value of <0.05 was considered significant.

Results

The baseline demographic and clinical characteristics are shown in table 1. The mean age was 64.3 years, 55.7% were male and 42.9% were current smokers. The patients were highly symptomatic with a mean SGRQ score of 53.9, and median CAT and mMRC scores of 21 and 4.0, respectively. The majority of patients (>95%) were using regular maintenance inhaled treatments, with 60% using triple therapy (inhaled corticosteroids plus two long-acting bronchodilators). The mean exacerbation rate in the previous 12 months was 1.1. Most patients (94.3%) had at least one concomitant disease, with cardiovascular disease being the most prevalent (supplementary table S1).

View this table:
TABLE 1

Baseline clinical characteristics#

Presence of EFL

69 and 54 patients provided technically acceptable IOS data at baseline and 6 months, respectively. Details of patients who were lost to follow-up are presented in supplementary table S2. 33 (47.8%) patients at baseline and 19 (35.2%) at 6 months were classified as EFLHigh (figure 1). 17.4% were classed as EFLIntermediate and 34.8% as EFLNone at baseline, while at 6 months these proportions were 20.4% and 44.4% respectively (figure 1).

FIGURE 1
FIGURE 1

Proportion of patients in different expiratory flow limitation (EFL) groups at baseline and 6 months. EFL groups defined as difference in total reactance between inspiration and expiration (ΔX5) <0.10 kPa·L−1·s−1 (EFLNone), ΔX5 0.10–0.27 kPa·L−1·s−1 (EFLIntermediate) and ΔX5 ≥0.28 kPa·L−1·s−1 (EFLHigh). n=69 at baseline and n=54 at 6 months.

54 patients provided IOS data at both baseline and 6-month visits. There was a positive correlation between ΔX5 measurements at baseline and 6 months (ρ=0.78, p<0.0001; figure 2a), with an ICC of 0.88 indicating excellent repeatability. Other IOS parameters showed positive correlations and excellent repeatability over 6 months (figure 2); resistance at 5 Hz (R5) (ρ=0.83, p<0.0001, ICC=0.90), resistance at 20 Hz (R20) (ρ=0.89, p<0.0001, ICC=0.93) and R5–20 (ρ=0.76, p<0.0001, ICC=0.85). FEV1 % predicted and absolute volume also showed excellent correlations between visits (ρ=0.84 and 0.96, p<0.0001 for both, ICC 0.92 and 0.98, respectively; figure 2e and f).

FIGURE 2
FIGURE 2

Association between lung function parameters over 6 months. a) Difference in total reactance between inspiration and expiration at 5 Hz (ΔX5); b) resistance at 5 Hz (R5); c) resistance at 20 Hz (R20); d) R5–R20; e) forced expiratory volume in 1 s (FEV1) (% predicted); and f) FEV1 (absolute). n=64 (10 patients did not provide impulse oscillometry data at 6 months). ICC: intraclass correlation coefficient. p-value corresponds to a Spearman's rank test and Pearson's correlation for nonparametric and parametric data, respectively. p<0.05 was considered statistically significant.

A Bland–Altman analysis between baseline and 6-month measurements of ΔX5 is presented in figure 3. Visual inspection of the plot shows that the difference between measurements was greater for higher EFL measurements. The differences between measurements were not normally distributed, and remained so after log transformation; therefore, the mean difference and limits of agreement could not be calculated [26].

FIGURE 3
FIGURE 3

Bland–Altman plot of the difference versus the mean of two repeat measurements of the difference in total reactance between inspiration and expiration at 5 Hz (ΔX5) over 6 months. n=54.

Figure 4 shows that 18 (69.2%) out of the 26 EFLHigh patients at baseline remained EFLHigh at 6 months, while six (23.1%) moved to EFLIntermediate. The majority of EFLNone patients remained in the same category at 6 months (89.5%). There were significant correlations between baseline and 6-month ΔX5 measurements for EFLNone and EFLHigh patients (ρ=0.75 and ρ=0.43, p<0.001 and p=0.03, respectively), with ICC values 0.77 and 0.65, respectively. In contrast, there was no correlation for EFLIntermediate (ρ= −0.03, p=0.95, ICC 0.07), with only three out of nine patients (33.3%) remaining in the same category at 6 months.

FIGURE 4
FIGURE 4

Repeatability of difference in total reactance between inspiration and expiration at 5 Hz (ΔX5) within different groups; expiratory flow limitation (EFL). a) EFLNone (ΔX5 <0.10 kPa·L−1·s−1), b) EFLIntermediate (ΔX5 0.10–0.27 kPa·L−1·s−1) and c) EFLHigh (ΔX5 ≥0.28 kPa·L−1·s−1). n=54. ICC: intraclass correlation. Dotted lines represent thresholds of X5 for EFLIntermediate and EFLHigh groups. Number of patients in different groups at each time point are presented in boxes.

EFL and clinical characteristics

Table 2 shows that EFLHigh patients at baseline had a higher body mass index (BMI) compared to EFLNone (30.2 versus 25.8 kg·m−2, p<0.01); lower FEV1 (56.8% pred versus 76.3% pred, p<0.0001); lower FEV1/forced vital capacity ratio (47.5% versus 57.8%, p<0.001); and higher total SGRQ score (57.7 versus 48.0, p=0.04), with increased scores in the activity and impact domains. Furthermore, a relationship was observed between change in total SGRQ score over 6 months and change in ΔX5 and R5–R20 (ρ=0.42 and ρ=0.28, p=0.002 and p=0.04, respectively; figure 5a and b); an increase in ΔX5 or R5–R20 was associated with an increase in SGRQ score. DLCO and transfer coefficient of the lung for carbon monoxide (KCO) were similar between groups. Presence of concomitant diseases were mostly similar between groups (supplementary table S1).

View this table:
TABLE 2

Baseline characteristics in different expiratory flow limitation (EFL)# groups (n=69)

FIGURE 5
FIGURE 5

Change in a) difference in total reactance between inspiration and expiration at 5 Hz (ΔX5) and b) R5–R20 over 6 months associated with a change in total St George's Respiratory Questionnaire (SGRQ) scores, n=54 for both. Association between ΔX5 and R5–R20 at c) baseline and d) 6 months, n=69 and 54, respectively. R5: resistance at 5 Hz; R20: resistance at 20 Hz. p-value corresponds to a Spearman's rank test. p<0.05 was considered statistically significant.

EFL and other IOS measurements

Table 2 shows that X5 was more negative and R5, R5–R20 and reactance area were higher in EFLHigh and EFLIntermediate patients compared to EFLNone at baseline, with measurements being higher in EFLHigh compared to EFLIntermediate. Similar results were observed at 6 months (supplementary table S3). ΔX5 was positively correlated with R5–R20 at baseline and 6 months (ρ=0.84 and ρ=0.86, respectively, p<0.0001 for both; figure 5c and d).

EFL and lung volumes

64 patients had technically acceptable data collected for IOS and body plethysmography at baseline. Table 2 shows that both EFLHigh and EFLIntermediate patients at baseline displayed higher residual volume (RV)/total lung capacity (TLC) ratio compared to EFLNone patients, while EFLHigh patients showed a significantly higher RV % predicted versus EFLNone. No differences in DLCO or KCO were observed between groups. Similar results were observed at 6 months (supplementary material).

Figure 6 shows that ΔX5 was positively correlated with RV (%) and RV/TLC at both baseline (ρ=0.31 and ρ=0.42, p=0.01 and p<0.001, respectively) and 6 months (ρ=0.29 and ρ=0.39, p=0.03 and p<0.01, respectively). Negative correlations were observed between ΔX5 and FEV1 % predicted (figure 6a and d).

FIGURE 6
FIGURE 6

Association between difference in total reactance between inspiration and expiration at 5 Hz (ΔX5) and other lung function parameters a–c) at baseline: a) forced expiratory volume in 1 s (FEV1) (% predicted), b) residual volume (RV) (% predicted), c) RV/total lung capacity (TLC) ratio; and d–f) 6 months: d) FEV1 (% predicted), e) RV (% predicted), f) RV/TLC ratio. n=64 and 54, respectively (one patient did not have RV data at 6 months). p-value corresponds to a Spearman's rank test. p<0.05 was considered statistically significant.

Discussion

In this cohort of highly symptomatic COPD patients, 48% were categorised as EFLHigh at baseline. This finding highlights that EFL is relatively common among highly symptomatic COPD patients, and represents a potential target for treatment (a treatable trait [16]). The majority of these EFLHigh patients (69%) remained in the same category or were classified as EFLIntermediate (23%) at 6 months, indicating that most EFLHigh patients exhibit some degree of EFL (either “high” or “intermediate”) during longitudinal follow-up. Overall, the ΔX5 ICC of 0.88 indicated excellent repeatability, in line with the stability of EFL phenotype observed in the majority of patients.

The clinical features associated with EFLHigh included reduced quality of life and higher BMI. Additionally, changes in ΔX5 or R5–R20 were associated with changes in quality of life over 6 months, measures of which have previously been shown as highly repeatable [27]. Previous cross-sectional analyses have shown associations between ΔX5 and clinical characteristics including dyspnoea and exacerbation rates (n=425 [8] and n=147 [6]). Our 6-month longitudinal analysis provides further evidence of the clinical relevance of EFL, showing an association between changes in ΔX5 and changes in quality of life. Additionally, at baseline EFLHigh patients had higher SGRQ scores driven by worse scores within the activity and impact domains, consistent with the potential for EFL to reduce exercise capacity. Other studies have produced similar findings for the relationship between ΔX5 and total SGRQ score (n=425 [4]) and the activity domain (n=147 [6]).

Small airways are defined as those <2 mm in internal diameter, which are generally found between the 4th and 12th generation of the bronchial tree [2]. The clinical relevance of EFL was highlighted by worse airflow obstruction and increased small airway resistance (measured by R5–R20) in EFLHigh patients. This finding alone highlights the usefulness of oscillometry measurements in detecting patients with flow limitation at rest, which is associated with worse disease severity [9]. R20 is considered to be a measure of proximal airway resistance [28] and was similar between those with and without EFL (0.36 and 0.39 kPa·L−1·s−1, respectively; p=0.49). Expiratory dynamic airways collapse (EDAC) shows similar reactance patterns to EFL reported here, although R20 was numerically lower in COPD patients versus COPD + EDAC (0.33 versus 1.07 cmH2O·L−1·s−1) [29]. Hence, it is likely that EFL is a continuous process that can occur throughout the airways.

The majority of EFLNone patients (89%) remained in the same category at 6 months, indicating that the absence of EFL is a relatively stable phenotype. EFLNone patients had the lowest variability over time for ΔX5 measurements when assessed using ICC (0.77). ICC is a well-accepted method for assessing repeatability over time. Bland–Altman analysis was designed to compare differences between methods, rather than repeatability of the same method [26]. Nevertheless, visual inspection of the Bland–Altman plot allows the “widening trend” of the differences between measurements with increasing ΔX5 values to be observed. This trend has been described previously as “proportional difference variability” [26]. Fluctuations in COPD patients with EFL have been attributed to variation in lung volumes between visits [8]; for the EFLNone group, the absence of EFL and associated gas trapping or hyperinflation would lead to less variability between visits. Similarly, it was noted, in a sample size of 425 COPD patients, that ΔX5 measurements show greater variation in individuals with more EFL [4], although formal statistical analysis of reproducibility was not reported. Here, ICC analysis confirms higher variability for ΔX5 in EFLHigh and EFLIntermediate patients (ICC 0.65 and 0.07, respectively) versus EFLNone patients (ICC 0.77).

The poor reproducibility of EFLIntermediate patients (ICC 0.07) was associated with only 33% remaining in the same category. This suggests that EFLIntermediate represents a relatively small heterogeneous group (17.4% at baseline) who, on repeated testing, are often classified into the group above or below. Using thresholds can lead to reclassification of individuals over time due to relatively small changes. Nevertheless, our results (in highly symptomatic COPD patients) suggest that a single ΔX5 measurement can allocate the majority of patients to either EFLHigh or EFLNone, with these groups being relatively stable over time. Similarly, in a broad group of COPD patients (not recruited on the basis of symptoms as in our current study), 70% within the EFLHigh group remained in the same category after 2 years [6].

We observed no difference in dyspnoea or CAT scores between EFL groups, in contrast to previous reports [4, 6]. It has been reported that a ΔX5 threshold of 0.1 kPa·L−1·s−1 predicted breathlessness in COPD patients (sensitivity 64%, specificity 72%), while a threshold of 0.26 kPa·L−1·s−1 provided a specificity of 95% for detecting breathlessness (area under the curve 0.70) [4]. The absence of any association between EFL and symptoms in the current study can be explained by the inclusion criteria, only allowing patients with higher mMRC and CAT scores to participate, thus reducing the potential to find differences between groups for these patient reported outcome measures. We observed a higher prevalence of EFLHigh (48%) compared to previous studies using the same ΔX5 threshold (18–37%) [4, 6]. As EFL is known to be associated with a greater symptom burden [6, 8], the recruitment of highly symptomatic patients in this study cohort would be expected to increase the proportion of EFLHigh patients.

There was an association between BMI and ΔX5, consistent with a previous report that noted a relationship between obesity and EFL [30]. Obesity is known to influence lung function through mechanical alterations caused by increased adipose deposition around the chest wall and abdomen [4, 30]. This causes decreased chest wall and lung compliance, increased work of breathing and reduced functionality of the diaphragm [31], culminating in a reduction in expiratory reserve volume (ERV) and thereby inducing flow limitation [32]. Other factors may also reduce ERV, thereby promoting lower flow rates and facilitating EFL; for example, chronic heart failure (due to an increase in volume of the heart, vascular engorgement and interstitial oedema) and acute respiratory distress syndrome (due to oedema and atelectasis) [33]. Therefore, the presence of comorbidities may represent a source of variation in EFL in some COPD patients. Our results support previous observations in similarly sized cohorts that R5–R20 and ΔX5 are significantly associated (n=74 [34]), and that EFLHigh (and to a lesser extent EFLIntermediate) patients had more gas trapping and pulmonary hyperinflation (in studies with sample sizes n=55 [35], n=147 [6] and n=74 [34]). The associations between ΔX5 and small airway resistance, gas trapping and pulmonary hyperinflation [6, 34, 35] support the concepts that small airway narrowing (measured by R5–R20) and collapse (measured by EFL) are linked to gas trapping and hyperinflation [36]. There was greater small airway resistance at ΔX5 >0.10 kPa·L−1·s−1, with increasing severity from EFLIntermediate to EFLHigh patients, aligning to the clinical findings showing worse SGRQ scores in EFLHigh patients. Future studies may consider investigating the relationship between EFL and computed tomography scanning parameters of small airway disease and emphysema to further understand our findings.

EFLHigh patients may benefit from inhaled treatments that target the small airways. A recent clinical trial showed that the long-acting bronchodilator components of an extra-fine triple therapy formulation (particle size <2 µm) were able to improve R5–R20 with associated improvements in lung volumes [37]. Targeting the small airways may improve dyspnoea and quality of life [38, 39].

Devices utilising the forced oscillation technique such as IOS and airwave oscillometry (AOS) (tremoFlo, USA) differ in airflow perturbation signal and have been directly compared in regard to parameter outputs [40]. It has been noted that resistance is typically greater and reactance more abnormal when comparing IOS to AOS, in healthy and patient populations [28, 40]. These differences were more pronounced in post-bronchodilator measurements and in those with more severe airway obstruction [28]. Therefore, it is important to consider methodologies when comparing clinical studies of oscillation mechanics.

This was an exploratory study, with a limited sample size; our findings need to be confirmed in larger datasets. A limitation of this study was patient withdrawal between visits reducing the sample size at 6 months. The thresholds of ΔX5 used here are based on mean measures of inspiratory and expiratory reactance and although this gives indication EFL presence, it cannot define the precise point(s) during the expiratory limb of tidal breathing at which EFL occurs. As described by Lorx et al. [41], this highlights further heterogeneity within flow-limited patients. Furthermore, using the multiple-breath method to define EFL and trichotomising patients into categories may classify some patients as EFLIntermediate or EFLHigh­­, despite not meeting the ΔX5 threshold for every breath.

Conclusion

In conclusion, we report that EFLHigh was present in approximately half of the individuals in this highly symptomatic COPD cohort. EFLHigh and EFLNone were relatively stable phenotypes over time. EFLHigh was associated with worse small airway disease, a reduced quality of life and higher BMI. Overall, these data indicate that EFLHigh is a common, and relatively stable, component of disease pathophysiology in highly symptomatic COPD patients.

Supplementary material

Supplementary Material

Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

Supplementary material 00680-2021.SUPPLEMENT

Supplementary material ONLINE_SUPPLEMENT_CLEAN_13.01.22

Acknowledgements

D. Singh and A. Beech are supported by the National Institute for Health Research Manchester Biomedical Research Centre.

Footnotes

  • Provenance: Submitted article, peer reviewed.

  • Ethics statement: The study was conducted according to the guidelines of the Declaration of Helsinki, and the study protocol was reviewed and approved by the Ethics Committee of HRA, North West – Preston Research Ethics Committee (protocol code: 16/NW0836; date of approval: 13.12.2016). Written informed consent was obtained from all subjects involved in the study.

  • Data availability: The datasets generated and/or analysed during the current study and additional related documents are not publicly available.

  • Author contributions: A. Beech and D. Singh were responsible for the concept and design of the study. A. Beech, N. Jackson and D. Singh were involved in data acquisition. A. Beech analysed the data and D. Singh oversaw all analyses. A. Beech and D. Singh were responsible for data interpretation and drafting the manuscript. J. Dean revised the manuscript critically for intellectual content. All authors have approved the final version to be published and are jointly accountable for all aspects of the work.

  • Conflict of interest: D. Singh has received sponsorship to attend and speak at international meetings, honoraria for lecturing or attending advisory boards from the following companies: Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, EpiEndo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Teva, Theravance and Verona. A. Beech, N. Jackson and J. Dean have no conflicts of interest to declare.

  • Support statement: This work was supported by AstraZeneca. Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received December 2, 2021.
  • Accepted January 26, 2022.
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Expiratory flow limitation in a cohort of highly symptomatic COPD patients
Augusta Beech, Natalie Jackson, James Dean, Dave Singh
ERJ Open Research Apr 2022, 8 (2) 00680-2021; DOI: 10.1183/23120541.00680-2021
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