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ERJ Open Research logoLink to ERJ Open Research
. 2025 Jan 13;11(1):00410-2024. doi: 10.1183/23120541.00410-2024

Clinical improvements after endoscopic lung volume reduction with valves in patients with advanced emphysema and a 6-min walk test ≤140 m at baseline

Jacopo Saccomanno 1,, Lara Kilic 1, Thomas Sgarbossa 1, Konrad Neumann 2, Franz Stanzel 3, Angelique Holland 4, Christian Grah 5, Wolfgang Gesierich 6, Joanna Krist 7, Joachim H Ficker 8, Stephan Eggeling 9, Stefan Andreas 10, Bernd Schmidt 11, Stephan Eisenmann 12, Björn Schwick 13, Karl-Josef Franke 14,15, Andreas Fertl 16, Martin Witzenrath 1,17,18, Ralf-Harto Hübner 1
PMCID: PMC11726540  PMID: 39811547

Abstract

Background

Data regarding the effectiveness and safety of endoscopic lung volume reduction with valves (ELVR) in emphysema patients with a very low 6-min walk test (6MWT) are limited. Patients with severe emphysema and very low exercise capacity, as indicated by a 6MWT ≤140 m, are often excluded from clinical studies on ELVR, assuming limited therapeutic benefits and increased complication risk.

Study designs and methods

This study utilised data from the Lungenemphysemregister e.V., a large German national multi-centre prospective open-label clinical trial, and aimed to assess the outcomes of ELVR in patients with a baseline 6MWT ≤140 m and dyspnoea primarily attributed to hyperinflation.

Results

54 patients with a baseline 6MWT ≤140 m and 365 patients with a baseline 6MWT between 140 and 450 m were included in the study. Baseline characteristics were representative for patients with advanced lung emphysema. Patients with a 6MWT ≤140 m at baseline had a lower forced expiratory volume in 1 s and diffusing capacity of the lung for carbon monoxide and higher symptom burden. In the 3-month follow-up, patients of both groups showed statistically significant improvements in lung function parameters, exercise capacity and quality of life parameters compared to baseline. Patients with a 6MWT ≤140 m at baseline showed significantly more 6MWT improvement compared to patients with baseline 6MWT between 140 and 450 m. Moreover, complication rates were similar in both groups.

Interpretation

In summary, the data indicate that ELVR may be an effective and safe treatment for emphysema patients with a very low 6MWT of ≤140 m if very limited exercise capacity is predominately caused by lung emphysema. Therefore future studies should include emphysema patients with a very low 6MWT.

Shareable abstract

Patients with advanced lung emphysema and a 6MWT ≤140m might benefit from an ELVR with valves and complications are not increased https://bit.ly/4cVoUcK

Introduction

Today, COPD is one of the leading causes of death worldwide with an increasing prevalence [1]. Advanced lung emphysema represents a severe and debilitating manifestation of COPD. Chronic inflammation, often linked to cigarette smoking, causes a destruction of alveolar walls and airway narrowing of the small airways. Alveolar wall destruction leads to decreased tension in the alveoli after inspiration and is associated with a loss of elastic recoil. The stored energy usually determines expiratory force at the level of the alveoli and its lack limits expiration through two mechanisms. Firstly, reduced elastic recoil as a result of alveolar wall destruction limits intraluminal air pressure. Secondly, due to the lack of supporting cartilage in the peripheral airways, luminal patency is mainly maintained by intraluminal air pressure. These changes cause reduced airway patency and lead to airway collapse, especially during forced expiratory manoeuvres, resulting in an effort independent airflow limitation. The following hyperinflation at the level of the alveoli further compromises breathing mechanics and leads to severe dyspnoea and exercise intolerance [24].

The 6-min walk test (6MWT) is a cost-effective and simple test to evaluate exercise capacity, assessing the response of various systems during physical activity, including the cardiovascular, respiratory and musculoskeletal system [5]. In particular, the test is very valuable in COPD patients to monitor mobility disability. It is easy to reproduce and has a strong association with forced expiratory volume in 1 s (FEV1). Furthermore, the 6MWT is accepted as a reliable prognostic indicator for survival in COPD patients [68].

In recent years, lung volume reduction therapy has emerged as a treatment option to address hyperinflation in advanced forms of emphysema [917]. Carefully selected patients experienced improved lung function and quality of life and increased exercise capacity through this therapy [11, 18]. Currently, endoscopic lung volume reduction with valves (ELVR), as a potentially reversible procedure, and surgical resection are the most studied and frequently applied techniques of lung volume reduction [19]. Notably, the National Emphysema Treatment Trial (NETT), an early randomised controlled trial of surgical lung volume reduction, showed a significant 30-day overall post-operative mortality of 5.2% and 16% in high-risk patients [20]. Given the 6MWT's established role as a good marker for frailty and mortality in COPD patients, those with a very low 6MWT (≤140 m) were excluded from large randomised controlled trials evaluating ELVR, coils or vapour. This exclusion was based on the assumption that the treatment benefit might be minimal, and the risk of complication significantly increased [917, 2123].

Despite the lack of data, clinical experience with ELVR suggests benefits for patients with advanced lung emphysema and a very low 6MWT. Hence, the latest expert panel recommendation for ELVR suggests considering patients with a 6MWT between 100 and 500 m for lung volume reduction therapy, although scientific data are lacking [24]. Since patients with a very low 6MWT were not excluded from the lung emphysema registry in Germany, we questioned if patients with 6MWT ≤140 m demonstrated similar improvements after ELVR compared to patients with a 6MWT between 140 and 450 m.

Material and methods

The analysed data were obtained from lung emphysema patients who received an ELVR according to standards of the lung emphysema registry. The lung emphysema registry (www.lungenemhysemregister.de) is a German national multi-centre prospective open-label clinical trial. The study was approved by the local ethics committee of study centres (A2/149/17 and EA1/136/13) and all patients provided informed consent. Study data were managed by REDCap electronic data capture tools hosted at Charité – Universitätsmedizin Berlin [25].

Inclusion and exclusion criteria

Patients were considered as eligible candidates for ELVR if they were diagnosed with an advanced lung emphysema with the following lung function parameters: FEV1 <45%, residual volume (RV) >180%. There was no restriction to diffusing capacity of the lung for carbon monoxide (DLCO). They had to receive optimal medical treatment for COPD and had to be proven nonsmokers for >3 months (carboxyhaemoglobin (COHb) <2% or no evidence of cotinine in urine sample) before receiving a lung volume reduction treatment. Additionally, patients had to present with a partial pressure of carbon dioxide (PCO2) <55 mmHg [26]. At baseline, 6MWT had to be lower than 450 m. All patients were instructed of the necessity of a structured exercise programme prior to or after therapy, organised according to each centre's specifications. Patients were excluded if dyspnoea was not primarily attributed to hyperinflation and if they were unable to provide informed consent [27, 28].

Evaluation procedure

All patients underwent a structured evaluation before lung volume reduction therapy. This included a lung function test with body plethysmography, diffusion test, 6MWT, arterial/capillary blood gas analysis, echocardiography and urine analysis for cotinine if COHb was not available. Besides, all patients received a computed tomography of the lungs without contrast media and a software-based quantification of the fissure integrity and emphysema destruction per lobe. Patients underwent a bronchoscopy with in vivo assessment of collateral ventilation (Chartis assessment system; Pulmonx Inc., Redwood City, CA, USA) if it was not fully excluded by the assessment of fissure integrity. Depending on local diagnostic workup algorithms, Chartis assessment was either performed before the multidisciplinary emphysema board during a baseline bronchoscopy or before ELVR with valves. In most cases, Chartis assessment was performed if the fissure score was intermediate between 80% and 95% or depending on the interventional pulmonologist's choice. Additionally, ventilation perfusion scintigraphies of the lungs was part of standard workup in some centres. However, these data are not included in the REDCap data base, due to not being a requirement of the standard evaluation procedure of the lung emphysema registry. The same applied to radiological assessment of atelectasis rates at follow-ups.

Endoscopic lung volume reduction with valves

All cases were discussed by a multidisciplinary emphysema board with interventional pulmonologists, thoracic surgeons and radiologists, where a target lobe for lung volume reduction therapy was identified. Subsequently, patients suitable for ELVR underwent bronchoscopy and the target lobe was treated with Zephyr valve system (Pulmonx) or Spiration Valve System (Olympus, Center Valley, PA, USA). Valve systems were selected by the interventional pulmonologist based on local anatomy of the bronchial system.

Treatment responders

To detect treatment responders, the minimal clinically important difference (MCID) was calculated. The following values for MCID improvement after ELVR were used, as previously reported: FEV1 at least 10% increase, RV reduction of equal to 0.43 L or more, increase in 6MWT of 26 m or more and decrease of Modified Medical Research Council (mMRC) of at least 1 point and St. George's Respiratory Questionnaire (SGRQ) of at least 7 points [2932].

Statistical analysis

Categorical variables are presented as numbers and percentages, while continuous variables are expressed as the mean±sd. Baseline characteristics were assessed with an independent t-test. Changes in lung function test, quality of life and exercise capacity were evaluated using the Wilcoxon rank test. The mean difference (Δ) was determined as the difference between the baseline and the 3-month follow-up values. p-values less than or equal to 0.05 were considered significant. Changes in MCID and other categorical outcomes were compared through crosstabulations and Pearson's Chi-square test. All statistical analyses were conducted using SPSS software (version 24.0.0.0; IBM, Armonk, NY, USA).

Results

Study population

Table 1 outlines baseline characteristics. 54 patients had a 6MWT ≤140 m (very low 6MWT) and 365 patients had a 6MWT between 140 and 450 m (low 6MWT). Both groups demonstrated comparable age, body mass index (BMI) and sex ratio. Comorbidities had a similar distribution, except for a higher prevalence of osteoporosis among very low 6MWT patients (p<0.001). The emphysema score showed no difference between the groups. FEV1 and DLCO were lower in patients with a very low 6MWT. Both groups exhibited comparable RV and PCO2 levels. The COPD Assessment Test (CAT) score, mMRC and SGRQ were higher among patients with a 6MWT ≤140 m showing more pronounced symptoms in this group (p<0.001).

TABLE 1.

Baseline parameters of study population

6MWT ≤140 m 6MWT 140–450 m p-value
Subjects, n 54 365
Age years 67.4±6.9 65.6± 7.1 0.093
BMI kg·m−2 23.6±6.7 23.7±5.2 0.584
Male 30 (56) 186 (51) 0.562
Female 24 (44) 179 (49)
Comorbidities
α1-antitrypsin deficiency 1 (2) 20 (5) 0.330
Cardiovascular disease 9 (17) 65 (18) 0.853
Pulmonary hypertension 3 (6) 17 (5) 0.732
Atrial fibrillation 3 (6) 21 (6) N/A
Arterial hypertension 23 (43) 160 (44) 0.884
Osteoporosis 11 (20) 26 (7) <0.001
Diabetes mellitus type II 5 (9) 21 (6) 0.359
Lung cancer 0 (0) 5 (1) N/A
Active tumours 1 (2) 4 (1) 0.500
Emphysema score (−950 HU) % 43.2±12.9 43.7±13.7 0.770
Heterogeneity index % 13.6±11.1 16.4±13.0 0.217
Lung function test at baseline
FEV1 % pred 26.1±7.1 29.1±6.8 0.004
RV % pred 258.9±54.1 255.1±46.5 0.778
DLCO % pred 26.1±12.4 29.9±11.5 0.019
PCO2 mmHg 42.3±6.4 40.8±5.2 0.100
6MWT m 98.8±30.3 271.9±76.5 <0.001
CAT score 28.1±5.8 24.5±6.2 <0.001
mMRC score 3.7±0.7 2.9±0.8 <0.001
SGRQ score 75.7±11.8 64.9±12.7 <0.001

Data are presented as n (%) or mean±sd, unless otherwise stated. p-values in bold indicate statistically significant results. 6MWT: 6-min walk test; BMI: body mass index; HU: Hounsfield Units; FEV1: forced expiratory capacity in 1 s; RV: residual volume; DLCO: diffusing capacity of the lungs for carbon monoxide; PCO2: partial pressure of carbon dioxide; CAT: COPD Assessment Test; mMRC: Modified Medical Research Council; N/A: not applicable; SGRQ: St. George's Respiratory Questionnaire.

Changes between baseline and 3-month follow-up

Significant improvements occurred in FEV1, RV, PCO2, 6MWT, mMRC and SGRQ between baseline and 3-month follow-up in both groups (table 2). DLCO and CAT improved only in patients with a low 6MWT at baseline.

TABLE 2.

Changes between baseline and 3 -month follow-up

6MWT ≤140 m
Baseline
6MWT ≤140 m
3moFU
p-value 6MWT 140–450 m
Baseline
6MWT 140–450 m
3moFU
p-value
Subjects, n 54 54 365 365
FEV1 L 0.7±0.2 0.8±0.2 <0.001 0.8±0.2 0.9±0.3 <0.001
FEV1 % 26.1±7.1 30.4±7.9 <0.001 29.1±6.8 33.9±9.8 <0.001
RV L 5.9±1.1 5.2±1.5 0.014 5.7±1.2 5.0±1.4 <0.001
RV % 258.9±51.6 228.7±64.2 0.005 255.1±46.5 221.8±59.3 <0.001
DLCO mmHg 2.1±1.1 2.5±1.4 0.061 2.5±1.2 2.7±1.3 <0.001
DLCO % 26.1 ±12.4 30.6 ±15.6 0.084 29.9±11.5 32.4±12.9 0.009
PCO2 mmHg 42.3±6.4 40.7±6.7 0.034 40.8±5.2 39.6±5.8 <0.001
6MWT m 98.8±30.3 199.7±85.1 <0.001 271.9±76.5 295.9±97.6 <0.001
CAT score 28.1±5.8 21.7±7.0 0.081 24.5±6.2 21.7±7.0 <0.001
mMRC score 3.6±0.7 2.5±0.9 0.004 2.9±0.8 2.5±0.9 <0.001
SGRQ score 75.7±11.87 55.9±17.8 0.031 64.9±12.7 55.9±17.5 <0.001

Data are presented as mean±sd, unless otherwise stated. p-values in bold indicate statistically significant results. 6MWT: 6-min walk test; 3moFU: 3-month follow-up; FEV1: forced expiratory capacity in 1 s; RV: residual volume; DLCO: diffusing capacity of the lungs for carbon monoxide; PCO2: partial pressure of carbon dioxide; CAT: COPD Assessment Test; mMRC: Modified Medical Research Council; SGRQ: St. George's Respiratory Questionnaire.

Comparisons of 3 month-outcome between both groups

There were no differences in changes between baseline and 3-month follow-up for FEV1, RV, DLCO, PCO2, CAT, mMRC and SGRQ when comparing both groups (table 3). However, patients with a very low 6MWT showed a significantly higher improvement in Δ6MWT than those with a low 6MWT (p<0.001). The MCID for FEV1, RV and SGRQ was comparable for both groups. However, MCID of 6MWT was higher in very low 6MWT patients compared to those with low 6MWT at baseline (p<0.001) (table 4).

TABLE 3.

Comparisons of 3-month outcome between both groups

6MWT ≤140 m
absolute change
6MWT ≤140 m
change in %
6MWT 140–450 m
absolute change
6MWT 140–450 m
change in %
p-value
Subjects, n 54 54 365 365
ΔFEV1 L 0.1±0.1 14.3 0.1±0.2 12.5 0.970
ΔFEV1 % 3.9±5.6 16.5 4.5±7.5 16.5 0.767
ΔRV L −0.6±1.5 −11.9 −0.7±1.2 −12.3 0.956
ΔRV % −29.0±60.1 −11.7 −33.4±55.8 −13.1 0.838
ΔDLCO mmol·min−1·kPa−1 0.2±0.6 19.1 0.3±0.8 8.0 0.662
ΔDLCO % 2.4±7.85 17.2 2.7±8.8 8.4 0.891
ΔPCO2 mmHg −2.0±5.2 −3.8 −1.2±5.2 −2.9 0.348
Δ6MWT m 100.0±93.0 102.1 21.7±85.9 8.8 <0.001
ΔCAT score −2.6±7.8 −22.8 −2.6±6.4 −11.4 0.593
ΔmMRC score −0.6±1.1 −30.6 −0.5±1.0 −13.8 0.371
ΔSGRQ score −7.8±15.9 −26.2 −8.6±15.1 −13.9 0.753

Data are presented as mean±sd, unless otherwise stated. p-values in bold indicate statistically significant results. 6MWT: 6-min walk test; FEV1: forced expiratory capacity in 1 s; RV: residual volume; DLCO: diffusing capacity of the lungs for carbon monoxide; PCO2: partial pressure of carbon dioxide; CAT: COPD Assessment Test; mMRC: Modified Medical Research Council; SGRQ: St. George's Respiratory Questionnaire.

TABLE 4.

Patients with minimal clinically important difference (MCID)

6MWT ≤140 m 6MWT 140–450 m p-value
Subjects, n 54 365
FEV1 %, MCID ≥+10% 8 (15) 55 (15) N/A
RV L, MCID ≥−0.43L 25 (46) 154 (42) 0.659
6MWT m, MCID ≥+26m 26 (48) 86 (23) <0.001
SGRQ score, MCID ≤−7points 12 (22) 89 (24) 0.574

Data are presented as n (%), unless otherwise stated. p-value in bold indicates statistically significant result. 6MWT: 6-min walk test; FEV1: forced expiratory capacity in 1 s; RV: residual volume; SGRQ: St. George's Respiratory Questionnaire; N/A: not applicable.

Adverse events

No significant difference in the occurrence of complications was observed between both groups (table 5). There were two deaths in the group with a low 6MWT that were not related to the ELVR. Main complications included pneumothorax, COPD exacerbation and pneumonia. Among very low 6MWT patients, 2% were admitted to the intensive care unit (ICU), 2% reported a bleeding complication, 4% developed pneumonia, 13% reported COPD exacerbations and 15% were diagnosed with pneumothorax. Patients with a low 6MWT were admitted to ICU in 3% of cases, 2% underwent mechanical ventilation and 0.5% had a septic complication. A bleeding event was reported in 1%, 3% had pneumonia, 8% had a COPD exacerbation and 14% of cases developed a pneumothorax. During the 4- to 6-month follow-up adverse events were comparable in both groups as well (table 6).

TABLE 5.

Adverse events during the 3-month follow-up period

6MWT ≤140 m 6MWT 140–450 m p-value
Subjects, n 54 365
ICU admission 1 (2) 12 (3) N/A
Mechanical ventilation 0 (0) 6 (2) N/A
Death 0 (0) 2 (0.5) N/A
Sepsis 0 (0) 2 (0.5) N/A
Bleeding 1 (2) 3 (1) 0.425
Pneumonia 2 (4) 11 (3) 0.138
AECOPD 7 (13) 29 (8) 0.158
Pneumothorax 8 (15) 51 (14) 0.840

Data are presented as n (%), unless otherwise stated. 6MWT: 6-min walk test; ICU: intensive care unit; AECOPD: acute exacerbation of COPD; N/A: not applicable.

TABLE 6.

Adverse events during the 4- to 6-month follow-up period

6MWT ≤140 m 6MWT 140–450 m p-value
Subjects, n 54 365
ICU admission 0 (0) 2 (0.5) N/A
Mechanical ventilation 0 (0) 6 (2) N/A
Death 0 (0) 1 (0.3) N/A
Sepsis 0 (0) 0 (0) N/A
Bleeding 1 (2) 4 (1) 0.500
Pneumonia 1 (2) 7 (2) N/A
AECOPD 1 (2) 12 (3) N/A
Pneumothorax 0 (0) 5 (1) N/A

Data are presented as n (%), unless otherwise stated. 6MWT: 6-min walk test; ICU: intensive care unit; AECOPD: acute exacerbation of COPD; N/A: not applicable.

Discussion

This study evaluated the impact of ELVR on patients with a very low 6MWT. Traditionally, those with advanced lung emphysema and a very low 6MWT were often excluded from this intervention due to concerns about negligible benefits and increased complications linked to muscular deconditioning and lack of respiratory reserves [917]. However, this study revealed that patients with a very low 6MWT have comparable improvements in lung function and quality of life at the 3-month follow-up compared to a control group with a low 6MWT. Notably, the increase of 6MWT at 3 months was significantly higher in patients with a very low 6MWT at baseline compared to the control group. Adverse events were similar between both groups suggesting the safety of ELVR for patients with a very low 6MWT.

The 6MWT represents an efficient clinical tool for assessing exercise capacity in COPD patients, which is easy to reproduce and demonstrates a good correlation with FEV1 [68, 33]. Additionally, the 6MWT is considered a good predictor for overall survival in COPD patients. Given the significantly increased post-operative mortality rate observed in lung volume reduction surgery, particularly in high-risk patients defined by FEV1 ≤20%, DLCO ≤20% and a homogeneous emphysema during the NETT trial, patients with a very low 6MWT were excluded from further large randomised controlled trials with ELVR [20]. Notably, studies like VENT, EMPROVE, IMPACT and TRANSFORM excluded patients with a very low 6MWT [9, 10, 12, 16, 20], while REACH and BeLieVeR-HIFi officially had no lower 6MWT limit, although, patients with frailty or inability to tolerate a potential pneumothorax were excluded [14, 15]. The LIBERATE study set the lower 6MWT limit at 100 m [13]. Most of the aforementioned studies excluded patients with a 6MWT <140 m, and the mean 6MWT distance of remaining studies exceeded 300 m leaving uncertainty about the inclusion of patients with a very low 6MWT. Especially because scientific evidence was lacking, clinical experience suggested that carefully selected patients, where dyspnoea was primarily attributed to advanced lung emphysema, might respond to ELVR. As consequence, a cut-off value of 140 m for the 6MWT was chosen for this analysis.

The lung emphysema registry (Lungenemphysemregister e.V.) plays a pivotal role as a large manufacturer-independent registry evaluating lung volume reduction therapies in emphysema patients in Germany, and no lower limit for the 6MWT is defined in its inclusion criteria. Treatment responses observed in patients from the lung emphysema registry after ELVR were comparable to the large randomised controlled studies with one-way valves [916]. Comparisons with studies such as LIBERATE, EMPROVE and TRANSFORM revealed similar improvements in relative and absolute changes for FEV1, 6MWT and quality of life. Although the MCID for FEV1 was lower in this study compared to the randomised controlled trials, the MCID for 6MWT was similar.

When comparing treatment response at 3-month follow-up, remarkable increases in 6MWT were noted in the patients with a very low 6MWT. The MCID further confirmed these findings, revealing a significantly higher MCID for 6MWT at 3-month follow-up for patients with a very low 6MWT, while FEV1, RV and SGRQ revealed similar MCID. Interestingly, both groups had representative baseline characteristics for patients with advanced lung emphysema and no difference in comorbidities, excepts for a higher prevalence of osteoporosis in the group with a very low 6MWT. However, the high increase in the 6MWT of patients with a very low 6MWT might be attributed to the “regression towards the mean” bias.

In this study, patients were carefully selected and only included if dyspnoea was predominately attributed to lung emphysema, and not to comorbidities or extreme frailty. Patients with lung emphysema often present multiple associated comorbidities, including cardiovascular diseases, musculoskeletal dysfunction, osteoporosis and metabolic disorders [34]. Our analysis indicated that a 6MWT cut-off of ≤140 m for the 6MWT should not impede the decision for ELVR imperatively, if advanced lung emphysema is the main cause of a very impaired walking distance. Therefore, it is crucial to evaluate suitable patients with a very low 6MWT carefully, focusing on muscular deconditioning.

The main limitation of this study is the relatively small sample size for the group with a very low 6MWT. Another possible limitation is that not all patients included in the lung emphysema registry had a 6MWT at baseline or 3-month follow-up. Additionally data from the lung emphysema registry do not capture data on participation in rehabilitation programmes before or after ELVR, which might potentially impact outcome of the 6MWT. Nevertheless, the results clearly show that patients with a very low 6MWT benefit from ELVR, improving lung function, 6MWT and quality of life without increased risk of complications. This study is a retrospective multicentric analysis, introducing a potential selection bias among patients with a very low 6MWT, although both groups have comparable baseline parameters. We are confident that our findings will be confirmed in future larger controlled studies.

In conclusion, this study demonstrated that endoscopic lung volume reduction with one-way valves in emphysema patients with a very low 6MWT leads to improvements in lung function parameters, exercise capacity and quality of life. Furthermore, no increased complication risk was detected in this study. Thus, endoscopic lung volume reduction with one-way valves appears to be an efficient treatment tool for this vulnerable patient group.

Acknowledgements

The authors sincerely thank CAPNETZ, Berlin Institute of Health, Laura Grebe for data management and Andreas Hetay for editing support.

Provenance: Submitted article, peer reviewed.

Ethics statement: The research presented in this article was conducted according to the standards of the World Medical Association Declaration of Helsinki and the appropriate guidelines for human studies. All data were derived from prospective open-label clinical studies in our institution which were approved by the Ethics Committee of the Charité Universitätsmedizin Berlin, Germany (EA2/149/17 and EA1/136/13). All patients consented to participation. Inability to sign the consent form was an exclusion criterion.

Author contributions: J. Saccomanno: drafting the work, literature research, writing, interpretation and critically revising the manuscript. L. Kilic: drafting the work, writing, interpretation, critically revising the manuscript. T. Sgarbossa: drafting the work, writing, interpretation, critically revising the manuscript. K. Neumann: data analysis and interpretation, writing, critically revising the manuscript. F. Stanzel: data analysis and interpretation, writing, critically revising the manuscript. A. Holland: data analysis and interpretation, writing, critically revising the manuscript. C. Grah: data analysis and interpretation, writing, critically revising the manuscript. W. Gesierich: data analysis and interpretation, writing, critically revising the manuscript. J. Krist: data analysis and interpretation, writing, critically revising the manuscript. J.H. Ficker: data analysis and interpretation, writing, critically revising the manuscript. S. Eggeling: data analysis and interpretation, writing, critically revising the manuscript. S. Andreas: data analysis and interpretation, writing, critically revising the manuscript. B. Schmidt: data analysis and interpretation, writing, critically revising the manuscript. S. Eisenmann: data analysis and interpretation, writing, critically revising the manuscript. B. Schwick: data analysis and interpretation, writing, critically revising the manuscript. K-J. Franke: data analysis and interpretation, writing, critically revising the manuscript. A. Fertl: data analysis and interpretation, writing, critically revising the manuscript. M. Witzenrath: data analysis and interpretation, writing, critically revising the manuscript. R-H. Hübner: drafting the work, data acquisition, data analysis and interpretation, writing, critically revising the manuscript.

Conflict of interest: J. Saccomanno reports payment or honoraria for lectures or presentations for PulmonX, support for attending meetings and/or travel from Medtronic and is a member of Lungenemphysemregister e.V.

Conflict of interest: L. Kilic, T. Sgarbossa, K. Neumann, F. Stanzel, A. Holland and C. Grah have nothing to disclose.

Conflict of interest: W. Gesierich reports speaker/presenter fees from AstraZeneca and PulmonX.

Conflict of interest: J. Krist, J.H. Ficker and S. Eggeling have nothing to disclose.

Conflict of interest: S. Andreas reports grants/contracts from Boehringer; consulting fees from GSK and AstraZeneca; payment or honoraria from Actelion, AstraZeneca, Almirall, Berlin Chemie, Boehringer Ingelheim, GSK, Janssen and Novartis; and leadership or fiduciary roles in DGP, ABNR, HKG and DGIM.

Conflict of interest: B. Schmidt has nothing to disclose.

Conflict of interest: S. Eisenmann reports consulting fees from AstraZeneca, payment or honoraria from GSK and AstraZeneca; support for attending meetings/travel from Nuvaira and Sanofi; and participation on data safety monitoring or advisory boards for Novartis and AstraZeneca.

Conflict of interest: B. Schwick has nothing to disclose.

Conflict of interest: K-J. Franke reports payment or honoraria for lectures from GlaxoSmithKline and Boehringer; support for attending meetings from Boehringer Ingelheim.

Conflict of interest: A. Fertl has nothing to disclose.

Conflict of interest: M. Witzenrath reports grants from Biotest and Pantherna; personal fees from Biotest, Pantherna, Aptarion, AstraZeneca, Chiesi, Insmed, Gilead, Pfizer and Boehringer.

Conflict of interest: R-H. Hübner reports a study fee (Convert) from Pulmonx; presenter fees from Berlin Chemie, Astra, Chiesi and Pulmonx; and travel support from Medtronic.

Data availability

Data can be made available on request to the corresponding author.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data can be made available on request to the corresponding author.


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