Endobronchial valve (EBV) insertion for severe emphysema does not improve skeletal muscle mass or function

Endobronchial valve (EBV) insertion for severe emphysema does not improve skeletal muscle mass or function | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Endobronchial valve (EBV) insertion for severe emphysema does not improve skeletal muscle mass or function Julia Rubenstein, Ilyes Benlala, Anne-Claire Toublanc, Marina Guecamburu, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4423314/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Endobronchial valve (EBV) insertion for severe emphysema allows to reduce hyperinflation and alleviates respiratory symptoms in patients with chronic obstructive pulmonary disease (COPD). However, few studies investigate their effect on extra-pulmonary manifestations of emphysema. We sought to assess the effect of EBV insertion on skeletal muscle mass and function, as well as determine if skeletal muscle parameters could represent a prognosis factor for response to EBV insertion. Methods: We conducted a monocentric prospective study including 19 patients. Exhaustive evaluation of lung & skeletal muscle parameters was performed at baseline and 3 and 6 months after EBV insertion. Evaluation included assessment of COPD severity (CAT-score, mMRC, pulmonary function tests, 6-minutes walking test (6MWT)), assessment of body composition with bioimpedance analysis, of thoracic muscles surface and density on CT-scans, and of upper limb force with handgrip test. Results: EBV insertion led to a significant improvement of lung function after 3 months, that persisted 6 months after the procedure, with a significant decrease in target love volume, residual volume, total lung capacity and a significant increase in forced expiratory volume at 1 second (FEV1). Respiratory symptoms were also alleviated with a significant decrease in mMRC. In contrast, no improvement was observed in skeletal muscle parameters, whether whole-body muscle mass (appendicular skeletal muscle index), thoracic muscles surface or density, or muscle force. Besides, no muscle-related parameter was found to predict response to EBV insertion. Conclusions: These results strongly advocate for a more thorough referral to pulmonary rehabilitation after the procedure, as well as emphasize the need to find bottom-up drug strategies for COPD-associated sarcopenia. Health sciences/Signs and symptoms/Comorbidities Health sciences/Signs and symptoms/Respiratory signs and symptoms Health sciences/Diseases/Respiratory tract diseases endobronchial valve sarcopenia skeletal muscle wasting emphysema body composition Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Emphysema represents a severe phenotype in patients with chronic obstructive pulmonary disease (COPD), associated with increased mortality and increased risk of extra-pulmonary manifestations within a global multi-organ loss of tissue phenotype [ 1 ]. Several strategies have been developed over the past years to overcome lung hyperinflation. Lung volume reduction strategies were initially surgical procedures with a marked improvement on exercise capacity [ 2 , 3 ]; however, mortality rate was relatively high among a subgroup of patients (particularly those with severe lung function impairment at baseline), leading to the development of minimally invasive strategies. As such, the development of endoscopic lung volume reduction using unidirectional endobronchial valves (EBV) insertion started ∼20 years ago and was included in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines in 2017 [ 4 ], based on positive outcomes on lung function, exercise capacity and quality of life in several randomized controlled trials [ 5 – 7 ]. Unidirectional endobronchial valves (EBV) are one-way valves that allow expiratory flow but prevent inspiratory flow, ultimately causing collapse of distal lung segments. However, the impact of EBV on extra-pulmonary manifestations of COPD, such as skeletal muscle mass and function is vastly unknown. Muscle wasting plays a prominent role in COPD as both muscle weakness [ 8 ] and atrophy [ 9 ] are associated with an increased risk of mortality. The evaluation of sarcopenia, characterized by a loss of muscle mass and force below a fixed level, is challenging and includes measures of (preferably) whole-body muscle mass and muscle force [ 10 ]. While alternative indexes such as thoracic muscle surface have shown a stronger association with increased mortality than emphysema [ 11 ], their correlation with whole-body muscle mass requires further investigation [ 12 ]. Therefore, a multimodal evaluation of muscle status is strongly recommended. In this study, our objective was to explore whether reducing hyperinflation through EBV insertion improves skeletal muscle parameters, involving a comprehensive assessment of skeletal muscle mass and force. A secondary aim was to determine if baseline muscle parameters could predict the response to EBV insertion. Methods Study and patients Between March 2021 and November 2022, we conducted a prospective monocentric study in Bordeaux University Hospital, including consecutive patients treated with EBV, determined eligible based on consensus guidelines [ 13 ], following usual criteria (smoking cessation for at least three months, post bronchodilator forced expiratory volume 100 m, modified Medical research council (mMRC) score of 2 or more). The majority of patients (16/19, 84%) undertook pulmonary rehabilitation prior to the procedure. Lobar fissure integrity was determined by quantitative CT with StratX® (PulmonX Corp., Redwood City, CA). When fissure integrity was assessed to be higher than 80%, collateral ventilation was systematically evaluated by the Chartis® system (PulmonX Inc., Redwood City, CA, USA), during the procedure. Lobe volume reduction was also measured. Comprehensive clinical and paraclinical evaluation was performed at baseline, 3 months, and 6 months post-procedure. Respiratory parameters included spirometry and body plethysmography, COPD assessment test (CAT) score, modified Medical Research Council (mMRC) dyspnea scale, 6-minutes walking test (6MWT). Whole-body muscle mass was assessed with bioelectrical impedance analysis (BIA: Biacorpus RX 4004M, MEDI CAL HealthCare), providing a reliable estimation of the appendicular skeletal muscle mass index (ASMI in kg/m 2 , which represents the sum of the lean muscle mass of the upper and lower extremities adjusted with height), and also allowing to know the percentage of fat mass, and the value of phase angle. Sarcopenia was defined as per the criteria published by Janssen and colleagues for severe sarcopenia and adapted for the BIA technique (ASMI < 8.50 kg/m 2 for men and 5.50 kg/m 2 for women) [ 14 ]. Additionally, muscle surface and density on thoracic CT scans (psoas, 5th intercostal, pectoralis above the aortic arch, and erector spinae muscle at the 12th thoracic vertebra) were measured as previously described [ 15 ]. Briefly, CT axial slices were analyzed at the level of the lower margin of the 12th thoracic vertebrae for the psoas, the 5th intercostal, and the erector spinae, and above the aortic arch for the pectoralis. A predefined attenuation range of -50 and − 90 Hounsfield units (HU) was used. Muscle strength was assessed at the upper arm (handgrip test) with an electronic dynamometer (Jamar Health Products Inc, China). Safety data including occurrence of pneumothorax, pneumonia, and exacerbations, were collected. Outcomes The primary outcome was the 3-month change from baseline after EBV insertion in skeletal muscle parameters: skeletal muscle mass assessed by BIA, and muscle strength assessed with handgrip test. Secondary outcomes were (i) to assess the change in thoracic muscle surfaces or densities after EBV insertion, (ii) to compare muscle parameters in responders to EBV insertion versus non-responders, and (iii) to compare the response to EBV insertion in sarcopenic patients versus non-sarcopenic ones, in order to determine if sarcopenia can be considered as a predictive factor. Statistical analysis and ethical considerations All statistical tests were performed with a type I error rate of 5%. Qualitative variables were described with numbers and percentages, and quantitative variables with numbers of non-missing data, median and inter-quartile range. The qualitative variables were compared with a Chi² test, corrected Chi² test or with non-parametric Fisher's exact test. The quantitative variables were compared with a Student t test (parametric) or a Wilcoxon test (non-parametric) in case of two groups only, and with two-way Anova with Tukey’s multiple comparisons for all data assessed in time and compared between two groups. All statistical analyses were performed using GraphPad Prism (La Jolla, CA, USA). The study was conducted in accordance with French legislation and ethical codes. This work complies to the protection of personal health data and the protection of privacy with the framework of application provided for by article 65 − 2 of the amended Data Protection Act and the general data protection regulations and was registered with the following number CHUBX2020RE0270. The study was designed according to the STROBE guidelines. Results Within the study period of 20 months, 104 subjects were screened for EBV insertion in Bordeaux University Hospital and 22 consecutive subjects were enrolled. Of those patients, 2 underwent valve removal within six months after the procedure (one due to a persistent pneumothorax despite chest drain, and one due to deterioration of respiratory function) and one was rapidly lost to follow-up. Nineteen remaining patients were subsequently included in the study (Supplementary Fig. 1). Clinical and demographic data at baseline Of the 19 included patients, 12 were women (63%), and the overall mean age was 65.2 ± 8.0 years (Table 1 ). They exhibited a substantial symptom burden, with a mean mMRC dyspnea scale and CAT scores of 2.6 ± 0.7 and 18.4 ± 6 points, respectively. Severe COPD was evident with a mean forced expiratory volume in one second (FEV1) of 33.8 ± 8.2%pred, a mean residual volume (RV) of 231.3 ± 45.1%pred, a mean total lung capacity (TLC) of 133.5 ± 22.3%pred and a mean diffusing capacity of the lung for carbon monoxide (DLCO) of 27.9 ± 16.3%pred. The mean 6MWT was 355 ± 89 m, and the mean body mass index (BMI) was 24.7 ± 5.7 kg/m². Concerning body composition, the mean appendicular skeletal muscle mass index (ASMI) was 6.9 ± 1.9 kg/m2 (9.4 ± 1.4 kg/m 2 in men and 5.9 ± 0.8 kg/m 2 in women), and the mean percentage of fat mass was 30.4 ± 9.7 (30.5 ± 5.7 in men and 32.8 ± 7.3 in women). Mean phase angle value was 5.2 ± 1 °. Concerning skeletal muscle function, the mean upper limb force assessed by the handgrip test was 29.7 ± 9.7 kg (39 ± 5.6 kg in men and 23.9 ± 6.6 kg in women). Table 1 Patients’ characteristics at baseline. Total population (n = 19) Demographic data Age, years 65.7 ± 7.8 Sex, n (%) Female 12 (63) BMI, kg/ m2 24.7 ± 5.7 Smoking : active, n (%) 0 (0) Former smoking, n (%) 17 (89) Smoking history, pack-years 32.5 ± 18.2 Non-drug therapies Patients on LTOT, n (%) 10 (52.6) Patients on NIV, n (%) 2 (10.5) Rehabilitation within 6 months before the procedure, n (%) 16 (84.2) Symptoms & COPD severity Severe exacerbation the year before EBV, n (%) 3 (15.8) BODE index 4.7 ± 1.5 mMRC, points 2.6 ± 0.7 CAT, points 18.4 ± 6 a Pulmonary function tests FEV 1 , L FEV 1 , % pred 0.81 ± 0.3 33.8 ± 8.2 FEV 1 / FVC 37.9 ± 11.4 RV, %pred 231.3 ± 45.1 TLC, %pred 133.5 ± 22.3 DLCOc, %pred 27.9 ± 16.3 Arterial blood gas PaO 2 , mmHg 68.2 ± 10.5 PaCO 2 , mmHg 41.2 ± 4.2 Cardiac assessment LVEF, % 64.9 ± 6.7 Exercice capacity 6MWT, m 355 ± 89 6MWT, %pred 69 ± 19.3 Average walking speed*, m/s 0.99 ± 0.25 Body composition ASMI, kg/m2 6.9 ± 1.9 a Fat mass, % 30.4 ± 9.7 b Phase angle, ° 5.2 ± 1 a Skeletal muscle force Handgrip test, kg 29.7 ± 9.7 c BMI: body mass index, LTOT: Long term oxygen therapy, NIV: non-invasive ventilation, mMRC: modified Medical Research Council Dyspnea Scale, CAT: COPD assessment test, LVEF: left ventricle ejection fraction, 6MWT: 6-minutes walk test, FEV1: forced expiratory volume in 1s, FVC: forced vital capacity, RV: residual volume, TLC: total lung capacity, DLCO: carbon monoxide diffusing capacity, pred: predicted value, ASMI: appendicular skeletal muscle mass index. *average walking speed over 6 minutes. Values are mean ± SD. a: 2 missing data, b: 1 missing data, c:6 missing data. Adverse events after EBV insertion Adverse events were consistent with other studies: 5 (26%) COPD exacerbations, 3 (16%) procedure-related pneumothoraces (one requiring valve removal, the two others resolved with chest drainage), 1 pneumonia, 1 pleuritis, and 2 patients with hemoptysis. Respiratory related adverse events occurred in 7 patients (37%) (Table 2 ). The management of pneumothorax was performed following protocolized algorithms [ 16 ]. Two patients had iterative COPD exacerbations or pneumoniae and improved after new endoscopy for valve repositioning or the replacement of a proximal valve by several distal valves. Table 2 adverse events (total: n = 7 (37%)). Outcomes N = 10 (%) Death 0 (0) Pneumothorax 3 (16) COPD exacerbation 5 (26) Pneumonia 1 (5) Pleuresia 1 (5) Hemoptysis 2 (10) Valve removal 3 (16) Arrythmia 0 (0) Evolution of respiratory parameters In agreement with previously published data [ 5 , 17 ], patients had improvement on respiratory function after EBV insertion at three months. We observed a significant decrease in target lobe volume at 3 months and persisting at 6 months (p < 0.0001 in both cases, Fig. 1 A), as well as a significant decrease in hyperinflation as represented by the decrease in TLC and RV (p = 0.0002 and p < 0.0001, respectively, at 3 months, Fig. 1 A). Lung function as represented by FEV1 improved significantly (p = 0.02 at 3 months, Fig. 1 B). The overall gain of FEV1 was 190 ± 260 mL, which represented 26 ± 31.8% of its initial value. Dyspnea assessed by mMRC also improved (p = 0.008 at 3 months, Fig. 1 B). However, we observed no significant improvement in DLCO and exercise capacity as represented by 6WMT (p = 0.81 et p = 0.47, respectively, at 3 months, Fig. 1 B). Quality of life assessed by COPD assessment test (CAT-score) also did not change significantly (p = 0.77 at 3 months) (data not shown). In terms of local response to EBV insertion, complete target lobe atelectasis was achieved in 18/19 (94%) patients at 3 months with a mean decrease in CT-measured volume of the treated lung of 882 ± 429 mL. In terms of response criteria as proposed by Hartman and colleagues [ 18 ], FEV 1 increased more than 12% (or more than 10%) in 11 patients (58%) according to STELVIO study, RV increased more than 430 mL in 14 patients (74%) and more than 310 mL in 16 patients (84%) (LIBERATE), 6-min walk distance (6MWD) increased more than 25 m in 4 patients (21%) and quality of life (assessed by CAT variation as a proxy of St George's Respiratory Questionnaire (SGRQ)) increased more than 4 points in 6 patients (31%). Evolution of skeletal muscle parameters In contrast to respiratory parameters, we observed no significant improvement in body composition (ASMI or fat mass) or phase angle value (an independent predictor of mortality [ 19 ]) at 3 or 6 months (Fig. 2 A, Supplementary Fig. 2). ASMI overall mean gain was 0.27 ± 0.79 kg/m 2 at 3 months and 0.28 ± 0.58 kg/m 2 at 6 months (p = 0.11 and p = 0.17, respectively). Fat mass overall mean gain was − 0.81 ± 2.8% at 3 months and 1.36 ± 4.2% at 6 months (p = 0.99 and p = 0.22, respectively). Handgrip strength remained perfectly stable over 6 months (Fig. 2 B). Concerning CT-based thoracic muscles assessment (pectoralis, 5th intercostal, erector spinal and psoas), we did also not observe any significant change in muscles surface over the course of 6 months (Fig. 2 C), nor in their densities (Supplementary Fig. 3). No significant correlation was observed between the gain of skeletal muscle mass (whether assessed by the ASMI or by the pectoralis surface) and lung function parameters (data not shown). Of note, very few patients underwent pulmonary rehabilitation following the procedure (1 patient (5%) in the following three months and 2 patients (11%) in the following six months). Focus on responders to EBV insertion No significant difference was observed in baseline skeletal muscle parameters according to the response to EBV insertion status, whatever the chosen criteria (data not shown). When response to EBV insertion was assessed on the basis of mMRC improvement (≥ 1), we observed some minor differences. There was a significant increase in phase angle value in responders compared to non-responders at 3 months (p = 0.04, Fig. 3 A), such increase being associated with a lower mortality [ 19 , 20 ]. However, statistical significance did not persist at M6. We also observed a slight tendency toward a greater gain in ASMI and handgrip strength in responders compared to non-responders, but without reaching statistical significance (p = 0.48 and p = 0.35, respectively, at 3 months, Fig. 3 A, B). Fat mass did not differ between the two groups (p = 0.73 at 3 months, Fig. 3 A). Concerning thoracic muscles, only erector spinal surface was significantly higher in responders at 3 months (p = 0.02 at 3 months, Fig. 3 C), but not at 6 months. Focus on sarcopenic patients at baseline Five patients (26%) (4 women and 1 man) were considered as sarcopenic at baseline (severe sarcopenia on the basis of low muscle mass according to the criteria published by Janssen and colleagues [ 14 ]: ASMI < 8.50 kg/m2 in men and < 5.75 kg/m2 in women). Of note, 18 out of 19 patients (95%) were considered to suffer from moderate sarcopenia according to the same criteria. At baseline, sarcopenic patients exhibited (as per definition) a significantly lower muscle mass than non-sarcopenic ones (ASMI 5.54 ± 1.2 versus 7.52 ± 1.8 kg/m 2 , p = 0.04, Table S1 ). As expected, handgrip strength was also significantly decreased in sarcopenic patients (19.8 ± 6.4 versus 34.1 ± 7.4 kg, p = 0.01). However, the percentage of fat mass was similar, as well as the value of phase angle. Exercise capacity was significantly decreased in sarcopenic patients (6MWT 54.4 ± 17.1 versus 74.1 ± 17.7%pred, p = 0.04). However, there was no other significant difference in baseline parameters, including demographic parameters, pulmonary function tests results and indicators of COPD severity (Table S1 ). Of note, there was a tendency towards a poorer quality of life with a higher CAT-score in sarcopenic patients (22.6 ± 4.5 versus 16.6 ± 5.9 points, p = 0.06). FEV1 was not statistically different between the two groups (30.2 ± 7.2 versus 35.1 ± 8.3%pred, p = 0.26). Altogether, there was no significant difference in the evolution of respiratory endpoints between sarcopenic and non-sarcopenic patients (Fig. 4 A, B), whether in the improvement in target lobe volume, TLC, RV, FEV1, mMRC, DLCO, or 6MWT, at 3 or 6 months. We observed some minor differences in favor of a greater improvement in sarcopenic patients: target lobe volume tended to decrease more in sarcopenic patients at 3 months (p = 0.08, Fig. 4 A), but not at 6 months; RV tended to decrease more in sarcopenic patients at 3 months (p = 0.09, Fig. 4 A). There was also no significant difference in muscle mass evolution (ASMI) between sarcopenic and non-sarcopenic patients, despite a tendency towards a greater improvement in non-sarcopenic patients (p = 0.14 at 3 months and p = 0.05 at 6 months; Fig. 4 C). However, such improvement was overall mild. Fat mass tended to decrease more in sarcopenic patients at 3 months (p = 0.27; Fig. 4 C), but this did not persist at 6 months. Of the 5 sarcopenic patients at baseline, one was not considered sarcopenic any more at 3 months, but fell under the cut-off value again at 6 months. At 6 months, the overall proportion of sarcopenic patients remained identic to baseline (5/19 = 26%), but with one patient exchange between the two groups. Discussion Altogether, our data indicate that EBV insertion brings little to no improvement in skeletal muscle mass and force over the course of six months. Although very few studies tackled the effect of EBV on skeletal muscle parameters, our results are contradictory with the study of Sanders and colleagues, who observed a significant improvement in CT-measured skeletal muscles six months after EBV insertion [ 21 ]. However, such difference might come from the different endpoint analyzed: we measured separately thoracic muscles at two different levels (12th thoracic vertebrae and above the aortic arch), whereas in the cited study, skeletal muscle cross-sectional area was analyzed as a whole at the L1 level. Another study evidenced a correlation between the reduction in RV and the increase in parasternal thickness with ultrasound assessment [ 22 ]. However, diaphragm thickness did not change after EBV insertion. Last, a recent study on 300 EBV-treated patients did not observe a significant change in muscle volume (as assessed by CT) 6 months after the procedure [ 23 ]. Overall, very few studies assess the benefit of EBV insertion on extra-pulmonary features of emphysema, emphasizing the need for further studies. In addition to skeletal muscle parameters, other extra-pulmonary parameters should be assessed such as cardiac function, as lung volume reduction (with surgical procedure) has been shown to improve right ventricular performance [ 24 ]. In our study, no muscle-related parameter was able to predict response to EBV insertion, regardless of the chosen criteria. These findings align with recent data suggesting that disease severity parameters do not predict response to EBV treatment; rather, local lung parameters such as the degree of air trapping and perfusion in the target lobe play a major role [ 25 ]. Our study presents several limitations. First, the small sample size prevents generalization of the results. It is also possible that this small sample size led to a lack of power, preventing us from observing significant differences. Nevertheless, our cohort appears representative of the general EBV-treated population, in terms of severity of included patients or rate of adverse events [ 5 , 17 , 21 ]. The results of our study on lung function are also close to those of the previous studies with a significant improvement in pulmonary functional tests, exercise capacity and in scores of dyspnea and quality of life. Out of 19 patients, 11 (58%) were responders on FEV1, compared to 55.5% in the TRANSFORM study and 47.7% in the LIBERATE study. The patients had an average gain of 25% which is similar to 17% in the LIBERATE study and 20% in the TRANSFORM study. Patients also experienced a clinical benefit with an average reduction of 0.53 point in mMRC score, lowered lung distension with reduction of pulmonary volume of 882 ml and a mean increase of 23 m increase in 6MWT. Finally, the proportion of sarcopenic patients is in adequation with what has been reported in the literature [ 26 , 27 ], although such proportion can greatly vary according to the selected population. Other limitations include the evaluation of muscle force (with handgrip test only) and function (with 6MWT only), which did not allow to cover every aspect of this dimension. Follow-up studies will aim to incorporate additional functional tests such as 5-times sit to stand test and more thorough evaluation of patients’ level of physical activity as well as nutritional assessme,t. However, very few studies on the same topic include a multimodal evaluation of skeletal muscle mass (with BIA and CT-based measures) and function. We chose to measure thoracic muscles surface and density as a surrogate marker for sarcopenia. Other studies rather used quadriceps surface [ 9 ] or paraspinal muscle volume at L3 [ 28 ]. Nevertheless, several recent studies have shown that thoracic muscle surface was a validated surrogate marker for sarcopenia in COPD patients [ 29 ] [ 30 ]. Measuring thoracic muscles brings the advantage of using thoracic CT-scans data, a routine examination in COPD patients, whereas abdominal or quadricipital CT-scan is not part of usual care. Finally, whole-body skeletal muscle mass was assessed with BIA and not dual-X-ray absorptiometry; however, numerous studies have validated the use of BIA to assess skeletal muscle mass, including in patients with COPD [ 31 , 32 ]. Altogether, our study suggests that treatment options for patients with advanced emphysema should be holistic and not focused on emphysema itself. This emphasizes the need for a multimodal for a systematic referral to pulmonary rehabilitation in conjunction with the EBV procedure, as recently reported before EBV insertion [ 33 ], but probably also after the procedure. In our study, the percentage of patients that had undergone pulmonary rehabilitation was high before the procedure, but dramatically low after, similarly to the global percentage of patients with COPD referred to pulmonary rehabilitation in France outside the context of EBV [ 34 ]. Tailored rehabilitation programs, considering patients’ baseline measurements, are crucial, particularly with the overarching goal of gaining muscle force. Such combination of EBV and rehabilitation procedures could address the multiscale loss of tissue phenotype described in emphysema [ 35 ]. However, we postulate that the absence of clear improvement in skeletal muscle mass or function also highlights the need for innovative, bottom-up drug treatment strategies for COPD, with a specific focus on skeletal muscle wasting. Conclusion Endobronchial valve (EBV) insertion in severe emphysema brings little to no improvement to skeletal muscle mass and handgrip strength over the course of six months. This challenges conventional assumptions and emphasizes the need for a multimodal approach, including – but not limited to - pulmonary rehabilitation, in managing emphysema. Abbreviations ASMI: appendicular skeletal muscle mass index BIA: bioimpedance analysis BMI: body mass index CAT: COPD assessment test COPD: chronic obstructive pulmonary disease CT: computed tomography EBV: endobronchial valve DLCO: carbon monoxide diffusing capacity FEV1: forced expiratory volume in 1s FVC: forced vital capacity GOLD: global initiative for chronic obstructive lung disease LTOT: Long term oxygen therapy LVEF: left ventricle ejection fraction mMRC: modified Medical Research Council NIV: non-invasive ventilation RV: residual volume TLC: total lung capacity 6MWT: 6-minutes walk test Declarations Ethics approval and consent to participate: The study was conducted in accordance with French legislation and ethical codes. According to French Law, this anonymous retrospective observational database study does not require approval by an ethics committee or informed signed consent from the patients. The study was designed according to the STROBE guidelines and registered with the following number CHUBX2020RE0270. Consent for publication : not applicable Availability of data and materials: The datasets used and/or analyzed in the study are available from the corresponding author on reasonable request. Competing interests : JR reports no conflict of interest, IB reports no conflict of interest, ACT reports no conflict of interest, MG reports no conflict of interest, AM reports no conflict of interest, reports no conflict of interest, CV reports no conflict of interest, LG non-financial support from ASTEN, AIR LIQUIDE, SANOFI GENZYME, SOS Oxygene, AstraZeneca, ASV, Boerhinger, GM non-financial support from IPSEN, PD reports no conflict of interest, PH reports grants and non-financial support from AVAD, and non-financial support from Chiesi and GSK, outside the submitted work. MZ reports grants and personal fees from Menarini, personal fees from Sanofi, personal fees from Chiesi, personal fees from AstraZeneca, personal fees from CSLBehring and personal fees from GSK outside the submitted work, grants from AVAD, grants from FRM. Funding : This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors' contributions : Conceptualization : PH, MZ, Methodology : PH, MZ, GM, PD, Validation : PH, MZ, Formal analysis : JR, IB, PH, MZ, Investigation : JR, IB, ACT, MG, Resources : AM, CB, CV, LG, Writing - Original Draft : JR, PH, MZ, Writing - Review & Editing : all authors JR, IB, ACT, MG, AM, CB, CV, LG, GM, PD, PH, MZ, Visualization : PH, MZ, Supervision : PH, MZ Acknowledgements : We thank the nurses from the Pneumology Department of Bordeaux University Hospital for BIA measurements. 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Raw Bioelectrical Impedance Analysis Variables Are Independent Predictors of Early All-Cause Mortality in Patients With COPD. Chest. 2019;155:1148–57. De Benedetto F, Marinari S, De Blasio F. Phase angle in assessment and monitoring treatment of individuals with respiratory disease. Rev Endocr Metab Disord. 2023; Sanders KJC, Klooster K, Vanfleteren LEGW, Slebos D-J, Schols AMWJ. CT-derived muscle remodelling after bronchoscopic lung volume reduction in advanced emphysema. Thorax. 2019;74:206–7. Wallbridge P, Hew M, Parry SM, Irving L, Steinfort D. Reduction of COPD Hyperinflation by Endobronchial Valves Improves Intercostal Muscle Morphology on Ultrasound. Int J Chron Obstruct Pulmon Dis. 2020;15:3251–9. Wienker J, Darwiche K, Rüsche N, Büscher E, Karpf-Wissel R, Winantea J, et al. Body composition impacts outcome of bronchoscopic lung volume reduction in patients with severe emphysema: a fully automated CT-based analysis. Sci Rep. 2024;14:8718. Mineo TC, Pompeo E, Rogliani P, Dauri M, Turani F, Bollero P, et al. Effect of lung volume reduction surgery for severe emphysema on right ventricular function. Am J Respir Crit Care Med. 2002;165:489–94. Hartman JE, Roodenburg SA, van Dijk M, Koster TD, Klooster K, Slebos D-J. Response to endobronchial valve treatment: it’s all about the target lobe. ERJ Open Res. 2023;9:00155–2023. Maltais F, Decramer M, Casaburi R, Barreiro E, Burelle Y, Debigaré R, et al. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014;189:e15-62. Benz E, Trajanoska K, Lahousse L, Schoufour JD, Terzikhan N, Roos ED, et al. Sarcopenia in COPD: a systematic review and meta-analysis. European Respiratory Review [Internet]. 2019 [cited 2020 Mar 19];28. Available from: https://err.ersjournals.com/content/28/154/190049 Schweitzer L, Geisler C, Pourhassan M, Braun W, Glüer C-C, Bosy-Westphal A, et al. What is the best reference site for a single MRI slice to assess whole-body skeletal muscle and adipose tissue volumes in healthy adults?1. The American Journal of Clinical Nutrition. 2015;102:58–65. Kanezaki M, Terada K, Tanabe N, Shima H, Hamakawa Y, Sato S. Effects of Sarcopenia on Ventilatory Behavior and the Multidimensional Nature of Dyspnea in Patients With Chronic Obstructive Pulmonary Disease. Journal of the American Medical Directors Association. 2021;22:827–33. Ezponda A, Casanova C, Cabrera C, Martin-Palmero Á, Marin-Oto M, Marín JM, et al. Psoas Muscle Density Evaluated by Chest CT and Long-Term Mortality in COPD Patients. Arch Bronconeumol (Engl Ed). 2021;S0300-2896(21)00133-2. Blasio F de, Alicante P, Gregorio AD, Blasio F de, Berlingieri GM, Bellofiore B, et al. Systematic review on the use of bioelectrical impedance analysis in chronic obstructive pulmonary disease. European Respiratory Journal [Internet]. 2017 [cited 2021 Feb 18];50. Available from: https://erj.ersjournals.com/content/50/suppl_61/PA1093 Schols AMWJ, Broekhuizen R, Weling-Scheepers CA, Wouters EF. Body composition and mortality in chronic obstructive pulmonary disease. Am J Clin Nutr. 2005;82:53–9. Maria BJ, Konstantina K, Sciurba FC, Criner GJ, Felix H. Utility of Rehabilitation prior to bronchoscopic lung volume reduction – post-hoc analysis of the VENT trial. ERJ Open Research [Internet]. 2023 [cited 2024 Apr 25]; Available from: https://openres.ersjournals.com/content/early/2023/10/19/23120541.00735-2023 Guecamburu M, Coquelin A, Rapin A, Le Guen N, Solomiac A, Henrot P, et al. Pulmonary rehabilitation after severe exacerbation of COPD: a nationwide population study. Respir Res. 2023;24:102. Celli BR, Locantore N, Tal-Singer R, Riley J, Miller B, Vestbo J, et al. Emphysema and extrapulmonary tissue loss in COPD: a multi-organ loss of tissue phenotype. Eur Respir J. 2018;51. Additional Declarations No competing interests reported. Supplementary Files SupplementalrespirresVf.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4423314","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":305845365,"identity":"4d881583-ba5f-43a0-ba1d-cdd7b9beee7a","order_by":0,"name":"Julia Rubenstein","email":"","orcid":"","institution":"CHU Bordeaux","correspondingAuthor":false,"prefix":"","firstName":"Julia","middleName":"","lastName":"Rubenstein","suffix":""},{"id":305845366,"identity":"573e61a4-d249-4643-96f8-122034bdf0d4","order_by":1,"name":"Ilyes Benlala","email":"","orcid":"","institution":"Univ-Bordeaux, Centre de Recherche cardio-thoracique de Bordeaux","correspondingAuthor":false,"prefix":"","firstName":"Ilyes","middleName":"","lastName":"Benlala","suffix":""},{"id":305845367,"identity":"8da4686a-8cc2-4664-bd29-60ac76dd5625","order_by":2,"name":"Anne-Claire Toublanc","email":"","orcid":"","institution":"CHU Bordeaux","correspondingAuthor":false,"prefix":"","firstName":"Anne-Claire","middleName":"","lastName":"Toublanc","suffix":""},{"id":305845368,"identity":"63d4c22b-101a-47e8-9f14-8deaa07a7128","order_by":3,"name":"Marina Guecamburu","email":"","orcid":"","institution":"CHU Bordeaux","correspondingAuthor":false,"prefix":"","firstName":"Marina","middleName":"","lastName":"Guecamburu","suffix":""},{"id":305845369,"identity":"b92d4325-2b48-4b91-8f85-f80ddc105763","order_by":4,"name":"Arnaud Maurac","email":"","orcid":"","institution":"CHU 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Bordeaux","correspondingAuthor":false,"prefix":"","firstName":"Pauline","middleName":"","lastName":"Henrot","suffix":""},{"id":305845379,"identity":"810633e6-2956-4071-8547-c52a4d871796","order_by":11,"name":"maeva zysman","email":"data:image/png;base64,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","orcid":"","institution":"Univ-Bordeaux, Centre de Recherche cardio-thoracique de Bordeaux","correspondingAuthor":true,"prefix":"","firstName":"maeva","middleName":"","lastName":"zysman","suffix":""}],"badges":[],"createdAt":"2024-05-15 07:25:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4423314/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4423314/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57518420,"identity":"e35369a5-8ed0-486a-a64b-2399612b6816","added_by":"auto","created_at":"2024-05-31 20:33:37","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":165718,"visible":true,"origin":"","legend":"\u003cp\u003eEvolution of respiratory parameters at 3 and 6 months after EBV insertion.\u003c/p\u003e\n\u003cp\u003eA: Evaluation of EBV insertion efficacy: target lobe volume, total lung capacity (TLC) (%pred) and residual volume (RV) (%pred).\u003c/p\u003e\n\u003cp\u003eB: Evaluation of EBV insertion effect on lung function, dyspnea and exercise capacity: forced expiratory volume in 1 second (FEV1) (%pred), score at the modified Medical Research Council scale (mMRC), carbon monoxide diffusion (DLCO) (%pred) and 6-minutes walking test distance (6MWT) (%pred).\u003c/p\u003e\n\u003cp\u003e* p \u0026lt;0.05, ** p \u0026lt;0.01, *** p \u0026lt;0.001\u003c/p\u003e","description":"","filename":"floatimage1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4423314/v1/cf24a46e850fc2bcc10ecd86.jpg"},{"id":57519454,"identity":"0c3b1c97-cdf2-4a53-a598-1f0f97cef2b8","added_by":"auto","created_at":"2024-05-31 20:41:37","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":136662,"visible":true,"origin":"","legend":"\u003cp\u003eEvolution of skeletal muscle parameters at 3 and 6 months after EBV insertion.\u003c/p\u003e\n\u003cp\u003eA: Evolution of body composition: Appendicular Skeletal Muscle Mass Index (ASMI, kg/m2), fat mass (as %age of total body mass), phase angle.\u003c/p\u003e\n\u003cp\u003eB: Evolution of upper limb strength (hand grip test, kg).\u003c/p\u003e\n\u003cp\u003eC: Evolution of thoracic muscle surfaces (mm2): Pectoralis, 5\u003csup\u003eth\u003c/sup\u003e intercostal muscle, Erector Spinal, Psoas.\u003c/p\u003e","description":"","filename":"floatimage2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4423314/v1/97ac853791df077dff754efe.jpg"},{"id":57517860,"identity":"ab3f063c-58d5-4d89-8195-aed5003e3324","added_by":"auto","created_at":"2024-05-31 20:25:37","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":200481,"visible":true,"origin":"","legend":"\u003cp\u003eEvolution of skeletal muscle parameters according to the response to EBV insertion (as defined by mMRC evolution ≥ -1 at 3 months after EBV insertion), over the course of 6 months.\u003c/p\u003e\n\u003cp\u003eA: Evolution of body composition: Appendicular Skeletal Muscle Mass Index (ASMI, kg/m2), fat mass (as %age of total body mass), phase angle.\u003c/p\u003e\n\u003cp\u003eB: Evolution of upper limb strength (hand grip test, kg).\u003c/p\u003e\n\u003cp\u003eC: Evolution of thoracic muscle surfaces (mm2): Pectoralis, 5\u003csup\u003eth\u003c/sup\u003e intercostal muscle, Erector Spinal, Psoas.\u003c/p\u003e\n\u003cp\u003e* p \u0026lt;0.05\u003c/p\u003e","description":"","filename":"floatimage3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4423314/v1/02a5199f3af42f6ed286349e.jpg"},{"id":57517857,"identity":"ebcd70ff-4763-4cb8-a7b1-854e1db32d34","added_by":"auto","created_at":"2024-05-31 20:25:37","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":484178,"visible":true,"origin":"","legend":"\u003cp\u003eEvolution of respiratory and skeletal muscle parameters in sarcopenic patients vs non-sarcopenic.\u003c/p\u003e\n\u003cp\u003eA: Evolution parameters evaluating EBV insertion efficacy: Target lobe volume (mL), TLC (%pred), RV (%pred).\u003c/p\u003e\n\u003cp\u003eB: Evolution of other respiratory and functional parameters:\u0026nbsp; FEV1 (%pred), mMRC, DLCO (%pred), 6WMT (%pred).\u003c/p\u003e\n\u003cp\u003eC: Evolution of body composition parameters: ASMI (kg/m\u003csup\u003e2\u003c/sup\u003e) and fat mass (% of total body mass). Each column represents individual subject data for sarcopenic patients (white bars) and non-sarcopenic patients (black bars). P1, P2… represent individual patient number.\u003c/p\u003e\n\u003cp\u003e** p \u0026lt;0.01\u003c/p\u003e","description":"","filename":"floatimage4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4423314/v1/bd21c94061a780556e32b843.jpg"},{"id":59901780,"identity":"15aa4ed0-8d1a-4baa-a155-d40dace85561","added_by":"auto","created_at":"2024-07-09 05:56:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1511463,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4423314/v1/ac3e5177-2fac-4656-8b67-a8b40f7a6bda.pdf"},{"id":57517861,"identity":"f967684b-34c4-455e-a007-fc54e2fabffb","added_by":"auto","created_at":"2024-05-31 20:25:37","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":152346,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalrespirresVf.docx","url":"https://assets-eu.researchsquare.com/files/rs-4423314/v1/4bf409d145af4d6aa1cd105f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Endobronchial valve (EBV) insertion for severe emphysema does not improve skeletal muscle mass or function","fulltext":[{"header":"Background","content":"\u003cp\u003eEmphysema represents a severe phenotype in patients with chronic obstructive pulmonary disease (COPD), associated with increased mortality and increased risk of extra-pulmonary manifestations within a global multi-organ loss of tissue phenotype [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Several strategies have been developed over the past years to overcome lung hyperinflation. Lung volume reduction strategies were initially surgical procedures with a marked improvement on exercise capacity [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]; however, mortality rate was relatively high among a subgroup of patients (particularly those with severe lung function impairment at baseline), leading to the development of minimally invasive strategies. As such, the development of endoscopic lung volume reduction using unidirectional endobronchial valves (EBV) insertion started \u0026sim;20 years ago and was included in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines in 2017 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], based on positive outcomes on lung function, exercise capacity and quality of life in several randomized controlled trials [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Unidirectional endobronchial valves (EBV) are one-way valves that allow expiratory flow but prevent inspiratory flow, ultimately causing collapse of distal lung segments. However, the impact of EBV on extra-pulmonary manifestations of COPD, such as skeletal muscle mass and function is vastly unknown.\u003c/p\u003e \u003cp\u003eMuscle wasting plays a prominent role in COPD as both muscle weakness [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and atrophy [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] are associated with an increased risk of mortality. The evaluation of sarcopenia, characterized by a loss of muscle mass and force below a fixed level, is challenging and includes measures of (preferably) whole-body muscle mass and muscle force [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. While alternative indexes such as thoracic muscle surface have shown a stronger association with increased mortality than emphysema [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], their correlation with whole-body muscle mass requires further investigation [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Therefore, a multimodal evaluation of muscle status is strongly recommended.\u003c/p\u003e \u003cp\u003eIn this study, our objective was to explore whether reducing hyperinflation through EBV insertion improves skeletal muscle parameters, involving a comprehensive assessment of skeletal muscle mass and force. A secondary aim was to determine if baseline muscle parameters could predict the response to EBV insertion.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy and patients\u003c/h2\u003e \u003cp\u003eBetween March 2021 and November 2022, we conducted a prospective monocentric study in Bordeaux University Hospital, including consecutive patients treated with EBV, determined eligible based on consensus guidelines [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], following usual criteria (smoking cessation for at least three months, post bronchodilator forced expiratory volume\u0026thinsp;\u0026lt;\u0026thinsp;50%, residual volume (RV) greater than 175%, a 6-min walking distance\u0026thinsp;\u0026gt;\u0026thinsp;100 m, modified Medical research council (mMRC) score of 2 or more). The majority of patients (16/19, 84%) undertook pulmonary rehabilitation prior to the procedure. Lobar fissure integrity was determined by quantitative CT with StratX\u0026reg; (PulmonX Corp., Redwood City, CA). When fissure integrity was assessed to be higher than 80%, collateral ventilation was systematically evaluated by the Chartis\u0026reg; system (PulmonX Inc., Redwood City, CA, USA), during the procedure. Lobe volume reduction was also measured. Comprehensive clinical and paraclinical evaluation was performed at baseline, 3 months, and 6 months post-procedure. Respiratory parameters included spirometry and body plethysmography, COPD assessment test (CAT) score, modified Medical Research Council (mMRC) dyspnea scale, 6-minutes walking test (6MWT). Whole-body muscle mass was assessed with bioelectrical impedance analysis (BIA: Biacorpus RX 4004M, MEDI CAL HealthCare), providing a reliable estimation of the appendicular skeletal muscle mass index (ASMI in kg/m\u003csup\u003e2\u003c/sup\u003e, which represents the sum of the lean muscle mass of the upper and lower extremities adjusted with height), and also allowing to know the percentage of fat mass, and the value of phase angle. Sarcopenia was defined as per the criteria published by Janssen and colleagues for severe sarcopenia and adapted for the BIA technique (ASMI\u0026thinsp;\u0026lt;\u0026thinsp;8.50 kg/m\u003csup\u003e2\u003c/sup\u003e for men and 5.50 kg/m\u003csup\u003e2\u003c/sup\u003e for women) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Additionally, muscle surface and density on thoracic CT scans (psoas, 5th intercostal, pectoralis above the aortic arch, and erector spinae muscle at the 12th thoracic vertebra) were measured as previously described [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Briefly, CT axial slices were analyzed at the level of the lower margin of the 12th thoracic vertebrae for the psoas, the 5th intercostal, and the erector spinae, and above the aortic arch for the pectoralis. A predefined attenuation range of -50 and \u0026minus;\u0026thinsp;90 Hounsfield units (HU) was used. Muscle strength was assessed at the upper arm (handgrip test) with an electronic dynamometer (Jamar Health Products Inc, China). Safety data including occurrence of pneumothorax, pneumonia, and exacerbations, were collected.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eThe primary outcome was the 3-month change from baseline after EBV insertion in skeletal muscle parameters: skeletal muscle mass assessed by BIA, and muscle strength assessed with handgrip test. Secondary outcomes were (i) to assess the change in thoracic muscle surfaces or densities after EBV insertion, (ii) to compare muscle parameters in responders to EBV insertion versus non-responders, and (iii) to compare the response to EBV insertion in sarcopenic patients versus non-sarcopenic ones, in order to determine if sarcopenia can be considered as a predictive factor.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis and ethical considerations\u003c/h2\u003e \u003cp\u003eAll statistical tests were performed with a type I error rate of 5%. Qualitative variables were described with numbers and percentages, and quantitative variables with numbers of non-missing data, median and inter-quartile range. The qualitative variables were compared with a Chi\u0026sup2; test, corrected Chi\u0026sup2; test or with non-parametric Fisher's exact test. The quantitative variables were compared with a Student t test (parametric) or a Wilcoxon test (non-parametric) in case of two groups only, and with two-way Anova with Tukey\u0026rsquo;s multiple comparisons for all data assessed in time and compared between two groups. All statistical analyses were performed using GraphPad Prism (La Jolla, CA, USA). The study was conducted in accordance with French legislation and ethical codes. This work complies to the protection of personal health data and the protection of privacy with the framework of application provided for by article 65\u0026thinsp;\u0026minus;\u0026thinsp;2 of the amended Data Protection Act and the general data protection regulations and was registered with the following number CHUBX2020RE0270. The study was designed according to the STROBE guidelines.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eWithin the study period of 20 months, 104 subjects were screened for EBV insertion in Bordeaux University Hospital and 22 consecutive subjects were enrolled. Of those patients, 2 underwent valve removal within six months after the procedure (one due to a persistent pneumothorax despite chest drain, and one due to deterioration of respiratory function) and one was rapidly lost to follow-up. Nineteen remaining patients were subsequently included in the study (Supplementary Fig.\u0026nbsp;1).\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eClinical and demographic data at baseline\u003c/h2\u003e \u003cp\u003eOf the 19 included patients, 12 were women (63%), and the overall mean age was 65.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.0 years (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). They exhibited a substantial symptom burden, with a mean mMRC dyspnea scale and CAT scores of 2.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7 and 18.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6 points, respectively. Severe COPD was evident with a mean forced expiratory volume in one second (FEV1) of 33.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2%pred, a mean residual volume (RV) of 231.3\u0026thinsp;\u0026plusmn;\u0026thinsp;45.1%pred, a mean total lung capacity (TLC) of 133.5\u0026thinsp;\u0026plusmn;\u0026thinsp;22.3%pred and a mean diffusing capacity of the lung for carbon monoxide (DLCO) of 27.9\u0026thinsp;\u0026plusmn;\u0026thinsp;16.3%pred. The mean 6MWT was 355\u0026thinsp;\u0026plusmn;\u0026thinsp;89 m, and the mean body mass index (BMI) was 24.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.7 kg/m\u0026sup2;. Concerning body composition, the mean appendicular skeletal muscle mass index (ASMI) was 6.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9 kg/m2 (9.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4 kg/m\u003csup\u003e2\u003c/sup\u003e in men and 5.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8 kg/m\u003csup\u003e2\u003c/sup\u003e in women), and the mean percentage of fat mass was 30.4\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7 (30.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.7 in men and 32.8\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3 in women). Mean phase angle value was 5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1 \u0026deg;. Concerning skeletal muscle function, the mean upper limb force assessed by the handgrip test was 29.7\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7 kg (39\u0026thinsp;\u0026plusmn;\u0026thinsp;5.6 kg in men and 23.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.6 kg in women).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatients\u0026rsquo; characteristics at baseline.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal population (n\u0026thinsp;=\u0026thinsp;19)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDemographic data\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.7\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSex, n (%)\u003c/p\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (63)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBMI, kg/ m2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSmoking\u0026nbsp;: active, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFormer smoking, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (89)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSmoking history, pack-years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.5\u0026thinsp;\u0026plusmn;\u0026thinsp;18.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-drug therapies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients on LTOT, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (52.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatients on NIV, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (10.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRehabilitation within 6 months before the procedure, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (84.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSymptoms\u0026nbsp;\u0026amp; COPD severity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSevere exacerbation the year before EBV, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (15.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBODE index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emMRC, points\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCAT, points\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePulmonary function tests\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFEV\u003csub\u003e1\u003c/sub\u003e, L\u003c/p\u003e \u003cp\u003eFEV\u003csub\u003e1\u003c/sub\u003e, %\u0026nbsp;pred\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003cp\u003e33.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFEV\u003csub\u003e1\u003c/sub\u003e / FVC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.9\u0026thinsp;\u0026plusmn;\u0026thinsp;11.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRV, %pred\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e231.3\u0026thinsp;\u0026plusmn;\u0026thinsp;45.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTLC, %pred\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e133.5\u0026thinsp;\u0026plusmn;\u0026thinsp;22.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDLCOc, %pred\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.9\u0026thinsp;\u0026plusmn;\u0026thinsp;16.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArterial blood gas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePaO\u003csub\u003e2\u003c/sub\u003e, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68.2\u0026thinsp;\u0026plusmn;\u0026thinsp;10.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePaCO\u003csub\u003e2\u003c/sub\u003e, mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac assessment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLVEF, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExercice capacity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6MWT, m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e355\u0026thinsp;\u0026plusmn;\u0026thinsp;89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6MWT, %pred\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69\u0026thinsp;\u0026plusmn;\u0026thinsp;19.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAverage walking speed*, m/s\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody composition\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eASMI, kg/m2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFat mass, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.4\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePhase angle, \u0026deg;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkeletal muscle force\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHandgrip test, kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.7\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eBMI: body mass index, LTOT: Long term oxygen therapy, NIV: non-invasive ventilation, mMRC: modified Medical Research Council Dyspnea Scale, CAT: COPD assessment test, LVEF: left ventricle ejection fraction, 6MWT: 6-minutes walk test, FEV1: forced expiratory volume in 1s, FVC: forced vital capacity, RV: residual volume, TLC: total lung capacity, DLCO: carbon monoxide diffusing capacity, pred: predicted value, ASMI: appendicular skeletal muscle mass index. *average walking speed over 6 minutes.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eValues are mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. a: 2 missing data, b: 1 missing data, c:6 missing data.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAdverse events after EBV insertion\u003c/h2\u003e \u003cp\u003eAdverse events were consistent with other studies: 5 (26%) COPD exacerbations, 3 (16%) procedure-related pneumothoraces (one requiring valve removal, the two others resolved with chest drainage), 1 pneumonia, 1 pleuritis, and 2 patients with hemoptysis. Respiratory related adverse events occurred in 7 patients (37%) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The management of pneumothorax was performed following protocolized algorithms [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Two patients had iterative COPD exacerbations or pneumoniae and improved after new endoscopy for valve repositioning or the replacement of a proximal valve by several distal valves.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eadverse events (total: n\u0026thinsp;=\u0026thinsp;7 (37%)).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;10 (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumothorax\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOPD exacerbation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (26)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePleuresia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoptysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (10)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eValve removal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArrythmia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eEvolution of respiratory parameters\u003c/h2\u003e \u003cp\u003eIn agreement with previously published data [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], patients had improvement on respiratory function after EBV insertion at three months. We observed a significant decrease in target lobe volume at 3 months and persisting at 6 months (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 in both cases, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA), as well as a significant decrease in hyperinflation as represented by the decrease in TLC and RV (p\u0026thinsp;=\u0026thinsp;0.0002 and p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, respectively, at 3 months, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Lung function as represented by FEV1 improved significantly (p\u0026thinsp;=\u0026thinsp;0.02 at 3 months, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). The overall gain of FEV1 was 190\u0026thinsp;\u0026plusmn;\u0026thinsp;260 mL, which represented 26\u0026thinsp;\u0026plusmn;\u0026thinsp;31.8% of its initial value. Dyspnea assessed by mMRC also improved (p\u0026thinsp;=\u0026thinsp;0.008 at 3 months, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). However, we observed no significant improvement in DLCO and exercise capacity as represented by 6WMT (p\u0026thinsp;=\u0026thinsp;0.81 et p\u0026thinsp;=\u0026thinsp;0.47, respectively, at 3 months, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Quality of life assessed by COPD assessment test (CAT-score) also did not change significantly (p\u0026thinsp;=\u0026thinsp;0.77 at 3 months) (data not shown).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn terms of local response to EBV insertion, complete target lobe atelectasis was achieved in 18/19 (94%) patients at 3 months with a mean decrease in CT-measured volume of the treated lung of 882\u0026thinsp;\u0026plusmn;\u0026thinsp;429 mL. In terms of response criteria as proposed by Hartman and colleagues [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], FEV\u003csub\u003e1\u003c/sub\u003e increased more than 12% (or more than 10%) in 11 patients (58%) according to STELVIO study, RV increased more than 430 mL in 14 patients (74%) and more than 310 mL in 16 patients (84%) (LIBERATE), 6-min walk distance (6MWD) increased more than 25 m in 4 patients (21%) and quality of life (assessed by CAT variation as a proxy of St George's Respiratory Questionnaire (SGRQ)) increased more than 4 points in 6 patients (31%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eEvolution of skeletal muscle parameters\u003c/h2\u003e \u003cp\u003eIn contrast to respiratory parameters, we observed no significant improvement in body composition (ASMI or fat mass) or phase angle value (an independent predictor of mortality [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]) at 3 or 6 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, Supplementary Fig.\u0026nbsp;2). ASMI overall mean gain was 0.27\u0026thinsp;\u0026plusmn;\u0026thinsp;0.79 kg/m\u003csup\u003e2\u003c/sup\u003e at 3 months and 0.28\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58 kg/m\u003csup\u003e2\u003c/sup\u003e at 6 months (p\u0026thinsp;=\u0026thinsp;0.11 and p\u0026thinsp;=\u0026thinsp;0.17, respectively). Fat mass overall mean gain was \u0026minus;\u0026thinsp;0.81\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8% at 3 months and 1.36\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2% at 6 months (p\u0026thinsp;=\u0026thinsp;0.99 and p\u0026thinsp;=\u0026thinsp;0.22, respectively). Handgrip strength remained perfectly stable over 6 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Concerning CT-based thoracic muscles assessment (pectoralis, 5th intercostal, erector spinal and psoas), we did also not observe any significant change in muscles surface over the course of 6 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC), nor in their densities (Supplementary Fig.\u0026nbsp;3). No significant correlation was observed between the gain of skeletal muscle mass (whether assessed by the ASMI or by the pectoralis surface) and lung function parameters (data not shown). Of note, very few patients underwent pulmonary rehabilitation following the procedure (1 patient (5%) in the following three months and 2 patients (11%) in the following six months).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eFocus on responders to EBV insertion\u003c/h2\u003e \u003cp\u003eNo significant difference was observed in baseline skeletal muscle parameters according to the response to EBV insertion status, whatever the chosen criteria (data not shown). When response to EBV insertion was assessed on the basis of mMRC improvement (\u0026ge;\u0026thinsp;1), we observed some minor differences. There was a significant increase in phase angle value in responders compared to non-responders at 3 months (p\u0026thinsp;=\u0026thinsp;0.04, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA), such increase being associated with a lower mortality [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. However, statistical significance did not persist at M6. We also observed a slight tendency toward a greater gain in ASMI and handgrip strength in responders compared to non-responders, but without reaching statistical significance (p\u0026thinsp;=\u0026thinsp;0.48 and p\u0026thinsp;=\u0026thinsp;0.35, respectively, at 3 months, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, B). Fat mass did not differ between the two groups (p\u0026thinsp;=\u0026thinsp;0.73 at 3 months, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Concerning thoracic muscles, only erector spinal surface was significantly higher in responders at 3 months (p\u0026thinsp;=\u0026thinsp;0.02 at 3 months, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC), but not at 6 months.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eFocus on sarcopenic patients at baseline\u003c/h2\u003e \u003cp\u003eFive patients (26%) (4 women and 1 man) were considered as sarcopenic at baseline (severe sarcopenia on the basis of low muscle mass according to the criteria published by Janssen and colleagues [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]: ASMI\u0026thinsp;\u0026lt;\u0026thinsp;8.50 kg/m2 in men and \u0026lt;\u0026thinsp;5.75 kg/m2 in women). Of note, 18 out of 19 patients (95%) were considered to suffer from moderate sarcopenia according to the same criteria.\u003c/p\u003e \u003cp\u003eAt baseline, sarcopenic patients exhibited (as per definition) a significantly lower muscle mass than non-sarcopenic ones (ASMI 5.54\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2 versus 7.52\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8 kg/m\u003csup\u003e2\u003c/sup\u003e, p\u0026thinsp;=\u0026thinsp;0.04, Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). As expected, handgrip strength was also significantly decreased in sarcopenic patients (19.8\u0026thinsp;\u0026plusmn;\u0026thinsp;6.4 versus 34.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.4 kg, p\u0026thinsp;=\u0026thinsp;0.01). However, the percentage of fat mass was similar, as well as the value of phase angle. Exercise capacity was significantly decreased in sarcopenic patients (6MWT 54.4\u0026thinsp;\u0026plusmn;\u0026thinsp;17.1 versus 74.1\u0026thinsp;\u0026plusmn;\u0026thinsp;17.7%pred, p\u0026thinsp;=\u0026thinsp;0.04). However, there was no other significant difference in baseline parameters, including demographic parameters, pulmonary function tests results and indicators of COPD severity (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). Of note, there was a tendency towards a poorer quality of life with a higher CAT-score in sarcopenic patients (22.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5 versus 16.6\u0026thinsp;\u0026plusmn;\u0026thinsp;5.9 points, p\u0026thinsp;=\u0026thinsp;0.06). FEV1 was not statistically different between the two groups (30.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2 versus 35.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3%pred, p\u0026thinsp;=\u0026thinsp;0.26).\u003c/p\u003e \u003cp\u003eAltogether, there was no significant difference in the evolution of respiratory endpoints between sarcopenic and non-sarcopenic patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA, B), whether in the improvement in target lobe volume, TLC, RV, FEV1, mMRC, DLCO, or 6MWT, at 3 or 6 months. We observed some minor differences in favor of a greater improvement in sarcopenic patients: target lobe volume tended to decrease more in sarcopenic patients at 3 months (p\u0026thinsp;=\u0026thinsp;0.08, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA), but not at 6 months; RV tended to decrease more in sarcopenic patients at 3 months (p\u0026thinsp;=\u0026thinsp;0.09, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThere was also no significant difference in muscle mass evolution (ASMI) between sarcopenic and non-sarcopenic patients, despite a tendency towards a greater improvement in non-sarcopenic patients (p\u0026thinsp;=\u0026thinsp;0.14 at 3 months and p\u0026thinsp;=\u0026thinsp;0.05 at 6 months; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC). However, such improvement was overall mild. Fat mass tended to decrease more in sarcopenic patients at 3 months (p\u0026thinsp;=\u0026thinsp;0.27; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC), but this did not persist at 6 months. Of the 5 sarcopenic patients at baseline, one was not considered sarcopenic any more at 3 months, but fell under the cut-off value again at 6 months. At 6 months, the overall proportion of sarcopenic patients remained identic to baseline (5/19\u0026thinsp;=\u0026thinsp;26%), but with one patient exchange between the two groups.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAltogether, our data indicate that EBV insertion brings little to no improvement in skeletal muscle mass and force over the course of six months. Although very few studies tackled the effect of EBV on skeletal muscle parameters, our results are contradictory with the study of Sanders and colleagues, who observed a significant improvement in CT-measured skeletal muscles six months after EBV insertion [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, such difference might come from the different endpoint analyzed: we measured separately thoracic muscles at two different levels (12th thoracic vertebrae and above the aortic arch), whereas in the cited study, skeletal muscle cross-sectional area was analyzed as a whole at the L1 level. Another study evidenced a correlation between the reduction in RV and the increase in parasternal thickness with ultrasound assessment [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, diaphragm thickness did not change after EBV insertion. Last, a recent study on 300 EBV-treated patients did not observe a significant change in muscle volume (as assessed by CT) 6 months after the procedure [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Overall, very few studies assess the benefit of EBV insertion on extra-pulmonary features of emphysema, emphasizing the need for further studies. In addition to skeletal muscle parameters, other extra-pulmonary parameters should be assessed such as cardiac function, as lung volume reduction (with surgical procedure) has been shown to improve right ventricular performance [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our study, no muscle-related parameter was able to predict response to EBV insertion, regardless of the chosen criteria. These findings align with recent data suggesting that disease severity parameters do not predict response to EBV treatment; rather, local lung parameters such as the degree of air trapping and perfusion in the target lobe play a major role [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur study presents several limitations. First, the small sample size prevents generalization of the results. It is also possible that this small sample size led to a lack of power, preventing us from observing significant differences. Nevertheless, our cohort appears representative of the general EBV-treated population, in terms of severity of included patients or rate of adverse events [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The results of our study on lung function are also close to those of the previous studies with a significant improvement in pulmonary functional tests, exercise capacity and in scores of dyspnea and quality of life. Out of 19 patients, 11 (58%) were responders on FEV1, compared to 55.5% in the TRANSFORM study and 47.7% in the LIBERATE study. The patients had an average gain of 25% which is similar to 17% in the LIBERATE study and 20% in the TRANSFORM study. Patients also experienced a clinical benefit with an average reduction of 0.53 point in mMRC score, lowered lung distension with reduction of pulmonary volume of 882 ml and a mean increase of 23 m increase in 6MWT. Finally, the proportion of sarcopenic patients is in adequation with what has been reported in the literature [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], although such proportion can greatly vary according to the selected population.\u003c/p\u003e \u003cp\u003eOther limitations include the evaluation of muscle force (with handgrip test only) and function (with 6MWT only), which did not allow to cover every aspect of this dimension. Follow-up studies will aim to incorporate additional functional tests such as 5-times sit to stand test and more thorough evaluation of patients\u0026rsquo; level of physical activity as well as nutritional assessme,t. However, very few studies on the same topic include a multimodal evaluation of skeletal muscle mass (with BIA and CT-based measures) and function. We chose to measure thoracic muscles surface and density as a surrogate marker for sarcopenia. Other studies rather used quadriceps surface [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] or paraspinal muscle volume at L3 [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Nevertheless, several recent studies have shown that thoracic muscle surface was a validated surrogate marker for sarcopenia in COPD patients [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Measuring thoracic muscles brings the advantage of using thoracic CT-scans data, a routine examination in COPD patients, whereas abdominal or quadricipital CT-scan is not part of usual care. Finally, whole-body skeletal muscle mass was assessed with BIA and not dual-X-ray absorptiometry; however, numerous studies have validated the use of BIA to assess skeletal muscle mass, including in patients with COPD [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAltogether, our study suggests that treatment options for patients with advanced emphysema should be holistic and not focused on emphysema itself. This emphasizes the need for a multimodal for a systematic referral to pulmonary rehabilitation in conjunction with the EBV procedure, as recently reported before EBV insertion [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], but probably also after the procedure. In our study, the percentage of patients that had undergone pulmonary rehabilitation was high before the procedure, but dramatically low after, similarly to the global percentage of patients with COPD referred to pulmonary rehabilitation in France outside the context of EBV [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Tailored rehabilitation programs, considering patients\u0026rsquo; baseline measurements, are crucial, particularly with the overarching goal of gaining muscle force. Such combination of EBV and rehabilitation procedures could address the multiscale loss of tissue phenotype described in emphysema [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. However, we postulate that the absence of clear improvement in skeletal muscle mass or function also highlights the need for innovative, bottom-up drug treatment strategies for COPD, with a specific focus on skeletal muscle wasting.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eEndobronchial valve (EBV) insertion in severe emphysema brings little to no improvement to skeletal muscle mass and handgrip strength over the course of six months. This challenges conventional assumptions and emphasizes the need for a multimodal approach, including \u0026ndash; but not limited to - pulmonary rehabilitation, in managing emphysema.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eASMI: appendicular skeletal muscle mass index\u003c/p\u003e\n\u003cp\u003eBIA: bioimpedance analysis\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBMI: body mass index\u003c/p\u003e\n\u003cp\u003eCAT: COPD assessment test\u003c/p\u003e\n\u003cp\u003eCOPD: chronic obstructive pulmonary disease\u003c/p\u003e\n\u003cp\u003eCT: computed tomography\u003c/p\u003e\n\u003cp\u003eEBV: endobronchial valve\u003c/p\u003e\n\u003cp\u003eDLCO: carbon monoxide diffusing capacity\u003c/p\u003e\n\u003cp\u003eFEV1: forced expiratory volume in 1s\u003c/p\u003e\n\u003cp\u003eFVC: forced vital capacity\u003c/p\u003e\n\u003cp\u003eGOLD: global initiative for\u0026nbsp;chronic obstructive lung disease\u003c/p\u003e\n\u003cp\u003eLTOT: Long term oxygen therapy\u003c/p\u003e\n\u003cp\u003eLVEF: left ventricle ejection fraction\u003c/p\u003e\n\u003cp\u003emMRC:\u0026nbsp;modified Medical Research Council\u003c/p\u003e\n\u003cp\u003eNIV: non-invasive ventilation\u003c/p\u003e\n\u003cp\u003eRV: residual volume\u003c/p\u003e\n\u003cp\u003eTLC: total lung capacity\u003c/p\u003e\n\u003cp\u003e6MWT: 6-minutes walk test\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate: The study was conducted in accordance with French legislation and ethical codes. According to French Law, this anonymous retrospective observational database study does not require approval by an ethics committee or informed signed consent from the patients. The study was designed according to the STROBE guidelines and registered with the following number\u0026nbsp;CHUBX2020RE0270.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u0026nbsp;: not applicable\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials:\u0026nbsp;The datasets used and/or analyzed in the study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompeting interests :\u0026nbsp;JR reports no conflict of interest, IB reports no conflict of interest, ACT reports no conflict of interest, MG reports no conflict of interest, AM reports no conflict of interest, reports no conflict of interest, CV reports no conflict of interest, LG\u0026nbsp;non-financial support from ASTEN,\u0026nbsp;AIR LIQUIDE, SANOFI GENZYME, SOS Oxygene,\u0026nbsp;AstraZeneca, ASV, Boerhinger, GM\u0026nbsp;non-financial support from IPSEN, PD reports no conflict of interest,\u0026nbsp;PH reports grants and non-financial support from AVAD, and non-financial support from Chiesi and GSK, outside the submitted work. MZ reports grants and personal fees from Menarini, personal fees from Sanofi, personal fees from Chiesi, personal fees from AstraZeneca, personal fees from CSLBehring and personal fees from GSK outside the submitted work, grants from AVAD, grants from FRM.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFunding\u0026nbsp;: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003eAuthors' contributions :\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConceptualization\u0026nbsp;: PH, MZ, Methodology\u0026nbsp;: PH, MZ, GM, PD, Validation\u0026nbsp;: PH, MZ, Formal analysis\u0026nbsp;: JR, IB, PH, MZ, Investigation\u0026nbsp;: JR, IB, ACT, MG, Resources\u0026nbsp;: AM, CB, CV, LG, Writing - Original Draft\u0026nbsp;: JR, PH, MZ, Writing - Review \u0026amp; Editing\u0026nbsp;: all authors JR, IB, ACT, MG, AM, CB, CV, LG, GM, PD, PH, MZ, Visualization\u0026nbsp;: PH, MZ, Supervision\u0026nbsp;: PH, MZ\u003c/p\u003e\n\u003cp\u003eAcknowledgements : We thank the nurses from the Pneumology Department of Bordeaux University Hospital for BIA measurements.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthors' information (optional) : not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCelli BR, Locantore N, Tal-Singer R, Riley J, Miller B, Vestbo J, et al. 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Thorax. 2007;62:115\u0026ndash;20. \u003c/li\u003e\n\u003cli\u003eMarquis K, Debigar\u0026eacute; R, Lacasse Y, LeBlanc P, Jobin J, Carrier G, et al. Midthigh muscle cross-sectional area is a better predictor of mortality than body mass index in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002;166:809\u0026ndash;13. \u003c/li\u003e\n\u003cli\u003eCruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruy\u0026egrave;re O, Cederholm T, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019;48:16\u0026ndash;31. \u003c/li\u003e\n\u003cli\u003eTanimura K, Sato S, Sato A, Tanabe N, Hasegawa K, Uemasu K, et al. Accelerated Loss of Antigravity Muscles Is Associated with Mortality in Patients with COPD. Respiration. 2020;99:298\u0026ndash;306. \u003c/li\u003e\n\u003cli\u003eBrath MSG, Sahakyan M, Mark EB, Fr\u0026oslash;kj\u0026aelig;r JB, Rasmussen HH, \u0026Oslash;stergaard LR, et al. Association between thoracic and third lumbar CT-derived muscle mass and density in Caucasian patients without chronic disease: a proof-of-concept study. Eur Radiol Exp. 2023;7:26. \u003c/li\u003e\n\u003cli\u003eSlebos D-J, Shah PL, Herth FJF, Valipour A. Endobronchial Valves for Endoscopic Lung Volume Reduction: Best Practice Recommendations from Expert Panel on Endoscopic Lung Volume Reduction. Respiration. 2017;93:138\u0026ndash;50. \u003c/li\u003e\n\u003cli\u003eJanssen I, Baumgartner RN, Ross R, Rosenberg IH, Roubenoff R. Skeletal muscle cutpoints associated with elevated physical disability risk in older men and women. Am J Epidemiol. 2004;159:413\u0026ndash;21. \u003c/li\u003e\n\u003cli\u003eTanabe N, Sato S, Tanimura K, Oguma T, Sato A, Muro S, et al. Associations of CT evaluations of antigravity muscles, emphysema and airway disease with longitudinal outcomes in patients with COPD. Thorax. 2021;76:295\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eValipour A, Slebos D-J, de Oliveira HG, Eberhardt R, Freitag L, Criner GJ, et al. Expert statement: pneumothorax associated with endoscopic valve therapy for emphysema--potential mechanisms, treatment algorithm, and case examples. Respiration. 2014;87:513\u0026ndash;21. \u003c/li\u003e\n\u003cli\u003eKlooster K, ten Hacken NHT, Hartman JE, Kerstjens HAM, van Rikxoort EM, Slebos D-J. Endobronchial Valves for Emphysema without Interlobar Collateral Ventilation. N Engl J Med. 2015;373:2325\u0026ndash;35. \u003c/li\u003e\n\u003cli\u003eHartman JE, Vanfleteren LEGW, van Rikxoort EM, Klooster K, Slebos D-J. Endobronchial valves for severe emphysema. Eur Respir Rev. 2019;28:180121. \u003c/li\u003e\n\u003cli\u003ede Blasio F, Scalfi L, Di Gregorio A, Alicante P, Bianco A, Tantucci C, et al. Raw Bioelectrical Impedance Analysis Variables Are Independent Predictors of Early All-Cause Mortality in Patients With COPD. Chest. 2019;155:1148\u0026ndash;57. \u003c/li\u003e\n\u003cli\u003eDe Benedetto F, Marinari S, De Blasio F. Phase angle in assessment and monitoring treatment of individuals with respiratory disease. Rev Endocr Metab Disord. 2023; \u003c/li\u003e\n\u003cli\u003eSanders KJC, Klooster K, Vanfleteren LEGW, Slebos D-J, Schols AMWJ. CT-derived muscle remodelling after bronchoscopic lung volume reduction in advanced emphysema. Thorax. 2019;74:206\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eWallbridge P, Hew M, Parry SM, Irving L, Steinfort D. Reduction of COPD Hyperinflation by Endobronchial Valves Improves Intercostal Muscle Morphology on Ultrasound. Int J Chron Obstruct Pulmon Dis. 2020;15:3251\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eWienker J, Darwiche K, R\u0026uuml;sche N, B\u0026uuml;scher E, Karpf-Wissel R, Winantea J, et al. Body composition impacts outcome of bronchoscopic lung volume reduction in patients with severe emphysema: a fully automated CT-based analysis. Sci Rep. 2024;14:8718. \u003c/li\u003e\n\u003cli\u003eMineo TC, Pompeo E, Rogliani P, Dauri M, Turani F, Bollero P, et al. Effect of lung volume reduction surgery for severe emphysema on right ventricular function. Am J Respir Crit Care Med. 2002;165:489\u0026ndash;94. \u003c/li\u003e\n\u003cli\u003eHartman JE, Roodenburg SA, van Dijk M, Koster TD, Klooster K, Slebos D-J. Response to endobronchial valve treatment: it\u0026rsquo;s all about the target lobe. ERJ Open Res. 2023;9:00155\u0026ndash;2023. \u003c/li\u003e\n\u003cli\u003eMaltais F, Decramer M, Casaburi R, Barreiro E, Burelle Y, Debigar\u0026eacute; R, et al. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014;189:e15-62. \u003c/li\u003e\n\u003cli\u003eBenz E, Trajanoska K, Lahousse L, Schoufour JD, Terzikhan N, Roos ED, et al. Sarcopenia in COPD: a systematic review and meta-analysis. European Respiratory Review [Internet]. 2019 [cited 2020 Mar 19];28. Available from: https://err.ersjournals.com/content/28/154/190049\u003c/li\u003e\n\u003cli\u003eSchweitzer L, Geisler C, Pourhassan M, Braun W, Gl\u0026uuml;er C-C, Bosy-Westphal A, et al. What is the best reference site for a single MRI slice to assess whole-body skeletal muscle and adipose tissue volumes in healthy adults?1. The American Journal of Clinical Nutrition. 2015;102:58\u0026ndash;65. \u003c/li\u003e\n\u003cli\u003eKanezaki M, Terada K, Tanabe N, Shima H, Hamakawa Y, Sato S. Effects of Sarcopenia on Ventilatory Behavior and the Multidimensional Nature of Dyspnea in Patients With Chronic Obstructive Pulmonary Disease. Journal of the American Medical Directors Association. 2021;22:827\u0026ndash;33. \u003c/li\u003e\n\u003cli\u003eEzponda A, Casanova C, Cabrera C, Martin-Palmero \u0026Aacute;, Marin-Oto M, Mar\u0026iacute;n JM, et al. Psoas Muscle Density Evaluated by Chest CT and Long-Term Mortality in COPD Patients. Arch Bronconeumol (Engl Ed). 2021;S0300-2896(21)00133-2. \u003c/li\u003e\n\u003cli\u003eBlasio F de, Alicante P, Gregorio AD, Blasio F de, Berlingieri GM, Bellofiore B, et al. Systematic review on the use of bioelectrical impedance analysis in chronic obstructive pulmonary disease. European Respiratory Journal [Internet]. 2017 [cited 2021 Feb 18];50. Available from: https://erj.ersjournals.com/content/50/suppl_61/PA1093\u003c/li\u003e\n\u003cli\u003eSchols AMWJ, Broekhuizen R, Weling-Scheepers CA, Wouters EF. Body composition and mortality in chronic obstructive pulmonary disease. Am J Clin Nutr. 2005;82:53\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eMaria BJ, Konstantina K, Sciurba FC, Criner GJ, Felix H. Utility of Rehabilitation prior to bronchoscopic lung volume reduction \u0026ndash; post-hoc analysis of the VENT trial. ERJ Open Research [Internet]. 2023 [cited 2024 Apr 25]; Available from: https://openres.ersjournals.com/content/early/2023/10/19/23120541.00735-2023\u003c/li\u003e\n\u003cli\u003eGuecamburu M, Coquelin A, Rapin A, Le Guen N, Solomiac A, Henrot P, et al. Pulmonary rehabilitation after severe exacerbation of COPD: a nationwide population study. Respir Res. 2023;24:102. \u003c/li\u003e\n\u003cli\u003eCelli BR, Locantore N, Tal-Singer R, Riley J, Miller B, Vestbo J, et al. Emphysema and extrapulmonary tissue loss in COPD: a multi-organ loss of tissue phenotype. Eur Respir J. 2018;51. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"endobronchial valve, sarcopenia, skeletal muscle wasting, emphysema, body composition","lastPublishedDoi":"10.21203/rs.3.rs-4423314/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4423314/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Endobronchial valve (EBV) insertion for severe emphysema allows to reduce hyperinflation and alleviates respiratory symptoms in patients with chronic obstructive pulmonary disease (COPD). However, few studies investigate their effect on extra-pulmonary manifestations of emphysema. We sought to assess the effect of EBV insertion on skeletal muscle mass and function, as well as determine if skeletal muscle parameters could represent a prognosis factor for response to EBV insertion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe conducted a monocentric prospective study including 19 patients. Exhaustive evaluation of lung \u0026amp; skeletal muscle parameters was performed at baseline and 3 and 6 months after EBV insertion. Evaluation included assessment of COPD severity (CAT-score, mMRC, pulmonary function tests, 6-minutes walking test (6MWT)), assessment of body composition with bioimpedance analysis, of thoracic muscles surface and density on CT-scans, and of upper limb force with handgrip test.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e EBV insertion led to a significant improvement of lung function after 3 months, that persisted 6 months after the procedure, with a significant decrease in target love volume, residual volume, total lung capacity and a significant increase in forced expiratory volume at 1 second (FEV1). Respiratory symptoms were also alleviated with a significant decrease in mMRC. In contrast, no improvement was observed in skeletal muscle parameters, whether whole-body muscle mass (appendicular skeletal muscle index), thoracic muscles surface or density, or muscle force. Besides, no muscle-related parameter was found to predict response to EBV insertion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e These results strongly advocate for a more thorough referral to pulmonary rehabilitation after the procedure, as well as emphasize the need to find bottom-up drug strategies for COPD-associated sarcopenia.\u003c/p\u003e","manuscriptTitle":"Endobronchial valve (EBV) insertion for severe emphysema does not improve skeletal muscle mass or function","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-31 20:25:32","doi":"10.21203/rs.3.rs-4423314/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"880d7953-3122-411d-927c-d7b401781624","owner":[],"postedDate":"May 31st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":32298913,"name":"Health sciences/Signs and symptoms/Comorbidities"},{"id":32298914,"name":"Health sciences/Signs and symptoms/Respiratory signs and symptoms"},{"id":32298915,"name":"Health sciences/Diseases/Respiratory tract diseases"}],"tags":[],"updatedAt":"2024-07-09T05:48:09+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-31 20:25:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4423314","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4423314","identity":"rs-4423314","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}