Chronic Obstructive Pulmonary Disease (COPD) is marked by persistent airflow limitation and ranks among the leading causes of death worldwide. In a subset of COPD patients characterized by severe emphysema and severe static lung hyperinflation, bronchoscopic lung volume reduction with endobronchial valves (BLVR-EBV) has emerged as a minimally invasive alternative to surgical procedures to reduce static lung hyperinflation, leading to improved lung function, exercise capacity, and quality of life.1

COPD is known to have multiple extrapulmonary manifestations, including abnormal body composition. characterized by low muscle mass and an excess of adipose tissue, particularly in the form of visceral fat.2,3 An abnormal body composition is frequently present among patients with COPD, and has been shown to negatively impact a patients’ morbidity and mortality.4,5 An excess of adipose tissue, and in particular visceral fat mass, is associated with enhanced systemic inflammation and reduced insulin sensitivity, thereby increasing the risk of cardiovascular diseases.6–8 Moreover, low body weight and unintentional weight loss are independent predictors of mortality in this population.9–12 Especially patients with emphysema and hyperinflation are prone to low body weight and low muscle mass.13

So far, limited is known about the effect of reducing hyperinflation on extrapulmonary manifestations like body composition, muscle function or metabolism. One study did find an increase in skeletal muscle mass after BLVR-EBV and after lung volume reduction surgery an increase was found in body mass index and fat-free mass index.14,15 Pulmonary rehabilitation (PR) has been shown to positively influence metabolism, body composition and muscle function, which is due to supervised resistance training, physical activity coaching in combination with nutritional supplements, as appropriate.2,16 The addition of pulmonary rehabilitation to BLVR-EBV could have a cumulative effect on these outcomes but this has never been investigated before to our knowledge. Therefore, this study aimed to assess the effect of BLVR-EBV on body composition, muscle function and metabolic markers and whether PR has an additional impact on these outcomes.

To our knowledge, this is the first study to examine the impact of BLVR-EBV as a standalone intervention compared to a combination with PR on alterations in body composition, muscle strength, physical activity, and blood markers. Our findings demonstrate that reducing hyperinflation by BLVR-EBV leads to substantial increases in body weight, lean mass, fat mass (including visceral fat mass), as well as muscle strength and physical activity, and impacts on adipokine profile, regardless of PR and its timing relative to BLVR-EBV.

We observed an overall increase in body weight and lean mass. In the context of COPD, unintended weight loss and a low body weight have been associated with increased mortality.9,10 Conversely, weight gain in patients with a BMI below 25 has been shown to improve survival outcomes, and patients with moderate levels of obesity exhibit lower mortality rates compared to those with a BMI below 25 (the so called ‘obesity paradox’).9,26,27 However, it has been suggested that lean body mass serves as a better predictor for survival compared to total body weight.11,12,28 Earlier findings have demonstrated that the presence of cachexia reduced the median survival by nearly half, irrespective of the extent of airflow obstruction.28 In addition to an increase in lean mass, we also observed a rise in fat mass, including visceral fat. It is well known that obesity – and in particular, excessive visceral fat – is strongly associated with insulin resistance, hypertension, and dyslipidaemia. And also in COPD, these metabolic disorders are known to contribute to high rates of mortality and morbidity, potentially through the involvement of fat tissue in promoting low-grade systemic inflammation.29 The question that emerges from our findings is whether the increases in fat mass, including visceral fat, translate into increased health risks in this patient group.

Several underlying factors have been described that can result in increased energy requirements and that may result in weight loss and a deteriorated nutritional state in patients with COPD, such as higher energy expenditure both at rest and during activity, disuse muscle atrophy, low-grade systemic inflammation, arterial hypoxemia, and hormonal insufficiency.30 In our study population, it is conceivable that a portion of the weight gain can be explained by lower resting energy expenditures as a result of reduced work of breathing due to improved respiratory mechanics following BLVR-EBV. But also loss of appetite due to systemic inflammation has been described in COPD, along with a reduced dietary intake to reduce symptoms of dyspnea.31 In line, previously, it was shown that after EBV treatment meal-related dyspnea decreased.32 Furthermore, it has been shown that lung volume reduction surgery leads to increased BMI, lean mass, and fat mass, and decreased resting energy expenditure and oxygen consumption.14,33 In lung volume reduction surgery, these decreases in resting energy expenditure and oxygen volume consumption were associated with a decrease in RV and increases in FEV1 and BMI.33 Although it is reasonable to expect similar findings in BLVR-EBV as observed in lung volume reduction surgery, this was not evident in a previous study involving a small group of patients who underwent BLVR-EBV.32 Therefore, additional research is needed to evaluate the impact of BLVR-EBV on resting energy expenditure in this population.

It is tempting to speculate that the increase in lean mass may be attributed to an increase in muscle function as a result of enhanced physical activities prompted by the improved lung function following BLVR-EBV. However, despite increases in muscle mass and strength, no changes in muscle density were found. Muscle density serves as an indicator of muscle quality, with lower attenuation scores indicating higher levels of intramuscular fat deposition.34 Although against conventional expectations, these findings are consistent with what was observed on lumbar level CT scans in patients who underwent BLVR-EBV.15 Notwithstanding the relatively large improvements in exercise capacity and muscle strength, it could be that there is still an insufficient training stimulus to effectively enhance muscle quality, particularly when considering the persistent very inactive lifestyle in this patient group. Another possible contributing factor is that in patients with COPD, a catabolic state due to an enhanced protein breakdown has been found, possibly attributed to low-grade systemic inflammation.30 But it is also possible that there may be other aspects of muscle quality improvement that a CT scan does not capture, such as enhanced blood circulation or a decrease in the proportion of type II muscle fibers.

In our study, we found a decline in leptin/fat mass ratio at follow-up. Leptin is a pro-inflammatory cytokine that regulates body weight by enhancing energy expenditure through activity-independent thermogenesis and reducing food intake by inducing satiety.35 Leptin/fat mass ratios have been inversely associated with dietary intake and body weight changes after nutritional interventions in patients with emphysema.36 Although our findings of lower leptin/fat mass ratios and increases in body weight seem compatible with each other, the mechanism behind the decrease in leptin/fat mass ratio after the interventions remains unclear. Given that leptin levels are known to increase in obesity and systemic inflammation, it might be hypothesized that inflammation becomes less pronounced following BLVR-EBV.35 However, data on this are lacking, and further research would be needed to investigate this. Adiponectin exhibits contrasting effects compared to leptin. Adiponectin is an anti-inflammatory cytokine that plays a protective role in the onset of insulin resistance, and adiponectin levels decrease in obesity, potentially due to systemic inflammation.37 Despite the increases in fat and visceral fat mass, we found no changes in adiponectin levels. This might align with an earlier hypothesis suggesting varying roles for adiponectin and leptin in COPD, potentially dependent on the phenotype, with a more pronounced impact of leptin in patients with emphysema.38 We found no changes in serum insulin level. Besides an inactive lifestyle, insulin resistance has also been described as a response to hypoxemia, systemic inflammation, and the use of glucocorticoids in the context of COPD.39

In our study, we observed an overall increase in triglyceride levels, approaching normal values at follow-up. In severe COPD, lower triglyceride levels have been described compared to those without COPD or with less advanced stages of the disease.40 Possible explanations for these changes in triglyceride levels include an increased dietary intake or metabolic shift from lipid catabolism to the utilization of glucose for energy production after the treatments.41

In our study we did not find that the addition of PR resulted in further improvements in body composition. While this does not imply that PR lacks an effect on body composition in general, it did not provide an additional benefit beyond the BLVR-EBV treatment. The effect of PR on body composition is variable and not extensively studied in the literature. One recent study investigated the effect of a PR program with additional dietary counseling and found a statistically significant decrease in fat mass between week 10 and 3 months after starting rehabilitation, but no other changes in body composition outcomes.42 Another randomized controlled trial compared the effects of PR with and without the addition of anabolic steroids on body composition, where the ‘regular’ PR group did not show a change in fat-free mass but did show a statistical significant increase in fat mass. Adding anabolic steroids resulted in a significant increase in fat-free mass, though no significant change in fat-mass was observed.43 A third study demonstrated that exercise alone did not lead to significant changes in body composition, but combining with either nutritional support or anabolic steroids led to improvements in body composition.44

In contrast to our study, one study found that PR prior to lung volume reduction surgery (LVRS) was effective.45 However, in that cohort, all patients underwent PR before LVRS, and there was no comparison group that did not follow a PR program Additionally, the impact of PR on the effectiveness of LVRS was not investigated, nor were changes in body composition or muscle function assessed. A key distinction with bronchoscopic treatment is that it is less invasive than surgery, making the requirement for patients to be ‘fit for surgery’ less critical for those undergoing a bronchoscopic procedure.

Our study has limitations. A limitation of our study is that the groups that underwent both BLVR-EBV and PR had a longer follow-up time (mean: 11.2 or 11.6 months) in comparison to the group that only underwent BLVR-EBV (mean: 8.9 months). The effects of PR are known to wane over time, which might have negatively impacted the results of the group that underwent PR before BLVR-EBV.46 Another limitation is that baseline blood samples for the group that underwent PR before BLVR-EBV were taken before BLVR-EBV for patient convenience, making it impossible to compare the three groups as intended in the study design. Finally, it would have been interesting to include a fourth group of patients who underwent pulmonary rehabilitation alone.

In conclusion, we found that BLVR-EBV leads to substantial increases in body weight, lean mass, fat mass (including visceral fat mass), as well as muscle strength, but not muscle density. Furthermore, our results showed that BLVR-EBV impacts the adipokine profile. The addition of a PR program before or after BLVR-EBV did not lead to additional benefits. This underscores the systemic benefits of addressing lung hyperinflation in patients with severe COPD.

None of the material was produced with help of any artificial intelligence software.

This study was funded by Lung Foundation Netherlands (grant number 5.1.17.171.0). The funder was not involved in the study design, conduct of the trial, data collection or analysis, interpretation, manuscript preparation, or decision to submit the manuscript for publication.

MCvdM, JEH, AV, HRG. TPW, ARV and RP have nothing to disclose. LEGWV reports to have received a research grant for this work from the Dutch Lung Foundation, grants or contracts from The Family Kamprad Foundation (20190024), the Swedish government and country council ALF grant (ALFGBG-824371), The Swedish Heart and Lung Foundation (20200150), Svensk Lungmedicinsk Förening (all paid to institution) and payment or honoraria for lectures, presentation, speakers, bureaus, manuscript writing or educational events from GSK, Astrazeneca, Boehringer, Novartis, Chiesi, Resmed, Pulmonx, Grifols (paid personally). DJS reports to have received grants or contracts from Pulmonx corp, USA, Nuvaira, USA, PulmAir, USA, Apreo, USA and FreeFlowmedical (clinical trial expenses), consulting fees from Nuvaira USA, MoreAir USA, Apreo USA and PulmonX USA (all paid to institution), payment or honoraria for lectures, presentation, speakers, bureaus, manuscript writing or educational events from PulmonX USA, Nuvaira USA (paid to institution), and support for attending meetings and/or travel from PulmonX USA. MS reports to have received grants or contracts from Netherlands Lung Foundation, Stichting Astma Bestrijding, Astra Zeneca, Boehringer Ingelheim, Chiesi, TEVA and Sanofi and consulting fees from AstraZeneca, Boehringer Ingelheim, and GSK.

The data that support the findings of this study are available from the corresponding author upon reasonable request.