# Computed tomographic airway morphology after targeted lung denervation treatment in COPD

Jorine E. Hartman, Felix J.F. Herth, Pallav Shah, Christophe Pison, Arschang

Valipour, Dirk-Jan Slebos, Arschang Valipour, Christine Abele, Irene

Firlinger, Kiran Kothakuzhakal, et al.

► To cite this version:

Jorine E. Hartman, Felix J.F. Herth, Pallav Shah, Christophe Pison, Arschang Valipour, et al. Computed tomographic airway morphology after targeted lung denervation treatment in COPD. Respiratory Medicine, 2023, Respiratory Medicine, 206, pp.107059. 10.1016/j.rmed.2022.107059. hal-04557196

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# Computed tomographic airway morphology after targeted lung denervation treatment in COPD

Jorine E. Hartman, Felix J.F. Herth, Pallav Shah, Christophe Pison, Arschang Valipour, Dirk-Jan Slebos, Arschang Valipour, Christine Abele, Irene Firlinger, Kiran Kothakuzhakal, et al.

<figure><img src="image_1.png" /></figure>

## To cite this version:

Jorine E. Hartman, Felix J.F. Herth, Pallav Shah, Christophe Pison, Arschang Valipour, et al. Computed tomographic airway morphology after targeted lung denervation treatment in COPD. Respiratory Medicine, 2023, Respiratory Medicine, 206, pp.107059. 10.1016/j.rmed.2022.107059. hal-04557196

HAL Id: hal-04557196

https://lilloa.hal.science/hal-04557196v1

Submitted on 25 Apr 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

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recherche français ou étrangers, des laboratoires
publics ou privés.

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# Computed tomographic airway morphology after targeted lung denervation treatment in COPD

Jorine E. Hartman<sup>a,b,*</sup>, Felix J.F. Herth<sup>c</sup>, Pallav Shah<sup>d,e,f</sup>, Christophe Pison<sup>g,h,i</sup>,
Arschang Valipour<sup>j</sup>, Dirk-Jan Slebos<sup>a,b</sup>, AIRFLOW-2 Study Group

## ABSTRACT

This post-hoc analysis of the AIRFLOW-2 trial investigated the changes in airway CT-parameters after targeted lung denervation (TLD) and whether these changes are associated with treatment response. In the treatment group (n = 32), an improvement in air trapping was significantly associated with an improvement in residual volume (RV). Furthermore, improvements in Pi10 and airway lumen were significantly associated with an improvement in both RV and FEV1. Our results could suggest that when improving airway characteristics like decreasing airway wall thickness and increasing the airway lumen, this leads to less air trapping and an improvement in clinical outcomes.

The bronchoscopic targeted lung denervation (TLD) treatment is a potential new therapy for COPD patients with frequent exacerbations [1]. So far, positive outcomes of the treatment were reported on the frequency of COPD exacerbations and stabilization of lung function and deterioration of lung function decline in the longer term [2–5]. By use of radiofrequency the TLD treatment aims to disrupt the peribronchial vagal innervation of the airways and consequently decrease the release of acetylcholine. Potentially, the treatment could also improve airway characteristics like airway wall thickness and consequently air trapping in the lung. However, this has not been investigated so far. Therefore, the aim of this post-hoc analysis of the AIRFLOW-2 trial (NCT20258459) [4] was to investigate the changes in airway CT-parameters after the TLD treatment and furthermore whether these changes are associated with treatment response.

The AIRFLOW-2 trial investigated the safety and impact of the TLD treatment by comparing the treatment with sham-controlled placebo [4]. Ethics committees of participating hospitals approved the trial and all 82 patients provided informed consent. As part of the trial, computed tomography (CT) scans were performed at baseline and after 1 year

follow-up. Furthermore, patients performed spirometry, body plethysmography and filled out the St. George's respiratory questionnaire (SGRQ) at the same timepoints. For this post-hoc analysis, a quantitative CT-scan analysis (QCT) was performed using LungQ-software (Thirona, The Netherlands). Outcomes of the quantitative analysis were lung volumes, quantification of emphysema and air trapping and airway measurements (Pi10, airway wall thickness and lumen diameter).

In total 66 patients had QCT analysable scans at both baseline and 1 year follow-up and were included (mean age 64 ± 7, FEV1 0.94 ± 0.28 L, SGRQ total score 55 ± 16; see Table S1, Online supplement). Baseline characteristics did not differ between the patients with QCT analysable or non-analysable scans (Table S2, Online supplement). In the treatment group, 32 patients had analysable inspiratory scans (of which 24 had both in- and expiratory scans) and 34 in the sham-control group (24 with in- and expiratory scans).

No significant differences (p-value<0.05) were found between the treatment and sham-control group for changes in CT-parameters. Furthermore, in the treatment group we only found a significant increase in air trapping due to emphysema, and in the control group only a

<footnote><sup>a</sup> Department of Pulmonary Diseases, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands</footnote>

<footnote><sup>b</sup> Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands</footnote>

<footnote><sup>c</sup> Department of Pneumology and Critical Care Medicine, Thoraxklinik and Translational Lung Research Center, University of Heidelberg, Germany</footnote>

<footnote><sup>d</sup> Royal Brompton Hospital, London, United Kingdom</footnote>

<footnote><sup>e</sup> Chelsea & Westminster Hospital, London, United Kingdom</footnote>

<footnote><sup>f</sup> National Heart and Lung Institute, Imperial College London, London, United Kingdom</footnote>

<footnote><sup>g</sup> Service Hospitalier Universitaire de Pneumologie Physiologie, Pôle Thorax et Vaisseaux, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France</footnote>

<footnote><sup>h</sup> Centre de Pneumologie Henri Bazire, Saint Julien de Ratz, France</footnote>

<footnote><sup>i</sup> Département Universitaire des Patients Grenoble Alpes, Faculté de Médecine Pharmacie, Université Grenoble Alpes, La Tronche, France</footnote>

<footnote><sup>j</sup> Department of Respiratory and Critical Care Medicine, Vienna Health Care Group, Klinik Floridsdorf, Vienna, Austria</footnote>

<footnote>* Corresponding author. Department of Pulmonary diseases AA11, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, the Netherlands. E-mail address: j.hartman@umcg.nl (J.E. Hartman).</footnote>
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# Computed tomographic airway morphology after targeted lung denervation treatment in COPD

Jorine E. Hartman<sup>a,b,*</sup>, Felix J.F. Herth<sup>c</sup>, Pallav Shah<sup>d,e,f</sup>, Christophe Pison<sup>g,h,i</sup>,
Arschang Valipour<sup>j</sup>, Dirk-Jan Slebos<sup>a,b</sup>, AIRFLOW-2 Study Group

## ABSTRACT

This post-hoc analysis of the AIRFLOW-2 trial investigated the changes in airway CT-parameters after targeted lung denervation (TLD) and whether these changes are associated with treatment response. In the treatment group (n = 32), an improvement in air trapping was significantly associated with an improvement in residual volume (RV). Furthermore, improvements in Pi10 and airway lumen were significantly associated with an improvement in both RV and FEV1. Our results could suggest that when improving airway characteristics like decreasing airway wall thickness and increasing the airway lumen, this leads to less air trapping and an improvement in clinical outcomes.

The bronchoscopic targeted lung denervation (TLD) treatment is a potential new therapy for COPD patients with frequent exacerbations [1]. So far, positive outcomes of the treatment were reported on the frequency of COPD exacerbations and stabilization of lung function and deterioration of lung function decline in the longer term [2–5]. By use of radiofrequency the TLD treatment aims to disrupt the peribronchial vagal innervation of the airways and consequently decrease the release of acetylcholine. Potentially, the treatment could also improve airway characteristics like airway wall thickness and consequently air trapping in the lung. However, this has not been investigated so far. Therefore, the aim of this post-hoc analysis of the AIRFLOW-2 trial (NCT20258459) [4] was to investigate the changes in airway CT-parameters after the TLD treatment and furthermore whether these changes are associated with treatment response.

The AIRFLOW-2 trial investigated the safety and impact of the TLD treatment by comparing the treatment with sham-controlled placebo [4]. Ethics committees of participating hospitals approved the trial and all 82 patients provided informed consent. As part of the trial, computed tomography (CT) scans were performed at baseline and after 1 year

follow-up. Furthermore, patients performed spirometry, body plethysmography and filled out the St. George's respiratory questionnaire (SGRQ) at the same timepoints. For this post-hoc analysis, a quantitative CT-scan analysis (QCT) was performed using LungQ-software (Thirona, The Netherlands). Outcomes of the quantitative analysis were lung volumes, quantification of emphysema and air trapping and airway measurements (Pi10, airway wall thickness and lumen diameter).

In total 66 patients had QCT analysable scans at both baseline and 1 year follow-up and were included (mean age 64 ± 7, FEV1 0.94 ± 0.28 L, SGRQ total score 55 ± 16; see Table S1, Online supplement). Baseline characteristics did not differ between the patients with QCT analysable or non-analysable scans (Table S2, Online supplement). In the treatment group, 32 patients had analysable inspiratory scans (of which 24 had both in- and expiratory scans) and 34 in the sham-control group (24 with in- and expiratory scans).

No significant differences (p-value<0.05) were found between the treatment and sham-control group for changes in CT-parameters. Furthermore, in the treatment group we only found a significant increase in air trapping due to emphysema, and in the control group only a

<footnote><sup>a</sup> Department of Pulmonary Diseases, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands</footnote>

<footnote><sup>b</sup> Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands</footnote>

<footnote><sup>c</sup> Department of Pneumology and Critical Care Medicine, Thoraxklinik and Translational Lung Research Center, University of Heidelberg, Germany</footnote>

<footnote><sup>d</sup> Royal Brompton Hospital, London, United Kingdom</footnote>

<footnote><sup>e</sup> Chelsea & Westminster Hospital, London, United Kingdom</footnote>

<footnote><sup>f</sup> National Heart and Lung Institute, Imperial College London, London, United Kingdom</footnote>

<footnote><sup>g</sup> Service Hospitalier Universitaire de Pneumologie Physiologie, Pôle Thorax et Vaisseaux, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France</footnote>

<footnote><sup>h</sup> Centre de Pneumologie Henri Bazire, Saint Julien de Ratz, France</footnote>

<footnote><sup>i</sup> Département Universitaire des Patients Grenoble Alpes, Faculté de Médecine Pharmacie, Université Grenoble Alpes, La Tronche, France</footnote>

<footnote><sup>j</sup> Department of Respiratory and Critical Care Medicine, Vienna Health Care Group, Klinik Floridsdorf, Vienna, Austria</footnote>

<footnote>* Corresponding author. Department of Pulmonary diseases AA11, University Medical Center Groningen, PO Box 30001, 9700 RB, Groningen, the Netherlands. E-mail address: j.hartman@umcg.nl (J.E. Hartman).</footnote>
<table><caption>**Table 1**
Changes in CT characteristics between baseline and 12 month follow up.</caption><thead><tr><th rowspan="2"></th><th rowspan="2">Treatment group</th><th rowspan="2">n</th><th rowspan="2">Within group p-value</th><th rowspan="2">Sham-control group</th><th rowspan="2">n</th><th rowspan="2">Within group p-value</th><th colspan="2">Between group</th></tr><tr><th>Difference</th><th>p-value</th></tr></thead><tbody><tr><td>Δ Lung volume inspiratory, mL</td><td>-77.9 ± 505.6</td><td>32</td><td>0.39</td><td>-87.2 ± 262.6</td><td>34</td><td>0.061</td><td>9.36 ± 98.3</td><td>0.92</td></tr><tr><td>Δ VERA normal, %</td><td>-1.04 ± 3.5</td><td>23</td><td>0.17</td><td>-1.08 ± 6.5</td><td>24</td><td>0.42</td><td>0.04 ± 1.53</td><td>0.98</td></tr><tr><td>Δ VERA emphysema, %</td><td>0.10 ± 5.0</td><td>23</td><td>0.35*</td><td>0.1 ± 2.7</td><td>24</td><td>0.81*</td><td>0.005 ± 1.16</td><td>0.55**</td></tr><tr><td>Δ VERA air trapping general, %</td><td>-0.34 ± 4.4</td><td>23</td><td>0.72</td><td>0.60 ± 7.1</td><td>24</td><td>0.68</td><td>-0.94 ± 1.73</td><td>0.59</td></tr><tr><td>Δ VERA air trapping emphysema, %</td><td>1.28 ± 2.2</td><td>23</td><td><strong>0.011</strong></td><td>0.38 ± 2.0</td><td>24</td><td>0.35</td><td>0.90 ± 0.61</td><td>0.15</td></tr><tr><td>Δ Pi10, mm</td><td>0.004 ± 0.19</td><td>32</td><td>0.91</td><td>0.066 ± 0.28</td><td>33</td><td>0.19</td><td>-0.06 ± 0.06</td><td>0.31</td></tr><tr><td>Δ Airway wall thickness (segmental), mm</td><td>0.00 ± 0.20</td><td>32</td><td>0.25*</td><td>0.014 ± 0.11</td><td>33</td><td>0.43*</td><td>-0.01 ± 0.04</td><td>0.16**</td></tr><tr><td>Δ Airway lumen (segmental), mm</td><td>-0.013 ± 0.32</td><td>32</td><td>0.82</td><td>-0.146 ± 0.38</td><td>33</td><td><strong>0.033</strong></td><td>0.13 ± 0.09</td><td>0.13</td></tr></tbody></table>

Within group differences between baseline and 12 month follow up were tested with a paired t-test or **Wilcoxon signed-rank test. Between group differences were tested with an independent sample t-test or **Mann-Whitney U test. Significant values (p < 0.05) are depicted in bold.

N: valid number, Δ: change between baseline and 12 month follow up, mL: milliliter, mm: millimeter, VERA: Ventilation estimation from registered analysis (an AI registration-based method that identifies regions in the lung that empty more slowly than expected during expiration. Based on inspiration-expiration image registration, this analysis extracts local differences in how lung regions empty during expiration. By estimating which regions empty abnormally slow, quantitative information can be deducted on air that remains trapped after expiration (air trapping)), Pi10: the square root of wall area at airways with a perimeter of 10 mm.

significant decrease in airway lumen at segmental level (Table 1). However, these changes were small and not clinically relevant. No differences were found between patients who were treated in all 8 quadrants versus 7 or 6 quadrants (8 quadrants is a complete treatment). We also investigated whether there were significant associations between change in residual volume (RV), forced expiratory volume in 1 s (FEV₁) or SGRQ and change in CT-parameters. In the treatment group, an improvement in general air trapping was significantly associated with an improvement in RV. Furthermore, improvements in Pi10 (the square root of wall area at airways with a perimeter of 10 mm) and airway lumen were significantly associated with an improvement in both RV and FEV₁(Table 2).

We performed a cluster analysis in the treatment group using Viscovery-SOMine v7.2 (Viscovery-Software-GmbH, Austria) which is based on the Kohonen algorithm [6,7]. The following variables were entered in the software: age, gender, BMI, change in lung lumen diameter segmental, change in Pi10, change in air trapping (non-emphysema), change in RV, change in FEV₁, change in SGRQ and number of quadrants treated (entered with equal weight). The cluster analysis, using the SOM-Ward algorithm, generated 4 clusters of which one could be defined as a 'responder' cluster. This cluster, including 11 patients, had significant changes in lumen diameter, Pi10, air trapping, RV, FEV₁ and SGRQ compared to the total population (Fig. 1-cluster 3'Yellow').

We investigated whether there were differences at baseline between the 'responder' group and the other patients. The responder group had a larger difference between with and without using pulmonary medication in FEV₁ (p = 0.029) and borderline significant difference between with and without using pulmonary medication in CAT score (p = 0.080). No other differences between groups were found (Table S3, online supplement).

To summarize, we did not find a clinically relevant change in airway parameters measured on CT scan after TLD treatment between the treatment and control group. We did find that an improvement in airway parameters and air trapping was associated with an improvement in lung function and quality of life and a group of responders was identified through a cluster analysis.

Our results could suggest that when improving airway characteristics like decreasing airway wall thickness and increasing the airway lumen, this leads to less air trapping and an improvement in clinical outcomes. Pharmacological treatment with anticholinergic drugs like tiotropium has a comparable mechanism of action to the TLD treatment, as both block the acetylcholine release in airway smooth muscle. Two previous studies have shown that the inhalation of anticholinergic agents led to an increase in luminal area and this increase in luminal area was significantly associated with an improvement in pulmonary function

<caption>**Table 2**</caption>

Associations between change in CT characteristics and change in clinical outcomes.

<table><thead><tr><th rowspan="2">TREATMENT GROUP</th><th colspan="2">Δ RV</th><th colspan="2">Δ FEV<sub>1</sub></th><th colspan="2">Δ SGRQ total score</th></tr><tr><th>cc</th><th>p-value</th><th>cc</th><th>p-value</th><th>cc</th><th>p-value</th></tr></thead><tbody><tr><td>Δ Lung volume inspiratory</td><td>-0.299</td><td>0.097</td><td>0.023</td><td>0.90</td><td><strong>-0.364</strong></td><td><strong>0.040</strong></td></tr><tr><td>Δ VERA normal</td><td>-0.210</td><td>0.34</td><td>0.124</td><td>0.57</td><td>0.125</td><td>0.57</td></tr><tr><td>Δ VERA emphysema</td><td>-0.228*</td><td>0.30</td><td>0.154*</td><td>0.48</td><td>-0.142*</td><td>0.52</td></tr><tr><td>Δ VERA air trapping general</td><td><strong>0.524</strong></td><td><strong>0.010</strong></td><td>-0.146</td><td>0.51</td><td>0.112</td><td>0.61</td></tr><tr><td>Δ VERA air trapping emphysema</td><td>-0.026</td><td>0.91</td><td>-0.016</td><td>0.94</td><td>0.247</td><td>0.26</td></tr><tr><td>Δ Pi10</td><td><strong>0.359*</strong></td><td><strong>0.044</strong></td><td><strong>-0.482*</strong></td><td><strong>0.005</strong></td><td>0.347*</td><td>0.052</td></tr><tr><td>Δ Airway wall thickness (segmental)</td><td>-0.001*</td><td>0.997</td><td>-0.081*</td><td>0.66</td><td>0.245*</td><td>0.18</td></tr><tr><td>Δ Airway lumen (segmental)</td><td><strong>-0.358*</strong></td><td><strong>0.044</strong></td><td><strong>0.444*</strong></td><td><strong>0.011</strong></td><td>-0.119*</td><td>0.52</td></tr></tbody></table>

<table><thead><tr><th rowspan="2">CONTROL GROUP</th><th colspan="2">Δ RV</th><th colspan="2">Δ FEV<sub>1</sub></th><th colspan="2">Δ SGRQ total score</th></tr><tr><th>cc</th><th>p-value</th><th>cc</th><th>p-value</th><th>cc</th><th>p-value</th></tr></thead><tbody><tr><td>Δ Lung volume inspiratory</td><td><strong>0.457</strong></td><td><strong>0.007</strong></td><td>-0.111</td><td>0.53</td><td>-0.016</td><td>0.93</td></tr><tr><td>Δ VERA normal</td><td>-0.301</td><td>0.15</td><td>0.349</td><td>0.062</td><td>0.031</td><td>0.89</td></tr><tr><td>Δ VERA emphysema</td><td>0.237*</td><td>0.27</td><td><strong>-0.634*</strong></td><td><strong>0.001</strong></td><td>-0.084*</td><td>0.70</td></tr><tr><td>Δ VERA air trapping general</td><td>0.143</td><td>0.51</td><td>-0.023</td><td>0.91</td><td>-0.081</td><td>0.71</td></tr><tr><td>Δ VERA air trapping emphysema</td><td>0.332</td><td>0.11</td><td>-0.314</td><td>0.14</td><td>0.039</td><td>0.86</td></tr><tr><td>Δ Pi10</td><td>0.216*</td><td>0.23</td><td><strong>-0.359*</strong></td><td><strong>0.040</strong></td><td>-0.124*</td><td>0.49</td></tr><tr><td>Δ Airway wall thickness (segmental)</td><td>0.203*</td><td>0.26</td><td>-0.072*</td><td>0.69</td><td>-0.069*</td><td>0.70</td></tr><tr><td>Δ Airway lumen (segmental)</td><td>0.024*</td><td>0.90</td><td>0.063*</td><td>0.73</td><td><strong>0.355*</strong></td><td><strong>0.043</strong></td></tr></tbody></table>

Data are presented as Pearson correlation coefficient or * Spearman's rho. Significant values (p < 0.05) are depicted in bold.

Cc: Correlation coefficient, Δ: change between baseline and 12 month follow up, mL: milliliter, mm: millimeter, VERA: Ventilation estimation from registered analysis (see Table 1 for further explanation), Pi10: the square root of wall area at airways with a perimeter of 10 mm, RV: residual volume, FEV₁: Forced expiratory volume in 1 s, SGRQ: St. George's respiratory questionnaire.
<table><caption>**Table 1**
Changes in CT characteristics between baseline and 12 month follow up.</caption><thead><tr><th rowspan="2"></th><th rowspan="2">Treatment group</th><th rowspan="2">n</th><th rowspan="2">Within group p-value</th><th rowspan="2">Sham-control group</th><th rowspan="2">n</th><th rowspan="2">Within group p-value</th><th colspan="2">Between group</th></tr><tr><th>Difference</th><th>p-value</th></tr></thead><tbody><tr><td>Δ Lung volume inspiratory, mL</td><td>-77.9 ± 505.6</td><td>32</td><td>0.39</td><td>-87.2 ± 262.6</td><td>34</td><td>0.061</td><td>9.36 ± 98.3</td><td>0.92</td></tr><tr><td>Δ VERA normal, %</td><td>-1.04 ± 3.5</td><td>23</td><td>0.17</td><td>-1.08 ± 6.5</td><td>24</td><td>0.42</td><td>0.04 ± 1.53</td><td>0.98</td></tr><tr><td>Δ VERA emphysema, %</td><td>0.10 ± 5.0</td><td>23</td><td>0.35*</td><td>0.1 ± 2.7</td><td>24</td><td>0.81*</td><td>0.005 ± 1.16</td><td>0.55**</td></tr><tr><td>Δ VERA air trapping general, %</td><td>-0.34 ± 4.4</td><td>23</td><td>0.72</td><td>0.60 ± 7.1</td><td>24</td><td>0.68</td><td>-0.94 ± 1.73</td><td>0.59</td></tr><tr><td>Δ VERA air trapping emphysema, %</td><td>1.28 ± 2.2</td><td>23</td><td><strong>0.011</strong></td><td>0.38 ± 2.0</td><td>24</td><td>0.35</td><td>0.90 ± 0.61</td><td>0.15</td></tr><tr><td>Δ Pi10, mm</td><td>0.004 ± 0.19</td><td>32</td><td>0.91</td><td>0.066 ± 0.28</td><td>33</td><td>0.19</td><td>-0.06 ± 0.06</td><td>0.31</td></tr><tr><td>Δ Airway wall thickness (segmental), mm</td><td>0.00 ± 0.20</td><td>32</td><td>0.25*</td><td>0.014 ± 0.11</td><td>33</td><td>0.43*</td><td>-0.01 ± 0.04</td><td>0.16**</td></tr><tr><td>Δ Airway lumen (segmental), mm</td><td>-0.013 ± 0.32</td><td>32</td><td>0.82</td><td>-0.146 ± 0.38</td><td>33</td><td><strong>0.033</strong></td><td>0.13 ± 0.09</td><td>0.13</td></tr></tbody></table>

Within group differences between baseline and 12 month follow up were tested with a paired t-test or **Wilcoxon signed-rank test. Between group differences were tested with an independent sample t-test or **Mann-Whitney U test. Significant values (p < 0.05) are depicted in bold.

N: valid number, Δ: change between baseline and 12 month follow up, mL: milliliter, mm: millimeter, VERA: Ventilation estimation from registered analysis (an AI registration-based method that identifies regions in the lung that empty more slowly than expected during expiration. Based on inspiration-expiration image registration, this analysis extracts local differences in how lung regions empty during expiration. By estimating which regions empty abnormally slow, quantitative information can be deducted on air that remains trapped after expiration (air trapping)), Pi10: the square root of wall area at airways with a perimeter of 10 mm.

significant decrease in airway lumen at segmental level (Table 1). However, these changes were small and not clinically relevant. No differences were found between patients who were treated in all 8 quadrants versus 7 or 6 quadrants (8 quadrants is a complete treatment). We also investigated whether there were significant associations between change in residual volume (RV), forced expiratory volume in 1 s (FEV₁) or SGRQ and change in CT-parameters. In the treatment group, an improvement in general air trapping was significantly associated with an improvement in RV. Furthermore, improvements in Pi10 (the square root of wall area at airways with a perimeter of 10 mm) and airway lumen were significantly associated with an improvement in both RV and FEV₁(Table 2).

We performed a cluster analysis in the treatment group using Viscovery-SOMine v7.2 (Viscovery-Software-GmbH, Austria) which is based on the Kohonen algorithm [6,7]. The following variables were entered in the software: age, gender, BMI, change in lung lumen diameter segmental, change in Pi10, change in air trapping (non-emphysema), change in RV, change in FEV₁, change in SGRQ and number of quadrants treated (entered with equal weight). The cluster analysis, using the SOM-Ward algorithm, generated 4 clusters of which one could be defined as a 'responder' cluster. This cluster, including 11 patients, had significant changes in lumen diameter, Pi10, air trapping, RV, FEV₁ and SGRQ compared to the total population (Fig. 1-cluster 3'Yellow').

We investigated whether there were differences at baseline between the 'responder' group and the other patients. The responder group had a larger difference between with and without using pulmonary medication in FEV₁ (p = 0.029) and borderline significant difference between with and without using pulmonary medication in CAT score (p = 0.080). No other differences between groups were found (Table S3, online supplement).

To summarize, we did not find a clinically relevant change in airway parameters measured on CT scan after TLD treatment between the treatment and control group. We did find that an improvement in airway parameters and air trapping was associated with an improvement in lung function and quality of life and a group of responders was identified through a cluster analysis.

Our results could suggest that when improving airway characteristics like decreasing airway wall thickness and increasing the airway lumen, this leads to less air trapping and an improvement in clinical outcomes. Pharmacological treatment with anticholinergic drugs like tiotropium has a comparable mechanism of action to the TLD treatment, as both block the acetylcholine release in airway smooth muscle. Two previous studies have shown that the inhalation of anticholinergic agents led to an increase in luminal area and this increase in luminal area was significantly associated with an improvement in pulmonary function

<caption>**Table 2**</caption>

Associations between change in CT characteristics and change in clinical outcomes.

<table><thead><tr><th rowspan="2">TREATMENT GROUP</th><th colspan="2">Δ RV</th><th colspan="2">Δ FEV<sub>1</sub></th><th colspan="2">Δ SGRQ total score</th></tr><tr><th>cc</th><th>p-value</th><th>cc</th><th>p-value</th><th>cc</th><th>p-value</th></tr></thead><tbody><tr><td>Δ Lung volume inspiratory</td><td>-0.299</td><td>0.097</td><td>0.023</td><td>0.90</td><td><strong>-0.364</strong></td><td><strong>0.040</strong></td></tr><tr><td>Δ VERA normal</td><td>-0.210</td><td>0.34</td><td>0.124</td><td>0.57</td><td>0.125</td><td>0.57</td></tr><tr><td>Δ VERA emphysema</td><td>-0.228*</td><td>0.30</td><td>0.154*</td><td>0.48</td><td>-0.142*</td><td>0.52</td></tr><tr><td>Δ VERA air trapping general</td><td><strong>0.524</strong></td><td><strong>0.010</strong></td><td>-0.146</td><td>0.51</td><td>0.112</td><td>0.61</td></tr><tr><td>Δ VERA air trapping emphysema</td><td>-0.026</td><td>0.91</td><td>-0.016</td><td>0.94</td><td>0.247</td><td>0.26</td></tr><tr><td>Δ Pi10</td><td><strong>0.359*</strong></td><td><strong>0.044</strong></td><td><strong>-0.482*</strong></td><td><strong>0.005</strong></td><td>0.347*</td><td>0.052</td></tr><tr><td>Δ Airway wall thickness (segmental)</td><td>-0.001*</td><td>0.997</td><td>-0.081*</td><td>0.66</td><td>0.245*</td><td>0.18</td></tr><tr><td>Δ Airway lumen (segmental)</td><td><strong>-0.358*</strong></td><td><strong>0.044</strong></td><td><strong>0.444*</strong></td><td><strong>0.011</strong></td><td>-0.119*</td><td>0.52</td></tr></tbody></table>

<table><thead><tr><th rowspan="2">CONTROL GROUP</th><th colspan="2">Δ RV</th><th colspan="2">Δ FEV<sub>1</sub></th><th colspan="2">Δ SGRQ total score</th></tr><tr><th>cc</th><th>p-value</th><th>cc</th><th>p-value</th><th>cc</th><th>p-value</th></tr></thead><tbody><tr><td>Δ Lung volume inspiratory</td><td><strong>0.457</strong></td><td><strong>0.007</strong></td><td>-0.111</td><td>0.53</td><td>-0.016</td><td>0.93</td></tr><tr><td>Δ VERA normal</td><td>-0.301</td><td>0.15</td><td>0.349</td><td>0.062</td><td>0.031</td><td>0.89</td></tr><tr><td>Δ VERA emphysema</td><td>0.237*</td><td>0.27</td><td><strong>-0.634*</strong></td><td><strong>0.001</strong></td><td>-0.084*</td><td>0.70</td></tr><tr><td>Δ VERA air trapping general</td><td>0.143</td><td>0.51</td><td>-0.023</td><td>0.91</td><td>-0.081</td><td>0.71</td></tr><tr><td>Δ VERA air trapping emphysema</td><td>0.332</td><td>0.11</td><td>-0.314</td><td>0.14</td><td>0.039</td><td>0.86</td></tr><tr><td>Δ Pi10</td><td>0.216*</td><td>0.23</td><td><strong>-0.359*</strong></td><td><strong>0.040</strong></td><td>-0.124*</td><td>0.49</td></tr><tr><td>Δ Airway wall thickness (segmental)</td><td>0.203*</td><td>0.26</td><td>-0.072*</td><td>0.69</td><td>-0.069*</td><td>0.70</td></tr><tr><td>Δ Airway lumen (segmental)</td><td>0.024*</td><td>0.90</td><td>0.063*</td><td>0.73</td><td><strong>0.355*</strong></td><td><strong>0.043</strong></td></tr></tbody></table>

Data are presented as Pearson correlation coefficient or * Spearman's rho. Significant values (p < 0.05) are depicted in bold.

Cc: Correlation coefficient, Δ: change between baseline and 12 month follow up, mL: milliliter, mm: millimeter, VERA: Ventilation estimation from registered analysis (see Table 1 for further explanation), Pi10: the square root of wall area at airways with a perimeter of 10 mm, RV: residual volume, FEV₁: Forced expiratory volume in 1 s, SGRQ: St. George's respiratory questionnaire.
<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Cluster analysis in the treatment group (n = 37).</figcaption></figure>

**Legend:** Figure created with Viscovery software (Viscovery-Software-GmbH, Austria). The cluster analysis placed patients on the map based on their multidimensional response profile and created 4 clusters. The more subjects are similar the closer they are on the map and the more they differ the further away they are from each other. The colours represent the size of the attribute. A red colour indicates the highest value or response and the blue colour the lowest value or response.

<table><thead><tr><th>Cluster</th><th>N</th><th>Age</th><th>Gender</th><th>BMI</th><th>Δlumen diameter-segmental</th><th>ΔPI10</th><th>ΔAirtrapping general</th><th>ΔRV</th><th>ΔFEV<sub>1</sub></th><th>ΔSGRQ</th><th>Quadrants treated</th></tr></thead><tbody><tr><td>1. Blue</td><td>13</td><td>69*</td><td>0.15*</td><td>25.8</td><td>-0.09</td><td>0.06</td><td>0.68</td><td>0.029</td><td>-0.112*</td><td>0.96</td><td>6.8</td></tr><tr><td>2: Red</td><td>9</td><td>60*</td><td>1.00*</td><td>22.8*</td><td>-0.10</td><td>0.03</td><td>0.99</td><td>0.316</td><td>0.012</td><td>-5.37</td><td>7.3</td></tr><tr><td>3: Yellow</td><td>11</td><td>63</td><td>0.46</td><td>25.8</td><td>0.31*</td><td>-0.19*</td><td>-3.20*</td><td>-0.644*</td><td>0.177*</td><td>-13.6*</td><td>7.3</td></tr><tr><td>4: Green</td><td>4</td><td>54*</td><td>0.00</td><td>31.3*</td><td>-0.58</td><td>0.38*</td><td>6.5</td><td>0.445</td><td>-0.198</td><td>7.07</td><td>6.8</td></tr></tbody></table>

*Values were significantly different (p<0.05) from the total population (n=37), performed with a t-test.

Gender 0=male. Δ= change between baseline and 12 month follow up.
<figure><img src="image_6.png" /><figcaption>**Fig. 1.** Cluster analysis in the treatment group (n = 37).</figcaption></figure>

**Legend:** Figure created with Viscovery software (Viscovery-Software-GmbH, Austria). The cluster analysis placed patients on the map based on their multidimensional response profile and created 4 clusters. The more subjects are similar the closer they are on the map and the more they differ the further away they are from each other. The colours represent the size of the attribute. A red colour indicates the highest value or response and the blue colour the lowest value or response.

<table><thead><tr><th>Cluster</th><th>N</th><th>Age</th><th>Gender</th><th>BMI</th><th>Δlumen diameter-segmental</th><th>ΔPI10</th><th>ΔAirtrapping general</th><th>ΔRV</th><th>ΔFEV<sub>1</sub></th><th>ΔSGRQ</th><th>Quadrants treated</th></tr></thead><tbody><tr><td>1. Blue</td><td>13</td><td>69*</td><td>0.15*</td><td>25.8</td><td>-0.09</td><td>0.06</td><td>0.68</td><td>0.029</td><td>-0.112*</td><td>0.96</td><td>6.8</td></tr><tr><td>2: Red</td><td>9</td><td>60*</td><td>1.00*</td><td>22.8*</td><td>-0.10</td><td>0.03</td><td>0.99</td><td>0.316</td><td>0.012</td><td>-5.37</td><td>7.3</td></tr><tr><td>3: Yellow</td><td>11</td><td>63</td><td>0.46</td><td>25.8</td><td>0.31*</td><td>-0.19*</td><td>-3.20*</td><td>-0.644*</td><td>0.177*</td><td>-13.6*</td><td>7.3</td></tr><tr><td>4: Green</td><td>4</td><td>54*</td><td>0.00</td><td>31.3*</td><td>-0.58</td><td>0.38*</td><td>6.5</td><td>0.445</td><td>-0.198</td><td>7.07</td><td>6.8</td></tr></tbody></table>

*Values were significantly different (p<0.05) from the total population (n=37), performed with a t-test.
Gender 0=male. Δ= change between baseline and 12 month follow up.
(both FEV₁ and RV) [8,9]. These findings are in line with our results.

The cluster analysis identified a responder group and we were interested whether we could find baseline predictors that identify these patients. We found that these patients had a significantly larger positive difference in FEV₁ and borderline in CAT between after washout of their inhaler therapy and with the regular use of inhaler therapy. During washout period, patients were not allowed to use LAMA drugs for at least 7 days (all washout requirements are shown in Table S4 in the online supplement). These results could indicate that better responders to LAMA or other pulmonary medication also better respond to TLD treatment.

To conclude, our results suggest that when the TLD treatment leads to an improvement in airway parameters, like airway wall thickness and lumen area, that this is associated with a favourable treatment response. Patients with a greater response to bronchodilators are the best responders.

## Author's contributions

JEH and DJS designed the analysis, wrote the first draft of the manuscript, and made revisions after feedback from co-authors. All the authors meet the definition of an author as stated by the International Committee of Medical Journal Editors, and all have seen and approved the final manuscript.

## Funding statement

The AIRFLOW-2 trial was funded by Nuvaira Inc, Minneapolis, MN, USA. The funding source had no involvement in this analysis or in the writing of this manuscript.

## Declaration of competing interest

DJS is a PI for Nuvaira, USA and reports consultancy fees from Nuvaira paid to the institution. AV reports speaker fees from Nuvaira in the past. PS reports clinical trial expenses reimbursed to the host institutions in the past 36 months. CP reports payments for lectures and to CHUGA to conduct phase 3 trials from Nuvaira (AIRFLOW 2 and 3

trials), GSK, AZ, Boehringer Ingelheim, Novartis and Chiesi. JH and FH have nothing to disclose.

## Acknowledgements

We would like to thank the Dutch Foundation for Asthma Prevention (Noorderlijke CARA stichting) for the grant we received which allowed us to purchase the software used for this analysis.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmed.2022.107059.

## References

[1] J.E. Hartman, J.L. Garner, P.L. Shah, et al., New bronchoscopic treatment modalities for patients with chronic bronchitis, Eur. Respir. Rev. (2021) 30, https://doi.org/10.1183/16000617.0281-2020.

[2] J. Hartman, F. Conway, B. Degano, et al., Rate of lung function decline slows in the 3 years after targeted lung denervation in COPD, Respir. Med. (2021) 188, https://doi.org/10.1016/j.rmed.2021.106604.

[3] C. Pison, P. Shah, D.-J. Slebos, et al., Safety of denervation following targeted lung denervation therapy for COPD: AIRFLOW-1 three-year outcomes, Respir. Res. 22 (2021).

[4] D.-J. Slebos, P.L. Shah, F.J. Herth, et al., Safety and adverse events after targeted lung denervation for symptomatic moderate to severe COPD (AIRFLOW): a multicenter randomized controlled trial, Am. J. Respir. Crit. Care Med. 200 (2019) 1477-1486, https://doi.org/10.1164/rccm.201903-0624oc.

[5] D.J. Slebos, K. Klooster, C.F. Koegelenberg, et al., Targeted lung denervation for moderate to severe COPD: a pilot study, Thorax 70 (2015) 411-419, https://doi.org/10.1136/thoraxjnl-2014-206146 [doi].

[6] T.T.A.-T.T.-. Kohonen, Self-Organizing Maps (2001), https://doi.org/10.1007/978-3-642-56927-2, LK, https://rug.on.worldcat.org/oclc/851768192.

[7] T. Kohonen, Essentials of the self-organizing map, Neural Network. 37 (2013) 52-65, https://doi.org/10.1016/j.neunet.2012.09.018. LK, https://rug.on.worldcat.org/oclc/820269958.

[8] M. Hasegawa, H. Makita, Y. Nasuhara, et al., Relationship between improved airflow limitation and changes in airway calibre induced by inhaled anticholinergic agents in COPD, Thorax 64 (2009) 332-338, https://doi.org/10.1136/thx.2008.103671.

[9] N. Tanabe, S. Muro, T. Oguma, et al., Computed tomography assessment of pharmacological lung volume reduction induced by bronchodilators in COPD, COPD 9 (2012) 401-408, https://doi.org/10.3109/15412555.2012.674986.
(both FEV₁ and RV) [8,9]. These findings are in line with our results.

The cluster analysis identified a responder group and we were interested whether we could find baseline predictors that identify these patients. We found that these patients had a significantly larger positive difference in FEV₁ and borderline in CAT between after washout of their inhaler therapy and with the regular use of inhaler therapy. During washout period, patients were not allowed to use LAMA drugs for at least 7 days (all washout requirements are shown in Table S4 in the online supplement). These results could indicate that better responders to LAMA or other pulmonary medication also better respond to TLD treatment.

To conclude, our results suggest that when the TLD treatment leads to an improvement in airway parameters, like airway wall thickness and lumen area, that this is associated with a favourable treatment response. Patients with a greater response to bronchodilators are the best responders.

## Author's contributions

JEH and DJS designed the analysis, wrote the first draft of the manuscript, and made revisions after feedback from co-authors. All the authors meet the definition of an author as stated by the International Committee of Medical Journal Editors, and all have seen and approved the final manuscript.

## Funding statement

The AIRFLOW-2 trial was funded by Nuvaira Inc, Minneapolis, MN, USA. The funding source had no involvement in this analysis or in the writing of this manuscript.

## Declaration of competing interest

DJS is a PI for Nuvaira, USA and reports consultancy fees from Nuvaira paid to the institution. AV reports speaker fees from Nuvaira in the past. PS reports clinical trial expenses reimbursed to the host institutions in the past 36 months. CP reports payments for lectures and to CHUGA to conduct phase 3 trials from Nuvaira (AIRFLOW 2 and 3

trials), GSK, AZ, Boehringer Ingelheim, Novartis and Chiesi. JH and FH have nothing to disclose.

## Acknowledgements

We would like to thank the Dutch Foundation for Asthma Prevention (Noorderlijke CARA stichting) for the grant we received which allowed us to purchase the software used for this analysis.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmed.2022.107059.

## References

[1] J.E. Hartman, J.L. Garner, P.L. Shah, et al., New bronchoscopic treatment modalities for patients with chronic bronchitis, Eur. Respir. Rev. (2021) 30, https://doi.org/10.1183/16000617.0281-2020.

[2] J. Hartman, F. Conway, B. Degano, et al., Rate of lung function decline slows in the 3 years after targeted lung denervation in COPD, Respir. Med. (2021) 188, https://doi.org/10.1016/j.rmed.2021.106604.

[3] C. Pison, P. Shah, D.-J. Slebos, et al., Safety of denervation following targeted lung denervation therapy for COPD: AIRFLOW-1 three-year outcomes, Respir. Res. 22 (2021).

[4] D.-J. Slebos, P.L. Shah, F.J. Herth, et al., Safety and adverse events after targeted lung denervation for symptomatic moderate to severe COPD (AIRFLOW): a multicenter randomized controlled trial, Am. J. Respir. Crit. Care Med. 200 (2019) 1477-1486, https://doi.org/10.1164/rccm.201903-0624oc.

[5] D.J. Slebos, K. Klooster, C.F. Koegelenberg, et al., Targeted lung denervation for moderate to severe COPD: a pilot study, Thorax 70 (2015) 411-419, https://doi.org/10.1136/thoraxjnl-2014-206146 [doi].

[6] T.T.A.-T.T.-. Kohonen, Self-Organizing Maps (2001), https://doi.org/10.1007/978-3-642-56927-2, LK, https://rug.on.worldcat.org/oclc/851768192.

[7] T. Kohonen, Essentials of the self-organizing map, Neural Network. 37 (2013) 52-65, https://doi.org/10.1016/j.neunet.2012.09.018. LK, https://rug.on.worldcat.org/oclc/820269958.

[8] M. Hasegawa, H. Makita, Y. Nasuhara, et al., Relationship between improved airflow limitation and changes in airway calibre induced by inhaled anticholinergic agents in COPD, Thorax 64 (2009) 332-338, https://doi.org/10.1136/thx.2008.103671.

[9] N. Tanabe, S. Muro, T. Oguma, et al., Computed tomography assessment of pharmacological lung volume reduction induced by bronchodilators in COPD, COPD 9 (2012) 401-408, https://doi.org/10.3109/15412555.2012.674986.