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Exhaled volatile organic compounds and lung microbiome in COPD: a pilot randomised controlled trial

Divya Mohan, Holly R. Keir, Hollian Richardson, David Mayhew, Joseph Boyer, Marc P. van der Schee, Max D. Allsworth, Bruce E. Miller, Ruth Tal-Singer, James D. Chalmers
ERJ Open Research 2021 7: 00253-2021; DOI: 10.1183/23120541.00253-2021
Divya Mohan
1GSK R&D, Collegeville, PA, USA
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  • ORCID record for Divya Mohan
Holly R. Keir
2Ninewells Clinical Research Centre, University of Dundee, Dundee, UK
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Hollian Richardson
2Ninewells Clinical Research Centre, University of Dundee, Dundee, UK
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David Mayhew
1GSK R&D, Collegeville, PA, USA
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Joseph Boyer
1GSK R&D, Collegeville, PA, USA
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Marc P. van der Schee
3Owlstone Medical, Cambridge, UK
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Max D. Allsworth
3Owlstone Medical, Cambridge, UK
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Bruce E. Miller
1GSK R&D, Collegeville, PA, USA
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Ruth Tal-Singer
1GSK R&D, Collegeville, PA, USA
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James D. Chalmers
2Ninewells Clinical Research Centre, University of Dundee, Dundee, UK
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  • For correspondence: j.chalmers@dundee.ac.uk
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  • FIGURE 1
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    FIGURE 1

    Consolidated Standards of Reporting Trials diagram for trial participants. The “primary completer” population was defined via subjects who provided “good”- or “acceptable”-quality sputum samples (based on percentage of squamous cells and viable leukocytes) at baseline and day 14. The primary completer population was used for sputum neutrophil extracellular traps (NETs) analyses, but the entire study population was used for the microbiome analysis. VOC: volatile organic compound.

  • FIGURE 2
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    FIGURE 2

    Changes in lung microbiome composition and bacterial load during study. a) (Shannon-) α-diversity showed no significant differences by treatment group (p=0.858, Wilcoxon rank-sum test) using pooled samples across visits between treatment groups. b) Changes in relative abundance of Proteobacteria (including Haemophilus) during the study. No significant differences in a linear mixed-effects (LME) model (using the patient as a random effect) were observed between danirixin (n=12) and placebo (n=5) groups (p=0.174). c) No significant differences in bacterial load as measured via 16S quantitative PCR between danirixin and placebo groups were observed (p=0.8551, LME). d,e) Overall microbiome composition was similar between danirixin and placebo groups at the d) phylum and e) genus levels.

  • FIGURE 3
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    FIGURE 3

    Joint-effects model to evaluate predictive ability of volatile organic compounds (VOCs) for Haemophilus influenzae relative abundance. Plot of predicted values for joint-effects model for VOCs against the measured values of Haemophilus relative abundance. Each point represents the predicted and measured value for a single sample at the screening visit (n=31). The dashed line represents the line for a perfect model.

  • FIGURE 4
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    FIGURE 4

    Individual volatile organic compounds (VOCs) ordered by correlation with Haemophilus influenzae relative abundance, percentage sputum neutrophils and sputum neutrophil extracellular traps (NETs) area as measured by gas chromatography mass spectrometry (GC-MS). Individual VOCs or molecular features of interest (MFs), measured by GC-MS, ordered by correlation against a) Haemophilus influenzae relative abundance; b) percentage sputum neutrophils; and c) sputum NET area. MF 78 has strongest correlation with Haemophilus influenzae relative abundance; MFs 65, 57 and 11 with percentage sputum neutrophils; and MFs 50, 43, 8 and 63 with sputum NET area, showing overall lack of overlap between VOCs that may relate to host microbiome, sputum neutrophils and sputum NETs.

Tables

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  • TABLE 1

    Baseline demographics of trial participants

    PlaceboDanirixin
    Participants514
    Age, years62±665±7
    Male/female2/36/8
    White/Caucasian/European514
    Current smoker, %20434320
    Smoking history, pack-years48±1344±19
    Body mass index, kg·m−230.927.1
    FEV1, L2.49±0.641.94±0.71
    FEV1, % predicted79.1±7.569.5±18.4
    FVC, L4.07±1.163.34±1.17
    FEV1/FVC0.62±0.080.59±0.08
    CAT score17.0±1.0017.3±5.97
    Medications
     Long-acting muscarinic antagonist3 (60)9 (64)
     Short-acting β2-agonist4 (80)8 (57)
     Inhaled corticosteroid3 (60)6 (43)
     Long-acting β2-agonist3 (60)9 (64)
     Systemic corticosteroid01 (7)
     Anti-infectives01 (7)

    Data are presented as n, mean±sd or n (%), unless otherwise stated. FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; CAT: COPD Assessment Test.

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    Exhaled volatile organic compounds and lung microbiome in COPD: a pilot randomised controlled trial
    Divya Mohan, Holly R. Keir, Hollian Richardson, David Mayhew, Joseph Boyer, Marc P. van der Schee, Max D. Allsworth, Bruce E. Miller, Ruth Tal-Singer, James D. Chalmers
    ERJ Open Research Oct 2021, 7 (4) 00253-2021; DOI: 10.1183/23120541.00253-2021

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    Exhaled volatile organic compounds and lung microbiome in COPD: a pilot randomised controlled trial
    Divya Mohan, Holly R. Keir, Hollian Richardson, David Mayhew, Joseph Boyer, Marc P. van der Schee, Max D. Allsworth, Bruce E. Miller, Ruth Tal-Singer, James D. Chalmers
    ERJ Open Research Oct 2021, 7 (4) 00253-2021; DOI: 10.1183/23120541.00253-2021
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