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The sputum transcriptome better predicts COPD exacerbations after the withdrawal of inhaled corticosteroids than sputum eosinophils

Benedikt Ditz, Aartik Sarma, Huib A.M. Kerstjens, Jeroen J.W. Liesker, Erik Bathoorn, Judith M. Vonk, Victor Bernal, Peter Horvatovich, Victor Guryev, Saharai Caldera, Chaz Langelier, Alen Faiz, Stephanie A. Christenson, Maarten van den Berge
ERJ Open Research 2021 7: 00097-2021; DOI: 10.1183/23120541.00097-2021
Benedikt Ditz
1Dept of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
2University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands
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Aartik Sarma
3University of California, San Francisco, CA, USA
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Huib A.M. Kerstjens
1Dept of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
2University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands
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  • ORCID record for Huib A.M. Kerstjens
Jeroen J.W. Liesker
1Dept of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
2University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands
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Erik Bathoorn
4Dept of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Judith M. Vonk
2University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands
5Dept of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Victor Bernal
6Dept of Analytical Biochemistry, Groningen Research Institute of Pharmacy, Groningen, The Netherlands
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Peter Horvatovich
6Dept of Analytical Biochemistry, Groningen Research Institute of Pharmacy, Groningen, The Netherlands
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Victor Guryev
7European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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  • ORCID record for Victor Guryev
Saharai Caldera
8Division of Infectious Diseases, Dept of Medicine, University of California, San Francisco, CA, USA
9Chan Zuckerberg Biohub, San Francisco, CA, USA
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Chaz Langelier
8Division of Infectious Diseases, Dept of Medicine, University of California, San Francisco, CA, USA
9Chan Zuckerberg Biohub, San Francisco, CA, USA
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Alen Faiz
1Dept of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
2University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands
10University of Technology Sydney, Respiratory Bioinformatics and Molecular Biology (RBMB), School of Life Sciences, Sydney, Australia
11These authors contributed equally
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Stephanie A. Christenson
3University of California, San Francisco, CA, USA
11These authors contributed equally
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Maarten van den Berge
1Dept of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
2University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands
11These authors contributed equally
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  • For correspondence: m.van.den.berge@umcg.nl
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  • FIGURE 1
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    FIGURE 1

    Differential gene expression of sputum RNA-sequencing data. a) Volcano-plot of differentially expressed genes concerning time to exacerbation after inhaled corticosteroid (ICS) withdrawal (false discovery rate <0.1). Blue and red dots represent differentially expressed genes with negative and positive log2 fold change, respectively. b) Heat map of differentially expressed genes. Subjects were clustered according to time to exacerbation (days; log2 transformed). c–e) Spearman correlation testing comparing the enrichment score of PRISE #1 with the c) time to exacerbation, d) sputum eosinophil counts (log10), and e) macrophage cell counts (log10).

  • FIGURE 2
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    FIGURE 2

    Cumulative hazard plots of risk of exacerbations. PRISE #1 enrichment scores are stratified by tertiles. The first tertile served as the reference for second and third tertiles. HR: hazard ratio. *: p<0.05.

  • FIGURE 3
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    FIGURE 3

    Bayesian network model predicting exacerbation phenotype. The binary exacerbation phenotype is based on “time to exacerbation” (dichotomised (> or < mean) into early (n=20) versus late/nonexacerbators (n=23)). Colour coding represents genes that were part of PRISE #1 and #2.

Tables

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  • TABLE 1

    Baseline participant clinical and demographic characteristics

    Number of patients43
    Current/former smokers23/20
    Number of exacerbations38
    Males/females36/7
    Number of exacerbations in the past 12 months)
     019
     117
     ≥27
    Age (years)64.5 (59.4–70.8)
    Smoking history (pack-years)38.0 (25.5–53.0)
    Body mass index (kg·m−2)25.9 (23.6–28.0)
    Daily dose of ICS (µg)#800 (500–1000)
    Pre-study treatment regimen
     ICS¶8
     ICS+LABA¶30
     ICS+LAMA¶2
     ICS+LAMA+LABA¶3
    Post-bronchodilator lung function
     FEV1 (% pred)64.1 (52.0–76.1)
     FEV1/FVC0.52 (0.44–0.56)
     TLC (% pred)112.1 (105.9–122.0)
     RV (% pred)135.5 (124.9–158.5)
     RV/TLC (% pred)114.9 (103.4–127.4)
    Baseline inflammatory characteristics
     Sputum cells
      Eosinophils (%)1.8 (0.7–4.0)
      Neutrophils (%)72.8 (67.0–80.3)
      Macrophages (%)18.0 (13.4–25.3)
      Lymphocytes (%)0.7 (0.1–1.2)
      Bronchial epithelial cells (%)2.0 (0.65–3.55)
     Sputum supernatant proteins
      ECP (µg·L−1)194.0 (58.6–718.0)
      LTB4 (ng·mL−1)0.49 (0.28–1.21)

    Data are presented as n or median (interquartile range). ICS: inhaled corticosteroid; LABA: long-acting β-agonist; LAMA: long-acting muscarinic antagonist; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; TLC: total lung capacity; RV: residual volume; ECP: eosinophilic cationic protein; LTB4: leukotriene-B4. #: daily dose of ICS calculated for indexed budesonide equivalent; ¶: additional short-acting β-agonist and/or short-acting muscarinic antagonist as needed.

    • TABLE 2

      Monovariate Cox regression hazard ratios

      Hazard ratio (95% CI)p-valueGeneralised R2
      History of exacerbations1.5 (1–2.1)0.046*0.08
      Season of ICS withdrawal (not in November, December or January#)0.3 (0.13–0.68)0.004*0.152
      Sex (male)0.31 (0.13–0.78)0.012*0.12
      Smoking status (current smoker)0.68 (0.36–1.30)0.240.03
      Pack-years smoking ≥38¶0.49 (0.25–0.96)0.038*0.095
      Sputum eosinophils ≥3%+2.3 (1.1–4.6)0.021*0.11
      % Sputum eosinophils (stratified by tertiles)
       Second tertile (N=15)1.4 (0.62–3.2)0.420.124
       Third tertile (N=15)2.8 (1.17–6.5)0.02*
      PRISE #1 (ES stratified by tertiles)
       Second tertile§ (N=13)2.3 (0.99–5.2)0.0520.202
       Third tertile§ (N=15)3.7 (1.57–8.5)0.003*

      ICS: inhaled corticosteroid; ES: enrichment score. #: dichotomised as “outside” versus “in” the period; ¶: dichotomised using the median value at baseline; +: dichotomised ≥3% (N=15), <3% (N=28). §: compared to the first tertile. *: p<0.05.

      • TABLE 3

        Multiple linear Cox regression including either sputum eosinophils or PRISE #1

        Hazard ratio (95% CI)p-valueGeneralised R2
        Sputum eosinophils
         History of exacerbations1.40 (0.97–2.03)0.0710.377
         Sex (male)0.33 (0.13–0.85)0.022*
         Season of ICS withdrawal (not in November, December, or January#)0.36 (0.15–0.88)0.025*
         Pack-years smoking ≥38¶0.70 (0.3301.46)0.337
         Sputum eosinophils ≥3%+2.24 (1.09–4.58)0.027*
        PRISE #1
         History of exacerbations1.53 (1.03–2.28)0.0350.495
         Sex (male)0.47 (0.17–1.28)0.14
         Season of ICS withdrawal (not in November, December, or January#)0.27 (0.10–0.69)0.006*
         Pack-years smoking ≥38¶0.50 (0.22–1.15)0.105
         PRISE #1 (ES stratified by tertiles)
          Second tertile (N=13)2.59 (1.11–6.05)0.027*
          Third tertile (N=15) 5.35 (2.12–13.47)<0.001*

        ICS: inhaled corticosteroid; ES: enrichment score. #: dichotomised as “outside” versus “in” the period; ¶: dichotomised using the median value at baseline; +: dichotomised as ≥3% (N=15) or <3% (N=28). *: p<0.05.

        • TABLE 4

          ICS sensitivity of PRISE #1 and #2 genes in SYMBEXCO and independent RNA-sequencing dataset

          GeneSYMBEXCO: ICS treatment → no ICS (8 weeks)Independent RNA-seq dataset: no ICS → ICS treatment (8 weeks)
          Log2 fold changeNominal p-valueLog2 fold changeNominal p-value
          CLC (PRISE #1)0.76<0.01*−2.880.01*
          LGALS12 (PRISE #1)0.520.01*−1.520.01*
          CD24 (PRISE #1)0.300.04*NANA
          ALOX15 (PRISE #1)0.420.04*−1.17<0.01*
          EMR4P (PRISE #1)0.220.13−0.630.16
          IL1RL1 (PRISE #1)0.150.36−1.320.03*
          ALG3 (PRISE #2)−0.020.85−0.490.02*
          CCDC152 (PRISE #2)−0.020.910.270.16
          SEPP1 (PRISE #2)0.010.96−0.220.08

          ICS: inhaled corticosteroid. *: p<0.05.

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            Supplementary material 00097-2021.SUPPLEMENT

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          The sputum transcriptome better predicts COPD exacerbations after the withdrawal of inhaled corticosteroids than sputum eosinophils
          Benedikt Ditz, Aartik Sarma, Huib A.M. Kerstjens, Jeroen J.W. Liesker, Erik Bathoorn, Judith M. Vonk, Victor Bernal, Peter Horvatovich, Victor Guryev, Saharai Caldera, Chaz Langelier, Alen Faiz, Stephanie A. Christenson, Maarten van den Berge
          ERJ Open Research Jul 2021, 7 (3) 00097-2021; DOI: 10.1183/23120541.00097-2021

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          The sputum transcriptome better predicts COPD exacerbations after the withdrawal of inhaled corticosteroids than sputum eosinophils
          Benedikt Ditz, Aartik Sarma, Huib A.M. Kerstjens, Jeroen J.W. Liesker, Erik Bathoorn, Judith M. Vonk, Victor Bernal, Peter Horvatovich, Victor Guryev, Saharai Caldera, Chaz Langelier, Alen Faiz, Stephanie A. Christenson, Maarten van den Berge
          ERJ Open Research Jul 2021, 7 (3) 00097-2021; DOI: 10.1183/23120541.00097-2021
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