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Does the use of inhaled corticosteroids in asthma benefit lung function in the long-term? A systematic review and meta-analysis

Daniel J. Tan, Din S. Bui, Xin Dai, Caroline J. Lodge, Adrian J. Lowe, Paul S. Thomas, Deborah Jarvis, Michael J. Abramson, E. Haydn Walters, Jennifer L. Perret, Shyamali C. Dharmage
European Respiratory Review 2021 30: 200185; DOI: 10.1183/16000617.0185-2020
Daniel J. Tan
1Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Australia
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Din S. Bui
1Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Australia
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Xin Dai
1Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Australia
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Caroline J. Lodge
1Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Australia
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Adrian J. Lowe
1Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Australia
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Paul S. Thomas
2Faculty of Medicine, University of New South Wales, Randwick, Australia
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Deborah Jarvis
3National Health and Lung Institute, Imperial College London, London, UK
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Michael J. Abramson
4School of Public Health & Preventive Medicine, Monash University, Melbourne, Australia
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E. Haydn Walters
1Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Australia
5School of Medicine, University of Tasmania, Tasmania, Australia
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Jennifer L. Perret
1Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Australia
6Institute for Breathing and Sleep, Melbourne, Australia
7Equal senior authors
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Shyamali C. Dharmage
1Allergy and Lung Health Unit, Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Australia
7Equal senior authors
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  • For correspondence: s.dharmage@unimelb.edu.au
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Figures

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  • FIGURE 1
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    FIGURE 1

    PRISMA flow diagram for the study selection process. ICS: inhaled corticosteroid.

  • FIGURE 2
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    FIGURE 2

    Cochrane Collaboration Tool (randomised controlled trials): risk of bias assessments for each included study.

  • FIGURE 3
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    FIGURE 3

    Forest plot comparison (randomised controlled trials): change in pre-bronchodilator forced expiratory volume in 1 s (% predicted) stratified by age. ICS: inhaled corticosteroid.

  • FIGURE 4
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    FIGURE 4

    Forest plot comparison (randomised controlled trials): change in post-bronchodilator forced expiratory volume in 1 s (% predicted) stratified by age. ICS: inhaled corticosteroid.

Tables

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  • TABLE 1

    Study characteristics of the included randomised controlled trials

    First author [ref.]Age groupDuration yearsAsthma definitionAsthma severityICS interventionSample sizeMean age yearsFemale %Pre-BD FEV1
    L% pred
    Beasley [17]Adults1Physician-diagnosed asthma; treatment with SABA only last 3 monthsMildBudesonide 200 µg twice daily#22534.95790.3
    No placebo (open-label)22335.85189.2
    Becker [18]Children1Physician-diagnosed asthma; ≥6 months of symptoms, FEV1 >75% predMildBeclomethasone 200µg twice daily¶1197.632.81.3991.3
    Placebo, twice daily1217.734.71.4292.0
    Boulet [19]Adults1Physician-diagnosed asthma; BHR and FEV1 >70% predMildFluticasone 100–250µg daily#352754.23.5597.2
    Placebo daily342669.73.3398.5
    den Otter [20]Adults2Symptoms typical of asthma; BHR or BDR; FEV1 decline ≥80 mL·year−1No restrictionFluticasone 250 µg daily#23
    Placebo daily22
    Jonasson [21]Children2.3Physician-diagnosed asthma; ≥1 exacerbation in last 12 months or ≥3 exacerbations everMildBudesonide 200 µg daily#3210.046.92.23102.1
    Placebo daily349.435.32.04104.6
    Juniper [22]Adults1Physician-diagnosed asthma; BHR and FEV1 >70% predNo restrictionBudesonide 200 µg twice daily#1642.462.589.9
    Placebo twice daily1635.156.392.1
    Merkus [23]Children2–3Physician-diagnosed asthma; BHR and FEV1 55–90% pred or FEV1/FVC 50–75% predModerate-severeBudesonide 100 µg three times daily¶3411.462.972.2
    Placebo three times daily2010.976.773.5
    O'Byrne [24]Mostly adults1Physician-diagnosed asthma; BHRMildBudesonide 200 µg twice daily#128239.062.284.2
    Placebo, twice daily127740.060.484.1
    Osterman [25]Adults1Physician-diagnosed asthma diagnosed within the last year; BHRNo restrictionBudesonide 200 µg twice daily#3833.057.93.3193.1
    Placebo twice daily3735.054.13.2388.7
    Pauwels [3]Adults and children3Physician-diagnosed asthma; recent onset ≤2 years; variable airflow limitationMildBudesonide 200–400 µg daily#359724.054.286.3
    Placebo daily356824.054.086.6
    Simons [26]Children1Physician-diagnosed asthma; BHR and BDR and FEV1>70% predMildBeclomethasone 200 µg twice daily¶819.641.01.8992.0
    Placebo twice daily809.545.01.8896.0
    Tonascia [27]Children4.3Physician-diagnosed asthma; BHRMild-moderateBudesonide 200 µg twice daily¶3119.041.893.6
    Placebo, twice daily4189.044.094.2
    Ward [12]Adults1Physician-diagnosed asthma; positive skin prick testing to ≥3 common aeroallergensMild-moderateFluticasone 750 µg twice daily+1796.0
    Placebo twice daily1894.0

    ICS: inhaled corticosteroid; BD: bronchodilator; FEV1: forced expiratory volume in 1 s; SABA: short-acting β2-agonist; BHR: bronchial hyperresponsiveness; BDR: bronchodilator reversibility; FVC: forced vital capacity. #: low-dose ICS; ¶: medium-dose ICS; +: high-dose ICS.

    • TABLE 2

      Meta-analysis of randomised controlled trials for pre-bronchodilator (BD) outcomes stratified by age group

      Outcome or subgroupStudies nParticipants nStatistical methodEffect estimatep-valueI2GRADE
      ΔPre-BD FEV1 % pred88332MD (Random, 95% CI)2.22 (1.32–3.12)<0.000141%Moderate#
       Adults54181MD (Random, 95% CI)2.47 (1.64–3.29)<0.00010%High
       Children44151MD (Random, 95% CI)2.08 (0.71–3.44)0.00364%Moderate#
      ΔPre-BD FEV1 mL43603MD (Random, 95% CI)74.14 (54.47–93.81)<0.000187%Moderate#
       Adults22634MD (Random, 95% CI)108.82 (84.40–133.23)<0.00010%High
       Children2969MD (Random, 95% CI)10.00 (−23.21–43.21)0.560%Moderate#
      ΔPre-BD FEV1 SMD1011131SMD (Random, 95% CI)0.21 (0.12–0.30)<0.000168%Moderate#
       Adults66740SMD (Random, 95% CI)0.28 (0.15–0.41)<0.000163%Moderate#
       Children54391SMD (Random, 95% CI)0.16 (0.04–0.28)0.00860%Moderate#
      ΔPre-BD FVC % pred2804MD (Fixed, 95% CI)0.10 (−1.23–1.43)0.880%Moderate#
       Adults175MD (Fixed, 95% CI)2.30 (−2.29–6.89)0.33Low#,¶
       Children1729MD (Fixed, 95% CI)−0.10 (−1.49–1.29)0.89Low#,¶
      ΔPre-BD FVC mL2804MD (Random, 95% CI)−12.84 (−149.33–123.65)0.8553%Moderate#
       Adults175MD (Random, 95% CI)90.00 (−100.51–280.51)0.35Low#,¶
       Children1729MD (Random, 95% CI)−60.00 (−124.87–4.87)0.07Low¶,¶
      ΔPre-BD FVC SMD2804SMD (Fixed, 95% CI)0.01 (−0.13–0.15)0.860%Moderate#
       Adults175SMD (Fixed, 95% CI)0.23 (−0.23–0.68)0.33Low#,¶
       Children1729SMD (Fixed, 95% CI)−0.01 (−0.16–0.14)0.89Low#,¶
      ΔPre-BD FEV1/FVC % pred00MD (Fixed, 95% CI)
       Adults00MD (Fixed, 95% CI)
       Children00MD (Fixed, 95% CI)
      ΔPre-BD FEV1/FVC ratio1729MD (Fixed, 95% CI)1.60 (0.64–2.56)0.001Moderate#
       Adults00MD (Fixed, 95% CI)
       Children1729MD (Fixed, 95% CI)1.60 (0.64–2.56)0.001Moderate#
      ΔPre-BD FEV1/FVC SMD1729SMD (Fixed, 95% CI)0.25 (0.10–0.39)0.001Moderate#
       Adults00SMD (Fixed, 95% CI)
       Children1729SMD (Fixed, 95% CI)0.25 (0.10–0.39)0.001Moderate#

      FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; MD: mean difference; SMD: standardised mean difference. #: GRADE score downgraded for heterogeneity or inconsistency of results between studies; ¶: GRADE score downgraded for imprecision, 95% CI includes important benefit and potential harm.

      • TABLE 3

        Meta-analysis of randomised controlled trials for post-bronchodilator (BD) outcomes stratified by age group

        Outcome or subgroupStudies nParticipants nStatistical methodEffect estimatep-valueI2GRADE
        ΔPost-BD FEV1 % pred27894MD (Random, 95% CI)0.61 (−0.31–1.54)0.1971%Moderate#
         Adults13970MD (Random, 95% CI)1.54 (0.87–2.21)<0.0001Moderate#
         Children23924MD (Random, 95% CI)0.20 (−0.49–0.90)0.5712%High
        ΔPost-BD FEV1 mL1729MD (Fixed, 95% CI)−40.00 (−115.38–35.38)0.30Moderate#
         Adults00MD (Fixed, 95% CI)
         Children1729MD (Fixed, 95% CI)−40.00 (−115.38–35.38)0.30Moderate#
        ΔPost-BD FEV1 SMD28894SMD (Random, 95% CI)0.06 (−0.03–0.15)0.1869%Moderate#
         Adults13970SMD (Random, 95% CI)0.14 (0.08–0.21)<0.0001Moderate#
         Children24924SMD (Random, 95% CI)0.02 (−0.05–0.09)0.5715%High
        ΔPost-BD FVC % pred1729MD (Fixed, 95% CI)−0.20 (−1.40–1.00)0.74Low#,¶
         Adults00MD (Fixed, 95% CI)
         Children1729MD (Fixed, 95% CI)−0.20 (−1.40–1.00)0.74Low#,¶
        ΔPost-BD FVC mL1729MD (Fixed, 95% CI)−60.00 (−119.99– −0.03)0.05Low#,¶
         Adults00MD (Fixed, 95% CI)
         Children1729MD (Fixed, 95% CI)−60.00 (−119.99– −0.03)0.05Low#,¶
        ΔPost-BD FVC SMD1729SMD (Fixed, 95% CI)−0.02 (−0.17–0.13)0.77Low#,¶
         Adults00SMD (Fixed, 95% CI)
         Children1729SMD (Fixed, 95% CI)−0.02 (−0.17–0.13)0.77Low#,¶
        ΔPost-BD FEV1/FVC % pred00MD (Fixed, 95% CI)
         Adults00MD (Fixed, 95% CI)
         Children00MD. (Fixed, 95% CI)
        ΔPost-BD FEV1/FVC ratio1729MD (Fixed, 95% CI)0.70 (−0.08–1.48)0.08Low#,¶
         Adults00MD (Fixed, 95% CI)
         Children1729MD (Fixed, 95% CI)0.70 (−0.08–1.48)0.08Low#,¶
        ΔPost-BD FEV1/FVC SMD1729SMD (Random, 95% CI)0.13 (−0.01–0.28)0.07Low#,¶
         Adults00SMD (Random, 95% CI)
         Children1729SMD (Random, 95% CI)0.13 (−0.01–0.28)0.07Low#,¶

        FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; MD: mean difference; SMD: standardised mean difference. #: GRADE score downgraded for heterogeneity or inconsistency of results between studies; ¶: GRADE score downgraded for imprecision, 95% CI includes important benefit and potential harm.

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        Does the use of inhaled corticosteroids in asthma benefit lung function in the long-term? A systematic review and meta-analysis
        Daniel J. Tan, Din S. Bui, Xin Dai, Caroline J. Lodge, Adrian J. Lowe, Paul S. Thomas, Deborah Jarvis, Michael J. Abramson, E. Haydn Walters, Jennifer L. Perret, Shyamali C. Dharmage
        European Respiratory Review Mar 2021, 30 (159) 200185; DOI: 10.1183/16000617.0185-2020

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        Does the use of inhaled corticosteroids in asthma benefit lung function in the long-term? A systematic review and meta-analysis
        Daniel J. Tan, Din S. Bui, Xin Dai, Caroline J. Lodge, Adrian J. Lowe, Paul S. Thomas, Deborah Jarvis, Michael J. Abramson, E. Haydn Walters, Jennifer L. Perret, Shyamali C. Dharmage
        European Respiratory Review Mar 2021, 30 (159) 200185; DOI: 10.1183/16000617.0185-2020
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