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Discordant diagnostic criteria for pneumonia in COPD trials: a review

Robert A. Wise, Mona Bafadhel, Courtney Crim, Gerard J. Criner, Nicola C. Day, David M.G. Halpin, MeiLan K. Han, Peter Lange, David A. Lipson, Fernando J. Martinez, Diego J. Maselli, Dawn Midwinter, Dave Singh, Maeva Zysman, Mark T. Dransfield, Richard E.K. Russell
European Respiratory Review 2021 30: 210124; DOI: 10.1183/16000617.0124-2021
Robert A. Wise
1Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Mona Bafadhel
2Nuffield Dept of Medicine, University of Oxford, Oxford, UK
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Courtney Crim
3Clinical Sciences – Respiratory, GSK, Research Triangle Park, NC, USA
18Affiliation at the time of writing
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Gerard J. Criner
4Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
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Nicola C. Day
5GlaxoSmithKline, GSK House, Brentford, UK
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David M.G. Halpin
6University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK
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MeiLan K. Han
7University of Michigan, Pulmonary & Critical Care, Ann Arbor, MI, USA
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Peter Lange
8Section of Epidemiology, Dept of Public Health, University of Copenhagen, Copenhagen, Denmark
9Medical Dept, Herlev and Gentofte Hospital, Herlev, Denmark
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David A. Lipson
10Clinical Sciences, GSK, Collegeville, PA, USA
11Pulmonary, Allergy and Critical Care Division, Dept of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Fernando J. Martinez
12New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY, USA
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Diego J. Maselli
13Dept of Medicine, University of Texas Health at San Antonio, San Antonio, TX, USA
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Dawn Midwinter
5GlaxoSmithKline, GSK House, Brentford, UK
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Dave Singh
14Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester, Manchester University NHS Foundation Hospital Trust, Manchester, UK
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Maeva Zysman
15Service des Maladies Respiratoires, CHU Bordeaux, Pessac, France
16Univ-Bordeaux, Centre de Recherche cardio-thoracique de Bordeaux, U1045, CIC 1401, Pessac, France
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Mark T. Dransfield
17Division of Pulmonary, Allergy, and Critical Care Medicine, Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA
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Richard E.K. Russell
2Nuffield Dept of Medicine, University of Oxford, Oxford, UK
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  • For correspondence: richard.russell@ndm.ox.ac.uk
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    FIGURE 1

    Flowchart describing study selection. ICS: inhaled corticosteroid.

  • FIGURE 2
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    FIGURE 2

    COPD trials by pneumonia capture methodology. Some trials included multiple pneumonia capture methodologies.

Tables

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  • TABLE 1

    Pneumonia incidence in identified COPD clinical trials, ordered by treatment comparison and pneumonia capture

    CitationStudy and study lengthStudy populationPneumonia capture method#Pneumonia incidence, % (n/N)¶Increased incidence of pneumonia versus comparator arm
    ICS armComparator armComparisonFold increase in risk+
    Studies comparing ICS/LAMA/LABA triple therapy with non-ICS-containing treatment
     Pneumonia capture: investigator reporting confirmed by radiographic imaging and independent adjudication
      Rabe, 2020 [14]ETHOS (52 weeks)Post-bronchodilator FEV1 25–50% pred and ≥1 moderate/severe exacerbation or post-bronchodilator FEV1 50–65% pred and ≥2 moderate or ≥1 severe exacerbation in the year prior to screening
    CAT total score ≥10
    Investigator reported, adjudicated by a clinical end-point independent committee
    Radiographic imaging compatible with the diagnosis of pneumonia, ≥2 of a list of clinical signs, symptoms or laboratory findings, and treatment with antibiotics and/or antiviral and/or antifungal agents were also required to support the adjudication
    BUD/GLY/FOR 320/18/9.6 µg twice daily: 4.2% (90/2144)
    BUD/GLY/FOR 160/18/9.6 µg twice daily: 3.5% (75/2124)
    BUD/FOR 320/9.6 µg twice daily: 4.5% (96/2136)
    GLY/FOR 18/9.6 µg twice daily: 2.3% (48/2125)BUD/GLY/FOR 320/18/9.6 µg versus GLY/FOR1.9
    BUD/GLY/FOR 160/18/9.6 µg versus GLY/FOR1.6
    BUD/FOR versus GLY/FOR2.0
      Ferguson, 2018    [26]KRONOS (24 weeks)Post-bronchodilator FEV1 ≥25% and <80% pred
    CAT total score ≥10
    Investigator reported, adjudicated by an independent committee
    Radiographic imaging compatible with the diagnosis of pneumonia, ≥2 of a list of clinical signs, symptoms or laboratory findings, and treatment with antibiotics and/or antiviral and/or antifungal agents were also required
    BUD/GLY/FOR 320/18/9.6 μg twice daily via MDI: 1.9% (12/639)
    BUD/FOR 320/9.6 μg twice daily via MDI: 1.9% (6/314)
    BUD/FOR 400/12 µg twice daily via DPI: 1.3% (4/318)
    GLY/FOR 18/9.6 μg twice daily via MDI: 1.6% (10/625)BUD/GLY/FOR versus GLY/FOR1.2
    BUD/FOR 320/9.6 µg via MDI versus GLY/FOR1.2
    BUD/FOR 400/12 µg via DPI versus GLY/FOR0.8
     Pneumonia capture: investigator reporting confirmed by radiographic imaging
      Chapman, 2018    [27]SUNSET (26 weeks)Post-bronchodilator FEV1 ≥40% and <80% pred
    ≤1 moderate/severe exacerbation in the year prior to screening
    Investigator reported
    Radiographic imaging was required to confirm the diagnosis of pneumonia
    TIO 18 µg once daily plus SAL/FP 50/500 µg twice daily: 1.7% (9/526)IND/GLY 110/50 µg once daily: 1.1% (6/527)TIO+SAL/FP versus IND/GLY1.5
      Lipson, 2018   [13]IMPACT (52 weeks)Post-bronchodilator FEV1 <50% pred with ≥1 moderate/severe exacerbation in the year prior to screening, or post-bronchodilator FEV1 50–80% pred and ≥2 moderate or ≥1 severe exacerbation in the year prior to screening
    CAT total score ≥10
    Investigator reported
    Radiographic imaging was required to confirm the diagnosis of pneumonia
    FF/UMEC/VI 100/62.5/25 µg once daily: 7.6% (317/4151)
    FF/VI 100/25 µg once daily: 7.1% (292/4134)
    UMEC/VI 62.5/25 µg once daily: 4.7% (97/2070)FF/UMEC/VI versus UMEC/VI1.6
    FF/VI versus UMEC/VI1.5
      Magnussen,   2014 [28]WISDOM (52 weeks)Post-bronchodilator FEV1 <50% pred
    ≥1 exacerbation in the year prior to screening
    Investigator reported
    Radiographic imaging was requested when pneumonia was suspected
    FP/SAL/TIO (500 µg twice daily/50 µg twice daily/18 µg once daily): 5.8% (72/1243)SAL/TIO (50 µg twice daily/18 µg once daily): 5.5% (68/1242)FP/SAL/TIO versus SAL/TIO1.1
     Pneumonia capture: investigator reporting
      Papi, 2018 [12]TRIBUTE (52 weeks)Post-bronchodilator FEV1 <50% pred
    ≥1 moderate/severe exacerbation in the year prior to screening
    CAT total score ≥10
    Investigator reportedBDP/FOR/GLY 87/5/9 µg twice daily: 3.7% (28/764)IND/GLY 85/43 µg: 3.6% (27/768)BDP/FOR/GLY versus IND/GLY1.0
      Vestbo, 2017   [29]TRINITY (52 weeks)Post-bronchodilator FEV1 <50% pred
    ≥1 moderate/severe exacerbation in the year prior to screening
    CAT total score ≥10
    Investigator reportedBDP/FOR/GLY 100/6/12.5 µg (2 actuations twice daily): 2.6% (28/1077)
    BDP/FOR 100/6 µg (2 actuations twice daily)+TIO 18 µg (1 actuation once daily): 2.2% (12/537)
    TIO 18 µg once daily: 1.8% (19/1076)BDP/FOR/GLY versus TIO1.5
    BDP/FOR+TIO versus TIO1.3
      Jung, 2012 [30](24 weeks)Post-bronchodilator FEV1 <65% predInvestigator reportedTIO 18 µg once daily+FP/SAL 250/50 µg twice daily: 0.9% (2/223)TIO 18 µg once daily: 0.9% (2/232)TIO+FP/SAL versus TIO1.0
    Studies comparing ICS/LABA dual therapy with non-ICS-containing treatment
     Pneumonia capture: investigator reporting and independent adjudication with/without confirmation by radiographic imaging
      Hanania, 2020   [31]SOPHOS (52 weeks)Post-bronchodilator FEV1 ≥25% and <80% pred
    ≥1 moderate/severe exacerbation in the year prior to screening
    CAT total score ≥10
    Investigator reported, adjudicated by an independent committeeBUD/FOR 320/10 µg twice daily: 1.6% (10/619)
    BUD/FOR 160/10 µg twice daily: 2.4% (15/617)
    FOR 10 µg twice daily: 2.3% (14/607)BUD/FOR 320/10 µg versus FOR
    BUD/FOR 160/10 µg versus FOR
    0.7
    1.1
      Ferguson, 2018    [32]TELOS (24 weeks)Post-bronchodilator FEV1 <80% pred
    CAT total score ≥10
    Investigator reported, adjudicated by an independent committee
    Radiographic imaging compatible with the diagnosis of pneumonia, ≥2 of a list of clinical signs, symptoms or laboratory findings, and treatment with antibiotics and/or antiviral and/or antifungal agents were also required
    BUD/FOR 320/10 μg twice daily via MDI: 0.8% (5/655)
    BUD/FOR 160/10 μg twice daily via MDI: 1.1% (7/637)
    BUD 320 µg twice daily via MDI: 0.5% (1/206)
    BUD/FOR 400/12 µg twice daily via DPI: 1.4% (3/219)
    FOR 10 µg twice daily via MDI: 1.4% (9/644)BUD/FOR 320/10 μg versus FOR0.5
    BUD/FOR 160/10 μg versus FOR0.8
    BUD versus FOR0.3
    BUD/FOR 400/12 µg via DPI versus FOR1.0
     Pneumonia capture: investigator reporting confirmed by radiographic imaging
      Ferguson, 2017   [33]RISE (26 weeks)Post-bronchodilator FEV1 ≤70% pred
    ≥1 moderate/severe exacerbation in the year prior to screening
    mMRC dyspnoea score ≥2
    Investigator reported
    Radiographic imaging compatible with the diagnosis of pneumonia and ≥2 of a list of clinical signs, symptoms or laboratory findings were also required
    BUD/FOR 320/9 µg twice daily: 0.5% (3/605)FOR DPI 9 µg twice daily: 1.0% (6/613)BUD/FOR versus FOR0.5
      Papi, 2017 [24]EFFECT (52 weeks)Post-bronchodilator FEV1 ≤50% pred
    ≥1 moderate/severe exacerbation in the year prior to screening
    Investigator reported
    Radiologically and/or clinically confirmed per British Thoracic Society criteria
    FP/FOR 500/20 μg twice daily: 2.9% (17/587)
    FP/FOR 250/10 μg twice daily: 3.9% (23/588)
    FOR 12 µg twice daily: 1.9% (11/590)FP/FOR 500/20 μg versus FOR1.6
    FP/FOR 250/10 μg versus FOR2.1
      Wedzicha, 2016   [34]FLAME (52 weeks)Post-bronchodilator FEV1 ≥25 to <60% pred
    ≥1 moderate/severe exacerbation in the year prior to screening
    mMRC dyspnoea score ≥2
    Investigator reported
    Radiographic imaging was required
    FP/SAL 500/50 µg twice daily: 4.8% (80/1680)IND/GLY 110/50 µg once daily: 3.2% (53/1678)FP/SAL versus IND/GLY1.5
      Ohar, 2014 [35]NCT01110200 (26 weeks)Post-bronchodilator FEV1 <70% pred
    Recent exacerbation (≤14 days)
    Investigator reported
    Radiographic imaging was required
    FP/SAL 250/50 µg twice daily: 4.1% (13/314)SAL 50 µg twice daily: 3.1% (10/325)FP/SAL versus SAL1.3
      Vogelmeier,   2013 [36]ILLUMINATE (26 weeks)Post-bronchodilator FEV1 40–80% pred
    0 moderate/severe exacerbations in the year prior to screening
    Investigator reported
    Radiographic imaging was required
    FP/SAL 500/50 µg twice daily: 1.5% (4/264)IND/GLY 110/50 µg once daily: 0 (0/258)
      Anzueto, 2009   [10]NCT00115492 (52 weeks)Post-bronchodilator FEV1 ≤50% pred
    ≥1 moderate/severe exacerbation in the year prior to screening
    Investigator reported
    Radiographic imaging was required
    FP/SAL 250/50 µg twice daily: 6.6% (26/394)SAL 50 µg twice daily: 2.5% (10/403)FP/SAL versus SAL2.7
     Pneumonia capture: investigator reporting
      Suissa, 2018   [37]Up to 1-year follow-upCohort of patients aged ≥55 years with COPD initiating treatment with a LAMA or ICS/LABA during 2002–2015 from the UK's Clinical Practice Research DatalinkHospital admissions due to severe pneumonia (according to diagnostic codes)ICS/LABA: 3.1% (380/12 366)LAMA: 2.3% (279/12 366) of patientsICS/LABA versus LAMA1.4
      Vestbo, 2016   [38],   Crim, 2017   [39]SUMMIT (event driven, common end date of 3 years)Post-bronchodilator FEV1 ≥50% and ≤70% pred
    History or increased risk of cardiovascular disease
    mMRC dyspnoea score ≥2
    Investigator reportedFF/VI 100/25 µg once daily: 5.7% (237/4140)
    FF 100 µg once daily: 5.5% (228/4157)
    VI 25 µg once daily: 3.9% (163/4140)
    Placebo: 5.2% (214/4131)
    FF/VI versus VI1.5
    FF versus placebo1.1
      Vestbo, 2016   [40]Salford Lung Study (52 weeks)≥1 COPD exacerbations in the previous 3 yearsInvestigator reported pneumonia SAEsFF/VI 100/25 µg once daily: 6.7% (94/1396)Usual care: 5.9% (83/1403)FF/VI 100/25 µg versus usual care1.1
      Vogelmeier,   2016 [41]AFFIRM (24 weeks)Post-bronchodilator FEV1 <80% pred
    CAT total score ≥10
    Investigator reportedFP/SAL 500/50 µg twice daily: 1.9% (9/466)ACL/FOR 400/12 µg twice daily: 0.6% (3/467)FP/SAL versus ACL/FOR3.2
      Zheng, 2015   [42]NCT01376245 (24 weeks)Asian patients
    Post-bronchodilator FEV1 ≤70% pred
    mMRC dyspnoea score ≥2
    Investigator reportedFF/VI 50/25 µg: 1.3% (2/160)
    FF/VI 100/25 µg: 0.6% (1/161)
    FF/VI 200/25 µg: 3.1% (5/160)
    Placebo: 2.5% (4/162)FF/VI 50/25 µg versus placebo0.5
    FF/VI 100/25 µg versus placebo0.3
    FF/VI 200/25 µg versus placebo1.3
      Zhong, 2015   [43]LANTERN (26 weeks)Post-bronchodilator FEV1 ≥30% and <80% pred
    ≤1 moderate/severe exacerbation in the year prior to screening
    mMRC dyspnoea score ≥2
    Investigator reportedFP/SAL 500/50 µg: 2.7% (10/369)IND/GLY 110/50 µg: 0.8% (3/372)FP/SAL versus IND/GLY3.4
      Rossi, 2014   [44]INSTEAD (26 weeks)GOLD stage II
    0 moderate/severe exacerbation in the year prior to screening
    Investigator-reported pneumonia SAEsFP/SAL 500/50 µg twice daily: 0.7% (2/288)IND 150 µg once daily: 0 (0/293)FP/SAL versus IND
      Wedzicha, 2014   [45]FORWARD (48 weeks)Post-bronchodilator FEV1 ≥30% and <50% pred
    ≥1 moderate/severe exacerbation in the year prior to screening
    Investigator reportedBDP/FOR 200/12 µg twice daily: 3.8% (23/601)FOR 12 µg twice daily: 1.8% (11/596)BDP/FOR versus FOR2.1
      Dransfield,   2013 [46],   Crim, 2015   [47]NCT01009463, NCT01017952 (52 weeks)Post-bronchodilator FEV1 <70% pred
    ≥1 moderate/severe exacerbation in the year prior to screening
    Investigator reportedFF/VI 200/25 µg once daily: 6.8% (55/811)
    FF/VI 100/25 µg once daily: 6.3% (51/806)
    FF/VI 50/25 µg once daily: 5.9% (48/820)
    VI 25 µg once daily: 3.3% (27/818)FF/VI 50/25 µg versus VI1.8
    FF/VI 100/25 µg versus VI1.9
    FF/VI 200/25 µg versus VI2.1
      Kerwin, 2013   [48]NCT01053988 (24 weeks)Post-bronchodilator FEV1 ≤70% pred
    mMRC dyspnoea score ≥2
    Investigator reportedFF/VI 100/25 µg once daily: 2.4% (5/206)
    FF/VI 50/25 µg once daily: 1.5% (3/206)
    FF 100 µg once daily: 1.9% (4/206)
    VI 25 µg once daily: 2.4% (5/205)
    Placebo: 1.4% (3/207)
    FF/VI 100/25 µg versus VI1.0
    FF/VI 50/25 µg versus VI0.6
    FF versus placebo1.3
      Martinez, 2013   [49]NCT01054885 (24 weeks)Post-bronchodilator FEV1 ≤70% pred
    mMRC dyspnoea score ≥2
    Investigator reportedFF/VI 200/25 µg once daily: 2.0% (4/205)
    FF/VI 100/25 µg once daily: 0.5% (1/204)
    FF 200 µg once daily: 1.5% (3/203)
    FF 100 µg once daily: 1.0% (2/204)
    VI 25 µg once daily: 1.0% (2/203)
    Placebo: 0 (0/205)
    FF/VI 200/25 µg versus VI2.0
    FF/VI 100/25 µg versus VI0.5
    FF 200 µg versus VI1.5
    FF 100 µg versus VI1.0
      Doherty, 2012   [50](52 weeks)Post-bronchodilator FEV1 25–60% pred
    Symptoms of COPD for ≥24 months prior to enrolment
    Investigator reportedMF/FOR 400/10 µg twice daily: 3.1% (7/225)
    MF/FOR 200/10 µg twice daily: 1.7% (4/239)
    MF 400 µg twice daily: 2.0% (5/253)
    FOR 10 µg twice daily: 1.6% (4/243)
    Placebo: 0.8% (2/236)
    MF/FOR 400/10 µg versus FOR1.9
    MF/FOR 200/10 µg versus FOR1.0
    MF versus placebo2.3
      Tashkin, 2012   [51]NCT00383435 (52 weeks)Post-bronchodilator FEV1 ≥25% and ≤60% pred
    Symptoms of COPD for ≥24 months
    Investigator reportedMF/FOR 400/10 µg twice daily: 1.8% (4/217)
    MF/FOR 200/10 µg twice daily: 0.5% (1/207)
    MF 400 µg twice daily: 1.0% (2/210)
    FOR 10 µg twice daily: 1.9% (4/209)MF/FOR 400/10 µg versus FOR1.0
    MF/FOR 200/10 µg versus FOR0.3
    MF versus FOR0.5
      Sharafkhaneh,   2012 [52]NCT00419744 (52 weeks)Pre-bronchodilator FEV1 ≤50% pred
    ≥1 moderate/severe exacerbation in the year prior to screening
    Investigator reportedBUD/FOR 320/9 µg twice daily: 6.4% (26/407)
    BUD/FOR 160/9 µg:
    4.7% (19/408)
    FOR 9 µg twice daily: 2.7% (11/403)BUD/FOR 320/9 µg versus FOR2.3
    BUD/FOR 160/9 µg versus FOR1.7
      Calverley, 2010   [53]NCT00476099 (48 weeks)Post-bronchodilator FEV1 30–50% pred
    ≥1 moderate/severe exacerbation in the year prior to screening
    Investigator reportedBDP/FOR 200/12 µg twice daily: 2.2% (5/232)
    BUD/FOR 400/12 µg twice daily: 2.9% (7/238)
    FOR 12 µg twice daily: 0.4% (1/233)BDP/FOR versus FOR5.0
    BUD/FOR versus FOR6.9
      Rennard, 2009   [54]NCT00206167 (52 weeks)Post-bronchodilator FEV1 ≤50% pred
    ≥1 moderate/severe exacerbation in the year prior to screening
    mMRC dyspnoea score ≥2
    Investigator reportedBUD/FOR 320/9 µg twice daily: 4.0% (20/494)
    BUD/FOR 160/9 µg twice daily: 3.4% (17/494)
    FOR 9 µg twice daily: 3.4% (17/495)
    Placebo: 5.0% (24/481)
    BUD/FOR 320/9 µg versus FOR1.2
    BUD/FOR 160/9 µg versus FOR1.0
      Ferguson, 2008   [11]NCT00144911 (52 weeks)Post-bronchodilator FEV1 ≤50% pred
    ≥1 moderate/severe exacerbation in the year prior to screening
    Investigator reportedFP/SAL 250/50 µg twice daily: 7.4% (29/394)SAL 50 µg twice daily: 3.9% (15/388)FP/SAL versus SAL1.9
      Tashkin, 2008   [55]NCT00206154 (26 weeks)Pre-bronchodilator FEV1 ≤50% pred
    ≥1 moderate/severe exacerbation in the year prior to screening
    mMRC dyspnoea score ≥2
    Investigator reportedBUD/FOR 320/9 µg twice daily: 0.4% (1/277)
    BUD/FOR 160/9 µg twice daily: 0.7% (2/281)
    BUD 320 µg twice daily+FOR 9 µg twice daily: 0.7% (2/287)
    BUD 320 µg twice daily: 1.1% (3/275)
    FOR 9 µg twice daily: 0.4% (1/284)
    Placebo: 0.3% (1/300)
    BUD/FOR 320/9 µg versus FOR1.0
    BUD/FOR 160/9 µg versus FOR2.0
    BUD 320 µg+FOR 9 µg versus FOR2.0
    BUD versus placebo3.3
      Wedzicha, 2008   [56],   Calverley,   2011 [57]INSPIRE (2 years)Post-bronchodilator FEV1 <50% pred, mMRC dyspnoea score ≥2, clinical history of exacerbationsInvestigator reportedFP/SAL 500/50 µg twice daily: 7.6% (50/658)TIO 18 µg once daily: 3.6% (24/665)FP/SAL versus TIO2.1
      Calverley, 2007   [58],   Crim, 2009   [59]TORCH (3 years) (pneumonia incidences from a post hoc analysis focusing on pneumonia are reported here)Pre-bronchodilator FEV1 <60% predInvestigator reportedFP 500 µg twice daily: 14.4% (224/1552)
    FP/SAL 500/50 µg twice daily: 16.0% (248/1546)
    SAL 50 µg twice daily: 10.5% (162/1542)
    Placebo: 9.0% (139/1544)
    FP/SAL versus SAL1.5
    FP versus placebo1.6

    ICS: inhaled corticosteroid; LAMA: long-acting muscarinic antagonist; LABA: long-acting β2-agonist; FEV1: forced expiratory volume in 1 s; CAT: COPD Assessment Test; BUD: budesonide; GLY: glycopyrronium; FOR: formoterol; MDI: metered-dose inhaler; DPI: dry powder inhaler; TIO: tiotropium; SAL: salmeterol; FP: fluticasone propionate; FF: fluticasone furoate; UMEC: umeclidinium; VI: vilanterol; BDP: beclomethasone dipropionate; mMRC: modified Medical Research Council; SAE: serious adverse event; ACL: aclidinium; IND: indacaterol; GOLD: Global Initiative for Chronic Obstructive Lung Disease; MF: mometasone furoate. #: when a study uses different sets of criteria to define pneumonia and reports different pneumonia incidences when using these different criteria, only the pneumonia incidence for the most stringent pneumonia capture method is reported. The corresponding method is summarised in the “pneumonia capture method” column; ¶: N is the total number of patients in the subgroup of interest, n the number of patients with events; +: fold increase calculated as (incidence in treatment arm of interest)/(incidence in comparator arm).

    • TABLE 2

      Pneumonia incidence determined by clinical end-point committee

      Study and treatment groupPatients, nPneumonia events submitted to clinical end-point committee, n (%)Pneumonia events confirmed by clinical end-point committee, n (%)
      ETHOS [14]
       BUD/GLY/FOR (160/18/9.6 µg)2124100 (4.7)75 (3.5)
       BUD/GLY/FOR (320/18/9.6 µg)2144115 (5.4)90 (4.2)
       BUD/FOR (320/9.6 µg)2136118 (5.5)96 (4.5)
       GLY/FOR (18/9.6 µg)212566 (3.1)48 (2.3)
      KRONOS [26]
       BUD/GLY/FOR (320/18/9.6 µg; via MDI)63916 (2.5)12 (1.9)
       BUD/FOR (320/9.6 µg; via MDI)3147 (2.2)6 (1.9)
       BUD/FOR (400/12 µg; via DPI)3186 (1.9)4 (1.3)
       GLY/FOR (18/9.6 µg; via MDI)62511 (1.8)10 (1.6)

      BUD: budesonide; GLY: glycopyrronium; FOR: formoterol; MDI: metered dose inhaler; DPI: dry powder inhaler.

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      Discordant diagnostic criteria for pneumonia in COPD trials: a review
      Robert A. Wise, Mona Bafadhel, Courtney Crim, Gerard J. Criner, Nicola C. Day, David M.G. Halpin, MeiLan K. Han, Peter Lange, David A. Lipson, Fernando J. Martinez, Diego J. Maselli, Dawn Midwinter, Dave Singh, Maeva Zysman, Mark T. Dransfield, Richard E.K. Russell
      European Respiratory Review Dec 2021, 30 (162) 210124; DOI: 10.1183/16000617.0124-2021

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      Discordant diagnostic criteria for pneumonia in COPD trials: a review
      Robert A. Wise, Mona Bafadhel, Courtney Crim, Gerard J. Criner, Nicola C. Day, David M.G. Halpin, MeiLan K. Han, Peter Lange, David A. Lipson, Fernando J. Martinez, Diego J. Maselli, Dawn Midwinter, Dave Singh, Maeva Zysman, Mark T. Dransfield, Richard E.K. Russell
      European Respiratory Review Dec 2021, 30 (162) 210124; DOI: 10.1183/16000617.0124-2021
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      • Article
        • Abstract
        • Abstract
        • Introduction
        • Methods
        • Differences in pneumonia capture and reporting
        • Distinguishing between pneumonia and COPD exacerbations
        • Differences in study design and population characteristics
        • Towards a standardised definition of pneumonia for COPD clinical trials
        • Conclusions
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