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COPD heterogeneityGuy Brusselle, MD, PhD
Dept Respiratory Medicine
University Hospital Ghent
GHENT, BELGIUM
Firenze, 21/02/2013
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COPD heterogeneity: overview
• Introduction
• Heterogeneity of COPD patients
• Heterogeneity of COPD exacerbations
• Heterogeneity of COPD cohorts
• Conclusion
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Heterogeneity of COPD: phenotypes
1)Male, 60 y:
FEV1: 70%
CAT: 112 exac./last year
R/ AB
Bronchiectasis
2) Female, 65 y:
FEV1: 49%
CAT: 25No exacerbations
Depression
3) Male, 70 y:
FEV1: 33%
CAT: 223 exac./last year
R/ OCS
Ischemic CMP
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(C)
(B)(A)
(D)
Symptoms(mMRC or CAT score)
R i s k
( E x a c e r b a t i o n h i s t o r y )
S p i r o m e
t r y
( G O L D
C l a s s i f i c a t i o n o f A
i r f l o w
L i m i t a t i o n )
1
2
3
4
0
1
≥ 2
mMRC < 2
CAT < 10
mMRC ≥ 2
CAT ≥ 10
Management of COPD according to Symptoms, Spirometric
classification and Future Risk of Exacerbations
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Heterogeneity of COPD: phenotypes
1)Male, 60 y:
FEV1: 70%
CAT: 11
2 exac./last year
R/ AB
Bronchiectasis
GOLD: D
2) Female, 65 y:
FEV1: 49%
CAT: 25
No exacerbations
Depression
GOLD: D
3) Male, 70 y:
FEV1: 33%
CAT: 26
3 exac./last year
R/ OCS
Ischemic CMP
GOLD: D
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1) ICS +
LABA or
LAAC
2) LAAC +
LABA
LAAC or
LABA
SAAC or
SAAB
SOS
1) ICS +LABA or
LAAC
2) ICS +
LABA +
LAAC
Symptoms(mMRC or CAT score)
R i s k
( E x a c e r b a t i o n h i s t o r y )
S p i r o m e
t r y
( G O L D
C l a s s i f i c a t i o n o f A
i r f l o w
L i m i t a t i o n )
1
2
3
4
0
1
≥ 2
mMRC < 2
CAT < 10
mMRC ≥ 2
CAT ≥ 10
Management of COPD according to Symptoms, Spirometric
classification and Future Risk of Exacerbations
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Heterogeneity of COPD: phenotypes
1)Male, 60 y:
FEV1: 70%
CAT: 11
2 exac./last year
R/ AB
Bronchiectasis
GOLD: D
2) Female, 65 y:
FEV1: 49%
CAT: 25
No exacerbations
Depression
GOLD: D
3) Male, 70 y:
FEV1: 33%
CAT: 26
3 exac./last year
R/ OCS
Ischemic CMP
GOLD: D
R/ Same Treatment to all three patients ? despite different phenotypes and comorbidities:
R/ ICS + LABA or LAMA or ICS + LABA + LAMA ?
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__________________ ________________
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COPD heterogeneity: overview
• Introduction
• Heterogeneity of COPD patients:
COPD phenotypes
• Heterogeneity of COPD exacerbations
•Heterogeneity of COPD cohorts
• Conclusion
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COPD phenotypes
1. Frequent exacerbators versus never-exacerbators
2. Airway- versus emphysema-predominant COPD
3. COPD in never-smokers versus smokers
4. Biomarkers / Genetics (α1-AT deficiency)
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Emphysema
Parenchymal destructionLoss of alveolar attachments
Decrease of elastic recoil
Small airways diseaseAirway inflammation
Airway remodeling
AIRFLOW LIMITATION
GOLD 2001
INFLAMMATION
Bronchiolitis
www.goldcopd.orgPathogenesis of COPD
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COPD patient heterogeneity
“Blue Bloater”: chronic bronchitis “Pink Puffer”: emphysema
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COPD patients: heterogeneity
Blue Bloater: chronic bronchitisComorbidities: cor pulmonale,
OSAS R/ nasal CPAP; rehabilitation
Pink Puffer: emphysemaComorbidities: osteoporosis,
muscle weakness R/ rehabilitation
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FEV1 = 35% PredictedandSevere Emphysema
FEV1 = 35% PredictedandTrivial Emphysema
HRCT / Spirometry: (lack of) Correlation
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COPD in non-smokers
Salvi S. and Barnes P., Lancet 2009.
________________________________________ __________________________
________________________________
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Proportion of COPD patients who are non-smokers
S. Salvi and P. Barnes, Lancet 2009.
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Incidence according to age,
gender and smoking behaviour
Age-specific incidence of COPD in women
0
4
8
12
16
20
24
55-59 60-64 65-69 70-74 75-79 >=80
Age categories
I n c i d e n c e
/ 1 0 0 0
p e r s o n -
y e a r s
Inc idence in women Inc idence in female non-smokers Inc idence in female smokers
Y. van Durme et al, Chest 2009;135:368-77.
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COPD heterogeneity: overview
• Introduction
• Heterogeneity of COPD patients
• Heterogeneity of COPD exacerbations
• Heterogeneity of COPD cohorts
• Conclusion
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The ‘frequent exacerbator phenotype’: Frequency/Severity of Exacerbations by GOLD stage
Hurst J. et al, NEJM 2010; 363: 1128-38.
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The ‘frequent exacerbator phenotype’:
ECLIPSE: Stability of the Exacerbator Phenotype
74% of patients having no exacerbations in Years 1 and 2 had
no exacerbations in Year 3Hurst JR, et al. N Engl J Med. 2010;363:1128-38.ECLIPSE 3 year data
71% of Frequent Exacerbators in Years 1 and 2 were Frequent
Exacerbators in Year 3
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The ‘frequent exacerbator phenotype’: ECLIPSEFrequency/Severity of Exacerbations by GOLD stage
Hurst JR, et al. N Engl J Med. 2010;363:1128-38.ECLIPSE 1 year data
• Exacerbation rates increased with GOLD stage,
irrespective of severity of exacerbation.
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Acute exacerbations of COPD: heterogeneity
Bafadhel M. et al, AJRCCM 2011; 184: 662-671.
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Distribution of bacteria in
normal and diseased airways
M. Hilty et al,
Plos One 2010; 5: e8578.
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Vicious-circle hypothesis of
infection and inflammation in COPD
S. Sethi and T. Murphy, NEJM 2008; 359: 2355-65.
PAMPsDAMPs
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Azithromycin prevents exacerbations in COPD
Albert R. et al, NEJM 2011; 689-98.
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Azithromycin prevents exacerbations in patients with
non-CF bronchiectasis
Wong C. et al, Lancet 2012; 380: 660-667. EMBRACE study.
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______________
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ICS in COPD: risk of pneumonias
Suissa S., Thorax 2012.
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Acute exacerbations of COPD: heterogeneity
Bafadhel M. et al, AJRCCM 2011; 184: 662-671.
R/ AZI
R/ ICS
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COPD heterogeneity: overview
• Introduction
• Heterogeneity of COPD patients
•
Heterogeneity of COPD exacerbations
• Heterogeneity of COPD cohorts
• Conclusion
H i f h di
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Heterogeneity of cohort studies
ECLIPSE study Rotterdam Study
Setting Clinic-based3 years FU
Population-based22 years FU
CareSecondary and
tertiary care
Primary (and secondary)
care
Subjects
N: 2.180
Smokers (ex)
Prevalent COPD
N = 15.000 (N: 1.700)
Non-, ex-, smokers
Incident COPD
Comorbid. Self-reported Physician-diagnosed
External
validityModerate High
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ECLIPSE: Secondary / tertiary care
Inclusion Criteria
Vestbo J. et al. Eur Respir J. 2008;31:869-873.
COPD Smoking Controls Non-SmokingControls
Male/female subjects aged
40 –75 years
Male/female subjects aged 40 –75 years, who are free
from significant disease as determined by history, physical
examination and screening investigations
Baseline post-bronchodilator FEV1 of
85% pred. andFEV1/FVC of >0.7
Current or ex-smokers with
a smoking history of ≥10 pack years
Non-smokers with a
smoking history of
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The ‘frequent exacerbator phenotype’: Frequency/Severity of Exacerbations by GOLD stage
Hurst J. et al, NEJM 2010; 363: 1128-38.
ECLIPSE study
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Risk factors for COPD exacerbations
Hurst J. et al, NEJM 2010; 363: 1128-38.
Chronic bronchitis? 1.04
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Severity / frequency of COPD exacerbations
according to GOLD stage
Lahousse L. et al; submitted.
Ch i b hiti i i k f t f th f t
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Chronic bronchitis is a risk factor for the frequent
exacerbator COPD phenotype
Lahousse L. et al, Rotterdam Study, submitted.
*
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COPD heterogeneity: overview
• Introduction
• Heterogeneity of COPD patients
•
Heterogeneity of COPD exacerbations
• Heterogeneity of COPD cohorts
• Conclusion
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COPD heterogeneity: conclusion
•
COPD patients are heterogeneous: – Frequent vs never exacerbator
– Airway vs emphysema-predominant COPD
– Comorbidities
• COPD exacerbations are heterogeneous: – Bacterial / neutrophilic
– Viral and/or eosinophilic
•
COPD cohorts are heterogeneous: – Population-based cohorts (Rotterdam; Copenhagen)
– Clinic-based cohorts (e.g. ECLIPSE)
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Heterogeneity of COPD: conclusion
• Long-acting bronchodilators (LABA and/or LAMA) are
mainstay treatment of COPD.
• Additional therapies (e.g. rehabilitation; ICS,
azithro, PDE4 inhibitors …) in COPD according tophenotype: – Exacerbation history (heterogeneity!)
– Airway- or emphysema-predominant COPD
– Comorbidities
– Biomarkers / Genetics.
S i f O di S i
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SABA ± SAAC SOS
Maintenance:
LAMAor
LABA
Maintenance:
LAMA
andLABA
Maintenance:LAMA
and
LABA
Plus:
1) ICS
and/or
2) AZI
or
3) Roflumilast?
Smoking cessation
Vaccination(influenza)
Patient education
Self-management
Pulmonaryrehabilatation:if mMRC ≥ 2
Oxygen therapy:
if PaO2 < 60 mmHgSTEP 1
Spiro 1 or 2
mMRC < 2
No exac
STEP 2
Spiro 1 or 2
mMRC ≥ 2
≤ 1 exac
STEP 3
Spiro 3 or 4
≤ 1 exac
STEP 4
Spiro 2, 3 or 4
mMRC ≥ 2
≥ 2 exac
Reliever:SABA
or
SAMA
Stepwise treatment of COPD according to Severity:
spirometry, symptoms, exacerbations
Brusselle G., personal opinion.
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Heterogeneity of COPD: phenotypes
1)Male, 60 y:
FEV1: 70%
CAT: 11
2 exac./last year
R/ ABBronchiectasis
R/ LAMA (step 2)
+ Azithromycin
+ Physiotherapy
2) Female, 65 y:
FEV1: 49%
CAT: 25
No exacerbations
Depression
R/ LAMA + LABA
(step 3)
3) Male, 70 y:
FEV1: 33%
CAT: 26
3 exac./last year
R/ OCS
Ischemic CMP
R/ Triple therapy
(step 4)+ Pulm rehab.
ACKNOWLEDGMENTS: Lab for Translational Research of
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Obstructive Pulmonary Disease
Guy Brusselle
Guy Joos
Karim VermaelenKen Bracke
Tania Maes
Sharen Provoost
Lies LahousseIngel Demedts
Geert Van Pottelberge
Yannick v an Durme
Eliane Castrique
Ann Neesen
Indra De Borle
Philippe De Gryze
Katleen De Saedeleer
Marie-Rose Mouton
Greet Barbier
Anouck Goethals
Christelle Snauwaert
Department of Respiratory Medicine
Ghent University, Ghent, Belgium
Leen Seys
Griet Conickx
Fien VerhammeLisa Dupont
Ellen Lanckacker
Tine Demoor
Nele Pauwels
An D’Hulst
Chris Van Hove
Katrien Moerloose
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Prof Dr B Stricker
Prof Dr A Hofman
Prof A Uitterlinden
Prof C Van DuijnProf H Hoogsteden
Dr A Ikram
Dr M Vernooij
Dr J Heeringa
Dr L Lahousse
Dr Y van Durme
Dr D Loth
Dr J AertsDr K Verhamme
Dr M Eijgelsheim
Lic F van Rooij
Mevr J verkroost
And all other colleagues and researchers at
the Erasmus University / Ommoord research centre (ERGO);
the CHARGE consortium: ARIC, CHS, FHS and RS.
Acknowledgments
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The spectrum of asthma and COPD
ASTHMA COPD
Severity
Control
Phenotype
Severity
Risk
PhenotypeComorbidities
*: included in trials (RCTs)
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Asthma and COPD spectrum: therapeutic implications
ASTHMA COPD
allergen avoidance smoking cessation
patient education rehabilitationself-management
Severity
Control
Phenotype
Severity
Activity
Phenotype
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COPDGene Study: Chronic bronchitis is a risk factor for
frequent exacerbations in COPD
Kim V. et al, Chest 2011.
Severity / frequency of COPD exacerbations
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Severity / frequency of COPD exacerbations
according to GOLD stage
Lange P. et al, AJRCCM 2012.
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