BPCO Una Condizione Eterogenea

8/18/2019 BPCO Una Condizione Eterogenea

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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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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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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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• Introduction

• Heterogeneity of COPD patients:

COPD phenotypes


•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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• Introduction




• 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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• Introduction


•

Heterogeneity of COPD exacerbations


• 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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• Introduction


•

Heterogeneity of COPD exacerbations


• 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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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.



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according to GOLD stage

Lange P. et al, AJRCCM 2012.


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