1 COPD Phenotypes Stephen I Rennard University of Nebraska Florianopolis, Brazil October 2009

1

COPD PhenotypesCOPD Phenotypes

Stephen I RennardUniversity of Nebraska

Florianopolis, BrazilOctober 2009

COPD Phenotypes: Studies

• ECLIPSE N= 2,165• COPDgene N= 10,000• SPIROMICS N= 3,200• Others

““COPD HETEROGENEITY”COPD HETEROGENEITY”PT # 1PT # 158 y58 yFEV1: 28 %FEV1: 28 %

PT # 2PT # 262 y62 yFEV1: 33%FEV1: 33%

PT # 3PT # 369 y69 yFEV1: 35%FEV1: 35%

PT # 4PT # 472 y72 yFEV1: 34%FEV1: 34%

Cote & Celli

““COPD HETEROGENEITY”COPD HETEROGENEITY”PT # 1PT # 158 y58 yFEV1: 28 %FEV1: 28 %MRC: 2/4MRC: 2/4PaO2: 70 mmHgPaO2: 70 mmHg6MWD: 540 mt6MWD: 540 mtBMI: 30BMI: 30

PT # 2PT # 262 y62 yFEV1: 33%FEV1: 33%MRC: 2/4MRC: 2/4PaO2: 57 mmHgPaO2: 57 mmHg6MWD: 400 m6MWD: 400 mBMI: 21BMI: 21



Cote & Celli

BODE Index ScoringBODE Index ScoringCelli et al. New Engl. J. Med. 350: 1005, 2004

““COPD HETEROGENEITY”COPD HETEROGENEITY”PT # 1PT # 158 y58 yFEV1: 28 %FEV1: 28 %MRC: 2/4MRC: 2/4PaO2: 70 mmHgPaO2: 70 mmHg6MWD: 540 mt6MWD: 540 mtBMI: 30BMI: 30SCORESCORE: 33

PT # 2PT # 262 y62 yFEV1: 33%FEV1: 33%MRC: 2/4MRC: 2/4PaO2: 57 mmHgPaO2: 57 mmHg6MWD: 400 m6MWD: 400 mBMI: 21BMI: 21SCORE: 6SCORE: 6



Cote & Celli

COPD is a Collection of Syndromes/Diseases

• Many little COPDs

• COPD = ∑ (copd)n John Reillyn=1n=1

??

Lessons From Breast Cancer: Better with Sub-phenotyping

• Predict prognosis: homogeneous

• Assess treatments: smaller numbers

• Implement treatments: smaller numbers needed to treat

Breast Cancer PhenotypesBreast Cancer PhenotypesDiaz et al. Adv. Anat. Pathol. 14: 419, 2007

Triple Negative Breast Cancers

Breast Cancer 1Basal Phenotype

Breast Cancer PhenotypesBreast Cancer PhenotypesDiaz et al. Adv. Anat. Pathol. 14: 419, 2007

Triple Negative Breast Cancers

Breast Cancer 1Basal Phenotype

Breast Cancer: Breast Cancer: Molecular Phenotype and PrognosisMolecular Phenotype and Prognosis

Rakha et al. Cancer 109: 25, 2007

•1726 cases•Phenotype

•Estrogen receptor•Progesterone receptor•HER2

•Triple negative = 282 (16.3%)•Overall survival





Neutrophils in Bronchial LavageNeutrophils in Bronchial LavageThompson et al. Am. Rev. Resp. Dis. 140: 1527, 1989

Neutrophils in Bronchial Lavage: predictor

• Research subjects

• Lung function• Bronchoscopy • Bronchial lavage

(first 20 ml aliquot)

• Follow up• 41 subjects• Mean 11.4

years• Lung function• Induced sputum

Hepp et al.

-50 -25 0 25 50 75 100 125 150 175

10

20

30

40

50

Decline in FEV1 (ml/year)

Bronchial PMNs (%)at first visit) p =0.0119

r2 =0.1514

• 162 subjects• FEV1/FVC < 0.7• FEV1 40-80%

predicted• <10% and <200 ml

increase after BD

• Randomize: placebo vs. salmeterol/fluticasone (50/500)

• Induced sputum• Biopsy

Anti-inflammatory Effects of Salmeterol/Fluticasone Propionate in

Chronic Obstructive Pulmonary DiseaseBarnes, N. et al. Am. J. Res. Crit Care Med. 173: 736, 2006

Anti-inflammatory Effects of Salmeterol/Fluticasone Propionate in

Chronic Obstructive Pulmonary Disease

n = 59 n = 50> 10% reduction 6 (10%) 19 (38%)> 35% reduction 2 (3%) 5 (10%)

Barnes, N. et al. Am. J. Res. Crit Care Med. 173: 736, 2006

Magnitude Control Sal/flutic

Neutrophils in Bronchial LavageNeutrophils in Bronchial LavageThompson et al. Am. Rev. Resp. Dis. 140: 1527, 1989

New Therapies: What are we doing?New Therapies: What are we doing?

Roflumilast Improves FEV1 in COPD Patients

* p < .0001 vs placebo.PlaceboRoflumilast 250 µgRoflumilast 500 µg

Time, weeks

LS

mea

n d

iffe

ren

ce

in

po

st-b

ron

cho

dil

ato

r F

EV

1 (T

las

t), m

L * *

Endpoint-50-50

-25-25

00

2525

5050

7575

100100

00 44 88 1212 1616 2020 2424

* * * ** *

**

* *

* p < 0.03 vs placebo

*

97 mL 97 mL

74 mL 74 mL

Placebo

Roflumilast250 µg

Roflumilast 500 µg

*

Rabe et al. Lancet 366: 563, 2005

Effect of Roflumilast in COPD: 1 year trial

• COPD• Smokers, ex-smokers• FEV1 < 50%

• Outcome• FEV1• Exacerbations

• Moderate exacerbations = change in medications

• Severe = hospitalization

00

0.250.25

0.50.5

0.750.75

11Moderate or Severe ExacerbationsModerate or Severe Exacerbations

Systemic steroidsSystemic steroids

RoflumilastRoflumilastPlaceboPlacebo

AllAll

p=0.451p=0.451

p=0.183p=0.183

Calverley et al. Am. J. Resp. Crit. Care Med. 176: 154, 2007

Effect of Roflumilast in COPD: 1 year trials

• COPD• Smokers, ex-smokers• FEV1 < 50%• Chronic cough and

sputum• At least one

exacerbation requiring systemic glucocorticoids or hospitalization in the previous year

• Outcome• Moderate exacerbations

= systemic glucocorticoids


Calverley et al. Lancet 374: 685, 2009








0

0.5

1

1.5

M2-124 M2-125


p=0.0278p=0.0278

p=0.0035p=0.0035

Moderate or Severe ExacerbationsModerate or Severe Exacerbations









0

0.5

1

1.5

M2-124 M2-125


p=0.0240p=0.0240p=0.0055p=0.0055

Exacerbations: Glucocorticoids or Exacerbations: Glucocorticoids or AntibioticsAntibiotics






Research Activity: Disease and Phenotyping


Medline Papers

Cancer Breast Cancer COPD100

1000

10000

100000

1000000

10000000

2,262,114

201,112

26,278


Medline Papers

Cancer Breast Cancer COPD100

1000

10000

100000

1000000

10000000

Cancer Breast Cancer COPD

Medline Phenotype Papers

2,262,114

201,112

26,278

57,389

5,601

363

COPD is a Collection of Syndromes/Diseases

• Many little COPDs

• COPD = ∑ (copd)n John Reillyn=1n=1

??

Defining COPD subsets:Defining COPD subsets:natural historynatural historytreatmenttreatment

Documents

1 COPD Phenotypes Stephen I Rennard University of Nebraska Florianopolis, Brazil October 2009