current status & future mission for chronic ... · & future mission for chronic...

Current status & future mission

for chronic obstrutive airway diseases (COAD) in Asia

Sang-Do Lee, M.D., Ph.D.Division of Pulmonary & Critcal Care Med

Asan Medical CenterCollege of Med, Univ. of Ulsan

Concept of Heterogeneity in COAD- Why is it important ?- Is it a real phenomenon ?- Dose it have clinical relevance ?

How to solve the problems related to heterogeneity

Data from ANOLD (2008-)

Contents

Percent Change in Age-Adjusted Death Rates

U.S., 1965-1998

00

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0Proportion of 1965 RateProportion of 1965 Rate

0.0

0.5

1.0

1.5

2.0

2.5

3.0

1965 - 19981965 - 1998 1965 - 19981965 - 1998 1965 - 19981965 - 1998 1965 - 19981965 - 1998 1965 - 19981965 - 1998

–59%–59% –64%–64% –35%–35% +163%+163% –7%–7%

CoronaryHeartDisease

CoronaryHeartDisease

StrokeStroke Other CVDOther CVD COPDCOPD All OtherCausesAll OtherCauses

airflow obstruction due to chronic bronchitis or emphysema

DEFINITION

Air flow obstructionprogressive, may be accompanied by airway hyperreactivity, and may be partially reversible. (ATS Statement, 1995)

- A common preventable and treatable disease

- Characterized by persistent airflow limitation that is usually progressive

- Associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases

- Exacerbations and comorbidities contribute to the overall severity in individual patients

(GOLD 2011)

DEFINITION Of COPD

“Can we modify the natural course of COPD ?”

- Summary -

Clinically meaningful, but statistically equivocal effect on mortality (TORCH)Statistically significant, but clinically equivocal effect on annual FEV1 decline(UPLIFT, TORCH)Clinically significant effect on exacerbationCurrent clinical trials show promising evidences, but not optimal

airflow obstruction due to chronic bronchitis or emphysema

DEFINITION

Air flow obstructionprogressive, may be accompanied by airway hyperreactivity, and may be partially reversible. (ATS Statement, 1995)

COPDClinicalPhenotypes

Petty TL, Pul Pharm Thera2002;15:341

Concept of Heterogeneity in COAD- Why is it important ?- Is it a real phenomenon ?- Dose it have clinical relevance ?

How to solve the problems related to heterogeneity

Data from ANOLD (2008-)

Contents

Three phenotypes of obstructive lung disease

in the elderly - Cluster Analysis -

KOLD Study Group

Jo et. al., Int J Tuberc Resp Dis, 2010;14(11):1481-1488

Subjects

• Inclusion191 subjects older than 60 years– had chronic respiratory symptom(s) AND – obstructive spirometry

• Exclusion–tuberculous destroyed lung–Bronchiectasis–lung resection, etc.

Factor AnalysisÜFind “key variables”ÜCluster AnalysisÜFind “phenotypes of OLD”

Methods

- Variables related to medical history, physical examination, and QOL

Factor analysis

(1) Modified MRC score (2) History of wheezing in past 1 year (3) BMI (4) Smoking history (pack years)(5) Total score on SGRQ

- Variables related to pulmonary function and exercise capacity

(6) post-BD FEV1/FVC (7) post-BD FEV1

(8) post-BD FEV1 increase (9) TLC(10) FRC (11) Hb-corrected DLCO(12) IC/TLC (13) 6MWD

- Variables of CT scan (14) MLDexp/MLDinsp (15) MLDexp

(16) CT wall area (17) V950insp

IC/TLC

Cluster 1Cluster 2Cluster 3

SGRQ

Jo et. al., IJTRD , 2010;14(11):1-8

Three clusters for 191 elderely subjects with obstructive lung disease

Cluster 1 Cluster 2 Cluster 3 P-valve

Number of subjects 59 77 55

Smoking amount (pack-years) 36.6±30.0 48.8±31.0 42.9±25.5 0.039

Post-BD FEV1 (%pred) 49.8±9.3 57.1±14.1 38.0±13.2 < 0.001

Post-BD FEV1 increase (%pred) 11.3±3.9 3.7±2.7 3.9±3.4 < 0.001

IC / TLC 0.31±0.06 0.35±0.07 0.21±0.06 < 0.001

Hb-corrected DLCO (%pred) 83.2±26.1 84.1±26.2 51.5±19.1 < 0.001

V950insp (%) 20.1±6.14 17.0±14.0 38.4±12.1 < 0.001

Body-mass index (kg/m2) 23.7±3.0 23.9±3.2 20.7±3.3 < 0.001

Total score on SGRQ 27.3±14.2 28.2±13.9 55.0±13.2 < 0.001

Modified MRC score 1.2±0.9 1.5±1.0 2.4±0.9 < 0.001

6-minute walk distance (m) 450.5±9.2 431.7±96.0 361.0±107.5 < 0.001

The reality of an intermediate type between asthma and COPD in practice

• To investigate the reality of an intermediate type between asthma and COPD when diagnosed by physicians in Korea

• 633 with asthma, 157 with COPD, and 41 with an intermediate type (from KOLD and COREA cohort)

• Diagnoses were dependent on physicians’ clinical decision

(Kim et al., Respiratory Care 2012)KOLD Study Group

(Kim et al., Respiratory Care 2012)

(Kim et al., Respiratory Care 2012)

KOLD Study Group

(Kim et al., Respiratory Care 2012)

KOLD Study Group

(Kim et al., Respiratory Care 2012)

KOLD Study Group

COPD is heterogeneous

EtiologicallyPhenotypically

? related to different etiology? related to different pathogenesis? related to different host response

May be related to the natural historyDifferent response to treatment

(Pillai et al., Am J Resp Crit Care Med, 2010;182:1498)

• GWAS have shown significant associations between variants near HHIP, FAM13A, and CHRNA3/5 with increased risk of COPD

• To identify the association between replicated loci and COPD-related phenotypes assessed in ECLIPSE cohort

• The results were validated in the family-based International COPD Genetics Network (ICGN)

Genotype-Phenotype Association

• CHRNA3/5 locus was associated with increased smoking intensity and emphysema

• HHIP locus was associated with the systemic components of COPD and with the frequency of COPD exacerbations

• FAM13A locus was associated with lung function

(Pillai et al., Am J Resp Crit Care Med, 2010;182:1498)

• SNP (rs 12910984) in CHRNA3 was associated with COPD (in submission)

• Two SNPs (rs10013495 and rs11938704) near

HHIP were associated with FEV1 (in submission)

• ADRB2 gene polymorphism(Gly16) was associated with airway wall phenotypes measured using CT scanning in COPD patients

(Kim et al., Resp Med, 2008)

Genotype-Phenotype AssociationIn Korean Population

KOLD Study Group

• There was no association between ADRB2genotype and the effect on lung function of 12-week treatment with ICS/LABA inhalation or on the immediate bronchodilator response to a short-acting ß2 agonist in patients with COPD

(Kim et al., Lung, 2008)

Genotype-Tx Response AssociationIn Korean Population

KOLD Study Group

(Kim et al., Respirology, 2009)

KOLD Study Group

Concept of Heterogeneity in COAD- Why is it important ?- Is it a real phenomenon ?- Dose it have clinical relevance ?

How to solve the problems related to heterogeneity

Data from ANOLD (2008-)

Contents

Lesson from Roflumilast Development

Leukocyte PDE isoform Structural Cells PDE isoform

Mast cells 4, 7

Eosinophils 4, 7

Neutrophils 4, 7

Monocytes 1, 3, 4, 7

Macrophages 1, 3, 4, 5, 7

T-cells (CD4+ and CD8+) 3, 4, 7

Airway smooth muscle 1, 2, 3, 4, 5, 7

Epithelial cells 1, 2, 3, 4, 5, 7, 8

Endothelial 2, 3, 4, 5

Sensory nerve s 1, 3, 4

Cholinergic nerves 1, 3, 4

Adapted from: Giembycz MA. Monaldi Arch Chest Dis 2002;57:48-64

Pooled analysis revealed lower exacerbation rates with roflumilast

Study M2-111 Study M2-112 Pooled analysis post hoc

Rennard et al. Respiratory Research 2011;12:18

IDENTIFICATION OF RESPONSIVE

SUBGROUP(study M2-111, M2-112)

Rennard et al. Respiratory Research 2011;12:18

The effect of roflumilast on exacerbations was greatest in patients with chronic cough & sputum

Rennard et al. Respiratory Research 2011;12:18

-Strengthen the efficacy-Personalized Treatment

Lessons from Roflumilast Development

IDENTIFICATION OF TARGET PATIENT POPULATION

PhenotypeIdentification

Nonresponsive

Responsive

Quantitative Assessment of Regional Heterogeneity of Emphysema

The severity of emphysema in lower lung affects values of PFT more significantly than the severity of emphysema in upper lung.

Chae EJ, Seo JB, AJR 2010(Chae et al., AJR 2010;194:w248)

FEV1 = 24.9 FEV1 = 22.5

KOLD Study Group

A: High risk for op.

B: Survival Exercise CapacityHealth status

C,D: Survival Exercise CapacityHealth status

E: Mortality

vs. Medical Treatment

(ATS/ERS, 2004)

Lung Volume Reduction Surgery

Nishimura M et. al., Am J Respir Crit Care Med, 2012;185(1):44

Han MK et. al., Radiology, 2011;261(1);274

Exa

cerb

atio

n F

requency

Phenotypes in COPD

Friedlander et al., COPD 2007;4:355

Responses to LABA & ICSaccording to

COPD Subgroups

- Classified by Phenotypes -(Morphology & Physiology)

KOLD Study Group

Lee JH, et. al. Respiratory Medicine 2009;104:542-9

FEV1%Pred Vs. Emphysema Index at

end-inspiration

0

20

40

60

0 20 40 60 80 100

FEV1% predicted

Emphysema Index

0

1

2

3

Morphology – Physiology Subgroups

Severe ObstructionMild Emphysema

Mild Obstruction Severe Emphysema

Lee et al., Resp Med, 2009

0

2

4

6

8

10

mild ob & mild emmild ob & severe emsevere ob & mild emsevere ob & severe em

dFEV1 %predictedP<0.05

Response after 3mo. with ‘LABA + ICS’

(Lee et al., Resp Med, 2009)

-1

0

mild ob & mild emmild ob & severe emsevere ob & mild emsevere ob & severe em

∆Dyspnea, MRC Scale

P<0.05

Response after 3mo. with ‘LABA + ICS’

(Lee et al., Resp Med, 2009)

To solve the problems related to heterogeneity

-Long-term cohort with comprehensive information and biologic samples

-New tools to dissect heterogeneity and identify new phenotypes or biomarkers with clinical relevance

Images (CT/MR), genes, proteins, small molecules (metabolites), etc.

-Systems biology/Network medicine

COPD: Journal of Chronic Obstructive Pulmonary Disease, 8:121–135, 2011

International COPD Genetics Consortium

Korean Obstructive Lung Disease Patient Cohort Study

(KOLD Study)

Clinical Research Center for Chronic Obstructive Airway Diseases

Supported by a grant of the Korean Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea

2004-2013, $7,000,000

KOLD Study

Nine year longitudinal study Patient cohort entitled ‘Korean ObstructiveLung Disease (KOLD) cohort’

which comprises patients with chronic obstructive pulmonary disease (COPD)

The KOLD cohort was designed primarily to develop a systematic diagnostic model and an integrative prognostic factor of obstructive lung diseases

Endpoints Measured

Pulmonary endpoints- Lung function measurements- Pulmonary body box plethysmography

measurementsEpidemiology endpoints

- Exacerbation assessment - SGRQ - Dyspnea assessment using the modified

MRC dyspnea scale- Depression score- BODE Index

DNA/Proteomic & Biomarker Endpointsserum, plasma, DNA, urine

Other endpointsCTBody Composition (Whole Body Impedance) Resting oxygen saturationSix-minute walk testEchocardiographyFOT (Peripheral airways resistance)

Endpoints measuredEndpoints Measured

CT evaluation of COPD

• Heterogeneity at anatomical level of airway obstruction– Quantitative assessment with CT

• Parenchyma: Emphysema index (total, regional)Texture analysis

• Small airway: air trapping, airway dimension• Large airway: airway dimension

• Heterogeneity in perfusion– Contrast enhanced perfusion MR– Dual energy perfusion CT

• Heterogeneity in ventilation– Oxygen-enhanced MR– Xenon Ventilation Dual-energy CT

http://www.anold.org

Sri Lanka

ChinaSouthKorea

Philippines

Malaysia

Singapore

India

Vietnam

Taiwan

Thailand

Japan

Asian Network for Obstructive Lung Disease (ANOLD)

Main Research TopicsHeterogeneity of COPD in Asians

Genetic heterogeneity of susceptible genesEtiologic heterogeneity Morphologic heterogeneity Physiologic heterogeneityClinical heterogeneiry

Standardization of Methods Clinical epidemiologyLung function Imaging Genetics

Other topics

Exposure

94%

6%

yes

no

Cigarette Smoking

Dusty job

52%

48%

yesno

Dusty Job

(N=935)

Biomass Fuel

No65.8%

Yes34.2%

NoYes

85.2%

3.9%2.3% 11.6%

woodagricultural crop residuescharcoal

For cooking or/and heating, have you ever been exposed to biomass fuel such as wood, agricultural crop residues, animal dung, charcoal, and others?

(N =935) (N =310)

Multivariable analysis of risk factors for respiratory symptoms

Cough Phlegm Chronicbronchitis Wheeze Dyspnea

Age, years 0.99 (0.97-1.01)* 1.00 (0.98-1.02) 1.00 (0.98-1.01) 0.99 (0.97-1.02) 1.04 (1.01-1.07)

Gender, male 1.16 (0.58-2.33) 0.80 (0.38-1.69) 0.61 (0.31-1.20) 0.89 (0.43-1.84) 0.13 (0.03-0.53)

GOLD stage II† 1.43 (0.90-2.29) 1.67 (1.03-2.69) 1.37 (0.83-2.26) 1.80 (1.17-2.75) 2.33 (1.41-3.85)

stage III† 1.58 (0.95-2.62) 1.73 (1.03-2.89) 1.61 (0.95-2.73) 2.76 (1.70-4.49) 5.83 (3.03-11.20)

stage IV† 1.20 (0.62-2.35) 2.48 (1.21-5.08) 1.96 (1.00-3.82) 9.34 (3.44-25.33) 10.94 (3.54-33.77)

Biomass exposure 1.20 (0.79-1.81) 1.72 (1.08-2.75) 1.15 (0.77-1.73) 1.73 (1.05-2.85) 1.68 (0.95-2.94)

Dusty job 1.54 (1.11-2.14) 1.93 (1.36-2.74) 1.40 (1.01-1.95) 2.09 (1.45-3.02) 1.46 (0.93-2.28)

Cigarette smoking 1.65 (0.77-3.52) 2.00 (0.99-4.03) 2.21 (1.01-4.81) 0.91 (0.37-2.22) 8.67 (3.05-24.65)

Thank you

Steering Committee Members• Arvind Bhome, India• Watchara Boonsawat, Thailand• Kirthi Dias Gunasekera, Sri Lanka• Luisito Idolor, Camilo Roa, Philippines• Han-Pin Kuo, Taiwan• Le Thi Tuyet Lan, Vietnam• Sang Do Lee & Dr. Oh, Korea• Richard Loh & Dr. Ong, Malaysia• Alan Ng, Singapore• Masaharu Nishimura, Japan • Chen Wang & Dr. Lin & Dr. Zhang, China• Edwin Silverman, USA

Organizaton of ANOLD

Gender

94%

6%

M F

(N =935)

80

70

60

40

Age Distribution

(68 ± 8, N =935)

Severity of COPD

Post-BD FEV1

Post-BD FEV1 = 56 ± 21%

Post-BD FEV150~80% pred.

(N =935)

Chronic Bronchitis by Country

Phlegm & Cough ≥ 3 months for 2 yrs or moreN =935

Do you usually have a cough and bring up phlegm from your chest?

0%10%20%30%40%50%60%70%80%90%

100%

Wheeze in the last 12 months

52.1%47.9% Yes

No

In the last 12 months, have you had wheezing orwhistling in your chest at any time?

(N =935)

Background

DLco measurements have been shown to be highlycorrelated with the severity of emphysema.The RV/TLC ratio is a preferential marker of small airway disease in patients with COPD.

FEV1 FVC

TLC VC

FRC RV

Normal DLco and RV/TLC Low DLco and normal RV/TLC

Normal DLco and high RV/TLC Low DLco and high RV/TLC

† †

*#‡

†

†

#

†‡

# #†‡ †‡

*#

*#

*#

*#

*#

*#

†‡ †‡

†‡ †‡

†‡

Therapeutic responses of 4 subgroups to 3 months of combined inhalation of LABA/ICS

mL

Inclusion Criteria

Smoker COPD Subjects- Age ≥ 40 years- Smoking history of ≥ 10 pack-years- COPD by GOLD criteria

(post-BD FEV1/FVC<0.7)

- Asian ethnicity

Nonsmoker COPD Subjects- Smoking history of ≤100 cigarettes

Contents

Contact InformationPhysical assessmentStandardized questionnaires

- Modified version of ATS-Division of Lung Diseases Respiratory Epidemiology Questionnaire

- St. George’s Respiratory Questionnaire

Pre- & post-BD spirometrySimple Chest Radiography

BMI

Mean BMI = 22.0 ± 3.74 kg/m2

Underweight = body mass index < 18.5 kg/m2

overweight = body mass index ≥ 25 kg/m2

20%

59%

21%

UnderweightNormal weightOverweight

(N =935)

SGRQ

0

10

20

30

40

50

60

Symptomsscore

Activityscore

Impactscore

Total score

N =935

Chronic Bronchitis

Phlegm & Cough ≥ 3 months for 2 yrs or more

N =935

Do you usually have a cough and bring up phlegm from your chest?

21.7%

78.3 %

YesNo

Yes44.5%

No55.5%

Yes34.0%

No66.0%

Exacerbation in the past year

Treatments d/t Chest illnessAntibiotics Steroid

In the past year, have you been treated with antibiotics or steroid pills or injections for a chest illness?

(N =935)

Exacerbation in the past year

ER or Hospitalization d/t Lung Problem

26.5%

73.5%

Yes

No

In the past year, have you been to the emergency room or hospitalized for lung problems?

(N =935)

Multivariate analysis of risk factors for severe airflow limitation

Odds Ratio (95%CI) P value

Age, years 0.99 (0.97-1.01) 0.27

Gender, male 1.26 (0.67-2.37) 0.48

Biomass exposure 0.91 (0.61-1.36) 0.64

Dusty job 1.66 (1.23-2.25) < 0.001

Cigarette smoking 1.47 (0.76-2.83) 0.25

The odds ratios were adjusted for country.

Conclusion

• We could identify and characterize an intermediate type, lying btw asthma and COPD in clinical characteristics.

• Further investigations are required to determine whether these 3 conditions are part of the chronic obstructive airway diseases spectrum or are rather distinct clinical entities.

(Kim et al., Respiratory Care 2012)

KOLD Study Group

Current Understandings of OLD

Chronic Obstructive Bronchiolitis

EmphysemaAsthma

Airway disease

Alveolar disease

Comparison of subjects who were exposed to biomass with non-exposure

Exposure (n=320) Non-exposure (615) p-value

Gender 0.11 male 295(92.2%) 583(94.8%) female 25(7.8%) 32(5.2%)

Cigarette Smoking 294(91.9%) 585(95.1%) 0.047

Cough 219(68.4%) 248(40.3%) <0.001 Phlegm 262(81.9%) 299(48.6%) <0.001 Chronic bronchitis 91(28.4%) 112(18.2%) <0.001 Wheeze 267(83.4%) 436(70.9%) <0.001

Dyspnea, MMRC dyspnea grade

0 28(8.8%) 101(16.4%) <0.001 1 61(19.1%) 206(33.6%) 2 75(23.4%) 170(27.7%) 3 136(42.5%) 93(15.1%) 4 20(6.3%) 44(7.2%)

Post-bronchodilator FEV1,

(%predicted)

54.5 57.2 0.054

Comparison of subjects who were exposed to dusty job with non-exposure

Exposure (n=320) Non-exposure (615) p-value

Gender 0.045male 396(95.7%) 482(92.5%)female 18(4.3%) 39(7.5%)

Cigarette Smoking 388(93.7%) 491(94.2%) 0.745

Cough 259(62.6%) 208(39.9%) <0.001Phlegm 301(72.7%) 260(49.9%) <0.001Chronic bronchitis 113(27.3%) 90(17.3%) <0.001Wheeze 348(84.1%) 355(68.1%) <0.001

Dyspnea, MMRC dyspnea grade

0 41(9.9%) 88(16.9%) <0.0011 85(20.5%) 182(35.0%)2 103(24.9%) 142(27.3%)3 156(37.7%) 73(14.0%)4 29(7.0%) 35(6.7%)

Post-bronchodilator FEV1, (%predicted)

52.9%predicted 59.0%predicted <0.001