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