Current status & future mission for chronic obstrutive airway diseases (COAD) in Asia

Transcription

1 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 Center College of Med, Univ. of Ulsan

2 Contents 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-)

3 Percent Change in Age- Adjusted Death Rates Proportion of 1965 Rate Coronary Heart Disease Stroke Other CVD U.S., COPD All Other Causes % 64% 35% +163% 7%

4 DEFINITION airflow obstruction due to chronic bronchitis or emphysema Air flow obstruction progressive, may be accompanied by airway hyperreactivity, and may be partially reversible. (ATS Statement, 1995)

5 DEFINITION Of COPD - 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)

6 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 FEV 1 decline (UPLIFT, TORCH) Clinically significant effect on exacerbation Current clinical trials show promising evidences, but not optimal

7 DEFINITION airflow obstruction due to chronic bronchitis or emphysema Air flow obstruction progressive, may be accompanied by airway hyperreactivity, and may be partially reversible. (ATS Statement, 1995)

8 COPD Clinical Phenotypes Petty TL, Pul Pharm Thera 2002;15:341

9 Contents 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-)

10 KOLD Study Group Three phenotypes of obstructive lung disease in the elderly - Cluster Analysis - Jo et. al., Int J Tuberc Resp Dis, 2010;14(11):

11 Subjects Inclusion 191 subjects older than 60 years had chronic respiratory symptom(s) AND obstructive spirometry Exclusion tuberculous destroyed lung Bronchiectasis lung resection, etc.

12 Methods Factor Analysis Ü Find key variables Ü Cluster Analysis Ü Find phenotypes of OLD

13 Factor analysis - Variables related to medical history, physical examination, and QOL (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 FEV 1 /FVC (7) post-bd FEV 1 (8) post-bd FEV 1 increase (9) TLC (10) FRC (11) Hb-corrected D L CO (12) IC/TLC (13) 6MWD - Variables of CT scan (14) MLD exp /MLD insp (15) MLD exp (16) CT wall area (17) V950 insp

14 IC/TLC Cluster 1 Cluster 2 Cluster 3 SGRQ Jo et. al., IJTRD, 2010;14(11):1-8

15 Three clusters for 191 elderely subjects with obstructive lung disease Cluster 1 Cluster 2 Cluster 3 P-valve Number of subjects Smoking amount (pack-years) 36.6± ± ± Post-BD FEV 1 (%pred) 49.8± ± ±13.2 < Post-BD FEV 1 increase (%pred) 11.3± ± ±3.4 < IC / TLC 0.31± ± ±0.06 < Hb-corrected D L CO (%pred) 83.2± ± ±19.1 < V 950insp (%) 20.1± ± ±12.1 < Body-mass index (kg/m 2 ) 23.7± ± ±3.3 < Total score on SGRQ 27.3± ± ±13.2 < Modified MRC score 1.2± ± ±0.9 < minute walk distance (m) 450.5± ± ±107.5 < 0.001

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

17 (Kim et al., Respiratory Care 2012)

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

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

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

21 COPD is heterogeneous Etiologically Phenotypically? related to different etiology? related to different pathogenesis? related to different host response May be related to the natural history Different response to treatment

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

23 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)

24 SNP (rs ) in CHRNA3 was associated with COPD (in submission) Two SNPs (rs and rs ) near HHIP were associated with FEV 1 (in submission) ADRB2 gene polymorphism(gly16) was associated with airway wall phenotypes measured using CT scanning in COPD patients KOLD Study Group Genotype-Phenotype Association In Korean Population (Kim et al., Resp Med, 2008)

25 KOLD Study Group Genotype-Tx Response Association In Korean Population There was no association between ADRB2 genotype and the effect on lung function of 12-week treatment with ICS/LABA inhalation or on the immediate bronchodilator response to a short-acting ß 2 agonist in patients with COPD (Kim et al., Lung, 2008)

26 KOLD Study Group (Kim et al., Respirology, 2009)

27 Contents 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-)

28 Lesson from Roflumilast Development Leukocyte PDE isoform Structural Cells PDE isoform Mast cells 4, 7 Airway smooth muscle 1, 2, 3, 4, 5, 7 Eosinophils 4, 7 Epithelial cells 1, 2, 3, 4, 5, 7, 8 Neutrophils 4, 7 Endothelial 2, 3, 4, 5 Monocytes 1, 3, 4, 7 Macrophages 1, 3, 4, 5, 7 T-cells (CD4 + and CD8 + ) 3, 4, 7 Sensory nerve s 1, 3, 4 Cholinergic nerves 1, 3, 4 Adapted from: Giembycz MA. Monaldi Arch Chest Dis 2002;57:48-64

29 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

30 IDENTIFICATION OF RESPONSIVE SUBGROUP (study M2-111, M2-112) Rennard et al. Respiratory Research 2011;12:18

31 The effect of roflumilast on exacerbations was greatest in patients with chronic cough & sputum Rennard et al. Respiratory Research 2011;12:18

32 Lessons from Roflumilast Development IDENTIFICATION OF TARGET PATIENT POPULATION Nonresponsive Phenotype Identification Responsive - Strengthen the efficacy - Personalized Treatment

33 Quantitative Assessment of Regional Heterogeneity of Emphysema FEV 1 = 24.9 FEV 1 = 22.5 The severity of emphysema in lower lung affects values of PFT more significantly than the severity of emphysema in upper lung. KOLD Study Group (Chae Chae et al., EJ, AJR Seo 2010;194:w248) JB, AJR

34 Lung Volume Reduction Surgery vs. Medical Treatment A: High risk for op. B: Survival Exercise Capacity Health status C,D: Survival Exercise Capacity Health status E: Mortality (ATS/ERS, 2004)

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

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

37 Phenotypes in COPD Friedlander et al., COPD 2007;4:355

38 KOLD Study Group Responses to LABA & ICS according to COPD Subgroups - Classified by Phenotypes - (Morphology & Physiology) Lee JH, et. al. Respiratory Medicine 2009;104:542-9

39 Emphysema Index Morphology Physiology Subgroups FEV1%Pred Vs. Emphysema Index at end-inspiration 60 Mild Obstruction Severe Emphysema Severe Obstruction Mild Emphysema FEV 1 % predicted Lee et al., Resp Med, 2009

40 Response after 3mo. with LABA + ICS dfev1 %predicted 10 P< mild ob & mild em mild ob & severe em severe ob & mild em severe ob & severe em 2 0 (Lee et al., Resp Med, 2009)

41 Response after 3mo. with LABA + ICS 0 Dyspnea, MRC Scale mild ob & mild em mild ob & severe em severe ob & mild em severe ob & severe em P< (Lee et al., Resp Med, 2009)

42 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

43 International COPD Genetics Consortium COPD: Journal of Chronic Obstructive Pulmonary Disease, 8: , 2011

44 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 , $7,000,000

45 KOLD Study Nine year longitudinal study Patient cohort entitled Korean Obstructive Lung 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

46 Endpoints Measured Pulmonary endpoints - Lung function measurements - Pulmonary body box plethysmography measurements Epidemiology endpoints - Exacerbation assessment - SGRQ - Dyspnea assessment using the modified MRC dyspnea scale - Depression score - BODE Index

47 Endpoints Measured Endpoints measured DNA/Proteomic & Biomarker Endpoints serum, plasma, DNA, urine Other endpoints CT Body Composition (Whole Body Impedance) Resting oxygen saturation Six-minute walk test Echocardiography FOT (Peripheral airways resistance)

48 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

49

50 Asian Network for Obstructive Lung Disease (ANOLD) China South Korea Japan Taiwan India Vietnam Philippines Sri Lanka Thailand Malaysia Singapore

51

52 Main Research Topics Heterogeneity of COPD in Asians Genetic heterogeneity of susceptible genes Etiologic heterogeneity Morphologic heterogeneity Physiologic heterogeneity Clinical heterogeneiry Standardization of Methods Clinical epidemiology Lung function Imaging Genetics Other topics

53 Exposure Cigarette Smoking Dusty Job 6% yes no 48% 52% yes no 94% Dusty job (N=935)

54 For cooking or/and heating, have you ever been exposed to biomass fuel such as wood, agricultural crop residues, animal dung, charcoal, and others? Biomass Fuel 2.3% 3.9% 11.6% No 65.8% Yes 34.2% 85.2% No Yes wood agricultural crop residues charcoal (N =935) (N =310)

55 Multivariable analysis of risk factors for respiratory symptoms Cough Phlegm Chronic bronchitis Wheeze Dyspnea Age, years 0.99 ( )* 1.00 ( ) 1.00 ( ) 0.99 ( ) 1.04 ( ) Gender, male 1.16 ( ) 0.80 ( ) 0.61 ( ) 0.89 ( ) 0.13 ( ) GOLD stage II 1.43 ( ) 1.67 ( ) 1.37 ( ) 1.80 ( ) 2.33 ( ) stage III 1.58 ( ) 1.73 ( ) 1.61 ( ) 2.76 ( ) 5.83 ( ) stage IV 1.20 ( ) 2.48 ( ) 1.96 ( ) 9.34 ( ) ( ) Biomass exposure 1.20 ( ) 1.72 ( ) 1.15 ( ) 1.73 ( ) 1.68 ( ) Dusty job 1.54 ( ) 1.93 ( ) 1.40 ( ) 2.09 ( ) 1.46 ( ) Cigarette smoking 1.65 ( ) 2.00 ( ) 2.21 ( ) 0.91 ( ) 8.67 ( )

56 Thank you

57

58

59

60

61

62

63 Organizaton of ANOLD 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

64 Gender 6% M F 94% (N =935)

65 Age Distribution (68 ± 8, N =935)

66 Severity of COPD Post-BD FEV1 50~80% pred. Post-BD FEV1 Post-BD FEV1 = 56 ± 21% (N =935)

67 Do you usually have a cough and bring up phlegm from your chest? Chronic Bronchitis by Country 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Phlegm & Cough 3 months for 2 yrs or more N =935

68 In the last 12 months, have you had wheezing or whistling in your chest at any time? Wheeze in the last 12 months 47.9% 52.1% Yes No (N =935)

69 Background D Lco measurements have been shown to be highly correlated with the severity of emphysema. The RV/TLC ratio is a preferential marker of small airway disease in patients with COPD.

70 Therapeutic responses of 4 subgroups to 3 months of combined inhalation of LABA/ICS ml *# # *# *# # # FRC RV FEV 1 FVC TLC VC *# *# *# *# Normal D Lco and RV/TLC Normal D Lco and high RV/TLC Low D Lco and normal RV/TLC Low D Lco and high RV/TLC

71 Inclusion Criteria Smoker COPD Subjects - Age 40 years - Smoking history of 10 pack-years - COPD by GOLD criteria (post-bd FEV 1 /FVC<0.7) - Asian ethnicity Nonsmoker COPD Subjects - Smoking history of 100 cigarettes

72 Contents Contact Information Physical assessment Standardized questionnaires - Modified version of ATS-Division of Lung Diseases Respiratory Epidemiology Questionnaire - St. George s Respiratory Questionnaire Pre- & post-bd spirometry Simple Chest Radiography

73 BMI 21% 20% Underweight Normal weight Overweight 59% Mean BMI = 22.0 ± 3.74 kg/m 2 Underweight = body mass index < 18.5 kg/m 2 overweight = body mass index 25 kg/m 2 (N =935)

74 SGRQ Symptoms score Activity score Impact score Total score N =935

75 Do you usually have a cough and bring up phlegm from your chest? Chronic Bronchitis 21.7% 78.3 % Yes No N =935 Phlegm & Cough 3 months for 2 yrs or more

76 In the past year, have you been treated with antibiotics or steroid pills or injections for a chest illness? Exacerbation in the past year Treatments d/t Chest illness Antibiotics Steroid No 55.5% Yes 44.5% No 66.0% Yes 34.0% (N =935)

77 In the past year, have you been to the emergency room or hospitalized for lung problems? Exacerbation in the past year ER or Hospitalization d/t Lung Problem 26.5% Yes No 73.5% (N =935)

78 Multivariate analysis of risk factors for severe airflow limitation Odds Ratio (95%CI) P value Age, years 0.99 ( ) 0.27 Gender, male 1.26 ( ) 0.48 Biomass exposure 0.91 ( ) 0.64 Dusty job 1.66 ( ) < Cigarette smoking 1.47 ( ) 0.25 The odds ratios were adjusted for country.

79 Conclusion KOLD Study Group 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)

80 Current Understandings of OLD Airway disease Chronic Obstructive Bronchiolitis Asthma Emphysema Alveolar disease

81 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%) 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%) < (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,

82 Comparison of subjects who were exposed to dusty job with non-exposure Exposure (n=320) Non-exposure (615) p-value Gender male 396(95.7%) 482(92.5%) female 18(4.3%) 39(7.5%) Cigarette Smoking 388(93.7%) 491(94.2%) Cough 259(62.6%) 208(39.9%) <0.001 Phlegm 301(72.7%) 260(49.9%) <0.001 Chronic bronchitis 113(27.3%) 90(17.3%) <0.001 Wheeze 348(84.1%) 355(68.1%) <0.001 Dyspnea, MMRC dyspnea grade 0 41(9.9%) 88(16.9%) < (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