Heterogeneity of COPD and Asthma

Transcription

1 Heterogeneity of COPD and Asthma from Heterogeneity to Stratification Dr. Y-M Oh Asan Medical Center Seoul

2 Congratulations & Welcome Lee,SD Ohno, Y Park, JS Seo, JB 8 th Internat nal Workshop on Pul. Functional Imaging 16 th Meeting of Korean Society of Thoracic Radiology

3 Heterogeneity of COPD and Asthma Oh my god 어떻게하지

4 Hurray! 만세 Meilan Han: COPD Phenotypes to Endotype Early COPD Fan Chung: Endotyping Severe Asthma Norbert F. Voelkel: COPD-vascular alterations Hae Sim Park: Phenotypes & endotypes of AERD David Lynch: CT imaging in COPD Yasutaka Nakano: Practical approach to ACOS Edwin Silverman: Network Medicine Approaches to COPD Genetics in COPD

5 Heterogeneity is NOT my goal. Heterogeneity Complex Stratification Phenotype Endotype Best Treatment Precise

6 To Overcome Heterogeneity 1 Phenotype stratification 2 Endotype stratification Molecular pathogenesis 3 Treatability stratification Treatable traits Best Treatment 4

7 COPD Phenotypes Frequent Exacerbation LAMA + LABA Severe Emphysema Lung Vol. Reduction Asthma - COPD overlap Inhaled Steroid + BD CS, corticosteroid ; BD, bronchodilator of LAMA or LABA GOLD 2017 update

8 To Overcome Heterogeneity 1 Phenotype stratification 2 Endotype stratification Pathobiological mechanism 3 Treatability approach 4 Treatable traits Practical Ideal GOLD 2017

9 Asthma Endotypes T H 2-high T H 2-low

10 Asthma Endotypes Unsupervised Hierarchical Clustering Lung Function FEV1 POSTN CLCA1 SERPINB T H 2-high T H 2-high T H 2-low 0 T H 2-low -0.2 Ideal Practical! ICS initiated 8wks Airway epithelial brushings Modified. Woodruff. P, et al. AJRCCM 2009

11 To Overcome Heterogeneity 1 Phenotype stratification Practical 2 Endotype stratification Molecular pathogenesis 3 Treatability stratification Treatable traits Ideal Individualized 4

12 Modified. Agusti A. Eur Respir J 2016; 47: 410 COPD Treatable Traits for each individual patient Smooth m. contraction Emphysema Airway eosionphilia Chronic bronchitis Hypoxemia Bronchodilator Oxygen Lung Vol. Reduction Smoking Cessation Inhaled Steroid Individualized Validation

13 To Overcome Heterogeneity 1 Phenotype 2 Endotype 3 Treatability Best or Precise Treatment 4 Severity

14 COPD, Progress & Heterogeneity Severity Predisposition Genetic Small Lung Etiology Heterogeneity Exposure Cigarette Biomass Pathology Heterogeneity Molecular & cellular change Phenotype Heterogeneity Morphologic Treatability Heterogeneity Functional Dyspnea Exacerbation change Airflow limitation Hyperinflation change Bronchitis & -olitis Emphysema Time Decramer M et al. Thorax 2010; 65: Sutherland & Cherniack. N Engl J Med 2004; 350:

15 COPD Heterogeneity in Pathology Chronic Bronchiolitis Emphysema Chronic Bronchitis There are non-obstructive chr. bronchitis, chr. bronchiolitis, & emphysema. Vascular Alteration Pathology Heterogeneity

16 COPD Heterogeneity in Pathology large airway Chronic Bronchiolitis small airway Chronic Bronchitis Vascular Emphysema A patient may have all pathologies or may not

17 COPD Heterogeneity in Pathology Stratification & Current Therapy Emphysema Chronic Bronchiolitis Vascular Alteration Chronic Bronchitis LVR, LAMA/LABA, ICS, PDE4I, O2, Mucolytics, PDE4I

18 COPD Heterogeneity in Pathology Stratification & Future Therapy Emphysema Chronic Bronchiolitis Vascular Alteration Chronic Bronchitis Alveolar Regeneration Anti-Neutrophilic, Anti-Fibrotic Vascular targeting Anti-mucus

19 Spirometry Symptoms, QoL Exacerbation Diagnostic Tools Biomarkers Outcomes Emphysema CT Chronic Bronchiolitis? Vascular Change Echocardio. Chronic Bronchitis Sputum amount

20 KOLD COPD pts Emphysema vs. Bronchiolitis Emphysema severity by CT Emphysema Bronchiolitis FEV1 % by Spirometry Lee, et al. Respir Med (2010) 104, 542

21 KOLD COPD pts Emphysema may NOT be treatable with Inhaler Therapy Emphysema severity by CT Emphysema FEV1 increase %pred. Bronchiolitis FEV1 % Lee, et al. Respir Med (2010) 104, 542 ICS & LABA

22 KOLD COPD pts Vascular Alteration in COPD patients High PA pressure Cf. normal spap 15~30mmHg Lee JW. IJTLD 2011

23 COPD Heterogeneity in Treatability Treatable w/ inhaled CS Sputum/blood eosionphilia or ACOS Treatable with bronchodilators LABA vs. LAMA

24 COPD Heterogeneity in Treatability Treatable w/ LABA or LAMA Δ FEV1, liter liter LAMA -only Responders 0.6 Both Responders Non-Responders liter LABA -only Responders r = -0.14, p = 0.26 Δ FEV1, liter

25 COPD Heterogeneity in Treatability Cross-over Design 73 COPD pts. w/ Tx Naïve or Wash-out LABA LABA LAMA LAMA 4wks 4wks 4wks Δ FEV1 1 FEV 1, 70 % pred. (Post-BD) 2 CAT score, 10 Unpublished data

26 COPD Heterogeneity in Treatability Prediction of Treatability LABA vs. LAMA To Find Treatable Traits Clinical Characteristics Gene Expression Gene Damage Score 13 Variables Microarray Exome Seq.

27 Clinical Variables, Factor Analysis 13 6 variables BMI Ex-smoker vs. current Cigarette smoke, PYs CAT mmrc FEV1 %pred post-bd FEV1 %pred BDR %pred DLCO %pred TLC %pred IC/TLC RV %pred RV/TLC

28 Gene Expression Correlation Δ FEV1 & expression level P < 0.05 highest R 28 genes Linear Regression Y = Δ FEV1 X = expression level of 28 genes 7 genes Factor analysis 7 3 genes CLN8 PCSK5 SKP2 Treatability with LABA

29 Predict Treatability w/ LABA R Y = Δ FEV1, liter Correlation or Regression Analyses

30 Predict Treatability w/ LAMA R Δ FEV1, liter Correlation or Regression Analyses

31 Prediction of Treatability LABA or LAMA Clinical + Expression + Gene Damage R= 0.6 for LABA R= 0.7 for LAMA R ~ 0.49 Not Sufficient

32 COPD Heterogeneity in Etiology Cigarette Smoke Biomass Combustion Pollutants COPD Extracellular Vesicles in Indoor Dusts ~100 nm

33 COPD Heterogeneity in Etiology Extracellular Vesicles in Indoor Dusts Bedroom Gho YS. Proteomics 2009

34 COPD Heterogeneity in Etiology IgG of Anti-Extracellular Vesicles in Indoor Dusts higher risk of COPD Risk Factors for COPD Odds ratio 95% CI p-value Age, years < % N =90 Female Cigarette smoke High anti-dust EV* % N =242 Kim YS, et.al. Allergy Asthma Immunol Res. 2016:8;198

35 COPD Heterogeneity in Etiology Extracellular Vesicles in Indoor Dusts Inflammation Emphysema 100 ng 1000 ng Emphysema Dust EV 0, 100, 1000 ng Kim YS, et al. Clin & Exp All, 2013: 43; 443 E.coli EV 0, 1, 10, 100 ng Kim YS, et.al. J Immunology, 2015, 194: 3361

36 Asthma Heterogeneity & Progress Severity Predisposition Genetic Etiology Heterogeneity Exposure Allergen Pathology Heterogeneity Molecular & cellular change Treatability Heterogeneity Phenotype Heterogeneity Morphologic change Functional change Th2 inflammation Symptoms Exacerbation Airflow limitation Hyperresponsive Time

37 Asthma Heterogeneity in Pathology Paucigranulocytic Eosinophilic Mixed or Neutrophilic Controlled Uncontrolled Severe

38 Proportion of Eosionphilic or Th2 Asthma in a General Population, NHANES, US % High blood Eosinophil 300/mL 41% High specific IgE to any 9 allergens 61 High serum IgE & blood eosionophil 37 73% = 0 Eosionphilic Atopic Th2-high Any of Asthma, self-report, aged yrs Tran. Ann Allergy Asthma Immunol 2016

39 Asthma Heterogeneity in Pathology Stable Persistent, Controlled Asthma Subject No Eosionphilic Paucigranulocytic Mixed Neutrophilic 20 0 Base N=94, stable persistent asthma, New Zealand Most of pts. = atopic early onset, on ICS with well controlled Cowan. New Zealand. Thorax 2010;65:384

40 Cowan. New Zealand. Thorax 2010;65:384 Eosinophilic Asthma Stable Persistent, Controlled Asthma Subject No Base 2 2 Eos Pau Mix Neu

41 Pauci-granulocytic Asthma Stable Persistent, Controlled Asthma Subject No Base Eos Pau Mix Neu

42 Controllability & Phenotype Global Asthma Guidelines, GINA 2016 Update Stratification Treatment Controlled vs. Uncontrolled ICS + LABA + LAMA High IgE, severe uncontrolled High eosinophil, severe uncontrolled Aspirin exacerbated Anti-IgE Anti-IL5 LTRA GINA 2016 update

43 Summary Heterogeneity 1 Etiology 2 Pathology Stratification 1 Phenotype 2 Endotype 3 Treatability Best Treatment

44 Conclusion Heterogeneity expands understandings on COPD & asthma. Keep you not overwhelmed by heterogeneity but with stratification for best treatment

45 Thank you for KOLD & ANOLD Researchers 감사ありがとう ขอบค ณ Cảm ơn 谢谢

46 Treatability w/ LABA Δ FEV1, liter Δ FEV1, liter Δ FEV1, liter CLN8 PCSK5 SKP2 Gene Expression

47 Asthma Heterogeneity in Pathology Current & Future Therapy Eosinophilic Inhaled Steoid, LTRA Smooth m. LABA, LAMB, Thermoplasty Neutrophilic Anti-Neutrophilic Mucus Anti-mucus

48 Asthma Heterogeneity in Pathology Spirometry ACQ, ACT Exacerbation Diagnostic Tools Eosinophilic Sputum eosino., eno Smooth m.? Neutrophilic Sputum neutro. Mucus Sputum amount