1. Kiat Ruxrungtham, M.D. Division of Allergy and Clinical Immunology Department of Medicine, Faculty of Medicine Chulalongkorn University A STHMA A H IGHLY V ARIABLE D ISEASE

2. Case Study 1: PM, age 44(cont’d) Variation of Clinical symptoms and PEF SinusitisSinusitis Sinusitis Lost FU LABA/ICS LABA/ICS

3. Case Study 2: VN, Male age 60 Known of Asthma for 30 years, non-smoker Variation of Clinical symptoms and PEF LABA/ICS LABA/ICS Lost FU Non-adherence worsening AR

4. Case Study 5: AC, Male age 37 Asthma and AR since childhood, non-smoker ICS ICS/LABA INCS/H1 inh URI Cigarette smoke ICS

5. Asthma : Characteristics Key characteristics Reversible airway obstructionReversible airway obstruction Chronic eosinophilic airway inflammationChronic eosinophilic airway inflammation Airway hyperresponsivenessAirway hyperresponsiveness Clinical features episodic cough and dyspnea, wheezingepisodic cough and dyspnea, wheezing Variation of PEF or FEV1 >15-20% with/without bronchodilatorsVariation of PEF or FEV1 >15-20% with/without bronchodilators

6. Asthma: Risk Factors Environmental Genetic ~5 % in Adults 13 % in Children Clinical Asthma Aeroallergens Pollutants Triggers Thailand ~19 genes 5q: IL4, CD14, B2ADR 6p: DRB1, TNF 11q: FCERB1, CC16 16p: IL4RA AllergyChula

7. Immediate and Late Phase Asthmatic Reactions (IPAR and LPAR) mins12345678910 -hrs//-------- days Time after Allergen Challenge FEV1 BHR AllergyChula Allergen IPAR LPAR

8. Asthma 2001 Airway Inflammation Smooth Muscle Dysfunction Airway Remodeling Barnes P 2001

9. Fatal Asthma Normal subject (postmortem) Living severe asthma (opened lung biopsy): markedly folded bronchial epithelia and mucosa, thickened airway wall, and epithelial cell aggregate in the airway lumen. Fatal asthma (autopsy): goblet cell hyperplasia and eosinophilic inflammation. The airway lumen is occupied with a mucus plug. Busse W JACI 2000 Reliable markers for predicting of severe and fatal prone asthma is needed AllergyChula

10. Smooth Muscle Dysfunction in Asthma Increase contraction Increase contraction Increase smooth muscle mass, hyperplasia Increase smooth muscle mass, hyperplasia Increase release of inflammatory mediators Increase release of inflammatory mediators AllergyChula

11. Airway Remodeling in Asthma Cells proliferation: smooth muscle cells, mucous glands Increase matrix protein deposition Reticular basement membrane thickening Angiogenesis AllergyChula

12. Cells Involved in Asthma AllergyChula

13. Cells, cytokines and molecules in AsthmaIL-1IL-12 Antigenpresentation CD4 ICAM-3 ICAM-1 CD8 Johnson M et al 2000 and Vignola M Nice 2001 AllergyChulaIL-10IL-4 IL-3 IL-5 IL-6 IL-13 IL-1  GM-CSF TNF  SCF IL-10 IL-4 IL-3 IL-5 IL-6 IL-13 IL-1  GM-CSF TNF  IL-2 IL-8 MIP-1  PDGFL-selectin MCP-1 15-HETE RANTES ICAM-1 TXB2 IFN-  CR3 EDP MBP LTB4 TGF  HB-EGF O2-O2-O2-O2- MAC-1 PAF LTC4 ECP EPO EDN IL-10 IL-4 IL-3 IL-5 IL-6 IL-13 IL-1 GM-CSF TNF  IL- 8 MIP-1  MCP-3 RANTES IFN-  LTB4 LTD4 LTE4 SCF eotaxinhistaminePGD2 IL-14 NCF Tryptase LTC4 PAF IL-6IL-8 GM-CSF TNF  SCF PGE 2 RANTES eotaxin MCP-1 IL-10 IL-4 IL-3 IL-5 IL-6 IL-13 IL-1  GM-CSF TNF  IL-11 IL-17 IL-1  IL-8 IL-16 PGF2  PGE2 IGF-1 CGRP FGF cPLA2 NO SLPI NEP COX2 iNOS 15-LO MIP-1  VIP PDGF E-selectin eotaxin MCP-1 ET-1 MCP-4 15-HETE RANTES MCP-2 MMP-9 GRO-B ICAM-1

14. Comparable Asthma Severity in the Two Study Populations Severity classified by NIH Symptom Severity Index Moderate AllergyChula AIRE AIA Intermittent

15. AdrenalineIsoprenaline Salbutamol, terbutaline Salmeterol, Fomoterol Synergy of CS and LABA Adrenal extract Cortisol BDP, Bud FP CombinationCS+LABA 1900 1999 P Barnes Berlin 1999

16. Synergy of ICS and LABAIL-10 IL-4 IL-3 IL-5 IL-6 IL-13 IL-1  GM-CSF TNF  IL-2 IL-8 MIP-1  PDGFL-selectin MCP-1 15-HETE RANTES ICAM-1 TXB2 IFN-  CR3 EDP MBP LTB4 TGF  HB-EGF O2-O2-O2-O2- MAC-1 PAF LTC4 ECP EPO EDN IL-10IL-4 IL-3 IL-5 IL-6 IL-13 IL-1  GM-CSF TNF  SC F IL-10 IL-4 IL-3 IL-5 IL-6 IL-13 IL-1 GM-CSF TNF  IL-8 MIP-1  MCP-3 RANTES IFN-  LTB4 LTD4 LTE4 SCF eotaxinhistaminePGD2 IL-14 NCF Tryptase LTC4 PAF IL-6IL-8 GM-CSF TNF  SCF PGE 2 RANTES eotaxin MCP-1 IL-10 IL-4 IL-3 IL-5 IL-6 IL-13 IL-1  GM-CSF TNF  IL-11 IL-17 IL-1  IL-8 IL-16 PGF2  PGE2 IGF-1 CGRP FGF cPLA2 NO SLPI NEP COX2 iNOS 15-LO MIP-1  VIP PDGF E-selectin eotaxin MCP-1 ET-1 MCP-4 15-HETE RANTES MCP-2 MMP-9 GRO-B ICAM-1 15-LTs Johnson M et al 2000 and Vignola M Nice 2001

17. Synergistic Effects of ICS+LABA on Eosinophil IL-10 IL-4 IL-3 IL-5 IL-6 IL-13 IL-1  GM-CSF TNF  IL-2 IL-8 MIP-1  PDGF L-selectin MCP-1 15-HETE RANTES ICAM-1 TXB2 IFN-  CR3 EDP MBP LTB4 TGF  HB-EGF O2-O2-O2-O2- MAC-1 PAF LTC4 ECP EPO EDN IL-10 IL-4 IL-3 IL-5 IL-6 IL-13 IL-1  GM-CSF TNF  IL-2 IL-8 MIP-1  PDGF L-selectin MCP-1 15-HETE RANTES ICAM-1 TXB2 IFN-  CR3 EDP MBP LTB4 TGF  HB-EGF O2-O2-O2-O2- MAC-1 PAF LTC4 ECP EPO EDN

18. Synergistic Effects of ICS+LABA on Mast Cells

19. Synergy of CS and LABA on Epithelial Cells in Asthma IL-10 IL-4 IL-3 IL-5 IL-6 IL-13 IL-1  GM-CSF TNF  IL-11 IL-17 IL-1  IL-8 IL-16 PGF2  PGE2 IGF-1 CGRP FGF cPLA2 NO SLPI NEP COX2 iNOS 15-LO MIP-1  VIP PDGF E-selectin eotaxin MCP-1 ET-1 MCP-4 15-HETE RANTES MCP-2 MMP-9 GRO-B ICAM-1 IL-10 IL-4 IL-3 IL-5 IL-6 IL-13 IL-1  GM-CSF TNF  IL-11 IL-17 IL-1  IL- 8 IL-16 PGF2  PGE2 IGF-1 CGRP FGF cPLA2 NO SLPI NEP COX2 iNOS 15-LO MIP-1  VIP PDGF E-selectin eotaxin MCP-1 ET-1 MCP-4 15-HETE RANTES MCP-2 MMP-9 GRO-B ICAM-1 15-LTs

20. Synergy of CS and LABA on Smooth muscle cell in Asthma IL-6 IL-8 GM-CSF TNF  SCF PGE 2 RANTES eotaxin MCP-1 IL-6 IL-8 GM-CSF TNF  SCF PGE 2 RANTES eotaxin MCP-1

21. Asthma: A Highly Variable Disease Airway Inflammation Smooth Muscle Dysfunction Airway Remodeling Infection Allergens AR Pollutants Sinusitis Cold air Excercise Drugs ASA/NSAIDS Psychological Variable Asthmatic Symptoms Intermittent Intermittent Persistent Persistent Mild Mild Moderate Moderate Severe Severe Irreversibility Irreversibility Treatment Adherence Avoidance Genetics AHR ReversibleAirwayObstruction Treating Asthma: Individualized and Dynamics Approach

22. Co-existence of Asthma and AR 306 former students with Allergic Rhinitis 84 former students with Asthma Asthma no AR no Greisner WA et al Allergy Asthma Proc 1998; 19:185-8 86 % 79 % 21 % 23-Years Follow-up Study of Former Brown University Students (N=738)

23. Ragweed Hay Fever with Seasonal Asthma Placebo Welsh et al. Mayo Clin Proc 1987;62:125-34

24. Mean Changes in PEFR (L/min) in Treated AR with Mild Asthma Corren J, et al J Allergy Clin Immuno 1997; 100:781-788 Morning (AM)Evening (PM) * * ** * * * * * * * * * <0.05 P=0.002

25. SINUSITIS

26. A Thai Cohort of NSAIDs/Analgesic Sensitivity Mean (range)  Age at visit: 37 (14-64)  Age of first episode: 25 (10-37) N=31 Ruxrungtham K. 2001 AllergyChula Gender Female: Male 3:1

27. Clinical Features of NSAIDs/Analgesic Sensitivity A Thai Cohort (N=31) Angioedema Anaphylactoid 2 Aspirin disease (ASA Triad) Asthma+ Urticaria+ angioedema Nasoocular+ angioedema Ruxrungtham K. 2001 AllergyChula

28. NSAIDs/Analgesic Sensitivity A Thai Cohort Ruxrungtham K. 2001 AllergyChula Type of Agents N=31

29. NSAIDs/Analgesic Sensitivity A Thai Cohort Cross-reaction with paracetamol N=25 Ruxrungtham K. 2001 AllergyChula

30. Case study: Diagnosis Aspirin Triad  Rhinosinusitis with nasal polyps  Chronic asthma  ASA sensitivity AllergyChula More specific diagnosis: Aspirin Disease

31. AIRE Survey Findings N=2803 in 7 European Countries AllergyChula

32. AIRE Survey Findings N=2803 in 7 European Countries AllergyChula

33. Asthma: A Highly Variable Disease Airway Inflammation Smooth Muscle Dysfunction Airway Remodeling Infection Allergens AR Pollutants Sinusitis Cold air Excercise Drugs ASA/NSAIDS Psychological Variable Asthmatic Symptoms Intermittent Intermittent Persistent Persistent Mild Mild Moderate Moderate Severe Severe Irreversibility Irreversibility Treatment Adherence Avoidance Genetics AHR ReversibleAirwayObstruction Treating Asthma: Individualized and Dynamics Approach