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Kiat Ruxrungtham, M.D. Division of Allergy and Clinical Immunology Department of Medicine,

A STHMA A H IGHLY V ARIABLE D ISEASE. Kiat Ruxrungtham, M.D. Division of Allergy and Clinical Immunology Department of Medicine, Faculty of Medicine Chulalongkorn University. Case Study 1 : PM, age 44(cont’d). Variation of Clinical symptoms and PEF. LABA/ICS. LABA/ICS. Lost FU.

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Kiat Ruxrungtham, M.D. Division of Allergy and Clinical Immunology Department of Medicine,

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  1. ASTHMAA HIGHLY VARIABLE DISEASE Kiat Ruxrungtham, M.D. Division of Allergy and Clinical Immunology Department of Medicine, Faculty of Medicine Chulalongkorn University

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

  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 Non-adherence worsening AR Lost FU Lost FU

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

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

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

  7. Immediate and Late Phase Asthmatic Reactions (IPAR and LPAR) FEV1 IPAR LPAR Allergen BHR mins 1 2 3 4 5 6 7 8 9 10 -hrs//-------- days Time after Allergen Challenge AllergyChula

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

  9. Fatal Asthma 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. Normal subject (postmortem) Reliable markers for predicting of severe and fatal prone asthma is needed AllergyChula Busse W JACI 2000

  10. Smooth Muscle Dysfunction in Asthma • Increase contraction • Increase smooth muscle mass, hyperplasia • 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. PDGF IL-1a PDGF IL-2 TGFb IL-1a IGF-1 IL-1b histamine IL-1 HB-EGF VIP Tryptase IL-3 IL-3 ET-1 IL-3 ECP CGRP IL-4 EDN IL-4 IL-4 IL-10 GRO-B IL-5 IL-6 NCF IL-1 EDP EPO IL-5 IL-5 SLPI IL-6 IL-8 NEP IL-8 IL-12 GM-CSF SCF GM-CSF MBP IL-6 IL-4 IL-6 FGF IL-10 CR3 IL-8 IL-8 CD8 ICAM-1 LTE4 IL-11 ICAM-1 eotaxin E-selectin ICAM-1 IL-10 IL-10 TNFa TNFa IL-3 PGD2 IL-13 iNOS L-selectin IL-16 NO IL-13 RANTES LTD4 IL-13 O2- CD4 SCF IL-17 cPLA2 IL-5 ICAM-3 TXB2 IL-14 LTC4 TNFa COX2 TNFa MCP-1 IL-1a IL-6 GM-CSF TNFa PGF2a SCF PAF PGE2 LTB4 IFN-g eotaxin Antigen presentation PGE2 IL-13 LTB4 PAF IFN-g MCP-1 MAC-1 15-LO LTC4 MCP-2 eotaxin 15-HETE MCP-4 GM-CSF GM-CSF 15-HETE MMP-9 RANTES MIP-1a RANTES MCP-3 MCP-1 MIP-1a MIP-1a RANTES Cells, cytokines and molecules in Asthma AllergyChula Johnson M et al 2000 and Vignola M Nice 2001

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

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

  16. PDGF IL-2 TGFb IL-1a histamine IL-1 HB-EGF Tryptase IL-3 IL-3 ECP EDN IL-4 IL-4 NCF EDP EPO IL-5 IL-5 SCF MBP IL-6 IL-6 IL-10 CR3 IL-8 IL-8 LTE4 GM-CSF IL-4 ICAM-1 IL-10 IL-10 TNFa PGD2 IL-3 IL-1a PDGF L-selectin IL-1b IGF-1 SCF VIP IL-13 LTD4 IL-13 O2- ET-1 IL-3 IL-5 CGRP IL-4 IL-6 GRO-B IL-5 IL-1a IL-6 TXB2 IL-14 SLPI LTC4 GM-CSF IL-13 IL-6 IL-8 TNFa NEP IL-8 FGF IL-10 TNFa PAF ICAM-1 LTB4 TNFa IFN-g eotaxin IL-11 E-selectin LTB4 IL-13 iNOS PAF IFN-g IL-16 MAC-1 RANTES NO LTC4 cPLA2 IL-17 eotaxin MCP-1 TNFa COX2 SCF GM-CSF GM-CSF PGF2a PGE2 GM-CSF 15-HETE PGE2 RANTES eotaxin 15-LTs MCP-3 MCP-1 MCP-1 MIP-1a MIP-1a RANTES 15-LO MCP-2 15-HETE MCP-4 MMP-9 MIP-1a RANTES Synergy of ICS and LABA Johnson M et al 2000 and Vignola M Nice 2001

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

  18. histamine histamine IL-1 IL-1 Tryptase IL-3 Tryptase IL-3 IL-4 IL-4 NCF NCF IL-5 IL-5 SCF IL-6 SCF IL-6 IL-8 LTE4 IL-8 LTE4 IL-10 IL-10 PGD2 PGD2 IL-13 LTD4 IL-13 LTD4 IL-14 LTC4 IL-14 LTC4 TNFa LTB4 TNFa LTB4 PAF IFN-g PAF IFN-g eotaxin GM-CSF eotaxin RANTES GM-CSF RANTES MCP-3 MIP-1a MCP-3 MIP-1a Synergistic Effects of ICS+LABA on Mast Cells

  19. Synergy of CS and LABA on Epithelial Cells in Asthma IL-1a PDGF IL-1a IGF-1 IL-1b PDGF IGF-1 IL-1b VIP VIP IL-3 ET-1 ET-1 IL-3 CGRP IL-4 CGRP IL-4 GRO-B IL-5 GRO-B IL-5 SLPI IL-6 SLPI NEP IL-6 IL-8 NEP FGF IL-10 IL-8 FGF ICAM-1 IL-10 IL-11 ICAM-1 E-selectin IL-11 E-selectin IL-13 iNOS IL-13 iNOS IL-16 NO IL-16 IL-17 NO cPLA2 cPLA2 IL-17 TNFa COX2 TNFa COX2 GM-CSF PGF2a PGE2 PGF2a GM-CSF eotaxin PGE2 eotaxin MCP-1 15-LO 15-LTs MCP-1 MCP-2 15-LO 15-HETE MCP-4 MCP-2 15-HETE MMP-9 MCP-4 MIP-1a RANTES MMP-9 MIP-1a RANTES

  20. Synergy of CS and LABA on Smooth muscle cell in Asthma IL-6 IL-6 IL-8 GM-CSF IL-8 GM-CSF eotaxin eotaxin TNFa TNFa RANTES RANTES MCP-1 MCP-1 SCF SCF PGE2 PGE2

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

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

  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 Morning (AM) Evening (PM) * * * * * * * P=0.002 * * * * *<0.05 * Corren J, et al J Allergy Clin Immuno 1997; 100:781-788

  25. SINUSITIS

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

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

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

  29. NSAIDs/Analgesic SensitivityA Thai CohortCross-reaction with paracetamol N=25 Ruxrungtham K. 2001 AllergyChula

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

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

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