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Nov 23 at 8am

Nov 23 at 8am. Sala Dios Candangos. Non-Eosinophilic Asthma: Mechanisms and Treatment. Prof Peter G Gibson NHMRC Centre for Respiratory and Sleep Medicine Newcastle, Australia. FEV 1 %: 70% pred BDR%: 15% PC 20 : 0.13 SABA : 6.5. 88% 13% 0.45 mg/ml 3.8 puffs/day.

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Nov 23 at 8am

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  1. Nov 23 at 8am Sala Dios Candangos

  2. Non-Eosinophilic Asthma: Mechanisms and Treatment Prof Peter G Gibson NHMRC Centre for Respiratory and Sleep Medicine Newcastle, Australia

  3. FEV1%: 70% pred BDR%: 15% PC20 : 0.13 SABA : 6.5 88% 13% 0.45 mg/ml 3.8 puffs/day 2 people with asthma… Turner MO etal Thorax 1995;50:1057

  4. GINA guidelines “…….a condition in which many cells and cellular elements play a role…….” HETEROGENEITY

  5. Inflammatory Phenotypes: relevance • diagnosis • pathophysiology • response to treatment

  6. Treatment response depends on inflammatory phenotype Meijer Clin Exp Allergy 2002

  7. Sputum strategy reduced Eosinophilic exacerbations: Jayaram, Pizzichini ERJ 2006 Eosinophilic Exacerbations Noneosinophilic Exacerbations sputum

  8. Mechanisms

  9. Allergens Acquired Immunity IgE Activated TH2 Cells IL-4, 5, 9,13 Eosinophils MBP ECP LTC-4 Eosinophilic Asthma

  10. Allergen avoidance Allergens Acquired Immunity Omalizumab IgE Immunotherapy Activated TH2 Cells Corticosteroids IL-5 Eosinophils MBP ECP LTRA LTC-4 Eosinophilic Asthma

  11. Non-Eosinophilic asthma • Symptoms • Increased Airway responsiveness • Eosinophils within normal range

  12. Particulates, Pollutants, Virus, Endotoxin, Bacteria Allergens Acquired Immunity Innate Immunity IgE TLR Activated TH2 Cells Macrophages and Epithelial Cells ICS X X LABA Neutrophilic Asthma Eosinophilic Asthma Inflammatory cell activation X LABA hyperresponsiveness

  13. Inflammatory Phenotypes Eosinophilic Neutrophilic Paucigranulocytic

  14. Inflammatory Phenotypes in Stable Asthma 31% 41% 28% Simpson J et al, Respirology 2006;11:54-61

  15. Bronchial Biopsy Eosinophils/sq. mm • EA n=12, HC n=10, NEA n=11 • Bronchial biopsy, BAL, Ind sputum • Immunopathology • NON-response to ICS confirmed in rct Berry M etal Thorax, 2008

  16. Pathology of NEA um Cells / sq.mm Berry M etal, 2008

  17. HRCT in Neutrophilic Asthma Emphysema Score Bronchial Wall Thickening * * Simpson J, Milne D, Gibson PG submitted

  18. Neutrophilic Asthma: how is it different ?

  19. Characteristics of Neutrophilic Asthma • Stable asthma: n=259 • Eosinophilic n=135, 52% • Neutrophilic alone n=60, 23% • B2 only n=35 • Less atopy • Older • Later onset asthma Green RH et al Thorax 2002;57:875-9

  20. Neutrophil Elastase * 107 mg/mL 56 mg/mL * p<0.04 versus Eosinophilic & Paucigranulocytic Asthma Simpson J Am J Resp Crit Care Med 2005;172:559

  21. Zymography: MMP-9 201kDa 118kDa Pro MMP-9 ~ 92kDa Active MMP-9~ 88kDa 83kDa MMP-2 ~ 72kDa 48kDa Ladder Control NA HC PGA EA Simpson J Am J Resp Crit Care Med 2005;172:559

  22. % Active MMP-9 * * p<0.001 versus all other groups Simpson J Am J Resp Crit Care Med 2005

  23. Non-Eosinophilic Asthma Eosinophilic Asthma Enhanced IL-8 Release Resting LPS Stimulated * * spont. LPS Katie Baines subm. Baines K etal

  24. Resting Neutrophils: Distinct Gene Profiles in Asthma Subtypes Tues 27/3 ASIG 3.30pm Baines K Eosinophilic Asthma Eosinophilic Asthma Eosinophilic Asthma Neutrophilic Asthma Neutrophilic Asthma ... Tues 27/3 ASIG 3.30pm Baines K Baines K, submitted

  25. Neutrophilic Asthma is different….. • In the airway • In the blood • Different genes • Different mediators • ……….…different disease ?

  26. Neutrophilic Asthma: why is it different ?

  27. Gene array: Classification of biological function + + + + means more genes than expected (category is overrepresented)

  28. What do we know about the NF-kB pathway ? • Innate immune response • Input: • Toll-Like Receptors • Oxidant stress • Output: • I L-8 • Neutrophils

  29. Acquired antigen dependent antigen specific late memory cytokines T/B/macrophage Innate antigen independent pattern recognition early immediate antimicrobial molecules neutrophil What is innate immunity? Hoebe K, etal. Adv Immunol 2006; 91:175

  30. Innate immune responses

  31. Non-allergic triggers TLRs and SPs Innate Immune Activation NF-kB Noneosinophilic asthma IL-8, IL-6 Inflammation Douwes, Gibson, Pearce etal Thorax; 2002:57:643

  32. Innate Immune Activation in Asthma Phenotypes Asthma N=49 Eos Paucigranulocytic Neuts Bronchiectasis, n=9 Healthy Control n=12 Simpson JL, Thorax 2007;63:211

  33. Inflammatory Cell Counts Neutrophilic Eosinophilic Paucigranulocytic Bronchiectasis 6 5 4 3 Eosinophil, % 2 Simpson JL, Thorax 2007;63:211 1 0

  34. Sputum IL-8 mRNA *†º *†º * versus Healthy Controls † versus Eosinophilic Asthma º versus Paucigranulocytic Asthma Simpson JL, Thorax 2007

  35. * TLR2 protein * * Simpson JL, Thorax 2007;63:211

  36. Non-allergic triggers Clarithromycin Reduces IL-8 TLRs and SPs NF-kB * Neutrophilic asthma IL-8, IL-6 Inflammation

  37. Non-allergic triggers…. Pollution Particulates TLR2/4 Bacteria, endotoxin TLR 4 Virus RSV TLR4/SP-D …also trigger innate immune activation

  38. Stable Asthma, no ICS nonsmokers smokers Chalmers, CHEST 2001

  39. Particulates, Pollutants, Virus, Endotoxin Allergens Acquired Immunity Innate Immunity IgE TLR Activated TH2 Cells Macrophages and Epithelial Cells NF-kB Oxidative stress IL-5 IL-8 Eosinophils Neutrophils MBP ECP MMP-9 NE Eosinophilic Asthma Neutrophilic Asthma

  40. 10 days: low antioxidant diet

  41. Effects of Antioxidant withdrawal on Asthma Asthma Control Sputum Neuts * * Wood LG, Free Radic Biol 2008

  42. Antioxidant Supplement : lycopene reduces neutrophilic inflammation Lycopene Elastase Wood LG, Free Rad Biol

  43. What about treatment ?

  44. Particulates, Pollutants, Virus, Endotoxin, Bacteria Allergens Acquired Immunity Innate Immunity IgE TLR Activated TH2 Cells Macrophages and Epithelial Cells ICS X Neutrophilic Asthma Eosinophilic Asthma Inflammatory cell activation X LABA hyperresponsiveness

  45. LABA reduces Neutrophilic Inflammation * * * Barnes PJ, Chest 2005 128:1936 Reid DW, ERJ, 2003

  46. Symptomatic Asthma AHR to hypertonic saline Severe Persistent asthma according to the 2002 GINA guidelines No sensitivity to macrolide antibiotics Macrolides for Persistent Asthma: Inclusion Criteria Clarithromycin Simpson JL, AJRCCM, 208

  47. V1 V2 V3 V4 V5 CAM 1000mg Follow Up Screening R Placebo t=-4 t=0 t=8 t=12 Study Design

  48. Enrolment n=79 Excluded (n=33) Allocated n=46 Placebo =23 Active n=23 1 lost to follow up Completed n=22 placebo, n=23 active Consort Chart

  49. Participant Characteristics

  50. Non-Eosinophilic Asthma • 28 participants with NEA • Similar age, gender, ICS dose, lung function and asthma control

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