1. Are rhinitis and asthma two manifestations of one disease? Stephen R. Durham Allergy and Clinical Immunology Royal Brompton Hospital and Imperial College London WAO Cancun Dec 7 th 2011

2. Relationship between rhinitis and asthma – implications for treatment Is there a relationship between rhinitis and asthma ? Is the relationship causal ? Does treating rhinitis improve asthma?

3. Jarvis D et al Allergy 2011 Nov 4. [Epub ahead of print] Asthma in adults and its association with chronic rhinosinusitis: The GA(2)LEN survey in Europe. 52,000 adults (18 -75 yr) 19 centres,12 countries. Strong association of asthma with CRS (adjusted OR: 3.47; 95% CI: 3.20-3.76). Association stronger in those with CRS and allergic rhinitis (adjusted OR: 11.85; 95% CI: 10.57-13.17).

4. Allergic rhinitis is a risk factor for asthma Allergic rhinitis increased the risk of asthma ~3-fold 23-year follow-up of college freshmen undergoing allergy testing; data based on 738 individuals (69% male) with average age of 40 years. 12 10 8 6 4 2 0 % of patients who developed asthma 10.5 Allergic rhinitis at baseline (n=162) 3.6 No allergic rhinitis at baseline (n=528) p<0.002 Settipane RJ et al Allergy Proc 1994;15:21-25.

5. The nose is that part of the lung which is accessible to the finger

6. Rhinitis / Asthma : Similarities Frequently coexist Respiratory pseudostratified epithelium IgE-dependent mechanisms Th2 T lymphocyte activation Eosinophil rcruitment Mast cell / basophil activation and transepithelial migration

7. Rhinitis / Asthma: Differences Epithelium intact Basement membrane normal No airway smooth muscle Venous sinusoids Submucosal glands prominent Remodelling absent Antihistamines effective  2 -agonists ineffective Epithelium disrupted Basement membrane abnormal Bronchial smooth muscle No venous sinusoids Submucosal glands few Remodelling present Antihistamines ineffective (?)  2 -agonists effective RhinitisAsthma

8. Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower airways. Braunstahl G-J, Overbeek SE, KleinJan A, Prins J- B, Hoogsteden HC, Fokkens WJ. J Allergy Clin Immunol 2001;107:469-76.

9. Study design

10. Ag Nasal Ag provocation

11. Nasal mucosaBronchial mucosa T 24h T 0h ICAM-1VCAM-1ICAM-1VCAM-1

12. 024 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 Allergic Rhinitis Controls (n=9) 0240 0 0 0 ICAM-1/CD31 VCAM-1/CD31 ELAM-1/CD31 ICAM-1/CD31 VCAM-1/CD31 ELAM-1/CD31 Percent positive Nose Bronchus Nose Bronchus * * * * * * * p<0.05 Influence of nasal challenge on expression of adhesion molecules on blood vessels in the nasal ( ) and bronchial ( ) mucosa

13. Treatment of allergic rhinitis mild intermittent mild persistent moderate severe intermittent moderate severe persistent Allergen and irritant avoidance Immunotherapy Intra-nasal steroid (+/- antileukotriene) Oral or topical antihistamine http://www.whiar.org/

14. Does treating hayfever help patients with asthma? Antihistamines Leukotriene antagonists Nasal corticosteroids Allergen immunotherapy

15. High-dose H 1 receptor antagonist treatment in persistent asthma Simons FER. Clin Exp Allergy 1999; 29: S98–104

16. Effect of cetirizine in patients with seasonal rhinitis and concomitant asthma placebo cetirizine 123456 123456 2 4 6 8 0 2 4 6 8 0 10 Study week Mean total rhinitis score Mean total asthma score Grant et al. J Allergy Clin Immmunol 1995; 97: 923–732

17. Does treating hayfever help patients with asthma? Antihistamines Leukotriene antagonists Nasal corticosteroids Allergen immunotherapy

18. Philip G. Curr Med Res Opin. 2004 Oct;20(10):1549-58.

19. Montelukast: Effect on hayfever in patients with asthma (n=631) * p < 0.001 compared with placebo Philip G. Curr Med Res Opin. 2004 Oct;20(10):1549-58.

20. Montelukast: Effect on hayfever in patients with asthma (n=631) Philip G. Curr Med Res Opin. 2004 Oct;20(10):1549-58.

21. Does treating hayfever help patients with asthma? Antihistamines Leukotriene antagonists Nasal corticosteroids Allergen immunotherapy

22. Welsh PW, Stricker WE, Chu CP, Naessens JM, Reese ME, Reed CE and Marcoux. Efficacy of beclomethasone nasal solution flunisolide, and cromolyn in relieving symptoms of ragweed allergy. Mayo Clin Proc.1987;62:125-34. All three treatments superior to placebo (p< 0.001). Glucocorticoids more effective than cromolyn (p<0.001). All 3 intranasal treatments ALSO reduced seasonal asthma. Study randomised but NOT blinded:

23. 100 80 60 40 20 0 7.117.248.78.219.4 9.18 7.177.318.148.289.11 1984 Treatment Mean weekly hay fever raw score Nasalcrom Placebo Nasalide Beconase aqueous Welsh PW. Mayo Clinic Proceedings 1987; 62: 125-34. Efficacy of beclomethasone nasal solution, flunisolide, and cromolyn in relieving symptoms of ragweed rhinitis

24. Efficacy of beclomethasone nasal solution, flunisolide, and cromolyn in relieving symptoms of ragweed asthma 15 10 5 0 -5 Asthma score mean weekly difference from baseline Treatment Nasalcrom Placebo Nasalide Beconase aqueous Welsh PW. Mayo Clinic Proceedings 1987; 62: 125-34.

25. Dahl R. Allergy 2005: 60: 875–881 - DBPC double-dummy study in seasonal rhinitis and asthma - no effect of intranasal steroids on asthma outcomes - no effect of inhaled steroids on nasal outcomes - but ? too mild disease to show an effect

26. Intranasal and inhaled fluticasone propionate for pollen-induced rhinitis and asthma Dahl R. Allergy 2005: 60: 875–881 Geometric mean PD20 methacholine measured at baseline ( ) and after 4 weeks treatment ( ) (*** p < 0.001 IHFP ± INFP vs INFP or placebo). INFP, fluticasone proprionate nasal spray; IHFP, inhaled fluticasone propionate.

27. Does treating hayfever help patients with asthma? Antihistamines Leukotriene antagonists Nasal corticosteroids Allergen immunotherapy

28. Allergens of Proven Efficacy in Double-Blind Placebo-Controlled Studies Birch Cat Mites Grass

29. Walker SM. J Allergy Clin Immunol 2001; 107: 87-93

30. % reduction from baseline (1998/1996) Subcutaneous immunotherapy for hayfever: effect on symptoms and rescue medication 0 -50 -100 P =.01 P =.007 Immunotherapy group Placebo group SymptomsMedication Walker SM et al JACI 2001; 107: 87-93 50% decrease in nasal Symptoms 85% decrease in asthma symptoms

31. Walker SM. J Allergy Clin Immunol 2001; 107: 87-93 Effect of immunotherapy on airway responsiveness to methacholine

32. Does treating hayfever help patients with asthma? Antihistamines Leukotriene antagonists Nasal corticosteroids Allergen immunotherapy

33. Adams RJ et al. J Allergy Clin Immunol 2002; 109: 636-42.

34. Retrospective study of 13,844 asthmatics 1031 had emergency dept visit (7.4%) Relative risk-INS 1/yr = 0.7, >3/yr = 0.5 RR anti-histamine = 0.9 Effect of rhinitis treatment on asthma exacerbations Adams RJ et al. J Allergy Clin Immunol 2002; 109: 636-42.

35. Corren J. J Allergy Clin Immunol 2004; 113: 415-9.

36. Rhinitis therapy and the prevention of hospital care for asthma: A case-control study Adjusted odds ratios for asthma-related hospital care in relation to intranasal corticosteroid and second generation antihistamine use during 1-year period before the index date

37. Is there a relationship between rhinitis and asthma ? Yes Is the relationship causal ?Yes Does treating rhinitis Maybe improve asthma? Relationship between rhinitis and asthma – implications for treatment

38. Patients with rhinitis should be evaluated for asthma Patients with asthma should be evaluated for rhinitis A strategy should combine the treatment of upper and lower airways in terms of efficacy and safety Recommendations