1. The impact of allergic rhinitis on asthma Gert-Jan Braunstahl Pulmonary medicine, EMCR, Rotterdam

2. ARIA Objectives: Update knowledge of AR Update knowledge of AR Recognise AR as global health problem Recognise AR as global health problem Asthma and AR commonly occur together Asthma and AR commonly occur together Evidence-based approach to diagnosis and treatment Evidence-based approach to diagnosis and treatment Management of allergic airways disease Management of allergic airways disease Bousquet et al, J Allergy Clin Immunol 2001

3. Why do we have a nose?

4. Functional relationship

5. Macroscopic view Nose Lung normaldisease Rhinitis Asthma

6. Rhinitis Microscopic view

7. Dendritic cell Th1-cellTh2-cell IFN-  IL-10 IL-1 Th0-cell VCAM-1 ICAM-1 E-selectin IL-4 IL-13 B-cell IgE Allergen Mast cell histamine LTs PGs PAF Eotaxin IL-5 RANTES Eosinophil MBP ECP Systemic circulation Airway inflammation

8. Pathogenesis allergic airway disease Genetic factors Environmental factors Atopic sensitization Structural changes Mucosal inflammation Phenotype

9. Association rhinitis/sinusitis and asthma 0 2 4 6 8 10 R-S-R+S-R-S+R+S+ OR 1 * * * p < 0.001 Guerra, J Allergy Clin Immunol 2002

10. 80-95% of asthmatic patients have rhinitis. 80-95% of asthmatic patients have rhinitis. 76% asthmatic patients reported presence of rhinitis before onset asthma. 76% asthmatic patients reported presence of rhinitis before onset asthma. Asthma presence associated with duration and severity of rhinitis. Asthma presence associated with duration and severity of rhinitis. Epidemiology Leynaert, J Allergy Clin Immunol 2004

11. Causal relationship rhinitis asthma Disease severity time Togias, Allergy 1999

12. Questions What is the relationship between allergic rhinitis and asthma? What is the relationship between allergic rhinitis and asthma? Is there any interaction between upper and lower airways? Is there any interaction between upper and lower airways? What are the mechanisms that may play a role in nasobronchial cross-talk? What are the mechanisms that may play a role in nasobronchial cross-talk?

13. Questions What is the relationship between allergic rhinitis and asthma? What is the relationship between allergic rhinitis and asthma? Is there any interaction between upper and lower airways? Is there any interaction between upper and lower airways? What are the mechanisms that may play a role in nasobronchial cross-talk? What are the mechanisms that may play a role in nasobronchial cross-talk?

14. Australia asthma 18% rhinitis 25% Canada asthma 13% rhinitis 25% Sweden asthma 8% rhinitis 15% China asthma 5% rhinitis 10% Brasil asthma 10% rhinitis 22% Kenya asthma 8% rhinitis 13% ISAAC study, Lancet 1998 Worldwide prevalence

15. Prevalence asthma and rhinitis in NL Non- allergic 68 Allergic no symptoms 10 Rhinitis 12 Asthma + Rhinitis 8 Asthma 2

16. Nasal inflammation in asthma Gaga M. et al, Clin Exp Allergy 2000 16 ARANRHC EG2 + cells per field 12 8 4 0 p<0.001

17. Nasal inflammation and BHR Nasal eosinophil number 20 22 absent 3 low 11 moderate 12 high 10 0 PD20 methacholine Ciprandi G. et al, Int Arch Allergy Immunol 2004

18. Lower airway involvement in atopic patients

19. Bronchial remodeling in asthma and rhinitis Chakir et al, Lab Invest 1996 0 5 10 15 20 25 basement membrane thickness (µm) controlsrhinitisasthma type I collagen 0 5 10 15 20 25 controlsrhinitisasthma type III collagen 0 5 10 15 20 25 controlsrhinitisasthma fibronectin

20. Nasal and bronchial mucosa in asthma and rhinitis nosebronchus Epithelium shedding0 to ++++ shedding0 to ++++ metaplasia 00 metaplasia 00 Basement membrane pseudo-thickening0 to + ++ to +++ collagen deposition0 to +++ to +++ other proteins?++ to +++ Fibroblasts sub-mucosa0 to + ?++ to +++ Collagen in sub-mucosa?+ to ++ Courtesy of Jean Bousquet

21. Summary Mucosal inflammation is present in the entire airway of patients with allergic rhinitis and/or asthma. Upper airway inflammation is associated with bronchial hyperresponsiveness Lower airway remodeling is present in asthmatic, but also in allergic rhinitis patients.

22. Questions What is the relationship between allergic rhinitis and asthma? What is the relationship between allergic rhinitis and asthma? Is there any interaction between upper and lower airways? Is there any interaction between upper and lower airways? What are the mechanisms that may play a role in nasobronchial cross-talk? What are the mechanisms that may play a role in nasobronchial cross-talk?

23. NP in allergic rhinitis influence on lower airways

24. Symptoms (VAS)

25. Airway function

26. Baseline nose lung VCAM-1Eosinophils Allergic inflammation

27. Bronchial inflammation after NP

28. SBP in allergic rhinitis influence on upper airways

29. Methods

30. Nasal inflammation after SBP Before 100 x After MBP bronchial challenge

31. Nasal inflammation after SBP Nasal inflammation after SBP MBP Lamina propria controls allergic before * after 0 20 40 60 80 Lung Cell/mm 2 before * after 0 10 20 30 40 Nose Cell/mm 2 Braunstahl GJ et al, AJRCCM, 2000

32. Chymase (C) and Tryptase (T) 400x Nasal inflammation after SBP Nasal inflammation after SBP MC TC Lamina propria MC T MC C MC TC before * after 0 50 100 150 200 Cell/mm 2 controls allergic Braunstahl GJ et al, AJRCCM, 2001 Nose

33. Summary The interaction between nose and lung in allergic airways disease is a bi-directional process

34. Questions What is the relationship between allergic rhinitis and asthma? What is the relationship between allergic rhinitis and asthma? Is there any interaction between upper and lower airways? Is there any interaction between upper and lower airways? What are the mechanisms that may play a role in nasobronchial cross-talk? What are the mechanisms that may play a role in nasobronchial cross-talk?

35. Nasal vs. oral ventilation effect of cold air inhalation McLane, J. Appl. Physiol. 2000 B = baseline R = frigid air NHV OHV NR cm H 2 O/L/sec FEV 1 P value 0.010.27<0.001 B R B R B R FEV 1 0 5 0 4 0 4

36. Pulmonary aspiration? Radio-active markers Bardin et al, JACI, 1990 Maxillary sinus nasopharynx Oesophagus stomach Rest of GI tract 99m Tc 1 hr6 hr24 hr

37. Naso-bronchial reflex? effect of intranasal methacholine base peak controls base peak asthmatics LAR cmH 2 0/L/sec 543210543210 * * Lidocaine: no blockage base peak controls base peak asthmatics NAR cmH 2 0/L/sec 20 15 10 5 0 * * * = p < 0.05 vs baseline Littell et al, Am Rev Respir Dis, 1990 Phenylephrine: blockage

38. Systemic interaction? effect of NP on IL-5 plasma Beeh et al, Clin Exp Allergy, 2003 IL-5 (pg/mL) Allergen prepost 80 * Placebo prepost 60 40 20 0 * p < 0.001

39. control allergic before * after 0 10 20 30 40 50 IL-5 pg/mL before * after 0 100 200 300 400 eosinophils cell x 10 6 Braunstahl GJ et al, AJRCCM, 2001 Systemic interaction? effect of SBP on IL-5 and eosinophils

40. Summary

41. Take home messages Allergic rhinitis often precedes asthma. Allergic rhinitis often precedes asthma. Allergic rhinitis and asthma characterized by global airway inflammation. Allergic rhinitis and asthma characterized by global airway inflammation. There is a bi-directional influence between upper and lower airways. There is a bi-directional influence between upper and lower airways. The systemic pathway plays an important role in the interaction between nose and lung The systemic pathway plays an important role in the interaction between nose and lung