The impact of allergic rhinitis on asthma

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

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

3. Why do we have a nose?

4. Functional relationship

5. Nose Rhinitis Lung Asthma normal disease Macroscopic view

6. Rhinitis Asthma Microscopic view

7. Allergen Dendritic cell MBP ECP LTs PGs PAF IL-1 IgE Th0-cell B-cell Eosinophil Mast cell IL-4 IL-13 IL-10 Eotaxin IL-5 RANTES IFN- histamine Th1-cell Th2-cell VCAM-1 ICAM-1 E-selectin Systemic circulation Airway inflammation

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

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

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

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

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

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

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

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

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

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

18. Lower airway involvement in atopic patients

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

20. nose bronchus Epithelium shedding 0 to + +++ metaplasia 0 0 Basement membrane pseudo-thickening 0 to + ++ to +++ collagen deposition 0 to + ++ to +++ other proteins ? ++ to +++ Fibroblasts sub-mucosa 0 to + ? ++ to +++ Collagen in sub-mucosa ? + to ++ Nasal and bronchial mucosa in asthma and rhinitis 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? • Is there any interaction between upper and lower airways? • 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 VCAM-1 Eosinophils nose lung Allergic inflammation

27. Bronchial inflammation after NP

28. SBP in allergic rhinitisinfluence on upper airways

29. Methods

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

31. Cell/mm2 Lung Nose * 80 40 60 30 40 20 20 10 0 0 before after controls allergic Nasal inflammation after SBPMBP Lamina propria Cell/mm2 * before after Braunstahl GJ et al, AJRCCM, 2000

32. MCC MCT controls allergic MCTC Nasal inflammation after SBPMCTC Lamina propria Cell/mm2 Nose 200 * 150 100 50 0 before after Chymase (C) and Tryptase (T) 400x Braunstahl GJ et al, AJRCCM, 2001

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? • Is there any interaction between upper and lower airways? • What are the mechanisms that may play a role in nasobronchial cross-talk?

35. NHV NHV OHV 5 4 4 FEV1 FEV1 NR cm H2O/L/sec B = baseline R = frigid air 0 0 0 R R R B B B 0.01 0.27 <0.001 P value Nasal vs. oral ventilationeffect of cold air inhalation McLane, J. Appl. Physiol. 2000

36. 99mTc 1 hr 6 hr 24 hr Maxillary sinus nasopharynx Oesophagus stomach Rest of GI tract Bardin et al, JACI, 1990 Pulmonary aspiration?Radio-active markers

37. NAR cmH20/L/sec LAR cmH20/L/sec 20 15 10 5 0 5 4 3 2 1 0 * * * * base peak controls base peak asthmatics base peak controls base peak asthmatics Lidocaine: no blockage * = p < 0.05 vs baseline Phenylephrine: blockage Naso-bronchial reflex?effect of intranasal methacholine Littell et al, Am Rev Respir Dis, 1990

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

39. cell x 106 eosinophils pg/mL IL-5 400 50 * * 300 40 30 200 20 100 10 0 0 before after before after control allergic 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 and asthma characterized by global airway inflammation. • 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