Asthmatic Cough (Cough variant asthma) & Nonasthmatic Eosinophilic Bronchitis

1. Asthmatic Cough (Cough variant asthma) & Nonasthmatic Eosinophilic Bronchitis Necla Songür, MD Süleyman Demirel University School of Medicine Department of Chest Diseases

2. Spontaneous or induced sputum eosinophils ratio > 2.5 % Eosinophilic Bronchitis Gibson PG et al, Thorax 2002

3. Asthma Cough variant asthma Nonasthmatic eosinophilic bronchitis Atopic cough Allergic rhinitis Gastro-esophageal reflux disease (GERD) Chronic obstructive pulmonary disease (COPD) Eosinophilic BronchitisClinical Presentation

4. Eosinophilic BronchitisPrevalance 100 80 60 % 40 20 Healthy Rhinitis Cough ERS CVA Asthma Gibson PG et al, Thorax 2002

5. Eosinophilic BronchitisPathogenesis • Asthma • Chronic cough IL5 • COPD • Allergic rhinitis? • GERD? Gibson PG et al, J Allergy Clin Immunol 1998 Brightling CE et al, Am J Respir Crit Care Med 2000 Saette et al, Clin Exp Allergy 1996

6. Eosinophilic BronchitisChronic Cough • Cough variant asthma • Nonasthmatic eosinophilic bronchitis • Atopic cough

7. Chronic Cough & Eosinophilic Bronchitis G E C A B

9. Cough Variant AsthmaDiagnosis • Chronic cough lasting more than 8 weeks • Absence of a history of wheezing or dyspnea • Absence of post-nasal drip • Physical examination of lungs is normal • Chest roentgenography is normal Corrao et al, N EJM 1979

10. Cough Variant AsthmaDiagnosis • FEV1> 80% (pred), FVC>80%(pred) FEV1 / FVC ≥ 70 %(pred) • PC20-FEV1< 10 mg/ml • Relief of cough after bronchodilator theraphy Corrao et al, NEJM 1979

11. Cough Variant Asthma Is a subgroup of asthma ?

12. Detection of Eosinophils in Hypertonic Saline-Induced Sputum in Patients with Chronic Nonproductive Cough Songür N et al, J Asthma 1997

13. Presence of Eosinophils in Induced sputum in Each Patients Group Eosinophils 1-25 % 26-75 % 76-100% Songür N et al, J Asthma 1997

14. Percentage of Eosinophils in BAL and Number of Eosinophils in Bronchial Tissue Niimi A et al, Eur Res J 1998

15. Subepithelial layer thickness (µm) Eosinophilic inflammation in patients with CVA may cause remodelling of the airway. Control Asthma CVA NiimiA et al, Lancet 2001

16. Cough variant asthma and asthma share a similar airway inflammatory marker profile IL5 IL8TNFά De Diego et al, Allergy 2005

17. Cough variant asthma comprises a subgroup of asthma • Eosinophilic airway inflammation in asthma and cough variant asthma is similar. • The ratio of eosinophilic inflammation is not related to differences between symptoms of cough variant asthma and classic asthma

18. Cough • Heightened airway cough receptor sensitivity( C5≤ 3.9uM) • Bronchoconstruction Songür N et al, Respirology, 2000 Fujimura M et al, Thorax 1992 Fujimura M et al, Eur Res J 1992

19. Cough receptor sensitivity is within normal limits in patients with cough variant asthma and inhale corticosteroids does not affect the sensitivity Patients without ICS Patients with ICS Fujimura M et al, Cough 2005 Songür N et al, J Asthma 1997

20. Cough Variant Asthma“Cough Reflex Sensitivity” • within normal limits (C5>3.9µM) • not a feature of disease Fujimura M et al, Eur Res J 1992 Fujimura M et al, J Asthma 1994 Songür N et al, J Asthma 1997 Fujimura M et al, Cough 2005

21. Cough Variant Asthma • Cough in the middle of the night and early in the morning • PEFR monitoring → morning dip • Increase in FEV1 after therapy • Relief of cough with bronchodilator therapy Shirata et al, Respirology 2005 Sano T et al, Lung 2004 Fujimura M et al, Clin Exp Allergy 2003 Kim CK etal, Clin Exp Allergy 2003

22. Cough Variant asthma Small degree contractions of airway smooth muscle trigger cough.

23. Cough Variant Asthma • Pre-asthmatic state • Early stage of mild persistant asthma

24. Nearly 30% of cough variant asthma develop typical asthma within several years Study/Year CVA (n) Median fallow up (year) Asthma (%) Corrao et al 1979 6 1 2 (33) Braman et al 1985 16 3-5 6 (37) Kim et al 2003 51 4 24 (47) Fujimura et al 2003 55 4 8 (14) Fujimura et al 2005 20 3 3 (15) Fujimura et al 2005 27 4 7 (29)

25. Cough Variant Asthma Predictor of Subsequent Development of Classic Asthma An increased ratio of eosinophil in induced sputum can predict the subsequent development of classic asthma Development of Classic Asthma % 2.5-4.7 4.8-8.2 0-2.4 8.3-17.3 Sputum eosinophil (%) Kim CK et al, Clin Exp Allergy 2003

26. Univariate analysis Bronchial hyperresponsiveness Blood eosinophils (%) No use of inhaled corticosteroids Multivariate analysis Bronchial hyperresponsiveness CoughVariant AsthmaPredictors of Subsequent Development of Classic Asthma Fujimura M et al, J Asthma 2005

27. Cough Variant AsthmaTreatment ? Inhaled bronchodilators (β agonist) Inhaled corticosteroids (mean: 400mcg, 200-800 mcg) Leukotriene receptor antogonists Oral corticosteroids (30 or 40mg prednizone/daily / for one week) Suplatast tosilate Dicpinigaitis PV, Thorax 2004 Dicpinigaitis PV, Chest 2006

28. Nonasthmatic Eosinophilic BronchitisDiagnosis • Isolated chronic cough lasting more than 8 weeks • Absence of a history of wheezing and dyspnea • Absence of post-nasal drip • Physical examination of lungs is normal • Chest roentgenography is normal Gibson PG et al, Lancet 1989

29. Nonasthmatic Eosinophilic BronchitisDiagnosis FEV1> 80% (pred), FVC> 80% (pred) FEV1/FVC ≥70% (pred) PC20-FEV1> 16 mg/ml Sputum eosinophil > 3% (11% - 85%) Relief of cough treatment with inhaled corticosteroids or oral corticosteroids Gibson PG et al, Lancet 1989

30. Nonasthmatic Eosinophilic Bronchitis Clinical Features Brightling CE et al, Thorax 2003

31. Eosinophil counts in induced sputum, bronşial wash and BAL fluid in patients with nonasthmatic eosinophilic bronchitis *p<0.05,**p<0.01, Brightling CE et al, Thorax 2003

32. Nonasthmatic Eosinophilic Bronchitis Pathogenesis **p<0.01 Brightling CE et al, Thorax 2003

33. Conclusion Airway inflammation is similar in both conditions and the site of inflammation is mainly in the lower airway.

34. Why is NAEB not asthma ?

35. The difference in symptoms of NAEB is not due to the differences in mediator production Brightling CE et al, AJCCM 2000

36. Mast cell infiltration of airway smooth muscle in asthma Brightling CE et al , NEJM 2002

37. There is no mast cell infiltration of airway smooth muscle in nonasthmatic eosinophilic bronchitis Brightling CE et al, NEJM 2002 p<0.001

38. Why is Eosinophilic Bronchitis not Asthma

39. Why is Eosinophilic Bronchitis not Asthma

40. Nonasthmatic Eosinophilic Bronchitis“Cough Reflex Sensitivity” • The cause of cough is the hightened cough reflex sensitivity (C5< 3.9uM ). • The therapy of inhaled or oral corticosteroid suppresse of coughing, sputum eosinophilia, and cough reflex sensitivity to inhaled capsaicin. Gibson PG et al, Clin Exp Allergy 1998 Brightling CE et al, Eur Respir J 2000

41. The specific role of mast cells in the bronchial epithelium of patients with nonasthmatic eosinophilic bronchitis and its interactions with cough sensory afferents needs further study.

42. NAEB is generally benign and self-limiting disease (?) Hancox RJ et al, Lancet 2001

43. NAEBmay be forerunner the subsequent development of classic asthma and COPD 52 patients with NAEB (1996-2003) 32 patients (follow up >1year) • 3 (9%) patients developedclassic asthma • 5 (16%) patients developedfixed airflow obstruction Berry MA et al, Clin Exp Allegy 2005

44. Nonasthmatic Eosinophilic BronchitisTreatment • Inhale corticosteroids (200-400 mcg) • Oral corticosteroids • Avoidance strategies Brightling CE, Chest 2006

45. Nonasthmatic Eosinophilic Bronchitis Persistent eosinophilic inflammation Airway remodelling Progressive irreversible airflow obstruction

46. The early diagnosis and suscessful treatment is very important in patients with NAEB.