1. Eosinophilic bronchitis

2. Exercise, cold air Eosinophilic bronchitis Airway hyperresponsiveness Late asthmatic reaction Early asthmatic reaction Allergen Th2 IL-5 IL-4Mast cell Th2 Mast cell

3. Inflammation Variable airflow limitation Chronic airflow limitation Symptoms Airway hyperresponsiveness Symptoms are nonspecific Other respiratory and non-respiratory conditions Hargreave F, AAAAI 2006

4. Induced sputum in OA: usefulness To identify occupational eosinophilic bronchitis (due to an allergen or chemical sensitizer) with or without asthma. This is done by serial measurements of induced sputum following periods at work and away from work. Eosinophils that increase at work and fall away from work indicate eosinophilic bronchitis. To support the diagnosis when the workplace sensitizer is unknown. To monitor airway inflammation before/after specific inhalation challenge (SIC).

5. Compatible clinical history Asthma diagnosis Reversible airflow obstruction AHR Work-relatedness Sensitization Skin prick tests Sepecific IgE Methacholine test + – Still at work No Asthma No longer at work SIC + Occupacional asthma – Return to work SIC PEF monitoring +– Non-occupational asthma Chan-Yeung M, Malo JL. N Eng J Med 1995 Induced sputum

6. Changes in induced sputum after specific inhalation challenges

7. Lemière C et al. J Allergy Clin Immunol 2001;107:1063-8 Clinically significant increase:  0.26 x10 6 eosinophils/mL

8. bas102030 min1h2h4h6h8h10h24h 0 20 40 60 80 100 120 0 20 40 60 80 % Fall in FEV 1 % eosinophils in sputum PC 20 methacholine > 16 mg/ml PC 20 > 16 mg/ml Latex-induced eosinophilic bronchitis Allergen challenge After budesonide 800 mcg/day one month Latex 99 ng/m 3 60 minutes Quirce et al. JACI 2001

9. Normal Peak Expiratory Flow variability PEF L/min Days at work

10. Eosinophilic bronchitis Isolated chronic cough,  productive of sputum Normal lung function without variable airflow limitation Airway hyperresponsiveness absent Eosinophilia in sputum and BAL Cough reflex to capsaicin increased Normal daily variability in peak expiratory flow (<20%) Upper airway symptoms are common Middle age patients Smoking is unusual Prevalence of atopy similar to general population Cough, sputum eosinophilia and cough reflex to capsaicin improve with inhaled corticosteroids Gibson et al. Lancet 1989

11. Causes of isolated chronic cough Brightling CE et al. AJRCCM 1999

13. Brightling CE et al. N Eng J Med 2002 Microlocalization of mast cells in the airway smooth muscle

14. A D C B * * * * Sastre B et al (submitted).

15. * † † AB PGE 2 LTC 4 Sastre B et al (submitted).

17. Diagnostic criteria for occupational eosinophilic bronchitis Isolated chronic cough (lasting more than 3 weeks) that worsens at work Sputum eosinophilia  3% in sputum Increases in sputum eosinophils are related to exposure to the offending agent (either at work or after SIC) Spirometric parameters are normal and are not significantly affected by exposure to the offending agent Absence of bronchial hyperresponsiveness to methacholine both at work and away from work Other causes of chronic cough are rule out. Quirce S. Curr Opin Allergy Clin Immunol 2004;4:87-91

18. Causative agent No. of workers Confirmed Author, year Tetrahydrophtalic anhydride 1?Kobayashi, 1994 Cyanoacrylate Methacrylate 1At/off work SIC in the lab Lemière, 1997 Latex1At/off work/SIC labQuirce, 2001 Mushroom spores3 (7.1%)At workTanaka, 2002 Lysozyme1 (4.7%)SIC in the labQuirce, 2004 Welding fumes1At/off work/SIC labYacoub, 2005 Formaldehyde1SIC in the labYacoub, 2005 Chloramine T1SIC in the labKrakowiak, 2005 Isocyanate (MDI)1At/off work/SIC labDi Stefano, 2005 Cereal flour1Di Stefano, 2005

19. Remarks The examination of induced sputum should be part of the diagnostic algorithm for workers who complain of asthma-like symptoms in the workplace. Induced sputum is a diagnostic tool complementary to objective monitoring of lung function during periods at work and away from work, and before/after specific inhalation challenge Eosinophilic bronchitis (without asthma) should be regarded as an occupationally-induced condition when work related changes in sputum samples are significant and reproducible.

21. Recommendations In patients with chronic cough due to nonasthmatic eosinophilic bronchitis, –the possibility of an occupation-related cause needs to be considered. (Level of evidence, expert opinion; benefit, substantial; grade of recommendation, E/A) –when a causal allergen or occupational sensitizer is identified, avoidance is the best treatment. (Level of evidence, expert opinion; benefit, substantial; grade of recommendation, E/A) –first line treatment is inhaled corticosteroids (except when a causal allergen or sensitizer is identified). Level of evidence low; benefit, substantial; grade of recommendation, B. –If symptoms are persistently troublesome and/or the natural history of eosinophilic airway inflammation progresses despite treatment with high dose inhaled corticosteroids, oral corticosteroids should be given. (Level of evidence, expert opinion; benefit, substantial; grade of recommendation, E/A) Brightling CE. Chest 2006;129:116S-21S

22. Park SW et al. Chest 2004 Follow-up of patients with EB after treatment with ICS

23. Observational study of the natural history of eosinophilic bronchitis 52 patients with EB, 32 with follow-up  1 year Mean duration of follow-up: 3.1 years (1-6 years) –3 patients developed asthma (9%) –5 patients FEV 1 /FVC (post-bd) <70% (16%) –1 complete resolution of cough and eosinophilia (3%) –13 persistent cough and eosinophilia >3% on one or more occasions (41%) –7 persistent cough and eosinophilia < 3% (22%) –3 symptom free and eosinophilia >3% occasionally (9%) Berry MA et al. Clin Exp Allergy 2005

24. Not all cases of occupational asthma are associated with airway eosinophilia, and airway inflammation with eosinophils may occur in the absence of asthma

25. Wardlaw AJ et al. Multidimensional phenotyping: towards a new taxonomy for airway disease. Clin Exp Allergy 2005;35:1254-62.