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Occupational asthma Persistence and remodeling

2 nd Jack Pepys Workshop in Occupational Asthma May 21-22, 2004 Toronto, Ontario, Canada. Occupational asthma Persistence and remodeling. A.Siracusa University of Perugia and Terni Hospital Italy. Occupational asthma (OA) Persistence and remodeling.

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Occupational asthma Persistence and remodeling

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  1. 2nd Jack Pepys Workshop in Occupational Asthma May 21-22, 2004 Toronto, Ontario, Canada Occupational asthmaPersistence and remodeling A.Siracusa University of Perugia and Terni Hospital Italy

  2. Occupational asthma (OA)Persistence and remodeling • Outcome in patients removed from exposure • Determinants of unfavourable outcome • Outcome in patients with continuous exposure • Pathologic features in OA, irritant-induced asthma/RADS • Open questions

  3. Outcome of occupational asthma (OA)Do symptoms of OA and NSBH persist after removal from exposure? Retrospective Evidence for the Persistence of Symptoms and Bronchial Hyperresponsiveness After Removal from the Offending Agent Duration of follow-up (years) Persistence of symptoms (%) NSBH (%) Agent Red cedar 0.5-4 29100 Red cedar 1-9 49 76 Colophony 1.3-3.8 90 35 Snow-crab 0.5-2 61 90 Snow-crab 4.8-6 100 84 Various 0.5-4 93 97 Isocyanates 1-3 66 58 Isocyanates >4 82 63 Isocyanates 0.5-4 50 75 Isocyanates 1 77 77 Various 4-11 100 96 (M Chang-Yeung & J-L Malo 1999)

  4. Outcome in patients with OA removed from exposureIs there an improvement? (1) Some authors showed no improvement in symptoms, airway caliber, or NSBH until 6 years after cessation of exposure (C Allard 1989)

  5. Outcome in patients with OA removed from exposureIs there an improvement? (2) Others observed improvements in FEV1 and NSBH which tend to reach a plateau 1-2 years after workers leave exposure (J-L Malo 1988; H-S Park 1997)

  6. Subjects with normal NSBR at follow-up Outcome in patients with OA removed from exposureIs there an improvement? (3) p=0.003 45.5 % 11.9 time of removal from exposure (L Perfetti 1998)

  7. Outcome in patients with OA removed from exposureIs there an improvement? (4)Long-term follow-up of TDI-induced asthma Removed from exposure Still at work (n=13) At follow-up for < 10 yrs (n=44) for > 10 yrs (n=30) Respiratory symptoms (%) 85 75 60 PD-20 methacholine, mg (geometric mean) 0.855 1.045 1.173 (M Padoan 2003)

  8. Outcome in patients with OA removed from exposureDo inhaled CS improve outcome? • 2,000 µg a day of inhaled BDP for 1 yr small improvement in • respiratory symptoms • PEFR • QOL • 2,000 µg a day of inhaled BDP for 5 months fourfold improvement in NSBH (P Maestrelli 1993) (J-L Malo 1996)

  9. Determinants of unfavourable outcome at diagnosis • Longer duration of exposure and symptoms (M Chan-Yeung 1982; P Hudson 1985; PL Paggiaro 1994) • Lower FEV1 (M Chan-Yeung 1977&1982) • High eosinophil and neutrophil counts in BALF (PL Paggiaro 1990) • Delayed treatment with inhaled CS (J-L Malo 1996)

  10. Outcome in patients with continuous exposureIs there a deterioration if exposure persists? Most studies have shown that subjects with OA deteriorate if they continue to be exposed improved deteriorated 10.4% 37.5% 52.1% stable (J Cote 1990)

  11. Outcome in patients with continuous exposureDo inhaled CS have an effect in subjects with OA and ongoing exposure? 1,000 µg a day of inhaled BDP and 50 µg bid of salmeterol for 3 yrs no change in • respiratory symptoms • FEV1 • NSBH • PEF variability • use of rescue salbutamol (A Marabini 2003)

  12. Pathologic features in OA (1)10-20 days after stopping exposure to TDI Total E/mm2 in the submucosa Thickness of total BM (µm) p<0.01 p<0.05 67 2 (M Saetta 1992)

  13. (PJ Barnes 1997)

  14. Pathologic features in OA (2)Outcome in patients removed from exposure Asymptomatic subjects Symptomatic subjects (M Chan-Yeung 1988) PC20 nethacholine (mg/ml) p<0.05 Persistence of respiratory symptoms was associated with • NSBH (>1 year) (>1 year)

  15. Pathologic features in OA (3)Outcome in patients removed from exposure Follow-up after removal from exposure (>1 year) (M Chan-Yeung 1988) Eosinophils % <0.05 Persistence of respiratory symptoms was associated with • NSBH • airway inflammation

  16. Pathologic features in OA (4)Outcome in patients removed from exposure for 3-39 months Persistence of NSBH was associated with • eosinophil airway inflammation • specific hypersensitivity • reversibility of airway remodeling (PL Paggiaro 1990; M Saetta 1992 & 1995)

  17. Pathologic features in OA (5)Outcome of patients removed from exposure for a mean interval of 8.7 years In 98 subjects persistence of respiratory symptoms was associated with • more eosinophils and neutrophils in sputum (K Maghni 2004)

  18. Pathologic features in irritant-induced asthma (IIA)/RADS (1) • In pulpmill workers with a history of multiple “gassing” episodes onset of persistent symptoms was followed, 4-28 months later, by • thickened BM • eosinophil inflammation • minimal T-lymphocyte inflammation (M Chan-Yeung 1994)

  19. Pathologic features in IIA/RADS (2) Compared with OA, IIA/RADS are associated with • less reversibility of airflow limitation 2 years aftercessation of repeated exposure to chlorine (D Gautrin 1994)

  20. Pathologic features in IIA/RADS (3) Lymphocytes in the bronchial mucosa Compared with OA, IIA/RADS are associated with • less reversibility of airflow limitation • more lymphocytes 2 years after cessation of repeated exposure to chlorine Lymphocytes (x 10-3/mm2) (n=10) Subjects with IIA/RADS (D Gautrin 1994) Controls

  21. Pathologic features in IIA/RADS (4) Compared with OA, IIA/RADS are associated with • more extensive epithelial desquamation • more lymphocytes, but not eosinophils, in the bronchial mucosa • coarse bronchial fibrosis with thickening of the subepithelial collagen 3-6 years after causal exposure (SM Brooks 1985; D Deschamps 1992 & 1994; C Lemière 1996)

  22. Pathologic features in IIA/RADS (5)Do inhaled CS improve outcome? • A worker with RADS due to isocyanates • 3 months after exposure and treatment (beclomethasone, 2 mg daily) • regeneration of epithelial layer • less collagen deposition (C Lemière 1996) • A worker with RADS due to chlorine • 5 months after exposure and treatment (budesonide 1.6 mg daily) • asymptomatic • normal FEV1, FVC and bronchial responsiveness • reduced inflammatory infiltrate • greatly improved epithelium (C Lemière 1997)

  23. OA, IIA/RADS Pathologic features • OA • airway inflammation and remodeling similar to those described in nonoccupational asthma • IIA/RADS • minimal lymphocyte inflammation without eosinophilia • epithelial desquamation and coarse bronchial fibrosis more pronounced than in OA • OA, IIA/RADS • removal from exposure and early administration of inhaled CS reverse, at least partially, pathologic features

  24. Open questions • Is persistence of symptoms and NSBH due to an interaction between airway inflammation and remodeling? • How long do airway inflammation and remodeling persist after removal from exposure? • After stopping exposure do improvements in NSBH, airway inflammation and remodeling reach a plateau? Or do they continue progressively? If so, how long does it take to reach normality after leaving exposure? • Does early, long-term treatment with ICS hasten improvements after removal from exposure? Does it prevent deterioration in subjects who cannot avoid exposure?

  25. Occupational asthma (OA)Persistence and remodeling • Outcome in patients removed from exposure • Determinants of unfavourable outcome • Outcome in patients with continuous exposure • Pathologic features in OA, irritant-induced asthma/RADS • Open questions

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