Talk given to the Aspergillosis Patients Outreach Meeting in London entitled "ABPA and SAFS" by National Aspergillosis Centre Director Professor David Denning

1. SECOND OUTREACH MEETING, LONDON LED BY GRAHAM ATHERTON SUPPORTED BY GEORGINA POWELL, MARIE KIRWAN & DEBBIE KENNEDY NAC CENTRE MANAGER CHRIS HARRIS TALKS GIVEN BY PHILIP LANGRIDGE & DAVID DENNING NATIONAL ASPERGILLOSIS CENTRE UHSM MANCHESTER Support Meeting for Aspergillosis Patients Fungal Research Trust

2. ABPA and SAFS David W. Denning National Aspergillosis Centre University Hospital of South Manchester The University of Manchester

3. Early descriptions of Aspergillus First descriptions: A. flavus – Link, 1809 A. fumigatus – Fresnius, 1863 A. niger - v. Tiegham, 1867 A. nidulans - (Eidam) Winter, 1884

4. Isolates obtained from human lung tissue A. fumigatus by JB Georg W Fresnius Fresnius, Beiträge zur Mykologie, 1863 Isolates obtained from the bronchi and the lung of a bustard

8. ABPA and severe asthma www.emphysema-copd.co.uk

9. Asthma – variable airflow obstruction Patient SY, Aspergillus Website Inhaled steroids

10. O’Driscoll, unpublished Skin prick testing – example of SAFS result Cladosporium +ve

12. ABPA - March – doing well FEV1 = 3.00 Aspergillus IgE = 31 IgE = 1900. No treatment

13. September – episode of pneumonia FEV1 = 1.6. IgE = 3000 Aspergillus IgE = 52.5. Exacerbation of ABPA

14. Sputum in ABPA www.aspergillus.org.uk

15. ABPA – bronchoscopy views showing mucous plugging www.aspergillus.org.uk

16. A. fumigatus in BAL and in bronchial tissue in ABPA

17. Charcot Leyden crystals

19. Central bronchiectasis as a complication of ABPA www.aspergillus.org.uk

21. Hospital admission and sensitisation Allergen Asthma, no admission (n=82) Asthma, 2+ admissions (n=46) House dust mite 56 % 67 % Grass pollen 46 % 63 % Cat 37 % 59 % Dog 18 % 48 % Any non fungal allergen 70% 74% O’Driscoll et al, BMC Pulmonary Medicine 2005;5:4

22. Hospital admission and m ould a llergy Allergen Asthma, no admission (n=82) Asthma, 2+ admissions (n=46) Aspergillus 7 % 37 % Alternaria 5 % 26 % Cladosporium 1 % 41 % Penicillium 2 % 30 % Candida 10 % 33 % Any fungal allergen 16% 76% O’Driscoll et al, BMC Pulmonary Medicine 2005;5:4

23. 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 Mean sensitization score (mm) (Mean and 95% CI) O’Driscoll et al, BMC Pulmonary Medicine 2005;5:4 Non-Mould allergens No Hospital Admission Single Admission Multiple Admissions Mould allergens No Hospital Admission Single Admission Multiple Admissions P= <0.0001

24. Asthma and Aspergillus Fairs et al, Am J Respir Crit Care Med 2010; July 16 79 adult asthmatics and 14 controls Patients sensitised to A. fumigatus compared with non-sensitised asthmatics had: lower lung function (% pred. FEV1 68% vs 88% p < 0.05), more bronchiectasis (68% versus 35% p < 0.05) and more sputum neutrophils (80.9% vs 49.5% p < 0.01).

25. Comparison of ABPA and SAFS serology ABPA results normal range date 1 date 2 SAFS results Patient 1 2

26. Fungal sensitisation in severe asthma – skin prick test or RAST for diagnosis? N= 121 patients screened O’Driscoll et al, Clin Exp Allergy 2009;39:1677-83. SPT + RAST both positive 100% 50% 43 10 13 34 SPT positive RAST negative SPT negative RAST positive SPT negative RAST negative } > 23% discordant results

27. Fungal sensitisation in severe asthma – number sensitised to one or more fungi O’Driscoll et al, Clin Exp Allergy 2009;39:1677-83. 1 2 3 4 5 6 7 N = 40 N = 20 29 11 11 12 3 7 7 Sensitisation to one or more fungi 13 sensitised to only Aspergillus 8 to Candida 3 to Trichophyton 3 to Penicillium 1 to Alternaria 1 to Cladosporium

28. Chronic cavitary pulmonary aspergillosis as a complication of ABPA www.aspergillus.org.uk

29. ABPA and development of CPA www.aspergillus.org.uk 1981 1985 1993 1995 2002

30. Morphology of Aspergillus Weichel et al, Clin Exp Allergy 2003;33:72, www.aspergillus.org.uk

31. Airborne fungal fragments Green et al, J Allergy Clin Immunol 2005; 115:1043 Fungal fragment Diffusing allergen leeching out of fungus in contact with liquid

32. Effect of A. fumigatus proteases on airways Kauffmann et al

33. Surfactant A and D Kishore et al Mol Immunol 2006;43:1293

34. Immune roles of surfactant Wright JR Nat Rev Immunol 2005;5:58.

36. Toll-like Receptor genetic differences and ABPA vs. SAFS Carvalho, J Infect Dis 2008;197:618

37. Randomised studies of antifungals and ABPA and/or asthma Disease Antifungal, duration Benefit? Author, year ABPA Natamycin inh, 52 wks No Currie, 1990 ABPA Itraconazole, 32 wks Yes Stevens, 2000 ABPA Itraconazole, 16 wks Yes Wark, 2003 “ Trichophyton” asthma Fluconazole, 20 wks Yes Ward, 1999 SAFS Itraconazole, 32 wks Yes Denning, 2009

39. Denning et al, unpublished data How common is ABPA?