SECOND OUTREACH MEETING, LONDON LED BY GRAHAM ATHERTON SUPPORTED BY GEORGINA POWELL, MARIE KIRWAN & DEBBIE KENNEDY NAC CEN...
ABPA and SAFS David W. Denning National Aspergillosis Centre University Hospital of South Manchester The University of Man...
Early descriptions of Aspergillus First descriptions: A. flavus  – Link, 1809 A. fumigatus  – Fresnius,  1863 A. niger  - ...
Isolates obtained from human lung tissue A. fumigatus   by JB Georg W Fresnius Fresnius,  Beiträge zur Mykologie,  1863 Is...
Early reports of asthma exacerbated by fungi Denning et al Eur Resp J 2006:27:615 <ul><li>1698 - ‘asthmatic who fell into ...
Early reports of asthma exacerbated by fungi Denning et al Eur Resp J 2006:27:615 <ul><li>1925 – Van Leewen found 50% of D...
<ul><li>Fungal exposure in asthmatics is related to: </li></ul><ul><li>Life-threatening asthmatic attacks (ie thunderstorm...
ABPA and severe asthma www.emphysema-copd.co.uk
Asthma – variable airflow obstruction Patient SY, Aspergillus Website  Inhaled steroids
O’Driscoll, unpublished Skin prick testing – example of SAFS result Cladosporium +ve
ABPA – Diagnostic clues <ul><li>Asthma/CF not well controlled </li></ul><ul><li>History of ‘pneumonia’ </li></ul><ul><li>H...
ABPA - March – doing well FEV1 = 3.00  Aspergillus IgE = 31 IgE = 1900. No treatment
September – episode of pneumonia FEV1 = 1.6.  IgE = 3000 Aspergillus IgE = 52.5.  Exacerbation of ABPA
Sputum in ABPA www.aspergillus.org.uk
ABPA – bronchoscopy views showing mucous plugging www.aspergillus.org.uk
A. fumigatus  in BAL and in bronchial tissue in ABPA
Charcot Leyden crystals
Eosinophilic Fungal Rhinosinusitis <ul><li>Sinus opacification </li></ul><ul><li>Expansion </li></ul><ul><li>Bony erosion ...
Central bronchiectasis as a complication of ABPA www.aspergillus.org.uk
Severe asthma with fungal sensitisation (SAFS) Denning et al, Eur Resp J 2006; 27;27:615 <ul><li>Criteria for diagnosis </...
Hospital admission and sensitisation Allergen Asthma, no admission (n=82)  Asthma, 2+ admissions (n=46) House dust mite 56...
Hospital admission and m ould  a llergy Allergen Asthma, no admission (n=82)  Asthma, 2+ admissions (n=46) Aspergillus   7...
  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...
Asthma and Aspergillus Fairs et al, Am J Respir Crit Care Med 2010; July 16 79 adult asthmatics and 14 controls Patients s...
Comparison of ABPA and SAFS serology ABPA results   normal range  date 1  date 2 SAFS results Patient 1 2
Fungal sensitisation in severe asthma –  skin prick test or RAST for diagnosis? N= 121 patients screened O’Driscoll et al,...
Fungal sensitisation in severe asthma –  number sensitised to one or more fungi O’Driscoll et al, Clin Exp Allergy 2009;39...
Chronic cavitary pulmonary aspergillosis as a complication of ABPA www.aspergillus.org.uk
ABPA and development of CPA www.aspergillus.org.uk  1981 1985 1993 1995 2002
Morphology of  Aspergillus Weichel et al, Clin Exp Allergy 2003;33:72, www.aspergillus.org.uk
Airborne fungal fragments Green et al,  J Allergy Clin Immunol 2005; 115:1043  Fungal fragment Diffusing allergen leeching...
Effect of  A. fumigatus  proteases on airways  Kauffmann et al
Surfactant A and D Kishore et al Mol Immunol 2006;43:1293
Immune roles of surfactant Wright JR  Nat Rev Immunol 2005;5:58.
ABPA and surfactant defects <ul><li>ABPA patients have a higher frequency of SP-A2 A1660G SNP compared with with control s...
Toll-like Receptor genetic differences and ABPA vs. SAFS Carvalho, J Infect Dis 2008;197:618
Randomised studies of antifungals and ABPA and/or asthma Disease Antifungal, duration Benefit? Author, year ABPA  Natamyci...
Chishimba et al, unpublished data Second and third line antifungal therapy for ABPA and/or asthma <ul><li>26 patients, ABP...
Denning et al, unpublished data How common is ABPA?
Conclusions <ul><li>ABPA and SAFS are more common than diagnosed </li></ul><ul><li>Neither blood allergy or skin allergy t...
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Aspergillosis Patients Support Outreach Meeting London June 2011 - David Denning

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

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Aspergillosis Patients Support Outreach Meeting London June 2011 - David Denning

  1. 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. 2. ABPA and SAFS David W. Denning National Aspergillosis Centre University Hospital of South Manchester The University of Manchester
  3. 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. 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
  5. 5. Early reports of asthma exacerbated by fungi Denning et al Eur Resp J 2006:27:615 <ul><li>1698 - ‘asthmatic who fell into a violent fit, by going into a wine cellar where the must was fermenting’ </li></ul><ul><li>1873 – Dr Charles Blackley self experimented with Penicillium glaucum which on inhalation of a large number of spores, induced hoarseness, aphonia and an attack of 'bronchial catarrh‘ </li></ul><ul><li>1897 – Renon noted wheezing in pigeon-crammers and hair combers exposed to Aspergillus </li></ul><ul><li>1924 – Cadham attributed asthma to wheat rust ( Puccinia graminis ) exposure </li></ul><ul><li>1924 - Storm Van Leeuwen showed asthma was more prevalent in the humid parts of the Netherlands, and relief with the use of filtered air </li></ul>
  6. 6. Early reports of asthma exacerbated by fungi Denning et al Eur Resp J 2006:27:615 <ul><li>1925 – Van Leewen found 50% of Dutch asthmatics had mould skin sensitivity esp. to Mucor, Penicillium and A. fumigatus, niger, flavus and nidulans </li></ul><ul><li>1928 - Hansen found 15% of asthmatics had positive skin tests to Aspergillus or Penicillium grown from their environment and that inhalation challenge reproduced symptoms </li></ul><ul><li>1928 - Jimines-Diaz and Sanchez Cuenca demonstrated that ‘house dust’ sensitivity was often due to moulds </li></ul><ul><li>1930 - 3 separate case reports of asthma related to Alternaria , A. fumigatus and Trichopyton </li></ul><ul><li>1939 - Cohen showed that mattresses, pillows and furniture were potent sources of ‘house dust antigen’ which when removed abolished asthmatic symptoms in those with mould allergy </li></ul>
  7. 7. <ul><li>Fungal exposure in asthmatics is related to: </li></ul><ul><li>Life-threatening asthmatic attacks (ie thunderstorm asthma) </li></ul><ul><li>Severe asthma and hospital admission </li></ul>O'Hollaren, N Engl J Med 1991; 324: 359; and many others
  8. 8. ABPA and severe asthma www.emphysema-copd.co.uk
  9. 9. Asthma – variable airflow obstruction Patient SY, Aspergillus Website Inhaled steroids
  10. 10. O’Driscoll, unpublished Skin prick testing – example of SAFS result Cladosporium +ve
  11. 11. ABPA – Diagnostic clues <ul><li>Asthma/CF not well controlled </li></ul><ul><li>History of ‘pneumonia’ </li></ul><ul><li>History of coughing up plugs, or paroxysms of coughing that clear when chest clears </li></ul><ul><li>Central bronchiectasis on CT scan, or mucoid impaction </li></ul><ul><li>Eosinophilia </li></ul><ul><li>Rare cases in non-asthmatics, non-CF patients </li></ul>
  12. 12. ABPA - March – doing well FEV1 = 3.00 Aspergillus IgE = 31 IgE = 1900. No treatment
  13. 13. September – episode of pneumonia FEV1 = 1.6. IgE = 3000 Aspergillus IgE = 52.5. Exacerbation of ABPA
  14. 14. Sputum in ABPA www.aspergillus.org.uk
  15. 15. ABPA – bronchoscopy views showing mucous plugging www.aspergillus.org.uk
  16. 16. A. fumigatus in BAL and in bronchial tissue in ABPA
  17. 17. Charcot Leyden crystals
  18. 18. Eosinophilic Fungal Rhinosinusitis <ul><li>Sinus opacification </li></ul><ul><li>Expansion </li></ul><ul><li>Bony erosion (extreme cases) </li></ul><ul><li>No tissue invasion </li></ul>From Saleh
  19. 19. Central bronchiectasis as a complication of ABPA www.aspergillus.org.uk
  20. 20. Severe asthma with fungal sensitisation (SAFS) Denning et al, Eur Resp J 2006; 27;27:615 <ul><li>Criteria for diagnosis </li></ul><ul><li>Severe asthma (BTS step 4 or 5) </li></ul><ul><li>AND </li></ul><ul><li>RAST (IgE) positive for any fungus </li></ul><ul><li>OR </li></ul><ul><li>Skin prick test positive for any fungus </li></ul><ul><li>AND </li></ul><ul><li>Exclude ABPA (ie total IgE <1,000 iu/mL) </li></ul>
  21. 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. 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. 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. 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. 25. Comparison of ABPA and SAFS serology ABPA results normal range date 1 date 2 SAFS results Patient 1 2
  26. 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. 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. 28. Chronic cavitary pulmonary aspergillosis as a complication of ABPA www.aspergillus.org.uk
  29. 29. ABPA and development of CPA www.aspergillus.org.uk 1981 1985 1993 1995 2002
  30. 30. Morphology of Aspergillus Weichel et al, Clin Exp Allergy 2003;33:72, www.aspergillus.org.uk
  31. 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. 32. Effect of A. fumigatus proteases on airways Kauffmann et al
  33. 33. Surfactant A and D Kishore et al Mol Immunol 2006;43:1293
  34. 34. Immune roles of surfactant Wright JR Nat Rev Immunol 2005;5:58.
  35. 35. ABPA and surfactant defects <ul><li>ABPA patients have a higher frequency of SP-A2 A1660G SNP compared with with control subjects (OR = 4.78). In combination with SP-A2 G1649C more significant (OR = 10.4) </li></ul><ul><li>(P=0.016 and p=0.008) </li></ul>Vaid et al, Clin Chem Lab Med 2007;45:183; Saxena et al, J All Clin Immunol 2003;111:1001
  36. 36. Toll-like Receptor genetic differences and ABPA vs. SAFS Carvalho, J Infect Dis 2008;197:618
  37. 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
  38. 38. Chishimba et al, unpublished data Second and third line antifungal therapy for ABPA and/or asthma <ul><li>26 patients, ABPA (n = 21) or SAFS (n = 5). </li></ul><ul><li>All patients had failed itraconazole (n=14) or developed adverse events (AEs) (n=12) </li></ul><ul><li>34 courses of therapy, 25 with voriconazole and 9 with posaconazole. </li></ul><ul><li>Voriconazole responses: 17/25 (68%) at 3 months, 15/20 (75%) at 6 months and 12/16 (75%) at 12 months, </li></ul><ul><li>Posaconazole responses: 7/9 (78%) at 3, 6 and 12 months for posaconazole. </li></ul><ul><li>18/24 (75%) discontinued oral corticosteroids, 12 of them within 3 months of starting antifungal therapy. </li></ul><ul><li>6/23 (26%) patients on voriconazole had AEs requiring discontinuation before 6 months compared to none on posaconazole (p=0.15). </li></ul><ul><li>4 relapsed (57%), 1 at 3 months and 3 at 12 months after discontinuation. </li></ul>
  39. 39. Denning et al, unpublished data How common is ABPA?
  40. 40. Conclusions <ul><li>ABPA and SAFS are more common than diagnosed </li></ul><ul><li>Neither blood allergy or skin allergy tests are 100% sensitive, so both may be necessary to identify SAFS </li></ul><ul><li>Genetic risk factors are the most likely difference between different patients – probably several genes </li></ul><ul><li>Current treatments are partially successful - better results can be obtained with monitoring levels in blood </li></ul><ul><li>We need more antifungals, and we need to learn better how to minimise steroid usage </li></ul><ul><li>Antifungal resistance is an increasing problem </li></ul><ul><li>Opportunities for immune therapies going forward </li></ul>

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