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The extraordinary spectrum of diseases caused by Aspergillus

The extraordinary spectrum of diseases caused by Aspergillus. David W. Denning Wythenshawe Hospital University of Manchester. cause invasive and allergic disease in humans and other animals: A. fumigatus. cause plant and food spoilage and produce mycotoxins:

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The extraordinary spectrum of diseases caused by Aspergillus

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  1. The extraordinary spectrum of diseases caused by Aspergillus David W. Denning Wythenshawe Hospital University of Manchester

  2. cause invasive and allergic disease in humans and other animals: A. fumigatus cause plant and food spoilage and produce mycotoxins: A. flavus and A. parasiticus The genus Aspergillus - importance to humanity on the negative side: www.aspergillus.man.ac.uk

  3. The genus Aspergillus - importance to humanity on the positive side: composting well-established model organism in cell biology and genetics: A. nidulans food production: enzymes and organic acids: A. niger East Asian foods: A. oryzae and A. sojae pharmaceuticals: echinocandins: A. nidulans and A. sydowi lovastatin: A. terreus fumagillin: A. fumigatus www.aspergillus.man.ac.uk

  4. Aspergillus Life-cycle Spores inhaled Germination Mass of hyphae (plateau phase) Hyphal elongation and branching www.aspergillus.man.ac.uk

  5. A. niger Aspergillus fumigatusconidial head A. nidulans – may be amphotericin B resistant A. flavus -sometimes amphotericin B resistant A. fumigatus low frequency of azole resistance A. terreus – resistant to AmB The genus Aspergillus – ~180 species, 38 have caused disease (able to grow at 37C) Common in the environment www.aspergillus.man.ac.uk

  6. CLASSIFICATION OF ASPERGILLOSIS Invasive aspergillosis • Acute (<1 month course) • Subacute/chronic necrotising (1-3 months) Airways/nasal exposure to airborne Aspergillus Persistence without disease - colonisation of the airways or nose/sinuses Chronic aspergillosis (>3 months) • Chronic cavitary pulmonary • Aspergilloma of lung • Chronic fibrosing pulmonary • Chronic invasive sinusitis • Maxillary (sinus) aspergilloma Allergic • Allergic bronchopulmonary (ABPA) • Extrinsic allergic (broncho)alveolitis (EAA) • Asthma with fungal sensitisation • Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)

  7. Immunosuppression and infection • Inhalation of aspergillus spores is a common daily occurrence. A healthy immune system would normally remove the spores and no symptoms or infection would occur. • In individuals whose immune system may be suppressed either because of illness eg AIDS, cancer patients or drugs, spores may germinate and resulting tissue or systemic aspergillus invasion can result. • Individuals with allergies such as asthma, can also be vulnerable to aspergillus disease.

  8. Acute IA ABPA Allergic sinusitis Interaction of Aspergillus with the hostA unique microbial-host interaction Subacute IA Frequency of aspergillosis Frequency of aspergillosis Tracheobronchitis Aspergilloma Chronic cavitary Chronic fibrosing Immune dysfunction Immune hyperactivity Normal immune function . www.aspergillus.man.ac.uk

  9. Changing incidence of fatal invasive mycoses in non-HIV patients in USA Rate per 100,000 population 0.0 0.2 0.4 0.6 0.8 Candidiasis Aspergillosis 1981 1986 1991 1996 McNeil et al, Clin Infect Dis 2001;33:641

  10. Invasive pulmonary aspergillosis Normal lung IPA IPA occurs in ~7% of acute leukaemia patients, 10-15% allogeneic BMT patients www.aspergillus.man.ac.uk

  11. Unequivocal ‘Halo sign’ surrounding a nodule Halo sign Herbrecht, Denning et al, NEJM 2002;347:408-15.

  12. Recent examples of the frequency of invasive aspergillosis

  13. Bleeding as an aspect of disseminated invasive aspergillosis Fumagillin is anti-angiogenic A haemolysin described from Aspergillus fumigatus Other factors that contribute to thrombosis or a coagulopathy? Gillies & Campbell, www.aspergillus.man.ac.uk

  14. How does Aspergillus fumigatus cause thrombosis (clottingof vessels) and also bleeding? Interaction of conidia and endothelial cell projections Internalisation of conidia (and hyphae) by endothelial cells with injury apparent at 4 hours Filler et al, Blood 2004;103:2134; Paris et al, Infect Immun 1997;65:1510.

  15. Cerebral aspergillosis (abscess) in chronic lymphocytic leukaemia Dissemination via the blood stream to the brain occurs in ~5% of cases of invasive aspergillosis, and in ~40% of allogeneic bone marrow (HSCT) recipients www.aspergillus.man.ac.uk

  16. Early diagnosis of invasive aspergillosis is important Treatment started <10d >11d Mortality 40% 90% Von Eiff et al, Respiration 1995;62:241-7.

  17. Sputum Cultures for Fungus Bacteriological media inferior to fungal media – 32% higher yield on fungal media A four day A. fumigatus culture on malt extract agar (above). Light microscopy pictures are taken at 1000x, stained withlacto-phenol cotton blue.

  18. Aspergillus Antigen Test • Diagnosis or surveillance? • Only blood, or BAL, CSF etc • Best OD cut-off - 0.7 • False positives in kids / antibiotics • False negative with antifungal • prophylaxis • Not as useful for non-hematology • Not useful if pre-existing antibody Herbrecht et al, J Clin Microbiol 2002;20:1898-906; and others

  19. Outcome from invasive aspergillosis – amphotericin B therapy Lin et al, Clin Infect Dis 2001;32:358

  20. Sub-acute invasive aspergillosis in AIDS www.aspergillus.man.ac.uk

  21. Sub-acute invasive aspergillosis • Less immunocompromised patients • Slower progression of disease (> 1 month) • Cavitary or nodular pulmonary disease typical • Vascular invasion less common • Dissemination less common • Antigen testing less useful • Antibody testing may be helpful in diagnosis www.aspergillus.man.ac.uk

  22. Chronic necrotizing aspergillosis(CNPA) Chronic necrotizing pulmonary aspergillosis (CNPA) is a subacute process usually found in patients with some degree of immunosuppression. Usually it is associated with underlying lung disease, alcoholism, or chronic corticosteroid therapy. Because it is uncommon, CNPA often remains unrecognized for weeks or months and causes a progressive cavitary pulmonary infiltrate.

  23. Right lobe shows huge cavity containing some debris, with +ve aspergillus precipitins.Pt MS 1999 Right upper lobe showing circular shadow partly filled by a mass. PT MS 1996 Right upper lobe. Patient has diabetes and pulmonary mycobacterium avium- shows small cavitary lesion PT MS 1995. Same lobe shows expansion of the shadow, still partially filled with a mass. Pt MS 1998 Chronic necrotising pulmonary aspergillosis Denning, Clin Microbiol Infect 2001;7(Suppl 2):25-31.

  24. CLASSIFICATION OF ASPERGILLOSIS Invasive aspergillosis • Acute (<1 month course) • Subacute/chronic necrotising (1-3 months) Airways/nasal exposure to airborne Aspergillus Persistence without disease - colonisation of the airways or nose/sinuses Chronic aspergillosis (>3 months) • Chronic cavitary pulmonary • Aspergilloma of lung • Chronic fibrosing pulmonary • Chronic invasive sinusitis • Maxillary (sinus) aspergilloma Allergic • Allergic bronchopulmonary (ABPA) • Extrinsic allergic (broncho)alveolitis (EAA) • Asthma with fungal sensitisation • Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)

  25. Aspergillus and airways • Types of aspergillosis of the airways • Colonisation (no disease – could be at risk) • ObstructingAspergillus tracheobronchitis /Mucus impaction (non-invasive) • Aspergillus bronchitis/tracheobronchitis (superficially invasive only) • Ulcerative Aspergillus tracheobroncitis (locally invasive) (lung transplants – at anastomosis) • Pseudomembranous Aspergillus tracheobronchitis (Extensive disease, locally invasive, associated with IPA and may disseminate) Langley, ATS 2004

  26. Aspergillus tracheobronchitis Autopsy drawing of a ‘normal’ 3 year old who died over 10 days Wheaton, Path Trans 1890; 41:34-37

  27. Aspergillus tracheobronchitis Review of 58 patients in literature for normal and immuno compromised patients - risk factors % None (ie normal) 25 Heart / Lung transplant 18 Solid tumour 15 BMT 13 Leukaemia 13 HIV/AIDS 8 Other 8 Kemper et al, Clin Infect Dis 1993; 17: 344

  28. Aspergilloma Fungus ball Patient RT December 2002

  29. Chronic pulmonary aspergillosis – pre-existing disease All 18 patients had prior pulmonary disease 9 TB, 5 with atypical mycobacteria 13 smokers or ex-smokers All 18 non-immunocompromised 3 excess alcohol Denning DW et al, Clin Infect Dis 2003; 37:S265

  30. Chronic pulmonary aspergillosis - presentation Weight loss 16 / 18 (89%) Cough 15 / 18 (83%) Shortness of breath 9 / 18 (50%) Haemoptysis 9 / 18 (50%) Fatigue / malaise 5 / 18 (28%) Chest pain 3 / 18 (17%) Sputum production ++ 3 / 18 (17%) Fever 2 / 18 (11%) Denning DW et al, Clin Infect Dis 2003; 37:S265

  31. Chronic pulmonary aspergillosis - serology All 18 patients had positive Aspergillus precipitins (1+ - 4+) All 18 patients had elevated inflammatory markers, CRP, PV and / or ESR 14 of 18 (78%) had elevated total IgE (>20), 13 >200 and 7 >400 9 of 14 (67%) had Aspergillus specific IgE (RAST) Denning DW et al, Clin Infect Dis 2003; 37:S265

  32. Chronic cavitary pulmonary aspergillosis (CCPA) Patient RW September 1992 Relapse in normal lung Patient RW December 1991 Pre surgical resection www.aspergillus.man.ac.uk

  33. Chronic cavitary pulmonary aspergillosis Patient RW July 1993 www.aspergillus.man.ac.uk

  34. Chronic Cavitary Pulmonary Aspergillosis Patient JA Jan 2001

  35. Chronic Cavitary Pulmonary Aspergillosis Patient JA Feb 2002

  36. Chronic Cavitary Pulmonary Aspergillosis Patient JA April 2003

  37. Chronic Cavitary Pulmonary Aspergillosis Patient JA July 2003

  38. Chronic cavitary pulmonary aspergillosis Patient JP June 1999 Denning DW et al, Clin Infect Dis 2003; 37:S265

  39. Chronic Cavitary Pulmonary Aspergillosis, with aspergilloma Patient JP July 2001 Denning DW et al, Clin Infect Dis 2003; 37:S265

  40. Chronic Fibrosing Pulmonary Aspergillosis Patient JP April 2002 Denning DW et al, Clin Infect Dis 2003; 37:S265

  41. Mannose Binding Lectin (MBL)- a key part of the innate immune system Crosdale et al J Infect Dis 2001;184:653

  42. Mannose Binding Protein Mutations 5mutations described 2 in promoter region (less important) 3 in open reading frame (M52, M54, M57) Codon 54 mutation present in 16% of Caucasian homozygous in 2% Defects associated with bacterial infections in children and hepatitis B carriage Eisen & Minchinton Clin Infect Dis 2003;37:1496

  43. CCPA and human gene defects • 8 of 11 (72%) had low MBL genotypes p=<0.05 (compared to normal controls) • 8 of 17 (47%) had low MBL genotypes p=0.0002 • 32% and 21.5% frequency of 2 SPA2 mutations, compared with normals (18% and 11%) (p=0.021 and p=0.044) • not related to coeliac disease (<1 in 30) Crosdale et al J Infect Dis 2001;184:653; Vaid et al, unpublished.

  44. CLASSIFICATION OF ASPERGILLOSIS Invasive aspergillosis • Acute (<1 month course) • Subacute/chronic necrotising (1-3 months) Airways/nasal exposure to airborne Aspergillus Persistence without disease - colonisation of the airways or nose/sinuses Chronic aspergillosis (>3 months) • Chronic cavitary pulmonary • Aspergilloma of lung • Chronic fibrosing pulmonary • Chronic invasive sinusitis • Maxillary (sinus) aspergilloma Allergic • Allergic bronchopulmonary (ABPA) • Extrinsic allergic (broncho)alveolitis (EAA) • Asthma with fungal sensitisation • Allergic Aspergillus sinusitis (eosinophilicfungal rhinosinusitis)

  45. ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS – Key diagnostic criteria ABPA possible ABPA possible ABPA probable ABPA almost certain • Asthma • Blood eosinophilia (>1,000 / cu mm) • History of pulmonary infiltrates • Central bronchiectasis • Precipitins against A. fumigatus positive • Aspergillus IgE antibody >2x asthma control • Aspergillus IgG antibody >2x asthma control • Total serum IgE concentration, >1000 iu/mL If 3 tests +ve, then ABPA very likely, If all 4 +ve the diagnosis established Rickett et al. Arch Intern Med 1983; 143: 1553; Patterson, Chest 2000;118:7

  46. ABPA After bronchoscopy Before bronchoscopy www.aspergillus.man.ac.uk

  47. ABPA mucous plugging www.aspergillus.man.ac.uk

  48. ABPA - CT showing central bronchiectasis www.aspergillus.man.ac.uk

  49. ABPA and surfactant 5 surfactant proteins in man, SPA1, SPA2, SPB, SPC and SPD – all ‘collectin’ family Mason et al, Am J Physiol 1998;275:L1-13.

  50. ABPA – surfactant defects 2 exonic polymorphisms, and 2 intronic polymorphisms in SP-A2 associated with ABPA A1660G = OR of 4.78; or if combined with G1649C = OR 10.4 Also associated with higher peripheral eosinophilia Saxena et al, J Allergy Clin Immunol 2003;111:1001-7.

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