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Powerpoint on aspergillosis
- 1. The extraordinary spectrumof diseases caused by Aspergillus David W. Denning Wythenshawe Hospital University of Manchester
- 2. The genus Aspergillus- importance to humanity on the negative side: 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 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 Hyphal elongation (plateau phase) and branching www.aspergillus.man.ac.uk
- 5. The genus Aspergillus– ~180 species, 38 have caused disease (able to grow at 37C) Common in the environment Aspergillus A. nidulans – may be amphotericin B resistant fumigatus conidial head A. niger A. flavus -sometimes to AmB of azole resistance A. fumigatus low frequency A. terreus – resistant amphotericin B resistant www.aspergillus.man.ac.uk
- 6. CLASSIFICATION OF ASPERGILLOSIS Invasive aspergillosis • Acute (<1 month course) Airways/nasal • Subacute/chronic necrotising (1-3 months) exposure to airborne Chronic aspergillosis (>3 months) Aspergillus • Chronic cavitary pulmonary • Aspergilloma of lung • Chronic fibrosing pulmonary • Chronic invasive sinusitis Persistence • Maxillary (sinus) aspergilloma without disease - colonisation of the airways or Allergic nose/sinuses • 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. Interaction of Aspergilluswith the host A unique microbial-host interaction Frequency of aspergillosis Frequency of aspergillosis Acute IA ABPA Allergic sinusitis Subacute IA Tracheobronchitis Aspergilloma Chronic cavitary Chronic fibrosing Immune dysfunction Normal Immune hyperactivity immune function . www.aspergillus.man.ac.uk
- 9. Changing incidence offatal invasive mycoses in non-HIV patients in USA 0.8 Rate per 100,000 population 0.2 0.4 0.6 Candidiasis Aspergillosis 0.0 1981 1986 1991 1996 McNeil et al, Clin Infect Dis 2001;33:641
- 10. Invasive pulmonary aspergillosis IPA Normal lung 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 ofthe frequency of invasive aspergillosis Underlying condition Incidence Reference/year Acute myeloid leukaemia 8% Cornet, 2002 Acute lymphatic leukaemia 6.3% Cornet, 2002 Allogeneic HSCT 11-15% Grow, 2002; Marr, 2002 Lung transplantation 6.2-12.8% Minari, 2002; Singh,2003 Heart-lung transplantation 11% Duchini, 2002 Small bowel tranplantation 11% Duchini, 2002 AIDS 2.9% Libanore, 2002
- 13. Bleeding as anaspect 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 Aspergillusfumigatus cause thrombosis (clotting of vessels) and also bleeding? Interaction of conidia and endothelial cell Internalisation of projections 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 ofinvasive aspergillosis is important Treatment started <10d >11d Mortality 40% 90% Von Eiff et al, Respiration 1995;62:241-7.
- 17. Sputum Cultures forFungus 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 with lacto-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 invasiveaspergillosis – amphotericin B therapy Survival Functions by Site of Infection 1.0 .9 .8 Sinusitis (n =17) .7 .6 Multi-site (n =11) .5 Aspe rgilloma (n =10) .4 .3 .2 Pu lmonary (n =83) .1 CNS o r Dissemin ated (n =35) 0.0 0 30 60 90 120 150 180 210 240 270 300 330 360 Days Lin et al, Clin Infect Dis 2001;32:358
- 20. Sub-acute invasive aspergillosisin 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. Chronic necrotising pulmonaryaspergillosis Right upper lobe showing circular Right lobe shows huge cavity shadow partly filled by a mass. PT MS containing some debris, with 1996 +ve aspergillus precipitins.Pt MS 1999 Right upper lobe. Patient has Same lobe shows expansion of diabetes and pulmonary the shadow, still partially filled mycobacterium avium- shows small with a mass. Pt MS 1998 cavitary lesion PT MS 1995. Denning, Clin Microbiol Infect 2001;7(Suppl 2):25-31.
- 24. CLASSIFICATION OF ASPERGILLOSIS Invasive aspergillosis • Acute (<1 month course) Airways/nasal • Subacute/chronic necrotising (1-3 months) exposure to airborne Chronic aspergillosis (>3 months) Aspergillus • Chronic cavitary pulmonary • Aspergilloma of lung • Chronic fibrosing pulmonary • Chronic invasive sinusitis Persistence • Maxillary (sinus) aspergilloma without disease - colonisation of the airways or Allergic nose/sinuses • Allergic bronchopulmonary (ABPA) • Extrinsic allergic (broncho)alveolitis (EAA) • Asthma with fungal sensitisation • Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)
- 25. Aspergillus and airways Typesof aspergillosis of the airways • Colonisation (no disease – could be at risk) • Obstructing Aspergillus 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 drawingof a ‘normal’ 3 year old who died over 10 days Wheaton, Path Trans 1890; 41:34-37
- 27. Aspergillus tracheobronchitis Review of58 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 pulmonaryaspergillosis (CCPA) Patient RW Patient RW September 1992 December 1991 Relapse in normal lung Pre surgical resection www.aspergillus.man.ac.uk
- 33. Chronic cavitary pulmonaryaspergillosis Patient RW July 1993 www.aspergillus.man.ac.uk
- 34. Chronic Cavitary PulmonaryAspergillosis Patient JA Jan 2001
- 35. Chronic Cavitary PulmonaryAspergillosis Patient JA Feb 2002
- 36. Chronic Cavitary PulmonaryAspergillosis Patient JA April 2003
- 37. Chronic Cavitary PulmonaryAspergillosis Patient JA July 2003
- 38. Chronic cavitary pulmonaryaspergillosis Patient JP June 1999 Denning DW et al, Clin Infect Dis 2003; 37:S265
- 39. Chronic Cavitary PulmonaryAspergillosis, with aspergilloma Patient JP July 2001 Denning DW et al, Clin Infect Dis 2003; 37:S265
- 40. Chronic Fibrosing PulmonaryAspergillosis 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 Di b il dn sh o u ed p I ri w nt i tc t eo h an cc e o oi c r l tr p l n t e e E x on 1 I ri w nt i tc t eo h an MA SP E x on 2 C R D E x on 3 2n t + ne C di aii s bg E x on 4 Crosdale et al J Infect Dis 2001;184:653
- 42. Mannose Binding Protein Mutations 5 mutations 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 humangene 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) Airways/nasal • Subacute/chronic necrotising (1-3 months) exposure to airborne Chronic aspergillosis (>3 months) Aspergillus • Chronic cavitary pulmonary • Aspergilloma of lung • Chronic fibrosing pulmonary • Chronic invasive sinusitis Persistence • Maxillary (sinus) aspergilloma without disease - colonisation of the airways or Allergic nose/sinuses • Allergic bronchopulmonary (ABPA) • Extrinsic allergic (broncho)alveolitis (EAA) • Asthma with fungal sensitisation • Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)
- 45. ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS – Key diagnostic criteria ABPA possible • Asthma ABPA possible • Blood eosinophilia (>1,000 / cu mm) ABPA probable • History of pulmonary infiltrates ABPA almost certain • Central bronchiectasis • Precipitins against A. fumigatus positive If 3 tests +ve, • Aspergillus IgE antibody >2x asthma control then ABPA very • Aspergillus IgG antibody >2x asthma control likely, If all 4 +ve the • Total serum IgE concentration, >1000 iu/mL 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 - CTshowing central bronchiectasis www.aspergillus.man.ac.uk
- 49. ABPA and surfactant 5surfactant proteins in man, SPA1, SPA2, SPB, SPC and SPD – all ‘collectin’ family Mason et al, Am J Physiol 1998;275:L1-13.
- 50. ABPA – surfactantdefects 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.
- 51. Eosinophilic fungal rhinosinusitis or allergic fungal sinusitis Patient with chronic symptoms of nasal obstruction, loss of smell and nasal polyps Ponikau et al, Mayo Clinic Proc 1999;74:877 & WWW.aspergillus.man.ac.uk
- 52. Eosinophilic fungal rhinosinusitis (linkwith airborne fungi - ?which most important = Myelin basic protein, highly toxic to local epithelium Ponikau et al, Mayo Clinic Proc 1999;74:877
- 53. A link betweenAspergillus and asthma?
- 54. Fungal-associated asthma –evidence Severe asthma linked with fungal sensitisation Frequency of fungal sensitisation ABPA Fungal-associated asthma Treatment of ABPA High spore counts and and pilot data asthmatic attacks
- 55. Spore counts andasthma attacks and admission to hospital All circumstantial evidence • Thunderstorm asthma – linked to Alternaria • Asthma deaths (Chicago) linked to high ambient spores counts and season (summer autumn) when spore counts highest • Asthma hospital admission linked to high ambient spore counts (Derby, New Orleans, Ottawa • Asthma hospital attendance linked to high spore counts , but not pollen counts (Canada) • Asthma symptoms increased on days of high spore counts (California, Pennsylvania) O'Hollaren, N Engl J Med 1991; 324: 359; Newson, Occup Environ Med 2000; 57: 786-92.
- 56. Fungus at home Environmentaldata • Mouldy housing associated with worse asthma, with a correlation between asthma severity and degree of dampness in the home and separately with visible mould growth • In Germany bronchial reactivity in children was associated with damp housing • Mouldy and damp school associated with asthma symptoms and emergency room visits • Highest concentration of Aspergillus fumigatus is at home Williamson, Thorax 1997;52:229. Taskinen, Acta Paediatr 1999; 88:1373.
- 57. Mild asthma –564 (50%) Moderate asthma – 333 (29%) Severe asthma and moulds Severe asthma – 235 (21%) – linked with fungus skin test positivity Zureik et al, Br Med J 2002;325:411
- 58. Asthma severity, housedust mites, cats and moulds Allergen No asthma Mild asthma Moderate Severe n= 111 FEV1 >75% asthma FEV1 asthma FEV1 <90% >60% <75% >60% n= 67 n= 42 n= 42 House dust 61% 71% 45% 77% mite Cats* 49% 51% 38% 35% Moulds# 17% 19% 36% 31% * P = 0.05 # p = 0.01 Langley, ATS 2004