1. Chronic pulmonary aspergillosis
David W. Denning
Wythenshawe Hospital
University of Manchester

2. Interaction of Aspergillus with the host A unique microbial-host interaction
Acute IA
ABPA
Allergic sinusitis
Subacute IA
CNPA
Frequency of aspergillosis
Frequency of aspergillosis
Aspergilloma
Chronic cavitary
Chronic fibrosing
Immune dysfunction
Immune hyperactivity .

3. Sub-acute invasive aspergillosis in AIDS
2 month history of cough and weight loss

4. Sub-acute invasive aspergillosis in AIDS

5. 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

6. Timeframes IPA days/1-4 weeks Subacute IPA/CNPA weeks/2-3 months
CCPA months/years
Aspergilloma months/years

7. Aspergilloma Patient RT December 2002 Cough (mild) & tired
Wythenshawe Hospital

8. Aspergilloma – may be mobile in the cavity
Upright Prone
Severo on

9. Aspergilloma
Severo on

10. Histology of an aspergilloma
Severo on

11. Aspergilloma due to A. niger and oxalosis
Renal oxalosis
Oxalate crystals in wall of the aspergilloma
Severo on

12. Early Aspergillus infection of a pulmonary cavity – ‘pre-aspergilloma’
Orderly hyphal growth on the inside of the cavity
Aspergillus growth on the surface of a pulmonary cavity
Severo on

13. Bilateral fibrocystic sarcoidosis
Pt AR, Feb 2003
Wythenshawe Hospital

14. Bilateral fibrocystic sarcoidosis
Pre-existing cavities
Pt AR, Feb 2004
Wythenshawe Hospital

15. Bilateral fibrocystic sarcoidosis, after 2 months of corticosteroids
New cavity formation
Pleural thickening
Small aspergilloma
Pt AR, April 2004
Wythenshawe Hospital

16. Bilateral fibrocystic sarcoidosis, 3 months later, off steroids – now chronic cavitary aspergillosis
New cavity formation
Larger aspergilloma
Pt AR, July 2004
Wythenshawe Hospital

17. Chronic Cavitary Pulmonary Aspergillosis
Patient JA
Jan 2001

18. Chronic Cavitary Pulmonary Aspergillosis
Patient JA
Feb 2002

19. Chronic Cavitary Pulmonary Aspergillosis
Patient JA
April 2003

20. Chronic Cavitary Pulmonary Aspergillosis
Patient JA
July 2003

21. Chronic Cavitary Pulmonary Aspergillosis complicating ABPA
Patient KM
May 2004
Wythenshawe Hospital

22. 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

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

24. Chronic pulmonary aspergillosis - serology
All 18 patients had positive Aspergillus precipitins ( )
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

25. Chronic pulmonary aspergillosis – invasive procedures
Lung resection - histological confirmation in 4 patients, hyphae in cavities, not tissue
Bronchoscopic biopsy - negative for hyphae in 8/9 - chronic inflammatory changes, fibrosis ± granuloma formation (n=1)
Percutaneous biopsy – hyphae in 1/7 cases - chronic inflammatory changes and fibrosis
Denning DW et al, Clin Infect Dis 2003; 37:S265

26. Chronic pulmonary aspergillosis -microbiology
Sputum culture was positive - 10 patients sporadically
Sputum microscopy was positive - 1 patient
BAL culture positive in 4 of 10 (40%)
Lung biopsy positive 1 of 5 patients (20%)
Pleural aspiration 3 of 3 (100%)
Denning DW et al, Clin Infect Dis 2003; 37:S265

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

28. 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 Caucasians
homozygous in 2%
Defects associated with bacterial infections in children and hepatitis B carriage
Eisen & Minchinton Clin Infect Dis 2003;37:1496

29. CPA and human gene defects
Probably not related to coeliac disease (<1 in 30)
Unpublished
Innate immunity
8 of 11pts had low MBL genotypes p=<0.05 (compared to normal controls)
Crosdale et al J Infect Dis 2001;184:653.

30. Treatment failure / progression
Treatment of chronic cavitary pulmonary aspergillosis
Treatment
No of courses
Stable or improved (%)
Treatment failure / progression
Toxicity
Itraconazole primary therapy 17
12 (71) 5 3
Voriconazole
9/11 (82) 2 12
Amphotericin B IV 11
9 (82) 7
Gamma IFN with itraconazole
Itraconazole maintenance after AmB IV 6
Denning DW et al, Clin Infect Dis 2003; 37:S265; Jain AAA 2004

31. Chronic cavitary pulmonary aspergillosis an example of radiographic failure
Patient SS
April 2004
Patient SS
July 2004, despite receiving itraconazole for 3 months

32. Chronic cavitary pulmonary aspergillosis
Patient RW
September 1992

33. Chronic cavitary pulmonary aspergillosis
Patient RW
July 1993

34. Chronic cavitary pulmonary aspergillosis
Patient RW
June 2002
Stable, asymptomatic, normal inflammatory markers, just detectable Aspergillus precipitins
Itraconazole stopped after 5 years

35. Chronic cavitary pulmonary aspergillosis - relapse
Patient RW
January 2003
Marked change, with new cough, weight loss, increased inflammatory markers and Aspergillus precipitins
Itraconazole restarted

36. Chronic cavitary pulmonary aspergillosis
Patient RW
September 1992
Patient RW
June 2003

37. Conceptual framework Normal Massive Hyphal load in tissue
Immune function
Hyphal load in tissue
Normal
Massive
Chronic inflammation and fibrosis
Vascular invasion, necrosis, dissemination
Granulomas, acute inflammation, central necrosis
Aspergilloma - CCPA - CNPA/subacute IPA - acute IPA

38. Chronic fibrosing pulmonary aspergillosis
Patient RS
March 2004
Denning DW et al, Clin Infect Dis 2003; 37:S265

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

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

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

42. Pathogenesis of cavity formation Pathogenesis of unilateral fibrosis?