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

2. CLASSIFICATION OF ASPERGILLOSIS
Invasive aspergillosis
Acute (<1 month course)
Subacute/chronic necrotising (1-3 months)
Airways/nasal exposure to airborne Aspergillus
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 (SAFS)
Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)
Persistence
without disease
colonisation of
the airways or nose/sinuses
Exposure to individual Aspergillus spores or conidia is almost constant. If eradicated immediately, as is usual in normal people, no disease results. If colonisation occurs, it may be short or long term. The pattern of disease is mostly determined by the host group (see next slide), with probably a component of the inoculum size contributing to invasive disease.

3. CLASSIFICATION OF ASPERGILLOSIS
Invasive aspergillosis
Acute (<1 month course)
Subacute/chronic necrotising (1-3 months)
Airways/nasal exposure to airborne Aspergillus
Chronic aspergillosis (>3 months)
Chronic cavitary pulmonary
Aspergilloma of lung
Chronic fibrosing pulmonary
Chronic invasive sinusitis
Maxillary (sinus) aspergilloma
Persistence without disease - colonisation of the airways or nose/sinuses
Allergic
Allergic bronchopulmonary (ABPA)
Extrinsic allergic (broncho)alveolitis (EAA)
Asthma with fungal sensitisation
Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)
Exposure to individual Aspergillus spores or conidia is almost constant. If eradicated immediately, as is usual in normal people, no disease results. If colonisation occurs, it may be short or long term. The pattern of disease is mostly determined by the host group (see next slide), with probably a component of the inoculum size contributing to invasive disease.
However chronic disease if usually seen in patients with apparently normal immune systems.

4. Simple (single) aspergilloma
Patient RT
December 2002
Cough (mild) &
tired
Wythenshawe Hospital

5. Aspergilloma
Severo on

6. Aspergillus precipitins
Severo on

7. Chronic Cavitary Pulmonary Aspergillosis Normal 30 year female smoker
Patient JA
Jan 2001

8. Chronic Cavitary Pulmonary Aspergillosis
Patient JA
Feb 2002

9. Chronic Cavitary Pulmonary Aspergillosis
Patient JA
April 2003

10. Chronic Cavitary Pulmonary Aspergillosis
Patient JA
July 2003

11. ‘Multicavity’ disease is the hallmark of chronic cavitary pulmonary aspergillosis (CCPA)
Wythenshawe Hospital

12. Chronic cavitary pulmonary aspergillosis
Patient JP
June 1999
Denning DW et al, Clin Infect Dis 2003; 37(Suppl 3):S265-80

13. Chronic Cavitary Pulmonary Aspergillosis, with aspergilloma
Patient JP
July 2001,
untreated
Denning DW et al, Clin Infect Dis 2003; 37(Suppl 3):S

14. Chronic Fibrosing Pulmonary Aspergillosis
Patient JP
April 2002,
Untreated
Denning DW et al, Clin Infect Dis 2003; 37(Suppl 3):S

15. Chronic pulmonary aspergillosis – pre-existing disease
Prior pulmonary disease esp:
Atypical mycobacteria pulmonary infection
Sarcoidosis
Tuberculosis
Recurrent pneumothorax
Prior pulmonary surgery
ABPA
Denning DW et al, Clin Infect Dis 2003; 37:S265

16. 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
May have elevated total IgE and Aspergillus specific IgE (RAST)
Denning DW et al, Clin Infect Dis 2003; 37:S265

17. Mannose Binding Protein - Mutations
MBP sticks avidly to A. fumigatus hyphae in vitro
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

18. CPA and MBL defects Study 1
8 of 11 (72%) had low MBL genotypes p=<0.05
(compared to normal controls)
Study 2
8 of 17 (47%) had low MBL genotypes p=0.0002
Crosdale et al J Infect Dis 2001;184:653. Vaid et al, unpublished

19. Innate immunity proteins - surfactant
5 surfactant proteins in man, SPA1, SPA2, SPB, SPC and SPD – all ‘collectin’ family
SPB - single ORF polymorphism (Thr131Ile) associated with ARDS
Exogenous SPD protective against murine IA
Sano H & Kuroki Y. Molecular Immunology 2006;42:

20. Role of surfactant
Wright JR Nat Rev Immunol 2005;5:58.

21. CPA and surfactant A2 defects
CCPA patients had 32% and 22% frequency of 2 SPA2 mutations, compared with normals (18% and 11%)
(p=0.021 and p=0.044)
Vaid et al, unpublished

22. CPA and cytokine gene defects
3 groups of patients:
CCPA (n=24)
Other aspergillosis, mostly allergic (n=15)
Other caucasian controls (n= )
Polymorphisms in IL-10, IL-15, αTNF, γIFN and TGFβ detected by PCR
Sambatakou et al, Int J Immunogenet 2006 In press

23. CPA and IL-10 (-1082)
IL-10 (-1082) G allele (low IL-10, reduced inflammation) OR=0.38 p=0.0006
Sambatakou et al, Int J Immunogenet 2006 In press

24. CPA and cytokine gene defects
3 groups of patients:
CCPA (n=24)
Other aspergillosis, mostly allergic (n=15)
Other caucasian controls (n= )
Polymorphisms in IL-10, IL-15, αTNF, γIFN and TGFβ detected by PCR
CCPA patients have genotypes consistent with low IL-10, low TGFβ, low αTNF , high IL-15 and high γIFN
= a TH2-driven response and poor inflammatory control, esp if chronically infected
Sambatakou et al Int J Immunogenetic 2006 In press

25. 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 & Denning. J Infect 2006;52:e133-7.

26. CPA treatment – IFN gamma?
Denning DW et al, Clin Infect Dis 2003; 37(Suppl 3):S

27. CPA treatment - principles
Important defects in innate immunity so long term (i.e. life-long) antifungal treatment, if possible
May fail itraconazole initially, respond to IV amphotericin B, and be successfully maintained on itraconazole
Itraconazole failures may respond to voriconazole
Caspofungin not very effective (personal observation)
Gamma IFN helpful in some cases
Monitor for azole resistance
Jain & Denning J Infect 2006;52:e133-7.

28. Chronic cavitary pulmonary aspergillosis an example of radiographic failure
Patient SS
April 2004
Patient SS
July 2004, after receiving itraconazole for 3 months and no clinical improvement

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

30. Chronic cavitary pulmonary aspergillosis - relapse
Patient RW
January 2003
Marked change, with new cough, weight loss, ↑CRP/ESR and ↑Aspergillus precipitins
Itraconazole restarted

31. Chronic fibrosing pulmonary aspergillosis, with bilateral aspergillomas and azole resistance
Patient SM
June 2004
After treatment with Itraconazole and Voriconazole
MICs 02/04 06/04
Itra >8 >8 Gly138Cys mutation
Vori
Posa
Howard et al, Int J Antimicrob Ag In press

32. Photosensitivity an issue – use sun block
Long term voriconazole
Photosensitivity an issue – use sun block
Denning & Griffiths J Exp Dermatol 2001;26:648