1. Aspergillosis in AIDS David W. Denning
Director, National Aspergillosis Centre
University Hospital South Manchester
[Wythenshawe Hospital]
The University of Manchester
Myconostica Ltd

2. New manifestations of aspergillosis Aspergillosis in AIDS
Denning et al, New Engl J Med 1991:324:654

3. Frequency

4. EU caseload of aspergillosis
167,500 ABPA cases
680,000 -1,700,000 SAFS cases
11,200,000 CFRS cases
30, ,000 cases
Acute Invasive
ABPA
Severe asthma with
fungal sensitisation
Allergic sinusitis
Subacute Invasive
Frequency of aspergillosis
Frequency of aspergillosis
Aspergilloma
Chronic cavitary
Chronic fibrosing
Locally invasive
~7,500 cases
Immune dysfunction
Immune hyperactivity .
After Casadevall & Pirofski, Infect Immun 1999;67:3703

5. Trends over time in IFDs in AIDS – autopsy series
1630 autopsies in 2101 deaths (77.6%)
IFD found in 297 (18.2%)
IA was diagnosed during life in only 12%
Antinori et al, Am J Clin Pathol 2009;132:221

6. CDC surveillance National survey in US 35,252 patients 1990 - 1998
IA diagnosed in 228 patients
Incidence of 3.5/1000 person years
Holding et al, Clin Infect Dis 2000;31:1253

7. Mumbai autopsy series
Lanjewar & Duggal, HIV Med 2001;2:266

8. Risk factors

9. CDC surveillance
Holding et al, Clin Infect Dis 2000;31:1253

10. Italian experience of aspergillosis in AIDS
Libanore et al, Infection 2002;30:341

11. Risk factors for invasive aspergillosis in AIDS
Stage of AIDS CDC Group II (1%) CDC Group IV (72%)
Neutropenia <1000 x 106/L 92/202 (46%)
Corticosteroid therapy 79/202 (39%)
Prior pulmonary infection 124/169 (73%)
Khoo & Denning, Clin Infect Dis 1994; 19 (S1) 541

12. Clinical suspicion

13. Missed IFDs in AIDS – autopsy series
Antinori et al, Am J Clin Pathol 2009;132:221

14. Aspergillosis in AIDS Site of disease in 293 published cases
Respiratory Other
Sinuses CNS
Otomastoiditis Cardiac 10
Larynx Renal
Tracheobronchitis Thyroid 4
Obstructing bronchial Miscellaneous 16
Invasive Pulmonary
Empyema/pleural mass
Aspergilloma ≥ 2 organs involved = 47
Khoo & Denning, Clin Infect Dis 1994; 19 (S1) 541

15. Invasive pulmonary aspergillosis in AIDS
Presenting features (in 78 patients)
Cough 92 %
Fever 91 %
Dypsnoea %
Chest pain 24 %
Haemoptysis 9 %
Khoo & Denning, Clin Infect Dis 1994; 19 (S1) 541

16. Italian experience of aspergillosis in AIDS
Libanore et al, Infection 2002;30:341

17. Invasive Pulmonary Aspergillosis in AIDS
Patient JJ
Late stage AIDS, unresponsive to ITZ (Af90 and Af91)
Patient JB
Denning et al, New Engl J Med 1991;324: 654

18. Invasive Pulmonary Aspergillosis, with dissemination, in AIDS
Patient JA
31st May
Patient JA
25th June, 3 days before death
Denning et al, New Engl J Med 1991;324: 654

19. Invasive pulmonary aspergillosis in AIDS,
showing nodules with cavitation

20. Invasive pulmonary aspergillosis in AIDS, showing upper lobe cavities
Denning et al, New Engl J Med 1991;324: 654

21. Invasive pulmonary aspergillosis in AIDS
Patient DF
A. niger grown 5x from sputum

22. Italian experience of aspergillosis in AIDS
Libanore et al, Infection 2002;30:341

23. Radiology and diagnostic accuracy
8 radiologists compared with 8 internists
25 IPA and 25 other diagnoses in AIDS
Analysed with and without clinical information
Zaspel et al, Eur Radiol 2004;14: 2030

24. Radiology and diagnostic accuracy
Zaspel et al, Eur Radiol 2004;14: 2030

25. Radiology and diagnostic accuracy
AUC = 0.84
AUC = 0.75
Radiology and diagnostic accuracy
Zaspel et al, Eur Radiol 2004;14: 2030

26. Obstructing bronchial aspergillosis
Patient ML
Pre-bronchscopy
Patient ML
After bronchoscopy
Denning et al, New Engl J Med 1991;324: 654

27. Invasive Aspergillus tracheobronchitis in AIDS
Lortholary et al, Am J Med 1993;95:177

28. Ear and sinus aspergillosis in AIDS
Sinusitis
Headache, facial, neck or ear pain;
Nasal discharge
Often chronic
Invasive fungal otomastoiditis
Ear pain (often severe), otorrhoea, without fever

29. Sphenoid sinusitis leading to local spread to the brain and cerebral aspergillosis
Presented with headache over the vertex of the skull

30. Establishing a diagnosis

31. Significance of positive respiratory cultures
45/972 (4.6%) incidence of positive cultures
5/45 (11%) invasive aspergillosis
4/13 (23%) neutropenic AIDS patients had invasive aspergillosis if positive sputum culture for Aspergillus
Pursell et al. Clin Infect Dis 1992;14:141

32. Aspergillus in AIDS Species isolated (n = 82) A. fumigatus 69 (84%)
A. flavus (9%)
A. niger (5%)
A. terreus (2%)
Khoo & Denning, Clin Infect Dis 1994; 19 (S1) 541

33. Early French experience of aspergillosis in AIDS
“The mycologic culture from BAL was the method of choice for the diagnosis of invasive pulmonary disease”
Of 28 patients with a positive BAL culture for Aspergillus, 15 underwent a biopsy or autopsy and 14 were positive at histology.
Serum antigen detection was positive in only 4 of 16 tested patients.
Lortholary et al, Am J Med 1993;95:177

34. Italian experience of aspergillosis in AIDS
Libanore et al, Infection 2002;30:341

35. Would PCR help?

36. MycAssay™: Aspergillus MycAssay™: Pneumocystis
Real-time molecular based in vitro diagnostic tests for Aspergillus spp. and Pneumocystis jirovecii
Aspergillus based on 18S rRNA
Pneumocystis based on mitochondrial LSU
CE marked, but not FDA cleared 36

37. MycAssay™: Aspergillus
Establishing a tentative clinical cut-off, for use in prospective regulatory studies 37

38. Treatment

39. Choice of antifungal for aspergillosis
Priority sequence
Voriconazole (unless drug interaction)
AmBisome 3mg/Kg (if not ‘nephro-critical’) OR
caspofungin/micafungin (if not neutropenic)
3. Posaconazole (oral only, if no drug interactions)
4. Itraconazole

40. When not to use voriconazole as primary therapy?
Absolute contraindications
Drug interactions (ie rifampicin, carbamazepine, phenytoin etc)
Voriconazole used as prophylaxis (but not itraconazole or posaconazole)
Resistance to voriconazole (esp zygomycosis, A. lentulus or azole resistance)
Relative contraindications
Renal failure (IV only)
Young children (need higher dose ?+ other agent)
Severe hepatic dysfunction
Interacting drugs (ie sirolimus)

41. HIV therapy and azole interactions
Beware!

42. IRIS

43. Immune reconstitution in invasive pulmonary aspergillosis, in AIDS
Patient HB
Day +14, CD4 cells 84/uL
Patient HB
Day +42, after AmB and ITZ
Sambatakou, Eur J Clin Microbiol Infect Dis 2005;24:628

44. Immune reconstitution in invasive pulmonary aspergillosis, in AIDS
Patient HB
Day +64, CD4 cells 340/uL, on VRC
Patient HB
Day +87, day of death
Sambatakou, Eur J Clin Microbiol Infect Dis 2005;24:628

45. Azole resistance

46. Chronic cavitary pulmonary aspergillosis (CCPA) in HIV February 2005
32 yr old from Malawi, on HAART Rx - haemoptysis - Aspergillus precipitin titre 1/16 CT scan shows 2 large cavities with aspergillomas, with additional lesions (October 2005)
Surgical removal would require a pneumonectomy So treated with itraconazole

47. CCPA in HIV February 2007
On HAART Rx, with low viral load, CD4 count >200 - New haemoptysis - Aspergillus precipitin titre 1/32 CXR & CT scan showed expansion of inferior cavity
MICs A. fumigatus Feb 2007 Itraconazole = >8.0mg/mL Voriconazole = 0.5 mg/mL Posaconazole = 1.0 mg/mL
February 2007
April 2007

48. CCPA in HIV - low itraconazole concentrations
Itraconazole concentrations Nov mg/L Dec mg/L March mg/L July mg/L Feb mg/L
Do low concentrations of antifungal predispose to the development of resistance?

49. Azole resistance in Manchester in A. fumigatus
11%
17% 7% 5% 0% 3%
Howard et al, Emerg Infect Dis 2009;15:1068

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