Aspergillosis in AIDS

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 1991324654
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 - 70,000 cases
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
1999673703
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 2009132221
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 2000311253
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Mumbai autopsy series
Lanjewar Duggal, HIV Med 20012266
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Risk factors
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CDC surveillance
Holding et al, Clin Infect Dis 2000311253
10
Italian experience of aspergillosis in AIDS
Libanore et al, Infection 200230341
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Risk factors for invasive aspergillosis in AIDS

• Stage of AIDS CDC Group II 4 (1)
  CDC Group IV 289 (72)
• Neutropenia lt1000 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
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Clinical suspicion
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Missed IFDs in AIDS autopsy series
Antinori et al, Am J Clin Pathol 2009132221
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Aspergillosis in AIDS

• Site of disease in 293 published cases
• Respiratory Other
• Sinuses 9 CNS 30
• Otomastoiditis 5 Cardiac 10
• Larynx 2 Renal 12
• Tracheobronchitis 11 Thyroid 4
• Obstructing bronchial 5 Miscellaneous
  16
• Invasive Pulmonary 208
• Empyema/pleural mass 5
• Aspergilloma 4 2 organs involved
  47

Khoo Denning, Clin Infect Dis 1994 19 (S1) 541
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Invasive pulmonary aspergillosis in AIDS

• Presenting features (in 78 patients)
• Cough 92
• Fever 91
• Dypsnoea 65
• Chest pain 24
• Haemoptysis 9

Khoo Denning, Clin Infect Dis 1994 19 (S1) 541
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Italian experience of aspergillosis in AIDS
Libanore et al, Infection 200230341
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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 1991324 654
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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 1991324 654
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Invasive pulmonary aspergillosis in AIDS, showing
nodules with cavitation
WWW.aspergillus.org.uk
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Invasive pulmonary aspergillosis in AIDS, showing
upper lobe cavities
Denning et al, New Engl J Med 1991324 654
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Invasive pulmonary aspergillosis in AIDS
Patient DF A. niger grown 5x from sputum
WWW.aspergillus.org.uk
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Italian experience of aspergillosis in AIDS
Libanore et al, Infection 200230341
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 200414 2030
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Radiology and diagnostic accuracy
Zaspel et al, Eur Radiol 200414 2030
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AUC 0.84
AUC 0.75
Radiology and diagnostic accuracy
Zaspel et al, Eur Radiol 200414 2030
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Obstructing bronchial aspergillosis
Patient ML Pre-bronchscopy
Patient ML After bronchoscopy
Denning et al, New Engl J Med 1991324 654
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Invasive Aspergillus tracheobronchitis in AIDS
Lortholary et al, Am J Med 199395177
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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
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Sphenoid sinusitis leading to local spread to
the brain and cerebral aspergillosis
Presented with headache over the vertex of the
skull
www.aspergillus.man.ac.uk
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Establishing a diagnosis
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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 199214141
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Aspergillus in AIDS

• Species isolated (n 82)
• A. fumigatus 69 (84)
• A. flavus 7 (9)
• A. niger 4 (5)
• A. terreus 2 (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 199395177
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Italian experience of aspergillosis in AIDS
Libanore et al, Infection 200230341
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Would PCR help?
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MycAssay AspergillusMycAssay 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
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MycAssay Aspergillus
Establishing a tentative clinical cut-off, for
use in prospective regulatory studies
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Treatment
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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

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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)

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HIV therapy and azole interactions Beware!
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IRIS
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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
200524628
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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
200524628
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Azole resistance
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32 yr old from Malawi, on HAART Rx-
haemoptysis- Aspergillus precipitin titre
1/16CT scan shows 2 large cavities with
aspergillomas, with additional lesions (October
2005)
Chronic cavitary pulmonary aspergillosis (CCPA)
in HIV February 2005
Surgical removal would require a pneumonectomySo
treated with itraconazole
47
On HAART Rx, with low viral load, CD4 count
gt200- New haemoptysis- Aspergillus precipitin
titre 1/32CXR CT scan showed expansion of
inferior cavity
CCPA in HIV February 2007
MICs A. fumigatus Feb 2007Itraconazole
gt8.0mg/mLVoriconazole 0.5 mg/mLPosaconazole
1.0 mg/mL
48
Itraconazole concentrationsNov 05 2.5 mg/LDec
05 3.4 mg/LMarch 06 4.5 mg/LJuly 06 6.7
mg/LFeb 07 8.4 mg/L
CCPA in HIV - low itraconazole concentrations
Do low concentrations of antifungal predispose to
the development of resistance?
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Azole resistance in Manchester in A. fumigatus
Howard et al, Emerg Infect Dis 2009151068
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www.aspergillus.org.uk
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