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Aspergillosis in AIDS. David W. Denning Director, National Aspergillosis Centre University Hospital South Manchester [Wythenshawe Hospital] The University of Manchester Myconostica Ltd. New manifestations of aspergillosis Aspergillosis in AIDS. Denning et al, New Engl J Med 1991:324:654. - PowerPoint PPT Presentation
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Aspergillosis in AIDS
David W. DenningDirector, National Aspergillosis CentreUniversity Hospital South Manchester
[Wythenshawe Hospital]The University of Manchester
Myconostica Ltd
New manifestations of aspergillosis Aspergillosis in AIDS
Denning et al, New Engl J Med 1991:324:654
EU caseload of aspergillosis
Immune dysfunction
Frequency
of a
sperg
illosis
Immune hyperactivity
Frequency
of
asp
erg
illosi
s
Acute Invasive
Subacute Invasive
AspergillomaChronic cavitaryChronic fibrosingLocally invasive
ABPASevere asthma with fungal sensitisationAllergic sinusitis
. After Casadevall & Pirofski, Infect Immun 1999;67:3703
30,000 - 70,000 cases
~7,500 cases
167,500 ABPA cases680,000 -1,700,000 SAFS cases11,200,000 CFRS cases
Trends over time in IFDs in AIDS – autopsy series
Antinori et al, Am J Clin Pathol 2009;132:221
1630 autopsies in 2101 deaths (77.6%)IFD found in 297 (18.2%)
IA was diagnosed during life in only 12%
CDC surveillance
Holding et al, Clin Infect Dis 2000;31:1253
National survey in US35,252 patients 1990 - 1998IA diagnosed in 228 patients
Incidence of 3.5/1000 person years
Risk factors for invasive aspergillosis in AIDS
Stage of AIDS CDC Group II 4 (1%) CDC Group IV 289 (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
Aspergillosis in AIDS
Site of disease in 293 published cases
Respiratory OtherSinuses 9 CNS 30Otomastoiditis 5 Cardiac 10Larynx 2 Renal 12Tracheobronchitis 11 Thyroid 4Obstructing bronchial 5 Miscellaneous 16Invasive Pulmonary 208Empyema/pleural mass 5Aspergilloma 4 ≥ 2 organs involved = 47
Khoo & Denning, Clin Infect Dis 1994; 19 (S1) 541
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
Invasive Pulmonary Aspergillosis in AIDS
Patient JJ Late stage AIDS,
unresponsive to ITZ (Af90 and Af91) Denning et al, New Engl J Med 1991;324: 654
Patient JB
Invasive Pulmonary Aspergillosis, with dissemination, in AIDS
Patient JA 31st May
Denning et al, New Engl J Med 1991;324: 654
Patient JA 25th June, 3 days before death
Invasive pulmonary
aspergillosis in AIDS, showing
upper lobe cavities
Denning et al, New Engl J Med 1991;324: 654
Invasive pulmonary aspergillosis in AIDS
WWW.aspergillus.org.uk;
Patient DF A. niger grown 5x from
sputum
Radiology and diagnostic accuracy
Zaspel et al, Eur Radiol 2004;14: 2030
8 radiologists compared with 8 internists25 IPA and 25 other diagnoses in AIDS
Analysed with and without clinical information
Obstructing bronchial aspergillosis
Patient ML Pre-bronchscopy
Denning et al, New Engl J Med 1991;324: 654
Patient ML After bronchoscopy
Ear and sinus aspergillosis in AIDS
Sinusitis• Headache, facial, neck or ear pain;• Nasal discharge• Often chronic
Invasive fungal otomastoiditisEar pain (often severe), otorrhoea,
without fever
www.aspergillus.man.ac.uk
Sphenoid sinusitis leading to local Sphenoid sinusitis leading to local spread to the brain and cerebral spread to the brain and cerebral
aspergillosisaspergillosis
Presented with headache over the vertex of the skull
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
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
Early French experience of aspergillosis in AIDS
Lortholary et al, Am J Med 1993;95:177
“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.
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, b
ut not F
DA cleared
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
18.0
20.0
22.0
24.0
26.0
28.0
30.0
32.0
34.0
36.0
38.0
40.0
0 1 2 3
Diagnostic Category
Ct
valu
e u
sin
g M
ycA
ssay
TM A
sper
gil
lus
Key to Diagnostic Category:1 = Proven2 = Probable3 = Normal
Clinical cut-off
MycAssay™: Aspergillus
Establishing a tentative clinical cut-off, for use in prospective regulatory studies
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
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)
Immune reconstitution in invasive pulmonary aspergillosis, in AIDS
Patient HB Day +14, CD4 cells 84/uL
Sambatakou, Eur J Clin Microbiol Infect Dis 2005;24:628
Patient HB Day +42, after AmB and ITZ
Immune reconstitution in invasive pulmonary aspergillosis, in AIDS
Patient HB Day +64, CD4 cells 340/uL, on
VRCSambatakou, Eur J Clin Microbiol Infect Dis 2005;24:628
Patient HB Day +87, day of death
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)
Chronic cavitary pulmonary aspergillosis (CCPA) in HIV February 2005
Surgical removal would require a pneumonectomySo treated with itraconazole
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
CCPA in HIV February 2007
February 2007 April 2007
MICs A. fumigatus Feb 2007Itraconazole = >8.0mg/mLVoriconazole = 0.5 mg/mLPosaconazole = 1.0 mg/mL
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?
Azole resistance in Manchester in A. fumigatus
Howard et al, Emerg Infect Dis 2009;15:1068
11%
17%
7%
5%
5%
0%
0%
5%
3%
7%
0%0%