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

Frequency

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

Mumbai autopsy series

Lanjewar & Duggal, HIV Med 2001;2:266

Risk factors

CDC surveillance

Holding et al, Clin Infect Dis 2000;31:1253

Italian experience of aspergillosis in AIDS

Libanore et al, Infection 2002;30:341

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

Clinical suspicion

Missed IFDs in AIDS – autopsy series

Antinori et al, Am J Clin Pathol 2009;132:221

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

Italian experience of aspergillosis in AIDS

Libanore et al, Infection 2002;30:341

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 nodules with

cavitation

WWW.aspergillus.org.uk

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

Italian experience of aspergillosis in AIDS

Libanore et al, Infection 2002;30:341

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

Radiology and diagnostic accuracy

Zaspel et al, Eur Radiol 2004;14: 2030

Radiology and

diagnostic accuracy

Zaspel et al, Eur Radiol 2004;14: 2030

AUC = 0.75

AUC = 0.84

Obstructing bronchial aspergillosis

Patient ML Pre-bronchscopy

Denning et al, New Engl J Med 1991;324: 654

Patient ML After bronchoscopy

Invasive Aspergillus tracheobronchitis in AIDS

Lortholary et al, Am J Med 1993;95:177

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

Establishing a diagnosis

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.

Italian experience of aspergillosis in AIDS

Libanore et al, Infection 2002;30:341

Would PCR help?

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

Treatment

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)

HIV therapy and azole interactions

Beware!

IRIS

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

Azole resistance

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%

www.aspergillus.org.uk