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

Frequency

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 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

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

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

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 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

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

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

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 Patient DF A. niger grown 5x from sputum WWW.aspergillus.org.uk;

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

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

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

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

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

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 otomastoiditis Ear pain (often severe), otorrhoea, without fever

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

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 “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

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

Would PCR help?

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

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

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 Patient HB Day +42, after AmB and ITZ Sambatakou, Eur J Clin Microbiol Infect Dis 2005;24:628

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

Azole resistance

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

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

CCPA in HIV - low itraconazole concentrations Itraconazole concentrations Nov 05 2.5 mg/L Dec 05 3.4 mg/L March 06 4.5 mg/L July 06 6.7 mg/L Feb 07 8.4 mg/L Do low concentrations of antifungal predispose to the development of resistance?

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

www.aspergillus.org.uk

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