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

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Presentation on theme: "Aspergillosis in AIDS David W. Denning Director, National Aspergillosis Centre University Hospital South Manchester [Wythenshawe Hospital] The University."— Presentation transcript:

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

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

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

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 AIDSCDC Group II 4 (1%) CDC Group IV 289 (72%) Neutropenia <1000 x 10 6 /L92/202 (46%) Corticosteroid therapy79/202 (39%) Prior pulmonary infection124/169 (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 RespiratoryOther Sinuses 9CNS 30 Otomastoiditis 5Cardiac 10 Larynx 2Renal 12 Tracheobronchitis 11Thyroid 4 Obstructing bronchial 5Miscellaneous 16 Invasive Pulmonary 208 Empyema/pleural mass 5 Aspergilloma 4 2 organs involved = 47 Khoo & Denning, Clin Infect Dis 1994; 19 (S1) 541

15 Invasive pulmonary aspergillosis in AIDS Presenting features (in 78 patients) Cough92 % Fever91 % Dypsnoea 65 % Chest pain24 % 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) Denning et al, New Engl J Med 1991;324: 654 Patient JB

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

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

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

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

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

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 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. fumigatus69 (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 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.

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

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

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

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

45 Azole resistance

46 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 pneumonectomy So treated with itraconazole

47 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 2007 Itraconazole = >8.0mg/mL Voriconazole = 0.5 mg/mL Posaconazole = 1.0 mg/mL

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

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

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