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Aspergillosis in AIDS

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.

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Aspergillosis in AIDS

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  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. ABPA Severe asthma with fungal sensitisation Allergic sinusitis Acute Invasive 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 1999;67:3703

  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 2009;132:221

  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 2000;31:1253

  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 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

  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 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

  15. 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

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

  18. 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

  19. Invasive pulmonary aspergillosis in AIDS, showing nodules with cavitation WWW.aspergillus.org.uk

  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 WWW.aspergillus.org.uk;

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

  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 2004;14: 2030

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

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

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

  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 Presented with headache over the vertex of the skull www.aspergillus.man.ac.uk

  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. 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 1993;95:177

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

  35. Would PCR help?

  36. 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

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

  44. 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

  45. Azole resistance

  46. Chronic cavitary pulmonary aspergillosis (CCPA) in HIV February 2005 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) Surgical removal would require a pneumonectomySo treated with itraconazole

  47. February 2007 April 2007 CCPA in HIV February 2007 On HAART Rx, with low viral load, CD4 count >200- New haemoptysis- Aspergillus precipitin titre 1/32CXR & CT scan showed expansion of inferior cavity MICs A. fumigatus Feb 2007Itraconazole = >8.0mg/mLVoriconazole = 0.5 mg/mLPosaconazole = 1.0 mg/mL

  48. CCPA in HIV - low itraconazole concentrations 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 Do low concentrations of antifungal predispose to the development of resistance?

  49. 11% 5% 17% 7% 5% 3% 0% 0% 5% 7% 0% 0% Azole resistance in Manchester in A. fumigatus Howard et al, Emerg Infect Dis 2009;15:1068

  50. www.aspergillus.org.uk

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