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Alessandro C. Pasqualotto pasqualotto@santacasahe.br Porto Alegre, Brazil

What are we looking at? Challenges in the diagnosis of Invasive Mould Diseases. Alessandro C. Pasqualotto pasqualotto@santacasa.tche.br Porto Alegre, Brazil. Potential conflicts of interest. Research Grants Myconostica , Pfizer, Merck, Sigma-Tau, CAPES, CNPq , Fungal Research Trust

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Alessandro C. Pasqualotto pasqualotto@santacasahe.br Porto Alegre, Brazil

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  1. What are we looking at? Challenges in the diagnosis of Invasive Mould Diseases Alessandro C. Pasqualottopasqualotto@santacasa.tche.brPorto Alegre, Brazil

  2. Potential conflicts of interest • Research Grants • Myconostica, Pfizer, Merck, Sigma-Tau, CAPES, CNPq,Fungal Research Trust • Travel Grants • Pfizer, United Medical, Schering (now Merck), Bagó, Merck • Speaker honoraria • Pfizer, United Medical, Merck, Schering (now Merck), Biometrix

  3. First assumption: IFD are highly lethal diseases

  4. p<0.001 Incidence 13.3% in lung transplant recipients • Xavier MO, Pasqualotto AC, et al. ECCMID 2009

  5. Rapidly evolving diseases 4 days later • www.aspergillus.org.uk

  6. Disseminated infection • www.aspergillus.org.uk

  7. Second assumption: We need to intervene asap

  8. Early versus late intervention Mortality rate (%) Von Eiff, et al. Respiration 1995; 62: 241-7

  9. Early versus late intervention Mortality rate (%) Von Eiff, et al. Respiration 1995; 62: 241-7

  10. But how can we achieve such an early diagnosis?

  11. A small black scar 2 days earlier + serum GM Patient died 1 day after this picture was taken

  12. A small black scar 2 days earlier + serum GM Patient died 1 day after this picture was taken Zygo + A. flavus

  13. MD Anderson Cancer Centre Necropsy study over a 15-years period • IFD detected in 31% over 1,017 necropsies • Antemortem diagnosis in only 25% Chamilos G, et al. Haematologica 2006; 91: 986-9

  14. MD Anderson Cancer Centre Necropsy rate has reduced over time % Chamilos G, et al. Haematologica 2006; 91: 986-9

  15. By the way, what is the necropsy rate in your institution? • >40% • 10-39% • 1-10% • <1% • Are you kidding?

  16. MD Anderson Cancer Centre Trends in the prevalence of IFD % Chamilos G, et al. Haematologica 2006; 91: 986-9

  17. No need to worry! CT scan and galactomannan are there to help us out!

  18. Day 0: halo Day 7: air crescent Day 4: size, halo ‘Halo sign’ surrounding a nodule Caillot, et al. J Clin Oncol 1997; 15: 139-47

  19. The sign is not specific for IA • Vasculitis • Metastasis • Pseudomonas infections • Zygomycosis and other angio-invasive infections Greene RE, et al. Clin Infect Dis 2007; 44: 373-9

  20. Absence of typical findings at chest CT scan • COPD • Steroids • Other non-neutropenic patients / ICU • Lung transplant recipients • ? Monoclonal antibodies

  21. ‘Reversed halo sign’ Organising cryptogenic pneumonia Wahba H, et al. Clin Infect Dis 2008; 46: 1733-7

  22. ‘Reversed halo sign’ • Review of 189 cases of invasive mould disease • Overall frequency 4% Wahba H, et al. Clin Infect Dis 2008; 46: 1733-7

  23. ‘Reversed halo sign’ • Review of 189 cases of invasive mould disease • Overall frequency 4% • Zygomycosis 19% • Aspergillosis <1% • Fusariosis 0% (p<0.01) Wahba H, et al. Clin Infect Dis 2008; 46: 1733-7

  24. Other predictors of zygomycosis • >10 nodules • Pleural effusion • Concomitant sinusitis • Treatment with voriconazole Chamilos G, et al. Clin Infect Dis 2005; 41: 60-6

  25. Meta-analysis of GM testing Low PPV High NPV Pfeiffer CD, et al. Clin Infect Dis 2006; 42: 1417-27

  26. Reproducibility Caution with low +ve indexes! Upton A, et al. J Clin Microbiol 2005; 43: 4796-800

  27. GM release by non-Aspergillus fungi • Penicillium marneffei • Geotricum capitatum • Acremonium species • Alternaria alternata • Rhodotorula rubra • Trichophyton species • Paecilomyces variotii • Botrytis tulipae • Cladosporium species • Exophiala dermatitidis Aquino VR, Goldani LZ, Pasqualotto AC. Mycopathologia 2007; 163: 191-202

  28. Cross-reaction with GM testing % Xavier MO, Pasqualotto AC, Severo LC. Clin Vaccin Immunol 2009; 16: 132-3

  29. Clinical case • 19 year-old man, refractory leukaemia • Febrile neutropenia • Amox-clav for E. Coli bacteremia Maertens J, et al. Clin Infect Dis 2004; 39: 289-90

  30. Clinical case • 19 year-old man, refractory leukaemia • Febrile neutropenia • Amox-clav for E. Coli bacteremia • Daily GM determination • D1 after antibiotic: GM index of >1.5 • 5 +ve tests afterwards Maertens J, et al. Clin Infect Dis 2004; 39: 289-90

  31. Clinical case • 19 year-old man, refractory leukaemia • Febrile neutropenia • Amox-clav for E. Coli bacteremia • Daily GM determination • D1 after antibiotic: GM index of >1.5 • 5 +ve tests afterwards • Fluoroquinolone: gradual reduction in GM index Maertens J, et al. Clin Infect Dis 2004; 39: 289-90

  32. Clinical case • 1 wk later • Pipe-tazo for appendicitis • GM >2.5; bilateral nodular infiltrate Maertens J, et al. Clin Infect Dis 2004; 39: 289-90

  33. Clinical case • 1 wk later • Pipe-tazo for appendicitis • GM >2.5; bilateral nodular infiltrate • Probable IA (EORTC / MSG) • Antifungal therapy + meropenem • Gradual ↓ in GM index Maertens J, et al. Clin Infect Dis 2004; 39: 289-90

  34. Clinical case • 1 wk later • Pipe-tazo for appendicitis • GM >2.5; bilateral nodular infiltrate • Probable IA (EORTC / MSG) • Antifungal therapy + meropenem • Gradual ↓ in GM index • Necropsy: leukaemia infiltrate • Absence of IA Maertens J, et al. Clin Infect Dis 2004; 39: 289-90

  35. Meta-analysis of GM testing Pfeiffer CD, et al. Clin Infect Dis 2006; 42: 1417-27

  36. Specificity 94% Sensitivity 79% Marked heterogeneity (particularly for sensitivity) BAL PCR testing Tuon FF. Rev IberoamMicol 2007; 24: 89-94

  37. PCR Critical points • Variable sensitivity / specificity • Lack of standardised targets / reagents • Extraction method • Platform (conventional PCR vs Real time) • Poor understanding of DNA kinetics • Not yet part of the EORTC/MSG criteria De Pauw B, et al. Clin Infect Dis 2008; 46: 1813-21

  38. Beta-Glucan • Detected in IFDs caused by • Candida and Aspergillus Fungal cell wall Phospholipid bilayer of the fungal cell membrane -(1,3)-glucan -(1,3)-glucan synthase Ergosterol Yoshida M, et al. J Med Veter Mycol 1997; 35: 371-4

  39. Beta-Glucan • Detected in IFDs caused by • Candida and Aspergillus • Trichosporon • Fusarium • Acremonium • Saccharomyces • Pneumocystis Yoshida M, et al. J Med Veter Mycol 1997; 35: 371-4

  40. There he is again, speaking about a test that nobody uses in Brazil …

  41. The reality in Brazil • A survey performed in collaboration with ANVISA • 140 hospitals • >42,000 beds • 65% teaching hospitals • 90% belonging to the Sentinel Network

  42. Complexity in hospital care %

  43. Is IFD a problem in your centre? 38.7% n=140

  44. Do you know your local epidemiology? 40.1% n=140

  45. Specialised media for fungi 19.7% n=140

  46. Aspergillus identification at the species level 58.5% n=140

  47. Fungal staining - biopsies 51.1% n=140

  48. Biopsy specimens are sent in formalin only? 26.0% n=140

  49. Access to high resolution CT 34.3% n=140

  50. Galactomannan 83.6% n=140

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