Perché è Difficile Diagnosticare e Trattare l’Aspergillosi Invasiva?

1. Perché è Difficile Diagnosticare e Trattare l’Aspergillosi Invasiva?

2. TOPICS • Behavior of Aspergillus • -characteristics • Principles of management • -detection • -treatment • when and what

3. TOPICS • Behavior of Aspergillus • -characteristics • Principles of management • -detection • -treatment • when and what

4. INFECTION!

5. INFECTION!

6. bacteria viruses fungi

7. EUKARYOTIC ORGANISM!! MRS. FUNGUS cell membrane -ergosterol cell wall cholesterol

8. ASPERGILLUS 1729 FIRST DESCRIPTION “brush-shapedstructure” MICHELI catholicpriest

10. ASPERGILLUS IS EVERYWHERE environment moss soil decaying material

11. According to Odds

12. DEFENSE SYSTEMS T-cell function Humoral immunity Commensal flora Granulocytes Mucosa / Skin removes viruses, fungi and tumor cells antibody production micro-organisms in the gut against bacteria – pus formation border control of our body

13. DEFENSE SYSTEMS T-cell function Humoral immunity Commensal flora Granulocytes Mucosa / Skin day 40 100

14. T-cell function Humoral immunity Granulocytes Commensal flora Mucosa COURSE OF DEFENSE SYSTEMS ASPERGILLUS INFECTIONS / Skin day 40 100

15. time INFECTIOUS AGENTS IN RELATION TO THE COURSE OF DEFENSE SYSTEMSGarcia-Vidal et al. Clin Infect Dis 2008; 47:1041-1050 ASPERGILLUS

16. immuno- suppression epidemiologic exposure BASIC RISK FACTORS FOR FUNGAL INFECTIONS Adapted from RH Rubin, Boston

17. money shops OPPORTUNISTS!

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19. TRENDS INCIDENCE INVASIVE FUNGAL INFECTIONSPagano et al. Haematologica 2006; 91:1068-1075 80 70 ASPERGILLUS 60 50 number of cases 40 30 20 10 0 87-88 92-93 97-98 2002-2003

20. INVASIVE FUNGAL DISEASE AFTER NON-MYELOABLATIVE ALLO-BMTFukuda et al. Blood 2003; 102:827-833 22% non-relapse mortality 39% mould-related n = 163 9% mould-related deaths

21. MORTALITY OF INVASIVE ASPERGILLOSIS • Variation due to: • timing of intervention • timely diagnosis • patients’ defense system • treatment given

22. 97% 42% MORTALITY OF INVASIVE ASPERGILLOSIS • Variation due to: • timing of intervention • timely diagnosis • patients’ defense system • treatment given

23. GROWTH OF ASPERGILLUS 1-2 cm per 24 hours

24. MAKE YOUR CHOICE!

25. ONE WEEK LATER….

26. INFECTION -- DISEASE

27. TOPICS • Behavior of Aspergillus • -characteristics • Principles of management • -detection • -treatment • when and what

28. TOPICS • Behavior of Aspergillus • -characteristics • Principles of management • -detection • -treatment • when and what

29. TOPICS • Behavior of Aspergillus • -characteristics • Principles of management • -detection • -treatment • when and what

30. spores hyphae spore WELCOME TO MYCOLOGY ASPERGILLUS

31. ADMISSION TO THE HUMAN BODY

32. Caso MK - 5

33. 97% 42% EVOLUTION OF AN INFECTION AND MORTALITY TRADITIONAL DIAGNOSIS FUNGAL BURDEN

34. 97% diagnostics 42% AWAY FROM EMPIRISM? TRADITIONAL DIAGNOSIS NEW TOOLS FUNGAL BURDEN

35. CT culture histology serology FIRST TEST POSITIVE FOR ASPERGILLOSIS IN HEMATOLOGICAL MALIGNANCIESFlorent et al. J Infect Dis 2006;193:741-747 0 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 DAYS 55 patients

36. TOPICS • Behavior of Aspergillus • -characteristics • Principles of management • -detection • -treatment • when and what

37. TOPICS • Behavior of Aspergillus • -characteristics • Principles of management • -detection • -treatment • when and what

38. TOPICS • Behavior of Aspergillus • -characteristics • Principles of management • -detection • -treatment • whenand what

39. antibacterials Empiricalanti- fungals ADMINISTRATION OF ANTIMICROBIALS IN RELATION TO THE COURSE OF NEUTROPENIA 100% 75% 50% >1000 1000 GRANULOCYTES 500 <100 0 10 20 30 days

40. Aspergillus antigen infiltrate Peter Donnelly & Ben dePauw ESTIMATING TIME FOR INTERVENTION • Persisting fever + • very high risk • or • a suggestive symptom • or • a suspected sign • or • any positive test day 1 5 7 12 // 28 > 42

41. BRAZILIAN: -no defense -intuitive attack TACTICS ITALIAN: -strong defense -efficient attack

42. TOPICS • Behavior of Aspergillus • -characteristics • Principles of management • -detection • -treatment • when and what

43. isavuconazole anidulafungin micafungin caspofungin posaconazole voriconazole Adapted from Rex & Edwards, 1997 AmBisome Amphocil Abelcet itraconazole fluconazole terbinafine ketoconazole miconazole 5-flucytosine Amphotericin B Nystatin Griseofulvin 1960 1970 1980 1990 2000 PACE OF DEVELOPMENT OF NEW ANTIFUNGAL AGENTS 1950

44. EORTC EORTC IFICG IFICG % response 60 50 40 30 25/51 (49%) 42/133 (32%) 76/144 (53%) 53/107 (50%) 20 10 0 RESULTS FIRST LINE TREATMENT OFINVASIVE ASPERGILLOSISHerbrecht et al N Engl J Med 2002; 347:408-415 Cornely et al. Clin Infect Dis 2007; 44:1289-1297Viscoli et al. J Chemother 2007; 19, suppl 5:36 Caspofungin Lipo-AmB Ampho B Voriconazole

45. OUTCOME OF ASPERGILLOSIS IN RELATION TO INITIAL ANTIFUNGAL THERAPYNivoix, Y et al. Clin Infect Dis 2008; 47:1176-1184 n = 289 n = 51 n = 127 n = 62 SURVIVAL 70% P=0.016 47%

46. OUTCOME OF THERAPY FOR ASPERGILLOSIS ARISING DURING AML IN DAILY PRACTICEPagano et al. SEIFEM 2008 140 cases First line therapy 40 30 20 10 0 28% 27% 21% 16% N° of patients treated voriconazole caspofungin combo L-AmB

47. OUTCOME OF THERAPY FOR ASPERGILLOSIS ARISING DURING AML IN DAILY PRACTICEPagano et al. SEIFEM 2008 140 cases Aspergillosis attributable mortality 40 30 20 10 0 N° of patients treated 18% 24% 32% 23% voriconazole caspofungin combo L-AmB

48. low dose corticosteroids high dose CORTICOSTEROIDS AND SURVIVAL OF ASPERGILLOSIS IN HSCTCordonnier et al. Clin Infect Dis 2006;42:955-963 51 patients with aspergillosis 41 allo HSCT 10 auto S U R V I V A L

49. RELATION OUTCOME OF FUNGAL INFECTIONSAND GRANULOCYTE COUNT n = 63 DECREASING GRANULOCYTES Response 36% INCREASING GRANULOCYTES Response 86%

50. RELATION OUTCOME OF FUNGAL INFECTIONSAND STATE OF UNDERLYING DISEASE SUCCESSFUL OUTCOME REMISSION 61% n = 63 REFRACTORY UNDERLYING DISEASE 8%