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Pr Faouzi SALIBA faouzi.saliba@ pbr.aphp.fr Faculté de Médecine Paris Sud Réanimation - Centre Hépato-Biliaire Hôpital P

Aspergillosis in Transplant patients. Pr Faouzi SALIBA faouzi.saliba@ pbr.aphp.fr Faculté de Médecine Paris Sud Réanimation - Centre Hépato-Biliaire Hôpital Paul Brousse - Villejuif- France . Incidence of Fungal Infections after SOT.

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Pr Faouzi SALIBA faouzi.saliba@ pbr.aphp.fr Faculté de Médecine Paris Sud Réanimation - Centre Hépato-Biliaire Hôpital P

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  1. Aspergillosis in Transplant patients Pr Faouzi SALIBA faouzi.saliba@ pbr.aphp.fr Faculté de Médecine Paris Sud Réanimation - Centre Hépato-Biliaire Hôpital Paul Brousse - Villejuif- France

  2. Incidence of Fungal Infections after SOT Gabardi S. et al. Transplant Int 2007;20:993–1015, Singh N. Clin Infect Dis 2000:31;545–53.

  3. Outcome of Patients according to the presence of Fungal Infections after LT 91% 85% 77% No Fungal Infection 69% 69% Fungal Colonisation 48% Treated fungal infection Logrank p <0.0001 667 LT (1999-2005) years Saliba F et al, European Society of Organ transplantation (ESOT), Paris Sept 2009 Saliba F et al, International Conference on Antimicrobial Agents and Chemotherapy (ICAAC) San Francisco, Sept 2009

  4. Incidence and mortality of IA after SOT Singh N. and Paterson DL, Clin Microb Reviews; 2005, 18, N°1: 44-69. Singh N et al, AJT 2009; 9, S180-191

  5. Invasive Aspergillose : Mortality

  6. Mortality of IA after LT Death directly related to aspergillosis : 16 patients (68 %) Other causes of death : Technical Complications: 2 patients Recurrent disease : 1 patient Sepsis : 5 patients 13/24 patients had autopsy : 7 positive 4 confirming the diagnosis 3 revealing the diagnosis C.H.B. 1985 - 1997: 26/1307 patients (2 %) 24/26 (92 %) patients Saliba F. et al, Paul Brousse expeirence

  7. Mortality at 3 months after the diagnosis of IFI A prospective Survey 25 US Transplant Centers (2001-2002) Pappas PG et al, ICAAC 2003, Chicago, Abstract actualisé N° M-1010

  8. Invasive Fungal Infections: Time of occurrence Earlier Reports Most of the cases occurred within the first three months (CNS involvement++) Recent studies* * 55% of the cases occurred > 3 months ** 43% of the cases occurred > 3 months • * Singh N, Clin Infect Dis 2003; 36:46–52 • ** Gavaldà J et al, Clin Inf Dis 2005; 41:52-9

  9. Invasive Aspergillosis : Time of diagnosis • A retrospective case-control study : • 156 cases of proven or probable invasive aspergillosis • 11 Spanish centers (RESITRA) • Since the start of the centers’ transplantation programs to December 2001 Gavaldà J et al, Clin Inf Dis 2005; 41:52-9

  10. Pattern of Fungal Infections in SOT Patients • Immunosuppression impairs inflammatory response • Scarcity of clinical and/or radiologic signs associated with inflammation • Progress of infection prior to clinical presentation • Infection often advanced at time of diagnosis • Rapidly progressive • Absence of surrogate markers that could allow early diagnosis • Efficacy of therapeutic agents limited by toxicity and drug interactions

  11. Diagnosis of Pulmonary Aspergillosis • Pulmonary Infection • Early diagnosis difficult • radiographs often normal • Sputum cultures often negative • "halo" sign on chest CT scan highly suggestive in BMT is exceptionally present in SOT • Broncho-alveolar lavage ++ • Direct exam, Culture, Ag, PCR Halo sign ??

  12. Galactomannan for Diagnosis of IA Meta-analysis 1996- 2005: 27 studies • Real-time PCR performed on the first positive GM increased • sensitivity to 62% (Botterel F et al, Transpl Infect Dis 2008, 10: 333-8.) Pfeiffer CD et al, Clin Infect Dis 2006; 42: 1417-27

  13. Risk factors of IA

  14. Invasive Aspergillosis : role of the environement C.H.B. Old ICU New protected ICU E n v i r o n e m e n t culture + + - + - - - - + - 12/767 pts (1.6 %) 4/541 pts (0.7 %) Saliba F et al. 40th ICAAC, Toronto 2000.

  15. Ventilation System - Liver transplantation ICU(Paul Brousse Hospital) Characteristics 1. HEPA Filters (99.97 %) 2. Unidirectionnel airflow 3. Room positive air pressure 4. Hermetic rooms 5. Air renewal rate (20times/h) 6. Air velocity (2.5-3m/s) Maintenance Cultures air and surfaces (3 months) Disinfection and HEPA filter change (1/year) C.H.B. Noise Reduction Blowing filtered air HEPA Filtre Double vitrage + store intérieur Trappe Blowing Blowing : 800 m3/h Double glass + interior storage Bed rail support Double glass + interior storage EXTRACTION : 800 m3/h Blowing 300 m3/h Double vitrage + store intérieur EXTRACTION Interior corridor Saliba F et al. 40th ICAAC, Toronto, September 2000.

  16. Risk Factors for IFI in Liver Transplant Recipients C.H.B.

  17. Invasive Aspergillosis: Risk factors of early IA (1) Gavaldà J et al, Clin Inf Dis 2005; 41:52-9

  18. Invasive Aspergillosis : Risk factors of late IA (2) Gavaldà J et al, Clin Inf Dis 2005; 41:52-9

  19. Risk factors of occurrence of IA during the first year post LT (Multivariate analysis)667 LT (1999-2005) Saliba F et al, personnal experience

  20. Risk factors of IA after Lung transplantation Early Fungal Infections Single lung transplant Surgical factors include: Lung/airway denervation anastomotic ischemia provides nidus for fungal infection Stents predispose to tracheal infection Diffuse airway ischemia Acute allograft rejection CMV infection Pre and post transplant Aspergillus colonisation Acquired hypogammagloblinemia (IgG < 400mg/dl) Transmission with the allograft Late Fungal Infections Bronchiolitis obliterans syndrome ?

  21. Isolation of Aspergillus from redspiratory tract cultures Reintervention CMV disease Hemodialysis Existence of an episode of IA in the program in the program 2 months before or after heart transplant Overall mortality : 67% Risk factors of IA after Heart transplantation Munoz P et al, Curr Opin Infect Dis 2006; 19: 365-370 Singh N et al, Am J Transplant 2009, 9, S180-S191 .

  22. High doses or prolonged duration of corticosteroids Graft failure requiring Hemodialysis Potent immunosuppressive therapy for rejection Overall mortality : 67-75 % Risk factors of IA after Renal transplantation Singh N et al, Am J Transplant 2009, 9, S180-S191 .

  23. ProphylaxisTargeted prophylaxisPreemptive Therapy

  24. Fungal Prophylaxis after Liver transplantation Drugs that have been shown to non efficaceous in preventing IFI after transplantation Nystatin Fungizone Conventional low dose of Amphotericin B 0.2 - 0.5 mg/kg/day x 7 - 21 days

  25. Prophylaxis of IFI after LTx Itraconazole 5 mg/kg prior to LTx then 2.5 mg/kg BID after LTx All IFI were due to Candida Study was not sufficient to show any efficacy against IA A randomized controlled study itraconazole vs placebo p = 0.049 (24%) 1 (4%) Colby WD. 39th ICAAC, San Francisco, 1999 Abstract N°1650.

  26. Prophylaxis with Liposomal Amphotericin B after Liver Transplantation Randomized study of liposomal amphotericin B(1 mg/kg/day x 5 days) vs placebo Tollemar JG, et al. Transplant Proc 1995;27:1195-8

  27. Targeted Prophylaxis (preemptive) in Liver transplant recipients requiring Hemodialysis n = 38; dialysis: 11, others: 27 ABLC/L-AmB 5 mg/kg/j n = 148; dialysis: 22, others: 126 No prophylaxis 1997 Singh N et al, Transplantation 2001

  28. Fungal prophylaxis Prophylaxis was targeted to high-risk patients mainly ALF, Retransplantation, End-stage cirrhosis in the ICU A total of 198 high-risk patients received a fungal prophylaxis 146 high-risk patients (21.9%) received Amphotericin B lipid complex (ABLC) fungal prophylaxis Dosage: 1mg/kg/day x 1w then 2.5 mg/kg biw Day 1 to day 7 (mean) : 76 ± 16 mg Cumulated dose (mean) : 955 ± 609 mg Mean duration : 23 ± 12 days 50 patients received Fluconazole Mean dose : 245 ± 108 mg/day (median : 200 mg) Mean duration : 18 ± 11 days Saliba F et al, European Society of Organ transplantation (ESOT), Paris Sept 2009 Saliba F et al, International Conference on Antimicrobial Agents and Chemotherapy (ICAAC) San Francisco, Sept 2009

  29. Results : Candida infection p= NS p=0.0001 p=0.009 p= 0.03 p=0.0002 Saliba F et al, European Society of Organ transplantation (ESOT), Paris Sept 2009 Saliba F et al, International Conference on Antimicrobial Agents and Chemotherapy (ICAAC) San Francisco, Sept 2009

  30. Results : Aspergillosis ABLC prophylaxis : 1mg/Kg/day x 3 weeks P= NS Saliba F et al, European Society of Organ transplantation (ESOT), Paris Sept 2009 Saliba F et al, International Conference on Antimicrobial Agents and Chemotherapy (ICAAC) San Francisco, Sept 2009

  31. Prophylaxis with Caspofungin in High-risk Liver Transplant Recipients • A prospective multicentre Spanish study • Duration of prophylaxis: 21 days (range 5–54 days) • Successful response: 88.7% • 2 patients developed IFI after end of therapy: Mucor and Candida albicans Fortun J and GESITRA study group. Transplantation 2009;87:424-37

  32. Attitude towards prophylaxis of Liver transplant Centers in USA Traitement of choice: Fluconazole (86%) Traitement of choice for moulds: Echinocandins (41%) Voriconazole (25%) Polyene (18%) Combination therapy : Primary therapy for IA: 47% For salvage therapy IA: 80% • Survey : electronic questionnaire • 67/106 (63%) of the centers answered Prophylaxis Fluconazole vs non-Fluconazole Higher rate of mould infections (Aspergillosis, zygomycosis and scedosporiosis) RR 1.5 (95% CI 1.0-2.2; p=0.04) Singh N et al, Am J Transplant 2008, 8:426-31.

  33. Lipid formulation of AmB (II 2) 3-5 mg/kg/day Or an Echinocandin (II 3) Duration 3-4 weeks or until resolution of risk factors Prophylaxis of high-risk patients after Liver transplantation(Recommendations of the AST Infectious disease Community of Practice) Singh N et al, Am J Transplant 2009, 9, S180-S191 .

  34. Prophylaxis for high-risk patients after Lung transplantation(recommendations of the AST Infectious disease Community of Practice) Inhaled amphotericin B 6-30 mg/day - 25 mg/day Inhaled lipid formulations of amphotericin B Nebulized ABLC (II 3) 50 mg/every 2 days for 2 weeks Once a week x 13 weeks (minimum) Nebulized L-AmB 25 mg three times per week x 2 months Then once a week x 6 months Then twice per month In high-risk patients Voriconazole* : 400 mg/day x 4 months Itraconazole*: 400 mg/day x 4 months Monitor liver enzymes and azole and Immunosuppressive drugs +++ Singh N et al, Am J Transplant 2009, 9, S180-S191 .

  35. Voriconazole for Prophylaxis after Lung transplantation Husain S et al, AJT 2006; 6:3008-16

  36. Voriconazole 200mg BID for 50-150 days Prophylaxis for high-risk patients after Heart transplantation(Recommendations of the AST Infectious disease Community of Practice) Singh N et al, Am J Transplant 2009, 9, S180-S191 .

  37. Management of Invasive Fungal Infection Early specific diagnosis often requires invasive procedure Effective therapy must take into consideration: Common altered liver and kidney functions Drug toxicities Liver, kidney, brain… Drug interactions Immunosuppressive drugs: Calcineurine inhibitors: Cyclosporine, tacrolimus mTOR inhibitors: sirolimus, everolimus Antimicrobials Glycopeptides, aminoglycosides, rifampicin…

  38. ABLC in the treatment of IA after SOT ABLC (5mg/Kg/day) compared to an historical group of c-AmB (1.1 mg/kg/day) Mortality (%) Linden PK et al, CID 2003; 37:17-25

  39. Survival after treatment of IA after SOT 100 Caspofungine + Voriconazole 75 50 L-AmB 25 0 0 50 100 Days after the diagnosis A prospective and retrospective study • First-line treatment : • Caspofungine + Voriconazole (n=40) between 2003 et 2005 • Historical group : L-AmB (n=47) between 1999 and 2002 L-AmB (n=47) between 1999 and 2002 67% 51% Probability of Survival (%) Singh et al. Transplantation 2006

  40. Survival after treatment of IA after SOT 70% P=0.048 P=0.08 52,5% 51% P=0.79 29,8% 21,3% 17,5% Total success Complete response Partial response A prospective and retrospective study • First-line treatment : • Caspofungine + Voriconazole (n=40) between 2003 et 2005 • Historical group : L-AmB (n=47) between 1999 and 2002L-AmB (n=47) between 1999 and 2002 Response rate (%) Singh et al. Transplantation 2006

  41. Caspofungine for treatment of IA after SOT • A retrospective study : 81 SOT patients with IFI • IA : 22 patients, 19 treated with Caspofungine • Proven : 7 patients • Probable 12 patients 74% 78% 70% Winkler M et al, Transplant inf Dis 2010

  42. Conclusion Invasive Aspergillosis has a major impact on patient survival Risk factors for developping IA are now well known Serum, sputum and BAL galactomannan could be of help but need further evaluation Prophylaxis should be administered only to high-risk patients Further multicenter trials are needed to evaluate their efficacy Echinocandins are currently under evaluation Management of IA is comparable to the non-transplant setting

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