Presentation on theme: "Pr Faouzi SALIBA pbr.aphp.fr Faculté de Médecine Paris Sud Réanimation - Centre Hépato-Biliaire Hôpital Paul Brousse - Villejuif- France."— Presentation transcript:
Pr Faouzi SALIBA pbr.aphp.fr Faculté de Médecine Paris Sud Réanimation - Centre Hépato-Biliaire Hôpital Paul Brousse - Villejuif- France Aspergillosis in Transplant patients
Invasive Fungal InfectionsAspergillusCandida Kidney 1.4–14%0–10%90–100% Heart 5–20%77–91%8–23% Liver 7–42%9–34%35–91% Lungs/Heart- Lungs 15–35%25–50%43–72% Small Intestine 40–59%0–3.6%80–100% Pancreas 18–38%0–3%97–100% Gabardi S. et al. Transplant Int 2007;20:993–1015, Singh N. Clin Infect Dis 2000:31;545–53. Incidence of Fungal Infections after SOT
Outcome of Patients according to the presence of Fungal Infections after LT 85% 69% 91% 69% 48% 77% Logrank p < No Fungal Infection Fungal Colonisation Treated fungal infection 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 LT ( ) years
Singh N. and Paterson DL, Clin Microb Reviews; 2005, 18, N°1: Singh N et al, AJT 2009; 9, S Incidence and mortality of IA after SOT Type of transplantation Incidence (% pts) Time (days) (Extremes) Mortality (% pts) Liver2 (1-8)17 ( )87 Lung6 (3-14)120 (4-1410)68 Heart5.2 (1-15)45 (12-365)78 Kidney0.7 (0-4)82 (20-801)77 Pancreas Intestine2.2 (0-10)289 (10-956)66
24/26 (92 %) patients Mortality of IA after LT Death directly related to aspergillosis : 16 patients (68 %) Other causes of death : w Technical Complications: 2 patients w Recurrent disease : 1 patient w Sepsis : 5 patients 13/24 patients had autopsy : 7 positive w 4 confirming the diagnosis w 3 revealing the diagnosis C.H.B. Saliba F. et al, Paul Brousse expeirence : 26/1307 patients (2 %)
Total IFIBMT N = 251 SOT N = 316 Invasive Fungal Infections 46%67% 30% (p= < 0.001) Invasive Aspergillosis 60%6945% Invasive Candidosis 36%61%29% Mortality at 3 months after the diagnosis of IFI Pappas PG et al, ICAAC 2003, Chicago, Abstract actualisé N° M-1010 A prospective Survey 25 US Transplant Centers ( )
Invasive Fungal Infections: Time of occurrence Earlier Reports u Most of the cases occurred within the first three months (CNS involvement++) Recent studies* u * 55% of the cases occurred > 3 months u ** 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
Gavaldà J et al, Clin Inf Dis 2005; 41:52-9 A retrospective case-control study : cases of proven or probable invasive aspergillosis - 11 Spanish centers (RESITRA) - Since the start of the centers transplantation programs to December 2001 Invasive Aspergillosis : Time of diagnosis
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
Diagnosis of Pulmonary Aspergillosis Pulmonary Infection u Early diagnosis difficult w radiographs often normal w Sputum cultures often negative u "halo" sign on chest CT scan highly suggestive in BMT is exceptionally present in SOT u Broncho-alveolar lavage ++ w Direct exam, Culture, Ag, PCR Halo sign ??
Galactomannan for Diagnosis of IA Population Sensitivity (%) Specificty (%) Hematologic malgnancy 7092 BMT 8286 Pediatric BMT + malignancy 8985 Solid organ transplant 2284 Meta-analysis : 27 studies Pfeiffer CD et al, Clin Infect Dis 2006; 42: Real-time PCR performed on the first positive GM increased sensitivity to 62% (Botterel F et al, Transpl Infect Dis 2008, 10: )
Risk factors of IA
E n v i r o n e m e n t culture Old ICU New protected ICU 12/767 pts (1.6 %)4/541 pts (0.7 %) Saliba F et al. 40th ICAAC, Toronto Invasive Aspergillosis : role of the environement C.H.B.
Double vitrage + store intérieur Double glass + interior storage Double vitrage + store intérieur Bed rail support Blowing 300 m 3 /h EXTRACTION : 800 m 3 /h EXTRACTION Blowing filtered air Noise Reduction HEPA Filtre Blowing Blowing : 800 m 3 /h Trappe Interior corridor C.H.B. Saliba F et al. 40 th ICAAC, Toronto, September 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 u Cultures air and surfaces (3 months) u Disinfection and HEPA filter u change (1/year) Double glass + interior storage
Clinical parameters Fungal Infections RetransplantationAspergillus spp + Candida spp Need for hemodialysisAspergillus spp + Candida spp Prophylaxis of SBPCandida spp Dysfunction of the graftAspergillus spp CMV InfectionAspergillus spp + Candida spp HHV6 InfectionAspergillus spp + Candida spp C.H.B. Risk Factors for IFI in Liver Transplant Recipients
Invasive Aspergillosis: Risk factors of early IA (1) Early IA < 3 months OR (95% CI) p Use of vascular amines > 24h 2.2 ( ) < Renal failure after SOT 4.9 ( ) < Hemodialysis after SOT 3.2 ( ) > 1 episode of bacterial infetion 3.2 ( ) < CMV disease 2.3 ( ) < Gavaldà J et al, Clin Inf Dis 2005; 41:52-9
Invasive Aspergillosis : Risk factors of late IA (2) Late IA > 3 months OR (95% CI) p Age > 50 years 2.5 ( ) Renal failure after SOT 3.9 ( ) < High levels of CNI 2.5 ( ) 0.01 > 1 episode of bacterial infetion 7.5 ( ) < De novo cancer 69.3 ( ) < Chronic graft rejection 5 ( ) Gavaldà J et al, Clin Inf Dis 2005; 41:52-9
RR95% CIp Hemodialysis prior to LT 2.7[ ]0.03 Arterial Hypertension prior to LT 2.7[ ]0.01 Acute fulminant hepatic failure 3.7[ ]0.01 CMV disease (1rst month) 3.5[ ]0.01 Risk factors of occurrence of IA during the first year post LT (Multivariate analysis) 667 LT ( ) Saliba F et al, personnal experience
Risk factors of IA after Lung transplantation Early Fungal Infections u Single lung transplant u Surgical factors include: w Lung/airway denervation w anastomotic ischemia provides nidus for fungal infection w Stents predispose to tracheal infection u Diffuse airway ischemia u Acute allograft rejection u CMV infection u Pre and post transplant Aspergillus colonisation u Acquired hypogammagloblinemia (IgG < 400mg/dl) u Transmission with the allograft Late Fungal Infections u Bronchiolitis obliterans syndrome ?
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: Singh N et al, Am J Transplant 2009, 9, S180-S191.
High doses or prolonged duration of corticosteroids Graft failure requiring Hemodialysis Potent immunosuppressive therapy for rejection Overall mortality : % Risk factors of IA after Renal transplantation Singh N et al, Am J Transplant 2009, 9, S180-S191.
Fungal Prophylaxis after Liver transplantation Drugs that have been shown to non efficaceous in preventing IFI after transplantation u Nystatin u Fungizone u Conventional low dose of Amphotericin B w mg/kg/day x days
A randomized controlled study itraconazole vs placebo Colby WD. 39 th ICAAC, San Francisco, 1999 Abstract N°1650. 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 (24%) 1 (4%) p = 0.049
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: Placebo (n=37) Liposomal amphotericin B (n=40) Infection (1 month)6 (16 %)0 Infection (>1 month to 1 year)5 (IA:1)4 (IA:3) Survival (1 year)78%80% Mortality (1 year) due to IFI31
1997 n = 148; dialysis: 22, others: 126 No prophylaxis n = 38; dialysis: 11, others: 27 ABLC/L-AmB 5 mg/kg/j Targeted Prophylaxis (preemptive) in Liver transplant recipients requiring Hemodialysis Singh N et al, Transplantation 2001
Fungal prophylaxis Prophylaxis was targeted to high-risk patients mainly u 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 u Dosage: 1mg/kg/day x 1w then 2.5 mg/kg biw w Day 1 to day 7 (mean) : 76 ± 16 mg w Cumulated dose (mean) : 955 ± 609 mg u Mean duration : 23 ± 12 days 50 patients received Fluconazole u Mean dose : 245 ± 108 mg/day (median : 200 mg) u 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
Results : Candida infection p= p= p= NS p=0.009p= 0.03 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
Results : Aspergillosis P= NS ABLC prophylaxis : 1mg/Kg/day x 3 weeks 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
Prophylaxis with Caspofungin in High-risk Liver Transplant Recipients Fortun J and GESITRA study group. Transplantation 2009;87: 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
Attitude towards prophylaxis of Liver transplant Centers in USA Traitement of choice: u Fluconazole (86%) Traitement of choice for moulds: u Echinocandins (41%) u Voriconazole (25%) u Polyene (18%) u Combination therapy : w Primary therapy for IA: 47% w For salvage therapy IA: 80% Survey : electronic questionnaire 67/106 (63%) of the centers answered Singh N et al, Am J Transplant 2008, 8: Prophylaxis Fluconazole vs non-Fluconazole Higher rate of mould infections (Aspergillosis, zygomycosis and scedosporiosis) RR 1.5 (95% CI ; p=0.04)
Lipid formulation of AmB (II 2) u 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.
Prophylaxis for high-risk patients after Lung transplantation (recommendations of the AST Infectious disease Community of Practice) Inhaled amphotericin B u 6-30 mg/day - 25 mg/day Inhaled lipid formulations of amphotericin B u Nebulized ABLC (II 3) w 50 mg/every 2 days for 2 weeks w Once a week x 13 weeks (minimum) u Nebulized L-AmB w 25 mg three times per week x 2 months w Then once a week x 6 months w Then twice per month In high-risk patients u Voriconazole* : 400 mg/day x 4 months u Itraconazole*: 400 mg/day x 4 months w Monitor liver enzymes and azole and Immunosuppressive drugs +++ Singh N et al, Am J Transplant 2009, 9, S180-S191.
Voriconazole for Prophylaxis after Lung transplantation Voriconazole N= 65 Targeted prophylaxis Itraconazole or Inhaled ampho B N= 30 p IFI1 (1.5%)7 (23%)0.001 Non- Aspergillus infections at 1 year 2 (3%)7 (23%)0.004 Husain S et al, AJT 2006; 6:
Voriconazole u 200mg BID for 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.
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 w Liver, kidney, brain… Drug interactions Immunosuppressive drugs: w Calcineurine inhibitors: Cyclosporine, tacrolimus w mTOR inhibitors: sirolimus, everolimus Antimicrobials w Glycopeptides, aminoglycosides, rifampicin…
ABLC in the treatment of IA after SOT Linden PK et al, CID 2003; 37:17-25 ABLC (5mg/Kg/day) compared to an historical group of c-AmB (1.1 mg/kg/day) Mortality (%)
Survival after treatment of IA after SOT Probability of Survival (%) Caspofungine + Voriconazole L-AmB Days after the diagnosis Singh et al. Transplantation 2006 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 A prospective and retrospective study 51% 67%
Survival after treatment of IA after SOT Response rate (%) Singh et al. Transplantation 2006 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 A prospective and retrospective study P=0.08 Total success 70% 51% P=0.79 Complete response 17,5% 21,3% P=0.048 Partial response 52,5% 29,8%
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 Winkler M et al, Transplant inf Dis % 70% 74%
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 u Further multicenter trials are needed to evaluate their efficacy u Echinocandins are currently under evaluation Management of IA is comparable to the non-transplant setting