Presentation on theme: "Aspergillosis in Transplant patients"— Presentation transcript:
1 Aspergillosis in Transplant patients Pr Faouzi SALIBApbr.aphp.frFaculté de Médecine Paris SudRéanimation - Centre Hépato-BiliaireHôpital Paul Brousse - Villejuif- France
2 Incidence of Fungal Infections after SOT Invasive Fungal Infections AspergillusCandidaKidney1.4–14%0–10%90–100%Heart5–20%77–91%8–23%Liver7–42%9–34%35–91%Lungs/Heart-Lungs15–35%25–50%43–72%Small Intestine40–59%0–3.6%80–100%Pancreas18–38%0–3%97–100%Gabardi S. et al. Transplant Int 2007;20:993–1015, Singh N. Clin Infect Dis 2000:31;545–53.2
3 Outcome of Patients according to the presence of Fungal Infections after LT 85%69%91%48%77%Logrank p <0.0001No Fungal InfectionFungal ColonisationTreated fungal infectionyearsSaliba F et al, European Society of Organ transplantation (ESOT), Paris Sept 2009Saliba F et al, International Conference on Antimicrobial Agents and Chemotherapy (ICAAC) San Francisco, Sept 20093
4 Incidence and mortality of IA after SOT Type of transplantation Incidence (% pts)Time (days)(Extremes)Mortality (% pts)Liver2 (1-8)17 ( )87Lung6 (3-14)120 (4-1410)68Heart5.2 (1-15)45 (12-365)78Kidney0.7 (0-4)82 (20-801)77Pancreas-100Intestine2.2 (0-10)289 (10-956)66Singh N. and Paterson DL, Clin Microb Reviews; 2005, 18, N°1:Singh N et al, AJT 2009; 9, S
6 Mortality of IA after LT : 26/1307 patients (2 %)24/26 (92 %) patientsDeath directly related to aspergillosis : 16 patients (68 %)Other causes of death :Technical Complications: 2 patientsRecurrent disease : 1 patientSepsis : 5 patients13/24 patients had autopsy : 7 positive4 confirming the diagnosis3 revealing the diagnosisC.H.B.Saliba F. et al, Paul Brousse expeirence
7 Mortality at 3 months after the diagnosis of IFI A prospective Survey 25 US Transplant Centers ( )Total IFIBMTN = 251SOTN = 316Invasive FungalInfections46%67%30%(p= < 0.001)Invasive Aspergillosis60%6945%Invasive Candidosis36%61%29%Pappas PG et al, ICAAC 2003, Chicago, Abstract actualisé N° M-1010
9 Invasive Fungal Infections: Time of occurrence Earlier ReportsMost 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
10 Invasive Aspergillosis : Time of diagnosis A retrospective case-control study :156 cases of proven or probable invasive aspergillosis11 Spanish centers (RESITRA)Since the start of the centers’ transplantation programs to December 2001Gavaldà J et al, Clin Inf Dis 2005; 41:52-9
11 Pattern of Fungal Infections in SOT Patients Immunosuppression impairs inflammatory responseScarcity of clinical and/or radiologic signs associated with inflammationProgress of infection prior to clinical presentationInfection often advanced at time of diagnosisRapidly progressiveAbsence of surrogate markers that could allow early diagnosisEfficacy of therapeutic agents limited by toxicity and drug interactions
12 Diagnosis of Pulmonary Aspergillosis Pulmonary InfectionEarly diagnosis difficultradiographs often normalSputum cultures often negative"halo" sign on chest CT scan highly suggestive in BMT is exceptionally present in SOTBroncho-alveolar lavage ++Direct exam, Culture, Ag, PCRHalo sign ??
13 Galactomannan for Diagnosis of IA Meta-analysis : 27 studiesPopulationSensitivity(%)SpecifictyHematologic malgnancy7092BMT8286Pediatric BMT + malignancy8985Solid organ transplant2284Real-time PCR performed on the first positive GM increasedsensitivity to 62% (Botterel F et al, Transpl Infect Dis 2008, 10: )Pfeiffer CD et al, Clin Infect Dis 2006; 42:
15 Invasive Aspergillosis : role of the environement Old ICUNew protected ICUE n v i r o n e m e n t culture+++-+-----12/767 pts (1.6 %)4/541 pts (0.7 %)C.H.B.Saliba F et al. 40th ICAAC, Toronto 2000.
16 Ventilation System - Liver transplantation ICU (Paul Brousse Hospital) Characteristics1. HEPA Filters (99.97 %)2. Unidirectionnel airflow3. Room positive air pressure4. Hermetic rooms5. Air renewal rate (20times/h)6. Air velocity (2.5-3m/s)MaintenanceCultures air and surfaces (3 months)Disinfection and HEPA filterchange (1/year)NoiseReductionHEPA FiltreBlowing filtered airDouble vitrage + store intérieurTrappeBlowingBlowing : 800 m3/hDouble glass + interior storagerail supportBedDouble glass + interior storageEXTRACTION : 800 m3/hBlowing300 m3/hDouble vitrage + store intérieurEXTRACTIONC.H.B.Interior corridorSaliba F et al. 40th ICAAC, Toronto, September 2000.
17 Risk Factors for IFI in Liver Transplant Recipients Clinical parametersFungal InfectionsRetransplantationAspergillus spp + Candida sppNeed for hemodialysisProphylaxis of SBPCandida sppDysfunction of the graftAspergillus sppCMV InfectionHHV6 InfectionC.H.B.
18 Invasive Aspergillosis: Risk factors of early IA (1) < 3 monthsOR (95% CI)pUse of vascular amines > 24h2.2( )<Renal failure after SOT4.9( )Hemodialysis after SOT3.2( )0.014> 1 episode of bacterial infetion( )< 0.006CMV disease2.3( )< 0.029Gavaldà J et al, Clin Inf Dis 2005; 41:52-9
19 Invasive Aspergillosis : Risk factors of late IA (2) > 3 monthsOR (95% CI)pAge > 50 years2.5( )0.009Renal failure after SOT3.9( )<High levels of CNI( )0.01> 1 episode of bacterial infetion7.5( )De novo cancer69.3( )Chronic graft rejection5( )0.001Gavaldà J et al, Clin Inf Dis 2005; 41:52-9
20 Risk factors of occurrence of IA during the first year post LT (Multivariate analysis) 667 LT ( )RR95% CIpHemodialysis prior to LT2.7[ ]0.03Arterial Hypertension prior to LT[ ]0.01Acute fulminant hepatic failure3.7[ ]CMV disease (1rst month)3.5[ ]Saliba F et al, personnal experience
21 Risk factors of IA after Lung transplantation Early Fungal InfectionsSingle lung transplantSurgical factors include:Lung/airway denervationanastomotic ischemia provides nidus for fungal infectionStents predispose to tracheal infectionDiffuse airway ischemiaAcute allograft rejectionCMV infectionPre and post transplant Aspergillus colonisationAcquired hypogammagloblinemia (IgG < 400mg/dl)Transmission with the allograftLate Fungal InfectionsBronchiolitis obliterans syndrome ?
22 Risk factors of IA after Heart transplantation Isolation of Aspergillus from redspiratory tract culturesReinterventionCMV diseaseHemodialysisExistence of an episode of IA in the program in the program 2 months before or after heart transplantOverall mortality : 67%Munoz P et al, Curr Opin Infect Dis 2006; 19:Singh N et al, Am J Transplant 2009, 9, S180-S191 .
23 Risk factors of IA after Renal transplantation High doses or prolonged duration of corticosteroidsGraft failure requiring HemodialysisPotent immunosuppressive therapy for rejectionOverall mortality : %Singh N et al, Am J Transplant 2009, 9, S180-S191 .
25 Fungal Prophylaxis after Liver transplantation Drugs that have been shown to non efficaceous in preventing IFI after transplantationNystatinFungizoneConventional low dose of Amphotericin Bmg/kg/day x days
26 Prophylaxis of IFI after LTx A randomized controlled study itraconazole vs placeboItraconazole 5 mg/kg prior to LTx then mg/kg BID after LTxAll IFI were due to CandidaStudy was not sufficient toshow any efficacy against IAp = 0.0491 (4%)(24%)Colby WD. 39th ICAAC, San Francisco, 1999 Abstract N°1650.
27 Prophylaxis with Liposomal Amphotericin B after Liver Transplantation Randomized study of liposomal amphotericin B (1 mg/kg/day x 5 days) vs placeboPlacebo (n=37)Liposomal amphotericin B (n=40)Infection (1 month)6 (16 %)Infection (>1 month to 1 year)5 (IA:1)4 (IA:3)Survival (1 year)78%80%Mortality (1 year) due to IFI31Tollemar JG, et al. Transplant Proc 1995;27:1195-827
28 Targeted Prophylaxis (preemptive) in Liver transplant recipients requiring Hemodialysis n = 148; dialysis: 22, others: 126No prophylaxisn = 38; dialysis: 11, others: 27ABLC/L-AmB 5 mg/kg/j1997Singh N et al, Transplantation 2001
29 Fungal prophylaxisProphylaxis was targeted to high-risk patients mainlyALF, Retransplantation, End-stage cirrhosis in the ICUA total of 198 high-risk patients received a fungal prophylaxis146 high-risk patients (21.9%) received Amphotericin B lipid complex (ABLC) fungal prophylaxisDosage: 1mg/kg/day x 1w then 2.5 mg/kg biwDay 1 to day 7 (mean) : 76 ± 16 mgCumulated dose (mean) : 955 ± 609 mgMean duration : 23 ± 12 days50 patients received FluconazoleMean dose : 245 ± 108 mg/day (median : 200 mg)Mean duration : 18 ± 11 daysSaliba F et al, European Society of Organ transplantation (ESOT), Paris Sept 2009Saliba F et al, International Conference on Antimicrobial Agents and Chemotherapy (ICAAC) San Francisco, Sept 2009
30 Results : Candida infection p=0.0002p=0.0001p= NSp=0.009p= 0.03Saliba F et al, European Society of Organ transplantation (ESOT), Paris Sept 2009Saliba F et al, International Conference on Antimicrobial Agents and Chemotherapy (ICAAC) San Francisco, Sept 2009
31 Results : Aspergillosis ABLC prophylaxis : 1mg/Kg/day x 3 weeksP= NSSaliba F et al, European Society of Organ transplantation (ESOT), Paris Sept 2009Saliba F et al, International Conference on Antimicrobial Agents and Chemotherapy (ICAAC) San Francisco, Sept 2009
32 Prophylaxis with Caspofungin in High-risk Liver Transplant Recipients A prospective multicentre Spanish studyDuration of prophylaxis: 21 days (range 5–54 days)Successful response: 88.7%2 patients developed IFI after end of therapy: Mucor and Candida albicansFortun J and GESITRA study group. Transplantation 2009;87:424-37
33 Attitude towards prophylaxis of Liver transplant Centers in USA Survey : electronic questionnaire67/106 (63%) of the centers answeredTraitement 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%Prophylaxis Fluconazole vs non-Fluconazole Higher rate of mould infections (Aspergillosis, zygomycosis and scedosporiosis)RR 1.5 (95% CI ; p=0.04)Singh N et al, Am J Transplant 2008, 8:
34 Prophylaxis of high-risk patients after Liver transplantation (Recommendations of the AST Infectious disease Community of Practice)Lipid formulation of AmB (II 2)3-5 mg/kg/dayOr an Echinocandin (II 3)Duration 3-4 weeks or until resolution of risk factorsSingh N et al, Am J Transplant 2009, 9, S180-S191 .
35 Prophylaxis for high-risk patients after Lung transplantation (recommendations of the AST Infectious disease Community of Practice)Inhaled amphotericin B6-30 mg/day mg/dayInhaled lipid formulations of amphotericin BNebulized ABLC (II 3)50 mg/every 2 days for 2 weeksOnce a week x 13 weeks (minimum)Nebulized L-AmB25 mg three times per week x 2 monthsThen once a week x 6 monthsThen twice per monthIn high-risk patientsVoriconazole* : 400 mg/day x 4 monthsItraconazole*: 400 mg/day x 4 monthsMonitor liver enzymes and azole and Immunosuppressive drugs +++Singh N et al, Am J Transplant 2009, 9, S180-S191 .
36 Voriconazole for Prophylaxis after Lung transplantation Targeted prophylaxisItraconazole orInhaled ampho BN= 30pIFI1 (1.5%)7 (23%)0.001Non-Aspergillus infections at 1 year2 (3%)0.004Husain S et al, AJT 2006; 6:
37 Prophylaxis for high-risk patients after Heart transplantation (Recommendations of the AST Infectious disease Community of Practice)Voriconazole200mg BID for daysSingh N et al, Am J Transplant 2009, 9, S180-S191 .
38 Management of Invasive Fungal Infection Early specific diagnosis often requires invasive procedureEffective therapy must take into consideration:Common altered liver and kidney functionsDrug toxicitiesLiver, kidney, brain…Drug interactionsImmunosuppressive drugs:Calcineurine inhibitors: Cyclosporine, tacrolimusmTOR inhibitors: sirolimus, everolimusAntimicrobialsGlycopeptides, aminoglycosides, rifampicin…38
39 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
40 Survival after treatment of IA after SOT A prospective and retrospective studyCaspofungine + VoriconazoleL-AmBDays after the diagnosis100755025First-line treatment :Caspofungine + Voriconazole (n=40) between 2003 et 2005Historical group : L-AmB (n=47) between 1999 and 2002 L-AmB (n=47) between 1999 and 200267%51%Probability of Survival (%)Singh et al. Transplantation 2006
41 Survival after treatment of IA after SOT A prospective and retrospective studyP=0.08Totalsuccess70%51%P=0.79Completeresponse17,5%21,3%P=0.048Partial52,5%29,8%First-line treatment :Caspofungine + Voriconazole (n=40) between 2003 et 2005Historical group : L-AmB (n=47) between 1999 and 2002L-AmB (n=47) between 1999 and 2002Response rate (%)Singh et al. Transplantation 2006
42 Caspofungine for treatment of IA after SOT A retrospective study : 81 SOT patients with IFIIA : 22 patients, 19 treated with CaspofungineProven : 7 patientsProbable 12 patients74%78%70%Winkler M et al, Transplant inf Dis 2010
43 ConclusionInvasive Aspergillosis has a major impact on patient survivalRisk factors for developping IA are now well knownSerum, sputum and BAL galactomannan could be of help but need further evaluationProphylaxis should be administered only to high-risk patientsFurther multicenter trials are needed to evaluate their efficacyEchinocandins are currently under evaluationManagement of IA is comparable to the non-transplant setting