Pr Faouzi SALIBA

1
Aspergillosis in Transplant patients

• Pr Faouzi SALIBA
• faouzi.saliba_at_ 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
2007209931015, Singh N. Clin Infect Dis
20003154553.
3
Outcome of Patients according to the presence of
Fungal Infections after LT
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, N1 44-69. Singh N et al, AJT 2009
9, S180-191
5
Invasive Aspergillose Mortality
6
Mortality of IA after LT
1985 - 1997 26/1307 patients (2 )
24/26 (92 ) patients

• 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

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
(No Transcript)
9
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 gt 3 months
• 43 of the cases occurred gt 3 months

• Singh N, Clin Infect Dis 2003 364652
• Gavaldà J et al, Clin Inf Dis 2005 4152-9

10
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 4152-9
11
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

12
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 ??
13
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
14
Risk factors of IA
15
Invasive Aspergillosis role of the environement
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.
16
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)

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.
17
Risk Factors for IFI in Liver Transplant
Recipients
18
Invasive Aspergillosis Risk factors of early IA
(1)
Gavaldà J et al, Clin Inf Dis 2005 4152-9
19
Invasive Aspergillosis Risk factors of late IA
(2)
Gavaldà J et al, Clin Inf Dis 2005 4152-9
20
Risk factors of occurrence of IA during the first
year post LT (Multivariate analysis)667 LT
(1999-2005)
Saliba F et al, personnal experience
21
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 lt 400mg/dl)
• Transmission with the allograft
• Late Fungal Infections
• Bronchiolitis obliterans syndrome ?

22
Risk factors of IA after Heart transplantation

• 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

Munoz P et al, Curr Opin Infect Dis 2006 19
365-370
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
  corticosteroids
• Graft failure requiring Hemodialysis
• Potent immunosuppressive therapy for rejection
• Overall mortality 67-75

Singh N et al, Am J Transplant 2009, 9, S180-S191
.
24
ProphylaxisTargeted prophylaxisPreemptive
Therapy
25
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

26
Prophylaxis of IFI after LTx
A randomized controlled study itraconazole vs
placebo

• 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

p 0.049
(24)
1 (4)
Colby WD. 39th ICAAC, San Francisco, 1999
Abstract N1650.
27
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 1995271195-8
28
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
29
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
30
Results Candida infection
p NS
p0.0001
p0.009
p 0.03
p0.0002
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
31
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
32
Prophylaxis with Caspofungin in High-risk Liver
Transplant Recipients

• A prospective multicentre Spanish study
• Duration of prophylaxis 21 days (range 554 days)

• Successful response 88.7
• 2 patients developed IFI after end of therapy
  Mucor and Candida albicans

Fortun J and GESITRA study group. Transplantation
200987424-37
33
Attitude towards prophylaxis of Liver transplant
Centers in USA

• Survey electronic questionnaire
• 67/106 (63) of the centers answered

• 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

Prophylaxis Fluconazole vs non-Fluconazole Higher
rate of mould infections (Aspergillosis,
zygomycosis and scedosporiosis) RR 1.5 (95 CI
1.0-2.2 p0.04)
Singh N et al, Am J Transplant 2008, 8426-31.
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/day
• Or an Echinocandin (II 3)
• Duration 3-4 weeks or until resolution of risk
  factors

Singh 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 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
.
36
Voriconazole for Prophylaxis after Lung
transplantation
Husain S et al, AJT 2006 63008-16
37
Prophylaxis for high-risk patients after Heart
transplantation (Recommendations of the AST
Infectious disease Community of Practice)

• Voriconazole
• 200mg BID for 50-150 days

Singh N et al, Am J Transplant 2009, 9, S180-S191
.
38
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

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 3717-25
40
Survival after treatment of IA after SOT
A prospective and retrospective study

• First-line treatment
• Caspofungine Voriconazole (n40) between 2003
  et 2005
• Historical group L-AmB (n47) between 1999 and
  2002 L-AmB (n47) between 1999 and 2002

67
51
Probability of Survival ()
Singh et al. Transplantation 2006
41
Survival after treatment of IA after SOT
A prospective and retrospective study

• First-line treatment
• Caspofungine Voriconazole (n40) between 2003
  et 2005
• Historical group L-AmB (n47) between 1999 and
  2002L-AmB (n47) between 1999 and 2002

Response rate ()
Singh et al. Transplantation 2006
42
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
43
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