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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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slide1

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

slide2

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.

outcome of patients according to the presence of fungal infections after lt
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

slide4

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

mortality of ia after lt
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

mortality at 3 months after the diagnosis of ifi
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

invasive fungal infections time of occurrence
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
slide10

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

pattern of fungal infections in sot patients
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
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 ??

galactomannan for diagnosis of ia
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

invasive aspergillosis role of the environement
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.

ventilation system liver transplantation icu paul brousse hospital
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.

invasive aspergillosis risk factors of early ia 1
Invasive Aspergillosis: Risk factors of early IA (1)

Gavaldà J et al, Clin Inf Dis 2005; 41:52-9

invasive aspergillosis risk factors of late ia 2
Invasive Aspergillosis : Risk factors of late IA (2)

Gavaldà J et al, Clin Inf Dis 2005; 41:52-9

slide20
Risk factors of occurrence of IA during the first year post LT (Multivariate analysis)667 LT (1999-2005)

Saliba F et al, personnal experience

risk factors of ia after lung transplantation
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 ?

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%

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 .

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 %

Risk factors of IA after Renal transplantation

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

fungal prophylaxis after liver transplantation
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

prophylaxis of ifi after ltx
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.

prophylaxis with liposomal amphotericin b after liver transplantation
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

targeted prophylaxis preemptive in liver trans plant recipients requiring hemodialysis
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

fungal prophylaxis
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

results candida infection
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

results aspergillosis
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

prophylaxis with caspofungin in high risk liver transplant recipients
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

attitude towards prophylaxis of liver transplant centers in usa
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.

slide34
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 .

slide35
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 .

slide37
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 .

management of invasive fungal infection
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…

ablc in the treatment of ia after sot
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

survival after treatment of ia after sot
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

survival after treatment of ia after sot41
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

caspofungine for treatment of ia after sot
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

conclusion
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