Pr Faouzi SALIBAfaouzi.saliba@ pbr.aphp.fr

Faculté de Médecine Paris Sud

Réanimation - Centre Hépato-Biliaire

Hôpital Paul Brousse - Villejuif- France

Aspergillosis Aspergillosis in Transplant patientsin Transplant patients

Invasive Fungal Infections Aspergillus Candida

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 <0.0001

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 2009

667 LT (1999-2005)

years

QuickTime™ et undécompresseur

sont requis pour visionner cette image.

Singh N. and Paterson DL, Clin Microb Reviews; 2005, 18, N°1: 44-69. Singh N et al, AJT 2009; 9, S180-191

Incidence and mortality of IA after SOT

Type of transplantati

on

Incidence (% pts)

Time (days)

(Extremes)Mortality (% pts)

Liver 2 (1-8) 17 (6- 1107) 87

Lung 6 (3-14) 120 (4-1410) 68

Heart 5.2 (1-15) 45 (12-365) 78

Kidney 0.7 (0-4) 82 (20-801) 77

Pancreas 1.1-2.9 - 100

Intestine 2.2 (0-10) 289 (10-956) 66

Denning DWDenning DWClin Infect Clin Infect

DisDistill 1995till 1995

Paterson DL, Singh Paterson DL, Singh NN

MedicineMedicine1987-19971987-1997

Lin QYLin QYClin Infect Clin Infect

DisDis1995-19991995-1999

Bone marrowBone marrow 90 % 92 % 86.7 %

AIDS/HIVAIDS/HIV 81 % - 85.7 %

Liver Liver transplant.transplant.

93 %93 % 87 %87 % 67.6 %67.6 %

Kidney Kidney transplant.transplant.

70 % 75 % 62.5 %

Lung Transplant.Lung Transplant. 77 % 55 % 62.5 %

Heart Heart transplant.transplant.

50 % 78 % 43.6 %

Pancreas Pancreas transplanttransplant

100 % -

Invasive Aspergillose : Mortality

24/26 (92 %) patients

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.Saliba F. et al, Paul Brousse expeirence

1985 - 1997: 26/1307 patients (2 %)

Total IFI

BMTN = 251

SOTN = 316

Invasive FungalInfections 46% 67%

30%(p= < 0.001)

Invasive Aspergillosis 60% 69 45%

Invasive Candidosis 36% 61% 29%

Mortality at 3 months after the diagnosis of IFI

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 (2001-2002)

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

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

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

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 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

PopulationSensitivit

y(%)

Specificty(%)

Hematologic malgnancy 70 92

BMT 82 86Pediatric BMT + malignancy 89 85

Solid organ transplant 22 84

Meta-analysis 1996- 2005: 27 studies

Pfeiffer CD et al, Clin Infect Dis 2006; 42: 1417-27

• Real-time PCR performed on the first positive GM increased sensitivity to 62% (Botterel F et al, Transpl Infect Dis 2008, 10: 333-8.)

Risk factors of IA

0

1

2

3

4

5

6

7

8

9

10

84 86 88 90 92 94 96 98 2000

E n v i r o n e m e n t culture

Old ICUOld ICU New protected New protected ICUICU

12/767 pts (1.6 %)

4/541 pts (0.7 %)

+++ - --+ - - -

Saliba F et al. 40th ICAAC, Toronto 2000.

Invasive Aspergillosis : role of the environement

C.H.B.

Double vitrage + store intérieur

Double glass + interior storage

Double vitrage + store intérieur

Bed

rail support

Blowing300 m3/h

EXTRACTION : 800 m3/h

EXTRACTION

Blowing filtered air

Noise Reduction

HEPA Filtre

Blowing

Blowing : 800 m3/h

Trappe

Interior corridor C.H.B.Saliba F et al. 40th ICAAC, Toronto, September 2000.

Ventilation System - Liver transplantation ICU (Paul Brousse Hospital)

Characteristics1. 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)

Double glass + interior storage

Clinical parametersClinical parameters Fungal InfectionsFungal Infections

RetransplantationAspergillus spp + Candida spp

Need for hemodialysisAspergillus spp + Candida spp

Prophylaxis of SBP Candida spp

Dysfunction of the graft

Aspergillus 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 > 24h2.2

(1.2 - 4.1)< 0.0001

Renal failure after SOT4.9

(2.4 -9.8)< 0.0001

Hemodialysis after SOT3.2

(1.3 - 8.1)0.014

> 1 episode of bacterial infetion

3.2(3.2 - 17.4)

< 0.006

CMV disease2.3

(1.1 - 4.9)< 0.029

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 years2.5

(1.3 - 5.1)0.009

Renal failure after SOT3.9

(1.9 -7.8)< 0.0001

High levels of CNI2.5

(1.2 - 5)0.01

> 1 episode of bacterial infetion

7.5(3.2 - 17.4)

< 0.0001

De novo cancer69.3

(6.4 - 75.3)< 0.0001

Chronic graft rejection5

(1.9 - 13)0.001

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

RR 95% CI p

Hemodialysis prior to LT 2.7 [1.1-6.8] 0.03Arterial Hypertension prior to LT 2.7 [1.2-5.9] 0.01Acute fulminant hepatic failure 3.7 [1.6-8.8] 0.01CMV disease (1rst month) 3.5 [1.3-9.5] 0.01

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

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 ?

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 .

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 .

Prophylaxis

Targeted prophylaxis

Preemptive Therapy

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

A randomized controlled study itraconazole A randomized controlled study itraconazole vsvs placebo placebo

Colby WD. 39th 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 249

37

0

20

40

60

Itraconazole Placebo

(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;27:1195-8

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 IFI 3 1

36%

7%

14%

2% 0 0 0 00%

10%

20%

30%

40%

IFI IA IFI IA

Dialysis Others

1997n = 148; dialysis: 22, others: 126

No prophylaxisn = 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 2001Singh N et al, Transplantation 2001

Fungal prophylaxisProphylaxis 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 prophylaxis146 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 days50 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

33,3

18,7

32,4

17,7

2,5 2,510,9

4,511,5

6,10

102030405060708090

100

Candidainfection

Candidatreatedinfection

CandidemiaCandiduria CandidaAbdominal

No prophylaxis Fungal prophylaxis

p=0.0002 p=0.0001 p= NS p=0.009 p= 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

5,5 5,53,2 4,1 2,8 1,4

0

5

10

15

20

25

30

35

40

45

50

Aspergillosis Probable AspergillosisProven Aspergillosis

No prophylaxis ABLC prophylaxis

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;87:424-37

• 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

91

28

72

0

10

20

30

40

50

60

70

80

90

100

Antifungal

Prophylaxis

Universal

prophylaxis

High-risk

patients

prophylaxis

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 questionnaire67/106 (63%) of the centers answered

Singh N et al, Am J Transplant 2008, 8:426-31.

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)

Lipid formulation of AmB (II 2) 3-5 mg/kg/dayOr 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 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 .

Voriconazole for Prophylaxis after Lung transplantation

Voriconazole

N= 65

Targeted prophylaxis

Itraconazole orInhaled ampho B

N= 30

p

IFI 1 (1.5%) 7 (23%) 0.001

Non-Aspergillus infections at 1 year

2 (3%) 7 (23%) 0.004

Husain S et al, AJT 2006; 6:3008-16

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

• 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

33

83

25

76

0

10

20

30

40

50

60

70

80

90

Overall Mortality IA- related mortality

ABLC c-AmB

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

100

75

50

25

00 50 100

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

Totalsuccess

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

0

2

4

6

8

10

12

14

16

18

20

CASPOmonotherapy

CASPO combination Total

Survived Total treated patients

•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 2010

78% 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

Further multicenter trials are needed to evaluate their efficacy

Echinocandins are currently under evaluation

Management of IA is comparable to the non-transplant setting