Download Document

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
Invasive Fungal Infections
Aspergillus
Candida
1.4–14%
0–10%
90–100%
Heart
5–20%
77–91%
8–23%
Liver
7–42%
9–34%
35–91%
Lungs/HeartLungs
15–35%
25–50%
43–72%
Small Intestine
40–59%
0–3.6%
80–100%
Pancreas
18–38%
0–3%
97–100%
Kidney
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
667 LT (1999-2005)
91%
85%
69%
77%
No Fungal Infection
QuickTime™ et un
69%
décompresseur
sont requis pour visionner cette image.
48%
Fungal Colonisation
Treated fungal infection
Logrank p <0.0001
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
Incidence and mortality of IA after SOT
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
Type of
transplantation
Singh N. and Paterson DL, Clin Microb Reviews; 2005, 18, N°1: 44-69.
Singh N et al, AJT 2009; 9, S180-191
Invasive Aspergillose : Mortality
Denning DW
Clin Infect Dis
till 1995
Paterson DL, Singh N
Medicine
1987-1997
Lin QY
Clin Infect Dis
1995-1999
Bone marrow
90 %
92 %
86.7 %
AIDS/HIV
81 %
-
85.7 %
Liver transplant.
93 %
87 %
67.6 %
Kidney transplant.
70 %
75 %
62.5 %
Lung Transplant.
77 %
55 %
62.5 %
Heart transplant.
50 %
78 %
43.6 %
100 %
-
Pancreas transplant
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:
Recurrent disease :
Sepsis :
2 patients
1 patient
5 patients
13/24 patients had autopsy : 7 positive


4 confirming the diagnosis
3 revealing the diagnosis
Saliba F. et al, Paul Brousse expeirence
C.H.B.
Mortality at 3 months after the diagnosis of IFI
A prospective Survey
25 US Transplant Centers (2001-2002)
Invasive Fungal
Infections
Invasive
Aspergillosis
Invasive
Candidosis
Total IFI
BMT
N = 251
46%
67%
60%
69
45%
36%
61%
29%
Pappas PG et al, ICAAC 2003, Chicago, Abstract actualisé N° M-1010
SOT
N = 316
30%
(p= < 0.001)
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
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
• 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
Meta-analysis 1996- 2005: 27 studies
Sensitivity
(%)
Specificty
(%)
70
92
BMT
82
86
Pediatric BMT +
malignancy
89
85
Solid organ transplant
22
84
Population
Hematologic
malgnancy
• 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
Risk factors of IA
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 %)
Saliba F et al. 40th ICAAC, Toronto 2000.
4/541 pts (0.7 %)
C.H.B.
Ventilation System - Liver transplantation ICU
(Paul Brousse Hospital)
Noise
Double vitrage + store
intérieur
Reduction
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
2. Unidirectionnel airflow
HEPA Filtre
Blowing filtered air
Trappe
Blowing
Blowing : 800 m3/h
rail support
1. HEPA Filters (99.97 %)
Bed
EXTRACTION : 800 m3/h
Blowing
300 m3/h
Double glass + interior storage
Characteristics
Double vitrage + store intérieur
EXTRACTION
Saliba F et al.
40th
ICAAC, Toronto, September 2000.
Interior corridor
C.H.B.
Risk Factors for IFI in Liver Transplant
Recipients
Clinical parameters
Fungal Infections
Retransplantation
Aspergillus spp + Candida spp
Need for hemodialysis
Aspergillus spp + Candida spp
Prophylaxis of SBP
Candida spp
Dysfunction of the graft
Aspergillus spp
CMV Infection
Aspergillus spp + Candida spp
HHV6 Infection
Aspergillus spp + Candida spp
C.H.B.
Invasive Aspergillosis: Risk factors of early IA (1)
Use of vascular amines > 24h
Renal failure after SOT
Hemodialysis after SOT
> 1 episode of bacterial
infetion
CMV disease
Gavaldà J et al, Clin Inf Dis 2005; 41:52-9
Early IA
< 3 months
OR (95% CI)
2.2
(1.2 - 4.1)
4.9
(2.4 -9.8)
3.2
(1.3 - 8.1)
3.2
(3.2 - 17.4)
2.3
(1.1 - 4.9)
p
< 0.0001
< 0.0001
0.014
< 0.006
< 0.029
Invasive Aspergillosis : Risk factors of late IA (2)
Age > 50 years
Renal failure after SOT
High levels of CNI
> 1 episode of bacterial
De novo cancer
Chronic graft rejection
Gavaldà J et al, Clin Inf Dis 2005; 41:52-9
infetion
Late IA
> 3 months
OR (95% CI)
p
2.5
(1.3 - 5.1)
0.009
3.9
(1.9 -7.8)
2.5
(1.2 - 5)
7.5
(3.2 - 17.4)
69.3
(6.4 - 75.3)
5
(1.9 - 13)
< 0.0001
0.01
< 0.0001
< 0.0001
0.001
Risk factors of occurrence of IA
during the first
year post LT (Multivariate analysis)
667 LT (1999-2005)
Hemodialysis prior to LT
Arterial Hypertension prior
to LT
Acute fulminant hepatic
failure
CMV disease (1rst month)
Saliba F et al, personnal experience
RR
95% CI
p
2.7
[1.1-6.8]
0.03
2.7
[1.2-5.9]
0.01
3.7
[1.6-8.8]
0.01
3.5
[1.3-9.5]
0.01
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%
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 %
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
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
60
p = 0.049
40
20
0
Colby WD. 39th ICAAC, San Francisco, 1999 Abstract N°1650.
37
24
(24%)
1 (4%)
9
Itraconazole
Placebo
Prophylaxis with Liposomal Amphotericin B
after Liver Transplantation
• Randomized study of liposomal amphotericin B
(1 mg/kg/day x 5 days) vs placebo
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)
78%
80%
3
1
Survival (1 year)
Mortality (1 year) due to IFI
Tollemar JG, et al. Transplant Proc 1995;27:1195-8
Targeted Prophylaxis (preemptive) in Liver transplant
recipients requiring Hemodialysis
n = 148; dialysis: 22, others: 126
No prophylaxis
1997
Dialysis
40%
n = 38; dialysis: 11, others: 27
ABLC/L-AmB 5 mg/kg/j
Others
36%
30%
20%
10%
0%
14%
7%
IFI
Singh N et al, Transplantation 2001
2%
IA
0 0
IFI
0 0
IA
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
No prophylaxis
Fungal prophylaxis
100
90
80
70
60
p= NS
50 p=0.0002
p=0.0001
p=0.009
p= 0.03
40
33,3
32,4
30
18,7
17,7
20
10,9
11,5
6,1
10
4,5
2,5 2,5
0
Candida
Candida Candidemia Candiduria
Candida
infection
treated
Abdominal
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
Results : Aspergillosis
ABLC prophylaxis : 1mg/Kg/day x 3 weeks
50
45
No prophylaxis
40
ABLC prophylaxis
35
30
25
P= NS
20
15
10
5
0
5,5
5,5
Aspergillosis
3,2
4,1
Probable Aspergillosis
2,8
1,4
Proven Aspergillosis
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
• 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
Survey : electronic questionnaire
67/106 (63%) of the centers answered
100
90
Traitement of choice:
 Fluconazole (86%)
91
80
72
70
60
50
40
28
30
20
10
0
Traitement of choice for moulds:
 Echinocandins (41%)
 Voriconazole (25%)
 Polyene (18%)
 Combination therapy :

Antifungal
Prophylaxis
Universal
prophylaxis
High-risk
patients
prophylaxis
Singh N et al, Am J Transplant 2008, 8:426-31.

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; p=0.04)
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 .
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
IFI
NonAspergillus
infections
at 1 year
Voriconazole
N= 65
Targeted prophylaxis
Itraconazole or
Inhaled ampho B
N= 30
p
1 (1.5%)
7 (23%)
0.001
2 (3%)
7 (23%)
0.004
Husain S et al, AJT 2006; 6:3008-16
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 .
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 (5mg/Kg/day) compared to an historical group of c-AmB (1.1 mg/kg/day)
ABLC
90
c-AmB
83
76
80
Mortality (%)
70
60
50
40
33
25
30
20
10
0
Linden PK et al, CID 2003; 37:17-25
Overall Mortality
IA- related mortality
Survival after treatment of IA after SOT
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
Probability of Survival (%)
100
Caspofungine +
Voriconazole
75
67%
51%
50
L-AmB
25
0
0
Singh et al. Transplantation 2006
50
Days after the diagnosis
100
Survival after treatment of IA after SOT
A prospective and retrospective study
70%
• Caspofungine + Voriconazole
(n=40) between 2003 et 2005
• Historical group : L-AmB (n=47)
between 1999 and 2002L-AmB
Response rate (%)
• First-line treatment :
P=0.048
P=0.08
52,5%
51%
P=0.79
17,5%
29,8%
21,3%
(n=47) between 1999 and 2002
Total
success
Singh et al. Transplantation 2006
Complete
response
Partial
response
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
Survived
Total treated patients
20
18
16
14
74%
12
10
8
6
4
78%
70%
CASPO
monotherapy
CASPO combination
2
0
Winkler M et al, Transplant inf Dis 2010
Total
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