Transcript 2-2-Lattes

Chagas Disease in
Solid Organ
Transplant Recipients
Transplant Infectious Disease
13 August 2015
Cancún – México
Disclosures
No conflict of interest
Roberta Lattes
[email protected]
Buenos Aires – Argentina
Chagas disease
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Neglected disease:
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Established transmission risks in endemic areas:
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over 100 million at risk (c. 25% infected)
18 million infected in Latin-America
migration from rural to urban areas
vectorial transmission
unscreened blood transfusion
vertical transmission
organ transplantation
Emerging risk factors:
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migration to non-endemic countries
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300.000 - 1 million infected living in USA
13-48% prevalence in migrants from Latin America living in Europe
unscreened blood transfusion in non-endemic areas
transmission through transplanted organ
Chagas disease
Chagas disease
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Acute Infection (in adults)
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Mostly asymptomatic or unspecific febrile illness
Rarely: Myocarditis – encephalitis.
Mortality 2-8%
Effective treatment (60-100% cure)
If untreated  chronic infection
Chronic Infection
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Asymptomatic (indeterminate)
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Evolves to disease in 30%
Disease: Chronic cardiomyopathy - GI involvement
Diagnosis: Parasitemia
PCR
- PCR
Diagnosis: Sero-testing
PAHO 1986:
 2 positive results with different methodologies for diagnosis
WHO 2009 (TRANSFUSION 49:1076)
 EIA  7/11 sensitivity and specificity > 98%
 IHA  2/5 sensitivity and specificity > 95%
 PA and rapid test  low sensitivity and specificity
 RIPA  gold standard for confirmation
 IFA  confirmation if limited financial resources
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437 plasma units tested in 10 different blood bank facilities
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18 screening assays (11 EIA + 5 IHA + 2 PA + 1 rapid test)
4 confirmatory tests (IF – Wb – RIPA – RIB)
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A single EIA could be used for blood screening
Diagnosis: PCR
2011;5(1):e931
26 labs in 16 countries
70 samples checked
Inter-lab evaluation
Intra-lab evaluation
Primers
• K DNA PCR primers 121 & 122
PCR kDNA (330 bp)
PCR satellite (180 bp)
• Sat DNA PCR primers Cruzi I & Cruzi II
Highly repetitive sequences:
Detection of low parasitic loads
Useful for chronic infection
diagnosis
Early detection of
reactivation and transmission
Kinetoplast DNA
40.000-80.000
p/parasite
Nuclear DNA
50.000-100.000
p/parasite
Treatment
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Benznidazol:
Nifurtimox:
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Cure:
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15-20 mg/kg/qd
Acute infection: 60-100%
Chronic Infection: 30-60%
Clinical trials:
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5-7 mg/kg/qd
Posaconazol
Ravuconazol
Potentially Infected
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Born in endemic areas
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Born to mothers from endemic areas
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Lived for prolonged time in endemic areas
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Recipients of unscreened blood
Kotton C, Lattes R. Parasitic infections in solid organ transplant recipients
AST Infectious diseases guidelines AJT 2009;9(54) S4:S234-S251
Schwartz BS, Mawhorter SD . Parasitic infections in solid organ transplant recipients
The AST IDCOP. AJT 2013;13 (S4): S280-S303
The Chagas’ Disease Argentine Collaborative Transplant Consortium et al
Transpl Proc 2010; 42:3354-3359
Chin-Hong et al “The Chagas in transplant working group” AJT 2011;11:672-680
Scenarios and Questions
in Solid Organ Transplant
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The infected recipient:
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Is SOT feasible?
What is the risk of reactivation?
Is heart Tx the best choice for patients with end-stage
chronic chagasic cardiomyopathy?
The infected donor:
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Should the risk of transmission be a deterrent ?
What do we know about morbidity and mortality
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short term ?
long term ?
Challenges in SOT
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Pre-Tx Chagas sero-testing for donors and recipients
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Pre-transplant treatment
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in endemic areas
in non-endemic areas i.e. “the traveling parasites”
 immigration
 transplant tourism
of infected candidates
of infected living donors
Post-transplant management
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sequential monitoring of parasitemia
prophylaxis OR pre-emptive therapy
Pre-Tx evaluation
Serotesting
(2/3 positive tests)
Donor +
Deceased
Could use organs
EXCEPT heart
Recipient +
Living
Search for
parasitemia
Positive
Negative
TREAT
Treatment
optional
Infected transplant candidates
Waiting
list
Kidney
Liver
Lung
Heart
Pancreas
Total
Infected
%
4949
563
95
23
16
1
0.46
2.84
1.05
94
89
12
2
12.77
2.25
Published relevant papers:
Riarte et al 1999; Luders et al 1992; López Blanco et al 1992
Source:
INCUCAI
Solid organ transplant
recipients with Chagas infection
Recipients
Kidney
Liver
Heart
Total
Total
Infected
%
3057
1773
443
5273
71
36
35
142
2.32
2.03
7.9
2.7
Sources:
• The Chagas’ Disease Argentine Collaborative Transplant Consortium et al
Transpl Proc 2010; 42:3354-3359
• Burgos et al Clin Infect Dis 2010;51(5):485-495
• Preliminary data from an ongoing multicenter study. Period 2000-2011.
Kidney Trasplant in T.cruzi infected
recipients: Outcome
Total Kidney Tx
3057
Infected recipients
71 (2.3%)
Reactivation
11 (15,5%)
•
parasitemia alone
5
•
parasitemia + SCT
4
•
SCT
2
Time after Tx
Prior increase of IS
67 d (22 d- 40.7 m)
2
Benznidazol Treatment
30-60 d
Relapses on follow-up
NO
Patient or graft loss
NO
Good outcome
11
INBA
Liver Trasplant in T.cruzi infected
recipients: Outcome
Total liver Tx
1773
Infected recipients
36 (2.03%)
Reactivation
5 (13.9%)
•
clinical manifestations
2
•
parasitemia alone
3
Time after Tx
FF: 18 with no reactivation .
HIBA: 16 with 4 reactivations
M: 53 d (41d- 9.3m)
Relapses
NO
Patient or graft loss
NO
Induction
14
2
Triple therapy with MMF
28
2
Rejection
12
2
HIBA
Heart Trasplant in T.cruzi infected
recipients: Outcome
Total heart Tx
443
Infected recipients
35 (7.9%)
Reactivation *
14 (40%)
•
Clinical disease
8
•
Parasitemia alone
6
Prior increase of IS
5
Avg Time after Tx
Explanted heart
60 d (41d-9.3m)
Relapses
2
Deaths
2
Reactivation
* + PCR prior to Strout tests ; Skin-SCT: 4; Carditis: 2; Both: 2
Outcome in reactivation
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Good response to treatment  30 d
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Negative parasitemia  5-10 d
Cure of skin lesions 7-10 d
No relapses on follow-up  1 – 7 y
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CNS involvement: encephalitis/tumor (chagoma)
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Except in heart Tx
Not frequent, but have been described
Worse outcome
Requires prolonged treatment time
Solid organ transplant in T.cruzi infected individuals may
be performed with good results
Chagas infected donors
Effective infected donors in Argentina
700
583
600
519
486
500
500
455
407
400
300
200
4.6
100
2.5
10
3.7
17
5.1
4.6
25
24
23
2007
2008
2009
5.7
33
0
2005
2006
Donors
Source: INCUCAI Dec 2011
Infected
2010
Not all Tx teams
accept infected
donors
Transmission from donors
May 2010:
Deceased donor: male, 58y. Subarachnoid hemorrhage
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Retesting was performed:
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Lived in non endemic area. CMV (+), Toxo (+), Chagas HAI (-)
PA (-). Left ventricular hypertrophy
Lung, liver and 1 kidney were distributed to three different
transplant centers
EIA (+) – PA (+) – HAI (+)
The results became available after transplantation
Procurement organization and transplant centers
were notified
Clinical Vignette
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Lung recipient
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Male, 57, Chagas (-) pre-Tx
No induction. Tacro +MMF+C-S.
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+106 d  Admitted with febrile syndrome
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Positive PCR and Strout test.
Trypanocidal treatment  60 days
Liver recipient
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Male, 41, Chagas (-) pre-Tx
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No induction. Tacro+MMF+C-S
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+96 d 
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Positive Strout test and PCR
Trypanocidal treatment  60 days
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Clinical Vignette
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Kidney recipient
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Female, 38, Chagas (-) pre-Tx
Thymoglobulin induction, Tacro, MMF, C-S
PCR and Strout test negative to date
No sero-conversion to date
Comments
• Not all available tests have the same sensitivity and
specificity
• Transmission needs to be monitored
• It generally occurs early after Tx
Speculation:
• Parasitic load probably differs in different organs
Kidney transplant: D+/R- and D+/R+
Total D+/R- Kidney recipients
De novo infection ( transmission)
56 *
6 (10.7%)
Parasitemia
2
Parasitemia and clinical manifestations
4
Time after Tx
Relapse
Hematological toxicity with benznidazol
M: 48.5 (37-121)
1**
2
No patient or graft loss
* No benznidazol prophylaxis . ** After rejection treatment
Total D+/R+
6
Chagas Post Tx
1
Time after Tx
48 d
Skin nodules
Encephalitis
Fever
Non kidney Tx: D+/RTx
At risk
Transmission
Parasitemia
Clinical
manifestations
Liver
14
21.4% (3)
3
0
Kidney pancreas
1
no
Lung
1
yes
yes
Fever
Sources:
• The Chagas’ Disease Argentine Collaborative Transplant Consortium et al Transpl
Proc 2010; 42:3354-3359
• Barcán L et al. Liver Transpl 2005 11(9):1112
• Mc Cormack L et al Am J Transplant 2012 12(10):2832
• Preliminary data from an ongoing multicenter study. Period 2000-2011
Summary: Clinical Scenarios
in Solid Organ Transplantation
At
Risk
for
PostTx
Chagas
Solid organ
transplant
Reactivation
may occur
Heart
Reactivation and
relapses are more
frequent
R+/D-
Solid Organ
Transplant
Transmission
may occur
Heart
DO NOT USE
R-/D+
R+/D+
Transmission or
reactivation?
No higher
incidence of postTx disease
Summary
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Not possible at this time to define risk levels.
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High parasitemia levels
Positive PCR before other methods
Amastigotes in tissue samples
More frequent in Heart Tx
In general in early post Tx period
No significant differences with anti-R treatment
Some evidence of reactivation with MMF
Adverse events with trypanocidal drugs are infrequent
Summary
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SOT in infected individuals may be performed with good
clinical results
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has become the treatment of choice for chagasic cardiomyopathy.
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Expanding the donor pool with donors infected with
T.cruzi is feasible
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Reactivation and transmission are not exceedingly high
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mostly in the early post Tx period or
close to intensification of immunosuppression
Summary
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Sequential monitoring is crucial for timely diagnosis of
reactivation and of de novo infection.
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PCR is becoming the preferred monitoring tool
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positive earlier than conventional direct diagnostic methods (i.e.
Strout test)
correlation of some DTUs to reactivation and specific tissue
tropism has been shown
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Serology is of no diagnostic value after Tx
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Amastigotes have to be looked for in tissue samples:
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Skin and soft tissue
Endomyocardial biopsies
Summary
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Trypanocidal treatment yields good results and
should be promptly started
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Duration of treatment: 30-60 d ( except with CNS involvement)
Monitoring for toxicities
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Prophylactic treatment cannot be recommended
at this time and deserves further study
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Immunosuppression management needs to be better
defined
Thank you for your attention