Chagas Disease (American Trypanosomiasis) in Transplant Recipients

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Introduction

Chagas disease is according to the World Health Organization (WHO) one of the most neglected diseases (10). It is endemic in most Latin-American countries with 16-18 million infected people and about 100 million at risk. Due to immigration it is estimated that more than 100,000 infected people are living in United States of America (1) (2). Trypanosoma cruzi (T. cruzi) a flagellate protozoan parasite is the causing agent. Although 80% of transmission is related to a triatomine insect vector that serves as the parasite intermediate host (13), transmission by unscreened blood transfusion (5-20 %), from infected mother to fetus (0.5-8%), by laboratory accidents and by organ transplantation has been documented (13)

Human disease has two distinct phases of clinical presentations: the acute phase and the chronic infection. The acute infection can resolve spontaneously even if untreated; but without specific treatment the infection continues leading to chronic infection. The indeterminate phase (clinical latency) can last for life or evolve in approximately 30% of patients into irreversible disease of the heart (27%), the esophagus and the colon (6%) and the peripheral nervous system (3%) (7).

In the acute phase diagnosis is achieved by direct parasitological tests, including the examination of whole blood preparations and a concentration method (Strout test). In the intermediate and chronic stages, infection diagnosis is performed by serological tests. All have good sensitivity but less than optimal specificity, and show considerable variation in reproducibility and reliability of results. The most commonly used are: enzyme immuno-assay (EIA), indirect hemagglutination (IHA) and indirect immunofluorescence (IFA) (11). Recently, a new ELISA Test System (Ortho-Clinical Diagnostic) has been licensed by the FDA for blood screening purposes (9). (IFA and radioimmuno-precipitation assay (RIPA) are used mainly as “confirmatory” tests (9). Polymerase chain reaction (PCR) based assays, which have recently been standardized (personal communication), have been used in clinical research and should provide a useful tool for rapid diagnosis. However, WHO still recommends that at least two different methods of testing be used for Trypanosoma cruzi infection or disease diagnosis.

Definitions: Chronic T. cruzi infection is diagnosed with two positive anti-T. cruzi serological tests - using different methodologies – with a normal clinical exam, normal electrocardiogram and normal chest, esophagus and colon radiological images. Chagas disease is diagnosed in a patient with two positive anti-T. cruzi serological tests - using different methodologies- in association with cardiomyopathy or digestive mega-syndromes (megaesophagus or megacolon).

Transplant Candidates with Chagas Infection

Transplant recipients with chronic T. cruzi infection are at risk of reactivation. Chagas disease can also be transmitted from infected donors to naive recipients. In chagasic transplant recipients, serology has no utility in the diagnosis of reactivation. Direct parasitological tests should be used when searching for reactivation. Also, all available tissue specimens should be evaluated for the presence of amastigotes. PCR- based tests may prove to be beneficial and allow for earlier diagnosis.

Heart transplant in chagasic recipients differs from transplant in all other solid organ patients.

Heart Transplant

Reactivation after heart transplantation has been reported to occur in 26.5% (3) to 42.9% (6). Some authors, but not all, have related this high incidence of reactivation to rejection treatment and to mycophenolate mofetil use. Reactivation can occur early after transplant and relapses after treatment are not uncommon. Evidence of reactivation ranges from asymptomatic parasitemia to fever, sub-cutaneous involvement and myocarditis -that has to be differentiated from rejection. Early diagnosis, careful monitoring and good response to treatment allow for an adequate survival. Prophylactic treatment early after transplantation was of no benefit in a small cohort of patients and did not prevent reactivation. Long term follow-up does not differ from heart recipients from other causes (2, 3, 6).

Non-cardiac Solid Organ Transplantation

Most of the experience is related to kidney transplantation (12). Reports are very few for other organ transplants. Reactivation occurs mainly within the first post transplant year with an incidence of 15-35%. Good response to treatment, with adequate graft and patient survival in long term follow-up has been described. The most frequent reactivation feature is asymptomatic parasitemia, followed by panniculitis or other manifestations of sub-cutaneous involvement; myocarditis and encephalitis have also been reported.

Acceptability and Exclusion Criteria

1. Patients with chagasic cardiomyopathy are eligible for heart transplant.

2. Patients in the indeterminate phase of chagasic infection or with early chronic Chagas disease (cardiomyopathy grade 0-1 Kushnir classification) are suitable candidates for other solid organ transplant

3. Patients with Chagas disease (cardiomyopathy grade > 2 Kushnir classification) should be excluded as solid organ transplant candidates.

Pre-Transplant Evaluation and Management

All transplant candidates native from Latin-American countries, all born to a Latin-American mother, all that have received unscreened blood or blood product transfusions, all that have resided or travelled in a high risk geographical area for long periods of time (more than 6 months) should be tested for T. cruzi infection during pre-transplant evaluation.

1. Serology: As part of pre-transplant work-out: two diagnostic tests with different methodology.

2. Active parasitemia should be for in all infected candidates.

3. Pre-transplant trypanocidal treatment of chagasic transplant candidates (while on the waiting list) should be reserved only for those transplant candidates with proven T. cruzi parasitemia at the time of evaluation. Strout test and PCR could be useful to evaluate treatment efficacy in this setting.

Comment: The evidence supports that trypanocidal treatment modifies the outcome of indeterminate and chronic infection in immunocompetent patients (15, 16). However, this has not been proven to be true for immunocompromised patients. There is no prospective randomized evidence to support that pre-transplant trypanocidal treatment is useful to inhibit or to avoid post-transplant reactivation. Hence, no recommendation based on evidence can be made at this time. The risk of toxicity from trypanocidal drugs, especially in patients with end stage renal disease and liver insufficiency, largely outweighs its potential benefits. Trypanocidal treatment should therefore be reserved for transplant candidates with proven T. cruzi parasitemia at the time of evaluation.

Post-Transplant Follow-up for Infected Recipients

All transplant recipients with T. cruzi infection should be sequentially monitored for reactivation. This allows for pre-emptive therapy if parasitemia is diagnosed. A diagnosis of reactivation should always be considered with unexplained febrile illness, skin involvement, myocarditis or encephalitis.

Asymptomatic patients

a. Suggested timetable of monitoring:

From day 0 to day +60: Once a week
From day +61 to day +180 (6th month): Every two weeks
From day 181 to + month 12: Once a month
Tests should also be performed weekly, for 60 days, following intensification of immunosuppression (anti rejection treatment, re-transplant, chemotherapy, or other immunosuppressive drugs- even if unrelated to transplant). Thereafter, follow-up should return to basal schedule according to post- transplant time.

b. Laboratory tests

• Serology: Of no diagnostic value in this setting
• Parasitological tests (searching for parasitemia):

Strout Test
PCR in blood samples. PCR is not used -at the present time- as standard of care. Available observational studies suggest that positive PCRs after organ transplant are compatible with an increase in parasitemia.
Hemocultures should not be used for reactivation diagnosis.
Search for amastigotes in all tissue specimens of all biopsies: Standard Hematoxiline-Eosine, Giemsa staining and PCR.

Symptomatic Patients (Dependant on Clinical Manifestations)

• Strout test

• PCR (see before)

• Biopsy of all skin lesions or sub-cutaneous nodules and evaluate for amastigotes

• All endomyocardial biopsies should be evaluated for amastigotes.

• CSF: direct exam

All infected transplanted recipients should be periodically (once a year) assessed for cardiomyopathy and gastro-intestinal Chagas disease.

Treatment

All patients with a diagnosis of reactivation should receive specific treatment.

Drugs and Doses (1)

•Benznidazole is the drug of choice. Dose: 5mg/kg/ qd

• Nifurtimox is used as a second choice. It should be reserved for patients with benznidazole intolerance or with infections by resistant strains. Dose: 8mg/kg/qd.

• Length of treatment: 30 days (some prefer 60 days but no evidence of benefit)

• No recommendation can be made – at this time- for treatment duration in transplant recipients with chagasic CNS involvement. After the first 30 days, treatment time should be adjusted to clinical signs, imaging and lab follow-up results.

• Treatment should be stopped if toxicity occurs: WBC count less than 2500 or elevation (x3) of hepatic enzymes.

• Growth stimulating factors could be used to re-initiate treatment

• Parasitological tests should be performed weekly during reactivation and for 60 days after completion of treatment. Thereafter, follow-up should return to basal schedule according to post- transplant time.

Management of Immunosuppression

Maintenance immunosuppression should be kept to a minimum in reactivation episodes. However, since the response to specific treatment is good, patients should not be put at risk of acute rejection.

Heart transplant

It is suggested to avoid Thymoglobulin for rejection prevention and to replace mycophenolate with azathioprine for maintenance immunosuppression.

All other solid organ transplants

Evidence for a recommendation is lacking. However, on the basis of heart transplant experience it is suggested to avoid the use of Thymoglobulin for rejection prevention -when possible -, and to avoid or minimize the use of mycophenolate

Monitoring of mycophenolate levels could be used to define adequate doses of the drug

Donors with Trypanosoma cruzi Infection

Transmission by diagnosed infected donors into negative recipients has been reported in kidney transplant recipients who were prospectively evaluated (5, 14). Transmission from positive donors was detected by systematic search for parasitemia in 19% of seronegative recipients in the first 6 months after transplantation and all were cured with trypanocidal treatment (12). No new cases were diagnosed on long term follow-up. Two reports of transmission of acute Chagas infection by organ transplantation from unscreened deceased donors have been published in the US (4, 8) arising the question of who should be tested for T. cruzi in the US prior to organ donation.

Donors living or deceased with epidemiological risk should be sero-tested for T. cruzi infection. Acceptance of such donors is debatable. In countries where the disease is endemic some transplant teams do accept organs from infected donors provided no better donor is available in a reasonable time span.

Donors

Infected living donors: it has been suggested that such donors should receive trypanocidal treatment for 30 days prior to donation to allow for parasitemia (if present) to be cleared and donate as soon as possible after treatment is completed.

Infected deceased donors: Are unacceptable for heart transplantation. The allocation of other organs, with appropriate informed consent, could be acceptable for:

Recipeints

• infected recipients.

• uninfected kidney recipients; and, eventually, for uninfected lung and liver recipients in emergency situations.

All need to be monitored for disease transmission and promptly treated if transmission occurs.

REFERENCES

1. Bern C, Montgomery SP, Herwaldt BL, Rassi A Jr, Marin-Neto JA, Dantas RO, Maguire JH, Acquatella H, Morillo C, Kirchhoff LV, Gilman RH, Reyes PA, Salvatella R, Moore AC. Evaluation and treatment of Chagas disease in the United States: a systematic review. Jama 2007;298(18):2171-81. [PubMed]

2. Bocchi EA, Fiorelli A. The paradox of survival results after heart transplantation for cardiomyopathy caused by Trypanosoma cruzi. First Guidelines Group for Heart Transplantation of the Brazilian Society of Cardiology. The Annals of thoracic surgery 2001;71(6):1833-8. [PubMed]

3. Campos SV, Strabelli TM, Amato Neto V, Silva CP, Bacal F, Bocchi EA, Stolf NA. Risk factors for Chagas' disease reactivation after heart transplantation. J Heart Lung Transplant 2008;27(6):597-602. [PubMed]

4. Chagas disease after organ transplantation--Los Angeles, California, 2006. MMWR Morb Mortal Wkly Rep 2006;55(29):798-800 [PubMed]

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6. Diez M, Favaloro L, Bertolotti A, et al. Usefulness of PCR strategies for early diagnosis of Chagas' disease reactivation and treatment follow-up in heart transplantation. Am J Transplant 2007;7(6):1633-40 [PubMed]

7. Enfermedad de Chagas: control y eliminación. In: Organización Mundial de la Salud; 2008:4. [PubMed]

8. From the Centers for Disease Control and Prevention. Chagas disease after organ transplantation--United States, 2001. JAMA 2002;287(14):1795-6. [PubMed]

9. Gorlin J, Rossmann S, Robertson G, Stallone F, Hirschler N, Nguyen KA, Gilcher R, Fernandes H, Alvey S, Ajongwen P, Contestable P, Warren H. Evaluation of a new Trypanosoma cruzi antibody assay for blood donor screening. Transfusion 2008;48(3):531-40. [PubMed]

10. http://who.int/hq/2007/WHO_CDS_NTD_IDM_2007.2_eng.pdf Accessed Oct 14th, 2009. [PubMed]

11. Pirard M, Iihoshi N, Boelaert M, Basanta P, Lopez F, Van der Stuyft P. The validity of serologic tests for Trypanosoma cruzi and the effectiveness of transfusional screening strategies in a hyperendemic region. Transfusion 2005;45(4):554-61. [PubMed]

12. Riarte A, Luna C, Sabatiello R, Sinagra A, Schiavelli R, De Rissio A, Maiolo E, Garcìa MM, Jacob N, Pattin M, Lauricella M, Segura EL, Vázquez M. Chagas' disease in patients with kidney transplants: 7 years of experience 1989-1996. Clin Infect Dis 1999;29(3):561-7. [PubMed]

13. Rodriques Coura J, de Castro SL. A critical review on Chagas disease chemotherapy. Mem Inst Oswaldo Cruz 2002;97(1):3-24. [PubMed]

14. Vazquez MC, Riarte A, Pattin M, Lauricella M. Chagas' disease can be transmitted through kidney transplantation. Transplantation proceedings 1993;25(6):3259-60. [PubMed]

15. Viotti R, Vigliano C, Lococo B, Bertocchi G, Petti M, Alvarez MG, Postan M, Armenti A. Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment. Ann Intern Med. 2006; 144:724-734. [PubMed]

16. Viotti R, Vigliano C. Etiological treatment of chronic Chagas disease: neglected ‘evidence’ by evidence-based medicine. Expert review of anti-infective therapy 2007; 5(4):717-26. [PubMed]

None

Potera C. Heart Drug Helps to Beat Chagas, Leishmania Parasites. Microbe 2009;4:490-491.