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Transmission of T. cruzi infection via liver transplantation to a nonreactive recipient for Chagas' disease
Article first published online: 25 AUG 2005
Copyright © 2005 American Association for the Study of Liver Diseases
Volume 11, Issue 9, pages 1112–1116, September 2005
How to Cite
Barcán, L., Lunaó, C., Clara, L., Sinagra, A., Valledor, A., De Rissioí, A. M., Gadanoá, A., García, M. M., de Santibañes, E. and Riarte, A. (2005), Transmission of T. cruzi infection via liver transplantation to a nonreactive recipient for Chagas' disease. Liver Transpl, 11: 1112–1116. doi: 10.1002/lt.20522
- Issue published online: 25 AUG 2005
- Article first published online: 25 AUG 2005
- Manuscript Accepted: 19 MAY 2005
- Manuscript Received: 18 MAY 2005
Chagas' disease is an endemic zoonosis of South America caused by a protozoan parasite Trypanosoma cruzi. About 30% of infected people develop the disease. This disease is known to reactivate in immunocompromised hosts, such as patients with acquired immunodeficiency syndrome, leukemia, and transplantation. There is some experience with transplantation of infected renal grafts into negative recipients, resulting in an index of transmission of 35%. No cases have been reported involving other organ transplants up to 2002, when the Centers for Disease Control and Prevention reported 3 cases of Chagas' disease transmission to 3 recipients (liver, kidney, and pancreas-kidney) from a single chagas infected donor. Here we report on a case of orthotopic liver transplant from a chagas infected donor into a negative recipient in clinical emergency status. The recipient was monitored by direct parasitological Strout method and serological tests with detection of transmission on the 84th day by both studies, without clinical signs. The patient was put on benznidazole with rapid clearance of the parasitemia. However, we propose that chagas infected donors may be accepted for liver transplant recipients only in emergency status. (Liver Transpl 2005;11:1112–1116.)
Chagas' disease is an endemic zoonosis of South America, although the parasite exists from the south of the United States to the southernmost end of Argentina. Ninety million people are estimated to live in endemic areas at risk for infection, and 25% of them are considered to be infected.1
The etiological agent of Chagas' disease is a protozoan parasite, Trypanosoma cruzi. This parasite possesses a complex cycle of transmission, developing in the vector insect and in blood and tissues of mammalians and human beings. Transmission in endemic areas occurs mainly through the vectorial route. Triatoma infestans is the most common hematophagous vector insect in South America.2
The second most common route of transmission is through blood transfusions, occurring mainly in urban areas.3, 4 Other ways are through vertical transmission (4.88%)5 and through organ transplants,6–8 the latter having acquired relevance in the last 2 decades.
The acute phase of Chagas' disease is characterized by high levels of T. cruzi parasitemia and clinical signs due to severe and extensive tissue invasion. The more severe acute manifestations, such as meningoencephalitis and myocarditis, are seen mainly in children. Direct parasitological methods, such as the Strout method (SM),8 are sensitive for detecting parasitemia in the acute phase. For SM, 10 mL of venous blood is obtained without heparin. After clot retraction, the obtained sera is centrifuged at 93g for 2 minutes. Next, supernatant is again centrifuged at 508 to 907g for 10 minutes, and the sediment is observed at ×40 under light microscopy, at least 6 slides per patient. In the chronic stage, T. cruzi persists in low levels in blood and tissues, where it may persist throughout the infected host's life. Xenodiagnosis9 and blood culture,10 both enrichment methods, are the elective but less sensitive tests to search for low levels of parasitemia in the chronic phase.
In this chronic phase, diagnosis is done by serological tests: enzyme-linked immunosorbent assay (ELISA), indirect hemagglutination (IHA) and indirect immunofluorescence assay (IFA). Optical density ≥0.20 for ELISA and titers ≥1/32 for IHA and IFA are considered reactive serology.
After long periods, around 20 to 30 years, 30% of infected patients will develop myocardial involvement and/or visceromegaly. Reactivation of chronic Chagas' disease has been described in patients with acquired immunodeficiency syndrome or after hematological diseases as well as in patients who underwent renal,11–13 bone marrow,14–16 and cardiac transplantation.17–20
Transmission of T. cruzi infection from infected renal grafts to recipients nonreactive for Chagas' disease has also been reported.6–8, 21–23 However, to date, there are very scarse data on T. cruzi transmission from other types of solid organ transplants.
Here we report on what is to our knowledge the second case of T. cruzi transmitted from a positive donor to a serologically negative recipient after liver transplantation.
A 33-year-old woman underwent orthotopic liver transplantation at our center (Hospital Italiano, Buenos Aires, Argentina) on October 16, 1998, in a state of clinical emergency due to fulminant autoimmune hepatitis. The patient was in hepatic coma, with elevated intracranial pressure. As described elsewhere,24 the patient had received extracorporeal perfusion with pig hepatocytes in the hours prior to the transplant.
Pretransplant serology was performed on both recipient and donor according to standardized protocol at the Fatala Chabén Institute. Recipient pretransplant serology for HIV (ELISA-), Chagas disease (ELISA, IHA-, and IFA-), C (ELISA), B (hepatitis B virus surface antigen, ELISA), and A (ELISA) hepatitis, Epstein-Barr virus (viral capside antigen IgG), syphilis (venereal disease research laboratory, fluorescent treponemal antibody absortion), and histoplasmosis (radial immunodiffusion) were all negative, while tests for cytomegalovirus (IFA immunoglobulin G) and toxoplasmosis (IFA immunoglobulin G) were positive. The donor was a 58-year-old female, born in an area endemic for Chagas' disease (rural area from Catamarca) whose cause of death had been hemorrhagic stroke. Her serologic tests against cytomegalovirus, Chagas' disease, and toxoplasmosis were positive. Positive donor serology for Chagas' disease and potential risk of Chagas' transmission (based on kidney transplantation experience) were communicated to her family. Her husband understood and accepted the risk.
During surgery, the patient received 8 units of red blood cells, 5 units of platelets and 28 units of frozen plasma, all of which tested negative for Chagas' disease. Primary immunosuppression was performed with mycophenolate mofetil, steroids, and tacrolimus.
Postoperative weekly screening for cytomegalovirus antigens (Ag pp65) in the recipient did not demonstrate cytomegalovirus reactivation. Due to the donor reactive serology for Chagas' disease, the recipient was scheduled for follow-up for potential T. cruzi transmission. According to World Health Organization criteria, patients were considered infected by T. cruzi when at least 2 of 3 serological tests were positive. The conventional serological tests standardized at the Fatala Chabén Institute are ELISA, IHA, and IFA. Serology was considered reactive when antibody titers were ≥0.20 of optical density at 490 nm for ELISA, and ≥ 1/32 for IHA and IFA. Monitoring for T. cruzi infection was carried out according to previous reports.17 In brief, serological and parasitological methods were performed weekly during the first 2 months, every 2 weeks during the 3rd month, and monthly thereafter. Requirement for considering transmission of T. cruzi infection was serologic conversion from nonreactive to reactive titers at least by 2 techniques, or positive parasitemia detected by the direct SM, or T. cruzi positive lesions in clinically involved tissue samples (skin, central nervous system, heart, etc.).
At day 7 after transplant, a moderate rejection was diagnosed by liver biopsy that was treated with a 1 g bolus of methylprednisolone for 3 days, with favorable response.
Magnetic resonance imaging of the brain performed due to persisting coma showed diffuse severe brain damage presumably caused by hypoxia or toxicity. At day 42, a repeated magnetic resonance imaging demonstrated improvement of brain lesions and severe cortical atrophy that were considered probable sequelae of pretransplant encephalopathy.
Table 1 shows a summary of serologic and parasitological data observed after transplant during the monitoring period. At day 76, an ELISA testing for T. cruzi antigen was positive close to cutoff, and at day 84 primary T. cruzi infection was diagnosed according to positive parasitemia by the SM and serological conversion by ELISA and IFA. Neither clinical signs nor laboratory abnormalities were observed during the primary infection. Treatment with benznidazole (Radanil, Roche Laboratory, Buenos Aires, Argentina) was administered at 5 mg/kg/day for 60 days. Parasitemia decreased rapidly, becoming negative 11 days after therapy began. During and after parasiticidal therapy, antibody titers detected by ELISA and IFA decreased, showing a variable result (positive alternating with negative values) becoming consistently negative at day 196, about 3 months after the acute episode.
|Post Tx Day||Strout Test||ELISA (optical density units)||IHA||IFA (dilutions)|
No changes in her immunosuppressive treatment were made. She required treatment for only 1 episode of moderate rejection with 3g of methylprednisolone at day 7 after transplant.
The patient did not present other episodes of either recurrence of parasitemia (SM was performed as scheduled) or clinical signs attributable to Chagas' disease up to her death. In addition, there was no serological, parasitological, or clinical evidence that the patient had suffered an acute T. cruzi infection.
The patient's neurological condition remained stable. She died at 18 months posttransplant due to infectious complications secondary to her deteriorated neurological status. She never recovered full conscience, she presented swallowing dysfunction, and she required permanent bladder catheterization. An autopsy was not performed.
Diagnosis of T. cruzi infection transmitted through the infected graft in immunosupressed patients is based on isolated patent parasitemia and/or serological conversion at least by 2 standardized methods and/ or T. cruzi–positive lesions associated or not with other manifestations of acute Chagas'disease, such as fever, cutaneous nodules, hepatosplenomegaly, and lymph node enlargement. Specific therapy with benznidazole, which is the recommended treatment for T. cruzi infection in renal transplantation2, 4, 21, 22 also proved effective in the case reported here. Benznidazole and nifurtimox are trypanocidal drugs used in Chagas' disease. Benznidazole is the only treatment available in Latin America. Adverse reactions to this drug include usually rash, itching, less frequently nausea, vomiting, and exceptionally bone marrow depression and liver toxicity. A strict supervision of drug administration and monitoring of side effects allow patients to complete treatment. A recent study25 suggesting an association between benznidazole treatment and the development of neoplasia in heart transplantation, directed the use of the parasiticidal agent as a specific therapy for diagnosed Chagas' disease, rather than as a prophylactic agent.
The scheduled monitoring described always yielded expedite and accurate results to detect early reactivation or infection episodes, as in this case and in other types of transplants such as kidney8 heart.20 and bone marrow.14, 15
In this immunosuppressed patient, causes of T. cruzi infection could have been reactivation of chronic Chagas' disease or a new primary infection. Since reactivation was ruled out by a pretransplant negative serological status of the recipient, this case was therefore considered a primary infection. Environmental conditions of endemicity and transmission through blood transfusions after orthotopic liver transplantation were also discarded due to the recipient's continuous hospitalization and because the pig hepatocytes, blood, platelets, and plasma transfusions administered before and during surgery were tested seronegative for Chagas'disease. The graft is therefore the most probable source of the T. cruzi infection.
Up to 2002, there were no reports of Chagas' disease transmission by liver transplantation. Recently the Centers for Disease Control and Prevention were notified of the transmission of Chagas'disease to 3 patients who received organs from a single donor: pancreas-kidney, kidney, and liver.26 All of them died because of acute Chagas' disease.
The difference between our patient and the recipients of chagasic organs reported in the United States was our awareness of the serologic status of the donor, and so, based on the experience accumulated in kidney transplantation, we performed a strict and scheduled follow-up of the patient, looking for the presence of T. cruzi parasitemia or serological conversion every week.
Due to the scarcity of data about Chagas'disease in orthotopic liver transplantation, we reviewed data concerning Chagas' transmission in kidney transplants. Table 2 shows the cases of Chagas' positive donors and negative recipients of kidney transplantation reported until the present date.6–8, 21–23, 27 There are 34 cases reported, with transmission of infection in 12 patients (35%). In these patients, the average time of presentation was 80.5 days, with a range of 36 to 165 days. Transmission was detected as long as 14 months after transplantation. Diagnosis was made by patent parasitemia in all patients investigated. Serologic conversion was detected in 10 of them. Fever, the most common clinical sign, was observed in 11, hepatosplenomegaly in 4, and cutaneous nodules, headaches, and myalgias in 1 patient each. All were treated with benznidazole, and the response to the specific therapy was satisfactory, with abrogation of the parasitemia and regression of clinical signs. Of interest, 2 patients never showed serologic conversion.6, 8
|Author||Donor Number||Recipient||Immunosuppression||Prophylaxis||Follow-up (months)||Parasitemia*||Seroconversion||Chagas' Disease†||Benznidazole|
|Chocair, 198126||4 LRD||4||P + AZA||NO||ND||Positive (4)||Positive (4)||YES (4)||YES (2)†|
|Figueiredo, 199021||1 LRD||1||P + AZA||NO||3 and 9||Positive||Positive||YES||YES|
|Lopes de Faria, 19936||1 cadaveric||2||P + AZA + CsA||NO||ND||Positive (2)*||Negative (1)Positive (1)||YES (2)||YES (2)|
|de Arteaga, 199223||6 cadaveric1 LRD||7||P + CsA||NO||12-54||ND||Negative||NO||NO|
|Ferraz, 199322||1 cadaveric||2||P + AZA + CsA||NO||ND||Positive (2)||Positive (2)||YES||YES (2)|
|Riarte, 19998||15 cadaveric1 LRD||16||P + AZA + CsA||NO||12-60||Positive (3)||Positive (2)Negative (1)||YES (1)||YES (3)|
|Deboni, 19967||1 cadaveric||2||P + AZA + CsA||NO||12||ND||Negative||NO||NO|
Polymerase chain reaction (PCR) seems to be a sensitive test for the early detection of primary infection or reactivation events. In a recent report, PCR was used to detect reactivation of Chagas'disease in 4 chagasic heart transplant recipients. PCR results were positive 30 days before onset of clinical illness in 3 patients and was the only method that provided a positive diagnosis in one patient.28 Further investigation of larger populations are necessary to establish the validity of PCR as an early marker of infection or reactivation events in transplant patients.
Because of the high serologic prevalence of Chagas' disease in South America and the limited organ supply, physicians are faced with the dilemma of transplanting grafts positive for Chagas' disease to nonreactive recipients. This situation is highly controversial. However, all over the world, “marginal” donors are becoming more and more accepted because mortality on waiting lists is increasing. Up to date, there is no convincing evidence regarding evolution to chronic Chagas' disease in patients who acquired the infection through kidney transplantation.
Chagas' serology is performed on all organ and blood donors in Argentina. Positive serology for Chagas' disease is not an absolute contraindication for procuring organs in our country. Kidneys are allowed for distribution by our national regulatory authority for organ transplantation. The acceptance of chagasic organs depends on the policy of each center (our center doesn't accept chagasic kidneys). In the case of livers and lungs, these organs are distributed; most centers would accept them only for recipients in emergency status.
More data are necessary to thoroughly assess the real danger involved in grafting organs infected with Chagas' disease into nonchagasic recipients. Knowing donor positive serology is of major relevance, because in these cases, we know that the recipient must be strictly and frequently followed with parasitologic methods—Strout or PCR. So, in case of positive results of any of the methods performed, “preemptive therapy” for Chagas' disease must be initiated, to abate the parasitemia and avoid the clinical illness.
With this in mind and with the limited experience reported to date in kidney as well as in other organ transplants, it is our feeling that donors positive for Chagas' disease may be used for negative recipients who need urgent transplant, if adequate follow-up is performed or treatment is provided if necessary.
In conclusion, larger numbers of patients need to be evaluated on this strict protocol, perhaps adding PCR as an earlier detection method of parasitemia, before general recommendations can be made.
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