© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Transplant Infectious Disease, ISSN 1398-2273
Images in transplant infectious disease
Cerebral trypanosomiasis in a renal transplant recipient F. Cicora, V. Escurra, J. Bibolini, J. Petroni, I. Gonzalez, J. Roberti. Cerebral trypanosomiasis in a renal transplant recipient. Transpl Infect Dis 2014: 16: 813–817. All rights reserved Abstract: Chagas disease is a lifelong, systemic, parasitic infection caused by the protozoan Trypanosoma cruzi. The main form of disease transmission is vector borne, but vertical transmission, such as by organ transplantation from a chronically infected donor, is also possible. The brain tumor-like form can occur years after infection and has been described in patients with acquired immunodeficiency syndrome, and in a very few cases in transplant recipients. We describe the case of a kidney transplant patient who was human immunodeficiency virus negative and infected with T. cruzi, and developed cerebral trypanosomiasis that was successfully treated with benznidazole at 7 mg/kg/day for 60 days. The risk of Chagas disease transmission should not be underestimated in renal transplant patients, even in non-endemic areas. Chagas disease can present as a tumor-like brain lesion, very difficult to differentiate from other opportunistic infectious or neoplastic processes. Frequent monitoring for T. cruzi infection is essential to promptly implement treatment, which, in our patient, proved to be effective and safe.
F. Cicora1,2, V. Escurra1, J. Bibolini1, J. Petroni1, I. Gonzalez1, J. Roberti2 1
Renal Transplantation, Hospital de Alta Complejidad JD Peron, Formosa, Argentina, 2Foundation for Research and Assistance in Renal Disease (FINAER), Buenos Aires, Argentina Key words: kidney transplant; Chagas disease; Trypanosoma cruzi; trypanosomiasis; brain chagoma Correspondence to: Javier Roberti, Foundation for Research and Assistance in Renal Disease (FINAER), Austria 2381, 5D, 1425 Buenos Aires, Argentina Tel: +54 11 48027423 Fax: +54 11 48027423 E-mail: [email protected],
Received 25 March 2014, revised 15 April 2014, accepted for publication 4 May 2014 DOI: 10.1111/tid.12265 Transpl Infect Dis 2014: 16: 813–817
Chagas disease is a lifelong, systemic, parasitic infection caused by the protozoan Trypanosoma cruzi that affects approximately 8–10 million people in Latin America. Infected people may develop cardiomyopathy, digestive megasyndromes, or both (1, 2). The main form of disease transmission is vector borne, by reduviid bugs of the subfamily Triatominae, but vertical transmission, such as via an unscreened blood transfusion or organ transplantation from a chronically infected donor, is also possible; furthermore, oral transmission has also been reported (1, 3). Parasitic diseases are being found more frequently after organ transplantation, as a result of immigration and travel to and from endemic areas (4). The acute phase of Chagas disease is typically asymptomatic or a self-limiting febrile illness, although, in a few cases, severe myocarditis and meningoencephalitis can occur (1, 2). About 60–70% of patients will develop an asymptomatic, indeterminate form of chronic Chagas disease; the
remaining 30–40% will develop a determinate form – cardiac, digestive, or cardiodigestive – that can lead to severe illness and premature death (1, 2). Transmission of T. cruzi from deceased and living donors with infected kidneys has been demonstrated (5, 6), and reactivation of the disease may occur in immunosuppressed patients (7–9). The use of grafts from infected donors is acceptable when patients are monitored closely and treated promptly (6). However, we and others frequently perform and have reported kidney transplants of infected organs with good results, even when recipients are not administered prophylactic therapies (10–12). The tumor-like form can occur years after infection (13) and has been described in patients with acquired immunodeficiency syndrome (AIDS), and in a very few cases in transplant recipients (13–19). Here, we describe the case of a patient who was transplanted with a kidney infected with T. cruzi, was
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Cicora et al: Brain trypanosomiasis in renal transplant
human immunodeficiency virus (HIV) negative, and later developed cerebral trypanosomiasis.
Case report A 27-year-old white male underwent kidney transplantation with a living-related donor at our center, located in the city of Formosa, northern Argentina, in 2007. Both donor and recipient lived in a rural area in the province of Formosa, an endemic area for Chagas disease. The serologic diagnosis of T. cruzi infection is defined by at least 2 different positive serologic tests, and the donor showed positivity for T. cruzi in indirect hemagglutination assay at 1/2048 and by enzymelinked immunosorbent assay (ELISA); a Strout test was negative. However, the donor did not receive any treatment for Chagas disease. On the other hand, the transplant recipient showed negative serologic test results for T. cruzi. In addition, the recipient was HIV negative. Transplant surgery occurred with no complication, and 7 days later, the patient was discharged, with a serum creatinine of 1.3 mg/dL. No induction therapy was administered and the immunosuppressive regimen included tacrolimus (0.1–0.2 mg/kg day, trough level of 6–10 ng), mycophenolate sodium (1440 mg daily), and corticosteroids (1 mg/kg daily during the first week, 20 mg daily at 1 month, and then tapered to 4 mg daily). Over some time, the patient showed poor adherence to treatment and follow-up visits. At 4 years after the transplant, a borderline cellular graft rejection occurred; it was successfully treated with 3 pulses of methylprednisolone, 500 mg each, and 4 months later, a Banff IA graft rejection was managed with the same therapy. Some weeks after the last rejection, indirect hemagglutination and ELISA tests confirmed positive seroconversion. Treatment was not initiated because benznidazole was not locally available for some weeks, and then the patient did not attend our center for treatment. From year 4 to 6 after transplantation, the patient only attended the center for follow-up visits very sporadically. At these visits, as seroconversion had been confirmed, direct parasitologic Strout test was performed. At 6 years after transplantation, the patient was admitted to our hospital with ophthalmologic herpes and complaining of severe headaches. Administration of tacrolimus and mycophenolate sodium was suspended and treatment with acyclovir was initiated at 10 mg/kg/day for 10 days. In addition, a non-contrast
814
computed tomography (CT) scan of the brain was performed. Images showed a right frontal, subcortical, white matter lesion with surrounding edema (Fig. 1). Toxoplasmosis, brain abscess, and lymphoma or even metastatic disease had to be considered in the differential diagnosis. Unfortunately, magnetic resonance imaging of the brain could not be performed because of problems related to the patient’s medical insurance. One month earlier, during a regular followup visit, the Strout test had been negative for T. cruzi. Owing to the possibility of central nervous system (CNS) infection, the patient underwent a lumbar puncture. The cerebrospinal fluid (CSF) was clear, and the examination showed 2 blood cells/mm3, 0 white cells/mm3 (lymphocytes), lactic acid 1.2 mmol/L, total protein 0.29 g/L, and glucose 61 mg/dL (blood glucose 73 mg/dL). Fifteen days after the first CT, a new non-contrast CT of the brain was performed (Fig. 2), which showed hypodensity in the central area, suggesting necrosis or liquefaction and persistent edema. Tests performed for antigenemia and with India ink staining were negative for Cryptococcus. Analysis of the CSF was negative for toxoplasmosis and venereal disease VDRL test. Direct and culture tests for fungal infections were negative. However, polymerase chain reaction (PCR) tests for T. cruzi in CSF and blood showed positive results. The patient presented with concomitant cough and dyspnea. Pneumocystis jirovecii was detected in bronchoalveolar
Fig. 1. Renal transplant patient; non-contrast axial computed tomography of the brain showing a right frontal lesion with surrounding edema.
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Cicora et al: Brain trypanosomiasis in renal transplant
Fig. 2. At 15 days after first computed tomography (CT) (Fig. 1), a new non-contrast axial CT of the brain showed a ring frontal lesion with edema. In an immunocompromised patient, differential diagnosis would include toxoplasmosis, brain abscess, lymphoma, or even metastatic lesion. At this point, polymerase chain reaction tests for Trypanosoma cruzi in cerebrospinal fluid and blood showed positive results.
lavage fluid, so the patient was treated with sulfamethoxazole-trimethoprim, received mechanical ventilation over 4 days, and stayed in the intensive care unit for 7 days. Based on the PCR test results, therapy with benznidazole was started at 7 mg/kg/day for 60 days. At 10 days after initiation, tacrolimus and mycophenolate sodium were restarted. Of note, the patient did not receive steroid treatment for the edema; immunosuppressive doses of steroids consisted of 4 mg daily. At 15 days after beginning benznidazole, a third noncontract CT of the brain showed a significant reduction in the edema (Fig. 3). The patient presented no adverse effects with benznidazole. At 30 days after the initiation of treatment, another CT again showed a significant reduction of the central nodule and the edema. The patient’s creatinine level was 2.2 mg/dL.
Discussion Our center is located in an endemic area with a high risk of transmission of Chagas disease, and infected kidney grafts are used for transplantation with appropriate
Fig. 3. At 15 days after beginning treatment with benznidazole, noncontrast axial computed tomography of the brain showed a significant reduction in the edema.
informed consent from the recipient. Considering the implications of confirming the infection for management of the patient, and the potential for drug toxicity, careful and strict monitoring has been recommended over prophylactic treatment (4). Table 1 shows recommendations for screening of solid organ transplant recipients from the Argentine Society of Infectious Diseases (20). Transmission of T. cruzi infection through a transplanted kidney to a non-infected recipient is rare, but has been reported (5, 6). Reasons for the wide variation in the presentation of Chagas disease are not completely understood (17). In an immunodeficient state, the probabilities of de novo infection and reactivation are both increased (19). It is impossible to know if this case is a donor-derived infection or a new infection. The patient lives in an endemic region of Argentina, in which house infestation was significantly reduced as a result of interventions coordinated by a National Program for Chagas Vector Control, such as insecticide spraying (21). Nevertheless, vector-borne transmission was not interrupted in this province (21). In the case of vector-borne transmission, the signs of portal of entry of T. cruzi through the skin (chagoma) or via the ~a sign) (1) should ocular mucous membranes (Roman have been visible or reported by the patient, but this was not the case. Oral transmission in humans, involving food or beverages contaminated with infected
Transplant Infectious Disease 2014: 16: 813–817
815
Cicora et al: Brain trypanosomiasis in renal transplant
Post-transplant screening of Chagas-seropositive recipients or seronegative patients receiving an organ from a seropositive donor Screening timing
POD 0 to 60: weekly
Screening techniques
Serologic tests, only in seronegative patients ELISA, indirect hemagglutination, particle indirect agglutination, indirect immunofluorescence. (Two different positive tests for diagnosis)
POD 61 to month 6: bimonthly Month 6 to year 1: monthly
Strout PCR Pathologic examination and PCR in tissue samples. Hematoxylin and eosin stain, Giemsa stain Screening techniques in patients with clinical reactivation
Skin lesion biopsy Endomyocardial biopsy (heart transplant) CSF direct examination
POD, postoperative day; ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain reaction; CSF, cerebrospinal fluid. Adapted from the guidelines published by the Argentine Society of Infectious Diseases (20).
Table 1
triatomine or their feces, has been registered in Brazil, Colombia, and rural Venezuela (3), but not in Argentina. Certainly, seroconversion 4 years after transplantation is atypical. An underlying chronic Chagas infection may become acute and produce diffuse myocarditis, lesions in the CNS, and severe meningoencephalitis (17). The use of corticosteroids, immunosuppression therapy, and the appearance of AIDS made the acute CNS form of chronic Chagas disease more common (17, 22). In 1913, Carlos Chagas described CNS involvement with T. cruzi in a small number of patients who developed encephalitis in the acute phase (17). Three aspects characterize CNS involvement in immunosuppressed patients: (a) encephalitis in multiple foci may present with necrosis; (b) it is common to find a tumorlike form with one or various necro-hemorrhagic lesions in the cerebral hemispheres, brain stem, or cerebellum, often called cerebral tumor-like American trypanosomiasis; and (c) an abundance of amastigotes are present within macrophages, glial cells, and neurons (17, 22). Common non-specific characteristics are ring- and nodular-enhancing patterns (14). The lesions appear mostly in the supratentorial white matter, but masses have been reported everywhere in the CNS, including the infratentorial region and basal ganglia (14).
816
Cordova et al. (15) described immunosuppressed HIV patients with Chagas disease involving the CNS; the most common manifestations were headache, which was the only symptom noted by our patient, focal neurologic deficits, and fever. However, these symptoms were indistinguishable from those related to other causes of meningoencephalitis. Although the patient described here was not HIV positive, the list of differential diagnosis possibilities is similar and includes, primarily, toxoplasmosis and lymphoma, but also progressive multifocal leukoencephalopathy, and infections with fungi, bacteria, and mycobacteria (14, 16). In our patient, a brain magnetic resonance imaging would probably have revealed more information for the presumptive diagnosis, but this could not be performed owing to problems with the patient’s health insurance. Serology for T. cruzi is of no diagnostic value, and detection of the parasite in the CSF or a brain tissue biopsy specimen would be necessary (14). At our center, once seroconversion is confirmed, reactivation is monitored with the Strout test because PCR is not always available. In fact, one of the limitations of this report is incomplete data on PCR. Parasitemia is probably the defining feature of reactivation, as this is typically increased before the onset of symptoms (8). In this patient, the Strout test had shown negative results for T. cruzi only 30 days before the first CT scan, and the presence of the parasite could only be confirmed by analyzing the CSF and blood using PCR. After this confirmation, the Strout test was not performed, as the treatment protocol to be followed would not change. Only benznidazole and nifurtimox have shown efficacy against Chagas disease (1) and in Argentina, only benznidazole is available. Benznidazole has the best safety and efficacy profile, and the recommended dose is 5–7 mg/kg/day in 2 daily divided doses for 60 days (1, 4). Treatment with either of these 2 drugs is strongly recommended when clinical and/or parasitologic reactivation is suspected (8). When the tumor-like lesion was observed, our patient received benznidazole for 60 days and did not require a longer treatment because of a positive clinical response and the improvement seen in brain CT. It had been impossible to initiate treatment when seroconversion occurred in 2010, because the drug was not readily available and the patient was non-compliant. The risk of Chagas disease transmission should not be underestimated in renal transplant patients, even in non-endemic areas, because immigration and travel to and from developing countries may make this disease more common than expected. We cannot confirm that the transmission was definitely from the infected graft, because the recipient lives in an endemic area.
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Cicora et al: Brain trypanosomiasis in renal transplant
In conclusion, our case report demonstrates that Chagas disease can present as a tumor-like brain lesion, whose image is difficult to differentiate from other opportunistic infections, such as toxoplasmosis or neoplastic processes. Frequent and rigorous monitoring for T. cruzi infection is essential to promptly implement treatment, which, in our patient, proved to be effective and safe.
Acknowledgements: Author contributions: F.C. participated in research idea, data collection, and revision of the paper. V.E., J.B., and I.G. participated in data collection and revision of the paper. J.P. participated in revision of the paper. J.R. participated in research design, literature search, data revision, and writing of the paper. Disclosure: The authors of this manuscript have no conflicts of interest to disclose.
References 1. Rassi A, Marin-Neto JA. Chagas disease. Lancet 2010; 375: 1388–1402. 2. Bern C. Antitrypanosomal therapy for chronic Chagas’ disease. N Engl J Med 2011; 364: 2527–2534. 3. Shikanai-Yasuda MA, Carvalho NB. Oral transmission of Chagas disease. Clin Infect Dis 2012; 54: 845–852. 4. Schwartz BS, Mawhorter SD. Parasitic infections in solid organ transplantation. Am J Transplantat 2013; 13: 280–303. 5. Riarte A, Luna C, Sabatiello R, et al. Chagas’ disease in patients with kidney transplants: 7 years of experience, 1989–1996. Clin Infect Dis 1999; 29: 561–567. 6. Huprikar S, Bosserman E, Patel G, et al. Donor-derived Trypanosoma cruzi infection in solid organ recipients in the United States, 2001–2011. Am J Transplant 2013; 13 (9): 2418–2425. 7. Kun H, Moore A, Mascola L, et al. Transmission of Trypanosoma cruzi by heart transplantation. Clin Infect Dis 2009; 48: 1534–1540.
8. Pinazo M-J, Espinosa G, Cortes-Lletget C, et al. Immunosuppression and Chagas disease: a management challenge. PLoS Negl Trop Dis 2013; 7: e1965. 9. Bern C. Chagas disease in the immunosuppressed host. Curr Opin Infect Dis 2012; 25: 450–457. 10. Marquez E, Crespo M, Mir M, et al. Chagas’ disease and kidney donation. Nefrologia 2013; 33: 128–133. 11. Cicora F, Escurra V, Silguero S, Gonzalez IM, Roberti JE. Use of kidneys from Trypanosoma cruzi-infected donors in naive transplant recipients without prophylactic therapy: the experience in a high-risk area. Transplantation 2014; 97: e3–e4. 12. Kotton CN, Lattes R. Parasitic infections in solid organ transplant recipients. Am J Transpl 2009; 9: S234–S251. 13. Py MO. Neurologic manifestations of Chagas disease. Curr Neurol Neurosci Rep 2011; 11: 536–542. 14. Antunes ACM, Cecchini FMDL, Bolli FVB, et al. Cerebral trypanosomiasis and AIDS. Arq Neuropsiquiatr 2002; 60: 730–733. 15. Cordova E, Boschi A, Ambrosioni J, Cudos C, Corti M. Reactivation of Chagas disease with central nervous system involvement in HIV-infected patients in Argentina, 1992-2007. Int J Infect Dis 2008; 12: 587–592. 16. Gluckstein D, Ciferri F, Ruskin J. Chagas’ disease: another cause of cerebral mass in the acquired immunodeficiency syndrome. Am J Med 1992; 92: 429–432. 17. Pittella JEH. Central nervous system involvement in Chagas disease: a hundred-year-old history. Trans R Soc Trop Med Hyg 2009; 103: 973–978. 18. De Queiroz AC. Tumor-like lesion of the brain caused by Trypanosoma cruzi. Am J Trop Med Hyg 1973; 22: 473–476. 19. Marchiori PE, Alexandre PL, Britto N, et al. Late reactivation of Chagas’ disease presenting in a recipient as an expansive mass lesion in the brain after heart transplantation of chagasic myocardiopathy. J Heart Lung Transplant 2007; 26: 1091–1096. n infectolo gica para 20. Afeltra J, Arselan S, Barcan L, et al. Evaluacio rganos so lidos. Sociedad Argentina receptores de trasplante de o de Infectologıa, recomendaciones y consensos, 2012. Available at: http://www.sadi.org.ar (accessed February 19, 2014). n 21. Spillmann C, Burrone S, Coto H. Analisis de la situacio gica de la enfermedad de Chagas en Argentina: Avances epidemiolo blica 2012; 4: 40–44. en el control, 2012. Rev Argent Salud Pu 22. Chimelli L, Scaravilli F. Trypanosomiasis. Brain Pathol 1997; 7: 599–611.
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Images in transplant infectious disease
Cerebral trypanosomiasis in a renal transplant recipient F. Cicora, V. Escurra, J. Bibolini, J. Petroni, I. Gonzalez, J. Roberti. Cerebral trypanosomiasis in a renal transplant recipient. Transpl Infect Dis 2014: 16: 813–817. All rights reserved Abstract: Chagas disease is a lifelong, systemic, parasitic infection caused by the protozoan Trypanosoma cruzi. The main form of disease transmission is vector borne, but vertical transmission, such as by organ transplantation from a chronically infected donor, is also possible. The brain tumor-like form can occur years after infection and has been described in patients with acquired immunodeficiency syndrome, and in a very few cases in transplant recipients. We describe the case of a kidney transplant patient who was human immunodeficiency virus negative and infected with T. cruzi, and developed cerebral trypanosomiasis that was successfully treated with benznidazole at 7 mg/kg/day for 60 days. The risk of Chagas disease transmission should not be underestimated in renal transplant patients, even in non-endemic areas. Chagas disease can present as a tumor-like brain lesion, very difficult to differentiate from other opportunistic infectious or neoplastic processes. Frequent monitoring for T. cruzi infection is essential to promptly implement treatment, which, in our patient, proved to be effective and safe.
F. Cicora1,2, V. Escurra1, J. Bibolini1, J. Petroni1, I. Gonzalez1, J. Roberti2 1
Renal Transplantation, Hospital de Alta Complejidad JD Peron, Formosa, Argentina, 2Foundation for Research and Assistance in Renal Disease (FINAER), Buenos Aires, Argentina Key words: kidney transplant; Chagas disease; Trypanosoma cruzi; trypanosomiasis; brain chagoma Correspondence to: Javier Roberti, Foundation for Research and Assistance in Renal Disease (FINAER), Austria 2381, 5D, 1425 Buenos Aires, Argentina Tel: +54 11 48027423 Fax: +54 11 48027423 E-mail: [email protected],
Received 25 March 2014, revised 15 April 2014, accepted for publication 4 May 2014 DOI: 10.1111/tid.12265 Transpl Infect Dis 2014: 16: 813–817
Chagas disease is a lifelong, systemic, parasitic infection caused by the protozoan Trypanosoma cruzi that affects approximately 8–10 million people in Latin America. Infected people may develop cardiomyopathy, digestive megasyndromes, or both (1, 2). The main form of disease transmission is vector borne, by reduviid bugs of the subfamily Triatominae, but vertical transmission, such as via an unscreened blood transfusion or organ transplantation from a chronically infected donor, is also possible; furthermore, oral transmission has also been reported (1, 3). Parasitic diseases are being found more frequently after organ transplantation, as a result of immigration and travel to and from endemic areas (4). The acute phase of Chagas disease is typically asymptomatic or a self-limiting febrile illness, although, in a few cases, severe myocarditis and meningoencephalitis can occur (1, 2). About 60–70% of patients will develop an asymptomatic, indeterminate form of chronic Chagas disease; the
remaining 30–40% will develop a determinate form – cardiac, digestive, or cardiodigestive – that can lead to severe illness and premature death (1, 2). Transmission of T. cruzi from deceased and living donors with infected kidneys has been demonstrated (5, 6), and reactivation of the disease may occur in immunosuppressed patients (7–9). The use of grafts from infected donors is acceptable when patients are monitored closely and treated promptly (6). However, we and others frequently perform and have reported kidney transplants of infected organs with good results, even when recipients are not administered prophylactic therapies (10–12). The tumor-like form can occur years after infection (13) and has been described in patients with acquired immunodeficiency syndrome (AIDS), and in a very few cases in transplant recipients (13–19). Here, we describe the case of a patient who was transplanted with a kidney infected with T. cruzi, was
813
Cicora et al: Brain trypanosomiasis in renal transplant
human immunodeficiency virus (HIV) negative, and later developed cerebral trypanosomiasis.
Case report A 27-year-old white male underwent kidney transplantation with a living-related donor at our center, located in the city of Formosa, northern Argentina, in 2007. Both donor and recipient lived in a rural area in the province of Formosa, an endemic area for Chagas disease. The serologic diagnosis of T. cruzi infection is defined by at least 2 different positive serologic tests, and the donor showed positivity for T. cruzi in indirect hemagglutination assay at 1/2048 and by enzymelinked immunosorbent assay (ELISA); a Strout test was negative. However, the donor did not receive any treatment for Chagas disease. On the other hand, the transplant recipient showed negative serologic test results for T. cruzi. In addition, the recipient was HIV negative. Transplant surgery occurred with no complication, and 7 days later, the patient was discharged, with a serum creatinine of 1.3 mg/dL. No induction therapy was administered and the immunosuppressive regimen included tacrolimus (0.1–0.2 mg/kg day, trough level of 6–10 ng), mycophenolate sodium (1440 mg daily), and corticosteroids (1 mg/kg daily during the first week, 20 mg daily at 1 month, and then tapered to 4 mg daily). Over some time, the patient showed poor adherence to treatment and follow-up visits. At 4 years after the transplant, a borderline cellular graft rejection occurred; it was successfully treated with 3 pulses of methylprednisolone, 500 mg each, and 4 months later, a Banff IA graft rejection was managed with the same therapy. Some weeks after the last rejection, indirect hemagglutination and ELISA tests confirmed positive seroconversion. Treatment was not initiated because benznidazole was not locally available for some weeks, and then the patient did not attend our center for treatment. From year 4 to 6 after transplantation, the patient only attended the center for follow-up visits very sporadically. At these visits, as seroconversion had been confirmed, direct parasitologic Strout test was performed. At 6 years after transplantation, the patient was admitted to our hospital with ophthalmologic herpes and complaining of severe headaches. Administration of tacrolimus and mycophenolate sodium was suspended and treatment with acyclovir was initiated at 10 mg/kg/day for 10 days. In addition, a non-contrast
814
computed tomography (CT) scan of the brain was performed. Images showed a right frontal, subcortical, white matter lesion with surrounding edema (Fig. 1). Toxoplasmosis, brain abscess, and lymphoma or even metastatic disease had to be considered in the differential diagnosis. Unfortunately, magnetic resonance imaging of the brain could not be performed because of problems related to the patient’s medical insurance. One month earlier, during a regular followup visit, the Strout test had been negative for T. cruzi. Owing to the possibility of central nervous system (CNS) infection, the patient underwent a lumbar puncture. The cerebrospinal fluid (CSF) was clear, and the examination showed 2 blood cells/mm3, 0 white cells/mm3 (lymphocytes), lactic acid 1.2 mmol/L, total protein 0.29 g/L, and glucose 61 mg/dL (blood glucose 73 mg/dL). Fifteen days after the first CT, a new non-contrast CT of the brain was performed (Fig. 2), which showed hypodensity in the central area, suggesting necrosis or liquefaction and persistent edema. Tests performed for antigenemia and with India ink staining were negative for Cryptococcus. Analysis of the CSF was negative for toxoplasmosis and venereal disease VDRL test. Direct and culture tests for fungal infections were negative. However, polymerase chain reaction (PCR) tests for T. cruzi in CSF and blood showed positive results. The patient presented with concomitant cough and dyspnea. Pneumocystis jirovecii was detected in bronchoalveolar
Fig. 1. Renal transplant patient; non-contrast axial computed tomography of the brain showing a right frontal lesion with surrounding edema.
Transplant Infectious Disease 2014: 16: 813–817
Cicora et al: Brain trypanosomiasis in renal transplant
Fig. 2. At 15 days after first computed tomography (CT) (Fig. 1), a new non-contrast axial CT of the brain showed a ring frontal lesion with edema. In an immunocompromised patient, differential diagnosis would include toxoplasmosis, brain abscess, lymphoma, or even metastatic lesion. At this point, polymerase chain reaction tests for Trypanosoma cruzi in cerebrospinal fluid and blood showed positive results.
lavage fluid, so the patient was treated with sulfamethoxazole-trimethoprim, received mechanical ventilation over 4 days, and stayed in the intensive care unit for 7 days. Based on the PCR test results, therapy with benznidazole was started at 7 mg/kg/day for 60 days. At 10 days after initiation, tacrolimus and mycophenolate sodium were restarted. Of note, the patient did not receive steroid treatment for the edema; immunosuppressive doses of steroids consisted of 4 mg daily. At 15 days after beginning benznidazole, a third noncontract CT of the brain showed a significant reduction in the edema (Fig. 3). The patient presented no adverse effects with benznidazole. At 30 days after the initiation of treatment, another CT again showed a significant reduction of the central nodule and the edema. The patient’s creatinine level was 2.2 mg/dL.
Discussion Our center is located in an endemic area with a high risk of transmission of Chagas disease, and infected kidney grafts are used for transplantation with appropriate
Fig. 3. At 15 days after beginning treatment with benznidazole, noncontrast axial computed tomography of the brain showed a significant reduction in the edema.
informed consent from the recipient. Considering the implications of confirming the infection for management of the patient, and the potential for drug toxicity, careful and strict monitoring has been recommended over prophylactic treatment (4). Table 1 shows recommendations for screening of solid organ transplant recipients from the Argentine Society of Infectious Diseases (20). Transmission of T. cruzi infection through a transplanted kidney to a non-infected recipient is rare, but has been reported (5, 6). Reasons for the wide variation in the presentation of Chagas disease are not completely understood (17). In an immunodeficient state, the probabilities of de novo infection and reactivation are both increased (19). It is impossible to know if this case is a donor-derived infection or a new infection. The patient lives in an endemic region of Argentina, in which house infestation was significantly reduced as a result of interventions coordinated by a National Program for Chagas Vector Control, such as insecticide spraying (21). Nevertheless, vector-borne transmission was not interrupted in this province (21). In the case of vector-borne transmission, the signs of portal of entry of T. cruzi through the skin (chagoma) or via the ~a sign) (1) should ocular mucous membranes (Roman have been visible or reported by the patient, but this was not the case. Oral transmission in humans, involving food or beverages contaminated with infected
Transplant Infectious Disease 2014: 16: 813–817
815
Cicora et al: Brain trypanosomiasis in renal transplant
Post-transplant screening of Chagas-seropositive recipients or seronegative patients receiving an organ from a seropositive donor Screening timing
POD 0 to 60: weekly
Screening techniques
Serologic tests, only in seronegative patients ELISA, indirect hemagglutination, particle indirect agglutination, indirect immunofluorescence. (Two different positive tests for diagnosis)
POD 61 to month 6: bimonthly Month 6 to year 1: monthly
Strout PCR Pathologic examination and PCR in tissue samples. Hematoxylin and eosin stain, Giemsa stain Screening techniques in patients with clinical reactivation
Skin lesion biopsy Endomyocardial biopsy (heart transplant) CSF direct examination
POD, postoperative day; ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain reaction; CSF, cerebrospinal fluid. Adapted from the guidelines published by the Argentine Society of Infectious Diseases (20).
Table 1
triatomine or their feces, has been registered in Brazil, Colombia, and rural Venezuela (3), but not in Argentina. Certainly, seroconversion 4 years after transplantation is atypical. An underlying chronic Chagas infection may become acute and produce diffuse myocarditis, lesions in the CNS, and severe meningoencephalitis (17). The use of corticosteroids, immunosuppression therapy, and the appearance of AIDS made the acute CNS form of chronic Chagas disease more common (17, 22). In 1913, Carlos Chagas described CNS involvement with T. cruzi in a small number of patients who developed encephalitis in the acute phase (17). Three aspects characterize CNS involvement in immunosuppressed patients: (a) encephalitis in multiple foci may present with necrosis; (b) it is common to find a tumorlike form with one or various necro-hemorrhagic lesions in the cerebral hemispheres, brain stem, or cerebellum, often called cerebral tumor-like American trypanosomiasis; and (c) an abundance of amastigotes are present within macrophages, glial cells, and neurons (17, 22). Common non-specific characteristics are ring- and nodular-enhancing patterns (14). The lesions appear mostly in the supratentorial white matter, but masses have been reported everywhere in the CNS, including the infratentorial region and basal ganglia (14).
816
Cordova et al. (15) described immunosuppressed HIV patients with Chagas disease involving the CNS; the most common manifestations were headache, which was the only symptom noted by our patient, focal neurologic deficits, and fever. However, these symptoms were indistinguishable from those related to other causes of meningoencephalitis. Although the patient described here was not HIV positive, the list of differential diagnosis possibilities is similar and includes, primarily, toxoplasmosis and lymphoma, but also progressive multifocal leukoencephalopathy, and infections with fungi, bacteria, and mycobacteria (14, 16). In our patient, a brain magnetic resonance imaging would probably have revealed more information for the presumptive diagnosis, but this could not be performed owing to problems with the patient’s health insurance. Serology for T. cruzi is of no diagnostic value, and detection of the parasite in the CSF or a brain tissue biopsy specimen would be necessary (14). At our center, once seroconversion is confirmed, reactivation is monitored with the Strout test because PCR is not always available. In fact, one of the limitations of this report is incomplete data on PCR. Parasitemia is probably the defining feature of reactivation, as this is typically increased before the onset of symptoms (8). In this patient, the Strout test had shown negative results for T. cruzi only 30 days before the first CT scan, and the presence of the parasite could only be confirmed by analyzing the CSF and blood using PCR. After this confirmation, the Strout test was not performed, as the treatment protocol to be followed would not change. Only benznidazole and nifurtimox have shown efficacy against Chagas disease (1) and in Argentina, only benznidazole is available. Benznidazole has the best safety and efficacy profile, and the recommended dose is 5–7 mg/kg/day in 2 daily divided doses for 60 days (1, 4). Treatment with either of these 2 drugs is strongly recommended when clinical and/or parasitologic reactivation is suspected (8). When the tumor-like lesion was observed, our patient received benznidazole for 60 days and did not require a longer treatment because of a positive clinical response and the improvement seen in brain CT. It had been impossible to initiate treatment when seroconversion occurred in 2010, because the drug was not readily available and the patient was non-compliant. The risk of Chagas disease transmission should not be underestimated in renal transplant patients, even in non-endemic areas, because immigration and travel to and from developing countries may make this disease more common than expected. We cannot confirm that the transmission was definitely from the infected graft, because the recipient lives in an endemic area.
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Cicora et al: Brain trypanosomiasis in renal transplant
In conclusion, our case report demonstrates that Chagas disease can present as a tumor-like brain lesion, whose image is difficult to differentiate from other opportunistic infections, such as toxoplasmosis or neoplastic processes. Frequent and rigorous monitoring for T. cruzi infection is essential to promptly implement treatment, which, in our patient, proved to be effective and safe.
Acknowledgements: Author contributions: F.C. participated in research idea, data collection, and revision of the paper. V.E., J.B., and I.G. participated in data collection and revision of the paper. J.P. participated in revision of the paper. J.R. participated in research design, literature search, data revision, and writing of the paper. Disclosure: The authors of this manuscript have no conflicts of interest to disclose.
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