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Ann Thorac Surg 1996;61:1727-1733
© 1996 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Heart Transplantation for Chronic Chagas' Heart Disease

Heart Institute, São Paulo University Medical School, São Paulo, Brazil

Accepted for publication February 6, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Background. Chagas' disease has been considered a contraindication to heart transplantation as Trypanosoma cruzi infection could recur after immunosuppression.

Methods. We report the follow-up of 22 patients who underwent orthotopic heart transplantation for treatment of end-stage chronic Chagas' heart disease, divided in two groups. Group 1 consisted of 9 patients operated on from September 1985 to June 1991, and group 2 patients underwent transplantation from July 1991 Aug 91 in text to June 1995. After our early experience with group 1, we attempted to use a lower cyclosporine dosage in group 2.

Results. Total actuarial survival at 24 months was 60%, and it was better for group 2 (33% for group 1, 80% for group 2, p = 0.008). Parasitemia occurred similarly in both groups, but Chagas' disease reactivation was seen in 5 group 1 patients and in 1 group 2 member (p < 0.002). Neoplasia developed in 5 group 1 patients and 1 group 2 patient, and contributed to death in 3 of them.

Conclusions. These data demonstrate satisfactory outcome of cardiac transplantation in patients with end-stage Chagas` heart disease in the second phase of our experience. Further progress is necessary to improve the results and evaluate its proper role in the management of this disease.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
A merican trypanosomiasis (Chagas' disease), a chronic infection caused by the protozoan Trypanosoma cruzi, is endemic in South and Central America, where it affects almost 20 million people. Symptomatic disease will develop in about 30% of them, most frequently affecting the heart [1]. It remains a major cause of morbidity and mortality in endemic regions, causing 18% of the cases of refractory heart failure seen at the Heart Institute, São Paulo University Medical School [2]. Being a systemic chronic infection, Chagas' disease has been considered a potential contraindication to cardiac transplantation, as it could recur acutely or chronically in the allograft or in a remote organ after immunosuppression. A small number of patients who had reactivations of the disease after kidney or heart transplantation have been reported [1, 3].

The objective of this investigation was to study the outcomes of patients submitted to heart transplantation due to their desperate clinical condition and to evaluate its value as a treatment for end-stage Chagas' heart disease. In addition, we divided the patients in two groups according to transplantation date.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Studied Population
Between March 1985 and June 1995, 22 patients (21 men), age ranged from 11 to 57 years (mean, 36 ± 13 years), with end-stage chronic Chagas' heart disease underwent orthotopic cardiac transplantation at the Heart Institute, São Paulo University Medical School. Nineteen patients were in New York Heart Association functional class IV including 1 patient with circulatory support with a heterotopic left ventricular assist device. Two patients were in functional class III, one of them with recurrent sustained ventricular tachycardia episodes. The remaining patient was in functional class II with repeated episodes of refractory sustained ventricular tachycardia. The diagnostic criteria for chronic Chagas' heart disease were a combination of epidemiologic data, positive serologic tests for anti-T cruzi antibodies (complement fixation and indirect immunofluorescence), a compatible clinical syndrome, and in addition, no evidence of any other cause for the cardiomyopathy [4]. Complement-fixation tests (Machado-Guerrero) were considered positive when the reaction was observed in a serum dilution equal to or greater than 1:8 and the indirect immunofluorescence was equal to or greater than 1:32 in at least two different assays. Myocarditis was documented by histopathologic studies of the explanted heart in all patients. Criteria and contraindications for patient selection for transplantation among Chagas' disease patients were similar to those used for nonchagasic patients, except for chagasic megaesophagus or megacolon, which were considered contraindications for heart transplant [5]. Table 1 shows characteristics of the patients before heart transplantation and the duration of follow-up. Table 2 compares patient characteristics between those submitted to heart transplantation in the interval from September 1985 to June 1991 (group 1) and from July 1991 abstract states July 91 to June 1995 (group 2).

Immunosuppression
The patients were submitted to immunosuppressive protocols used in our heart transplantation program from 1985 to 1995. Triple therapy using cyclosporine, azathioprine, and steroids was the cornerstone of maintenance immunosuppressive therapy. Intravenous methylprednisolone was begun immediately before removal of the aortic cross-clamp and continued for 2 days. It was followed by 1 mg • kg^-1 • day^-1 of oral prednisone, gradually tapered to 0.1 to 0.3 mg • kg ^-1 • day^-1 over a 4- to 6-week period. Azathioprine was given orally or intravenously administered before and after operation at 1.5 to 2.5 mg • kg^-1 • day^-1 followed by oral administration in the last 21 patients, with the dose adjusted to maintain a white blood cell count of more than or equal to 4,000/µL. The first four patients received 6 ± 2 mg • kg ^-1 • day^-1 of oral cyclosporine before operation. The other patients received continuous intravenous infusion of cyclosporine (1 to 1.5 mg • kg ^-1 • day^-1) during the procedure and it was maintained for 2 days in the absence of renal failure or severe circulatory deterioration. On the third postoperative day or whenever possible, we usually switched to oral cyclosporine, which was started at 3 to 6 mg • kg ^-1 • day^-1. Six patients who were hemodynamically unstable or had renal dysfunction (serum creatinine level equal to or greater than 2.5 mg/dL) received intravenous anti-thymocyte globulin (10 to 15 mg • kg^-1 • day^-1) (Pasteur Merrier, France or Butancor, São Paulo, Brazil) for 5 to 11 days in the immediate postoperative period. In these patients cyclosporine was instituted after the renal dysfunction resolved. We deliberately attempted to keep cyclosporine dosages at a lower range in the group of 13 patients transplanted after July 1991 because of the high incidence of Chagas' disease reactivation and neoplasias in our initial experience. Dosages of cyclosporine were adjusted according to cyclosporine blood levels, serum creatinine levels, toxicity, drug intolerance, and occurrences of rejection, Chagas' disease reactivation, parasitemia by T cruzi, or infection.

Monitoring and Treatment of Rejection
Endomyocardial biopsies for rejection surveillance were performed according to a standard schedule. The biopsy results were considered indicative of allograft rejection if an inflammatory infiltrate was detected in the absence of infectious agents, especially T cruzi. Episodes of rejection were treated if biopsies were graded III or higher by the International Society for Heart Transplantation Standardized Grading System criteria [7] or as moderate or more severe rejection by the Stanford criteria [8], and there was no evidence of Chagas' disease reactivation. These rejection episodes were usually treated with an increased dose of steroids, either intravenous methylprednisolone (1 g/day for 3 days) or a short course of oral prednisone (1 mg • kg^-1 • day^-1 for 3 days) tapered to 20 mg/day over 12 days.

Monitoring for Trypanosoma cruzi Infection
Trypanosoma cruzi infection was specifically investigated at the time of routine endomyocardial biopsies in the blood and myocardium tissue and if there was clinical or laboratorial evidence or suspicion of Chagas' disease reactivation. The parasite was searched for in peripheral blood, in endomyocardial biopsies, and in other suspected tissues. The investigation was repeated after completing specific treatment. After 1987 T cruzi monitoring was enhanced by the use of immunoperoxidase staining of tissue sections using anti-T cruzi polyclonal antibody [9]. The diagnosis of Chagas' disease reactivation was considered when the parasite was detected in blood or tissues with inflammatory process surrounding it, in association with symptoms or signs attributable to infection by T cruzi. Chagasic myocarditis was diagnosed by the demonstration of the parasite surrounded by a myocardial inflammatory infiltrate according to the Dallas' criteria [10]. Parasitemia was diagnosed when T cruzi was detected in blood. Episodes of parasitemia or Chagas' disease reactivation were treated with benznidazole in a 10 mg • kg^-1 • day^-1 dosage for 60 days. Four patients, all of them of group 1, received prophylaxis with benznidazole for 60 days (10 mg • kg^-1 • day^-1) while waiting for transplantation or in the immediate postoperative period.

Statistical Analysis
Results are expressed as mean ± 1 standard deviation. Kaplan-Meier estimates for event-free interval were calculated for survival, rejection, infection, parasitemia, and Chagas' disease reactivation. The results of heart transplantation performed before June 1991 were compared with results of heart transplantation performed from July 1991 check Aug vs July to June 1995. Event-free survival was compared using the log-rank test. Immunosuppressive drug dosages and other variables were compared using Student's t test. A significance level of p less than 0.05 was adopted. Calculations were performed using the Statistical Analysis System software.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Survival
Survival for the entire group at 1, 6, and 12 months after heart transplantation was 91 ± 4%, 86 ± 7%, and 60 ± 11%, respectively and remained stable thereafter (Fig 1). The actuarial survival rate of patients submitted to heart transplantation from September 1985 to June 1991 at 1, 6, and 12 months was 89 ± 10%, 66 ± 17%, and 33 ± 16%, respectively. Patients who underwent heart transplantation from July 1991 to June 1995 had actuarial survival at 1, 6, and 12 months of 100%, 100%, and 80 ± 13%, respectively. Survival was significantly better for patients transplanted after July 1991 compared with group 1 patients (p < 0.008, by the log-rank and Wilcoxon test). Two patients submitted to transplantation before June 1991 died in the early postoperative period. The causes of late death in group 1 were lymphoproliferative disorders (2 patients with 200 and 283 days of follow-up), lymphoproliferative disease and Pneumocystis carinii infection (1 patient with 217 days of follow-up), and allograft rejection (1 patient with 110 days of follow-up). In the second group only 2 patients died, one from Kaposi's sarcoma (358 days of follow-up) and another from allograft rejection due to nonadherence to immunosuppressive drugs (360 days of follow-up). All surviving patients are well in stable clinical condition and were able to resume working. Mean follow-up was 1,298 ± 1,159 days. In the surviving patients, the most common findings were Cushing's syndrome, hypercholesterolemia, renal insufficiency, and arterial hypertension.

View larger version (22K): [in this window] [in a new window]   Fig 1. . Kaplan-Meier survival curve after heart transplantation for all studied patients, for those who underwent transplantation from September 1985 to June 1991 (group 1), and for those who underwent transplantation from July 1991 to June 1995 (group 2). Survival was significantly better for group 2 patients (p = 0.008 by log-rank test).

Trypanosoma cruzi Parasitemia or Chagas' Disease Reactivation
Actuarial freedom from parasitemia at 1, 6, and 12 months for the entire group was 71 ± 10%, 33 ± 11%, and 26 ± 10%, respectively. For group 1 these estimates were 63 ± 17%, 31 ± 18%, and 16 ± 14%, respectively, and for group 2, 85 ± 10%, 33 ± 14%, and 33 ± 14%, respectively (p = 0.28). Chagas' disease reactivations developed during follow-up in 5 group 1 patients and 1 group 2 patient. Actuarial freedom from Chagas' disease reactivation at 1, 6, and 12 months for the entire group was 100%, 84 ± 9%, and 78 ± 10%, respectively (Fig 2). For group 1 these estimates were 100%, 54 ± 20%, and 36 ± 20%, respectively, compared to 100% during the first follow-up year for group 2. The linearized rate for reactivation of Chagas' disease per patient per month during the first year was 0.03 ± 0.05 episodes and for parasitemia was 0.10 ± 0.09 episodes. Linearized rates for Chagas' disease reactivation and parasitemia for group 1 and group 2 are shown in Table 4. Parasitemia was detected at least once in 15 patients (68%). Five group 1 patients suffered at least one episode of Chagas' disease reactivation during the follow-up. One patient presented four and another patient, three successfully treated episodes of Chagas' disease reactivation during follow-up. Three patients had received prophylactic benznidazole. Two episodes of myocarditis developed after the first posttransplantation year in 1 group 2 patient. Clinical findings of Chagas' reactivation included fever, subcutaneous nodules, and myocarditis. Acute myocarditis predominated and was diagnosed 11 times in five patients. All episodes of reactivation of Chagas' disease were successfully treated with benznidazole with reactivation regression. Most episodes of Chagas' disease reactivation were preceded or associated with parasitemia, except in 1 patient. However, only 5 of 15 (33%) parasitemia episodes preceded or were associated with Chagas' disease reactivation. Parasitemia incidence was similar between both patient groups. Only the hemagglutination test showed changes of titers during episodes of T cruzi infection reactivation or parasitemia.

View larger version (23K): [in this window] [in a new window]   Fig 2. . Actuarial freedom from Chagas' disease reactivation. Reactivation-free rate was significantly better for group 2 patients (p < 0.002 by log-rank test).

Neoplasia
Malignant diseases developed during follow-up in 6 patients, 5 belonging to group 1. Three lymphomas were detected during the first posttransplantation year, one of them an autopsy finding after the patient died of P carinii infection, and the other two were fatal. Kaposi's sarcoma developed in 2 patients, 1 of them dying of allograft rejection after immunosuppression reduction. Squamous carcinoma of the lip developed in another patient and was excised with good results.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
This investigation demonstrated in the second phase of our experience that heart transplantation for treatment of chronic Chagas' heart disease may be performed with acceptable results. Overall, parasitemia, reactivations of Chagas' disease with myocarditis, and neoplasias were common findings after heart transplantation in the first phase. The reduction of cyclosporine dose associated to an increasing experience with this subset of patients may have led to a lower rate of Chagas' disease reactivation, neoplasias, and improved survival.

Most patients showed recurrence of parasitemia, associated in some patients with Chagas' disease reactivation. However, the clinical manifestations of Chagas' disease reactivation were different from those reported for acute Chagas' disease ref.#?. Fever, myocarditis, and subcutaneous nodules predominated in posttransplant reactivation of Chagas' disease, whereas in acute Chagas' disease, fever, inoculation stigmata, lymphadenopathy, hepatosplenomegaly, and cardiac dysfunction are the predominant signs. Reasons for Chagas' heart disease reactivation after heart transplantation are not fully known. In concordance with findings of other researchers, the frequent detection of T cruzi in our results strongly suggests the continued presence of the parasite hidden in body tissues after the primary infection [11]. Achieving a balance between preventing rejection and preventing infections and other complications after transplantation has proven to be difficult [12]. Recurrence of acute infectious myocarditis due to other causes in the transplanted donor heart has been reported [13]. The most important factor accounting for the reactivation of a latent infection after organ transplantation seems to be the use of immunosuppressive drugs. However, the role of each immunosuppressive agent is not fully known. Experimental data demonstrated higher intensity of Chagas' disease in infected mice treated with combined immunosuppressive drugs [14, 15]. In humans, acute Chagas' disease developed after renal transplantation from chagasic donors into nonchagasic recipients under azathioprine and corticosteroid therapy, but the clinical course was not severe and treatment with benznidazole was successful [16]. Also, our finding that the reduction of the cyclosporine dosages associated with higher doses of azathioprine may lead to a lower incidence of Chagas' disease reactivation provides evidence for a role of cyclosporine in the reactivation of this disease in humans. Reactivation of T cruzi infection was also observed during chemotherapy for treatment of acute lymphocytic leukemia, and was attributed to chemotherapy-related changes in cellular immune responses [17]. However, despite the incidence of Chagas' disease reactivation, T cruzi infection should not be viewed as an absolute contraindication for heart transplantation. Each Chagas' disease reactivation episode was successfully treated with benznidazole, even in patients who had more than one reactivation episode. The long-term viability of transplanted hearts was demonstrated despite myocarditis episodes and the immunosuppression could be managed with reduction of cyclosporine dosages, attempting to obtain a lower rate of Chagas' disease reactivation. However, close monitoring for signs and symptoms of Chagas' heart disease reactivation should be performed routinely.

Whether chronic Chagas' disease myocarditis will recur in the allograft with a longer follow-up is an unsolved question. Chronic Chagas' inflammatory cardiomyopathy may occur in 20% to 30% of infected subjects, 5 to 20 years after primary infection [1]. Theoretically, the mechanisms involved in chronic Chagas' disease cardiomyopathy could affect the graft after a similar time lag. Further studies with a longer follow-up are necessary to investigate the recurrence of chronic Chagas' disease myocarditis in this group of patients. Furthermore, anti-T cruzi agents used in these patients such as benznidazole are effective only in reducing parasitemia, without eliminating the parasite [1]. In experimental studies these drugs did not prevent progression of acute myocarditis to chronic Chagas' disease cardiomyopathy.

Concerning survival, the operative mortality rate of 11%, defined as death before hospital discharge, is close to that reported by the Registry of the International Society for Heart and Lung Transplantation and by other investigators [18]. On the other hand, late survival was compromised by the high incidence of neoplasias (22%) mainly in group 1. Neoplasia development after heart transplantation has been linked to immunosuppressive therapy, Epstein-Barr virus infection, and prolonged antigen stimulation of the lymphoreticular system by the donor organ itself. However, studies using triple-drug immunosuppressive regimen similar to the regimen used in our report were associated to a low incidence of lymphoproliferative disorder in heart recipients. Thus, additional factors such as benznidazole use [1], periodic reactivation of a latent infection, and specific immunologic disturbances peculiar to Chagas' disease associated to immunosuppression may determine the higher incidence of neoplasia after heart transplantation for Chagas' cardiomyopathy treatment. The long-term survival for patients who survived the first year is similar to that of patients transplanted for other causes at our institution and comparable with that of other reports in the literature [19].

Concerning the rejection episodes, they occurred frequently during the first year of follow-up and the incidence was similar to that reported at our Institution and by other researchers after heart transplantations for ischemic and idiopathic cardiomyopathy using triple immunosuppression [20]. A poor outcome due to increased incidence of severe rejection has been described in patients with preoperative diagnosis of myocarditis [21]. In contrast, despite the preoperative diagnosis of myocarditis in all patients, in our study rejection was the primary cause of death in only 1 patient. Apart from the discussed events, the morbidity of surviving patients was similar to that reported for heart transplants for other causes.

Limitations
This study is limited by the small number of patients. Concerning anti-T cruzi drugs, benznidazole was the only drug used for treatment or prophylaxis of Chagas' disease reactivation. A question that will arise is whether nifurtimox could be more effective than benznidazole. However, benznidazole was the only drug available in our country and available evidence suggests that nifurtimox treatment is also unsatisfactory. Limitations should be considered concerning our criteria for diagnosis of Chagas' disease reactivation. The parasitemia detected in some patients could be an early manifestation of Chagas' disease reactivation and benznidazole treatment may have altered its course. However, there is no ideal tool or criteria for differential diagnosis between a simple parasitemia and an early parasitemia preceding Chagas' disease reactivation.

Conclusions and Clinical Implications
Chagas' disease should not be viewed as an absolute contraindication to heart transplantation, as parasitemia episodes and Chagas' disease reactivations were successfully treated and allograft function was preserved on long-term follow-up. Routine prophylaxis for Chagas' disease after heart transplantation with benznidazole seems not to be justified. Development of more effective drugs for treatment of T cruzi infection, and a better understanding of T cruzi infection pathogenesis and of Chagas' disease reactivation could improve management and survival of these patients after heart transplantation. We think that heart transplantation has potential to become a useful option for treatment of end-stage heart failure due to Chagas' heart disease.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Address reprint requests to Dr Bocchi, Rua Oscar Freire, 2077 ap. 161, CEP 05409-011, São Paulo SP, Brazil.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Edimar A. Bocchi Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bocchi, E. A. Articles by Pileggi, F. Search for Related Content PubMed PubMed Citation Articles by Bocchi, E. A. Articles by Pileggi, F.