The indications and contraindications for HT in the setting of CD follow the classic HT guideline criteria for other HF etiologies.^1–2,5 A patient with severe terminal HF refractory to optimal medical treatment and without formal contraindications, might benefit from the procedure and should be included on the waiting list for a heart transplant.^1,2,5. Clinical treatment needs to be optimized for symptom relief and to improve survival, necessarily including the following drugs: an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker, or angiotensin receptor-neprilysin inhibitor added to a beta blocker (in maximum tolerated doses) and a mineralocorticoid antagonist if possible.^15–17

Some peculiarities in the selection of HT potential donors and recipients in the context of CD should be observed.^2,5

Chagas patients usually have lower values of pulmonary arterial pressure, which can reduce right ventricular dysfunction, a frequent complication in the postoperative period of HT. Thus, cardiac manometry by right cardiac catheterization may not be always necessary before HT.^2,5 Most of these patients come from poor rural areas. Social inequalities may influence results and survival rates after HT, but these issues are still not well understood. However, it seems that the patient's socioeconomic condition has no impact on outcomes after HT.¹⁸ The megaesophagus and megacolon may occur in CD as a cardio-digestive form and should be evaluated. Depending on the severity of digestive manifestation, these may constitute contraindications to the procedure.⁵

Chagas cardiomyopathy is a highly arrhythmogenic disease, and sudden cardiac death corresponds to 55%-65% of all deaths, frequently caused by malignant arrhythmias, such as tachycardia and ventricular fibrillation.¹⁸ Patients with malignant ventricular arrhythmias usually receive an implantable cardioverter-defibrillator (ICD). They may require multiple ICD therapies, more than 4 shocks per day, featuring an electrical storm. This group of patients might also benefit from a heart transplant.¹⁹

In Brazil, according to governmental regulation, serology for T. cruzi infection in all potential donors and recipients is mandatory, and a positive donor for heart recipients is not accepted.¹³ Potential organ donors and recipients should always be screened for Chagas disease, in both endemic and non-endemic countries whose potential donor/recipient has a positive epidemiology.^6,13

Mechanical circulatory support has a potential benefit as a bridge for HT in chagasic patients. However, due to the high costs, this device is not available in the Public Health System (SUS in Portuguese) in Brazil, which funds more than 90% of heart transplants in the country.⁵

Induction therapy for HT, regardless of the etiology of HF, consists of intense immunosuppressive therapy during the transplant procedures or in its immediate postoperative period. It is recommended in high-risk patients in an attempt to reduce the risk of hyperacute rejection or delay the use of higher doses of calcineurin inhibitors, thus minimizing kidney damage.^19,20 The most widely used inducing agents are polyclonal anti-thymocyte immunoglobulins (polyclonal antibody - thymoglobulin) and interleukin 2 receptor inhibitors, which have low immunogenicity, such as daclizumab and basiliximab^.21

Basic immunosuppressive therapy for the maintenance of heart transplant patients generally includes a calcineurin inhibitor agent (Cyclosporin A or tacrolimus). These agents must be associated with mycophenolate mofetil, mycophenolic acid, azathioprine, rapamycin, or everolimus. Prednisone is associated with this standard regimen and, in most patients, can be suspended six months after the transplant, in the absence of rejection.²¹ In the context of Chagas disease, induction and/or maintenance immunosuppressive therapy can reactivate T. cruzi infection.^2,5,13

There are no randomized control clinical studies comparing the various immunosuppressive regimens in HT chagasic patients. However, a greater number of reactivations have been described in recipients using mycophenolate mofetil.⁽²²⁾ Therefore, it is recommended that Chagas patients receive the lightest immunosuppressive therapy, as long as there is no rejection.⁵

The instituted immunosuppressive therapy increases the risk of T. cruzi infection reactivation. The incidence after HT varies from 19.6% to 90% in Brazil.^9,20,24 A recent publication from a United States case series shows a rate of CD reactivation of 61%, which is within the broad range reported here.⁽²⁶⁾

The Latin America Guideline for the Diagnosis and Treatment of Chagas Heart Disease has established several risk factors for reactivation, as follows:^25,26

Considering the potential morbidity and mortality, the diagnosis and appropriate management of Chagas disease reactivation in the context of organ transplants is extremely important. Therefore, this procedure must be performed within a structured clinical and laboratory protocol to monitor the reactivation of the infection and its subsequent treatment.^5,9,13 The diagnosis of reactivation is based on clinical signs and symptoms and/or the presence of parasites in blood, cerebrospinal fluid and other fluids, bone marrow, or tissues.^5.9 After HT, the patient must be closely and regularly monitored. Clinical monitoring aims to identify the first signs of reactivation and promptly establish anti-T. cruzi treatment. Clinical reactivation has cardiac and extra-cardiac manifestations including: myocarditis, ventricular dysfunction, arrhythmias, new atrioventricular/intraventricular blocks on the ECG, new skin lesions (subcutaneous nodules, panniculitis), fever, bone marrow involvement or neurological manifestations. The central nervous system involvement is a rare and severe clinical manifestation. It manifests through meningoencephalitis, chagoma, brain abscess, or stroke, as well as through spacing-occupying lesions in the white matter of the brain.^5,9,27 Figure 1 is an example of post-heart transplant Chagas reactivation.

The myocarditis of the reactivation can be mistakenly diagnosed as a graft rejection, receiving intensified immunosuppressive treatment, which will aggravate the reactivation of the infection.²⁸ The differential diagnosis between rejection and reactivation myocarditis is still a major challenge. In the presence of inflammatory infiltrate, amastigote nests and/or positive PCR for T. cruzi in the myocardium, it can be said that there is a reactivation, but it is impossible to safely exclude associated allograft rejection. Despite this complexity, the survival rates of chagasic patients undergoing HT do not differ from other etiologies.^9,20

The purpose of laboratory monitoring is to identify any subclinical signs of reactivation before cardiac and extra-cardiac symptoms, as well as allograft dysfunction.^5,13 Serological tests are useful only in potential donors, in the diagnosis of chagasic cardiomyopathy in potential recipients, and in seronegative recipients who receive organs from seropositive donors.^5,13 These tests play no role in the diagnosis of reactivation. Traditionally, laboratory monitoring has used parasitological methods (direct blood search of T. cruzi and blood cultures) and serial histological examinations of EMB, in search of T. cruzi amastigotes, in tests with low sensitivity.^5,13 In recent years, several studies have demonstrated the value of the PCR test in peripheral blood and EMB fragments in detecting early reactivation, before the appearance of symptoms and/or cardiac allograft dysfunction.^29–32 Several studies have shown that PCR analysis is able to detect T.cruzi either in the blood or in EMB before clinical manifestations of reactivation by two or more months. Currently, PCR diagnosis is a precious tool to help physicians decide whether patients should begin treatment with anti-parasite drugs or changes in the immunosuppression protocol.^29–32

It is very important to monitor HT recipients for early detection of T.cruzi reactivation, allowing etiological treatment before clinical manifestations appear. However, no specific definition about when and how the monitoring protocol should be applied is available. Some centers agree that Chagas recipients should be routinely monitored for T.cruzi reactivation as they are monitored for rejection and any time when clinical suspicion occurs. Variations in the protocol can occur depending on the transplant team's policy.^5,17,26,33

Thus, concerning the frequency of clinical visits, laboratory monitoring, and EMB, there is still no consensus in the literature. Table 1 is our suggestion for a clinical, laboratory, and histological monitoring protocol for chagasic patients undergoing HT and the etiological treatment, which is in line with main available guidelines.^5,17,26,33 In countries where Chagas disease is not endemic, failure to identify patients with Chagas disease reactivation constitutes a major medical problem, as severe or fatal outcomes may supervene the incapacity to establish a proper diagnosis.^33,34

Benznidazole and nifurtimox are the anti-trypanosomal drugs of choice and have proven to be effective when administered to patients in the acute phase of Chagas disease and in those showing T.cruzi infection reactivation.^5,13 However, their efficacy upon the chronic phase has been a subject of debate.

Thus, etiological treatment for Chagas disease is recommended for patients with acute infection, congenital infection, women of childbearing age for the prevention of vertical transmission, and reactivated infection in immunosuppressed patients. Other chronically infected people in the early chronic phase (especially children less than 15 years of age) may also benefit from treatment.¹³

Antiparasitic treatment is not recommended for patients in the chronic phase with advanced cardiomyopathy, as is the case of the heart transplant candidates, since there is no evidence of benefit. There is no evidence to support the prophylactic anti-T.cruzi treatment strategy for reactivation.¹³

In the heart transplant scenario, the presence of clinical manifestations of T.cruzi infection reactivation or identification of the parasite in the blood, cerebrospinal fluid, EMB fragments, or in other tissues constitute sufficient evidence to begin etiological treatment without delay. Benznidazole, a nitroimidazole derivative, is the first-line treatment drug of choice.^5,13 Each tablet contains 100mg of the active substance. It is absorbed by the gastrointestinal tract and predominantly excreted by the kidneys, with a half-life of 12 hours. The recommended dose is 5mg/kg/day, for 60 days, with the daily dose being divided into two or three times.^5,13 Its most important side effect is urticarial dermatitis, which occurs in about 30% to 60% of all patients, commonly occurring early at the end of the first week of treatment, presenting a good therapeutic response with the use of antihistamines or small doses of corticosteroids. In a few cases, fever and adenomegaly may appear, in which case the medication should be discontinued. Other adverse effects include polyneuropathy, with pain and/or tingling in the lower limbs. Anorexia, significant leukopenia, and agranulocytosis are rare, and when present, the interruption of treatment is mandatory.⁽¹³⁾ Nifurtimox is not available in Brazil. These trypanosomicidal medications are contraindicated in pregnant women and in patients with either renal or hepatic impairment.¹³ A patient may have more than one reactivation episode after treatment. Therefore, it is necessary to maintain the monitoring of reactivation after anti-T.cruzi treatment.^5,13