The relationship between Chagas disease and immunosuppressive therapy

Dear Sir,

We read the article “Reactivation of Chagas disease after a bone marrow transplant in Italy: first case report” by Angheben et al¹. It is well known that Chagas disease, caused by a protozoa, Trypanosoma cruzi, is an autochthonous disease with a widespread distribution from the south of the United States to Mexico and South America. The disease can also affect people in Europe with its presence related to migratory flows. In non-endemic countries, Chagas disease can be acquired by congenital transmission, blood transfusion and organ transplantation. Transfusion is considered the second most common mode of transmission for T. cruzi; it is estimated that approximately 10–20% of blood from chronically infected donors is infective considering that T. cruzi remains viable in stored whole blood and citrated blood samples stored at refrigerator and room temperatures, respectively. Furthermore, it is known that this disease can be fatal, especially in immunosuppressed patients², following reactivation of latent infections. The most common symptoms of Chagas disease reactivation are both cardiac and gastrointestinal manifestations. Most of the infected people are not aware of their status because the disease frequently causes few or no symptoms during the acute phase and evolves commonly to a clinically silent phase.

Several cases of acute Chagas disease following solid organ and bone marrow transplantation have been described in the past. The first case of Chagas disease reactivation after a bone marrow transplant recorded in Italy is of great interest: the case was a 9-year old Argentinean girl with a diagnosed acute lymphoblastic leukaemia¹. The authors of the case report hypothesised that a probable cause of reactivation of Chagas disease in the patient could have been immunosuppression secondary to the bone marrow transplant and Graft-versus-Host disease prophylaxis (cyclosporine A and a short course of methotrexate). In accordance with this hypothesis, there is another report of immunosuppression associated with cord blood transplantation seeming to be responsible for the fatal outcome of Chagas disease in a 25-year old male with high-risk acute myeloid leukemia³.

Immunosuppression, which has become an increasingly relevant clinical condition in the last 50 years, modifies the natural history of several diseases, including T. cruzi infection: patients become predisposed to the development or reactivation of opportunistic infections with particular and often severe clinical outcomes.

Several guidelines for the treatment of immunosuppressed patients with Chagas disease have been published recently, but there is no international consensus on the management of reactivation in these patients. In cases of reactivation, early anti-parasitic treatment with benznidazole and/or nifurtimox has proven to be highly effective and posaconazole should be indicated when these fail.

Importantly, little is known about the relationship between the incidence of neoplastic disease and T. cruzi infection, or about whether the immune response, induced by this infection, modifies the development or localisation of neoplasms. Based on clinical observations in immunosuppressed patients some authors have speculated that benznidazole treatment might actually cause neoplasms. The relationship between immunosuppression and neoplastic disease in patients with T. cruzi infection has been analysed from three perspectives as reported by Pinazo et al.⁴: (i) neoplastic disease as a potentially immunosuppressive condition that increases the likelihood of reactivation of infections; (ii) neoplastic disease occurring as a result of treatment with benznidazole, either alone or in combination with immunosuppressive drugs; and (iii) neoplastic disease as a condition that is potentially more common in patients with Chagas disease. Clinical studies with long-term follow-up have found no evidence of a higher incidence of histological signs of malignancy with immunosuppressive therapy, concluding that benznidazole and its association with other immunosuppressive drugs do not contribute to an increased incidence of neoplastic disease⁴. However, reactivation of T. cruzi infection must be considered in patients with chronic Chagas disease and neoplastic diseases requiring intensive and/or long-term pharmacological immunosuppression⁴.

Currently, it is not easy to make general evidence-based recommendations for the management of T. cruzi-infected patients or for the prevention of reactivation. Clinicians should bear in mind that the natural course of T. cruzi infection can be modified by other diseases or their treatment. Furthermore, there have been no reports of a relationship between Chagas disease reactivation and other immunosuppressive drugs used in the treatment of systemic autoimmune diseases and it has not been shown that these diseases have a direct role in the progression of T. cruzi infection.

The main goal in T. cruzi-infected patients with an immunosuppressive condition could be to prevent reactivation by close monitoring. To do this, an early diagnosis of T. cruzi infection in immunosuppressed individuals is extremely important and should be considered prior to immunosuppressive treatment. For this reason, investigations for parasitaemia, detectable by Strout or quantitative buffy coat testing or microhaematocrit methods, are recommended, especially in immunosuppressed patients during follow-up. The only effective form of prevention for T. cruzi infection would be to avoid the use of blood or organs from donors who come from countries where Chagas disease is endemic or to perform serological screening for T. cruzi on these donors.

Chagas disease is considered an emerging problem in Italy⁵. Since chronic T. cruzi infection is often asymptomatic, most infected organ donors will not have a known history of the disease and laboratory screening is essential.

Although there is already some infrastructure at a national level⁵, there is not yet a systematic programme of reference centres for neglected diseases. Thus, Italy should implement a national network to prevent donations of blood and/or organs from T. cruzi-infected donors, improving the access to diagnosis. In addition, an infrastructure that ensures detection and treatment of acute and chronic cases, as well as congenital infections, should be developed.

In conclusion, it is important to extend epidemiological programmes to control Chagas disease in blood donors, stem cell donors and recipients by serological screening, in order to prevent adverse outcomes, especially in immunosuppressed patients.