Chagas Disease Reactivation after Heart Transplant: Importance of New Predictors

Chagas Disease; Latent Infection; Risk Factors

Chronic Chagas disease (CD) affects around 3.7 million Brazilians according to the most recent estimative.¹ As around 30-40% of this population present with the cardiac form, it comes as no surprise that CD is the third most frequent etiology among patients undergoing heart transplant in Brazil.² As induction and/or maintenance immunosuppressive therapy carry the risk of CD reactivation (CDR),³ heart transplant safety could be questioned in CD. However, the experience in Brazil established heart transplants as the leading alternative treatment for CD patients with end-stage heart failure.² In fact, the post-transplant survival of patients with CD in Brazil is 76%, 71%, and, 46% after 6 months, five, and 10 years, respectively, and better than the survival of heart transplant recipients with either ischemic or idiopathic cardiomyopathies.⁴,⁵

CDR incidence after heart transplant varies from 19.6% to 90%.³ CDR can induce symptoms of acute CD (fever, anemia, jaundice), myocarditis, panniculitis, meningoencephalitis, and brain abscess. Myocarditis is the most frequent complication and may present severe symptoms compatible with heart failure, cardiac arrhythmia, and even cardiogenic shock.⁶ Fortunately, CDR properly diagnosed and treated results in less than 1% mortality.⁶

However, rejection episodes may also present with similar findings and an equivocal diagnosis of rejection instead of CDR can lead to ominous consequences if an intensification of the immunosuppressive regimen is ensued.⁶ CDR diagnosis is classically based on the presence of suggestive clinical findings and evidence of the parasite in blood, liquor, bone marrow, or tissues.³,⁴ Therefore, protocols for monitoring CDR were developed and nowadays include PCR for T. cruzi in blood and endomyocardial biopsies, which are more sensitive than standard parasitological methods in such as direct observation of the parasite in a blood smear or an endomyocardial biopsy or a positive blood culture. The objective is an early diagnosis of CDR prompting trypanocidal treatment before the onset of severe symptoms and damage to the transplanted heart. Importantly, a positive PCR for T. cruzi in blood precedes the appearance of clinical signs of CDR with considerable sensitivity and specificity.⁷ Furthermore, a negative blood PCR for T. cruzi rules out CDR.⁸ PCR results are fundamental to guide therapeutic decisions between trypanocidal drugs or changes in immunosuppression regimens.⁸,⁹ Some authors consider that CDR diagnosis should be redefined as present even in the absence of evident clinical symptoms as long as an increase in parasitemia can be detected either by direct parasitological techniques or by PCR.⁶

Beyond a correct diagnosis of CDR, the recognition of the risk factors for such an event is important. Those are listed as follows, the number of rejection episodes, presence of malignancy, immunosuppression grade, autoimmune diseases, HIV infection, and other immunosuppression status.¹⁰ Therefore, strategies to prevent rejection-induced reactivation generally include the use of the lowest immunosuppressive therapy doses of several drugs.⁴,⁶

Due to the importance of CDR, the identification of risk factors that allow an early diagnosis and treatment is fundamental. In this issue of the Arquivos Brasileiros de Cardiologia, Wolf et al.¹¹ described that absolute lymphocyte count under 550/mm³ during the first 2 weeks after heart transplant was a predictor of a subsequent positive blood PCR for T. cruzi.¹¹ In fact, as induction immunosuppressive therapy induces lymphodepletion and CD4⁺ and CD8⁺ T cell immune response against T. cruzi is relevant for both parasite control and disease pathogenesis,¹² a low lymphocyte count can occur before CDR. This early and readily available risk factor for a positive blood PCR for T. cruzi can become very useful for the follow-up after a heart transplant in CD recipients. A low lymphocyte count can prompt an earlier PCR evaluation or a change in immunosuppressive treatment. Also, a high lymphocyte count could postpone a PCR evaluation, which can be useful for services with more difficult access to PCR techniques. Another possibility is preemptive trypanocidal treatment based on low lymphocyte count. All these possible clinical applications for lymphocyte count during the first two weeks after a heart transplant should be confirmed by properly designed clinical trials.

Referências

• ¹
  Laporta GZ, Lima MM, Costa VM, Lima Neto MM, Palmeira SL, Rodovalho SR, et al. Estimativa de prevalência de doença de Chagas crônica nos municípios brasileiros. Rev Panam Salud Publica. 2024;48:e28. doi: 10.26633/RPSP.2024.28.
  » https://doi.org/10.26633/RPSP.2024.28
• ²
  Fiorelli AI, Santos RH, Oliveira JL Jr, Lourenço-Filho DD, Dias RR, Oliveira AS, et al. Heart Transplantation in 107 Cases of Chagas' Disease. Transplant Proc. 2011;43(1):220-4. doi: 10.1016/j.transproceed.2010.12.046.
  » https://doi.org/10.1016/j.transproceed.2010.12.046
• ³
  Marin-Neto JA, Rassi A Jr, Oliveira GMM, Correia LCL, Ramos AN Jr, Luquetti AO, et al. SBC Guideline on the Diagnosis and Treatment of Patients with Cardiomyopathy of Chagas Disease - 2023. Arq Bras Cardiol. 2023;120(6):e20230269. doi: 10.36660/abc.20230269.
  » https://doi.org/10.36660/abc.20230269
• ⁴
  Bocchi EA, Fiorelli A. The Brazilian Experience with Heart Transplantation: A Multicenter Report. J Heart Lung Transplant. 2001;20(6):637-45. doi: 10.1016/s1053-2498(00)00235-7.
  » https://doi.org/10.1016/s1053-2498(00)00235-7
• ⁵
  Bestetti RB, Theodoropoulos TA. A Systematic Review of Studies on Heart Transplantation for Patients with End-stage Chagas' Heart Disease. J Card Fail. 2009;15(3):249-55. doi: 10.1016/j.cardfail.2008.10.023.
• ⁶
  Moreira MDCV, Cunha-Melo JR. Chagas Disease Infection Reactivation After Heart Transplant. Trop Med Infect Dis. 2020;5(3):106. doi: 10.3390/tropicalmed5030106.
• ⁷
  Costa PA, Segatto M, Durso DF, Moreira WJC, Junqueira LL, Castilho FM, et al. Early Polymerase Chain Reaction Detection of Chagas Disease Reactivation in Heart Transplant Patients. J Heart Lung Transplant. 2017;36(7):797-805. doi: 10.1016/j.healun.2017.02.018.
  » https://doi.org/10.1016/j.healun.2017.02.018
• ⁸
  Benvenuti LA, Freitas VLT, Roggério A, Nishiya AS, Mangini S, Strabelli TMV. Usefulness of PCR for Trypanosoma cruzi DNA in Blood and Endomyocardial Biopsies for Detection of Chagas Disease Reactivation After Heart Transplantation: A Comparative Study. Transpl Infect Dis. 2021;23(4):e13567. doi: 10.1111/tid.13567.
• ⁹
  Diez M, Favaloro L, Bertolotti A, Burgos JM, Vigliano C, Lastra MP, et al. Usefulness of PCR Strategies for Early Diagnosis of Chagas' Disease Reactivation and Treatment Follow-up in Heart Transplantation. Am J Transplant. 2007;7(6):1633-40. doi: 10.1111/j.1600-6143.2007.01820.x.
• ¹⁰
  Campos SV, Strabelli TM, Amato Neto V, Silva CP, Bacal F, Bocchi EA, Stolf NA. Risk Factors for Chagas' Disease Reactivation After Heart Transplantation. J Heart Lung Transplant. 2008;27(6):597-602. doi: 10.1016/j.healun.2008.02.017.
• ¹¹
  Wolf PJW, Finger MA, Rossi Neto JM, Santos CC, Mattos VBM, Rossi R, et al. Contagem Absoluta de Linfócitos: um Preditor de PCR Sérica Positiva para o Trypanosoma cruzi em Pacientes com Chagas Submetidos ao Transplante Cardíaco. Arq Bras Cardiol. 2024; 121(6):e20240588. DOI: https://doi.org/10.36660/abc.20230588
  » https://doi.org/10.36660/abc.20230588
• ¹²
  Ferragut F, Acevedo GR, Gómez KA. T Cell Specificity: A Great Challenge in Chagas Disease. Front Immunol. 2021;12:674078. doi: 10.3389/fimmu.2021.674078.
  » https://doi.org/10.3389/fimmu.2021.674078

Publication Dates

• Publication in this collection
  15 July 2024
• Date of issue
  June 2024

History

• Received
  28 Apr 2024
• Reviewed
  08 May 2024
• Accepted
  08 May 2024