Total Artificial Heart as Bridge to Heart Transplantation in Chagas Cardiomyopathy: Case Report A. Ruzzaa, L.S.C. Czerb,*, M. De Robertisa, D. Luthringerc, J. Moriguchib, J. Kobashigawab, A. Trentoa, and F. Arabiaa Divisions of aCardiothoracic Surgery and bCardiology, Cedars-Sinai Heart Institute, Los Angeles, California, USA; and the cDepartment of Pathology, Cedars Sinai Medical Center, Los Angeles, California, USA
ABSTRACT Chagas disease (CD) is becoming an increasingly recognized cause of dilated cardiomyopathy outside of Latin America, where it is endemic, due to population shifts and migration. Heart transplantation (HTx) is a therapeutic option for end-stage cardiomyopathy due to CD, but may be considered a relative contraindication due to potential reactivation of the causative organism with immunosuppression therapy. The total artificial heart (TAH) can provide mechanical circulatory support in decompensated patients with severe biventricular dysfunction until the time of HTx, while avoiding immunosuppressive therapy and removing the organ most affected by the causative organism. We report herein a patient with CD and severe biventricular dysfunction, who had mechanical circulatory support with a TAH for more than 6 months, followed by successful orthotopic HTx and treatment with benznidazole for 3 months. The patient had no evidence of recurrent disease in the transplanted heart based on endomyocardial biopsy up to 1 year post-transplantation, and remains alive more than 30 months after insertion of a TAH and 24 months after HTx.
C
HAGAS DISEASE (CD) is a life-threatening disease caused by a tropical parasite, Trypanosoma cruzi. Approximately 7 to 8 million people, mostly in Central and South America, where it is endemic, have CD [1]. Population movements and migration have increased the areas where CD is diagnosed, and these areas now include the United States and Europe [1,2]. Up to 30% to 40% of people develop symptoms, usually within 10 to 30 years after the initial infection [3]. The heart is the most affected organ, causing severe endstage dilated cardiomyopathy leading to heart failure (HF) [3]. Patients with Chagas cardiomyopathy (CC) and HF have a higher mortality compared with other causes of cardiomyopathy [4]. Heart transplantation (HTx) may be considered a relative contraindication in patient with CC and HF due to the risk of reactivation of the causative infectious agent with immunosuppression therapy, thus potentially affecting the outcome of the HTx [5]. We present the first case of total artificial heart (TAH) insertion as a bridge to HTx in a patient with CC and HF. ª 2016 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 48, 279e281 (2016)
CASE REPORT A 53-year-old woman (body surface area [BSA] 1.61 m2) had a dilated cardiomyopathy, HF, ventricular ectopy, prior pacemakercardioverter-defibrillator placement, atrial fibrillation, hypothyroidism, hypertension, hyperlipidemia, and diabetes. The patient was born in a country in Central America where CD was endemic, and immigrated to the United States. She developed decompensated HF. Serologies (immunoglobulin [Ig]G) for T cruzi were positive in July 2011 (>1:512) and October 2012. The patient was referred for evaluation and management of CC, and was admitted for decompensated HF in April 2013. An echocardiogram showed a left ventricular ejection fraction (EF) of 10%e15%, severe tricuspid and mitral valve regurgitation, severe diastolic dysfunction, and a left ventricle end-diastolic diameter of 6.9 cm. Right-sided heart catheterization showed right atrial (RA) No funding was provided for this study. F. Arabia, MD, is a trainer for Syncardia System. The other authors have no conflicts of interest to disclose. *Address correspondence to Lawrence S.C. Czer, MD, Medical Director, Heart Transplantation Program, Cedars-Sinai Heart Institute, 127 S. San Vicente Blvd, Suite A3100, Los Angeles, CA 90048, USA. E-mail: [email protected] 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2015.12.017
279
280 pressure of 19 mm Hg, right ventricular (RV) pressure of 48/15 mm Hg, pulmonary arterial (PA) pressure of 47/29 mm Hg (mean, 36 mm Hg), and pulmonary capillary wedge (PCW) pressure of 30 mm Hg. Cardiac output (CO) was 4.7 L/min; cardiac index (CI) was 3.1 L/min/m2. The patient was diuresed for volume overload, and after a marked decrease in the CO and CI, she was placed on intravenous dopamine and dobutamine infusions. However, the patient continued to deteriorate hemodynamically. She developed a Klebsiella urinary tract infection and intravenous antibiotic therapy was initiated. Blood cultures were negative. The patient continued to worsen and developed hypotension with cardiogenic shock, requiring the addition of epinephrine. She was brought emergently to the operating room and placed on extra-corporeal membrane oxygenation (ECMO) support in May 2013. After 48 hours, biventricular cardiac function remained severely impaired but end organ perfusion was adequate and no donors were available, so a decision was made to bridge the patient with TAH (Syncardia Inc, Tucson, Ariz, United States) [6] in May 2013. Operative findings included severely depressed biventricular function, thin ventricular walls, and a defibrillator lead perforated through the tricuspid valve posterior leaflet. The pathology of the explanted heart showed myocarditis (diffuse mixed inflammatory infiltrate of eosinophils, plasma cells, lymphocytes, giant cells), left ventricular wall thinning with fibrosis, and an apical aneurysm. No intracytoplasmic parasites (amastigotes) were noted morphologically. Eighteen days after TAH placement, she developed transient left-sided weakness and aphasia. A computed tomography (CT) scan showed a subarachnoid hemorrhage. She gradually had complete resolution and recovery from the neurological symptoms after brief discontinuation of anticoagulation (later resumed). On postimplantation day 79, she was discharged home, fully recovered. A compatible organ donor became available on postimplantation day 197 (November 2013). Postoperative immunosuppressive therapy consisted of triple-drug immunosuppression with tacrolimus, mycophenolate mofetil, and prednisone. Endomyocardial biopsies were performed per protocol [7]. Recovery was uncomplicated, and the patient was extubated on posttransplantation day 1. She was discharged in good condition on post-transplantation day 8. At discharge after HTx, blood pressure was 115/70 mm Hg with heart rate of 95 bpm, RA pressure of 4 mm Hg, RV pressure of 26/6 mm Hg, PA pressure of 26/12 mm Hg (mean, 17 mm Hg), and PCW pressure of 10 mm Hg; CO was 5.48 L/min and CI was 3.51 L/min/m2. Serology (IgG) for T cruzi remained positive on the day of the HTx (November 2013). The patient was monitored with weekly polymerase chain reaction (PCR) for T cruzi after transplantation, and these returned positive in December 2013. Therapy with benznidazole was initiated in late December 2013 and was continued for 3 months. Mycophenolate mofetil was changed to azathioprine (later discontinued due to leukopenia), and prednisone was weaned off. The patient was maintained on tacrolimus monotherapy. The PCR measurements for T cruzi from midJanuary through December 2014 were negative. Endomyocardial biopsies through 1 year post-transplantation showed, at most, mild (grade 1R-1A) cellular rejection and no evidence of antibody-mediated rejection [7]. There was no evidence of T cruzi on the post-transplantation biopsy specimens, and there were no intracytoplasmic parasites (amastigotes). Doppler echocardiograms showed normal left and right ventricular function. Renal function was normal. The patient remained alive in November 2015 at 30 months after TAH insertion and 24 months after HTx.
RUZZA, CZER, DE ROBERTIS ET AL
DISCUSSION
CD is a major cause of end-stage cardiomyopathy in Central and South America, and CC is the third leading indication for HTx in Brazil [8]. This cause of cardiomyopathy is having a serious economic impact on the United States, Europe, and other areas outside of Central and South America. In a 2009 publication, it was estimated that there were 300,000 persons with chronic CD in the United States, resulting in 30,000e45,000 cases of CC [9]. The cost of treatment in the United States is estimated to be $900 million annually, which includes hospitalization and medical devices such as pacemakers. The global cost is estimated at $7 billion [10]. HTx is considered to be a relative contraindication in patients with CD, due to potential reactivation of the causative agent with immunosuppressive therapy after HTx, yet HTx is often considered for this endstage cardiomyopathy [5]. Mechanical circulatory support with a left ventricular assist device as a bridge to HTx in CD was previously described by Moreira et al [11]. In contrast, TAH can provide mechanical circulatory support in decompensated HF patients with severe biventricular dysfunction from CC until the time of HTx, avoiding immunosuppressive therapy and potentially allowing treatment of extracardiac CD and parasitemia prior to HTx. Moreover, removal of the organ most affected by the disease process (the heart) as a consequence of TAH insertion, as opposed to insertion of a ventricular assist device, may reduce the infectious burden of the causative organism, T cruzi. In a recent randomized clinical trial, treatment with benznidazole reduced parasitemia but did not prevent progression of chronic CC [12], implying continued worsening of biventricular function if the heart was left in place, as would occur with the placement of a left ventricular assist device. The patient in the present report underwent successful HTx after 197 days (more than 6 months) of mechanical circulatory support with the TAH. Serial PCR determinations for T cruzi were used to detect reactivation of the infection after HTx, whereupon disease-specific therapy with benznidazole [2,12e15] was initiated within 2 months post-transplantation. With modification of the immunosuppressive therapy and continuation of benznidazole, the subsequent PCR determinations were negative, allowing discontinuation of the benznidazole after 3 months. Endomyocardial biopsies up to 1 year after transplantation showed no evidence of T cruzi in the transplanted heart. To date (November 2015), there has been no recurrence of CD in this patient, who is alive and doing well, with normal left and right ventricular function, 30 months after TAH insertion and 24 months after HTx. REFERENCES [1] Chagas disease (American trypanosomiasis), Fact sheet No. 340, updated March 2015. In., March 2015 edn: World Health Organization; 2015. Available from http://www.who.int/ mediacentre/factsheets/fs340/en/. Accessed November 28, 2015. [2] Kransdorf EP, Czer LS, Luthringer DJ, Patel JK, Montgomery SP, Velleca A, et al. Heart transplantation for Chagas
CHAGAS CARDIOMYOPATHY cardiomyopathy in the United States. Am J Transplant 2013;13(12): 3262e8. [3] Rassi Jr A, Rassi A, Marin-Neto JA. Chagas disease. Lancet 2010;375(9723):1388e402. [4] Freitas HF, Chizzola PR, Paes AT, Lima AC, Mansur AJ. Risk stratification in a Brazilian hospital-based cohort of 1220 outpatients with heart failure: role of Chagas’ heart disease. Int J Cardiol 2005;102(2):239e47. [5] Chin-Hong PV, Schwartz BS, Bern C, Montgomery SP, Kontak S, Kubak B, et al. Screening and treatment of chagas disease in organ transplant recipients in the United States: recommendations from the chagas in transplant working group. Am J Transplant 2011;11(4):672e80. [6] Arabia FA, Copeland JG, Pavie A, Smith RG. Implantation technique for the CardioWest total artificial heart. Ann Thorac Surg 1999;68(2):698e704. [7] Czer LS, Phan A, Ruzza A, Rafiei M, Setareh-Shenas S, Caceres M, et al. Antithymocyte globulin induction therapy adjusted for immunologic risk after heart transplantation. Transplant Proc 2013;45(6):2393e8. [8] Fiorelli AI, Santos RH, Oliveira Jr JL, Lourenco-Filho DD, Dias RR, Oliveira AS, et al. Heart transplantation in 107 cases of Chagas’ disease. Transplant Proc 2011;43(1):220e4.
281 [9] Bern C, Montgomery SP. An estimate of the burden of Chagas disease in the United States. Clin Infect Dis 2009;49(5): e52e4. [10] Schmunis G. Status of and cost of Chagas disease worldwide. Lancet Infect Dis 2013;13(4):283e4. [11] Moreira LF, Galantier J, Benicio A, Leirner AA, Cestari IA, Stolf NA. Left ventricular circulatory support as bridge to heart transplantation in Chagas’ disease cardiomyopathy. Artif Organs 2007;31(4): 253e8. [12] Morillo CA, Marin-Neto JA, Avezum A, Sosa-Estani S, Rassi Jr A, Rosas F, et al. Randomized trial of Benznidazole for chronic Chagas’ cardiomyopathy. N Engl J Med 2015;373(14): 1295e306. [13] Rojo G, Castillo C, Duaso J, Liempi A, Droguett D, Galanti N, et al. Toxic and therapeutic effects of Nifurtimox and Benznidazol on Trypanosoma cruzi ex vivo infection of human placental chorionic villi explants. Acta Trop 2014;132:112e8. [14] Bern C. Antitrypanosomal therapy for chronic Chagas’ disease. N Engl J Med 2011;364(26):2527e34. [15] Molina I, Gomez i Prat J, Salvador F, Trevino B, Sulleiro E, Serre N, et al. Randomized trial of posaconazole and benznidazole for chronic Chagas’ disease. N Engl J Med 2014;370(20):1899e908.
ABSTRACT Chagas disease (CD) is becoming an increasingly recognized cause of dilated cardiomyopathy outside of Latin America, where it is endemic, due to population shifts and migration. Heart transplantation (HTx) is a therapeutic option for end-stage cardiomyopathy due to CD, but may be considered a relative contraindication due to potential reactivation of the causative organism with immunosuppression therapy. The total artificial heart (TAH) can provide mechanical circulatory support in decompensated patients with severe biventricular dysfunction until the time of HTx, while avoiding immunosuppressive therapy and removing the organ most affected by the causative organism. We report herein a patient with CD and severe biventricular dysfunction, who had mechanical circulatory support with a TAH for more than 6 months, followed by successful orthotopic HTx and treatment with benznidazole for 3 months. The patient had no evidence of recurrent disease in the transplanted heart based on endomyocardial biopsy up to 1 year post-transplantation, and remains alive more than 30 months after insertion of a TAH and 24 months after HTx.
C
HAGAS DISEASE (CD) is a life-threatening disease caused by a tropical parasite, Trypanosoma cruzi. Approximately 7 to 8 million people, mostly in Central and South America, where it is endemic, have CD [1]. Population movements and migration have increased the areas where CD is diagnosed, and these areas now include the United States and Europe [1,2]. Up to 30% to 40% of people develop symptoms, usually within 10 to 30 years after the initial infection [3]. The heart is the most affected organ, causing severe endstage dilated cardiomyopathy leading to heart failure (HF) [3]. Patients with Chagas cardiomyopathy (CC) and HF have a higher mortality compared with other causes of cardiomyopathy [4]. Heart transplantation (HTx) may be considered a relative contraindication in patient with CC and HF due to the risk of reactivation of the causative infectious agent with immunosuppression therapy, thus potentially affecting the outcome of the HTx [5]. We present the first case of total artificial heart (TAH) insertion as a bridge to HTx in a patient with CC and HF. ª 2016 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 48, 279e281 (2016)
CASE REPORT A 53-year-old woman (body surface area [BSA] 1.61 m2) had a dilated cardiomyopathy, HF, ventricular ectopy, prior pacemakercardioverter-defibrillator placement, atrial fibrillation, hypothyroidism, hypertension, hyperlipidemia, and diabetes. The patient was born in a country in Central America where CD was endemic, and immigrated to the United States. She developed decompensated HF. Serologies (immunoglobulin [Ig]G) for T cruzi were positive in July 2011 (>1:512) and October 2012. The patient was referred for evaluation and management of CC, and was admitted for decompensated HF in April 2013. An echocardiogram showed a left ventricular ejection fraction (EF) of 10%e15%, severe tricuspid and mitral valve regurgitation, severe diastolic dysfunction, and a left ventricle end-diastolic diameter of 6.9 cm. Right-sided heart catheterization showed right atrial (RA) No funding was provided for this study. F. Arabia, MD, is a trainer for Syncardia System. The other authors have no conflicts of interest to disclose. *Address correspondence to Lawrence S.C. Czer, MD, Medical Director, Heart Transplantation Program, Cedars-Sinai Heart Institute, 127 S. San Vicente Blvd, Suite A3100, Los Angeles, CA 90048, USA. E-mail: [email protected] 0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2015.12.017
279
280 pressure of 19 mm Hg, right ventricular (RV) pressure of 48/15 mm Hg, pulmonary arterial (PA) pressure of 47/29 mm Hg (mean, 36 mm Hg), and pulmonary capillary wedge (PCW) pressure of 30 mm Hg. Cardiac output (CO) was 4.7 L/min; cardiac index (CI) was 3.1 L/min/m2. The patient was diuresed for volume overload, and after a marked decrease in the CO and CI, she was placed on intravenous dopamine and dobutamine infusions. However, the patient continued to deteriorate hemodynamically. She developed a Klebsiella urinary tract infection and intravenous antibiotic therapy was initiated. Blood cultures were negative. The patient continued to worsen and developed hypotension with cardiogenic shock, requiring the addition of epinephrine. She was brought emergently to the operating room and placed on extra-corporeal membrane oxygenation (ECMO) support in May 2013. After 48 hours, biventricular cardiac function remained severely impaired but end organ perfusion was adequate and no donors were available, so a decision was made to bridge the patient with TAH (Syncardia Inc, Tucson, Ariz, United States) [6] in May 2013. Operative findings included severely depressed biventricular function, thin ventricular walls, and a defibrillator lead perforated through the tricuspid valve posterior leaflet. The pathology of the explanted heart showed myocarditis (diffuse mixed inflammatory infiltrate of eosinophils, plasma cells, lymphocytes, giant cells), left ventricular wall thinning with fibrosis, and an apical aneurysm. No intracytoplasmic parasites (amastigotes) were noted morphologically. Eighteen days after TAH placement, she developed transient left-sided weakness and aphasia. A computed tomography (CT) scan showed a subarachnoid hemorrhage. She gradually had complete resolution and recovery from the neurological symptoms after brief discontinuation of anticoagulation (later resumed). On postimplantation day 79, she was discharged home, fully recovered. A compatible organ donor became available on postimplantation day 197 (November 2013). Postoperative immunosuppressive therapy consisted of triple-drug immunosuppression with tacrolimus, mycophenolate mofetil, and prednisone. Endomyocardial biopsies were performed per protocol [7]. Recovery was uncomplicated, and the patient was extubated on posttransplantation day 1. She was discharged in good condition on post-transplantation day 8. At discharge after HTx, blood pressure was 115/70 mm Hg with heart rate of 95 bpm, RA pressure of 4 mm Hg, RV pressure of 26/6 mm Hg, PA pressure of 26/12 mm Hg (mean, 17 mm Hg), and PCW pressure of 10 mm Hg; CO was 5.48 L/min and CI was 3.51 L/min/m2. Serology (IgG) for T cruzi remained positive on the day of the HTx (November 2013). The patient was monitored with weekly polymerase chain reaction (PCR) for T cruzi after transplantation, and these returned positive in December 2013. Therapy with benznidazole was initiated in late December 2013 and was continued for 3 months. Mycophenolate mofetil was changed to azathioprine (later discontinued due to leukopenia), and prednisone was weaned off. The patient was maintained on tacrolimus monotherapy. The PCR measurements for T cruzi from midJanuary through December 2014 were negative. Endomyocardial biopsies through 1 year post-transplantation showed, at most, mild (grade 1R-1A) cellular rejection and no evidence of antibody-mediated rejection [7]. There was no evidence of T cruzi on the post-transplantation biopsy specimens, and there were no intracytoplasmic parasites (amastigotes). Doppler echocardiograms showed normal left and right ventricular function. Renal function was normal. The patient remained alive in November 2015 at 30 months after TAH insertion and 24 months after HTx.
RUZZA, CZER, DE ROBERTIS ET AL
DISCUSSION
CD is a major cause of end-stage cardiomyopathy in Central and South America, and CC is the third leading indication for HTx in Brazil [8]. This cause of cardiomyopathy is having a serious economic impact on the United States, Europe, and other areas outside of Central and South America. In a 2009 publication, it was estimated that there were 300,000 persons with chronic CD in the United States, resulting in 30,000e45,000 cases of CC [9]. The cost of treatment in the United States is estimated to be $900 million annually, which includes hospitalization and medical devices such as pacemakers. The global cost is estimated at $7 billion [10]. HTx is considered to be a relative contraindication in patients with CD, due to potential reactivation of the causative agent with immunosuppressive therapy after HTx, yet HTx is often considered for this endstage cardiomyopathy [5]. Mechanical circulatory support with a left ventricular assist device as a bridge to HTx in CD was previously described by Moreira et al [11]. In contrast, TAH can provide mechanical circulatory support in decompensated HF patients with severe biventricular dysfunction from CC until the time of HTx, avoiding immunosuppressive therapy and potentially allowing treatment of extracardiac CD and parasitemia prior to HTx. Moreover, removal of the organ most affected by the disease process (the heart) as a consequence of TAH insertion, as opposed to insertion of a ventricular assist device, may reduce the infectious burden of the causative organism, T cruzi. In a recent randomized clinical trial, treatment with benznidazole reduced parasitemia but did not prevent progression of chronic CC [12], implying continued worsening of biventricular function if the heart was left in place, as would occur with the placement of a left ventricular assist device. The patient in the present report underwent successful HTx after 197 days (more than 6 months) of mechanical circulatory support with the TAH. Serial PCR determinations for T cruzi were used to detect reactivation of the infection after HTx, whereupon disease-specific therapy with benznidazole [2,12e15] was initiated within 2 months post-transplantation. With modification of the immunosuppressive therapy and continuation of benznidazole, the subsequent PCR determinations were negative, allowing discontinuation of the benznidazole after 3 months. Endomyocardial biopsies up to 1 year after transplantation showed no evidence of T cruzi in the transplanted heart. To date (November 2015), there has been no recurrence of CD in this patient, who is alive and doing well, with normal left and right ventricular function, 30 months after TAH insertion and 24 months after HTx. REFERENCES [1] Chagas disease (American trypanosomiasis), Fact sheet No. 340, updated March 2015. In., March 2015 edn: World Health Organization; 2015. Available from http://www.who.int/ mediacentre/factsheets/fs340/en/. Accessed November 28, 2015. [2] Kransdorf EP, Czer LS, Luthringer DJ, Patel JK, Montgomery SP, Velleca A, et al. Heart transplantation for Chagas
CHAGAS CARDIOMYOPATHY cardiomyopathy in the United States. Am J Transplant 2013;13(12): 3262e8. [3] Rassi Jr A, Rassi A, Marin-Neto JA. Chagas disease. Lancet 2010;375(9723):1388e402. [4] Freitas HF, Chizzola PR, Paes AT, Lima AC, Mansur AJ. Risk stratification in a Brazilian hospital-based cohort of 1220 outpatients with heart failure: role of Chagas’ heart disease. Int J Cardiol 2005;102(2):239e47. [5] Chin-Hong PV, Schwartz BS, Bern C, Montgomery SP, Kontak S, Kubak B, et al. Screening and treatment of chagas disease in organ transplant recipients in the United States: recommendations from the chagas in transplant working group. Am J Transplant 2011;11(4):672e80. [6] Arabia FA, Copeland JG, Pavie A, Smith RG. Implantation technique for the CardioWest total artificial heart. Ann Thorac Surg 1999;68(2):698e704. [7] Czer LS, Phan A, Ruzza A, Rafiei M, Setareh-Shenas S, Caceres M, et al. Antithymocyte globulin induction therapy adjusted for immunologic risk after heart transplantation. Transplant Proc 2013;45(6):2393e8. [8] Fiorelli AI, Santos RH, Oliveira Jr JL, Lourenco-Filho DD, Dias RR, Oliveira AS, et al. Heart transplantation in 107 cases of Chagas’ disease. Transplant Proc 2011;43(1):220e4.
281 [9] Bern C, Montgomery SP. An estimate of the burden of Chagas disease in the United States. Clin Infect Dis 2009;49(5): e52e4. [10] Schmunis G. Status of and cost of Chagas disease worldwide. Lancet Infect Dis 2013;13(4):283e4. [11] Moreira LF, Galantier J, Benicio A, Leirner AA, Cestari IA, Stolf NA. Left ventricular circulatory support as bridge to heart transplantation in Chagas’ disease cardiomyopathy. Artif Organs 2007;31(4): 253e8. [12] Morillo CA, Marin-Neto JA, Avezum A, Sosa-Estani S, Rassi Jr A, Rosas F, et al. Randomized trial of Benznidazole for chronic Chagas’ cardiomyopathy. N Engl J Med 2015;373(14): 1295e306. [13] Rojo G, Castillo C, Duaso J, Liempi A, Droguett D, Galanti N, et al. Toxic and therapeutic effects of Nifurtimox and Benznidazol on Trypanosoma cruzi ex vivo infection of human placental chorionic villi explants. Acta Trop 2014;132:112e8. [14] Bern C. Antitrypanosomal therapy for chronic Chagas’ disease. N Engl J Med 2011;364(26):2527e34. [15] Molina I, Gomez i Prat J, Salvador F, Trevino B, Sulleiro E, Serre N, et al. Randomized trial of posaconazole and benznidazole for chronic Chagas’ disease. N Engl J Med 2014;370(20):1899e908.
