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Visceral Leishmaniasis in Renal Transplant Recipients: Report of 2 Cases
Visceral Leishmaniasis in Renal Transplant Recipients: Report of 2 Cases F. Clavijo Sáncheza,*, T. Vázquez Sánchezb, M. Cabello Díazb, V.E. Sola Moyanob, C. Jironada Gallegob, and D. Hernández Marrerob a Nephrology Department, Torrecárdenas Hospital Complex, Almería, Spain; and bNephrology Department, Regional University Hospital of Málaga, Málaga, Spain
ABSTRACT Visceral leishmaniasis is a disease caused by the protozoan Leishmania and is transmitted by Lutzomyia longipalpis (sand fly). It is an endemic parasitic infection in numerous areas around the Mediterranean basin. Though immunocompetent patients may not develop the disease, in transplant recipients the use of corticoids and intensified immunosuppressants to prevent graft rejection may accelerate the disease, causing severe damage to the liver, spleen, and hematopoietic system. We report 2 cases of visceral leishmaniasis with an atypical presentation in transplant recipients. The first patient, who had a kidney transplant, was treated successfully with liposomal amphotericin B, and the second patient, a combined kidney-pancreas transplant recipient, suffered a relapse 3 years after treatment. Visceral leishmaniasis should be considered in the differential diagnosis of pancytopenia or unexplained fever occurring after organ transplantation in patients living in endemic areas or returning from endemic countries.
V
ISCERAL leishmaniasis (VL) is a parasitic disease caused by an obligate intracellular protozoan of the genus Leishmania. It is transmitted by the phlebotomine Lutzomyia longipalpis (sand fly). The primary hosts are humans and domestic vertebrate animals. VL is an endemic parasitic infection due to Leishmania infantum in the Mediterranean area and South America, and to Leishmania donovani in South Asia and East Africa. This infection reflects dissemination of Leishmania parasites throughout the reticuloendothelial system and is potentially life-threatening without treatment. It is an opportunistic infection in persons with human immunodeficiency virus and acquired immunodeficiency syndrome or other causes of cell-mediated immunosuppression. In the last 20 years, the increasing frequency of organ transplantations and improvement in the associated immunosuppressive treatments have led to the recognition of several cases of VL complicating organ transplantation [1]. Endemic and opportunistic infections such as VL have become a major concern to transplantation teams, because these infections are directly associated with both graft dysfunction and survival of renal transplant recipients. VL has multiple clinical forms, but its diagnosis and therapeutic management are not well established and the risk factors are still poorly defined [2]. ª 2017 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 581e582 (2018)
We report 2 cases of VL in transplant recipients with an atypical presentation. CASE REPORTS Patient 1 A 57-year-old Spanish man with end-stage renal disease due to chronic tubulointerstitial nephritis received a deceased donor kidney transplant in May 2013, receiving immunosuppressive treatment with prednisone, tacrolimus, and mycophenolate mofetil. Two years later he was admitted because of acute diverticulitis. Abdominal computed tomography (CT) showed mesenteric and para-aortic adenopathies. An extended cervical and thoracic CT study showed neck and supraclavicular adenopathies, with no hepatosplenomegaly. The patient was treated with intravenous antibiotics, with a favorable evolution. Because fever persisted after hospital discharge, he was rehospitalized for further study. Tacrolimus and mycophenolate mofetil were suspended and treatment was started with sirolimus due to an initial suspicion of the
*Address correspondence to Fuensanta Clavijo Sánchez, Nephrology Department, Torrecárdenas Hospital Complex, Calle Hermandad de Donantes de Sangre, s/n, 04009 Almería, Spain. Tel: þ34 950016342, Fax: þ34 950016058. E-mail: [email protected] 0041-1345/18 https://doi.org/10.1016/j.transproceed.2017.12.031
581
582 lymphoproliferative syndrome. Blood count was normal. A lymph node biopsy showed Leishmania amastigotes, and a polymerase chain reaction (PCR) test for L donovani complex in peripheral blood was positive. Treatment was started with liposomal amphotericin B (L-AmB) 3 mg/kg per day intravenously for 5 days. The patient became clinically stable and the fever disappeared. Since then, there has been no evidence of clinical or biological relapse. Kidney function is now stable, with a current serum creatinine of 2.1 mg/dL.
Patient 2 A 40-year-old Spanish woman with end-stage renal disease due to diabetic nephropathy started hemodialysis at the age of 23. She received a deceased donor kidney transplant in 1998. A first pancreas transplant in 2004 failed due to donor-specific antibody rejection in 2009. She received a second pancreas allograft in 2011. The immunosuppressive treatment was prednisone, tacrolimus, and mycophenolate mofetil. In June 2014 she was admitted due to an unexplained fever, predominant at night. The laboratory tests showed pancytopenia (hemoglobin 7 g/dL, white blood cells 1600/mm3 with neutropenia and lymphopenia, platelets 95,000/mm3). There was no adenopathy or organomegaly. A bone marrow aspiration showed reactive findings, with no parasites or any other abnormal element. Mycobacteria culture and Quantiferon and Leishmania antigen in urine were all negative. Rickettsia conorii IgG and IgM were positive. Despite treatment with doxycycline, there was no response. A PCR test for Leishmania in peripheral blood was positive, and she started treatment with L-AmB 3 mg/kg per day intravenously for 5 days, with clinical and laboratory test responses. In February 2017 the patient required hospitalization again for high fever and pancytopenia. Given a suspected relapse of VL, treatment was started with L-AmB. A PCR for Leishmania in peripheral blood was later positive. Both kidney and pancreas graft function remained normal throughout both the infective events. Mycophenolate mofetil was suspended due to leukopenia and severity of the infection. It has been recently reintroduced.
DISCUSSION
VL should be considered in the differential diagnosis of unexplained fever and pancytopenia in kidney transplant recipients living in endemic areas or returning from endemic countries, especially in the early post-transplant period [3]. Relapse is defined as the reappearance of clinical manifestations and a secondary diagnosis of VL within 6 months after treatment in patients who had been previously treated and cured. A relapse of VL should always be expected in a kidney transplant patient with a history of leishmaniasis, and such patients should be strictly monitored not only for this potential life-threatening condition but also for the potential role of VL in graft dysfunction and loss [4].
CLAVIJO SÁNCHEZ, VÁZQUEZ SÁNCHEZ, CABELLO DÍAZ ET AL
Certain conditions have been identified, like infection after transplantation (cytomegalovirus, bacterial infections) or pets living in the house (mainly dogs and cats), that increase the risk of VL and relapse in renal transplant recipients living in VL endemic areas [2,5]. Serology for leishmaniasis is not yet a part of the pretransplant evaluation protocol in many transplant centers. We suggest that patients coming from or living in countries endemic for Leishmania should be screened (either by serology or PCR) before undergoing transplantation. Ideally this screening should also be applied to the donor. Liposomal amphotericin B is recommended as the drug of choice for immunosuppressed persons with VL. These patients should be monitored for VL post-treatment relapse for a minimum of 1 year. Confirmed VL therapeutic failure can typically be managed by retreatment using L-AmB at the same or a higher total dose [6]. ACKNOWLEDGMENTS The present study was supported in part by grants from the Instituto de Salud Carlos III cofunded by the Fondo Europeo de Desarrollo RegionaldFEDER (RD16/0009/0006; grant ICI14/00016) from the Spanish Ministry of Economy and Competitiveness. The authors thank the renal transplantation team of Carlos Haya University Regional Hospital for their collaboration. We also thank Ian Johnstone for linguistic assistance in the preparation of the text.
REFERENCES [1] Bouchekoua M, Trabelsi S, Ben Abdallah T, Khaled S. Visceral leishmaniasis after kidney transplantation: report of a new case and a review of the literature. Transplant Rev 2014;28:32e5. [2] Alves da Silva A, Pacheco-Silva A, de Castro Cintra Sesso R, Esmeraldo RM, Costa de Oliveira CM, Fernandes PF, et al. The risk factors for and effects of visceral leishmaniasis in graft and renal transplant recipients. Transplantation 2013;95:721e7. [3] Veroux M, Corona D, Giuffrida G, Cacopardo B, Sinagra N, Tallarita T, et al. Visceral leishmaniasis in the early post-transplant period after kidney transplantation: clinical features and therapeutic management. Transpl Infect Dis 2010;12:387e91. [4] Simon I, Wissing KM, Del Marmol V, Antinori S, Remmelink M, Nilufer Broeders E, et al. Recurrent leishmaniasis in kidney transplant recipients: report of 2 cases and systematic review of the literature. Transpl Infect Dis 2011;13:397e406. [5] Dantas-Torres F. The role of dogs as reservoirs of Leishmania parasites with emphasis on Leishmania (Leishmania) infantum and Leishmania (Viannia) braziliensis. Vet Parasitol 2007;149: 139e46. [6] Aronson N, Herwaldt BL, Libman M, Pearson R, LopezVelez R, Weina P, et al. Diagnosis and treatment of leishmaniasis: clinical practice guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH) (2016). Am J Trop Med Hyg 2017;96: 24e45.
ABSTRACT Visceral leishmaniasis is a disease caused by the protozoan Leishmania and is transmitted by Lutzomyia longipalpis (sand fly). It is an endemic parasitic infection in numerous areas around the Mediterranean basin. Though immunocompetent patients may not develop the disease, in transplant recipients the use of corticoids and intensified immunosuppressants to prevent graft rejection may accelerate the disease, causing severe damage to the liver, spleen, and hematopoietic system. We report 2 cases of visceral leishmaniasis with an atypical presentation in transplant recipients. The first patient, who had a kidney transplant, was treated successfully with liposomal amphotericin B, and the second patient, a combined kidney-pancreas transplant recipient, suffered a relapse 3 years after treatment. Visceral leishmaniasis should be considered in the differential diagnosis of pancytopenia or unexplained fever occurring after organ transplantation in patients living in endemic areas or returning from endemic countries.
V
ISCERAL leishmaniasis (VL) is a parasitic disease caused by an obligate intracellular protozoan of the genus Leishmania. It is transmitted by the phlebotomine Lutzomyia longipalpis (sand fly). The primary hosts are humans and domestic vertebrate animals. VL is an endemic parasitic infection due to Leishmania infantum in the Mediterranean area and South America, and to Leishmania donovani in South Asia and East Africa. This infection reflects dissemination of Leishmania parasites throughout the reticuloendothelial system and is potentially life-threatening without treatment. It is an opportunistic infection in persons with human immunodeficiency virus and acquired immunodeficiency syndrome or other causes of cell-mediated immunosuppression. In the last 20 years, the increasing frequency of organ transplantations and improvement in the associated immunosuppressive treatments have led to the recognition of several cases of VL complicating organ transplantation [1]. Endemic and opportunistic infections such as VL have become a major concern to transplantation teams, because these infections are directly associated with both graft dysfunction and survival of renal transplant recipients. VL has multiple clinical forms, but its diagnosis and therapeutic management are not well established and the risk factors are still poorly defined [2]. ª 2017 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 581e582 (2018)
We report 2 cases of VL in transplant recipients with an atypical presentation. CASE REPORTS Patient 1 A 57-year-old Spanish man with end-stage renal disease due to chronic tubulointerstitial nephritis received a deceased donor kidney transplant in May 2013, receiving immunosuppressive treatment with prednisone, tacrolimus, and mycophenolate mofetil. Two years later he was admitted because of acute diverticulitis. Abdominal computed tomography (CT) showed mesenteric and para-aortic adenopathies. An extended cervical and thoracic CT study showed neck and supraclavicular adenopathies, with no hepatosplenomegaly. The patient was treated with intravenous antibiotics, with a favorable evolution. Because fever persisted after hospital discharge, he was rehospitalized for further study. Tacrolimus and mycophenolate mofetil were suspended and treatment was started with sirolimus due to an initial suspicion of the
*Address correspondence to Fuensanta Clavijo Sánchez, Nephrology Department, Torrecárdenas Hospital Complex, Calle Hermandad de Donantes de Sangre, s/n, 04009 Almería, Spain. Tel: þ34 950016342, Fax: þ34 950016058. E-mail: [email protected] 0041-1345/18 https://doi.org/10.1016/j.transproceed.2017.12.031
581
582 lymphoproliferative syndrome. Blood count was normal. A lymph node biopsy showed Leishmania amastigotes, and a polymerase chain reaction (PCR) test for L donovani complex in peripheral blood was positive. Treatment was started with liposomal amphotericin B (L-AmB) 3 mg/kg per day intravenously for 5 days. The patient became clinically stable and the fever disappeared. Since then, there has been no evidence of clinical or biological relapse. Kidney function is now stable, with a current serum creatinine of 2.1 mg/dL.
Patient 2 A 40-year-old Spanish woman with end-stage renal disease due to diabetic nephropathy started hemodialysis at the age of 23. She received a deceased donor kidney transplant in 1998. A first pancreas transplant in 2004 failed due to donor-specific antibody rejection in 2009. She received a second pancreas allograft in 2011. The immunosuppressive treatment was prednisone, tacrolimus, and mycophenolate mofetil. In June 2014 she was admitted due to an unexplained fever, predominant at night. The laboratory tests showed pancytopenia (hemoglobin 7 g/dL, white blood cells 1600/mm3 with neutropenia and lymphopenia, platelets 95,000/mm3). There was no adenopathy or organomegaly. A bone marrow aspiration showed reactive findings, with no parasites or any other abnormal element. Mycobacteria culture and Quantiferon and Leishmania antigen in urine were all negative. Rickettsia conorii IgG and IgM were positive. Despite treatment with doxycycline, there was no response. A PCR test for Leishmania in peripheral blood was positive, and she started treatment with L-AmB 3 mg/kg per day intravenously for 5 days, with clinical and laboratory test responses. In February 2017 the patient required hospitalization again for high fever and pancytopenia. Given a suspected relapse of VL, treatment was started with L-AmB. A PCR for Leishmania in peripheral blood was later positive. Both kidney and pancreas graft function remained normal throughout both the infective events. Mycophenolate mofetil was suspended due to leukopenia and severity of the infection. It has been recently reintroduced.
DISCUSSION
VL should be considered in the differential diagnosis of unexplained fever and pancytopenia in kidney transplant recipients living in endemic areas or returning from endemic countries, especially in the early post-transplant period [3]. Relapse is defined as the reappearance of clinical manifestations and a secondary diagnosis of VL within 6 months after treatment in patients who had been previously treated and cured. A relapse of VL should always be expected in a kidney transplant patient with a history of leishmaniasis, and such patients should be strictly monitored not only for this potential life-threatening condition but also for the potential role of VL in graft dysfunction and loss [4].
CLAVIJO SÁNCHEZ, VÁZQUEZ SÁNCHEZ, CABELLO DÍAZ ET AL
Certain conditions have been identified, like infection after transplantation (cytomegalovirus, bacterial infections) or pets living in the house (mainly dogs and cats), that increase the risk of VL and relapse in renal transplant recipients living in VL endemic areas [2,5]. Serology for leishmaniasis is not yet a part of the pretransplant evaluation protocol in many transplant centers. We suggest that patients coming from or living in countries endemic for Leishmania should be screened (either by serology or PCR) before undergoing transplantation. Ideally this screening should also be applied to the donor. Liposomal amphotericin B is recommended as the drug of choice for immunosuppressed persons with VL. These patients should be monitored for VL post-treatment relapse for a minimum of 1 year. Confirmed VL therapeutic failure can typically be managed by retreatment using L-AmB at the same or a higher total dose [6]. ACKNOWLEDGMENTS The present study was supported in part by grants from the Instituto de Salud Carlos III cofunded by the Fondo Europeo de Desarrollo RegionaldFEDER (RD16/0009/0006; grant ICI14/00016) from the Spanish Ministry of Economy and Competitiveness. The authors thank the renal transplantation team of Carlos Haya University Regional Hospital for their collaboration. We also thank Ian Johnstone for linguistic assistance in the preparation of the text.
REFERENCES [1] Bouchekoua M, Trabelsi S, Ben Abdallah T, Khaled S. Visceral leishmaniasis after kidney transplantation: report of a new case and a review of the literature. Transplant Rev 2014;28:32e5. [2] Alves da Silva A, Pacheco-Silva A, de Castro Cintra Sesso R, Esmeraldo RM, Costa de Oliveira CM, Fernandes PF, et al. The risk factors for and effects of visceral leishmaniasis in graft and renal transplant recipients. Transplantation 2013;95:721e7. [3] Veroux M, Corona D, Giuffrida G, Cacopardo B, Sinagra N, Tallarita T, et al. Visceral leishmaniasis in the early post-transplant period after kidney transplantation: clinical features and therapeutic management. Transpl Infect Dis 2010;12:387e91. [4] Simon I, Wissing KM, Del Marmol V, Antinori S, Remmelink M, Nilufer Broeders E, et al. Recurrent leishmaniasis in kidney transplant recipients: report of 2 cases and systematic review of the literature. Transpl Infect Dis 2011;13:397e406. [5] Dantas-Torres F. The role of dogs as reservoirs of Leishmania parasites with emphasis on Leishmania (Leishmania) infantum and Leishmania (Viannia) braziliensis. Vet Parasitol 2007;149: 139e46. [6] Aronson N, Herwaldt BL, Libman M, Pearson R, LopezVelez R, Weina P, et al. Diagnosis and treatment of leishmaniasis: clinical practice guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH) (2016). Am J Trop Med Hyg 2017;96: 24e45.