Visceral Leishmaniasis Among Liver Transplant Recipients: An Overview

There has been an increase in the incidence of visceral leishmaniasis (VL), especially among hemopoietic and renal transplant recipients.1-3 Remarkably, very few cases have been described among liver transplant recipients. We report a case of VL in a liver transplant recipient and analyze the other 9 cases published in the literature.3-9 A 51-year-old man, who had been splenectomized during childhood, underwent liver transplantation in July 2003 because of end-stage liver disease due to autoimmune hepatic cirrhosis associated with chronic hepatitis B virus infection. Immunosuppression was based on tacrolimus and prednisone and was withdrawn 8 months post-transplantation. He received lamivudine and long-term hepatitis B immune globulin treatment for the prevention of hepatitis B virus reinfection. Liver and renal function were normal. No blood transfusion was required, and he did not experience any episode of rejection. In December 2004, the patient was visited in the outpatient clinic because of the appearance of an enlarged lymph node in the left upper cervical area without fever, weight loss, or dysphonia. A cervical computed tomography scan (Fig. 1) showed multiple enlarged lymph nodes in the left submaxillary, jugular, and supraclavicular regions. A fine needle aspiration biopsy was performed, and cytological extension demonstrated the presence of Leishmania amastigotes (Fig. 2). Blood and cytological aspiration cultures were negative. A bone marrow aspiration was normal. Pretransplantation Leishmania serology was negative in both the donor and recipient. The antileishmanial serum-specific antibody titer (indirect immunofluorescence) was 1/128, human immunodeficiency virus (HIV) tested negative, hepatitis B surface antigen continued to be negative, and no blood cytopenias were observed. A cervical computed tomography scan showed multiple enlarged lymph nodes in the left submaxillary region. Infected macrophages showed intracellular Leishmania (Giemsa staining). Treatment with liposomal amphotericin B (4 mg/kg/day) was given daily for 5 days and once every 7 days subsequently to complete 10 cycles with clinical resolution. After 3 years of follow-up, the infection has not relapsed. BM, bone marrow; D/R, donor/recipient; F, female; HIV, human immunodeficiency virus; IS, immunosuppressants; LAB, liposomal amphotericin B; M, male; pretx, pretransplantation; VL, visceral leishmaniasis. VL is a parasitic disease endemic in the Mediterranean area, India, the Amazon basin, Ethiopia, and Sudan. Asymptomatic infection predominates, and apparent cases occur in only 10% of patients.1, 2 Because specific antibody responses are not protective,10 suppression of the host T cell response (HIV infection, cancer chemotherapy, or immunosuppressant drugs for autoimmune disease or after organ transplantation) conveys a risk of reactivation and development of VL. The parasite is transmitted to humans through the bite of an infected female Phlebotomus fly (or Lutzomyia in America).1 The full-blown clinical picture is characterized by fever, weight loss, organomegaly, blood cytopenias, and hypergammaglobulinemia. Very few cases have been described among liver transplant recipients. We carried out a Medline search using the terms “kala-azar” or “leishmania” and “transplant,” and we found 9 additional cases of VL reported among liver transplant recipients. Clinical and epidemiological characteristics are shown in Table 1. The diagnosis of VL was established by the demonstration of Leishmania amastigotes in tissue samples or by the isolation of promastigotes in a culture predominantly made of bone marrow aspirates. The presence of antibodies against Leishmania was detected in all of the patients, except one, by indirect immunofluorescence. The serological status before transplantation was known for only 2 recipients and 4 donors; testing was negative in all cases. Amphotericin as a unique treatment was used in 7 of 10 patients (70%); antimonial compounds alone were used in 1 patient; antimonial compounds with allopurinol were used in 1 patient; and another patient was treated with a combination of antimonial compounds, ciprofloxacin, and liposomal amphotericin B. All of the patients, except one, recovered, and no relapse was observed. In our institution, more than 800 liver transplant procedures have been performed, and the present case is the first documented case of VL. Among liver transplant recipients, clinical features are different from those of VL among acquired immune deficiency syndrome patients,11 We found less incidence of fever, hepatosplenomegaly, and blood cytopenias. The absence of blood cytopenia in our patient might be explained by the fact that he had been splenectomized. Although VL is very uncommon, it should always be included in the differential diagnosis of patients with fever, pancytopenia, and hepatosplenomegaly.2 Leishmania infection may occur in 1 of 4 ways.2 First, the recipient may be infected via the graft. Second, cases of transfusion-associated VL have been reported.12 Third, a previously infected recipient might reactivate a latent infection.13 Finally, immunosuppressed patients might develop a de novo infection. Knowledge of the serological status of both the donor and recipient before transplantation would be useful in identifying the origin of the infection. In the present case, pretransplantation serology from the donor and recipient was negative, thus suggesting that the infection may have been acquired after the liver transplant. Serological testing has been proposed for leishmaniasis in the preoperative checkup of transplant candidates and their donors under the assumption that parasitemia might occur in asymptomatic Leishmania-seropositive patients with no history of VL.3, 14 Transfusion-transmitted leishmaniasis has also been suggested by the significantly increased prevalence of anti-Leishmania antibodies among polytransfused patients.15 In this setting, deleukocytation of blood products (which eliminates several pathogens, decreases alloimmunization, and improves the well-being of the blood recipient) has been formally accepted in current guidelines. We, like others,16 believe that routine serological screening of organ donors from endemic areas cannot be currently recommended without evidence of transmission of Leishmania spp. through transplanted grafts. In any event, if an available donor or recipient serology is known to be positive, monitoring of the recipient during the posttransplant period (rather than organ rejection) should be recommended. In this review, all of the infected patients, except one, were seropositive at the time of diagnosis of VL. This suggests that, at least in active infection, serological testing has a high diagnostic sensitivity similar to that found in other patient populations, with the exception of HIV-infected patients, among whom sensitivity is lower than 50%.2, 6, 12 It should be taken into account that serology may test positive in individuals from endemic areas because of past exposure in the absence of active infection.17 Finally, confirmation of the parasite in bone marrow or other tissues would provide a definitive diagnosis. Liposomal amphotericin B should be considered the first-line therapy with minimal nephrotoxicity even in the presence of cyclosporine or tacrolimus and absence of relapse after treatment.2 To our knowledge, primary prophylaxis is not used in any center. In contrast to HIV patients in whom it is recommended,2, 18, 19 in liver transplant patients, secondary prophylaxis does not seem to be required according to the experience reported in the literature.