First Report of Visceral Leishmaniasis In An Orthotopic Heart Transplant Recipient

Abstract

Visceral leishmaniasis is an opportunistic infection affecting patients with a deficiency in their cellular immune system. We describe the first case of this parasitic disease in a heart transplant recipient reported in the literature. The incubation period usually ranges from weeks to months but can be as long as years, as occurs in this case. The patient presented with typical clinical features including fever, pancytopenia, hepatosplenomegaly, and progressive functional debility. The final diagnosis was made by the observation of amastigotes of Leishmania in bone marrow smears and by the presence of a positive antileishmanial serum titer by ELISA. Liposomal amphotericin B is becoming the first choice of treatment for leishmaniasis in these immunosuppressed patients owing to its effectiveness and reduced side effects. Despite this treatment, our patient developed acute renal failure. We conclude that visceral leishmaniasis should be suspected in heart and other solid organs transplant patients with fever of unknown origin and hematological cytopenias. Visceral leishmaniasis, also known as kala-azar, is an infectious disease caused by obligate intracellular protozoa of the Leishmania species. Disease establishment results from infection of macrophages throughout the mononuclear-phagocyte system. It is endemic in Mediterranean littoral countries where the domestic dog constitutes an important reservoir in urban areas. The clinical course is often insidious because it is conditioned by the cellular immunity status of the host. Thus, processes that favor an immunodeficient state such as human immunodeficiency virus infection, mal- nutrition, antineoplastic chemotherapy, and immunosuppressive treatments can facilitate the development of visceral leishmaniasis (1). Although kala-azar is a well-known complication in kidney and liver transplant recipients, it has not been previously reported, to our knowledge, in heart transplant patients. Case report. In May 1995, a 67-year-old man with dilated cardiomyopathy secondary to chronic alcoholism underwent orthotopic heart transplantation and had an uneventful perioperative course. After the initial immunosuppressive regimen with cyclosporine, corticosteroids, and azathioprine, basal immunosuppression consisted of low-dose prednisone and cyclosporine. The follow-up during 40 months was only complicated by three low-grade rejection episodes not requiring changes in immunosuppressive treatment. In September 1998 he became abruptly worse, reporting a 5-day history of myalgias, asthenia, anorexia, and fever peaking daily at 39°C, with chills and night sweats. On admission, the patient was highly febrile, and physical examination revealed a moderate hepatosplenomegaly and the presence of petechiae and ecchymosis in the extremities. Hematological findings at entrance were as follows: hemoglobin 7.8 g/dL, white blood cell count 1.0×109/L (60% of granulocytes), and platelet count 44×109/L. Serum biochemical determinations, including total proteins and proteinogram, were within the normal range, except for a serum creatinine concentration value of 2.8 mg/dL. Blood and urine cultures performed at this moment were negative. A chest roentgenograph was clear, and the abdominal ultrasonography revealed a slight homogeneous enlargement of both liver and spleen with an increase of the caliber of the portal vein (15 mm). No abdominal lymphadenomegaly was noted. Over the next 7 days, the patient remained febrile despite empirical antimicrobial therapy with cefepime, teicoplanin, fluconazole, and ganciclovir. Aggravation of hematological cytopenias was observed during this time. Serologic tests for cytomegalovirus, herpes simplex virus, Epstein-Barr virus, and Toxoplasma gondii were all negative. A bone marrow aspiration was performed showing a normal cellularity and the presence of intrahistiocytic parasites with the amastigote morphology of Leishmania on stained slides (May-Grünwald-Giemsa) (Fig. 1Figure 1: Bone marrow aspirate smear showing a histiocytic cell filled with parasites (May-Grünwald-Giemsa, original magnification ×1200).). In vitro culture (Novy-MacNeal-Nicole) of bone marrow after 21 days showed abundant Leishmania promastigotes. A test for Leishmania IgG antibody by ELISA was also positive at a 1:68 titer. Due to the high risk of heart and kidney toxicity with pentavalent antimonial agents in this patient, treatment with a liposomal amphotericin B formulation was started at a dose of 3 mg/kg/day. In view of persisting neutropenia, human recombinant granulocyte colony-stimulating factor (G-CSF) 5 μg/kg/day was also started. At the end of the fifth day of therapy (total dose of amphotericin 1 g), the patient developed an acute renal failure that required hemodialysis and cessation of amphotericin B treatment, however, the general status improved and the fever disappeared. Recovery of leukocytes was observed after 5 days of G-CSF administration (white blood cell count 4.4×109/L, with 84% of granulocytes). The patient was discharged and remained without signs of active infection until December 1998, when he presented again with fever, leukopenia (1.0×109/L), and thrombocytopenia (30×109/L). A new bone marrow aspirate showed the persistence of Leishmania amastigotes. Treatment with liposomal amphotericin B at 3 mg/kg/day for 10 days followed by three infusions of the same drug at 210 mg/day × 1 day administered at 7-day intervals was applied, obtaining a good clinical and hematological response. To avoid impairment of renal function, dopamine infusion was administrated during the treatment with amphotericin B. At the moment, the patient maintains a good stable condition and the recovery of hematological counts persists. Discussion. The success of organ transplantation has been possible due to the development of immunosuppressive treatments. Infectious complications are the major cause of morbidity and mortality after solid organ transplantation. In this context, the presence of fever in the first month after the transplantation is usually attributed to bacterial pathogens; however, late infections occurring after the first month and within the first year of transplantation also include parasites, fungi, and viral infections, with Pneumocystis carinii and Toxoplasma gondii the most frequent of the parasitic infections. Development of other parasitic infections, such as visceral leishmaniasis, is less common, but some cases have been reported affecting kidney and liver transplant patients in endemic areas (2). Although forms of cutaneous (3) and mucosal leishmaniasis (4) have been previously described in association with heart transplants, we herein report the first case of visceral leishmaniasis associated with orthotopic cardiac transplantation. Numerous clinical observations have indicated that the normal function of T cell-mediated immunity is essential in protecting and controlling many protozoal infections (5). In addition, experimental studies show that the extent of invasive leishmaniasis and its recurrence depend on the state of cell-mediated immunity. Eradication of amastigotes in kala-azar depends on T helper cell activation by macrophages through the production of cytokines, mainly interferon-γ, or by direct contact. Immunosuppressive treatment used for avoiding transplant rejection acts by inhibiting cellular immunity. Both cyclosporine and corticosteroids are highly selective inhibitors of T-cell function, suppressing the early cellular response to antigenic stimulus and diminishing the production of cytokines (6). Furthermore, corticosteroids have a powerful and unspecific anti-inflammatory response. In our patient, immunosuppressive treatment with cyclosporine and prednisone may have played a role in the development of visceral leishmaniasis. Although clinical features of leishmaniasis constitute a well-recognized picture presenting with fever, weight loss, splenomegaly, pancytopenia, and polyclonal hypergammaglobulinemia, a nonspecific presentation can delay the diagnosis of kala-azar in immunosuppressed patients (2). Frequently, the diagnosis of leishmaniasis is made while studying the origin of unexplained fever in these patients, as occurred in our case. Identification of amastigotes in bone marrow and serologic assays are good diagnostic tools for immunocompromised patients, however, neither of them are 100% sensitive. In this context, some authors have proposed to include serologic assays for Leishmania in the pretransplantation evaluation (8). In this high-risk population, cases of kala-azar have a substantial mortality if not diagnosed soon enough and appropriately treated, so highly effective therapy is essential. Pentavalent antimonial compounds (meglumine antimonate or sodium stibogluconate) alone or in combination with aminosidine or allopurinol are the mainstays of therapy for visceral leishmaniasis. However, secondary effects of these regimens are frequent. The most serious complications include nephrotoxicity, particularly cyclosporine-induced renal failure, cardiotoxicity, and pancreatitis. To avoid this damage, amphotericin B, pentamidine, and interferon-γ have been advocated as alternatives to antimony salts and may have merit in some circumstances (1, 2, 9). In immunosuppressed patients, amphotericin B is becoming the first choice drug for visceral leishmaniasis treatment. Moreover, the liposomal form of this drug is preferred when the patient presents with heart or kidney damage. As both factors were present in our patient, the liposomal form of the drug was used. The recommended dose of liposomal amphotericin B for the treatment of visceral leishmaniasis is 1–1.5 mg/kg/day for 21 days or 3 mg/kg/day for 10 days. With these regimens, patients feel better and become afebrile during the first week of treatment. However, in kala-azar the positive response to treatment is related to the recovery of the immune system, and the T-cell function impaired by the immunosuppressive treatment may take a long time to recover. So, relapse rates are high, mainly in those patients with cell-mediated immunodeficiency (10). Probably, the relapse in the present case was due to the early cessation of the amphotericin treatment because of the complication with an acute renal failure. To avoid this complication, during the treatment with amphotericin because of leishmaniasis recurrence in our patient, renal protection with dopamine infusion was made. Although there is not definitive evidence about the best maintenance regimen to prevent the relapse (11), our patient received a weekly dose of liposomal amphotericin B (3 mg/kg) for a month, with no recurrence a year ago. Visceral leishmaniasis causes pancytopenia in most cases. Neutropenia is a serious problem in immunosuppressed patients because of the risk of intercurrent bacterial infections (2, 7). G-CSF is a hematopoietic growth factor required for proliferation and differentiation of hematopoietic precursors. In this setting, recent reports have considered that G-CSF administration is an adjuvant treatment for infections because of its capacity to recover peripheral blood cell counts and enhance the adherence and phagocytic capacity on neutrophils (12). This approach has improved the evolution in neutropenic infected patients and could also be useful in managing the leukopenia of visceral leishmaniasis, as the present patient supports. We conclude that visceral leishmaniasis should be suspected in heart transplant patients with unexplained fever, cytopenias, and hypergammaglobulinemia, who are living in or travelling to areas in which this parasitic disease is endemic. Liposomal amphotericin B should be considered a therapeutic alternative due to its reduced nephrotoxicity and cardiotoxicity even when simultaneous treatment with cyclosporine is performed. Furthermore, because it is necessary to improve the therapeutic schedules to obtain less relapse rates and less toxicity, the use of G-CSF may result in an earlier recovery of blood cell counts and a better evolution of these patients. Carlos Panizo1 Pablo Rodríguez-Wilhelmi1 Virginia González-Toda2 Braulia Cuesta1 Gregorio Rábago2 Eduardo Rocha13