Transplantation Reviews 28 (2014) 32–35
Contents lists available at ScienceDirect
Transplantation Reviews journal homepage: www.elsevier.com/locate/trre
Visceral leishmaniasis after kidney transplantation: Report of a new case and a review of the literature Myriam Bouchekoua a,⁎, Sonia Trabelsi a, Taieb Ben Abdallah b, Samira Khaled a a b
Parasitology–Mycology Laboratory, Charles Nicolle Hospital, Rue 9 Avril 1938, 1006 Tunis, Tunisia Department of Internal Medecine, Charles Nicolle Hospital, Rue 9 Avril 1938, 1006 Tunis, Tunisia
a b s t r a c t Visceral leishmaniasis (VL) is a parasitic disease, caused by protozoa of the genus Leishmania, transmitted by the phlebotomies sand fly. In the last 20 years, the increasing frequency of organ transplantations and the improvement of associated immunosuppressive treatments have led to the recognition of several cases of VL complicating organ transplantation. Actually, less than 100 cases of VL after kidney transplantation are reported in the literature. In this context, VL is fatal without antileishmanial treatment which constitutes a difficult challenge. We report a case of VL in Tunisian renal transplant recipient treated successfully by liposomal amphotericin B (Ambisome®, Gilead Sciences Inc). Also, we review the epidemiological, clinical, biological and therapeutic aspects of VL associated with renal transplantation reported in the literature. Our report identifies that VL should be suspected in renal transplant recipients presenting unexplained fever, splenomegaly and pancytopeny. It also suggests a serological testing for leishmaniasis in the pre-operative check-up of transplant patients and donors living or traveling in endemic areas of leishmaniasis. Moreover, recipients should be tested regularly for leishmaniasis after transplantation. Liposomal amphotericin B may be considered the treatment of choice of VL, since it has a lower incidence of side effects. © 2014 Elsevier Inc. All rights reserved.
1. Introduction
2. Case report
Visceral leishmaniasis (VL) is a parasitic disease, caused by protozoa of the genus Leishmania, transmitted by the bite of insect vectors, the phlebotomine sand flies. This zoonotic infection is endemic in numerous areas: India, China, East Africa, South America and Mediterranean basin. Since 1985, the prevalence of VL has increased significantly in several countries, mainly in Southern Europe, due to immunosuppression associated with HIV infection [1]. Other immunosuppressive states can occasionally lead to the appearance of clinically overt VL in previously asymptomatic patients, such as neoplasic disease, use of corticosteroids and cytotoxics [2]. In the last 20 years, the increasing frequency of organ transplantations and improvement of the associated immunosuppressive treatments have led to the recognition of several cases of VL complicating organ transplantation [3]. In this context, VL is fatal without antileishmanial treatment which constitutes a difficult challenge. In the present paper, we report a case of VL in Tunisian renal transplant recipient treated successfully by liposomal amphotericin B (Ambisome®, Gilead Sciences Inc). Also, we review the epidemiological, clinical, biological and therapeutic aspects of VL among renal transplant recipients reported in the literature.
Z.A., 29-year-old Caucasian man, with end-stage renal disease whose etiology was not determined, received a kidney allograft in 2008 from a cadaveric donor. He originally came from the North of Tunisia (Tunis), and he has always lived there, before and after transplantation. He was hospitalized 17 months after transplantation, with complaints of high fever, anorexia, asthenia and weight loss of 4 kg. At physical examination, the patient was pale and he had hepatosplenomegaly without lymph node enlargement. The laboratory tests revealed the following data: pancytopenia (hemoglobin 6.7 g/dl, white blood cells 1600/mm 3 with neutropenia 800/mm 3 and lymphopenia 500/mm 3, platelets 90,000/mm 3), serum creatinine 370 μmol/l, C-reactive protein 75 mg/l, albumin 29 g/l and gammaglobulin 6.6 g/l. A bone marrow aspiration showed a huge number of swollen macrophages containing spheroid parasites typical of Leishmania amastigotes (Fig. 1). Leishmania serology by indirect immunofluorescence test (IFI) was positive (titer of Ig 1/200). This serological test was using Leishmania infantum promastigotes as antigen. Retrospectively, the serological testing of stored serum sample collected before transplantation was negative. Serology of the donor was not possible. The patient was treated with Glucantime®, a pentavalent antimonial (Sanofi-Aventis, Paris, France), at 20 mg/kg per day
⁎ Corresponding author. E-mail address: [email protected] (M. Bouchekoua). 0955-470X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.trre.2013.10.007
M. Bouchekoua et al. / Transplantation Reviews 28 (2014) 32–35
endovenously. However, he presented at the seventh day a pancreatitis, the antimonial was stopped. Liposomal amphotericin B (Ambisome®) was initiated at 3 mg/kg per day endovenously for 5 days. The patient became clinically stable with disappearance of fever, rapid improvement in total blood count and disappearance of Leishmania in the bone marrow. Liposomal amphotericin B injection was continued for 5 more weeks (3 mg/kg per week). Since the, there was no evidence of clinical or biological relapse (IFI was negative).
4 3
2 2
33
Spain 18
Southern France
5
Brazil 10 13 12
Italy Greece India other countries
2.1. Discussion and a literature review Fig. 2. Repartition of cases per country.
Visceral leishmaniasis is an endemic parasitic infection due to L. infantum in the Mediterranean area and South America, and to Leishmania donovani in South Asia and East Africa. It mostly affects young children and immunosuppressed individuals, especially HIV patients. Since 1979, when the first report of a renal transplant patient affected by VL appeared in the literature [4], a steady increase of all forms of leishmaniasis has been observed among transplant recipients. This infectious complication in organ transplant requires clinical appraisal for several reasons. Firstly, the number of organ transplantations performed worldwide is ever growing, as well as the frequency of travel to endemic areas for the disease. Furthermore, there is limited knowledge of the infection among clinicians involved in transplant operations. VL is predominantly described with kidney transplantation [5]. This might be related to relative frequency of kidney compared to other organ transplantation. A total of 71 cases of VL are reported in the literature, after kidney transplantations. The other transplanted organs were liver (nine cases), heart (six cases), lung (six cases), bone marrow (one case) and kidney plus pancreas (one case). Generally, it is recognized that VL occurs in transplanted patients who are living in endemic areas. Most patients reported in the literature were from the Mediterranean basin (Fig. 2): Spain (18 cases) [6–12], Southern France (13cases) [3,13–15], Italy (10 cases) [16–20], Greece (5cases) [21,22], Portugal (1case) [23], Turkey (1case) [24] and Malta (1case) [4]. Spain, France and Italy are not only the Mediterranean basin countries with the highest prevalence of leishmaniasis disease, but they have also the highest number of organ donation and transplantations in Europe [5]. The other published
Fig. 1. Bone marrow smear showing intracellular Leishmania parasites.
cases were from Brazil (12 cases) [25,26], India (4cases) [27–30], Saudi Arabia (2 cases) [31,32], and Iran (1case) [33]. Thus, the risk of developing leishmaniasis among transplant recipients is associated with the geographical region in which they and their organ donors reside [4]. However, in several instances, travel to an endemic region following transplantation has been reported in transplant patients from non-endemic areas with leishmaniasis. An example is the case of a Swiss renal transplant recipient who developed VL after vacations in Tunisia and Spain [34]. In Tunisia, two cases are reported [35] (the present paper). Our patient has always lived in an urban area (Tunis) before and after transplantation. VL occurs under an endemic mode and its clinical profile is typical of the Mediterranean infantile form and it presents a public health problem. Moreover, during the last years, the geographic distribution area of VL has increased with spreading of the disease, from the Northern parts of the country to the central and even to the Southern areas [36]. In immunocompetent patients, the disease may occur as late as 30 years after the initial infection [3]. In transplanted patients, the use of corticoids and intensified immunosuppressant to prevent graft rejection may accelerate disease [13,37]. Generally, infection occurs early after the transplantation and the average time is about 8 months [38]. In our case, the patient had a gap of 17 months between transplantation and VL. The clinical signs observed in literature were predominantly irregular fever, hepatomegaly, weight loss and blood cytopenia. Clinical splenomegaly can be absent. These symptoms closely resemble those observed in immunocompetent and HIV-positive patients [39]. In some cases, diarrhea was also an important manifestation [26,27]. However, diagnosis of VL in transplant recipients can be particularly challenging because the disease is frequently concealed by the presence of concomitant opportunistic infections with similar symptoms. In fact, there are published reports of cases of sepsis [10], pulmonary tuberculosis, and human cytomegalovirus disease [10]. In our case, the clinical manifestations were typical (hepatosplemegaly, fever). The most frequent biological abnormality is leucopenia with neutropenia followed by anemia and thrombocytopenia. The bone marrow aspiration followed by direct microscopic examination is the most frequently used diagnostic procedures for confirmation of VL. In single cases, the diagnosis was achieved only after liver biopsy [33] or spleen biopsy, which has a higher sensibility than bone marrow aspiration [27]. Leishmania serology was found positive in the majority of cases reported in the literature. This is in sharp contrasts with the results found in HIV-LV co-infection, where diagnostic sensitivity is much lower. Several serological methods are developed for the diagnosis of the disease with differences in term of sensitivity and specificity. IFI is the reference technique, using promastigotes as antigen but it requires fluorescence microscope. ELISA is used as a potential serodiagnostic tool for almost all infectious diseases, including leishmaniasis. This technique is highly sensitive, but its specificity depends on the antigen used. Several antigens have been tried. The
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M. Bouchekoua et al. / Transplantation Reviews 28 (2014) 32–35
commonly used antigen is a crude soluble antigen (CSA) but the use of a 36-kDa glycoprotein present throughout the life cycle (amastigote and promastigote stages) has given good results (sensitivity of 100% and specificity of 96%) [40]. Western blotting, using promastigotes of L. donovani/L. infantum as antigen is a highly specific test. However, the process is time-consuming, technically cumbersome, and expansive. It is using to confirm other tests such as IFI or ELISA. The testing of k-39 antigen was performed in four cases and it was positive in three of these. In one case, it was the only test capable of establishing the diagnosis [26]. In an evaluation of the performance of using the recombinant k-39 antigen in the diagnosis of VL in Brazil, the sensitivity and the specificity were found to be 90% and 100%, respectively [41]. Leishmania PCR was almost positive in all cases when it is performed. Notably, in two of these cases, molecular amplification was the only positive method used (both from blood and bone marrow) for establishing the diagnosis [5]. Lachaud et al. [42] and Gatti et al. [43] confirm the high sensitivity of PCR for the diagnosis of VL in a limited number of patients. In addition to its unrivalled sensitivity, which is already demonstrated in both immunocompetent and HIV-infected patients, PCR offers the advantage of achieving a non-invasive diagnosis of the disease through the use of peripheral blood as template. Furthermore, quantitative PCR assays allow the in vivo measurement of the blood parasite load, which is a useful surrogate marker of disease activity, response to specific therapy, and monitoring of disease recurrence. For these reasons, quantitative PCR should be recommended as the method of choice for the diagnosis and follow-up of VL in transplant recipients. In our case, the diagnosis was based on direct detection of the parasite in bone marrow smears and the serology. The diagnosis of VL in a transplant patient raises the question of the time of Leishmania infection in relation to the organ transplantation. There are three main possibilities, leading to different subsequent prophylaxis measures. The first possibility is that the donor has undiagnosed VL and infects the recipient. Even in hypo-endemic areas (southern Europe for example), it is now recognized that asymptomatic infection is much more frequent than patent cases. Moreover, the geographical origin of the donor is not always a valid criterion, as travel is possible, and infection can occur even during a short stay in an endemic area [4]. Transmission by blood transfusion, while unusual, cannot be excluded [44]. In general, donors should be tested serologically [16]. In our case, unfortunately, the serology was not possible because the transplant came from an anonymous cadaveric donor. In the second eventuality, the recipient is already infected with Leishmania when transplanted. The number of asymptomatic cases in endemic countries has led to the recommendation of including a routine serological testing for leishmaniasis in the pre-operative check-up of transplant patients. After transplantation, the appearance of a fever, particularly if associated with a decrease in one or more blood cell lines, is highly suggestive of VL. In the third eventuality, the recipient is infected by Leishmania after transplantation. This is possible for transplant patients living in endemic countries. The immunosuppressive treatment enhances their susceptibility to infectious agents. In our case, this hypothesis could be possible, since the serology was negative before transplantation. It is recommended that transplant patients living or traveling in endemic areas should be tested regularly for leishmaniasis [16]. Annual antileishmanial serology carried out in December should be sufficient to detect the new cases appearing after the transmission season which takes place during the summer in the Mediterranean countries with temperate climates such as Tunisia [16]. Without adequate treatment, VL in transplant recipient is fatal. However, the treatment in immunocompromised patients is an unresolved question. For more than 60 years, pentavalent antimonial compounds (meglumine antimoniate and sodium stibogluconate)
given intravenously or intramuscularly for 28 consecutive days have been the treatment of choice for VL [45]. Pentavalent antimonials have established toxic effects on the heart, liver, pancreas, and kidney. Additionally, possible additive side effects with immunosuppressive drugs should be considered. For example, azathioprine may cause pancreatitis, reversible hepatitis, rash, and gastrointestinal disturbances, raising the issues of cumulative toxicities. Moreover, antimonials are mainly excreted by the kidney and dose adjustments are recommended when the glomerular filtration rate is lower than 15 ml/min [46]. Amphotericin B is used in treatment of VL, but it has renal and hematologic toxicity. Liposomal amphotericin B is superior over pentavalent antimonials in terms of toxicity, ease of administration and time spent in hospital but it is much more expensive [47]. In fact, the liposomal form of amphotericin B is the first drug that has been approved by the US Food and Drug administration for the treatment of VL [48,49] and it has been established as the first-line drug in view of its tolerability and short course of treatment [50,51]. Miltefosine is a new oral drug recently registered for the treatment of VL in India and Germany and for cutaneous leishmaniasis and VL in Colombia, but, to our knowledge, it has not yet been used in transplant patients [52]. However, the follow-up of transplant patients is necessary because relapses are not exceptional. Relapses were documented in a limited number of reports and generally cover a period of less than 24 months [4,26,35] with only few studies covering a more prolonged period of post-therapeutic observation. In patients living in Leishmania-endemic areas, it may be difficult to determine whether clinical relapses of VL are caused by reactivation of the same parasite strain or by multiple reinfection episodes, particularly when the relapse occurs after a protracted period of time from the initial episode. 3. Conclusions Visceral leishmaniasis should be considered in the differential diagnosis of fever and/or pancytopenia occurring after organ transplantation in patients living in endemic areas or returning from endemic countries. VL may be caused by ex novo sand fly transmission, reactivation of latent infection, or transmission via an infected allograft or blood transfusion. The number of asymptomatic cases in endemic countries has led to the recommendation of including a routine serological testing for leishmaniasis in the preoperative check-up of transplant patients and donors. Moreover, transplant patients living or traveling in endemic areas should be tested regularly for leishmaniasis, at least one annual serology after the leishmanial transmission season, in order to identify a group of patients who could benefit from preemptive anti-Leishmania therapy. The combination of these simple measures should lead in the future to a decrease in the frequency of VL occurring in transplant patients. Liposomal amphotericin B is presently the treatment of choice to VL in renal transplants. No conflict of interest. References [1] Desjeux P, Alvar J. Leishmania/HIV co-infection: epidemiology in Europe. Ann Trop Med Parasitol 2002;97:3-15. [2] Dedet JP, Pratlong F, Ripert C. Epidémiologie des Maladies Parasitaires Opportunistes. Ed Méd Int 2003;3:221-41. [3] Basset D, Faraut F, Marty P, et al. Visceral leishmaniasis in organ transplant recipients: 11 new cases and a review of the literature. Microbes Infect 2005;7: 1370-5. [4] Ma DD, Concannon AJ, Hayes J. Fatal leishmaniasis in renal transplant patient. Lancet 1979;2:311-2. [5] Antinori S, Cascio A, Parravicini C, Bianchi R, Corbellino M. Leishmaniasis among organ transplant recipients. Lancet Infect Dis 2008;8:191-9. [6] Aguado JM, Bonnet F, Plaza JJ, Escudero A. Visceral leishmaniasis in renal transplant recipient. J Infect 1986;133:01-303.
M. Bouchekoua et al. / Transplantation Reviews 28 (2014) 32–35 [7] Rousaud F, Sola R, Oliver A, Ayats R, Del Rio G. Recaida de leishmaniasis visceral tras terapia inmunosupresora antirrechazo en un paciente trasplantado de riñon. Buena evolution a largo plazo. Nefrologia 1991;11:72-4. [8] Orofino L, Marcen R, Gamez C, et al. Visceral leishmaniasis in renal transplant patients. Nephrol Dial Transplant 1992;7:71. [9] Jokipii L, Salmela K, Saha H, et al. Leishmaniasis diagnosed from bronchoalveolar lavage. Scand J Infect Dis 1992;24:677-81. [10] Torregrosa JV, Ricart MJ, Montesinos M, Campistol JM, Moreno A, Claramonte X. Visceral leishmaniasis-like cause of unexplained fever in a reno-pancreatic graft recipient. Nephron 1993;65:318-9. [11] Berenguer J, Gomez-Campdera F, Padilla B, et al. Visceral leishmaniasis (kalaazar) in transplant recipients: case report and review. Transplant 1998;65:1401-4. [12] Hernandez-Perez J, Yebra-Bango M, Jimenez-Martinez E, et al. Visceral leishmaniasis (Kala-azar) in solid organ transplantation: report of five cases and review. Clin Infect Dis 1999;29:918-21. [13] Brokaert-Van Orshoven A, Michielsen P, Vandepitte J. Fatal leishmaniasis in renal transplant patient. Lancet 1979;2:740-1. [14] Moulin B, Ollier J, Bouchouareb D, Purgus R, Olmer M. Leishmaniasis: a rare case of unexplained fever in a renal graft recipient. Nephron 1992;60:360-2. [15] Dunan S, Mary C, Gambarelli F, et al. Quatre observations de leishmaniose viscérale chez des greffés du rein. Considérations pathogéniques et thérapeutiques. Med Mal Infect 1993;23:297-301. [16] Moroni G, Bossi L. Don't forget visceral leishmaniasis in transplant patients. Nephrol Dial Transplant 1995;10:563-4. [17] Sabbatini M, Pisani A, Ragosta A, Gallo R, Borrelli F, Cianciaruso B. Visceral leishmaniasis in renal transplant recipients: is it a challenge to the nephrologist? Transplant 2002;73:299-301. [18] Veroux M, Corona D, Giuffrida G, et al. Visceral leishmaniasis in the early posttransplant period after kidney transplantation: clinical features and therapeutic management. Transpl Infect Dis 2010 Oct;12:387-91. [19] Postorino MC, Bellantoni M, Catalano C, et al. Visceral leishmaniasis reactivation in transplant patients: a minireview with report of new case. J Nephrol 2011 Jul;24: 530-4. [20] Simon I, Wissing KM, Del Marmol V, et al. Recurrent leishmaniasis in kidney transplant recipients: report of 2 cases and systematic review of the literature. Transpl Infect Dis 2011;13:397-406. [21] Boletis JN, Pefanis A, Stathakis C, Helioti H, Kostakis A, Giamarellou H. Visceral leishmaniasis in renal transplant recipients: successful treatment with liposomal amphotericin B (AmBisome). Clin Infect Dis 1999;28:1308-9. [22] Sipsas NV, Boletis J. Fever, hepatomegaly and pancytopenia in a renal transplant recipient. Transpl Infect Dis 2003;5:47-52. [23] Le Cacheux P, Hurault de Ligny B, Reman O, Ryckelynck JP. Leishmaniose viscérale d'évolution favorable chez un transplanté rénal. Rev Med Interna 1990;11:250-1. [24] Zümrütdal A, Erken E, Turunç T, et al. Delayed and overlooked diagnosis of an unusual opportunistic infection in a renal transplant recipient: visceral leishmaniasis. Turkiye Parazitol Derg 2010;34:183-5. [25] Oliveira CMC, Oliveira MLMB, Andrade SCA, et al. Visceral leishmaniasis in renal transplant recipients: clinical aspects, diagnostic problems, and response to treatment. Transplant Proc 2008;40:755-60. [26] Oliveira RA, Silva LSV, Carvalho VP, et al. Visceral leishmaniasis after renal transplantation: report of 4 cases in northeastern Brazil. Transpl Infect Dis 2008;10(5):364-8. [27] Kher V, Ghosh AK, Gupta A, Arora P, Dhole TN. Visceral leishmaniasis: an unusual case of fever in renal transplant recipients. Nephrol Dial Transplant 1991;6:736-8. [28] Sharma RK, Jha R, Kumar P, et al. Visceral leishmaniasis in a renal transplant recipient: diagnostic and therapeutic problems. Am J Nephrol 1996;16:358-60.
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[29] Rajaram KG, Sud K, Kohli HS, Gupta KL, Sakhuja V. Visceral leishmaniasis: a rare cause of post-transplant fever and pancytopenia. J Assoc Physicians India 2002;50:979-80. [30] Aleya A, Pranaw J, Kishiore B, Vishwanath S, Ballal S. Rare infection in renal transplant recipient. Indian J Transplant 2011;1:9-45. [31] Halim MA, Alfurayh O, Kalin ME, Dammas S, al Eisa A, Damanhouri G. Successful treatment of visceral leishmaniasis with allopurinol plus ketoconazole in a renal transplant recipient after the occurrence of pancreatitis due to stibogluconate. Clin Infect Dis 1993;16:397-9. [32] Hussein MM, Mooij JM, Roujouleh HM, Hamour AOA, Felemban H. Non-typhoid Salmonella septicemia and visceral leishmaniasis in a renal transplant patient. Transplant 2001;71:479-81. [33] Malek Hosseini SA, Javid R, Salahi H, Nezakatgoo N, Ahmad E, Ghahramani N. A case report of Kala-azar in a kidney transplant patient. Transplant Proc 1995;27:2715. [34] Dettwiler S, Mckee T, Hadaya K, Chappuiss F, Van Delden C. Visceral leishmaniasis in a kidney transplant recipient: parasitic interstitial nephritis, a cause of renal dysfunction. Am J Transplant 2010 June;10:1486-9. [35] Harzallah K, Belhadj R, Jemli B, et al. Visceral leishmaniasis in a renal transplant recipient treated with allopurinol. Saudi J Kidney Dis Transpl 2010;21:105-8. [36] Aoun K, Jeddi F, Amri F, Ghrab J, Bouratbine A. Actualités épidémiologiques de la leishmaniose viscérale en Tunisie. Med Mal Infect 2009;39:775-9. [37] Aguado JM, Bonet F, Plazza J, Escudero A. Visceral leishmaniasis in a renal transplant patient: a diagnostic and therapeutic challenge. Clin Transplant 1986;135. [38] Sabbatini M, Pisani A, Ragosta A, et al. Visceral leishmaniasis in renal transplant recipients: is it still a challenge to the nephrologist? Transplantation 2002;73:299. [39] Pintado V, Martin-Rabadan P, Rivera ML, Moreno S, Bouza E. Visceral leishmaniasis in human immunodeficiency virus (HIV)-infected and non-HIV-infected patients. Medicine 2001;80:54-73. [40] Shyam S, Rai M. Laboratory diagnosis of visceral leishmaniasis. Clin Diagn Immunol 2002;9:951-8. [41] Carvalho SF, Lemos EM, Corey R, et al. Performance of recombinant k-39 antigen in the diagnosis of Brazilian leishmaniasis. Am J Trop Med Hyg 2003;68:321-4. [42] Lachaud L, Dereure J, Chabbert E, et al. Optimized PCR using patient blood samples for diagnosis and follow-up of visceral leishmaniasis, with special reference to AIDS patients. J Clin Microbiol 2000;38:236-40. [43] Gatti S, Gramegna M, Klersy C. Diagnosis of visceral leishmaniasis: the sensitivities and specificities of traditional methods and a nested PCR assay. Ann Trop Med Parasitol 2004;7:667-76. [44] Kubar J, Quaranta JF, Marty P, Lelievre A, Le Fichoux Y, Aufeuvre JP. Transmission of Leishmania infantum by blood donors. Nat Med 1997;3:368. [45] Goodwin LG. Pentostam (sodium stibogluconate): a 50 year personal reminiscence. Trans R Soc Trop Med Hyg 1995;89:339-41. [46] Buffet P, Deray G, Grogl M. Tolerance and pharmacokinetics of antimony in a patient with renal failure. Nephrol Dial Transplant 1995;10:1477. [47] Gradoni L, Bryceson A, Desjeux P. Treatment of Mediterranean visceral leishmaniasis. Bull World Health Org 1995;73:191. [48] Meyerhoff A. US Food and Drug Administration approval of Ambisome (liposomal amphotericin B) for treatment of visceral leishmaniasis. Clin Infect Dis 1999;28:42-8. [49] Berman JD. US Food and Drug Administration approval of Ambisome (liposomal amphotericin B) for treatment of visceral leishmaniasis. Clin Infect Dis 1999;28:49-51. [50] Gradoni L, Gramiccia M, Scalone A. Visceral leishmaniasis treatment in Italy. Emerg Infect Dis 2003;9:1617-20. [51] Bern C, Adler-Moore J, Berenguer JL. Liposomal amphotericin B for the treatment of visceral leishmaniasis. Clin Infect Dis 2006;43:917-24. [52] Soto J, Soto P. Miltefosine: oral treatment of leishmaniasis. Expert Rev Anti Infect Ther 2006;4:177-85.
Contents lists available at ScienceDirect
Transplantation Reviews journal homepage: www.elsevier.com/locate/trre
Visceral leishmaniasis after kidney transplantation: Report of a new case and a review of the literature Myriam Bouchekoua a,⁎, Sonia Trabelsi a, Taieb Ben Abdallah b, Samira Khaled a a b
Parasitology–Mycology Laboratory, Charles Nicolle Hospital, Rue 9 Avril 1938, 1006 Tunis, Tunisia Department of Internal Medecine, Charles Nicolle Hospital, Rue 9 Avril 1938, 1006 Tunis, Tunisia
a b s t r a c t Visceral leishmaniasis (VL) is a parasitic disease, caused by protozoa of the genus Leishmania, transmitted by the phlebotomies sand fly. In the last 20 years, the increasing frequency of organ transplantations and the improvement of associated immunosuppressive treatments have led to the recognition of several cases of VL complicating organ transplantation. Actually, less than 100 cases of VL after kidney transplantation are reported in the literature. In this context, VL is fatal without antileishmanial treatment which constitutes a difficult challenge. We report a case of VL in Tunisian renal transplant recipient treated successfully by liposomal amphotericin B (Ambisome®, Gilead Sciences Inc). Also, we review the epidemiological, clinical, biological and therapeutic aspects of VL associated with renal transplantation reported in the literature. Our report identifies that VL should be suspected in renal transplant recipients presenting unexplained fever, splenomegaly and pancytopeny. It also suggests a serological testing for leishmaniasis in the pre-operative check-up of transplant patients and donors living or traveling in endemic areas of leishmaniasis. Moreover, recipients should be tested regularly for leishmaniasis after transplantation. Liposomal amphotericin B may be considered the treatment of choice of VL, since it has a lower incidence of side effects. © 2014 Elsevier Inc. All rights reserved.
1. Introduction
2. Case report
Visceral leishmaniasis (VL) is a parasitic disease, caused by protozoa of the genus Leishmania, transmitted by the bite of insect vectors, the phlebotomine sand flies. This zoonotic infection is endemic in numerous areas: India, China, East Africa, South America and Mediterranean basin. Since 1985, the prevalence of VL has increased significantly in several countries, mainly in Southern Europe, due to immunosuppression associated with HIV infection [1]. Other immunosuppressive states can occasionally lead to the appearance of clinically overt VL in previously asymptomatic patients, such as neoplasic disease, use of corticosteroids and cytotoxics [2]. In the last 20 years, the increasing frequency of organ transplantations and improvement of the associated immunosuppressive treatments have led to the recognition of several cases of VL complicating organ transplantation [3]. In this context, VL is fatal without antileishmanial treatment which constitutes a difficult challenge. In the present paper, we report a case of VL in Tunisian renal transplant recipient treated successfully by liposomal amphotericin B (Ambisome®, Gilead Sciences Inc). Also, we review the epidemiological, clinical, biological and therapeutic aspects of VL among renal transplant recipients reported in the literature.
Z.A., 29-year-old Caucasian man, with end-stage renal disease whose etiology was not determined, received a kidney allograft in 2008 from a cadaveric donor. He originally came from the North of Tunisia (Tunis), and he has always lived there, before and after transplantation. He was hospitalized 17 months after transplantation, with complaints of high fever, anorexia, asthenia and weight loss of 4 kg. At physical examination, the patient was pale and he had hepatosplenomegaly without lymph node enlargement. The laboratory tests revealed the following data: pancytopenia (hemoglobin 6.7 g/dl, white blood cells 1600/mm 3 with neutropenia 800/mm 3 and lymphopenia 500/mm 3, platelets 90,000/mm 3), serum creatinine 370 μmol/l, C-reactive protein 75 mg/l, albumin 29 g/l and gammaglobulin 6.6 g/l. A bone marrow aspiration showed a huge number of swollen macrophages containing spheroid parasites typical of Leishmania amastigotes (Fig. 1). Leishmania serology by indirect immunofluorescence test (IFI) was positive (titer of Ig 1/200). This serological test was using Leishmania infantum promastigotes as antigen. Retrospectively, the serological testing of stored serum sample collected before transplantation was negative. Serology of the donor was not possible. The patient was treated with Glucantime®, a pentavalent antimonial (Sanofi-Aventis, Paris, France), at 20 mg/kg per day
⁎ Corresponding author. E-mail address: [email protected] (M. Bouchekoua). 0955-470X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.trre.2013.10.007
M. Bouchekoua et al. / Transplantation Reviews 28 (2014) 32–35
endovenously. However, he presented at the seventh day a pancreatitis, the antimonial was stopped. Liposomal amphotericin B (Ambisome®) was initiated at 3 mg/kg per day endovenously for 5 days. The patient became clinically stable with disappearance of fever, rapid improvement in total blood count and disappearance of Leishmania in the bone marrow. Liposomal amphotericin B injection was continued for 5 more weeks (3 mg/kg per week). Since the, there was no evidence of clinical or biological relapse (IFI was negative).
4 3
2 2
33
Spain 18
Southern France
5
Brazil 10 13 12
Italy Greece India other countries
2.1. Discussion and a literature review Fig. 2. Repartition of cases per country.
Visceral leishmaniasis is an endemic parasitic infection due to L. infantum in the Mediterranean area and South America, and to Leishmania donovani in South Asia and East Africa. It mostly affects young children and immunosuppressed individuals, especially HIV patients. Since 1979, when the first report of a renal transplant patient affected by VL appeared in the literature [4], a steady increase of all forms of leishmaniasis has been observed among transplant recipients. This infectious complication in organ transplant requires clinical appraisal for several reasons. Firstly, the number of organ transplantations performed worldwide is ever growing, as well as the frequency of travel to endemic areas for the disease. Furthermore, there is limited knowledge of the infection among clinicians involved in transplant operations. VL is predominantly described with kidney transplantation [5]. This might be related to relative frequency of kidney compared to other organ transplantation. A total of 71 cases of VL are reported in the literature, after kidney transplantations. The other transplanted organs were liver (nine cases), heart (six cases), lung (six cases), bone marrow (one case) and kidney plus pancreas (one case). Generally, it is recognized that VL occurs in transplanted patients who are living in endemic areas. Most patients reported in the literature were from the Mediterranean basin (Fig. 2): Spain (18 cases) [6–12], Southern France (13cases) [3,13–15], Italy (10 cases) [16–20], Greece (5cases) [21,22], Portugal (1case) [23], Turkey (1case) [24] and Malta (1case) [4]. Spain, France and Italy are not only the Mediterranean basin countries with the highest prevalence of leishmaniasis disease, but they have also the highest number of organ donation and transplantations in Europe [5]. The other published
Fig. 1. Bone marrow smear showing intracellular Leishmania parasites.
cases were from Brazil (12 cases) [25,26], India (4cases) [27–30], Saudi Arabia (2 cases) [31,32], and Iran (1case) [33]. Thus, the risk of developing leishmaniasis among transplant recipients is associated with the geographical region in which they and their organ donors reside [4]. However, in several instances, travel to an endemic region following transplantation has been reported in transplant patients from non-endemic areas with leishmaniasis. An example is the case of a Swiss renal transplant recipient who developed VL after vacations in Tunisia and Spain [34]. In Tunisia, two cases are reported [35] (the present paper). Our patient has always lived in an urban area (Tunis) before and after transplantation. VL occurs under an endemic mode and its clinical profile is typical of the Mediterranean infantile form and it presents a public health problem. Moreover, during the last years, the geographic distribution area of VL has increased with spreading of the disease, from the Northern parts of the country to the central and even to the Southern areas [36]. In immunocompetent patients, the disease may occur as late as 30 years after the initial infection [3]. In transplanted patients, the use of corticoids and intensified immunosuppressant to prevent graft rejection may accelerate disease [13,37]. Generally, infection occurs early after the transplantation and the average time is about 8 months [38]. In our case, the patient had a gap of 17 months between transplantation and VL. The clinical signs observed in literature were predominantly irregular fever, hepatomegaly, weight loss and blood cytopenia. Clinical splenomegaly can be absent. These symptoms closely resemble those observed in immunocompetent and HIV-positive patients [39]. In some cases, diarrhea was also an important manifestation [26,27]. However, diagnosis of VL in transplant recipients can be particularly challenging because the disease is frequently concealed by the presence of concomitant opportunistic infections with similar symptoms. In fact, there are published reports of cases of sepsis [10], pulmonary tuberculosis, and human cytomegalovirus disease [10]. In our case, the clinical manifestations were typical (hepatosplemegaly, fever). The most frequent biological abnormality is leucopenia with neutropenia followed by anemia and thrombocytopenia. The bone marrow aspiration followed by direct microscopic examination is the most frequently used diagnostic procedures for confirmation of VL. In single cases, the diagnosis was achieved only after liver biopsy [33] or spleen biopsy, which has a higher sensibility than bone marrow aspiration [27]. Leishmania serology was found positive in the majority of cases reported in the literature. This is in sharp contrasts with the results found in HIV-LV co-infection, where diagnostic sensitivity is much lower. Several serological methods are developed for the diagnosis of the disease with differences in term of sensitivity and specificity. IFI is the reference technique, using promastigotes as antigen but it requires fluorescence microscope. ELISA is used as a potential serodiagnostic tool for almost all infectious diseases, including leishmaniasis. This technique is highly sensitive, but its specificity depends on the antigen used. Several antigens have been tried. The
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commonly used antigen is a crude soluble antigen (CSA) but the use of a 36-kDa glycoprotein present throughout the life cycle (amastigote and promastigote stages) has given good results (sensitivity of 100% and specificity of 96%) [40]. Western blotting, using promastigotes of L. donovani/L. infantum as antigen is a highly specific test. However, the process is time-consuming, technically cumbersome, and expansive. It is using to confirm other tests such as IFI or ELISA. The testing of k-39 antigen was performed in four cases and it was positive in three of these. In one case, it was the only test capable of establishing the diagnosis [26]. In an evaluation of the performance of using the recombinant k-39 antigen in the diagnosis of VL in Brazil, the sensitivity and the specificity were found to be 90% and 100%, respectively [41]. Leishmania PCR was almost positive in all cases when it is performed. Notably, in two of these cases, molecular amplification was the only positive method used (both from blood and bone marrow) for establishing the diagnosis [5]. Lachaud et al. [42] and Gatti et al. [43] confirm the high sensitivity of PCR for the diagnosis of VL in a limited number of patients. In addition to its unrivalled sensitivity, which is already demonstrated in both immunocompetent and HIV-infected patients, PCR offers the advantage of achieving a non-invasive diagnosis of the disease through the use of peripheral blood as template. Furthermore, quantitative PCR assays allow the in vivo measurement of the blood parasite load, which is a useful surrogate marker of disease activity, response to specific therapy, and monitoring of disease recurrence. For these reasons, quantitative PCR should be recommended as the method of choice for the diagnosis and follow-up of VL in transplant recipients. In our case, the diagnosis was based on direct detection of the parasite in bone marrow smears and the serology. The diagnosis of VL in a transplant patient raises the question of the time of Leishmania infection in relation to the organ transplantation. There are three main possibilities, leading to different subsequent prophylaxis measures. The first possibility is that the donor has undiagnosed VL and infects the recipient. Even in hypo-endemic areas (southern Europe for example), it is now recognized that asymptomatic infection is much more frequent than patent cases. Moreover, the geographical origin of the donor is not always a valid criterion, as travel is possible, and infection can occur even during a short stay in an endemic area [4]. Transmission by blood transfusion, while unusual, cannot be excluded [44]. In general, donors should be tested serologically [16]. In our case, unfortunately, the serology was not possible because the transplant came from an anonymous cadaveric donor. In the second eventuality, the recipient is already infected with Leishmania when transplanted. The number of asymptomatic cases in endemic countries has led to the recommendation of including a routine serological testing for leishmaniasis in the pre-operative check-up of transplant patients. After transplantation, the appearance of a fever, particularly if associated with a decrease in one or more blood cell lines, is highly suggestive of VL. In the third eventuality, the recipient is infected by Leishmania after transplantation. This is possible for transplant patients living in endemic countries. The immunosuppressive treatment enhances their susceptibility to infectious agents. In our case, this hypothesis could be possible, since the serology was negative before transplantation. It is recommended that transplant patients living or traveling in endemic areas should be tested regularly for leishmaniasis [16]. Annual antileishmanial serology carried out in December should be sufficient to detect the new cases appearing after the transmission season which takes place during the summer in the Mediterranean countries with temperate climates such as Tunisia [16]. Without adequate treatment, VL in transplant recipient is fatal. However, the treatment in immunocompromised patients is an unresolved question. For more than 60 years, pentavalent antimonial compounds (meglumine antimoniate and sodium stibogluconate)
given intravenously or intramuscularly for 28 consecutive days have been the treatment of choice for VL [45]. Pentavalent antimonials have established toxic effects on the heart, liver, pancreas, and kidney. Additionally, possible additive side effects with immunosuppressive drugs should be considered. For example, azathioprine may cause pancreatitis, reversible hepatitis, rash, and gastrointestinal disturbances, raising the issues of cumulative toxicities. Moreover, antimonials are mainly excreted by the kidney and dose adjustments are recommended when the glomerular filtration rate is lower than 15 ml/min [46]. Amphotericin B is used in treatment of VL, but it has renal and hematologic toxicity. Liposomal amphotericin B is superior over pentavalent antimonials in terms of toxicity, ease of administration and time spent in hospital but it is much more expensive [47]. In fact, the liposomal form of amphotericin B is the first drug that has been approved by the US Food and Drug administration for the treatment of VL [48,49] and it has been established as the first-line drug in view of its tolerability and short course of treatment [50,51]. Miltefosine is a new oral drug recently registered for the treatment of VL in India and Germany and for cutaneous leishmaniasis and VL in Colombia, but, to our knowledge, it has not yet been used in transplant patients [52]. However, the follow-up of transplant patients is necessary because relapses are not exceptional. Relapses were documented in a limited number of reports and generally cover a period of less than 24 months [4,26,35] with only few studies covering a more prolonged period of post-therapeutic observation. In patients living in Leishmania-endemic areas, it may be difficult to determine whether clinical relapses of VL are caused by reactivation of the same parasite strain or by multiple reinfection episodes, particularly when the relapse occurs after a protracted period of time from the initial episode. 3. Conclusions Visceral leishmaniasis should be considered in the differential diagnosis of fever and/or pancytopenia occurring after organ transplantation in patients living in endemic areas or returning from endemic countries. VL may be caused by ex novo sand fly transmission, reactivation of latent infection, or transmission via an infected allograft or blood transfusion. The number of asymptomatic cases in endemic countries has led to the recommendation of including a routine serological testing for leishmaniasis in the preoperative check-up of transplant patients and donors. Moreover, transplant patients living or traveling in endemic areas should be tested regularly for leishmaniasis, at least one annual serology after the leishmanial transmission season, in order to identify a group of patients who could benefit from preemptive anti-Leishmania therapy. The combination of these simple measures should lead in the future to a decrease in the frequency of VL occurring in transplant patients. Liposomal amphotericin B is presently the treatment of choice to VL in renal transplants. No conflict of interest. References [1] Desjeux P, Alvar J. Leishmania/HIV co-infection: epidemiology in Europe. Ann Trop Med Parasitol 2002;97:3-15. [2] Dedet JP, Pratlong F, Ripert C. Epidémiologie des Maladies Parasitaires Opportunistes. Ed Méd Int 2003;3:221-41. [3] Basset D, Faraut F, Marty P, et al. Visceral leishmaniasis in organ transplant recipients: 11 new cases and a review of the literature. Microbes Infect 2005;7: 1370-5. [4] Ma DD, Concannon AJ, Hayes J. Fatal leishmaniasis in renal transplant patient. Lancet 1979;2:311-2. [5] Antinori S, Cascio A, Parravicini C, Bianchi R, Corbellino M. Leishmaniasis among organ transplant recipients. Lancet Infect Dis 2008;8:191-9. [6] Aguado JM, Bonnet F, Plaza JJ, Escudero A. Visceral leishmaniasis in renal transplant recipient. J Infect 1986;133:01-303.
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