VISCERAL LEISHMANIASIS (KALA-AZAR) IN TRANSPLANT RECIPIENTS: Case Report and Review

May 27, 1998

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VISCERAL LEISHMANIASIS (KALA-AZAR) IN TRANSPLANT RECIPIENTS CASE REPORT

AND

REVIEW

´ ´ PADILLA,1 MARISA RODR´IGUEZ-FERRERO,3 JUAN BERENGUER,1,2 FRANCISCO GOMEZ -CAMPDERA´ ,3 BELEN 3 3 ´ FERNANDO ANAYA, SANTIAGO MORENO,1 AND FERNANDO VALDERRABANO Servicio de Microbiologı´a Clı´nica y Unidad de Enfermedades Infecciosas and Servicio de Nefrologı´a, Hospital General Universitario “Gregorio Maran˜o´n,” Madrid, Spain

Background. In endemic areas, visceral leishmaniasis has been identified as an opportunistic infection in patients with derangements in their cellular immune system. Methods. We report a renal transplant patient with visceral leishmaniasis. We also reviewed the previously published cases of 17 organ transplant recipients with this parasitic disease. Results. Visceral leishmaniasis occurred a median time of 8 months after transplantation, and the clinical picture was characterized by fever, splenomegaly, and blood cytopenias. Leishmaniae were detected in bone marrow in 16 of 18 patients and diagnostic serology results were found in 8 of 10 tested patients. Pentavalent antimonials were used to treat 16 patients, five of which developed pancreatitis. Five of 18 patients died, including two untreated patients. Relapses of visceral leishmaniasis occurred in 4 of 13 survivors. Conclusions. In endemic areas, visceral leishmaniasis may complicate the clinical course of organ transplantation and can have fatal consequences, particularly when untreated. Visceral leishmaniasis (also known as Kala-Azar) is normally caused by a subspecies of the genus Leishmania donovani, although several other species may occasionally cause this syndrome (1). The full blown clinical picture is characterized by fever, weight loss, organomegaly, blood cytopenias, and hypergammaglobulinemia. It is believed that most of the human infections by L donovani are subclinical because of the protective role of the cell-mediated host-defense mechanisms. Nevertheless, some apparently nonimmunocompromised individuals including children and the malnourished may develop visceral leishmaniasis (2). In the last decade, visceral leishmaniasis has been clearly identified as an opportunistic infection in patients with derangements in their cellular immune system, especially that induced by human immunodeficiency virus infection (3, 4), and less commonly by organ transplantation or malignant diseases (5). The purpose of this article is to report a new case of visceral leishmaniasis complicating the course of organ transplantation and to review the published cases of visceral leishman1 Servicio de Microbiologı´a Clı´nica y Unidad de Enfermedades Infecciosas. 2 Address correspondence to: Dr. Juan Berenguer, Servicio de Microbiologı´a y Unidad de Enfermedades Infecciosas-VIH, Hospital General Universitario “Gregorio Maran˜o´n.” C/Doctor Esquerdo 46, 28007 Madrid, Spain. 3 Servicio de Nefrologı´a.

iasis in organ transplant recipients. We also want to highlight the successful outcome of the infection with liposomal amphotericin B after an episode of pancreatitis secondary to treatment with antimonials. A 63-year-old woman was admitted to our institution in February 1994 complaining of remittent fever and malaise of 3 months duration. In 1990, she received a cadaveric renal graft because of end-stage renal disease. Complications occurring during the first 3 months after transplantation included lymphocele, corticosteroid-sensitive acute rejection, and primary bacteremia by Salmonella enteritidis. The immunosuppression regimen consisted of azathioprine, prednisone (10 mg per day), and cyclosporine. On admission, the temperature was 39°C; physical examination revealed enlargement of liver and spleen (2 cm below the left costal margin). Initial laboratory data revealed a white blood cell count of 2,900/mm3, a hemoglobin concentration of 11 g/dl, and a platelet count of 119,000/mm3. The serum chemistry values, including liver function tests, were within the normal range except for a serum creatinine concentration of 1.5 mg/dl. During the first days after admission, the etiology of the fever remained undiagnosed despite an intensive work-up that included blood and urine cultures for viruses, bacteria, and mycobacteria; viral, bacterial, and fungal serologies; chest x-ray; CT scan of chest, abdomen, and pelvis; and an echocardiographic examination. On the 17th day of hospitalization, a bone marrow aspiration was performed and numerous Leishmania amastigotes were observed. Culture of the bone marrow in a modified Schneider’s Drosophila medium yielded L donovani. Antileishmanial serum titer by an indirect fluorescence method was 1:640. Treatment with intramuscular N-methylglucamine antimoniate (Glucantime, Rhone-Poulenc Farma, Madrid, Spain) was initiated (850 mg of pentavalent antimony per day) and the patient defervesced 2 days later. On the 21st hospital day, the patient developed pneumococcal pneumonia that resolved with antibiotics. On the 23rd hospital day, the serum amylase levels rose to 1302 U/L from a baseline of 100 U/L without abdominal pain and treatment with glucantime was stopped. Therapeutic alternatives considered included conventional amphotericin B, azoles, and lipid formulations of amphotericin B. The first two options were discarded because of potential nephrotoxicity and drug-drug interactions with cyclosporine. Treatment with liposomal amphotericin B (AmBisome, Nexstar Farmace´utica, S. A., Madrid, Spain) at 200 mg per day was initiated. Five days later, the serum amylase levels descended and ultimately reached baseline values. During the third week of liposomal amphotericin B treatment, a catheter-related bacteremia by Pseudomonas

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TABLE 1. Demographics, epidemiology, clinical manifestations, diagnosis, treatment, and outcome of organ transplant recipients with visceral leishmaniasis Patient Age/ (Ref) Sex

Country

Type of Transplantation (Immunosuppression)

Onseta

Clinical Manifestations

Parasitological diagnosis Serology

Treatment

Tolerance

b

Superinfections

Relapses

Outcome

8 yr

Fever, splenomegaly, lethargy, pancitopenia

17 mo

Fever, pancitopenia

18 mo

Fever, leukopenia, thrombopenia

None BM (smear) Other organs: spleen and liver (autopsy) Serology: not reported BM (smear) Antimonials (MA), 10 Serology: positive (titer days not reported) Spleen and liver (autopsy) None Serology: not reported

4 mo

Fever, myalgia, trombopenia

BM (smear) Antimonials (MA) Serology: positive (1:128)

5 mo

Fever, malaise, leukopenia

BM (smear) Serology: positive (1:20)

Antimonials (MA), 2 courses of 10 days

6 yr

Malaise, weight loss, pancytopenia

BM (smear) Serology: not reported

Antimonials (SS)

3 mo

Fever, splenomegaly, pancytopenia

BM (smear) Serology: not reported

Antimonials (MA)

18 mo

Fever, splenomegaly, adenophaty, pancytopenia Fever, hepatosplenomegaly, leucopenia, thrombopenia

BM (smear and culture) Serology: not reported

Antimonials (SS), 3 weeks

BM (smear) Serology: not reported

Antimonials (SS), 4 weeks

Kidney 5 mo (corticosteroids and cyclosporine) Kidney 4 mo (azathioprine, corticosteroids, and cyclosporine)

Fever, splenomegaly, leukopenia, thrombopenia Fever, cough, pancytopenia

Cytomegalovirus disease

12 (17) 50/F Switzerland

Liver 13 mo (azathioprine, corticosteroids, and cyclosporine)

Fever, hepatosplenomegaly, pancytopenia

13 (18) 45/M Spain

Kidney and pancreas 8 mo (azathioprine, corticosteroids, and cyclosporine) Kidney 8 mo (azathioprine, corticosteroids, and cyclosporine)

Fever, splenomegaly, pancytopenia

BM (smear) Antimonials (MA) and Cyclosporine Serology: positive (1:100) allopurinol for 3 induced renal weeks failure BM (smear and culture) Antimonials (SS), 10 BAL, blood mg/kg/day for 20 Serology: positive (titer days not reported) BM (smear and culture) Antimonials (SS) plus Liver biopsy amphotericin B Serology: positive (1:1280) BM (smear) Antimonials (MA), 3 Serology: not reported weeks

Cytomegalovirus disease, tuberculosis

Cured

BM (smear and culture) Negative

Antimonials (SS) 4 Pancreatitis days, then allopurinol plus ketoconazole BM (smear and culture) Antimonials (MA), Pancreatitis Serology: positive (1:640) then liposomal amphotericin B (200 mg/day 3 24 days) BM (smear and culture) Antimonials (MA) and Pancreatitis Serology: positive (titer allopurinol not reported) Liver biopsy Antimonials (MA), 15 Serology: positive (1:128) mg/kg 3 20 days

Escherichia coli urinary tract infection

Cured

Pneumococcal pneumonia, Pseudomonas fluorescens bacteremia (catheter)

Cured

Aspergillus fumigatus and Bramhamella catharralis pneumonia

Died

BM (smear) Serology: not reported

Pseudomonas aeruginosa pneumonia

37/M Australia (travel to Malta)

2 (7)

51/M Belgium Kidney (travel to France) (azathioprine and corticosteroids) 46/M Spain Kidney (azathioprine and corticosteroids) 43/M Spain Kidney (azathioprine and corticosteroids) 23/M Spain Kidney (azathioprine and corticosteroids) 30/M United Kingdom Kidney (azathioprine and corticosteroids) 50/M France Kidney (azathioprine and corticosteroids) 51/M India Kidney (azathioprine, corticosteroids, and cyclosporine) 51/M Spain Kidney (corticosteroids and cyclosporine)

3 (8) 4 (9) 5 (10) 6 (11) 7 (12) 8 (13) 9 (14)

10 (15) 38/M France 11 (16) 51/F Finland (travel to Spain)

14 (19) 30/F Saudi Arabia

Kidney (azathioprine and corticosteroids)

5 mo

Fever, malaise, weight loss, hepatosplenomegaly, anemia, leukopenia Fever, splenomegaly, leukopenia

Kidney 3 yr (azathioprine, corticosteroids, and cyclosporine)

16 (23) 32

Kidney 12 mo (azathioprine, corticosteroids, and cyclosporine) Kidney 12 mo (Not reported)

Fever, malaise, weight loss, hepatosplenomegaly, pancytopenia Fever, splenomegaly, pancytopenia

Kidney 5 mo (azathioprine, corticosteroids, and cyclosporine)

Fever, splenomegaly, leucopenia, anemia, lymphadenopathy, tongue hyperpigmentation

Italy

17 (24) 33/M Iran

18 (25) 40/F India

a b

Died

Enterococcus spp. and Candida tropicalis suppurative phlebitis

Died

Intra-abdominal abscess

Died

Pseudomonas aeruginosa bacteremia

Died Cured

Pancreatitis, arthritis

Antimonials (SS), 10 mg/kg 3 21 days

After transplantation Abbreviations used in table: BAL, bronchoalveolar lavage; BM, bone marrow; MA, N-methylglucamine antimoniate; PR, present report; SS, sodium stibogluconate.

One relapse at 6 mo (antimonials [SS])

Cured Cured

Klebsiella pneumoniae pneumonia

Cured One relapse at 6 mo (antimonials [MA] plus allopurinol) One relapse at 7 mo (amphotericin B)

Cured

Cured Cured

Cured

One relapse at 2 mo (antimonials [MA], 20 mg/kg 3 20 days) One relapse at 9 mo (antimonials [MA] plus allopurinol) One relapse at 3 mo (antimonials [SS], 20 mg/kg 3 30 days)

Cured

Cured

Vol. 65, No. 10

15 (PR)63/F Spain

Pancreatitis

Streptococcal bacteremia, Pseudomonas aeruginosa pneumonia

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fluorescens was documented that responded to removal of the peripheral catheter and antibiotics. The patient completed a 24-day course of liposomal amphotericin B without deterioration of the renal function and without alteration in the cyclosporine serum levels. She was discharged 66 days after admission in good clinical status. After a follow-up of 24 months, she is free of relapses. To identify previously published cases of visceral leishmaniasis in transplant recipients, we performed a computerized search of the MEDLINE data base. The key words used were “Kala-Azar,” “leishmaniasis,” and “transplantation.” To the best of our knowledge, 18 cases of visceral leishmaniasis in transplant recipients (including the case studied in this article) have been reported (6 –19, 20 –22) (see table 1 for data). Of the transplant patients with leishmaniasis, the majority were adult male recipients of renal allografts, and all but one (17) lived or traveled to areas in which visceral leishmaniasis is endemic, including southern Europe, Malta, the Middle East, and India. Six of 18 cases were reported from Spain, a country in which a relatively large number of cases of visceral leishmaniasis have also been reported in persons with infection caused by the human immunodeficiency virus. The clinical manifestations of the parasitic infection started a median time of 8 months after transplantation, with cases ranging from 3 months to 8 years after transplantation. In seven cases, the infection occurred after the first year of transplantation. The dominant manifestations of visceral leishmaniasis were fever, splenomegaly, and some type of blood cytopenia. Superinfections by bacteria, mycobacteria, viruses, or fungi occurred in 11 patients, with fatal consequences in 5 of them. Of note, one patient developed fever, anemia, leucopenia, and interstitial pneumonitis in the fourth month after his second renal transplantation. Leishmaniae were identified in the bronchoalveolar lavage and the patient was treated with intramuscular sodium stibogluconate with rapid recovery (16). Examination of bone marrow smears was the first diagnostic method in 16 patients. Of the remaining patients, one was diagnosed by liver biopsy (21) and the other, with a negative bone marrow smear, was diagnosed postmortem by histopathological examination of the liver and spleen (6). Leishmaniae were recovered from bone marrow cultures in six patients. Significant elevations of antileishmanial serum titers were found in 8 of 10 (75%) tested patients. These figures indicate that the yield of serology may be higher in transplant recipients than in patients with human immunodeficiency virus infection, a population group with a higher degree of immunosuppression in which the diagnostic sensitivity of leishmanial serology ranges between 6% and 25% (3, 4, 23). Pentavalent antimony salts, either N-methylglucamine antimoniate (Glucantime) or sodium stibogluconate (Pentostan), are the drugs of choice for visceral leishmanasis for reasons of cost, availability, efficacy, and familiarity. The effectiveness and toxicity of these two products is similar when used in equivalent antimony doses (24). Alternatives to antimony salts include amphotericin B, pentamidine, azoles, and a combination of antimonial compounds with allopurinol, aminosidine, or interferon-g (25). In this review, 16 patients were treated with pentavalent antimony salts, for periods ranging from 10 days to 4 weeks.

Side effects of pentavalent antimonials were common, particularly pancreatitis, which complicated the clinical course in 5 of the 16 (31.2%) treated patients (7, 11, 19, 20 and in the present report). Pancreatitis was a major contributor to death in one patient (7) and determined a change in treatment in two additional patients. One of them was treated with allopurinol plus ketoconazole (19), and the other one (present report) had a long-lasting cure after a 21-day course of liposomal amphotericin B (AmBisome) at doses of 3 mg/ kg/day. The serum creatinine values in this patient remained unchanged from baseline during the treatment course despite the concurrent administration of cyclosporine, a drug with a known nephrotoxic synergistic potential when administered along with conventional amphotericin B (26). A favorable outcome of recalcitrant or relapsing visceral leishmaniasis in five human immunodeficiency virus-infected patients with the same commercial formulation of liposomal amphotericin has been recently reported, with no significant toxicity (27). Other side effects attributed to antimony compounds were cyclosporine-induced renal failure (15) and palindromic arthropathy with effusions (11). Overall, 5 of 18 (27.7%) patients with visceral leishmaniasis and organ transplantation died, including two untreated patients (6 –9, 20). A superinfection was the immediate cause of death in all the fatalities. Four of 13 survivors (30.7%) suffered a relapse of visceral leishmaniasis at 2, 3, or 6 months after completing anti-leishmanial treatment and were retreated with antimonials with or without allopurinol (11, 14, 21, 22). Two of them had a second relapse: the first patient relapsed 1 month later and was treated with amphotericin B (total dose 2000 mg), remaining free of the infection after a follow up of 6 months (14); and the second one had the relapse 9 months later and was treated with meglumine antimoniate and allopurinol (21). In summary, visceral leishmaniasis should be considered in the differential diagnosis of fever ocurring after the first trimester of organ transplantation in patients living in or traveling to areas in which this parasitic disease is endemic. Bone marrow smears and serology are good diagnostic methods in this population group, although neither of them are 100% sensitive. Pancreatitis is a common complication of treatment with antimony compounds. In this population group, liposomal amphotericin B should be considered a therapeutic alternative due to its reduced nephrotoxicity even in the presence of cyclosporine. The infection can be fatal, particularly when untreated. Relapses may occur months after the completion of apparently effective anti-leishmanial treatment. REFERENCES 1. Pearson RD, De Queiroz Sousa A. Leishmania species: visceral (Kala-Azar), cutaneous, and mucosal leishmaniasis. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases, vol 2. New York: Churchill Livingstone, 1995: 2428. 2. Badaro R, Jones TC, Carvalho EM, et al. New perspectives on a subclinical form of visceral leishmaniasis. J Infect Dis 1986; 154: 1003. 3. Berenguer J, Moreno S, Cercenado E, Bernaldo de Quiro´s JCL, Garcı´a de la Fuente A, Bouza E. Visceral leishmaniasis in patients infected with human immunodeficiency virus (HIV). Ann Intern Med 1989; 111(2): 129.

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Received 28 October 1997. Accepted 4 February 1998.