Introduction
Visceral leishmaniasis had been formerly known as "kalaazar" (black fever) in India. Its pathogen is Leishmania (Leishmania) donovani found in 1900 by William Leishman (1). Now, visceral leishmaniasis is widely distributed in Middle East, East Africa, Europe, South America, Central America and Asia. Over 1 million cases of leishmaniasis and 5,000 deaths are estimated to occur each year. However, it is rare to encounter the disease in Japan, which makes it difficult to make the correct diagnosis. Recently we treated a 30-year-old womanwith a complaint of fever of unknownorigin, whoreturned to Japan from India and the United States (US). This case will be presented herein.
Case Report
A 30-year-old Japanese womanwas admitted to our hospital with a complaint offever of unknownorigin on August 8, 1994. The patient was a graduate student. She was born in the US and brought up in Japan, then moved back to the US at the age of 15. She went to India at the age of 28 to carry out research, and had spent the last 2 and half years in Bangalore, India. Soon after returning to the USon May21, 1994, she started to suffer with chilling fevers of up to 40°C. She was admitted to NewEngland Medical Center in Boston, MAon June 24. Blood examination revealed mild pancytopenia and increased serum lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase and erythrocyte sedimentation rate (Table 1) . Hepatosplenomegaly was found on physical examination and by abdominal computed tomography (CT). An infectious etiology was suspected from herrecent history of a stay in India. But blood cultures and smears yielded no pathogenic microorganisms. All serological studies were negative for viral infections. Underthe suspicion of relapse of tuberculosis, as she had a past history of tuberculosis, empirical antituberculous medication with a four-drug regimenwas started on July 1. Nevertheless, her fever persisted and pancytopenia developed gradually.
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Liver biopsy and bone marrow biopsy revealed a remarkable infiltration ofmonocytesand plasmacells. At this stage, malignant lymphomawas highly suspected, and she went through splenectomy on July 18. But no evidence of malignancy was obtained on pathological examination. Administration of prednisone orally in a dose of 120 mga day was started for a symptomatic relief from July 24. Soon her fever went down and pancytopenia improved (Fig. 1) . She was discharged on August 7. The next day she returned to Japan and was admitted to our hospital to have her condition followed up. Her family history showed nothing in particular. Her past history revealed that she was diagnosed as tuberculous hilar adenopathy at the age of 6, and treated with oral medications. She never smoked, and consumed little alcohol. She had had no blood transfusion. On admission her consciousness was alert. Blood pressure was 1 15/68 mmHg.Body temperature was 36.6°C. Onphysical examination an enlarged liver was felt 2 cmbelow the right Visceral Leishmaniasis Serological studies only revealed past infection of EpsteinBarr virus and toxoplasma as shownin Table 2 , and no other antibodies to viruses, bacteria or parasites were detected. Rheumatoid factor, anti-DNA and anti-nuclear antibodies were negative. Complementswere within normal values. C-reactive protein had been increased to 3.8 mg/dl. Electrocardiogram and abdominal X-ray revealed nothing in particular. Dullness of the left costo-phrenic angle on chest X-ray indicated the presence of pleural effusion. Abdominal and pelvic CT scan showed an enlarged liver, small quantity of ascites and the evidence of splenectomy (Fig. 2) . All blood cultures on admission and those cultured in the US remained negative, and the blood smear was negative for microorganisms including malaria parasites. Then, bone marrow aspiration performed on August 1 5 revealed an infiltration of monocytes, but no evidence of malignancy. Antituberculous medication was discontinued. As the definitive diagnosis of malignant lymphoma was not made, tapering the dose of prednisone wasstarted. On October 3 , when the dose ofprednisone had been reduced to 10 mg a day, chilling fevers reappeared climbing to 39°C with two peaks a day. Serumaspartate aminotransferase wasstarting to increase. Peripheral blood showed progressive leukopenia and absolute monocytosis. Remarkable polyclonal hypergammaglobulinemia was also recognized (Fig. 1) . The patient was administered antibiotics (cefazolin sodium 2 g/day, followed by cefmetazole sodium 2 g/day). On October 17, bone marrow biopsy was performed again, and the smear sample showednumerousmonocytesfilled with rounded bodies (amastigotes) containing a nucleus and a kinetoplast (Fig. 3) . Morphologically and based on the clinical course, they were suspected to be amastigotes of Leishmania (Leishmania) donovani. To confirm the diagnosis, peripheral blood culture on a mediumcontaining humanleukocytes was performed and three days later promastigotes were found moving actively in the medium (Fig. 4) . Thus, the present case was diagnosed as visceral leishmaniasis. Immediately antileishmanial therapy with pentamidine isetionate given intravenously in a dose of 200 mg a day was started on October 19. Three days after the initation of the therapy, her fever went down. Leukopenia and monocytosis also disappeared by the end of November.Pentavalent sodium stibogluconate was additionally given intravenously in a dose of 500 mg a day for 20 days for the prevention of relapse of visceral leishmaniasis Bone marrow biopsy and peripheral blood culture performed on November 21 were negative for amastigotes. By the beginning of December, serum gammaglobulin and liver function tests returned to almost normal values. She was discharged on December 4 with no medication. No relapse has been recognized to date, and she has completed her study in the US and has since returned to Japan.
Discussion
The first case of visceral leishmaniasis in Japan was reported by Endo in 191 1 (2). Since then there have been more than 300 cases reported, most of which occurred in the 1940's because many Japanese stayed in South Asian countries during World War II; there were fewer than 10 cases in the 1980's (3). All of the cases reported in Japan were thought to be infected with the disease in the epidemic areas and then broke out after return to Japan. In the present case, for two and half years the patient lived in Bangalore, which is a city located at a high altitude and where leishmaniasis is rarely found. However, she madea short trip to Calcutta four monthsbefore the onset of fever. Calcutta is knownas an endemic area of visceral leishmaniasis. It is speculated that she wasinfected there. Twostages in the life history ofL. (L.) donovani are known: a rounded or oval-shaped amastigote (2 to 3 jam in length) in mammalianhosts, and a motile, spindle-shaped promastigote with a single flagellum (15 to 25 |im in length) in the sandfly vector. An amastigote is taken up by a sandfly in blood meal from an infected host, then transforms into a promastigote in its midgut. It is inoculated into the victim when the sandfly pricks his skin, transforms into an amastigote and is taken in the reticuloendothelial systems of spleen, liver, bone marrow and so on, then multiples in monocytes or macrophages and destroys them. The incubation period varies from 10 days to a year, but it usually is 2 to 4 months (4). The first symptomconsists of malaise, headache, weakness, weight loss and high-grade intermittent fever. The spleen progressively becomes huge. Hyperpigmentasion is also common(black fever). Peripheral blood shows progressive leukopenia with first relative and later absolute monocytosis, normocytic anemia, and thrombocytopenia. There is a marked increase in serum gammaglobulin due to an elevated IgG fraction (4).
Definitive diagnosis is made by the demonstration of Leishmania parasites in stained smears or biopsies, or in the culture on Novy-MacNeal-Nicolle medium, which contains leukocytes. The drug of choice is pentavalent sodium stibogluconate. Treatment is started with a 200 mg test dose followed by 20 mg/ kg/day, but there is no upper limit on the maximumdaily dose (4). Response to the therapy is usually good. Cure rate is expected to be up to 90% in early treated cases. However, resistance to the agent and relapse are increasing in frequency in many countries. Alternative drugs are pentamidine isetionate, alloprinol and amphotericin B (5-9). Of the untreated cases, 85 to 95%die within a few years. In the present case, pentavalent sodium stibogluconate was not given at first, because it was not available whenthe definitive diagnosis was made. This is a case of visceral leishmaniasis which was misdiagnosed as malignant lymphoma.Fever of unknown origin, hepatosplenomegaly, leukopenia, increased serum lactate dehydrogenase and erythrocyte sedimentation rate and the presentations of liver and bone marrow biopsy might have led the physicians to the misdiagnosis. She went through splenectomy and the administration of prednisone and these treatments might have concealed clinical manifestations such as high grade fever, splenomegaly and hypergammaglobulinemia.
However, despite the improvement of clinical findings, proliferation of leishmania might have been accelerated by humoral and cellular immunosuppression. Imported parasitic diseases such as visceral leishmaniasis are thought to be encountered more frequently in Japan with the increase of Japanese whotravel or live abroad. The present case emphasizes not only the necessity of the knowledgeof imported parasitic diseases, but also the possibility that therapy only aimed at symptomatic relief makes it more difficult to make a definitive diagnosis.

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