An Unusually Mild Imported Case of Falciparum Malaria That Was Diagnosed and Successfully Treated during Concurrent Acute Leukemia Chemotherapy in Japan

ABSTRACT.

A 30-year-old Japanese man who traveled to the Republic of Ghana was diagnosed with falciparum malaria while undergoing chemotherapy for acute leukemia in Japan. We considered him to be at high risk of severe disease; however, he showed no signs of severe malaria and was treated with 3 days of oral artemether/lumefantrine. The patient’s medical history may have contributed to the suppression and successful treatment of falciparum malaria without severe complications.

INTRODUCTION

Malaria is nonendemic in Japan, and most cases of falciparum malaria are imported.¹ The incubation period is 9–14 days, and most cases develop within 30 days. Herein, we report a Japanese patient who was undergoing chemotherapy for acute leukemia when he was diagnosed with falciparum malaria outside the incubation period and was successfully treated.

CASE REPORT

A 30-year-old Japanese man had traveled several times since the age of 20 to areas with a high endemic risk of malaria infection but reported no history of suspected malaria infection or prophylactic medication.

He had recently traveled to the Republic of Ghana on business for 47 days without taking malaria prophylaxis. While in Ghana, the patient visited a local doctor because of a chief complaint of epistaxis for 13 days. Acute leukemia was suspected because of a low platelet count and an elevated white blood cell count. Two days later, the patient returned to Japan and was referred to the hematology department of our hospital the next day, where he was diagnosed with T-lymphoblastic leukemia. A blood test revealed leukopenia (Supplemental Table 1).

On the second day of hospitalization, the patient developed a fever of 38.0°C. Thus, a broad-spectrum antibiotic (cefozopran) was initiated. His fever was alleviated the next day. Induction therapy (dexamethasone [days 1–7], prednisolone [days 8–28], vincristine [days 1 and 8], pirarubicin [days 1 and 2], cyclophosphamide [day 3], and L-asparaginase [every other day from day 8 to day 22]) was started on the third day of hospitalization. Fever in the range of 38.0°C occurred several times during induction therapy, but all instances resolved after treatment with cefozopran or meropenem. A bone marrow analysis was performed after induction therapy, but remission was not achieved.

On day 46 of hospitalization, the patient developed a fever of 37.6°C and was started on meropenem. The cause was later discovered to be bacteremia resulting from an Achromobacter xylosoxidans infection. The fever persisted, but the patient’s general condition was good. Consequently, salvage chemotherapy (cytarabine [days 1–6], cyclophosphamide [day 1], and pirarubicin [days 1 and 2]) were initiated on day 58 of hospitalization. Moreover, all fever symptoms had resolved after the third day.

On the 7th day of salvage therapy (64th day of hospitalization), May–Giemsa staining that was performed for a routine blood test incidentally revealed ring forms of intraerythrocytic trophozoites (parasitemia 2.0%) and some gametocytes (Figure 1). Pancytopenia resulting from chemotherapy was also observed; however, there were no other notable findings (Supplemental Table 2). The patient was conscious, and his vital signs were normal. He presented with no fever, headache, or gastrointestinal symptoms. Subsequently, falciparum malaria was diagnosed microscopically, and a nested polymerase chain reaction test confirmed infection with Plasmodium falciparum (P. falciparum). An analysis of the stored samples from previous blood tests revealed 1 or 2 gametocytes and several ring forms of intraerythrocytic trophozoites on one glass slide up to day 37 of hospitalization. These findings were not detected in earlier samples.

Figure 1.

May–Giemsa staining of a thin peripheral blood smear (1,000×).

We observed no signs of severe malaria, such as impaired consciousness, hypotension, acute kidney injury, or bleeding tendency. Additionally, no anemia severe enough to meet the criteria for severe malaria² was observed (Supplemental Table 2). Chemotherapy was interrupted for the administration of treatment with 80 mg artemether and 480 mg lumefantrine twice daily for 3 days. On the second day of treatment, the patient developed a fever of 38.2°C. Thus, meropenem was initiated as a treatment for febrile neutropenia. The parasitemia rate decreased with time, and no intraerythrocytic rings were observed on the fifth day after starting treatment. The patient’s fever resolved on the seventh day after starting treatment. On the 13th day after starting treatment, chemotherapy for T-lymphoblastic leukemia was resumed.

Complete hematologic remission was achieved after chemotherapy. After two courses of consolidation therapy, the patient underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Two months after undergoing allo-HSCT, the patient died because of transplantation associated-thrombotic microangiopathy and steroid refractory acute graft versus host disease.

DISCUSSION

People from nonendemic countries who travel to malaria-endemic countries are at high risk of developing severe falciparum malaria, especially if they do not receive chemoprophylaxis. Despite recent advances in medical technology and facilities, the course of severe cases of imported falciparum malaria can still be relatively rapid and life-threatening.³ In most cases, the lack of prompt and proper diagnosis and treatment leads to death. Furthermore, patients with acute leukemia who are undergoing chemotherapy are at high risk for severe disease resulting from a variety of infections because leukopenia suppresses cellular immunity.⁴ T cells and neutrophils are known to be involved in the defense mechanism against malaria,^5,6 which may also be affected. In the present case, the patient was diagnosed with falciparum malaria during chemotherapy for leukemia >8 weeks after returning to Japan; however, his parasitemia was 2.0%, and he exhibited a good treatment course. The following three reasons may have contributed to the patient’s relatively mild course of infection:

1. Chemotherapy for leukemia may have suppressed the multiplication of P. falciparum.

   L-asparaginase exerts good therapeutic effects against acute lymphoblastic leukemia by depleting L-asparagine. Nagaraj et al.⁷ reported that the treatment of Plasmodium berghei with L-asparaginase inhibited progression to the liver stages and the formation of the sexual stages in vivo. The asparagine content of P. falciparum is higher than that of other malaria species,⁸ indicating that asparagine plays an important role in falciparum malaria. The asparagine content in P. falciparum increases the tendency for protein aggregation, especially at higher temperatures, and is involved in the refolding of asparagine-rich polypeptides via the exported chaperone machinery.⁹ The depletion of asparaginase may have inhibited P. falciparum protein synthesis.

   Doxorubicin, an anthracycline agent like pirarubicin, has been reported to suppress the activity of P. falciparum in vitro by decreasing erythrocyte hemolysis¹⁰ and inhibiting DNA helicase.¹¹

   Vincristine has also been reported to inhibit the activity of P. falciparum in vivo,¹² whereas cyclophosphamide has been reported to inhibit infection by malaria species in mice.¹³

2. The suppression of the inflammatory response to leukemia or chemotherapy for leukemia may have suppressed the activity of P. falciparum. Elevated tumor necrosis factor-α and interleukin-8 have been reported to be positively associated with P. falciparum activity and severity, whereas tumor necrosis factor-β is negatively associated with P. falciparum activity and severity.^14,15

3. The patient may have had antimalarial immunity because of previous infections with P. falciparum during his travels. However, such immunity acquisition usually seems to take time.

CONCLUSION

We reported a case of falciparum malaria with mildly progressing symptoms are detected during chemotherapy for acute leukemia. Falciparum malaria can have an unusual course in patients undergoing chemotherapy for acute leukemia. Additionally, a history of travel to endemic areas, even outside the incubation period, should be considered as a potential source of infection.

Note: Supplemental materials appear at www.ajtmh.org.