Hepatosplenic Abscess Caused by Curvularia boedijn in a Patient with Acute Monocytic Leukemia

Intensive treatment of leukemia provides opportunities for the development of severe infections, especially in patients with acute nonlymphocytic leukemias.1 Fungal infections are important causes of morbidity and mortality in patients with hematologic malignancies.2 Among fungal infections Candida and Aspergillus species are the most common pathogens. Curvularia fungi are dematiaceous hyphomycetes causing phaeohyphomycoses and rarely cause serious disease in humans. However, several cases of Curvularia acting as a human pathogen have been documented in healthy and immunocompromised patients.3-10 Although six cases of Curvularia infections have been reported in patients with neutropenia,4-6 no case involving a hepatosplenic abscess has been documented in the literature thus far. We report here the case of a patient with an acute monocytic leukemia who developed a hepatosplenic abscess caused by Curvularia boedijn. Case report. A 10-year-old girl was admitted to a hospital with generalized fatigue and a low grade fever. The patient was diagnosed with acute monocytic leukemia by morphologic and histochemical studies. Hematologic remission was achieved with chemotherapy consisting of vincristine (VCR), Adriamycin®, cytosine arabinoside (AraC) and prednisolone. The first bone marrow relapse occurred 18 months after achievement of the first bone marrow remission. At the age of 15 years the patient was first admitted to our hospital on August 19, 1991, with her third bone marrow relapse. On admission the white cell count was 6100/mm3 with 91% blast forms; hemoglobin, 13.3 g/dl; and platelets, 57 000/mm3. Bone marrow aspirates showed a diffuse infiltration with 94% blast cells that reacted with esterase stain but were inhibited by NaF. She was treated with Adriamycin®, VCR, AraC, prednisolone and cyclophosphamide, resulting in her fourth remission. During maintenance treatment with VCR, cyclophosphamide, AraC, Adriamycin®, prednisolone and 6-mercaptopurine, leukemic cells in the patient increased with 12% of the nucleated bone marrow cells consisting of monoblasts. More intensive chemotherapy was instituted, consisting of pirarubicin, VCR and high dose AraC. On July 17, 1992, the patient became febrile during a period of aplasia (WBC, 420/mm3 with 10% neutrophils) resulting from myelotoxicity. The fever did not respond to broad spectrum antibiotics (imipenem 2 g/day intravenously and minocycline 200 mg/day by drip infusion) and antifungal agents (fluconazole 200 mg/day intravenously) or the infusion of immunoglobulin. One month after fever started the patient was still febrile and developed abdominal pain, localized to her left abdomen. Computed tomography revealed multiple abscesses in her liver and spleen (Fig. 1). Although the pathogen of the abscess was unclear, we changed antibiotics from imipenem and minocycline to piperacillin (4 g/day intravenously) and gentamicin (80 mg/day by drip infusion) and latamoxef (4 g/day intravenously) and also changed the antifungal agent from fluconazole to miconazole (400 mg/day drip infusion). The patient's neutropenia had been already improved (neutrophils >500/mm3) when antimicrobial agents were changed. Because the patient had ongoing fevers despite the treatment, aspiration of the liver abscess via a closed surgical procedure was performed. Examination of the purulent aspirate revealed that the cause of the liver abscess was a fungal pathogen. We changed the antifungal infusion therapy from miconazole to amphotericin B (0.28 mg/kg/day initially, increasing to 0.6 mg/kg/day) because of the lack of clinical improvement with miconazole. The general condition of the patient greatly improved after the initiation of amphotericin B therapy with a concomitant improvement in laboratory data (the concentration of C-reactive protein decreased). Follow-up computerized tomography, performed 2 months after the start of the amphotericin B, showed decrease in the size and number of abscesses in her liver and spleen. The pathogen in the aspirate was later identified as C. boedijn(Fig. 2). Susceptibility tests were performed on these isolates. Minimum inhibitory concentrations for C. boedijn were 25.0 μg/ml of amphotericin B, 12.5 μg/ml of miconazole and >100 μg/ml of fluconazole in synthetic amino acid medium. Although the hepatosplenic abscesses diminished in size, a fourth bone marrow relapse occurred during the treatment of the fungal abscess. The patient was again treated with a remission induction regimen (cyclophosphamide, vindesine and AraC) but remission was not achieved. She later developed sepsis (bacteria not isolated) and died of disseminated intravascular coagulation 6 years after the development of leukemia. Discussion. Curvularia sp. is a saprobic dematiaceous mold that resides primarily in soil and is mainly a plant pathogen. Clinical infections with Curvularia sp. are seldom encountered in humans. Among the reported cases of Curvularia infection the sites of involvement have included the lower respiratory system, endocardium, skin and subcutaneous tissue, nose and eyes.7 Those patients were not always immunocompromised but included those with allergic disease or local trauma. There is another small number of patients with neutropenia who have been reported and only three patients with leukemia. The first involved a 47-year-old man with chronic granulocytic leukemia who developed Curvularia infection of the nasal septum.4 Another case occurred in a patient with acute megakaryocytic leukemia who developed pneumonia,6 and the last case involved a patient with acute promyelocytic leukemia who developed sinusitis.10 No documented case of hepatosplenic abscess caused by Curvularia sp. was found on a review of the literature. Our patient had normal serum immunoglobulin concentrations (IgG 1135 mg/dl, IgM 116.5 mg/dl, IgA 40 mg/dl). However, her long term neutropenia (<500/mm3), which lasted for nearly 1 month before the diagnosis of hepatosplenic abscesses, was thought to have been the main risk factor for the development of this condition. The source of her infection is unclear. The liver can be invaded by microorganisms in several ways. Multiple embolic abscesses may originate from foci anywhere in the body via the hepatic artery. Most cases of liver abscess are secondary to generalized septicemia in children, usually originating from pathogens in the oral cavity.11 Although C. boedijn was not isolated from blood cultures in this case, the route of the organism to the liver and spleen was thought to be via the blood stream. Treatment of Curvularia infection is usually with amphotericin B,5, 6, 10 but miconazole,3 itraconazole,2 terbinafine,8 flucytosine and ketoconazole9 also have been used with successful results. In vitro susceptibility studies for Curvularia sp. have been performed in some cases,3, 4, 7 and minimum inhibitory concentrations for both amphotericin B and miconazole were considered to be susceptible, but treatment with miconazole was not clinically effective in this patient. However, the patient was successfully treated with amphotericin B, and the results of an in vitro susceptibility study for C. boedijn seemed to support the clinical improvement. With increasing myelosuppression with present day chemotherapy, Curvularia sp. may be increasingly observed to cause infection in immunocompromised hosts. Masahiko Shigemori, M.D.; Kiyoshi Kawakami, M.D.; Takuma Kitahara, M.D.; Osamu Ijichi, M.D.; Michiyo Mizota, M.D.; Naoaki Ikarimoto, M.D.; Koichiro Miyata, M.D. Department of Pediatrics; Faculty of Medicine; Kagoshima University; Kagoshima, JapanFIG. 1: Computed tomography performed August 26, 1992, revealing multiple abscesses in the liver and spleen.FIG. 2: C. boedijn isolated from the liver abscess. Geniculate macroconidia with transverse septations are visible, typical of the Curvularia species.