Successful Outcome of Treatment of a Disseminated Infection Due to Fusarium dimerum in a Leukemia Patient

Abstract

We report the first case of proven disseminated infection due to Fusarium dimerum associated with a favorable outcome in a patient with acute leukemia and prolonged neutropenia. The patient presented persistent fever, multiple necrotic skin lesions, and bilateral pneumopathy. F. dimerum was first isolated from three blood cultures and then from a skin biopsy and a mouth wash. Microscopy of positive blood cultures showed hyphae with phialides and few curved unicellular and some rare bicellular phialoconidia, permitting immediate presumptive identification of the genus Fusarium. The patient failed to respond to conventional amphotericin B but recovered after treatment was switched to amphotericin B-lipid complex and neutrophil recovery.

Fusarium species are common soil saprophytes and plant pathogens. In humans, several species have been recognized as agents of superficial infections (keratitis, cutaneous infections, onychomycosis, and infection of wounds or burns) (8). In recent years, deep-seated and disseminated infections have been increasingly described in immunocompromised patients, especially in neutropenic patients (3, 8, 16). The prognosis is very poor, and death occurs in up to 70% of the cases despite antifungal therapy (3, 13, 16). The Fusarium species most frequently involved in human infections are Fusarium solani, F. oxysporum and F. moniliforme (8). F. dimerum has been involved in superficial infections (19, 24) but has been involved only rarely in invasive infections (2, 4).

Case report.

A 61-year-old woman was admitted in December 1998 for relapse of acute lymphoblastic leukemia. Sequential induction chemotherapy was started and resulted in prolonged aplasia and severe mucositis. Antibacterial gut decontamination and antifungal prophylaxis with fluconazole (oral suspension; 150 mg/day) were instituted. The patient experienced two episodes of bacteremia that were treated with piperacillin, tazocillin, and vancomycin.

On day 32 of aplasia, the patient became febrile again (38.8°C). She was still severely neutropenic (neutrophil count, 0/μl) despite the administration of granulocyte colony-stimulating factor, and the mucositis had not completely disappeared. A chest X-ray revealed a left basal infiltrate. Three separate blood samples drawn into fungal medium vials (Mycosis-IC/F; Becton Dickinson, New York, N.Y.) grew F. dimerum. Two days later, multiple ecchymotic papules measuring 0.5 to 1 cm in diameter and sensitive to palpation appeared on the right thigh and on the inside of the left knee.

Fluconazole therapy was discontinued, and intravenous amphotericin B therapy (1 mg/kg/day) was initiated. Gomori methenamine silver staining of a skin biopsy showed rare, irregular, hyaline, septate, and 45°-branching hyphae, and culture on Sabouraud's glucose agar at 27°C grew F. dimerum within 5 days. A mouth wash culture also grew F. dimerum. Only one sputum sample could be obtained, and it was culture negative. Bronchoalveolar lavage was not considered. The central venous line was removed, and it was culture negative. The fingernails and toenails were normal.

After 5 days of conventional amphotericin B therapy, blood cultures were negative but the fever persisted (39.8°C). The skin lesions became nodular and necrotic, and new lesions appeared (Fig. 1). Pulmonary infection extended to the left upper lung and to the right lung. Neutropenia persisted (neutrophil count, 150/μl). Conventional amphotericin B was replaced with amphotericin B-lipid complex (ABLC; 5.3 mg/kg/day). After 4 days, the patient recovered from neutropenia (neutrophil count, 610/μl) and became afebrile. The skin lesions regressed slowly and disappeared within 1 month. The pneumopathy transiently worsened concurrently with granulocyte recovery and then gradually improved.

FIG. 1.

Multiple necrotic skin nodules located on both legs.

ABLC therapy was continued for 25 days with a cumulative dose of 7,500 mg (132 mg/kg). Apart from moderate hypokalemia, the treatment was well tolerated. Renal function remained normal (baseline, 76 μmol/liter; final serum creatinine, 51 μmol/liter). The patient was discharged with no sign of infection and in complete hematological remission. The patient suffered from a leukemia relapse 7 months later and again received induction chemotherapy. She experienced no relapse of fusariosis.

Mycological findings.

F. dimerum was first isolated from three blood cultures and then from one skin biopsy and one mouth wash.

Blood cultures were drawn into specific fungal medium vials (Mycosis-IC/F; Becton Dickinson). Fungal growth was detected after 3 days of incubation at 35°C in the Bactec 9240 system (Becton Dickinson). Microscopic examination showed hyaline, septate, branched hyphae with phialides and a few curved unicellular and some rare bicellular phialoconidia, allowing initial presumptive identification of the genus Fusarium (Fig. 2).

FIG. 2.

Microscopy of a positive blood culture showing hyaline, septate, branched hyphae with phialides, phialoconidia, and bicellular curved macroconidia.

A definitive diagnosis of F. dimerum was obtained after subculture on Sabouraud's glucose agar and potato dextrose agar media incubated for 14 days at 27°C. Species identification was based on morphological criteria after subculture. The colonies grew slowly, attaining a diameter of 2 cm after 5 days. The colonies appeared moist and orange with a reverse turning to orange. Microscopic examination showed hyaline septate hyphae with swollen monophialides (10 to 20 by 4 to 5 μm) arising from the mycelium or from simple or occasionally branched short conidiophores. Phialides produced numerous curved hyaline macroconidia (5 to 23 by 2 to 4 μm), mostly one septate and in rare cases two septate (Fig. 3). Microconidia were absent or indistinguishable from the young macroconidia. After 7 days, spherical smooth-walled chlamydospores appeared, mostly intercalate, sometimes terminal.

FIG. 3.

Seven-day-old culture showing typical bicellular curved conidia produced by swollen monophialides.

The F. dimerum strain was tested for antifungal susceptibility by the E-Test (AB Biodisk, Solna, Sweden) method. The MICs of amphotericin B and fluconazole were, respectively, 0.38 μg/ml and greater than 256 μg/ml.

Invasive fusariosis is an increasingly life-threatening complication in patients with hematological malignancies, in hematopoietic stem cell transplant recipients, and, to a lesser extent, in solid-organ transplant recipients (3, 11, 13, 20). Infection usually occurs during profound and prolonged neutropenia. The most frequent species are F. solani, F. oxysporum, and F. moniliforme (3, 8).

Here, we report the first case of a proven disseminated infection due to F. dimerum associated with a favorable outcome. This species is a common agent of keratitis and superficial infections (8, 19, 24). Only two cases of deep infection caused by F. dimerum have been reported, and both were fatal. Camin et al. described a case of endocarditis involving a native aortic valve after coronary artery bypass grafting in an immunocompetent patient (4). Despite valve replacement and combined antifungal therapy with amphotericin B and flucytosine followed by itraconazole, the aortic vegetations recurred and the patient died 8 weeks after surgery. Blood cultures were negative throughout the course of the infection. Austen et al. observed a disseminated infection in an acute lymphoblastic leukemia patient (2). The patient died despite neutrophil recovery and conventional amphotericin B treatment.

Fusarium species are widely present in the environment. It has been suggested that airborne conidia might invade the respiratory tract with primary lung or sinus localization or might be inoculated through a skin disruption such as an indwelling central venous catheter, a wound, or a burn (3). Dissemination from preexisting onychomycosis or gastrointestinal colonization has also been described (3, 11). In our case, the portal of entry remains unclear. The culture of the central venous catheter was negative, and no primary cutaneous lesion or onychomycosis could be demonstrated. We could hypothesize two possible portals of entry. The first is the oropharyngeal mucosa, as the patient experienced severe mucositis and the pathogen was found in a mouth wash fluid culture. The second is the respiratory tract, since pulmonary signs were present at the onset of fever.

In contrast to aspergillosis, disseminated fusariosis is associated with isolation of the fungus in the bloodstream in 50% of cases (3, 10). In our patient, three blood cultures drawn into fungus-specific medium were positive while simultaneous blood samples drawn into bacterial medium remained negative. Moreover, microscopy of the positive blood culture showed hyaline septate branched hyphae with phialides and a few curved unicellular and some rare bicellular phialoconidia that allowed immediate presumptive identification of the genus Fusarium. This confirms the advantage of specific fungal media over standard microbiological media in patients with invasive fungal infections.

The prognosis of invasive fusariosis is poor, with a mortality rate reaching 70 to 80% in disseminated cases (3, 11, 16). Systemic antifungal agents demonstrate poor efficiency in vitro and in vivo (15, 17, 18). Among these agents, amphotericin B seems to have the highest in vitro activity, with about 50% of isolates being susceptible to this drug (11) and MICs for 90% of the strains tested ranging from 1 to 4 μg/ml (15, 17, 18). Unfortunately the correlation between in vitro values and clinical efficacy is low and many patients remain unresponsive to treatment despite in vitro susceptibility. Lipid formulations of amphotericin B seem to be more effective in vivo than conventional amphotericin B, with a response rate of 82% for ABLC in a study of 11 cases of fusariosis, including five disseminated infections (23). Several individual case reports of invasive fusariosis also favor the use of a lipid formulation of amphotericin B (5, 6, 7, 9, 14, 21).

The best prognosis factor remains recovery from neutropenia, as shown by Martino et al. (11). The survival rate was 76% in patients who recovered from neutropenia, as opposed to 6% in patients with persistent neutropenia. The use of hematopoietic growth factors appears to be mandatory in neutropenic patients with invasive fusariosis, as well as for other invasive fungal infections (22).

New azoles, including voriconazole, posaconazole, and ravuconazole, might be promising and provide alternative therapy (22). In vitro studies are encouraging, but the clinical data are insufficient to allow firm conclusions to be drawn (1, 12).

In conclusion, the case we report is remarkable due to the unusual species involved, the successful outcome despite extensive dissemination of the disease, and the immediate presumptive identification of the genus Fusarium due to sporulation of the fungus in blood culture vials.