Disseminated Fusariosis in a Pediatric Patient With Acute Lymphoblastic Leukemia

To the Editors: Invasive fungal infections (IFI) are a significant cause of morbidity and mortality in immunocompromised patients. The fungal agents other than Aspergillus spp. account for 10%–25% of all invasive fungal diseases following hematologic malignancies or hematopoietic stem cell transplantation, and this incidence is increasing. This increase is likely associated with the rise in the number of patients undergoing treatment for hematologic malignancies or following hematopoietic stem cell transplantation, new cancer therapies leading to prolonged and deep immunosuppression, and the increasing use of broad-spectrum antifungal prophylaxis, which causes selective pressure.1,2Fusarium spp. are hyaline molds that are predominantly found in soil. It is one of the leading fungal infections that can cause multiorgan involvement and high mortality. Patients with hematologic malignancies most frequently experience cases during induction chemotherapy.3,4 In 68%–91% of fusariosis cases, cutaneous lesions have been reported, which are generally painful, erythematous, papular or nodular. In some patients, these lesions may appear as target lesions and can present with central necrotic areas resembling ecthyma gangrenosum.5,6 Here, we present a case of a child with acute lymphoblastic leukemia (ALL) who developed disseminated Fusarium spp. infection during induction chemotherapy. A 4-year-old male patient diagnosed with high-risk ALL developed fever on the 23rd day of induction chemotherapy. Peripheral and central catheter cultures were obtained, and treatment with cefoperazone-sulbactam (150 mg/kg/day) was initiated. Laboratory findings revealed a white blood cell count of 560/mm³, neutrophil count of 170/mm³, hemoglobin level of 10.2 g/dL, platelet count of 30,000/mm³ and a C-reactive protein level of 22 mg/L. The respiratory bacterial-viral polymerase chain reaction (PCR) panel was positive for Rhinovirus, and the serum sepsis PCR panel showed low positivity for Enterobacteriaceae spp. During follow-up, painful, nonblanching, maculopapular lesions measuring 1–2 cm, suggestive of ecthyma gangrenosum, were observed, predominantly affecting the extremities (Fig. 1a–c). The antibiotic regimen was adjusted to include meropenem (120 mg/kg/day), teicoplanin (10 mg/kg/day) and liposomal amphotericin B (5 mg/kg/day). A skin biopsy was performed. Microscopic examination showed macroconidia with 2 or 3 septa, and the fungal culture grew Fusarium spp. (Fig. 2). Samples were sent to the National Reference Laboratory for antifungal susceptibility testing and both Aspergillus PCR and galactomannan tests were negative. Abdominal ultrasound and chest computed tomography (CT) were both normal. Due to the presence of a papular target lesion on the left cheek, a paranasal CT scan was performed, revealing mucosal thickening in the left maxillary sinus and occlusion of the left osteomeatal unit. Endoscopic examination revealed a black, hemorrhagic dry spot located posteriorly at the level of the left inferior nasal turbinate, from which a biopsy was taken. The patient’s antifungal regimen was adjusted to liposomal amphotericin B (7 mg/kg/day), voriconazole (8 mg/kg/day) and intranasal liposomal amphotericin B (50 mg of liposomal amphotericin B is added into 500 mL of saline and 20 cc every 4 hours in each nasal cavity). Due to severe neutropenia, the patient was given 0.5 g/kg/day IV immunoglobulin therapy for 3 days and underwent 2 days of granulocyte transfusion. No new lesions appeared, and the existing lesions regressed. Cultures from blood, catheter and urine showed no growth. The antifungal susceptibility testing of a previous Fusarium spp. isolate, conducted using the broth microdilution method, revealed the following minimum inhibitory concentrations: liposomal amphotericin B at 8 µg/mL, itraconazole at 4 µg/mL, voriconazole at 1 µg/mL and anidulafungin at 32 µg/mL. Induction therapy was restarted on the 15th day of antifungal treatment. The nasal cavity biopsy revealed microorganisms consistent with fungal tissue invasion within fibrin, suggesting an IFI. On the 27th day of treatment, there was noticeable progression of the lesions, accompanied by the onset of pain, fever and swelling in the right knee. Following joint aspiration, direct examination revealed a white blood cell count of 11,200/mm³, with no fungal growth detected in the culture. The dose of liposomal amphotericin B (10 mg/kg/day) was increased. On the 36th day of treatment, blinatumomab was started and completed on day 28. The patient’s chemotherapy is ongoing, and there are no additional clinical findings suggestive of IFI.FIGURE 1.: The appearance of the skin lesions that developed in the patient. A, A maculopapular skin lesion presenting on the left cheek. B, Painful, nonblanching maculopapular skin lesions, measuring 1–2 cm in size, were observed on the lower extremity. A biopsy was obtained from this area. C, A magnified view of the lesions on the lower extremity.FIGURE 2.: Misroscopic examination of fungus typical banana shaped macroconidia with 2 or 3 septa of Fusarium species.Fusarium spp. can cause localized, focal invasive, or disseminated disease in humans. Localized infections include septic arthritis, endophthalmitis, osteomyelitis, cystitis and brain abscesses.7 Patients at highest risk for developing sinopulmonary disease or disseminated infection include those with deep neutropenia, including patients with acute leukemia and aplastic anemia.8 Skin lesions are often a clue for diagnosis, as cutaneous lesions are observed in 85% of patients with disseminated fusariosis and can frequently represent one of the initial signs of infection.3 In our case, the underlying condition was ALL, and fusariosis developed during induction chemotherapy while the patient was neutropenic for 23 days. The presence of sinusitis, along with skin, joint and bone involvement, was considered indicative of a disseminated infection. Lesions may present as multiple erythematous, painful, papular or nodular lesions, often with central necrosis resembling ecthyma gangrenosum, as observed in our patient. Fewer than 10% of patients develop target lesions, which are characterized by a fine erythematous halo measuring 1–3 cm in diameter around the papules or nodules, whereas bullae are extremely rare. Metastatic skin lesions in fusariosis can affect any area, though they predominantly involve the extremities, and typically develop rapidly within a matter of days. Approximately one-third of patients with disseminated fusariosis present with skin lesions in various stages, including papules, nodules and necrotic lesions.9 Our patient exhibited papules and nodules on the trunk and extremities, along with target lesions on the face. The patient also experienced weakness and pain, particularly in the extremities where the lesions were most pronounced. Clinical and radiological bone/joint involvement is reported as in our patient2 There is experience in the use of intranasal antifungal therapy for IFIs in localized sinusitis as a case report.10 In our case, we performed endoscopic surgery and intranasal liposomal amphotericin B treatment with a successful response. Histopathology reveals hyaline acute branching septate hyphae like those found in aspergillosis. Unlike patients with aspergillosis, approximately 40% of those with fusariosis have positive blood cultures. Intermittent blood culture sampling is recommended for diagnosing our patient.1 The diagnosis was confirmed through histopathology and culture; however, the organism could not be isolated from the blood cultures. In invasive fusariosis, treatment with liposomal amphotericin B or voriconazole is recommended as first-line therapy. In the study by Nucci et al, 110 patients received amphotericin B deoxycholate, 38 received voriconazole, 34 received the lipid formulation of amphotericin B and 21 received combination therapy (mostly voriconazole and amphotericin B). The 90-day survival probability was 27% in those treated with amphotericin B deoxycholate, 53% for voriconazole and 48% for liposomal amphotericin B.9 In our case, we used a combination of liposomal amphotericin B and voriconazole, and due to the development of new organ involvement, the dose of amphotericin B was increased. In conclusion, early diagnosis is crucial due to the high mortality rate of invasive fusariosis (IFE). In cases of suspicion, a biopsy of the lesion should be performed immediately, and treatment must be initiated without delay. In immunosuppressed patients, antifungal prophylaxis and consideration of pathogens other than Aspergillus spp. can be lifesaving.