A 7-year-old girl is admitted to the hospital because of a 3-week history of fever, leukopenia, nausea, abdominal pain, and arm weakness. The patient had undergone a workup for infection at an outside facility prior to admission and was given a 5-day course of doxycycline to treat a fever of unknown cause. On this presentation, a peripheral blood smear is obtained and shows numerous leukoblasts. Subsequent bone marrow biopsy reveals acute lymphoblastic leukemia (ALL). Induction therapy, which includes dexamethasone, vincristine, pegylated (PEG)-asparaginase, and intrathecal methotrexate, is initiated.
Nine days after therapy begins, the patient has 2 tender, slightly raised, and erythematous lesions on her right arm. Her WBC count is 1.81 X 10/L (1810/ÁL) cm2 with a platelet count of 39 X 109/L (39 X 10/ÁL). The next morning, the largest lesion, which measures 15 mm, has a 5-mm darkened center. The lesions progress, and, by the next day, measure 20 mm with a 10-mm central area with dark discoloration (see Image 1).
Cefepime is administered for a suspected diagnosis of ecthyma gangrenosum, and fluconazole as prophylactic therapy is continued. Despite treatment with the antimicrobials, the lesion continues to grow and becomes increasingly tender to palpation, with progression to small surrounding satellite areas.
The patient is taken to an operating room, where the lesions are widely resected and samples are obtained to be sent to pathology and microbiology for examination. In addition to the tissue undergoing standard Gram staining and aerobic and anaerobic culture, acid-fast staining, mycobacterial culture, fungal staining, and viral culture are also performed.
Histopathology of the resected specimen reveals a 2.6 X 1.5 X 0.8-cm ellipse of skin that contains several lesions. The largest lesion is 1.0 X 1.3 cm and has a 1- to 2-mm rim of erythema around its dark center. About 4 mm from the largest lesion, a second lesion measures 3 X 2 mm and has surrounding erythema. The epidermis is laterally intact but centrally affected by ischemic necrosis (see Image 2). The dermis and subcutaneous tissues contain an extensive infiltrate of fungal hyphal elements involving the walls of the blood vessels, surrounding tissues, and focal perineural areas (see Image 3). Fungal elements are noted within 1 mm of each lateral resection margin (see Image 4).
[HIDE]Cutaneous zygomycosis: The wound biopsy cultures grew out Rhizopus species, a fungus in the Mucorales order. Because of this finding, in conjunction with the findings on histopathology, dermatomycosis, specifically cutaneous zygomycosis, was diagnosed. Zygomycosis is an uncommon and potentially fatal infection caused by fungi of the class Zygomycetes. The incidence of zygomycosis is increased among immunocompromised patients (Gonzalez, 2002; Roden, 2005). The class Zygomycetes includes 2 orders of pathogens: Mucorales, which is responsible for most cases of human disease, and Entomophthorales (Gonzalez, 2002). Entomophthorales-related disease classically occurs in only tropical and subtropical areas, where it causes a mild form of disease limited to the nasal, sinus, and subcutaneous tissues. However, the geographic distribution and clinical characteristics of disease have increasingly broadened. Because the features of disease caused by Mucorales and Entomophthorales are nearly identical both clinically and histologically, the term mucormycosis is taxonomically inaccurate but nevertheless accepted in the medical terminology (Gonzalez, 2002).
Risk factors for zygomycosis include organ transplantation, malignancy, diabetes, corticosteroid therapy, neutropenia, desferoxamine therapy, HIV infection, metabolic acidosis, burns, and traumatic inoculation (Kontoyiannis, 2000; Dromer, 2002; Gonzalez, 2002; Greenberg, 2004; Roden, 2005). Patients with ketoacidosis are at particular risk for zygomycosis because the acidic environment appears to hinder neutrophil function (Gonzalez, 2002).
This patient had several of these risk factors, including ALL, hyperglycemia secondary to corticosteroid therapy, and neutropenia. Because neutrophils are the predominant mediators of the host defense's against fungal hyphae, the patient's state of neutropenia gave rise to invasive disease. Leukemia is the underlying risk factor in 15% of patients with zygomycotic infections (Dromer, 2002). This patient developed a cutaneous infection, which is generally less severe than rhinocerebral or pulmonary infection, but it may indicate disseminated infection (Gonzalez, 2002; Sundararajan, 2004). The incidence of disseminated infection is highest in patients with a hematologic malignancy (Dromer, 2002). Thorough examination and imaging studies should be performed to rule out disseminated infection (Gonzalez, 2002; Roden, 2005). Tissue biopsy and cultures are necessary to diagnose zygomycotic infection (Dromer, 2002; Gonzalez, 2002).
The management of zygomycosis starts with a high index of suspicion in appropriate populations, early diagnosis, and aggressive therapy (Dromer, 2002; Gonzalez, 2002). The most effective therapy is a combination of surgical debridement; high-dose amphotericin-B; and treatment of underlying conditions, such as neutropenia or hyperglycemia (Kontoyiannis, 2000; Dromer, 2002; Gonzalez, 2002; Pagano, 2004). Liposomal amphotericin-B continues to be the drug of choice, even though new antifungal agents have emerged (Kontoyiannis, 2000; Gonzalez, 2002; Pagano, 2004; Roden, 2005). No therapy prevents this infection (Kontoyiannis, 2000; Dromer, 2002; Gonzalez, 2002; Pagano, 2004).
In our case, liposomal amphotericin B at 5 mg/kg was started empirically shortly before the histopathologic diagnosis on clinical suspicion and was continued along with daily wet-to-dry dressings for general wound care. Computed tomography scans of the head, chest, abdomen, and pelvis were performed to evaluate for potential disseminated disease and were negative. Additionally, an ophthalmologic examination was performed and was unremarkable. After 6 days of therapy, the area around the excision site darkened and a repeat debridement and biopsy of the previous margins failed to reveal any fungal elements. The patient received liposomal amphotericin B for a total of 6 weeks with weekly monitoring of electrolyte levels. After treatment was completed, a skin graft was performed on the affected areas of her right forearm which took well and healed without complication.[/HIDE]