FINAL DIAGNOSIS: Invasive fungal sinusitis with Fusarium species.
Fusarium species infections are classified as hyalohyphomycoses, which are a heterogeneous group of fungal infections in which only hyaline, or non-pigmented, septate hyphae are seen in tissues. Other species in this group are Penicillium, Scedosporium, Acremonium, Paecilomyces, and Scopulariopsis. Fusarium species are common soil saprophytes and plant pathogens that can also produce a broad spectrum of human disease, including superficial, locally invasive, and disseminated infections. The most frequent species implicated in human disease are F. solani, F. oxysporum, and F. moniliforme. Additional pathogenic species are F. proliferatum, F. chlamydosporum, F. anthophilum, F. dimerum, F. sacchari, and F. verticillioides. Fusarium species possess several virulence factors including the ability to produce trichothecene and other mycotoxins that suppress humoral and cellular immunity. The organisms also produce proteases and collagenases causing tissue breakdown, and have the ability to adhere to prosthetic material. (1,2)
Definitive diagnosis requires the isolation of Fusarium species from clinical specimens. Fusarium species grow rapidly on various media producing white, lavender, pink, salmon, or gray colonies on potato dextrose agar. Colonies have velvety or cottony surfaces and some species change color during incubation. Microscopically, the hyphae are hyaline and septate with 90-degree or acute-angle branching, and measure 3 to 8 um in diameter. Fusarium species characteristically produce microconidia and macroconidia. Microconidia are unicellular and ovoid with zero to three septae forming false heads at the ends of conidiophores. Macroconidia are multicellular sickle-shaped clusters with three to five septae and foot-shaped basal cells. Chlamydoconidia are sometimes present, occurring singly or in groups, with rough or smooth walls [Figures 8, 9 and 10].
Culture identification is important because of the morphologic similarities in histologic tissue sections between Fusarium, Aspergillus, and other members of the hyalohyphomycosis family. Like Aspergillus, Fusarium species appear as acute branching septate hyphae, and can invade blood vessels leading to thrombosis and tissue infarction. Immunohistochemical staining using polyclonal fluorescent antibodies can also be performed to distinguish these two organisms (3).
Fusarium species may be acquired in the community among normal hosts, but are also causative agents of severe opportunistic infections among immunocompromised individuals. A spectrum of fusarial infections is seen in immunocompetent individuals, with post-traumatic keratitis among contact lens wearers as the most common. Cutaneous lesions, otitis media, and onychomycosis also occur. Deeper or invasive infections in immunocompetent hosts are rare, but can be seen after trauma and direct inoculation of various body sites. Fusarial peritonitis may occur in patients undergoing continuous ambulatory peritoneal dialysis. Treatment with foreign body removal and antifungal therapy is usually curative among immunocompetent patients.
In immunocompromised patients, fusarial infection has emerged as a significant cause of morbidity and mortality. These organisms can cause disseminated disease and are the second most common pathogenic molds (after Aspergillus) in hematologic cancer patients and solid organ or allogeneic bone marrow transplant recipients (3). Patients with extensive burns are also susceptible to life-threatening fusariosis. Although still relatively low, the incidence of fusarial infection in immunocompromised patients has increased in the United States. At one institution from 1975 to 1995, the rate of infection increased from 0.5 to 3.8 cases per year. The hospital water system was later found to be a reservoir for Fusarium species (3).
Disseminated fusariosis typically presents with persistent fever refractory to antibacterial and antifungal therapy. Almost any organ can be involved, but the most frequently affected sites are the skin (70-90%) followed by the lungs and sinuses (3). Few cases of nasal fusarial involvement have been published to date (4). Disseminated fusariosis may mimic aspergillosis clinically as well as histologically. However, fusarial infection is associated with a higher incidence of skin and subcutaneous lesions and blood cultures are more likely to be positive (3).
Fusarium species are highly drug-resistant. Susceptibility data indicate resistance to many of the antifungal agents in our arsenal. Relatively low MICs for amphotericin B, voriconazole, and natamycin are reported (5). While caspofungin alone is not effective, the combination of caspofungin with amphotericin B appears to have a synergistic effect against some Fusarium isolates. However, in-vitro data does not always correlate with clinical outcome and many cases remain resistant.
Although some patients respond to antifungal therapy, prevention of fusarial infection is paramount for the immunocompromised individual, given the high associated risk of life-threatening disease. It has been shown that hospital water systems can be a reservoir for Fusarium species and other pathogenic molds, leading to secondary aerosolization with patient exposure and infection. The skin may also be a primary source, usually at the site of a pre-existing onychomycosis or tissue breakdown, leading to cellulitis and disseminated disease. Avoiding exposure to tap water, conducting thorough skin examinations, and cleaning water-related environmental surfaces frequently are preventative measures thought to reduce the risk of fusarial infection.
In immunocompromised patients, overall mortality from fusarial infections ranges from 50 to 80%, with the worst prognosis associated with persistent and severe immunosuppression (4). Among patients undergoing solid organ transplantation, infections tend to be more localized and have a better prognosis than among hematologic cancer patients or bone marrow transplant recipients (1). Immune status is the single most important factor predicting development and outcome of disseminated infection (6). Therefore, recovery of immunosuppression is critical to achieving a favorable outcome. Every effort should be made to enhance the immune status of the patient including tapering or discontinuing immunosuppressive drugs, treatment with colony stimulating factors, and transfusion of donor-stimulated white blood cells. Despite aggressive therapy with antifungal agents, many patients with disseminated fusariosis and persistent and profound neutropenia die of the infection.
This patient was treated with surgery, amphotericin B, and caspofungin. Most importantly, his immunosuppression was adjusted and he received granulocyte colony stimulating factor injections along with multiple red blood cell and platelet transfusions. He responded gradually and, after a 70-day hospital stay, had no evidence of persistent infection on physical examination. However, a follow-up CT demonstrated a possible left first molar apical abscess. Throughout his hospital course, the patient did not display evidence of disseminated fusariosis. Blood cultures remained negative and cutaneous or other sites of fungal involvement were not seen. At discharge, the patient's white blood cell count improved to 2,200/cu mm with 62% neutrophils and bone marrow transplant was deemed unnecessary. He continues to be treated for aplastic anemia with infectious disease prophylaxis.
Contributed by Teresa LaCaria, M.D. and William Pasculle, ScD.