Version May 2024
INTRODUCTION — Fusarium species cause a broad spectrum of infections in humans including superficial infections, such as keratitis and onychomycosis, as well as locally invasive and disseminated infections; invasive and disseminated infections occur almost exclusively in severely immunocompromised patients [1]. Fusarium species may also cause allergic diseases, such as sinusitis in immunocompetent individuals [2], and mycotoxicosis following ingestion of food contaminated by toxin-producing Fusarium species [3]. Fusarium species are also important plant pathogens that cause various diseases on cereal grains [3] and occasionally cause infection in animals [4].
The mycology, pathogenesis, and epidemiology of fusariosis will be reviewed here. The clinical manifestations, diagnosis, treatment, and prevention of fusariosis are discussed separately. (See "Clinical manifestations and diagnosis of Fusarium infection" and "Treatment and prevention of Fusarium infection".)
MYCOLOGY — Fusarium species are widely distributed in soil, subterranean and aerial plant parts, plant debris, and other organic matter [3]. They are also present in water worldwide [5].
Growth in vitro — Fusarium species grow rapidly on many media that do not contain cycloheximide, which inhibits its growth. On potato dextrose agar, Fusarium species produce white-, lavender-, pink-, salmon-, or gray-colored colonies with velvety or cottony surfaces [6].
Microscopic appearance — Microscopically, the hyphae of Fusarium in tissue resemble those of Aspergillus species, with septate hyaline hyphae 3 to 8 microns in diameter that typically branch at acute angles (picture 1 and picture 2). Adventitious sporulation, which is the ability to sporulate in tissue and blood, may be present [7]; the identification of hyphal and yeast-like structures in the same specimen is highly suggestive of fusariosis in high-risk patients.
In cultures, the production of both fusoid macroconidia (hyaline, multicellular, banana-like clusters with foot cells at the base) (picture 3 and picture 4) and microconidia (hyaline, unicellular, ovoid to cylindrical) are characteristic of the genus Fusarium.
Species identification — The characteristic appearance of Fusarium macroconidia can be used for identification (picture 3 and picture 4), but species identification is difficult and often requires molecular methods [8-10]. Mass spectrometry using matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) has been shown to correctly identify clinical isolates to the species level [11,12].
Species prevalence — More than 300 species of Fusarium have been identified, but only a few cause infections in humans [13,14]. Fusarium species are grouped into >20 phylogenetic species complexes, 7 of which have been reported to cause significant human disease [15]: Fusarium solani species complex (FSSC), Fusarium oxysporum species complex (FOSC), Fusarium fujikuroi species complex (FFSC), Fusarium incarnatum-equiseti species complex, Fusarium chlamidosporum species complex, Fusarium dimerum species complex, and Fusarium sporotrichoides species complex, with various species within each complex. Approximately 50 percent of cases of invasive fusariosis are caused by FSSC, followed by FOSC and FFSC [1,16]. The distribution of species causing infection varies geographically. For example, in Brazil FSSC is the predominant species complex [17], whereas in various European countries FFSC is the most frequent (especially Fusarium verticillioides and Fusarium proliferatum) [18]. Fusarial keratitis is most commonly caused by FSSC [19], while fusarial onychomycosis is most commonly caused by F. oxysporum [20-22].
PATHOGENESIS — Fusarium spp cause invasive disease by angioinvasion and direct tissue destruction [3,23]. Fusarium species possess several virulence factors including mycotoxins, which suppress humoral and cellular immunity and can also cause allergic reactions [3]. Fusarium spp also have the ability to adhere to prosthetic material [3] and to produce proteases and collagenases [24]. F. solani is thought to be the most virulent Fusarium species [25]. Some Fusarium species produce mycotoxins that are destructive to crops and can cause human disease when ingested with heavily contaminated grains [21].
Immune response — Innate immunity plays a major role in the defense against Fusarium species [26]. Macrophages and neutrophils damage fusarial hyphae, and their effect is primed by interferon-gamma, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor [27], and interleukin (IL)-15 [28]. The effect of IL-15 is mediated by the release of IL-8 and by direct stimulation of hyphal damage. The role of toll-like receptors in the innate immune recognition of fungi is increasingly being recognized [29], and, although little is known about fusariosis and toll-like receptors, this system is likely to be important in invasive fusariosis.
EPIDEMIOLOGY — Fusarium species cause a broad spectrum of infections in humans, including superficial, locally invasive, and disseminated infections. The clinical form of infection depends upon the immune status of the host and the portal of entry of the pathogen [1].
Immunocompetent hosts — Keratitis and onychomycosis are the most common infections in immunocompetent patients. Other sites of infection have also been reported (table 1) [30-42].
Keratitis — Fusarium spp are a common cause of fungal keratitis, which may develop following the traumatic introduction of Fusarium-contaminated soil or plant material or due to poor hygiene practices of soft contact lens wearers, particularly in patients using glucocorticoid eye drops. A large international outbreak of fusarial keratitis between 2004 and 2006 was linked to the use of a specific contact lens solution (ReNu with MoistureLoc) [43-47]. The solution was not intrinsically contaminated. One study has suggested that in the setting of storage at high temperatures, the antimicrobial agent in the solution, alexidine dihydrochloride, permeates the walls of the plastic bottle, resulting in decreased concentrations in the solution [48]. The fungicidal action of the solution was diminished, allowing Fusarium that had been introduced by the wearer while caring for his or her lenses to grow and contaminate the contact lens and the lens case. The solution was recalled in the United States in 2006, and rates of contact lens-associated Fusarium keratitis have declined since then [49].
The incidence of fungal keratitis caused by Fusarium species is highly variable and depends largely upon the geographic location. For example, in several studies performed at different times over a span of 10 years, the incidence has been noted to range from 8 percent in India to 25 percent in Pennsylvania, 63 percent in Florida, and 75 percent in Tanzania [19,50,51]. These variable rates are probably related to climate characteristics, with tropical and subtropical areas exhibiting the highest rates [19].
Onychomycosis — Fusarium species have been reported as agents of onychomycosis with increasing frequency among immunocompetent individuals [52,53] with variable rates reported from different regions. As an example, in a study from central Italy, fewer than 2 percent of cases of onychomycosis were caused by Fusarium spp [54], compared with more than 8 percent in a study of onychomycosis cases from the northeast region of Brazil [20].
Meningitis — Although rare, Fusarium meningitis has been reported from health care-associated sources. Two separate outbreaks have occurred, one in late 2022 and another between January 1 and May 13, 2023, among individuals who underwent epidural anesthesia for plastic surgery procedures performed at specific clinics in Durango and Matamoros, Mexico [55,56]. (See "Aseptic meningitis in adults", section on 'Fusarium outbreaks'.)
Immunocompromised patients
Portals of entry — Invasive fusariosis has been reported worldwide and may be acquired both in the community and in the hospital setting. The principal modes of infection are airborne or via direct inoculation at various sites (skin and others) of Fusarium-contaminated material, including water (table 2). Airborne infection typically results from the inhalation of fusarial conidia from the air [57], but in some cases have been associated with aerosolization of conidia from a water source [58]. In addition, pre-existing skin breakdown or onychomycosis may facilitate direct introduction of Fusarium spp. An increase in cases of invasive fusariosis with a cutaneous portal of entry has been reported in Brazil [59]. Onychomycosis and intertrigo were the predominant primary lesions. A subsequent study from the same group showed that in hematologic patients at high risk of developing invasive fusariosis, the presence of such lesions growing Fusarium spp at the time of admission increased the risk for the subsequent occurrence of invasive disease [60].
Central venous catheter-related Fusarium infection has also been reported; in one report, 7 cases of genetically related F. oxysporum bloodstream infection occurred in children with cancer who had central venous catheters [61]. Although an environmental source was not identified, the outbreak was presumed to be due to central line manipulation in a specific room as the outbreak ended after implementation of a multidisciplinary central line insertion care bundle.
Risk factors — Patients with compromised immune function are at increased risk for invasive fusariosis, particularly in the setting of prolonged and profound neutropenia and/or severe T cell immunodeficiency [62]. Unlike infection in normal hosts, fusariosis in the immunocompromised population is typically invasive and disseminated [30].
The overall incidence of fusariosis among hematopoietic cell transplant (HCT) recipients and patients with acute myeloid leukemia (AML) is low, usually less than 1 percent, as reported in studies conducted in the United States and Italy [63-65]. By contrast, in a multicenter study conducted between 2007 and 2009 in Brazil, invasive fusariosis was the second most common cause of invasive fungal disease among patients with AML (3.8 percent) and the most common cause among allogeneic HCT recipients (5.2 percent) [66]. In a more recent study from Brazil, invasive fusariosis was the third most-frequent invasive fungal disease among patients with hematologic cancers (3 cases among 192 patients [1.6 percent]) [67]. These geographic differences in the incidence of invasive fusariosis must be taken into account in the management of high-risk patients.
Among patients with hematologic malignancy, the infection predominates during periods of neutropenia, typically among patients with leukemia receiving induction chemotherapy [68]. Smoking also appears to be a risk factor in patients with AML or myelodysplastic syndrome [69]. Ibrutinib, a Bruton tyrosine kinase inhibitor, has been associated with invasive fungal infections, including invasive fusariosis [70]. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Bruton tyrosine kinase inhibitors'.)
Invasive fusariosis also occurs with an increased frequency among allogeneic HCT recipients in whom a trimodal distribution of infection has been identified [71]. The first peak occurs during the first 30 days following transplantation and is associated with neutropenia. Severe T cell immunodeficiency (but not neutropenia) is the major risk factor for fusariosis that develops after engraftment and which occurs at a median of 70 days after HCT, commonly in the setting of acute graft-versus-host disease (GVHD) and therapy with glucocorticoids. The third peak is observed >1 year after HCT during treatment for extensive chronic GVHD. In one study, risk factors for invasive fusariosis during the early phase following allogeneic HCT included receipt of antithymocyte globulin, hyperglycemia, and AML [69]. During the late phase following allogeneic HCT, risk factors included nonmyeloablative conditioning regimen, grade III/IV GVHD, and previous invasive mold disease.
The prognosis of fusariosis is directly related to the patient's immune status, with high death rates in patients with persistent immunodeficiencies. In a series of 84 patients with fusariosis and an underlying hematologic malignancy, persistent neutropenia and recent glucocorticoid therapy were the only independent factors associated with poor outcome [68]. (See "Treatment and prevention of Fusarium infection", section on 'Prognosis'.)
Locally invasive Fusarium infections occur occasionally among solid organ transplant recipients, typically during the late post-transplant period; disseminated infections have been reported rarely in such patients [72]. Cases of chronic cutaneous fusariosis have also been reported in patients with STAT3 Hyper-IgE Syndrome [73].
Invasive fungal disease has also been reported in previously immunocompetent individuals who developed severe forms of COVID-19. While most infections were caused by aspergillosis, cases of invasive fusariosis were also reported [74]. The use of glucocorticosteroids for the treatment of severe COVID-19 pneumonia is thought to contribute to the development of these fungal infections [74].
The clinical manifestations of fusariosis are discussed separately. (See "Clinical manifestations and diagnosis of Fusarium infection".)
SUMMARY
●Spectrum of disease – Fusarium species are important plant pathogens that cause various diseases on cereal grains and occasionally cause infection in animals. In humans, Fusarium species cause a broad spectrum of infections including superficial infections, such as keratitis and onychomycosis, as well as locally invasive and disseminated infections; invasive and disseminated infections occur almost exclusively in severely immunocompromised patients. (See 'Introduction' above and "Clinical manifestations and diagnosis of Fusarium infection".)
●Reservoir – Fusarium species are widely distributed in soil, subterranean and aerial plant parts, plant debris, and other organic matter. They are also present in water. (See 'Mycology' above.)
●Microbiology – Microscopically, the hyphae of Fusarium in tissue resemble those of Aspergillus species, with septate hyaline hyphae 3 to 8 microns in diameter that typically branch at acute angles (picture 1). The production of both fusoid macroconidia (hyaline, multicellular, banana-like clusters with foot cells at the base) (picture 3 and picture 4), and microconidia (hyaline, unicellular, ovoid to cylindrical) are characteristic of the genus Fusarium. (See 'Microscopic appearance' above.)
The characteristic appearance of Fusarium macroconidia is used for identification (picture 3 and picture 4), but species identification is difficult and often requires molecular methods or matrix-assisted laser desorption/ionization time of flight (MALDI-TOF). (See 'Species identification' above.)
●Taxonomy – More than 300 species of Fusarium have been identified, but only a few cause infections in humans. Fusarium species are grouped into various phylogenetic species complexes (more than 20), 7 of which have been reported to cause significant disease in humans: Fusarium solani species complex (50 percent of infections), Fusarium oxysporum species complex, Fusarium fujikuroi species complex, Fusarium incarnatum-equiseti species complex, Fusarium chlamidosporum species complex, Fusarium dimerum species complex, and Fusarium sporotrichoides species complex. (See 'Species prevalence' above.)
●Pathophysiology – Fusarium species cause invasive disease by angioinvasion and direct tissue destruction. Innate immunity plays a major role in the defense against various molds, including Fusarium species. Macrophages and neutrophils damage fusarial hyphae, and their effect is primed by interferon-gamma, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and interleukin-15. (See 'Pathogenesis' above.)
●Risk factors – Fusarium species cause a broad spectrum of infections in humans, including superficial, locally invasive, and disseminated infections. The clinical form of infection depends upon the immune status of the host and the portal of entry of the pathogen (table 1). (See 'Epidemiology' above.)
Patients with compromised immune function are at high risk for invasive fusariosis, particularly in the setting of prolonged and profound neutropenia and/or severe T cell immunodeficiency, such as in patients with hematologic malignancies receiving induction chemotherapy or allogeneic hematopoietic cell transplantation. (See 'Risk factors' above.)
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