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 [1]. Invasive and disseminated infections occur almost exclusively in severely immunocompromised patients, particularly among those with prolonged and profound neutropenia and/or severe T cell immunodeficiency. Among patients with hematologic malignancy, the infection predominates during periods of neutropenia, typically among patients with leukemia receiving induction chemotherapy.
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 of cereal grains [3] and occasionally cause infection in animals [4].
The clinical manifestations and diagnosis of fusariosis will be reviewed here. The mycology, pathogenesis, epidemiology, treatment, and prevention of fusariosis are discussed separately. (See "Mycology, pathogenesis, and epidemiology of Fusarium infection" and "Treatment and prevention of Fusarium infection".)
CLINICAL MANIFESTATIONS
Immunocompetent patients — Keratitis and onychomycosis are the most common manifestations of fusariosis among immunocompetent hosts.
Keratitis — Keratitis is inflammation of the cornea and can be caused by a variety of infectious and noninfectious causes [5] (see 'Keratitis' below). Fusarium spp are a common cause of fungal keratitis and were responsible for an outbreak among contact lens users between 2004 and 2006, which was linked to a specific brand of contact lens solution, ReNu with MoistureLoc. (See "Mycology, pathogenesis, and epidemiology of Fusarium infection", section on 'Keratitis'.)
The clinical manifestations of fusarial keratitis are similar to keratitis caused by other agents and include eye pain, light sensitivity, conjunctival injection, and tearing; discharge is usually absent (picture 1) [5]. Compared with bacterial keratitis, patients with fungal keratitis typically have fewer inflammatory signs and symptoms and can have a more indolent presentation [5]. In later stages, suppuration and a hypopyon may occur [5]. Keratitis may result in corneal perforation and endophthalmitis [6].
Onychomycosis and superficial skin infections — The clinical manifestations of fusarial onychomycosis are similar to those seen with other fungi. The infection begins as whitish, yellowish, or brownish discoloration of one part of the nail and gradually extends to cover it completely. Some features suggest a fusarial etiology for the onychomycosis, including a predilection for the toenails rather than the fingernails, involvement of the proximal subungual areas, and coexisting subacute or acute paronychia (picture 2) [7]. Pre-existing damage to the nail and/or infection by dermatophytes may predispose patients to fusarial onychomycosis [7].
Fusarium species may also cause superficial infections typical of dermatophytes, such as interdigital intertrigo (picture 3 and picture 4) [8], tinea pedis, and hyperkeratotic plantar lesions [9]. The contribution of Fusarium species to nondermatophyte skin infections appears to be increasing [10].
Deep cutaneous infections — In addition to superficial infections, Fusarium species may infect deeper layers of the skin in immunocompetent hosts. Lesions are usually localized and occur after skin breakdown, such as at sites of trauma, burns, or pre-existing onychomycosis [11]. Cellulitis, ulcers (picture 5), abscesses, and lesions resembling chromoblastomycosis and mycetoma have been reported [11].
Other infections — Fusarium species may occasionally cause other infections in immunocompetent hosts, including chronic sinusitis, pneumonia, endophthalmitis, osteomyelitis, septic arthritis, brain abscess, cystitis, and peritonitis (table 1) [11-23]. The clinical manifestations of these infections are similar to those caused by other fungal pathogens.
In 2023, a cluster of cases of fungal meningitis most likely due to Fusarium solani was identified among individuals who underwent epidural anesthesia at specific clinics in Matamoros, Mexico between January 1 and May 13, 2023 [24,25]. Patients presented with a range of symptoms, including fever, headache, meningismus, nausea, emesis, light sensitivity, and confusion. In some cases, initial symptoms were mild or absent, but rapid progression to severe illness was observed; in some cases, increased intracranial pressure, brain edema, vasculitis, strokes, and intracranial hemorrhage occurred. Onset of illness sometimes took weeks from the date of the procedure. Details regarding this outbreak are available on the CDC website and the fungus education hub. This outbreak is very similar to a previous outbreak in late 2022 that was related to epidural anesthesia administered in certain clinics in Durango, Mexico.
Immunocompromised patients — The most common presentation of fusarial infection in immunosuppressed patients is persistent fever refractory to antibacterial and antifungal therapy in the setting of profound and prolonged neutropenia. Other findings at presentation may include sinusitis, pneumonia, cellulitis at the site of pre-existing skin breakdown, and metastatic skin lesion. Endophthalmitis, rhinocerebral infection, myositis, arthritis, and infections of the central nervous system have also been reported (table 1) [1,26-28]. In non-neutropenic allogeneic hematopoietic cell transplant recipients, fusariosis has been reported to occur in the setting of treatment with corticosteroids for graft versus host disease and presents with disseminated disease in the majority of cases [29].
The epidemiology of fusariosis is discussed separately. (See "Mycology, pathogenesis, and epidemiology of Fusarium infection", section on 'Epidemiology'.)
Sinusitis — Sinusitis caused by Fusarium species may develop either as a single organ infection or coexist with fusarial pneumonia. When immunosuppression is severe, sinusitis may result in disseminated fusariosis. The clinical manifestations of fusarial sinusitis are indistinguishable from those caused by Aspergillus species, including nasal discharge and obstruction, with a propensity for periorbital and paranasal cellulitis (picture 6) [26]. Necrosis of the mucosa is a hallmark and is a consequence of the angioinvasive nature of these mycoses (picture 7).
Pneumonia — Lung involvement is common in invasive fusariosis in immunocompromised hosts, occurring in almost 50 percent of cases [30]. In patients with disseminated infection, pneumonia may be the primary site of the infection or may be secondary to hematogenous dissemination. In the setting of disseminated infection, bilateral lung involvement is more likely to occur [30]. The clinical presentation is usually nonspecific, with some patients presenting with a clinical picture similar to that seen in invasive aspergillosis, including dry cough, pleuritic chest pain, and shortness of breath.
Radiographic findings include alveolar infiltrates (image 1), nodules with or without the halo sign (image 2), and cavitary lesions, particularly when fusarial pneumonia is the only site of infection [26,30]. A study compared the radiologic pattern of 13 cases of invasive fusariosis with 32 cases of invasive aspergillosis [31]. Macronodules (>1 cm) were as frequent in fusariosis as in aspergillosis, but the halo sign was less common in fusariosis (23 versus 62 percent). Other findings, including small airway lesions (centrilobular micronodules and tree-in-bud infiltrates), occurred with similar frequencies.
Cutaneous lesions — Fusarial skin lesions in immunocompromised patients may be either localized or disseminated. Localized lesions usually present as cellulitis (picture 8) at sites of skin breakdown caused by trauma, onychomycosis, or interdigital intertrigo (picture 3 and picture 4) [32,33]. Lymphangitic spread may be seen, and the infection may progress to cause disseminated fusariosis. Patients with disseminated disease may develop multiple erythematous papular or nodular and painful lesions, frequently with central necrosis giving the lesions an ecthyma gangrenosum-like appearance (picture 9). Target lesions, which have a thin rim of erythema of 1 to 3 cm in diameter surrounding papular or nodular lesions, are present in <10 percent of patients (picture 10), and bullae are very rare (picture 11).
Fusarial metastatic skin lesions may involve any site, with predominance for the extremities, and evolve rapidly, usually over a few days (picture 12). Approximately one-third of the patients with disseminated fusariosis and skin lesions present with lesions at different stages of evolution (papules, nodules, and necrotic lesions) (picture 13); concomitant myalgias (suggesting muscle involvement) occurred in 15 percent of patients in one series [11].
Fungemia — In contrast with aspergillosis and most other invasive mold infections, a striking characteristic of fusarial infections in immunocompromised hosts is the high frequency of positive blood cultures. This is probably because Fusarium species sporulate in vivo, facilitating hematogenous dissemination and hence a high rate of positive blood cultures [34]. (See 'Diagnosis' below.)
Among 294 cases of invasive fusariosis in immunocompromised hosts, blood cultures were positive in 199 patients (41 percent) [1]. Although fungemia typically occurs in the context of disseminated disease, occasional cases of fungemia without organ involvement have been reported, some of which were related to central venous catheters [35-42]. Catheter-related fusariosis does not usually progress to disseminated disease.
Disseminated disease — Disseminated disease is the most frequent clinical form of fusariosis in immunocompromised patients, occurring in approximately 70 percent of such patients [1]. It may present as antibiotic-refractory fever in patients with prolonged (>10 days) and profound (<100 cells/mm3) neutropenia, with subsequent development of widespread cutaneous lesions and positive blood cultures (picture 10 and picture 12 and picture 13). Involvement of other sites (either as primary or secondary infections) may be seen, particularly pneumonia, sinusitis, and extremity cellulitis. A clue to the diagnosis of disseminated fusariosis is the presence of refractory fever in a profoundly neutropenic patient with multiple skin lesions and a blood culture growing a mold.
Disseminated Fusarium infections are associated with poor outcomes, with mortality rates of 60 to 80 percent [1,43-46]. (See "Treatment and prevention of Fusarium infection", section on 'Prognosis'.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of fusariosis depends upon the host's immune status and the site(s) of infection.
Keratitis — A variety of microbes can cause keratitis, including bacteria (eg, staphylococci, streptococci, gram-negative bacilli, Nocardia spp, mycobacteria), viruses (eg, herpes simplex virus, varicella-zoster virus, adenovirus), fungi, and parasites, including the free-living protozoan, Acanthamoeba [5]. Fusarium is a common cause of fungal keratitis, but other possible causes include Candida spp, Aspergillus spp, and others. Both Fusarium spp and Acanthamoeba have been associated with outbreaks among contact lens users [47,48]. Culturing corneal scrapings is essential for establishing the diagnosis of keratitis when an infectious cause of keratitis is suspected because the microbial etiology cannot be determined based upon the clinical presentation. (See 'Diagnosis' below.)
Noninfectious causes of keratitis include trauma, hypersensitivity reactions, and immune-mediated conditions [5].
Onychomycosis — The differential diagnosis of onychomycosis includes dermatophytes (eg, Trichophyton rubrum), which are by far the most common cause, and, less commonly, molds, such as Scopulariopsis brevicaulis and Aspergillus spp. Candida spp can also cause onychomycosis. (See "Onychomycosis: Epidemiology, clinical features, and diagnosis".)
Invasive disease — In patients with invasive disease, including sinusitis, pneumonia, and disseminated disease, fusariosis is most often confused with aspergillosis since both Fusarium and Aspergillus spp cause similar clinical manifestations and appear similar on histopathology, with branching septate hyphae. Infection with Fusarium spp is much more likely to cause positive blood cultures than Aspergillus spp and other molds and is more commonly associated with onychomycosis as the source of systemic infection. In addition to Fusarium species, other molds may have a combination of angioinvasive disease with positive blood cultures and metastatic skin lesions. These include Purpureocillium lilacinum, Aspergillus terreus, Scedosporium spp, Lomentospora prolificans, and Acremonium spp. (See "Epidemiology and clinical manifestations of invasive aspergillosis" and "Epidemiology, clinical manifestations, and diagnosis of Scedosporium and Lomentospora infections".)
DIAGNOSIS — The approach to the diagnosis of fusariosis depends upon the clinical form of the disease.
Approach to diagnosis — In general, the diagnosis is confirmed by the isolation of Fusarium species in cultures of involved biologic materials, such as nail scrapings (onychomycosis), corneal scrapings (keratitis), skin biopsy (metastatic skin lesions), skin scrapings (interdigital intertrigo), sinus aspirates (sinusitis), respiratory secretions (pneumonia), and/or blood cultures (fungemia, disseminated disease). Tissue biopsy with culture and histopathology provides definitive evidence of invasive disease. The following discussion focuses on invasive Fusarium infections in immunocompromised hosts.
In severely immunocompromised patients, two characteristics suggest the diagnosis of disseminated fusariosis: the presence of skin lesions (either cellulitis at sites of skin breakdown caused by trauma or onychomycosis, or metastatic lesions) and mold growing from blood cultures (figure 1). Skin biopsies should be performed in all immunocompromised patients with suspicious skin lesions and should be sent for both histopathology and microbiology studies. In patients with metastatic skin lesions, the fastest and easiest way of reaching the diagnosis is by direct examination of the skin biopsy, with the finding of septate hyaline hyphae obtained in a few hours. Blood cultures should also be obtained. In individuals with lung involvement, a sputum sample should be sent for fungal stain and culture as well as other microbiologic studies when feasible. (See 'Histopathology' below and 'Blood cultures' below.)
If the diagnosis has not been established by skin biopsy, blood culture, or sputum fungal stain and culture, then an attempt should be made to obtain a biopsy of involved tissues (eg, lungs, sinuses). (See 'Histopathology' below.)
The diagnostic evaluation of immunocompromised patients with fusariosis should be accompanied by a clinical and radiologic assessment of disease extent, including computed tomography of the paranasal sinuses and chest. A small study suggested that fluorine-18-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) may be helpful to assess the extent of disease [49].
Patients with radiographic findings that are suggestive of an invasive fungal infection of the lungs, in whom previously obtained specimens (eg, sputum fungal stain and culture, blood cultures, skin biopsy) have not yielded a diagnosis, should ideally undergo bronchoscopy with bronchoalveolar lavage. Lung biopsy should be performed if feasible. The diagnostic approach for such patients is discussed in greater detail separately. (See "Diagnosis of invasive aspergillosis", section on 'Approach to diagnosis'.)
Blood cultures — Unlike patients with aspergillosis, blood cultures are frequently positive in fusariosis, possibly due to the fact that Fusarium spp sporulate in vivo, facilitating dissemination and growth in the bloodstream [34]. Blood cultures are positive in approximately 40 percent of patients with invasive fusariosis [1] and usually become positive at a median of three days of incubation using commercial blood culture systems with aerobic bottles [50].
Growth of cultures — 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 [51].
The interpretation of fusarial growth from different specimen types depends upon several variables, with the patient's immune status representing the single most important factor. For example, culture of Fusarium spp from sinus aspirates or respiratory secretions in severely immunocompromised hosts should always be considered diagnostic of fusarial infection, whereas the growth of Fusarium spp from skin scrapings in an immunocompetent host may represent colonization or contamination of laboratory specimens. Pseudo-outbreaks of fusariosis have been reported [52].
In cultures, the production of both fusoid macroconidia (hyaline, multicellular, banana-like clusters with foot cells at the base) (picture 14 and picture 15) and microconidia (hyaline, unicellular, ovoid to cylindrical) are characteristic of the genus Fusarium and are important in identification of different species.
Histopathology — The diagnosis of fusariosis may require histopathologic confirmation. In tissue, the hyphae are similar to those observed in aspergillosis and scedosporiosis as narrow (3 to 8 microns wide), septated hyaline hyphae with dichotomous acute angle (45°) branching (picture 16 and picture 17). Adventitious sporulation, which is the ability to sporulate in tissue and blood, may be present [34]; the identification of hyphal and yeast-like structures in the same specimen is highly suggestive of fusariosis in high-risk patients. Because of the histopathologic similarities between fusariosis and other mold infections, a definitive diagnosis requires microbial growth or species identification using in situ hybridization or multiple real-time quantitative PCR in paraffin-embedded tissue specimens [53,54].
The site of biopsy depends upon the clinical manifestations in each patient, but the skin is a frequent site of infection and is the most accessible site for biopsy when multiple sites are affected. In a study of 181 patients with fusariosis (148 of whom had disseminated skin lesions), the skin was the only source of diagnostic material in 55 percent of the patients. Furthermore, skin lesions preceded fungemia in a significant proportion of cases [11]. Skin biopsies are safe and easy to perform and may provide a rapid diagnosis. Tissue biopsies should always be sent for microbiologic (direct exam and culture) and histopathologic examination.
Beta-D-glucan and galactomannan antigen — Fusarium releases 1,3-beta-D-glucan, and the test is positive in patients with invasive fusariosis. However, its lack of specificity does not help to establish Fusarium spp as the cause of an invasive fungal disease [55,56]. In one study, 13 patients with invasive fusariosis were tested for 1,3-beta-D-glucan in the serum; the test was positive in 12. In 11 patients, the test was positive at a median of 10 days (range 1 to 32) before the diagnosis of invasive fusariosis. Using 2 consecutive positive tests, the sensitivity, specificity, positive, and negative predictive values were 85 percent, 69 percent, 7 percent, and 99 percent, respectively [57]. Given the low positive predictive value, beta-D-glucan appears to have greater utility as a screening assay rather than a diagnostic assay. One special circumstance for which beta-D-glucan testing is proving to be useful is measurement of this substance in cerebrospinal fluid of patients with suspected fungal meningitis due to many different fungi, including Fusarium species [25,58,59].
The Aspergillus galactomannan antigen assay is a fairly specific test for invasive aspergillosis, but Fusarium species have been reported to cross-react with this assay [60,61]. A study in three Brazilian centers reviewed 18 cases of invasive fusariosis in patients who had galactomannan tests performed at least twice a week as screening. The test was positive in 15 patients, giving a sensitivity of 83 percent and specificity of 67 percent. The galactomannan test was positive at a median of 10 days before the diagnosis was established in 11 of 15 cases [50]. Therefore, positive galactomannan tests in high-risk patients should be interpreted as indicative of invasive aspergillosis or perhaps invasive fusariosis, especially in centers or regions in which invasive fusariosis is more prevalent. (See "Diagnosis of invasive aspergillosis", section on 'Galactomannan antigen detection'.)
Other techniques — Other techniques for the diagnosis of fusariosis include the polymerase chain reaction (PCR) and in situ hybridization, which have been shown in some studies to have good sensitivity and to have positive results several days before the diagnosis was made using conventional methods [62]. Reference laboratories can use PCR-based techniques for species identification. (See "Mycology, pathogenesis, and epidemiology of Fusarium infection", section on 'Species identification'.)
For suspected central nervous system (CNS) infection, PCR and metagenomic tests have been used on cerebrospinal fluid samples. For example, these tests are recommended by the Centers for Disease Control and Prevention (CDC) for symptomatic and asymptomatic patients involved in an outbreak of presumed Fusarium solani meningitis associated with epidural anesthesia in Mexico [24,25,63]. Details regarding this outbreak are available on the CDC website and the fungus education hub. (See "Aseptic meningitis in adults", section on 'Fusarium outbreaks'.)
In situ hybridization can be performed on histopathology specimens showing hyphal forms when the cultures are negative in order to identify the mold [53].
SUMMARY AND RECOMMENDATIONS
●Clinical manifestations – 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. (See 'Introduction' above.)
•Immunocompromised individuals – The most common presentation of fusarial infection in immunosuppressed patients is persistent fever refractory to antibacterial and antifungal therapy in the setting of profound and prolonged neutropenia. Other findings at presentation may include sinusitis, pneumonia, cellulitis at the site of pre-existing skin breakdown, and metastatic skin lesions. Endophthalmitis, rhinocerebral infection, myositis, and infections of the central nervous system have also been reported (table 1). (See 'Immunocompromised patients' above.)
•Fungemia and skin findings in invasive disease – In contrast with aspergillosis and most other invasive mold infections, a striking characteristic of fusarial infections in immunocompromised hosts is the high frequency of positive blood cultures and metastatic skin lesions. Disseminated disease is the most frequent clinical form of fusariosis in immunocompromised patients, occurring in approximately 70 percent of such patients. (See 'Fungemia' above and 'Disseminated disease' above.)
●Diagnosis – The diagnosis of fusariosis is confirmed by the isolation of Fusarium species in cultures of involved biologic materials, such as nail scrapings (onychomycosis), corneal scrapings (keratitis), skin biopsy (metastatic skin lesions), skin scrapings (interdigital intertrigo), sinus aspirates (sinusitis), respiratory secretions (pneumonia), and/or blood cultures (fungemia, disseminated disease). Tissue biopsy with culture and histopathology provides definitive evidence of invasive disease. (See 'Approach to diagnosis' above.)
•Importance of skin biopsy and blood cultures – In severely immunocompromised patients, two characteristics suggest the diagnosis of disseminated fusariosis: the presence of skin lesions (either cellulitis at sites of skin breakdown caused by trauma, interdigital intertrigo, or onychomycosis, or metastatic lesions) and mold growing from blood cultures (figure 1). Skin biopsies should be performed in all immunocompromised patients with suspicious skin lesions and should be sent for both histopathology and microbiology studies. Blood cultures should also be obtained. In individuals with lung involvement, a sputum sample should be sent for fungal stain and culture as well as other microbiologic studies when feasible. (See 'Approach to diagnosis' above.)
•Histopathology – In tissue, the hyphae of Fusarium spp are similar to those observed in aspergillosis and scedosporiosis as narrow (3 to 8 microns wide), septated hyaline hyphae with dichotomous acute angle (45°) branching (picture 16 and picture 17). Adventitious sporulation, which is the ability to sporulate in tissue and blood, may be present; the identification of hyphal and yeast-like structures in the same specimen is highly suggestive of fusariosis in high-risk patients. (See 'Histopathology' above.)
●Clinical work-up – The diagnostic evaluation of immunocompromised patients with fusariosis should be accompanied by a clinical and radiologic assessment of disease extent, including computed tomography of the paranasal sinuses and chest. Serum galactomannan antigen testing may be positive. (See 'Approach to diagnosis' above.)
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