Onychomycosis Caused by Fusarium Species

Onychomycosis is a nail fungal infection that produces nail discolouration, thickness, and separation from the nail bed. The species of the Fusarium genus that cause onychomycosis are emerging and the number of cases has increased throughout the years. Microscopic examination, as well as cultures, are required for the accurate diagnosis of onychomycosis. The goal of treatment is to eliminate the organism that causes the disease and restore the nail’s normal appearance. Here, we provide an overview of the onychomycosis cases that have been reported in literature over the last 24 years, which have been caused by the Fusarium species. We performed a review on the onychomycosis cases caused by the Fusarium species from January 1997 to January 2021. Patients aged between 40 and 49 years made up 30.23% of the cases. The most common aetiologic species was Fusarium solani species complex (FSSC), which accounted for 44.11% of the cases, followed by F. fujikuroi species complex (FFSC), which accounted for 17.64%; 14.70% of the cases were due to F. dimerum species complex (FDSC) and 14.70% of the cases were due F. oxysporum species complex (FOSC). Europe accounted for 29.06% of the cases caused by FOSC, whereas Africa accounted for 46.67% of the cases due to FSSC. The clinical presentation of onychomycosis due to Fusarium spp. is commonly the distal–lateral pattern of onychomycosis. Identification of the infectious agent in onychomycosis cases due to Fusarium is crucial in deciding the proper treatment. Although antifungal susceptibility tests have only been performed in a few cases, susceptibility testing can help with patient management.


Introduction
As some of the most common infections worldwide, superficial mycoses are becoming a major public health concern [1]. In some cases, superficial fungal infections can progress to invasive infections, which are becoming more common in at-risk populations [2]. Dermatophytes (tinea unguium), non-dermatophyte moulds, and yeasts can all cause onychomycosis [3]. Dermatophytes, particularly Trichophyton mentagrophytes and Trichophyton rubrum, cause approximately 90% of toenail and 75% of fingernail onychomycosis [4]. Non-dermatophyte moulds (NDMs) are an ecologically varied group of fungi that have major habitats such as saprotrophs and plant pathogens, but they are also involved in the aetiology of onychomycosis [5]. The Fusarium species, Aspergillus species, Scopulariopsis brevicaulis, Neoscytalidium dimidiatum, and Acremonium species are the most commonly isolated NDMs from clinics and hospitals around the world. NDM agents are thought to be responsible for 2-25% of all onychomycosis cases [5]. Fusarium species have been implicated as causative agents of opportunistic infections in both humans and animals. Local or systemic predisposing factors frequently trigger human infections, and disseminated illness is linked to weakened immune responses [6]. Onychomycosis caused by the Fusarium spp. almost always affects the big toenails, particularly those with traumatic and dystrophic abnormalities, as well as nails infected with dermatophytes [7]. Although early management of mycotic nails in immunocompromised and diabetic patients is critical to avoid life-threatening disease, research on the treatment of onychomycosis caused by the Fusarium species is sparse. Onychomycosis caused by the Fusarium spp. is little understood in terms of prevalence, clinical symptoms, and mycological features. The clinical, mycological, and epidemiological aspects of onychomycosis caused by Fusarium spp. are examined in this review.

Materials and Methods
The authors used the PubMed database to conduct literature review to find all human clinical episodes of onychomycosis caused by the Fusarium spp. Case reports and case series published in the last 24 years, from January 1997 to January 2021, were included in the search approach. The search was limited to English-language literature. The following keywords and concepts were used in conjunction with the "AND" operator: "Onychomycosis and Fusarium," "non-dermatophyte moulds and Fusarium," and "case reports," "case series," and "clinical cases." In addition, all pertinent references referenced in the case reports and reviews were manually searched to uncover other articles not found in the database search. We only included studies in this review that used repeated culture isolations and at least three of the following criteria to identify the Fusarium spp. as the sole pathogen causing toenail onychomycosis at the baseline: direct microscopic examination (DME), fungal culture, excluding the dermatophytes, histology, and polymerase chain reaction (PCR) testing. This review only included the Fusarium onychomycosis. Non-Fusarium species NDMs were excluded, as were NDMs that did not meet our inclusion criteria. First author, year of publication, country, age, gender, aetiologic agents, underlying diseases and risk factors, methods of diagnosis, clinical type, result, treatment, and minimum inhibitory concentration (MIC) values were retrieved from every connected study. We employed the same criteria stated to define the result-mycological, clinical, and cure [5]. Negative KOH microscopy and negative fungal culture were used to determine mycological cure; clinical cure was defined as the development of a completely normal-looking nail; and cure was defined as achieving both the mycological and clinical cure.

Results
There were 29 studies documenting the Fusarium spp. onychomycosis that met our criteria (Figure 1), representing 86 clinical cases from 16 countries (Table 1 and Supplementary Material Table S1). Patients aged 40 to 49 years accounted for 30.23% (26/86) of the 86 cases. The majority of the cases, 66.27% (57/86), included women (Table 1). Table 1 lists the clinical and epidemiological characteristics.       In Europe, FOSC is the most common Fusarium group (ranging from 35% to 56%), followed by the FSSC species (31% to 33% of cases). In the Americas and Asia, however, the FSSC species are the most common Fusarium group (65% to 76%), followed by FOSC (24% to 33%), which is consistent with our results (71.43% FSSC and 28.57% FOSC) ( Table 3).

Underlying Conditions and Exposure to Risk Conditions
The presence of underlying diseases was recorded in only 16.27% of the Fusarium onychomycosis case reports (14/86). Prior to the onset of the fungal infection, 42.8% (6/14) of the cases had a traumatic injury, followed by diabetes mellitus in 28.5% (4/14) of the cases; arterial hypertension in 14.2% (2/14) of the cases; and HIV and autoimmune illness in 7.1% (1/14) of the cases (Table 1).

Diagnosis
NDMs isolated from onychomycotic nail samples are classified as (i) contaminant, (ii) commensal, (iii) temporary saprobic coloniser, (iv) persistent secondary coloniser, (v) successional invader, and (vi) primary invader. Direct microscopy, fungal culture, histopathology, PCR, flow cytometry, and dermoscopy are some of the diagnostic procedures that have been utilised to diagnose NDMs. The presence of fungal elements such as hyphae, mycelium, and arthrospores can be detected through direct microscopic examination using potassium or sodium hydroxide (KOH or NaOH), sodium sulphide, or Parker's blue-black permanent ink. In 98.83% (85/86) of the Fusarium clinical cases, direct microscopic examination was performed ( Table 1).
The vitality of an isolated pathogen is demonstrated by a fungal culture, which verifies the clinical suspicion of onychomycosis. In the laboratory, Sabouraud dextrose agar (SDA) is widely used with antibiotics such as chloramphenicol, with or without cycloheximide added. When NDMs are sown in SDA, they tend to outgrow the slowergrowing dermatophytes; however, cycloheximide suppresses the NDM growth while permitting dermatophytes to proliferate. In 100% of the cases (86/86), fungal culture was found (Table 1). Only 36.86% (36/86) of the cases were identified molecularly; DME and culture were also used to identify the cases (Table 1).

Treatment and Outcome
Oral itraconazole was utilised in 26.74% (23/86) of the cases, oral terbinafine in 17.44% (15/86) of the cases, and topical amphotericin B in 8.13% (7/86) of the cases. Thymol solution 3% consists of a colorless crystalline monoterpene phenol that has in vitro antifungal activity, and is considered a potential treatment for onychomycosis. It was used in 8.13% (7/86) of the cases, while nail avulsion was used in 5.81% (5/86), photodynamic therapy was used in 2.32% (2/86), frequent drilling was used in 1.16% (1/86), and diluted clorox soaks were used in 1.16% (1/86) of the cases. A clinical cure was attained in 26.74% of the patients (23/86) and a mycological cure was achieved in 13.95% (12/86) (Supplementary Material Table S1). Table 4 summarises the MIC values of oral and topical antifungal medications against Fusarium clinical isolates from onychomycosis. Due to the wide range of susceptibility, it is crucial to identify the causal organism down to the species level to choose the right antifungal therapy.

Discussion
According to the literature, the prevalence of onychomycosis caused by Fusarium spp. in North America is 13.8%, with global prevalence ranging from 2% to 18% [8,9]. Fusarium falciforme and F. keratoplasticum were the most common Fusarium spp. recovered from individuals with onychomycosis in Thailand [10]. The Fusarium solani species complex and the FOSC species complex were the most common species in patients with onychomycosis, according to Brazilian research [11]. With immigration, travel across nations, changes in climatic conditions, and demographics, the prevalence and distribution of the Fusarium spp. that cause onychomycosis may fluctuate among regions. As a result, clinicians need to be aware of the presence of the common fungal species in their area.
Predisposition to onychomycosis is known to be caused by genetic, environmental, and systemic factors, as well as local nail features. These variables may be related to a poor antifungal treatment response [12]. Risk factors for NDM onychomycosis include climate, age, occlusive footwear, hyperhidrosis, local nail damage, family history, chronic skin illnesses, and occupational exposures. In addition, diabetes, and peripheral vascular disease, as well as immunological suppression, particularly after HIV infection, predispose individuals to Fusarium spp.-caused proximal subungual onychomycosis (PSO) [13,14]. In our study, onychomycosis was found as a lesion before dissemination in 259 published cases of invasive fusariosis. As a result, patients with immunodeficiency and onychomycosis caused by the Fusarium spp. must be closely monitored [15].
Toenails are more commonly affected by onychomycosis than fingernails due to recurrent trauma, slower growth, a larger nail plate, regular exposure to a damp environment in enclosed footwear, and limited blood flow to the underlying tissues [16,17]. The clinical classification is based on the location and mode of invasion of the nail unit, the clinical pattern of the infection, and histopathological findings. The type of lesion discovered in the nail unit can aid in determining the aetiological agent. Onychomycosis is classified into five types: distal and lateral subungual onychomycosis (DLSO), superficial onychomycosis (SO), proximal subungual onychomycosis (PSO), total dystrophic onychomycosis (TDO), endonyx onychomycosis (EO), and, more recently, mixed pattern onychomycosis (MPO) [18]. The organisms that cause onychomycosis are dermatophytes, non-dermatophyte moulds (NDMs), and yeasts. Most dermatophyte nail infections (60-70%) are caused by Trichophyton rubrum and Trichophyton mentagrophytes [9]. Several studies have found that the Fusarium spp. cause up to 10% of onychomycosis when aetiological agents are classified to the species level [11].
New diagnostic tools, such as molecular biology techniques, are increasingly being utilised. The fungal DNA extracted from clinical samples is amplified by polymerase chain reaction (PCR), which can then be analysed qualitatively and quantitatively using real-time PCR (RT-PCR). By amplification of 28S rDNA, nested PCR has been utilised to detect Aspergillus spp., Fusarium oxysporum, and Scopulariopsis brevicaulis [19,20].
Treatment options for NDM onychomycosis are still restricted and unoptimised, according to the literature; unlike dermatophytes, these fungi do not respond well to systemic antifungal medications [21,22]. However, onychomycosis caused by the Fusarium species has not yet been explored. Itraconazole pulse therapy (400 mg per pulse for three pulses; one pulse is 400 mg per day for 1 week, with 3 weeks off therapy) and the other itraconazole pulse therapy regimens have shown modest evidence of clearing Fusarium toenail infections [23,24]. Fusarium onychomycosis has been successfully treated in Japan using topical efinaconazole, oral itraconazole, and oral fosravuconazole (licenced in Japan since 2018 for tinea unguium) [25]. In an onychomycosis patient infected with Fusarium falciforme which was resistant to itraconazole and terbinafine, posaconazole pulse therapy (800 mg pulse for four pulses; one pulse is 800 mg/day for 1 week, with 3 weeks off medication) achieved mycological and clinical cure [14]. After performing antifungal susceptibility testing, case studies in the literature have indicated successful treatment of terbinafine-and itraconazole-resistant Fusarium species with posaconazole therapy [14]. Polyenes, such as topical amphotericin B, which has a broad antifungal spectrum, have been used successfully in treating a series of Fusarium onychomycosis cases in patients who had shown resistance to oral and topical antifungal medications [26]. In recent years, several studies on the susceptibility of dermatophytes, yeasts, and NDMs in vitro have been published in the literature [27][28][29]. To determine the minimum inhibitory concentration (MIC), fungal growth is measured in the presence of various antifungal drug concentrations. This confirms the efficacy of antifungal medications [30,31].

Conclusions
In conclusion, with a higher prevalence of onychomycosis cases in Asia and Europe, respectively, the Fusarium species are emerging pathogens according to this review. Adults, particularly women, are the most afflicted, and the toenail is the most common site of the infection. Although these nail infections are mostly seen in immunocompetent patients, they could possibly serve as a gateway for widespread infections in immunocompromised people. Direct microscopic examination and culture have been used to diagnose fungal infections in most patients. It is critical to identify the infectious agent in onychomycosis at the species level to provide proper treatment. Although this study does not reveal a high mycological or clinical cure rate, it is well recognised that cure is not always attained, even when antifungal medications are adequate for the identified aetiological agent. Although antifungal susceptibility tests have only been performed in a few cases, susceptibility testing can help with treatment management.