Introduction

Onychomycosis, fungal infection of the nail, is a common medical problem of adults. Recently, it has been reported that about 20% of persons between 40 and 60 years of age have onychomycosis [1–3]. Frequent exposure to fungus, irrational use of antibiotics, HIV infection and immunosuppressive drug therapy are some predisposing factors for onychomycosis [4]. Other contributory factors comprise diabetes mellitus, peripheral vascular disease, chronic smoking and trauma to aged nails. Strikingly, one in every five patients with HIV is having nail-related mycoses [5]. Moreover, onychomycosis is now considered as one of the premonitory signs of HIV infection [6]. On the other hand, agricultural workers, laborers, housewives, fish mongers, tea makers, athletes and launderers often get onychomycosis exhibiting an occupational risk for the disease [1, 7].

Mainly, three kinds of fungi are implicated in onychomycosis: dermatophytes, Candida species and nondermatophytic molds [8]. Candida species that inhabit human skin and mucosa as innocuous commensals are known to incite opportunistic infections ranging from less severe superficial lesions to dangerous systemic conditions when the host immunity is weak. Superficial candidiasis, the commonest form of Candida-related infections may involve one or more mucocutaneous tissues including skin, mucous membrane, nails and hair, while candidal infection limited to nails and finger web is better known as candidal onychomycosis [7]. Intriguingly, onychomycosis induced by Candida species has inclined recently, and some investigators have argued that Candida species are the leading cause for all forms of onychomycoses [1, 2, 7]. Hence, this is an attempt to review recent literature on onychomycosis caused by Candida species.

Epidemiology

An extensive survey of cutaneous mycoses from patients of eleven states in the USA from 1999 up to 2002 has demonstrated that more than 70% of onychomycoses are due to Candida species [9]. Conversely, further comprehensive studies have pointed out that Candida still remains as the second commonest etiology for onychomycosis [4, 5, 8, 10]. Onychomycosis is one of the characteristic features in patients with chronic mucocutaneous candidiasis (CMC) whose cell-mediated immunity is poor [11, 12]. Moreover, a survey of 500 HIV-positive patients from North and South America has reported that the prevalence of onychomycosis was 23.2%, and the responsible organisms were dermatophytes followed by Candida species [5]. It has also been suggested that candidal onychomycosis in an otherwise healthy individual warrants laboratory evaluation of immune system including HIV assays [13]. Collectively, foregoing data support the fact that Candida species are potential pathogens to cause onychomycosis especially in immunocompromised patients.

Resembling many other Candida-associated infections like oral or vaginal candidiasis, out of about 150 Candida species, Candida albicans is the principal pathogen responsible for candidal onychomycosis [1]. Interestingly, a study of onychomycosis in Polish children has revealed that almost 10% of the participants had fingernail or toenail fungal infections, while predominant pathogen from fingernail was C. albicans [4]. It has been reported that C. albicans-induced onychomycosis could aggressively involve all twenty nails in severe immunocompromised status like in premature babies [14]. Intriguingly, Candida species other than C. albicans such as Candida krusei, Candida parapsilosis, Candida glabrata and Candida tropicalis have also been found to cause onychomycosis [10, 15]. It has been found that C. parapsilosis is the leading cause for onychomycosis in a group of patients from Malta followed by C. tropicalis and Candida guilliermondii [16]. As such, it is interesting to note that Candida species other than C. albicans are emerging as important pathogens for nail infections following the trends seen in oral and systemic candidiasis among immunocompromised patients globally.

Some investigators have claimed that children below 3 years of age are vulnerable to have candidal onychomycosis [4]. Furthermore, it has been noticed that children are prone to onychomycosis caused by Candida species other than C. albicans such as C. glabrata [17]. Two recent case reports have stated that C. parapsilosis [18] and C. tropicalis [19] were responsible for onychomycosis in infants. Interestingly, a Brazilian study that examined 200 mycological samples from infected nails has shown that the leading pathogen is C. parapsilosis (40.5%) followed by C. albicans (31.5%), C. tropicalis (26%) and C. guilliermondii (2%) [20]. Such an increased tendency for non-albicans Candida infections of the nail poses a challenge in the disease management as the latter Candida species are often notorious to develop antifungal resistance. In addition, multiple nail involvement with multi-species of Candida that resist routine treatment protocols is also a serious problem in the management of candidal onychomycosis in HIV-affected patients [6].

Pathogenesis and Associated Disorders

Candidal commensalism is determined by the fine balance between fungal virulence and the host immunity [21]. Opportunistic infections due to Candida usually herald underlying problems of host immunity. Accordingly, onychomycosis is common in patients having DiGeorge syndrome, agammaglobulinemia and thymus dysplasia, where cellular and humoral immunity are defective. Congenital or acquired ectodermal defects, endocrine disorders such as hypothyroidism, hypoparathyroidism, hypoadrenalism and diabetes mellitus are some of the common systemic diseases that facilitate candidal nail infections via suppression of host immunity [8, 11]. Syndrome of candidiasis associated with endocrine abnormalities mentioned earlier is thought to be genetically determined and often identified as a familial disease [11].

Furthermore, Candida can be a primary or secondary pathogen in causing onychomycosis. Its role as a primary pathogen is almost always seen in severe immunosuppression such as HIV infection and CMC [19, 22]. Peripheral vascular diseases, malnutrition, personal habits such as smoking and chronic trauma to the aged nails may compromise the host immunity at the nail complex leaving a greater predilection for onychomycosis [1, 11]. In such conditions, Candida may act as a secondary pathogen.

Fingernail onychomycosis is often attributed to occupational trauma in housewives, farmers and fishermen [1, 8]. This could be due to the fact that these individuals’ nails are exposed to moisture and contaminants that carry fungi at large. Regarding the house wives, prolonged contact with water and detergents is an important risk factor that suppresses the local immunity at the nail complex [10]. Onychomycosis has also been attributed to the low socioeconomic conditions with poor personal hygiene, and it has been noticed that prevalence of onychomycosis among primary school children is high in a rural low socioeconomic community [17]. Although the iatrogenic immunosuppression has not been confirmed as a predisposing factor for candidal onychomycosis, it has been found that out of 102 renal transplant patients on immunosuppressive therapy, 12.7% had onychomycosis exclusively due to C. albicans [23]. However, those investigators did not find a significant difference when compared with the healthy control group, and it was speculated that both immunosuppression either systemically or locally at the nail complex and the exposure to the fungus are important factors to incite mycoses in the study population of Güleç et al. [23]. Taken together, it is tempting to speculate that both tissue integrity that determines local immunity of the nail complex and systemic immunity go hand in hand in the maintenance of healthy nails.

Moreover, Candida species have developed several virulence mechanisms that help pathogenesis of onychomycosis. Candida is known to produce extracellular hydrolases including proteinases, phospholipases and lipases that help tissue invasion [24]. These pleomorphic fungi produce filamentous hyphae when invading the host epithelium. For instance, Jayatilake et al. [25, 26] have demonstrated profuse hyphal invasion and associated cavitations of artificial human oral epithelium and rabbit oral epithelium infected with Candida. These investigators suggested that the cavitations of the epithelium were created by extracellular enzyme activity of fungi. It has also been reported that extracellular proteinase production by Candida species increases markedly when the culture medium is supplemented with keratin [27]. This shows that keratin which makes most of the nail substance, would act as an excellent growth environment for virulent Candida strains. There are antimicrobial peptides that can resist pathogenic challenge within the nail complex [28]. However, it has been demonstrated that candidal hyphal invasion inhibits the expression of antimicrobial peptides such as human beta defensins in reconstituted human oral epithelium [29]. Therefore, it is conceivable that Candida may also alter the expression of effector molecules such as defensins within the nail, and this phenomenon needs further investigations. On the other hand, it has been demonstrated that C. albicans produces melanin particles in vitro as well as during infection of tissues [30]. These investigators have attributed fungal melanin to protect fungi from antifungals, antimicrobial peptides, ultraviolet light and temperature. Ultimately, above findings suggest that multiple virulence mechanisms of Candida are involved in the pathogenesis of nail infections.

Clinical Features and Classification

Candidal onychomycosis commonly affects fingernails when compared with toenails and nearly half of the fingernail-related onychomycoses are due to Candida species [4, 8, 9]. It has also been reported that candidal onychomycosis is common in women [8, 16]. Thus, it has been postulated that women self-inoculate their nails from their vaginal candidal flora [31]. Yet another possible cause for high frequency of onychomycosis in women is that they frequently handle water, detergents and soap during household work, and their fingernails are prone to trauma in case of housewives. However, exact causes for Candida to infect fingernails and to show a sex predilection are yet to be uncovered.

Candida affected nails show severe dystrophic changes of the nail fold and marked thickening, distortion and fragmentation of the nail substance. Pigmentation of nail tissue is a remarkable clinical feature of candidal onychomycosis. Sometimes, candidal onychomycosis may appear with paronychia with white yellow discoloration and with a wavy structure of affected nail plates [4]. Strikingly, diffused melanonychia (black nail), which became intense with the paronychial inflammation due to C. albicans has been demonstrated in a fingernail of a white male [32]. These investigators noted that the infected nail was fragile with the increasing intensity of the pigmentation. The pigmentation was attributed to melanin produced by C. albicans, and it was suggested that formation of melanin pigments is one of the virulence mechanisms of this fungi in response to antifungal treatment [32].

Due to multifactorial etiopathogenesis and differing clinical presentations, candidal onychomycosis deserves proper classification. Elewski [31] in an extensive review of the literature on onychomycosis, classified Candida-associated nail infections: (a) candidal paronychia, (b) candidal granuloma and (c) candidal onycholysis. This classification is based on clinical presentation and the route of invasion of the nail plate by the fungi.

Candidal paronychia

It is the most common type of candidal onychomycosis, and its incidence is higher among individuals whose nails are constantly exposed to moisture [1]. Candidal paronychia is characterized by Candida invasion of the nail plate after having affected the soft tissue around the nail. Surrounding soft tissues demonstrate inflammation and will be red and edematous (Fig. 1). Once the nail matrix is infected, transverse depressions, known as “Beau’s lines”, may become apparent in the nail plate. Progressive infection results in a rough, irregular, convex and finally dystrophic nail. Paronychia has been clinically identified as acute and chronic paronychia. Acute paronychia is mostly due to bacterial infection, whereas 95% chronic paronychia is due to candidal infection [33, 34]. Thus, some investigators have claimed that C. albicans is the leading pathogen for paronychia [1]. Histopathologically, candidal paronychia is characterized by fungal invasion into the nail plate secondarily to the soft tissue infection around the nail [31].

Fig. 1
figure 1

Candidal paronychia resulting rough, irregular dystrophic nail. Surrounding soft tissues demonstrate inflammation with swelling (arrow)

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Candidal granuloma

Candidal granuloma is unique to patients with CMC. In this severe form of onychomycosis, Candida invades the full thickness of the nail. Advanced cases with the swelling of lateral and proximal nail folds may cause digit deformity called pseudo-clubbing or “chicken drumstick” appearance [31]. Direct invasion of Candida into the nail plate results in brittle nails.

Candidal onycholysis

Initial stages of the onycholysis show distal subungual hyperkeratosis with a yellowish-gray mass that lifts off the nail plate. This condition leads to separation or lysis of the nail. Hence, it is known as candidal onycholysis, and it is commonly found on hands compared to feet [31].

Further, a recent descriptive classification has identified four entities of candidal onychomycosis namely: (1) chronic paronychia with secondary nail dystrophy; (2) distal nail infection; (3) CMC and (4) Secondary candidiasis [35]. Chronic paronychia is often associated with prolonged exposure to moisture or irritants with possible allergic reactions leading to detachment of the nail cuticle facilitating candidal invasion. Distal nail infections are associated with peripheral vascular diseases such as Reynaud’s disease. Chronic mucocutaneous candidiasis in which there is gross immune dysfunction often leads to candidal granulomas of the nails. Secondary candidal infections occur in morbid nails in conditions like psoriasis or lichen planus. This classification is mainly based on the contributory factors of candidal infection when compared with the previous classification by Elewski [31], and there is considerable overlap in either classification. However, it is vital to have a uniform classification of candidal nail infections considering many aspects including etiopathogenesis and clinical manifestations.

Diagnosis

Diagnosis of candidal onychomycosis is imperative as it exhibits the immune status of an individual. For example, there are instances where diagnosis of candidal onychomycosis has helped in identification of advanced HIV infection [13]. Clinical examination and the detailed history of nail dystrophy help diagnosis immensely. More than half of onychomycosis cases are associated with fungal infections at other sites of the body and complete examination of entire skin is important to find concurrent infections [8]. It is also important to note that nail dystrophies are not solely due to fungal infections. Several entities have to be considered in differential diagnosis, and some investigators have claimed that accurate diagnosis of onychomycosis is unattainable only on clinical grounds [36]. Nail dystrophy alerts nail infection by fungi or bacteria as well as conditions like psoriasis, lichen planus and dermatitis. Therefore, accurate diagnosis of onychomycosis depends on direct microscopic investigation, mycological culture followed by histopathological examination [31].

Dermatophyte infections of skin and nails are often misinterpreted as candidiasis and microbiological investigations are important for definitive diagnosis [12]. Firstly, obtaining a good specimen for microscopic examination and culture is an important step in the diagnostic process. Regarding the suspected candidal onychomycosis, samples should be collected from the proximal and the lateral nail edges. In case of onycholysis, it is advisable to scrape the lifted nail bed [31]. Thus, collected samples can be used for direct microscopy and mycological culture. Usually, routine diagnostics are done using direct microscopy with 10% KOH. More effective mycological cultures are done using Sabouraud dextrose agar. Positive microbiological cultures would provide characteristic cream to white color colony growth on Sabouraud dextrose agar. As part of the diagnosis, antifungal susceptibility test may be useful for selection of the most suitable drug for treatment [31]. Interestingly, the simplest direct microscopy has yielded better results when compared with culture techniques in the diagnosis of onychomycosis [1, 17]. Microscopic investigations into nail clippings show characteristic hyphal invasion of nail substance particularly via hyponychial epithelium [19]. Such invasion can be clearly demonstrated using Periodic acid Schiff (PAS) or Grocott’s methanamine silver stains (Fig. 2). Scanning electron microscopy has also been utilized to identify invasive characteristics of Candida into nail substance, and it has been found that candidal pseudohyphae penetrates ventral surface of the nail plate causing multiple cavities [37]. However, further ultrastructural investigations into the nail–Candida interface during onychomycosis may help demystify important host–fungus interactions.

Fig. 2
figure 2

Microscopic investigations into nail clippings after Periodic acid Schiff stain show characteristic candidal hyphae (arrow) invading the nail substance

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For histopathological observations, nail clippings must be softened using chitin-softening agent (10% trichloroacetic acid in formalin) prior to processing and staining with PAS or Grocott’s methanamine silver stain. Histology with nail biopsies is not compulsory when the direct microscopy indicates fungal invasion of the nail. However, some discrepancies have been reported between negative direct microscopy and positive histopathological examination [32]. Histopathological preparation of candidal onychomycosis demonstrates hyphal invasion of the nail plate, and it helps confirming the diagnosis (Fig. 2) [8]. Yet, it is important to note that it is not unusual to see candidal blastospores in a KOH specimen of a nail scraping or in a histopathological specimen as Candida is a common commensal of the human skin. However, demonstration of pseudomycelia using either KOH or PAS staining strongly suggests invasive candidal infection [22].

Management and Prevention

Onychomycosis is often recalcitrant to conventional treatment. El Sayed et al. [36] reported that, out of all superficial fungal infections, onychomycosis is the most difficult one to manage. Its chronic nature, with high propensity of recurrence, is often attributed to the difficulty in elimination of the pathogen. However, onychomycosis in compromised status such as diabetes mellitus, elderly age and HIV infection should be treated promptly, as it can worsen into fungal cellulitis or even systemic candidiasis [36]. First of all, it is important to get rid of the predisposing factor, and host immunity should be restored in order to see the maximum effect of antifungal therapy.

Antifungal drugs play an important role in the elimination of Candida from the nail tissue. However, mere clinical evidence does not indicate antifungal therapy for onychomycosis [35]. Several other factors such as patient’s general heath, antifungal sensitivity of the organism, degree of fungal invasion and patients’ compliance have to be taken into account when selecting an appropriate antifungal drug. Slow rate of nail growth, hardness of nail plate and the location of infectious process between the nail bed and the nail plate are major factors interfering with eradication of fungal elements during the treatment. Compliance of patient is also a determinant of the success of the treatment and some patients do not seek treatment because the disease is often minimal or they are embarrassed to seek treatment [38].

Systemic Antifungals

The primary objective of antifungal therapy is to eliminate fungi from the affected nail. Antifungal drugs from various categories including polyenes (amphotericin), triazoles (fluconazole, itraconazole), imidazoles (clotrimazole, ketoconazole, miconazole) and morpholines (amorolfine) are used in the management of candidal onychomycosis [15]. Although amphotericin B is given intravenously for CMC, nail infections respond slowly since it is highly protein bound and less penetrative into the tissues [37]. Itraconazole given systemically has been suggested as highly effective in the management of candidal onychomycosis, while several other drugs are being used currently [32]. Furthermore, Elewski [31] suggested that onychomycosis due to Candida species can be successfully treated with itraconazole or fluconazole. Hepatotoxicity, effects on the bone marrow, hypersensitivity reactions and drug interactions with contraceptives, barbiturates, warfarin, etc. should be considered in the use of both older (griseofulvin, ketoconazole) and newer (itraconazole, fluconazole, terbinafine) antifungal drugs [31]. In vitro studies have shown that most of the antifungals including ketoconazole, fluconazole, itraconazole, amorolfine, clotrimazole and miconazole show similar activities against many of the Candida species isolated from mucocutaneous candidal infections [15]. Supporting these observations, Warshaw et al. [39] found no significant differences in the mycological cure rates in patients who were given terbinafine or itraconazole for Candida infections in the toenails. It was also suggested that more than 3 months of terbinafine or itraconazole therapy was necessary to clear candidal infection from the toenails [39]. Forgoing data suggest that many of the currently used antifungal drugs share similar activities against Candida causing onychomycosis, whereas the total cure requires long durations of therapy.

Griseofulvin has been used orally against candidal onychomycosis, because it is selectively concentrated in keratin [31]. Unfortunately, clinical and mycological cure rates are low, and recurrence is frequent with griseofulvin. Recent availability of new antifungal drugs with high therapeutic efficacy and minimal systemic toxicity has revolutionized the management of nail infections.

Topical Antifungals

Topical antifungal treatment for onychomycosis is generally ineffective, since the drug penetration via nail is low when compared with other tissues [12, 31]. However, several antifungals in the form of solutions, creams and topical nail lacquer have been used for the treatment of mild to moderate onychomycoses. For instance, amorolfine having different chemical character from other antifungal drugs has been used successfully in the management of candidal onychomycosis in the form of cream and lacquer [15].

Surgical Procedures

Sometimes, antifungal treatment alone will not suffice to arrest fungal infections of the nail. It is important to remove the source of the organism in immune-deficient subjects. Most of the time, infected nails act as a reservoir of fungi in reinfection process. Therefore, severely infected nails may require surgical removal in order to facilitate regrowth of a completely normal nail [11]. However, surgical removal of the infected nails is not always recommended for the treatment of onychomycosis as it is a painful and disfiguring procedure that should be reserved for isolated cases such as contraindications to the use of systemic antifungals, drugresistance and severe disfiguration. Sometimes, less severe acute nail infections could be managed with warm water soak, oral antibiotics/antifungals and surgical debridement [33].

While acting as a reservoir of yeast to be self-inoculated to skin and other body niches infected nails can lead to cross-infection among close associates such as family members [4]. Furthermore, chronic fungal existence within the nail complex may give rise to systemic mycoses and development of antifungal resistance. Most importantly, patients having onychomycosis experience significant negative effect on the quality of life in the form of physical, psychological, social or occupational problems [7, 31]. Therefore, it is vital to choose an appropriate treatment protocol considering many factors including patient’s medical, psychological and social status along with fungal virulence and susceptibility. Overall, everybody should be enlightened regarding the importance of good nail hygiene in averting number of infections including candidal onychomycosis.

Conclusions

The importance of onychomycosis is often underestimated. Far more than being a simple cosmetic problem, infected nail serves as a chronic reservoir of infection, which can give rise to repeated mycotic infections of the skin and mucous membrane. Candida species have emerged as important pathogens to cause onychomycosis with the increased immunocompromised population and altered fungal virulence. Proper history and clinical examination followed by microbiological and histopathological investigations assist in the diagnosis of onychomycosis. Effective antifungal therapy and surgery as well as the correction of underlying immune defects are key factors in the management of candidal onychomycosis. Besides, improvement of patient awareness on the nail hygiene and appropriate treatment procedures help in the management of patients with candidal onychomycosis.