**1. Introduction**

Onychomycosis is a common nail infection caused by fungi, namely yeasts, dermatophytes, and non-dermatophyte molds (NDMs) [1]. The prevalence keeps increasing with age and it is commonly identified in elderly populations. Approximately 20% of adults in their second to fourth decades are affected by this disease. Yeasts contribute to 24–50% cases of onychomycosis with *Candida* species as the most common agent [2]. Various factors are associated with the event of onychomycosis, e.g. host's comorbidities (human immunodeficiency virus [HIV] infection, diabetes mellitus, peripheral circulation disturbances), repeated nail trauma, smoking, antibiotic therapy, immunosuppressive therapy, repeated exposure to fungi, humid climates, genetic predisposition, and occlusive footwear [2, 3]. Establishing the diagnosis of Candida onychomycosis (CO) is challenging. Albeit frequently identified in culture and direct microscopic examination, the presence of *Candida* species might only be colonization, not necessarily the cause of nail diseases. A careful interpretation of diagnostic tests' results and correlation with

results of clinical examination are necessary to establish the diagnosis of CO which will aid the clinicians in providing correct treatment for the patients [4].

### **2. Epidemiology**

The prevalence of onychomycosis differs based on geographical location with worldwide prevalence of approximately 10% [5]. The incidence onychomycosis in North America ranges from 8.7–13.8% while the prevalence in Southeast Asia ranges from 2–6% [2, 3]. Higher prevalence is reported in countries with humid climates, such as Greece (27.99%) and Ethiopia (60,4%), [6, 7]. While there are three groups of fungi responsible for onychomycosis, dermatophytes are the most common cause of onychomycosis (60–70%) [3].

Yeasts, most commonly identified as *Candida* species in onychomycosis, contributes in approximately 40% of the onychomycosis cases in Southeast Asia. Other studies reported that the prevalence of CO varies between 24–50% of onychomycosis cases [2]. NDMs and yeasts onychomycosis is more common in subtropical and tropical climates while dermatophytes is more common in temperate climates [7]. *Candida albicans* is identified as the most common isolated species, followed by *C. parapsilosis, C. krusei, C. tropicalis,* and *C. glabrata* [2]*.* CO is more frequently to be identified in fingernails than toenails, especially in patients with hands continuously immersed in water [3].

## **3. Prognostic factors**

In assessing the treatment outcome of CO patients, there are three types of cure to be considered, which area mycological cure, clinical cure, and complete cure. Clinical cure is described as a previously infected nail without signs and symptoms of onychomycosis. Mycological cure is described as negative results on both direct microscopic examination and culture. Complete cure is described as achieving both clinical and mycological cure [8]. Various prognostic factors have been identified for the treatment outcome of onychomycosis. In general, they can be divided into three groups, which are patient's characteristics, nail features, and the infectious agents (**Table 1**) [9].

Most studies reported that the onychomycosis is more commonly diagnosed in men. Male patients are associated with poor outcome because they are more likely to be exposed to repeated nail trauma and they usually do not seek health care until the disease becomes too advanced. Furthermore, they are more likely to have low compliance; hence, male patients become more resilient when it comes to treatment and have 2,6 times risk of not achieving clinical cure [8]. Increasing age is also known to be associated with poor prognosis in onychomycosis patients because elderly populations usually suffer from poor circulation system, poor immune status, decreased nail growth, and mixed fungal infections. Hence, their response to therapy might be lacking and they have 3,7 times risk of not achieving clinical cure [8, 9].

Nail trauma can exert significant and irreversible damage which will predispose patients to onychomycosis. Patients who have abnormal nails with positive mycology examination had 5,4 times risk of developing onychomycosis [9]. Other poor prognostic factor is history of onychomycosis. Patients with prior infection have 2,3 times risk of not achieving clinical cure. These patients are more likely not to respond standard treatment course since they have been treated before. There might also be involvement of genetic susceptibility in the development of recurrent onychomycosis [8].


#### **Table 1.**

*Poor prognostic factors in onychomycosis [4, 8–10].*

As most fungi are opportunistic agents, poor immune status can predispose patients to onychomycosis, especially in HIV patients with CD4 count <400/mm3 . The onychomycosis is more likely to involve fingernails and toenails also more severe [9]. Patients with hand and foot involvement have 1.1 times risk of not achieving complete cure and if the patients have more than 3 infected nails, they have 1.5 times risk of not achieving complete cure [4]. Furthermore, hallux involvement presents as poor prognostic sign because it is more likely to suffer repeated trauma lead to predisposition of continuous infection.

In addition, poor peripheral circulation caused by chronic venous disease is associated with poor prognosis. Chronic venous disease can cause nail dystrophy, hyperkeratosis, discoloration, hyperplastic nail bed, and onychogryphosis. Only 25% of patients treated with itraconazole are cured [9]. Poor peripheral circulation can also identified in patients with uncontrolled diabetes mellitus which associates with secondary infections and nonhealing ulcers. This population is also reported to have more severe onychomycosis, high recurrence rate and longer duration to achieve complete cure [9].

Repeated exposure to water and detergents will predispose patients to chronic paronychia and affect the drug delivery since the tissue is more edematous and inflamed. While repeated exposure to mud and soil, also barefoot walking will predispose the patients to repeated minor trauma. Most fungi are saprophytic; hence, they can invade nails easily in this condition. This often happened in tropical countries [10].

Subungual hyperkeratosis is host's reaction towards fungal infection by thickening the stratum corneum. The thick debris presents as a barrier to antifungal agents, both systemic and topical agents [9]. Furthermore, patients with matrix involvement have 2.1 times risk of not achieving complete cure [8]. Matrix is known to be the nail's origin [11]. Hence, matrix involvement in onychomycosis will affect the nail growth and drug delivery [8]. In addition, the slow nail growth is also a poor prognostic factor since the patients shed the infected portion of the nail more slowly. This association is also described in elderly populations. Slow nail growth is also seen in significant nail plate involvement. Greater surface involved is associated with greater fungi load; hence, lower cure rates [9].

Significant lateral disease affects the treatment outcome since there is poor attachment of the lateral edge to the nail groove. This can reduce the drug delivery about two thirds of normal nail. Similar cases are seen in severe onycholysis [9]. Patients with lateral disease have 3,5 times risk of not achieving complete cure [8]. Another poor prognostic factor is dermatophytoma, a dense thick-walled fungal elements presenting as white to yellow patch or longitudinal streak in nail plate. This dense mass is difficult to be penetrated by antifungal agents. Therefore, the patients with dermatophytoma have 2.9 times risk of not achieving clinical cure [8, 9].

Melanonychia is black pigmentation identified on the nail plate. This feature is associated with poor prognosis in onychomycosis. However, the association has not been elucidated yet. Total dystrophic onychomycosis (TDO) is the final destructive stage of onychomycosis, in which there is thickened nail bed, crumbling nail plate, and significant involvement of nail matrix. Patients with TDO have 1.1 times risk of not achieving complete cure [4, 9].

As for the infectious agents, CO and NDMs onychomycosis indicate poor prognosis. CO is associated with immunosuppression, especially in case of chronic mucocutaneous candidiasis (CMC) and HIV patients. While NDMs infections are difficult to be diagnosed and lack of data for treatment course. In addition, fungal and bacterial infections can complicate the treatment. Therefore, these factors can implicate in poor prognosis of onychomycosis patients [9].

In order to aid the clinicians in have better treatment outcome, several instruments have been developed to predict the prognosis in onychomycosis patients. The first developed instrument was Scoring Clinical Index for Onychomycosis (SCIO Index). This scoring assesses the nail's clinical component based on its clinical form, nail involvement, and subungual hyperkeratosis. In addition, it assesses the growth component based on the patient's age and location of onychomycosis. As the score increases, the onychomycosis might be more difficult to treat [12]. However, this scoring has not been validated and has other limitations, such as exclusion of important prognostic factors and complex calculation [9].

Another scoring was developed by Baran et al. (**Table 2**). The higher the score, the more likely the treatment failure will happen [13]. Albeit being the most comprehensive instrument, this index has not been validated and time-consuming [9].

The most commonly used instrument is Onychomycosis Severity Index (OSI). OSI is simpler by assessing three major components, which are area of involvement, proximity of disease to matrix, presence of dermatophytoma or subungual


#### **Table 2.**

*Baran-Hay's severity index for onychomycosis [13].*

hyperkeratosis >2 mm (**Table 3**). The score is multiplication of score for area of involvement with score for proximity of disease and addition of score for the presence of dermatophytoma or subungual hyperkeratosis >2 mm. Score 1–5 indicates mild onychomycosis; 6–15 indicates moderate onychomycosis; and 16–35 indicates severe onychomycosis [14]. This index has been validated with high reliability. However, this index only assesses one nail, does not correlate the severity of disease with treatment outcome, and excludes other important prognostic factor [9].


#### **Table 3.**

*Onychomycosis severity index [14].*

## **4. Pathogenesis and causative agent**

The most common causative agent of yeast onychomycosis is candida species. Fingernails are the predilection site of CO, especially in patients who are regularly submerging their hands in water [3]. Candida species are a commensal part of the normal skin flora, which are present in nature. However, these species may exhibit opportunistic quality in an immunocompromised host. Candida species can be either primary or secondary causative agent in onychomycosis. Primary CO can be commonly encountered in a severe immunocompromised host, for example, in HIV patient. On the contrary, secondary CO is usually related to predisposing diseases or circumstances, for instance, diabetes mellitus, malnutrition, peripheral vascular disease, chronic nail trauma, smoking, and vulnerable age (elderly and children). Particular occupations such as housekeepers, fishers, and farmers are also at risk of CO due to the frequent trauma and excessive moisture on the nails, exposure to contaminants, and contact with chemicals [2].

Instead of appearing as individual spores and hyphae, fungal organisms tend to integrate, forming a biofilm which is a syntrophic group of fungi adhering to the host's surface. When not infiltrating a substrate, fungi may fluctuate between freefloating types and parts of a superficial biofilm. This particular feature provides benefits for fungi development while being surrounded by extracellular matrix (ECM). The surrounding ECM defends fungi from the host's immune response and antifungal treatments. ECM also supports fungi to distribute nutrients to the biofilm. Fungi biofilm contributes to the rationale of why onychomycosis is relatively refractory to antifungal treatment and challenging to eliminate the spores in chronic manifestation entirely [3].

The biofilm development by *C. albicans* is initially started with the adhesion and colonization of *C. albicans* cells on an appropriate substrate. Several features that influence the attachment process of *C. albicans* are non-specific factors (electrostatic forces and hydrophobic part of the cell membrane) and specific factors (adhesin on the extracellular layer of *C. albicans,* which connects the ligands on

#### *Candida Onychomycosis: Mini Review DOI: http://dx.doi.org/10.5772/intechopen.96650*

the film). Besides attaching to their counterparts, *Candida* species can also occur secondary to bacteria that have previously colonized their host. When the attachment process followed by microcolonies formation has completed, *C. albicans* began to proliferate characterized by the budding yeasts, production of filamentous structure, and deposition of ECM materials, ultimately resulting in biofilm formation. The filamentous structure supports the biofilm scaffolding and protects the adhesion spots for the budding yeasts [15].

There are 3 definite stages of *C. albicans* observed through microscopic examination, including early stage (0–11 hours), intermediate stage (12–30 hours), and maturation stage (72 hours) [15, 16]. During the 3rd and 4th hour, budding yeasts' microcolonies can be observed, while pseudo-hyphae and true hyphae start to appear in the 4th hour and 8th hour, respectively. Throughout the intermediate stage, microcolonies are later bounded by hyphae, which eventually results a single coalescent layer formation. An opaque film overlaying the microcolonies can be observed at this stage, which is mainly composed of non-cellular material such as polysaccharides. The basal layer is composed of yeast cells, while the filamentous cells constitute the underlying structure. Eventually, the maturation stage is characterized by the multiplication of extracellular material in a time-dependent manner until the mature biofilm covering the entire fungi has been developed [15].

In addition to biofilm, yeast factors that contribute to the virulency of CO are synthetization of hydrolytic enzymes, including proteinase, hemolysin, and phospholipase, which are unique between each type of Candida species. Moreover, proteinase plays a part in the breakdown of protein and phospholipase contributes to the destruction of the host cell, allowing *Candida* species to invade the host [2]. The reported prevalence of CO is 5–10% of all onychomycosis cases. The most common causative species of CO are *C. albicans* and *C. parapsilosis* [17].
