Pathogenesis, Immunology and Management of Dermatophytosis: Comparison
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Dermatophytic infections of the skin and appendages are common skin diseases. The pathogenesis involves complex interplay of agent (dermatophytes), host (inherent host defense and host immune response) and the environment. Infection management has become an important public health issue, due to increased incidence of recurrent, recalcitrant or extensive infections. Recent years have seen a significant rise in incidence of chronic infections which have been difficult to treat.

  • dermatophytes
  • treatment
  • pathogenesis

1. Introduction

Dermatophytoses are superficial fungal infections caused by dermatophytes affecting the skin, hair and/or nails [1]. They are also termed as tinea infections. Dermatophytes are filamentous fungi that invade and feed on keratinized tissue like skin, hair and nails, causing an infection [2]. Dermatophytes are divided into nine genera, of which Trichophyton (usually affecting skin, hair and nails), Epidermophyton (usually affecting skin) and Microsporum (usually affecting skin and hair) cause infection in humans. Trichophyton rubrum is the most common isolate observed in infections of the feet, body and nails. Depending on the mode of transmission, they are classified as anthropophilic (from humans), zoophilic (from animals) and geophilic (from soil). They are clinically classified by infection site as tinea capitis (head), tinea faciei (face), tinea barbae (beard), tinea corporis (body), tinea manuum (hand), tinea cruris (groin), tinea pedis (foot) and tinea unguium (nails). Other clinical variants include tinea imbricata, pseudoimbricata, and Majocchi granuloma [3]. Recent years have seen an increasing prevalence of dermatophytic infections across the world, especially in tropics. Though not a life-threatening disease alone, it may significantly affect the quality of life [4]. A recent increase in the prevalence, recurrence and resistance could be attributed to the changing epidemiology.

2. Changing Trends in Epidemiology

Dermatophytoses, as common superficial fungal infections worldwide, have a higher incidence in tropical and subtropical countries like India due to the presence of high humidity and environmental temperature. Increased urbanization, occlusive footwear, and tight clothing also predispose to higher prevalence [5]. In the last few years, studies have shown a rising trend in the prevalence and also noted a change in the spectrum of infection along with the isolation of previously uncommon species [6,7,8,9][6][7][8][9]. The rising trend of recalcitrant dermatophytoses could be due to an epidemiological shift in the growth patterns of dermatophytes providing them with advantages of better survival and persistence, an evolution in the genetic make-up of the fungi, enhancing their virulence and pathogenicity, rapid emergence of drug-resistant species due to the rampant use of inadequate doses of potent antifungals. Studies reported a recent shift in the organisms isolated from T. rubrum to T mentagrophytes complex [8] in Western India and M audounii [7]. Recent studies have shown increasing proportion of TT mentagrophytes mentagrophytes complex, mainly TT mentagrophytes mentagrophytes var mentagrophytes. Also, these species showed increased minimum inhibitory concentrations to the commonly used antifungal agents [10].

3. Predisposing Factors

The complex interplay between agent, host and the environment plays a role in the pathogenesis of dermatophytoses. The predisposing factors in the host include immunocompromised states such as diabetes mellitus, lymphoma and chronic illnesses, which can lead to extensive, recurrent or recalcitrant dermatophytoses. Intertriginous areas including groin, axilla, inter-web spaces are more susceptible to infection due to excess sweating, rubbing and alkaline pH. Environmental factors which predispose people to higher chances of infection include high humidity, high temperature, increased urbanization, use of tight-fitting clothes and occlusive footwear. In most parts of the world, anthropophilic T. rubrum is the most common isolate, but it is being increasingly replaced by T. interdigitale and T. mentagrophytes complex in some geographical locations [11,12,13][11][12][13]. T. interdigitale is responsible for mild and chronic infections [9]. Variations in fungal virulence in various species of dermatophytes are likely to play a role in the recurrence or resistance of infections. A few clinical types like onychomycosis may have a genetic predisposition. Distal subungual onychomycosis may be inherited in an autosomal dominant fashion [14] with incomplete or variable penetrance. Dermatophytic infections is commonly spread in family members, especially in the case of tinea capitis and tinea pedis.
Under favorable conditions, after inoculation into the host skin, epidermal adhesion occurs within an hour, mediated by adhesins present on the fungal cell wall [15,16][15][16]. This is followed by penetration mediated by proteases, serine subtilisin and fungalysin, which digests the keratin and also acts as a potent immunogenic stimulus [15]. Upon antigenic exposure, keratinocytes produce a wide range of cytokines—IL- 8, 16, 22, 1beta, TNF alpha, IFN gamma, etc. to destroy the dermatophytes [17]. In addition, the mannans produced by T rubrum result in lymphocyte inhibition.

4. Immunopathogenesis of Dermatophytoses

There are various host defense mechanisms that avoid establishment of infection, including composition (physical or chemical) of skin, exposure to UV light, lack of humidity, temperature, etc. [16,18][16][18]. The several host defense mechanisms against dermatophytoses include increase in cell turnover rate, increase in antimicrobial peptides—beta defensin 2, 3, psoriasin, RNAse7, neutrophil and macrophage-mediated fungal phagocytosis and a complex immune response. The immune responses to dermatophytoses range from an innate immune response to humoral- and cell-mediated immune responses. Cell-mediated immunity plays an important role in the control of dermatophytoses.

4.1. Innate Immune Response

Reduction in the number of epidermal dendritic cells, especially Langerhan cells, in the epidermis, increases the risk of dermatophytosis [19]. These cells contain pattern recognition receptors (PRP) like toll−like receptors (TLR), C-type lectin receptors (CLR) and galectins, which sense the pathogen- associated molecular patterns (PAMPs) on the fungi. Dectins 1 and 2, CLRs expressed in most dendritic cells, recognize the cell wall carbohydrate molecule β-glucan, which activates TLR 2 and 4, causing production of pro-inflammatory cytokines like IL- 6, 10,12, 17 and TNF α, all of which stimulate the adaptive immunity [20,21][20][21]. In addition to keratinocytes and dendritic cells, neutrophils also play a pivotal role in innate immunity against dermatophytes. Neutrophils and macrophages are considered to be the final effector cells in mediating extra and intracellular lysis of the fungus via oxidative pathway and through release of TNF α [22,23][22][23]. 

4.2. Acquired Immune Response

Cell-mediated immunity increases the epidermal proliferation, thus increasing cell turnover and facilitating the elimination of fungi [11,25][11][24]. Overall, elimination of dermatophytoses is mediated by Th 1 type of cell-mediated immunity while Th2 response predisposes to infection or results in an allergic response. Th1 cells produce cytokines like IFN α and stimulate phagocytosis [26,27][25][26]. Th2 response results in production of immunoglobulins and IL- 4, 5, 13 [24,28][27][28]. Initially IFN γ levels are low and IL-10 is high, inhibiting the Th1 response. Over time, there is decrease in IL-10 and a rise in IFN γ. Thus, IL-10 induces a Th2 response and also plays a significant role in innate immunity and immune response regulation. IL-10 also prevents TNF α production, enabling development of a specific immune response [29]. 

5. Management

Laboratory Diagnosis

The evolution of clinical presentation and varied manifestation poses a practical difficulty in differentiating dermatophytoses from non-dermatophytic or non-mycotic dermatoses. Hence, to initiate appropriate therapy, there is a need for appropriate laboratory diagnoses. To obtain optimal results, the quality and quantity of the clinical material examined is critical. Skin scrapings should be collected from the edge of the lesion and transported on a sterile black chart paper to keep the sample dry, thus preventing bacterial contamination. This practice is in accordance with the expert consensus [34][30] and also reappraised by Pihet [35][31] et al. in a recent review. The skin scrapings can be collected using scalpel blades, curettes or the edge of a slide [36,37][32][33]. In onychomycosis, the nail clippings should be collected as proximal as possible due to the fact that there are more hyphae and more viable hyphae in the proximal part of the nail.
Molecular methods [47][34] have been developed to provide more rapid and accurate alternatives to existing dermatophyte identification methods due to overlapping phenotypic characteristics, variability and pleomorphism. These include gene-specific PCR, sequencing of r-RNA gene, chitin synthase encoding gene, PCR fingerprinting and DNA hybridization. Sequencing of internal transcribed spaces (ITS) regions has proved to be a useful method for the phylogenetic analysis and identification of dermatophytes. Though useful, the main hindrance to its application in routine practice is the high cost associated with the sequencing.
Reflectance confocal microscopy, a new diagnostic technique that provides in-vivo imaging of epidermis and superficial dermis at cellular level to detect fungal infections and parasitic infestations on skin [49][35]. It is noninvasive and has shown to have 100% sensitivity in a retrospective analysis [49][35].

6. Treatment

An ideal treatment should have a high cure rate with a low relapse rate, strong anti-inflammatory action, rapid onset of action, short duration of action with no side effects, minimal systemic absorption and should be cost effective, safe to be used in pregnancy ad lactation and in renal and hepatic failure.

6.1. General Measures

Use of loose-fitting clothes made of cotton should be encouraged. Emphasis should be given on importance of regular use of medicines. Sharing of bed linens, towels, clothes and shoes should be avoided. All the clothing, especially socks, caps, undergarments, should be washed in boiling water, sun dried and ironed before reuse. Patients with risk factors like obesity or excessive sweating should be encouraged to use absorbent powders, deodorants (to reduce perspiration), frequent changes of clothes and advised weight reduction appropriately. In tinea pedis, prophylactic use of anti-fungal powders is advised. Patients should avoid the use of occlusive footwear.

6.2. Medical Management

Topical anti-fungal therapy forms the mainstay of treatment in localized and naive dermatophytic infections. Topical anti-fungal agents are recommended for dermatophytoses affecting skin and presenting as localized infections. Systemic drugs are indicated for more extensive infections. Combination therapy is expected to have a better clinical and mycological cure than topical or systemic agents used alone. It is preferred to use combination from different group of antifungals not only for wide coverage, but also for preventing emergence of resistance.

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