Management of tinea corporis, tinea cruris, and tinea pedis: A comprehensive review

Genetics of dermatophytosis

All people are not equally susceptible to fungal infection, even when they have similar risk factors. There is evidence of familial or genetic predispositions that could be mediated by specific defects in innate and adaptive immunity. One of the first fungal diseases thought to have a genetic predisposition was Tokelau or tinea imbricata. According to Jaradat et al., patients with low defensin beta 4 may be predisposed to all dermatophytes.[14]

The pathogenesis of dermatophyte infection involves complex interaction between the host, agent and the environment. The factors which predispose to such an infection are underlying diseases such as diabetes mellitus, lymphomas, immunocompromised status, or Cushing's syndrome, older age, which could produce severe, widespread, or recalcitrant dermatophytosis. Some areas of the body are more susceptible to the development of dermatophyte infections such as intertriginous areas (web spaces and groins) where excess sweating, maceration, and alkaline pH favor the growth of the fungus. After inoculation into the host skin, suitable condition favor the infection to progress through adherence followed by penetration mediated by proteases, serine-subtilisins, and fungolysin, which causes digestion of keratin network into oligopeptide or aminoacid and also act as a potent immunogenic stimuli.[15] In addition, the mannans produced by T. rubrum lead to inhibition of lymphocytes. Impaired function of Th17 cells leading decreased production of interleukin-17 (IL-17), IL-22 (key cytokine in clearing mucocutaneous fungal infection) results in persistence of infection.[15]

Immunology of dermatophytosis

The immune response to infection by dermatophytes ranges from a nonspecific host mechanism to a humoral and cell-mediated immune response. The currently accepted view is that a cell-mediated immune response is responsible for the control of dermatophytosis.

Laboratory investigations

For a laboratory to provide optimal results, quantity and quality of material examined is critical. Scraping should be collected from active margin and transported in a presterilized black chart paper which keeps the specimen dry thus, preventing over growth of bacteria contaminants. Following are the various laboratory tests that can be used for confirming a diagnosis of dermatophytosis.

• Direct microscopic examination:[20] Treatment of skin specimen with 10–20% potassium hydroxide (KOH) is a quick and inexpensive bedside tool to provide evidence of dermatophytic infection. Positive scrapings are characterized by presence of refractile, long, smooth, undulating, branching, and septate hyphal filaments with or without arthroconidiospores. False negative results are seen in 15% cases. Fluorescent staining with optical brighteners (diaminostilbene) is the most sensitive method to microscopically detect fungi in skin scales as well as in specimens from nails and hair.[21] These substances bind to chitin, the main cell wall component of fungi

• Culture and antifungal sensitivity:[22] Sabouraud dextrose agar (SDA, 4% peptone, 1% glucose, agar, water) is the most commonly used isolation media for dermatophytosis and serves as the medium on which most morphologic descriptions are based. Development of colony takes 7–14 days. Modified SDA, with addition of gentamicin, chloramphenicol and cycloheximide is more selective for dermatophytes as chroramphenicol inhibits the growth of saprophytic fungus. Dermatophyte test medium is an alternative to isolation media that contain pH indicator phenol red. It is incubated at room temperature for 5–14 days. Dermatophytes utilize the protein resulting in excess ammonium ion and alkaline environment which turn the medium from yellow to bright red.

Histopathology

Histology may be used in diagnosis of Majocchi's granuloma in which KOH examination of scale on the surface may more often be negative. When present, hyphae may be appreciated in stratum corneum on hematoxylin and eosin staining. Special stains most commonly used are periodic acid-Schiff and Gomori methanamine silver which helps to highlight hyphae.

Dermoscopy

The comma hairs, which are slightly curved, fractured hair shafts, and corkscrew hair shave been described as the dermoscopic marker of tinea capitis. Broken and dystrophic hairs are also seen. However, in tinea corporis, the involvement of vellus hair as seen on dermoscopy is an indicator of systemic therapy.[24]

Polymerase chain reaction and nucleic acid sequence based amplification

These tests not only help in the rapid and early diagnosis of infection but also help in determining drug resistance,[25] and include:

• Uniplex PCR for direct dermatophyte detection in clinical samples: A PCR for the direct detection of dermatophytes in skin scales is available as in-house PCR-ELISA assay which separately identifies numerous dermatophyte species. In a pilot study, the sensitivity and specificity of the test compared to cultures was 80.1% and 80.6%
• Multiplex PCR for fungal detection in dermatophytes: Commercially available multiplex PCR tests enable simultaneous amplification of 21 dermatomycotic pathogens with subsequent DNA detection by means of agarose gel electrophoresis.

New molecular methods like matrix-assisted laser desorption ionization-time of flight mass spectrometry

It is based on the detection of biochemical characteristics, proteolytic degradation product which is a result of the activity of mycological infections or noninfectious diseases. These are represented by proteolytic degradation products of native proteins. The peptide patterns of affected samples are identified by comparison with known peptide spectra from skin disorders stored in an already existing database. This procedure is immensely time saving, as it enables simultaneous identification of up to 64 dermatophyte strains, with results coming back within 24 h.[26]

Reflectance confocal microscopy

It provides in vivo imaging of the epidermis and superficial dermis at cellular level resolution and can be used to detect cutaneous fungi and parasitic infestations.[27] Branching fungal hyphae can be detected over an erythematous annular scaly patch. Advantage of the test being noninvasive and in a retrospective analysis of the test by Friedman et al. sensitivity was found to be 100%.

Summarizing it can be safely recommended that a clinical diagnosis of cutaneous dermatophytic infection should always be supplemented by a mycologic confirmation. While traditional methods like direct demonstration of fungus by KOH offer a reasonably sensitive and inexpensive option, newer noninvasive methods such as dermoscopy have additional advantage of ease of use, ability to detect involvement of vellus hair and thus, influence the choice of treatment (topical versus systemic). Fungal culture and antifungal testing are costlier and more specialized investigations, but such infrastructure needs to build up at most centers, especially in the present scenario of rising prevalence of nonresponsive dermatophytosis. Other methods such as PCR and reflectance confocal microscopy are still used primarily for research purposes.

Nonpharmacologic measures

Patients should be encouraged to wear loose-fitting garments made of cotton or synthetic materials designed to wick moisture away from the surface. Socks should have similar properties. Areas likely to become infected should be dried completely before being covered with clothes. Patients should also be advised to avoid walking barefoot and sharing garments.

Medical management with antifungals

A variety of traditional agents without specific antimicrobial function are still in use, including Whitfield's ointment and Castellani's (Carbol fuchsin solution) paint. The efficacy of these preparations has not been well quantified.[28] Table 1 summarizes the classification of commonly employed antifungals.[293031] Lesions covering a large body surface area fail to clear with repeated treatment using different topical agents should be considered for systemic therapy.[28] There is no definite comparative study on combination of systemic and topical versus monotherapy with systemic antifungal treatment. Topical medications have better pharmacokinetics than their systemic counterparts. Hence, combination is expected to have better mycological clearance than systemic and topical alone. Combination should be from different groups for wide coverage and also to prevent emergence of resistance. Drugs given for shorter duration with higher dose there has a less chance of development of resistance compared to lower dose for longer duration. Drug with keratophilic and lipophilic property, when given in higher doses will have reservoir effect and will lead to better mycological clearance.

Table 1

Classification of antifungal therapy based on their structure

Topical antifungal therapy for tinea cruris, corporis, and pedis

Reviewing the evidence on the use of existing topical antifungals

Various topical antifungal agents are available for the treatment of localized tinea corporis, tineacruris, tinea faciei, and tinea pedis. It may also be used as an adjunct to oral antifungals for more extensive infection. Most of the studies in the treatment of tinea corporis and cruris have looked at the efficacy of topical antifungals with very few studies on the use of oral antifungals. A meta-analysis by Rotta et al.[32] evaluated the efficacy of antifungal treatment involving 14 different topical antifungals and included 65 randomized controlled trials (RCTs), comparing topical antifungal with one another or with placebo. Efficacy was evaluated in the form of mycological cure at the end of treatment and sustained cure. They found no statistically significant differences among the antifungals concerning the outcome of mycologic cure at the end of treatment. For sustained cure, butenafine and terbinafine each was found to be superior to clotrimazole. Pairwise comparison of topical antifungals for the outcome of fungal cure showed butenafine and terbinafine each to be superior to clotrimazole, oxiconazole, and sertaconazole; terbinafine to be superior to ciclopirox, and naftifine to be superior to oxiconazole.

Similarly, Cochrane review[6] on the topical antifungal treatments for tinea cruris and tinea corporis suggests that the individual treatments with terbinafine and naftifine are effective with few adverse effects. Other topical antifungals like azoles treatments are also effective in terms of clinical and mycological cure rates. Regarding combinations therapy of topical steroids and antifungals though there is no standard guideline.[333435] There is insufficient evidence to confidently assess relapse rates in the individual or combination treatments. Difference between the different antifungals is mostly regarding fewer application and shorter duration of treatment with some class of topical antifungals compared to others. Topical antifungal are usually given once or twice daily for 2–4 weeks as illustrated in Table 2. The end point of treatment is clinical resolution in most of the cases.

Table 2

Summary of the use of topical antifungals used in the treatment of tinea corporis, cruris and pedis

Moriarty et al., also emphasize upon the use of topical therapy in treating tinea corporis, cruris and pedis. They also enlist the common reasons of failure of therapy, namely; poor adherence to treatment, reinfection from close contact, drug resistance, misdiagnosis, and infection with uncommon species. Such patients should be referred to a higher center for appropriate management. They also suggest use of topical hydrocortisone for a short time in inflamed lesions. Studies have also shown that addition of topical steroid also increases the bioavailability of topical antifungals mostly imidazole groups in addition to better symptomatic relief in early inflammatory stage.[33] While it may be of benefit to patients with inflammatory lesions, such practice should be strongly discouraged in countries like India where easy over the counter availability of topical steroids render then to frequent misuse by patients who finally end up with tinea incognito. Steroids may helpful in initial improvement in symptoms but chronic use lead to a complication like atrophy, telangiectasia which is more prominent when lesions are present in flexures. Topical antifungals with potent anti-inflammatory action such as sertaconazole or luliconazole may be a better option than an antifungal-steroid combination.

Tinea pedis is usually treated with a topical antifungal cream for 4 weeks; interdigital tinea pedis may only require 1 week of therapy. Various topical antifungal effective against tinea pedis include azoles, allylamines, butenafine, ciclopirox, tolnaftate, and amorolfine as evidenced by a meta-analysis finding strong evidence of superiority of topical antifungal agents over placebo.[7] A meta-analysis of 11 randomized trials concluded that treatment with terbinafine or naftifine produces a slightly higher cure rate than treatment with an azole.[36] Nystatin is not effective for the treatment of dermatophyte infections. Naftifine hydrochloride gel was also found to be effective both for interdigital and moccasin type of tinea pedis.[37]

Oral antifungal therapy in Tinea corporis, cruris, and pedis

Reviewing the evidence on the use of existing oral antifungals

Systemic antifungals are indicated in case of extensive involvement and patients who fail topical therapy.[46] Out of the various systemic antifungals, terbinafine, and itraconazole are commonly prescribed. Griseofulvin and fluconazole are also effective but require long-term treatment. RCTs support the efficacy of systemic antifungals [Table 3].[47484950] Comparative trial between itraconazole 100 mg/day with ultramicronized griseofulvin 500 mg/day for tinea corporis or tinea cruris showed significantly better clinical and mycological outcome in favor of itraconazole after 2 weeks of therapy.[47] Similar study comparing terbinafine with griseofulvin (both 500 mg daily for 6 weeks) for tinea corporis found mycological cure rate of about 87% in former group compared to 73% in latter.[48] A double-blinded study between itraconazole (100 mg/day) and griseofulvin (500 mg/day) found itraconazole to be superior in providing mycological cure.[49]

Table 3

Recommended dosing of different systemic antifungals in dermatophytosis

Topical therapy is less effective than oral antifungals for the treatment of tinea pedis, and oral treatment is generally given for 4–8 weeks. In a systematic review of efficacy of oral antifungals in, terbinafine was found to be more effective than griseofulvin, whereas the efficacy of terbinafine and itraconazole were similar.[8] In addition to antifungal therapy, Burrow's (1% aluminum acetate or 5% aluminum subacetate) wet dressings, applied for 20 min 2–3 times/day, may be helpful if vesiculation or maceration is present. Of various types of tinea pedis, hyperkeratotic variety is more recalcitrant to treatment due to thick scales leading to ineffectiveness of topical antifungals and need for longer duration of systemic antifungals. Use of keratolytic agents and topical antifungals along with systemic antifungals has been found to be more useful in early achievement of clinical and mycological cure as well as decreasing the duration of oral antifungals leading to better patient compliance.[51] Secondary bacterial infection should be treated with oral antibiotics. Other adjunctive therapies include use of antifungal powder may help to prevent maceration and avoidance of occlusive footwear.

New and potential therapies

Other than the antifungals already mentioned, few plant extract (Chinese herbals) are also found to be effective against common dermatophytic infection. One of them is macrocarpal C, an active ingredient obtained from the fresh leaves of Eucalyptus globulus Labill with antifungal action against T. mentagrophytes and T. rubrum.[53] Demicidin, an antimicrobial peptide has antifungal action at a concentration normally present in sweat providing an insight to newer therapeutic target for dermatophytic infection.[54]

Majocchi's granuloma

It is a deep dermatophytosis that occurs when a long-standing superficial fungal infection causes progressive dissemination into the subcutaneous tissue. The most common etiological agent is T. rubrum.[55] Mechanical damage to the skin resulting from trauma may allow penetration of fungi into the reticular dermis, and the resulting cellular destruction and decreased dermal pH makes the milieu more suitable for its survival.[56] It is mostly seen in immunocompromised hosts.[57] Topical steroid application leads to local immunosuppression and development of majocchi granuloma. Systemic antifungals such as terbinafine in a dose of 250 mg/day for 4–6 weeks, itraconazole 200 mg twice daily for 1 week/month for 2 months have been successfully used.[5859] Treatment regimens with griseofulvin and daily itraconazole have also been suggested.[60]

Tinea imbricate and pseudoimbricata

Tinea imbricata is a chronic superficial fungal infection of the glabrous skin caused by Trichophyton concentricum. Disease results from close contact with spores and filaments of T. concentricum especially between the mother and her child. It is postulated that genetic, environmental, and immunologic factors play an important part in the development of this fungal infection. The mode of inheritance is autosomal recessive pattern with a minority of autosomal dominant cases.[61] Most patients have specific antibodies to T. concentricum, thus suggesting that there is a decrease in the cellular immunity.[62] Dietary influences, iron deficiency, and malnutrition have been cited as associated factors.[63] Diagnosis is essentially clinical and isolation on culture. The disease is highly recurrent. The treatment should involve a combination of topical and systemic antifungal agents since topical therapy alone is insufficient. Griseofulvin, azole agents, such as ketoconazole and itraconazole, has been used for many years with variable success. Currently, terbinafine is the best therapeutic option, in the dose of 250 mg/day in adults.[64] Recently, there have been reports of tinea imbricate like lesions in patients abusing topical steroids. T. mentagrophytes, instead of T. concentricum is usually isolated from these lesions.[65]

Antifungal therapy in immunosuppressed and pregnancy

A special subgroup of population like with HIV infection usually present with more extensive involvement. However, characteristic morphology may be missing due to reduced inflammatory component of lesion attributed to suppressed immunity.[66] In a patient with associated comorbidities such as renal, hepatic impairment, and caution should be exercised while prescribing systemic antifungals. Terbinafine clearance significantly reduced in patient in renal impairment. So dose should be adjusted accordingly, or drug from different group should be preferred. Similarly, itraconazole should be avoided in patient with hepatic impairment. Terbinafine is a category B drug in pregnancy. However, there is no clear cut guideline available for managing dermatophytic infection and treatment should be individualized and based upon risk-benefit ratio.[67]

Chronic dermatophytosis

It has also been described in literature as T. rubrum syndrome, generalized chronically persistent rubrophytia, tinea corporis generalisata and dry-type T. rubrum infection. It is characterized by involvement of at least four body sites such as feet (plantar), hands (palmar), nails, as well as one other site with exclusion of inguinal area along with identification of T. rubrum in microscopy and culture.[68] Chronic dermatophytosis refers to persistent dermatophytosis that runs a chronic course with episodes of remission and exacerbation. Chronicity can be considered in terms of duration and recurrences of infection although there is no standard definition for chronicity. The emergence of such cases could be attributed to various pathogenic agent, host and pharmacologic factors. At present, there are no guidelines on management of chronic dermatophytosis. Although there are few studies to suggest that antifungal resistance is not common in tinea capitis, such data are lacking with respect to tinea cruris and corporis. This should also be seen with respect to the currently prevailing clinical scenario in India where there is an increasing recognition of a rising trend of nonresponsive cutaneous dermatophytosis.[6970] The detailed recount on pathogenesis and management of chronic/recurrent dermatophytosis is beyond scope of this manuscript.

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Conflicts of interest

There are no conflicts of interest.