Submitted: 25.8.2013
`Accepted: 19.9.2013
`Conflict of interest
`None.
`
`CME Article
`DOI: 10.1111/ddg.12245
`
`Mycology – an update. Part 1:
`Dermatomycoses: Causative agents,
`epidemiology and pathogenesis
`
`Pietro Nenoff1, Constanze
` Krüger1, Gabriele Ginter-
`Hanselmayer2, Hans-Jürgen
`Tietz3
`(1) Laboratory for Medical Microbiology,
`Mölbis, Germany
`(2) Department of Dermatology and
` Venereology, Medical University of
`Graz, Austria
`(3) Institute of Fungal Diseases and
`Microbiology, Berlin, Germany
`
`Section Editor
`Prof. Dr. Jan C. Simon, Leipzig
`
`Summary
`Dermatomycoses are caused most commonly by dermatophytes. The anthropophi-
`lic dermatophyte Trichophyton rubrum is still the most frequent causative agent
`worldwide. Keratinolytic enzymes, e.g. hydrolases and keratinases, are important
`virulence factors of T. rubrum. Recently, the cysteine dioxygenase was found as new
`virulence factor. Predisposing host factors play a similarly important role for the
` development of dermatophytosis of the skin and nails. Chronic venous insufficiency,
`diabetes mellitus, disorders of cellular immunity, and genetic predisposition should
`be considered as risk factors for onychomycosis. A new alarming trend is the increa-
`sing number of cases of onychomycosis – mostly due to T. rubrum – in infancy.
`In Germany, tinea capitis is mostly caused by zoophilic dermatophytes, in par-
`ticular Microsporum canis. New zoophilic fungi, primarily Trichophyton species of
`Arthroderma benhamiae, should be taken into differential diagnostic considerations
`of tinea capitis, tinea faciei, and tinea corporis. Source of infection are small house-
`hold pets, particularly rodents, like guinea pigs. Anthropophilic dermatophytes may
`be introduced by families which immigrate from Africa or Asia to Europe. The anthro-
`pophilic dermatophytes T. violaceum, T. tonsurans (infections occurring in fighting
`sports clubs as “tinea gladiatorum capitis et corporis”) and M. audouinii are causing
`outbreaks of small epidemics of tinea corporis and tinea capitis in kindergartens and
`schools.
`Superficial infections of the skin and mucous membranes due to yeasts are
` caused by Candida species. Also common are infections due to the lipophilic yeast
`fungus Malassezia. Today, within the genus Malassezia more than 10 different species
`are known. Malassezia globosa seems to play the crucial role in pityriasis versicolor.
`Molds (also designated non-dermatophyte molds, NDM) are increasingly found
`as causative agents in onychomycosis. Besides Scopulariopsis brevicaulis, several
` species of Fusarium and Aspergillus are found.
`
`Introduction
`
`Dermatomycoses may be divided according to the responsible pathogen into
` dermatophyte, yeast, and mold infections. Fungi on the skin, or dermatophytes,
`
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`Trichophyton rubrum is the most com-
`mon dermatophyte in Germany and
`worldwide.
`The prevalence of fungal nail infections
`in certain risk groups, e.g., diabetics
`and psoriasis patients, is higher than in
`the general population.
`
`Yeasts – primarily Candida albicans –
`cause candidiasis affecting the skin and
`mucous membranes.
`Malassezia-related superficial skin
` infections, primarily pityriasis versico-
`lor, are very common.
`
`Non-dermatophyte molds (NDM) are
`increasingly found to be the cause of
`onychomycosis of the toenails.
`
`The most common pathogens
` identified in children and adolescents
`are zoophilic dermatophytes.
`
`The target structures for Trichophyton
`rubrum are the stratum corneum of the
`epidermis and the nail keratin.
`
`are the cause of dermatophytosis, also referred to as tinea (ringworm). The most
`common dermatophyte in Germany, and probably the world, is Trichophyton
`rubrum. Fungal nail infections, or onychomycosis, are very common disorders
`in industrialized nations [1]. The prevalence of fungal nail infections among
`certain risk groups, e.g., diabetics, is higher than in the general population; it
`is also higher in patients with disorders of keratinization affecting the skin and
`nails, e.g., psoriasis patients. The clinical diagnosis is often difficult, given that
`nail disorders due to other causes must be ruled out. A new epidemiological
`development is the increase in onychomycoses, usually due to T. rubrum, in
`children [2].
`Yeasts – primarily Candida albicans – cause candidiasis of the skin and mu-
`cous membranes, also known as thrush. Although the term “thrush” (sponge) is
`still frequently used, it is considered obsolete. Malassezia-related superficial skin
`infections, primarily pityriasis versicolor, are very common; Malassezia folliculitis
`is less so. The lipophilic yeasts belonging to the Malassezia species are also associ-
`ated with seborrheic and atopic eczema. Molds rarely cause cutaneous infections.
`Occasionally, secondary (hematogenic) skin infections can occur in immunosup-
`pressed patients, e.g., with leukemia and after stem cell transplantation; primary
`skin infections due to molds are even rarer (e.g., due to Aspergillus fumigatus).
`Yet, non-dermatophyte molds (NDM) are considered emerging pathogens in ony-
`chomycosis of the toenails.
`The most common pathogens among children and adolescents are zoophilic
`dermatophytes. The sources of infection are house pets and, less often farm ani-
`mals. In Germany – probably due to immigration and greater urban densities com-
`pared to Austria – anthropophilic dermatophytes are becoming more common.
`Anthropophilic dermatophytes which are isolated in pediatric patients include
`T. tonsurans (associated with wrestling mats) and – becoming more common in
`kindergartens and schools – Microsporum audouinii. The latter fungus is from
`Africa and is transmitted, directly or indirectly, by immigrating families. A pro-
`blem is chronic hyperkeratotic infections, which often involve pus and absces-
`ses formation, on the scalp (e.g., tinea capitis profunda). These may be caused
`by well-known (M. canis) and “new” (T. species von Arthroderma benhamiae)
`zoophilic pathogens. Only rapid mycological diagnosis, also with molecu-
`lar biological techniques for dermatophyte DNA detection, and immediate
` systemic antifungal treatment can prevent scarring of the scalp or pseudopelade
`of Brocq.
`
`Trichophyton rubrum – the most common
` dermatophyte
`
`T. rubrum continues to be the most common dermatophyte in the world with the
`highest incidence in Europe (Figure 1). Trichophyton is derived from the Greek
`words “θριχóς” “hair” and “ϕυτóν” “plant”; “rubrum” (Latin for red) refers to
`the red-brown pigmentation found in the fungal culture on the underside of the
`colony of the white thallus. Yet unlike most other dermatophytes, T. rubrum (“red
`hairy plant”), only rarely affects the hair and hair roots. Its target structures are
`the stratum corneum of the epidermis and the nail keratin. The percentage of the
`anthropophilic fungus T. rubrum among the dermatophytes causing tinea ungui-
`um is 91% in Germany [3]. T. rubrum and T. interdigitale (previously known as
`T. mentagrophytes) are also responsible for about 90% of all cases of dermat-
`ophytosis in Poland. The same figures have been reported in Great Britain
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`Figure 1 Trichophyton rubrum: Typical white thallus on Sabouraud’s dextrose agar.
`The isolate originated from woman with tinea unguium.
`
`The percentage of the anthropophilic
`fungus T. rubrum among the
` dermatophytes causing tinea unguium
`is more than 90%.
`
`T. rubrum infections are increasingly
`occurring at other sites on the body
`than previously reported.
`
`and Sweden [4]. In Poland, the most common forms of fungal skin infections,
`irrespective of causative dermatophytes, are tinea unguium pedum (42.2%) and
`tinea pedis (41.4%); tinea corporis (5,6%), tinea manuum (4.1%), tinea ungui-
`um manuum (3.0%), tinea capitis (2.4%), and tinea cruris (1.3%) are much less
` common [5].
`Along with tinea pedis and tinea unguium, T. rubrum infections are increa-
`singly occurring at other sites on the body than previously reported [6]. An ex-
`ample is tinea faciei due to T. rubrum after autoinoculation with tinea pedis et
`unguium of the lower extremities [7]. Tinea capitis due to T. rubrum is unusual.
`
`Tinea pedis and onychomycosis are
`caused by the anthropophilic dermat-
`ophytes T. rubrum, T. interdigitale and
`Epidermophyton floccosum.
`
`Dermatophyte transmission in the home
`
`The pathogen reservoir for tinea pedis and onychomycosis are anthropophilic
`dermatophytes, i.e., T. rubrum and T. interdigitale (only anthropophilic strains)
`and Epidermophyton floccosum (Table 1). The most common source of infec-
`tion is the bath; and transmission among family members is the most common
`route. Spread may be horizontal, e.g., between spouses, or vertical between
`the generations. The latter, for instance, between a father or grandfather and
`(grand-) child, is much more common than horizontal spread. Other sources of
`infection are showers in fitness studios, changing rooms at public pools, mats in
`sports facilities (wrestling or martial arts facilities, tropical baths, and hotels and
`mosques) [1].
`
`Molecular epidemiology and transmission of
`Trichophyton rubrum in the home
`
`The results of a recent study done in the United States confirmed the transmission
`of dermatophytes within homes in which individual family members had tinea
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`Table 1 Anthropophilic dermatophytes. The list is based on the current Centraalbureau Voor Schimmelcultures (Utrecht, The
`Netherlands) suggested and established taxonomy and nomenclature of fungi [8]. Species and subspecies or varieties that are
`no longer considered distinct have been omitted.
`
`Epidermophyton floccosum
`
`Increasingly rare in Germany, infections of feet, toenails, and groin
`
`Microsporum audouinii
`
`Mainly in Sub-Saharan African
`
`Microsporum ferrugineum
`
`Mainly found in Asia, rarely in Africa or Eastern Europe
`
`Trichophyton concentricum
`
`Limited to Southeast Asia, cause of tinea imbricata (“Tokelau”) as cockade-like fungal infection
`
`Trichophyton interdigitale
`(anthropophilic strains)
`
`Second most common dermatophyte in Germany
`
`Trichophyton megninii
`
`Very rare in Germany; tinea pedis, tinea manuum, tinea unguium, tinea barbae
`
`Trichophyton rubrum
`
`Most common dermatophyte in the world, tinea unguium, tinea pedis et corporis, rarely
`invades hair and hair roots
`
`Trichophyton rubrum var.
` raubischekii
`
`Variant of T. rubrum, found nearly only in Africa; recent isolated reports in Germany,
` Turkey, Spain, and Asia (Japan)
`
`Trichophyton schoenleinii
`
`Favus pathogen, rare in Europe
`
`Trichophyton tonsurans
`
`Tinea capitis pathogen in America; in Germany tinea gladiatorum occurs in martial arts
`participants
`
`Trichophyton violaceum
`
`Most important dermatophyte in Africa
`
`Trichophyton soudanense
`
`Found in Africa; genotypically, but not phenotypically, identical to T. violaceum
`
`Trichophyton vanbreuseghemii Very rarely isolated from humans (skin) or soil
`
`pedis or onychomycosis. The dermatophytes were detected using molecular bio-
`logical methods with polymerase chain reaction (PCR). The primer used was the
`internal transcribed spacer (ITS) region (ITS1 und ITS4). For stem cell differen-
`tiation, a ribosomal-DNA-specific probe (containing ITS1, 5.8S ribosomal DNA
`and ITS2) was used to detect restriction fragment length polymorphism (RFLP).
`In 50 households, 18 family members had multiple infections [9]. T. rubrum was
`the most common dermatophyte, followed by T. mentagrophytes (T. interdigitale)
`and Epidermophyton floccosum. Sixteen T. rubrum strains were found in 8 house-
`holds with multiple infections. Certain T. rubrum strains had a significantly higher
`tendency toward spreading; there was also an association with a history of tinea
`pedis and onychomycosis, with plantar scaling, and nail plate discoloration.
`
`Pathogenesis of dermatophytosis
`
`Predisposing host factors for dermatophyte infections
`Predisposing host factors allow tinea pedis and onychomycosis to occur. As a rule,
`a healthy nail is not susceptible to fungal infection. Among predisposing factors for
`tinea pedis et unguium are circulatory disorders affecting the lower extremities as
`well as metabolic disorders such as diabetes mellitus (Table 2).
`
`Psoriasis vulgaris and onychomycosis
`
`In treatment-refractory onychomycosis, keratinization disorders affecting the skin
`and nails are more common than previously thought. Most patients have undetected
`
`191
`
`As a rule, a healthy nail is not
` susceptible to fungal infection.
`Predisposing factors for tinea pedis et
`unguium include circulatory disorders
`affecting the lower extremities as well
`as metabolic disorders such as diabetes
`mellitus.
`In treatment-refractory onychomycosis,
`keratinization disorders affecting the
`skin and nails are more common than
`previously thought.
`
`CME Article Mykologie - an update. Part 1
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`Table 2 Predisposition factors for athlete’s foot and onychomycosis.
`
`  Circulatory disorders (chronic venous insufficiency, peripheral arterial
` circulatory disorder)
`  Lymphedema in the lower extremities
`  Malalignment of the feet including hallux valgus, hammer toe
`  Toenail deformities/onychodystrophy
`  Psoriasis vulgaris and psoriasis unguium
`  Ichthyosis vulgaris
`  Diabetes mellitus
`  Nail and nail bed microtrauma due to sporting activities (track and field,
` jogging, marathon running, soccer)
`  Strong perspiration/hyperhidrosis pedum
`  Immunosuppression (HIV/AIDS)
`  Patients with trisomy 21
`
`psoriasis vulgaris and psoriasis unguium; atopic eczema and ichthyosis vulgaris
`are also related to more pronounced keratinization, which is a predisposing factor
`in dermatophyte infections. Twenty-seven percent of patients with psoriasis who
`have nail changes have onychomycosis involving the toenails [10]. The findings of
`in vitro studies show that scale taken from patients with psoriasis can promote the
`growth of dermatophytes, yeasts, and molds [11].
`In patients with psoriasis vulgaris, there is a significantly higher rate of Can-
`dida colonization of the toenails [12]. Kaçar and colleagues [13] studied patients
`with onychomycosis, 168 of whom had concomitant psoriasis and 164 who did
`not. Using fungal tests, onychomycosis was diagnosed in 22 patients with psoriasis
`(13.1%) and in 13 controls (7.9%). In the psoriasis group, primarily dermatophytes
`were found to be the pathogens in onychomycosis; in the control group, it was
`mainly molds. Dermatophytes were isolated significantly more often in psoriasis
`patients than in the control group.
`In one study with patients in Bulgaria and Greece on the prevalence of fungal
`nail infections in psoriasis vulgaris, out of 228 patients with nail changes and pso-
`riasis vulgaris, 62% had a positive fungal culture [14]. In 67% of these patients,
`a dermatophyte was isolated; in 24% a yeast was found; and in 6%, a mold was
`identified. The incidence of onychomycosis in psoriatic patients was higher.
`
`Ichthyosis as a predisposing disease for dermatophytosis due to
` Trichophyton rubrum
`
`A 10-month old child with congenital lamellar ichthyosis had a treatment-refractory
`T. rubrum infection. Tests revealed a high total IgE and specific IgE to T. rubrum
`[15]. Ichthyosis, a keratinization disorder affecting the epidermis is a risk factor
`for chronic dermatophytosis; both the excessive amounts of keratin as well as the
`barrier defect are predisposing factors. A type IV immune response (delayed type
`of hypersensitivity) to T. rubrum promotes healing of tinea. Immediate hypersen-
`sitivity and IgE do not protect against tinea; chronic infection may be expected.
`
`Cellular immunity as a predisposing factor for dermatophytosis
`
`The host-specific side of dermatophyte infections, that is, the cellular immune respon-
`se, has been studied in patients with severe dermatophytosis due to T. rubrum [16].
`
`27% of psoriasis patients who have nail
`changes have onychomycosis involving
`the toenails.
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`Disorders of cellular immunity are
`among the predisposing factors for
` dermatophytosis.
`
`Immunophenotyping showed no differences between affected patients and con-
`trols. In the control group, a lymphocyte proliferation test showed significantly
`higher stimulation rates of lymphocytes to American pokeweed mitogen, Candida
`spp., and T. rubrum extract with the main fungal epitope (TriR2). Cytokine analysis
`showed a significant difference between the groups only for IFN-γ, after stimulation
`by PHA and TriR2.
`
`Diabetics have a higher risk of tinea
` pedis and onychomycosis.
`
`Onychomycosis is now considered to be
`a predictor of diabetic foot syndrome.
`
`Onychomycosis is significantly more
`common if the feet were not washed on
`a daily basis.
`
`Diabetics who are using hemodialysis
`have about an 88% higher probability
`of onychomycosis than non-diabetics.
`
`A family history of disease is considered
`to be a risk factor in onychomycosis
`
`Autosomal dominant inheritance of a su-
`sceptibility factor promotes the develop-
`ment of distal subungual onychomycosis
`due to Trichophyton rubrum.
`
`Diabetes mellitus and onychomycosis
`
`Diabetics have a higher risk of tinea pedis and onychomycosis. Compared to pa-
`tients with gastroesophageal reflux, they have a much higher risk of bacterial and
`fungal infections (odds ratios of 5.95 and 2.66) [17]. Onychomycosis is now consi-
`dered to be a predictor of diabetic foot syndrome [18]. Diabetics with onychomy-
`cosis have a 1.6 times greater risk of having a diabetic foot ulcer [19].
`In a prospective study [20], the prevalence of onychomycosis in diabetics (type
`II) was 22%; most infections were due to dermatophytes, and only in four patients
`were yeasts identified. In another study, 383 out of 1,245 Taiwanese patients with
`diabetes mellitus were reported to have onychomycosis, which corresponds to a
`prevalence of 30.76% [18]. Older age, being male, metabolic syndrome, being over-
`weight, elevated triglyceride levels, and poor control of blood sugar levels (elevated
`HbA1c) were associated with onychomycosis.
`The results of one study found that, out of 95 patients with type I diabetes in
`Germany (average duration of disease: 35.8 years), 82.1% had changes affecting
`the feet that were suggestive of mycosis; in 84.6%, fungal infection was confirmed
`by a plain specimen and mycological culture [21]. Twenty-eight patients had a fun-
`gal nail infection, and another 28 had both cutaneous and nail infections.
`In a cross-sectional study conducted in Japan, 51.3% of patients with diabetes
`had onychomycosis of the toenails [22]. Nail thickness was significantly correlated
`with an elevated HbA1c value. Onychomycosis was significantly more common if
`the feet were not washed on a daily basis.
`
`Onychomycosis in patients with diabetes and chronic hemodialysis
`
`Out of 100 patients who were on chronic hemodialysis, 39% had onychomycosis [23].
`The most common pathogens were dermatophytes (ca. 70%), Candida spp. (15%),
`and non-dermatophyte molds (NDM; 15%). T. interdigitale was the most common
`pathogen, followed by Candida spp. and T. rubrum. The risk of onychomycosis in-
`creased with every year of life by around 1.9%. Diabetics who are using hemodialysis
`have about an 88% higher probability of onychomycosis than non-diabetics.
`
`Genetic predisposition for onychomycosis
`
`A family history of disease is considered to be a risk factor in onychomycosis.
` Genetic factors – such as autosomal dominant inheritance of susceptibility to di-
`stal subungual onychomycosis due to T. rubrum – promote the development of
`onychomycosis [24]. This often leads to the vertical transmission of onychomycosis
`between family members.
`Faergemann and colleagues [25] have shown that the high prevalence of ony-
`chomycosis in certain families is apparently the result of intra-family transmission
`(and predisposition?). Family members who married into the family are less likely
`to have onychomycosis, yet their children do have a high prevalence of onychomy-
`cosis, which supports the suggestion of autosomal dominant inheritance.
`
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`Ashkenazi Jews are protected from
` onychomycosis by the human leukocyte
`antigen DR4 (HLA-DR4).
`
`Ashkenazi Jews are protected from onychomycosis by the human leukocyte
`antigen DR4 (HLA-DR4) [26]. HLA-DR6 has been identified by one study in 7 out
`of 21 Mexican mestizos with onychomycosis (33%) and in 45% of controls [27].
`Six patients (29%) and 3 controls (7%) had children with a nail infection. Thirteen
`of the patients (62%) with onychomycosis, and 12 of the controls (29%), had a
`first-degree relative who also had onychomycosis. Among Mexican mestizos, the
`HLA-DR6 antigen has been found to be a protective factor. In people who have
`a first-degree relative with onychomycosis, there is a significantly elevated risk of
`onychomycosis; this supports the hypothesis of genetically determined susceptibi-
`lity for onychomycosis.
`
`Virulence factors of dermatophytes
`
`The target structure for infection and
`dermatophyte proliferation in the
` stratum corneum of the epidermis is
`the hard, firm cytokeratin found in the
`skin, hair, and nails.
`Dermatophytes destroy the complex
`protein, keratin, found in the nails and
`epidermis via keratinase.
`Due to the high level of enzyme activity
`at normal body temperature and skin
`pH levels, dermatophytes (e.g.,
`Trichophyton spp.) are well-suited to
`the skin’s surface in human beings.
`Thus, the pathogen reservoir of
`T. rubrum, as an anthropophilic
` dermatophyte, is only found on the
`person himself or in his home.
`
`Although various factors related to the potential host create the conditions for
`dermatophytosis (predisposition), dermatophyte virulence factors must also be
`present for a cutaneous infection to occur. The target structure for infection and
`dermatophyte proliferation in the stratum corneum of the epidermis is the hard,
`firm cytokeratin found in the skin, hair, and nails. Dermatophytes degrade these
`complex proteins via keratinase. A recent study measured the keratolytic activity
`of T. rubrum, T. interdigitale, M. canis, and M. gypseum using spectrophotome-
`try. At temperatures of 30–40°C, and in a slightly alkaline milieu (pH: 7.0–8.0),
`Trichophyton spp. produced the highest keratinase activity [28]. The high level
`of enzyme activity of Trichophyton spp. at normal body temperatures and pH
`levels of the skin is presumably responsible for the adaptation of certain dermat-
`ophytes to the surface of human skin. This is referred to as “anthropozation.”
`Thus, the pathogen reservoir of T. rubrum, as an anthropophilic dermatophyte,
`is only found on the person himself or in his home. The infection pathways
`for dermatophytes are thus either direct (rarely, via skin contact from one per-
`son to another) or indirect (most common, from walking barefoot on surfa-
`ces that have been contaminated with infectious material from the skin, floors,
`rugs, etc.).
`
`Adherence, hydrolase activity, and cysteine dioxygenase of dermatophytes
`
`The adherence of dermatophytes to the epithelial tissue of the host, which cont-
`ains keratin, is mediated by mannan glycoproteins in the cell wall of the fungus
`[29]. Maturation of the arthroconidia produces hyphae, which are able to pe-
`netrate the deeper layers of the skin tissue. Other factors include the nutritive
`medium for the fungus, host-pathogen interactions (signals), transport proteins,
`synthesis of structural proteins in the fungus and secretion of proteolytic en-
`zymes, predominantly hydrolase (keratinase, nuclease). The hydrolase activity
`is inhibited by disulfide bridges, which link epidermal keratins. These disulfide
`bonds must be broken by cysteine dioxygenase to set the process of keratinolysis
`in motion.
`Keratin degradation is caused by keratinase, cysteine dioxygenase, and a
` sulfite efflux pump [30]. A recent hypothesis suggests that keratin breakdown is
`facilitated by secretion of the reducing compound, sulfite, which can break the ke-
`ratin-stabilizing cysteine bonds. A working group led by Peter Staib at the Leibniz
`Institute in Jena found that dermatophytes can form sulfite from cysteine found in
`the environment. At higher concentrations, cysteine has a toxic effect on microor-
`ganisms as well as human beings. Sulfite formation from cysteine is due to the
`effect of the key enzyme cysteine dioxygenase Cdo1 and is supported by the sulfite
`
`Along with the keratinases, cysteine di-
`oxygenase and a sulfite efflux pump are
`also responsible for keratin degradation.
`Proteolytic enzymes, such as hydrolase
`(keratinases, nucleases) and cysteine
`dioxygenase, allow keratin degradation
`by dermatophytes. They are considered
`virulence factors.
`
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`A comparative genomic analysis of
`T. rubrum and closely-related dermato-
`phyte species studied the candidate ge-
`nes which are responsible for infection.
`The dermatophyte species exhibited
`various biological behaviors related to
`host specificity, reproductive behavior,
`and disease course.
`
`efflux pump Ssu1. Because keratin is rich in cysteine, the cysteine transformation
`and sulfite efflux pump appear to contribute to cysteine and sulfite tolerance and
`to keratin degradation.
`
`Marker candidate genes for the dermatophyte virulence
`
`To understand the pathogenesis of dermatophytosis, knowledge of genes and
`the proteins they code (or enzymes) is essential. A comparative genomic ana-
`lysis of T. rubrum and closely-related dermatophyte species (T. tonsurans,
`T. equinum, M. canis and M. gypseum) focused on the candidate genes which
`are responsible for infection [31]. The dermatophyte species demonstrated various
`biological behaviors related to host specificity, reproductive behavior, and disease
`course. Although the genome of the various dermatophytes is relatively uniform,
`there are genetic segments which do not seem to be present in other pathogenic fun-
`gi that cause disease in humans. According to the authors of the aforementioned
`molecular biological study, the dermatophyte genome contains gene families of the
`LysM domains, which are needed to bind chitin and carbohydrates. Other genes
`code fungus-specific gene kinases and pseudokinases, which may competitively in-
`hibit phosphorylation; this can have an effect on cellular signal transduction. Still
`other genes code enzymes that synthesize secondary metabolites. In addition, the
`dermatophytes contain genes for various classes of proteases which enable fungal
`growth as a result of keratin degradation.
`
`Impaired quality of life due to fungal nail infections
`
`Although fungal nail infections are not
`life-threatening, they can significantly
`impair the patient’s quality of life.
`
`The most common problems affecting
`the patients’ attitude toward life were
`issues concerning cutting the nails, cos-
`metically disturbing disfigurement, and
`ill-fitting shoes.
`
`Although fungal nail infections are not life-threatening, they can significantly
`impair the quality of life of those affected [32]. The influence of onychomycosis
`on quality of life was recently described in a Polish study on 140 patients [33].
`Not only women, but patients in general who had onychomycosis of the toenails
`for more than two years, had a poorer disease-specific quality of life. The most
`common problems affecting the patients’ attitude toward life were cutting the
`nails, cosmetically disturbing disfigurement, and ill-fitting shoes. An important
`aspect was the concern among patients that the infection would spread to other
`nails or to other people. Industrial workers and craftsmen, i.e., blue collar wor-
`kers, reported greater impairment as a result of the nail infection than did white
`collar workers.
`
`Patients with onychomycosis have
` lacking self-esteem as well as a feeling
`of shame, along with a decreased
`willingness to participate in social
` activities, and a fear of transmitting the
`infection to others.
`
`Onychomycosis was found to lead to a
`similar level of stigmatization as psoria-
`sis vulgaris.
`
`Stigmatization due to onychomycosis
`
`Szepietowski and Reich [34] found that patients with onychomycosis have lacking
`self-esteem as well as a feeling of shame, along with a decreased willingness to
`participate in social activities, and a fear of transmitting the infection to others.
`This study was also conducted in Poland, with 1,684 onychomycosis patients, and
`reported an average score of stigmatization of 5.3 points (range: 0–17 points). Pa-
`tients felt the greatest impairment if their disease was considered to be contagious;
`this was followed by the feeling that other people would stare at their nails; in third
`place was a feeling of unattractiveness. Women reported significantly more often
`that they felt unattractive, and that others were looking at their nails. Onychomy-
`cosis was found to lead to a similar level of stigmatization as psoriasis vulgaris.
`Antifungal treatment improved not only physical symptoms but also emotional
`well-being and quality of life.
`
`195
`
`CME Article Mykologie - an update. Part 1
`
`© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1203
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2081 - 8/52
`
`

`
`Table 3 Zoophilic dermatophytes and their source of infection (referring to Brasch [36]). The list is based on the current
` Centraalbureau Voor Schimmelcultures (Utrecht, The Netherlands) suggested and established taxonomy and nomenclature
`of fungi [8]. Species and subspecies or varieties that are no longer considered distinct have been omitted.
`
`Dermatophyte
`
`Animal
`
`Microsporum amazonicum
`
`Rats
`
`Microsporum bullosum
`
`Horses, donkeys
`
`Microsporum canis
`
`Cats, rarely dogs (usually in South America)
`
`Microsporum gallinae
`
`Chickens (very rarely transmitted to humans)
`
`Microsporum nanum
`
`Pigs, cows
`
`Microsporum persicolor
`
`Moles, other rodents, e.g., mice
`
`Microsporum praecox
`
`Horses
`
`Trichophyton equinum
`
`Horses, morphology strongly resembles T. tonsurans
`
`Trichophyton erinacei
`
`Hedgehogs
`
`Trichophyton interdigitale
`(zoophilic strains)
`
`Rodents (e.g., guinea pigs, golden hamsters, rats, mice, chinchillas), rabbits, dwarf rabbits,
`ferrets
`
`Trichophyton mentagrophytes Mice and camels (almost never in Germany, only in Middle East)
`
`Trichophyton simii
`
`Monkeys, chickens, guinea pigs, shrews
`
`Trichophyton species of
`Arthroderma benhamiae
`
`Guinea pigs, other small rodents
`
`Trichophyton verrucosum
`
`Calves, cows, other farm animals (e.g., horses, pigs, dogs, and cats)
`
`Along with cats, especially rodents (e.g.,
`guinea pigs) are a source of infection
`and transmission of dermatophytes.
`
`Because these diseases are not notifiab-
`le in Germany, there has been a nearly
`invisible shift in pathogens toward
`infections by Trichophyton species of
`Arthroderma benhamiae.
`
`House pets as a pathogen reservoir for dermatomycosis
`
`Children and adolescents are often affected by zoophilic dermatophytosis as a re-
`sult of direct transmission from animals or due to an outbreak in the family or
`school/daycare. Along with cats, especially rodents (e.g., guinea pigs) are a source
`of infection and transmission of dermatophytes. There are no current data on in-
`fection rates of small animals with dermatophytes (T. interdigitale, Trichophyton
`species of Arthroderma benhamiae, M. canis) in Germany.
`