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Fungal Infections

  • Peter MayserEmail author
Living reference work entry
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Abstract

Superficial mycoses are among the most common infectious diseases in dermatological practice. Migration and tourism are responsible for changes in the spectrum of pathogens that cause dermatophytosis, and new, especially molecular, methods have changed the classification of dermatophytes. Consideration of predisposing factors is important for the diagnosis and therapy of opportunistic yeast infections. Subcutaneous mycoses are mainly found in tropical and subtropical regions (an exception being cutaneous alternariosis) and often have a broad differential diagnosis. In systemic fungal infections, the skin can be the organ of first manifestation or the target organ in hematogenous spread (aspergillosis, fusariosis, zygomycosis). Successful local and systemic therapy requires an exact diagnosis, with identification of the pathogen for all mycoses. These data are crucial for the choice of the antimycotic, the route of administration, dose, and duration.

1 Introduction

Fungi are ubiquitously distributed, heterotrophic organisms that, unlike plants, are not capable of photosynthesis, but depend on organic substrates. In contrast to bacteria, their genome is organized in a cell nucleus (eukaryotes). While the bacterial cell wall consists of teichoic and muraminic acids, the cell wall of fungi is characterized by chitin as a structural element, together with polysaccharides such as mannan and glucan. Due to these differences, the fungi form their own kingdom, with over 100,000 known species, of which only a few hundred are known to cause mycoses.

Fungi reproduce sexually or asexually (vegetatively). All cells used for propagation are referred to as spores. Important mechanisms of asexual reproduction are budding, segmentation of hyphae into individual fragments with formation of arthrospores, and formation of spores on pre-existing hyphae or spore carriers (conidia). Microconidia (up to two cells) and macroconidia are distinguished according to the number of cells of which these are made up.

Structure and morphology are helpful for the micromorphological differentiation of fungi. Typical characteristics of chlamydospores are thickened outer walls (to protect against dehydration), the rounded shape, and the enrichment of the cell interior with reserve substances. These organisms have great resistance, which ensures better survival in unfavorable living conditions. Following dissolution of a part of the cell wall during budding, the cell content of the mother cell forms into a daughter cell, from which another new cell then emerges. If the cells adhere to each other and form a branched network, this leads to a pseudomycelium. In contrast to regular mycelium, there are no septae at the contact points of cells, only constrictions. Dimorphic fungi occur in both yeast and mold form. Asexually reproducing fungi are called anamorphic or fungi imperfecti. Most of the clinically important fungi fall into this group.

Fungi can reproduce both sexually and asexually via different spore forms. Until recently, in their anamorphic and teleomorphic life cycles, these different morphologies led to them being called different names (where asexual reproduction was given an anamorphic species name, while a sexual reproduction cycle was assigned a teleomorphic species name). With the introduction of molecular methods, however, it quickly became clear that the genetic material of a fungus is almost identical in both cycles. Consequently, in 2012, the Amsterdam Declaration on Fungal Nomenclature decided to delete Article 59 of the Code of Botanical Nomenclature, thereby abolishing dual naming. As of 1 January 2013, under the new Code of Nomenclature of Algae, Fungi, and Plants, the old system was no longer applied. This also changed the criteria for classification, away from the phenotype and towards the genotype. This meant that the analysis of variable sequences had a decisive influence on the taxonomy, and, for the future taxonomy, the oldest name (whether anamorphic or teleomorphic) was the one that was kept, being the valid one according to the new regulations. Subsequently, in the vast majority of cases, this is also the name that is now most frequently used. For clinically relevant dermatophytes, this is usually the anamorphic name (Table 1).
Table 1

Selected dermatophytes and the change in taxonomy

New name

Old names (Anamorphe, Teleomorphe)

Microsporum (M. canis)

M. canis, Arthroderma (A.) otae

Trichophyton (T.) mentagrophytes

T. mentagrophytes, A. vanbreuseghemii

T. benhamiae

T. mentagrophytes, A. benhamiae

T. simii

T. simii, A. simii

Nannizzia (N.) gypsea

M. gypseum, A. gypseum

N. fulva

M. fulvum, A. fulvum

Taxonomically, the fungal kingdom is hierarchically subdivided into divisions (-mycota), classes (-mycetes), orders (-ales), and families (-aceae). The latter are made up of different genera (e.g., Genus Candida), which, in turn, are made up of different species (for example C. albicans). Four divisions are currently distinguished: (1) Chytridiomycota, (2) Zygomycota, (3) Ascomycota, and (4) Basidiomycota.

In Germany, the medical classification of fungal pathogens does not follow the biological classification, but assigns the significant pathogens to the following three forms of taxonomic groups, according to their clinical-therapeutic features (DHS system):
  • Dermatophytes

  • Yeasts (German: “Hefen”)

  • Molds (German: “Schimmelpilze”).

Representatives of these three groups are able to cause infections in humans and animals.

From a clinical perspective, a further distinction can be made in terms of:
  • Superficial mycoses (dermatomycoses)

  • Subcutaneous mycoses

  • Systemic mycotic infections in which the skin organ can be affected in the course of sepsis.

Diagnostic Procedure

The diagnosis of a fungal infection is based on clinical and laboratory examinations. The former consists essentially of anamnesis, inspection, and, if necessary, examination by UV light (~365 nm; Wood’s lamp), while the latter consists of direct microscopic, and if necessary histological (especially PAS (periodic acid-Schiff) staining) and serological examinations, as well as the identification of the pathogen. A prerequisite for valid test results is optimal sampling. Sterile instruments (scalpel, curette, scissors, tweezer) should be used. In order to reduce contaminants, lesions suspected of having a mycosis are cleaned with 70% ethyl alcohol or isopropanol. To examine the glabrous skin for mycoses, fine scales should be removed from the marginal area of the lesion. In trichomycoses, hair must be epilated with sterile instruments. Pluckings of hair can be examined microscopically directly, or they can be inoculated directly into the culture medium for growing the pathogen.

In endothrix infections, the hair breaks off within the follicle. In this case, scales should be obtained, and the scalp should be brushed with a sterile hair brush or toothbrush. Afterwards, the brush is pushed directly into the agar of a culture plate.

In cases where onychomycosis is suspected, after removal of destroyed nail tissue, nail material is removed as far proximal from the lesion as is possible, by means of a Brocq curette, sharp spoon, or abrasion. Fine material below the nail plate (subungual hyperkeratosis) is often rich in fungal elements, and therefore particularly suitable for the application of direct microscopy, culture, or molecular diagnostics. Whole nail pieces can be used for histological diagnostics.

For lesions of the mucous membranes, material must be removed from the surface, either with a sterile loop or a cotton swab. If swabs are not directly examined or further inoculated, they should be stored in transport media.

In the case of a yeast infection of the orogastrointestinal tract, it may be useful to carry out quantitative examinations. Pharyngeal gargle fluid is useful for the examination of the pharynx.

If a subcutaneous mycosis or septic metastasis of a systemic fungal infection is suspected, in addition to histological examination (PAS, Gomori methenamine, fontana masson in melanized fungi, optical brighteners), parts of the sample should also be inoculated into a suitable agar and/or obtained for polymerase chain reaction (PCR)-assisted analysis.

Microscopic Examination

A direct examination (KOH examination) is helpful for the immediate detection of the pathogen (Figs. 1e, 1f, and 2). In general, though, with the exception of Pityriasis versicolor, no diagnosis can be made about the fungal genus or species present from a KOH examination. Several small particles (15–20) are placed on a glass slide with 1–2 drops of a 15–20% potassium hydroxide solution (KOH), covered with a coverslip, and incubated for 20–60 min (nail material) in a wet chamber. Smears are directly examined at 250–400× magnification. By staining with methylene blue, or after Gram staining, the fungal elements come to the foreground even more clearly. They appear strongly blue (Gram-positive).
Fig. 1

Macroscopy and microscopy of selected fungal cultures. (a, b) Scopulariopsis brevicaulis (mold fungus). (c) Macroculture C. albicans (yeast). (d) Chlamydospores on rice agar. (e) Positive KOH. (f) Ectothrix Infection (Microsporosis)

Fig. 2

Macroscopy and microscopy of selected fungal cultures. (a, b) Macroculture Trichophyton rubrum. (c, d) T. mentagrophytes. (e, f) Epidermophyton floccosum. (g, h) Microsporum canis

After the addition of potassium hydroxide solution, hair should be microscopically examined very quickly, as it decomposes easily, which means that it is no longer possible to identify the pathogen in a growth form.

A distinction can be made between endothrix (in particular T. tonsurans, T. violaceum, T. soudanense) and ectothrix infections (large spores of T. verrucosum, T. mentagrophytes; small spores in microsporum species).

If tetraethylammonium hydroxide (TEAH) is used instead of KOH, microscopy can be performed immediately. However, the fungal elements are destroyed during prolonged incubation. The direct preparation is evaluated by light microscopy, initially with scanning magnification 100–150×. Hyphae are of constant width in longitudinal alignment, and are mostly divided by septae. Cell nuclei are also visible at high magnification. Possible confusion (false-positive results) can occur with fibers, potassium hydroxide crystals, mosaic "fungi" (interaction of KOH and epidermal lipids; oriented towards cell boundaries), and Russell bodies (which resemble budding yeast cells and consist of lipofuscin).

Certain stains (congo red, methylene blue, chlorazole black) can enhance the contrast of fungal cells. For fluorescence microscopy with optical brighteners, dyes such as acridine orange or calcofluor white are used. At ~366 nm, fungal elements fluoresce greenish against a black background. However, cellulose (i.e., cotton fibers) also fluoresce, resulting in possible confusion with hyphae.

Culture

For culture, the material is inoculated on media such as sabouraud glucose agar, either in plastic petri dishes or in slant tubes, and incubated at 25°C. The incubation period is 14–21 days for dermatophytes, 2–5 days for yeasts, and 5–14 days for molds. Culture media with cycloheximide prevent the overgrowth of relevant cultures by rapidly growing contaminants, but should only be used in combination with cycloheximide-free media, since significant pathogens – such as Cr. neoformans and C. glabrata – can also be suppressed. Dermatophytes are conventionally differentiated by macroscopic and microscopic criteria (lactophenol blue preparation; in particular by micro- and macroconidia) (Fig. 2), and by their physiological properties (urease test, pigment formation on potato glucose agar, hair perforation, auxotrophy). In the identification of yeasts, the germ tube test and the microscopic differentiation on rice agar (Fig. 1) allow particularly rapid differentiation between Candida albicans and non-Candida albicans species. Special media include the dermatophyte test medium of Rebell and Taplin for dermatophyte diagnostics (containing phenol red as an indicator; red coloring due to alkalization of the environment, but not specific for dermatophytes), and coloring media for yeast differentiation (e.g., CHROMagar CandidaTM, CandiSelect 4TM). Molecular methods also allow differentiation directly from the clinical material. Highly sensitive and specific methods have been developed for differentiation up to the species level, but RFLP, RAPD, PCR fingerprinting, and MALDI-TOF mass spectrometry are based on a time-consuming primary culture. Methods that use DNA extracted directly from the clinical material therefore enable significantly faster results. These include real-time PCR and various PCR (ELISA) kits, some of which are offered commercially. However, several nested PCRs may have to be performed to differentiate a pathogen while the vitality of the pathogen is not yet shown (important for treatment control in tinea capitis). On the other hand, molecular methods are significantly faster (24–48 h compared to 2–6 weeks for cultural methods) and, according to the published data, are also more sensitive than KOH examination and culture.

Further Diagnostic Tests

In vitro sensitivity of yeasts, but also dermatophytes, to different antimycotics can be determined by microdilution techniques. A special clinical-mycological diagnostic procedure for some pathogens is the examination of suspicious skin areas using the UV radiation of Wood’s lamp (365 nm). In cases of infection by Trichophyton schoenleinii, blue-white fluorescence is to be expected, while yellow-green fluorescence has been described in cases of Microsporum audouinii, Microsporum canis, Nannizzia gypsea, as well as Microsporum ferrugineum. However, a negative Wood’s lamp examination never excludes a fungal infection.

While serological investigations currently play no significant role in the diagnostics of mycoses of the skin and adjacent mucous membranes, they do in subcutaneous and systemic mycotic infections.

2 Superficial Mycoses – Dermatophytoses

Dermatomycoses include diseases caused by infection of the skin and its appendages with fungi (Nenoff 2014a, 2014b). The main pathogens are dermatophytes, which, as keratinophilic fungi, cause superficial mycoses in the stratum corneum and in the keratinized appendages (hair, nails) (dermatophytoses). The opportunistic infections of skin, mucous membranes, and nails with Candida yeasts are also classified as dermatomycoses. Molds usually infect secondary, already pathologically altered, skin or nails.

Dermatophytes are keratinophilic fungi that can utilize keratinized structures (hair, nails, stratum corneum) originating from humans and animals. As dermatophytosis, all infections of the skin and/or its adnexa that are caused by species of the genera Epidermophyton, Microsporum, Trichophyton, and Nannizzia shall be grouped together. They form a clinical entity. Clinical entities of dermatophytosis are called tinea, with a suffix describing the infected body part. At the beginning of the nineteenth century, the term tinea (Latin: moth, woodworm) was used to describe the assumption that the skin changes described in this way could be caused by pathogens. In 1841, Gruby confirmed this for tinea capitis. Keratinophilic fungi are thus among the first pathogens to be recognized as such. The dermatophytes belong, according to the development of their vegetative (asexual) reproductive organs (conidia), to the following anamorphic genera of Deuteromycetes (fungi imperfecti), with the following characteristics (De Hoog et al. 2017):
  • Trichophyton spp. Macroconidia – smooth and mostly thin-walled, cylindrical (pencil-like), 1–12 septa, individually or in groups on the hyphae. Microconidia are more frequent than macroconidia, and are round, pear- or club-shaped, single, or in bundles, and are situated on the hyphae.

  • Epidermophyton spp. Macroconidia – smooth, pyriform, two- to (rarely more) nine-chambered, either standing alone or in groups. There are no microconidia.

  • Microsporum spp./Nannizzia spp. Macroconidia – thin to thick-walled, fusiform, rough, multi-chambered (up to 15 septa), individually sitting on hyphae. Microconidia are present.

Classification

Dermatophytes are divided into three groups according to their occurrence:

Anthropophilic dermatophytes are generally well adapted to the human host, in whom they usually cause only mild inflammatory chronic infections. Thus, they are hard to eliminate. Transmission occurs from person to person or through fungal material, which remains viable in the environment for up to 18 months. An asymptomatic carrier status is possible. By far the most common pathogen worldwide is T. rubrum. Further anthropophilic dermatophytes with worldwide distribution are Trichophyton interdigitale, Trichophyton tonsurans, Microsporum audouinii, and Epidermophyton floccosum. Dermatophytes that have specific areas of distribution are:
  • Trichophyton concentricum (Pacific Islands, Southeast Asia, Central America), causative organism of tinea imbricata

  • Trichophyton schoenleinii (Eurasia, North Africa)

  • Trichophyton soudanense (Africa)

  • Trichophyton violaceum (Eastern Europe, Africa, Asia, Central America).

Zoophilic species are mainly restricted to warm-blooded animals, but contact infections can lead to highly inflammatory infections in humans. The animals are often not themselves affected, but are asymptomatic carriers. Further transmission from person to person is possible, whereby the infectivity weakens with the number of passages, and usually expires after three to four passages. Important pathogens (with main host) are:
  • Trichophyton benhamiae (guinea pigs, other rodents)

  • Trichophyton mentagrophytes (rodents)

  • Trichophyton verrucosum (cattle)

  • Trichophyton erinacei (hedgehogs)

  • Trichophyton equinum (horses)

  • Microsporum canis (cats, dogs).

Geophilic species live as saprophytes in the soil or on vegetable matter, and rarely cause mycoses in humans. However, when humans become infected, most of these infections are highly inflammatory, because the pathogen is not adapted. The most important pathogens are Nannizzia gypsea, N. incurvata, and N. fulva.

Etiopathogenesis

Dermatophytes have the ability to break down keratin. They are thus able to infect keratinized structures such as the stratum corneum, hair, and nails, and induce the clinical picture of a tinea. In addition to pathogen-dependent factors, the host response also determines the clinical manifestation of the disease (Almeida 2008; Hube et al. 2015). After the adherence/inoculation of infectious fungal elements to the target tissue, the keratin-containing structures develop from the formation of mycelium, and keratinases and other enzymes play an important role. Animal models and analyses of proteins isolated from the infected nail bed of patients with onychomycosis show that endoproteases of the subtilisin family (Sub1, Sub2, Sub7, and especially Sub6) as well as the dipeptidyl peptidase DppV are the most important proteases during infection. Sub6 and DppV were recently identified in T. rubrum as the main allergens of dermatophytes, Tri r2 and Tri r4, respectively. Tri r2, in particular, can induce a delayed immune response.

Penetration into the cutis and upper subcutis can primarily occur via an invasion of the hair follicles. On the one hand, the epidermal barrier is destroyed; on the other hand, the proliferation of the epidermis increases (as a defense mechanism) and defensins are expressed. Further factors of non-specific and specific immune defense are the activation of neutrophil granulocytes, macrophages, antibodies, and T cells, the latter being responsible for healing. In patients with tinea, antibodies against dermatophytes in the blood or tissue can often be detected. However, this Th2-associated humoral immune response does not provide protection against dermatophytosis, and even seems to be associated with persistent infections.

In addition to neutrophil granulocytes and macrophages, CD4-positive T cells can be detected in lesional dermis. Tinea develops a specific delayed Th1-mediated immune response similar to that of allergic contact dermatitis, which is also responsible for infection-associated sterile remote reactions (dermatophytides). These can be confirmed by a positive trichophytin test. Since the pathogens are not adapted, and humans are therefore a false host, infections with zoophilic and geophilic dermatophytes cause acute inflammatory dermatophytoses in humans with an intact immune system. The strong reaction often leads to spontaneous healing within a short time. Which specific factors lead to protracted courses in anthropophilic pathogens has not been clarified yet.

Important factors for the development of dermatophytosis are extrinsic factors such as immunosuppression, diabetes mellitus, advanced age, environmental conditions (e.g., occlusive footwear, humidity), contact with contaminated objects and surfaces, as well as direct transmission by infected humans or animals. On the other hand, there is also evidence of a family or genetic predisposition to dermatophytosis, since – with identical risk factors – not all people are equally susceptible to infection. Examples are special forms of dermatophytosis in small isolated communities (tinea imbricata in Polynesians) and a high incidence of dermatophytosis in some families. Specific defects have been identified for the dectin-1 receptors, the caspase recruitment domain-containing protein 9, MHC class II genes, and the defensin beta 4 gene (DEFB4) (Garcia-Romero and Arenas 2015).

A special situation exists with onychomycosis as well as in areas of terminal hair follicles, in particular on the scalp and beard area. The infection of the immunological niche nail causes a permanent infection, especially in the presence of structural changes of the nail and limited growth, because the nail then cannot eliminate a penetrating fungus through faster growth. In the case of endothrix hair infection, inflammatory changes are usually only slight, since the fungal elements remain relatively isolated within the hair, whereas granulocytic or granulomatous progression can result during the penetration and subsequent rupture of the follicular epithelium. Dermatophytes can also spread to the deeper dermis and even the subcutis if the host is severely immunosuppressed.

Treatment

Successful local and systemic treatment requires an exact diagnosis, if possible, with detection and identification of a fungus in direct microscopy, culture, or by means of PCR-assisted methods/MALDI-TOF (Verrier and Monod 2017). These data are crucial for the choice of the antimycotic, route of administration, dose, and duration. In systemic treatment, the age of the patient, the body weight of children, and possible interactions with other drugs should be taken into account. If a zoophilic species is detected, the animal, which may be sick or be an asymptomatic carrier, should be treated by a veterinarian. For tinea capitis, tinea of the glabrous skin, and onychomycosis regularly updated guidelines are available.

The central point of attack for various antifungal drugs is fungal ergosterol biosynthesis. Ergosterol is an important component of the cytoplasmic membrane. Inhibition of ergosterol biosynthesis considerably disrupts the function of the membrane. Antimycotics that are effective apart from ergosterol synthesis, such as griseofulvin (DNA- and RNA-dependent protein synthesis) and ciclopirox olamine (mitochondria, cell wall), can have synergistic effects on ergosterol synthesis inhibitors (Fig. 3). Polyenes are not effective in dermatophytosis. Characteristics of important classes of antimycotics are summarized in Table 2.
Fig. 3

Antimycotic targets. (a) Antimycotic targets on the fungal cell. (b) Influence of individual active substances on ergosterol biosynthesis

Table 2

Important antifungal classes

Class

Active ingredient∗

Indication

Application

Administration

Allylamines

Terbinafine

Dermatophytosis onychomycosis

Oral, topical

Tablet, cream, solution

Benzofurane

Griseofulvin

Tinea capitis (especially microsporum infections)

Oral

Tablet, suspension (GB, USA)

Imidazole

Clotrimazole miconazole bifonazole

sertaconazole

Dermatophytosis candidosis pityriasis versicolor

seborrheic eczema

Topical

Solution, cream, lotion, shampoo, vaginal tablet

Echinocandine

Caspofungin

anidulafungin

micafungin

Systemic mycotic infections (candidosis, aspergillosis)

IV (intravenously)

Solution

Triazole

Itraconazole

fluconazole

Onychomycosis, dermatophytosis candidosis

Oral

Oral

Capsule, liquid

Polyene

Amphotericin B

nystatin

Candidosis

Topical, oral (none resorption), IV (amphotericin B)

Cream, gel, paste, suspension, vaginal tablet

Pyridones

Ciclopirox ciclopirox-olamine

Dermatophytosis onychomycosis candidosis

Topical

Cream, solution, nail lacquer, powder, suppository

Morpholine

Amorolfine

Dermatophytosis onychomycosis candidosis

Topical

Cream, nail lacquer

∗Examples

Terbinafine 250 mg can be given once a day for 4 weeks in the case of widespread mycoses, mycoses of the ridged skin, and failure of topical treatment. Alternatively, itraconazole is given orally in the form of a 100-mg capsule for 2–4 weeks for infection of the palms and soles of the feet. In fluconazole, the capsule is administered 50 mg once a day for 2–7 weeks.

The introduction of a 1% terbinafine cream has brought about therapeutic progress, at least in the case of very common tinea pedis. This cream is applied twice a day for 1 week, and is superior to the application of a comparable azole preparation several times a day for 4 weeks. A one-time treatment of 1% terbinafine in a film-forming solution in this indication is approved.

In the case of mycoses caused by zoophilic dermatophytes or in dyshidrotic mycoses, the inflammation, usually characterized by severe itching, is often in the foreground for the patient. Combination preparations of a potent antimycotic and a glucocorticoid enable a faster improvement than monotherapy, and thus promote compliance. They are generally approved for 1–2 weeks of treatment twice a day, and are therefore suitable for initial treatment.

Special Therapeutic Situations

Special measures must be considered for children, pregnant and breastfeeding women, and in cases of immunosuppression.

Pregnancy and Lactation

Due to embryotoxicity, pregnancy (as well as during the lactation period) is a contraindication for systemic antifungal treatment. Systemic treatment with fluconazole, itraconazole, posaconazole, or voriconazole may only be carried out in case of an urgent indication, and not in the first trimester. Treatment does not justify a risk-based abortion, and a high-resolution ultrasound should be offered. Clotrimazole and nystatin (for yeast infections) are preferred topical treatments.

Immunosuppressed/Transplant Patients

In immunosuppressed patients, interactions of fluconazole and itraconazole must be considered. Due to inhibition of cytochrome-P450 3A4, a reduced degradation of cyclosporin occurs, and the risk of glucocorticoid-related myopathy is higher. Terbinafine increases the plasma clearance of cyclosporine by 15%, so that appropriate dose adjustments should be made. Interactions of terbinafine and tacrolimus are not known.

Children

The special features of systemic treatment are dealt with in the treatment of tinea capitis (“Sect. 2.2”). Amorolfine and ciclopirox olamine are not approved for topical treatment in children in Germany, Terbinafine can be used only for children over 5 years of age.

2.1 Tinea of the Glabrous Skin (Epidermomycosis)

The classic criteria for epidermomycosis include a sharp border, scaling (especially at the margin), a pale to intense erythema, and a centrifugal spreading of the lesion. The reactions of the affected skin range from slight redness and scaling, which can be associated with itching, to severe vesicular, purulent-absceding, or (rarely) granulomatous changes.

2.1.1 Tinea Faciei/Corporis

Clinical Features

Tinea faciei/corporis is an inflammatory dermatophytosis of the skin covered with lanugo, including the face (Figs. 4, 5, and 6). It is characterized by mostly disc-like, erythematous, itchy lesions, with marginal scaling. Remarkable are the healing of the foci in the center, and their peripheral progression. This results in characteristic ring shapes (“ring worm”). However, in case of inadequate (only symptomatic) treatment with glucocorticoid-containing topicals, the typical signs of inflammation are suppressed, and the diagnosis becomes more difficult. All dermatophyte species can cause the clinical picture. Especially in the case of tinea faciei, zoophilic pathogens (contact with animals that can be asymptomatic) are frequent. One special feature is the tinea corporis gladiatorum caused by T. tonsurans that frequently occurs in athletes (wrestlers, judoka).
Fig. 4

Tinea faciei

Fig. 5

(a) Tinea faciei/corporis. (b) Typical annular lesions (ring worm)

Fig. 6

Tinea corporis et colli

Differential Diagnosis

Eczema, psoriasis vulgaris, parapsoriasis en plaques, mycosis fungoides, pityriasis rosea, discoid or subacute cutaneous lupus erythematosus. "If a lesion scales, a mycotic infection should be ruled out."

2.1.2 Tinea Inguinalis

Tinea inguinalis (Hebra 1860) was formerly mostly caused by E. floccosum; today the usual cause is T. rubrum (Fig. 7). Favored sites are the inner sides of the thighs at the contact surfaces of the scrotum and the scrotum itself. From here, the disease often spreads to the gluteal region. Further intertriginous areas can be the submammary folds in obese women, as well as the armpits, elbows, and back of the knees. The infection occurs either through contact (examination of the partner needs to take place) or through autoinoculation of a foot mycosis existing simultaneously. The latter should not be overlooked in patients with tinea inguinalis.
Fig. 7

Tinea inguinalis et abdominalis

Differential Diagnosis

Erythrasma (no accentuation of the margin, brick-red fluorescence in Wood’s lamp), eczema (blurred borders with maximum changes in the center, possible scattering phenomena), intertrigo, and intertriginous psoriasis.

2.1.3 Tinea Manus

Clinical Features

Tinea manus (Fig. 8) is predominantly unilaterally localized and only spreads to the other hand after a longer existence. Most common is the squamous-hyperkeratotic or hyperkeratotic-rhagadiform tinea manus localized on palmae, palmar finger parts, and on the fingertips. On the palm, there is a fine, partly collarette-like scaling, with accentuation of the palm lines. On the back of the hand and on the fingers, the picture resembles that of tinea corporis with erythematosquamous, sharply defined, peripherally accentuated, polycyclic lesions, which spread towards the margin and often show small pustules. Onychomycosis is often present simultaneously. The dyshidrosiform tinea manus is characterized by itchy blisters and pustules on the palms of the hand, as well as the lateral and volar finger regions. A special form is the one-hand/two-feet mycosis, in which both soles of the foot and one palm (usually the dominant hand) are affected.
Fig. 8

Tinea manus

Differential Diagnosis

Hyperkeratotic rhagadiform or dyshidrotic hand eczema (bilateral), atopic hand eczema, contact eczema, psoriasis palmaris (psoriasis elsewhere), mycid reaction of the hands (as in foot mycosis).

2.1.4 Tinea Pedis

Tinea pedis is one of the most common dermatological diseases. In Germany, its prevalence among adults is thought to be about 20%. There are three different clinical manifestations, and overlaps are common:
  • Interdigital form (most frequent) (Fig. 9): Maceration, peeling, and fissures, most frequent particularly in the tight third and fourth interdigital space. Erosions and rhagades result from the detachment of the macerated layers. The process often extends to the sole. Hyperhidrosis (wearing of rubber boots, sports shoes) can lead to acute inflammation, with severe itching.
    Fig. 9

    Tinea pedis, interdigital form

  • Squamous hyperkeratotic form (Fig. 10): It is mostly characterized by non-inflammatory, diffusely scaling keratosis of the entire sole of the foot (often interpreted as dry skin). At the edges of the feet, there is a sharply defined, marginal scaling on erythematous ground (“moccasin mycosis”). A co-infection of the nails is frequent.

Fig. 10

Tinea pedum, hyperkeratotic

  • Vesiculo-dyshidrotic form (Fig. 11): Dyshidrosis-like, often slightly turbid vesicles and blisters on a slightly inflammatory reddened base occur particularly at the arch of the foot, as well as on small and large toe-balls. There is severe itching; occasionally there is a dyshidrotic mycid of the hands. Larger blisters seldom appear (pompholyx or bullous type of tinea pedis). If there is no scaling, the fungus can be detected (frequently T. interdigitale) from the roof of a blister (direct microscopy, histology).

Fig. 11

Dyshidrosiform tinea pedis

An important complication of tinea pedis is erysipelas of the lower legs, for which erosions and rhagades between the toes are a frequent site of entry.

Differential Diagnosis

Intertriginous type: Simple intertrigo, bacterial foot infections (especially Gram-negative toe web infections) and candidosis; squamous-hyperkeratotic type: hyperkeratotic or hyperkeratotic rhagadiform foot eczema, psoriasis plantaris, lichen planus, and hereditary keratoses. The dyshidrotic type may be similar to dyshidrotic eczema (usually bilateral) and psoriasis pustulosa palmaris et plantaris.

2.1.5 Onychomycosis

(Meissner 1853; Virchow 1854)

Onychomycosis (tinea unguium) is often associated with mycoses of the ridged skin. Its clinical symptoms range from a slightly yellowish discoloration to complete crumbly decay of the nail plate. Onychomycoses account for 18–40% of nail diseases. They represent 30% of all dermatomycoses, and affect 20% of adults. Over 80% of all onychomycoses are caused by a dermatophyte infection (10–20% yeasts or molds such as Scopulariopsis brevicaulis, Fusarium spp., Onychocola canadensis, Neoscytalidium dimidiatum; in the case of molds, repeated detection is required to rule out false-positive results by contamination) (Gupta et al. 2012). Onychomycosis affects the feet more frequently (starting from a tinea pedis) than the hands; if the hands are involved, the feet are usually also affected.

From a therapeutic point of view, a distinction is made between the following forms (Figs. 12 and 13):
Fig. 12

(a) Scheme of onychomycosis I. Distolateral subungual onychomycosis (DLSO); II. White superficial onychomycosis (WSO); III. Proximal subungual onychomycosis (PSO). (b) Onychomycosis

Fig. 13

Onychomycosis with dystrophy

  • Distolateral subungual onychomycosis (DLSO) is the most common form, in which the fungus (mostly T. rubrum) penetrates the underside of the nail plate via the hyponychium, and spreads slowly from the distal to the matrix.

  • White superficial onychomycosis (WSO; Leukonychia trichophytica), characterized by whitish maculae with fungal elements (often T. interdigitale) in the superficial layers of the nail plate.

  • Proximal subungual onychomycosis (PSO), with penetration of the fungus via the eponychium to the nail matrix and into the nail plate.

  • Total dystrophic onychomycosis (TDO), with extensive destruction of the nail plate as the final state of the three forms mentioned above.

Onychomycosis is often associated with factors such as genetic disposition, recurrent trauma due to inadequate footwear (especially DLSO), foot malpositions, angiopathies, and polyneuropathies.

Differential Diagnosis

Psoriasis vulgaris of the nail organ, lichen planus, trauma of the nail organ, and periungual eczema must be differentiated. The detection of a fungus does not rule out psoriasis of the nail. Some studies show an increased prevalence of onychomycosis/fungal colonization, especially by yeasts or molds, in nail psoriasis.

Treatment

(Ameen et al. 2014)

Topical monotherapy (especially nail lacquers with ciclopirox or amorolfine) is indicated for WSO and DLSO with less than 50% involvement and without involvement of the matrix. Cure rates can be improved noticeably by means of atraumatic avulsion of the nail (20–40% urea paste, perhaps in combination with an antimycotic agent such as bifonazole, and abrasion of the nail plate by cutting or laser). Surgical nail extraction is obsolete. For all other forms of onychomycosis, an additional systemic treatment is indicated. Prerequisites for this are a still-present nail growth (≥0.5 mm/week), as well as compliance and exclusion of possible contraindications/interactions with other given medication.

For systemic treatment, fluconazole, itraconazole, and terbinafine are available. Due to low cure rates, griseofulvin is no longer used. Terbinafine is currently considered standard (250 mg/day over 6 weeks for onychomycoses of the fingernails, over 12 weeks for toenails, also as pulse treatment [no standardized scheme]). The spectrum of side effects includes headache, nausea (usually in the first week; apply medication in the evening), and (rarely) usually reversible taste disorders. In individual cases, severe liver damage and/or severe skin reactions may occur. Terbinafine can worsen psoriasis or provoke it de novo (usually within the first 4 weeks of treatment), and drug-induced subacute-cutaneous LE can also occur, especially if risk factors (pre-existing collagenosis) are present. Itraconazole is also approved – both as a continuous dose of 200 mg/day for 3 months and as an intermittent pulse treatment for 3 months (1 pulse = 200 mg/day twice daily for 1 week, then 3 weeks break; maximum 3 pulses). A pre-existing liver disease as well as the use of other drugs requires a particularly strict indication. Fluconazole is an alternative, especially in an interval treatment form (150 mg or 300 mg administered perorally on the first day of each week; in the case of an infection of the fingernails, over 6–9 months, the toenails, over 9–12 months).

The laser treatment of onychomycosis is primarily based on the use of Nd:YAG lasers. Firstly, in their criteria, however, very heterogenous studies show a complete healing in at least 50% of the treated patients, with good tolerability, so that this treatment could represent an alternative option in patients with contraindications for systemic antimycotic treatment.

In order to avoid recurrences, appropriate measures should be taken with each treatment: disinfection of contaminated material – in particular shoes and stockings, washing at a minimum of 60 °C, as well as use of quaternary ammonium compounds.

2.2 Trichomycoses

Dermatophytoses of terminal hair are called trichomycoses. From a clinical and practical point of view, a distinction is made between tinea capitis sensu stricto, epidemic tinea capitis (microsporosis), and favus (tinea favosa). Trichomycoses are caused by the spread of pathogens from the stratum corneum into the hair follicle and hair shaft to the zone of keratinization (Adamson’s fringe). Only anagen hair is affected. When the hair grows to the surface, spores are spread. Depending on the pathogen and the immune response, the clinical form results, which can range from largely aphlegmasic courses to deeply infiltrating and abscessing infections (kerion). Cup-shaped crusts (scutula), which can coalesce to larger masses, are found with the favus (tinea favosa).

2.2.1 Tinea Capitis (Sensu Stricto)

(Gruby 1841)

Tinea capitis is the most common dermatophytosis in childhood (Figs. 14 and 15) (Fuller et al. 2014; Mayser et al. 2020). With puberty, the rising sebum triglycerides exert a fungistatic effect, so that adults are affected less frequently. The spectrum of tinea capitis pathogens in Europe has changed. While zoophilic M. canis, followed by T. mentagrophytes, dominated in central Europe and the Mediterranean area, in Western Europe an increase of the anthropophilic T. tonsurans – almost exclusively the cause of tinea capitis in the USA – and T. soudanense, as well as M. audouinii, was observed. Anthropophilic pathogens (in particular T. tonsurans, T. violaceum, T. soudanense) cause an endothrix infection of the hair.
Fig. 14

Tinea capitis diffusa

Fig. 15

Tinea capitis (Kerion celsi)

In this form of infection, the hair shaft is filled with spores while the cuticle is intact, resulting in trichomalacia, recognizable as a small black dot in the follicle opening (black-dot ring worm). The scalp often shows local hair loss and only pityriasiform scaling, with no or little redness. Often, asymptomatic carriers are also involved (at-risk populations up to 15% – especially adults). Follicular pustules and massive purulent secretion occur, especially when zoophilic fungi penetrate deep into the hair follicles; this can be associated with general symptoms such as fever and headache, as well as lymph node swelling. With disc-shaped development and massive purulent secretion (like the "honey from a honeycomb") one speaks of a kerion (Greek: honeycomb). Triggers are mostly zoophilic dermatophytes such as T. verrucosum, T. mentagrophytes, or T. benhamiae. Destruction of the hair follicles – with permanent alopecia (pseudopélade state) – is possible.

Diagnostic Procedure

Detection of a fungus is most important. Investigation of scales, and, in the case of follicular forms, plucked hair stumps (with sterile epilation forceps) is essential. In the case of less inflammatory endothrix infections, a brush swab of the scalp (with a sterile massage brush/single toothbrush) can also be performed. The brush is then pushed directly into the agar of a culture plate. Especially in the case of endothrix infections, dermatoscopy can also be helpful in diagnostics (comma and corkscrew hair) and for follow-up.

In direct examination, a distinction between endothrix and ectothrix infections provides an indication of the pathogen. Swab tests often provide evidence of a superinfection with Staphylococcus aureus, and are not suitable for the detection of fungi.

Treatment

Tinea capitis must be treated systemically with adjuvant topical treatment. The aim of the treatment must be the mycologically confirmed healing (negative culture and negative KOH examination). In addition to griseofulvin, the antifungal drugs terbinafine, itraconazole, and fluconazole can also be used for the oral treatment of adults. For the treatment of children, only griseofulvin (10 mg/kg body weight(bw)/day) is currently authorized in Germany. The use of terbinafine, fluconazole, or itraconazole in childhood is still considered a medical trial, according to the German Medicines Act. Terbinafine is the most effective substance in the trichophyton species (dosage body weight-adapted <20 kg: 62.5 mg/day, 20–40 kg: 125 mg/day, >40 kg: 250 mg/day). However, it has been shown to be significantly less effective in infections involving the microsporum species. Griseofulvin (20 mg/kg bw/day) or itraconazole (5 mg/kg bw/day as a tablet, with a high-fat meal or as solution) is recommended.

Systemic treatment should be supplemented by a topical antimycotic (i.e., clotrimazole, miconazole, econazole, bifonazole, sertaconazole, tioconazole, ciclopiroxolamine, naftifine, terbinafine, or amorolfine). While azoles and pyridones are broad-spectrum antifungals, allylamines have a greater effect on dermatophytes than on other fungi found on the skin. In the case of an infection by anthropophilic species (in particular T. tonsurans, T. violaceum, and M. audouinii), all family members and close contacts should be examined and treated if necessary. Asymptomatic carriers (no clinically visible infection, but culture and/or PCR positive) with a high spore load should be treated systemically (White et al. 2007). Topical measures may be sufficient for low spore loads. Epidemic occurrence includes further measures such as isolation of sick people and removal/decontamination of shared objects (Gray et al. 2015).

2.2.2 Small-Spored Ectothrix Tinea Capitis (Microsporosis)

This condition is a non-abscessing, almost reactionless deep folliculitis caused by the anthropophilic M. audouinii or by M. canis (zoophilic – especially infection of cats, which may also be asymptomatic vectors) (Fig. 16). In almost all cases, prepubescent children are affected. Inflammatory redness is usually completely absent. Lackluster hair has broken off in the lesions, which appear to be dusted with flour, just above the scalp. The presence of many small spores (diameter 2–3 μm) around the hair shaft on microscopic examination led to the German name of “Mikrosporie,” and is reflected in the English term microsporosis. Wood’s lamp can be helpful in screenings, as well as in the screening of animals (but is only positive in about 40% of cases).
Fig. 16

Microsporosis

2.2.3 Favus

(Hube 1837; Schönlein 1839)

Favus is characterized by sulfur-yellow scales and crusts containing mycelial masses, which are called scutula (Lat. scutulum, little shield) and which develop in and around the hair follicle, enclose one or more hair shafts in the center, and heal with scarring alopecia (pseudopélade). The pathogen is the anthropophilic Trichophyton schoenleinii, the first dermatophyte to be described. The possible transmission from one generation to the next previously led to it being suspected of being a hereditary disease. The incidence of tinea capitis favosa has decreased significantly worldwide, with the exception of China, Nigeria, and Iran. About 95% of the patients have clinical symptoms, especially scutula, hair loss, atrophy, and scarring.

Incidence peaks in childhood (6–10 years, predominantly in boys), but the disease may not regress with puberty, and can last a lifetime. The average duration of the disease is 5 years (10 days–59 years). Seven percent of tinea favosa cases include glabrous skin and nails. Favus is less contagious than other dermatophytoses due to the growth of the pathogen within the hair shaft (endothrix favosa). On the other hand, it is also located in a niche that is difficult to access in terms of immune defense and environmental influences. The pathogen can thus survive for up to 54 months in depilated hair.

2.2.4 Tinea Barbae

This condition is a deep abscessing folliculitis of the beard hair, in particular, due to T. verrucosum as well as T. mentagrophytes. It is often accompanied by general symptoms (Fig. 17). In farmers, the disease can be caused by contact with infected large animals, and is a reportable occupational dermatosis in Germany. The disease begins with a purulent folliculitis, with the pathogens spreading during shaving. The initially superficial inflammation – with redness, scaling, and pustules – quickly penetrates into the depths of the hair follicles, creating soft, infiltrated, furunculoid nodules. The lesion is covered with follicular pustules. The most severe form of tinea barbae is the undermined, confluent abscess of large areas of beard. The affected beard hairs can be painlessly epilated for diagnostic purposes. Lymph node swelling and general symptoms occur.
Fig. 17

Tinea barbae

Differential Diagnosis

Bacterial folliculitis must be differentiated, in particular staphylococcal and Gram-negative folliculitis, Candida folliculitis, actinomycosis, and tuberculosis cutis colliquativa.

2.2.5 Nodular Granulomatous Perifolliculitis (Granuloma Trichophyticum)

(Majocchi 1883)

Majocchi distinguished the clinical picture of this condition from the deep follicular trichophytosis, and defined its clinical characteristics as "intracutaneous roundish, superficially flattened, indolent, only under finger pressure dolent nodules, which are covered by normal or slightly reddened, not scaly skin". In the classic perifolliculitic type, which is situated rather dermally, immunocompetent individuals with chronic dermatophytosis develop a rupture of hair follicles with a granulomatous tissue reaction following trauma (e.g., shaving of the lower leg hair). The dislocated keratin serves as substrate for the pathogen. The subcutaneous nodular form occurs primarily in immunosuppressed patients (also with topical application of potent steroids) and is characterized by livid-red papules and nodes. T. rubrum is usually found.

Differential Diagnosis

Deep bacterial folliculitis can be distinguished, but also erythema induratum bazin and erythema nodosum, due to its frequent localization on the lower leg. Almost always, however, an already existing tinea pedis, cruris, or unguis can be detected, which facilitates the diagnosis.

2.3 Mycid

A specific delayed Th1-mediated immune response developing in a tinea similar to that in allergic contact dermatitis may be associated with an infection-associated sterile remote response (dermatophytide). It can be confirmed by a positive trichophytin test. Clinically, these are symmetrical, dyshidrosiform eruptions of the hands and feet (negative direct examination, negative culture) or nodular or multiform erythema-like lesions, especially on the extremities. Lichen trichophyticus – pale, erythematous, grouped, or scattered follicular papules on the trunk – is easy to overlook. An indication is the simultaneous existence of an often massive dermatophytosis. Mycids can also occur or worsen during intensive treatment of a manifest mycosis, possibly because of increased antigen resorption when the pathogens are killed. They disappear spontaneously when the mycosis heals during the treatment.

3 Superficial Mycoses – Candidosis and Other Yeast Infections

Yeasts are opportunistic pathogens that require certain predisposing factors to trigger diseases. Yeast infections therefore mainly affect people with a weakened immune system ("very young, very old, very sick").

3.1 Candidosis

Candida mycoses are caused by yeasts of the genus Candida, with a large proportion caused by Candida albicans. Local Candida mycoses of the skin and adjacent mucous membranes are distinguished from systemic Candida mycoses.

Natural occurrence

Imperfect yeasts of the genus Candida account for about a quarter of all known yeasts. The ubiquitously distributed organisms comprise a very heterogeneous group, with a high morphological and physiological diversity. Yeasts of the genus Candida are found in humans as commensals in the gastrointestinal tract, the upper respiratory tract, and in the female genital area. The skin is not a natural reservoir for Candida albicans or for other species. However, in the adjacent skin areas of body orifices, as well as on the fingers (which have frequent contact with the mouth) and intertriginously, colonization with these yeasts is frequently observed. Note that this is a colonization, not an infection, although the latter can manifest relatively quickly when certain predisposing factors occur. Candida yeasts are found as pathogens in 10–15% of all dermatologically significant fungal infections.

Etiopathogenesis

Candida species are facultatively pathogenic, opportunistic yeasts. The occurrence of certain local and systemic conditions on the part of the host can be triggers for the conversion of the commensal into the pathogenic form (Polke et al. 2015). Morphologically, this step is characterized by the transition from the yeast phase to the mycelium phase (with the exception of C. glabrata). The induction of the hyphae is favored by various factors. The production of hyphae is one of the most important virulence factors. Through adhesion (1) the contact between yeast cells and host epithelium takes place. Candida yeasts acquire the ability to adhere through adhesins, predominantly mannan or protein components of the cell wall. On the host side, mannan-binding proteins (MBPs) are expressed by the mucosal epithelial cells. Furthermore, local microflora and the mucosal milieu influence adhesion. After adhesion, the Candida yeasts spread mainly in the upper layers of the epidermis. The invasion (2) occurs by means of enzymes (3) (proteinases – in particular secretory aspartate proteases [SAPs], phospholipases, and lysophospholipases) with hydrolytic properties that can be detected – concentrated in the yeast cells – on the part facing the mucosal epithelium. The enzymatic build-up of the cells finally results in a tissue defect, with inflammation of the skin area, which looks clinically different, depending on the location of the infection. Another virulence factor (of Candida yeasts) is the formation of toxins, (4) which, with adhesive, cytotoxic, enzymatic, pharmacological, and immunological properties, support the progression of infection. Through phenotype switching (5) and molecular mimicry (6) Candida yeasts can evade the immune response of the host.

Conditions of the Host/Predisposing Factors

A healthy skin and a healthy mucous membrane environment represent an effective barrier function against external noxae and pathogens. Local and systemic factors can weaken this barrier function and facilitate the manifestation of a candidosis (Holland and Vinh 2009, Netea 2015).

Local Predisposing Factors

Existing skin and mucous membrane diseases, locally applied steroids, chronic maceration of the skin/intertrigines, increased tendency to sweat, occlusion by bandages, closed footwear, entry ports through plastic parts, for example, intravenous catheters, implants.

Systemic Predisposition Factors ("very old, very young, very sick")

The following factors play a role in this regard:
  • Disturbed cell-mediated immune response in newborns and the elderly, congenital immune deficiency syndromes, HIV infection, seriously ill patients (lymphomas, leukemia, carcinomas), cytotoxic and immunosuppressive treatment

  • Disturbed phagocytosis ability for diabetes mellitus, neutropenia

  • Endocrine factors in pregnancy, diabetes mellitus, Cushing's disease, Addison's disease, hypoparathyroidism, hypothyroidism

  • Metabolic disorders such as hyperalimentation and marasmus, iron/zinc deficiency

  • Iatrogenic treatment – in particular, with estrogens, corticosteroids, immunosuppressants, cytotoxic drugs, antibiotics.

Diagnostic Procedure

If a yeast infection is suspected, the aim should be to identify the causative species. With regard to the resistance of some Candida species to certain antifungal agents, the mere detection of a yeast infection or candidosis is often insufficient. In particular, the identification of the species in all chronic recurrent processes, in immunosuppressed patients and in suspected cases of Candida glabrata or other Non-albicans species should be performed, as they may have reduced sensitivity/resistance to various azole derivatives.

In standard media, Candida species usually show the typical growth behavior of yeasts after 1–4 days: aerial mycelium is not present, and smooth, white, cream-colored, or red colonies with a matt surface can be found. A differentiation of yeast species on the basis of culture macromorphology is generally not possible. Differentiation is carried out, using chromogenic culture media or micromorphology by inoculation on rice extract agar (according to Taschdjian). The yeasts are incubated, under semianaerobic conditions, under a cover slide, for 1–4 days at 22°C, and directly microscopied at 400-fold magnification. The rice extract agar is a deficiency medium, and in various species, evokes a typical growth pattern of (pseudo)mycelium and blastospores. C. albicans forms very characteristic, thick-walled permanent spores named chlamydospores (1–4 days at 22°C; at 37°C no formation of chlamydospores). The germ tube test is a further specific diagnostic agent for C. albicans. Incubation with serum at 37°C for 2–4 h results in germ tubes, preforms of hyphae up to the formation of the first septum. If species identification is not successful, Candida yeasts are further differentiated by their physiological properties (assimilation and fermentation tests; available commercial tests such as Auxacolor 2TM, Bio-Rad; ID 32C TM, BioMerieux) or by molecular methods (PCR, MALDI-TOF).

Treatment

The treatment of opportunistic infections by yeasts of the genus Candida is based on the elimination of predisposing factors, as well as a topical, and, if necessary, systemic antifungal treatment. In most cases, topical treatment of Candida infections of the skin is successful. The effective substance classes for Candida infections are polyenes (nystatin, amphotericin B) and azoles, as well as allylamines (terbinafine, naftifine), morpholines (amorolfine), and pyridones (ciclopiroxolamine). The most suitable base is selected according to the localization: creams and ointments (skin on trunk and extremities), pastes (intertrigines), lacquers (nails), suppositories/vaginal tablets (vagina), lozenges, and suspensions (oral mucosa). In cases of severe inflammation, short-term combination treatment with topical steroids may be considered.

Griseofulvin and tolciclate/tolnaftate are not effective in the treatment of yeasts.

Only a few cases of resistance have been observed against polyenes. C. krusei is resistant to fluconazole and itraconazole, and a reduced sensitivity to azole derivatives is observed with C. glabrata and C. guilliermondii. There is no development of resistance to ciclopiroxolamine. In individual cases, systemic treatment of a local candidosis may be necessary, especially in chronic Candida paronychia/onychomycosis, vulvovaginal candidosis, or chronic mucocutaneous candidosis. Here, fluconazole, itraconazole, voriconazole, or posaconazole are available (the latter effective in non-albicans pathogens that are resistant to fluconazole and/or itraconazole; currently only approved for the treatment of systemic mycoses). Amphotericin, echinocandine, and flucytosine must be administered intravenously, and are also reserved for the treatment of invasive candidoses. In order to achieve synergistic effects, the combination of a systemic antimycotic with a topical one of a different class is recommended. Since polyenes, azoles, allylamines, as well as amorolfine interfere with the ergosterol metabolism of the fungi, a combination with the hydroxypyridone cyclopiroxolamine (chelating complex former and cytotoxicity by hydrogen peroxide induction in the fungal cells) is useful. Systemically administered terbinafine is not sufficiently effective in candidoses.

3.1.1 Candida Intertrigo

Synonym

Intertrigo candidomycetica

Epidemiology

This condition is the most common complication of intertrigo, with factors such as obesity, diabetes mellitus, and general immune deficiency playing a major role.

Etiopathogenesis

Erosive, macerative skin in the moist warm intertriginous areas encourages the growth of Candida spp., and therefore candidosis is the most common complication of an intertrigo. Cause and consequence cannot be clearly distinguished: The pathogen provokes the inflammation; the inflammation in turn favors the pathogen, for example by disruption of the skin barrier. Other factors that promote this are heavy sweating, tight and airtight clothing, and poor hygiene.

Clinical Features

The main localizations are the intertriginous areas (axillae, groin, abdominal folds, submammary, perigenital, and perianal regions) (Fig. 18). Typical are the relatively sharp limitation by a scaly collarette facing the inflammatory erythematous and weeping center of the lesion, and sometimes small pustules with white-yellowish content as primary efflorescence (in contrast to the mostly staphylogenic osteofolliculitis not bound to the hair follicle). Papules and pustules also occur as satellite lesions in the vicinity of the itchy areas (“islands in front of the coast”). Bacterial superinfections of the lesions are possible.
Fig. 18

Candida intertrigo

Differential Diagnosis

Simple intertrigo, toxic or allergic contact dermatitis, intertriginous psoriasis vulgaris, Hailey-Hailey disease.

Treatment

Careful drying of the intertriginous areas, weight reduction, wearing of cotton clothing, as well as insertion of small strips of linen are important. Antimycotic treatment is generally carried out topically (polyenes, azoles). Depending on the skin condition, suitable vehicles, in particular pastes (intertriginous area) or creams, should be selected. A disadvantage is the additional occlusive effect with oily substances.

3.1.2 Interdigital Candidosis

Synonyms

Erosio interdigitalis candidomycetica; Erosio interdigitalis blastomycetica

Clinical Features

A Candida infection of the interdigital spaces of the fingers is characterized by a strong maceration of the horny layer. It is swollen and tends towards rhagades (Fig. 19). Gram-negative bacteria are often found as co-pathogens. Constant moisturization of the hands and occlusion through the wearing of rings have a positive effect.
Fig. 19

Interdigital candidosis

3.1.3 Candidosis in the Diaper Area (Napkin Dermatitis)

Etiopathogenesis and Clinical Features

In case of incontinence, diapers in the functional intertriginous space can easily lead to a maceratively erosive intertrigo. Diaper dermatitis is a primary irritant disease of multifactorial origin with secondary superinfection by bacteria and yeasts of the genus Candida. A primary candidosis in the diaper area is rather rare. A typical distinguishing feature is the omission of deep skin folds in the irritative form (W-shape), while these areas are also affected in primary candidosis. In the case of genitoanal candidosis, stool examination often proves a strong colonization of the intestine as a source of infection.

Differential Diagnosis

Diaper dermatitis, inverse psoriasis, seborrheic eczema, acrodermatitis enteropathica.

Treatment

Reduction of predisposing factors: frequent diaper changes, use of non-occlusive, absorbent diapers/cotton diapers, diaper-free periods as far as possible. Mild cleansing measures of the skin, oil baths, drying – especially with a blow dryer – as well as insertion of strips of linen into the skin folds are all suitable procedures. Other options include soft zinc paste for skin protection. In case of secondary colonization by Candida yeasts, external treatment is recommended, especially polyenes (nystatin) and azoles in paste form. In the case of severe courses, hydrocortisone 1% in paste form should be used for a short time, if necessary.

Cave: Agents applied externally in the intertrigines are absorbed 20 times higher than in other localizations.

Fluorinated glucocorticoids (granuloma gluteale infantum) are contraindicated.

3.1.4 Candida Paronychia and Candida Onychomycosis

Etiopathogenesis

The condition occurs mainly during chronic strain of the hands, due to constant exposure to moisture during housework and in cooks and other occupational groups. The toenails are usually free. Peripheral circulatory disorders, immunodeficiencies, diabetes mellitus, and excessive nail manicuring are also factors. Women are affected about three times more often than men.

Clinical Features

It is characterized by a painful, pus-laden, red, swollen nail fold and nail bed on one or more fingers (Fig. 20). Often there is chronic damage of the cuticle, either through manipulation or persistent exposure to moisture. In addition to loss of the cuticle, a recessus occurs due to the removal of the nail fold from the nail plate. This can spontaneously (or under pressure) empty thick white material consisting of horny components, fungal elements, and inflammatory cells. With longer existence, it can develop into nail growth disturbances, with thickening, discoloration, and a bumpy deformation of the nail plate, as well as onycholysis. Candida onychomycosis can result from a chronic Candida paronychia. In contrast to onychomycosis caused by dermatophytes, it is much rarer, but clinically indistinguishable. Both pathogen groups can also occur together. Typically they start at the nail fold and nail bed as paronychia (proximal subungual onychomycosis) with a secondary invasion of the nail plate. Green-black discoloration of the nail, especially in its lateral parts, can be an indication of an accompanying bacterial infection (especially Pseudomonas aeruginosa, Klebsiella spp. or green nail dyschromia). In the context of chronic mucocutaneous candidosis, it is not uncommon for the nail organs to be strongly involved, so that a regular nail plate is no longer formed; this is referred to as dystrophic onychomycosis.
Fig. 20

Candida paronychia

Differential Diagnosis

Paronychia and onychodystrophy by dermatophytes and bacteria (staphylococci, streptococci, Pseudomonas aeruginosa, Proteus mirabilis), and (rarely) also by molds.

Treatment

Predisposing factors must be eliminated. Local treatment such as local antimycotics and antiseptic measures are indicated for uncomplicated infection. More severe infections should be treated with yeast-effective systemic antifungals, e.g., fluconazole 50 mg/day or itraconazole, preferably continuously 100 mg/day, until cure. If a distal manifestation of onychomycosis is present (maximum 50% of the nail plate affected), local treatment can be attempted. Adjuvant atraumatic removal of the diseased nail plate parts should be performed.

3.1.5 Candidosis of the Oral Mucosa

Synonyms

Stomatitis candidomycetica; Oral thrush

Etiopathogenesis

An oral candidosis – caused by Candida albicans – can already be present in newborns. The child is infected in the birth canal, and the disease manifests itself in the first days of life. In old age, oral thrush is often found with toothlessness or poorly fitting dentures. Predisposing factors are also erosive diseases of the oral mucosa, such as pemphigus vulgaris and lichen planus. Oral candidosis is the most common opportunistic infection in HIV-infected individuals. However, the sole detection of a yeast does not define an oral candidosis. The various clinical pictures result from the presence of a Candida species with simultaneously existing predisposing factors (diabetes mellitus, impaired immune defense; in the area of the oral mucosa, there is reduced saliva production as well as increased carbohydrate concentration in the saliva; chemical stimuli such as nicotine abuse; mechanical stimuli such as dentures).

Clinical Features

Several forms of manifestation can be distinguished (Figs. 21 and 22):
Fig. 21

Pseudomembranous candidosis

Fig. 22

Atrophic candidosis

  • Acute pseudomembranous candidosis (oral thrush)

  • Acute atrophic candidosis

  • Chronic atrophic candidosis (dental carrier stomatitis)

  • Chronic hyperplastic candidosis (Candida leukoplakia).

The acute pseudomembranous form is the most common manifestation of oral candidosis, and occurs predominantly in newborns and in cases of immunodeficiency. Preferably on the buccal mucosa and palate, stipple-shaped, later confluent, white, easily removable plaques (differentiation to leukoplakia) develop, under which a bright red, easily bleeding mucous membrane is found. In case of massive infection, the tongue, pharynx, and esophagus may also be affected. In general, the course of the disease is often mild, with abnormal sensations (taste disorders, furry sensation) as leading symptoms. However, it can manifest itself – particularly in severe immunosuppression – through very painful, erosive mucous membrane changes, which significantly impair food intake.

Acute erythematous candidosis is accompanied by burning in the mouth. It usually develops from acute pseudomembranous candidosis, and rarely develops primarily. The main predisposing factors are antibiotic treatment and HIV infection. There is a smooth, shiny, erythematous mucous membrane, with flattened papillae, mostly on the back of the tongue.

Predisposing for the manifestation of chronic atrophic candidosis is chronic mechanical irritation accompanied by bacterial overgrowth of the oral mucosa. Approximately one-quarter of all dental occlusal carriers show mucosal lesions in the area of the denture, and these are frequently associated with Candida infection. The arrangement of the lesions mainly reflects the shape of the denture on the hard palate and gums of the upper jaw. Light to dark red lesions with a shiny, atrophic surface characterize the clinical picture, especially at contact points with denture parts, and therefore predominantly on the hard palate. Subjectively, there is slight discomfort or even no complaints.

Candida leukoplakia is often found in cases of immunodeficiency. It is characterized by white plaques of the oral mucosa, which irregularly cover the buccal mucosa and tongue. In contrast to the acute pseudomembranous type of oral candidosis, these films are rather firm and not easily detached. In the nodular variant, the hypertrophic, paver-stone-like mucous membrane changes are partly surrounded by an erythematous border, and atrophy and edema are also observed. It is important here to distinguish it from other forms of leukoplakia, some of which are in situ carcinomas.

Often attributed to oral candidosis is the angular cheilitis (perlèche) where fissures covered by crusts appear at the corner of the mouth. Other causes of angular cheilitis include mechanical factors as well as mixed infections with bacteria. As with other candidoses, local (atopic eczema) and systemic underlying diseases (diabetes mellitus, iron deficiency anemia, vitamin B12 deficiency, avitaminosis) are also important for the development of angular cheilitis.

Differential Diagnosis

Of essential importance are the easily removable (with a spatula) whitish plaques. In HIV-infected people, hairy leukoplakia on the sides of the tongue, lichen planus of the oral cavity, and plaques muqueuses in secondary syphilis should be considered.

Treatment

Non-absorbable antifungals of the polyene type, such as amphotericin B, nystatin, or azole in suitable preparations (solutions, suspensions, lozenges, or oral gels, and in cases of lip involvement, also creams) for 10 days. The administration of polyene antifungal drugs in tablet form results in local treatment of the orogastrointestinal tract, and cannot be interpreted as systemic treatment due to the lack of absorption. If oropharyngeal candidosis cannot be controlled by topical treatment, azoles are predominantly used (e.g., fluconazole 100 mg/day, 7–14 days). In cases of azole resistance, fluconazole in very high doses (800–1,600 mg/day), itraconazole (available also as a solution), voriconazole, or posaconazole can be used. Miconazole mouth gel is the drug of choice for immunocompetent infants. In addition, the polyenes nystatin and amphotericin B are well suited as suspensions for the treatment of oral candidosis in infancy.

If a candidosis of the oral cavity and/or the esophagus develops in the presence of a primary or secondary immunodeficiency, systemic treatment should be initiated, even in the absence of fever (Worthington et al. 2007).

3.1.6 Candida Folliculitis

Synonym

Folliculitis (barbae) candidomycetica

Etiopathogenesis

Predisposing factors are diabetes mellitus and general or local weakening of the immune system in malignant lymphomas, leukemias, HIV/AIDS, glucocorticoid and cytostatic treatment, as well as inadequate long-term pretreatment of skin lesions with glucocorticoids and antibiotics.

Clinical Features

Honey-yellow crusts, small follicular pustules or papules, and nodules covered with crusts and interspersed with pustules appear in the beard area.

Diagnostic Procedure

The infection occasionally represents the first manifestation of diabetes mellitus. Chronic progression and lack of response to antibiotic treatment are indicative, as is the detection of Candida albicans in crusts and epilated beard hair.

Differential Diagnosis

Impetigo contagiosa, tinea barbae, staphylococcal osteofolliculitis, Gram-negative folliculitis.

3.1.7 Chronic Mucocutaneous Candidosis

(Thorpe and Handley 1929)

Definition

Chronic mucocutaneous candidosis (CMC) comprises a heterogeneous group of rare and congenital syndromes caused by chronic and recurrent infections of the skin and mucous membrane by Candida yeasts (Fig. 23) (Eyerich et al. 2010). They occur simultaneously on the skin, nails, and mucous membranes of different parts of the body, often even in childhood. Rarely, disseminated or systemic infections are found in these patients.
Fig. 23

Eyelid involvement in chronic mucocutaneous candidosis

Etiopathogenesis

Defects of dendritic cells and Th1 cells are important for inadequate defense, while defects of innate (phagocytosis, migration of neutrophil granulocytes) and humoral immunity play a minor role. Th17 cells play an important role (Sparber and LeibundGut-Landmann 2015). By IL-23 and IL-17, they exert a synergistic effect on the epithelial synthesis of cationic antimicrobial peptides, such as defensins. These defects lead to an inability to fight off Candida infections, especially at the surface barrier. Primary forms usually occur in the first years of life, and are frequently associated with autoimmune diseases of the endocrine glands. The genetic defects identified to date include:
  • Autosomal recessive forms: autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome (APECED or APS-1) – mutation in the autoimmune regulator gene (AIRE); associated with endocrine gland dysfunctions; mutation in the PTPN22-gene associated with autoimmune endocrinopathies and antibody deficiency; mutation in caspase-associated recruitment-domain 9 gene (CARD9)

  • Autosomal dominant forms: mutations in STAT1-genes. Mutation on chromosome 2p - associated with a malfunction of the thyroid gland. Hyper IgE syndrome (Job syndrome): Mutation in STAT3-gene, CMC, atopic eczema, and increased susceptibility to infections with extracellular bacteria; furthermore, microdeletion syndrome 22q11 – DiGeorge syndrome (thymus hypoplasia)

  • Secondary forms: chronic infections (HIV infection), metabolic diseases (diabetes, overweight), malignant tumors, especially lymphomas/thymomas, treatment-induced immune deficiency (immunosuppressants, cytotoxic drugs, glucocorticoids).

Clinical Features

Various treatment-resistant forms of candidosis of the skin and mucous membranes occur simultaneously, for example orally (oral thrush) – characterized by whitish films on a reddish ground, reaching down to the pharynx and esophagus, perlèche, conjunctivitis and blepharitis, intestinal disorders, erosive, macerative intertrigo, tinea corporis-like anular or serpiginous candidosis of the glabrous skin, urethritis, cystitis, vulvovaginitis, purulent paronychia, onychodystrophy, and granulomas of the skin. Special risks are strictures of the esophagus, maldigestion and malnutrition, and development of neoplasia.

Treatment

Since resistance to antimycotics is an increasing problem, a rapid and, if possible, pathogenesis-adapted, approach is essential. The treatment of choice is initially the long-term administration of fluconazole 100–200 mg/day. If resistance occurs (regular tests required), itraconazole, voriconazole, and posaconazole can be used according to the sensitivity data. Echinocandines (inhibition of glucan synthesis and thus the formation of the cell wall) show good tolerability, but are not available orally. Polyenes (nystatin, amphotericin B) are standard for topical long-term treatment, or as a third choice for systemic treatment (amphotericin B).

3.1.8 Vulvovaginal Candidosis

Synonyms

Vulvovaginitis candidomycetica; Candida vulvovaginitis; Candidosis of the vagina; Vaginal thrush; Candida-colpitis

Etiopathogenesis

Probably three out of four women suffer from vulvovaginal candidosis at least once in their lives. Approximately 5% of patients suffer from chronic recurrent vulvovaginal candidosis (CRVVC), defined as at least four recurrences within 1 year (Achkar and Fries 2010; Mendling et al. 2015). In 80–90% of cases, Candida albicans is the pathogen; in 5–10% C. glabrata; in 1–3% C. krusei, C. parapsilosis, C. guilliermondii, and others. Vaginal yeast colonization depends on the amount of glucose in the vagina, which varies cyclically under the influence of sexual steroids. Therefore, vaginal colonization by yeasts or vaginal candidosis is rare in girls during hormonal breaks and in later postmenopausal women. A variety of different factors are considered to be favorable: pregnancy, diabetes mellitus, oral contraceptives, glucocorticoid treatment, antimicrobial chemotherapy (systemic and local), mechanical stimuli (intrauterine pessaries, coitus), as well as mechanical and chemical irritation (vaginal flushing). Transmission from the rectum is considered significant in the case of its colonization. Sexual transmission does not regularly occur. With CRVVC, there are often no predisposing factors.

Clinical Features

The yeast-related diseases of the external genitals affect both the vulva and the vagina, and manifest themselves in abundant discharge, with whitish, wipeable deposits on the vaginal wall and a pronounced erythema of the vulva and adjacent inguinal region. Premenopausal women mostly suffer from vaginal mycosis with involvement of the introitus and the vulva. Postmenopausal women primarily suffer from a vulva candidosis. Subjective symptoms include soreness of the vaginal atrium and perianal region, itching, and vaginal discharge. Characteristic is a whitish-creamy to cheesy-crumbly discharge. Candida glabrata vaginitis is characterized by a usually occasional, mild, premenstrual, or postcoital itching, sometimes a more or less creamy discharge, with no particular odor, and less redness of the vagina. The diagnosis must be based on direct microscopy and culture, considering the full spectrum of possible pathogens. A stool examination for Candida is particularly indicated for relapses.

Differential Diagnosis

Bacterial vaginosis, bacterial vaginitis – in particular with detection of Group A streptococci, trichomoniasis, genital herpes, chlamydia infection, gonorrhea, lichen sclerosus et atrophicus, lichen planus planus, lichen planus mucosae, psoriasis, various forms of eczema, (rarely) extramammary Paget's disease, burning vulva syndrome, and vulvodynia.

Treatment

Colonization with yeast fungi does not normally require any treatment in gynecological patients. Acute vaginal candidosis can be treated locally or systemically. For local treatment, polyene- (nystatin, amphotericin B), imidazole- (single-use treatment possible; also effective against some bacteria and trichomonas; cave missing or minor efficacy: C. glabrata, C. krusei, C. guilliermondii), and ciclopiroxolamin-containing preparations (also effective against azole-resistant yeasts) are available. Vaginal tablets or ovules must be inserted deep into the vagina on one, three, or six consecutive days (depending on the drug). In the case of inflammation of the vulva, a yeast-effective antifungal ointment or cream should be applied to the affected areas once or twice a day. If the candidosis of the skin extends to the inguinal area, nystatin or azole preparations should be used in a paste or cream preparation.

If the sole local treatment does not lead to success, and C. albicans or other Candida species are repeatedly isolated in vaginal secretion, systemic treatment with the oral triazoles fluconazole and itraconazole (150-mg one-time treatment or 2 × 200 mg one-day treatment) (contraindicated in pregnancy, especially in the first trimester) is recommended. But the efficacy against C. glabrata and C. krusei is weak, so that in the case of C. glabrata, a fluconazole dosage of 800 mg/day and for C. krusei a trial with topical treatment with ciclopiroxolamine vaginal suppository/cream is recommended.

The duration of treatment is generally 12 days; mycological controls should be carried out (at the earliest) 7–10 days after the end of treatment. Simultaneous topical treatment with ciclopiroxolamine is useful due to its different mechanism of action from azoles. For CRVVC, also recommended are: stool culture, examination of the oral cavity (carious teeth), disinfection of possible prostheses, examination of the partner, and partner treatment. An "intestinal sanitation" is normally not necessary. In the case of CRVVC and detection of identical yeast species in the vagina and mouth or stool, however, treatment might be indicated.

CRVVC is treated intermittently with suppressive treatment (fluconazole orally, three times in the first week, 200 mg each, and with no symptoms or fungus, a dose-reducing maintenance treatment over a whole year, with eventually 1 × 200 mg per month). In previous studies, the recurrence rate for weekly to monthly treatment is about 50% after the end of suppression treatment.

3.1.9 Candida Balanitis

Synonyms

Balanitis candidomycetica; Thrush balanitis

Etiopathogenesis

This is an infection of the glans penis and prepuce by Candida spp., in particular C. albicans, and more rarely C. glabrata. Predisposing factors are the warm and humid environment of the preputial space, inadequate hygiene, especially insufficient drying after washing, or Candida vulvovaginitis in sexual partners. It is a sexually transmitted disease. Other predisposing factors are, in particular, poor body hygiene, phimosis, and diabetes mellitus (occasionally first manifestation).

Clinical Features

Circumscribed erythema, gray-white deposits, or weeping erosions in the foreskin area (balanoposthitis) are indicative. In the course of the disease, inflammatory swelling of the inner layer of the foreskin can occur acutely or subacutely, and lead to inflammatory phimosis and stronger purulent secretion resulting from secondary bacterial infection. Burning and itching exist subjectively (Fig. 24).
Fig. 24

Candida balanitis

Differential Diagnosis

Bacterial infections, allergic contact eczema, balanitis plasmacellularis zoon, lichen sclerosus et atrophicus, balanitis erosiva circinata, herpes simplex infections, psoriasis inversa, and erythroplasia queyrat must be differentiated.

Treatment

Antimycotics in cream form. In addition, baths, as well as the insertion of linen strips between the glans penis and the foreskin, can be useful. Partner treatment is recommended.

3.2 Diseases Caused by Malassezia Yeasts

Lipophilic yeasts of the genus Malassezia (formerly pityrosporum) belong to the resident microflora of human skin, and are found mainly in seborrheic areas due to their obligatory lipid dependence. However, they also play an important role in diseases such as pityriasis versicolor, seborrheic eczema, Malassezia folliculitis, and systemic infections. In addition, Malassezia yeasts can also be a trigger factor for atopic eczema (Theelen et al. 2018).

Molecular data have shown that the genus currently consists of 17 species (M. furfur, M. sympodialis, M. globosa, M. pachydermatis, M. obtusa, M. nana, M. restricta, M. slooffiae, M. dermatis, M. equina, M. japonica, M. caprae, M. cuniculi, M. yamatoensis, M. brasiliensis, M. psittaci, and M. arunalokei), which, with the exception of M. pachydermatis (mainly in animals and not always lipid dependent) may occupy different niches on the skin. A species-specific association with a single disease has not been reliably demonstrated. A standard medium for cultivation is modified (m) Dixon agar, with the lipid sources tween 40 and olive oil; differentiation is carried out with the tween auxanogram, and primarily by sequencing the ITS1 region of the rDNA.

3.2.1 Pityriasis Versicolor

(Eichstedt 1846)

Synonyms

Tinea versicolor (however, the term tinea should be reserved for dermatophytosis)

Definition

Already described by Willan in 1801, and recognized, in 1846, as pathogen-induced (by Eichstedt), pityriasis versicolor is considered one of the most frequent superficial mycoses of the skin. It is caused by lipophilic yeasts of the genus Malassezia, seemingly occurs exclusively in humans, and is widespread worldwide.

Epidemiology

Most affected are adolescents and younger people in the second to third decade of life; after the age of 60 years, the incidence is significantly lower. With the exception of in the tropics, the disease is rarely found in people under 10 years of age, since the change in the skin lipids during puberty is significant. There is no pronounced sexual preference. The influence of the macroclimate is clear. In tropical and subtropical regions, approximately every second individual is affected. In Northern and Central Europe, pityriasis versicolor has an incidence of only 0.5–1%, with a peak in the months of May to September.

Etiopathogenesis

Contagiosity is considered to be low or nonexistent. Epidemic incidence or partner infections have rarely been described. However, the disease could be reproduced experimentally in individual cases. Predisposing factors include tropical humid macroclimate, individual sweating tendencies (hyperthyroidism, tuberculosis, malignancies), microclimate influences (occlusion), as well as malnutrition, a positive family history, and the use of lipid-containing topicals.

The induction of hyphae by factors that are not fully understood is considered pathogenetically significant. Currently, M. globosa is seen as the pathogen responsible, but the development of both hyper- and depigmentation has not yet been satisfactorily clarified. M. furfur can form pigments from tryptophan, which both fluoresce and inhibit melanogenesis. The pigment pathway is only dependent on a single enzyme, transaminase 1 (TAM 1). The inhibition of this enzyme by a topically applied transaminase inhibitor leads to healing of the lesions (Mayser and Preuss 2012).

Diagnostic Procedure

A diagnosis is usually made clinically, supplemented by Wood’s lamp (yellowish-green fluorescence) and KOH examination. Since the infection is very superficially localized, sellotape stripping is a useful method for harvesting material for microscopy. Microscopically, very characteristic short, partly fragmented fungal hyphae are admixed with grape-like clusters of spores (resembling spaghetti and meatballs). It is not necessary to perform fungal culture (lipid-containing media such as Dixon or Leeming-Notman agar), as the pathogen belongs to the resident flora of the human skin. M. globosa was found to be the dominant species in the lesions in pityriasis versicolor, and was suspected of being a pathogenic agent due to the round blastospores.

Clinical Features

Light to dark brown, partly erythematous maculae are preferentially found in the areas of the trunk rich in sebaceous glands (Figs. 25 and 26). Lesions are initially 3–5 mm long, and tend to confluence. A fine, bran-like (pityriasiform) scaling develops when the lesions are scraped with a spatula. Frequently, under UV radiation, but also on covered body parts, the hyperpigmented areas can be transformed (versicolor) into white lesions that show no or only slight scaling (pityriasis versicolor alba). Repigmentation can take up to several months. Apart from cosmetic aspects, the patients are not affected; occasionally slight itching is described, especially in cases of heavy sweating. The atrophic pityriasis versicolor (Crowson and Magro 2003) is characterized by a bowl-shaped atrophy in the PV lesions, with detectable elastolysis. These changes are reversible with antifungal treatment.
Fig. 25

Hyperpigmented pityriasis versicolor

Fig. 26

Hypopigmented pityriasis versicolor

Differential Diagnosis

From hyperpigmented lesions, seborrheic eczema (stronger inflammatory component), pityriasis rosea, and tinea corporis must be differentiated; in intertriginous localization, erythrasma (carmine red fluorescence with Wood’s lamp); in the hypopigmented lesions, mainly vitiligo and post-inflammatory hypopigmentation; in the atrophic form, anetoderma, atrophoderma pierini pasini, morphea, parapsoriasis, mycosis fungoides, and sarcoidosis.

Histopathology

The histological changes are discrete: hyperkeratosis, parakeratosis, as well as minor acanthosis, with no or little superficial perivascular lymphocytic infiltrate.

Treatment

The disease is easily treatable, but has a strong tendency to relapse (Hu and Bigby 2010). General measures include frequent bathing/showering (using syndets), avoiding occlusive clothing, and eliminating predisposing factors. Topical imidazole preparations (shampoo, solutions with econazole or ketoconazole) as well as classical therapeutics such as sodium thiosulfate, pyrithione zinc, propylene glycol, and selenium disulfide are also effective. Topically, the entire body should always be treated. Systemic treatment is indicated for widespread disease and frequent recurrences (itraconazole 200 mg/day for 5–7 days, 400 mg per day per month for prophylaxis; fluconazole 50 mg/day for 2 weeks). Systemically applied terbinafine is not effective, as it is not excreted with the eccrine sweat.

3.2.2 Seborrheic Dermatitis

There is increasing evidence that Malasezzia spp. plays an important role in the pathogenesis of seborrheic dermatitis (see chapter “Other Types of Dermatitis”).

3.2.3 Malassezia Folliculitis

(Potter et al. 1973)

Synonym

Pityrosporum folliculitis

Clinical Features

This condition is characterized by follicularly bound, monomorphic, dome-shaped papules and pustules, mainly on the back, chest, and upper arms. Itching, the absence of comedones, and facial lesions may contribute to differentiation from acne as the most common differential diagnosis.

Etiopathogenesis

An increased growth of Malassezia yeasts in the hair follicle seem to be important, but histological diagnosis is also difficult, because Malassezia yeasts are regularly found in the follicular ostia of healthy skin. Molecular investigations show that the alterations are not caused by a defined Malassezia spp. In the case of Malassezia folliculitis, therefore, a mycological examination is not a prerequisite for diagnosis. Immunodeficiency is discussed as a predisposing factor. HIV/AIDS patients, in particular, suffer from severe itching. Neonatal cephalic pustulosis shows a similar picture (see chapter “Neonatal Dermatology”).

Treatment

As with pityriasis versicolor, topical antifungals such as econazole or ketoconazole solution are preferable; in cases of extensive manifestation, itraconazole 200 mg/day orally over 7–14 days can be used.

3.2.4 Further Malassezia-Associated Diseases

In atopic eczema, triggering can be caused by antigens of Malassezia yeasts. In particular, patients with a localization of the disease in the facial and neck area (head-and-neck dermatitis) can benefit from a treatment with antimycotics (topical, systemic) (Darabi et al. 2009).

Particularly affected by Malassezia sepsis are immunosuppressed adults, as well as newborns or premature infants who are fed parenterally with lipid infusions (catheter-associated sepsis). Frequently found pathogens are M. pachydermatis and M. furfur.

4 Rarer superficial dermatomycoses

4.1 Piedra

These are infections of the hair shaft characterized by nodular lesions composed of fungal elements (Spanish piedra: stone).

4.1.1 White Piedra

(Beigel 1869)

Pathogens of the white piedra of the head, beard, axilla, or pubic hair are yeasts of the genus Trichosporon, in particular T. mucoides, T. inkin, T. asahii, and T. ovoides. The disease occurs in both temperate and tropical regions. Both sexes are affected equally, but infection of the pubic hair occurs more often in young men. Irregular, soft, whitish nodules on the hair shafts are characteristic. Microscopically, the nodules are composed of hyphae, arthrospores, and blastospores.

Differential Diagnosis

Trichobacteriosis axillaris, pediculosis (nits)

4.1.2 Black Piedra

(Horta 1911)

Piedraia hortae, an ascomycete whose natural habitat is not known, is responsible. The disease occurs in warm and humid climates, mainly in young adults, exclusively in the area of the scalp hair. The hair is characterized by fusiform black nodules and concretions that are firmly attached to the hair shaft, but do not penetrate it. They consist of hyphae joined by a cementitious substance (direct examination).

Differential Diagnosis

Nits, trichomycosis axillaris, trichorrhexis nodosa, and other hair shaft anomalies can all be easily excluded under the microscope.

Treatment

For both forms of piedra, cutting off or shaving the affected hair is the simplest form of treatment. In addition, an imidazole-containing cream can be used.

4.2 Tinea nigra

(Cerqueira 1916)

The pathogen is the halophilic, melanized, yeast-like fungus Hortaea werneckii, which occurs in rotting plant material (Bonifaz et al. 2008). Due to the halophilia of the pathogen (Greek: salt; organisms living in environments with elevated salt concentration), the disease occurs primarily on the palms of the hands and soles of the feet (which have numerous eccrine sweat glands) (Fig. 27). It is characterized by asymptomatic, mostly solitary, brownish-black maculae with sharp boundaries. Women are affected three times more often than men, and manifestation is usually before the age of 20 years. Predisposing factors are hyperhidrosis, as well as staying in coastal areas or in a hypersaline environment, mainly in the tropics. Direct examination reveals hyaline, slightly yellowish to brown septated hyphae. Hortaea werneckii grows in a standard medium in 5–8 days, is initially yeast-like, and later filamentous.
Fig. 27

Tinea nigra

Differential Diagnosis

Acral melanoma/nevus cell nevus must be distinguished (dermatoscopy, direct microscopy).

Treatment

Daily application of a cream containing imidazole for 2–3 weeks.

5 Subcutaneous Mycoses

Definition

Subcutaneous mycoses are mainly found in tropical and subtropical regions (exception: cutaneous alternariosis). Case reports from Europe mostly concern immigrants, returnees, or people who have resided for professional reasons in these regions. In almost all cases, the mycotic infection is caused by traumatically inoculated foreign material.

5.1 Sporotrichosis

(Schenck 1898)

Sporotrichosis is a subacute-chronic subcutaneous mycosis caused by pathogens of the Sporothrix schenckii-complex. Sporothrix schenckii sensu stricto includes at least four other species: S. albicans, S. brasiliensis, S. globos, and S. Mexicana (Vásquez-del-Mercado et al. 2012; Lopes-Bezerra et al. 2018). The pathogens are found on plants, wood, and decaying vegetation in a climate with an average temperature of 20–25°C and humidity over 90%. They have also been found in (domestic) animals (cats, dogs, muskrats, horses, armadillos), so that sporotrichosis can also be regarded as zoonosis (transmission, e.g., by cat bites).

Etiopathogenesis

The pathogen is usually inoculated, together with plant material, into the skin, or more rarely, into the mucous membranes, for example when a splinter is drawn in. Hands and feet, in particular, are affected. The fungus can be inhaled and ingested, which primarily leads to extracutaneous, rarely systemic manifestation.

Clinical Features

Apart from the circumscribed cutaneous form (25%), the lymphocutaneous form is the most common form (70%); disseminated cutaneous, extracutaneous, or systemic forms are rarely observed (Figs. 28 and 29) (Bonifaz and Tirado-Sánchez 2017).
Fig. 28

Sporotrichosis

Fig. 29

Sporotrichosis, fixed cutaneous type

Lymphocutaneous Sporotrichosis

The incubation period is on average 3 weeks after inoculation (5 days to several months). The primary focus is an inflammatory papule, a papulopustule, an ulcer, or a cutaneous-subcutaneous nodule with ulceration due to necrotic decay. The primary focus can heal by scarring within months, while new nodules, over which the skin appears purple, develop proximally, corresponding to the lymphatic drainage of the original lesion. The distal nodes abscede, break through to the skin, and are covered by firmly adhering crusts. The nodes more distant from the primary focus show a gumma-like consistency, and have less tendency to necrosis. The general condition is usually not disturbed in this form, but the course extends over years.

Fixed Cutaneous Sporotrichosis

With this form, the phenomena remain limited to the inoculation site due to good immunity, based on previous exposure to the pathogen. Verrucous or crust-covered lesions that have livid-erythematous margins, and sometimes surrounded by satellites, are often found. Years of existence, spontaneous healing under scars, and even local recurrences are possible.

Disseminated Sporotrichosis

In disseminated sporotrichosis of the skin, numerous inflammatory nodules occur all over the body, 5–15 mm in size, subcutaneously located, suggesting hematogenous spread. They break through purulent to the outside, fistulate, or form chronic ulcers. Typical is the concurrence of blue-red, centrally umbillicated nodules, as well as ulcerating and fistulating lesions. Immunosuppression is often an associated factor.

Mucocutaneous Sporotrichosis

This form is present when mucous membranes are affected next to the skin. Extracutaneous systemic sporotrichosis: in immunosuppressive/HIV infections, lesions can occur not only in the skin, but also in any organ, especially the bone system and muscles.

Differential Diagnosis

Other sporotrichoid infections can be distinguished from the lymphocutaneous form: the bacterial causes are nocardiosis, atypical mycobacteriosis, tuberculosis, cat scratch disease, and anthrax, as well as leishmaniasis, caused by protozoa. For the fixed cutaneous form, the following must be taken into account: tuberculosis cutis colliquativa or verrucosa, atypical mycobacteriosis, leishmaniasis, cutaneous cryptococcosis, chromoblastomycosis, and syphilis III.

Diagnostic Procedure

Sporothrix schenckii is a dimorphic fungus characterized by leathery, whitish yellowish, and later often blackish colonies, with little air mycelium, which grow in 3–5 days on standard media. On rice agar, either oblong yeast-cells or single conidia appear; they are to be found on small conidiophores, are formed either (Marguerite-forms: flower-like arranged conidia on hyphae). A culture is performed from swabs or better yet biopsy material: the mycelial phase forms at 22°C, and the yeast phase at 37°C. Histologically, there is a granulomatous, partly abscessing inflammation, with cigar-shaped blastospores (4–6 μm), which are best detected by PAS, methenamine-silver staining, or fluorescence with optical brighteners. The sporothrix asteroid body is a distinctive yeast form surrounded by eosinophilic material with sunburst-like rays, and reaching a size of ~25 μm. This feature is also known as the Splendore-Hoeppli phenomenon, and is seen in many chronic infections. Serological examinations may be helpful in diagnosing the disseminated form.

Treatment

Potassium iodide (KJ) has been used to treat sporotrichosis for more than 100 years (Xu et al. 2009). Although the mechanism of action is unknown, it is still the treatment of choice in some countries, for cost reasons. A saturated solution is administered in gradually increasing doses, starting with three drops three times daily after response, up to a maximum dose of 40 drops/day (usually 6–8 weeks). Very bitter taste, hypersensitivity reactions, and strong side effects (nausea, vomiting, halogen acne, hypothyroidism) have restricted its use. Randomized, placebo-controlled (comparative) studies have not been published. Itraconazole has proven to be highly effective. In its 2007 guidelines, the American Society for Infectious Diseases therefore recommended continuous treatment with 200 mg/day for 3–6 months as the treatment of first choice (Kauffman 2007). Terbinafine is also effective (250 mg/day for up to 42 weeks). This is particularly important when contraindications/possible interactions limit the use of itraconazole. Systemic treatment should be continued for 4–6 weeks beyond clinical healing. Adjuvant local hyperthermia, as well as cryotherapy with liquid nitrogen, possibly after curettage, may speed resolution.

5.2 Chromoblastomycosis

(Lane 1915; Medlar 1915)

Synonyms

Dermatitis verrucosa; Chromomycosis

Etiopathogenesis

Different pathogens can cause this disease, characterized by nodular, papillomatous, or verrucous changes. They all belong to the melanized black fungi (dematiaceae) found in soil and on rotting wood, and can get into the skin if injured. The most significant are Fonsecaea (F.) pedrosoi (tropical regions), and Cladophialophora carrionii (semi-arid climate; transmission by Cactaceae), as well as F. monomorpha, F. nubica, Phialophora verrucosa, and Rhinocladiella aquaspersa. Chromoblastomycosis occurs worldwide, especially in the tropics and subtropics. In Europe, cases have been described that were caused by inoculation by crushing tropical wood and use of a sauna (Queiroz-Telles 2015).

Clinical Features

Common sites of infection are the legs, especially the lower legs and feet, as well as the hands, because of the greater possibility of injury (Fig. 30). In most cases, the infection is located on one side only. Most common are papules and pustules at the inoculation site, which slowly develop into massive verrucous or papillomatous granulomatous skin reactions. Ulcerations and bacterial superinfections are not uncommon. Complications are lymphedema and development of squamous cell carcinoma.
Fig. 30

Chromoblastomycosis

Diagnostic Procedure

The disease is confirmed by isolation of the pathogen by means of a biopsy (culture, PCR) and in histological section. In the tissue, the various causative fungi appear identical. Histologically, in addition to a granulomatous, abscessing, and fibrosing inflammation, a pseudoepitheliomatous hyperplasia of the epidermis is found. The often already brownish looking, melanized, 5–12 μm large fungal elements are characterized by a thick membrane with a central septum (fumagoid or sclerotic cells, medlar bodies, copper pennies). A Gomori-grocott or fontana-masson stain (melanin detection) is more sensitive. Cultures on sabouraud-glucose agar or cycloheximide containing media (~30°C, slow growth; incubation 4–6 weeks) are dark brown-black, occasionally yeast-like, and can be identified by their micromorphology. Species identification usually requires sequencing.

Differential Diagnosis

Mycetoma (especially affecting the bones), leprosy, sporotrichosis, tuberculosis cutis verrucosa, and (verrucous) carcinomas are to be distinguished.

Treatment

Treatment is often long-lasting and accompanied by a high recurrence rate. In early stages, surgical excision, electrodesiccation, cryotherapy, or, with knowledge of the optimum temperature for the pathogen, even local hyperthermia, are useful. Itraconazole 200–400 mg/day showed complete healing in 42% of patients after an average of 7.2 months of treatment. Terbinafine 500 mg/day showed healing rates of 74.2% after 12 months. A combination of itraconazole and terbinafine is also used. Other therapeutic options include posaconazole 800 mg/day and a combination of itraconazole with 5-flucytosine.

5.3 Phaeohyphomycosis

The term phaeohyphomycosis refers to a heterogeneous group of infections caused by melanized fungi (“black fungi”) whose morphological characteristics in tissue may include hyphae, yeast-like cells, or a combination of both. Pathogens belong to the genera Alternaria, Bipolaris, Exophiala, and Phialophora. A disseminated spread of Exophiala dermatidis can also occur in those who are immunocompetent. Exophiala jeanselmii is the pathogen of the phaeohyphomycotic cyst.

5.3.1 Cutaneous Alternariosis

Localized skin infections by melanized hyphomycetes of the genus alternaria (in particular A. alternata-complex, A. infectoria) are also increasingly being observed in temperate regions. Alternaria spp. are frequent saprophytes in plant components, dust, or other substrates. The mostly traumatically caused infection mainly affects (hobby) gardeners, florists, and farmers under long-term glucocorticoid treatment or immunosuppression related to organ transplantation (Bajwa et al. 2017).

Clinical Features

It is characterized by singular or multilocular weeping, non-healing ulcerations, encrusted vegetating lesions, reddish maculae or verruciform eczema-like lesions, which may also diascopically show a granulomatous infiltrate (Fig. 31). Sporotrichoid progression is described. Usually, the lesions are not painful, and the course is protracted. An invasive or systemic course with a fatal outcome is very rare.
Fig. 31

Cutaneous alternariosis

Diagnostic Procedure

Since Alternaria spp. are often found in the environment, it is sometimes difficult to decide whether a positive culture is a contaminant or the causal pathogen. Therefore, not only a positive culture is important for the diagnosis, but also the detection of fungal elements in the tissue. Histopathologically, microabcesses and a granulomatous inflammation in the dermis can be observed. Fungal elements can appear in tissue as branched, thick-walled filaments, as spherical cells of 10–15 μm in diameter, or as short chains of elongated cells. Because the rounded elements are often unpigmented, alternariosis is often initially misdiagnosed as cryptococcosis. Here, the detection of short hyphae (Gomori staining, Fig. 32) offers the possibility of differentiation. Sequencing of the rDNA-ITS region is another possibility for differentiation.
Fig. 32

Cutaneous alternariosis, Gomori staining

Differential Diagnosis

Granulomatous diseases, and, in sporotrichoid forms, atypical mycobacterioses or sporotrichosis must be differentiated.

Treatment

Surgical removal is indicated in early stages, including local hyperthermia with knowledge of the optimum temperature for the pathogen. In the case of extensive, multilocular, or sporotrichoid clinical lesions, antimycotic treatment is recommended, in addition to the reduction of (iatrogenic) immunosuppression. Systemic amphotericin B or itraconazole is preferred, whereby the optimal dose (100–600 mg/day) and duration of treatment vary widely. In transplanted patients, possible interactions of azole antifungals with the immunosuppressants tacrolimus and cyclosporin must be considered.

5.4 Mycetoma

(Carter 1860)

Synonyms

Madura foot; Madura mycosis (Madurai, until 1949 Madura – a district in India)

Definition

Mycetomas are chronic suppurating infections of the subcutaneous tissue, with possible involvement and destruction of skin, bones, and joints (Zijlstra et al. 2016).

Etiopathogenesis

Actinomycetomas caused by bacteria (genera Actinomyces, Nocardia, and Streptomyces) are distinguished from fungal eumycetomas (pathogens Madurella mycetomatis, M. grisea, Aspergillus spp., Acremonium spp., Leptosphaeria spp., Pseudallescheria boydii, Neotestudina rosatii, and, extremely rarely, also dermatophytes). The disease mainly occurs in tropical and subtropical areas (Tropic of Cancer); in India and South America, these diseases are endemic. Usually, a mycosis caused by a minor trauma inoculates the pathogen into the tissue. The diseases are therefore mostly localized on the legs (barefoot walking) (Fig. 33).
Fig. 33

Mycetoma

Clinical Features

They are independent of the particular type of pathogen. Nodules that can develop into abscesses initially grow subcutaneously over months to years, and cause little or no discomfort. As the size increases, tumor-like deforming swellings, fistulas, and sinus tracts occur, from which pus empties – spontaneously or under pressure. It contains the characteristic grains, macroscopically visible blackish, whitish, or yellowish granules, which represent colonies of the pathogen. Despite the often-monstrous clinical picture, there is usually relatively little pain. Staphylococcal superinfection is common. Hematogenous or lymphogenic generalization is rare.

Diagnostic Procedure

The pathogen is identified in the culture from pus containing grains or preferably from biopsy material. Grains can be crushed and plated directly onto Sabouraud dextrose agar. The color (black: eumycetoma; white-yellow: actinomycetoma) and the size of the grain allow conclusions to be drawn on the responsible pathogen (bacteria 1–2 μm, fungi 4–6 μm). Histologically, the grains are embedded in a fibrosing and granulomatous inflammation. They are Gram-, PAS-, or grocott-Gomori-positive.

Differential Diagnosis

Osteomyelitis, for example, with staphylococci or Mycobacterium tuberculosis, may drain towards the skin, producing a similar picture. In the head and neck region, actinomycosis can cause an inflammation with grains, but bone involvement does not occur.

Treatment

It should be based on identification of the pathogen and the result of sensitivity testing. Actinomycetomas can often be successfully treated with antibiotics. In the case of eumycetomas, a treatment trial with itraconazole is indicated (first 600 mg/day, then 400 mg/day under close laboratory controls). Smaller lesions can be removed surgically.

6 Systemic Fungal Infections

Systemic fungal infections can be divided into two large groups.

Systemic Fungal Infections Caused by Obligate Pathogenic Fungi

They occur in immunocompetent hosts; the route of entry is usually via the lung. All pathogens are dimorphic fungi. The initial infection of the lung is usually mild or subclinical, and heals spontaneously, so treatment is not necessary. In the vast majority of cases, a specific immunity is developed, which eventually leads to spontaneous healing. About 1% of the affected immunocompetent patients develop a more extensive or persistent disease. The occurrence is limited to certain areas of the world. The skin is often secondarily affected.

Systemic Fungal Infections Caused by Facultatively Pathogenic Fungi

Obligatory for the manifestation is immunodeficiency. The site of entry may vary. The prognosis is determined by the underlying disease. The tissue response is shown as necrosis, abscess, or granuloma. The diseases occur ubiquitously. The skin can be the organ of initial manifestation or the target organ in sepsis (aspergillosis, fusariosis, zygomycosis). Therefore a skin biopsy should be performed on each immunosuppressed patient with a papular, nodular, necrotizing, or ulcerative skin lesion, the etiology of which cannot be reliably assigned. The skin biopsy should provide material for a histopathological examination as well as for a cultural or molecular diagnosis of a possible pathogen. Early diagnosis can significantly improve the prognosis (Schelenz et al. 2015).

6.1 Cryptococcosis

(Busse 1894; Buschke 1895)

Synonyms

Cryptococcal mycosis; European blastomycosis; Torulosis; Busse-Buschke disease

Cutaneous cryptococcoses manifest either secondary to hematogenous spread or, much less frequently, primary to a direct cutaneous infection caused by Cryptoccoccus (Cr.) neoformans.

Etiopathogenesis

In addition to HIV infection and lymphoproliferative diseases as the most important risk factors, immunosuppressive treatment is also important, although low glucocorticoid doses may also be sufficient. Furthermore, immunosuppression, especially after transplantation or treatment with TNF-α inhibitors, should be considered. Cr. neoformans (capsule serotype A, D, and AD) and Cr. gattii (serotypes B and C) are considered as pathogenic species within the genus Filobasidiella. The encapsulated basidiomycetic yeasts do not belong to the physiological microflora of humans. Saprophytic Cr. species such as Cr. albidus are occasionally isolated from skin and nails. Cryptococcosis is always acquired exogenously (as opposed to candidosis). Bird droppings, especially by pigeons, but also droppings from ornamental birds, contain high numbers of pathogens. Basidiospores in dry, swirled up excrements are inhaled, transform into yeast cells, and lead to a primary cryptococcosis of the lung in the usually immunosuppressed patients. This results in disseminated hematogenic spread. Blastospores are excreted via the kidneys. The kidneys and prostate can also represent a lifelong reservoir subsequent to successful treatment (Perfect et al. 2010).

Clinical Features

Initial infection of the lung is usually asymptomatic and limited. Skin manifestations as secondary cryptococcosis occur in 10–20% of systemic infections. This makes the skin the most important manifestation site, after the central nervous system. Primary cryptococcosis of the skin can also occur in immunocompetent individuals, usually as a solitary lesion on the fingers or face. In immunocompromised patients, there are often several lesions on the trunk and extremities (Fig. 34). They consist of papules and pustules, cutaneous-subcutaneous infiltrates with draining sinuses, and nodules, which are acne-shaped or umbilicated (resembling mollusca contagiosa). Ulcers often develop around the nose and mouth. Transepithelial and transfollicular elimination of the pathogens from the lesions may be hazardous to the health of contact people.
Fig. 34

Cryptococcosis in non-Hodgkin's lymphoma

Diagnostic Procedure

In the exudate from lesions or in cerebrospinal fluid, 5–15 μm large blastospores with a usually well-visible capsule (factor of pathogenicity) are seen, especially in the ink preparation according to Burri. Colonies on sabouraud glucose agar (no growth with addition of cycloheximide) are glossy and slimy (Biosafety-Level 2–3). On rice agar, the distances between the blastospores are noticeably large, and are caused by the mucus capsules, which become more visible when stained with ink. Serological testing for cryptococcus antigen in serum, cerebrospinal fluid, and urine is important. The concentration of antibodies correlates with the severity of the disease or the success of an antifungal treatment.

Differential Diagnosis

Cutaneous cryptococcosis can mimic a number of skin diseases: involvement of the skin in meningoencephalitis, molluscum contagiosum, vasculitis/pyoderma gangraenosum, malignant tumors such as carcinomas and basal cell carcinomas, tuberculosis, and other bacterial diseases.

Treatment

Rapid diagnosis and initiation of systemic antifungal treatment significantly reduce mortality (Migone et al. 2018; Baddley and Forrest 2019). Among the various forms of manifestation, cryptococcal meningitis is particularly threatening. Chemotherapeutics used for systemic treatment should therefore cross the blood-brain barrier. About 0.4–0.6 mg/kg bw amphotericin B (IV) is administered daily, as part of monotherapy, or together with flucytosin (75–100 mg/kg bw daily), divided into six individual doses. Fluconazole and voriconazole are also recommended. On the first day of treatment, 400 mg fluconazole/day is administered, followed by 200–400 mg once daily; at the end of treatment, at least 100 mg/day should be administered for prophylaxis, and in AIDS patients, lifelong.

6.2 Blastomycosis

(Gilchrist 1894)

Synonyms

North American blastomycosis; Gilchrist's disease; Chicago disease

Epidemiology

Blastomyces dermatitidis is a soil contaminant, usually present in moist areas. The disease occurs preferentially in North America (the Midwest and southern central regions of the USA), especially in the Ohio and Mississippi valleys, but also occasionally in Central America, and to a lesser extent, in South America and Africa (Smith and Gauthier 2015).

Etiopathogenesis

Adult men are particularly affected. B. dermatitidis is inhaled in its spore form, and grows in the lungs in its yeast form. From here, hematogenous spread can infest other organs, especially the skin next to the prostate and bone (in 50% of patients; especially asymptomatic osteolysis). Blastomycosis is not primarily a problem among immunosuppressed patients. It has a tendency to reactivate after many years.

Clinical Features

Of patients with extrapulmonary disease, 75% show skin involvement. Single or grouped papules, papulopustules, and cutaneous-subcutaneous nodules with a tendency to ulceration develop, mainly on the hands, feet, and face, and later also on the trunk (Fig. 35). Central healing results in arched, centrally scarred lesions, with raised and verrucous edges, often covered by crusts. Diagnostically important are small thrombotic papillary vessels in the partially healed center of the lesion (as in a viral wart). Inoculation blastomycoses or sporotrichoid forms are very rare.
Fig. 35

Blastomycosis (with permission from Prof. Robert H. Schosser, Greenville, NC, USA)

Diagnostic Procedure

Histologically, the epidermis shows pseudoepitheliomatous hyperplasia and intradermal microabcesses. The detection of the double contoured cell wall and the unipolar (Paracoccidioides brasiliensis multipolar) budding pathogen in the dermis, whose size can reach 40 μm, are decisive factors. Purulent secretions from abscesses are particularly suitable for examination. Direct microscopy, culture, and histological examination (PAS, grocott staining) contribute to the diagnosis. In culture (Sabouraud glucose agar; Biosafety Level 3 Biosafety Ordinance, Safety Laboratory), mycelial phase (white thallus with abundant air mycelium) at 30°C, or yeast phase at 37°C develop. PCR-assisted methods (18S rDNA, WI-1-Adhesin) are available.

Differential Diagnosis

Ulcerating tumors (basal cell carcinomas, squamous cell carcinomas), tuberculosis cutis verrucosa, as well as other granulomatous diseases and halogenoderma.

Treatment

The current recommendations of the Infectious Diseases Society of America can be found in the work of Chapman et al. (Chapman et al. 2008). Itraconazole is recommended for mild to moderate pulmonary blastomycosis. For mild extrapulmonary form, for severe progressions, as well as central nervous system involvement, amphotericin B is recommended.

6.3 Paracoccidioidomycosis

(Lutz 1908)

Synonyms

South American blastomycosis; Brazilian blastomycosis; Lutz-Splendore-Almeida disease

Etiopathogenesis

Paracoccidioidomycosis occurs in South and Central America, especially in Brazil, where it is a central health problem. The disease, which is usually chronic, is caused by Paracoccidioides brasiliensis and P. lutzii, whose actual habitat has not yet been clarified. It is typically a disease of people who work outdoors. Although the infection rate is the same for both sexes, the risk of disseminated infection is 15 times higher for men (Gonzalez and Hernandez 2016).

Clinical Features

The usual site of entry is the lung, with subclinical pneumonia. The acute pulmonary infection may be subclinical or resemble pneumonia. Reactivation can take place after years. In the context of dissemination, lymphadenopathy and adrenal involvement are frequent, but each organ can be affected, with pronounced destructions (Fig. 36). The chronic adult form leads to destruction of the lung and infestation of the oral, nasal, and intestinal mucosa. In the juvenile or acute form, there is a marked infection of the reticuloendothelial system, with hepatosplenomegaly and bone marrow dysfunction, mimicking a hematological malignancy. This form is often fatal. Lesions of the facial skin usually manifest themselves as perioral nodules that slowly enlarge and ulcerate. Crusted lesions can coalesce on the upper lip and around the nose. At the same time, painful ulcerations occur in the area of the nasal and oral mucosa. Cervical (often fistulating) lymphadenopathy is common.
Fig. 36

Paracoccidioidomycosis

Diagnostic Procedure

The pathogen can be detected microscopically and culturally in suitable (purulent) test material such as punctate from lymph nodes, sputum, and wound secretion. It has a size of up to 60 μm, and, due to multipolar, narrow-based buds, has a steering wheel appearance. Histopathologically, a pseudoepitheliomatous hyperplasia and a granulomatous inflammation are found, in which the pathogen can best be represented by Gomori staining. On Sabouraud glucose agar, a leather-like, white-brown colony grows at 24°C, with only a slightly pronounced aerial mycelium (Biosafety Level 3, Safety Laboratory). Serological tests are possible. Molecular biological diagnostics using polymerase chain reactions are based on primers for the 5.8S and 28S ribosomal DNA.

Differential Diagnosis

Leishmaniasis (especially the mucocutaneous form caused by L. brasiliensis), yaws, leprosy, and other granulomatous diseases.

Treatment

Amphotericin B (IV) is preferred for severe courses. Itraconazole can be administered in a daily dose of 100 mg over 5 months. There has also been experience with voriconazole.

6.4 Histoplasmosis

(Darling 1906)

Synonym

Darling disease

Epidemiology

Histoplasmosis is a disease that occurs particularly in the valleys of the Mississippi and Ohio (similar to blastomycosis), but also in (sub)tropical regions of South America, Asia, Australia, and Africa (var. duboisii). In endemic areas, 80% of the population show seroconversion, but active disease is uncommon.

Etiopathogenesis

The primary infection usually occurs in childhood. The pathogen enters the lungs through inhalation of dust. Histoplasm capsulatum occurs in soil enriched with excrements, especially with droppings from bats, chickens, and other birds. The former may also house the pathogen themselves.

Clinical Features

The primary infection of the lung is mild or latent, and is usually only noticed by chance in X-ray examinations of the lung or in serological tests. The severe disseminated form shows an acute course in children or HIV/AIDS patients, and a more chronic course in older people. Meningitis and endocarditis are common symptoms. Acute infections are often accompanied by erythema nodosum or erythema multiforme. In chronic disseminated disease, ulcerations of the oral mucosa, tongue, oropharynx, and upper gastrointestinal tract may occur. Skin involvement is most common in patients with HIV/AIDS, but here, too, it is less than 10%. Reddish papules, nodules, ulceration, and even panniculitic changes are observed by hematogenous dissemination. In the rarely observed primary inoculation histoplasmosis. direct inoculation of the pathogen by trauma causes ulcerated skin lesions.

Differential Diagnosis

The skin lesions are not diagnostic. Histoplasmosis should be considered in the presence of ulcerations of the oral mucosa and unexplained cutaneous inflammatory lesions, especially after a stay in the endemic areas.

Diagnostic Procedure

H. capsulatum is a dimorphic fungus that grows on Sabouraud dextrose agar as a filamentous mold (white, later brown) at 25°C, and in yeast form, at 37°C. As the culture is very infectious, it may only be carried out under appropriate safety devices (Biosafety Level 3). A culture of sputum, skin, mucosa, and bone marrow is possible. In biopsies, the pathogens (2–4 μm) can be easily visualized, using PAS and Grocott staining. Characteristic is the localization within macrophages. Often there is a clear halo around the organism, which (despite its name) is not a capsule. Serological tests (antigen detection, antibody titer) are possible.

Treatment

No treatment is required in the case of a mild pulmonary disease. The disseminated disease in an immunocompetent host without involvement of the central nervous system is treated with fluconazole, itraconazole, or voriconazole. In long-term applications, isolates with lower sensitivity can be selected. Alternatively, amphotericin B (IV) can be considered. This is especially true for involvement of the central nervous system or immunosuppression (Wheat et al. 2016).

6.5 Coccidioidomycosis

(Posadas 1892; Wernicke 1892)

Synonyms

Valley fever; Desert fever; San Joaquin fever

Epidemiology

The causative agents of this infectious disease, which is often inapparent and primarily affects the respiratory tract, are Coccidioides immitis (San Joaquin Valley in California) and C. posadasii (in other desert regions in the west of the USA, Mexico, as well as Central and South America, 34° north to 40° south latitude) (Garcia Garcia et al. 2015).

Etiopathogenesis

The transmission takes place via pathogen-containing soil, favored by a rainy spring and a hot, windy summer, in which the arthrospores (from fragmented mycelium) are blown around. The disease occurs endemically in hot and dry climates, especially in the southwest of the USA. It is highly contagious, even at low exposure.

Clinical Features

In most cases, the lung is the site of entry after inhalation of dust containing pathogens. More than half of the patients are asymptomatic; the others show only minor symptoms. Accompanying symptoms can be erythema nodosum, erythema multiforme, or a maculopapular exanthema. Sometimes a localized ball-like accumulation of fungi, a coccidioidoma, develops in the lung. Dissemination into the central nervous system (granulomatous meningitis) and skeletal system occurs at a frequency of 1:1000, especially in immunosuppressed patients, with high fatality if diagnosis is delayed. This can lead to papules and nodules in the head and neck area that resemble rosacea. Verruciform absceding granulomas with tissue destruction can occur in the further course.

Differential Diagnosis

This includes skin lesions (maculopapular exanthema) and symptoms after a stay in the endemic areas, as well as rosacea-like and granulomatous changes in the head and neck area.

Diagnostic Procedure

Pus or sputum is suitable for microscopic examination. Histopathologically, a granulomatous reaction is observed, in which the organism can usually be easily identified. The typical tissue form is a large spherule of 30–60 μm size, loaded with endospores, which are already recognizable in H&E staining. The cultivation of the pathogen succeeds without difficulty. Precautions to protect laboratory personnel from inhalation of highly infectious spores are essential, as this is a pathogen of the highest virulence (Biosafety Level 3, Safety Laboratory). Serologic testing is also helpful.

Treatment

(Galgani et al. 2016)

The harmless, typical, acute lung disease generally requires no treatment. Fluconazole or itraconazole is used for severe conditions; amphotericin B (IV) is an alternative. The same procedure is used for disseminated forms; if meningeal involvement is present, amphotericin B is preferred. Newer azoles such as voriconazole and posaconazole are used, in particular for therapy-resistant progression.

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Further Literature

  1. Boekhout T, Gueho E, Mayser P et al (2010) Malassezia and the skin. Springer, HeidelbergGoogle Scholar
  2. Calderone RA (2012) Candida and candidiasis. American Society for Microbiology, Washington, DCGoogle Scholar
  3. Calderone RA, Cihlar RL (2001) Fungal pathogenesis: principles and clinical applications. Decker, New YorkGoogle Scholar
  4. De Hoog GS, Guarro J, Gené J et al (2019) Atlas of clinical fungi, updated web-version Centraalbureau voor Schimmelcultures/University Rovira i Virgili; accessed 30.05.2019 http://www.clinicalfungi.org/
  5. Gupta AK, Versteeg SG, Shear NH (2018) Common drug-drug interactions in antifungal treatments for superficial fungal infections. Expert Opin Drug Metab Toxicol. 14(4):387–398PubMedGoogle Scholar
  6. Heitmann J, Howlett BJ, Crous PW et al (2017) The Fungal Kingdom. American Society for MicrobiologyGoogle Scholar
  7. Ilkit M, Durdu M, Karakaş M (2012) Cutaneous id reactions: a comprehensive review of clinical manifestations, epidemiology, etiology, and management. Crit Rev Microbiol. 38:191–212PubMedGoogle Scholar
  8. Lupi O, Tyring SK, McGinnis MR (2005) Tropical dermatology: fungal tropical diseases. J Am Acad Dermatol 53:931–951PubMedGoogle Scholar
  9. Merz WG, Hay RJ (2007) Topley and Wilson’s microbiology and microbial infections, medical mycology, 10th edn. Wiley, HobokenGoogle Scholar
  10. Schwartz RA (2004) Superficial fungal infections. Lancet 364:1173–1182PubMedGoogle Scholar
  11. Seebacher C, Lotti T, Roccia MG et al (2017) Outstanding personalities in German-speaking mycology. Vienna Med Wochenschr. https://​doi.​org/​10.​1007/​s10354-017-0546-6
  12. Tietz HJ, Sterry W (2011) Antimykotika von A-Z. Anwendung und Pharmakologie auf einen Blick, 5th edn. Ligatur, StuttgartGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  1. 1.BiebertalGermany

Section editors and affiliations

  • Thomas Ruzicka
    • 1
  1. 1.Department of DermatologyUniversity of MunichMunichGermany

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