Section 30. Fungal Diseases

Mycoses are divided among three forms: (1) superficial, involving stratum corneum, hair, nails, (2) subcutaneous, involving dermis and/or subcutaneous tissue, and (3) deep/systemic, representing hematogenous spread of organisms including opportunistic pathogens in immunocompromised hosts. The focus of this chapter is the superficial mycoses and their patterns of integumentary infections (Table 188-1). A glossary of terms used in this chapter is contained in Table 188-2.

The universe of fungi comprises more than 1.5 million species worldwide. Dermatophytes (term derived from the Greek words for “skin plant”) are contained in the family of arthrodermataceae and are represented by approximately 40 species divided among the three genera: Epidermophyton, Microsporum, and Trichophyton. In the United States, Trichophyton species, and namely T. rubrum and T. interdigitale, represent the most common species isolated. Dermatophytes are classified further according to their natural habitats—humans, animals, or soil. Their ability to attach to and invade keratinized tissue of animals and humans and to utilize degradation products as nutritional sources form the molecular basis for superficial fungal infections of skin, hair, and nails, termed dermatophytoses.1

Taxonomy and Epidemiology

Recent modifications to the taxonomical system of dermatophytes affecting clinical practice require mention. While previous taxonomy was based largely on phenotypical characteristics of dermatophytes, recent inclusion of genotypical analyses necessitated regrouping of some taxa since many of these genotypical differences were not reflected phenotypically, and vice versa.2 Current taxonomy includes a synthesis of new data based on sequencing of variable genomic regions such as the internal transcribed spacer (ITS) regions of fungal ribosomal DNA as well as classic phenotypical characterizations. The difficulty in devising such a taxonomical system for dermatophytes relates to reduced genetic diversity due to recent speciation and population of the same ecological niches. Phenotypically, this is reflected by similar clinical manifestations being caused by multiple taxonomically different dermatophyte species. It should be noted, however, that the current framework is still a work in progress, and the taxonomy will likely undergo further refinements in the future. Table 188-3 lists the most commonly encountered dermatophyte pathogens including the new taxonomy according to their natural habitats and reservoirs. The current medical literature on dermatophytes and infections, however, does not stringently follow the new taxonomy. In order to avoid confusion over the dynamic status of the taxonomy as well as to remain reflective of the current nomenclature in the literature, this chapter will use both nomenclatures, resulting in some apparent contradictions. The authors hope that a more unified nomenclature is accepted for future editions of this chapter.

The additional classification of superficial fungi according to natural habitat is clinically relevant, since anthropophilic, zoophilic, and geophilic dermatophytoses provide important information about the source of infection and demonstrate varied clinical features.

Anthropophilic

species are typically restricted to human hosts and are transmitted via direct contact. Infected skin or hair retained in clothing, combs, caps, socks, and towels, for example, also serve as source reservoirs. Unlike the sporadic geophilic and zoophilic infections, anthropophilic infections are often epidemic in nature. These dermatophytes have adapted to humans as hosts and as such elicit a mild to noninflammatory host response.

Zoophilic

species are transmitted to humans from animals. Cats, dogs, rabbits, guinea pigs, birds, horses, cattle and other animals are common sources of infection. Transmission may occur through direct contact with the animal itself, or indirectly via infected animal hair. Exposed areas such as the scalp, beard, face, and arms are favored sites of infection. Microsporum canis is often transmitted to humans from cats and dogs, while guinea pigs and rabbits are a frequent source of human infection with zoophilic strains of T. interdigitale. While host adaptation by zoophilic dermatophytes may lead to relatively silent infections, these dermatophytes tend to produce acute and intense inflammatory responses in humans.1

Geophilic

fungi cause sporadic human infection upon direct contact with the soil. Microsporum gypseum is the most common geophilic dermatophyte cultured from humans. There is a potential for epidemic spread due to the higher virulence of geophilic strains as well as an ability to form long-lived spores that may reside in blankets or grooming tools. As with zoophilic infections, geophilic dermatophytes typically result in intense inflammatory responses.3

Clinical presentations of dermatophytoses depend not only on the source, but also on host factors. Immunocompromised individuals are more susceptible to refractory dermatophyte infections or to deep mycoses.4,5 Interestingly, only the severity of dermatophytosis appears to be increased with HIV infection, and not the prevalence.6 Other host factors such as age, sex, and race appear to be additional epidemiologic factors for infection, although their relationship to dermatophyte susceptibility remains unclear. As an example, dermatophyte infections are five times more prevalent in males than females.

Superficial fungal infections are a worldwide problem that affects more than 20%–25% of the population.7 Some species demonstrate ubiquitous distribution whereas others are geographically limited. Accordingly, predominant species reflect considerable geographic differences, as in the case of tinea capitis. In the United States, Trichophyton tonsurans has replaced Microsporum audouinii as the most common cause of tinea capitis in the second half of the 20th century, and M. canis has now become the second most common cause.8 In Europe, M. canis remains the most common cause of tinea capitis despite a significantly increased incidence of T. tonsurans.9 The etiologic profile is quite different in Africa where M. audouinii, Trichophyton soudanense, and Trichophyton violaceum are the most prevalent pathogens.10 However, human travel and migration results in dynamic patterns of infection. As an example, T. soudanense and T. violaceum, typically restricted to Africa, were isolated in US cases of tinea capitis in 2007.11 Finally, local customs may also influence rates and patterns of dermatophytoses. The use of macerating occlusive footwear, for example, in industrialized nations has made tinea pedis and onychomycosis much more common in these regions.6

Pathogenesis

Dermatophytes exhibit a broad armamentarium of enzymes (keratinolytic proteases, lipases etc.) that act as virulence factors to allow adherence and invasion of skin, hair, and nails, and also to utilize keratin as a source of nutrients for survival. The initial steps in dermatophyte infections are adherence to keratin followed by invasion and growth of mycelial elements. As a consequence of keratin degradation and subsequent release of proinflammatory mediators, the host develops an inflammatory response of varying degree. The classic “ringworm,” or annular morphology of tinea corporis results from an inflammatory host response against a spreading dermatophyte followed by a reduction or clearance of fungal elements from within the plaque, and in many cases by spontaneous resolution of the infection.

Adherence

Dermatophytes overcome several lines of host defense before hyphae begin to thrive in keratinized tissues. The first step is successful adherence of arthroconidia, asexual spores formed by fragmentation of hyphae, to the surface of keratinized tissues.12 Early nonspecific lines of host defense include fungistatic fatty acids in sebum as well competing bacterial colonization.13,14 Several recent studies have focused on the molecular steps involved in arthroconidial adherence to keratinized surfaces. Dermatophytes have been shown make selective use of their proteolytic armamentarium during adherence and invasion.15,16 The basis for this highly concerted attack may be explained partially by specific upregulation of multiple genes induced by contact with keratin, as has been shown by differential gene expression analysis in T. rubrum.17 Following several hours of successful adherence, the spores begin to germinate in preparation for the next step in the infective chain of events, invasion.

Invasion

Trauma and maceration facilitate penetration of dermatophytes through the skin. Invasion of germinating fungal elements is further accomplished through secretion of specific proteases, lipases and ceramidases, the digestive products of which also serve as fungal nutrients.18 Interestingly mannans, which are components of the fungal cell wall, show inhibitory effects on keratinocyte proliferation and cell-mediated immunity.19,20

Host Response

Dermatophytes encounter a range of host responses from several lines of nonspecific mechanisms including fungistatic fatty acids, increased epidermal proliferation, and secretion of inflammatory mediators to cell mediated-immunity. In the line of defense mechanisms, keratinocytes represent the first frontier of living cells to encounter invading fungal elements. The key position of keratinocytes is reflected by their complex response to invasion including proliferation to increase shedding as well as secretion of antimicrobial peptides including human β defensin-221 as well as proinflammatory cytokines (IFN-α, TNFα, IL-1β, 8, 16, and 17) that further activate the immune system. Once deeper layers of epidermis are involved, new nonspecific defenses such as competition for iron by unsaturated transferrin emerge. The degree of host inflammatory reaction depends on the host's immune status as well as the natural habitat of the dermatophyte species involved. Interestingly, anthropophilic dermatophytes induce secretion of a limited cytokine profile from keratinocytes in vitro compared to zoophilic species.22,23 This difference may reflect the augmented inflammatory response generally observed with zoophilic species.

The next level of defense is cell-mediated immunity resulting in a specific delayed type hypersensitivity response against invading fungi. The inflammatory response associated with this hypersensitivity is associated with clinical resolution, while defective cell-mediated immunity may result in chronic or recurrent dermatophytoses. The Th2 response does not appear to be protective, since patients with elevated fungal antigen antibody titers are observed to have widespread dermatophyte infections.24 A possible role for the Th17 response to dermatophyte infections is suggested by the recent discovery of binding of hyphal elements to Dectin-2, a C-type lectin pattern recognition receptor on dendritic cells, critical for inducing Th17 responses.25,26 However, the relative importance of the Th17 immune response to dermatophytosis remains to be elucidated.

Genetics

Despite epidemiological observations suggesting a genetic predisposition to fungal infections, molecular insight confirming this hypothesis has been lacking. Recently, however, two families with increased susceptibility to fungal infections and mutations in the C-type lectin fungal pattern recognition pathway have been described. In addition, mutations in CARD9, an adaptor molecule downstream of Dectin-1 and Dectin-2, which result in failure of Th17 activation, were associated with susceptibility to chronic mucocutaneous candidiasis along with chronic dermatophyte infections.27

(Table 188-4)

The clinical diagnosis of a dermatophyte infection can be confirmed by microscopic detection of fungal elements, by identification of the species through culture, or by histologic evidence of the presence of hyphae in the stratum corneum. In addition, fluorescence patterns under Wood's light examination may support a clinical suspicion.

Microscopic Examination

Although microscopic evaluation of potassium hydroxide (KOH)-treated samples of scale does not allow for speciation or characterization of the susceptibility profile, it is used (or underused) as a quick and inexpensive bedside tool to provide evidence of dermatophytosis. In dermatophytosis involving the skin, hair or nails, septate and branching hyphae without constriction (Fig. 188-1) may be visualized under microscopic examination with 10%–20% KOH preparation. All superficial dermatophytes appear identical when visualized in this manner. Because KOH examination may yield false-negative results in up to 15% of cases,28 patients suspected of having dermatophytosis on clinical impression should be treated. Culture confirmation should be considered whenever systemic treatment is warranted, such as in the case of tinea capitis.

Scale from skin should be collected by scraping the involved area with a dull edge outward from the advancing margins. Full thickness nail clippings should involve the dystrophic portion, as proximal from the distal edge as possible without causing injury. Hairs should be plucked (not cut), placed on a glass slide and prepared with 10%–20% KOH and covered with a coverslip. Slightly warming the slide with a low intensity flame allows better penetration of the KOH solution into keratin. Low-power microscopy will reveal three possible patterns of infection (Fig. 188-2): (1) Ectothrix—small or large arthroconidia forming a sheath around the hair shaft, (2) Endothrix—arthroconidia within the hair shaft, or (3) Favus—hyphae and air spaces within the hair shaft.

Culture

Speciation of superficial fungi is based on macroscopic, microscopic and metabolic characteristics of the organism. While some dermatophytes are readily identified on the basis of their primary isolation cultures, most require further differentiation through subcultures on specific media (identification culture) or through specific biochemical tests.

Sabouraud's dextrose agar (SDA) is the most commonly used isolation medium for dermatophytes and it serves as the medium on which most morphologic descriptions are based. Elimination of contaminant molds, yeast and bacteria is achieved by the addition of cycloheximide and chloramphenicol (+/−gentamicin) to the medium making it highly selective for the isolation of dermatophytes. The development of colonies can take 5–7 days in the case of Epidermophyton floccosum and up to 4 weeks for Trichophyton verrucosum. Cultures are incubated at room temperature (20°C–25°C) for at least 4 weeks before being finalized as no growth. Dermatophyte test medium (DTM) is an alternative isolation medium that contains the pH indicator phenol red. The medium turns red when dermatophyte proteolytic activity increases the pH to 8 or above, and it remains amber with the growth of most saprophytes. Nondermatophyte acidic byproducts turn the medium yellow. While DTM serves as a good alternative for isolation of dermatophytes, it may not allow for their direct identification due to altered growth and thus morphology of dermatophytes in DTM. Table 188-5 describes general microscopic features of microconidia and macroconidia of the three genera of dermatophytes, while Table 188-6 describes colony and microscopic features of the most common dermatophyte species.

Identification of isolated fungi is facilitated by subculture on specific media such as potato dextrose agar (PDA) or Borelli's lactrimel agar (BLA) that stimulate sporulation, production of pigment and development of typical morphology. Finally, dermatophytes may be differentiated further by their ability to grow on autoclaved polished rice, perforate short strands of hair in vitro or hydrolyze urea (urease test), or require nutritional supplementation for growth (Table 188-7).

Histopathology

Skin biopsy is not often employed in the workup of typical dermatophytoses. Localized cutaneous eruptions suspected to represent dermatophytosis with equivocal KOH examination are often treated despite the lack of confirmation. Biopsy may confirm the diagnosis when a systemic agent is being considered for treatment of a recalcitrant or more widespread eruption. Biopsy may be used to aid in the diagnosis of Majocchi's granuloma in which KOH examination of scale on the surface may more often be negative. Biopsy is also sometimes useful in confirming the presence of hyphae involving hair shafts on the scalp in tinea capitis, although culture is necessary to allow speciation of the pathogen. When present, hyphae may be appreciated in the stratum corneum on hematoxylin and eosin staining. However special stains, most commonly periodic acid-Schiff (PAS) and methenamine silver stains, highlight hyphae that may otherwise be subtle in appearance on routine staining. Whereas culture is the most specific test for onychomycosis, PAS examination of nail clippings is the most sensitive29 and it obviates the need to wait weeks for a result.

Wood's Light Fluorescence

Examination of involved hair bearing areas, such as the scalp or beard, with a Wood's lamp (365 nm) may reveal pteridine fluorescence of hair infected with particular fungal pathogens. Hairs that fluoresce should be selected for further examination, including culture. While ectothrix organisms M. canis and M. audouinii will fluoresce on Wood's light examination, the endothrix organism T. tonsurans will not fluoresce. T. tonsurans, which is now the most common cause of tinea capitis in the United States, thus limits the use of Wood's light examination. Table 188-8 lists common patterns of dermatophyte hair involvement and fluorescence.

Tinea Capitis

Tinea capitis describes dermatophyte infection of hair and scalp, typically caused by Trichophyton and Microsporum species, with exception of Trichophyton concentricum.

Epidemiology

Tinea capitis is most commonly observed in children between 3 and 14 years of age. The fungistatic effect of fatty acids in sebum may help to explain the sharp decrease in incidence after puberty.30 Overall prevalence of the carrier state is around 4% in the United States with a peak prevalence of approximately 13% in girls of Sub-Saharan African American descent.31 In general, tinea capitis is more common among children of African descent for unknown reasons. Transmission is increased with decreased personal hygiene, overcrowding and low socioeconomic status. The anthropophilic dermatophyte T. tonsurans is the most prevalent species found in the United States, while M. canis remains the most common cause of tinea capitis in Europe.32 Organisms responsible for tinea capitis have been cultured from fomites such as combs, caps, pillowcases, toys and theater seats. Even after shedding, hairs may harbor infectious organisms for more than 1 year.33 The high prevalence of asymptomatic carriers thwarts eradication of the disease.

Pathogenesis

Infection of hair by dermatophytes follows 3 main patterns—ectothrix, endothrix and favus. Dermatophytes establish infection in the perifollicular stratum corneum and spread around and into the hair shaft of mid- to late-anagen hairs before descending into the follicle to penetrate the cortex. With hair growth, the infected part of the hair rises above the surface of the scalp where it may break because of its increased fragility.

In ectothrix infections (see Fig. 188-2), only the arthroconidia on the surface of the hair shaft may be visualized, although hyphae are also present within the hair shaft. The cuticle is destroyed. On Wood's lamp examination, a yellow–green fluorescence may be detected, depending on the causative organism. In endothrix infections (see Fig. 188-2), arthroconidia and hyphae remain within the hair shaft and leave the cortex and cuticle intact. This pattern of tinea capitis is associated with the appearance of “black dots” which represent broken hairs at the surface of the scalp. Endothrix organisms do not show fluorescence on Woods lamp exam. Favus is characterized by longitudinally arranged hyphae and air spaces within the hair shaft. Arthroconidia are not usually noted in infected hairs.

Clinical Findings

(Table 188-9).

The clinical appearance of tinea capitis depends on the causative species as well as other factors such as the host immune response. In general, dermatophyte infection of the scalp results in hair loss, scaling and varying degrees of an inflammatory response.

Noninflammatory Type

Also called the seborrheic form of tinea capitis since scale is the predominant feature,34 noninflammatory tinea capitis is seen most commonly with anthropophilic organisms such as M. audouinii or Microsporum ferrugineum. Arthroconidia may form a sheath around affected hairs turning them gray and causing them to break off just above the level of the scalp. Alopecia may be imperceptible or in more inflammatory cases there may be circumscribed erythematous scaly patches of nonscarring alopecia with breakage of hairs (“gray patch” type; Fig. 188-3). Patches often occur on the occiput.33 When involving an ectothrix pattern, infected hairs may exhibit green fluorescence under Wood's light (see Table 188-8).

“Black Dot” Tinea Capitis

(Fig. 188-4).

The “black dot” form of tinea capitis is typically caused by the anthropophilic endothrix organisms T. tonsurans and T. violaceum. Hairs broken off at the level of the scalp leave behind grouped black dots within patches of polygonal shaped alopecia with finger-like margins. Normal hairs also remain within patches of broken hairs. Diffuse scaling is also often present. While “black dot” tinea capitis tends to be minimally inflammatory, some patients may develop follicular pustules, furuncle-like nodules, or in rare cases kerion—a boggy, inflammatory mass studded with broken hairs and follicular orifices oozing with pus.35

Inflammatory Type

Zoophilic or geophilic pathogens, such as M. canis, M. gypseum, and T. verrucosum, are more like to cause an inflammatory type of tinea capitis. Inflammation, which is the result of a hypersensitivity reaction to the infection, in this setting ranges from follicular pustules to furunculosis (Fig. 188-5) or kerion (Fig. 188-6). Intense inflammation may also result in scarring alopecia. The scalp is usually pruritic or tender. Inflammatory tinea capitis is often associated with posterior cervical lymphadenopathy, which serves as a clinical pearl in differentiating tinea capitis from other inflammatory disorders involving the scalp.

Differential Diagnosis

(Box 188-1)

Laboratory Tests

(See Tables 188-4, 188-6)

Histopathology

(See Table 188-4).

In tinea capitis, PAS and methenamine silver stains readily reveal hyphae around and within hair shafts. The dermis demonstrates a perifollicular mixed cell infiltrate with lymphocytes, histiocytes, plasma cells, and eosinophils. Follicular disruption leads to an adjacent foreign-body giant cell reaction. Markedly inflammatory lesions such as a kerion demonstrate an acute infiltrate of polymorphonuclear leukocytes within the dermis and follicle.36 Organisms may not be visualized in kerion since the intense host response destroys many of the fungal organisms. However, fungal antigens may be detectable with immunofluorescent techniques.37

Tinea Favosa

Tinea favosa or favus (Latin, “honeycomb”) is a chronic dermatophyte infection of the scalp rarely involving glabrous skin, and/or nails characterized by thick yellow crusts (scutula) within the hair follicles which leads to scarring alopecia.

Epidemiology

Favus is usually acquired before adolescence, although it may extend into adulthood.38 Associated with malnutrition and poor hygiene, favus has become geographically limited over the past century, and it is now seen almost exclusively in Africa, the Middle East and parts of South America. Even in these regions, its incidence has declined dramatically, and studies from South Africa, Lybia, and Arabia suggest disappearance of favus over the last few decades.39–41

Etiology

Trichophyton schoenleinii is the most common cause of human favus, although T. violaceum and M. gypseum are also rare isolates.42 Although favus occurs in animals including domesticated birds (Microsporum gallinae) and mice (Trichophyton mentagrophytes formerly T. mentagrophytes var. quinckeanum), there exist only a few reports of humans infected by the pathogens responsible for animal favus.43

Clinical Findings

Early favus (first 3 weeks of infection) is characterized by patchy perifollicular erythema with slight scaling and matting of the hair. Progressive hyphal invasion distends the follicle, first producing a yellow–red follicular papule and then a yellow concave crust (scutulum) around a single dry hair (Fig. 188-7) that is less brittle than hair of endothrix infections. The scutulum may reach 1 cm in diameter, engulfing surrounding hairs and coalescing with other scutula to form large adherent mats with an unpleasant cheese-like or musky odor. Over several years, the plaques advance peripherally leaving behind central, atrophic areas of alopecia.42

Differential Diagnosis

(Box 188-1)

Laboratory Tests

(See Tables 188-4, 188-6).

T. schoenleinii exhibits subtle, blue–gray fluorescence along the entire hair with Wood's lamp examination. Microscopy with KOH preparation reveals hyphae arranged lengthwise around and within the hair shaft, rare arthroconidia, and vacant air spaces.42

Histopathology

(See Table 188-4)

Tinea Barbae

Epidemiology

Tinea barbae, as its name would imply, occurs predominantly in males. The incidence of tinea barbae has decreased as improved sanitation has reduced transmission by contaminated barbers’ razors. Direct exposure to cattle, horses, or dogs is now the more common mode of acquisition, and this accounts for a shift in prevalence toward farmers or ranchers in rural settings.

Etiology

Tinea barbae is most commonly caused by the zoophilic strains of T. interdigitale (former T. mentagrophytes var. mentagrophytes), T. verrucosum, and less commonly M. canis. Among the anthropophilic organisms, T. schoenleinii, T. violaceum and certain strains of T. rubrum (former T. megninii), cause tinea barbae in endemic areas.42

Clinical Findings

Tinea barbae affects the face unilaterally and involves the beard area more often than the moustache or upper lip. Two forms exist.

Superficial Type

Caused by anthropophiles such as T. violaceum, this form of tinea barbae is less inflammatory and resembles tinea corporis or bacterial folliculitis. The active border shows perifollicular papules and pustules accompanied by mild erythema (Fig. 188-8A). Alopecia, if present, is reversible.

Inflammatory Type

Usually caused by T. interdigitale (zoophilic strains) or T. verrucosum, inflammatory tinea barbae is the most common clinical presentation. It presents analogously to kerion formation in tinea capitis with boggy-crusted plaques and a seropurulent discharge (Fig. 188-8B). Hairs are lusterless, brittle, and easily epilated to demonstrate a purulent mass around the root. Perifollicular pustules may coalesce and eventuate in abscess-like collections of pus, sinus tracts, and scarring alopecia.

Differential Diagnosis

(Box 188-2)

Laboratory Tests

(See Tables 188-4, 188-6)

Histopathology

(See Table 188-4)

Tinea Corporis

Tinea corporis refers to any dermatophytosis of glabrous skin except palms, soles, and the groin.

Epidemiology

Tinea corporis may be transmitted directly from infected humans or animals, via fomites, or it may occur via autoinoculation from reservoirs of dermatophyte colonization on the feet.44 Children are more likely to contract zoophilic pathogens, especially M. canis, from dogs or cats. Occlusive clothing and a humid climate are associated with more frequent and severe eruptions.45 Wearing of occlusive clothing, frequent skin-to-skin contact, and minor traumas such as the mat burns competitive wrestling create an environment in which dermatophytes flourish. “Tinea corporis gladiatorum” is caused most commonly by T. tonsurans, and it occurs most frequently on the head, neck, and arms.46

Etiology

Although any dermatophyte may cause tinea corporis, it is caused most commonly by T. rubrum. T. rubrum is also the most likely candidate in cases with concomitant follicular involvement.35 Epidermophyton floccosum, T. interdigitale (anthropophilic and zoophilic strains), M. canis, and T. tonsurans are also common pathogens.1 Tinea imbricata, caused by T. concentricum, is limited geographically to areas of the Far East, South Pacific, and South and Central America.

Clinical Findings

The classic presentation is that of an annular (“ring-worm”-like; Fig. 188-9A) or serpiginous plaque with scale across the entire active erythematous border. The border, which may be vesicular, advances centrifugally. The center of the plaque is usually scaly but it may exhibit complete clearing. Whereas concentric vesicular rings suggest tinea incognito, often caused by T. rubrum, the erythematous concentric rings of tinea imbricata demonstrate little to no vesiculation. T. rubrum infections may also present as large, confluent polycyclic (Fig. 188-9B) or psoriasiform (Fig. 188-9C) plaques, especially in immunosuppressed individuals.

Majocchi's granuloma is a superficial and subcutaneous dermatophytic infection involving deeper portions of the hair follicles that presents as scaly follicular papules and nodules that coalesce in an annular arrangement (Fig. 188-10). It is caused most commonly by T. rubrum, T. interdigitale, and M. canis. Majocchi's granuloma is observed on the legs in women who become inoculated after shaving or who apply topical corticosteroids to the involved area, which facilitates infection. It is also observed increasingly among immunocompromised patients.47

Differential Diagnosis

(Box 188-3)

Laboratory Tests

(See Tables 188-4, 188-6)

Histopathology

(See Table 188-4)

Tinea Cruris

Tinea cruris is a dermatophytosis of the groin, genitalia, pubic area, and perineal and perianal skin. The designation is a misnomer, because in Latin “cruris” means of the leg. It is the second-most common type of dermatophytosis worldwide.

Epidemiology

Much like tinea corporis, tinea cruris spreads via direct contact or fomites, and it is exacerbated by occlusion and humid climates. Autoinfection from distant reservoirs of T. rubrum or T. interdigitale on the feet, for example, is common.44 Tinea cruris is three times more common in men, and adults are affected more commonly than children.

Etiology

Most tinea cruris is caused by T. rubrum and E. floccosum, the latter being most often responsible for epidemics.42 T. interdigitale and T. verrucosum are implicated less commonly.

Clinical Findings

Tinea cruris presents classically as a well-marginated annular plaque with a scaly raised border which extends from the inguinal fold on to the inner thigh, often bilaterally. Erythematous scaly patches with papules and vesicles involving the inner thighs is also a common but perhaps less obvious presentation. Pruritus is common, as is pain when plaques are macerated or secondarily infected. Plaques in tinea cruris due to E. floccosum are more likely to demonstrate central clearing, and are more often limited to the genitocrural crease and the medial upper thigh. In contrast, plaques in tinea cruris due to T. rubrum coalesce with extension to the pubic, perianal, buttock, and lower abdominal areas (Fig. 188-11). Genitalia including the scrotum are infrequently affected.42

Differential Diagnosis

(Box 188-4)

Laboratory Tests

(See Tables 188-4, 188-6)

Histopathology

(See Table 188-4)

Tinea Pedis and Tinea Manuum

Tinea pedis denotes dermatophytosis of the feet, whereas tinea manuum involves the palmar and interdigital areas of the hands. Infection of the dorsal aspects of feet and hands is considered to be tinea corporis.

Epidemiology

Occurring worldwide, tinea pedis and tinea manuum are the most common dermatophytoses. High prevalence, estimated to be around 10%, is attributed primarily to modern occlusive footwear, although increased worldwide travel has also been implicated.42 Incidence of tinea pedis is higher among those using communal baths, showers or pools. With the ubiquitous presence of dermatophytes in the environment, however, it may be that host factors such as an individual's immune response to dermatophytes, in addition to exposure, play a determining role in the acquisition of tinea pedis. The authors, however, are not aware of any studies formally addressing this question.

Tinea manuum is acquired through direct contact with an infected person or animal, the soil, or via autoinoculation. Most commonly only one hand (singular: tinea manus) is involved, concomitant with infection of feet and toenails for which the term “two feet–one hand” syndrome has been coined. This classic presentation of tinea manus represents a secondary infection of the hand acquired from excoriating and picking infected feet and toenails.48 Tinea manuum should be suspected in individuals who have fine dry scaling of the palm or palms, often accentuated in the creases.

Etiology

Tinea pedis and tinea manuum are caused predominantly by T. rubrum (most common), T. interdigitale, and E. floccosum.

Clinical Findings

Tinea pedis may present as any of four forms, or combinations thereof.

Interdigital Type

The most common presentation of tinea pedis begins as scaling, erythema and maceration of the interdigital and subdigital skin of the feet, and in particular between the lateral third and fourth and fourth and fifth toes (Fig. 188-12A). Under appropriate conditions, the infection will spread to the adjacent sole or instep, but it rarely involves the dorsum. Occlusion and bacterial coinfection (Pseudomonas, Proteus, and Staphylococcus aureus) soon produce the interdigital erosions with pruritus and malodor that are characteristic of the dermatophytosis complex, or “athlete's foot.”

Chronic Hyperkeratotic (Moccasin) Type

In chronic hyperkeratotic type tinea pedis, there is patchy or diffuse scaling on the soles and the lateral and medial aspects of the feet, in a distribution similar to a moccasin on a foot (Fig. 188-12B). The degree of erythema is variable, and there may also exist few minute vesicles that heal with collarets of scale less than 2 mm in diameter. The most common pathogen is T. rubrum followed by E. floccosum and anthropophilic strains of T. interdigitale.

Vesiculobullous Type

Vesiculobullous type of tinea pedis, typically caused by zoophilic strains of T. interdigitale (former T. mentagrophytes var. mentagrophytes), features tense vesicles larger than 3 mm in diameter, vesiculopustules, or bullae on the soles and periplantar areas (Fig. 188-12C). This type of tinea pedis is uncommon in childhood but has been caused by T. rubrum.49

Acute Ulcerative Type

Tinea pedis with zoophilic T. interdigitale along with rampant bacterial superinfection with Gram-negative organisms produces vesicles, pustules and purulent ulcers on the plantar surface. Cellulitis, lymphangitis, lymphadenopathy and fever are frequently associated.

Vesiculobullous and acute ulcerative types commonly produce a vesicular Id reaction, either on the lateral foot or toes, or on the lateral aspects of the fingers.

Tinea manus, dermatophyte infection of the hand, usually has a noninflammatory presentation with diffuse dry scaling and accentuation in the creases (Fig. 188-13). However, vesicles, pustules and exfoliation may be present, especially when zoophilic dermatophytes involved. Tinea manus commonly occurs in association with moccasin type tinea pedis and onychomycosis, which should also be treated to minimize relapse.50

Differential Diagnosis

(Box 188-5)

Laboratory Tests

(See Tables 188-4, 188-6).

KOH examination of blister roofs (vesicules or bullae) yields the highest rate of positive findings.

Histopathology

(See Table 188-4).

In tinea pedis, fungal organisms are highlighted in the stratum corneum by PAS or methenamine silver stains and are sometimes accompanied by foci of neutrophils.

There may also be a sparse, chronic, superficial perivascular infiltrate in the dermis. The vesiculobullous type demonstrates subcorneal or spongiotic intraepithelial vesiculation.

Dermatophytid (Id) Reaction

These inflammatory reactions, named apparently after the instinctual component of the psyche as defined by Freud, occur in 4%–5% of patients with dermatophytosis at sites distant from the primary inflammatory fungal infections such as tinea pedis or kerion.51 Although the precise mechanism is unknown, the Id reaction is associated with a DTH response to the Trichophyton test and may involve a local DTH response to systemically absorbed fungal antigen.52 Id reactions appear polymorphic, ranging in morphology from follicular or nonfollicular papules and vesicles of the hands and feet to reactive erythemas including erythema nodosum, erythema annulare centrifugum, or urticaria.53–56 Unlike the primary eruption, the Id eruption is KOH examination and culture negative. Criteria for establishing the presence of an Id eruption are the following: (1) dermatophytosis on another part of body, (2) absence of fungal elements from the id eruption, and (3) resolution of the id eruption with clearing of the primary dermatophyte infection.

Onychomycosis

Onychomycosis describes fungal infection of the nail caused by dermatophytes, nondermatophyte molds, or yeasts. Tinea unguium refers strictly to dermatophyte infection of the nail. Clinically, different three types of onychomycosis are distinguished: (1) distolateral subungual onychomycosis (DLSO), (2) proximal subungual onychomycosis (PSO), (3) white superficial onychomycosis (WSO).

Epidemiology

Onychomycosis is the most prevalent nail disease and accounts for approximately 50% of all causes of onychodystrophy. It affects up to 14% of the population with both an increasing prevalence among older individuals.57 and an overall increasing incidence.58 Onychomycosis is also increasing in incidence among children and adolescents and accounts for up to 20% of dermatophyte infections diagnosed in children.59 Risk factors for nail infection include nail trauma, immunosuppression such as HIV infection, diabetes mellitus, and peripheral vascular insufficiency.60 The increasing prevalence of this disease may be secondary to wearing of tight shoes, increasing numbers of individuals on immunosuppressive drugs, and an increased use of communal locker rooms. The dermatophytosis commonly begins as tinea pedis before extending to the nail bed, where eradication is more difficult. This site serves as a reservoir for local recurrence or for infections spreading to other areas. Up to 40% of patients with toenail onychomycosis show concomitant skin infections, most commonly tinea pedis (30%).61

Etiology

In the majority of cases, onychomycosis is caused by dermatophytes, and T. rubrum and T. interdigitale are responsible for approximately 90% of all cases. T. tonsurans and E. floccosum are also well documented causative agents.62 Yeast and nondermatophyte molds such as Acremonium, Aspergillus, Fusarium, Scopulariopsis brevicaulis, and Scytalidium are the source of approximately 10% of toenail onychomycosis. Interestingly, Candida species are responsible for up to 30% of fingernails cases, whereas nondermatophyte molds were not detected in diseased fingernails.63

Clinical Findings

Distolateral Subungual Type

DLSO is the most common form of onychomycosis and may be caused by any of the organisms listed above. It begins with invasion of the stratum corneum of the hyponychium and distal nail bed, forming a whitish to brownish–yellow opacification at the distal edge of the nail (Fig. 188-14A). The infection then spreads proximally up the nail bed to the ventral nail plate. Hyperproliferation or altered differentiation of the nail bed in response to the infection results in subungual hyperkeratosis, while progressive invasion of the nail plate results in an increasingly dystrophic nail.

Proximal Subungual Type

(Fig. 188-14B).

PSO results from infection of the proximal nail fold primarily with T. rubrum and T. megninii and is apparent as a white to beige opacity on the proximal nail plate. This opacity gradually enlarges to affect the entire nail and eventuates in subungual hyperkeratosis, leukonychia, proximal onycholysis, and/or destruction of the entire nail. Patients with PSO should be screened for HIV, as PSO has been considered a marker for this disease.6,64

White Superficial Type

(Fig. 188-14C).

WSO results from direct invasion of the dorsal nail plate resulting in white to dull yellow sharply bordered patches anywhere on the surface of the toenail. It is usually caused by T. interdigitale, although nondermatophyte molds such as Aspergillus, Scopulariopsis, and Fusarium are also known pathogens. Candida species may invade the hyponychial epithelium to eventually affect the entire thickness of the nail plate.65

Differential Diagnosis

(Box 188-6)

Laboratory Tests

(See Tables 188-4, 188-6).

Although onychomycosis is responsible for 50% of dystrophic nails, laboratory diagnostic confirmation prior to treatment with potentially toxic oral, antifungal treatments is judicious. KOH examination of subungual debris, culture of the nail plate and accompanying debris on SDA (with and without antimicrobials), and PAS staining of a nail clipping are most useful. However, KOH examination is often negative even when clinical suspicion is high, and nails with hyphae reported on KOH examination often yield negative cultures. The simplest measure to minimize false-negatives caused by sampling error is to maximize sample size and repeat collections. The following guidelines are suggested to discern pathogens from contaminants: (i) if a dermatophyte is isolated on culture, it is considered a pathogen; (ii) a nondermatophyte mold or yeast cultured is significant only if hyphae, spores, or yeast cells are seen on microscopic examination, and (iii) there is repeated heavy growth of a nondermatophyte mold without concurrent isolation of a dermatophyte.66 Whereas culture is the most specific test for onychomycosis, PAS examination of nail clippings is the most sensitive29 and it obviates the need to wait weeks for a result.

Histopathology

(See Table 188-4).

Hyphae are seen between the nail laminae parallel to the surface and have a predilection for the ventral nail and stratum corneum of the nail bed.67 The epidermis may show spongiosis and focal parakeratosis, and there is a minimal dermal inflammatory response. In WSO, the organisms are present superficially on the dorsal nail and display unique “perforating organs” and “eroding fronds.” In candidal onychomycosis there is invasion of pseudohyphae throughout the entire nail plate, adjacent cuticle, granular layer, and stratum spinosum of the nail bed, as well as the hyponychial stratum corneum.65

(Table 188-10)

Multiple systemic and topical antifungal agents are available to treat dermatophytoses of skin, hair and nails.

Tinea Capitis and Favus

Infections involving hair-bearing skin usually necessitate oral antifungal treatment since dermatophytes penetrating the follicle are usually out of reach for topically applied agents. Griseofulvin along with the allylamine (terbinafine) and oral triazoles (itraconazole and fluconazole) are considered safe and effective in the treatment of tinea capitis.

Griseofulvin

Griseofulvin along with terbinafine in patients older than 4 years are systemic treatments for tinea capitis approved by the US Food and Drug Administration. The previously recommended pediatric dosage was 10–20 mg/kg/day in divided doses for 6–8 weeks taken with a fatty meal to facilitate absorption.33 However, high failure rates with this regimen resulted in the current dosage recommendation of griseofulvin 20–25 mg/kg/day of the microsize form, and 15 mg/kg/day in divided doses of the ultramicrosize form for 8 weeks.68 Although the current recommendation is not based on outcomes of controlled trials, the collective clinical experience suggests its high therapeutic efficacy. Disadvantages of griseofulvin include poor compliance related to length of treatment and its bitter taste in liquid form. Common side effects include photosensitivity, headache, and gastrointestinal upset.69 Griseofulvin also is a potent inducer of cytochrome P450 enzymes.

Terbinafine

Doses of 3–6 mg/kg/day of terbinafine can cure Trichophyton tinea capitis in 2–4 weeks; however, 4–8 weeks of treatment may be required for eradication of Microsporum.68 Two randomized trials confirmed the increased efficacy of terbinafine (5–8 mg/kg/day) in the treatment of T. tonsurans infection with significantly higher cure rates compared to lower dose griseofulvin (10–20 mg/kg/day). However, even at this lower dose range, griseofulvin showed significantly higher cure rates for M. canis infections.70 Further, it is not clear that terbinafine (5–8 mg/kg/day) has a therapeutic advantage in curing tinea capitis over the higher dose regimen of griseofulvin (20–25 mg/kg/day). Terbinafine may cause gastrointestinal upset. As with itraconazole, there are reports of liver failure in patients using terbinafine. Terbinafine has an inhibitory effect on the CYP 2D6 subset of the cytochrome P450 system. While fewer medications are metabolized through this CYP 2D6 subset as than through the CYP 3A4 subset inhibited by itraconazole and ketoconazole, notable interactions still exist with β-blockers and tricyclic antidepressants.

Itraconazole

At doses of 5 mg/kg/day for 2–4 weeks, itraconazole effectively eradicates tinea capitis caused by either Microsporum or Trichophyton.68 Pulse therapy at 5 mg/kg/day for 1 week out of each month for one to three cycles is also effective. Possible adverse effects of itraconazole include gastrointestinal upset, diarrhea with the liquid formulation, and peripheral edema, especially when used in conjunction with calcium channel blockers. Itraconazole is better absorbed in the presence of food, which results in secretion of gastric acid and lower gastric pH. On the contrary, antacids such as H2 blockers may decrease the absorption of itraconazole by increasing the gastric pH. Like with fluconazole, hepatotoxicity with itraconazole occurs at lower rates than with ketoconazole.35 Itraconazole has also rarely been linked to congestive heart failure. Itraconazole is an inhibitor of the CYP 3A4 subset of cytochrome P450 system.

Fluconazole

Available as both tablets and a pleasant-tasting liquid, fluconazole at doses of 6 mg/kg/day for 20 days is effective in curing tinea capitis.68 Alternatively, fluconazole can be administered as a pulse, once weekly, regimen with 6 mg/kg/day for 8–12 weeks.71 Absorption of fluconazole is not affected by gastric pH, and gastrointestinal side effects are less common. Hepatitis has been reported but it occurs less frequently than with ketoconazole.35 Fluconazole is a potent inhibitor of cytochrome P450 enzymes, in particular CYP 2C9 and 2C19. Since most medications metabolized by the cytochrome P450 system are through the CYP 3A4 subset, fluconazole has less potential to interact with medications than other systemic imidazoles.

Adjuvant Therapy

Selenium sulfide (1% and 2.5%), zinc pyrithione (1% and 2%), povidone iodine (2.5%), and ketoconazole (2%) are shampoo preparations that help eradicate dermatophytes from the scalp of children. Adjunctive use of these shampoos is recommended 2–4 times weekly for 2–4 weeks.72 The use of ketoconazole 2% shampoo or selenium sulfide 2.5% three times weekly by all household members also reduces transmission by decreasing the shedding of spores.69

Oral glucocorticoids may reduce the incidence of scarring associated with markedly inflammatory varieties of tinea capitis. Although there is no consistent evidence for improved cure rates with use of oral glucocorticoids, they appear to relieve pain and swelling associated with infections. The usual regimen prednisone is 1–2 mg/kg each morning during the first week of therapy.

Tinea Barbae

Like tinea capitis, an oral antifungal is usually necessary in the treatment of tinea barbae. Ultramicronized griseofulvin 500 mg twice daily for 6 weeks, terbinafine 250 mg daily for 2–4 weeks, itraconazole 200 mg daily for 2–4 weeks, and fluconazole 200 mg daily for 4–6 weeks are regimens that have been used effectively. Systemic glucocorticoids used for the first week of therapy are helpful in cases with severe inflammation.

Tinea Corporis and Tinea Cruris

For isolated plaques on the glabrous skin, topical allylamines, imidazoles, tolnaftate, butenafine, or ciclopirox are effective. Most are applied twice daily for 2–4 weeks. Oral antifungal agents are reserved for widespread or more inflammatory eruptions. Comparative studies in adults show that terbinafine 250 mg daily for 2–4 weeks, itraconazole 200 mg daily for 1 week, and fluconazole 150–300 mg weekly for 4–6 weeks are preferable over griseofulvin 500 mg daily until cure is reached.73 Safe and effective regimens for children include terbinafine 3–6 mg/kg/day for 2 weeks, itraconazole 5 mg/kg/day for 1 week, and ultramicrosize griseofulvin 10–20 mg/kg/day for up to 2–4 weeks.

Tinea Pedis and Tinea Manuum

Mild interdigital tinea pedis without bacterial involvement is treated topically with allylamine, imidazole, ciclopirox, benzylamine, tolnaftate, or undecenoic acid based creams.74 Terbinafine cream applied twice daily for 1 week is effective in 66% of cases.75 The dosing schedule of oral terbinafine is 250 mg daily for 2 weeks. Itraconazole in adults is given 400 mg daily for 1 week, 200 mg daily for 2–4 weeks, or 100 mg daily for 4 weeks with similar efficacies of all regimens,76 whereas itraconazole in children is administered at 5 mg/kg/day for 2 weeks. Fluconazole 150 mg weekly for 3–4 weeks is also effective.71 Topical or systemic corticosteroids may be helpful for symptomatic relief during the initial period of antifungal treatment of vesiculobullous tinea pedis. Maceration, denudation, pruritus, and malodor obligate a search for bacterial coinfection by Gram stain and culture, the results of which most often demonstrate the presence of Gram-negative organisms including Pseudomonas and Proteus. Patients suspected of having Gram-negative coinfections should be treated with a topical or systemic antibacterial agent based on the culture and sensitivity report. Associated onychomycosis is common; if present, more durable treatment of the onychomycosis is necessary to prevent recurrence of tinea pedis. Newer oral antifungal agents have replaced griseofulvin as the treatments of choice for severe or refractory tinea pedis when this infection is also accompanied by onychomycosis.

Onychomycosis

The management of onychomycosis depends on several factors including the severity of nail involvement, associated tinea pedis, along with efficacy and potential adverse effects of any treatment regimen. While it seems reasonable not to treat minimal nail involvement, concurrent tinea pedis should always be treated, particularly in the setting of diabetes mellitus, to prevent cellulitis.

Topical Therapy

In those patients with distal nail involvement and/or contraindication for systemic treatment, topical therapy should be considered. Ciclopirox 8% lacquer applied daily for 48 weeks achieved mycologic cure in 29%–36% of cases and clear nails (clinical cure) in 7% of mild to moderate cases of onychomycosis caused by dermatophytes.77 Despite its much lower efficacy compared with oral antifungal agents, use of topical ciclopirox avoids risk of drug interactions. Amorolfine 5% applied twice weekly is another agent specifically prepared for use as a nail lacquer. It is the first member of a new class of antifungal drugs, the morpholine derivatives, which show activity against yeasts, dermatophytes and molds that cause onychomycosis. Amorolfine may have higher mycologic cure rates (38%–54% after 6 months of treatment) compared to ciclopirox lacquer; however, prospective controlled trials validating a significant difference are needed.78

Systemic Therapy

An oral antifungal is required for onychomycosis involving the matrix area, or when a shorter treatment regimen or higher chance for clearance or cure is desired. Selection of the antifungal agent should be based primarily on the causative organism, the potential adverse effects, and the risk of drug interactions in any particular patient.

Terbinafine is fungistatic and fungicidal against dermatophytes, Aspergillus, and less so against Scopulariopsis. Terbinafine is not recommended for candida onychomycosis since it demonstrates variable efficacy against Candida species. A course of terbinafine 250 mg daily for 6 weeks is effective for most fingernail infections, while a minimum 12-week course12–16 is required for toenail infections. Most adverse effects are gastrointestinal such as diarrhea, nausea, taste disturbance, and elevation of liver enzymes. Evidence suggests that a 3-month continuous regimen of terbinafine is the most effective oral treatment for onychomycosis of the toenails available today.79 Clinical cure rates among different studies are approximately 50%, although the success rate is lower in patients over 65 years.80 Itraconazole is fungistatic against dermatophytes, nondermatophyte molds and yeasts. Safe and effective schedules include pulse dosing with itraconazole 400 mg daily for 1 week per month or a continuous dose of 200 mg daily, both of which require 2 months or 2 pulses of treatment for fingernails and at least 3 months or 3 pulses for toenails.73 Itraconazole is dosed by weight in children at 5 mg/kg/day.81 Elevated liver enzymes occur in 0.3%–5% of patients during therapy and return to normal within 12 weeks of discontinuation. Although itraconazole has a broader spectrum of activity than terbinafine, studies have shown a significantly lower rate of cure (about 25% vs. 50%) and higher relapse rate (about 50% vs. 20%) with itraconazole compared with terbinafine.82,83 Fluconazole is fungistatic against dermatophytes, some nondermatophyte molds, and Candida. The usual regimen for fluconazole is 150–300 mg once weekly for 3–12 months.73 Griseofulvin is no longer considered standard treatment for onychomycosis because of its prolonged treatment course, potential for adverse effects and drug interactions, and its relatively low cure rates.

Combination therapy regimens may have a higher clearance rate than either oral or topical treatments alone. Oral terbinafine combined with amorolfine nail lacquer was shown to result in clinical cure and negative mycology in 59% of patients compared to 45% of patients treated with oral terbinafine alone.84 However, another study failed to show any additional benefit of combining oral terbinafine with ciclopirox 8% solution.85

In vitro fungicidal activity demonstrated by thymol, camphor, menthol, and oil of Eucalyptus citriodora86,87 offers the potential for additional therapeutic strategies to treat onychomycosis. Thymol 4% prepared in ethanol may be used as drops applied to the nail plate and hyponychium. The application to nails of commercially available topical preparations with thymol, such as Vicks VapoRub™, has anecdotally led to success. Final options for refractory cases include surgical avulsion or chemical removal of the nail with 40% urea compounds in combination with topical or oral antifungals.

Tinea Nigra

Tinea nigra is a superficial dermatomycosis caused by dematiaceous, darkly pigmented, Hortaea werneckii (formerly named Phaeoannellomyces werneckii and Exophiala werneckii).88

Epidemiology

Tinea nigra occurs in tropical or subtropical areas, including Central and South America, Africa, and Asia. Its incidence is low in the United States and Europe. While the majority of the approximately 150 North American cases reported since 1950 were associated with tropical travel,42 endemic foci exist in the coastal southeastern United States and in Texas. Person-to-person transmission is rare.89 Tinea nigra has a female/male predilection of 3:1.

Etiology

Tinea nigra is almost always caused by H. werneckii, although other dematiaceous fungi such as Stenella araguata may produce the same clinical picture. Dematiaceous fungi are commonly found in soil, sewage, and decaying vegetation.89 Tinea nigra arises after trauma to the skin, subsequent inoculation and a typical incubation period of 2–7 weeks.

Clinical Findings

Tinea nigra is found on otherwise healthy people and presents typically as an asymptomatic, mottled brown to greenish-black macule or patch with minimal to no scale on the palms or soles (Fig. 188-15). The macule is often darkest at the advancing border. Because of its coloration and location on palms and soles, tinea nigra is frequently misdiagnosed as acral lentiginous melanoma.

Differential Diagnosis

(Box 188-7)

Laboratory Tests

KOH examination of scrapings from the macule reveals brown to olive-colored, thick branching hyphae, along with oval to spindle-shaped yeast cells that occur singly or in pairs with a central transverse septum. Cultures performed on SDA with cycloheximide and chloramphenicol grow within 1 week. The colony is initially yeast-like with a brown to shiny black color and appears as typical two-celled yeast forms under microscopic examination. With time, mycelial growth predominates creating a fuzzy grayish-black colony.

Treatment

Tinea nigra responds readily to topical therapy with a keratolytic (Whitfield's ointment, 2% salicylic acid), tincture of iodine, or topical antifungal.90,91 Treatment should be continued for 2–4 weeks after clinical resolution in order to prevent relapse. Although oral ketoconazole, itraconazole and terbinafine are also effective, systemic therapies are rarely indicated.88

Piedra

Piedra is an asymptomatic superficial fungal infection of the hair shaft also known as trichomycosis nodularis. Black piedra is caused by Piedraia hortae, whereas white piedra is caused by pathogenic species of the Trichosporon genus, namely Trichosporon asahii, Trichosporon ovoides, Trichosporon inkin, Trichosporon mucoides, Trichosporon asteroides, and Trichosporon cutaneum.88

Epidemiology

Black piedra is seen commonly in humans and primates of tropical areas of South America, the Pacific Islands, and the Far East, and less commonly in Africa and Asia. P. hortae is present in the soil and in stagnant water and crops. Scalp hair is most commonly affected. In fact, infection is encouraged for religious and esthetic reasons by some indigenous cultures.92

White piedra is most common in temperate and semitropical climates of South America and Asia, the Middle East, India, Africa, and Japan. It occurs infrequently in the United States and Europe. White piedra affects facial, axillary, and genital hair more commonly than scalp hair. T. ovoides is found more commonly on scalp hair, T. inkin on pubic hair and T. asahii on other body surfaces. Person-to-person transmission is rare, and infection has not been associated with travel to endemic areas.93

Clinical Findings

Black piedra is characterized by firmly attached, hard or gritty, brown–black colored concretions on the hair shaft that vary in size from the microscopic range to a few millimeters in size. Concretions are most commonly noted on frontal portions of the scalp. Black piedra weakens the hair shaft and results in hair breakage.

White piedra consists of softer and less adherent whitish to beige colored concretions that are discrete or may coalesce into sleeve-like structures along the hair shaft. These concretions affect the outer layers of the hair shaft and may be easily detached. Broken hairs, although sometimes present, are less common than in black piedra.88

Microscopy readily differentiates piedra from nits, hair casts, developmental hair shaft defects, and trichomycosis axillaris. In addition, the nodules of trichomycosis axillaris are usually smaller and may fluoresce under a Wood's lamp.

Differential Diagnosis

(Box 188-8)

Laboratory Tests

Nodules of black piedra examined by KOH preparation display a periphery of aligned hyphae and a well-organized center of thick-walled cells packed closely together, sometimes termed pseudoparenchyma. These nodules are mostly outside of the hair shaft. P. hortae grows well, albeit slowly, on most laboratory media and is uninhibited by cycloheximide.

The nodules of white piedra have a less organized and more intrapilar appearance than do nodules of black piedra. Hyphae are arranged perpendicularly to the hair shaft. T. asahii thrives on SDA and it is inhibited by cycloheximide.

Treatment

Shaving the infected hair is curative and represents the best treatment for both black and white piedra, although this approach should be supplemented with a topical azole preparation. Because of high relapse rates as well as evidence for intrafollicular organisms in white piedra, some advocate the use of systemic antifungal agent such itraconazole.93

The genus Candida is comprised of a heterogeneous group of over 200 yeast species.1 Candida species are ubiquitous yeast-like fungi that form true hyphae, pseudohyphae, and budding yeasts. Candidiasis (or candidosis) refers to a diverse profile of yeast infections caused by members of the genus Candida, and predominantly by Candida albicans. Candida species are among the most common fungal pathogens to affect humans. While the skin, nails, mucous membranes, and gastrointestinal tract are typical sites of infection, Candida may involve any part of the body. Although considered opportunistic human pathogens, Candida species may also exist as commensal organisms of skin and mucosal membranes of the gastrointestinal, genitourinary, and respiratory tracts.

Epidemiology

Frequency

Candida are usually limited to human and animal hosts, however they have also been recovered from the hospital environment: countertops, air-conditioning vents, floors, respirators, and on medical personnel. Oropharyngeal colonization with Candida is observed in up to 50% of healthy individuals 2 and may also be detected in 40%–65% of normal stool samples. In addition, C. albicans exists as a commensal organism in the vaginal mucosa of 20%–25% of asymptomatic, healthy women3 and up to 30% of healthy pregnant women.4 Vulvovaginal candidiasis (VC) is the second most common cause of vaginitis in women.

Candida species are the most common cause of fungal infection in immunocompromised persons. More than 90% of persons infected with HIV not receiving highly active antiretroviral therapy (HAART) develop oropharyngeal candidiasis and 10% of these patients develop esophageal candidiasis.5–6 Candida species are now the fourth most commonly isolated pathogens from blood cultures in patients with systemic infections.7

Mortality/Morbidity

Most candidal infections are mucocutaneous. While in few cases there may be pronounced effect on morbidity, these infections do not lead to death. However, immunocompromised patients including hospitalized patients, may develop candidemia and disseminated candidiasis which have a 30%–40% mortality rate. In fact, systemic candidiasis causes more case fatalities than any other systemic mycosis.

Sex

Neither sex is predisposed to candidal colonization.

Age

Neonates and adults >65 years of age are most susceptible to candidal colonization and mucocutaneous candidiasis.

Etiology and Pathogenesis

Responsible for 50%–60% of all candidal infections, C. albicans is the most common candidal pathogen identified.8 C. albicans has its own virulence factors including adhesion molecules that permit attachment of the organism to other structures, proteinase secretions [aspartyl proteinases (SAP1-9)] that facilitate damage to cell envelopes, as well as the ability to convert to the hyphal form which is thought to be important for the virulence of C. albicans.9

The relative prevalence of C. albicans in clinical isolates is declining, and other species such as Candida glabrata, Candida parapsilosis,1,10 Candida tropicalis, Candida krusei,1,11 and Candida dubliniensis12 are increasingly being encountered as pathogens.13 C. glabrata and C. albicans account for approximately 70%–80% of Candida species recovered from patients with candidemia or invasive candidiasis. Other species of Candida have gained importance because of their frequent intrinsic resistance to systemic antifungal therapy. Certain patient populations are more susceptible to specific Candida species: the presence of C. parapsilosis should be considered in hospitalized patients and those with vascular catheters or prosthetic devices, while Candida tropicalis has been observed to cause candidemia in patients with leukemia and in those who have undergone bone marrow transplantation.

Clinical Manifestations

The mucocutaneous manifestations of candidiasis are represented by several distinct clinical syndromes.

Oral Candidiasis

Acute pseudomembranous candidiasis or thrush is the most common form of oral candidiasis. Predisposing factors include diabetes mellitus, systemic steroid and antibiotic use, pernicious anemia, malignancy, radiation to head and neck, and cell-mediated immunodeficiency2,15–16 (Table 189-1). Thrush appears as discrete white patches that may become confluent on the buccal mucosa, tongue, palate, and gingivae (Fig. 189-1A). This friable pseudomembrane resembles cottage cheese or milk curds and consists of desquamated epithelial cells, fungal elements, inflammatory cells, fibrin, and food debris (Figs. 189-1A–189-1C). Scraping the patches exposes a brightly erythematous surface underneath. Microscopic examination of this material reveals masses of tangled pseudohyphae and blastospores (Fig. 189-2). In severe cases, the mucosal surface may ulcerate.

Acute atrophic candidiasis (erythematous candidiasis), which occurs after sloughing of the thrush pseudomembrane,15 is observed most often in the setting of broad-spectrum antibiotic or systemic glucocorticoid therapy and human immunodeficiency virus infection.2 The most common location is on the dorsal surface of the tongue, where depapillated atrophic patches with minimal pseudomembrane formation are noted. There are both asymptomatic and symptomatic variants, the latter characterized by burning or pain.17

Chronic atrophic candidiasis (denture stomatitis) (Fig. 189-1B) is a common form of oral candidiasis seen in 24%–60% of denture wearers,18 and more commonly occurs in women. Chronic erythema and edema of the palatal mucosal surface in contact with the dentures is present. Presumably, the chronic low-grade trauma and occlusion caused by dentures predispose to candidal colonization and subsequent infection.19

Candidal cheilosis (angular cheilitis or perlèche) is characterized by erythema, fissuring, maceration, and soreness at the angles of the mouth (Fig. 189-1C). This condition is commonly encountered in habitual lip lickers and in elderly patients with sagging skin at the oral commissures. Loss of dentition, poorly fitting dentures, malocclusion, and riboflavin deficiency also predispose one to cheilosis. Cheilosis is often associated with chronic atrophic candidiasis in denture wearers.15

The differential diagnosis for oral candidiasis is summarized in Box 189-1.

Vaginal and Vulvovaginal Candidiasis

VC is the second most common cause of vaginitis, and approximately three-fourths of all women will experience an episode of VC in their lifetime. C. albicans causes 80%–90% of VC and is followed by C. glabrata in frequency.20 Risk factors for VC include systemic antibiotic or steroid use, diabetes mellitus, presence of an intrauterine device, wearing of tight-fitting and synthetic clothing, and immunosuppression.21,22 These factors disrupt vaginal flora of lactobacilli that serve to inhibit overgrowth of Candida.20

Recurrent VC, defined as four or more episodes per year, occurs in up to 10% of women.20 Changes in hormone levels during pregnancy and the luteal phase of the menstrual cycle may induce relapses. Use of genital cleansing solutions or douche may elicit a hypersensitivity response and increase susceptibility to Candida. Frequent sexual intercourse, resulting in vaginal abrasions and involving semen allergy, may also predispose women to recurrent VC.23 When none of the above mentioned factors is involved in VC, one should consider use of antibiotics, immunosuppression, or diabetes mellitus as potential contributors.24

Patients with VC present with a vaginal discharge associated with vulvar pruritus, burning, and occasional dysuria or dyspareunia. Examination shows thick curd-like whitish plaques on the vaginal wall with underlying erythema and surrounding edema that may extend to the labia and perineum. The cervix is normal upon speculum examination.25

Balanitis and Balanoposthitis

Candida spp. cause 30%–35% of infectious balanitis. Factors predisposing to candidal balanitis include diabetes mellitus, an uncircumcised state, and candidal vaginal infection in sexual partners. Occasionally, patients with balanitis complain of transient erythema and burning occurring shortly after intercourse. The eruption involving the penis is pruritic. Physical findings include white patches on the glans or prepuce. Small papules or fragile vesiculopustules on the glans or along the coronal sulcus (Fig. 189-3) break to leave erythematous erosions with a collarette of whitish scale. Infection may spread to the scrotum, gluteal folds, buttocks, and thighs. In diabetic or immunosuppressed patients, a severe edematous, ulcerative balanitis may occur.

Intertrigo

C. albicans has a predilection for colonizing skin folds, intertriginous zones in which the local environment is moist and warm. Usual locations for candidal intertrigo include the genitocrural, gluteal, interdigital, inframammary (Fig. 189-4) areas, and beneath the pannus and axillary areas. Predisposing conditions include obesity, diabetes mellitus, wearing of occlusive clothing and occupational factors.26 The pruritic eruption appears as macerated red erythematous patches and thin plaques with satellite vesiculopustules. These pustules enlarge and rupture, leaving an erythematous base with a collarette of easily detachable scale that contributes to further maceration and fissuring. Cutaneous candidal infection is diagnosed by the typical appearance of the eruption and confirmed by KOH examination and, when necessary, culture. See Box 189-2 for the differential diagnosis of intertriginous candidiasis.

Several clinical variants of Candida intertrigo deserve special mention. Candidal diaper dermatitis results from yeast colonization of the gastrointestinal tract and chronic occlusion with wet diapers. The eruption with pronounced red erythema first appears in the perianal region and spreads to the perineum and inguinal creases (Fig. 189-4C).27 Erosio interdigitalis blastomycetica refers to interdigital candidal or polymicrobial infection of the hands or feet, usually affects the third or fourth interdigital space, where moisture trapping is thought to underlie the condition (Fig. 189-4D). Candida miliaria affects the back in bedridden patients. The eruption begins as isolated vesiculopustules containing yeast, which spread over occluded regions on the back. Candida also colonizes and infects skin around wounds covered with occlusive dressings (Fig. 189-5). Broad-spectrum topical antibiotics contribute to these Candida wound infections.28

Generalized Cutaneous Candidiasis

This is an unusual form of cutaneous candidiasis that manifests as a diffuse eruption beginning as individual vesicles and spreading into confluent areas involving the trunk, thorax, and extremities. The associated generalized pruritus is increased in severity in the genitocrural folds, anal region, axillae, and hands and feet (Fig 189-6).

Candida Folliculitis

Superficial infection involving the infundibulum of hair follicles occurs also in the predisposed patient, most commonly in the setting of diabetes mellitus or immunocompromised states. KOH examination of the contents of follicular pustules distinguishes this condition from bacterial folliculitis.

Candidal Paronychia and Onychomycosis

Candidal infection of the nails and paronychial folds occurs most often in those with diabetes mellitus or who habitually immerse their hands in water (i.e., housekeepers, bakers, fishermen, and bartenders). In paronychia, there is initial redness, swelling and tenderness of the proximal and lateral nailfolds with retraction of the cuticle toward the proximal nail fold (Fig. 189-7). Pain and erythema may extend along the entire nail plate and nail bed.29,30 Candidal paronychia should be differentiated from acute bacterial paronychia or paronychia associated with hypoparathyroidism, celiac disease, acrodermatitis enteropathica (Chapter 130), reactive arthritis syndrome (Chapter 20), acrokeratosis paraneoplastica, and retinoid therapy. Candidal onychomycosis is associated with secondary nail thickening, ridging, whitish discoloration, and occasional nail loss.

Chronic mucocutaneous candidiasis (CMC) is characterized by chronic, treatment-resistant, superficial candidal infections of the skin, hair, nails, and mucous membranes. There is virtually no propensity for disseminated visceral candidiasis.

CMC is frequently associated with endocrinopathies including hypoparathyroidism, hypoadrenalism, and hypothyroidism, as well as conditions associated with specific abnormalities in cell-mediated immunity, such combined immune deficiency syndrome, DiGeorge syndrome, or patients with severely impaired T-cell function (i.e., AIDS). CMC first appearing in adulthood is often associated with thymoma.31 There are several more or less distinct clinical syndromes of CMC (Table 189-2)32–34 in which candidal infections cause oral thrush, diaper dermatitis, angular cheilitis (perlèche), lip fissures, nail and paronychial involvement, vulvovaginitis, and cutaneous involvement. The cutaneous eruption may appear with an erythematous, serpiginous border, or areas of brownish desquamation on a background of mild erythema (Fig. 189-8). Nail involvement is characterized by markedly thickened and dystrophic nail plates in which the entire thickness is invaded by Candida. The paronychial folds are red and edematous, there may be pus, and the fingertips are often bulbous (Fig. 189-7B).

The incidence of disseminated candidiasis is steadily rising as the prevalence of immunosuppressed patients with longer life spans has also increased. The responsible organisms, C. albicans, C. tropicalis, C. glabrata, and C. parapsilosis,35 gain hematogenous access from the oropharynx or gastrointestinal tract when mucosal barrier function is compromised (e.g., by mucositis secondary to chemotherapy), or when intravenous catheters become contaminated. Multiple organ systems including gastrointestinal and respiratory may become involved.36 Recognition of a candidal eruption in the context of disseminated infection may be important to early diagnosis, as ante-mortem blood cultures are negative in a high percentage of patients with autopsy-proven systemic candidiasis.36 Approximately 10% of patients with disseminated candidiasis develop metastatic 0.5–1.0-cm nontender erythematous papules with a hemorrhagic or pustular center (Fig. 189-9) over the trunk and extremities associated with fever and myalgias.37 Some papules may be necrotic in appearance. The differential diagnosis for disseminated candidiasis is provided in Box 189-3.

Laboratory Findings

Direct microscopic examination of specimens for the presence of yeast or isolation of yeast in culture confirms infection. In superficial candidal infections, the diagnosis can be confirmed by microscopic examination skin scrapings or smears obtained from skin, nails, or mucosal surfaces that reveal hyphae, pseudohyphae, or budding yeast cells (Fig. 189-2). Potassium hydroxide smear, or Gram or methylene blue stain is useful for direct demonstration of fungal cells. Cultures from affected nails may help identify the etiologic agent responsible for onychomycosis (dermatophyte vs. yeast). C. albicans readily produce whitish mucoid colonies within 2–5 days on Sabouraud's agar with added antibiotics.

In systemic candidiasis associated with an eruption, the diagnosis may be confirmed from histopathologic examination and tissue culture of lesional skin. Blood cultures are positive in only 50%–60% of cases of disseminated infection.35 Serologic studies using immunodiffusion, counterimmunoelectrophoresis, and latex agglutination methods are fraught with false-negative and false-positive reactions which limit their utility in confirming diagnosis. Newer techniques to detect circulating candidal antigens (e.g., mannan or enolase) or metabolic products (e.g., arabinitol) show improved sensitivities and specificities in serial testing.38 Specifically, the serum (1,3)β-D-glucan detection assay (Glucatell, Fungitell) is a nonculture assay that measures level of β-glucan, a component of the fungal cell wall. In a large multicenter study, the assay yielded high sensitivity (75%–100%), specificity (88%–100%) and positive predictive value with highly reproducible results.39

Microscopic Studies

Since Candida sp. may infect virtually any organ system, specimens for laboratory examination will vary from body fluids to tissue samples. Direct microscopic examination of scrapings from mucosa, skin or nails for the presence of yeast provides bedside evidence to support the clinical diagnosis. Body fluids such as urine and cerebrospinal fluid should be centrifuged and the sediment examined directly to increase the probability of detecting yeast. Specimens must be treated with a clearing agent such as 10% KOH and ink before the material is examined. Candida appears as oval budding cells, elongated filamentous cells connected end-to-end (pseudohyphae), or septate hyphae (Fig. 189-2).

Pathology

Superficial candidiasis is characterized by subcorneal pustules on histopathological examination. Organisms are seldom seen within the pustules but rather are highlighted in the stratum corneum with periodic acid-Schiff (PAS) staining. Examination of a candidal granuloma shows marked papillomatosis and hyperkeratosis and a dense dermal infiltrate consisting of lymphocytes, granulocytes, plasma cells, and multinucleated giant cells. In systemic candidiasis with skin involvement, foci of yeast are observed in the dermis and within dermal vessels. Organisms are identified using PAS, methenamine silver, or methylene blue stains.

Treatment

Treatments used to manage Candida infections may vary based on species of Candida responsible for infection, sensitivity to specific antifungal drugs, anatomic location of infection, underlying disease, and immune status of the patient.

Guidelines in the management of candidiasis were updated in 2009 by the Infectious Disease Society of America.40 These guidelines include recommendations on the appropriate use of echinocandins, caspofungin, micafungin, and anidulafungin, along with voriconazole and posaconazole, as well as lipid formulations of amphotericin B. Fluconazole is still considered a first-line agent in nonneutropenic patients with candidemia or suspected to have invasive candidiasis. Therapeutic options in the management of invasive candidiasis and candidemia include triazoles as well as newer agents such as echinocandins.41,42 A brief discussion on the treatment of candidal infections is included herein. For a detailed review on current therapeutic strategies, please refer to Chapter 232.

Oral Candidiasis

Uncomplicated oral candidiasis may be treated with nystatin suspension 400,000–600,000 units four times per day, or clotrimazole troches 10 mg dissolved in the mouth five times per day. For recurrent cases, oral azoles (see Chapter 232) are proven to be more effective.

Candidal Vulvovaginitis and Balanitis

Two therapeutic approaches exist when considering treatment for candidal vaginitis. Topical imidazole preparations available over the counter, such as butoconazole, miconazole, and clotrimazole, as well as those available by prescription, including tioconazole, econazole, and terconazole are easy to use and effective over 3–7 days of treatment.24 These agents are also safe to use during pregnancy.43 Oral fluconazole, itraconazole, and ketoconazole offer efficacy similar to that of topical therapy (see Chapter 219). Prophylactic regimens to prevent recurrences include weekly clotrimazole 500-mg tablet used intravaginally or fluconazole 150 mg/week orally.24 The recommended treatment for candidal balanitis is topical clotrimazole cream or a single oral 150-mg dose of fluconazole.

Cutaneous

Candidal intertrigo has been treated successfully with topical antifungals (e.g., clotrimazole, econazole, ciclopirox, miconazole, ketoconazole, and nystatin). Powder preparations also keep dry otherwise moist environments that facilitate candidal infections. Systemic antifungal therapy is recommended for extensive cutaneous infections, follicular involvement, or infections in immunocompromised patients.

Candidal Paronychia

Chronic paronychia due to Candida is often resistant to therapy. The most important aspects of therapy include minimizing contributing factors such as water exposures, as well as drainage of any abscess. Topical imidazole in solution form should be considered initially.26 Four percent thymol in ethyl alcohol (compounded by the pharmacy, as it is not commercially available) is drying to candida, and thus may be a suitable alternative. Oral azoles may also be used in otherwise refractory cases.29

Candidal Onychomycosis

Oral itraconazole or fluconazole (triazoles) appear to be most efficacious for candidal onychomycosis. Two treatment regimens are available: the daily dose or pulsed-dose regimen. Itraconazole, which is approved for use for onychomycosis in the United States, may be administered at 200 mg daily for 6 weeks for fingernails and for 12 weeks for toenails. It may also be administered in pulse therapy, 200 mg twice daily for 1 week per month, for a total of two pulses for fingernails and three pulses for toenails.44

Disseminated Candidiasis

Amphotericin B, available in newer lipid-based formulations, as well as caspofungin are effective in treating disseminated candidiasis (see Chapter 232).45

Chronic Mucocutaneous Candidiasis

Oral azoles are first line agents in the treatment of CMC. Regimens include fluconazole 100–400 mg/d or itraconazole 200–600 mg/d used until there is clinical improvement. Initial therapy for acute infection should always be followed by maintenance therapy with the same azole for life.

The genus Malassezia, formerly known as Pityrosporum, currently includes twelve species of lipophilic basidiomycetous yeast: Malassezia furfur, Malassezia pachydermatis, Malassezia sympodialis, Malassezia globosa, Malassezia restricta, Malassezia slooffiae, Malassezia obtusa, Malassezia dermatitis, Malassezia nana,46 Malassezia yamatoensis,47 Malassezia japonica,48 and Malassezia equi.49,50 In 1996, a new taxonomic classification 51 based specifically on morphologic, physiologic and ultrastructural features detected by molecular techniques allowed for the addition of several new species to the Malassezia genus.

The species of Malassezia may be differentiated by their nutritional requirements, morphology, and molecular biology.49,51 All Malassezia species require lipids for growth, because with the exception of M. pachydermatis which has the ability to produce phospholipase, they do not synthesize C14–C16 saturated fatty acids.52 Although previously recognized as a zoophilic organism, M. pachydermatis has been identified only recently as a human pathogen. In one study, the organism caused a series of infections in a neonatal care nursery, where M. pachydermatis was presumably spread to patients from health care workers whose pet dogs were colonized with the fungus.53 It was later shown that the vast majority of dog owners tested positive for M. pachydermatis on their hands.54 Other members of the genus, including M. sympodialis and M. slooffiae, are part of the normal skin flora.55 A few studies also linked M. sympodialis with neonatal cephalic pustulosis, also known as neonatal acne.56,57

Cutaneous infections with Malassezia take two main primary forms: (1) pityriasis versicolor and (2) pityrosporum folliculitis. However, Malassezia may also play some role in the course of other common skin diseases such as seborrheic dermatitis, atopic dermatitis, and psoriasis.49,58

Tinea (Pityriasis) Versicolor

Epidemiology

The prevalence of tinea versicolor in the United States is estimated to be 2%–8% of the population. The infection occurs more frequently in regions with higher temperatures and relative humidity. Tinea versicolor has a worldwide prevalence of up to 50% in the hot and humid environments and as low as 1.1% in colder climates.

Incidence of tinea versicolor is the same in all races, but the eruption is often more apparent in darker-skinned individuals due to resulting alteration in skin pigmentation. No sex predominance is apparent. Tinea versicolor is most common among adolescents and young adults, in whom lipid-producing sebaceous glands are more active.

Etiology and Pathogenesis

M. furfur can be cultured from both affected and normal skin and is considered part of the normal flora, particularly in sebum-rich areas of the body.59 Experimental inoculation of Malassezia under occlusion has resulted in infection.59 The resulting increase in humidity, temperature and CO2 tension appear to be important factors contributing to infection.60 While removal of occlusion promotes healing of the eruption, the organism may still be cultured from clinically uninvolved areas.60 Furthermore, this colonization of follicular structures facilitates a high recurrence rate.

M. furfur is a dimorphic, lipophilic organism that grows in vitro only with the addition of C12–C14 fatty acids such as olive oil and lanolin. Under appropriate conditions, it converts from the saprophytic yeast to the predominantly parasitic mycelial form, which causes clinical disease. Factors predisposing to mycelial transition include a warm, humid environment, hyperhidrosis, oral contraceptive, and systemic corticosteroid use, Cushing's disease, immunosuppression, and a malnourished state.59,61

The yeast may filter natural sunlight and interfere with normal tanning.62 Mayser et al discussed a specific compound synthesized by Malassezia called pityriacitrin that absorbs ultraviolet light.63 Other metabolites of M. furfur are listed on Box 189-4. Specifically, via lipases Malassezia metabolizes various fatty acids such as arachidonic or vaccenic acids and subsequently releases azelaic acid as one of the metabolites. Azelaic acid inhibits the action of the tyrosinase in the melanin production pathway, which results in persistent hypopigmentation of affected skin for months, and sometimes years.64 This hypopigmentation may be accentuated further in summer months if surrounding unaffected skin becomes tan.

While M. furfur had long been identified as the fungus causing tinea versicolor, M. globosa is now thought to be the predominant species involved in its pathogenesis.65

Clinical Findings

The typical presentation of tinea versicolor is scaly oval to round macules scattered over characteristic areas of the body, including the upper trunk, neck, and upper arms (Fig. 189-10). The macules often coalesce forming irregular shaped patches of pigmentary alteration. The color of patches varies from almost white to pink to reddish brown or fawn colored (Fig. 189-10C). The scale is characteristically described as dust-like or furfuraceous (Fig. 189-10D). Extensive scaling can be produced by lightly scraping a #15 scalpel blade over the involved skin.66 Patches may have a wrinkled surface appearance (Fig. 189-11) and this feature serves as a useful clinical pearl for the diagnosis. The presenting concern often relates to the cosmetic appearance of the eruption rather than any symptoms, since pruritus is usually mild or absent. The diagnosis made on clinical grounds is supported by Wood's light (365 nm) examination which may show yellow–orange fluorescence thought to be due to the presence of pteridine and is confirmed by microscopic KOH examination of the scale. Tinea versicolor tends to recur in warmer months of the year.

An inverse form of tinea versicolor is encountered predominantly in flexural areas.67 These sharply demarcated confluent pink erythematous patches may be confused with inverse psoriasis, seborrheic dermatitis, erythrasma, candidiasis, and dermatophytic infections. The differential diagnosis of tinea versicolor is presented in Box 189-5.

Laboratory Tests

Potassium hydroxide (KOH) preparation of skin scrapings demonstrates the characteristic fungal spores and short cigar-butt hyphae (“spaghetti and meatballs”). Visualization of fungal elements may be enhanced by the addition of methylene blue stain to the KOH preparation. Culture is rarely necessary and requires a lipid-containing medium (i.e., olive oil) to demonstrate growth.

Pathology

While the yeast may be identified with hematoxylin and eosin staining alone, visualization is enhanced through PAS stain. Microscopic examination reveals clusters of oval budding yeast cells 3.5 × 4.5 μm long with short, septate, and occasionally branching hyphae (Fig. 189-12) inhabiting the stratum corneum.

Diagnosis

The clinical appearance of tinea versicolor is usually characteristic, and KOH examination is confirmatory. A Wood's lamp examination may show orange–yellowish fluorescence of involved skin, suspected to be a due to pteridine. In some cases, however, the eruption may appear darker, rather than more fluorescent, than unaffected skin under the Wood's light.

Treatment

Tinea Versicolor

Several topical agents are useful in treating tinea versicolor, and these include selenium sulfide, zinc pyrithione, sodium sulfacetamide,68 ciclopiroxolamine,69 as well as azole70 and allylamine antifungal preparations.

A widely used and inexpensive protocol involves using selenium sulfide lotion 2.5%, which is applied liberally to affected areas for 7–10 minutes prior to rinsing. While daily use may be considered for extensive cases, application 3–4 times per week is adequate, and this frequency may be tapered further to once or twice monthly and used as a maintenance regimen to prevent recurrences. Alternatively, ketoconazole shampoo 2% is lathered on to affected areas and left for 5 minutes prior to rinsing; this treatment is repeated for three consecutive days.71 Terbinafine solution 1% applied twice daily to affected areas for 7 days has yielded cure rates of more than 80%.72

Although topical therapy is ideal for localized or mild infections, systemic treatment may be necessary for patients with extensive disease, frequent recurrences, or for whom topical agents have failed.73 Ketoconazole, fluconazole, and itraconazole are the preferred oral agents, and various dosing regimens are effective.74 Oral ketoconazole 200 mg daily for 7 or 10 days, or oral itraconazole 200–400 mg daily for 3–7 days is almost universally effective.75–76 Oral ketoconazole administered as a single 400 mg dose is an easy to use regimen with comparable results.75 Similarly, a single dose of oral itraconazole 400 mg has been shown to be more than 75% effective, and in one study, just as effective as itraconazole given for 1 week.77 Fluconazole is also effective when administered as a single oral dose of 400 mg.78 Oral terbinafine, an allylamine, is not recommended in the treatment of Malassezia related disorders, since the drug is not delivered efficiently to the skin's surface. The potential for drug toxicity and interactions via the influence of azoles on cytochrome p450 isoenzyme activity should be addressed when considering the use of oral azole agents to treat tinea versicolor.79

Prevention

Recurrence is common and regular maintenance application of any of the topical agents helps to reduce high rates of recurrence. While the condition does not leave any permanent scar or pigmentary changes, skin tone may take several months to return to normal. Prevention of recurrences is helpful in limiting long-lasting dyschromia. A regimen of one tablet a month of ketoconazole, fluconazole, and itraconazole has been used successfully to prevent recurrences.80

Pityrosporum (Malassezia) Folliculitis

Epidemiology

Malassezia organisms are observed as skin flora in 75%–98% of healthy people. Colonization by M. furfur begins soon after birth and peaks during adolescence and young adulthood, concomitant with an increase in sebaceous gland activity. No known racial or gender differences exist. Those living in warm and humid climates have higher incidences of Malassezia folliculitis.81

Etiology and Pathogenesis

Malassezia yeasts are classified as superficial mycoses that by definition do not invade past the cornified epithelium. However, in Pityrosporum folliculitis, follicular ostia, and central and deep segments of the hair follicle are involved by Malassezia, most commonly M furfur.82

Clinical Features

The chronic pruritic eruption of Malassezia (Pityrosporum) folliculitis appears as numerous monomorphic 2–4 mm follicular papules and papulopustules with perifollicular erythema on the upper trunk, neck, and upper arms of young and middle-aged adults (Fig. 189-13A). Some may have concomitant seborrheic dermatitis or tinea versicolor, and there have also been cases of associated recalcitrant acne vulgaris.83 KOH examination or culture may be required to distinguish this infection from the more common bacterial folliculitis. On occasion, histologic evaluation via skin biopsy may be necessary for diagnosis. Routine staining with hematoxylin and eosin may identify organisms, although Malassezia may be more easily visualized through PAS stain (Fig. 189-13B). Systemic diseases and pharmacologic agents that hasten growth of yeast, possibly through alterations in host immunity, facilitate infections of hair follicles. Some of these risk factors include pregnancy, diabetes mellitus, Hodgkin disease,84 cancer treated with epidermal growth factor receptor inhibitors,85 HIV infection, and therapy with oral antibiotics, corticosteroids and/or immunosuppressants. Other contributing factors include high heat and humidity and occlusion of the skin and hair follicles with cosmetics, lotions, sunscreens, emollients, olive oil, or clothing.86 As in the case of pityriasis versicolor, recurrence of Malassezia folliculitis is common. See Box 189-6 for the differential diagnosis of Malassezia folliculitis.

Laboratory Findings

To identify the Malassezia yeast forms, scale from involved skin should be scraped with a #15 scalpel blade onto a glass slide and treated with 10% KOH. Alternatively, cellophane tape used to pick up scales from the skin may be mounted on a glass slide with methylene blue that selectively stains the organisms.87 The microscopic appearance of the yeast is classically described as “spaghetti and meatballs” (Fig. 189-12), with fungal spores and short cigar-butt pseudohyphae.

Pathology

Malassezia organisms are noted in dilated follicular units, which may show keratin plugging and cellular debris (Fig. 189-10B). Staining with PAS or methenamine silver will reveal the oval single-budding yeast. When follicular walls rupture, there is a resulting mixed inflammatory infiltrate of lymphocytes, histiocytes, and neutrophils surrounding follicles. Microscopic examination of pustules usually shows budding yeast forms and spores, not hyphae.

Diagnosis

Diagnosis of Malassezia folliculitis is made on clinical grounds, and confirmed by KOH examination of scrapings. Skin biopsy is rarely necessary to make the diagnosis.

Treatment and Prognosis

Malassezia Folliculitis

Both topical and oral antifungal agents are effective agents in the treatment of Malassezia folliculitis and are commonly combined to hasten resolution and maintain clearance. Topical regimens include daily use of ketoconazole shampoo 2%, selenium sulfide lotion 2.5%, and ciclopirox olamine cream 0.77%. There are limited data on the use of systemic agents in treating Malassezia folliculitis. Commonly used regimens include oral ketoconazole 200 mg daily for 4 weeks, fluconazole 150 mg weekly for 2–4 weeks, and itraconazole 200 mg daily for 2 weeks.49,87 Oral terbinafine is not recommended in the treatment of Malassezia related disorders, since the drug is not delivered efficiently to the skin's surface.

Prevention

Recurrence is common. Because relapses almost always occur after treatment is complete, topical agents are continued indefinitely at reduced frequency as a preventative measure. Topical protocols used in the prevention of Malassezia folliculitis include selenium sulfide 2.5% lotion once weekly, ketoconazole 2% cream once weekly, and ketoconazole 2% shampoo 2–3 times weekly. Maintenance therapies with systemic agents include oral itraconazole 400 mg once monthly and oral fluconazole 200 mg once monthly.