Chapter 45: The Superficial and Subcutaneous Fungi: Dermatophytes, Malassezia, Sporothrix, and Pigmented Molds

The least invasive of the pathogenic fungi are the dermatophytes and other superficial fungi that are adapted to the keratinized outer layers of the skin. The subcutaneous fungi go a step farther by extending infection to the tissue beneath the skin but rarely invading deeper structures (Table 45–1).

Dermatophytes

Dermatophytoses are superficial infections of the skin and its appendages. Common names for these infections include ringworm (Figure 45–1), athlete’s foot, and jock itch. They are caused by species of three genera collectively known as dermatophytes. These fungi are highly adapted to the nonliving, keratinized tissues of nails, hair, and the stratum corneum of the skin. The source of infection may be humans, animals, or the soil.

MYCOLOGY

The three genera of medically important dermatophytes (literally, skin-plants) are Epidermophyton, Microsporum, and Trichophyton (Table 45–1). Most dermatophyte infections are diagnosed and treated as a clinical syndrome since determining the causative species will not usually affect therapeutic choices. These fungi require a few days to a few weeks to grow in culture, and they are typically isolated at 25°C on Sabouraud’s agar. The dermatophyte hyphae are septate, and their conidia may be borne directly on the hyphae or on conidiophores. Small microconidia may or may not be formed; however, the larger and more distinctive macroconidia are usually the basis for identification.

DERMATOPHYTE DISEASE

EPIDEMIOLOGY

Some dermatophyte species are primarily adapted to grow on the skin of humans (anthropophilic), others to animals (zoophilic), and various others to the environment (geophilic). Although these are their preferred habitats, all of the species discussed here may infect humans from these primary sources. Many wild and domestic animals, including dogs and cats, are infected with certain dermatophyte species and represent a large reservoir for infection of humans. Dermatophyte infections tend to occur more frequently in tropical climates as opposed to more temperate regions. However, many of these differences are changing with shifts in population, as well as altered interactions with animals and environmental sources of infection.

Transmission can occur after close contact with an infected person or animal. However, exposure to detached skin scales or hair containing the fungal elements (fomites) may also result in new infections. Many places for common dermatophyte transmission have been described, including locker rooms floors, barber shops, hotel carpets, and movie theater/airplane seats. Health-care workers do no need to take special precautions beyond handwashing after contact with an infected patient.

PATHOGENESIS

Dermatophytoses begin when the infecting fungus comes in contact with skin, especially if there are minor breaks in the skin integrity. Detached hair and skin scales containing dermatophytes can remain infectious for months in the environment. Once the stratum corneum is penetrated, the organism can proliferate in the keratinized layers of the skin, with a variety of proteinases helping to establish infection. Another class of proteins (LysM) suggested by genomic studies may bind to fungal cell wall components and mask them from the host immune response. The course of the infection depends on many factors: the anatomic location, the degree of skin moisture, the dynamics of skin growth and desquamation, the speed and extent of the inflammatory response, and the infecting species. For example, if the organism grows very slowly in the stratum corneum and if skin turnover by desquamation is rapid, the infection will probably be short-lived and cause minimal signs and symptoms. Inflammation tends to increase desquamation rates and helps to limit infection, whereas immunosuppressive agents such as topical corticosteroids decrease shedding of the keratinized layers and tend to prolong infection. Invasion of any deeper structures is extremely rare.

Most dermatophyte infections are self-limited, spontaneously resolving with time. However, those infections in which fungal growth rates and skin desquamation are balanced, and in which the inflammatory response is poor, tend to become chronic. The lateral spread of infection and its associated inflammation produce the characteristic sharp advancing margins that were once believed to be the burrows of worms. This characteristic is the origin of the common English name ringworm, as well as the Latin term tinea (worm), which is often applied to the clinical forms of the disease (Figure 45–1).

Infection may spread from skin to other keratinized structures, such as hair and nails, or may invade them primarily. The hair shaft is penetrated by hyphae (Figure 45–2), which extend either exclusively within the shaft (endothrix) or both within and outside the shaft (ectothrix). The end result is damage to the hair shaft structure, which often breaks off. Loss of hair at the root and plugging of the hair follicle with fungal elements may result. Invasion of the nail plate causes a hyperkeratotic reaction, which dislodges or distorts the nail (onychomycosis).

IMMUNITY

Most dermatophyte infections pass through an inflammatory stage to spontaneous healing. Phagocytes are able to use oxidative pathways to kill the fungi intracellularly and extracellularly. Little is known about the factors that mediate the host response in these self-limiting infections or whether they confer immunity to subsequent exposures. Antibodies may be formed during infection but play no known role in immunity. As with many other fungal infections, most evidence points to the importance of T-cell–mediated T_H1 responses in controlling dermatophytoses.

Occasionally, dermatophyte infections become chronic and widespread. This progression has been related to host and organism factors. Approximately half of these patients have underlying diseases affecting their immune responses or are receiving treatments that compromise T-lymphocyte function. These chronic infections are particularly associated with Trichophyton rubrum, to which both normal and immunocompromised persons appear to be hyporesponsive. Interestingly, the clinical manifestations of these infections are largely due to delayed-type hypersensitivity responses to these agents rather than from direct effects of the fungus on the host.

DERMATOPHYTOSES: CLINICAL ASPECTS

MANIFESTATIONS

Dermatophyte infections range from inapparent colonization to chronic progressive eruptions that last months or years, causing considerable discomfort and disfiguration. Dermatologists often give each infection its own “disease” name based on the Latin name for the anatomic site at which the infection is found. For example, these names include tinea capitis (scalp; Figure 45–3A), tinea pedis (feet, athlete’s foot), tinea manuum (hands), tinea cruris (groin), tinea barbae (beard, hair), and tinea unguium (nail beds). Skin infections otherwise not included in this anatomic list are called tinea corporis (body). There are certain clinical, etiologic, and epidemiologic differences among these syndromes, but they are basically the same disease in different locations. The primary differences among etiologic agents that infect different sites are shown in Table 45–1.

Tinea capitis. Infection of hair and scalp begins with an erythematous papule around the hair shaft, which progresses to scaling of the scalp, and discoloration/fracture of the shaft. Spread to adjacent hair follicles progresses in a ring-like fashion, leaving behind broken, discolored hairs, and sometimes black dots where the hair is absent but the infection has invaded the follicle. The degree of inflammatory response markedly affects the clinical appearance and, in some cases, can cause constitutional symptoms. In most cases, symptoms beyond itching are minimal.

Other sites. Skin lesions on other parts of the body begin in a similar manner and enlarge to form sharply delineated erythematous patches with central clearing (nearly normal skin appearance in the center). Multiple lesions can fuse to form unusual geometric patterns on the skin. Lesions may appear in any location, but they are particularly common in moist, sweaty skin folds. Obesity and the wearing of tight apparel increase susceptibility to infection in the groin and beneath the breasts. Another form of infection, which involves scaling and splitting of the skin between the toes, is commonly known as athlete’s foot. Excessive moisture and maceration of the skin provide the mode of entry.

Nail bed infections first cause discoloration of the subungual tissue, followed by hyperkeratosis and discoloration of the nail plate. Progression of infection causes disfigurement of the nail but few symptoms until the nail plate is so dislodged or distorted that it exposes or compresses adjacent soft tissue. All dermatophyte infections provide a potential site of entry for skin bacteria, predisposing to more acute and painful lesions around the nail, or to more extensive bacterial cellulitis.

DIAGNOSIS

The goal of diagnostic procedures is to distinguish dermatophytoses from other causes of skin inflammation. Infections caused by bacteria, other fungi, and noninfectious disorders (eg, psoriasis and contact dermatitis) may have similar features. The most important step is microscopic examination of material taken from lesions to detect the fungus. Potassium hydroxide (KOH) or calcofluor white preparations of scales scraped from the advancing edge of a dermatophyte lesion often demonstrate septate hyphae. Examination of infected hairs reveals hyphae and arthroconidia penetrating the hair shaft. Broken hairs give the best yield. Some species of dermatophyte fluoresce when exposed to ultraviolet light, and selection of hairs for examination can be aided by the use of an ultraviolet (Wood’s) lamp (Figure 45–3B).

The same material used for direct examination can be cultured for isolation of the offending dermatophyte (Figure 45–4). Mild infections with typical clinical findings and positive KOH preparations are often not cultured because clinical management is not influenced significantly by the identity of the etiologic species. Suspected dermatophyte infections with negative KOH preparations, especially those that fail to respond to empiric antifungal therapy, often require culture. The major reason for false-negative KOH results, however, is failure to collect the scrapings or hairs properly.

TREATMENT AND PREVENTION

Many local skin infections resolve spontaneously without therapy. Those that do not resolve may be treated with topical terbinafine or azoles (miconazole, ketoconazole). More extensive skin infections, especially those involving the scalp, often require systemic therapy with griseofulvin, itraconazole, or oral terbinafine, often combined with topical therapy. Nail infections are especially difficult to cure, likely due to the slow turnover of the infected nail and poor penetration of antifungal agents. Therapy for nail infections must be continued over weeks to months, and relapses may occur. Keratolytic agents (Whitfield’s ointment) may be useful for reducing the size of hyperkeratotic lesions. Dermatophyte infections can usually be prevented simply by observing general hygiene measures. No specific preventive measures such as vaccines exist.

Other Superficial Mycoses

Pityriasis (tinea) versicolor is a very common superficial fungal infection of the skin. It is characterized by discrete patches of either hypopigmentation or hyperpigmentation, especially on the skin of the torso and upper arms. These lesions are associated with some scaling but minimal induration. Fungi of the genus Malassezia, especially Malassezia furfur, most commonly cause pityriasis versicolor. These fungal species are common components of the skin microbiome, but they are present more abundantly in the setting of clinical infections. In scrapings of infected skin, they appear as clusters of budding yeast cells mixed with hyphae. Malassezia species grow in the yeast form in culture media enriched with lipids.

Tinea nigra, another superficial skin infection, is characterized by brown to black macular lesions, usually on the palms or soles. There is little associated inflammation or scaling, and skin architecture is well-preserved since the infection is confined to the stratum corneum. This feature distinguishes tinea nigra from other pigmented lesions such as melanomas, which tend to change the lines and markings of the skin. This infection is caused by melanized, black-pigmented fungi (“dematiaceous” fungi) such as Hortaea werneckii, commonly found in soil and other environmental sites. Scrapings of the lesion show brown to black–pigmented septate hyphae.

Piedra is an infection of the hair characterized by black or white nodules attached to the hair shaft. White piedra (caused by Trichosporon cutaneum) infects the shaft in a hyphal form that can fragment into component buds. Black piedra (caused by Piedraia hortae) grows as branched hyphae in the hair shaft (Figure 44–2).

SUBCUTANEOUS FUNGI

Many fungal pathogens can produce subcutaneous lesions as part of their disease spectrum. Those considered here are introduced traumatically through the skin, with infection typically limited to subcutaneous tissues, lymphatic vessels, and contiguous tissues. These fungi rarely spread to distant organs. The diseases they cause include sporotrichosis, chromoblastomycosis, and mycetoma. Only sporotrichosis has a single specific etiologic agent, Sporothrix schenckii. Chromoblastomycosis and mycetoma are clinical syndromes with multiple fungal etiologies.

Sporothrix

SPOROTHRIX SCHENCKII

Sporothrix schenckii is a dimorphic fungus that grows as a cigar-shaped, 3- to 5-mm yeast in tissues and in culture at 37°C. The mold, which grows in cultures incubated at 25°C, is presumably the infectious form in nature. The hyphae are thin and septate, producing clusters of conidia at the end of delicate conidiophores. Sporothrix schenckii is able to synthesize melanin which is present in the dark cell walls of the conidia.

SPOROTRICHOSIS

EPIDEMIOLOGY

Sporothrix schenckii is a ubiquitous saprophyte particularly found in hay, moss, soil (including potting soil), and decaying vegetation, as well as the surfaces of various plants. Infection is acquired by traumatic inoculation of the fungus through the skin. The skin of gardeners, farmers, and rural laborers is frequently traumatized by thorns or other material that may be contaminated with conidia of S schenckii. An unusual outbreak of sporotrichosis involving nearly 3000 miners was traced to S schenckii in the timbers used to support mine shafts. A 1988 outbreak covered 15 states and was traced to contaminated sphagnum moss. Zoonotic transmission has also been seen in association with infected cats.

PATHOGENESIS

The conidia and yeast cells of S schenckii are able to bind to extracellular matrix proteins such as fibronectin, laminin, and collagen. Local multiplication of the organism stimulates both acute pyogenic and granulomatous inflammatory reactions. The presence of melanin in the infectious conidia may facilitate survival in the early stages of infection, since it is known to protect against oxidative killing in tissues and macrophages. Proteinases similar to those seen in other fungal pathogens are present, but no connection to virulence has been established. The infection spreads along lymphatic drainage routes and reproduces the original inflammatory lesions at intervals. The organisms are infrequently visualized in biopsies of human lesions.

IMMUNITY

Some studies indicate that exposure to S schenckii is fairly common, and there is a high level of innate immunity protecting from sporotrichosis. The increased frequency and greater severity of disseminated disease in patients with T-cell defects suggests that T_H1 responses are the primary mechanism of acquired immunity. Antibody plays no known role in protection from infection.

SPOROTRICHOSIS: CLINICAL ASPECTS

MANIFESTATIONS

Skin lesions due to S schenckii begin as painless papules developing a few weeks to a few months after inoculation. Its location can usually be explained by occupational exposure; the hand is most often involved. The initial papule enlarges slowly and eventually ulcerates, leaving an open sore. Pustular or firm nodular lesions may appear around the primary site of infection or at other sites along the lymphatic drainage route (Figure 45–5). The spread of infection along lymphatic channels is so characteristic for this infection that lymphangitic progression of any infection is often referred to as having a “sporotrichoid” appearance. Ulcerated lesions can become chronic, and multiple ulcers develop if the disease is untreated. Symptoms are directly related to the local areas of infection, with constitutional signs and symptoms being unusual.

Occasionally, spread occurs by other routes. The bones, eyes, lungs, and central nervous system are susceptible to progressive infection if the organisms reach these organs; such spread, however, occurs in less than 1% of all cases. Primary pulmonary sporotrichosis occurs but is also exceedingly rare.

DIAGNOSIS

Direct microscopic examination for S schenckii is usually unrewarding because there are too few organisms to detect readily with KOH preparations. Even specially stained biopsy samples and serial sections are usually negative, although the presence of a histopathologic structure, the asteroid body, is suggestive. This structure is composed of S schenckii yeast cells surrounded by amorphous eosinophilic “rays.” Definitive diagnosis depends on culture of infected pus or tissue. The organism grows within 2 to 5 days on all media commonly used in medical mycology. Identification requires demonstration of the typical conidia and of dimorphism.

TREATMENT AND PREVENTION

Historically, cutaneous sporotrichosis was treated with a saturated solution of potassium iodide (SSKI) administered orally. Itraconazole is now preferred for all forms of disease, with oral terbinafine and SSKI as alternatives. Pulmonary and systemic infections may require the additional use of amphotericin B. Eradication of the environmental reservoir of S schenckii is not usually practical, although the mine outbreak mentioned previously was stopped by applying antifungal agents to the mine shaft timbers.

Chromoblastomycosis is a chronic form of skin infection caused by multiple species of pigmented saprophytic fungi, also known as melanized or “dematiaceous” fungi. Disease caused by Fonsecaea, Phialophora, and Cladophialophora (Cladosporium) species typically occurs on the foot or leg, the sites of skin inoculation by the fungus. Primary lesions appear as papules that develop into scaly, wart-like structures, usually under the feet. Fully developed lesions have been likened to the tips of a cauliflower. Extension occurs through painless, slowly progressive satellite lesions. The organisms are found in the soil of endemic areas, and most infections occur in individuals who work barefoot. Disseminated infections due to the dematiaceous molds are uncommon, observed almost exclusively in highly immunocompromised patients. In fact, in these patients certain pigmented molds have a predilection for infecting the central nervous system. Therefore, in highly immunocompromised patients, the isolation of a pigmented mold from a clinical specimen cannot necessarily be ignored as a contaminant.

The outstanding mycologic feature in chromoblastomycosis is the presence in histological sections of brown-pigmented, thick-walled, multiseptate, 5 to 12 mm globose structures called muriform bodies. Branching septate hyphae may also be demonstrated in KOH preparations of tissue scrapings. In culture, these fungi grow as darkly pigmented molds. Surgery and antifungal therapy have been used in chromoblastomycosis, but cure rates of advanced disease are disappointing. Flucytosine or itraconazole are the systemic antifungal agents most frequently used for this infection.

Mycetoma is the clinical term for a chronic, disfiguring infection associated with prior trauma to the foot. Varied microorganisms cause this infection, with more than a dozen fungi described as potential etiologies. Bacterial actinomycetes such as Nocardia (see Chapter 28) may produce a similar disease. The typical clinical appearance of mycetoma is that of massive induration with draining sinuses. Some of the fungi that cause mycetoma are geographically widespread; most cases, however, occur in the tropics, probably because of the chronically damp, macerated skin of the feet among those who go barefoot in tropical environments. An illustrative case of mycetoma occurred in a college rower in Seattle; he was the only member of his shell who insisted on rowing barefoot.

Once infection is established, treatment of mycetoma is difficult, often requiring combined surgical and antimicrobial therapy depending on the causative microbe. Mycetomas caused by environmental molds may demonstrate hyphae in biopsied tissue. However, these fungal elements may be difficult to demonstrate because of a tendency to form microcolony granules. The definitive diagnosis of the etiological agent often requires culture of infected tissue.