Chapter 45: Dermatophytes, Sporothrix, and Other Superficial and Subcutaneous Fungi

The least invasive of 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 to the tissue beneath the skin but rarely invade deeper. Both are discussed here and summarized in Table 45–1.

Dermatophytes

Dermatophytoses are superficial infections of the skin and its appendages, commonly known as 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. They are separated primarily by the morphology of their macroconidia and the presence of microconidia. Many species cause dermatophyte infections; the most common of these are listed in Table 45–1. They require a few days to a week or more to initiate growth. Most grow best at 25°C on Sabouraud's agar, which is usually used for culture. Although teleomorphic (sexual) forms have been discovered, the medically important dermatophytes continue to be identified in their more familiar anamorphic (asexual) state. The 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

There are ecologic as well as geographic differences in the occurrence of various dermatophyte species. Some are primarily adapted to the skin of humans (anthropophilic), others to animals (zoophilic), and various others to the environment (geophilic). Although these are their primary habitats, all of the species discussed here may infect humans from these 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. There are differences between temperate and tropical climates in the number of cases and isolations from nonhuman sources of the different species. Many of these differences are changing with shifts in population.

Human-to-human transmission usually requires close contact with an infected subject or infected person or animal, because dermatophytes are of low infectivity and virulence. Transmission usually takes place within families or in situations involving contact with detached skin or hair, such as barber shops and locker rooms. No special precautions beyond handwashing need be taken by the medical attendant after contact with an infected patient.

PATHOGENESIS

Dermatophytoses begin when minor traumatic skin lesions come in contact with dermatophyte hyphae or conidia shed from another infection. These forms may remain infectious for months in the environment. Susceptibility may be enhanced by local factors such as the composition surface fatty acids. Once the stratum corneum is penetrated, the organism can proliferate in the keratinized layers of the skin-aided digestion mediated by a variety of proteinases. Another class of proteins (LysM) suggested by genomic studies may bind to cell wall components and mask them from the host immune response. The course of the infection depends on the anatomic location, moisture, the dynamics of skin growth and desquamation, the speed and extent of the inflammatory response, and the infecting species. For example, if the organisms grow very slowly in the stratum corneum and if turnover by desquamation of this layer is not retarded, the infection will probably be short-lived and cause minimal signs and symptoms. Inflammation tends to increase skin growth and desquamation rates and helps limit infection, whereas immunosuppressive agents such as corticosteroids decrease shedding of the keratinized layers and tend to prolong infection. Invasion of any deeper structures is extremely rare.

Most infections are self-limiting, but those in which fungal growth rates and 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 name ringworm and 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 as arthroconidia 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 bed causes a hyperkeratotic reaction, which dislodges or distorts the nail.

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. Most clinical and experimental evidence points to the importance of T-cell–mediated T_H1 responses, as with other fungal infections. The timing of the inflammatory response to infection correlates with appearance of delayed-type hypersensitivity, and resolution of infection is associated with the blastogenic T-lymphocyte responses. Enhanced desquamation with the inflammatory response helps remove infected skin.

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. Although various mechanisms have been proposed, how this organism is able to grow without stimulating much inflammation remains unexplained.

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, for example, 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 not included in this anatomic list are called tinea corporis (body). There are certain general clinical, etiologic, and epidemiologic differences among these syndromes, but they are the same disease in different locations. The primary differences among etiologic agents that infect different sites are shown in Table 45–1.

Infection of hair begins with an erythematous papule around the hair shaft, which progresses to scaling of the scalp, discoloration, and eventually, 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 gone into 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.

Skin lesions begin in a similar pattern and enlarge to form sharply delineated erythematous borders with skin of nearly normal appearance in the center. Multiple lesions can fuse to form unusual geometric patterns on the skin. Lesions may appear in any location, but 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. Moisture and maceration of the skin provide the mode of entry.

Nail bed infections first cause discoloration of the subungual tissue, then hyperkeratosis and apparent discoloration of the nail plate by the underlying infection follow. Direct infection of the nail plate is uncommon. Progression of hyperkeratosis and associated inflammation cause disfigurement of the nail but few symptoms until the nail plate is so dislodged or distorted that it exposes or compresses adjacent soft tissue.

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 calcifluor white preparations of scales scraped from the advancing edge of a dermatophyte lesion 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, and selection of hairs for examination can be aided by the use of an ultraviolet lamp (Wood's) lamp (Figure 45–3B).

The same material used for direct examination can be cultured for isolation of the offending dermatophyte and demonstration of typical conidia (Figure 45–4) that are not produced in clinical lesions. 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. Clinically typical infections with negative KOH preparations require culture. The major reason for false-negative KOH results, however, is failure to collect the scrapings or hairs properly. Nucleic acid amplification procedures have been successfully applied to skin and nail scrapings, but their use is limited.

TREATMENT AND PREVENTION

Many local skin infections resolve spontaneously without chemotherapy. Those that do not may be treated with topical terbinafine or azoles (miconazole, ketoconazole). Nail bed and more extensive skin infections require systemic therapy with griseofulvin or itraconazole and oral terbinafine, often combined with topical therapy. Therapy 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 hygienic measures. No specific preventive measures such as vaccines exist.

Other Superficial Mycoses

Pityriasis (tinea) versicolor occurs in tropical and temperate climates; it is characterized by discrete areas of hypopigmentation or hyperpigmentation associated with induration and scaling. Lesions are found on the trunk and arms; some assume pigments ranging from pink to yellow-brown—hence the term versicolor. Members of the genus Malassezia, of which M furfur is the most common, are the cause of pityriasis versicolor; these organisms can be seen in skin scrapings as clusters of budding yeast cells mixed with hyphae. They grow in the yeast form in culture media enriched with lipids.

Tinea nigra, another tropical infection, is characterized by brown to black macular lesions, usually on the palms or soles. There is little inflammation or scaling, and the infection is confined to the stratum corneum. The cause, Hortaea werneckii, is a black-pigmented fungus found in soil and other environmental sites. Scrapings of the lesion show brown to black–pigmented septate hyphae. In culture, initial growth is in the yeast form, with slow development of hyphal elements.

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 hyphal forms, which fragment with occasional buds. Black piedra (caused by Piedraia hortae) shows branched hyphae in sections of the hair (Figure 44–2).

SUBCUTANEOUS FUNGI

Assignment of fungal organisms to the category of subcutaneous fungi is somewhat arbitrary because fungal pathogens can produce many subcutaneous manifestations as part of their disease spectrum. Those considered here are introduced traumatically through the skin and are typically limited to subcutaneous tissues, lymphatic vessels, and contiguous tissues. They 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 culture 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, and on the surfaces of various plants. Infection is acquired by traumatic inoculation through the skin of material containing the organism. Exposure is largely occupational or related to hobbies. 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 sphagnum moss. Infection is occasionally acquired by direct contact with infected pus or through the respiratory tract; these modes of infection, however, are much less common than the cutaneous route. 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 scanty in human lesions.

IMMUNITY

Some studies indicate that exposure to S schenckii is fairly common and there is a high level of innate immunity. The cellular response to infection is mixed. The increased frequency and greater severity of disseminated disease in patients with T-cell defects points to T_H1 responses as the primary immune mechanism. Antibody plays no known role in immunity.

SPOROTRICHOSIS: CLINICAL ASPECTS

MANIFESTATIONS

A skin lesion begins as a painless papule that develops 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 papule enlarges slowly and eventually ulcerates, leaving an open sore. Draining lymph channels are usually thickened. 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). Once ulcerated, lesions usually become chronic. Multiple ulcers often develop if the disease is untreated. Symptoms are those directly related to the local areas of infection. Constitutional signs and symptoms are 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 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

Cutaneous sporotrichosis was long 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 primarily a tropical disease caused by multiple species of pigmented saprophytic fungi. Disease caused by Fonsecaea, Phialophora, and Cladophialophora (Cladosporium) occurs typically on the foot or leg. It appears 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 is by satellite lesions; it is slow and painless and does not involve the lymphatic vessels. The organisms are found in the soil of endemic areas, and most infections occur in individuals who work barefoot. Another pigmented saprophytic mold, Exserohilum rostratum, was the most common isolate in the US outbreak of meningitis caused by contaminated products infused into the cerebrospinal fluid.

The outstanding mycologic feature is the presence of brown-pigmented, thick-walled, multiseptate, 5 to 12 mm globose structures called muriform bodies on histologic section. Branching septate hyphae may also be demonstrated in KOH preparations of scrapings. Cultures grow as dark molds, but may take weeks to appear and longer for demonstration of characteristic conidia. Surgery and antifungal therapy have been used in chromoblastomycosis, but results in advanced disease are disappointing. Flucytosine or itraconazole have been the antifungal agents most frequently used.

Mycetoma is a clinical term for an infection associated with trauma to the foot that causes inoculation of any of a dozen fungal species. Actinomycetes such as Nocardia (Chapter 28) may produce a similar disease. The typical clinical appearance is 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 the chronically damp, macerated skin of the feet that causes predisposition toward mycetoma occurs most often among those who go barefoot in the tropical environment. This finding is illustrated by the case of a college rower in Seattle who developed mycetoma; he was the only member of his shell who insisted on rowing barefoot. Once established, the treatment of mycetoma is difficult and depends on the specific agent involved. The precise microbiologic features depend on the agent involved. Hyphae are usually present in tissue but, maybe difficult to demonstrate because of a tendency to form microcolonial granules.