Fungal infections, Cutaneous

Cutaneous Fungal Infections encompasses a discussion of the major cutaneous host defense mechanisms and a description of the various superficial and deeper infections of the skin. The skin has a number of physical and chemical factors which make it difficult for microorganisms to survive and grow in this location. The immune system, particularly cell-mediated immunity and the activity of phagocytic cells, appears to be important in the defense against cutaneous fungal infections. Mechanisms involved in generating cutaneous immunologic reactions are particularly complex, with epidermal Langerhans cells, other dendritic cells, lymphocytes, microvascular endothelial cells, and the keratinocytes themselves all playing important roles. Infections involving the skin include both superficial and deep mycoses. The superficial mycoses are infections of the epidermis and cutaneous appendages with a number of yeasts and filamentous fungi that are well adapted for growth at this location. The resulting diseases include cutaneous candidiasis, dermatophytosis, tinea (pityriasis) versicolor, and some related mycoses. Deeper cutaneous mycoses, such as sporotrichosis, chromoblastomycosis, and mycetoma, may begin with direct implantation of the organisms into the skin through accidental punctures involving contaminated objects. The skin may also be involved by disseminated fungal infections such as North and South American blastomycosis, cryptococcosis, and several other types of fungal infections. 

I. CUTANEOUS HOST DEFENSES 

A. Structure of the skin The physical and chemical structure of the skin represents a form of defense against fungal pathogens. The skin surface is relatively inhospitable to fungal growth because of exposure to ultraviolet light, low moisture conditions, and competition from the normal bacterial flora of this site. Therefore, this surface acts as a barrier to the entry of fungi. The stratum corneum is made up of keratin, which most microorganisms cannot use for nutrition. However, Candida albicans and the dermatophytic fungi produce keratinases, which hydrolyze this substance and facilitate the growth of these organisms in the stratum corneum itself. This very superficial site of infection may protect the infecting organisms from direct contact with at least some of the effector cells of the immune system. Although neutrophils and small numbers of lymphocytes may enter the epidermis, the major infiltrates of cell-mediated immune responses are generally confined to the dermis. B. Keratinization and epidermal proliferation The process by which the stratum corneum is continually renewed through keratinization of the epidermal cells may also present a form of defense against organisms infecting this site. The basal epidermal cells produce continued growth of the epidermis as they undergo repeated cell divisions that move the resulting daughter cells (keratinocytes) outward, toward the surface. As they mature, these cells lose their nuclei and become flattened to form the keratinized cells. This process results in continuous shedding of the stratum corneum, which also may remove infecting fungal microorganisms residing there. Inflammation, including that produced by cellmediated immune reactions, appears to enhance epidermal proliferation so that rates of transit of epidermal cells towards the stratum corneum are increased. A number of studies have demonstrated that epidermal proliferation is important in the defense against superficial mycoses. C. Antifungal substances Lipids of adult hair contain saturated fatty acids that are fungistatic against Microsporum audouini, formerly a common cause of hair and scalp infections. In particular, various types of sphingosines have recently been found to be active against certain dermatophytes and C. albicans. Whereas the sebum of adults may not be significantly more fungistatic than that from children on a weight per weight basis, older individuals appear to produce quantitatively more of this material than do children. In addition, fungicidal proteins have been isolated from normal epidermis and could play some role in the defense against cutaneous fungal infections. 

D. Unsaturated transferrin In contrast to other fungal pathogens such as C albicans, Malassezia furfur, and Trichosporon beigelii, the dermatophytic fungi appear to be relatively incapable of causing disseminated disease, except for occasional local abscesses or granulomas in severely immunosuppressed patients. Thus, infections with dermatophytes are generally confined to the keratinized stratum corneum and the cutaneous appendages, such as the hair and nails. This phenomenon has been related to presence in the dermis of unsaturated transferrin, which may prevent growth of the organisms in the deeper layers of the skin by competition for iron. E. The inflammatory response With various kinds of superficial fungal infections, there appears to be an inverse relationship between the degree of inflammation produced by a particular fungal pathogen and the chronicity of that infection. M. furfur and the anthropophilic dermatophytes, Trichophyton rubrum and Epidermophyton floccosum, generally produce little inflammation in their cutaneous lesions and frequently cause infections that persist for long periods. On the other hand, many of the geophilic or zoophilic dermatophytes, e.g., T. verrucosum, produce highly inflammatory infections that are usually self-limited. Thus, the local inflammatory processes may indeed be involved in the defense against this group of pathogens. A variety of mechanisms have been described by which inflammatory cells are attracted into the sites of cutaneous fungal infections. Fungal organisms are generally capable of activating complement by the alternative pathway to produce chemotactic activity for neutrophils and can also produce low molecular weight chemotactic factors analogous to the ones made by growing bacteria. Keratinocytes themselves can generate chemotactic cytokines that could also be responsible for some of the inflammation in the lesions of cutaneous fungal infections. Neutrophils and monocytes/macrophages appear to be important in the defense against fungi, including those involved in the cutaneous mycoses. 

Neutrophils can directly attack pathogens using a variety of microbicidal processes. These processes depend upon either microbicidal oxidants or nonoxidative granule microbicidal substances. Most of these compounds have been studied primarily for their ability to kill the organisms, although lactoferrin may have both microbistatic and microbicidal effects. Macrophages have an additional antimicrobial mechanism whereby they can use production of nitric oxide  to inhibit growth of ingested fungal pathogens. Neutrophils also appear to have significant growth inhibitory activity in addition to their microbicidal processes. These cells contain large amounts of a calcium- and zinc-binding protein, called calprotectin, that has potent microbistatic activity against C. albicans and other fungi. F. The cutaneous immune system Since cutaneous fungal infections are more frequent and more severe in patients with immunologic defects, immune responses to fungal antigens would seem to play an important role in the host defense against these infections. Immunologic host defense mechanisms in normal hosts seem to be effective even when the infections are limited to superficial locations, such as the stratum corneum. Anumber of studies suggest that the epidermis not only represents a passive barrier against entry of infecting organisms, but also acts as an immunologic organ with some unique elements. 

An hypothesis regarding the skinassociated lymphoid tissue (SALT) has been advanced wherein the skin acts as an immune surveillance unit. A variety of cell types are believed to have involvement in this cutaneous immune system, including epidermal Langerhans cells, dermal dendritic cells, epidermal T-lymphocytes, keratinocytes, and microvascular endothelial cells. The mechanisms employed are complex, involving a network of fixed or mobile cells interacting either by the trafficking of the cells themselves from one site to another or by the production of cytokines that influence the function of other cells. Such skin-initiated immune responses act against a broad spectrum of foreign antigens including contact allergens, tumors, and transplants, and it is likely that they are also active against the fungal pathogens of interest here. Therefore, this system is probably responsible for initiating immune responses that work to eliminate the infecting organisms in the immune host. In addition, such responses may also produce some of the inflammation that results in much of the symptomatology of these infections. II. DESCRIPTION OF THE DISEASES A. Superficial fungal infections These infections are limited to the most superficial layers of the epidermis and/or its keratinized appendages, such as the hair and nails. The major cutaneous structures are shown in Fig. 41.1 and the most common pathogens causing superficial mycoses are listed in Table 41.1. 1. Cutaneous candidiasis Cutaneous candidiasis is an infection of the skin that is generally caused by the yeast-like fungus C. albicans and which can be either acute or chronic in nature. C. albicans is part of the normal flora of the gastrointestinal tract, rather than that of the skin, although it can be found on the skin on occasion. This organism can grow as either yeast cells or filamentous forms, with mixtures of the two phases generally seen in tissue infections. Acute cutaneous candidiasis may present as intertrigo, producing intense erythema, edema, creamy exudate, and satellite pustules within folds of the skin. 

Other infections may be more chronic, as in the feet where there can be a thick white layer of infected stratum corneum overlaying the epidermis of the interdigital spaces. Candida paronychia is marked by infection of the periungual skin and the nail itself, resulting in the typical swelling and redness of this type of candida infection. In some cases, superficial C. albicans infections may be particularly severe and recalcitrant to treatment, producing the uncommon disorder known as chronic mucocutaneous candidiasis. This condition consists of persistent and recurrent infections of the mucous membranes, skin, and nails, along with a variety of other manifestations. The superficial infections last for years in affected patients unless they are properly treated, although deep candida infections are very rare in this situation. Oral thrush and candida vaginitis are fairly common in patients with chronic mucocutaneous candidiasis. There is often infection of the esophagus, although further extension into the viscera is unusual. Epidermal neutrophilic microabscesses, which are common in acute cutaneous candidiasis, are rare in the lesions of chronic mucocutaneous candidiasis. The oral lesions are generally tender and painful. A number of other disorders are associated with the syndrome of chronic mucocutaneous candidiasis, including endocrine dysfunction, vitiligo, dysplasia of the dental enamel, congenital thymic dysplasia, thymomas, and certain other infections. Chronic mucocutaneous candidiasis, no doubt, represents a group of syndromes with a variety of predisposing or secondary abnormalities in host defense function, most commonly deficient cell-mediated immune responses against candida antigens. The diagnosis of superficial candidiasis is usually suspected on clinical grounds and can be confirmed in skin scrapings by demonstrating the organism using potassium hydroxide preparations and/or culture on appropriate antifugal media. Long term (3–9 months) treatment with azole antifungal drugs can produce good results in chronic mucocutaneous candidiasis, although occasional failures have occurred due to the development of resistant strains of C. albicans. Patients who present with chronic mucocutaneous candidiasis should be evaluated for the presence of infection with the human immunodeficiency virus and, if presenting as adults, for the possibility of thymoma. 2. Dermatophytosis Dermatophytoses are infections of keratinized structures, such as the nails, hair shafts, and stratum corneum of the skin, by organisms of three genera of fungi termed the dermatophytes. Although they are not part of the normal human skin flora, these organisms are particularly well adapted to infecting this location because they can use keratin as a source of nutrients—unlike most other fungal pathogens. The different types of dermatophytosis are classified according to body site, using the word “tinea,” followed by a term for the particular body site. The major types of dermatophytosis and the most frequent organisms associated with them are listed in Table 41.1. 

The degree of inflammation produced in the lesions appears to depend primarily on the particular organism and perhaps also to some extent on the immunological competence of the patient. Tinea pedis (athlete’s foot) is probably the most common form of dermatophytosis. This condition is a chronic toe web infection that can be scaly, vesicular, or ulcerative in form and which can sometimes produce hyperkeratosis of the sole of the foot. Tinea cruris is an expanding dermatophyte infection in the flexural areas of the groin and occurs much more frequently in males than in females. Dermatophytosis of the major surface areas of the body is termed tinea corporis. These infections frequently take the classical annular, or “ringworm,” shape. Involvement of the beard area in men, a condition known as tinea barbae, is often caused by zoophilic organisms such as T. verrucosum. Tinea unguium is a form of onychomycosis, or fungal infection of the nails, and is most frequently caused by T. rubrum. Nail infections, particularly of the toenails, are among the most difficult type of dermatophytosis to treat. Infection of the hair and skin on the scalp is called tinea capitis and is more common in children than adults. Dermatophytes rarely invade the deep tissues or produce systemic infections, even in severely immunocompromised patients. Diagnosis of dermatophytosis is made in a similar manner to that of cutaneous candidiasis, with examination of skin scrapings by potassium hydroxide preparations and culture on appropriate fungal media. The treatment of this condition has improved markedly in recent years with the development of new antifungal agents for topical application or oral administration. 

However, certain kinds of dermatophytosis, including widespread infections and those of hair and nails, will often respond poorly to topical therapy and will require prolonged courses of an oral antifungal agent, such as griseofulvin, ketoconazole, itraconazole, fluconazole, or terbinafine. There is an opportunistic fungal organism, Scytalidium dimidiatum (Hendersonula toruloidea), that can produce conditions clinically mimicking those caused by the usual dermatophyte species, but which does not respond well to conventional antifungal therapy. 3. Tinea (pityriasis) versicolor and malassezia folliculitis Tinea versicolor is a chronic superficial fungal infection of the skin generally affecting the trunk or proximal parts of the extremities and caused by the yeast M. furfur (Pityrosporum orbiculare). The organism is lipid-requiring and will not grow on most laboratory media. The lesions resulting from infection with M. furfur are macules that may coalesce into large, irregular patches characterized by fine (pityriasiform) scaling, along with hypopigmentation or hyperpigmentation. These infections can persist for years unless treated appropriately. M. furfur has also been postulated to play a role in certain other diseases, including atopic dermatitis, seborrheic dermatitis, psoriasis, and reticulate papillomatosis. Malassezia folliculitis is a condition that resembles several other cutaneous infections, including acne vulgaris, the macronodular lesions of disseminated candidiasis in immunosuppressed patients, the candidal papular folliculitis of heroin addicts and graft versus host disease in bone marrow transplant recipients. The papules of this condition begin as an inflammation of the hair follicles, instead of the macules typical of tinea versicolor, and may progress to frank pustules. In tinea versicolor, potassium hydroxide preparations of skin scrapings reveal the typical grape-like clusters of yeast and tangled webs of hyphae of the causative fungus, yielding the diagnosis of this condition. The organism is not usually cultured because of the requirement for specialized media. Tinea versicolor can be treated topically with lotions or creams containing selenium or sodium thiosulfate, specific antifungal agents, or sulfur–salicylic acid shampoo. Oral azole antifungal drugs can also be used for more difficult cases. Malassezia folliculitis can be treated using topical antifungal agents or an oral azole antifungal drug. 4. Miscellaneous superficial fungal infections Tinea nigra is a superficial mycosis of the palms that is most often caused by Phaeoannellomyces werneckii (Exophiala werneckii). The lesions are generally dark colored, non-scaling macules that are asymptomatic, but can be confused with melanomas and perhaps result in unnecessary surgery. Tinea nigra is most often seen in tropical or semitropical areas of Central and South America, Africa, and Asia, although some cases do occur in North America. This condition can be treated effectively with either keratinolytic agents or topical azoles. White piedra is an asymptomatic fungal infection of the hair shafts that is caused by Trichosporon beigelii. This infection produces lightcolored, soft nodules on the hair shafts and may cause the involved hairs to break. Otherwise, this condition appears to be asymptomatic, although the causative fungus can produce serious infections in immunocompromised patients. Black piedra is similar to white piedra in that it is a nodular, generally asymptomatic, fungal infection of the hair shafts. It is caused by Piedraia hortae and most commonly affects the scalp hair. Black and white piedra are generally treated by clipping off the affected hairs. 

B. Deeper cutaneous and subcutaneous mycoses The dermis and subcutaneous tissues can be infected by a variety of fungal agents that are directly implanted into the skin by punctures with sharp objects contaminated by the organisms. Dissemination to the skin from other infected sites, especially the lungs, is also possible. The most common organisms causing the deep cutaneous and subcutaneous mycoses are listed in Table 41.2. 1. Sporotrichosis This condition is generally caused by accidental implantation of the causative fungus Sporothrix schenckii into the skin. The lesions most often consist of cutaneous and subcutaneous nodules extending up the limb from the site of inoculation. However, spread may occur through the lymphatics or blood vessels to the bones, joints, or other organs. It is also possible to develop lesions in the lungs by inhalation of the fungal elements. The causative organism is a dimorphic fungus that exists as either hyphae or elongated yeast cells. The most common reservoir of the fungus in nature is on vegetation such as rose bushes, sphagnum moss, or in soil. The site of implantation may develop into a papule or pustule and cutaneous nodules may then develop proximally in a linear fashion. If the fungus is inhaled, it may cause a granulomatous pneumonitis that can cavitate and produce a clinical picture similar to tuberculosis. Immunosuppressed patients are more likely to develop disseminated disease. Demonstration of the characteristic small, cigarshaped yeast cells is diagnostic but often difficult. Multiple sections may have to be examined. Stellate, periodic acid-Schiff (PAS) positive eosinophilic material surrounding the organisms are known as asteroid bodies. The diagnosis of sporotrichosis is best made by culture of material from the lesions on appropriate fungal media. 

Isolation of this organism is usually indicative of sporotrichosis in that the fungus is not part of the normal flora of humans. Iodides may be given for cutaneous sporotrichosis, with oral itraconazole or fluconazole being used if these measures fail. For disseminated disease, either amphotericin B or itraconazole are generally effective, although relapse is common. 2. Chromoblastomycosis Certain species of the dematiaceous (darkly pigmented) fungi can cause chronic cutaneous and subcutaneous infections. A number of genera can be involved, but Fonsecaea, Phialophora, Cladophialophora, and Rhinocladiella are most common. The dark pigment of these organisms is dihydroxynaphthalene melanin, which is different from the dihydroxyphenylanine melanin associated with Cryptococcus neoformans. Dematiaceous fungi can also cause mycetoma. Chromoblastomycosis is characterized by the presence of sclerotic (muriform) bodies in the tissues. When yeastlike cells, pseudohyphae, or hyphae of the dematiaceous fungi are present in the tissues, the term “phaeohyphomycosis” is used. Chromoblastomycosis usually results from implantation of the organisms from local trauma, usually to the feet or legs. Usually, the first lesion is an erythematous papule, followed by scaling and crusting, with eventual development into a warty structure. The pathology is characteristic of a suppurative granuloma, often with overlying pseudoepitheliomatous hyperplasia. The distribution of cases is worldwide, although most come from Central and South America. The finding of the characteristic cross-walled, pigmented sclerotic bodies is pathognomonic of chromoblastomycosis. However, since those formed by all the relevant dematiaceous fungal species are similar, culture of the infecting organism on fungal media containing cycloheximide and antibiotics is necessary to identify it. Treatment may be difficult in that the organisms may not be sensitive to antifungal agents. Surgery or local heat may be other options in the early stages of the disease. 3. Mycotic mycetoma Mycetomas are swellings with draining sinuses and grains. 

They usually affect the feet, legs, or hands and begin with direct implantation of the causative organisms. The latter are either actinomycetes (actinomycotic mycetoma) or the true fungi (eumycotic mycetoma). About half of the cases of mycetoma are caused by true fungi, including the genera of Madurella, Leptosphaeria, Pseudoallescheria, Acremonium, and several others. Initially, pain and discomfort develop at the implantation site, followed weeks or months later by induration, abscess development, granulomas, and draining sinuses. The lesions may extend to bone and cause severe bony destruction. Eumycotic mycetoma are rare in the United States, although those caused by Pseudallescheria boydii are more common in the latter location. Specimens of exudate or biopsy material should be examined by the naked eye for the presence of grains. The latter can be gram-stained and examined microscopically to differentiate actinomycotic from eumycotic mycetoma. The grains should be washed with saline containing antibacterial compounds and then cultured on Sabouraud dextrose agar containing chloramphenicol and cycloheximide, as well as on media for bacterial and actinomycotic organisms. Identification of the organisms is based on gross colonial morphology, pigmentation, and mechanism of conidiogenesis. Treatment of eumycotic mycetoma is often unsatisfactory because the causative organisms generally show poor sensitivity to available antifungal agents. Amputation of an infected limb or surgical debridement of infected tissue may be necessary. Amphotericin B or azole antifungal drugs can be used if the particular fungal strain is sensitive. If not treated effectively, mycetomas may progress for years and produce marked tissue damage, deformity, and even death. C. Systemic mycoses with cutaneous manifestations A number of deep fungal infections may produce cutaneous lesions as part of a disseminated disease process. In these infections, the portal of entry is usually the lung, with development of a pneumonia and spread to other organs. Dissemination is most likely to occur in patients with compromised host defenses, although blastomycosis has a very high incidence of skin lesions in noncompromised individuals. The group of infections under discussion here is different from those in the last section, where direct implantation into the skin or subcutaneous tissues is the usual mode of entry. 

North American blastomycosis a systemic fungal infection well known to have cutaneous dissemination. Skin involvement occurs in approximately 60% of cases at some time during the illness, even though the pulmonary lesions may have healed at the time the skin manifestations develop. The latter generally consist of either verrucous lesions that look like squamous cell carcinomas or ulcerative lesions that begin as pustules or ulcerating nodules. The patient may either be quite ill with symptoms and signs from other manifestations of the infection or may have only skin lesions and be relatively asymptomatic otherwise. Coccidioidomycosis is a fairly similar disease which can produce papules, pustules, plaques, nodules, ulcers, abscesses, or large proliferative lesions. Dissemination to the skin is less common in coccidioidomycosis than in blastomycosis, although chronic meningitis is a more prominent feature of the former. The respective organisms of the two diseases are Blastomyces dermatitidis and Coccidioides immitis; they are endemic fungi found in different parts of the United States. A similar endemic fungal infection is histoplasmosis, caused by Histoplasma capsulatum; however, this disease is less likely to have cutaneous manifestations. South American blastomycosis (paracoccidioidomycosis) is an important systemic mycosis in Latin America; this infection begins in the lungs and then frequently disseminates to the skin, mucous membranes, reticuloendothelial system, and elsewhere. It is caused by Paracoccidioides braziliensis. The cutaneous lesions tend to appear around the natural orifices and may be verrucous, ulcerating, crusted, or indurated and granulomatous. Cryptococcosis is an infection beginning in the lungs and caused by Cryptococcus neoformans. 

Like coccidioidomycosis, this disease tends to disseminate to the central nervous system to cause a chronic meningitis, but it can also cause skin lesions. The latter are generally papules or nodules with surrounding erythema; they are often found on the face. Severely immunosuppressed patients are at risk for disseminated disease with a number of other fungi such as T. beigelii (the cause of white piedra, discussed previously), Blastoschizomyces capitatus, and Fusarium spp. Each of these agents causes erythematous papules or nodules, and, in some cases, these lesions may break down to form ulcers. Diagnosis of these various infections is usually obtained by demonstrating the organisms in specimens of sputum, blood, or biopsy material from the skin or other organs. Often, the individual fungi can be identified on appropriately stained smears or on histologic sections from biopsy material; otherwise, they may be cultured on appropriate fungal media. The latex agglutination test for cryptococcal antigen in serum or cerebrospinal fluid is very helpful for diagnosing and following cryptococcosis. Skin tests and other serological tests are generally less useful in diagnosis of the other fungal infections discussed above than is demonstration of the organisms. Treatment usually can be accomplished through the use of amphotericin B or the azole antifungal drugs. The various organisms vary somewhat in susceptibility, with   Coccidioides and Fusarium being relatively resistant and Cryptococcus and Blastomyces being more sensitive to the various agents. The presence of immunosuppression makes treatment of the various diseases much more difficult.