Dermatophytosis (Ringworm) and Other Superficial Mycoses

The superficial fungal infections include some of the most common infectious conditions, such as ringworm, tinea corporis, and pityriasis versicolor, and rare disorders such as tinea nigra. Their prevalence varies in different parts of the world, but in many tropical countries they are the most common causes of skin disease. Dermatophyte infections and other superficial mycoses are described in this chapter. Superficial candidiasis is discussed in Chapter 256 .

Dermatophytosis

The dermatophytes are molds that can invade the stratum corneum of the skin or other keratinized tissues derived from epidermis, such as hair and nails. They may cause infections (dermatophytoses) at most skin sites, although the feet, groin, scalp, and nails are most commonly affected. The dermatophytes are among the earliest microorganisms that were found to cause infections in humans. Trichophyton schoenleinii, the cause of the scalp infection favus, was isolated from a patient and the culture was shown to reproduce the typical lesions after inoculation onto human skin as early as 1841. Dermatophyte infections had been described many years before this, although the identity of the cause had not been recognized. The ancient Greek physicians knew about ringworm, and there are descriptions of the manifestations of dermatophytosis in more unlikely sources, such as the records of the early explorers of the 16th century who reported a strange disease of the skin, subsequently known as tinea imbricata, caused by Trichophyton concentricum, in the islanders of the western Pacific.

Dermatophytes

There are four main genera of dermatophyte fungi pathogenic in humans: Trichophyton, Microsporum, Nannizzia, and Epidermophyton. The last genus is represented by only a single species, Epidermophyton floccosum. These keratinophilic organisms probably arose as saprophytic soil fungi, and some dermatophytes, which have been isolated only from soil, have not been shown to cause disease in either animals or humans. Most of the dermatophyte species, however, are parasitic and can cause disease in either humans or animals, often being adapted to a single or narrow range of host species. The dermatophytes are referred to as zoophilic, anthropophilic, or geophilic, depending on whether their primary source is an animal, human, or soil, respectively. The most common geophilic species found in human infections is Nannizzia (previously Microsporum ) gypseum. Other soil genera such as Paraphyton do not appear to cause human infections

The exact taxonomic status of dermatophytes remains a subject of debate, although the wider use of molecular tools to determine species has enabled a scientifically based classification and consensus to evolve. The most recent version has the merit of restricting changes to established species names to a minimum.

The relationships among different dermatophytes are not simply a subject for intellectual dispute. To understand the spread of infections, for instance, it is important to attempt to differentiate strains of the same species. Significant advances have been made both in the molecular taxonomy of these organisms and in the development of schemes for strain differentiation through the use of molecular tools. Attempts have also been made to classify the dermatophytes according to their protein spectra, most recently using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) techniques Another new technique for identification is surface-enhanced Raman spectroscopy (SERS) coupled with principal component analysis (PCA).

Such techniques have also contributed to our understanding of key issues in pathogenesis, such as spread of infection in populations and relapse after apparently successful treatment. Proteinases produced by dermatophytes are inducible by, for instance, amino acids. Dermatophytes secrete a number of enzymes with different protein affinities, including keratin, the largest of which is a 200-kDa glycosylated metalloprotease, and the genes encoding subtilisin proteinases in Microsporum canis ( Sub1, Sub2, and so on) have been identified. Other significant gene products are heat shock proteins, thiol carbonases, and transporters. These have been shown to be expressed in vivo.

Epidemiology

The factors affecting the distribution and transmission of dermatophytosis are largely dependent on the source of the infection : animal, soil, or human.

Zoophilic Dermatophyte Infections

The main zoophilic dermatophyte fungi are listed in Table 266.1 . Each organism is primarily an animal pathogen that sometimes causes human infection. In each case there is usually a range of host specificities, from organisms such as Microsporum nanum, whose natural host is the pig and which does not infect other animals, to Trichophyton mentagrophytes, which affects a range of different rodent species or, rarely, cats, dogs, and horses.

TABLE 266.1

Classification of the Main Dermatophytes ( Trichophyton, Microsporum , Nannizzia, and Epidermophyton )

ORGANISM(S) AND THEIR SOURCES
HUMAN ORIGIN	SOIL ORIGIN	ANIMAL ORIGIN	MAIN ANIMAL SOURCE
Trichophyton concentricum	Nannizzia gypseum	Trichophyton benhamiae	Guinea pigs
Trichophyton interdigitale		Trichophyton erinacei	Hedgehogs
Trichophyton rubrum		Trichophyton equinum	Horses
Trichophyton schoenleinii		Trichophyton mentagrophytes	Rodents
Trichophyton soudanense		Trichophyton quinckeanum	Mice
Trichophyton tonsurans		Trichophyton simii	Monkeys
Trichophyton violaceum		Trichophyton verrucosum	Cattle
Microsporum audouinii		Microsporum canis	Cats, dogs
Microsporum ferrugineum		Nannizzia nana	Pigs
Epidermophyton floccosum		Nannizzia persicolor	Bank voles

The host preferences of T. mentagrophytes, coupled with small clinical and cultural differences, have led many mycologists to subdivide this group. Under this classification, T. mentagrophytes quinckeanum (T. quinckeanum) is used to describe the fungus that causes the clinical pattern of favus in mice, an infection associated with the formation of epithelial crusts. However, the organisms are difficult to distinguish genetically. In most temperate countries, Trichophyton verrucosum, the cause of cattle ringworm, and M. canis, a dermatophyte that causes infections in cats or dogs, are the most common zoophilic dermatophytes that cause human infections, such as tinea capitis.

Of all the zoophilic dermatophytes, M. canis is the most prevalent throughout the world, in both temperate regions and some tropical regions. On occasion, the distribution of zoophilic dermatophytes may appear to be difficult to explain, but usually it reflects the distribution of the animal host. For instance, Trichophyton erinacei (part of the Trichophyton benhamiae series) is confined mainly to Europe and New Zealand. It is carried by hedgehogs, which were introduced into New Zealand in the 19th century from England. T. benhamiae (previously Arthoderma benhamiae ) is increasingly recognized as a cause of scalp and skin infection acquired from guinea pigs, Trichophyton simii is associated with monkeys in India and the Far East, and infections in humans are observed only in these areas.

Geophilic Dermatophyte Infections

Dermatophytes originating from soil, such as N. gypseum, are infrequent causes of human disease, although they may be seen more commonly in certain parts of the tropics such as the western Pacific and Central America. In other areas, they usually cause sporadic infections, although on occasion they are responsible for outbreaks of disease among humans in appropriately exposed occupational groups, such as gardeners or farmworkers.

Anthropophilic Dermatophyte Infections

Dermatophytes that are natural pathogens of humans are the most common cause of human dermatophytosis. They include organisms that mainly cause infections of glabrous skin of the feet or hands and a range of pathogens whose invasion may involve penetration of the hair shaft. The most common of these organisms in most parts of the world is Trichophyton rubrum, which causes tinea pedis or tinea cruris in temperate climates and, particularly in the tropics, tinea corporis. Cases of infection that are caused by T. rubrum were once rare in the Western Hemisphere, but the infection has spread rapidly since the 1960s. In the feet, among other sites, this dermatophyte can cause noninflammatory chronic infections that are easily transmitted; this is probably an important factor that has determined its spread. The large population movements during World War II are also thought to have contributed to the spread of the disease. Despite this, a variant with distinct morphologic appearances may be isolated from patients with tinea corporis, particularly in the tropics, which suggests that although endemic disease caused by this species has been present for a considerable time, the key adaptation leading to spread was the appearance of strains capable of causing indolent and noninflammatory infections of peripheral skin sites.

The organisms that infect glabrous skin spread largely through contact with infected desquamated skin scales. Classically, this occurs in bathing areas or shower rooms where large numbers of individuals share common facilities—for instance, in military camps or factories. Workers in heavy industries such as mines or nuclear fuels may have a high frequency of foot infection, mainly caused by T. rubrum, although Trichophyton interdigitale (part of the T. mentagrophytes complex) may also be isolated. Changing rooms used by the police and armed forces, schools, and public swimming pools are also sites for infection. In contrast, transmission within the home as a reflection of conjugal or familial cases is not common, although it has been suggested that some patients show immunologic and genetic susceptibility. E. floccosum may also cause foot infections, although it is particularly associated with tinea cruris either as a sporadic disease or in institutions, such as prisons and military barracks. These infections are not geographically restricted, even though there are variations in different countries. In many tropical areas, particularly the Far East, T. mentagrophytes is less commonly a cause of interdigital foot disease, and patients are infected by the zoophilic variety of this species on sites other than the feet.

Tinea imbricata (a variant of tinea corporis), caused by the anthropophilic dermatophyte T. concentricum, has an unusual distribution confined to remote parts of the humid tropics. The main endemic areas are the western Pacific islands, Malaysia, Northeast India, and parts of the Amazon Basin in Brazil. Infants may be affected shortly after birth, and spontaneous recovery is unusual. Large numbers of viable organisms can be cultured from the houses of infected families. Visitors to areas in which the condition is endemic are rarely infected.

The distribution of some of the other anthropophilic dermatophytes that cause tinea capitis in children, and other clinical forms of disease such as tinea corporis or onychomycosis, may be more restricted. The reasons for this are not entirely clear, except that because these infections are prevalent in children, who form a relatively stable population with little opportunity for travel, the spread of the disease within the continent may be limited to certain localities. Whatever the reason, these scalp infections are often found in defined endemic areas ( Table 266.2 ). The situation is best illustrated by the distribution of Trichophyton spp. that cause tinea capitis in West Africa, where the endemic areas for Trichophyton soudanense and Trichophyton yaoundei, members of the T. rubrum complex, are distinct, although there is some overlap. However, this pattern is changing as Trichophyton tonsurans is now found increasingly in the region. The predominant cause of scalp infection is T. tonsurans in the United Kingdom, United States, and Mexico and Trichophyton violaceum in India, East Africa, and the Middle East. The situation does not always remain stable, and the slow increase in numbers of T. tonsurans in the United States was followed by spread to the United Kingdom and some parts of Europe, Latin America, and Africa. In addition, other anthropophilic Trichophyton infections such as T. violaceum and T. soudanense are seen in immigrants in Europe and elsewhere. Endemic anthropophilic scalp infections that are caused by Microsporum spp. are less common. For instance, Microsporum ferrugineum is now seldom found. The most widely distributed of this genus is Microsporum audouinii. Once common throughout Europe, it almost disappeared but has been reintroduced by immigration from regions in which it remained endemic, such as West Africa, and it is still a major cause of tinea capitis in Africa.

TABLE 266.2

Distribution of Trichophyton and Microsporum Species That Cause Tinea Capitis

DERMATOPHYTE	DISTRIBUTION
Trichophyton tonsurans	North, Central, and South America, Europe, Africa
Trichophyton soudanense	West and Central Africa
Trichophyton schoenleinii	North Africa United States, Middle East, South Africa, South America (sporadic)
Trichophyton verrucosum	Europe
Trichophyton violaceum	Indian subcontinent, Middle East, North and East Africa
Microsporum audouinii	Central America, West Africa Europe (uncommon)
Microsporum canis	Worldwide but uncommon in India and Far East
Microsporum ferrugineum	Central Africa, Far East

Favus—the infection caused by T. schoenleinii —has characteristic clinical manifestations. It was once common in Europe but has now largely disappeared from many areas, although pockets of infection still exist in parts of sub-Saharan Africa. One of the features of this disease is the development of crusts, or scutula, on the scalp. Hairs are invaded, but shedding is delayed because they are not structurally damaged until late in the course of the infection. Although tinea capitis is normally a disease of children, occasionally women have favus.

Dermatophytes causing scalp disease may be carried on the skin surface without invading the skin or hair. A small proportion of carriers develop infections within 6 months; in others the fungus disappears. Members of an infected individual's family can also become carriers. It is likely, however, that some carriers have limited but undetected infections.

Age Incidence

Tinea capitis is mainly a disease of childhood, and cases rarely occur after puberty. However, this infection may occur in adults and may also be associated with scarring alopecia. The reason for the preponderance of the disease in children is thought to be the presence of medium-chain fatty acids (C ₈ to C ₁₂ ) in sebum that inhibit the growth of dermatophytes in postpubertal individuals. In contrast, tinea pedis is usually seen in older children or young adults. Foot infections occasionally occur in young children, but in this age group the nails may be invaded without concomitant skin infection.

Pathogenesis

Transfer of infecting organisms from soil, animals, or humans is accomplished by means of arthrospores, which are vegetative cells with thickened cell walls formed by dermatophyte hyphae in vitro and in vivo. These structures are probably shed by the primary host with skin scales or hair. It has been shown that dermatophyte arthrospores can survive for considerable periods outside the host, in some cases for more than 15 months. Direct contact between the infected individual and another individual is not necessary for the development of dermatophytosis in the latter. The process of transfer itself is little understood, but invasion of the skin appears to follow adherence of fungal cells to keratinocytes in vitro, a process that is maximal after about 2 or 3 hours. Keratinocytes from different sites do not appear to differ in their binding capacity for arthrospores. Subsequent germination leads to invasion.

Susceptibility to infection is not universal. In humans it has been suggested that susceptibility to tinea imbricata is mediated through an autosomal recessive gene. Mutations in genes that convey increased susceptibility to unusual forms of dermatophytosis such as those associated with chronic mucocutaneous candidiasis (STAT1) or deep dermatophytosis (CARD9) are being identified and are associated with reduced interleukin (IL)-17 production.

However, at the point of contact between fungus and stratum corneum there are endogenous epidermal cell defense mechanisms, such as antimicrobial peptides, including human β-defensin, that are inhibitory to dermatophytes. After contact with the skin, virulence genes that aid penetration, such as the subtilisins or proteinase genes, are expressed. In experimentally infected mice and guinea pigs, the inflammatory response to dermatophytosis is maximal after 9 to 16 days, and after this stage there is resolution of the infection. The main efferent limb of immunologic resistance is the T lymphocyte. Studies of mice with T. quinckeanum infections have shown that resistance can be transferred to sublethally irradiated mice with T cells bearing the phenotype of helper-inducer T cells. Suppressor lymphocyte activity can be detected in cells from the draining lymph nodes at the peak of infection. Immunity cannot be transferred with antibody to uninfected animals. Although it is difficult to extrapolate these data to infected humans, there is evidence that the kinetics of the immune response in humans is similar. For instance, the development of delayed-type hypersensitivity in children with naturally acquired scalp ringworm caused by T. tonsurans is correlated with recovery. Experimentally infected humans develop both delayed-type skin reactions to trichophytin and T-lymphocyte blastogenic responses at the time of recovery. Patients with chronic T. rubrum or T. concentricum infections appear to have defective T-lymphocyte–mediated responses, and patients with persistent dermatophyte infections elicit a cytokine profile suggestive of a helper T-cell type 2 response. These observations suggest that appropriate T-lymphocyte activation is crucial for recovery in dermatophytosis.

The afferent limb of the immune response is provided by epidermal Langerhans cells, which have been shown to act as antigen-presenting cells in mixed cultures with human lymphocytes. The mechanisms by which T lymphocytes affect recovery are less well understood. Phagocytes—mainly neutrophils and, to a lesser extent, macrophages—can kill dermatophytes both intracellularly and extracellularly, mainly through oxidative pathways. Dermatophyte antigens have been shown to be chemotactic to human leukocytes and may activate the alternative pathway of complement activation. However, other mechanisms of fungal clearance must also be involved. It has been shown that increased epidermal turnover occurs during infection. Although this also occurs in heterologous skin grafted onto T-cell–deficient (nunu) mice, which suggests that an intrinsic response is involved, it is maximal at the time of development of the maximal immune responses. It is possible that elimination of dermatophytes is also accomplished by means of increased shedding of the stratum corneum and that the immune system amplifies an endogenous epidermal response to infection.

Different dermatophyte species vary in their ability to elicit an immune response; some organisms, such as T. rubrum, cause chronic or relapsing infections, and others, including T. verrucosum, lead to long-term resistance to reinfection. Some dermatophytes produce glycopeptides, which are capable of reversibly inhibiting T-lymphocyte blastogenesis in vitro. There is variation in the ability of different dermatophyte species to stimulate release of cytokines such as IL-12 from keratinocytes in vitro, which may provide an explanation of the differences in inflammatory responses in the skin.

Clinical Manifestations

The archetypal lesion of dermatophytosis is an annular scaling patch with a raised margin that exhibits a variable degree of inflammation; the center is usually less inflamed than the edge. The word tinea is used to refer to dermatophyte infections, and it is usually followed by the Latin description of the appropriate site. Hence, tinea pedis is an infection of the feet and tinea capitis is an infection of the scalp. The term tinea incognito is used to describe infections that do not have any of the usual characteristic features of dermatophytosis, often because of inappropriate application of corticosteroid creams. Disease associated with immunosuppression, including infection with the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), affects the clinical expression of dermatophytosis; the result is often diminished scaling but prominent folliculitis and the formation of pustules.

The clinical appearances of the infection vary with the site, the fungal species involved, and the host's immune response. Zoophilic fungi often cause inflammatory lesions, and in some cases large pustular lesions (kerions) may develop. In contrast, lesions caused by anthropophilic dermatophytes often exhibit little inflammation and may become chronic (see “ Pathogenesis ”).

Tinea Pedis

Tinea pedis is usually caused by infection with either T. rubrum or T. interdigitale (part of the T. mentagrophytes complex) or, less commonly, with E. floccosum. The infection usually starts in the lateral interdigital spaces of the foot or on the undersurface of the lateral aspects of the toes. The main symptom is itching, although the severity is variable. The skin usually cracks and may become severely macerated. In some cases, often when T. mentagrophytes is the causative organism, bullae are formed and itching is severe. The infection may also spread onto the dorsum of the feet, usually on the lateral side of the foot. Involvement of the sole is common in T. rubrum infections, and part of or the entire sole becomes erythematous and covered with dry scales. This is most noticeable along the lateral borders of the sole, where the appearance is often characterized as “moccasin” or “dry-type” infection. Blisters may also be formed in small clusters on the sole. The course of infection is variable. In noninflammatory forms, the interdigital scaling is often chronic or intermittent, whereas if blisters are formed, the infection usually resolves but may recur several months later. The main complications of tinea pedis are bacterial cellulitis and fungal invasion of the toenails (onychomycosis) or the skin of the dorsum of the foot and leg.

Tinea pedis usually occurs in young adults or teenagers. It is particularly common in institutions or places where common bathing facilities are used. The clinical manifestations of infection are altered in patients with T-lymphocyte abnormalities, in whom there is often extensive spread of the lesions onto the dorsal surface of the foot.

Scaling between the toes is often referred to as athlete's foot, but similar clinical signs may be produced by a variety of organisms. Erythrasma that is due to Corynebacterium minutissimum may manifest as scaling and, in particular, maceration of the toe webs. Gram-negative bacteria such as Pseudomonas and Proteus spp. may contribute to interdigital disease in patients with closely apposed web spaces or whose work involves immersion in water. These organisms may replace the original dermatophytes in this site, an infection known as dermatophytosis complex. Staphylococcus aureus may cause secondary infections of the foot, but this characteristically starts on the dorsum of the foot over the first two digits. The mold fungi Neoscytalidium dimidiatum (formerly known as Hendersonula toruloidea ) and Neoscytalidium hyalinum may cause interdigital scaling, nail disease, and sole involvement that is indistinguishable from dry-type infections caused by dermatophytes. Cracking between the toes is conducive to cellulitis in predisposed patients, such as those with chronic lymphedema.

Tinea Cruris

The most common dermatophytes associated with groin infections are T. rubrum and E. floccosum. This infection is also called jock itch. The infection starts with scaling and irritation in the groin. The rash usually involves the anterior aspect of the thighs, less commonly the scrotum. The leading edge extending onto the thighs is prominent and may contain follicular papules and pustules. The infection may also spread to the anal cleft. Although tinea cruris is mainly a disease of young men, it may affect women, particularly in the tropics, where the infection may spread in a band around the waist area.

As with tinea pedis, there may be clustering of cases of tinea cruris in institutionalized groups, such as those in military camps. The toe webs are also often infected in patients with tinea cruris.

Erythrasma of the groin may also cause a localized rash with itching. However, here the leading edge is less prominent than in tinea cruris and the rash is covered with fine wrinkles. Erythrasma fluoresces pink under Wood light. Candidiasis of the groin may also mimic tinea cruris, but an important clue to the presence of Candida is the appearance of small satellite pustules beyond the free margin of the rash. Flexural psoriasis causes a vivid red and uniformly scaling rash in the groin, and there is usually at least one other site with typical psoriatic plaques.

Tinea Corporis

Tinea corporis is one of the most commonly misdiagnosed skin diseases. Cases of this infection are not common in temperate climates, although it is seen more frequently in the tropics. This form of dermatophytosis has various clinical manifestations. Most lesions have a prominent edge that may contain pustules or follicular papules, and the center of the lesion is often less inflamed and scaly ( Fig. 266.1 ). Sites commonly involved are the trunk and legs. Itching is variable, and lesions may be single or multiple. In general, infections caused by anthropophilic dermatophytes such as T. rubrum are less inflammatory and less clearly demarcated, and in some patients it is necessary to search for the margin carefully to delineate the rash. Lesions are usually hyperpigmented in pigmented skins. An outbreak of very extensive tinea corporis (and tinea cruris) infection, refractory to treatment, has been highlighted in many areas of India. An association with the use of high-strength topical steroid antifungal-antibacterial combinations has been identified. Zoophilic infections such as those caused by M. canis and T. verrucosum are more inflammatory, and lesions may become elevated and contain pustules. Infections caused by N. gypseum are also usually inflammatory and may have a brick-red appearance.

These clinical patterns vary with the site of infection. In patients with defective T-lymphocyte function, scaling is often minimal, and the rash of tinea corporis consists of grouped papules or pustules without significant erythema. T. rubrum infections on the lower parts of the legs may lead to the formation of single or multiple deep nodules that may mimic erythema nodosum. The overlying skin is dry, red, and scaly, which is a useful clue to the correct diagnosis. This form of infection, nodular folliculitis, follows follicular penetration of the hair follicles of the lower portions of the legs by the fungus. It occurs mainly in women.

Tinea corporis can occur at any age.

A number of different conditions should be considered in the differential diagnosis of tinea corporis, including eczema, psoriasis, and annular erythema. The important points to look for are the annular scaling margin of lesions and follicular prominence, which are features of dermatophytosis. However, it may be necessary to take scrapings for laboratory culture when there is doubt.

Tinea Imbricata

Tinea imbricata is a variant of tinea corporis that is caused by T. concentricum. The geographic distribution of the disease is shown in Table 266.2 . Patients may be infected at any age, although infants and young children are most frequently affected. The main characteristic of the rash is the formation of concentric rings of scales ( Fig. 266.2 ) that amalgamate to form waves of scaling over large parts of the body. Other clinical varieties of tinea imbricata include the diffuse scaling variety, in which large flakes of skin are prominent. The disease gets its name imbricata (Latin, “tiled”) from this clinical pattern. Other patients may have itchy lichenified lesions on the forearms. The face may be affected, as may the sides of the fingers, but the feet, scalp, axillae, and groin are usually spared. Tinea imbricata is seldom mistaken for other diseases, and the inhabitants of areas in which the condition is endemic easily recognize the appearance of the infection and have specific names for it. In Papua New Guinea it is called sipoma or grille.

Tinea Manuum

The term tinea manuum is used for dermatophyte infections involving the hand. In some patients, the dorsum of the hand may be affected, but most commonly the disease occurs on the palmar surface. A characteristic of dry-type infections at this site is involvement of only one palm, although in some patients both may be affected. The clinical manifestations are identical to those seen with dry-type infections of the sole. The usual cause is T. rubrum, and the feet are often involved, in addition to the hands.

Dermatophytosis affecting the palm may be confused with eczema, but the unilateral distribution of the infection and the common accompanying findings of onychomycosis and tinea pedis are helpful clues. Patients with palmoplantar keratoderma (tylosis) are particularly susceptible to superinfection of the palms and soles with dermatophytes. This complication may be difficult to identify, but the skin may blister and the hand usually itches. In such patients, fungi other than T. rubrum may be implicated.

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