Fungal Infections

Fungal infections are a wide range of diseases that are caused by the multiplication and spread of fungi. Fungal infections, also known as mycoses, range from mild and barely noticed to severe and sometimes even fatal. (In addition to infections, fungi are also responsible for some allergic disorders, such as allergic alveolitis and asthma.)

Causes

Some fungi are harmlessly present all of the time in areas of the body such as the mouth, skin, intestines, and vagina. Usually, however, they are prevented from multiplying by competition from bacteria. Other fungi are kept from multiplying to a harmful degree by the body’s immune system. Fungal infections are therefore more common in people who are taking antibiotic drugs (which destroy the bacterial competition) and in those whose immune systems are suppressed by immunosuppressant drugs, corticosteroid drugs, by a disorder such as AIDS, or by chemotherapy. Such serious fungal infections are described as opportunistic infections because they take advantage of the body’s lowered defences. Some fungal infections are more common in people with diabetes mellitus. Fungi that cause skin infections thrive in warm, moist conditions, such as those that occur between the toes and in the genital area.

Types

Fungal infections can be broadly classified into three categories:

  1. superficial (affecting the skin, hair, nails, inside of the mouth, and genital organs);
  2. subcutaneous (beneath the skin); and
  3. deep (affecting internal organs).

The main superficial infections are tinea (including ringworm and athlete’s foot) and candidiasis (thrush), both of which are common. Tinea affects external areas of the body. Candidiasis is caused by the yeast Candida albicans and usually affects the genitals or inside of the mouth.

Subcutaneous infections are rare. The most common is sporotrichosis, which may follow contamination of a scratch. Most other conditions of this type, the most important of which is mycetoma, occur mainly in tropical countries.

Deep fungal infections are uncommon, but they can present a serious threat to people who have an immune deficiency disorder or those who are taking immunosuppressant drugs. Fungal infections of this sort include aspergillosis, histoplasmosis, cryptococcosis, and blastomycosis, all of which are caused by different species of fungi. The fungal spores enter the body through inhalation into the lungs. Candidiasis can also spread from its usual sites of infection to affect the oesophagus, the urinary tract, and other internal tissues.

Treatment

Treatment of fungal infections is with antifungal drugs, either used topically on the infected area or given by mouth for generalized infections.

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Fungal infections in detail - technical

Summary

The mycoses are disorders caused by fungi, which are saprophytic or parasitic organisms found in every continent and environment. Many are common commensals in nature, but others cause agricultural disease. The mycoses that are human infections include diseases ranging from those that are worldwide and common, such as dermatophytosis and candida infections, to those that are rare and often potentially life threatening, e.g. histoplasmosis. In humans, fungi usually adopt one of two morphologies: (1) the yeast form—where individual cells produce daughter cells by a process of budding and subsequently separate; or (2) the hyphal form—where cells do not separate but multiply to produce chains of cells joined end to end.

Diagnosis

Mycological diagnosis is often complex because many fungi are also commensals or transiently carried in humans, hence it is necessary to show both that the organisms are present and that they are causing disease, which is particularly difficult in the context of opportunistic fungal infection. The main laboratory diagnostic tests involve (1) visualization of fungi in tissue—by direct microscopy or histopathology; (2) culture—often using a glucose peptone agar (Sabouraud’s agar); (3) detection of antibody, fungal antigens or DNA fragments—assimilation of genetic tests such as PCR-based methods into routine diagnosis has been slow, and they are offered by few laboratories.

Superficial infections

Superficial fungal infections may reach prevalence rates of 15 to 25% in some communities, with the common infections being dermatophytosis or ringworm, pityriasis versicolor, and superficial candidosis.

Dermatophytoses—otherwise known as tinea infections—commonly affect the feet (tinea pedis), the body (tinea corporis), the scalp (tinea capitis) and the finger and toe nails (onychomycosis). They occur in all climates and usually present in primary care as scaly rashes. Diagnosis is made by direct microscopy of skin scales mounted in potassium hydroxide (20%) to demonstrate hyphae, and by culture.

Pityriasis versicolor—caused by a skin surface commensal, Malassezia globosa,and often triggered by sun exposure. Presentation is with hypo– or hyperpigmented scaling on the trunk. Laboratory diagnosis (if required) is by demonstration of the yeasts and hyphae in skin scales removed by scraping.

Superficial candidosis (candidiasis)—these infections affect the mouth, vagina, and body folds, often in the context of some form of predisposition, e.g. recent antibiotic therapy or, in the case or severe oral infection, immunosuppression including that associated with HIV/AIDS. Infections are diagnosed by microscopy and culture, the latter being particularly important where non-albicans Candida species may be involved.

Treatment—the main treatments for superficial mycoses are topical agents that include imidazole preparations (e.g. ketoconazole, clotrimazole), but for widespread infections or those involving hair or nails, oral imidazoles (e.g. itraconazole, fluconazole) or the allylamine, terbinafine, are employed.

Subcutaneous mycoses

Subcutaneous fungal infections, e.g. mycetoma (Madura foot), chromoblastomycosis and sporotrichosis, are not common and usually restricted to the tropics and subtropics. They may present in immigrants from tropical areas, sometimes years after the person has left the tropics, and hence cause diagnostic confusion. Diagnosis is by histological examination of affected tissues or culture. Treatment is often difficult, with only partial responses being achieved, but oral imidazole drugs or terbinafine are helpful in some cases.

Systemic mycoses

Systemic mycoses are deep and often disseminated infections that involve many different sites, including the blood and bone marrow. They may be caused by organisms which invade normal hosts (endemic mycoses) and those which only cause disease in compromised patients (opportunistic mycoses).

Endemic mycoses—these include histoplasmosis, coccidioidomycosis and infections due to Penicillium marneffei, all of which may occur in healthy people, although many are also common complications of HIV/AIDS. Initial manifestations are as respiratory infections, but they can spread haematogenously to other sites, e.g. skin, liver, and brain. Diagnosis is made on culture or biopsy of affected areas.

Opportunistic mycoses—these occur in those who are immunocompromised, e.g. patients with neutropenia secondary to cancer. The routes of fungal entry into the body are very variable, e.g. skin, gastrointestinal tract, lung. Infections include systemic candidosis, aspergillosis, and zygomycosis, but in severely compromised patients, e.g. those with profound neutropenia, many organisms not usually associated with human disease can cause invasive infections, e.g. Fusarium species. Cryptococcus neoformans, a yeast that can invade the lungs, often presents with meningitis or other signs of intracranial infection.

Prognosis and treatment—the endemic mycoses are often fatal if untreated, and even with treatment the mortality of opportunistic fungal infection can be high, e.g. over 40% for the severely neutropenic patient with aspergillosis. Aside from supportive care, oral or parenteral agents such as amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, and caspofungin are the treatments of choice, but detecting the organisms and successfully treating the infections remains a challenge.

Introduction

Fungi are saprophytic or parasitic organisms that are normally assigned to a distinct kingdom. As eukaryotes, they have the complex subcellular organization and highly organized genetic material seen in both animal and plant cells. The cell wall is a distinctive feature of fungi and has a complex cytoskeleton based on mannan, glucan, or chitin subunits. The arrangement and reproduction of individual cells is also characteristic. Most fungi form new cells terminally, which remain connected to form long, branching filaments or hyphae (the mould fungi). Some reproduce in a similar manner but each new cell separates from the parent by a process of budding (the yeast fungi). It is a feature of certain fungi to be yeast-like during one phase of their life history but hyphal at another, a phenomenon known as dimorphism. In culture, mould fungi usually form a cottony growth on laboratory media while yeasts normally have a smooth, shiny appearance.

Fungi adversely affect humans in a number of ways. They cause disease indirectly by spoilage and destruction of food crops, with subsequent malnutrition and starvation. Many of the common moulds produce and release spores, which may act as airborne allergens to produce asthma or hypersensitivity pneumonitis. Fungi elaborate complex metabolic by-products, some of which are useful to humans, such as the penicillins. However, others are toxic. Disease caused by the ingestion of fungal toxins includes both poisoning by eating certain mushrooms (mycetism) and damage caused by the ingestion of minute quantities of toxin (mycotoxicosis), e.g. in contaminated grain. The contribution of the latter mechanism to human disease remains largely unexplored, as does the question of whether inhalation of toxic fungal spores may cause pathology. Finally, fungi may invade human tissue. Medical mycology is largely concerned with this last group. Invasive fungal diseases are normally divided into three groups: the superficial, subcutaneous, and deep mycoses. In superficial infections, such as ringworm or thrush, fungi are confined to the skin and mucous membranes. Extension deeper than the surface epithelium is rare. Subcutaneous infections are usually tropical: the main site of involvement is within subcutaneous tissue, although secondary invasion of adjacent structures such as bone or skin may occur. In deep or systemic infections, deep organs such as the lung, spleen, or brain are invaded. This classification of mycoses is based on the main ‘sphere of involvement’ by the causal organisms, but there are exceptions. For instance, brain involvement has been recorded in patients with chromoblastomycosis, which is normally a subcutaneous infection.

The fungi causing systemic mycoses are often classified in two groups: the opportunists and the endemic pathogens. The former cause disease in overtly compromised individuals. These contrast with the true pathogens, which cause infection in all subjects inhaling airborne spores.

Superficial fungal infections

The main superficial mycoses are the dermatophyte infections, superficial candidosis, and tinea versicolor. These are both common and widespread. Rare superficial infections include tinea nigra, and black or white piedra.

Dermatophyte infections (dermatophytoses)

Aetiology

The dermatophyte or ringworm infections are caused by a group of organisms capable of existing in keratinized tissue such as stratum corneum, nail, or hair. The mechanism of invasion is thought to be linked to production of extracellular enzymes; three distinct metalloproteinase genes are found in Microsporum canis.

Epidemiology

Some dermatophyte fungi have a worldwide distribution; others are more restricted. The most common and most widely distributed is Trichophyton rubrum, which causes different types of infection in different parts of the world. It is commonly associated with athlete’s foot (tinea pedis) in temperate areas as well as tinea corporis or tinea cruris in the tropics. This distinction is not based solely on climatic factors, as immigrants from tropical countries, particularly eastern Asia, may still have tinea corporis caused by T. rubrum when living in northern Europe. Certain dermatophytes are limited to defined areas. For instance, tinea imbricata caused by T. concentricum, is found in hot, humid areas of the eastern Asia, Polynesia, and South America. Scalp ringworm tends to occur in well-defined endemic areas in Africa and elsewhere. In different regions, different species of dermatophytes may predominate.

Thus, in North Africa, the most common cause of tinea capitis is T. violaceum; in southern parts of the continent, the major agents may be Microsporum audouinii, M. ferrugineum, and T. soudanense. Not all dermatophyte infections are endemic and dominant species may disappear to be replaced by others. M. audouinii, once endemic and common in the United Kingdom, is now infrequent but associated with infections in African Caribbean children. By contrast, T tonsurans is now established as a major cause of tinea capitis in urban areas in the United Kingdom, parts of Europe, and the United States of America. Dermatophytes may be passed from person to person (anthropophilic infections), from animal to person (zoophilic), or from soil to person (geophilic). Sources of zoophilic organisms in Europe include cats and dogs, cattle, hedgehogs, and small rodents. Rarer sources include horses, monkeys, and chickens. Lesions produced by zoophilic species may be highly inflammatory.

Factors governing the invasion of stratum corneum are largely unknown, but heat, humidity, and occlusion have all been implicated. Susceptibility to certain infection, such as tinea imbricata, may be genetically determined.

Clinical features

The clinical features of dermatophyte infections are best considered in relation to the site involved. Often the term tinea, followed by the Latin name of the appropriate part (such as corporis, meaning ‘body’) is used to describe the clinical site of infection.

Tinea pedis

Scaling or maceration between the toes, particularly in the fourth interspace, is the most common form of dermatophytosis seen in temperate countries. Itching is variable, but may be severe. Sometimes blisters may form both between the toes and on the soles of the feet. The causative organisms are commonly T. rubrum and T. interdigitale, the latter being responsible for the vesicular forms. Similar appearances can be caused by Candida albicans and in the bacterial infection, erythrasma. Gram-negative bacterial infection causes erosive interdigital disease associated with discomfort.

‘Dry type’ infections of the soles and palms

These are normally caused by T. rubrum. Palms (Fig. 1) or soles have a dry, scaly appearance, which in the soles may encroach on to the lateral or dorsal surfaces of the foot. The palmar involvement is often unilateral, an important diagnostic feature. Nail invasion is often seen (see below). Itching is not prominent, and infections are usually chronic.

Palmar scaling due to Trichophyton rubrum

Figure 1: Palmar scaling due to Trichophyton rubrum.

Tinea cruris

Infections of the groin, most often caused by T. rubrum or Epidermophyton floccosum, are relatively common. They occur in both tropical and temperate climates, although in the former the infection may spread to involve the whole waist area in both males and females. Tinea cruris in females is uncommon in Europe. An erythematous and scaly rash with a distinct margin extends from the groin to the upper thighs or scrotum. Itching may be severe. Coincident tinea pedis is common, and patients should be examined for this. The rash of crural erythrasma shows uniform scaling without a margin, whereas in candidosis, satellite pustules occur distal to the rim.

Onychomycosis (caused by dermatophytes)

Invasion of the nail plate is most often seen with T. rubrum infections. The plate is invaded distally and becomes thickened and friable with terminal loss of the nail plate. Onycholysis may be seen. More rarely, and most often with T. interdigitale, the dorsal surface of the plate is invaded, causing superficial white onychomycosis.

Tinea corporis (body ringworm)

Dermatophyte or ringworm infection on the trunk or limbs may produce the characteristic annular plaque with a raised edge and central clearing (Fig. 2). Scaling and itching is variable. Lesions caused by zoophilic organisms may be highly inflammatory and in certain cases, particularly those caused by T. verrucosum, intense itching, oedema, and pustule formation (kerion) may develop. This reaction is seldom secondarily infected by bacteria but is a response to the fungus on hairy skin. Infections of the beard, tinea barbae, are often highly refractory to treatment. Facial dermatophyte infections may mimic a variety of nonfungal skin diseases, including acne, rosacea, and discoid lupus erythematosus. However, the underlying annular configuration can usually be distinguished. The term tinea incognito is used to describe such atypical lesions.

Tinea corporis due to Microsporum gypseum

Figure 2: Tinea corporis due to Microsporum gypseum.

Tinea capitis (scalp ringworm)

In the United Kingdom as in the United States of America, the most common cause of scalp ringworm is T. tonsurans, an anthropophilic fungus which mainly occurs in inner cities, particularly in black Caribbean or African children. This has now replaced Microsporum canis, originating from an infected cat or dog, although this dermatophyte is dominant elsewhere in the United Kingdom and Europe. Scalp ringworm is mainly a disease of childhood, but infections may occur in adult women. Spontaneous clearance at puberty is the rule. M. canis causes an ‘ectothrix’ infection where spores form on the outside of the hair shaft and the scalp hair breaks above the skin surface. Scaling, itching, and loss of hair occur.

Other causes of ectothrix infection include M. audouinii, which is becoming more common in Europe, and is still seen in West Africa. This infection can be spread from child to child and causes serious social handicap. The infection may occur in epidemic form, particularly in schools. By contrast, infections with M. canis are acquired from a primary animal source rather than by spread from human lesions. In endothrix infections where sporulation is within the hair shaft, scaling is less pronounced and hairs break at scalp level (black dot ringworm). Examples include T. tonsurans and T. violaceum, the latter being most prevalent in the Middle East, parts of Africa, and India, although it also is being recognized with increasing frequency in Europe.

Favus, now most often seen in isolated foci in the tropics, is a particularly chronic form of ringworm caused by T. schoenleinii or T. violaceum where hair shafts become surrounded by a necrotic crust or scutulum (Fig. 3). Individual crusts coalesce to form a pale, unpleasant-smelling mat over parts of the scalp. Such infections may cause extensive and permanent hair loss.

Advanced favus of scalp in a Nigerian cattle herder caused by Trichophyton schoenleinii

Figure 3: Advanced favus of scalp in a Nigerian cattle herder caused by Trichophyton schoenleinii.

Tinea imbricata (tokelau)

This infection is endemic in parts of eastern Asia, West Pacific, and Central and South America, and is caused by T. concentricum. In many cases the trunk is covered with scales laid down in concentric rings producing a ripple effect (Fig. 4). Alternatively, large, loose scales may form (hence the name; imbricata is the Latin word for ‘tiled’). The infection is often chronic, and may constitute a serious social handicap. There is some evidence that susceptibility of this disease in Papua New Guinea may be inherited as an autosomal recessive trait.

Dermatophyte Infection in HIV and immunocompromised patients

While dermatophyte infections are no more common in the immunocompromised patient, they may differ clinically. In patients with HIV infections there may be:

  1. more tinea facei,
  2. more widespread and atypical skin lesions, and
  3. a distinct pattern of nail infection characterized by white discoloration spreading rapidly through the nail plate from the proximal nail fold.
Laboratory diagnosis of dermatophyte infection

The mainstays of diagnosis are direct microscopy of skin scales mounted in potassium hydroxide (20%) to demonstrate hyphae, and culture. Scalp hairs may also be examined in a similar way, and the site of arthrospore formation, inside or outside the shaft, determined. Fluorescent whitening agents (Calcofluor) or chlorazol black stain have been used to highlight fungi in scales. Further tests, such as the ability to penetrate hair, may be used to separate similar cultures. Identification of organisms is important, as it will indicate the source of infection in scalp ringworm, for example. When large numbers of children are involved, screening of scalp infections with a filtered ultraviolet lamp (Wood’s light) is useful. Certain species, including M. canis and M. audouinii, cause infected hair to fluoresce with a vivid greenish light. Scalps can also be screened for infection by passing a sterile brush or scalp massager through the hair and plating this directly on to an agar plate.

Treatment of dermatophyte infection

The treatment of dermatophyte infections depends to an extent on the nature and severity of infection. Topical therapy is reserved for circumscribed infections such as athlete’s foot and tinea corporis, not involving hair or nail keratin. Scalp and nail infections, severe or widespread ringworm, and failures of topical therapy are usually treated orally with griseofulvin, itraconazole, or terbinafine.

Specific antifungal drugs in topical form are effective and well tolerated. The important compounds in this group are miconazole, clotrimazole, ketoconazole, and econazole, which are imidazole derivatives, undecenoic acid, and tolnaftate and the allylamine, terbinafine. Generally treatment is given for 7 to 30 days. They are all very similar in their clinical efficacy, but topical terbinafine is particularly rapid in foot infection (≤7 days). Adverse reactions are rare.

For oral therapy the main alternatives are terbinafine, itraconazole, or fluconazole. Terbinafine (250 mg/day) is rapidly effective in most forms of dermatophytosis that require oral therapy and also produces rapid responses in toe nail (12 weeks) and sole infections (2 to 4 weeks), without a high rate of relapse. Side effects include headache and nausea, but loss of taste may also occur. Itraconazole is somewhat similar in its profile, but is given intermittently (200 mg twice daily for 7 days). This course is given once for sole infections but repeated three times at monthly intervals for toe nail infections, as pulsed therapy. Side effects include nausea and abdominal discomfort. Fluconazole is also active and is given in a dose of 150 mg weekly; 300 mg may be necessary for toe nail infections. This side effect profile is similar to itraconazole. All three drugs are extremely rare causes of hepatic toxicity. Griseofulvin is still used for tinea capitis in a dose of 10 to 20 mg/kg daily. Treatment should be continued for at least 6 weeks in tinea capitis. Side effects are not common, but include headache, nausea, and urticaria. The drug can also precipitate acute intermittent porphyria and systemic lupus erythematosus in predisposed subjects.

Scytalidium infections

The organisms Scytalidium dimidiatum (Hendersonula toruloidea) and S hyalinum, can cause a superficial scaly condition that resembles the ‘dry type’ of dermatophyte infection on the palms or soles. Nail plate destruction may also occur, the lateral border of the nail being the initial site of invasion. The disease has been seen in Europe, almost invariably in immigrants from the tropics, particularly the Caribbean, West Africa, India, or Pakistan. Its prevalence in the tropics is unknown, although in some surveys it has been shown to be relatively common. In skin scrapings the tortuous hyphae may resemble those of a dermatophyte, but the organisms do not grow on media containing cycloheximide, which is often incorporated into agar for routine dermatophyte isolation.

Treatment is difficult, but some improvement may follow the use of keratolytic compounds such as salicylic acid. Nail infections do not respond to terbinafine, griseofulvin, or azoles.

Miscellaneous nail infections

Occasionally, fungi other than dermatophytes or Scytalidium species are isolated from dystrophic nails. These include Scopulariopsis brevicaulis, Onychocola canadensis, acremonium, and fusarium species, and certain types of aspergillus. These infections are usually seen in elderly or immunosuppressed individuals. It is often difficult, particularly with aspergillus species, to establish that the organism is playing a pathogenic role.

Pityriasis versicolor (tinea versicolor)

Aetiology

Pityriasis versicolor is a superficial infection caused by Malassezia species, usually M. globosa. Although most common in tropical countries, it has a worldwide distribution. Dermal penetration does not occur.

There are six species of malassezia that can be found on normal skin, the commonest of which are M. sympodialis and M. globosa. In pityriasis versicolor there is transformation of yeast cells to produce hyphae. It is likely that the state of host immunity plays some part in pathogenesis and depression; for instance, endogenous or exogenous corticosteroids potentiate the disease in some individuals. However, it is also commonly seen in normal individuals, and climatic factors or sun exposure are believed to trigger the infection in many cases. There is no effective animal model for studies of this disease.

Epidemiology

Pityriasis versicolor is very common in the tropics, where it may be widespread on the body. Its incidence in temperate climates has increased over the last 20 to 30 years. It is not more common in HIV-infected individuals.

Clinical features

The rash of pityriasis versicolor is asymptomatic or mildly pruritic. Its presents with scaling, confluent macules on the trunk, upper arms, or neck. These may be hypopigmented or hyperpigmented. In some people and in the tropics, other areas including face, forearms, and thighs may be involved.

The diagnosis is rarely confused with other complaints, although eczema or ringworm infections are sometimes considered. Patients are often anxious to exclude leprosy, but the two are unlikely to be mistaken. In vitiligo, depigmentation is complete and there is no scaling.

Laboratory diagnosis

The diagnosis is made by demonstration of the yeasts and hyphae of malassezia in skin scales removed by scraping. Culture is difficult and unnecessary.

Treatment

Topical ketoconazole, miconazole, clotrimazole, or econazole is effective. Oral itraconazole may be used in recalcitrant cases. Whatever the treatment, relapse is common.

Other malassezia-associated conditions

Malassezia yeasts have been implicated in the pathogenesis of a number of other skin diseases such as seborrhoeic dermatitis and a form of itchy folliculitis, malassezia folliculitis. The evidence connecting seborrhoeic dermatitis, one of the most common of skin diseases, and malassezia is largely concerned with the response of antifungal drugs and the observation that improvements in the rash mirror disappearance of organisms from the skin. Severity of the skin condition does not appear to reflect the numbers of yeasts on the skin surface.

Superficial candidosis (candidiasis)

Aetiology

Superficial candidosis is a term used to describe a group of infections of skin or mucous membranes caused by species of the genus Candida. They range in severity from oral thrush to chronic mucocutaneous candidosis, a chronic infection refractory to conventional antifungal treatment.

Candida albicans is the species most frequently involved. It is a saprophytic yeast often found as a commensal in the mouth and gastrointestinal tract, and is commonly present in the vagina. Several factors may influence the incidence of carriage. For instance, oral colonization is more common in hospital staff than in equivalent nonhospital employees. Vaginal carriage is more common in pregnancy. Other factors (Bullet list  1) are known that predispose to conversion from a commensal to a parasitic role with the causation of disease—candidosis. The list includes factors that influence host immunological response, such as carcinoma, AIDS, or cytotoxic therapy; those that disturb the population of other microorganisms, such as antibiotics; and those that affect the character of the epithelium, such as dentures.