Mycotic Infections

GENERAL CONCEPTS:

The fungi represent a diverse, heterogeneous group of eukaryotes. Most of these organisms are plant pathogens and relatively few cause disease in humans.
In nature, fungi generally grow by secreting enzymes that digest tissues but some are actually predacious.
The growth of the fungi generally involves two phases; vegetative and reproductive.
- In the vegetative phase, the cells are haploid and divide mitotically. Most fungi exist as molds with hyphae but some fungi exist as unicellular yeast cells. Some fungi can change their morphology and are termed dimorphic. For example, Candida is found in the yeast form at 37°C but changes to the mold form at 25°C.
- In the reproductive phase, fungi may undergo either asexual or sexual reproduction. Asexual reproduction involves the generation of spores; sexual reproduction requires specific cellular structures that are used for taxonomic differentiation.

The fungi are classified based on the characteristics of their sexual phase. For the kingdom Fungi, there are two phyla; Zygomycota and Dikaryomycota. The phylum Dikaryomycota is further divided into two subphyla; Ascomycotina and Basidiomycotina. A third group of the fungi for which a sexual phase has not been observed is termed Deuteromycotina. The table outlines this classification and gives representatives of each.

Group	Representative Genera
•Phylum Zygomycota	Rhizopus, Absidia, Mucor
•Phylum Dikaryomycota
•Subphylum Ascomycotina	Trichophyton, Histoplasma, Blastomyces
•Subphylum Basidiomycotina	Cryptococcus
•Form-class Deuteromycotina	Candida, Epidermophyton, Coccidioides

Fungal membranes contain ergosterol rather than cholesterol and this provides a target for chemotherapy (azole derivatives interfere with ergosterol synthesis). Nonetheless, most anti-fungal antibiotics are still relatively toxic to the human host.

DISTINCTIVE PROPERTIES:

Mycotic infections are classified by the tissue levels that are colonized.
- Superficial infections are generally limited to the outer layers of the skin and hair.
- Cutaneous infections are located deeper in the epidermis, hair and nails.
- Subcutaneous infections involve the dermis, subcutaneous tissues and muscle.
In addition, mycotic infections may be systemic, generally originating in the lungs.
Finally, some mycoses are termed opportunistic, and these may involve a variety of body sites.

The following table outlines these different types of mycotic infection, giving examples of representative agents.

Type and Sites of Infection	Representative Diseases	Representative Genera
Superficial: Limited to outer layers of skin and hair.	Pityriasis versicolor (skin) Tinea nigra (skin) Black/white piedra (hair)	Malassezia Exophiala Piedra/Trichosporum

Cutaneous: Involves deep epidermis and keratinized body areas (skin, hair, nails). Diseases are generally cosmetic, not life-threatening.	Diseases of the skin are termed Tinea; Diseases of hair and nails are termed Dermatophycoses.	Trichophyton Microsporum Epidermophyton

Subcutaneous: Involves dermis, subcutaneous tissues and muscle. Fungi are generally implanted in skin; fungal growth produces a lesion.	Lymphocutaneous sporotricosis Chromoblastomycosis Eumycotic mycetoma	Sporothrix Foncecaea Pseudallescheria Many others

Systemic: Originate in lungs, phagocytosis by macrophages, spread to many organs. Most primary infections are inapparent. Progression may produce pulmonary symptoms or ulcerative lesions. Host responses produce formation of syncytia, fibrous tissue, granulomas and calcified lesions. Representative organisms are dimorphic, except for Cryptococcus, which is a yeast.	Histoplasmosis: Endemic in Ohio and Mississippi Rivers valleys, most infections are asymptomatic.	Histoplasma capsulatus
	Blastomycosis: Endemic in Ohio and Mississippi Rivers valleys, important veterinary problem	Blastomyces dematitidis
	Paracoccidioidomycosis: Endemic in Central and South America, primarily Brazil	Paracoccidioides braziliensis
	Coccidioidomycosis: Endemic in Southwestern United States	Coccidioides immitis
	Cryptococcosis: Worldwide distribution. Most common clinical presentation is meningitis.	Cryptococcus neoformans

Opportunistic: These organisms generally have a low potential for virulence but can produce severe disease involving a variety of body tissues.	Candidiasis Aspergillosis Zygomycosis	Candida albicans Aspergillis Rhizopus

PATHOGENESIS:

Mycotic disease is often a consequence of predisposing factors including age, stress or other pathologic conditions (e.g. cancer, diabetes, AIDS).
Only the dermatophytes (Trichophyton, Microsporum) and Candida are communicable from human to human. The other agents are acquired from the environment (plants, soil, etc.).
Fungi generally cause one of three distinct tissue responses;
1. chronic inflammation (scarring, accumulation of lymphocytes)
2. granulomatous inflammation (collections of modified epithelial cells, lymphocytes)
3. acute suppurative inflammation (vascular congestion, exudation of plasma, accumulation of PMNs).
Some of the tissue responses may be due to mycotoxins, which are fungal metabolites that are toxic to the host. Some agents produce LPS-like endotoxins or hemolysins or steroid-like toxins that affect the nervous system
Aspergillus produces a toxin called aflatoxin that has a strong association with liver cancer. For example, in Thailand, where people generally consume about 25-times more aflatoxin in their diets, the incidence of cancer is about 10-fold greater.
Systemic mycoses are generally asymptomatic but may have generalized symptoms including low grade fever, shaking chills, night sweats, malaise or appetite loss.

HOST DEFENSES:

Host defenses against the fungi include nonspecific and specific factors:
- Nonspecific defenses include the skin (lipids, fatty acids, normal flora), internal factors (mucous membranes, ciliated cells, macrophages), blood components, temperature, genetic and hormonal factors. In other words, both physical and chemical factors and phagocytic defenses play major roles in prevention and control of mycotic disease.
- Specific defenses include both humoral and cell-mediated. The role of humoral defenses is somewhat controversial, since certain antibodies are not protective. It is possible that high titers of certain antibodies actually suppress the cell mediated defenses. Nevertheless, some antibodies may be protective (e.g. antitoxins or opsonins). Generally, however, the cell-mediated defenses are probably more important. Acquired resistance is usually T-cell mediated and persons with compromised cell-mediated defenses generally show more disseminated disease.

EPIDEMIOLOGY:

Dermatophytes may be communicated from person to person by combs, towels, etc. These infections (termed "tineas" when affecting the skin) include ringworm, athlete's foot, jock itch, etc. Candida is a member of the normal vaginal flora; candidiasis is often associated with diabetes.
In some cases of mycosis, occupation seems an important contributor. For example, Sporothrix is normally found in woody plants; hence, agricultural workers acquire disease more often. Similarly, Histoplasma is often found in bird or bat excreta; hence spelunkers (caves) or persons involved in community clean up may acquire more often.
Most of the systemic diseases are geographically distributed; histoplasmosis and blastomycosis predominate in the Ohio and Mississippi Rivers valleys, paracoccidioidomycosis is found primarily in Brazil, coccidioidomycosis predominates in the Southwestern United States while cryptococcosis has a worldwide distribution.

DIAGNOSIS:

Clinical: For the dermatophytes, appearance of the lesions is usually diagnostic. For systemic mycoses, the epidemiology and symptomology are useful clues.
Laboratory: Treatment of skin scrapings with 10% potassium hydroxide can reveal hyphae or spores. Most fungi can be grown on Sabouraud's dextrose agar but they are often very difficult to speciate. Some fungi show a yellow fluorescence under 365 nm ultraviolet light. Skin testing for a delayed hypersensitivity response is useful for epidemiologic purposes but often not for diagnosis.

CONTROL:

Sanitary: Control by sanitary means is difficult, but the incidence of communicable disease can be reduced by good hygiene.
Immunological: No vaccines are currently available.
Chemotherapeutic: Many antifungals are available but some are very toxic to the host and must be used with caution. Topical powders and creams often contain tolnaftate or azole derivatives (miconazole, clotrimazole, econazole) and are useful against superficial dermatophytes. Hair or nail disease may be treated with oral griseofulvin, but it is rather toxic. Sporotrichosis may be treated using potassium iodide or amphotericin B (oral). Systemic infections are generally treated by amphotericin B, 5-flourocytosine, miconazole or ketoconazole.