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Medical mycology

Contributed by: Carlyn Halde, Jon P. Woods Publication year: 2014

The study of fungi (molds and yeasts) that cause human disease. Some pathogenic molds and yeasts normally reside within soil or derive their nutrition from other organic matter until introduced into the body by inhalation or trauma; others are part of the normal body flora or are transmitted from an infected person. Because the immune status of the host plays an important role in susceptibility to fungal infection, highly immunodeficient persons are likely to develop an opportunistic fungal infection. See also: OPPORTUNISTIC INFECTIONS.

Fungal infections are classified according to the site of infection on the body or whether an opportunistic setting is necessary to establish disease. Fungal infections that occur in an opportunistic setting have become more common due to conditions that compromise host defenses, especially cell-mediated immunity. Such conditions include acquired immunodeficiency syndrome (AIDS), cancer, and immunosuppressive therapy to prevent transplant rejection or to control inflammatory syndromes. Additionally, opportunistic fungal infections have become more significant as severely debilitated individuals live longer because of advances in modern medicine, and nosocomial (hospital-acquired) fungal infections are an increasing problem. Early diagnosis with treatment of the fungal infection and control of the predisposing cause are essential.

Antifungal drug therapy is extremely challenging since fungi are eukaryotes, as are their human hosts, leading to a paucity of specific fungal drug targets and also to problems with toxicity or cross-reactivity with host molecules. Most antifungal drugs target the fungal cell membrane or wall. The “gold standard” for therapy of most severe fungal infections is amphotericin B, which binds to ergosterol, a membrane lipid found in most fungi and some other organisms but not in mammals. Unfortunately, minor cross-reactive binding of amphotericin B to cholesterol in mammalian cell membranes can lead to serious toxicity, especially in the kidney where the drug is concentrated. Azole drugs such as ketoconazole interfere with ergosterol biosynthesis by inhibiting the enzyme lanosterol demethylase, but can also cross-react with mammalian P-450 enzymes. Another class of drugs, the echinocandins, inhibit β-glucan synthesis, thereby interfering with a fungal cell wall component not found in mammalian cells. Recent advances in antifungal therapy include the use of liposomal amphotericin B and newer azoles such as fluconazole and itraconazole, which show reduced toxicity or greater specificity. Conversely, drug resistance in pathogenic fungi is an increasing problem, as it is in bacteria. AccessScience from McGraw-Hill Education Page 2 of 7 www.accessscience.com

Opportunistic diseases

Candidiasis is the most common opportunistic fungal infection, and it has also become a major nosocomial infection in hospitalized patients. Candida albicans is a dimorphic fungus with a yeast form that is a member of the normal flora of the surface of mucous membranes. In an opportunistic setting, the fungus may proliferate and convert to a hyphal form that invades these tissues, the blood, and other organs. Altered host resistance from different causes usually determines the site of invasion and degree of invasion. Abundant growth on the oral mucosa leads to superficial infection with white patches (thrush). Women, especially those who are diabetic or pregnant, may develop a similar invasion of the surface of the vagina (candida vaginitis). In addition, candidiasis may involve the respiratory or urinary tracts, with colonization followed by serious infection. The disease may extend to the blood or other organs from various infected sites in patients who are suffering from a grave underlying disease or who are immunocompromised.

Aspergilli, which are common saprophytic molds, cause a variety of diseases (aspergillosis). For some individuals, a respiratory tract allergy (allergic rhinitis) develops to airborne spores. For others, asthma may develop. These molds, as well as others, are able to colonize burn wounds and the ear canal and to grow in slowly moving mucus in the bronchi of persons with inhalation allergies (allergic bronchitis) as well as within cavities in the lung caused by tuberculosis (aspergilloma). In severely immune compromised individuals, such as those with acquired immune deficiency syndrome (AIDS) or cancer, eventual extension into surrounding normal tissue or the blood usually follows colonization and can be fatal. Some species of aspergilli produce toxins (aflatoxin) when growing on food (peanut products, stored grain); ingestion of the toxin may result in liver destruction or liver cancer. Toxin-related problems appear more commonly in tropical countries. See also: ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS); AFLATOXIN; ALLERGY; ASTHMA.

Mucormycosis, also known as zygomycosis, is an opportunistic fungal disease that can be caused by any of a number of related environmental molds. Most commonly, a ketoacidotic diabetic patient develops a mold infection of the sinus that spreads rapidly to the eye and brain (rhinocerebral mucormycosis). Necrosis of the tissue develops, and the patient dies within only a few days unless the predisposing factors are corrected and therapy is begun.

Cryptococcosis is seen in persons with AIDS, in other immunocompromised persons, and occasionally in individuals with no known predisposing conditions. The infection, which has increased greatly in incidence since 1980, is caused by Cryptococcus neoformans, an environmental yeast that grows abundantly in dried pigeon droppings. Respiratory disease follows inhalation of the yeast, and subsequently infection may spread to the brain and other organs. Meningitis and brain abscess are the most frequently seen manifestations of disease. See also: MENINGITIS.

Pneumonia caused by Pneumocystis carinii is one of the mostcommon and most serious diseases in AIDS patients and some other immunocompromised populations. This organism has presented challenges in laboratory study AccessScience from McGraw-Hill Education Page 3 of 7 www.accessscience.com

and in classification. There is currently no continuous in vitro culture system for P. carinii, and consequently most studies depend on passage of the organism in infected laboratory animals, making it impossible to obtain isolated clonal populations of the organism. It was long considered a protozoan parasite due to its morphology and also to other considerations, such as the presence of cholesterol and lack of ergosterol in its membranes, its consequent insensitivity to amphotericin B, and its sensitivity to some antiprotozoal drugs such as pentamidine. However, it does possess some fungal characteristics, and recently nucleic acid–based typing methods have clearly classified P. carinii as a fungus. An environmental reservoir or niche has not been identified, but it is thought that the organism is inhaled by humans very commonly, establishing a significant infection only when the host is severely immunocompromised. The most common clinical manifestation is severe pneumonia with significant respiratory compromise that can be fatal, but the fungus can also disseminate elsewhere in the body.

Nonopportunistic systemic diseases

Healthy persons can acquire disease from certain pathogenic fungi following inhalation of their fungal spores. The so-called deep or systemic mycoses are all caused by different species of soil molds; most infections are unrecognized and produce no or few symptoms. However, in some individuals infection may spread to all parts of the body from the lung, and so treatment with amphotericin B or an antifungal azole drug is essential. The deep mycoses are caused by certain white soil molds that change into either budding yeasts or spherules when growing within the body or in culture at 98.6◦F(37◦C). Each species of mold has a characteristic pathogenic and saprophytic morphology.

Coccidioides immitis, a mold of desert soil, converts into spherules containing endospores when growing within the body and causes coccidioidomycosis or valley fever. Although 60% of infections produce no symptoms, the other 40% develop symptoms that range from a flulike condition to pneumonia. Of the serious pulmonary infections, 1% spreads to other parts of the body. Meningitis and deep skin or bone lesions often develop.

Histoplasma capsulatum grows in moist, rich soil, often concentrated in areas contaminated by bird or bat droppings, and has a worldwide distribution. In the United States, it is associated mainly with the Mississippi and Ohio river valleys in the Midwest and South. In highly endemic areas, nearly the entire population has been infected. Present or past histoplasmosis in a person is indicated by a positive histoplasmin skin test, which uses an extract of the fungus to detect delayed-type hypersensitivity and is similar to tests for tuberculosis. Once infection has occurred by inhalation of mold spores, the fungus grows as a small budding yeast within mononuclear phagocytes of the body. Most infections produce no symptoms, whereas others bring on symptoms that resemble influenza. A few infected persons develop disseminated disease, with lesions in the spleen, liver, and lymph nodes and ulcerated lesions in the mouth. Once acquired, infection may persist for life even if no symptoms occur after primary exposure, and the persistent infection may reactivate and cause significant disease even years later if the human host becomes immunocompromised. AccessScience from McGraw-Hill Education Page 4 of 7 www.accessscience.com

Blastomycosis and paracoccidioidomycosis are two other deep mycoses. Blastomycosis occurs mostly in the eastern United States; paracoccidioidomycosis is endemic to tropical South and Central America. Following pulmonary infection, widespread ulcerous lesions may develop. In blastomycosis, bone lesions and meningitis often develop, whereas in paracoccidioidomycosis, ulcerated lesions of the mouth and gastrointestinal tract are common. Both diseases are caused by species of pathogenic soil molds that have the specific ability to develop into budding yeasts once they are within the host.

Subcutaneous diseases

Other fungal infections develop when certain species of soil molds are inoculated deep into the subcutaneous tissue, such as by a deep thorn prick or other trauma. A specific type of lesion develops with each fungus as it grows within the tissue. Proper wound hygiene will prevent these infections.

Sporotrichosis, caused by Sporothrix schenckii, appears as a chain of ulcerated lesions on the arm or leg following inoculation of a soil mold. Within the infected tissue, the mold converts into a yeast. Unlike other fungi, Sporothrix is susceptible to treatment with oral potassium iodide.

Chromoblastomycosis and mycetoma also follow inoculation deep into the skin. Each of these clinical diseases can be caused by multiple fungal agents. Chromoblastomycosis appears as persisting ulcerous or wartlike skin lesions and is caused by any of several kinds of black molds. Mycetoma is a chronic tumorlike lesion that drains small grains (colonies) of a mold or actinomycotic agent and can be caused by a number of black or white molds or actinomycetes. Both diseases require early treatment with specific drugs; the responsible agent must be isolated to permit an appropriate choice of drugs.

Actinomycosis and nocardiosis are two bacterial diseases that are caused by agents having characteristics reminiscent of fungi, such as a branching filamentous structure and the production of similar disease patterns. They require specific laboratory identification so that appropriate antibacterial treatment may be given.

Ringworm

Ringworm, also known as dermatophytosis or tinea, is the most common of all fungal infections. Some species of pathogenic molds can grow in the stratum corneum, the dead outermost layer of the skin. Disease results from host hypersensitivity to the metabolic products of the infecting mold as well as from the actual fungal invasion. Tinea corporis, ringworm of the body, appears as a lesion on smooth skin and has a red, circular margin that contains vesicles. The lesion heals with central clearing as the margin advances. On thick stratum corneum, such as the interdigital spaces of the feet, the red, itching lesions, known as athlete’s foot or tinea pedis, become more serious if secondary bacterial infection develops. The ringworm fungi may also invade the hair shaft (tinea capitis) or the nail (onychomycosis). Many pharmaceutical agents are available to treat or arrest such infections, but control of transmission to others is important. See also: FUNGI; YEAST. AccessScience from McGraw-Hill Education Page 5 of 7 www.accessscience.com

Carlyn Halde, Jon P. Woods

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Additional Readings

R. D. Adam et al., Mucormycosis: Emerging prominence of cutaneous infections, Clin. Infect. Dis., 19:67–76, 1994 DOI: http://doi.org/10.1093/clinids/19.1.67

H. S. A. Aluyi, F. D. Otajevwo, and O. Iweriebor, Incidence of pulmonary mycoses in patients with acquired immunodeficiency diseases, Niger. J. Clin. Pract., 13(1)78–83, 2010

K. L. Buchanan and J. W. Murphy, What makes Cryptococcus neoformans a pathogen?, Emerging Infect. Dis., 4:71–83, 1998 DOI: http://doi.org/10.3201/eid0401.980109 AccessScience from McGraw-Hill Education Page 6 of 7 www.accessscience.com

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C. A. Kauffman (ed.), Essentials of Clinical Mycology,2ded.,SpringerScience+Business Media, New York, 2011

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American Society for Microbiology

Coccidioidomycosis: A Reemerging Infectious Disease

Current and Emerging Azole Antifungal Agents

Emerging Disease Issues and Fungal Pathogens Associated with HIV Infection

Endemic Mycoses in AIDS: A Clinical Review

Epidemiology of nosocomial fungal infections

Fungal allergens AccessScience from McGraw-Hill Education Page 7 of 7 www.accessscience.com

Medical Mycology (University of Wisconsin-Madison)

Pneumocystis carinii: what is it, exactly?

Prospects for the development of fungal vaccines

The Dermatophytes

The Evolutionary Biology and Population Genetics Underlying Fungal Strain Typing

Virulence factors of medically important fungi