What are fungal infections?
The term “fungus” is a general one for plantlike organisms that do not produce their own food through photosynthesis but live as heterotrophs, absorbing complex carbon compounds from other living or dead organisms. Fungi were formerly classified in the plant kingdom (together with bacteria, all algae, mosses, and green plants); more recently, biologists have realized that there are fundamental differences in cell structure and organization separating the lower plants into a number of groups that merit recognition as kingdoms. Fungi differ from bacteria and actinomycetes in being eukaryotic, that is, in having an organized nucleus with chromosomes within the cell. One division of fungi, which is believed to be distantly related to certain aquatic algae, has spores that swim by means of flagella. These water molds include pathogens of fish and aquatic insect larvae and a few economically important plant pathogens, but none have yet been recorded as causing a defined, nonopportunistic human disease. The other division of fungi lacks flagellated spores at any stage in its life cycle. It encompasses most familiar fungi, including molds, mushrooms, yeasts, wood-rotting fungi, leaf spots, and all fungi reliably reported to cause disease in humans.
Fungi that lack flagellated stages in their life cycles are further divided into three classes and one form-class according to the manner in which the spores are produced. The first of these, the Zygomycetes (for example Rhizopus, the black bread mold), produce thick-walled, solitary sexual spores as a result of hyphal fusion; they are a diverse assemblage including many parasites of insects. Species in the genus Mucor cause a rare, fulminating, rapidly fatal systemic disease called mucormycosis, generally in acidotic diabetic patients. The Basidiomycetes, characterized by the production of sexual spores externally on a club-shaped structure called a basidium, include mushrooms, plant rusts (such as stem rust of wheat), and most wood-rotting fungi. There is one important basidiomycetous human pathogen (Filobasidiella neoformans) and a few confirmed opportunists. The Ascomycetes, including most yeasts and lichens, many plant pathogens (such as Dutch elm disease and chestnut blight), and a great diversity of saprophytes growing on wood and herbaceous material, produce sexual spores in a saclike structure called an ascus. One ascomycete, Piedraia nigra, regularly produces its characteristic fruiting bodies on its human host; others do so in culture. In addition, there is a form-class Deuteromycetes consisting of fungi that produce only asexual spores. Most are suspected of being stages in the life cycle of Ascomycetes, but some are Basidiomycetes or are of uncertain affinity. Human pathogens, at least as they occur on the host or in typical laboratory culture, are mostly Deuteromycetes.
Medical mycology (the study of fungi) would occupy only a single chapter in a book on the relationship of fungi to human affairs. Relatively few fungi have become adapted to living as parasites of human (or even mammalian) hosts, and of these, the most common ones cause superficial and cutaneous mycoses (fungal infections) with annoying but scarcely life-threatening effects. Serious fungal diseases are mercifully rare among people with normally functioning immune systems.
The majority of fungi are directly dependent on green plants as parasites, as symbionts living in a mutually beneficial association with a plant, or as saprophytes on dead plant material. One large, successful group of Ascomycetes lives in symbiotic association with algae, forming lichens. Fungi play a critical ecological role in maintaining stable plant communities. As plant pathogens, they cause serious economic loss, leading in extreme cases to famine. The ability of saprophytic fungi to transform chemically the substrate on which they are growing has been exploited by the brewing industry since antiquity and has been expanded to other industrial processes. Penicillin, other antibiotics, and some vitamins are extracted from fungi, which produce a vast array of complex organic compounds whose potential is only beginning to be explored and which constitutes a fertile field for those interested in genetic engineering.
This same chemical diversity and complexity also enable fungi to produce mycotoxins—chemicals that have an adverse effect on humans and animals. Saprophytic fungi growing on improperly stored food are a troublesome source of toxic compounds, some of which are carcinogenic. The old adage that “a little mold won’t hurt you” is true in the sense that common molds do not cause acute illness when ingested, but it is poor advice in terms of long-term health.
A mycotoxicity problem of considerable medical and veterinary interest is posed by Ascomycetes of the order Clavicipitaceae, which are widespread on grasses. Some species of grasses routinely harbor systemic, asymptomatic infections by these fungi, which produce compounds toxic to animals that graze on them. From the point of view of the grass, the relationship is symbiotic, since it discourages grazing; from the point of view of range management, the relationship is deleterious to stock. Claviceps purpurea, a pathogen of rye, causes a condition known as ergotism in humans, with symptoms including miscarriage, vascular constriction leading to gangrene of the limbs, and hallucinations. Outbreaks of hallucinatory ergotism are thought by some authors to be responsible for some of the more spectacular perceptions of witchcraft in premodern times. Better control of plant disease and a decreased reliance on rye as a staple grain have virtually eliminated ergotism as a human disease in the twentieth century.
Fungi exhibit a bewildering variety of forms and life cycles; nevertheless, certain generalizations can be made. A fungus starts life as a spore, which may be a single cell or a cluster of cells and is usually microscopic. Under proper conditions, the spore germinates, producing a filament of fungal cells oriented end to end, called a hypha. Hyphae grow into the substrate, secreting enzymes that dissolve structures to provide food for the growing fungus and to provide holes through which the fungus can grow. In an asexually reproducing fungus, some of the hyphae become differentiated, producing specialized cells (spores) that differ from the parent hypha in size and pigmentation and are adapted for dispersal, but that are genetically identical to the parent. In a sexually reproducing fungus, two hyphae (or a hypha and a spore from different individuals) fuse, their nuclei fuse, and meiosis takes place before spores are formed. Spores are often produced in a specialized fruiting body, such as a mushroom.
Fungus spores are ubiquitous. Common saprophytic fungi produce airborne spores in enormous quantities; thus it is difficult to avoid contact with them in all but the most hypersterile environments. In culture, fungi (including pathogenic species) produce large numbers of dry spores that can be transmitted in the air from host to host, making working with fungi in a medical laboratory potentially hazardous.
Human fungal diseases are generally placed in four broad categories according to the tissues they attack, and they are further subdivided according to specific pathologies and the organisms involved. The categories of disease are superficial mycoses, cutaneous mycoses, subcutaneous mycoses, and systemic mycoses.
Superficial mycoses affect hair and the outermost layer of the epidermis and do not evoke a cellular response. They include tinea versicolor and tinea nigra, deutermycete infections that cause discolored patches on skin, and black piedra, caused by an ascomycete growing on hair shafts. They can be treated with a topical fungicide, such as nystatin, or, in the case of piedra, by shaving off the affected hair.
Cutaneous mycoses involve living cells of the skin or mucous membrane and evoke a cellular response, generally localized inflammation. Dermatomycoses (dermatophytes), which affect skin and hair, include tinea capitis (ringworm of the scalp), tinea pedis (athlete’s foot), and favus, a scaly infection of the scalp. Domestic animals serve as a reservoir for some cutaneous mycoses. The organisms responsible are generally fungi imperfecti in the genera Microsporum and Trichophyton. Cutaneous mycoses can be successfully treated with topical nystatin or oral griseofulvin.
Candida albicans, a ubiquitous pleomorphic fungus with both a yeast and a mycelial form, causes a variety of cutaneous mycoses as well as systemic infections collectively named candidiasis. Thrush is a Candida yeast infection of the mouth that is most common in infants, especially in infants born to mothers with vaginal candidiasis. Vaginal yeast infections periodically affect 18 to 20 percent of the adult female population and more than 30 percent of pregnant women. Candida also causes paronychia, a nailbed infection. Small populations of Candida are normally present in the alimentary tract and genital tract of healthy individuals; candidiasis of the mucous membranes tends to develop in response to antibiotic treatment, which disturbs the normal bacterial flora of the body, or in response to metabolic changes or decreasing immune function.
None of the organisms causing cutaneous mycoses elicits a lasting immune response, so recurring infections by these agents is the rule rather than the exception. Even in temperate climates, under modern standards of hygiene, cutaneous mycoses are extremely common.
Subcutaneous mycoses, affecting skin and muscle tissue, are predominantly tropical in distribution and not particularly common. Chromomycosis and maduromycosis are caused by soil fungi that enter the skin through wounds, causing chronic localized tumors, usually on the feet. Sporotrichosis enters through wounds and spreads through the lymphatic system, causing skin ulcers associated with lymph nodes. Amphotericin B, a highly toxic systemic antifungal agent, has been used to treat all three conditions; potassium iodide is used to treat sporotrichosis, and localized chromomycosis and maduromycosis lesions can be surgically removed.
Systemic mycoses, the most serious of fungal infections, have the ability to become generally disseminated in the body. The main nonopportunistic systemic mycoses known in North America are histoplasmosis, caused by Histoplasma capsulatum; coccidiomycosis, caused by Coccidiodes immitis; blastomycosis, caused by Ajellomyces (or Blastomyces) dermatidis; and cryptococcosis, caused by Cryptococcus (or Filobasidiella) neoformans. Similar infections, caused by related species, occur in other parts of the world.
Coccidiomycosis, also called San Joaquin Valley fever or valley fever, will serve as an example of the etiology of systemic mycoses. The causative organism lives in arid soils in the American southwest; its spores are wind-disseminated. When inhaled, the fungus grows in the lungs, producing a mild respiratory infection that is self-limiting in perhaps 95 percent of the cases. The mild form of the disease is common in rural areas. In a minority of cases, a chronic lung disease whose symptoms resemble tuberculosis develops. There is also a disseminated form of the disease producing meningitis; chronic cutaneous disease, with the production of ulcers and granulomas; and attack of the bones, internal organs, and lymphatic system. A chronic pulmonary infection may become systemic in response to factors that undermine the body’s immune system. Factors involved in individual susceptibility among individuals with intact immune systems are poorly understood.
Histoplasmosis (also known as summer fever, cave fever, cave disease, Mississippi Valley fever, or Ohio Valley disease) is even more common; 90 percent of people tested in the southern Mississippi Valley show a positive reaction to this fungus, indicating prior, self-limiting lung infection. The fungus is associated with bird and bat droppings, and severe cases sometimes occur when previously unexposed individuals are exposed to high levels of inoculum in caves where bats roost. A related organism, Histoplasma duboisii, occurs in central Africa. Blastomycosis causes chronic pulmonary disease, chronic cutaneous disease, and systemic disease, all of which were usually fatal until the advent of chemotherapy with amphotericin B. The natural habitat of the fungus is unclear. Cryptococcus neoformans occurs in pigeon droppings and is worldwide in distribution. The subclinical pulmonary form of the disease is probably common; invasive disease occurs in patients with collagen diseases, such as lupus, and in patients with weakened immune systems. It is the leading cause of invasive fungal disease in patients with Acquired immunodeficiency syndrome (AIDS).
Systemic fungal diseases are notoriously difficult to treat. Chemotherapy of systemic, organismally caused diseases depends on finding a chemical compound that will selectively kill or inhibit the invading organism without damaging the host. Therefore, the more closely the parasite species is related biologically to the host species, the more difficult it is to find a compound that will act in such a selective manner. Fungi are, from a biological standpoint, more like humans than they are like bacteria, and antibacterial antibiotics are ineffective against them. If a fungus has invaded the skin or the digestive tract, it can be attacked with toxic substances that are not readily absorbed into the bloodstream, but this approach is not appropriate for a systemic infection. Amphotericin, itraconazole, and fluconazole, the drugs of choice for systemic fungal infections, are highly toxic to humans. Thus, dosage is critical, close clinical supervision is necessary, and long-term therapy may not be feasible.
Medical mycology textbooks written before 1980 tended to focus on two categories of fungal infection: the common, ubiquitous, and comparatively benign superficial and cutaneous mycoses, frequently seen in clinical practice in the industrialized world, and the subcutaneous and deep mycoses, treated as a rare and/or predominantly tropical problem. Opportunistic systemic infections, if mentioned at all, were regarded as a rare curiosity.
The rising population of patients with compromised immune systems, including cancer patients undergoing chemotherapy, people being treated with steroids for various conditions, transplant patients, and people with AIDS, has dramatically changed this clinical picture. Between 1980 and 1986, more than a hundred fungi, a few previously unknown and the majority common inhabitants of crop plants, rotting vegetable debris, and soil, were identified as causing human disease. The number continues to increase steadily. Compared to organisms routinely isolated from soil and plants, these opportunistic fungi do not seem to have any special characteristics other than the ability to grow at human body temperature; however, the possibility that an opportunistic pathogen might mutate into a form capable of attacking healthy humans is worrisome.
Systemic opportunistic human infections have been attributed to Alternaria alternata and Fusarium oxysporum, common plant pathogens that cause diseases of tomatoes and strawberries, respectively. Several species of Aspergillus, saprophytic molds (many of them thermophilic), have long been implicated in human disease. Colonizing aspergillosis, involving localized growth in the lungs of people exposed to high levels of aspergillus spores (notably agricultural workers working with silage), is not particularly rare among people with normal immune systems, but the more severe invasive form of the disease, in which massive lung lesions form, and disseminated aspergillosis, in which other organs are attacked, almost always involve immunocompromised patients. Ramichloridium schulzeri, described originally from wheat roots, causes “golden tongue” in leukemia patients; fortunately this infection responds to amphotericin B. Scelidosporium inflatum, first isolated from a serious bone infection in an immunocompromised patient in 1984, is being isolated with increasing frequency in cases of disseminated mycosis; it resists standard drug treatment.
Oral colonization by strains of Candida is often the first sign of AIDS-related complex or full-blown AIDS in an individual harboring the Human immunodeficiency virus (HIV). Drug therapy with fluconazole is effective against oral candidiasis, but relapse rates of up to 50 percent within a month of the cessation of drug therapy are reported. Reported rates of disseminated candidiasis in AIDS patients range from 1 to 10 percent. Invasive procedures such as intravenous catheters represent a significant risk of introducing Candida and other common fungi into the bloodstream of patients.
Pneumocystis jiroveci (formely called Pneumocystis carinii), the organism causing a form of pneumonia that is the single most important cause of death in patients with AIDS, was originally classified as a sporozoan—that is, as a parasitic protozoan—but detailed investigations of the life cycle, metabolism, and genetic material of Pneumocystis have convinced some biologists that it is actually an ascomycete, although an anomalous one that lacks a cell wall. Unfortunately, while antibiotics and corticosteroids are used to treat the illness, it does not respond to therapy with the antifungal drugs currently in use.
In general, antifungal drug therapy for mycoses in AIDS patients is not very successful. In the absence of significant patient immunity, it is difficult to eradicate a disseminated infection from the body entirely, making a resurgence likely once drug therapy is discontinued. Reinfection is also likely if the organism is a common component of the patient’s environment.
Given the increasing number of lethal systemic fungal infections seen in clinical practice, there is substantial impetus for a search for more effective, less toxic antifungal drugs. A number of compounds, produced by bacteria and chemically dissimilar to both antibacterial antibiotics and the most widely used antifungal compounds, have been identified and are being tested. It is also possible that the plant kingdom, which has been under assault by fungi for all its long geologic history, may prove a source for medically useful antifungal compounds.
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