55 Fungus Infections (Mycoses)

Although today, some 200 fungi are established as pathogenic for humans, causing a wide range of di­verse mycoses (with an incidence measured in mil­lions and a worldwide distribution), through the mid-nineteenth century, only two human diseases (or rather disease complexes) caused by fungi were generally recognized.

Fungi were the first pathogenic microorganisms to be recognized. Toward the end of the eighteenth century and the opening years of the nineteenth, they had been shown experimentally to cause dis­ease in plants and insects, and during the 1840s both ringworm and thrush were shown to be mycotic in origin. For a short period, fungi were blamed for causing many diseases. Cholera, for example, was attributed to fungi. But with the recognition of the major role played by bacteria (and later, viruses) in the etiology of human disease, fungi were neglected and medical mycology became very confused. It has been only since the 1930s, with the deployment of trained mycologists to work in conjunction with clini­cians, that the identity of the pathogenic fungi has been clarified, and studies on their ecology have done much to elucidate epidemiological problems. In general, the geographic distribution of mycoses (which at first tended to coincide with that of medi­cal mycologists) has been established, and the rela­tion of mycoses to other human diseases has been brought into perspective.

Some of the fungi causing human disease show clear adaptations for the pathogenic state, whereas others do not, and it is probable that none is depen­dent on a human or animal host for survival. Most are also pathogenic for animals, both domesticated and wild, which are also subject to mycoses caused by related species able to induce human infections.

Classification

Mycoses (which exhibit a wide range of symptoms) have often been named according to the part of the body affected (e.g., bronchomycosis, dermatomy­cosis, tinea capitis, ringworm of the scalp, athlete’s foot) or the name of the pathogen (e.g., aspergillosis, cryptococcosis, dermatophytosis, rhinosporidiosis), and they have been categorized as cutaneous, subcu­taneous, systemic, opportunistic, and iatrogenic, al­though these divisions are not mutually exclusive. In this study, for convenience, mycoses are consid­ered under ringworm, candidiasis (including thrush, which is oral candidiasis), systemic mycoses, and opportunistic and iatrogenic mycoses.

Ringworm (Tinea, Dermatophytosis)

History

Favus (Latin for “honeycomb”), a distinctive type of ringworm because of the characteristic scutula, was described by Celsus in the first century, A.D., in his De Medicina. He called it porrigo, a term also used by Pliny in his Historia Naturalis of the same cen­tury and by dermatologists up to the nineteenth century. It is now, however, obsolete, having been replaced by tinea (derived from Tineola, the generic name of the clothes moth). Celsus also described the inflammatory lesion of some forms of ringworm, which has been known ever since as the “kerion of Celsus.”

Not until the mid-1840s was the mycotic nature of favus recognized by three independent workers: J. L. Schoenlein and Robert Remak in Berlin, and David Gruby in Paris. The latter also differentiated mi- Crosporosis and the ectothrix and endothrix tricho­phytosis, which he showed to be caused by distinct fιmgi.

A period of mycologic confusion followed, compli­cated by the difficulty of determining the life histo­ries of the pathogens (largely due to deficiencies in culture technique) and settling the question as to whether there was one ringworm fungus or many.

Two historical landmarks in the treatment of ring­worm were the introduction of X-ray epilation for the therapy of head ringworm in the opening years of this century and the introduction of the antibiotic griseofulvin in 1958 as an orally administered antimycotic drug.

Distribution and Incidence

The geographic distribution of the ringworm fungi is interesting. In Sabouraud’s time the distribution cor­responded to that of interested dermatologists. Now the ringworm fungi of most countries have been surveyed, or at least sampled, so that a more accu­rate knowledge of their geographic distribution is available. Some, such as Trichophyton mentagro- phytes (causing tinea pedis and so forth) and Epidermophyton floccosum (tinea cruris), occur worldwide.

Microsporum audouinii (tinea capitis; the classi­cal cause of ringworm in children), which appears to have originated in Europe, is now endemic in North America. Although frequently introduced by Euro­pean children to the tropics, it has never established itself there in the indigenous population. Likewise Trichophyton concentricum (tinea imbricata) is en­demic in Southwest Asia and the South Sea islands, where it was first recorded by William Dampier in 1686 when circumnavigating the globe.

In similar fashion, Trichophyton ferrugineum es­tablished itself in western parts of the Soviet Union, after being introduced by soldiers returning from the Far East. Classical favus in western Europe is caused by Trichophyton schoenleinii, but typically by Trichophyton violaceum in North Africa and the Mediterranean basin. Microsporum canis (tinea canis [cat and dog ringworm], tinea capitis, and tinea corporis), coextensive with cats and dogs as pets, has become endemic in New Zealand in feral cats. Human infections are also contracted by con­tact with ringworm in cattle (Trichophyton verru­cosum), horses, and other farm animals. Mi- crosporum gypseum (which could be considered as an opportunistic dermatophyte) has a worldwide distri­bution, the outbreaks in humans usually being spo­radic, short-lived, and sometimes traceable to a group of people having access to the same soil in which the pathogen is an inhabitant.

Candidiasis (including “Thrush”)

Reports and studies of the many and diverse manifes­tations of candidiasis caused by Candida albicans and other species of Candida (e.g., Candida guiltier - mondii, Candida krusei, Candida Stellatoidea, Can­dida tropicalis) have made a major contribution to the literature of medical mycology, as they still do. As for ringworm, a stable taxonomic base was neces­sary to underpin both clinical and microbiological observations and research on this mycotic complex because C. albicans was described as new on a num­ber of occasions and acquired some 90 specific names distributed among a dozen genera. Much confusion resulted. One taxonomic error that the reader must still remember when consulting the earlier litera­ture is the assignment back in 1890 of the thrush fungus to the genus Monilia because “moniliasis” became the generally accepted, worldwide name for candidiasis.

Thrush (Oral Candidiasis)

This disease (infection of the mucous membrane, especially of the mouth) in infants was referred to in the Hippocratic corpus (400 B.C.) and later by Galen and other classical writers under the heading “aphthae.” Over the centuries, references to thrush in the young, as a feature of terminal illness and as a vaginal infection in women, continued, with the clinical descriptions being given increasing preci­sion (see Higgs 1972). Candidiasis, like ringworm, was demonstrated to be mycotic by three indepen­dent workers in the 1840s: B. Langenbeck in Berlin, F. T. Berg in Stockholm, and Gruby in Paris. Berg, who had studied under Gruby, subsequently pub­lished on thrush in infants and in 1844, J. H. Ben­nett described in Edinburgh what was probably C. albicans from the human lung.

A wide range of pathological conditions attributed to Candida were subsequently recorded; virtually all parts of the body, with the notable exception of the hair, were susceptible to such infection under favorable conditions. Numerous surveys have shown that many apparently normal individuals carry C. albicans: 10 percent, in the mouth; about the same proportion of women, in the vagina (with higher values in pregnant women); and 25 percent, in the feces and gut. Although C. albicans has occasionally been isolated from soil, from hospital bedding (the incidence of Candida in hospital patients is often high), and from a wide range of animals (especially domestic animals and birds), it is clear that most human infections have an endogenous origin. Infec­tion (clinical candidiasis) seems always to be deter­mined by predisposing factors that may be environ­mental: For example, having the hands frequently wet favors paronychia (candidiasis of the nail fold). Age, debility, dentures, and drug therapy also can predispose one to infection.

The patenting of the orally administered antibi­otic nystatin in 1956 was a notable contribution to the therapy of candidiasis, which has been the sub­ject of several monographs.

Systemic Mycoses

The pathogens of the five systemic mycoses to be considered all show specialization for parasitism. All are dimorphic - that is, the saprobic state is mycelial (filamentous) and the pathogenic phase is unicellular and yeastlike. It is possible to effect the mycelial-to-yeast conversion in vitro. For Blas­tomyces dermatitidis (blastomycosis), the transfor­mation is temperature dependent; for the others, nutritional adjustments are also necessary. On first description there was a tendency to assign these pathogens to the Protozoa.

Coccidioidomycosis

The first case of this disease was described from Argentina by Alejandro Posadas in 1892. About the same time a case was also studied in California by E. Rixford and T. C. Gilchrist, who attributed the cause to a protozoan, which, in 1896, they named Coccidioides immitis. In 1905, however, a fellow American, W. Opuls, established its mycotic nature. It was known only as a rather rare, acute, or chronic disseminating and often fatal disease. In 1938, Myrnie A. Grifford and E. Dickson, independently, and then in collaboration, established that “valley fever,” prevalent in the San Joaquin Valley of Cali­fornia, was a mild form of coccidioidomycosis. Fur­ther investigations showed mild, often Subclinical, respiratory Coccidioides infection to be widespread in arid parts of California and neighboring states and to induce lifelong immunity to subsequent at­tack. This immunity is demonstrable by a positive skin test with an antigen (coccidioidin) prepared from cultures of the pathogen.

C. immitis was isolated from soil, and when Em­mons showed desert rodents to be infected, they were at first thought perhaps to constitute an animal reser­voir of infection. But it soon became clear that these rodents, like humans, were subject to infection by this soil-inhabiting fungus. It also became clear that the dry, airborne (or dustborne) spores of the patho­gen were extremely infectious (there have been many accidental laboratory infections) and that coccidioido­mycosis could be contracted, for example, by servic­ing automobiles that had been driven through areas where the mycosis was endemic. In addition, dust storms were found to increase the rate of conversion from negative to positive skin tests with Coccidioidin in local inhabitants and their domestic animals. It may be noted, that although light- and dark-skinned peoples appear to be equally susceptible to C. immitis infection, the disease is more likely to be systemic in those with pigmented skin. Filipinos and blacks, along with the Portuguese, are those chiefly em­ployed in agriculture in the districts where coccidioi­domycosis is endemic.

Coccidioidomycosis is endemic and of high inci­dence in warm dry regions (the Lower Sonoran Life Zone) of the United States and Mexico and also in parts of Central and South America where the clima­tic conditions are similar. Records from other parts of the world are of doubtful validity.

Histoplasmosis

This disease (Histoplasma capsulatum) shows many parallels with coccidioidomycosis and may be viewed as the humid region equivalent. At first considered a rare protozoan disease, it has been shown to be mycotic, and to have a mild form affecting millions of the inhabitants of the midwestern United States. The pathogen shows a predilection for bird (chicken, starling) and bat droppings.

Blastomycosis and Paracoccidioidomycosis The former (North American blastomycosis), caused by B. dermatitidis, and the latter (South American blastomycosis), caused by Paracoccidioides brasilien- sis, are both chronic granulomatous diseases of the skin and internal organs, characterized by budding cells of the pathogen in the infected tissues. The two were at first confused both with each other and with cryptococcosis (called “European blastomycosis” or “torulosis” and caused by Cryptococcus neo formans), but these three mycoses are now well differentiated.

Blastomycosis was first described by Gilchrist in the United States in 1894, and paracoccidioidomyco­sis, by Adolfo Lutz in Brazil during 1908. Neither has a mild form such as that characteristic of coccidioidomycosis and histoplasmosis, and though there have been a few records of both pathogens from soil, the natural habitats of both these fungi have not been established with certainty.

Paracoccidioidomycosis is confined to Central and South America, where it has been the subject of intensive study. Blastomycosis is endemic to the western and southeastern states of the United States, where epidemics occur; there are also records of the disease from a number of tropical African countries.

Sporotrichosis

This disease shows certain parallels with mycetoma but is included here because the causal pathogen is dimorphic. It is a cutaneous and subcutaneous infec­tion characterized by the development of nodular le­sions, often in a series affecting successive lymph nodes. Infection is frequently initiated by a lesion, often of the hand. It is caused by Sporothrix schenckii and was first described in the United States by B. R. Schenck in 1898. Subsequently many cases were re­ported from Europe, especially France, where the disease was the subject of a massive monograph, Les Sporotrichoses, by C. L. de Beurmann and H. Gougerot in 1912. Sporotrichosis, which is sporadic in north temperate regions, has also been recorded in Central and South America. In Uruguay, J. E. Mackinnon (1949) attempted to correlate incidence of the disease with the weather, and obtained evidence that infection occurred during periods of moist warm weather, which he suggested encouraged growth of the pathogen on plant material from which humans are infected. S. schenckii is one of the rare fungus pathogens of humans that has been shown experimen­tally to cause disease in plants (carnations). The larg­est outbreak of sporotrichosis ever recorded was in the Witwatersrand gold mines in South Africa during 1941-3, when approximately 3,000 miners were in­fected. The epidemic was brought under control by potassium iodide therapy for the men affected and fungicidal treatment of the mine timbers from which the infection was contracted.

Opportunistic and Iatrogenic Infections

To categorize some fungal infections as opportunistic is convenient, if artificial. Most fungi pathogenic for humans, even those causing such significant mycoses as coccidioidomycosis and histoplasmosis, seem to have some natural habitat in the environment and infect humans only incidentally. Candida infections are different in that they are endogenous, and some types of ringworm are also to some extent opportunis­tic. The mycoses to be considered next include exam­ples of infection resulting from the exposure of a susceptible individual to the normal fungus flora of the environment, and attention is drawn to the in­creased risk shown by compromised patients.

Mycetoma

This disease is a well-defined clinical entity charac­terized by swelling that affects the subcutaneous tissues, with sinuses discharging grains or granules of the pathogen, which vary in color from white through yellow, red, and brown to black. The foot is most frequently involved (“Madura foot”), but the hand or other part may be infected. Its geographic distribution is mainly tropical.

The condition was first recorded in the Indian Vedic Medical treatises (c. 2000—1000 B.C.) as padaaυal- mika (“foot ant-hill”) and first described in modem times from southern India by members of the Indian Medical Service during the mid-nineteenth century. H. Vandyke Carter, who coined the designation “mycetoma,” wrote a monograph on the disease in 1874. Carter suspected the disease to be mycotic and submitted material to the Rev. M. J. Berkeley, the leading British mycologist of the time, who described a now unidentifiable fungus he obtained from the material as a new species. From the turn of the cen­tury onward, more than 25 diverse fungi (including representatives of the genera Acremonium, Asper­gillus, Curvularia, Leptosphaeria, Madurella, and Pseudallescheria) and actinomycetes (aerobic species of Actinomadura, Nocardia, and Streptomyces), re­sponsible for the condition, were identified by work­ers in North Africa and elsewhere, with the color of the grains often providing a clue to the identity of the pathogen.

Carter distinguished “melanoid” and “ochroid” mycetoma, and, as his illustrations show, his black­grained form was caused by the fungus that E. Brumpt in 1905 taxonomized as Madurella myceto­matis, which is the most important cause of myce­toma. In 1894, H. Vincent had described and named the actinomycete that he had isolated from yellow­grained mycetoma from Algeria as Streptothrix madurae (now designated Actinomadura madurae). Later, when differentiating the two classes, research­ers A. J. Chalmers and R. G. Archibald at the Well­come Laboratory for Tropical Medicine at Khartoum in the Sudan introduced the term “madura mycosis” for mycetoma caused by actinomycetes. Today the terms “Eumycetoma” (or “Eumycotic mycetoma”) and “Actinomycetoma” (or “Actinomycotic myce­toma”) are preferred. Classical actinomycosis caused by the anaerobic Actinomyces Israeli, which gives rise to yellow grains (“sulfur granules”), is excluded from the complex.

There have been many publications on the inci­dence and etiology of mycetoma, which occurs most frequently in a band of the tropics north of the equator extending from India, across Africa, to Cen­tral and South America. Incidence is particularly high in India, the Sudan, and Senegal (where M. mycetomatis predominates) and Mexico (where actinomycetoma predominates). All these regions are hot and arid. Pseudallescheria boydii seems to favor more humid conditions, with species of Nocardia responsible for mycetoma in temperate Europe and North America. Madurella grisea is lim­ited to South America, whereas Cephalosporium in­fections are cosmopolitan.

It was early thought probable that infection was initiated by injury, and a correlation between mycetoma and injury from plant thorns has fre­quently been made. Sometimes the pathogen may have been growing as a saprobe on the thorns (Lepto- sphaeria Senegalensis and Pyrenochaeta romeroi have been isolated from such sites, and M. myce­tomatis will grow on dead wood in sterile water); or the thorn may provide the point of entry for an organism present in the environment (dry granules from mycetoma have a long survival time), espe­cially in soil from which pathogenic species of Nocardia and P. boydii have been isolated. All this evidence points to mycetoma being a typical opportu­nistic infection.

Cryptococcosis

This disease is a subacute or chronic infection of the lungs, skin, or other parts, especially the central nervous system, caused by the yeast Cryptococcus neoformans, which is widely distributed in nature and is sometimes the dominant organism in the drop­pings and debris of pigeon roosts. Although the pi­geon is not infected and the yeast survives passage through the bird, human cases have frequently been associated with inhalation of the pathogen when clearing out old pigeon roosts. The most frequent infections are Subclinical and self-limiting, with fa­tal and more generalized infection occurring mostly in debilitated patients or in those “compromised” by drug treatment.

First recorded in Europe in 1894, human cryptococ­cosis has a worldwide distribution. In 1946, L. B. Cox and Jean C. Tolhurst published a monograph, based on 13 Australian cases termed “torulosis” caused by Torula histolytica; later a very comprehen­sive study of the disease was published by M. L. Littman and L. E. Zimmerman (1956).

Rbinosporidiosis

This disease, an infection of mucous tissue, espe­cially of the nose, results in the development of large polyps and is exceptional among mycoses in that the causal agent, Rhinosporidium seeberi, has not been cultured and its taxonomic position is uncertain. Outbreaks of the disease, which attacks both hu­mans and animals (especially bullocks set to the plough), have been associated with water and the soil. Rhinosporidiosis was first reported from Argen­tina in 1900, but it occurs sporadically throughout the tropics, the highest incidence being in southern India and Sri Lanka. A monograph was published by J. H. Ashworth (1923) in Edinburgh from a case involving an Indian student at the university.

Aspergillosis and Mucormycosis

Species of Aspergillus and mucoraceous fungi are a conspicuous and ubiquitous component of what has been called “common mold.” They are therefore not infrequently found as contaminants of cultures from morbid material and may be mistaken for patho­gens. On the other hand, human infections by these and similar molds do occur sporadically and have been reported worldwide.

The pathogenicity of Aspergillus fumigatus is well established. It is widespread in the environment; found on decaying vegetation, it has spores that are readily airborne. Because its growth is favored by high temperatures, and it is customary to incubate bacterial cultures at 37^o C (a temperature detrimen­tal to many common molds); A. fumigatus frequently occurs as a contaminant of cultures from sputum and other pathological material. Thus, its signifi­cance, when it is detected, is often uncertain, and clinical and other evidence must be considered in its detection.

A. fumigatus is able to cause fatal infections, par­ticularly in birds in which it was first recorded early in the nineteenth century, lining the airsacs with a profuse Sporulating growth. J. B. G. W. Fresenius in 1850 proposed the name Aspergillus fumigatus based on an isolate from a bustard {Otis tarda). Ru­dolf Virchow in Germany in 1856 described human pulmonary aspergillosis caused by the same species. The classical cases of human pulmonary aspergil­losis were those of French pigeon squab feeders in the late 1890s, who chewed in their own mouths the grain used for fattening the birds. Interest in aspergillosis in France was then at its height.

Several other species of Aspergillus are patho­genic. Aspergillus niger is often associated with in­fection of the ear, whereas aspergillomas or “fungus balls” Sporulating growths of the pathogen in lung tissues or cavities are not uncommonly associated with pulmonary disease.

Diverse mucoraceous fungi are regularly, if spo­radically, recorded in north temperate countries as responsible for human infections, especially of the rhino-facial-cerebral region when the outcome is fa­tal. Debility is a predisposing factor.

Dependent Mycoses

The attribution of disease to the human “constitu­tion” has a long history. Even at the beginning of the nineteenth century, dermatologists, unable to accept the concept of pathogenicity, were attributing ring­worm in children to constitutional factors, and nutri­tion does apparently affect symptom expression. Dur­ing World War II, for example, ringworm symptoms disappeared in European prisoners held under star­vation conditions by the Japanese, only to reappear on the restoration of a full diet. Also, tinea capitis (M. audouinii) in children, although a persistent infection, resolves spontaneously at puberty for rea­sons not yet fully understood. Tinea pedis has been claimed as an occupational disease of coal miners and soldiers who wear heavy boots. It is well estab­lished that Candida infection is affected by preg­nancy, and that metabolic disorders such as diabetes are also frequently associated with the disease.

Recently, iatrogenic mycoses have been aggra­vated by or have resulted from the use (or abuse) of antibacterials, which can cause a change in oral conditions whereby bacterial competition is elimi­nated and candidosis is thus induced. In addition, the introduction of heart surgery and organ trans­plantation following the use of immunosuppressive drugs has resulted in Candida endocarditis and mycotic septicemia so that antimycotic therapy is now a routine supplementary practice.

Geoffrey C. Ainsworth

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