- Email: [email protected]
Diseases Caused by Fungi
Diseases Caused by Fungi DH Walker, University of Texas Medical Branch-Galveston, Galveston, TX, USA MR McGinnis, University of Texas Medical Branch-Galveston, Galveston, TX, USA; University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Schreiner University, Kerrville, TX, USA; American College of Microbiology, Washington, DC, USA ã 2014 Elsevier Inc. All rights reserved.
Glossary Conidia Highly stable spores that are produced by fungi are released into the air and, upon implanting in a suitable environment, germinate and grow. Dimorphism The characteristic of having two life-forms for different environments, for example, a complex sporeproducing form at environmental temperatures (e.g., at 25 C) and a yeast form at higher temperatures (e.g., 37 C body temperature). The fungal species that are most often pathogenic for humans are dimorphic, releasing spores into the air that are inhaled, convert into yeast, and initiate infection in the lung. Hypha A long narrow tubular structure a few micrometers in diameter that contains fungal cells that in some species are separated from one another by septal walls.
Characteristics of Fungi Fungi belong to their own kingdom of eukaryotic organisms classified in the eukaryote domain because they lack chlorophyll and vascular tissue and live by decomposing and absorbing organic matter from dead or living sources. A critical role of many fungi in nature is breaking down and recycling nutrients of dead plants. Other fungi are symbionts of plants and animals. One distinguishing feature of fungi is the nature of their cell wall that contains chitin, which is similar to the exoskeleton of insects and arachnids. Fungi include unicellular yeasts that propagate by budding to molds that produce multicellular filaments (hyphae) that are often produced in specialized spore-forming structures called fruiting bodies.
Ecological Niches of Fungi Humans are the natural ecological niche of a few fungi such as Candida albicans that resides in the mouth, in the gastrointestinal tract, in the vagina, and on the skin as skin colonizers such as Malassezia furfur. Anthropophilic dermatophytes such as the pathogenic members of the genera Epidermophyton, Microsporum, and Trichophyton that cause ringworm, athletes foot, and jock itch. Most fungi reside in the soil or on decaying organic matter and produce spores, which are released into the air and spread to other suitable ecological niches where they can germinate and grow.
Mycology A distinct field with a unique body of knowledge that is expressed in what amounts to its own language consisting of words for the specialized fungal structures and concepts. Knowledge of at least a few of them is necessary. Pseudoepitheliomatous hyperplasia Squamous epithelial cell proliferation that somewhat resembles squamous cell carcinoma of skin. Pseudohypha A longitudinal series of budding yeast cells that remain connected to one another, thus superficially resembling a hypha. Yeast A spherical or oval single-celled fungus that propagates by budding to form a daughter cell.
hyphae, the nuclei of yeast, the doubly refractive cell wall of Blastomyces, and the endospore-containing spherule of Coccidioides. The extracellular eosinophilic product of Pneumocystis, colonies of fungi (grains and sclerotia) in eumyetomas and in fungus balls, and the clear spaces around yeast cells in tissue containing encapsulated Cryptococcus and the tissue reaction to the invasive fungi are also observable. However, special histochemical methods, such as Gomori methenamine silver stain, demonstrate clearly the cell wall of yeasts, hyphae, pseudohyphae, and spherules. Periodic acid– Schiff method also stains these structures. Mucicarmine and alcian blue stains for mucin identify the mucopolysaccharide capsule of Cryptococcus neoformans, and the Fontana–Masson stain detects melanin-like substances derived from dihydroxyphenylalanine in capsule-deficient Cryptococcus. These stains are quite useful for establishing a histopathologic diagnosis and confirming invasion of viable tissue.
Spectrum of Pathogenicity
Hematoxylin and eosin staining, the routine method for histopathologic evaluation of tissue sections, often reveals the
There are no fungi that are obligate human pathogens that must cause human disease in order to complete their life cycle and survive. Thus, to some degree, all fungi are opportunists especially in people whose immune system is compromised to some degree. The most pathogenic agents, the dimorphic fungi, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, and Paracoccidioides brasiliensis, are capable of establishing an infection even in immunocompetent persons. However, these infections are usually subclinical, causing asymptomatic infection or mild undiagnosed self-limited disease. Histoplasmosis, coccidioidomycosis, and paracoccidioidomycosis can be lifethreatening diseases in immunocompromised patients.
Pathobiology of Human Disease: A Dynamic Encyclopedia of Disease Mechanisms
http://dx.doi.org/10.1016/B978-0-12-386456-7.01710-X
Stains for Microscopic Visualization of Fungi in Tissue
217
218
Host-Pathogen Interactions | Diseases Caused by Fungi
In fact, opportunistic infections usually refer to diseases caused by fungi that are ubiquitous and cause no disease in immunocompetent hosts. There is a spectrum of compromised host defenses that ranges from a subtle, unrecognized defect in a single immune element to severe deficiencies involving many components of the immune system. Infections caused by Aspergillus species or Rhizopus species are examples of opportunistic infections that can cause life-threatening infections in some patients.
per microliter. In the setting of severe immunodeficiency, Histoplasma proliferates and spreads throughout the body infecting most prominently mononuclear phagocytes of the reticuloendothelial system. The accumulations of Histoplasmacontaining macrophages are often visible grossly in organs such as the spleen. Granulomas and multinucleated giant cells may be absent in patients with severely compromised cellular immunity.
Coccidioidomycosis Endemic Dimorphic Mycoses Soil characteristics, plant diversity, temperature, humidity, and other factors result in the evolution and establishment of particular fungi in certain ecological niches. In the United States, H. capsulatum infections occur mainly in the broad Mississippi and Ohio River valleys, C. immitis in the Sonoran Desert of the southwest, and B. dermatitidis in the central and southeastern states. Paracoccidioides is endemic in tropical and subtropical Latin America.
Histoplasmosis H. capsulatum resides in the soil, especially in environments heavily enriched with avian or bat excreta such as chicken coops and caves. Humans inhale spores released into the environment by the vegetative or mold form of the fungus, which is different from the yeast form that occurs in tissue. Dimorphism describes the ability of the fungus to grow in two entirely different growth forms based upon the temperature of incubation. The inhaled spores germinate, and 2–4 mm diameter yeasts propagate by narrow-based budding in tissue where they reside principally intracellularly in macrophages. The primary pulmonary focus of infection stimulates a neutrophil influx followed by macrophages. Cell-mediated immunity directed mainly by CD4þT cells produces cytokines including gamma interferon, interleukin-12, tumor necrosis factor, and granulocyte–macrophage colony-stimulating factor that activate macrophages to inhibit Histoplasma growth. Histoplasma spreads from the lung by lymphatic vessels to hilar lymph nodes. In most persons, immune control of the infection results in the formation of granulomas with multinucleate giant cells and fibrous encapsulation of the lesion, which may or may not contain caseous necrosis and undergo calcification. The observation of multiple subpleural and hilar lymph node calcifications is more likely healed histoplasmosis than a tuberculosis Ghon complex, which seldom has more than one subpleural focus. Prior to the development of skin test reagents, tuberculosis and histoplasmosis were often confused with each other. During the early part of the last century, a number of histoplasmosis patients were placed in tuberculosis sanatoriums because they were misdiagnosed. Many of these patients then developed tuberculosis. Humans do not develop sterilizing immunity. Histoplasmosis is a serious threat to patients with acquired immunodeficiency syndrome in whom reactivation of latent infection may occur when the CD4þT cell count falls below 200 cells
C. immitis and C. posadasii reside in nature as 2–4 mm diameter septate hyphae, some segments of which transform into 2–4 mm by 5–6 mm barrel-shaped arthroconidia. These arthroconidia are inhaled and cause asymptomatic infection or selflimited pneumonia associated with hilar lymphadenopathy in most persons, similar to histoplasmosis. The initial polymorphonuclear leukocyte response partially inhibits the growth but does not kill the Coccidioides. Cellular immunity with production of T helper cytokines, such as IL-12, activates macrophages leading to the formation of granulomas and clearance of the fungi. Progressive infection can result in chronic pulmonary cavities. Disseminated disease can occur in immunosuppressed patients and is observed more often in males, African Americans, and Filipinos. Exposure of large numbers of people can occur following dust storms in the endemic areas of California and Arizona. In tissue, the arthroconidia transform into round cells that develop into thick-walled endosporulating spherules that are 5–100 mm in diameter in which many endospores accumulate. Endospores 2–5 mm in diameter, which can develop into a second generation of spherules, are released from spherules and stimulate a suppurative reaction. The entire lesion contains central suppuration surrounded by granulomas, undergoes caseous necrosis that may or may not calcify, and is encapsulated by fibrosis surrounded by lymphocytes. Such lesions, which may occur also in histoplasmosis, can appear similar to a peripheral lung tumor and be resected for histopathologic diagnosis. Immunocompromising conditions predispose humans to disseminated infection that often involves the meninges, bone, and skin.
Blastomycosis B. dermatitidis is a dimorphic fungus that exists as a sporeproducing mold at 25–30 C. The spores have been detected in soil, but only rarely. Thus, the ecological origin except in a few outbreaks is uncertain. It has been speculated that the mold could be associated with wood. The veterinarian is extremely helpful in alerting physicians of the presence of blastomycosis because it is so common in dogs, especially hunting dogs. Human disease is generally sporadic, and the incidence of subclinical infections has not been determined. Pulmonary infection occurs following inhalation of spores, but primary lung infection is asymptomatic or causes only mild symptoms in immunocompetent persons. Dissemination via the bloodstream from the lung results in chronic cutaneous
Host-Pathogen Interactions | Diseases Caused by Fungi
inflammatory lesions with pseudoepitheliomatous hyperplasia, squamous epithelial cell proliferation that somewhat resembles squamous cell carcinoma of skin. Other patients may develop chronic progressive pneumonia that is fatal if untreated in 90% of patients and, in some cases, lesions in the bone and the male genitourinary tract. The focal primary pulmonary reaction to the yeasts that result from germination of spores comprises predominantly polymorphonuclear leukocytes during the first week and evolves to a mixture of purulent and granulomatous infection by the fifth week of infection. The 8–15 mm diameter yeasts have a thick doubly refractile wall and propagate by budding with a broad base of attachment of the parent and daughter cells, which is diagnostic. Virulence is associated with greater content of a-1,3-glycan, chitin, phospholipid, and WI-1 adhesin to macrophages. Males are affected much more often than females, and hormones such as testosterone appear to play a role.
Paracoccidioidomycosis Paracoccidioides brasiliensis, a dimorphic fungus, exists in the environment at 25 C in a spore-producing mycelial state that is distributed through South and Central America. Inhalation of spores is followed by transition to yeasts at 37 C. The yeasts exhibit multiple circumferential narrow-based buds that on cross section have been compared with a ship’s pilot wheel. Infection of the lungs and hilar lymph node complex may be followed by hematogenous dissemination. Primary pulmonary infection is usually subclinical with acute or subacute dissemination to lymphoid tissues, intestines, and bone occurring less frequently. Reactivation of quiescent infection may occur decades after primary infection, occurring as chronic pulmonary disease or disseminated lesions involving the lungs, adrenal glands, and mucous membranes. Lesions are typically a mixture of suppurative and granulomatous inflammation. The chronic pulmonary lesions are frequently fibrotic; the involved adrenal glands contain necrosis and/or granulomas; the involved mucous membranes are ulcerated; and necrosis may have a caseous appearance. Localized disease is associated with granulomas and functional T cells. Disseminated infection lacks granulomas owing to deficient T cell function. Males develop paracoccidioidomycosis more frequently than females, a situation that may be explained by estradiol binding to cytosolic proteins that inhibit mold or spores converting into yeast. Virulence is directly related to the content of a-1,3-glycan carbohydrate in the yeast cell wall.
Penicillium marneffei Penicillium marneffei is endemic in parts of southeastern Asia. Although it has been isolated from bamboo rats, the ecological niche in nature is unknown. The disease is an important endemic opportunistic infection of patients with acquired immunodeficiency syndrome with involvement of lungs, lymph nodes, liver, kidney, skin, and bone. Infection caused by P. marneffei is an indicator that the patient probably has HIV infection. The
219
pathology is dependent on the host response and varies from granulomatous or suppurative or mixed or necrotizing to anergic. The oblong yeasts, which measure 2–3 mm by 2–6 mm and divide by a central cross septum, are often intracellular.
Opportunistic Mycoses Candidiasis Candida spp. are commensal normal flora of the human gastrointestinal tract with particularly prominent colonization of the mouth and colon. Candida are also present in the vagina and on the skin. Pathogenicity is not critical to the Candida lifestyle. Candida albicans, the most abundant species, causes disease when the mucosal barrier is damaged, antibacterial treatment disturbs the normal flora leading to Candida overgrowth, or there are states of immunocompromise such as reduced CD4þT cells in AIDS or neutropenia. Other species including C. tropicalis, C. pseudotropicalis, C. parapsilosis, C. krusei, and C. glabrata can also cause human infections. Candida organisms typically exist as oval 3–6 mm yeast cells that propagate by budding. Pseudohyphae result from sequential budding after which the daughter yeast does not detach and then buds to form another daughter yeast. The chain of budding cells appears with branches occurring only at the septa between connected cells. Smaller degrees of cell wall protein mannosylation result in high cell surface hydrophobicity and increased virulence. Invasion of tissues is associated with transition to true hyphae. Virulence is associated with greater activity of phospholipase A and secretory aspartate proteases. The host response varies from neutrophilic microabscesses in acute invasive disease of immunocompetent persons to granulomas in chronic infections and coagulative necrosis in neutropenic patients. Diagnosis is made by identifying a mixture of Candida forms, which may include yeasts, pseudohyphae, and hyphae invading tissue. Candidal lesions of body surfaces such as the oral cavity or vagina, known as thrush or vaginitis, are friable white plaques. These pseudomembranes in the mouth and vagina consist of detached squamous epithelial cells and inflammatory cells. Moist skin folds of persons who are obese or diabetic are prone to superficial Candida infection. Infection in the oral cavity of AIDS patients is especially painful and can compromise their ability to drink and eat. Fungi seldom invade these tissues deeply although chronic inflammation is observed adjacent to the superficial infection. Chronic mucocutaneous candidiasis affects persons with defective cellular immunity. Although persistent and disfiguring, the fungi seldom invade beyond the hyperkeratotic epidermis, and the dermis contains a cellular response including multinucleate giant cells. Candidal urinary cystitis may lead to ascending pyelonephritis and papillary tip necrosis. Systemic candidiasis may manifest as ulcerative esophagitis or gastritis with invasive hyphae and pseudohyphae or hematogenous infection with abscesses or infarcts caused by invasion to blood vessels by hyphae and pseudohyphae in the lungs, kidneys, and heart.
Aspergillosis Aspergillus fumigatus, A. flavus, and A. niger, in that order, are the most common aspergilli that cause human disease.
220
Host-Pathogen Interactions | Diseases Caused by Fungi
Aspergillus organisms reside in soil and decaying organic matter where they produce conidia. These ubiquitous spores are inhaled daily and are eliminated by innate immunity of immunocompetent persons. The wide spectrum of human disease is determined by the immune system and ranges from allergic responses through noninvasive colonization and superficial infection to severe hematogenous dissemination. Human exposure consists of inhalation or rarely skin implantation of conidia. The respiratory allergic responses have several forms including allergic bronchopulmonary aspergillosis, chronic eosinophilic pneumonia, bronchial mucoid impaction, asthmatic bronchocentric granulomatosis, and granulomatous hypersensitivity pneumonitis. In addition to pure forms, there are overlapping features among these entities. Hypersensitivity lesions include luminal exudates containing eosinophils, Charcot–Leyden crystals, fibrin, mucus, necrotic neutrophils, fungal hyphae, or the cellular infiltrates in the interstitium and alveoli or granulomatous inflammation of the bronchial wall extending into the lumen. Aspergillus may colonize a pulmonary cavity, bronchus, or nasal sinus as a fungus ball, a fungal colony composed of hyphae that, because of exposure to air, can develop conidiophores that have a terminal vesicle and one or two rows of phialides producing columns of conidia that are diagnostically characteristic of each particular Aspergillus species. Although the hyphae do not invade the cavity wall, hemorrhage that can be life-threatening may occur. Diseases with chronic limited bronchial invasion and superficially invasive lesions of the skin, external auditory canal, and paranasal sinuses occur. However, invasive pulmonary aspergillosis and hematogenously disseminated lesions in the brain, heart, kidney, liver, and spleen threaten the lives of patients who are neutropenic or under treatment with cytotoxic drugs or corticosteroids. The 3–6 mm diameter hyphae of Aspergillus have a regular contour with parallel walls, regularly distributed septa, and 45 angle dichotomous branching. In invasive aspergillosis, the regularly radiating pattern of branching hyphae frequently invades veins and arteries, occludes them, and causes infarction of the involved tissue. In the lung, the pale ischemic necrotic infarct is surrounded by congestion and hemorrhage, manifesting the appearance of a target’s bull’s-eye grossly on cut section. The necrotic tissue may demarcate and separate from the viable tissue forming a cavity in which the fungi continue to grow in the nonviable lung tissue, superficially resembling a colonizing fungus ball. Aspergillus may also colonize the necrotic surface of a burn wound and, if not removed by debridement, invade viable tissue and disseminate hematogenously. Other fungi with hyphae similar to Aspergillus are Pseudallescheria boydii and Fusarium species. These three genera are most effectively identified by mycologic culture.
Mucormycosis (Synonym Zygomycosis) Rhizopus oryzae is the most common agent of mucormycosis. A comparison of aspergillosis and mucormycosis highlights numerous similarities and interesting differences. Both groups of diseases are usually initiated by inhalation of spores, feature invasive hyphae, and prominently invade and occlude blood
vessels resulting in infarcts and hematogenous dissemination. The hyphae in mucormycosis differ in being irregular in diameter, varying from 5 to 20 mm, having thin walls, only rare septa, and random branching at right angles. One form of disease, rhinoorbitocerebral mucormycosis, features invasion of hyphae from the nasal cavity through a nasal sinus and the orbit into the frontal lobe of the brain. Patients with invasive mucormycosis characteristically suffer from metabolic acidosis, often in association with diabetes mellitus. Endobronchial mucormycosis narrows a central bronchus in diabetic patients and may invade adjacent blood vessels leading to massive hemorrhage. Mucormycosis may involve ulcerated gastrointestinal mucosa particularly in the stomach or colon or the skin, for example, in burn patients. Hematogenously disseminated infection occurs in patients receiving cytotoxic chemotherapy with potential involvement of the lungs, central nervous system, kidneys, liver, and heart.
Cryptococcosis Cryptococcus neoformans is a ubiquitous soil saprophyte especially in habitats with abundant avian excreta, often from pigeons. Humans are infected by inhalation of the fungus, and pulmonary infection is usually subclinical. Occasionally, a pulmonary focus is discovered later as a fibrocaseous mass. The usual clinical form of cryptococcosis is meningitis following presumed hematogenous spread from the lung. Cryptococcal meningitis occurs as a sporadic disease of apparently immunocompetent persons and in patients immunocompromised by leukemia, lymphoma, cytotoxic chemotherapy, steroid treatment, diabetes, or acquired immunodeficiency syndrome. The host response that ranges from minimal response to well-formed granulomas is largely T cell-dependent with cryptococcosis occurring in AIDS patients with CD4þT cell counts less than 100 cells per microliter. In patients without a host response to the yeast as in AIDS patients with a low CD4þT cell count, masses of encapsulated yeast distend the subarachnoid space and extend into the brain along Virchow–Robin spaces. These lesions may appear grossly as cystic spaces with a very slippery surface owing to the abundant mucopolysaccharide capsule of the abundant fungi. In immunocompetent hosts, an initial neutrophil response and necrosis are followed by the formation of granulomas and a fibrocaseous lesion. Capsule-deficient cryptococci are associated with granulomas, caseation, and fibrosis and do not disseminate. The cryptococci are unicellular, spherical to oval, 4–6 mm yeasts with a thin wall and a thick extracellular halo. The halo represents the capsule, which displaces surrounding tissue and is demonstrated by mucin stains. The yeasts propagate by budding and have a small point of attachment that appears as a narrow base. Cryptococcal virulence factors include the mucopolysaccharide capsule and cell wall melanin, which is protective against oxidative stress and is identified by a modified Fontana–Masson strain.
Pneumocystosis Pneumocystis jiroveci is phylogenetically a member of the kingdom of fungi, and its cell wall contains b-1,3-glycan. However, its morphology resembles protozoa (trophozoites, sporozoites,
Host-Pathogen Interactions | Diseases Caused by Fungi
and cysts), and its cell wall does not contain the typical fungal component ergosterol. Moreover, pneumocystosis responds favorably to antiprotozoal therapy, but is not susceptible to antifungal therapy. Pneumocystis appears to initiate infection by inhalation. The 4–7 mm cysts are observed in alveoli surrounded by amorphous eosinophilic material produced by the organisms. Disease occurs with overgrowth of the organisms in immunocompromised persons such as AIDS patients.
Subcutaneous Mycoses Sporotrichosis Spores of Sporothrix schenckii, a dimorphic fungus that resides in nature in soil, on plants, and on other organic matter such as sphagnum moss, are typically inoculated into the skin by a thorn or splinter. The disease develops slowly from the initial lesion, a nodular lesion of the dermis and subcutaneous tissue with mixed suppurative and granulomatous host response and fibrosis. The overlying epidermis may ulcerate or undergo pseudoepitheliomatous hyperplasia resembling squamous cell carcinoma of the skin. The infection spreads along the draining lymphatic vessel resulting in a linear series of subcutaneous nodules. Rarely, particularly in immunocompromised patients, sporotrichosis disseminates to the joints, bones, meninges, and lungs. The yeasts are difficult to detect in lesions owing to their paucity. Fungal stains reveal 2–10 mm round yeasts with narrow-necked tear-shaped budding. Less often, 1–3 mm by 3–10 mm cigar-shaped yeasts are observed. A classic feature that may be observed in some cases is the Hoeppli–Splendore phenomenon, the deposition of eosinophilic material of host immune origin around the yeasts. Infection may occur by inhalation of the fungus resulting in a pulmonary infection.
Diseases Caused by Pigmented Fungi Many genera of fungi that appear dark because of the production of melanin cause human infections known as chromoblastomycosis or phaeohyphomycosis. Fonsecaea pedrosoi is a common pathogen of this category. The fungi reside on wood, plants, and decaying vegetable matter and are inoculated into the skin and cutaneous tissue often by a splinter. The infection is chronic, indolent, and progressive with contiguous spread. The host response is a mixture of suppurative microabscesses and granulomas often with pseudoepitheliomatous hyperplasia. The fungi are visible because of the brown pigment in hematoxylin–eosin-stained microscopic sections as structures resembling copper pennies that are known as sclerotic bodies. They are 5–12 mm brown, round or oval, thick-walled cells with septation in two planes, which is referred to as being muriform. The intraepidermal microabscesses containing fungi often rupture onto the surface of the skin, so-called transepithelial elimination. The clusters of dematiaceous muriform cells can be easily collected from a gauze bandage placed over the lesion. One species, Xylohypha bantiana, after entry via inhalation disseminates to the brain causing fatal infection.
221
Eumycetoma Inoculation of fungi such as Pseudallescheria boydii from soil into the dermis and subcutaneous tissue results in characteristic lesions of the skin, subcutaneous tissue, and bone containing compact colonies of fungal hyphae that are visible grossly as grains. These hyphal masses are surrounded by deposition of eosinophilic matter of host immune origin, the Hoeppli– Splendore reaction. The host response is a mixture of acute neutrophil accumulation, granulomas, and fibrosis. As in some other chronic fungal infections, there may be pseudoepitheliomatous hyperplasia. The most severe condition is osteomyelitis that occurs when the infection extends through muscle and fascia into bone. This fungus is a common cause of mycetoma in the United States.
Dermatophytoses Dermatophytes comprise a large group of fungi including organisms in the genera Epidermophyton, Microsporidium, and Trichophyton. These fungi normally reside in human skin (anthropophilic), animals (zoophilic), or soil (geophilic). Hyphal fragments or arthroconidia are deposited on the stratum corneum from contact with another person, fomites, or an infected animal or by airborne spread. The spores adhere to keratinized corneocytes and germinate within 4–6 h. The germ tubes grow horizontally and vertically assisted by the production of keratinases, other proteases, lipases, and phosphatases. They grow most efficiently in moist skin because it is hydrated. The clinical conditions bear names according to the affected part of the body: tinea corporis, tinea cruris, tinea faciei, tinea capitis, tinea pedis, and tinea unguium. Each condition is associated with a particular set of fungal species that are adapted to that anatomical location. The keratin layers of the hair and nails are also affected by particular fungal species. Dermatophytes colonize the nonliving superficial layer of the skin and seldom invade viable tissue. Most dermatophytoses are not truly infectious if invasion of viable tissue is a requirement for an infection. Host defenses likely include not only the mechanical epidermal barrier but also the cytokines produced by keratinocytes and CD4þ T cells. The histopathology may manifest mild-to-moderate hyperkeratosis, parakeratosis, acanthosis, and a mononuclear dermal infiltrate.
Further Reading Calderone, R.A., Cihlar, R.L., 2002. Fungal Pathogenesis: Principles and Clinical Applications, vol. 14. Marcel Dekker, Inc., New York, NY, xvi, 762 pp. Chandler, F.W., Watts, J.C., 1987. Pathologic Diagnosis of Fungal Infections. ASCP Press, Chicago, IL. Conner, D.H., Schwartz, D.A., Lack, E.E., Manz, H., Lack, E., Chandler, F.W., 1997. Pathology of Infectious Diseases. Appleton & Lange, Stamford, CT.
Relevant Websites http://www.doctorfungus.org. http://mycology.adelaide.edu.au.
Glossary Conidia Highly stable spores that are produced by fungi are released into the air and, upon implanting in a suitable environment, germinate and grow. Dimorphism The characteristic of having two life-forms for different environments, for example, a complex sporeproducing form at environmental temperatures (e.g., at 25 C) and a yeast form at higher temperatures (e.g., 37 C body temperature). The fungal species that are most often pathogenic for humans are dimorphic, releasing spores into the air that are inhaled, convert into yeast, and initiate infection in the lung. Hypha A long narrow tubular structure a few micrometers in diameter that contains fungal cells that in some species are separated from one another by septal walls.
Characteristics of Fungi Fungi belong to their own kingdom of eukaryotic organisms classified in the eukaryote domain because they lack chlorophyll and vascular tissue and live by decomposing and absorbing organic matter from dead or living sources. A critical role of many fungi in nature is breaking down and recycling nutrients of dead plants. Other fungi are symbionts of plants and animals. One distinguishing feature of fungi is the nature of their cell wall that contains chitin, which is similar to the exoskeleton of insects and arachnids. Fungi include unicellular yeasts that propagate by budding to molds that produce multicellular filaments (hyphae) that are often produced in specialized spore-forming structures called fruiting bodies.
Ecological Niches of Fungi Humans are the natural ecological niche of a few fungi such as Candida albicans that resides in the mouth, in the gastrointestinal tract, in the vagina, and on the skin as skin colonizers such as Malassezia furfur. Anthropophilic dermatophytes such as the pathogenic members of the genera Epidermophyton, Microsporum, and Trichophyton that cause ringworm, athletes foot, and jock itch. Most fungi reside in the soil or on decaying organic matter and produce spores, which are released into the air and spread to other suitable ecological niches where they can germinate and grow.
Mycology A distinct field with a unique body of knowledge that is expressed in what amounts to its own language consisting of words for the specialized fungal structures and concepts. Knowledge of at least a few of them is necessary. Pseudoepitheliomatous hyperplasia Squamous epithelial cell proliferation that somewhat resembles squamous cell carcinoma of skin. Pseudohypha A longitudinal series of budding yeast cells that remain connected to one another, thus superficially resembling a hypha. Yeast A spherical or oval single-celled fungus that propagates by budding to form a daughter cell.
hyphae, the nuclei of yeast, the doubly refractive cell wall of Blastomyces, and the endospore-containing spherule of Coccidioides. The extracellular eosinophilic product of Pneumocystis, colonies of fungi (grains and sclerotia) in eumyetomas and in fungus balls, and the clear spaces around yeast cells in tissue containing encapsulated Cryptococcus and the tissue reaction to the invasive fungi are also observable. However, special histochemical methods, such as Gomori methenamine silver stain, demonstrate clearly the cell wall of yeasts, hyphae, pseudohyphae, and spherules. Periodic acid– Schiff method also stains these structures. Mucicarmine and alcian blue stains for mucin identify the mucopolysaccharide capsule of Cryptococcus neoformans, and the Fontana–Masson stain detects melanin-like substances derived from dihydroxyphenylalanine in capsule-deficient Cryptococcus. These stains are quite useful for establishing a histopathologic diagnosis and confirming invasion of viable tissue.
Spectrum of Pathogenicity
Hematoxylin and eosin staining, the routine method for histopathologic evaluation of tissue sections, often reveals the
There are no fungi that are obligate human pathogens that must cause human disease in order to complete their life cycle and survive. Thus, to some degree, all fungi are opportunists especially in people whose immune system is compromised to some degree. The most pathogenic agents, the dimorphic fungi, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, and Paracoccidioides brasiliensis, are capable of establishing an infection even in immunocompetent persons. However, these infections are usually subclinical, causing asymptomatic infection or mild undiagnosed self-limited disease. Histoplasmosis, coccidioidomycosis, and paracoccidioidomycosis can be lifethreatening diseases in immunocompromised patients.
Pathobiology of Human Disease: A Dynamic Encyclopedia of Disease Mechanisms
http://dx.doi.org/10.1016/B978-0-12-386456-7.01710-X
Stains for Microscopic Visualization of Fungi in Tissue
217
218
Host-Pathogen Interactions | Diseases Caused by Fungi
In fact, opportunistic infections usually refer to diseases caused by fungi that are ubiquitous and cause no disease in immunocompetent hosts. There is a spectrum of compromised host defenses that ranges from a subtle, unrecognized defect in a single immune element to severe deficiencies involving many components of the immune system. Infections caused by Aspergillus species or Rhizopus species are examples of opportunistic infections that can cause life-threatening infections in some patients.
per microliter. In the setting of severe immunodeficiency, Histoplasma proliferates and spreads throughout the body infecting most prominently mononuclear phagocytes of the reticuloendothelial system. The accumulations of Histoplasmacontaining macrophages are often visible grossly in organs such as the spleen. Granulomas and multinucleated giant cells may be absent in patients with severely compromised cellular immunity.
Coccidioidomycosis Endemic Dimorphic Mycoses Soil characteristics, plant diversity, temperature, humidity, and other factors result in the evolution and establishment of particular fungi in certain ecological niches. In the United States, H. capsulatum infections occur mainly in the broad Mississippi and Ohio River valleys, C. immitis in the Sonoran Desert of the southwest, and B. dermatitidis in the central and southeastern states. Paracoccidioides is endemic in tropical and subtropical Latin America.
Histoplasmosis H. capsulatum resides in the soil, especially in environments heavily enriched with avian or bat excreta such as chicken coops and caves. Humans inhale spores released into the environment by the vegetative or mold form of the fungus, which is different from the yeast form that occurs in tissue. Dimorphism describes the ability of the fungus to grow in two entirely different growth forms based upon the temperature of incubation. The inhaled spores germinate, and 2–4 mm diameter yeasts propagate by narrow-based budding in tissue where they reside principally intracellularly in macrophages. The primary pulmonary focus of infection stimulates a neutrophil influx followed by macrophages. Cell-mediated immunity directed mainly by CD4þT cells produces cytokines including gamma interferon, interleukin-12, tumor necrosis factor, and granulocyte–macrophage colony-stimulating factor that activate macrophages to inhibit Histoplasma growth. Histoplasma spreads from the lung by lymphatic vessels to hilar lymph nodes. In most persons, immune control of the infection results in the formation of granulomas with multinucleate giant cells and fibrous encapsulation of the lesion, which may or may not contain caseous necrosis and undergo calcification. The observation of multiple subpleural and hilar lymph node calcifications is more likely healed histoplasmosis than a tuberculosis Ghon complex, which seldom has more than one subpleural focus. Prior to the development of skin test reagents, tuberculosis and histoplasmosis were often confused with each other. During the early part of the last century, a number of histoplasmosis patients were placed in tuberculosis sanatoriums because they were misdiagnosed. Many of these patients then developed tuberculosis. Humans do not develop sterilizing immunity. Histoplasmosis is a serious threat to patients with acquired immunodeficiency syndrome in whom reactivation of latent infection may occur when the CD4þT cell count falls below 200 cells
C. immitis and C. posadasii reside in nature as 2–4 mm diameter septate hyphae, some segments of which transform into 2–4 mm by 5–6 mm barrel-shaped arthroconidia. These arthroconidia are inhaled and cause asymptomatic infection or selflimited pneumonia associated with hilar lymphadenopathy in most persons, similar to histoplasmosis. The initial polymorphonuclear leukocyte response partially inhibits the growth but does not kill the Coccidioides. Cellular immunity with production of T helper cytokines, such as IL-12, activates macrophages leading to the formation of granulomas and clearance of the fungi. Progressive infection can result in chronic pulmonary cavities. Disseminated disease can occur in immunosuppressed patients and is observed more often in males, African Americans, and Filipinos. Exposure of large numbers of people can occur following dust storms in the endemic areas of California and Arizona. In tissue, the arthroconidia transform into round cells that develop into thick-walled endosporulating spherules that are 5–100 mm in diameter in which many endospores accumulate. Endospores 2–5 mm in diameter, which can develop into a second generation of spherules, are released from spherules and stimulate a suppurative reaction. The entire lesion contains central suppuration surrounded by granulomas, undergoes caseous necrosis that may or may not calcify, and is encapsulated by fibrosis surrounded by lymphocytes. Such lesions, which may occur also in histoplasmosis, can appear similar to a peripheral lung tumor and be resected for histopathologic diagnosis. Immunocompromising conditions predispose humans to disseminated infection that often involves the meninges, bone, and skin.
Blastomycosis B. dermatitidis is a dimorphic fungus that exists as a sporeproducing mold at 25–30 C. The spores have been detected in soil, but only rarely. Thus, the ecological origin except in a few outbreaks is uncertain. It has been speculated that the mold could be associated with wood. The veterinarian is extremely helpful in alerting physicians of the presence of blastomycosis because it is so common in dogs, especially hunting dogs. Human disease is generally sporadic, and the incidence of subclinical infections has not been determined. Pulmonary infection occurs following inhalation of spores, but primary lung infection is asymptomatic or causes only mild symptoms in immunocompetent persons. Dissemination via the bloodstream from the lung results in chronic cutaneous
Host-Pathogen Interactions | Diseases Caused by Fungi
inflammatory lesions with pseudoepitheliomatous hyperplasia, squamous epithelial cell proliferation that somewhat resembles squamous cell carcinoma of skin. Other patients may develop chronic progressive pneumonia that is fatal if untreated in 90% of patients and, in some cases, lesions in the bone and the male genitourinary tract. The focal primary pulmonary reaction to the yeasts that result from germination of spores comprises predominantly polymorphonuclear leukocytes during the first week and evolves to a mixture of purulent and granulomatous infection by the fifth week of infection. The 8–15 mm diameter yeasts have a thick doubly refractile wall and propagate by budding with a broad base of attachment of the parent and daughter cells, which is diagnostic. Virulence is associated with greater content of a-1,3-glycan, chitin, phospholipid, and WI-1 adhesin to macrophages. Males are affected much more often than females, and hormones such as testosterone appear to play a role.
Paracoccidioidomycosis Paracoccidioides brasiliensis, a dimorphic fungus, exists in the environment at 25 C in a spore-producing mycelial state that is distributed through South and Central America. Inhalation of spores is followed by transition to yeasts at 37 C. The yeasts exhibit multiple circumferential narrow-based buds that on cross section have been compared with a ship’s pilot wheel. Infection of the lungs and hilar lymph node complex may be followed by hematogenous dissemination. Primary pulmonary infection is usually subclinical with acute or subacute dissemination to lymphoid tissues, intestines, and bone occurring less frequently. Reactivation of quiescent infection may occur decades after primary infection, occurring as chronic pulmonary disease or disseminated lesions involving the lungs, adrenal glands, and mucous membranes. Lesions are typically a mixture of suppurative and granulomatous inflammation. The chronic pulmonary lesions are frequently fibrotic; the involved adrenal glands contain necrosis and/or granulomas; the involved mucous membranes are ulcerated; and necrosis may have a caseous appearance. Localized disease is associated with granulomas and functional T cells. Disseminated infection lacks granulomas owing to deficient T cell function. Males develop paracoccidioidomycosis more frequently than females, a situation that may be explained by estradiol binding to cytosolic proteins that inhibit mold or spores converting into yeast. Virulence is directly related to the content of a-1,3-glycan carbohydrate in the yeast cell wall.
Penicillium marneffei Penicillium marneffei is endemic in parts of southeastern Asia. Although it has been isolated from bamboo rats, the ecological niche in nature is unknown. The disease is an important endemic opportunistic infection of patients with acquired immunodeficiency syndrome with involvement of lungs, lymph nodes, liver, kidney, skin, and bone. Infection caused by P. marneffei is an indicator that the patient probably has HIV infection. The
219
pathology is dependent on the host response and varies from granulomatous or suppurative or mixed or necrotizing to anergic. The oblong yeasts, which measure 2–3 mm by 2–6 mm and divide by a central cross septum, are often intracellular.
Opportunistic Mycoses Candidiasis Candida spp. are commensal normal flora of the human gastrointestinal tract with particularly prominent colonization of the mouth and colon. Candida are also present in the vagina and on the skin. Pathogenicity is not critical to the Candida lifestyle. Candida albicans, the most abundant species, causes disease when the mucosal barrier is damaged, antibacterial treatment disturbs the normal flora leading to Candida overgrowth, or there are states of immunocompromise such as reduced CD4þT cells in AIDS or neutropenia. Other species including C. tropicalis, C. pseudotropicalis, C. parapsilosis, C. krusei, and C. glabrata can also cause human infections. Candida organisms typically exist as oval 3–6 mm yeast cells that propagate by budding. Pseudohyphae result from sequential budding after which the daughter yeast does not detach and then buds to form another daughter yeast. The chain of budding cells appears with branches occurring only at the septa between connected cells. Smaller degrees of cell wall protein mannosylation result in high cell surface hydrophobicity and increased virulence. Invasion of tissues is associated with transition to true hyphae. Virulence is associated with greater activity of phospholipase A and secretory aspartate proteases. The host response varies from neutrophilic microabscesses in acute invasive disease of immunocompetent persons to granulomas in chronic infections and coagulative necrosis in neutropenic patients. Diagnosis is made by identifying a mixture of Candida forms, which may include yeasts, pseudohyphae, and hyphae invading tissue. Candidal lesions of body surfaces such as the oral cavity or vagina, known as thrush or vaginitis, are friable white plaques. These pseudomembranes in the mouth and vagina consist of detached squamous epithelial cells and inflammatory cells. Moist skin folds of persons who are obese or diabetic are prone to superficial Candida infection. Infection in the oral cavity of AIDS patients is especially painful and can compromise their ability to drink and eat. Fungi seldom invade these tissues deeply although chronic inflammation is observed adjacent to the superficial infection. Chronic mucocutaneous candidiasis affects persons with defective cellular immunity. Although persistent and disfiguring, the fungi seldom invade beyond the hyperkeratotic epidermis, and the dermis contains a cellular response including multinucleate giant cells. Candidal urinary cystitis may lead to ascending pyelonephritis and papillary tip necrosis. Systemic candidiasis may manifest as ulcerative esophagitis or gastritis with invasive hyphae and pseudohyphae or hematogenous infection with abscesses or infarcts caused by invasion to blood vessels by hyphae and pseudohyphae in the lungs, kidneys, and heart.
Aspergillosis Aspergillus fumigatus, A. flavus, and A. niger, in that order, are the most common aspergilli that cause human disease.
220
Host-Pathogen Interactions | Diseases Caused by Fungi
Aspergillus organisms reside in soil and decaying organic matter where they produce conidia. These ubiquitous spores are inhaled daily and are eliminated by innate immunity of immunocompetent persons. The wide spectrum of human disease is determined by the immune system and ranges from allergic responses through noninvasive colonization and superficial infection to severe hematogenous dissemination. Human exposure consists of inhalation or rarely skin implantation of conidia. The respiratory allergic responses have several forms including allergic bronchopulmonary aspergillosis, chronic eosinophilic pneumonia, bronchial mucoid impaction, asthmatic bronchocentric granulomatosis, and granulomatous hypersensitivity pneumonitis. In addition to pure forms, there are overlapping features among these entities. Hypersensitivity lesions include luminal exudates containing eosinophils, Charcot–Leyden crystals, fibrin, mucus, necrotic neutrophils, fungal hyphae, or the cellular infiltrates in the interstitium and alveoli or granulomatous inflammation of the bronchial wall extending into the lumen. Aspergillus may colonize a pulmonary cavity, bronchus, or nasal sinus as a fungus ball, a fungal colony composed of hyphae that, because of exposure to air, can develop conidiophores that have a terminal vesicle and one or two rows of phialides producing columns of conidia that are diagnostically characteristic of each particular Aspergillus species. Although the hyphae do not invade the cavity wall, hemorrhage that can be life-threatening may occur. Diseases with chronic limited bronchial invasion and superficially invasive lesions of the skin, external auditory canal, and paranasal sinuses occur. However, invasive pulmonary aspergillosis and hematogenously disseminated lesions in the brain, heart, kidney, liver, and spleen threaten the lives of patients who are neutropenic or under treatment with cytotoxic drugs or corticosteroids. The 3–6 mm diameter hyphae of Aspergillus have a regular contour with parallel walls, regularly distributed septa, and 45 angle dichotomous branching. In invasive aspergillosis, the regularly radiating pattern of branching hyphae frequently invades veins and arteries, occludes them, and causes infarction of the involved tissue. In the lung, the pale ischemic necrotic infarct is surrounded by congestion and hemorrhage, manifesting the appearance of a target’s bull’s-eye grossly on cut section. The necrotic tissue may demarcate and separate from the viable tissue forming a cavity in which the fungi continue to grow in the nonviable lung tissue, superficially resembling a colonizing fungus ball. Aspergillus may also colonize the necrotic surface of a burn wound and, if not removed by debridement, invade viable tissue and disseminate hematogenously. Other fungi with hyphae similar to Aspergillus are Pseudallescheria boydii and Fusarium species. These three genera are most effectively identified by mycologic culture.
Mucormycosis (Synonym Zygomycosis) Rhizopus oryzae is the most common agent of mucormycosis. A comparison of aspergillosis and mucormycosis highlights numerous similarities and interesting differences. Both groups of diseases are usually initiated by inhalation of spores, feature invasive hyphae, and prominently invade and occlude blood
vessels resulting in infarcts and hematogenous dissemination. The hyphae in mucormycosis differ in being irregular in diameter, varying from 5 to 20 mm, having thin walls, only rare septa, and random branching at right angles. One form of disease, rhinoorbitocerebral mucormycosis, features invasion of hyphae from the nasal cavity through a nasal sinus and the orbit into the frontal lobe of the brain. Patients with invasive mucormycosis characteristically suffer from metabolic acidosis, often in association with diabetes mellitus. Endobronchial mucormycosis narrows a central bronchus in diabetic patients and may invade adjacent blood vessels leading to massive hemorrhage. Mucormycosis may involve ulcerated gastrointestinal mucosa particularly in the stomach or colon or the skin, for example, in burn patients. Hematogenously disseminated infection occurs in patients receiving cytotoxic chemotherapy with potential involvement of the lungs, central nervous system, kidneys, liver, and heart.
Cryptococcosis Cryptococcus neoformans is a ubiquitous soil saprophyte especially in habitats with abundant avian excreta, often from pigeons. Humans are infected by inhalation of the fungus, and pulmonary infection is usually subclinical. Occasionally, a pulmonary focus is discovered later as a fibrocaseous mass. The usual clinical form of cryptococcosis is meningitis following presumed hematogenous spread from the lung. Cryptococcal meningitis occurs as a sporadic disease of apparently immunocompetent persons and in patients immunocompromised by leukemia, lymphoma, cytotoxic chemotherapy, steroid treatment, diabetes, or acquired immunodeficiency syndrome. The host response that ranges from minimal response to well-formed granulomas is largely T cell-dependent with cryptococcosis occurring in AIDS patients with CD4þT cell counts less than 100 cells per microliter. In patients without a host response to the yeast as in AIDS patients with a low CD4þT cell count, masses of encapsulated yeast distend the subarachnoid space and extend into the brain along Virchow–Robin spaces. These lesions may appear grossly as cystic spaces with a very slippery surface owing to the abundant mucopolysaccharide capsule of the abundant fungi. In immunocompetent hosts, an initial neutrophil response and necrosis are followed by the formation of granulomas and a fibrocaseous lesion. Capsule-deficient cryptococci are associated with granulomas, caseation, and fibrosis and do not disseminate. The cryptococci are unicellular, spherical to oval, 4–6 mm yeasts with a thin wall and a thick extracellular halo. The halo represents the capsule, which displaces surrounding tissue and is demonstrated by mucin stains. The yeasts propagate by budding and have a small point of attachment that appears as a narrow base. Cryptococcal virulence factors include the mucopolysaccharide capsule and cell wall melanin, which is protective against oxidative stress and is identified by a modified Fontana–Masson strain.
Pneumocystosis Pneumocystis jiroveci is phylogenetically a member of the kingdom of fungi, and its cell wall contains b-1,3-glycan. However, its morphology resembles protozoa (trophozoites, sporozoites,
Host-Pathogen Interactions | Diseases Caused by Fungi
and cysts), and its cell wall does not contain the typical fungal component ergosterol. Moreover, pneumocystosis responds favorably to antiprotozoal therapy, but is not susceptible to antifungal therapy. Pneumocystis appears to initiate infection by inhalation. The 4–7 mm cysts are observed in alveoli surrounded by amorphous eosinophilic material produced by the organisms. Disease occurs with overgrowth of the organisms in immunocompromised persons such as AIDS patients.
Subcutaneous Mycoses Sporotrichosis Spores of Sporothrix schenckii, a dimorphic fungus that resides in nature in soil, on plants, and on other organic matter such as sphagnum moss, are typically inoculated into the skin by a thorn or splinter. The disease develops slowly from the initial lesion, a nodular lesion of the dermis and subcutaneous tissue with mixed suppurative and granulomatous host response and fibrosis. The overlying epidermis may ulcerate or undergo pseudoepitheliomatous hyperplasia resembling squamous cell carcinoma of the skin. The infection spreads along the draining lymphatic vessel resulting in a linear series of subcutaneous nodules. Rarely, particularly in immunocompromised patients, sporotrichosis disseminates to the joints, bones, meninges, and lungs. The yeasts are difficult to detect in lesions owing to their paucity. Fungal stains reveal 2–10 mm round yeasts with narrow-necked tear-shaped budding. Less often, 1–3 mm by 3–10 mm cigar-shaped yeasts are observed. A classic feature that may be observed in some cases is the Hoeppli–Splendore phenomenon, the deposition of eosinophilic material of host immune origin around the yeasts. Infection may occur by inhalation of the fungus resulting in a pulmonary infection.
Diseases Caused by Pigmented Fungi Many genera of fungi that appear dark because of the production of melanin cause human infections known as chromoblastomycosis or phaeohyphomycosis. Fonsecaea pedrosoi is a common pathogen of this category. The fungi reside on wood, plants, and decaying vegetable matter and are inoculated into the skin and cutaneous tissue often by a splinter. The infection is chronic, indolent, and progressive with contiguous spread. The host response is a mixture of suppurative microabscesses and granulomas often with pseudoepitheliomatous hyperplasia. The fungi are visible because of the brown pigment in hematoxylin–eosin-stained microscopic sections as structures resembling copper pennies that are known as sclerotic bodies. They are 5–12 mm brown, round or oval, thick-walled cells with septation in two planes, which is referred to as being muriform. The intraepidermal microabscesses containing fungi often rupture onto the surface of the skin, so-called transepithelial elimination. The clusters of dematiaceous muriform cells can be easily collected from a gauze bandage placed over the lesion. One species, Xylohypha bantiana, after entry via inhalation disseminates to the brain causing fatal infection.
221
Eumycetoma Inoculation of fungi such as Pseudallescheria boydii from soil into the dermis and subcutaneous tissue results in characteristic lesions of the skin, subcutaneous tissue, and bone containing compact colonies of fungal hyphae that are visible grossly as grains. These hyphal masses are surrounded by deposition of eosinophilic matter of host immune origin, the Hoeppli– Splendore reaction. The host response is a mixture of acute neutrophil accumulation, granulomas, and fibrosis. As in some other chronic fungal infections, there may be pseudoepitheliomatous hyperplasia. The most severe condition is osteomyelitis that occurs when the infection extends through muscle and fascia into bone. This fungus is a common cause of mycetoma in the United States.
Dermatophytoses Dermatophytes comprise a large group of fungi including organisms in the genera Epidermophyton, Microsporidium, and Trichophyton. These fungi normally reside in human skin (anthropophilic), animals (zoophilic), or soil (geophilic). Hyphal fragments or arthroconidia are deposited on the stratum corneum from contact with another person, fomites, or an infected animal or by airborne spread. The spores adhere to keratinized corneocytes and germinate within 4–6 h. The germ tubes grow horizontally and vertically assisted by the production of keratinases, other proteases, lipases, and phosphatases. They grow most efficiently in moist skin because it is hydrated. The clinical conditions bear names according to the affected part of the body: tinea corporis, tinea cruris, tinea faciei, tinea capitis, tinea pedis, and tinea unguium. Each condition is associated with a particular set of fungal species that are adapted to that anatomical location. The keratin layers of the hair and nails are also affected by particular fungal species. Dermatophytes colonize the nonliving superficial layer of the skin and seldom invade viable tissue. Most dermatophytoses are not truly infectious if invasion of viable tissue is a requirement for an infection. Host defenses likely include not only the mechanical epidermal barrier but also the cytokines produced by keratinocytes and CD4þ T cells. The histopathology may manifest mild-to-moderate hyperkeratosis, parakeratosis, acanthosis, and a mononuclear dermal infiltrate.
Further Reading Calderone, R.A., Cihlar, R.L., 2002. Fungal Pathogenesis: Principles and Clinical Applications, vol. 14. Marcel Dekker, Inc., New York, NY, xvi, 762 pp. Chandler, F.W., Watts, J.C., 1987. Pathologic Diagnosis of Fungal Infections. ASCP Press, Chicago, IL. Conner, D.H., Schwartz, D.A., Lack, E.E., Manz, H., Lack, E., Chandler, F.W., 1997. Pathology of Infectious Diseases. Appleton & Lange, Stamford, CT.
Relevant Websites http://www.doctorfungus.org. http://mycology.adelaide.edu.au.