Fungi (singular fungus) are eukaryotes. They generally occur in two forms: yeast, which can be round or oval and basically unicellular, but capable of forming long chains called pseudomycelium; and the mold or filamentous. Some pathogenic fungi can be yeast-like inside animal tissue and filamentous in their natural habitat. Also, fungi have a highly developed form of sexual reproduction, but most can also multiply asexually. The natural habitat of a majority of fungi is soil where they perform their primary function in nature, that is, decomposing plant material and recycling the biomass in the ecosystem. However, certain pathogenic fungi are more frequently associated with pigeon or bat excreta. A majority of fungi are harmless to humans and animals. Only a small number of species are known to cause diseases in humans and animals though a majority of plant diseases are caused by fungi. The tissue reaction is usually granulomatous. Fungal infections do not respond to antibacterial antibiotics.
As stated in the introduction, taxonomically, fungi are divided into four divisions, namely Phycomycota (Phycomycetes) or Zygomycota (Zygomycetes), Ascomycota (Ascomycetes), Basidiomycota (Basidiomycetes), and Fungi Imperfecti (Deuteromycetes). But from the perspective of medical mycology, pathogenic fungi are divided into following three groups:
• Yeast-like fungi
• Dimorphic fungi
• Filamentous fungi
YEAST-LIKE FUNGI
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| Figure 13.1. Depiction of budding and pseudomycelium formation by yeast-like fungi |
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| Figure 13.2. Illustration of the structure of two common molds |
spherical with a capsule. Most yeasts reproduce by asexual budding, but yeasts belonging to division Ascomycota demonstrate sexual reproduction. Yeasts typically multiply by a process called budding.
MOLDS OR FILAMENTOUS FUNGI
Filamentous fungi, also referred to as molds, are typically composed of a thallus, which includes mycelium, sporangiophore or conidiophore, spores, and a sporebearing structure sometimes called the head. The mycelium may be septate as in the case of Aspergillus or aseptate as are Mucor and Rhizopus spp. (Fig. 13.2).
DIMORPHIC FUNGI
A unique group of fungi that exhibit properties of both the yeasts and the molds. A majority of dimorphic fungi are pathogenic. In their natural habitat, these fungi occur in their filamentous or mold form, but in host tissue or at human body temperature (37°C), they exhibit yeast form.
Diseases caused by fungi are broadly divided into following categories:
Superficial Mycoses
The fungus infects mostly keratinized tissues, such as the epidermis, hair, and nails. The tissue invasion is minimal. We have also included infections involving the mucous membrane in this group. Certain forms of mucous membrane infections may involve some degree of tissue invasion. Most of the infections are acquired through close contact.
Subcutaneous Mycoses
Subcutaneous mycosis involves deeper layers of the skin and may eventually reach to the bones. The infections mostly result from the traumatic implantation of the pathogen into subcutaneous tissue. Most causal agents are soil-borne.
Systemic Mycoses
The etiologic agents of systemic mycoses are generally soil-borne and the respiratory tract is often (but not always) the portal of entry. Infections may involve any part of the body including the lungs, liver, kidneys, and brain.
For the sake of convenience, mycotic diseases have been divided into two chapters in this manual. This chapter includes a concise discussion on superficial mycotic disease, and the subcutaneous and systemic mycoses are summarized in the next chapter.
SUPERFICIAL MYCOSES
Black Piedra
The infection involves hair of the scalp. The fungus grows as a compact mass of cells forming a black nodule around the hair shaft. It may eventually invade the hair shaft. The size of the fungus mass may range from a few microns to greater than a millimeter in diameter. Piedra hortae is the main causal agent of black piedra. The infections are common in humid and warm countries. The laboratory diagnosis is mostly based on the microscopic examination of the hair shaft. Cultures can be made on Sabouraud agar on which it grows slowly and forms dark brown to black colonies. Multiple lines of treatment are available, but shaving off the hair appears to be the cheapest and most effective therapy.
White Piedra
White piedra is caused by Trichosporon beigelii, a yeast-like fungus that is considered dimorphic by some mycologists. The disease is characterized by white to creamy nodular fungal growth on the hair shaft. The fungus grows around and within the hair and mostly involves hairs of scalp. Unlike black piedra which is mostly restricted to scalp hair, white piedra may involve hairs of the beard and pelvic region. Cases of white piedra are seen all over the world, but the disease is more common in tropical regions. The laboratory diagnosis is often based on the microscopic examination of infected hair and demonstration of the mycelium (2–4 µm in diameter) and arthroconidia. Trichosporon beigelii grows well on Sabouraud agar. Heaped, cream-colored, yeast-like colonies can be seen after 4 or 5 days. Hyphae are septate and tend to break into small fragment called arthroconidia. A number of commercial over-the-counter products are available for the treatment. Topical prepa- rations containing azole derivatives are useful. As stated in the case of black piedra, shaving off the hair and observing good personal hygiene is an effective means of controlling white piedra.
Tinea Versicolor
Tinea versicolor, also known as pityriasis, is caused by a yeast-like fungus, Malassezia furfur. The fungus is normally present on human skin. Infection mostly occurs on the upper torso and other areas rich in sebaceous glands. The infection is characterized by altered skin pigmentation that may look lighter in color than the normal skin. No tissue invasion or inflammatory reaction is observed. Tinea versicolor occurs worldwide, but more commonly in tropical countries. The fungus is lipophilic and requires olive oil or any other vegetable oil for growth. Diagnosis is mostly based on clinical examination but the pathogen can be cultured on Sabouraud agar supplemented with olive oil and incubated at 35°C. Direct microscopic examination of skin using a 10% sodium hydroxide solution can be helpful. Spherical to elongated yeast- like cells can be easily seen. The condition can be treated using an aqueous solution (20% w/v) of sodium hyposulfite, or topical preparations containing azole deriva- tives. However, the recovery to normal skin is a long, drawn out process.
Dermatophytoses
Dermatophytosis (plural: dermatophytoses), also known as tinea or ringworm, is a clinical condition involving keratinized tissues including skin, nail, and hair. The causal agents usually belong to genera Trichophyton, Microsporum, and Epidermophyton, and are collectively called dermatophytes. The term “dermatophyte,” meaning skin-tree, goes back to the era when fungi were considered plants. Most dermatophytes produce keratinase, a proteolytic enzyme that hydrolyzes keratin. Therefore, many mycologists also refer to dermatophytes as keratinophilic fungi. With reference to their predilection and natural habitat, the dermatophytes are divided into three groups:
• Anthropophilic: These are primarily isolated from human sources and include species belonging to the genus Trichophyton (T. rubrum, T. tonsurans, T. violaceum and others), Microsporum (M. audouinii), and Epidermophyton (E. floccosum).
• Zoophilic: Animals are the primary reservoir of zoophilic dermatophytes. Important members include species of Microsporum (M. canis and M. nanum) and Trichophyton (T. mentagrophytes and T. verrucosum).
• Geophilic: Soil is the primary reservoir of geophilic dermatophytes. Notable species include Microsporum gypseum and Trichophyton terrestre.
Infections are acquired by direct contact with infected humans or animals or exposure of the bruised skin to soil. Dermatophytoses occur all over the world but they are more common in developing countries. There is a direct relationship between good personal hygiene and contracting dermatophytoses. A daily shower with generous soap application has dramatically reduced occurrences of dermatophytoses in much of the world. The lesions are initially localized, highly inflamed, and pruritic. The infection may remain localized, forming a round ring-like lesion, or may spread fast, covering a large area of skin. Some of the common clinical conditions along with the dermatologists’ classifications of dermatophytoses are summarized below:
Tinea Corporis
Tinea corporis, also known as ringworm of the glabrous skin, is perhaps the most common form of dermatophytoses. The infection is limited to skin and the lesions are characterized by inflammation, erythema, and vesicle formation. Species most frequently involved include T. rubrum, T. mentagrophytes, and M. canis.
Tinea Capitis
Tinea capitis refers to scalp infection. The lesions are characterized by inflammation, ulceration, and hair loss. Microsporum canis and T. tonsurans are most frequently involved in this clinical type.
Tinea Barbae
Tinea barbae is characterized by pustular folliculitis mostly affecting the hairs of the beard. Species commonly involved include T. rubrum, T. violaceum, and M. canis.
Tinea Pedis
Tinea pedis, also known as athlete’s foot, refers to infection involving toe-webs and sole. Infections are frequently associated with persistent moist conditions. The lesions are scaly, erythematous, and inflamed. Species most commonly involved include T. rubrum and T. mentagrophytes.
Tinea Unguium
Tinea unguium, also known as onychomycosis, refers to a clinical condition involving the nails. The infection may involve the nail-plate and spread to the area under the nail, resulting in a total deformation and loss of the infected nails. Species most commonly associated with tinea unguium include T. rubrum and T. mentagrophytes. Species of the yeast-like fungus Candida are also known to cause onychomycosis. Therefore, a differential diagnosis is required because of the differences in the effective therapeutic measures.
Laboratory Diagnosis
Dermatologists tend to diagnose dermatophytoses on the basis of affected sites and clinical symptoms. However, a definitive diagnosis requires isolation of the causal agents in culture. For a presumptive diagnosis, samples of skin scrapings are mixed with a 10% solution of sodium hydroxide and examined directly under a bright field microscope. The nail specimens should be cut into finer pieces and a 20% sodium hydroxide solution should be used. Fungal elements, if present, can be easily seen. Dermatophytes grow well on Sabouraud agar fortified with chloram- phenicol (50 mg/L) and cycloheximide (500 mg/L). Chloramphenicol will suppress bacterial growth and cycloheximide is toxic to most of the environmental fungi that are commonly present on the skin and nails as transient microbiota. Inoculated plates should be incubated at 25°C. Visible colonies appear within 1 week but sporulation may require a longer period of incubation, often up to 2–3 weeks. Species are identified on the basis of colony appearance and size and shape of conidia. Microsporum and Trichophyton spp. tend to produce two types of conidia, the macroconidia and the microconidia. Size and shape of macroconidia is most useful in species identification. The macroconidia of Microsporum are fusiform or spindle-shaped (Fig. 13.3), thick-walled, and measure 7–20 × 35–120 µm, and those of Trichophyton are clavate with smooth walls and measure 4–8 × 8–50 µm. The macroconidia of Epidermophyton spp. are widely clavate with smooth walls, rounded distal ends, and measure 6–10 × 8–15 µm. The macroconidia of all the three species are multinucleate. Sexual stage (perfect stage) has been recognized in many species.
Antibiotic Sensitivity
Ever since it was introduced in 1950s, griseofulvin has remained a drug of choice for the treatment of dermatophytoses. Griseofulvin is given orally and the dose and duration of the therapy varies widely. However, cases of drug resistance to griseofulvin are on rise and most dermatologists prefer newer azoles. It must be noted that the griseofulvin is not effective against Candida infection. Multiple lines of topical preparations are also available and reportedly effective in some cases.
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Figure 13.3. A photomicrograph showing spindle-shaped macroconidia of Microsporum gypseum
in a laboratory-grown culture stained by Lactophenol cotton blue (source: CDC |
Otomycosis
Otomycosis, also known as mycotic otitis externa and fungal ear infection, is a superficial chronic or subacute infection of the outer ear canal. Otomycosis is a common infection, reported from all over the world. Symptoms frequently noted include inflammation, scaling, pruritus, and pain. Partial deafness may ensue in some cases due to occlusion of the ear canal by plug of fungal hyphae and epithelial debris. In many cases, the inflammation and scaling extends all the way through ear canal. In most cases, the tympanic membrane is not perforated. Unlike bacterial otitis, which is characterized by foul smelling pus discharges, otomycosis is nonexudative.
The causal agents are common airborne fungi. The species most frequently incriminated belong to the genus Aspergillus and include A. niger, A. terreus and A. fumigatus. Species of other fungal genera, such as Penicillium, Scopulariopsis, Mucor, Rhizopus, Candida, and dermatophytes are occasionally indicated as well.
Laboratory Diagnosis
Otomycosis can be differentiated from bacterial otitis by its characteristic nonexudative symptoms. Confirmatory test can be performed by microscopic examination of ear plugs and scales. Hyphae, sporulating vesicles, and fungal spores are easily demonstrated. If too much cellular debris or wax is present, the specimen can be digested in 10% sodium hydroxide solution. Cultures can be notoriously unreliable in the absence of clearly formed hyphal plugs. If plugs can be obtained, they should be cultured on Sabouraud dextrose agar fortified with chloramphenicol and incu- bated at 35°C. Once again, slanted media in large test tubes are preferred over Petri dishes, because the later increases the risk of contamination. A simultaneous culture for bacteria can be helpful in ruling out bacterial infection.
Antibiotic Sensitivity
Otomycosis is easily treated with topical antifungal preparations. Older therapeutic choices containing 0.1%–1% thymol or iodochlorhydroxyquin are also quite effective. Keeping the ear canal free of moisture buildup and drying after exposure to water are helpful prophylactic means.
Mycotic Keratitis
Mycotic keratitis is usually manifested as a corneal ulcer and with the presence of pus-like fluid in the anterior chamber of the eye (hypopyon). The corneal ulcers are mostly raised with a white to greyish appearance and irregular margins. Other fea- tures may include delicately radiating lines at the perimeter anterior stromal infiltrate and satellite lesions. If not treated in a timely manner, mycotic keratitis can lead to blindness. The disease appears to be more common in farmers and laborers exposed to dust and prone to what might be called minor eye injuries. The rising incidence rate of mycotic keratitis is generally attributed to uninhibited use of eye drops containing antibacterial antibiotics and corticosteroids. The risk of infection is also higher if the patient has had an abraded cornea, or the eye has been subjected to surgical procedures. Glaucoma, corneal diseases, and corneal trauma are generally believed to be important predisposing conditions. The most important causal agents of mycotic keratitis are Fusarium solani, F. oxysporum, and F. nivale. Other species of Fusarium, Aspergillus fumigatus, Curvularia lunata, Penicillium citrinum, Phialophora verrucosa, and Candida albicans have also been occasionally implicated. Most of these fungi are normally present in soil and some (such as F. solani) are important plant pathogens. Their isolation from soil is fairly common.
Laboratory Diagnosis
A dependable laboratory diagnosis would require repeated isolation of the fungus from carefully collected clinical specimens obtained from the affected areas. A direct microscopic examination of corneal scrapping can be quite helpful.
Antibiotic Sensitivity
Mycotic keratitis has been successfully treated with topical application of amphoteric B and Pimaricin solutions. Pimaricin is believed to be more effective in the treatment of infection caused by Fusarium spp.
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| Table 13.1 Some Delineating Characteristics of Yeast-like Fungi Commonly Associated with Mucocutaneous Infections |
MUCOCUTANEOUS MYCOSES
Several pathogenic fungi, especially dimorphic fungi, are known to infect mucous membranes, often as a secondary complication. In this subsection, we will focus only on the mucous membrane infections by Candida spp. Some of the differentiating features of yeast-like fungi associated with mucocutaneous infections are depicted in Table 13.1. The common clinical conditions caused by Candida and related species can be divided into two distinct categories.
Thrush
Thrush is characterized by curd-like growth of the yeast on tongue and palate. A confluent growth of yeast-like cells and pseudomycelium can form a biomembrane on the surface. The causal agent is frequently Candida albicans, but other species are also occasionally incriminated. Thrush mostly occurs in newborns, who acquire the disease during passage through the birth canal. It can also be noted in immunecompromised patients, such as those with AIDS, persons on steroids, and diabetics. The condition is often indicative of host’s immune status. Thrush is frequently diagnosed on the basis of clinical symptoms. A definitive diagnosis can be made by direct microscopic examination of swabs or tongue scrapings, which would reveal yeast-like cells and abundant pseudomycelium. Cultures can be made on Sabouraud agar containing chloramphenicol. Most Candida spp., except C. albicans, are sensitive to cycloheximide. Thrush can be also an annoying complication in stomatitis. Topical medications are often sufficient to treat thrush but systemic treatment may be needed for more severe cases, most commonly with azoles.
Vulvovaginitis or Vaginitis
Vulvovaginitis or vaginitis is commonly referred to as yeast infection. The disease is characterized by the inflammation of vagina, labia, and surrounding areas. The symptoms may include burning, itching, and curd-like odorless vaginal discharge with painful intercourse. In some cases, as a complication of vaginitis or as a disease by itself, Candida spp. can cause urinary tract infection (UTI), especially urethritis, which can be painful and chronic. Vulvovaginitis is a common complication during the late stage of pregnancy. The primary cause of infection appears to be loss of resident microbiota in vagina, often due to prolonged antibiotic therapy and occa- sionally due to hormonal changes. Vulvovaginitis is also a common infection in postmenopausal women. The disease is sexually transmissible. In males, the infection may result in balanitis characterized by inflammation of the glans of penis, accompanied by a burning and itching sensation. However, in most males the infec- tion is mild and frequently unnoticed. Asymptomatic males can play a role in trans- mitting the disease to females. Candida vulvovaginitis occurs all over the world but the incidence rate seems to be higher in industrialized countries, perhaps due to excessive use of douche and other tools of intimate hygiene, which can disturb or even dislodge the resident microbiota. Though not a mucocutaneous infection, Candida spp. can also cause perianal infection in males and females. No well-defined virulence factor is known, but many strains of Candida albicans are known to produce proteinases and possibly certain extracellular toxins, which probably play important roles in the inflammation and tissue damage.
Laboratory Diagnosis
A vaginal swab can be cultured on Sabouraud agar supplemented with chloramphenicol. Inoculated plates should be incubated aerobically at 35°C. In some chronic cases of vaginitis, Candida spp. tend to form a biofilm which makes it hard to dislodge and isolate the fungus in culture. Species identification may not be considered essential for therapy, but it can be achieved by some simple tests and enforced by physiological tests including carbohydrate assimilation tests (see Table 13.1). Candida albicans forms a germ tube in serum and egg albumin, and produces chlamydospores on cornmeal agar (Fig. 13.4). Candida albicans is the principal causal agent of thrush and vulvovaginitis, responsible for infection in 70%–80% of cases. During the past few decades Torulopsis glabrata (formerly called Candida glabrata) and Candida tropicalis have emerged as important causal agents, especially in vaginitis and UTI.
Antibiotic Sensitivity
Therapy of candida vaginitis has a checkered history. In the pre-antibiotic era, the infection was mostly treated with Gentian violet (crystal violet) or by a long-term and generous application of natural yogurt on and in the vagina. Because Gentian violet leaves an intense violet/purple color that lasts for many days, its usage was
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Figure 13.4. Photomicrograph of a C. albicans culture on cornmeal agar containing Tween 80 and
showing chlamydospores (Lactophenol-Cotton blue stain).
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discontinued after nystatin and amphotericin cream and suppositories became available. Amphoteric B, otherwise a fine drug, was discontinued mostly because of its yellow color and the fecal appearance of the vaginal discharges following suppository application. Currently azoles, most commonly fluconazole given as a single dose, are popularly in use, as are topical therapies. However, strains resistant to azoles are emerging. In those cases, amphotericin B cream or suppository may still be the best option, if they can be obtained. Resistance to this agent is virtually unknown and the toxicity is limited because the drug is not absorbed. The infection tends to recur unless the normal vaginal microbiota is restored. For this purpose, some physicians recommend external application of Lactobacillus-containing products, and the old standby yogurt is not a bad option.
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