22 Pathogenic Fungi.

22 Pathogenic Fungi

An Overview of Medical Mycology
Diagnosis, management, and prevention of fungal diseases (mycoses) Mycoses are among the most difficult diseases to diagnose and treat Signs of mycoses are often missed or misinterpreted Fungi are often resistant to antifungal agents

The Epidemiology of Mycoses Fungi and their spores are almost everywhere in the environment Most people will experience a mycosis at some time Typically acquired via inhalation, trauma, or ingestion Infrequently spread from person to person Most mycoses are not contagious Dermatophytes are the major exception Epidemics due to mass exposure to environmental source of fungi Mycoses are generally not reportable Adequate information on their occurrence is often lacking

Categories of Fungal Agents: True Fungal Pathogens and Opportunistic Fungi Only four fungi usually considered true pathogens Other fungi are opportunistic Certain factors increase risk for opportunistic mycoses Invasive medical procedure Medical therapies Certain disease conditions Specific lifestyle factors True pathogens endemic primarily in the Americas Opportunists distributed throughout the world

Table 22.1 Factors That Predispose Individuals to Opportunistic Mycoses

Clinical Manifestations of Fungal Diseases Three categories of clinical manifestation: Fungal infections Most common mycoses Caused by presence of true pathogens or opportunists Fungal toxicoses Acquired through ingestion Occur when poisonous mushrooms are eaten Allergies Most often result from the inhalation of fungal spores

The Diagnosis of Fungal Infections Patient's history is critical for diagnosis of most mycoses Definitive diagnosis often requires morphological analysis of the fungus involved Sabouraud dextrose agar used to culture fungi This medium favors fungal growth Various techniques used to detect fungal cells in patient specimens Difficult to distinguish fungal infections from simple exposures Opportunistic infections especially challenging

Figure Fungal stains.

Antifungal Therapies Mycoses are among the most difficult diseases to heal Fungi often resist T cell–mediated immune responses Fungi biochemically similar to human cells Antifungal drugs can harm human tissues Ergosterol is often a target of antifungal drugs Amphotericin B is gold standard of antifungals One of the more toxic antifungal agents Less toxic alternatives include ketoconazole, itraconazole, and fluconazole

Antifungal Therapies Some antifungal drugs do not target ergosterol Griseofulvin Interferes with microtubule formation and mitosis 5-Fluorocytosine Nucleoside analog Echinocandins Inhibits a sugar that makes up part of the fungal cell wall Opportunistic infections require two-step treatment: High-dose treatment to reduce pathogens Low-dose maintenance therapy

Antifungal Vaccines Antifungal vaccines have been difficult to develop Fungal metabolism similar to our own Relatively few patients with severe fungal infections Vaccines are expensive to make

Antifungal Vaccines Scientists have developed vaccines against some fungi Coccidioides Blastomycosis Candida

Systemic Mycoses Caused by Pathogenic Fungi
Infections spread throughout the body Caused by four pathogenic fungi of the division Ascomycota: Histoplasma Blastomyces Coccidioides Paracoccidioides Acquired through inhalation Begins as generalized pulmonary infection Disseminates via the blood to the rest of the body

All four pathogenic fungi are dimorphic Grow as mycelial thalli in the environment Grow as spherical yeasts in the body Invasive form Individuals working with these fungi must take precautions to avoid exposure to spores

Figure 22.2 The dimorphic nature of true fungal pathogens.
Hypha Spores In environment (<30ºC) In human (37ºC) Budding yeast cells

Histoplasmosis Histoplasma capsulatum is the causative agent Most common fungal pathogen affecting humans Found in the eastern United States, Africa, and South America Fungi found in moist soils containing high nitrogen levels Most infections occur through inhalation of spores Cutaneous inoculations are extremely rare H. capsulatum is phagocytized by macrophages in the lungs Disperse the fungi beyond the lungs via the blood and lymph

Figure 22.3 Endemic areas for histoplasmosis.

Histoplasmosis Usually asymptomatic and resolves without damage Clinical histoplasmosis results in one of four diseases: Chronic pulmonary histoplasmosis Chronic cutaneous histoplasmosis Systemic histoplasmosis Ocular histoplasmosis Diagnosis based on identification of yeast in patient sample Infections in healthy individuals resolve on their own Treated with amphotericin B or ketoconazole when needed

Figure 22.4 The characteristic spiny spores of mycelial Histoplasma capsulatum.

Blastomycosis Blastomyces dermatitidis is the causative agent Endemic in the southeastern United States north to Canada Fungi found in soils rich in organic matter Pulmonary blastomycosis Most common manifestation Initial pulmonary lesions are mostly asymptomatic When symptoms occur they are nonspecific The disease resolves in most people but may become chronic

Figure 22.5 Geographic distribution of Blastomyces.

Blastomycosis Cutaneous blastomycosis Painless lesions on the face and upper body Osteoarticular blastomycosis Spread of the fungus to the spine, pelvis, cranium, ribs, long bones, or subcutaneous tissues surrounding joints Meningitis Dissemination of the fungus to the central nervous system Can occur in AIDS patients Diagnosis based on identification of fungi in culture or samples Treat with amphotericin B or oral itraconazole Relapse is common in AIDS patients

Figure 22.6 Cutaneous blastomycosis in an American woman.

Coccidioidomycosis Coccidioides immitis is the causative agent Almost exclusively in the southwestern United States and northern Mexico Fungi in desert soil, rodent burrows, archeological remains, mines Infection rates have risen in endemic areas Population expansion and increased recreational activities Inhaled arthroconidia germinate into spherules in the lung Spherules release large number of spores as they mature

Figure 22.7 Endemic areas of Coccidioides.

Figure 22.8 Spherules of Coccidioides immitis.
Spores

Coccidioidomycosis Coccidioidomycoses most often result in pulmonary conditions Many patients show no or few symptoms Infections in healthy individuals resolve on their own Some individuals develop more serious infections Dissemination to other sites occurs mostly in immunocompromised Diagnosis based on presence of spherules in patient samples or a positive coccidioidin skin test Amphotericin B is the drug of choice for treatment Maintenance therapy can help prevent relapse in AIDS patients Wearing protective masks in endemic areas can prevent exposure to spores

Figure 22.9 Coccidioidomycosis lesions in subcutaneous tissue.

Paracoccidioidomycosis Paracoccidioides brasiliensis is the causative agent Found in southern Mexico and regions of South America Disease found mostly in farm workers in endemic areas Similar to blastomycosis and coccidioidomycosis Infection begins as a pulmonary condition The fungus almost always spreads Produces chronic inflammatory disease of mucous membranes Diagnosis based on the presence of yeast in a "steering wheel" formation in patient samples Treatment is with itraconazole, ketoconazole, or amphotericin B

Figure 22.10 The "steering wheel" formation of buds characteristic of Paracoccidioides brasiliensis.

Systemic Mycoses Caused by Opportunistic Fungi
Opportunistic mycoses don't typically affect healthy humans Infections limited to people with poor immunity More important as the number of AIDS patients rises Difficult to identify because their symptoms are often atypical

Pneumocystis Pneumonia Pneumocystis jiroveci is the causative agent Formerly referred to as P. carinii Obligate parasite Majority of individuals exposed to P. jiroveci by age five Transmission most likely occurs through inhalation Infection in immunocompetent is usually asymptomatic Common opportunistic fungal infection of AIDS patients Presence of the disease is almost diagnostic for AIDS Can result in death if left untreated Diagnosed based on clinical and microscopic findings Treatment is with trimethoprim and sulfamethoxazole

Figure 22.11 Cysts of Pneumocystis jirovecii in lung tissue.

Candidiasis Includes various opportunistic infections and diseases Candida albicans is the most common causative agent Common microbiota of the skin and mucous membranes Candida is one of the few fungi transmitted between individuals All cases of disease result from an opportunistic infection Can produce a wide range of diseases Systemic disease seen mostly in immunocompromised individuals

Disease in Depth 22.1

Table 22.2 The Clinical Manifestations of Candidiasis

Disease in Depth 22.1 (12 of 16)

Candidiasis Diagnosis based on presence of clusters of budding yeasts and pseudohyphae Treatment depends on the particular disease Treat underlying problem in immunocompetent individuals Oral candidiasis in infants treated with nystatin Vaginal candidiasis treated with azole suppositories, creams, or oral fluconazole Infections in AIDS patients difficult to treat Oral fluconazole used for primary and maintenance therapy Amphotericin B or 5-fluorocytosine used for invasive candidiasis

The Nature of Infectious Disease
Dr. Bauman's Microbiology Video Tutor For more information, listen to the Disease in Depth video tutor on Candidiasis.

Aspergillosis Several diseases caused by fungi in the genus Aspergillus Can be found throughout the environment Disease occurs from the inhalation of the fungal spores Most commonly causes only allergies

Aspergillosis Three pulmonary diseases may develop: Hypersensitivity aspergillosis Manifests as asthma or other allergic symptoms Noninvasive aspergillomas Masses of fungal hyphae form in the cavities following pulmonary tuberculosis Acute invasive pulmonary aspergillosis May present as pneumonia Cutaneous and systemic aspergillosis also occur

Figure 22.12 An invasive aspergilloma near the eye.

Aspergillosis Presence of septate hyphae and distinctive conidia in patient samples is diagnostic Detection of antigens in the blood is confirmatory Hypersensitivity aspergillosis treated with allergy medications Invasive disease treated by surgical removal of aspergillomas and intravenous voriconazole Itraconazole is used as maintenance therapy for AIDS patients

Cryptococcosis Cryptococcus neoformans is the main causative agent Two varieties: Cryptococcus neoformans gattii Infects immunocompetent individuals Cryptococcus neoformans Infects AIDS patients Results from inhalation of spores or dried yeast in bird droppings Characteristics enhance the pathogenicity of the fungus Ability to resist phagocytosis Predilection for the central nervous system Occurs in individuals with little immune system function

Cryptococcosis Various diseases can result from infection Primary pulmonary cryptococcus Asymptomatic or mild pneumonia Cryptococcal meningitis Most common clinical form of cryptococcal infection Follows dissemination of the fungus to the CNS Cryptococcoma Rare condition in which solid fungal masses can form Cutaneous cryptococcosis Skin lesions or inflammation of subcutaneous tissues

Figure 22.13 GMS stain of Cryptococcus.

Cryptococcosis Diagnosis based on identification of fungus in appropriate patient sample Treatment is with amphotericin B and 5-fluorocytosine for several weeks Fluconazole is used as maintenance therapy for AIDS patients

Zygomycoses Infections caused by genera in the division Zygomycota Common in the environment with worldwide distribution Seen in several groups Individuals with uncontrolled diabetes People who inject illegal drugs Some cancer patients Some patients receiving antimicrobial drugs Infections usually develop in the face and head area

Zygomycoses Can spread and cause various conditions: Rhinocerebral zygomycosis Infection of the paranasal sinuses that can invade the brain Pulmonary zygomycosis Cavities form in the lungs following inhalation of spores Gastrointestinal zygomycosis Involves ulcers in the intestinal tract Cutaneous zygomycosis Introduction of fungi through the skin after trauma

Zygomycoses Diagnosis usually based on microscopic identification of fungus in patient samples Treatment involves removal of infected tissues and intravenous administration of amphotericin B

The Emergence of Fungal Opportunists in AIDS Patients AIDS patients vulnerable to opportunistic fungal infections Permanent immune dysfunction makes cure of infections unlikely Mycoses account for most deaths associated with AIDS Infection with various fungi partly define end-stage AIDS Emergence of new fungal opportunists Increase in immunocompromised individuals Use of antifungal drugs selects for fungi resistant to the drugs

The Emergence of Fungal Opportunists in AIDS Patients Three emerging pathogens are particularly problematic: Fusarium species Cause respiratory distress, disseminated infections, and fungemia Toxin accumulation can occur when fungi ingested in food Penicillium marneffei Produces pulmonary disease if inhaled Trichosporon beigelii Can cause fatal systemic disease in AIDS patients Enters through the lungs, gastrointestinal tract, or catheters

Superficial, Cutaneous, and Subcutaneous Mycoses
Are the most commonly reported fungal diseases All are opportunistic infections Localized at sites at or near the surface of the body Acquired by person-to-person contact or environmental exposure Diseases are usually not life threatening Can cause chronic or recurring infections

Superficial Mycoses Are the most common fungal infections Confined to the outer, dead layers of the skin, nails, or hair All composed of dead cells that contain keratin Primary food of these fungi

Superficial Mycoses Dermatophytoses Infections of the skin, nails, or hair caused by dermatophytes Previously called ringworms Fungi use keratin as nutrient source and colonize dead tissues May trigger cell-mediated immune response that damages living tissues Can be spread from person to person Genera of ascomycetes cause most dermatophytoses Dermatophytoses show a variety of clinical manifestations

Figure Athlete's foot.

Table 22.3 Common Dermatophytoses

Superficial Mycoses Dermatophytoses Most dermatophytoses are clinically distinctive Confirm by identification of hyphae or arthroconidia in patient samples Treat limited infections with topical antifungal agents Treat widespread infections with oral antifungal agents Terbinafine is usually effective Griseofulvin is used for chronic or difficult cases

Superficial Mycoses Malassezia Infections Caused by Malassezia furfur Normal microbiota of the skin Causes pityriasis Depigmented or hyperpigmented patches of scaly skin Diagnosis based on presence of budding yeast and short hyphal forms in clinical samples Superficial infections are treated with topical antifungal agents Extensive infections are treated with oral therapy Relapses of Malassezia infections are common

Figure Pityriasis.

Fungi are commonly found in the soil Less common than superficial mycoses Requires traumatic introduction of fungi beneath the outer layers of skin Most lesions remain localized to subepidermal tissues in the skin

Chromoblastomycosis and Phaeohyphomycosis Similar cutaneous and subcutaneous mycoses Caused by dark-pigmented ascomycetes Overall incidence of infection is relatively low People who work daily in the soil at risk for infection

Table 22.4 Some Ascomycete Genera of Cutaneous and Subcutaneous Mycoses

Chromoblastomycosis and Phaeohyphomycosis Chromoblastomycosis Produces lesions on skin surface that progressively worsen Phaeohyphomycosis Involves colonization of the nasal passages and sinuses Occurs in allergy sufferers and AIDS patients Distinguish the two diseases based on the morphology of fungal cells in tissue samples Both diseases are difficult to treat

Figure 22.16 A leg with extensive lesions of chromoblastomycosis.

Figure 22.17 Microscopic differences between chromoblastomycosis and phaeohyphomycosis.
Sclerotic body Hypha

Mycetomas Tumorlike infections Caused by mycelial fungi in the division Ascomycota Infections are most prevalent near the equator Fungi are found in the soil Fungi introduced via wounds from contaminated twigs, thorns, or leaves Individuals who work in the soil are most at risk Nodules form at site of infection and slowly worsen and spread Bone destruction can cause permanent deformity

Figure 22.18 A mycetoma of the ankle.

Mycetomas Diagnosis based on symptoms and presence of fungi in patient samples Surgical removal of the mycetoma is required for treatment Surgery followed by one to three years of therapy with ketoconazole

Sporotrichosis Sporothrix schenckii is the causative agent Subcutaneous infection usually limited to the arms and legs Fungi found in the soil Those who work with plant material at highest risk for infection Most infections occur in Latin America, Mexico, and Africa

Sporotrichosis Initially produces nodular lesions around the infection site Fungi may enter the lymphatic system from a primary lesion Secondary lesions occur on the skin along the course of lymphatic vessels Diagnosis based on patient history, clinical signs, and observation of dimorphic fungi in culture Effectively treated with topical agents Prevent inoculation of fungi by wearing proper clothing

Figure 22.19 Sporotrichosis on the arm.

Fungal Intoxications and Allergies
Some fungi produce mycotoxins or cause allergies Fungal mycotoxins can cause toxicosis Two types of toxicosis: Mycotoxicosis Caused by eating mycotoxins Mycetismus Mushroom poisoning from eating a fungus Fungal allergens can elicit hypersensitivity response in sensitive individuals

Mycotoxicoses Mycotoxins Produced by fungi during normal metabolic activities Often consumed in grains or vegetables Aflatoxins are the best-known mycotoxins Fatal to many vertebrates Carcinogenic at low levels when consumed continually Can cause liver damage and liver cancer Prevalent in the tropics Some mycotoxins are used to make drugs Include ergot alkaloids produced by Claviceps purpurea

Mushroom Poisoning (Mycetismus) Most mushrooms are not toxic Some produce extremely dangerous poisons Can cause neurological dysfunction, hallucinations, organ damage, or death Poisoning typically occurs when untrained individuals pick and eat wild mushrooms Deadliest mushroom toxins produced by the "death cap" mushroom Damage cell structure and inhibit mRNA synthesis Cause liver damage

Figure 22.20 Amanita phalloides, the "death cap" mushroom.

Mushroom Poisoning (Mycetismus) Other deadly mushrooms Gyromitra esculenta causes diarrhea, convulsions, and death Cortinarius gentilis causes thirst, nausea, and kidney failure Some mushrooms produce hallucinogenic toxins Psilocybe cubensis produces psilocybin Amanita muscaria produces ibotenic acid and muscimol Treatment involves induced vomiting and administration of activated charcoal to absorb toxins A liver transplant may be needed in cases of severe poisoning

Allergies to Fungi Fungal allergens are common both indoors and out Determining specific cause can be difficult Due to presence of fungi in the environment Fungal allergens usually cause type I hypersensitivity Result in asthma, eczema, and hay fever Type III hypersensitivity reactions occur much less frequently

22 Pathogenic Fungi.

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