Study Notes on Fungal Infections

An Overview of Fungal Infections

Objectives

  • By the end of the lecture, the student should be able to:

    • Describe the general features of fungi.

    • Explain the important structural components of fungi.

    • Enlist the main cutaneous, systemic, and opportunistic fungal infections and describe their major features.

Introduction to Fungi

  • Fungi are eukaryotic organisms.

  • Two types of fungi exist:

    • Yeasts: Grow as single cells that reproduce by asexual budding.

    • Molds: Grow as long filaments known as hyphae and form a mat called mycelium.

Structural Features of Fungi

Fungal Cell Wall

  • The fungal cell wall is primarily composed of chitin.

    • Chitin is a polysaccharide made up of long chains of N-acetylglucosamine.

  • Other polysaccharides in the fungal cell wall include β-glucan, a long polymer of D-glucose.

Fungal Cell Membrane

  • The fungal cell membrane contains ergosterol, contrasting with the human cell membrane, which contains cholesterol.

Hyphal Structure

  • Hyphae are thread-like structures that form the body of fungi.

  • Types of hyphae:

    • Septate Hyphae: Contain transverse walls.

    • Nonseptate Hyphae: Do not contain transverse walls.

Thermal Dimorphism

  • Some medically important fungi exhibit thermal dimorphism:

    • Form different structures at varying temperatures.

    • Exist as molds in the environment at ambient temperatures.

    • Convert to yeasts (or other structures, such as spherules of Coccidioides) in human tissues at body temperature.

Oxygen Requirement

  • Fungi can be classified based on oxygen requirements:

    • Obligate aerobes: Require oxygen.

    • Facultative anaerobes: Can grow in both oxygen and absence of oxygen.

    • Obligate anaerobes: None exist among fungi.

  • All fungi necessitate a preformed organic source of carbon, hence their common association with decaying matter.

Sexual Reproduction

  • Some fungi reproduce sexually, leading to the formation of sexual spores such as:

    • Zygospores

    • Ascospores

    • Basidiospores

Asexual Reproduction

  • Most medically significant fungi reproduce asexually by forming conidia (asexual spores) from the sides or ends of specialized structures.

  • The shape, color, and arrangement of conidia are essential for identifying fungi.

Types of Conidia

  • Important types of conidia include:

    • Arthrospores: Result from the fragmentation of hyphae and are responsible for the transmission of Coccidioides immitis.

    • Chlamydospores: Rounded and thick-walled, resistant types; terminal chlamydospores of C. albicans help in identification.

    • Blastospores: Formed by budding, characteristic of yeast reproduction (e.g., C. albicans can produce pseudohyphae).

    • Sporangiospores: Produced within a sac (sporangium) on a stalk by molds such as Rhizopus and Mucor.

Granuloma Formation

  • Many fungal infections induce the formation of granulomas.

  • Granulomas are observed in major systemic fungal diseases (e.g., coccidioidomycosis, histoplasmosis, blastomycosis).

  • Granuloma formation involves a cell-mediated immune response.

Fungal Toxins & Allergies

  • Apart from mycotic infections, two additional categories of fungal diseases exist:

    1. Mycotoxicoses: Arise from ingested fungal toxins.

    • Example: Amanita mushrooms can cause severe poisonings.

    • Aflatoxins can lead to liver damage and are carcinogenic.

    • Ergotoxins may produce vascular and neurological effects.

    1. Allergies to fungal spores.

Laboratory Diagnosis

  • Four diagnostic methods for fungal diseases:

    1. Direct microscopic examination

    2. Culture of the organism

    3. Polymerase chain reaction (PCR) tests

    4. Serologic tests

    • Specimens may be treated with 10% potassium hydroxide (KOH) to dissolve tissue, retaining the alkali-resistant fungi, or stained with specific fungal stains.

Culture Techniques

  • Fungi are typically cultured on Sabouraud’s agar to promote appearances of slow-growing fungi while suppressing bacterial growth.

  • The morphology of mycelium and characteristic asexual spores often suffice for organism identification.

Molecular Testing

  • PCR-based tests can expedite the identification of cultures growing earlier than visual detection.

  • Serological tests are significant in diagnosing systemic mycoses, such as:

    • Complement fixation test: Often used for coccidioidomycosis, histoplasmosis, and blastomycosis.

    • Cryptococcal meningitis: Presence of polysaccharide capsular antigens from C. neoformans can be assessed in spinal fluid via latex agglutination test.

Categories of Fungal Infections

  • Medical mycoses are categorized into:

    1. Cutaneous mycoses

    2. Subcutaneous mycoses

    3. Systemic mycoses

    4. Opportunistic mycoses

Cutaneous Mycoses: Dermatophytosis

  • Dermatophytoses are infections by fungi (dermatophytes) affecting only superficial keratinized structures:

    • Skin

    • Hair

    • Nails

  • These infections do not invade deeper tissues.

  • Tinea (ringworm) presents chronic infections often localized to warm, humid body areas (e.g., athlete’s foot, jock itch).

Classification of Dermatophytes

  • Major dermatophyte genera:

    1. Trichophyton

    2. Epidermophyton

    3. Microsporum

Transmission

  • Dermatophytes are spread through direct contact.

  • Microsporum can also be transmitted from animals (e.g., dogs, cats).

  • To prevent reinfection, treatment of the animal is necessary.

Appearance of Lesions

  • Ringworm lesions are characterized by:

    • Inflamed circular borders containing papules and vesicles, surrounding a clear area of relatively normal skin.

    • Lesions are typically pruritic (itchy).

    • Often exhibit broken hairs and damaged nails.

    • Reference: Cleveland Clinic

Nomenclature of Tinea

  • The disease is named based on the affected body part:

    • Tinea capitis: Scalp

    • Tinea corporis: Body

    • Tinea cruris: Groin

    • Tinea pedis: Foot

    • Tinea unguium: Also called onychomycosis, a nail infection causing thickened, broken, and discolored nails.

Specific Dermatophyte Infections

  • Trichophyton species are implicated in:

    • Inflammatory pustular lesions on the scalp (kerion).

    • Trichophyton tonsurans: Common cause of tinea capitis outbreaks in children, associated primarily with endothrix infections.

    • Trichophyton rubrum: Common causative agent in tinea capitis.

    • Trichophyton schoenleinii: Associated with favus, characterized by scaling crusts on the scalp.

Diagnosis of Cutaneous Mycoses

  • Skin or nail scrapings placed in 10% KOH on a glass slide reveal septate hyphae microscopically.

  • Cultures on Sabouraud’s agar at room temperature develop characteristic hyphae and conidia.

  • For tinea capitis caused by Microsporum species, fluorescence can be observed under ultraviolet light from a Wood’s lamp.

Tinea Versicolor

  • Tinea versicolor (pityriasis versicolor) is a superficial skin infection primarily caused by Malassezia species.

  • Typically manifests as hypopigmented areas, particularly noticeable on tanned skin during summer.

  • Infection often causes slight scaling or itching but is usually asymptomatic.

Diagnosis of Tinea Versicolor

  • Diagnosis is usually made by observing skin scrapings mixed with KOH preparations.

Tinea Nigra

  • Tinea nigra is an infection affecting keratinized skin layers caused by Cladosporium werneckii.

  • Appears as brownish spots caused by melanin-like pigments within hyphae.

Diagnosis of Tinea Nigra

  • Diagnosis is confirmed by microscopic examination and culture of skin scrapings.

Subcutaneous Mycoses

  • These infections arise from fungi in soil and vegetation, entering subcutaneous tissue through trauma.

Sporotrichosis

  • Caused by Sporothrix schenckii, a dimorphic fungus.

  • Typically introduced into the skin via thorns, resulting in:

    • Localized pustules or ulcers.

    • Nodules along draining lymphatics; lesions are often painless with minimal systemic illness.

    • In patients with HIV and low CD4 counts, disseminated sporotrichosis may occur.

Diagnosis of Sporotrichosis

  • In laboratory settings, round or cigar-shaped budding yeasts can be observed in tissue specimens.

Mycetoma

  • Soil fungi (e.g., Petriellidium, Madurella) can cause abscesses when introduced through wounds on feet, hands, or back, leading to pus discharge through sinuses.

  • The pus contains compact colored granules.

  • Actinomycetes (e.g., Nocardia) may cause similar lesions known as actinomycotic mycetoma.

Features Summary of Skin and Subcutaneous Fungal Diseases

  • Fungal diseases show varying features based on causative organisms, tissue affected, and transmission modes:

    • Trichophyton: Human to human; causes tinea capitis, tinea pedis, etc.

    • Epidermophyton: Human to human; similar infections.

    • Malassezia: Presents as scaly plaques; often nonpruritic.

    • Sporothrix: Introduced by penetrating skin lesions; leads to pustules or ulcers.

Systemic Fungal Infections

Introduction to Systemic Infections

  • Result from inhalation of spores from dimorphic fungi commonly found in soil.

  • Spores differentiate into yeasts or specialized forms within the lungs.

  • Most lung infections are asymptomatic and self-limiting, while some can lead to disseminated disease with destructive lesions and potential mortality.

Coccidioidomycosis

  • Caused by Coccidioides immitis and C. posadasii.

  • Clinical manifestations are similar, but geographical distribution varies.

  • Dissemination to other organs occurs in individuals with defects in cell-mediated immunity.

Pathogenesis of Coccidioidomycosis

  • Involves granulomatous lesions, particularly affecting bones and the central nervous system (e.g., meningitis).

  • Erythema nodosum (EN): Associated with red, tender nodules, a delayed hypersensitivity reaction indicating a good prognosis, with no organisms present in lesions.

Laboratory Diagnosis of Coccidioidomycosis

  • Spherules noted microscopically in tissue specimens are pathognomonic for Coccidioides infection.

  • Cultures grown on Sabouraud’s agar at 25°C yield septate hyphae and arthrospores.

  • Serological tests serve as common diagnostic methods.

Histoplasmosis

  • Caused by the dimorphic fungus Histoplasma capsulatum that exists in soil as a mold and as a yeast in tissue.

Pathogenesis of Histoplasmosis

  • Inhaled spores are phagocytized by macrophages and convert to yeast forms.

  • In tissues, H. capsulatum appears as an ovoid budding yeast inside macrophages.

  • The organism can spread widely throughout the body, particularly to the liver and spleen; most infections remain asymptomatic, leading to granulomas which eventually heal by calcification.

  • Intense exposure (e.g., in chicken coops or bat caves) can lead to pneumonia and cavitary lung lesions.

Laboratory Diagnosis of Histoplasmosis

  • Oval yeast cells within macrophages are observed microscopically in tissue or bone marrow samples.

  • Cultures on Sabouraud’s agar reveal hyphae with tuberculate macroconidia at lower temperatures (e.g., 25°C) and yeasts at higher (37°C).

  • Antigen detection tests via enzyme-linked immunosorbent assay (ELISA) and RNA detection using DNA probes are also deployed.

Blastomycosis

  • Caused by Blastomyces dermatitidis; known as North American blastomycosis.

Pathogenesis & Clinical Findings of Blastomycosis

  • Blastomyces dermatitidis exists as mold in soil and as yeast in tissue.

  • Infection primarily occurs via the respiratory route; asymptomatic or mild cases are often overlooked.

  • Severe cases can lead to ulcerated granulomas affecting skin, bone, or other organs.

Laboratory Diagnosis of Blastomycosis

  • Biopsy specimens reveal thick-walled yeast cells with single broad-based buds microscopically.

  • Culture shows hyphae with small, pear-shaped conidia.

  • Available PCR assay detects nucleic acids of Blastomyces.

Paracoccidioidomycosis

  • Caused by Paracoccidioides brasiliensis, also referred to as South American blastomycosis.

Properties of Paracoccidioides brasiliensis

  • This is also a dimorphic fungus, existing as mold in soil and yeast in tissue, characterized by thick walls and multiple buds.

Pathogenesis & Clinical Findings of Paracoccidioidomycosis

  • Inhalation leads to early lung lesions; asymptomatic infections are common.

  • Possible developments include lesions in oral mucosa, lymph node enlargement, and dissemination to various organs.

Laboratory Diagnosis of Paracoccidioidomycosis

  • Microscopic examination of pus or tissues shows yeast cells with multiple buds, resembling a “ship captain’s wheel.”

Clinical Features Comparing Systemic Fungal Diseases

  • Summary of important characteristics across systemic fungal diseases:

    • Coccidioides: Spherules in tissue; found mainly in Southwestern U.S. and Latin America; known for valley fever; severe risks for immunocompromised.

    • Histoplasma: Yeasts inside macrophages; detected in Ohio and Mississippi valleys; connects to bird/bat droppings; cavitary lesions can occur in immune-compromised patients.

    • Blastomyces: Thick-walled yeast cells noted; present in Central/Southeastern U.S. and Africa; can lead to skin ulceration.

    • Paracoccidioides: Yeasts with multiple buds observed; endemic in Latin America, particularly Brazil; causes broad systemic effects including oral lesions.

Opportunistic Fungal Infections

Introduction to Opportunistic Infections

  • Opportunistic fungi typically do not cause disease in healthy individuals but can elicit infections in those with impaired immune systems.

  • Principal genera of medically relevant fungi include:

    • Candida

    • Cryptococcus

    • Aspergillus

    • Mucor

    • Rhizopus

Candidiasis

  • Candida albicans is the primary species responsible for:

    • Thrush (oral candidiasis)

    • Vaginitis

    • Esophagitis

    • Diaper rash

    • Chronic mucocutaneous candidiasis

    • Disseminated infections, including right-sided endocarditis (particularly in IV drug users), bloodstream infections (candidemia), and endophthalmitis.

    • Infections arising from indwelling intravenous and urinary catheters are notably significant.

Cryptococcosis

  • Caused by Cryptococcus neoformans, particularly noted for cryptococcal meningitis.

Aspergillosis

  • Caused by Aspergillus species, especially Aspergillus fumigatus; infections can occur in skin, eyes, ears, lungs, and lead to conditions such as a “fungus ball” in the lungs, in addition to allergic bronchopulmonary aspergillosis.

Mucor & Rhizopus

  • Mucormycosis (also referred to as zygomycosis or phycomycosis) is a disease caused by saprophytic molds like Mucor, Rhizopus, and Absidia.

  • These molds proliferate in blood vessel walls (e.g., paranasal sinuses, lungs, gut), resulting in tissue necrosis due to occlusion of blood vessels.

Summary of Important Features of Opportunistic Fungal Diseases

  • Candida: Yeast forms; worldwide presence; clinical significance includes thrush, endocarditis, and pneumonia in immunocompromised patients.

  • Cryptococcus: Recognized by yeast forms with large capsules; presents primarily as meningitis; widespread geographical distribution.

  • Aspergillus: Identified by mold with septate hyphae; known for causing various infections and conditions.

  • Mucor and Rhizopus: Characterized by mold with nonseptate hyphae; associated with necrotic lesions when invading blood vessels, particularly high-risk in patients with diabetic ketoacidosis, renal acidosis, and cancer.

Conclusion

  • Understanding fungal infections is crucial due to their clinical implications in various hosts, particularly in immunocompromised individuals. Accurate diagnosis and appropriate treatment are vital for managing these infections effectively.