13.3 Medical Mycology: Cutaneous, Systemic, and Opportunistic Fungal Infections

Fungal Cell Biology and Laboratory Diagnostics

Fungi are eukaryotic organisms possessing distinct structural features that differentiate them from bacteria and mammalian cells. The fungal cell membrane incorporates ergosterol as its primary sterol, contrasting with cholesterol in human membranes. This biochemical distinction forms the basis for selective antifungal therapies: azoles inhibit 14-alpha-demethylase (blocking ergosterol synthesis), polyenes (amphotericin B, nystatin) bind directly to ergosterol creating membrane pores, and echinocandins (caspofungin) inhibit beta-1,3-D-glucan synthesis in the fungal cell wall.

The fungal cell wall is composed of chitin, glucans, and mannoproteins. Laboratory diagnosis relies on direct microscopic visualization and culture:

• 10-20% KOH Preparation: Potassium hydroxide dissolves host keratin and cellular elements, leaving alkali-resistant fungal hyphae, pseudohyphae, and yeast cells intact for microscopic review.
• Sabouraud Dextrose Agar: Selective culture medium with low pH (5.6) favoring fungal growth over bacterial contamination.
• Special Diagnostic Stains: GMS (Grocott's Methenamine Silver) stains fungal elements black; Periodic acid-Schiff (PAS) stains fungal cell walls bright magenta; India Ink demonstrates clear capsules against a dark background.

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Cutaneous Mycoses & Superficial Infections

Superficial and cutaneous mycoses infect the keratinized layers of the epidermis, hair, and nails.

Dermatophytoses

Caused by three genera of dermatophytic molds: Microsporum, Trichophyton, and Epidermophyton. These organisms produce keratinase, allowing colonization of keratinized tissue. Clinical presentations are designated by anatomical location (Tinea):

• Tinea capitis: Scalp ringworm, presenting with alopecia and scaling.
• Tinea pedis: Athlete's foot, causing interdigital maceration and pruritus.
• Tinea corporis: Ringworm of the body, exhibiting expanding erythematous annular lesions with central clearing.
• Tinea cruris: Jock itch, localized to the groin.
• Tinea unguium (Onychomycosis): Fungal infection of nails causing thickening, discoloration, and crumbling.

Microscopic KOH evaluation demonstrates branching septate hyphae.

Tinea Versicolor

Caused by Malassezia furfur, a lipid-dependent dimorphic fungus that forms part of normal skin flora. Overgrowth produces dicarboxylic acids that inhibit tyrosinase, resulting in hypopigmented or hyperpigmented macules on the chest and back. KOH prep reveals classic "spaghetti and meatballs" appearance (short, curved septate hyphae mixed with round yeast clusters).

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Systemic Thermally Dimorphic Fungal Pathogens

Systemic dimorphic fungi exist as molds (hyphae) in the environment at room temperature (20-25\u00b0C) and convert to yeasts in human tissue at body temperature (37\u00b0C) (mnemonic: "Cold mold, heat yeast"). All are transmitted via inhalation of airborne conidia/spores and cause granulomatous pulmonary disease that can mimic tuberculosis.

Clinical Findings

• Histoplasma: Ingested by alveolar macrophages; causes pulmonary granulomas, hilar calcifications, and hepatosplenomegaly in immunocompromised patients.
• Coccidioides: Inhalation of desert dust arthrospores leads to Valley Fever (fever, cough, arthralgias, and erythema nodosum on shins).
• Blastomyces: Causes granulomatous lung disease with hematogenous dissemination to skin, producing verrucous, ulcerated skin lesions and osteomyelitis.

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Opportunistic Fungal Pathogens

Opportunistic fungi primarily infect immunocompromised patients (AIDS, neutropenia, diabetic ketoacidosis, organ transplant recipients).

Candida albicans

Normal flora of skin, oral cavity, GI tract, and vagina. Uniquely dimorphic, but reverses the typical pattern: forms pseudohyphae and budding yeast at 20\u00b0C, but forms true germ tubes (hyphae) at 37\u00b0C.

• Clinical Manifestations: Oral thrush (white scraping pseudomembranes), vulvovaginal candidiasis (thick cottage cheese discharge), diaper rash, esophageal candidiasis (AIDS CD4 < 100), and right-sided endocarditis in IV drug users.

Aspergillus fumigatus

Monomorphic mold existing only as hyphae. Microscopic examination shows septate hyphae with acute 45-degree angle branching.

• Aspergilloma (Fungus Ball): Pre-existing tuberculous or emphysematous cavitary lung lesions colonized by Aspergillus, presenting with hemoptysis.
• Allergic Bronchopulmonary Aspergillosis (ABPA): Hypersensitivity reaction in asthma or cystic fibrosis patients, featuring elevated IgE, eosinophilia, and bronchiectasis.
• Mycotoxin Production: Produces aflatoxin, associated with consumption of contaminated peanuts/grains and increased incidence of hepatocellular carcinoma.

Cryptococcus neoformans

Heavily encapsulated yeast surrounded by a thick polysaccharide capsule (glucuronoxylomannan). Found in pigeon droppings and soil; transmitted via inhalation.

• Diagnostic Modalities: Cultured on Sabouraud agar; India ink stain shows a clear halo surrounding the encapsulated yeast; Mucicarmine stain stains the capsule bright red; latex agglutination detects capsular antigen in CSF.
• Clinical Manifestations: Causes cryptococcal meningitis in AIDS patients. Brain autopsy demonstrates characteristic "soap-bubble" cystic lesions within the basal ganglia.

Mucor and Rhizopus Species (Mucormycosis)

Molds featuring broad, non-septate hyphae branching at wide 90-degree right angles.

• Pathogenesis: Spores enter nasal passages in susceptible hosts, particularly patients with diabetic ketoacidosis (DKA) (ketone reductase allows fungal proliferation in high glucose/acidic state) and severe neutropenia. Organisms are angioinvasive, penetrating blood vessel walls to cause tissue infarction.
• Clinical Findings: Facial pain, headache, and black necrotic nasal/palatal eschars progressing rapidly to rhino-orbital-cerebral mucormycosis.

Pneumocystis jirovecii

An atypical fungus previously categorized as a protozoan. Cell membrane contains cholesterol rather than ergosterol, making amphotericin B and azoles ineffective.

• Diagnosis: Microscopic visualization of disc-shaped or cup-shaped cysts on GMS (Methenamine Silver) stain or direct immunofluorescence.
• Clinical Manifestations: Causes severe diffuse interstitial pneumonia (bilateral ground-glass infiltrates) in AIDS patients with CD4+ count < 200 cells/\u00b5L. Prophylaxis and treatment rely on trimethoprim-sulfamethoxazole (TMP-SMX).