Overview of fungal infections

Fungal infections are categorized by the anatomical location of the infection (i.e., as superficial or systemic) and the epidemiological class of the infecting organism (i.e., endemic fungal infection or opportunistic fungal infection). Infections in immunocompetent individuals are generally superficial or limited to the respiratory system. Immunocompromised individuals are susceptible to systemic fungal infections, which are associated with a high risk of mortality. Diagnosing a systemic fungal infection is often difficult because the symptoms are nonspecific and definitive test results may take days to weeks. Suspected systemic fungal infections are usually treated empirically until confirmatory testing is obtained.

See also “General mycology,” “Candidiasis,” “Aspergillosis,” and “Dermatophyte infections.”

• Superficial fungal infection: fungal infection limited to skin, hair, nails, superficial mucus membranes, and subcutaneous tissue, without involvement of internal organs
• Dermatomycoses: mycotic infections of tissue with high keratin content (skin, nails, hair) caused mainly by dermatophytes, but may also result from opportunistic infection with other species of fungus (e.g., Malassezia).

• Definition
  • Fungal infections that affect internal organs of the body and are not confined to skin, subcutaneous tissues, or mucus membranes.
  • Fungemia: the presence of a fungus in the bloodstream
• Etiology
  • Opportunistic infections: affects immunocompromised individuals (see “Opportunistic fungal infections”)
  • Endemic disease: affects both immunocompetent and immunocompromised individuals (see “Endemic fungal infections”)

Candida, Aspergillus, and Cryptococcus are opportunistic fungal pathogens with low inherent virulence. They commonly cause systemic mycoses in immunocompromised hosts but do not normally affect healthy hosts.

• Etiology
  • Pathogen: dimorphic fungi
  • No interpersonal transmission
• Clinical features: : pneumonia, disseminated systemic infection

“History of the hidden Ohio and Mississippi river valleys:” Histoplasma is hidden within macrophages and Ohio and Mississippi river valleys are the endemic regions of histoplasma.

“Paracoccidiomycosis steers the ship to South and Central America at the captain's wheel: ”Paracoccidiomycosis is endemic in South and Central America and its budding yeast has a captain's wheel appearance.

The yeast form of Blastomycosis forms broad-based buds.

Unlike most other dimorphic fungi, Blastomyces can cause disseminated disease even in immunocompetent hosts.

See also “Mycetoma.”

Sporotrichosis (rose gardener disease)

• Etiology
  • Pathogen: Sporothrix schenckii (a dimorphic fungus that feeds on decaying vegetation)
  • Risk factor: traumatic injury to the skin while gardening (e.g., thorn prick)
• Clinical features
  • Pustules and ulcers with ascending lymphangitis
  • Nodules along draining lymphatics
  • Disseminated disease (in immunocompromised patients): pneumonia, meningitis
• Diagnostics
  • Fungal culture; (sputum, pus, biopsy tissue) showing dimorphic, cigar-shaped yeast (this form exists in humans)
  • Septate hyphae, rosette-like clusters of conidia at the tips of the conidiophores (this form exists in soil/vegetation)
• Treatment ^[8]
  • Cutaneous or lymphocutaneous
    • First-line: itraconazole ^[8]
    • Alternative: saturated solution of potassium iodide
  • Disseminated: amphotericin B ^[8]

“A rose gardener plants roses in a pot while smoking a cigar:” sporotrichosis is associated with traumatic gardening injuries, treatment includes potassium iodide, and Sporothrix appears as a cigar-shaped yeast in culture.

Direct microscopy ^[9]

• Evaluation of fungal morphology
• Usually with KOH
• Used for preliminary identification

Wood lamp examination ^[9]

• A diagnostic test that employs a UV lamp to examine skin lesions
• Used to evaluate superficial fungal infections of the skin (e.g., tinea versicolor), which appear characteristically yellow-green fluorescent under ultraviolet light
• Can also be used to evaluate hypopigmented or depigmented lesions (e.g., vitiligo) which appear blue-white fluorescent

Fungal culture ^[9]

• Fungal growth usually takes from 24–72 hours.
• Sabouraud agar: a fungal growth medium that contains dextrose and peptones (e.g., for the cultivation of dermatophytes, Blastomyces, Histoplasma, Coccidioides)
• Selective media: e.g., inhibitory mold agar and dermatophyte test media

Histological stains ^[9]

• Silver stain
• PAS stain
• India ink stain: a type of negative stain with carbon that is most commonly used to identify organisms with a polysaccharide capsule such as Cryptococcus neoformans (the capsule is not penetrated by the ink and appears as a halo around the organism against a dark background)
• Mucicarmine: a staining method used to identify the thick polysaccharide capsule of some organisms (e.g., Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioides immitis) and mucin (e.g., in gastric tumors); mucicarmine stains bright red

Others ^[9]

• Immunohistochemistry: uses antibodies that bind to species-specific fungal antigens
• Serologic studies for antibody and antigen detection (e.g., ELISA, RIA, latex agglutination assay)
• PCR amplification of fungal DNA

Superficial fungal infections refer to those limited to hair, nails, epidermis, and/or mucosa.

Clinical evaluation ^[10]

Visual inspection of the location, color, shape, and surface characteristics of the lesion may assist in the diagnosis.

• Dermatophytosis
  • Tinea corporis
  • Tinea cruris
  • Tinea pedis
  • Tinea capitis
  • Tinea unguium
• Tinea versicolor
• Mucocutaneous candidiasis

Diagnostics ^[10]

Consider one of the following for diagnostic confirmation:

• KOH microscopy
• Wood lamp examination
• Fungal culture
• See “Diagnostics for fungal detection” for details.

The diagnosis of a superficial fungal infection is frequently based on visual inspection, but confirmation with diagnostic testing is recommended, especially if systemic treatment is planned. ^[11][12][13]

Treatment of superficial fungal infections

• Topical agent dosing rule of thumb: Estimate the required quantity (in grams) using finger-tip units (FTUs). ^[14]
  • Each FTU can cover an affected body surface area (BSA) equivalent to ∼ 2 closed handprints.
  • 1 g ≈ 2 FTUs, which can cover a BSA of ∼ 4 closed handprints.

Treatment of dermatophyte infections

• Tinea corporis and tinea cruris
  • Imidazoles: e.g., clotrimazole , ketoconazole
  • Allylamines: e.g., terbinafine
• Tinea pedis
  • Imidazoles: e.g., clotrimazole , ketoconazole
  • Allylamines: e.g., terbinafine
• Tinea capitis
  • Terbinafine
  • Griseofulvin
• Tinea unguium (onychomycosis)
  • Fingernail
    • Terbinafine
    • Itraconazole
  • Toenail
    • Terbinafine
    • Itraconazole

Oral antifungals can cause hepatotoxicity; LFTs should be monitored. ^[12][13]

Tinea capitis requires oral treatment. ^[11]

Treatment of tinea versicolor

Any one of the following:

• Imidazoles: e.g., clotrimazole , or ketoconazole
• Allylamines: e.g., terbinafine
• Other: selenium sulfide

Mucocutaneous candidiasis

• See “Treatment of mucocutaneous candidiasis.”

Clinical evaluation ^[15][16]

Estimate the probability of the fungal infection type based on history, physical examination, and individual risk factors.

• Endemic fungal infections ^[15][16]
  • Immunocompetent patients: Pulmonary symptoms are typical (e.g., cough, dyspnea); some patients may have latent infections.
  • Immunocompromised patients: Systemic symptoms are common, e.g., fever, weight loss, myalgias, meningeal irritation, skin changes.
• Opportunistic fungal infections ^[17]
  • Symptoms are variable and nonspecific, e.g., fever, weakness, myalgias, skin rash.
  • May involve pulmonary, cutaneous, CNS, renal, and/or gastrointestinal systems

Persistent fever in an immunocompromised patient despite broad-spectrum antibiotic therapy is a common manifestation of a systemic fungal infection. ^[18]

Risk factors for systemic fungal infection ^[17][18][19]

• Immunosuppressive therapy
• HIV/AIDS
• Chronic illness (e.g., liver disease, renal failure)
• Diabetes mellitus
• Hematologic malignancy
• IV drug use
• Iatrogenic
  • Major surgery
  • Broad-spectrum antimicrobial therapy
  • Parenteral nutrition
  • Prolonged ICU stay
  • Indwelling devices, e.g., central venous access, dialysis, and urinary catheters

Diagnostics ^[17][20][21]

Obtain rapid antigen testing and imaging while awaiting definitive diagnosis with culture and/or histopathology.

Fungal rapid antigen test ^[20][21][22]

Rapid antigen tests quickly identify the presence of fungus, but confirmatory studies are typically required to diagnose infection.

• β-d-glucan assay: detects cell wall components of many fungal species, including Candida spp., Aspergillus spp., and Pneumocystis jirovecii
• Galactomannan test: detects cell wall components; highly specific for Aspergillus spp.
• Serum and/or urine antigens: detects fungal antigens for specific fungal infections (e.g., histoplasmosis, blastomycosis, coccidioidomycosis)

Imaging ^[17][23][24]

• CXR: commonly nonspecific findings (e.g., pulmonary consolidations, bronchopneumonia)
  • Air crescent sign
  • Interstitial opacities
• CT chest
  • Halo sign: central consolidation with surrounding ground-glass opacities
  • Reverse halo sign: central ground-glass opacity surrounded by consolidation
  • Air crescent sign
  • Ground-glass opacities

Radiologists may be able to provide a preliminary diagnosis of invasive fungal infection based on distinguishing radiographic features if they are aware of the clinical suspicion at the time of imaging. ^[24]

Confirmatory studies

• Histopathology (gold standard): evidence of both fungal elements and tissue damage or inflammation ^[25]
• Fungal culture (e.g., from blood, respiratory secretions, tissue biopsy, CSF, abscess contents) ^[21]
  • Identifies species
  • Tests antifungal resistance
  • Limitations
    • Low sensitivity ^[20][23]
    • Delayed diagnosis ^[21]

Negative blood cultures do not exclude systemic fungal infection. ^[23]

Ancillary studies

• PCR: recommended for aspergillosis ^[20][26]
• Serology: recommended for suspected histoplasmosis, blastomycosis, and coccidiomycosis ^{[20] [22]}
• Fundoscopy: recommended for candidemia ^[27][28]
• Echocardiography: recommended for persistently positive blood cultures and/or fever despite appropriate treatment, new murmur, or embolic phenomena ^[29]

Treatment with systemic antifungals ^[30]

Consult infectious diseases for all suspected systemic fungal infections (e.g., fungemia).

Empiric and preemptive ^[31][32]

Commonly started since culture results can take weeks to return. ^[21]

• Empiric therapy: based on clinical suspicion, e.g., clinical features, risk factors for systemic fungal infection, exclusion of other organisms
• Preemptive therapy: based on nondefinitive diagnostics: e.g., RADT, PCR ^[33]
• Options ^[27][34][35]
  • Caspofungin : Preferred for suspected candidiasis
  • Voriconazole : Preferred for invasive mold infections (e.g., aspergillosis)
  • Amphotericin B : Preferred for suspected mucormycosis or invasive aspergillosis infection
  • See also “Empiric antifungal therapy for neutropenic fever.”

Empiric antifungal therapy is the standard of care in patients with neutropenia and persistent fever despite treatment with broad-spectrum antibiotics. ^[30][36]

Definitive ^[37]

Depends on the fungal pathogen identified

• Endemic pulmonary fungal infections ^[38]
  • Mild to moderate disease
    • Itraconazole: first-line for histoplasmosis, paracoccidioidomycosis, blastomycosis, sporotrichosis, and talaromycosis
    • Mild coccidioidomycosis does not typically require treatment.
  • Severe illness
    • Coccidioidomycosis
      • Immunocompetent patients: fluconazole
      • Immunocompromised patients: amphotericin B PLUS fluconazole
    • All other organisms: amphotericin B
  • See also “Overview of the most common endemic fungal infections.”
• Opportunistic fungal infections
  • See “Treatment of systemic candidiasis.”
  • See “Treatment” in “Aspergillosis.”
  • See “Treatment” in “Pneumocystis pneumonia.”
  • See “Systemic fungal infections in patients with HIV.”

Aspergillus and Candida are the most common fungal pathogens in patients with febrile neutropenia due to malignancy. ^[35][36]

Prevention ^[20][39]

Antifungal prophylaxis (e.g., with posaconazole or micafungin) is indicated for immunocompromised patients with:

• Expected prolonged neutropenia, e.g., chemotherapy.
• Corticosteroid use > 2 mg/kg/day for > 2 weeks
• Hemopoietic stem cell transplantation