General Mycology

Medical mycology is the study of fungi that cause disease in humans, the diseases they produce (mycoses), and the allergic and toxin mediated illnesses that fungi cause without tissue infection. Fungi are eukaryotic, non photosynthetic, absorptive heterotrophs with chitin containing cell walls and ergosterol containing membranes.

Estimates of total fungal species run from 1.5 to over 3 million. A few hundred have been reported to cause human disease, and a few dozen account for most clinical infection: Candida, Aspergillus, Cryptococcus, Pneumocystis, the dermatophytes, Malassezia, Mucorales and the endemic dimorphic fungi.

Fungal disease falls into three mechanistic groups:

• Infection: superficial, cutaneous, subcutaneous, mucosal, and invasive disease.
• Allergy: allergic bronchopulmonary aspergillosis, allergic fungal rhinosinusitis, severe asthma with fungal sensitisation, hypersensitivity pneumonitis.
• Toxin mediated disease: mycotoxicosis such as aflatoxin exposure.

Fungal cells share basic eukaryotic organisation with human cells. This narrows the range of selective drug targets and explains why antifungal toxicity and drug interactions are more prominent than with antibacterials. The differences that matter clinically are the cell wall and the membrane sterol.

Antibacterial therapy is ineffective against fungi. Broad spectrum antibacterials remove bacterial competition and promote overgrowth of commensal Candida species in the gut, mouth and vagina.

Superficial and cutaneous mycoses are among the commonest human infections worldwide. Invasive mycoses are far less frequent but cause over a million deaths annually by most estimates. Cryptococcosis, invasive candidiasis, invasive aspergillosis and Pneumocystis pneumonia account for most of this mortality, concentrated in advanced HIV disease, haematological malignancy, transplantation and intensive care.

Epidemiological shifts that shape current practice:

• Non albicans Candida species and multidrug resistant Candida auris are increasing in healthcare settings.
• Azole resistant Aspergillus fumigatus is linked to agricultural azole fungicide exposure in the environment.
• Invasive aspergillosis follows severe influenza and severe COVID-19; mucormycosis surged with COVID-19 in uncontrolled diabetes and corticosteroid exposure.
• The geographical range of Coccidioides and Cryptococcus gattii has widened.
• Antifungal therapy relies on a handful of drug classes, so resistance has few alternatives to fall back on.

Reservoirs:

• Soil: Coccidioides in arid alkaline soil; Blastomyces in moist soil near waterways; Histoplasma in soil enriched with bird and bat guano; Sporothrix in soil and decaying plant matter.
• Avian droppings and trees: Cryptococcus neoformans in pigeon droppings; Cryptococcus gattii with certain trees.
• Decaying vegetation and compost: Aspergillus conidia.
• Decaying organic matter, bread and fruit: Mucorales.
• Animals: zoophilic dermatophytes; Sporothrix brasiliensis from cats.

Person to person transmission is the exception: anthropophilic dermatophytes, Pneumocystis between susceptible hosts, and Candida auris on hands and surfaces. The endemic dimorphic fungi do not spread between people in ordinary clinical contact.

The human mycobiota is low in abundance and diversity compared with the bacterial microbiota.

• Candida species colonise the oral cavity, gut and vagina of a substantial proportion of healthy adults, Candida albicans being the commonest.
• Malassezia species dominate the fungal flora of sebum rich skin of the scalp, face and trunk.
• Saccharomyces and other yeasts occur transiently from diet.

Commensal fungi cause disease when barriers are breached, bacterial competition is disrupted, or immune defence fails.

The boundary is graded, not absolute. Primary pathogens, chiefly the endemic dimorphic fungi, infect people with intact immunity after a sufficient inoculum, but disease is more severe and disseminated when T cell immunity is impaired. Talaromyces marneffei and Emergomyces species cause disease predominantly in advanced HIV. Opportunistic fungi cause disease when a specific host defect exists, though Cryptococcus gattii infects immunocompetent hosts more often than Cryptococcus neoformans.

• Colonisation: organism present without tissue invasion or host response. Examples: Candida species in respiratory secretions, urine from catheterised patients, wounds and drains; Aspergillus in sputum from structurally abnormal lungs.
• Contamination: environmental fungi introduced at collection or processing. Typical contaminants: Penicillium, Cladosporium, Alternaria and non pathogenic Aspergillus on plates. Suggestive features are growth on one plate only or growth outside the inoculum streak.
• Infection: tissue invasion demonstrated histologically, or isolation from a normally sterile site with a compatible clinical picture.

Rules that follow from these definitions:

• Candida in blood culture is never dismissed as a contaminant.
• Any yeast in cerebrospinal fluid is significant, and Cryptococcus from any site is significant.
• A mould from a sterile site, or a mould on histology invading tissue, is significant.
• A mould from a respiratory sample carries high significance in a neutropenic or transplant patient and often little in a person with normal lungs.
• Hyphae invading tissue on histopathology is the discriminator for invasive mould infection.

• Direct microscopy of the specimen gives the fastest result and is always paired with culture.
• Cultures are incubated at 25 to 30 degrees Celsius and 35 to 37 degrees Celsius; dimorphic fungi may need up to 4 weeks.
• Cultures of the mould phase of Histoplasma, Blastomyces and Coccidioides are laboratory hazards, and the laboratory must be told when they are suspected. Coccidioides arthroconidia are highly infectious.
• Identification rests on colony and microscopic morphology, mass spectrometry and sequencing.
• Pneumocystis and Paracoccidioides loboi do not grow on routine culture, so detection relies on microscopy, molecular tests and biomarkers.