Fungi are eukaryotic organisms that exist as yeast, molds, or both forms (dimorphic fungi). Yeasts consist of solitary cells that reproduce by budding. Molds occur in filaments, also known as hyphae, which extend by apical elongation. Dimorphic fungi grow as mold in the environment and as yeast cells or spherules (sac-like cells that are the reproductive form of the fungus) in vivo.
Fungal infections are often classified as either:
Primary
Opportunistic
Primary infections are able to develop in immunocompetent hosts.
Opportunistic infections are those that develop mainly in immunocompromised hosts.
Fungal infections can be:
Local
Systemic
Local fungal infections typically involve the skin (see Fungal Skin Infections), oral mucosa (causing stomatitis), and/or vagina (causing candidal vaginitis) and may occur in immunocompetent or immunocompromised hosts.
Systemic fungal infections can affect organs such as the lungs, eyes, liver, and brain and typically occur in immunocompromised hosts (see Opportunistic fungal infections).
Primary fungal infections
Primary fungal infections usually result from inhalation of fungal spores, which can cause a localized pneumonia as the primary manifestation of infection.
In immunocompetent patients, systemic mycoses typically have a chronic course; dissemination is rare. If lung lesions develop (eg, aspergilloma), they usually progress slowly. Thus, months may elapse before medical attention is sought or a diagnosis is made. Symptoms are rarely intense in such chronic mycoses, but fever, chills, night sweats, anorexia, weight loss, malaise, and depression may occur. Various organs may be infected, causing symptoms and dysfunction.
Some primary fungal infections may have a characteristic geographic distribution, which is especially true for the endemic mycoses caused by certain dimorphic fungi:
Coccidioidomycosis: Confined primarily to the southwestern United States and also to northern Mexico and parts of Central and South America
Histoplasmosis: Occurring primarily in the eastern and midwestern United States (primarily the Ohio and Mississippi River Valleys) and parts of Central and South America, Africa, Asia, and Australia
Blastomycosis: Confined to North America (northwestern Midwest, Upstate New York), the Middle East, and Africa
Paracoccidioidomycosis: Confined to South America
Cryptococcosis: Worldwide distribution
However, the latency from transmission to infection varies, and symptoms may not appear until after travelers have returned from endemic areas.
When fungi disseminate from a primary focus in the lung, the manifestations may be characteristic, as for the following:
Coccidioidomycosis: Bone and joint infections, skin lesions, and meningitis
Histoplasmosis (progressive, disseminated): Generalized involvement of the reticuloendothelial system (liver, spleen, bone marrow)
Blastomycosis: Single or multiple skin lesions or involvement of the central nervous system, bone, or prostate
Cryptococcosis: Usually chronic meningitis
Opportunistic fungal infections
Many fungi are opportunists and are usually not pathogenic, except in an immunocompromised host. Causes of immunocompromise include advanced HIV infection, diabetes mellitus, lymphoma, leukemia, other hematologic cancers, burns, and therapy with glucocorticoids, immunosuppressants, or antimetabolites. Critically ill patients can become compromised because of medical procedures (eg, central venous catheters, major surgery), underlying disorders, and/or undernutrition.
Examples of opportunistic systemic fungal infections (mycoses) include:
Pneumocystis infections
Aspergillosis (which may also occur in immunocompetent patients, eg, allergic bronchopulmonary aspergillosis)
Fusariosis
Systemic mycoses affecting severely immunocompromised patients often manifest acutely with rapidly progressive pneumonia, fungemia, or manifestations of extrapulmonary dissemination.
Diagnosis of Fungal Infections
Cultures and stains (eg, of sputum via expectoration or bronchoalveolar lavage, or biopsy samples via transthoracic needle or surgery)
Histopathology
Serologic tests (mainly for Aspergillus, Blastomyces, Candida, Coccidioides, Cryptococcus, and Histoplasma)
Molecular diagnostics
Proteomic techniques
If clinicians suspect an acute or a chronic primary fungal infection, they should obtain a detailed travel and residential history to determine whether patients may have been exposed to certain endemic mycoses, even if the exposure occurred several years ago.
Pulmonary fungal infections must be distinguished from tumors and chronic lung lesions caused by nonfungal organisms such as mycobacteria (including Mycobacterium tuberculosis). Therefore, specimens should be obtained for fungal and mycobacterial culture and histopathology. Sputum samples may be adequate, but occasionally bronchoalveolar lavage, transthoracic needle biopsy, or even surgery may be required to obtain an acceptable specimen.
Fungi that cause primary systemic infections can be recognized by their histopathologic appearance. However, identifying the specific fungus may be difficult and usually requires confirmatory fungal culture or molecular diagnostics.
The clinical significance of positive sputum cultures may be unclear if they reveal commensal organisms (eg, Candida albicans) or fungi ubiquitous in the environment (eg, Aspergillus species). Therefore, establishing a diagnosis often necessitates clinical correlation and corroborating evidence (eg, host factors such as immunosuppression, serologic evidence, tissue invasion seen on biopsy, or radiologic findings).
Serologic tests may be used to evaluate for many systemic mycoses if culture and histopathology are unavailable or indeterminate, although few provide definitive diagnoses. Particularly useful tests include the following:
Organism-specific antigens, most notably from Cryptococcus neoformans, Histoplasma capsulatum, and Aspergillus species (occasional cross-reactivity with other fungi has been noted with each of these serologic tests)
Serum (1,3)beta-D-glucan, which is often positive in invasive candidiasis and aspergillosis as well as Pneumocystis jirovecii infections
Complement fixation and immunodiffusion assays for endemic mycoses (histoplasmosis, blastomycosis, coccidioidomycosis)
Most other tests for antifungal antibodies have low sensitivity and/or specificity. These tests are not typically used to guide initial therapy because measurement of acute and convalescent titers is required.
Molecular diagnostics are useful tools for identifying molecular components of certain fungal infections. DNA probes that use culture specimens to identify Histoplasma, Blastomyces, and Coccidioides and polymerase chain reaction or DNA hybridization tests that use blood culture specimens to identify Candida are available. Microbial cell-free DNA next-generation sequencing is an emerging technology for the detection of a broad array of fungal and other microbial pathogens from blood.
Proteomic techniques such as matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectrometry (MS) enable rapid and accurate identification of fungal pathogens (both yeasts and molds) from clinical specimens. The primary use of MALDI-TOF MS is in species-level identification after fungal growth in culture, which significantly reduces turnaround time when compared with conventional phenotypic or biochemical methods. MALDI-TOF MS is considered a standard adjunct to conventional methods in clinical mycology laboratories, enabling faster initiation of targeted antifungal therapy.
