Terminology and Microbiology
Traditionally, fungal infections have been classified into specific categories based on both anatomic location and epidemiology. The most common general anatomic categories are mucocutaneous and deep organ infection; the most common general epidemiologic categories are endemic and opportunistic. Although mucocutaneous infections can cause serious morbidity, they are rarely fatal. Deep organ infections also cause severe illness in many cases and, in contrast to mucocutaneous infections, are often fatal. The endemic mycoses (e.g., coccidioidomycosis) are infections caused by fungal organisms that are not part of the normal human microbial flora and are acquired from environmental sources. In contrast, opportunistic mycoses are caused by organisms (e.g., Candida and Aspergillus) that commonly are components of the normal human flora and whose ubiquity in nature renders them easily acquired by the immunocompromised host. Opportunistic fungi cause serious infections when the immunologic response of the host becomes ineffective, allowing the organisms to transition from harmless commensals to invasive pathogens. Frequently, the diminished effectiveness of the immune system is a result of advanced modern therapies that coincidentally either unbalance the host's microflora or directly interfere with immunologic responses. Endemic mycoses cause more severe illness in immunocompromised patients than in immunocompetent individuals.
Patients acquire deep organ infection with endemic fungi almost exclusively by inhalation. Cutaneous infections result either from hematogenous dissemination or, more often, from direct contact with soil—the natural reservoir for the vast majority of endemic mycoses. The dermatophytic fungi may be acquired by human-to-human transmission, but the majority of infections result from environmental contact. In contrast, the opportunistic fungus Candida invades the host from normal sites of colonization, usually the mucous membranes of the gastrointestinal tract. In general, innate immunity is the primary defense mechanism against fungi. Although antibodies are formed during many fungal infections (and even during commensalism), they generally do not constitute the primary mode of defense. Nevertheless, in selected infections, as discussed below, measurement of antibody titers may be a useful diagnostic test.
Three other terms frequently used in clinical discussions of fungal infections are yeast, mold, and dimorphic fungus. Yeasts are seen as rounded single cells or as budding organisms. Candida and Cryptococcus are traditionally classified as yeasts. Molds grow as filamentous forms called hyphae both at room temperature and in invaded tissue. Aspergillus, Rhizopus [the species that causes mucormycosis (zygomycosis)], and fungi commonly infecting the skin to cause ringworm and related cutaneous conditions are classified as molds. Variations occur within this classification of yeasts and molds. For instance, when Candida infects tissue, both yeasts and filamentous forms may occur (except with C. glabrata, which forms only yeasts in tissue); in contrast, Cryptococcus exists only in yeast form. Dimorphic is the term used to describe fungi that grow as yeasts or large spherical structures in tissue but as filamentous forms at room temperature in the environment. Classified in this group are the organisms causing blastomycosis, paracoccidioidomycosis, coccidioidomycosis, histoplasmosis, and sporotrichosis.
The incidence of nearly all fungal infections has risen substantially. Opportunistic infections have increased in frequency as a consequence of intentional immunosuppression in organ and stem cell transplantation and other diseases, the administration of cytotoxic chemotherapy for cancers, and the liberal use of antibacterial agents. The incidence of endemic mycoses has increased in geographic locations where there has been substantial population growth.
The definitive diagnosis of any fungal infection requires histopathologic identification of the fungus invading tissue, accompanied by evidence of an inflammatory response. The identification of an inflammatory response has been especially important with regard to Aspergillus infection. Aspergillus is ubiquitous and can float from the air onto biopsy material. Therefore, in rare but important instances, this fungus is an ex vivo contaminant during processing of a specimen for microscopy, with a consequent incorrect diagnosis. The stains most commonly used to identify fungi are periodic acid–Schiff and Gomori methenamine silver. Candida, unlike other fungi, is visible on gram-stained tissue smears. Hematoxylin and eosin stain is not sufficient to identify Candida in tissue specimens. When positive, an India ink preparation of cerebrospinal fluid (CSF) is diagnostic for cryptococcosis. Most laboratories now use calcofluor white staining coupled with fluorescent microscopy to identify fungi in fluid specimens.
Extensive investigations of the diagnosis of deep organ fungal infections have yielded a variety of tests with different degrees of specificity and sensitivity. The most reliable tests are the detection of antibody to Coccidioides immitis in serum and CSF; of Histoplasma capsulatum antigen in urine, serum, and CSF; and of cryptococcal polysaccharide antigen in serum and CSF. These tests have a general sensitivity and specificity of 90%; however, because there is variability among laboratories, testing on multiple occasions is advisable. The test for galactomannan has been used extensively in Europe and is now approved in the United States for diagnosis of aspergillosis. Sources of concern regarding galactomannan are the incidence of false-negative results and the need for multiple serial tests to reduce this incidence. The β-glucan test for Candida is also under evaluation but, like the galactomannan test, requires additional validation; this test has a negative predictive value of ∼90%. Numerous polymerase chain reaction assays to detect antigens are in the developmental stages, as are nucleic acid hybridization techniques.
Of the fungal organisms, Candida is by far the most frequently recovered from blood. Although Candida species can be detected with any of the automated blood culture systems widely used at present, the lysis-centrifugation technique increases the sensitivity of blood cultures for Candida and for less common organisms (e.g., H. capsulatum). Lysis-centrifugation should be used when disseminated fungal infection is suspected.
Except in the cases of coccidioidomycosis, cryptococcosis, and histoplasmosis, there are no fully validated and widely used tests for serodiagnosis of disseminated fungal infection. Skin tests for the endemic mycoses are no longer available.
Treatment: Fungal Infections