Michael R. McGinnis
Stephen K. Tyring
Fungi are eukaryotic microorganisms which are heterotrophic and essentially aerobic with limited anaerobic capabilities. Fungi synthesize lysine by the L-aadipic acid biosynthetic pathway. They possess chitinous cell walls, plasma membranes containing ergosterol, 80SrRNA and microtubules composed of tubulin. Fungi grow as yeasts, molds or a combination of both (i.e. dimorphism).
Fungal infections can present clinically in three general manners. Cutaneous presentations can include dermatophyte infections as well as more superficial manifestations seen in pityriasis versicolor. Subcutaneous infections, such as sporotrichosis, often result from traumatic inoculation of the responsible organism into the skin. Systemic mycoses usually follow inhalation and are subsequent to primary pulmonary infections. Alternatively, systemic fungal infections can occur in immunocompromised hosts from normal flora. For example, Candida albicans is frequently seen as part of normal vaginal flora but can produce systemic disease in cancer patients receiving chemotherapy or in AIDS patients. In addition, fungi can indirectly produce disease by eliciting an immune response in the host.
Fungi can grow as yeasts and/or as molds. Yeasts are single-celled forms that reproduce by budding, whereas molds form multicellular hyphae. Dimorphic fungi grow as yeasts or spherules in vivo, as well as in vitro at 37°C, but as molds at 25°C. Dimorphism is regulated by factors such as temperature, CO2 concentration, pH, and the levels of cysteine or other sulfhydryl-containing compounds, depending upon the dimorphic fungus.
Classification of fungi can be based on reproductive structures. Asexual structures are referred to as anamorphs; sexual structures are known as teleomorphs; and the whole fungus is known as the holomorph. Two independent, coexisting classification systems, one based on anamorphs and the other on teleomorphs are used to classify fungi. Fungal infections can also be classified according to the type and degree of tissue involvement and the host response to the pathogen. Fungi can also be classified as exogenous or endogenous depending on the route of infection. Endogenous fungi can cause infections if the host immune system is suboptimal. Such endogenous infections may originate from normal flora or via reactivation of a previous infection. Classification may be based on the interaction of the organism and the host immune response. Primary pathogens can cause disease even if the host immune system is intact while opportunistic pathogens generally cause disease only in immunocompromised persons.
Fungi may reproduce sexually or asexually. Spores may be either sexual or asexual in origin. Sexual spores include ascospores, basidiospores, oospores and zygospores, which are used to determine phylogenetic relationships. Sexual reproduction occurs by the fusion of two haploid nuclei (karyogamy), followed by meiotic division of the diploid nucleus. Asexual spores are produced in sac-like cells called sporangia and are called sporangiospores. Asexual reproduction results from division of nuclei by mitosis.
Fungi have developed many mechanisms to colonize human hosts. The ability to grow at 37°C is one of the most important. Production of keratinase allows dermatophytes to digest keratin in skin, hair and nails. Dimorphism allows many fungi that exist in nature as molds to change to a yeast form in the host and thus become pathogenic. In contrast, Candida albicans exists in the yeast form as normal flora but becomes invasive in the filamentous form. In addition, the antiphagocytic properties of the Cryptococcus neoformans capsule and the adherence abilities of C albicans allow pathogenic potential for these fungi. Fungi may spread locally such as dermatophytes on the skin or eumycotic mycetomas in subcutaneous tissue. Sporothix schenckii, another subcutaneous pathogen, spreads via local lymphatics. The fungi-producing systemic mycoses first cause pulmonary infections. These fungi are phagocytosed by alveolor macrophages but are not destroyed. Instead the fungi are spread hematogenously to distant sites in the body. An exception is Cryptococcus neoformans which disseminates without being phagocytosed. The pathogenesis of some fungi may be at least partly due to the host's reaction to the organism such as the allergic reactions elicited by some fungi.
While some fungi have more pathogenic potential than others, the immunologic status of the host is of paramount importance in determining whether an organism will cause disease and will help determine the severity of the infection. Both humoral and cell mediated immunity (CMI) are important in control of fungal infections, but CMI appears to be more important since patients with defects in CMI usually suffer more severe fungal infections than do persons with depressed humoral immunity. Nonspecific barriers to fungal infection must be crossed, however, before specific immune responses to fungi are elicited. These primary barriers to fungal infection include intact skin, naturally occurring long-chain unsaturated fatty acids, competition with normal bacterial flora and epithelial turnover rate. In addition the mucous membranes are covered with fluids containing antifungal substances. Furthermore, many epithelial cells of the mucous membranes contain cilia that actively remove microorganisms.
Whereas some fungi such as Sporothrix schenckii are found worldwide, it is most commonly encountered in persons engaged in professions or hobbies where the organism might gain entry into subcutaneous tissues via trauma (e.g. gardeners). Other fungi would be most commonly seen in persons living in or visiting specific geographic regions (e.g. Coccidioides immitis in the desert southwestern United States). More specific examples of the role of the environment in fungal infections include the increased rate of candidal vaginitis in women taking systemic antibacterial drugs and increased prevalence of mycotic mycetomas in barefoot persons living in tropical countries. While immunocompromising conditions result in increases in opportunistic fungal infections, the specific underlying disease partially determines the prevalence of such infections. For example, the rhinocerebral syndrome (a deeply invading, life threatening form of zygomycosis, also known as mucormycosis) might be seen in persons suffering from diabetic ketoacidosis while histoplasmosis would be more common in AIDS patients.
The first suspicion of a fungal infection is often the result of the clinical presentation. Microscopic examination of skin scrapings, a vaginal discharge or bronchoscopic washings might reveal dermatophytes, candidiasis or histoplasmosis, respectively. A chest radiograph would be useful in detecting most pulmonary fungal infections. In other cases a biopsy is required as is the use of special strains in order to visualize the responsible fungi. Cultures are frequently used in combination with direct microscopic examination of specimens and/or biopsies in order to confirm the diagnosis and to identify the responsible organism. For some fungal diseases serology is used to detect fungal antigens or host antibodies.
Control of fungal infections may include prevention as well as treatment. Prevention includes avoidance of environments and conditions conducive to fungal growth. Maintenance of a "spore-free" environment in hospitals can reduce the incidence of nosocomial fungal infections. In the case of immunocompromised patients, management of the underlying disease also may help reduce the incidence of fungal infections (e.g. control of diabetes via diet, oral hypoglycemics or insulin). In other situations such as AIDS, cancer patients receiving chemotherapy or organ transplant recipients, prophylaxis with antifungal agents may be necessary. Whether used for prophylaxis or treatment, many antifungal drugs take advantage of the fact the sterol in the fungal cell membrane is ergosterol instead of cholesterol as in humans. Inhibitors of ergosterol biosynthesis include azoles, allylamine and morpholine antifungal drugs. The polyenes form complexes with ergosterol in the membrane. Other antifungal agents inhibit DNA and RNA synthesis (e.g. 5-fluorocytosine) or mitosis (e.g. griseofulvin).