Fungal infections, Systemic

Systemic Fungal Infections are a major cause of mortality and morbidity in patients with impaired host defenses. A systemic fungal infection is one where the fungus invades past the skin and/or mucosal membranes to involve internal organs. The fungi responsible for systemic fungal infections are a biologically diverse group of species. Of the more than 100,000 fungal species known, only about 150 have been associated with human disease and, of these species, only 10 to 15 are commonly encountered in clinical practice. Table 42.1 lists some of the major fungal systemic fungal infections. Systemic fungal infections were relatively rare until the mid-20th century, when advancements in medicine led to the discovery of immune suppressive therapies and broad spectrum antibiotics. After 1950, the use of corticosteroids for the treatment of several medical conditions was associated with an increase in serious fungal infections as a consequence of corticosteroid-induced immune suppression. The use of broad spectrum antibiotic drugs contributed to an increased frequency of Candidiasis because these drugs can alter the balance of the host microbial flora and promote the growth of fungi. 

Similarly, medical progress allowed some individuals with life-threatening illnesses to survive at the price of impaired host defenses. For example, patients with major surgery, malignancies, organ transplants, and autoimmune diseases were often at high risk for fungal infection as a consequence of therapeutic interventions. Another major contributor to the increased prevalence of fungal infections in recent years has been the epidemic of HIV infection. Patients with advanced HIV infection have profound immunological derangements that place them at high risk for acquiring any of a variety of fungal pathogens (Table 42.1). Since systemic fungal infections are rare in patients with normal immune function, the prevalence of systemic fungal infections in a human population may be an index of its overall immunological health. The label “opportunistic” is often applied to systemic fungal infections because these tend to occur more frequently in patients with impaired immunity. However, this label is inexact because many fungal pathogens cause systemic infections in patients with normal immune function. For example, Cryptococcus neoformans and Histoplasma capsulatum cause infections in apparently normal individuals but are much more likely to cause systemic infections in populations with immune disorders. In contrast, systemic candidiasis is almost always associated with a breakdown in host defenses and Candida is a true opportunistic pathogen. The use of the term opportunistic is more applicable when used to refer to a fungal infection in the setting of impaired immunity than to specific types of fungal pathogens. The problem of invasive fungal infections is compounded by a relative paucity of antifungal drugs and, for many fungal pathogens, inadequate diagnostic tests. Amphotericin B remains the most effective antifungal drug against many fungal infections four decades after its introduction. Because systemic fungal infections tend to occur in individuals with immunological deficits, many become chronic and respond slowly to antifungal therapy. In fact, some infections like cryptococcosis, histoplasmosis, and coccidioidomycosis are essentially incurable when they occur in the setting of advanced HIV infection. 

I. ACQUISITION AND INFECTION 

Unlike other infectious diseases human-to-human transmission of systemic fungal infections is exceedingly rare. Except for C. albicans infections, which are usually acquired from the endogenous microbial flora, the overwhelming majority of fungal infections are acquired from the environment. Epidemics and outbreaks are often associated with unusual exposures to the pathogen or disruptions in the ecosystem. For example, there have been well documented descriptions of local epidemics of histoplasmosis associated with cutting trees or construction projects. The probability of acquiring a systemic fungal infection is usually a function of exposure and host immune function. Because systemic fungal infections are rarely communicable and because they tend to occur in groups with defined risk factors, most fungal pathogens have attracted relatively little attention from public health authorities. As a result, most fungal infections are not reportable to or the subject of active surveillance by public health authorities. Therefore, we have incomplete information on the incidence and prevalence of most types of systemic fungal infections. Among the common systemic fungal infections only candidiasis, cryptococcosis, and aspergillosis have worldwide distribution. Since candidiasis is usually an endogenous infection, it can be found wherever humans live. For cryptococcosis and aspergillosis, the worldwide occurrence of these infections reflects the fact that these fungi are prevalent throughout the world. In contrast, histoplasmosis, penicilliosis, paracoccidioidomycosis, blastomycoses, and coccidioidomycosis are found only in geographic areas of the world where those pathogens are found in the environment. Many fungal pathogens can induce a latent asymptomatic infection after primary infection. Latent infections can reactivate years later, especially if the individual develops a condition associated with impaired immunity. Latent infections combined with routine air travel means that individuals can present with systemic fungal infections in nonendemic areas. For example, an individual could develop coccidioidomycosis or histoplasmosis in New England (a nonendemic area) after living or visiting in the Southwest or Midwest, respectively. 

II. HOST DEFENSES AND SUSCEPTIBILITY TO INFECTION 

With some notable exceptions, which include candidiasis and sporotrichosis, most systemic fungal infections are initially acquired by inhaling infectious particles. Inhalation of infectious particles initially results in a localized pulmonary infection, which is usually contained in the lung by a granulomatous inflammatory response. However, dissemination can occur, especially in the setting of impaired immune function. The pathogenesis of some fungal, infections, such as histoplasmosis, cryptococcosis, blastomycosis, and coccidioidomycosis, has similarities to tuberculosis, including a pulmonary portal of entry and the potential for latent infection. Host defenses include humoral and cellular specific and nonspecific immune mechanisms. Animal experimentation has established that multiple components of the immune system are important for protection against fungi, including complement, antibody, neutrophils, macrophages, and T lymphocytes. Invasive fungal infections are usually associated with derangements of cellular immunity. For example, patients with HIV infection are at high risk for cryptococcosis, histoplasmosis, and coccidioidomycosis when their blood CD4_ T cell lymphocyte counts are below 200/mm3. Invasive aspergilloses and candidiasis are associated with neutrophil deficiencies, such as those caused by cancer therapy. There is general consensus in the field that cellular immune mechanisms play a critical role in containment and eradication of most fungal infections. Invasive fungal infections can occasionally occur in hosts with no apparent immunological deficits but it is not clear whether these cases are the result of unrecognized immunological disorders, unusual exposures, or more virulent fungal strains. 

III. INDIVIDUAL SYSTEMIC FUNGAL INFECTIONS 

A. Aspergillosis Systemic aspergillosis is caused by Aspergillus species (sp.) of which the most common are A. fumigatus and A. flavus. Most cases of human aspergillosis are believed to occur after inhalation of airborne conidia. However, infection following surgery can also follow the deposition of airborne spores in exposed tissues. Aspergillus sp. are very common in the environment and can be found in soil, plants, and decaying vegetation. Conidia germinate in the lung and can invade host tissue if not controlled by local defenses. The invasion can also originate from colonization of paranasal sinuses, the gastrointestinal tract, or the skin. Invasive aspergillosis is a devastating disease of severely immunocompromised patients. Individuals at high risk include those with leukemia, burns, and late-stage HIV infection, as well as those using intravenous drugs and receiving immunosuppressive therapies. Since most Aspergillus infections are acquired from the ambient air, precautions to limit the number of airborne spores, such as laminar flow rooms and filtered air, may reduce the risk of infection. In patients with neutropenia, Aspergillus hyphae often invade and extend along blood vessels, causing tissue infarction and necrosis. A diagnosis of aspergillosis is usually made by culture and pathological examination of tissue samples in the appropriate clinical setting. Amajor problem with aspergillosis is the absence of good diagnostic tests for the detection of early infection. 

Systemic aspergillosis has high mortality despite antifungal therapy. B. Blastomycosis Systemic blastomycosis is caused by the dimorphic fungus Blastomyces dermatitides. In North America, the infection is endemic in the Mississippi and Ohio river valleys and areas adjoining the Great Lakes and the St. Lawrence River. Blastomycosis also occurs in Africa, Central America, and the Middle East. B. dermatitides is believed to reside in soils and decaying vegetation but its exact environmental niche remains to be defined. Initial infection is believed to occur from inhalation of conidia that germinate to yeast cells in the lung. Several outbreaks of blastomycosis have been associated with recreational activities in sites near rivers. In immunologically normal individuals, the infection is contained in the lung and humans appear to have a high level of resistance to disseminated infection. Systemic blastomycosis results when pulmonary blastomycosis disseminates to other organs. Dissemination can occur to practically any organ but the skin is the site most commonly involved. The diagnosis of blastomycosis infection is made by culture or pathological examination of involved tissue in the appropriate clinical setting. Blastomycosis is also a major fungal infection in dogs. C. Candidiasis Systemic candidiasis can be caused by any of several Candida sp. and is the most common systemic fungal infection. Systemic candidiasis is distinguished from the more common type of candidal infections, such as thrush and vaginal candidiasis, by involvement of the blood stream and internal organs. The name Candida is used to refer to more than one hundred fungal species, of which about a dozen are important human pathogens. C. albicans is the most common Candida sp. that causes human disease. However, other species, such as C. glabrata, C. parapsilosis, and C. krusei, commonly cause serious infections in certain patient groups. Candida sp. are components of the human microbial flora and systemic candidiasis differs from the other systemic fungal infections in that this infection almost always originates from the endogenous microbial flora. Candidal infections are very common in hospitalized patients and Candida species are frequent causes of bacteremia and deep-seated organ infections. 

Most cases of systemic C. albicans infection are iatrogenic and are related to the use of antibiotics, the presence of indwelling catheters, and surgical implantations of prosthetic devices. Antibiotics predispose to infection by suppressing the normal bacterial flora and this, presumably, allows Candida to proliferate and invade the gut mucosa. Indwelling catheters provide a break in the skin that allows Candida access to the bloodstream and the internal skin layers. Prosthetic devices provide surfaces where the fungus can attach and escape clearance by host defense mechanisms. Systemic candidal infections can affect virtually any organ and the eye, liver, spleen, and kidneys are frequently involved. The diagnosis of systemic candidiasis is usually made by culture of Candida sp. from a normally sterile body site. However, in many patients, making a diagnosis of systemic candidiasis is difficult because the blood cultures are negative and there are few diagnostic tests to detect deep-seated organ infections. D. Coccidioidomycosis The causative agent of coccidioidomycosis is Coccidioides immitis, a dimorphic soil fungus. This infection is found in certain areas of North and South America. In the United States, coccidioidomycosis is highly prevalent in the Southwest. This infection is believed to be acquired by the inhalation of arthroconidia that swell in tissue to become spherule-containing internal spores. Primary infection is usually either asymptomatic or reassembles a common upper respiratory infection. Individuals with occupations that involve exposure to soils in endemic areas are at higher risk. Outbreaks of coccidioidomycosis have followed archeological investigations. Systemic coccidioidomycosis occurs in less than 1% of primary infections and can involve virtually any organ. Extrapulmonary coccidioidomycosis is more common in individuals with impaired immunity. However, pregnant women and individuals of Filipino, African, and Mexican ancestry might be at increased risk for disseminated infection. Coccidioidomycosis can present as acute infection, chronic pulmonary disease, or systemic infection. The diagnosis is made by culture, histological examination of tissue, and/or serological testing. 

E. Cryptococcosis The causative agent of cryptococcosis is Cryptococcus neoformans. The prevalence of C. neoformans infection with HIV infection. In New York City, there were more than 1200 cases of cryptococcosis in 1991, of which most occurred in patients with AIDS. Cryptococcal meningitis occurs in 5–10% of all patients with advanced HIV infection. Cryptococcal strains have been divided into two varieties known as neoformans and gattii. Variety neoformans is found worldwide, is associated with bird (usually pigeon) excreta, and is the predominant agent of cryptococcosis in patients with AIDS. Variety gattii is found in the tropics, is associated with eucalyptus trees, and can cause infections in apparently normal hosts. C. neoformans is unusual among fungal pathogens, in that it has a polysaccharide capsule that is important for virulence (Fig. 42.1). C. neoformans is acquired by inhalation, where it usually causes an asymptomatic pulmonary infection. In patients with impaired immunity, extrapulmonary dissemination can results in cryptococcal meningitis, the most common clinical presentation of cryptococcosis. Pathological examination of tissues infected with C. neoformans often reveals little or no inflammatory response and this phenomenon is believed to be caused, in part, by the immunosuppressive effects of the capsular polysaccharide. The diagnosis of cryptococcosis is usually made by culture from cerebrospinal fluid or blood. The capsular polysaccharide is shed into body fluid where it can be detected by serological assays. Detection of cryptococcal polysaccharide antigen is useful in diagnosis and in following the response to therapy. 

F. Histoplasmosis The causative agent of histoplasmosis is Histoplasma capsulatum, a soil organism that is common in the Ohio and Mississippi river valleys and in various parts of South America. H. capsulatum is often found in soils contaminated by bird excrement. Small epidemics have occurred because of large exposures created by disturbing contaminated sites during constructions, excavations, tree cuttings, etc. In 1978–1980, two major outbreaks of histoplasmosis occurred in the city of Indianapolis that may have been related to construction projects. H. capsulatum is a dimorphic fungus that grows as a mycelial form at environmental temperatures and as a yeast at mammalian body temperature. Two varieties of H. capsulatum are known: variety capsulatum is found in the Americas and variety duboisii is found in Africa. Infection presumably occurs by the inhalation of conidia and small mycelial fragments that convert to yeast forms in lung tissue. The clinical presentation of pulmonary histoplasmosis is similar to that of pulmonary tuberculosis, such that many cases of histoplasmosis were confused with tuberculosis until specific diagnostic methods became available. The overwhelming majority of primary pulmonary infections are asymptomatic. However, many infections become chronic and some disseminate. 

The probability of acquiring disseminated disease ranges from about 1 in 2000 for normal individuals to up to 27% for patients with advanced HIV infection. Disseminated disease can affect virtually any organ, with adrenal, skin, gastrointestinal, and central nervous system involvement being particularly common. The diagnosis of systemic histoplasmosis is made by culture of the fungus from blood, bone marrow, sputum, cerebrospinal fluid, or the affected body site. However, culture methods can yield false-negative results. A presumptive diagnosis can be made by visualizing yeast cells in infected tissues. In this regard, H. capsulatum can sometimes be detected in peripheral blood leukocytes of patients with disseminated histoplasmosis. Serological tests for histoplasma antibody and antigen can provide important clues to the  presence of H. capsulatum infection. Antigen detection in urine samples is particularly useful in cases where the diagnosis is suspected but cultures are negative. G. Other systemic fungal infections Many other fungal species can cause invasive infection besides the more common systemic fungal infections listed above. In Southeast Asia, Penicillium marneffei is a major cause of invasive fungal infection in patients with advanced HIV infection. Paracoccidioides brasiliensis is a major fungal pathogen in some areas of South America. P. brasiliensis causes asymptomatic infection in normal individuals that can remain latent and disseminate if the immune system subsequently becomes impaired. Recently, there have been several reports of systemic fungal infection with the Saccharomyces cerevisiae, which is commonly known as brewer’s or baker’s yeast. Although rare, these cases illustrate how a usually nonpathogenic organism can cause serious infection if it colonizes a susceptible host. Pseudallescheria boydii is a mold that causes severe infections in patients with prolonged neutropenia or who are receiving high-dose corticosteroid therapy. P. boydii infections are similar to those caused by Aspergillus sp. Sporothrix schenckii is a dimorphic fungus, found in soils and plants, that can cause sporotrichosis after inoculation in the skin. Sporotrichosis has been reported throughout the world but is associated primarily with activities that result in exposure to plants, such as gardening and farming. Mucormycosis is caused by a variety of fungal species with a complex taxonomy, including Rhizopus, Absidia, and Mucor. In diabetic patients with poorly controlled hyperglycemia, mucormycosis is a devastating and often incurable infection. Phaeohyphomycosis is caused by a variety of fungal species that have dark cell walls. Cerebral phaeohyphomycosis is a rare but rapidly lethal brain infection that has been commonly associated with the fungus Clasdosporium trichoides. 

IV. TREATMENT AND PREVENTION OF SYSTEMIC FUNGAL INFECTIONS 

Most systemic fungal infections are fatal without antifungal therapy. Unlike the situation for bacterial pathogens, the antibiotic arsenal against the fungi is small and consists of no more than half a dozen drugs. Since the late 1950s, Amphotericin B has been the mainstay of therapy for many invasive mycoses. Amphotericin B is a powerful fungicidal agent that binds to fungal sterols and kills the fungal cell by disrupting cellular membranes. Amphotericin B may also have important immunomodulatory effects that could contribute to its therapeutic efficacy. Amphotericin B has significant toxicity that can be lessened by incorporating it into liposomal preparations but these are significantly more expensive. In recent years, other agents that target the sterol metabolic pathways have been introduced, including fluconazole and itraconazole. These agents are usually fungistatic but are much less toxic than amphotericin B and have the added advantages of being available in oral formulations. 5-Fluorocytosine is another antifungal drug that is effective when used in combination with other antifungal drugs. Several antifungal agents are in preclinical and clinical development and newer agents with enhanced efficacy and reduced toxicity may be available in the future. A major problem in the therapy of systemic fungal infections is that antifungal chemotherapy is less effective in the setting of defective immunity. For example, antifungal therapy cannot usually eradicate C. neoformans, H. capsulatum, and C. immitis infections in patients with advanced HIV infection. As a result, affected individuals must be given lifelong suppressive therapy to reduce the likelihood of clinical recurrence of infection. The difficulties associated with the therapy of systemic fungal infections have stimulated interest in immunotherapy but this therapeutic strategy is still experimental. There are ongoing efforts to develop vaccines against coccidioidomycosis, histoplasmosis, and cryptococcosis but none is currently available. At this time, the two main strategies for the prevention of systemic infection in patients at risk for infection include avoidance of infection and the use of prophylactic antifungal drugs. For many systemic fungal infections, prevention is difficult because the fungal pathogen is highly prevalent in the environment. For example, C. neoformans is found in high concentration in pigeon excreta in urban areas such as New York City, where many patients with advanced HIV infection live. Similarly, H. capsulatum and C. immitis are prevalent in soils of specific geographic areas of the world and avoiding exposure may be difficult for residents in those regions. Nevertheless, it is prudent for individuals with immunological disorders to avoid sites likely to contain high concentrations of aerosolized fungal pathogens such as construction sites, aviaries, chicken farms, and compost sites. Prophylactic administration of antifungal drugs has been shown to reduce the incidence of certain fungal infections, such as cryptococcosis, in patients at high risk for infection. However, there are concerns that prophylactic drug use will encourage the selection of drug-resistant fungi, and drug prophylaxis is not used routinely for the prevention of fungal infection. Another preventive strategy to reduce invasive fungal infections in patients with neutropenia is to administer colony-stimulating factors that reduce the neutropenic interval by stimulating leukocyte production.