Fungal Infections in Immunocompromised Hosts: Focus on Epidemiologic Aspects of Infection

As the population of immunosuppressed individuals increases, so do the numbers and types of fungal infections noted in these patients. Although candidiasis remains the most common fungal infection in immunosuppressed patients, aspergillosis, zygomycosis, and other invasive filamentous fungal infections are a major problem for certain groups of patients. The endemic mycoses, especially histoplasmosis and coccidioidomycosis, constitute a risk for other groups of patients. Many emerging fungal pathogens are resistant to the currently available antifungal agents and, thus, pose a special risk for immunocompromised patients.

Patients At Risk for Fungal Infections

The immunocompromised state encompasses many diverse conditions (Table 1).On the one hand are those, such as bone marrow transplant recipients and patients with acquired immunodeficiency syndrome (AIDS), who have obvious defects of one or several immune system components. On the other are an increasing number of patients, such as those who have multiorgan failure and are in an intensive care unit (ICU) for long periods of time, whose immunosuppression is not easily defined by classic defects in host defenses. Nevertheless, this latter group of patients constitutes the largest group experiencing invasive fungal infections in many hospitals.

The development of a fungal infection depends on several (Table 2). Prophylactic antifungal agents can modulate the factors and prevent development of some fungal infections. This review will focus on current understanding of the relationship of these factors to fungal infections in the immunocompromised host.

Candidiasis

Exposure to candida species is universal since these organisms are part of the human gastrointestinal (GI) tract flora. The amount of growth in the GI tract and, hence, the potential inoculum, is increased by broad-spectrum antibiotic therapy. In patients with acute leukemia, the use of certain chemotherapeutic agents influences the potential for egress of candida from the GI tract. There is little to suggest major differences in virulence among the different species of candida with the possible exception of Candida tropicalis, which appears to cause a disproportionate number of serious infections in patients with hematologic malignancies.

The primary host defenses against candida are neutrophils, which are important in preventing hematogenous spread of the organism, and T lymphocytes, which are important in preventing mucosal candidiasis. Thus, the period of highest risk for developing candidiasis in a patient with acute leukemia is during the time of neutropenia, especially if prolonged. Bone marrow transplant (BMT) recipients with delayed engraftment and prolonged neutropenia and those who develop graft-versus-host disease (GVHD) are at high risk for invasive candidiasis. Solid organ transplant recipients usually have the greatest problem with candidiasis within the first 2 months after transplantation. Infection with cytomegalovirus (CMV) after transplant increases the risk of candidiasis.

In transplant recipients and patients with neutropenia, candida infection is usually manifested as disseminated disease. In contrast, patients with HIV infection are most likely to develop candidiasis after their CD4 counts have dropped to <200/mm3. However, even when the CD4 cells are extremely low, candida infection is limited to the mucosal surfaces in AIDS patients.

For many physicians, experience with serious candida infection is encountered primarily with patients who are in the ICU and have multiple underlying illnesses. For these patients, the major risk factors are poor functional status, prior surgery or perforation of the GI tract, treatment with broad-spectrum antibiotics, central intravenous (IV) catheters, and a variety of other variables. Although in these patients the immune system is not suppressed to the extent seen in transplant recipients, AIDS patients, or patients with hematologic malignancies, there is often dysregulation of the immune system that likely contributes to the occurrence of candidiasis.

In recent years, an important concern has been the prominence of nonalbicans species in some medical centers. Several of these species, specifically C. krusei and C. glabrata, are less susceptible to fluconazole, the primary azole antifungal agent used to treat candida infections. Whether fluconazole therapy is instrumental in selecting these more resistant species has not yet been clearly defined but it is likely that overuse of this azole does play a role in some settings. Another concern is the emergence of fluconazole-resistant C. albicans among AIDS patients who have frequent episodes of thrush that require treatment with multiple courses of fluconazole. Finally, an additional development in the epidemiology of candidiasis is the role played by nosocomial transmission of candida species in the ICU. Several outbreaks have linked spread of C. albicans and C. parapsilosis to contaminated devices or solutions or from colonized healthcare workers. Clues to diagnosing invasive candidiasis are shown in (Table 3).

Fluconazole prophylaxis can prevent candidiasis in BMT and liver transplant recipients when given during the period of highest risk but its usefulness in neutropenic patients with acute leukemia has not been convincingly shown. No studies have shown antifungal prophylaxis is effective in the ICU, in which risk factors for development of infection are not as clearly defined as in the neutropenic population. Although fluconazole prophylaxis can prevent mucosal candidiasis in AIDS patients, the negative aspects of prophylaxis (azole resistance, drug toxicity and interactions, costs) far outweigh the benefits of preventing localized mucosal candidiasis. Therefore, prophylaxis is not recommended.

Aspergillosis

Although less common than candidiasis, aspergillosis is more likely to result in life-threatening infection in immunosuppressed patients. Exposure to aspergillus is a common occurrence. The organisms grow on a wide variety of organic material and the conidia are easily aerosolized. Although exposure is universal, invasive infection is uncommon and occurs almost entirely in immunosuppressed individuals. Outbreaks have been described in BMT, solid organ transplant recipients, and leukemia patients in association with hospital construction and/or ventilation system contamination with aspergillus. The species of aspergillus most often implicated in causing invasive disease are Aspergillus fumigatus and A. flavus.

The most important host defenses against aspergillus are neutrophils and alveolar macrophages. Thus, neutropenic patients, especially when neutropenia is prolonged and they are also receiving corticosteroids, are at high risk for invasive aspergillosis. BMT patients develop aspergillosis early before engraftment and also later if they develop GVHD. Recipients of heart and lung transplants have higher rates of invasive aspergillosis than those receiving liver or kidney transplants. Solid organ transplant recipients have the highest risk in the first 2 to 3 months after transplant and, for both solid organ and BMT recipients, development of CMV infection is an additional risk factor for aspergillosis Table 4.

Although highly desired, aspergillosis prevention in immunosuppressed patients has been difficult to accomplish. Several studies using historical controls have shown benefit from using prophylactic IV amphotericin B in BMT recipients but other factors may have contributed to the decrease in aspergillosis in those studies. Intranasal and aerosolized amphotericin B have also been studied but the results are conflicting. Avoidance of construction areas likely to have high concentrations of aspergillus is mandatory for patients at risk and should be considered when hospital renovation projects are planned.

Mucormycosis (Zygomycosis)

Infection of immunosuppressed hosts with organisms belonging to the order Mucorales causes life-threatening pulmonary, rhinocerebral, or disseminated infection. The organisms causing mucormycosis (rhizopus and, less commonly, mucor and absidia) are routinely encountered in the environment. In spite of this common exposure, infection is rare and occurs only in immunosuppressed hosts or those with other specific risk factors.

The primary host defense against the Mucorales is the neutrophil and, thus, neutropenic patients are at risk for mucormycosis. Another important risk factor is poorly controlled diabetes mellitus with ketoacidosis, presumably because acidosis interferes with neutrophil chemotaxis, phagocytosis, and killing of the fungus. A third group of patients at risk are those receiving iron chelation therapy with deferoxamine. The Mucorales are able to usurp the function of the chelator to enhance their own growth and cause life-threatening infection. Prophylactic antifungal regimens are not available to prevent mucormycosis.

Cryptococcosis

Cryptococcus neoformans is acquired from the environment. The organism lives in soil and organic matter that contain high concentrations of pigeon and other bird excreta. For most patients, a discrete exposure history cannot be obtained and many may have had their primary infection years before. The initial pulmonary infection often goes unnoticed. Because C. neoformans is neurotropic, the most common clinical presentation is meningitis. Although the organism has multiple virulence factors, the polysaccharide capsule, which helps inhibit phagocytosis, is an important factor.

Although healthy people can develop cryptococcal meningitis, most patients with cryptococcal meningitis manifest a defect in cellular immunity. Thus, the infection is seen most frequently in association with lymphoma, AIDS, transplantation, and corticosteroid therapy. The greatest risk for AIDS patients is when CD4 counts are <50/mm3. Transplant recipients remain at risk throughout life.

Several studies have shown fluconazole or itraconazole prophylaxis can prevent infection in AIDS patients, the group with the highest incidence of cryptococcosis. However, current recommendations are that azole prophylaxis not be used because of the risk of developing azole resistance, the high cost, the frequent occurrence of drug interactions, and the fact that cryptococcal meningitis can be effectively treated if it occurs. For other risk groups, cryptococcosis is uncommon enough that prophylaxis is not recommended.

Histoplasmosis and Coccidioidomycosis

For the endemic mycoses, exposure is linked to certain geographic areas and, thus, irrespective of the extent of immunosuppression, an individual who remains outside the organism's ecologic niche is not at risk of infection. However, reactivation of prior infection can occur in immunosuppressed patients who previously resided in the endemic area for histoplasmosis or coccidioidomycosis. The usual environment of Histoplasma capsulatum is soil containing high concentrations of bird or bat guano, while Coccidioides immitis is most common in the Lower Sonoran desert of Arizona and California. The extent of environmental exposure is an important determinant of the severity of infection in both healthy and immunosuppressed hosts. The severity of infection increases with increasing immunosuppression.

H. capsulatum is an intracellular pathogen. Thus, patients at most risk for severe disease are those with cellular immune defects (especially AIDS), transplant recipients, and those on corticosteroids. Immunosuppressed hosts usually manifest the disseminated form of histoplasmosis involving lungs, spleen, liver, bone marrow, and other organs. Coccidioidomycosis appears to be more severe in those immunosuppressed patients who have received transplants or have AIDS. Dissemination to lungs, meninges, skin, and other tissues is common.

Itraconazole prophylaxis has been shown to prevent histoplasmosis in AIDS patients. However, because of the potential for development of azole resistance, drug toxicity and interactions, and high cost, prophylaxis is not recommended but could be considered for patients who have CD4 counts <100/mm3 and who live in an area highly endemic for histoplasmosis. Prophylactic regimens for coccidioidomycosis have not been established.

Emerging Fungal Pathogens

Depending on the type and severity of compromise of host defenses, immunosuppressed patients may develop infection with a variety of uncommon fungi Table 5.

Exposure may be uncommon except in unique circumstances. Thus, disseminated infection with Sporothrix schenckii, increasingly described in AIDS patients, is predicated on inoculation of the organism encountered in outdoor activities that involve contaminated moss or soil. Penicillium marneffei, another opportunistic pathogen that causes infection in AIDS patients, will be seen only in patients who have resided in or traveled to Southeast Asia, the area endemic for this fungus.

The group of filamentous fungi referred to as the dematiaceous or dark-walled fungi are common environmental saprophytes that cause a variety of different infections in immunosuppressed individuals. Solid organ transplant recipients develop indolent subcutaneous nodules due to organisms such as exophiala, alternaria, or phialophora usually found in soil or decaying vegetation. Disseminated infection with the dematiaceous fungi also occurs in transplant recipients and patients with hematologic malignancies. For many of these fungi, the most effective antifungal therapy is not known and the mortality rate for disseminated infection is high.

Fusarium, a common soil fungus, has emerged as an important cause of fungal infection in neutropenic patients in some institutions but is rarely noted in others. Although common in the environment, exposure of immunosuppressed patients to these organisms appears to be uncommon and fusariosis remains a rare infection that mimics many of the clinical and histologic characteristics of aspergillosis. However, therapy for fusariosis is more difficult since no available agents provide reliable antifungal activity against these organisms.

Trichosporon beigelii, a yeast-like fungus that can be isolated from the GI tract, causes fungemia and disseminated infection most often in neutropenic patients and those receiving corticosteroid therapy. The infection mimics candidiasis but therapy is more problematic and mortality rates are very high.

Carol A. Kauffman, MD

Division of Infectious Diseases

Department of Internal Medicine

Ann Arbor Veterans Affairs Health System

University of Michigan Medical School

Ann Arbor, Michigan

Fungal Infections in Immunocompromised Hosts: Focus on Epidemiologic Aspects of Infection

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