Pathophysiology

Fungal Infections in Patients with Cancer

Infections are a common cause of morbidity and mortality in patients with a wide variety of cancers. Autopsy studies show that most deaths from acute leukemia and half of deaths from lymphoma can be directly attributed to infection [Fauci et al., 1998].

Fungi are important causes of life-threatening infections in patients with certain cancers. At some cancer centers, for example, fungal infections have been the leading cause of death in patients undergoing intensive chemotherapy for the treatment of acute leukemia. Fungi have been reported to be responsible for two thirds of all superinfections in patients with hematologic malignancies and associated neutropenia. Invasive fungal infections have also been reported in up to 40% of autopsies in patients with hematologic malignancies [Mandell et al., 2000].

The following table lists some of the factors that predispose cancer patients to fungal infection and associated fungal pathogens.

Factors Predisposing to Fungal Infection in Patients with Cancer

Host Defense	Predisposing Factors	Fungal Pathogens
Skin	Intravenous and percutaneous catheters, total parenteral nutrition	Aspergillus species Candida species Malassezia furfur Trichosporon species
Gastrointestinal	Mucositis, nasogastric tubes, gastrointestinal surgery, antibiotic use	Candida species Trichosporon species
Neutrophils	Chemotherapy, hyperglycemia	Aspergillus species Candida species Agents of mucormycosis Fusarium species Pseudallescheria boydii Trichosporon species
Macrophages	Chemotherapy, corticosteroids, hyperglycemia	Aspergillus species Candida species Agents of mucormycosis Histoplasma capsulatum
Cell-mediated immunity	Infection with human immunodeficiency virus (HIV), Hodgkin's disease and non-Hodgkin's lymphomas, corticosteroids	Cryptococcus neoformans Histoplasma capsulatum Coccidioides immitis Pneumocystis carinii

Data from Francis and Walsh [1992] and [Mandell et al., 2000].

Aspergillus and Candida species account for most fungal infections in cancer patients. However, life-threatening infections caused by emerging pathogens such as Trichosporon beigelii, Fusarium species, Pseudallescheria boydii, Zygomycetes (agents of mucormycosis), and Malassezia furfur are increasing in frequency. The major risk factors for infections with these organisms are prolonged neutropenia and impaired cell-mediated immunity due either to the cancer or to the use of medications such as cytotoxic drugs or corticosteroids [Anaissie, 1992; Francis and Walsh, 1992; Mandell et al., 2000; Walsh and Lee, 1993].

In general, patients with hematologic malignancies such as leukemia or lymphoma are more severely immunocompromised and at higher risk of developing invasive mycoses than those with solid tumors. This reflects the impact of hematologic malignancies on the production and function of immune cells as well as the aggressive use of cytotoxic chemotherapy in their treatment. Patients with relapsed cancer or advanced metastatic disease are also at higher risk than are patients with newly diagnosed cancer. These patients may have [Walsh and Lee, 1993]; Walsh and Lee, 1994]:

• diminished bone marrow reserves related to prior chemotherapy
• a greater degree of fungal colonization due to prior antibiotic therapy
• undergone treatment for previous fungal infections and, thus, are at risk for relapse
• become colonized with fungi resistant to previously administered antifungal agents
• more intensive chemotherapy, resulting in profound neutropenia.

Aspergillosis

Aspergillus infection is increasingly reported as a cause of invasive disease in cancer patients. It usually occurs in association with profound neutropenia or high-dose corticosteroid therapy. Leukemic patients undergoing remission induction therapy are particularly at risk [Anaissie, 1992].

Aspergillus is spread by the airborne route and the lung is the primary site of invasion in most cases. Dissemination to other sites, particularly the central nervous system (CNS), occurs in 10-20% of cancer patients. Progression of aspergillosis can be extremely rapid and is frequently fatal [Anaissie, 1992; Francis and Walsh, 1992; Richardson and Warnock, 1997]. The following figure shows Aspergillus lesions in the brain.

The mortality rate due to invasive aspergillosis is very high, often despite antifungal therapy. The prognosis may be improved by early diagnosis and prompt institution of therapy combined with reversal of predisposing conditions such as neutropenia [Mandell et al., 2000; Richardson and Warnock, 1997].

Candidiasis

Candidiasis is the most common fungal infection in patients with cancer. Manifestations range from superficial infections of the mucous membranes to deeply invasive disease. Candida albicans is responsible for most candidal infections, although non-albicans species are encountered with increasing frequency [Anaissie, 1992; Francis and Walsh, 1992; Walsh and Lee, 1993].

Fungal infections of the oral cavity with Candida species are common in cancer patients, especially those receiving radiation to the head and neck and patients undergoing intensive chemotherapy for the treatment of acute leukemia. Oropharyngeal candidiasis has been reported in up to one third of leukemic patients. Significant predisposing factors in this population include [Epstein and Polsky, 1998; Poland, 1991]:

• mucositis and disruption of the oral mucosa
• salivary gland dysfunction, resulting in xerostomia
• changes in the microbial flora of the oral cavity that favor overgrowth of C. albicans
• immunosuppression.

Patients with mucositis, especially those with a compromised immune system, are also at high risk for developing esophageal candidiasis. This condition can occur as an extension of oropharyngeal candidiasis or as an isolated finding. Esophageal infection is most commonly seen in patients undergoing treatment for hematologic malignancies. The potential for esophageal lesions to serve as a point of entry of Candida into the bloodstream and a source of disseminated infection is a significant concern [Epstein and Polsky, 1998; Mandell et al., 2000].

Acute disseminated candidiasis, in which bloodstream infection (candidemia) is accompanied by invasion of deep organs, is a life-threatening complication of cancer therapy. Neutropenic patients with leukemia or lymphoma are at highest risk. The gastrointestinal (GI) tract and indwelling vascular catheters are the principal portals of entry of Candida into the bloodstream. Candida infection of multiple organs is common, particularly the kidney, brain, heart, and eye [Francis and Walsh, 1992; Mandell et al., 2000]. The following figure shows skin lesions caused by disseminated candidiasis in a patient with leukemia.

Macronodular Skin Lesions in a Patient with Disseminated Candidiasis

Courtesy of University of Washington; with permission.
Click on image for larger version.

A common presentation of acute disseminated candidiasis is fever that persists or recurs despite treatment with broad-spectrum antibacterial agents. In critically ill patients, the situation may be more acute. Candidemia progresses rapidly to overwhelming infection of the internal organs, resulting in signs and symptoms of septic shock. Without systemic antifungal therapy, death from acute disseminated candidiasis can occur in days [Anaissie, 1992; Francis and Walsh, 1992].

Definitive diagnosis of acute disseminated candidiasis may be difficult, which contributes to a high mortality rate. Infection of the eye and skin are important because they provide diagnostic clues. Although endophthalmitis occurs in 20-50% of patients with disseminated candidiasis, macronodular skin lesions are seen in only a small number of patients. Moreover, blood cultures frequently are negative. Because time is of the essence in treating disseminated candidiasis, antifungal therapy is often initiated empirically based on clinical suspicion [Reese and Betts, 1996].

Chronic disseminated candidiasis is another manifestation of infection reported with increasing frequency in cancer patients. It is usually encountered in individuals with hematologic malignancies who are recovering from chemotherapy-induced neutropenia. Patients may have had an episode of candidemia during the period of neutropenia. As the neutrophil count increases, the patient continues to exhibit fever, often accompanied by abdominal discomfort [Francis and Walsh, 1992; Sugar and Layman, 1997].

Chronic disseminated candidiasis has been referred to as hepatosplenic candidiasis because lesions are primarily found in the liver and spleen. The high frequency of liver and spleen involvement suggests that the infection arises from intestinal seeding of yeast into the hepatic portal circulation. However, other organs may also be involved [Fauci et al., 1998; Francis and Walsh, 1992; Richardson and Warnock, 1997].

Trichosporon beigelii

In immunocompetent hosts, T. beigelii is the causative agent of white piedra, a superficial infection of the hair shaft. In immunocompromised hosts, T. beigelii can cause localized deep-tissue infection or disseminated disease that is often fatal. Most cases are seen in patients with leukemia or lymphoma who are receiving cytotoxic or corticosteroid therapy. Disseminated trichosporonosis also occurs in bone marrow transplant (BMT) recipients, solid organ transplant recipients, and patients with acquired immunodeficiency syndrome (AIDS). The primary source of infection is believed to be the patient's own respiratory and GI flora. Clinical manifestations may be similar to disseminated candidiasis; they include fever, cutaneous lesions, pulmonary infiltrates, hematuria, chorioretinitis, and renal failure. In cancer patients, the presence of T. beigelii in cultures of sputum or urine is highly indicative of disseminated disease [Anaissie, 1992; Francis and Walsh, 1992; Richardson and Warnock, 1997; Sugar and Layman, 1997].

Fusarium species

Found commonly on plants and in soil, Fusarium species cause fungal infections of the skin, nails, and cornea. However, in the immunocompromised host — specifically neutropenic cancer patients and BMT recipients — these fungi cause disseminated infection. Manifestations include fever unresponsive to broad-spectrum antibiotics, sinusitis, pneumonia, and skin lesions. The clinical presentation of disseminated fusariosis resembles disseminated aspergillosis. Similar to the agents of mucormycosis and aspergillosis, Fusarium species are angioinvasive and cause thrombosis with tissue necrosis. Cutaneous lesions of fusariosis and aspergillosis are clinically indistinguishable. Mortality rates due to fusariosis are very high because of the immunocompromised state of the patient [Francis and Walsh, 1992; Rex et al., 1998; Richardson and Warnock, 1997; Sugar and Layman, 1997].

Pseudallescheria boydii

Pseudallescheria boydii is ubiquitous. Infection is acquired by direct implantation, inhalation, or aspiration of contaminated water. Pseudallescheriasis occurs in both immunocompetent and immunocompromised hosts. Prolonged neutropenia and corticosteroid therapy are known risk factors. Clinically and on histopathologic examination, pseudallescheriasis is indistinguishable from aspergillosis and fusariosis. Clinical manifestations include local invasion of the paranasal sinuses with progression to the orbit and brain. P. boydii may also disseminate hematogenously from the lung and sinuses to the orbit, brain, bone, joints, and skin.

Invasive pseudallescheriasis is difficult to treat and has a high mortality rate. Treatment usually involves surgery and antifungal agents [Francis and Walsh, 1992; Sugar and Layman, 1997].

Agents of Mucormycosis

These fungi are found in soil, decomposing organic matter, and food. In predisposed individuals such as neutropenic cancer patients, these molds typically produce rhinocerebral, pulmonary, or cutaneous infection, which can be very aggressive.

Rhinocerebral mucormycosis

Although this condition is most commonly seen in uncontrolled diabetes mellitus, it also occurs in neutropenic cancer patients and organ transplant recipients. Left untreated, rhinocerebral mucormycosis is rapidly fatal. Infection begins in the paranasal sinuses and spreads to the palate, producing a black necrotic exudate or eschar. The infection can then spread into the orbit, producing periorbital or perinasal swelling, ptosis, proptosis, ophthalmoplegia, dilation and fixation of the pupil, and loss of vision. Further spread to the brain then causes frontal lobe necrosis and abscess formation [Francis and Walsh, 1992; Richardson and Warnock, 1997].

Pulmonary mucormycosis

This form of mucormycosis is most commonly seen in neutropenic cancer patients undergoing remission induction therapy. Left untreated, hematogenous dissemination often occurs causing death within 2-3 weeks. Fever and cough are common symptoms. Clinical findings are similar to aspergillosis [Francis and Walsh, 1992; Richardson and Warnock, 1997].

Cutaneous mucormycosis

This presentation is more common in burn patients, although it may occur in other immunosuppressed patients at a catheter insertion site. The lesions begin as areas of painful cellulitis and develop into ulcers covered with a black necrotic eschar [Francis and Walsh, 1992; Richardson and Warnock, 1997; Sugar and Layman, 1997].

Malassezia furfur

In immunocompetent hosts, this lipophilic organism is the causative agent of pityriasis versicolor. In immunocompromised hosts, including low-birth-weight infants, Malassezia furfur causes systemic disease, primarily in association with the administration of lipid-supplemented total parenteral nutrition (TPN). Manifestations include fever, thrombocytopenia, and respiratory distress [Francis and Walsh, 1992; Richardson and Warnock, 1997; Sugar and Layman, 1997].

Fungal Infections in Bone Marrow Transplant Recipients

BMT recipients share with other groups of immunocompromised patients several known risk factors for fungal infections, including underlying diseases such as cancer, prolonged neutropenia, exposure to corticosteroids and broad-spectrum antibiotics, and use of indwelling venous catheters. In addition, there are risk factors unique to BMT recipients such as graft vs. host disease (GVHD) [Gubbins et al., 1998; Sable and Donowitz, 1994].

There are three periods during which most infections occur [Mandell et al., 2000]:

1. the first month after transplantation but before marrow engraftment
2. the second through third month after transplantation (after engraftment has occurred)
3. the late post-transplant period, from 3 months after transplantation until normal immune function is regained.

Specific risk factors associated with each time frame influence the incidence and severity of infections (see table below).

Host Defense Defects in Bone Marrow Transplantation

Phase of Transplantation	Host Defense Defects	Cause
Pre-engraftment	Neutropenia, disruption of anatomic barriers	Chemotherapy, radiation therapy
Postengraftment	Abnormal cell-mediated immunity, disruption of anatomic barriers	Recovering immune function, acute GVHD and immunosuppressive therapy
Late post-transplantation	Delayed recovery of immune function, disruption of anatomic barriers	Chronic GVHD and immunosuppressive therapy

Data from Sable and Donowitz [1994].

During the first post-transplant month, before engraftment, BMT recipients have severe neutropenia and mucosal damage due to pretransplant chemotherapy and radiation therapy. In this regard, they are similar to patients with hematologic malignancies undergoing remission induction therapy.

During the second and third months post-transplantation, after engraftment, patients continue to have profound defects of both cell-mediated and humoral immunity and impairment of phagocytosis. These abnormalities are more severe and persistent in patients with acute GVHD, which is the major risk factor for infection during this period. Thus, patients with allogeneic transplants are at greater risk of infection during this period than are recipients of autologous or syngeneic transplants.

The late post-transplantation period is characterized by gradual recovery of immune function over many months, which, in recipients of allogeneic transplants, may take 1-2 years. This process is delayed by chronic GVHD, which causes persistent immune defects [Mandell et al., 2000]. The following figure shows common pathogens causing infection during the different phases of recovery from BMT.

Common Infections After Bone Marrow Transplantation

Adapted from Finberg and Fineroth [1998]; with permission.
Click on image for larger version.

Fungal infections can occur at any stage of transplantation but are most frequently encountered during the pre-engraftment period and in association with GVHD. At most BMT centers, the median time of onset of fungal infections is 2 weeks after transplantation. The predominant pathogens are Aspergillus species and Candida species, predominantly C. albicans and C. tropicalis. However, other opportunistic fungi including Trichosporon, Fusarium, Pseudallescheria boydii, Scopulariopsis, agents of mucormycosis, Alternaria, and Curvularia species are emerging as significant pathogens [Mandell et al., 2000; Sable and Donowitz, 1994].

Because of the frequency with which mycoses occur in BMT recipients and the associated high mortality rates, antifungal prophylaxis is often administered during the pre-engraftment period. In some studies, prophylactic therapy has been shown to reduce fungal colonization and superficial infection due to Candida in this population. However, the effectiveness of prophylaxis against systemic fungal infections with Candida and other fungi is controversial and is still under investigation. Infections that occur despite prophylaxis may involve fungi that are resistant to the prophylactic agent [Gubbins et al., 1998; Mandell et al., 2000; Sable and Donowitz, 1994].

Aspergillosis

Aspergillosis is a particular problem in BMT recipients. Based on reports in the medical literature, 4-20% develop invasive Aspergillus infections [Sable and Donowitz, 1994]. Neutropenia is the most important predisposing factor for aspergillosis. However, long-term corticosteroid therapy and GVHD also increase susceptibility. Because the primary route of infection is exogenous (airborne) exposure, some researchers feel there is a benefit to using laminar airflow (LAF) with high-energy particulate air (HEPA) filters; however, results vary and this issue remains controversial. The major clinical manifestation of aspergillosis is pulmonary disease, although patients may present with sinus infection or involvement of the CNS [Gubbins et al., 1998; Mandell et al., 2000; Sable and Donowitz, 1994; Warnock, 1995].

Epidemiologic studies have described the bimodal distribution in frequency of aspergillosis in BMT recipients. The peaks of infection occur at a median of 16 and 96 days after BMT. Risk factors for invasive aspergillosis during the first peak include donor type, underlying disease, season (summer), and transplantation outside of an LAF environment. Risk factors for invasive aspergillosis during the second peak include donor type, underlying disease, age, GVHD, corticosteroid therapy, and neutropenia [Wald et al., 1997]. Mortality rates due to aspergillosis in BMT recipients remain high, in some reports exceeding 90% [Gubbins et al., 1998; Warnock, 1995].

Candidiasis

Candida infections are reported to occur in up to 11% of BMT recipients [Sable and Donowitz, 1994]. The most common manifestations during the pre-engraftment period are mucocutaneous infections such as oropharyngeal candidiasis. Candidemia, with or without deep-organ infection, may also occur. Although the syndrome of chronic disseminated (hepatosplenic) candidiasis may also develop during this period, it usually does not become evident until the postengraftment period. Oropharyngeal candidiasis is the most common fungal infection during the late post-transplant period, occurring most frequently in patients with chronic GVHD [Gubbins et al., 1998; Sable and Donowitz, 1994].

As in other groups of immunocompromised patients, establishing a diagnosis of deep fungal infection in BMT recipients is often difficult. Disseminated Candida infection is most commonly suspected when a patient develops persistent or recurrent fever while receiving broad-spectrum antibiotics [Richardson and Warnock, 1997]. The figure below shows the kidneys of a bone marrow transplant recipient with disseminated candidiasis.

Fungal Infections in Solid Organ Transplant Recipients

Except for malfunction and rejection of the transplanted organ, infection is the most important complication of organ transplantation and can be life-threatening. Most serious infections occur within 4 months after transplantation — i.e., the period when the patient is recovering from the surgery and immunosuppressive therapy is most intense. After this time, the risk of infection is reduced but remains as long as the patient is immunosuppressed [Mandell et al., 2000].

During the early post-transplantation period (<1 month after transplantation), common nosocomial infections predominate. Many of these infections occur in the surgical wound and surrounding tissues. Thus, the type of transplant is an important determinant of the kinds of infections seen. For example, the urinary tract is the most common site of infection in kidney transplant recipients, as is the abdomen and gastrointestinal tract in liver transplant recipients.

Surgical wounds are particularly susceptible to infection by bacterial skin flora. Organ transplant recipients are also at high risk of developing candidemia and disseminated candidiasis due to risk factors such as antibiotics, intravenous lines, and immunosuppression. In these infections, the Candida is usually endogenous in origin and is presumed to spread from the patient's own GI tract [Fauci et al., 1998; Hibberd and Rubin, 1994; Mandell et al., 2000].

After the first post-transplant month, opportunistic infections associated with immunosuppressive therapy assume greater importance. These may be caused by a wide variety of pathogens, including fungi. The infections seen are usually characteristic of patients with impaired cell-mediated immunity [Fauci et al., 1998; Mandell et al., 2000]. The following figure shows the occurrence of fungal infections in selected organ transplant recipients at a major transplant center in the United States.

Time of Onset and Peak Incidence of Fungal Infections in Organ Transplant Recipients at Massachusetts General Hospital, 1988-1993

From Hibberd and Rubin [1994]; with permission.
Click on image for larger version.

Overall, fungi are less common than bacteria or viruses as a cause of severe infections following solid organ transplantation. However, fungal infections generally carry a higher mortality rate. This may be attributed to [Paya, 1993]:

• the difficulty of early diagnosis of invasive fungal infections
• the lack of effective therapy for some infections, such as aspergillosis
• the difficulties encountered with the use of certain antifungal drugs due to their toxicity or interactions with immunosuppressive drugs, such as cyclosporine
• the limited data on effective antifungal prophylactic regimens in solid organ transplantation.

The type of transplant influences the frequency and severity of fungal infection following transplantation. Fungal infection occurs in as many as 14% of renal transplant recipients, and may reach even higher numbers in recipients of transplanted hearts (32%), heart and lung (35%), pancreas (38%), and liver (42%) [Hibberd and Rubin, 1994]. The difference in attack rates is due largely to technical issues related to the individual transplant procedures and the tendency to administer more immunosuppressive therapy to recipients of organs other than kidneys [Hibberd and Rubin, 1994].

Species of Aspergillus and Candida account for over 80% of fungal infections in recipients of organ transplants. Candida species predominate, especially during the early post-transplant period. The most common manifestations are oropharyngeal and esophageal infections, particularly in patients with diabetes and in those receiving broad-spectrum antibiotics. Deep, invasive Candida infections also occur, especially in patients with liver, pancreas, and combined heart-lung transplants [Hibberd and Rubin, 1994; Mandell et al., 2000; Paya, 1993].

Invasive aspergillosis is second only to candidiasis as a cause of deep fungal infection in organ transplant recipients and in some selected subgroups may even exceed candidiasis in frequency. In most cases, the lungs are the portal of entry, with the lung being the most common site of infection. Following tissue infection, invasion of blood vessels typically occurs. The angioinvasive nature of Aspergillus accounts for the three cardinal features of invasive aspergillosis in the organ transplant recipient: tissue infarction, hemorrhage, and dissemination with metastatic seeding (see figure). After metastasis has occurred, invasive aspergillosis is almost always fatal, despite aggressive antifungal therapy [Hibberd and Rubin, 1994; Paya, 1993; Warnock, 1995]. The following figure illustrates features of invasive aspergillosis.

Other fungal infections that may occur in solid organ transplant recipients include mucormycosis (previously described), cryptococcosis, coccidioidomycosis, histoplasmosis, and blastomycosis. Cryptococcus neoformans can cause pneumonia; dissemination to the CNS may follow pulmonary infection. Coccidioides immitis can cause pulmonary disease or disseminated disease, for which the mortality rates are about 25% and 72%, respectively [Armstrong and Cohen, 1999]. Disseminated disease may involve the liver, spleen, genitourinary tract, brain, joints, and skin. Transplant patients visiting or living in endemic areas (southwestern United States) are at highest risk for infection. Histoplasma capsulatum and Blastomyces dermatitidis are both acquired by inhalation of conidia with dissemination through the bloodstream and lymphatic vessels to the lymph nodes, liver, spleen, adrenal glands, and bone marrow. When skin lesions develop they may be biopsied and cultured to aid in diagnosis. Transplant patients living in endemic areas (Mississippi and Ohio River valleys in the United States) are at highest risk [Armstrong and Cohen, 1999; Richardson and Warnock, 1997].

Fungal Infections in Patients with HIV/AIDS

Virtually all patients infected with human immunodeficiency virus (HIV) experience some type of fungal infection over the course of their illness. Opportunistic mycoses encountered in this population include aspergillosis, candidiasis, cryptococcosis, histoplasmosis, coccidioidomycosis, Penicillium marneffei infection, and Pneumocystis carinii pneumonia [Richardson and Warnock, 1997].

Aspergillosis

Aspergillosis has not been well recognized as an AIDS-associated condition. However, the incidence of the disease is increasing as patients with AIDS are living longer and with greater degrees of immunosuppression. Aspergillosis is usually seen as a complication of advanced AIDS. Most patients have CD4 cell counts <50/µL and have had numerous previous opportunistic infections. Common conditions that increase the risk of infection include chronic lung disease from recurrent pneumonias, frequent use of broad-spectrum antibiotics and corticosteroids, and drug-induced neutropenia [Reese and Betts, 1996; Richardson and Warnock, 1997].

Aspergillus species are ubiquitous in the environment, and infections in patients with AIDS have been reported worldwide. Diagnosis of invasive aspergillosis remains difficult while the patient is alive, and the disease is frequently fatal despite aggressive treatment with currently available drugs [Khoo and Denning, 1995].

Candidiasis

Candida infections are the most common mycoses affecting patients with HIV disease. Virtually all patients experience some type of Candida infection over the course of their illness. Oropharyngeal candidiasis is the most common manifestation; it occurs in up to 90% of patients with HIV disease, often as the first clinical sign of immunodeficiency [Darouiche, 1998]. It becomes increasingly common as the CD4 T-cell count falls. Indeed, oropharyngeal candidiasis is one of several clinical signs that have been associated with an increased likelihood of progression to AIDS. Thus, it has become one of the criteria used in many staging systems for HIV infection. In many women with HIV infection, vaginal candidiasis is an early sign of immunodeficiency and may precede the development of oropharyngeal lesions [Darouiche, 1998; Fauci et al., 1998; Reese and Betts, 1996].

Candida infections of the esophagus, trachea, bronchi, or lungs may occur later in the course of HIV infection, usually in association with CD4 T-cell counts below 100/µL. These conditions are included in the list of AIDS-defining illnesses. The most common of these infections is esophageal candidiasis [Fauci et al., 1998].

Deeply invasive infections with Candida are uncommon in patients with AIDS. This reflects the specific nature of the immune deficit in HIV infection. Contrary to mucosal forms of candidiasis, which appear to result from defects in cell-mediated immunity, systemic candidiasis is most closely associated with neutropenia. Neutrophil function is usually preserved in HIV infection, at least until later stages of the illness. Most known cases of invasive candidiasis have occurred in the terminal phase of AIDS, primarily in association with the use of indwelling catheters, broad-spectrum antibiotics, and drug-induced neutropenia [Fauci et al., 1998; Sugar and Layman, 1997].

Mucosal candidiasis is generally easy to control early in the course of HIV disease. However, infections in patients with AIDS frequently relapse, requiring multiple and prolonged courses of antifungal therapy for treatment and prophylaxis. This results in the potential for the development of drug-resistant infections [Fauci et al., 1998; Sugar and Layman, 1997].

Cryptococcosis

Cryptococcus neoformans is the second most common fungal pathogen after Candida encountered in patients with HIV. Infection occurs in 6-12% of individuals, generally when the CD4 T-cell count drops below 100/µL [Fauci et al., 1998]

The spectrum of disease caused by C. neoformans includes asymptomatic pulmonary lesions, meningitis, and disseminated disease. Although the lungs are the primary portal of entry for the fungus, the CNS is the most frequent site of clinically apparent infection. C. neoformans is the most common cause of fungal meningitis in patients with AIDS. Extrapulmonary cryptococcosis, including meningitis, is an AIDS-defining illness [Fauci et al., 1998].

Histoplasmosis and Coccidioidomycosis

Histoplasmosis and coccidioidomycosis have emerged as a significant problem in HIV-infected patients residing in endemic areas. Immunosuppression predisposes patients to clinically significant primary infection and reactivation of previously healed infections. Primary infection is usually manifested as pulmonary disease, whereas reactivation frequently leads to extrapulmonary dissemination [Fauci et al., 1998].

Histoplasmosis is usually seen as a complication of advanced AIDS (CD4 T-cell counts below 50/µL), whereas coccidioidal infection may be seen fairly early in the course of immunosuppression (CD4 T-cell counts below 250/µL). Both diseases are AIDS-defining illnesses [Fauci et al., 1998].

Histoplasmosis occurs most frequently in AIDS patients residing in the Mississippi and Ohio River valleys in the United States, Puerto Rico, the Dominican Republic, and South America. Because of its limited geographic distribution, the overall percentage of AIDS patients with histoplasmosis in the United States is only 0.5%. However, the incidence is much higher in the endemic region (about 5%). Coccidioidomycosis is endemic in the southwest United States, where the annual incidence of infection in the AIDS population is about 3% [Fauci et al., 1998].

Penicillium marneffei Infection

Disseminated infection with Penicillium marneffei (penicilliosis) has been recognized as a complication of HIV infection in southeast Asia. It is the third most common opportunistic infection among patients with AIDS living in northern Thailand, where the incidence approaches 25%. Moreover, cases of penicilliosis have been diagnosed in European and North American patients with AIDS who have become infected during visits to the endemic region [Fauci et al., 1998; Richardson and Warnock, 1997].

Pneumocystis carinii Pneumonia

Pneumocystis carinii, until recent reclassification, was considered a protozoan. The organism is a common cause of pneumonia in immunocompromised patients.

P. carinii pneumonia (PCP) is one of the most common opportunistic diseases encountered in people with advanced HIV infection. Both the incidence of PCP and its relative contribution to mortality in patients with AIDS have been decreasing due to the development of effective prophylactic regimens. Nevertheless, up to 50% of HIV-infected patients experience at least one bout of infection with PCP in the course of their illness [Brooks et al., 1998; Fauci et al., 1998].

Although P. carinii has been recently determined to be a fungus, the organism is not susceptible to currently available antifungal agents. PCP is treated with a variety of antibiotics Fauci et al., 1998]. The following table presents a summary of the spectrum of fungal pathogens encountered in patients with HIV/AIDS and the incidence of infection.

Major Opportunistic Mycoses Associated with HIV/AIDS

Mycosis	Pathogen	Main Target Tissues	Incidence (%)*
Candidiasis	Candida spp., mostly C. albicans	Oral mucosa Esophageal mucosa	90 15-20
Cryptococcosis	Cryptococcus neoformans	Lungs, CNS, bone, prostate	6-12
Histoplasmosis	Histoplasma capsulatum	Lungs, CNS, disseminated disease	2-5†
Coccidioidomycosis	Coccidioides immitis	Lungs, CNS, disseminated disease	3†
Aspergillosis	Aspergillus spp.	Lungs, disseminated disease	4
Penicilliosis	Penicillium marneffei	Lungs, disseminated disease	2-25†
Pneumocystis carinii	Pneumocystis carinii	Lungs, disseminated disease	50

*Incidence data are derived largely from the period prior to the introduction of potent antiretroviral drug regimens.
†In geographically endemic areas.
Data from Darouiche [1998], Fauci et al. [1998], and Richardson and Warnock [1997].

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