Candida spp. can cause superficial (mucocutaneous) or deep infections (17). Candi-dal infections are extremely common, ranging from oral thrush to disseminated disease. Thrush most often occurs in patients on steroids or chronic antibiotics and in immunocompromised patients, especially those with HIV infection. In addition to the classic creamy white coating of the tongue and oral mucosa, oral candidiasis can present as an atrophic form, as angular cheilitis, or as Candida leukoplakia. In immuno-compromised patients, Candida esophagitis can occur and usually presents with odynophagia. In HIV patients, painful swallowing can often be treated with an empiric course of antifungal therapy, reserving diagnostic workup for patients who fail.
Candida vaginitis is an extremely common condition; up to 70% of women will experience a "yeast infection" at some time in their lives (see Chapter 11, this volume). Severe and/or recurrent disease may signal underlying diabetes mellitus or HIV
infection, or be secondary to antibiotic use which alters the normal flora. Cutaneous candidiasis can present as Candida balantis, folliculitis, intertrigo, perianal involvement, or generalized skin eruptions. Candida albicans is frequently implicated as a cause of paronychia and onychomycosis. A condition termed chronic mucocutaneous candidiasis presents with persistent Candida albicans infections which are quite recalcitrant to treatment owing to the inability of the patients' T cells to respond to this yeast.
Candida spp. can also cause a wide range of invasive infections, usually in immunocompromised patients, including candidemia and deep infections of the eyes, liver, spleen, genitourinary tract, central nervous system (CNS) or other sites. Candida spp. are now the fourth most common isolate in nosocomial bloodstream infections, and blood cultures may be negative in an additional 50% of all cases (18,19).
Candida organisms are normal commensals colonizing the skin and gastrointestinal (GI) tract. Most cases of candidiasis reflect proliferation of these colonizers in the setting of immunosuppression or alteration of the other normal flora by antibiotic therapy or steroids. However, Candida infections can be transmitted from human to human, as evidenced by thush of the newborn. In addition, acquisition from exogenous sources is increasing, for example, nosocomially due to catheters, monitoring devices, or prosthetic implants.
Aspergillus species can cause superficial infections, involving skin or the upper respiratory tract. For example, Aspergillus sinusitis is a serious problem in bone marrow/stem cell recipients, patients with hematologic malignancies, and individuals with HIV infection. Invasive disease can occur in immunocompromised patients and is a harbinger of poor prognosis; correction of the underlying disease process is critical to survival. Involvement of the lung, CNS, GI tract, and multiple other organs can occur. Histopathologic evaluation will reveal fungal invasion of blood vessels with thrombosis and infarction of involved tissues.
As the number of patients immunocompromised by HIV, transplantation, and cytotoxic therapies has increased, the incidence of invasive aspergillosis has grown accordingly. Risk factors include quantitative or qualitative defects of neutrophils, steroid therapy, and diabetes. As many as 40% of patients with chronic granulomatous disease will suffer from Aspergillus infection, as well as ~10% of patients with transplants, HIV infection, or hematologic malignancies. Aspergillus spores are most commonly acquired via the respiratory tract and may manifest in several ways in the lungs, often reflecting host immune conditions. Allergic bronchopulmonary aspergillosis represents an allergic reaction to Aspergillus antigen, and occurs most often in individuals with asthma. Manifestations include eosinophilia and fleeting lung infiltrates. Aspergillosis can also present as a fungus ball or aspergilloma, often developing in patients with preexisting lung cavities due to tuberculosis or previous bacterial lung abscess. These patients may present asymptomatically when routine chest films are obtained or can have massive hemophysis. Invasive pulmonary aspergillosis occurs in immunocompromised patients and rarely in immunocompetent patients exposed to a heavy inoculum of Aspergillus spores. Prognosis is most dependent upon recovery from the underlying disease, usually correction of neutropenia.
C. neoformans is ubiquitous in the environment and can cause disease in immunocompetent individuals as well as patients with abnormal cell-mediated immunity, especially those with HIV infection, bone marrow/stem cell transplants, or hematologic malignancies. The AIDS pandemic has been associated with a dramatic increase in cryp-tococcal infections. C. neoformans has a clear-cut prediction to cause CNS infections and cryptococcal meningitis is the most common invasive mycosis in AIDS, afflicting 5-10% of patients.
Cryptococcal infection usually presents as pneumonia or meningitis, but disseminated cases with multiorgan involvement can occur. Pulmonary cryptococcosis may be asymptomatic or cause frank pneumonia. The severity of cryptococcal pneumonia relates to the severity of underlying host immune defects, often remaining indolent in immunocompe-tent patients but potentially progressing rapidly in AIDS patients (20). Cryptococcal meningitis can present with a range of symptoms. Onset is often insidious with headache and somnolence, usually without obvious nuchal rigidity. Diagnosis depends upon the demonstration of the encapsulated yeast cells by India ink examination of cerebrospinal fluid and/or detection of capsular antigen. The severity and rapidity of the course of disease as well as the response to therapy appears to correlate with the immune status of the host.
These diseases (see Table 1) are endemic to specific geographic areas and cause widespread infection and disease. Blastomycosis and histoplasmosis are endemic to the Ohio River Valley states, coccidioidomycosis to the southwestern United States, while paracoccidioidomycosis is most frequent in Latin America and penicilliosis occurs in Southeast Asia and China. However, the mobility of patients around the globe necessitates the awareness that these diseases may have been acquired years earlier and manifest later during periods of immunosuppression after the individual has moved to a nonendemic area.
Blastomycosis is usually acquired by the respiratory route, and when symptomatic is manifested as pneumonia. Pulmonary involvement can be asymptomatic or cause nonspecific signs of fever, cough, and myalgias. Large inocula or underlying defects in immunity can result in severe pneumonia, including an adult respiratory distress syndrome (ARDS) picture. Later, patients can develop chronic pulmonary disease or can present with evidence of disseminated disease, especially skin or bone involvement. Complaints of bone or joint pain after a bout of blastomycosis should be investigated carefully with plain films and/or bone scan. Whether reactivation of blastomycosis due to immunosuppression occurs is controversial, but if it does it is clearly very unusual.
Coccidioidomycosis is increasing in incidence in the United States and has been classified as an emerging disease. The etiologic agent, C. immitis, is transmitted by inhalation of spores, especially in hot, dusty conditions. While many cases are asymptomatic, patients exposed to a heavy inoculum may develop nonspecific symptoms of fever, cough, and myalgias, with pneumonic infiltrates common. Individuals of African or Asian descent, Hispanics, Filipinos, pregnant women, and patients immunocompro-mised by HIV or other cell-mediated immune defects are at increased risk of severe, disseminated disease. Dissemination can result in involvement of bone, joints, skin, and visceral organs. CNS disease is a dreaded complication. Cutaneous hypersensitiv-ity reactions including erythema nodosum or erythema multiforme are frequent.
Histoplasmosis is also acquired by the airborne route, often after exposure to bird or bat droppings. Patients who are spelunkers, who have worked in old barns or chicken coops, or who have been involved in renovating old homes are at particular risk. Histo-plasmosis can cause a range of syndromes in the immunocompetent host, from asymptomatic infection to nonspecific flulike illness to frank pneumonia. In most cases, recovery will be complete, often without specific therapy. Infection can cause severe pneumonia if the inoculum is high and can progress to chronic pulmonary infection, particularly in patients with preexisting lung disease. Rarely, progressive fibrosis can develop, leading to mediastinal fibrosis and potentially compromising the esophagus, airways, or the superior vena cava and other blood vessels. Progressive, disseminated histoplasmosis can occur, especially in infants and immunocompromised adults. Patients with defective cell-mediated immunity, especially those with AIDS, are at particular risk. In addition, HIV-infected patients are at significant risk of developing reactivation of Histoplasma infection as immunosuppression progresses. Manifestations of disseminated disease include fever, pneumonia, sepsis syndrome, and visceral organ involvement.
Sporotrichosis is an endemic fungal infection that most often presents with cutaneous disease but extracutaneous syndromes can occur, especially in immunocompro-mised patients. Classically acquired by inoculation through the skin, infection most often presents with a lesion at the site of injury and lymphangitic spread of painless nodules. In unusual circumstances, the fungus disseminates hematogenously and causes bone, CNS, lung, or eye disease in the immunocompetent host or multifocal disease in immunocompromised individuals.
The zygomycetes, Rhizopus spp., Absidia spp., and Mucor spp., can cause subcutaneous or deep infections in immunocompromised patients. Neutropenic patients and those receiving steroid or cytotoxic therapy are at particular risk of disseminated disease. Infection may be rhinocerebral involving the sinuses and brain, pulmonary, or disseminated. The fungi invade blood vessels and cause thrombosis and infarction of tissue, resulting in black necrotic lesions and drainage. In patients immunocompro-mised by AIDS, disseminated infection can involve the lung, skin, and visceral organs. Pulmonary involvement is most characteristic of disease in renal transplant patients.
These mold infections occur almost exclusively in severely immunocompromised patients. Risk factors include cytotoxic chemotherapy, prolonged antibiotic therapy, organ transplantation, and HIV infection. Infection can present as noninvasive infection, especially of the skin, or as deep infection with pneumonia, sinusitis, or dissemination. Fusarium species may cause invasive sinus infections, skin involvement, pneumonia, or bloodstream infection and may disseminate to cause multifocal disease. Paecilomyces spp. have an interesting prediliction for ocular involvement and can manifest as keratitis and endophthalmitis. In other patients, disseminated disease with pneumonia, sinusitis, and fungemia may occur.
The dematiacecus fungi can cause a variety of diseases in immunocompromised patients. Initially, disease may manifest as skin, sinus, lung, or CNS involvement, but can progress to disseminated disease with involvement of multiple sites. Disease mimics that of other invasive fungal infections, but the diagnosis can be made with special stains of tissue samples to demonstrate the melanin characteristic of these organisms.
P. carinii has recently been reclassified as a fungus but clinical management of infections caused by this organism differs significantly from that of other fungi. P. carinii can be found in the lungs of many normal humans, but can cause severe pulmonary and extrapulmonary disease in immunocompromised individuals. Long recognized as a pathogen in malnourished or very premature babies and in patients with marked defects in cell-mediated immunity due to cytotoxic therapy, P. carinii has risen to prominence in the era of AIDS. P. carinii pneumonia (PCP) occurring in homosexual men was one of the first signals of the HIV pandemic and was the most important opportunistic infection early in the epidemic. Although interventions for prophylaxis and treatment of PCP are now widely available, it remains an important cause of morbidity and mortality in this population. Pneumocystis most often manifests as pneumonia. Although interstitial infiltrates are classic, it is important to remember that a wide variety of chest film findings can be present, including normal films. PCP should be included in the differential diagnosis of AIDS patients with shortness of breath and hypoxia, regardless of the X-ray findings. Extrapulmonary involvement with Pneumocystis may manifest in the lymph nodes, spleen, liver, bone marrow, GI tract, eyes, or thyroid. AIDS patients receiving PCP prophylaxis with aerosolized pentamidine are at particular risk of extrapulmonary involvement, as the drug protects only locally in the lung. As a result other systemic approaches to PCP prophylaxis are now preferred by many.
P. boydii has emerged as an important cause of disease in severely immunocompro-mised patients. Infection manifests most commonly as pneumonia, but sinusitis, skin infection, CNS or eye involvement, or disseminated disease can occur. Because this species is often resistant to amphotericin, prognosis is poor unless the underlying disease process can be corrected.
Other emerging infections are being recognized in severely immunocompromised patients. M. furfur is a lipophilic fungus that causes dermatophytosis in the normal host. However, as a result of its lipophilic nature, it can grow in lipid-rich solutions, including parenteral hyperalimentation supplemented with fatty acids. Immunocom-promised, especially neutropenic patients receiving such therapy, may develop Malassezia infection, manifested by follicular skin lesions or disseminated disease in the lungs and other organs. T. beigelii has also emerged as a feared fungal infection in neutropenic patients. Skin, lung, or sinus involvement can progress to disseminated disease with multifocal infection. Reversal of the neutropenia is critical to survival. Saccharomyces cerevisiae or Brewer's yeast has been recognized as a cause of vaginitis and can also rarely cause disseminated infection.
This chronic fungal infection occurs throughout the world, especially in tropical regions and manifests as verrucous lesions at a site of inoculation of the organism, usually on an extremity. Infection remains localized within the cutaneous and subcutaneous tissues but can cause disfiguring lesions that may interfere with function. Over time, the lesions can enlarge and become clumped together. Lesions can be pruritic but are rarely painful. Medical attention is usually sought because of bacterial superinfection, lymphedema, bulky lesions, or for cosmetic reasons. Invasion of bone does not occur, in contrast to mycetoma.
Also known as Madura foot, mycetoma is a chronic, slowly progressive fungal infection of skin, fascia, muscle, and bone. Infection is generally acquired via accidental inoculation, usually into an extremity. The localized swelling and granuloma formation can progress to produce a disfigured, swollen foot with multiple sinuses, usually over the course of years. Medical care is usually sought because of secondary bacterial infection or for cosmetic requests. Because mycetoma can also be caused by actino-mycetes, it is important to establish whether the etiology is fungal.
These mold infections are extremely common causes of superficial fungal lesions of the skin throughout the world (21). The annual cost in the United States exceeds $400 million. Dermatophytoses can be acquired from other people, animals, or the environment. Although they do not generally cause life-threatening illness, they do affect quality of life and social embarassment is a concern. Lesions may appear as annular patches with raised margins and inflammation. Clinical appearances varies with the site and host immune response, as well as with the causative fungal species. Tinea pedis is most often caused by T. rubrum and T. mentagrophytes and results in the well-known lesions of "athlete's foot." Tinea cruris may be caused by T. rubrum and E. flaccosum and manifests groin lesions. Tinea corporis or ringworm may be caused by several dermatophytes, and clinical patterns vary with the site of infection and causative organism. Scalp ringworm or tinea capitis is a disease of children and is widespread in the United States. Scaling of the scalp skin is associated with erythema and alopecia. Onychomycosis usually occurs in patients with adjacent dermatophyte infection of the toes or fingers, and should be distinguished from onychomycosis due to Candida spp. The dermatophyte infections may be associated with "id reactions," leading to additional rash, which have been attributed to delayed-type hypersensitivity reactions to intradermal trichophyton.
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