Miscellaneous Mycoses and Algal Infections

MYCOSES 

The clinical spectrum of fungal disease varies from superficial infections of the skin, hair, and nails to life-threatening systemic infections. Superficial infections involve the outermost layers of skin and hair and are associated with little or no inflammation. Cutaneous infections involve deeper layers of the skin, hair follicles, and nails and are accompanied by inflammation. Subcutaneous infections involve the dermis and subcutaneous tissues. Systemic disease involves deep tissue invasion of one or more internal organs and usually follows inhalation of the fungus. In immunocompromised patients, disseminated disease may result from superficial, cutaneous, or subcutaneous fungal infections. 

SUPERFICIAL INFECTIONS 

Malasseziasis Tinea (pityriasis) versicolor, caused by lipophilic yeasts of the genus Malassezia, is the most common superficial skin infection. The clinical presentation usually consists of scaly hypo- or hyperpigmented macular lesions on the chest, back, neck, and arms. Etiologic Agents Malassezia species are components of the human cutaneous flora that are dimorphic, existing in both yeast and mycelial phases. Each phase was originally classified as a separate genus: Pityrosporum for the yeast form and Malassezia for the mycelial form. The two genera were reclassified in 1986 as a single genus, Malassezia. Initially, only one species, M. furfur, was recognized, but seven distinct species have since been identified: M. furfur, M. sympodialis, M. obtusa, M. globosa, M. restricta, M. slooffiae, and M. pachydermatis. Epidemiology Malassezia species can be isolated from sebaceous-rich areas of the skin, most frequently from the chest and the midline of the back. The prevalence of tinea versicolor in susceptible age groups (primarily adolescents and young adults) is low in temperate climates but may reach 40–60% in tropical climates. Pathogenesis The pathogenesis of tinea versicolor is unclear but may involve the conversion of colonizing yeasts into the mycelial form, which then invades the stratum corneum. Clinical Manifestations The lesions of tinea versicolor are usually asymptomatic. Most patients seek medical advice for cosmetic reasons. Lesions typically appear as patches of pink or copperybrown skin but may appear paler than the surrounding skin, especially in dark-skinned individuals.Although some patients report mild pruritus, the lesions do not usually elicit an immune response. Other cutaneous manifestations associated with Malassezia species include seborrheic dermatitis, folliculitis, atopic dermatitis, and dandruff. Diagnosis Tinea versicolor is diagnosed on clinical grounds by the characteristic distribution and appearance of skin lesions. Lesions may fluoresce yellow-green under long-wave UVA (Wood’s light). Treatment of skin scrapings with potassium hydroxide (KOH) reveals yeasts and hyphal elements with a “spaghetti and meatballs” appearance.  Treatment: 

MALASSEZIASIS 

Malassezia species are susceptible to a variety of topical antifungal agents, including 2.5% selenium sulfide shampoo (a 10- to 15-min application followed by rinsing); topical azoles such as clotrimazole, miconazole, econazole,and ketoconazole; terbinafine gel; and ciclopirox cream/solution. The typical treatment duration is 2 weeks. In patients with extensive or persistent lesions, short-course or pulse therapy with oral ketoconazole (a single 400-mg dose), fluconazole (a single 400-mg dose or 150 mg every week for 4 weeks), or itraconazole (200 mg every other day for 7 days) has proved effective. Complications M. furfur is lipophilic and causes catheter-related fungemia in premature neonates and immunocompromised adults receiving IV lipids by central venous catheter. Infection of the lungs is pronounced and frequently results in respiratory failure. M. pachydermatis, although not lipophilic, is an increasingly important pathogen in neonatal intensive care units.When its presence is suspected, the microbiology laboratory should be notified because its isolation requires special culture conditions. Catheter-related Malassezia infections should be managed with prompt catheter removal and systemic antifungal therapy with amphotericin B or an azole (Table 110-1). Because transmission of both M. furfur and M. pachydermatis on the hands of health care workers has been documented, a strict hand-washing protocol should be enforced when outbreaks are identified. Prognosis In general, the prognosis in tinea versicolor is excellent, but the disease recurs in up to 80% of patients within 2 years after cessation of treatment. 

Early diagnosis and treatment in patients with disseminated infection improve outcome. Other Superficial Mycoses Tinea nigra is a rare infection of the palms caused by the dematiaceous fungus Hortaea (formerly Exophiala) werneckii. Two types of piedra characterized by nodules of fungal elements on the hair shaft have been reported: black piedra caused by Piedraia hortae and white piedra caused by Trichosporon species (which may also be associated with other superficial infections as well as with invasive trichosporonosis). T. beigelii has historically been the most significant pathogen in the genus Trichosporon. Recently proposed revisions in classification and nomenclature are based on analysis of 26S rRNA sequences and use of nonmolecular techniques to differentiate 17 species— only 6 of which cause human disease—and 5 varieties of Trichosporon. Under this system, T. beigelii will be designated T. cutaneum. The other five human pathogens included in this revised classification are T. asteroides, T. ovoides, T. inkin, T. asahii, and T. mucoides. In addition, four serotypes of Trichosporon (serotypes I, II, III, and I-III) have been recognized, of which only serotypes I (T. cutaneum and T. mucoides) and II (T. asahii, T. asteroides, T. inkin, and T. ovoides) are pathogenic. Given that this revised nomenclature has not been universally adopted, the previous classification system may remain in use for some time and may be a source of confusion. T. ovoides is usually associated with white piedra of the scalp, whereas T. inkin is primarily associated with white piedra of the groin. T. ovoides has also been implicated in summer-type hypersensitivity pneumonitis.The treatment of white piedra requires shaving off all the hair in the affected areas and applying a topical azole for 1–4 months. 

CUTANEOUS INFECTIONS 

The cutaneous mycoses are caused by dermatophytes, which infect keratinized tissues, including skin, hair follicles, and nails.These dermatophytic fungi invade the epidermis and elicit an inflammatory reaction, including redness and pruritus. Dermatophytic infections are designated according to the anatomic location of the lesions—e.g., tinea corporis (the trunk, shoulders, or limbs), tinea cruris (the warm moist areas of the groin, perianal, and perineal areas), tinea faciei (the nonhairy areas of the face), tinea pedis (the feet), tinea unguium (the nails), and tinea capitis (the scalp). Etiologic Agents Three genera of dermatophytes—Microsporum, Trichophyton, and Epidermophyton—are associated with human infections. Members of these genera can be divided into three groups according to their natural reservoir and potential for infection: anthropophilic, zoophilic, and geophilic organisms. Epidemiology Tinea is common worldwide. It is estimated that more than 8 million office visits to primary care physicians are made annually for tinea-related symptoms. Pathogenesis Dermatophytic fungi release proteolytic enzymes and keratinases into the skin. These exocellular enzymes release nutrients and facilitate dissemination through the stratum corneum. A specific host immune response is directed against the organisms. Clinical Manifestations Any dermatophyte can cause tinea corporis, which is commonly called “ringworm” because of the typical appearance of lesions: annular scaly patches with raised, erythematous vesicular borders and central clearing. Tinea faciei, like tinea corporis, can be caused by any dermatophyte. T. rubrum and E. floccosum are common causes of tinea cruris; similar lesions can be caused by Candida infection. Tinea pedis, the most common clinical dermatophytic infection, usually presents with interdigital cracking, scaling, and maceration. 

Hyperkeratosis and peeling of the soles of the feet are common, with a scaly red “moccasinlike” appearance in chronic cases. The most common cause of tinea pedis is T. rubrum. Clinical lesions similar to those of tinea pedis can be caused by nondermatophytic fungi, yeasts, and bacteria. Tinea unguium is caused by T. rubrum, T. mentagrophytes, and E. floccosum. The term onychomycosis encompasses nail infections due to either dermatophytes or nondermatophytic fungi. Dermatophytes cause 80–90% of cases of onychomycosis.The prevalence of these infections is ∼2% among young adults and increases to 20% among individuals 40–60 years of age. Onychomycosis occurs in diabetic patients at the same rate as in the general population but poses a greater risk of bacterial superinfection in diabetes. Tinea capitis is a common dermatophytic disease of children but is relatively rare among adults. The clinical presentation may vary from a diffuse scaly scalp to scattered areas of scale with or without alopecia. Hair may break off at the scalp (“black-dot ringworm”). Pruritus is not a constant symptom. Inflammatory responses may be minimal or severe, with the formation of a kerion characterized by alopecia, a tender or painful boggy scalp, purulent drainage, and localized lymphadenopathy. T. tonsurans is the most common dermatophyte associated with tinea capitis. Diagnosis Some skin lesions have distinctive characteristics that allow a presumptive diagnosis, and topical therapy is often initiated solely on the basis of the lesions’ appearance. However, the ease of obtaining specimens for microscopic examination and culture should encourage definitive diagnosis. Scrapings of skin lesions can be examined as a wet preparation, with a drop of 10% KOH used to dissolve cells and debris. Samples for fungal cultures should be obtained from patients whose history, physical examination, and KOH-treated specimens are inconclusive with regard to the diagnosis of dermatophytic infection. It is recommended that a definitive diagnosis be established in patients before systemic antifungal agents are administered.  Treatment: 

CUTANEOUS INFECTIONS 

Most tinea infections can be treated with topical agents alone. Many such antifungal agents are widely available as both prescription and over-the-counter products.Topical imidazoles (e.g., clotrimazole, miconazole, econazole, and ketoconazole) are generally well tolerated and efficacious when used twice daily for at least 2 weeks. The allylamines, including terbinafine and naftifine (available in 1% creams or 1% solutions), provide cure rates of ≥75% and require only once-daily application for shorter periods. Tolnaftate powder is best suited for prevention of tinea pedis. Systemic therapy is indicated for patients who are unresponsive to topical therapy; for those who have infections involving the scalp or bearded areas, who have hyperkeratotic areas on the palms or soles, or who have widespread disease; and for immunocompromised individuals. Once-daily itraconazole (200 mg), terbinafine (250 mg), and griseofulvin (500 mg of the microcrystalline formulation or 375 mg of the ultramicrocrystalline formulation) has proved effective. Treatment should be administered until lesions resolve. For patients with nail disease, itraconazole (200 mg/d) or terbinafine (250 mg/d) is preferred. The duration of therapy is 2–3 months for fingernails and 4–6 months for toenails. Pulse therapy with itraconazole and terbinafine is an option. Relapse of nail disease is common. Complications Sites of tinea pedis frequently become superinfected with bacteria. Sometimes these infections are serious, especially in diabetic patients, patients who have undergone saphenous-vein harvest for coronary artery bypass grafts, and patients with any significant venous incompetence.  

SUBCUTANEOUS INFECTIONS 

Fungal infections that primarily involve the dermis and subcutaneous tissue result from implantation of the organism in the skin through trauma.The major subcutaneous mycoses are sporotrichosis, mycetoma, chromoblastomycosis, and phaeohyphomycosis. Sporotrichosis Sporotrichosis most commonly presents as chronic cutaneous, lymphocutaneous, and/or subcutaneous disease. This infection may also be extracutaneous, occurring at pulmonary, osteoarticular, or disseminated sites. Etiologic Agent Sporotrichosis is caused by the thermally dimorphic fungus Sporothrix schenckii, which is found in soil, plants, and moss and on animals. S. schenckii exists worldwide but is most common in tropical and warmer temperate regions, such as Mexico and Central and South America. Epidemiology Sporotrichosis is usually an occupational disease of gardeners, farmers, forestry workers, florists, and horticulturists. There have been well-documented epidemics (e.g., among South African gold miners) as well as scattered outbreaks (e.g., among workers handling sphagnum, hay, and wood). Recent reports indicate that infection can be related to zoonotic spread from cats and armadillos. Pathogenesis Sporotrichosis most often follows inoculation of the organism into the skin. Clinical Manifestations The majority of infections with S. schenckii present either as fixed cutaneous sporotrichosis or as lymphangitic or lymphocutaneous disease. Fixed cutaneous disease (plaque sporotrichosis) is limited to the site of inoculation. The primary lesion enlarges and may ulcerate and become verrucous. In lymphocutaneous disease, which accounts for ∼80% of cases, secondary lesions ascend along the lymphatics that drain the area, producing small painless nodules that erupt, drain, and ulcerate. Other organisms (e.g., nontuberculous mycobacteria, Nocardia, Leishmania, and chromoblastomycotic agents) may cause similar lesions. Osteoarticular sporotrichosis is an uncommon complication but may cause granulomatous tenosynovitis and bursitis, particularly in alcoholic patients. Pulmonary sporotrichosis following inhalation of S. schenckii conidia has been reported in alcoholic patients with chronic obstructive pulmonary disease. Disseminated disease, including that involving the central nervous system, is most likely to occur in patients who have AIDS or are otherwise immunocompromised. Diagnosis A definitive diagnosis is made by culture of S. schenckii on any of a variety of media. Histopathologic examination of biopsy material may also contribute to the diagnosis, with detection of the characteristic ovoid or cigar-shaped yeast forms.  

SPOROTRICHOSIS 

Sporotrichosis requires systemic therapy (Table 110-1). Historically, oral therapy with a saturated solution of potassium iodide (SSKI; 5 drops 3 times daily, increasing to 40–50 drops 3 times daily as tolerated) has been successful, but the use of this intervention is often limited by its toxicity. Because it has fewer side effects and is better tolerated, oral itraconazole has replaced SSKI as the treatment of choice for cutaneous and lymphocutaneous sporotrichosis. Terbinafine has also been effective against lymphocutaneous disease, although it has not been approved for this indication by the U.S. Food and Drug Administration. Patients with non-life-threatening pulmonary disease and those with osteoarticular disease should be treated with itraconazole for at least 12 months. Amphotericin B is the preferred agent for patients with life-threatening pulmonary disease or disseminated infection, for patients who cannot tolerate itraconazole, and for patients in whom itraconazole treatment has failed.  Complications Hematogenous dissemination of S. schenckii is most common among immunocompromised patients, including those with HIV infection or AIDS. These patients may develop widespread cutaneous ulcers, granulomas, and systemic disease with pulmonary, meningeal, articular, or generalized infection. Prognosis Success rates of 90–100% have been reported for itraconazole treatment of lymphocutaneous sporotrichosis. A clinical response usually occurs within 4–6 weeks of the start of therapy. Patients who relapse usually respond to a second course of itraconazole. Mycetoma Mycetoma is a chronic suppurative infection that begins in the subcutaneous tissue and spreads to fascia and bone. 

Mycetoma due to fungi is called eumycetoma, while that caused by actinomycetes is referred to as actinomycetoma. Both diseases are characterized by abscesses containing grains composed of large aggregates of filaments (fungal or actinomycete). Traumatic inoculation is responsible for initial infection. Etiology and Epidemiology Mycetomas are common in Mexico, Central America, Venezuela, Brazil, Africa, the Middle East, India, Pakistan, and Bangladesh.The most common cause of eumycetoma worldwide is Madurella mycetomatis, while the rare cases that occur in the United States are associated with Pseudallescheria boydii. Actinomycetoma, the usual form of mycetoma in Mexico and Central America, is associated with Nocardia brasiliensis, Streptomyces somaliensis, Actinomadura madurae, and Actinomadura pelletieri. Clinical Manifestations Clinically, eumycetoma and actinomycetoma are similar, beginning as small, firm, painless subcutaneous plaques or nodules on the foot or leg and, less frequently, on the arms, torso, and scalp. Patients usually present with draining sinus tracts, subcutaneous abscesses, fibrosis with woody induration, and extension to fascia and bone. Diagnosis Diagnosis is based on visualization of grains in pus, sinus exudate, or tissue biopsy. Fungal hyphae must be distinguished from the filamentous forms seen in actinomycetoma. Organisms associated with mycetoma, whether fungi or actinomycetes, can be grown on a variety of culture media.  

MYCETOMA 

The treatment of mycetoma is problematic.A combined medical/surgical approach is the option of choice (Table 110-1). Because actinomycetoma does not respond to antifungal agents, the differentiation between eumycetoma and actinomycetoma is crucial. (For the treatment of actinomycetoma, see Chaps. 63 and 64.) Amphotericin B has not generally been effective for the treatment of eumycetoma. A limited number of patients have responded to long-term azole therapy. Posaconazole, an investigational agent,may have a role in the treatment of eumycetoma in the future. Dematiaceous Fungal Infections Of the many names applied to infections caused by brown- or black-pigmented soil fungi, phaeohyphomycosis and chromoblastomycosis are the most widely accepted. Phaeohyphomycosis refers to infections in which the organisms in tissue occur as pigmented yeast-like forms and/or hyphae. Chromoblastomycosis is distinguished by the presence of pigmented sclerotic bodies in tissue. Chromoblastomycosis is characterized by slow-growing verrucous plaques or nodules, usually on the lower extremities.The most common etiologic agents are Fonsecaea pedrosoi, F. compacta, Phialophora verrucosa, Rhinocladiella aquaspersa, and Cladosporium (Cladophialophora) carrionii. Most cases affect rural workers living in tropical and subtropical regions, and infection is acquired by traumatic inoculation. Small verrucous papules enlarge slowly but remain painless. Lesions seen in late stages may be superficial or raised purplish irregular plaques; less commonly, they may be nodular, tumorous, verrucous, or cicatricial. In advanced cases, secondary lymphedema, bacterial infections, and keratin necrosis can develop. Although histologic examination of scrapings or biopsy material for characteristic sclerotic bodies can lead to the diagnosis of chromoblastomycosis, culture is required for identification of the causative agent. Treatment is difficult, although many therapeutic interventions have been described (Table 110-1). 

Results are best when early surgical excision or cryosurgery is used in combination with antifungal therapy. Treatment with itraconazole—either alone or with 5-fluorocytosine— has had some success. Phaeohyphomycosis presents in four clinical forms: superficial, cutaneous-corneal, subcutaneous, and systemic. Exophiala jeanselmei, Wangiella dermatitidis, and Bipolaris species are the most common etiologic agents. The route of infection is most likely implantation, with the subsequent formation of an inflammatory cyst. A single inflammatory nondraining cyst located on a proximal limb is the most typical presentation.The diagnosis is usually made by histopathologic detection (in biopsy material) of a fibrous capsule with a granulomatous reaction and a necrotic center. Culture is required to identify specific organisms. Surgical excision of the lesion is essential. Itraconazole treatment reduces the size of large lesions before excision and prevents relapse afterward (Table 110-1). Cerebral phaeohyphomycosis is thought to be due to direct extension from adjacent paranasal sinuses or from a penetrating trauma to the head. Most cases present as a brain abscess with focal neurologic deficits and/or generalized seizures. A review of 101 cases revealed that one-half of patients had no apparent immunocompromising condition. Infections in immunocompromised patients are more likely to disseminate; disseminated infections have been reported in patients with HIV infection, solid-organ transplant recipients, patients with malignancies, and one pregnant woman. Rhinocerebral disease requires surgical drainage along with antifungal therapy.A combination of amphotericin B and itraconazole or voriconazole is recommended. 

SYSTEMIC MYCOSES 

Paracoccidioidomycosis Often referred to as South American blastomycosis, paracoccidioidomycosis is a systemic disease caused by the dimorphic fungus Paracoccidioides brasiliensis. Pulmonary infection follows inhalation of conidia and may disseminate to other organs, producing secondary lesions in the skin, lymph nodes, and adrenal glands. Subclinical infections have been documented in healthy residents of endemic regions. Paracoccidioidomycosis is most common in Venezuela, Colombia, Ecuador, Argentina, and Brazil. Histopathologic examination of clinical specimens may reveal globose yeast cells with multiple buds. Definitive diagnosis relies on culture of the organism. Itraconazole treatment has been effective (Table 110-1). An initial course of amphotericin B may be required in seriously ill patients. Penicilliosis Caused by the thermally dimorphic fungus Penicillium marneffei, penicilliosis is a disease of immunocompromised individuals living in or traveling to Southeast Asia.The primary portal of entry is the lungs, and hematologic dissemination follows. Clinical manifestations are similar to those of disseminated histoplasmosis and include fever, chills, weight loss, anemia, generalized lymphadenopathy, and hepatomegaly. Diffuse papular lesions similar to those of molluscum contagiosum are common in patients with HIV infection or AIDS. Small yeast cells may be seen on histopathologic examination of tissue, but definitive diagnosis depends on culture.Amphotericin B is the treatment of choice for severely ill patients (Table 110-1). Patients who have less severe disease or who have responded to an initial course of amphotericin B may be treated with itraconazole. 

Primary therapy is usually given for 2 months; in patients with HIV infection or AIDS, suppressive therapy with itraconazole may be useful in preventing relapse. Fusariosis Fusariosis is an invasive mold infection associated with Fusarium species, most commonly F. solani.The skin and respiratory tract are the primary portals of entry. Localized skin infections may occur at sites of trauma in immunocompetent hosts. Disease may disseminate from the skin or respiratory tract in immunocompromised patients; 90% of such cases are reported in neutropenic patients with leukemia or recipients of allogeneic bone marrow transplants.The clinical presentation is generally nonspecific, with fever and skin lesions that eventually become necrotic and resemble ecthyma gangrenosum. Clinical, radiographic, and pathologic findings are similar to those in invasive aspergillosis or zygomycosis. Blood cultures are positive in up to 50% of cases, and the presence of a mold in cultured blood from neutropenic patients suggests fusariosis. Fusarium species are often resistant to antifungal therapy. High-dose amphotericin B has met with limited success. Therapy with voriconazole (Table 110-1) has been successful in a few patients.Therapy is continued until neutropenia resolves and a clinical response is documented. The prognosis of disseminated infection is related to the reversal of neutropenia and other immunodeficiencies. 

Pseudallescheriasis and Scedosporiosis The emerging pathogens P. boydii, Scedosporium apiospermum (the asexual form of P. boydii), and S. prolificans are molds that cause rare sinopulmonary infections in immunocompetent hosts and that may present as fungus balls in the lungs or paranasal sinuses. Severe pneumonia, invasive sinusitis, and hematogenous dissemination (including brain abscess) occur in immunosuppressed hosts, especially bone marrow transplant recipients. The hyphal elements seen in the tissues of patients with Pseudallescheria and Scedosporium infections resemble those seen in intravascular invasion by Aspergillus.The outcome of treatment is poor, and most patients with disseminated disease die. Amphotericin B is not effective in the treatment of pseudallescheriasis or scedosporiosis. A small number of patients have been cured with voriconazole in the same doses listed for fusariosis (Table 110-1). Surgical debridement and drainage of abscesses may also be necessary. Trichosporonosis Trichosporon species, predominantly T. asahii and to a lesser extentT. mucoides, can cause disseminated trichosporonosis in immunocompromised patients, especially those with profound neutropenia. Unpublished studies describe isolation of Trichosporon from pubic sites of white piedra, sputum, skin lesions, and blood. T. pullulans (formerly Monilia pullulans) is a rare cause of systemic infection. Portals of entry include the skin, gastrointestinal tract, and lungs. The clinical presentation mimics candidiasis. Cultures of blood, skin lesions, or biopsy specimens confirm the diagnosis. Trichosporon shares antigens with Cryptococcus neoformans and produces positive results in the latex agglutination test.Treatment ofTrichosporon infections is complicated by resistance to amphotericin B. Mortality rates of 80% have been reported.The azoles, especially voriconazole, have been effective alone or in combination with amphotericin B (Table 110-1). Adjunctive therapy with granulocyte-macrophage colony-stimulating factor or interferon may be beneficial.The prognosis, however, is related to the resolution of neutropenia. 

ALGAL INFECTIONS

Prototheca, an achlorophyllic alga common in nature, has been associated with rare human infections in Europe, Asia, Oceania, and the United States (particularly the southeastern states). This organism has been isolated from slime flux of trees, industrial ponds, tap water, sewage systems, swimming pools, and soil. Infections with P. wickerhamii and P. zopfii occur primarily in immunocompromised patients. Protothecosis may present as a cutaneous disease with erythematous nodules, plaques, or superficial ulcers on exposed skin; as olecranon bursitis; or as a systemic infection. Histologic examination of biopsy material may reveal multinucleated giant cells and extraand intracellular, basophilic to amphiphilic organisms containing endospores. Prototheca can be cultured on Sabouraud’s agar. The most frequently used therapeutic agent is amphotericin B, which has proved effective even in patients with disseminated protothecosis. Azole antifungal agents such as itraconazole, ketoconazole, and fluconazole have also been used successfully. Surgical excision may play a role in the treatment of localized cutaneous lesions.

Mucormycosis

Mucormycosis (also called zygomycosis) is a serious, relatively uncommon invasive fungal infection and one of the most aggressive and lethal invasive mycoses. Physicians caring for patients with diabetes mellitus, immunocompromise (including that following organ transplantation), or iron overload syndromes (particularly those associated with hemodialysis) should be acutely aware of the enhanced susceptibility of these individuals to infection with the Mucorales.Timely diagnosis is critical to survival and minimization of morbidity. Institution of aggressive surgical and medical therapy is critical in maximizing the likelihood of a good outcome. Delay in considering the diagnosis and instituting appropriate therapeutic measures results in increasingly severe disfigurement at best and in death at worst. 

ETIOLOGY 

Fungi from the order Mucorales are the etiologic agents of mucormycosis. Despite the name of this infection, Mucor is not the most common genus recovered from patients. Rather, Rhizopus and Rhizomucor are the genera usually cultured from tissue samples. Other, less common fungi, including Absidia, Cunninghamella, Apophysomyces, and Saksenaea, are increasingly being isolated and, for the most part, cause similar clinical syndromes. Thus, there is no specific clinical feature that permits identification of the precise fungus involved. Submission of appropriate biopsy material to the microbiology laboratory is mandatory to ensure a pathogen’s identification. 

PATHOGENESIS 

Mucorales are found commonly in the environment, and spores of these usually nonpathogenic fungi are likely to be inhaled daily. In the normal human lung, spores are inhibited from germinating into hyphae by alveolar macrophages. However, in diabetic patients, especially those with elevated blood sugar levels and acidemia, the spores germinate, hyphae develop (Fig. 109-1), and the fungi begin an inexorable march throughout the lung tissue, invading blood vessels and surrounding tissues. As blood vessels become involved, thrombosis occurs, tissue necrosis results, and the fungi continue to grow in this devitalized tissue. The use of deferoxamine to treat iron overload is a risk factor for mucormycosis; the siderophore supplies the fungi with iron that enhances their growth.  Spores settle in the upper airways, lower airways, or gastrointestinal tract and can spread beyond the initial site of infection, causing disseminated mucormycosis. Increasingly, patients are presenting with extensive cutaneous involvement after direct implantation of spores into the skin as a result of trauma (e.g., that sustained in a motor vehicle accident). The pathology in all these sites is the same, with blood vessel invasion and tissue necrosis as hallmarks and specific organ dysfunction depending on the location of the infection. 

CLINICAL MANIFESTATIONS 

The manifestations of mucormycosis depend on the site of infection. Patients with rhinocerebral mucormycosis may present with symptoms typical of sinusitis. However, progression of symptoms over several days indicates a more serious process than the more common bacterial or viral sinusitis. As the infection spreads, hypesthesia or numbness of the face overlying the infection may develop. Concomitant symptoms include headache, bloody nasal discharge, and changes in mental status. The black eschar of the palate is widely described as a hallmark of rhinocerebral mucormycosis, but the astute clinician will recognize earlier manifestations of this end-stage lesion reflecting invasion of the palate. These subtler lesions, which may consist of discolored, often hyperemic areas on the palate, will, if untreated, progress rapidly to the commonly recognized black eschar, which indicates angioinvasion and tissue necrosis. Involvement of the orbit (Fig. 109-2) compromises proper ocular-muscle function and normal movement of the eye within the skull, resulting in double vision. If the blood supply to the eye is affected by invasion of the retinal artery, blindness develops, often quite rapidly. Proptosis and ptosis are late findings reflecting a mass lesion within the orbit and cranial nerve involvement, respectively. Progression of the infection into the brain results in the formation of brain abscesses and phlegmon; symptoms and signs depend on the location of these lesions. Cavernous sinus thrombosis is an ominous sign. CT and MRI reveal sinus opacification and destruction of contiguous bone, and brain involvement can be readily appreciated. Pulmonary mucormycosis presents as severe, progressive, tissue-destructive pneumonia. Neutropenia is a common predisposing factor.A high fever and a critical clinical condition are typical. Cavitation of involved lung develops rapidly, and hematogenous spread beyond the lungs to the brain and other organs may occur. Gastrointestinal mucormycosis occurs primarily in those patients with protein-calorie malnutrition and usually presents as a perforated viscus. Premortem diagnosis is rare, and most patients with this form of mucormycosis do not survive. Cutaneous mucormycosis is more common than disease at other sites and develops after traumatic injuries in which wounds are contaminated with dirt. Areas of tissue necrosis enlarge rapidly, involving all layers of the skin and underlying structures. 

DIAGNOSIS 

Laboratory Features There are no pathognomonic hematologic changes.The abnormalities that are found reflect underlying predisposing conditions (e.g., diabetic ketoacidosis) and general indications of infection, such as elevated white blood cell counts and acute-phase reactant levels. Blood cultures are virtually always negative. Microscopic examination and culture of biopsy samples from the involved area are critical in making an accurate diagnosis. As much tissue as possible should be submitted to the microbiology and histopathology laboratories. Swabs are insufficient. These fungi grow rapidly and are usually visible on culture plates within a day or two.Their identification is based on traditional morphologic features. Fixed tissue samples are treated with special stains for fungi; for example, Gomori methenamine silver stains the fungi black against a green background, and periodic acid–Schiff stains the hyphae red. Mucorales appear as broad (diameter, 6–50 m), usually nonseptate hyphae with branches at right angles; the organisms are often described as ribbon-like. Hyphae cut and viewed on end can deceptively appear yeast-like.The microscopic appearance of the Mucorales is sufficiently different from that of Aspergillus, Fusarium, and other pathogenic molds (which characteristically appear as narrow, septate hyphae with narrow-angle branching) that a pathologist can readily make a preliminary diagnosis of mucormycosis. Identification of the specific organism requires culture. In the laboratory, each species of Mucorales exhibits characteristic morphologic features that permit specific identification. Molecular methods of speciation are still used only as research tools. Differential Diagnosis Other fungal infections, including aspergillosis, fusariosis, and scedosporiosis, must be ruled out by culture and histopathologic analysis. Microscopic examination easily distinguishes the etiologic agents of these infections from the Mucorales. Aggressive pyogenic bacterial infections—e.g., those caused by Pseudomonas, Aeromonas, or Vibrio species; Staphylococcus aureus; and a variety of anaerobes—occasionally produce similar clinical presentations but can be ruled out by Gram’s staining, culture, and microscopic analysis of tissue samples.  Treatment: 

MUCORMYCOSIS 

Three factors are key to a successful outcome of therapy for mucormycosis: (1) reversal of the underlying predisposition; (2) aggressive surgical debridement; and (3) aggressive antifungal therapy, with early initiation and high drug doses. Failure to undertake all three of these interventions simultaneously has a significant and negative impact on outcome. Reversal of underlying disease is relatively easy in patients with diabetic ketoacidosis but is more difficult in patients who require continued immunosuppression for control of an underlying disease or after organ transplantation. In all cases, minimization of immunosuppressive medications enhances overall control of the fungal infection. Aggressive surgical debridement requires the removal of all dead tissue and of tissue that appears to be so severely compromised that its continued viability is in question. Extensive reconstructive surgery may be required once the infection has been cured. Traditionally, high-dose conventional amphotericin B has been used for the treatment of mucormycosis, but doses have been limited to 1.5 mg/kg per day because of the nearly universal development of nephrotoxicity. Use of lipid formulations at doses of 15–20 mg/kg per day (AmBisome) or 15 mg/kg per day (Abelcet) maximizes the amount of amphotericin B delivered to the tissues as well as the speed of its delivery. At these doses, nephrotoxicity occurs in 50% of patients. 

Posaconazole, an experimental triazole antifungal agent, has been shown to be active against mucormycosis in mouse models of infection and in patients who cannot tolerate or do not respond to other antifungal drugs. The precise clinical role for posaconazole in the treatment of mucormycosis is not clear, but this drug may prove to be a valuable alternative to amphotericin B in selected cases. Given the relative rarity of mucormycosis, it is not likely that a randomized study will rigorously compare the roles of the various antifungal agents. The optimal duration of therapy for mucormycosis is not known precisely. If possible, antifungal administration should be continued for at least 3 months after (1) all clinical abnormalities resolve or stabilize, leaving no clinical evidence of infection at the involved site(s); and (2) scans, x-rays, and laboratory studies yield normal or stable results. Careful follow-up should continue for at least 1 year to confirm that there is no evidence of recurrent infection. With this approach, recurrences should be rare.  

Aspergillosis

Aspergillosis is the collective term used to describe all disease entities caused by any one of ~35 pathogenic and allergenic species of Aspergillus. Only those species that grow at 37°C can cause invasive infection, although some species without this capability can cause allergic syndromes. A. fumigatus is responsible for most cases of invasive aspergillosis, almost all cases of chronic aspergillosis, and most allergic syndromes. A. flavus is more prevalent in some hospitals and causes a higher proportion of cases of sinus and cutaneous infection and keratitis than A. fumigatus. A. niger can cause invasive infection but more commonly colonizes the respiratory tract and causes external otitis. A. terreus causes only invasive disease, usually with a poor prognosis. A. nidulans occasionally causes invasive infection, primarily in patients with chronic granulomatous disease. 

EPIDEMIOLOGY AND ECOLOGY 

Aspergillus has a worldwide distribution, most commonly growing in decomposing plant materials (i.e., compost) and in bedding. This hyaline (nonpigmented), septate, branching mold produces vast numbers of conidia (spores) on stalks above the surface of mycelial growth. Aspergilli are found in indoor and outdoor air, on surfaces, and in water from surface reservoirs. Daily exposures vary from a few to many millions of conidia; the latter high numbers of conidia are encountered in hay barns and other very dusty environments. The required size of the infecting inoculum is uncertain; however, only intense exposures (e.g., during construction work, handling of moldy bark or hay, or composting) are sufficient to cause disease in healthy immunocompetent individuals.Allergic syndromes may be exacerbated by continuous antigenic exposure arising from sinus or airway colonization or from nail infection. High-efficiency particulate air (HEPA) filtration is often protective against infection; thus HEPA filters should be installed and monitored for efficiency in operating rooms and in hospital environments that house very–high-risk patients. The incubation period of invasive aspergillosis after exposure is highly variable, extending in documented cases from 2 to 90 days.Thus community-acquired acquisition of an infecting strain frequently manifests as invasive infection during hospitalization, although nosocomial acquisition is also common. Outbreaks usually are directly related to a contaminated air source in the hospital. 

RISK FACTORS AND PATHOGENESIS 

The primary risk factors for invasive aspergillosis are profound neutropenia and glucocorticoid use; risk increases with longer duration of these conditions. Higher doses of glucocorticoids increase the risk of both acquisition of invasive aspergillosis and death from the infection. Neutrophil and/or phagocyte dysfunction is also an important risk factor, as evidenced by aspergillosis in chronic granulomatous disease, advanced HIV infection, and relapsed leukemia. An increasing incidence of invasive aspergillosis in medical intensive care units suggests that, in patients who are not immunocompromised, temporary abrogation of protective responses as a result of glucocorticoid use or a general anti-inflammatory state is a significant risk factor. Many patients have some evidence of prior pulmonary disease— typically, a history of pneumonia or chronic obstructive pulmonary disease. Glucocorticoid use does not appear to predispose to invasive Aspergillus sinusitis but probably increases the risk of dissemination after pulmonary infection. Patients with chronic pulmonary aspergillosis have a wide spectrum of underlying pulmonary disease, often tuberculosis or sarcoidosis. Patients are immunocompetent except that a genetic defect in mannose-binding protein is common, as are some cytokine regulation defects, most of which are consistent with an inability to mount an inflammatory immune (TH1-like) response. Glucocorticoids accelerate disease progression. Allergic bronchopulmonary aspergillosis (ABPA) is associated with certain HLA class II types; polymorphisms of interleukin (IL) 4Ra, IL-10, and SPA2 genes; and heterozygosity of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.These associations suggest a strong genetic basis for the development of a TH2-like and “allergic” response to A. fumigatus; this response probably is also protective against invasive disease, since highdose glucocorticoid treatment for exacerbations of ABPA almost never leads to invasive aspergillosis. 

CLINICAL FEATURES AND APPROACH TO THE PATIENT (Table 108-1) 

Invasive Pulmonary Aspergillosis Both the frequency of invasive disease and the pace of its progression increase with greater degrees of immunocompromise (Fig. 108-1). Invasive aspergillosis is arbitrarily divided into acute and subacute forms that have courses of ≤1 month and 1–3 months, respectively. More than 80% of cases of invasive aspergillosis involve the lungs. The most common clinical features are no symptoms at all, fever, cough (sometimes productive), nondescript chest discomfort, trivial hemoptysis, and shortness of breath. Although the fever often responds to glucocorticoids, the disease progresses.The keys to early diagnosis in at-risk patients are a high index of suspicion, screening for circulating antigen, and urgent CT of the thorax. Invasive Sinusitis The sinuses are involved in 5–10% of cases of invasive aspergillosis, especially in patients with leukemia and recipients of hematopoietic stem cell transplants. In addition to fever, the most common features are nasal or facial discomfort, blocked nose, and nasal discharge (sometimes bloody). Direct examination of the interior of the nose reveals dusky or necrotic-looking tissue in any location. CT or MRI of the sinuses is essential but does not distinguish invasive Aspergillus sinusitis from pre-existing allergic sinusitis, bacterial sinusitis, or other fungal sinusitis early in the disease process. Disseminated Aspergillosis In the most severely immunocompromised patients, Aspergillus disseminates from the lungs to multiple organs—most often to the brain but also to the skin, thyroid, bone, kidney, liver, gastrointestinal tract, eye, and heart valve.Aside from cutaneous lesions, the most common features are gradual clinical deterioration over 1–3 days, with low-grade fever and features of mild sepsis, and multiple nonspecific abnormalities in laboratory tests. In most cases, at least one localization becomes apparent. Blood cultures are not helpful since they are almost always negative. 

Cerebral Aspergillosis Hematogenous dissemination to the brain is a devastating complication of invasive aspergillosis. Single or multiple lesions may develop. In acute disease, hemorrhagic infarction is most typical, and cerebral abscess is common. Rarer manifestations include meningitis, mycotic aneurysm, and cerebral granuloma. Local spread also occurs, resulting in a single abscess. Postoperative infection from cranial sinuses is occasionally recorded and is exacerbated by glucocorticoid use after neurosurgery. The presentation can be either acute or subacute, with mood changes, focal signs, seizures, and decline in mental status. Cerebral granuloma can mimic a primary or secondary tumor. MRI is the most useful immediate investigation; unenhanced CT of the brain is usually nonspecific, and contrast is often contraindicated in the affected patients because of poor renal function. Endocarditis Most cases of Aspergillus endocarditis are prosthetic valve infections resulting from contamination during surgery. Native valve disease is reported, especially as a feature of disseminated infection and in persons using illicit IV drugs. Culture-negative endocarditis with large vegetations is the most common presentation, but embolectomy reveals the diagnosis in a few cases. Cutaneous Aspergillosis Dissemination of Aspergillus occasionally results in cutaneous features, usually an erythematous or purplish nontender area that progresses to a necrotic eschar. Direct invasion of the skin occurs in neutropenic patients at the site of IV catheter insertion and in burn patients. Rapidly progressive local aspergillosis of the skin and underlying tissue may follow trauma, and wounds may become infected with Aspergillus after surgery. 

Chronic Pulmonary Aspergillosis The hallmark of chronic cavitary pulmonary aspergillosis (also called semi-invasive aspergillosis, chronic necrotizing aspergillosis, or complex aspergilloma) (Fig. 108-2) is one or more pulmonary cavities expanding over a period of months or years in association with pulmonary symptoms and systemic manifestations such as fatigue and weight loss. (Pulmonary aspergillosis developing over 3 months is better classified as subacute invasive aspergillosis.) Often mistaken initially for tuberculosis, almost all cases occur in patients with prior pulmonary disease (e.g., tuberculosis, atypical mycobacterial infection, sarcoidosis, ankylosing spondylitis, rheumatoid lung disease, pneumothorax, bullae) or prior lung surgery. The onset is insidious, and systemic features are sometimes more prominent than pulmonary symptoms. Cavities may have a fluid level or a well-formed fungal ball, but pericavitary infiltrates and multiple cavities—with or without pleural thickening— are typical. Antibodies to Aspergillus are almost always detectable in blood, usually as precipitating antibody and sometimes at high titers. Some patients have concurrent infections—even without a fungal ball—with atypical mycobacteria and/or other bacterial pathogens, such as Staphylococcus aureus or Pseudomonas aeruginosa. If untreated, chronic pulmonary aspergillosis typically progresses (sometimes relatively rapidly) to unilateral or upper-lobe fibrosis.This end-stage entity is termed chronic fibrosing pulmonary aspergillosis. Aspergilloma Aspergilloma (fungal ball) occurs in up to 20% of residual chest cavities ≥2 cm in diameter. Some fungal balls remain stable in a single cavity for many years, and 10% resolve spontaneously. However, aspergillomas are often a feature of chronic pulmonary aspergillosis with its associated features. Signs and symptoms associated with single (simple) aspergillomas are minor, including a cough (sometimes productive), hemoptysis, wheezing, and mild fatigue. 

More significant signs and symptoms are associated with chronic cavitary pulmonary aspergillosis.The vast majority of fungal balls are caused by A. fumigatus, but A. niger has been implicated, particularly in diabetic patients; aspergillomas due to A. niger can lead to oxalosis with renal dysfunction. The most significant complication of aspergilloma is lifethreatening hemoptysis, which may be the presenting manifestation. Chronic Sinusitis Three entities are subsumed under this broad label: sinus aspergilloma, chronic invasive sinusitis, and chronic granulomatous sinusitis. Sinus aspergilloma is limited to the maxillary sinus and consists of a chronic saprophytic entity in which the sinus cavity is filled with a fungal ball. This form of disease is associated with prior upper-jaw root canal work and chronic (bacterial) sinusitis.About 90% of CT scans show focal hyperattenuation related to concretions; on MRI scans, the T2-weighted signal is decreased, whereas that of bacterial sinusitis is increased. Removal of the fungal ball is curative. No tissue invasion is demonstrable histologically or radiologically. In contrast, chronic invasive sinusitis is a slowly destructive process that most commonly affects the ethmoid and sphenoid sinuses but can involve any sinus. Patients are usually but not always immunocompromised to some degree (e.g., as a result of diabetes or HIV infection). Imaging of the cranial sinuses shows opacification of one or more sinuses, local bone destruction, and invasion of local structures.The differential diagnosis is wide, as numerous other fungi may cause a similar disease and sphenoid sinusitis is often caused by bacteria.Apart from a history of chronic nasal discharge and blockage, loss of the sense of smell, and persistent headache, the usual presenting features are related to local involvement of critical structures. The orbital apex syndrome (blindness and proptosis) is characteristic. Facial swelling, cavernous sinus thrombosis, carotid artery occlusion, pituitary fossa, and brain and skull base invasion have been described. Chronic granulomatous sinusitis due to Aspergillus is most commonly seen in the Middle East and India and is often caused by A. flavus. It typically presents late, with facial swelling and unilateral proptosis.The prominent granulomatous reaction histologically distinguishes this disease from chronic invasive sinusitis, in which tissue necrosis with a low-grade mixed-cell infiltrate is typical. 

Allergic Bronchopulmonary Aspergillosis In almost all cases,ABPA represents a hypersensitivity reaction to A. fumigatus; rare cases are due to other aspergilli and other fungi. ABPA occurs in ∼1% of patients with asthma and in up to 15% of adults with cystic fibrosis, and occasional cases are reported in patients without either of these diseases. Episodes of bronchial obstruction with mucous plugs leading to coughing fits,“pneumonia,” consolidation, and breathlessness are typical. Many patients report coughing up thick sputum casts, usually brown or clear. Eosinophilia commonly develops before systemic glucocorticoids are given. The cardinal diagnostic tests include an elevated serum level of total IgE (usually 1000 IU/mL), a positive skin-prick test to A. fumigatus extract, or detection of Aspergillus-specific IgE and IgG (precipitating) antibodies. Central bronchiectasis is characteristic, but patients may present before it becomes apparent. Severe Asthma with Fungal Sensitization (SAFS) Many adults with severe asthma do not fulfill the criteria for ABPA and yet are allergic to fungi. Although A. fumigatus is a common allergen, numerous other fungi (e.g., Cladosporium and Alternaria spp.) are implicated by skin-prick testing and/or specific IgE radioallergosorbent (RAST) testing. Allergic Sinusitis Like the lungs, the sinuses manifest allergic responses to Aspergillus and other fungi.The affected patients present with chronic (i.e., perennial) sinusitis typically requiring multiple course of antibiotics that are of only limited benefit. Many of these patients have nasal polyps, and all have congested nasal mucosa and sinuses full of mucoid material. The histologic hallmark of allergic fungal sinusitis is local eosinophilia and the breakdown products of eosinophils, Charcot-Leyden crystals. Removal of abnormal mucus and polyps, with local and occasionally systemic administration of glucocorticoids, usually leads to resolution. Persistent or recurrent signs and symptoms may require more extensive surgery (ethmoidectomy) and possibly local antifungal therapy. Superficial Aspergillosis Aspergillus can cause keratitis and otitis externa. The former may be difficult to diagnose early enough to save the patient’s sight. Treatment requires local surgical debridement as well as both systemic and topical antifungal therapy. Otitis externa is a common problem for which local debridement and local application of antifungal agents constitute the most common approach to treatment. 

DIAGNOSIS 

Several techniques are required to establish the diagnosis of any form of aspergillosis with confidence. Patients with acute invasive aspergillosis have a relatively heavy load of fungus in the affected organ; thus culture, molecular diagnosis, antigen detection, and histopathology usually confirm the diagnosis. However, the pace of progression leaves only a narrow window for making the diagnosis without losing the patient, and some invasive procedures are not possible because of coagulopathy, respiratory compromise, and other factors. Currently, ∼40% of cases of invasive aspergillosis are missed clinically and are diagnosed only at autopsy. Histologic examination of affected tissue reveals either infarction, with invasion of blood vessels by many fungal hyphae, or acute necrosis, with limited inflammation and hyphae. Aspergillus hyphae are hyaline, narrow, and septate, with branching at 45°; no yeast forms are present in infected tissue. Hyphae can be seen in cytology or microscopy preparations, which therefore provide a rapid means of presumptive diagnosis. Culture is important in confirming the diagnosis, given that multiple other (rarer) fungi can mimic Aspergillus spp. histologically. Bacterial agar is less sensitive than fungal media for culture.Thus, if physicians do not request fungal culture, the diagnosis may be missed. Culture may be falsely positive (e.g., in patients whose airways are colonized by Aspergillus) or falsely negative. Only 10–30% of patients with invasive aspergillosis have a positive culture at any time. Molecular diagnostic techniques promise to be both faster and more sensitive than culture. The Aspergillus antigen test relies on detection of galactomannan release from Aspergillus spp. during growth. Antigen testing in high-risk patients is best done prospectively, as positive results usually precede clinical or radiologic features by several days. Antigen testing may be falsely positive in patients receiving certain -lactam/-lactamase inhibitor antibiotic combinations, such as tazocillin/sulbactam and amoxicillin/ clavulanic acid; in these cases, a second test is required for confirmation. 

Antigen testing and molecular testing on bronchoalveolar lavage fluid and cerebrospinal fluid are useful if performed before antifungal therapy has been given for more than a few days. The sensitivity of antigen detection is reduced by antifungal prophylaxis. Definitive confirmation of the diagnosis requires (1) a positive culture of a sample taken directly from an ordinarily sterile site (e.g., a brain abscess) or (2) positive results of both histologic testing and culture of a sample taken from an affected organ (e.g., sinuses or skin). Most diagnoses of invasive aspergillosis are inferred from fewer data, including the presence of the halo sign on a high-resolution thoracic CT scan, in which a localized ground-glass appearance representing hemorrhagic infarction surrounds a nodule. While a halo sign may be produced by other fungi, Aspergillus spp. are by far the most common cause. Halo signs are present for ∼7 days early in the course of infection in neutropenic patients and are a good prognostic feature. Thick CT sections can give the false appearance of a halo sign, as can other technical factors. Other common radiologic features of invasive pulmonary aspergillosis include pleural-based infarction or cavitation. For chronic invasive aspergillosis, Aspergillus antibody testing is invaluable although relatively imprecise. Titers fall with successful therapy. Cultures are infrequently positive. Some patients with chronic pulmonary aspergillosis also have elevated titers of total serum IgE and Aspergillusspecific IgE. ABPA and SAFS are diagnosed serologically or with skin-prick tests.Allergic Aspergillus sinusitis is usually diagnosed histologically, although precipitating antibodies in blood may also be useful.  Treatment: 

ASPERGILLOSIS Antifungal drugs active against Aspergillus include voriconazole, itraconazole, posaconazole, caspofungin, micafungin, and amphotericin B. Initial IV administration is preferred for acute invasive aspergillosis and oral administration for all other disease that requires antifungal therapy. Current recommendations are shown in Table 108-2. Voriconazole is the preferred agent for invasive aspergillosis; caspofungin, posaconazole, and lipid-associated amphotericin B are second-line agents. Amphotericin B is not active against A. terreus or A. nidulans. An infectious disease consultation is advised for patients with invasive disease, given the complexity of management. It is not clear whether combination therapy for acute invasive aspergillosis is beneficial, but it is widely used for very ill patients and for those with a poor prognosis. Commonly used combinations include an azole with either caspofungin or micafungin. The interactions of voriconazole and itraconazole with many drugs must be considered before these agents are prescribed. In addition, the effects of both drugs vary substantially from one patient to another, and many authorities recommend monitoring to ensure that drug concentrations are adequate but not excessive. The duration of therapy for invasive aspergillosis varies from ~3 months to several years, depending on the patient’s immune status and response to therapy. Relapse occurs if the response is suboptimal and immune reconstitution is not complete. Itraconazole is the preferred oral agent for chronic and allergic forms of aspergillosis. Voriconazole and posaconazole can be substituted when failure, emergence of resistance, or adverse events occur.An itraconazole dose of 200 mg twice daily is recommended, with monitoring of drug concentrations in the blood. Chronic cavitary pulmonary aspergillosis probably requires lifelong therapy, whereas the duration of treatment for other forms of chronic and allergic aspergillosis requires case-by-case evaluation. Resistance to one or more azoles, although uncommon, may develop during long-term treatment, and a positive culture during antifungal therapy is an indication for susceptibility testing. Glucocorticoids should be used with caution in chronic cavitary pulmonary aspergillosis. Surgical treatment is important in several forms of aspergillosis, including maxillary fungal ball and single aspergillomas, in which surgery is curative; invasive aspergillosis involving bone, heart valve, sinuses, proximal areas of the lung, and areas impinging on the great vessels; brain abscess; keratitis; and endophthalmitis. In allergic fungal sinusitis, removal of abnormal mucus and polyps, with local and occasionally systemic glucocorticoid treatment, usually leads to resolution. Persistent or recurrent signs and symptoms may require more extensive surgery (ethmoidectomy) and possibly local antifungal therapy. Surgery is problematic in chronic pulmonary aspergillosis, usually resulting in serious complications. Bronchial artery embolization is preferred for problematic hemoptysis.  

PROPHYLAXIS 

In situations in which moderate or high risk is predicted (e.g., after induction therapy for acute myeloid leukemia), the need for antifungal prophylaxis for superficial and systemic candidiasis and for invasive aspergillosis is generally accepted. Fluconazole is commonly used in these situations but has no activity against Aspergillus spp. Itraconazole capsules are ineffective, and itraconazole solution offers only modest efficacy. Posaconazole solution is probably more effective. Some data support the use of IV lowdose micafungin. No prophylactic regimen is completely successful. OUTCOME Invasive aspergillosis is curable if immune reconstitution occurs, whereas allergic and chronic forms are not.The mortality rate for invasive aspergillosis is ∼50% if the infection is diagnosed and treated but is 100% if the diagnosis is missed. Cerebral aspergillosis, Aspergillus endocarditis, and bilateral extensive invasive pulmonary aspergillosis have very poor outcomes, as does invasive infection in patients with late-stage AIDS, patients with relapsed uncontrolled leukemia, and recipients of allogeneic hematopoietic stem cell transplants.

Candidiasis

The genus Candida encompasses more than 150 species, only a few of which cause disease in humans.With rare exceptions, the human pathogens are C. albicans, C. guilliermondii, C. krusei, C. parapsilosis, C. tropicalis, C. kefyr, C. lusitaniae, C. dubliniensis, and C. glabrata. Ubiquitous in nature, these organisms are found on inanimate objects, in foods, and on animals and are normal commensals of humans. They inhabit the gastrointestinal tract (including the mouth and oropharynx), the female genital tract, and the skin. 

Although cases of candidiasis have been described since antiquity in debilitated patients, the advent of Candida species as common human pathogens dates to the introduction of modern therapeutic approaches that suppress normal host defense mechanisms. Of these relatively recent advances, the most important is the use of antibacterial agents that alter the normal human microbial flora and allow nonbacterial species to become more prevalent in the commensal flora.With the introduction of antifungal agents, the causes of Candida infections shifted from an almost complete dominance of C. albicans to the common involvement of C. glabrata and the other species listed above. The non-albicans species now account for approximately half of all cases of candidemia and hematogenously disseminated candidiasis. Recognition of this change is clinically important, since the various species differ in susceptibility to the newer antifungal agents. In developed countries, where medical therapeutics are commonly used, Candida species are now among the most common nosocomial pathogens. In the United States, these species are the fourth most common isolates from the blood of hospitalized patients. Candida is a small, thin-walled, ovoid yeast that measures 4–6 μm in diameter and reproduces by budding. Organisms of this genus occur in three forms in tissue: blastospores, pseudohyphae, and hyphae. Candida grows readily on simple medium; lysis centrifugation enhances its recovery from blood. Species are identified by biochemical testing (currently with automated devices) or on special agar. 

PATHOGENESIS 

In the most serious form of Candida infection, the organisms disseminate hematogenously and form microabscesses and small macroabscesses in major organs. Although the exact mechanism is not known, Candida probably enters the bloodstream from mucosal surfaces after growing to large numbers as a consequence of bacterial suppression by antibacterial drugs; alternatively, in some instances, the organism may enter from the skin. A change from the blastospore stage to the pseudohyphal and hyphal stages is generally considered integral to the organism’s penetration into tissue. However, C. glabrata can cause extensive infection even though it does not transform into pseudohyphae or hyphae. Numerous reviews of cases of hematogenously disseminated candidiasis have identified the following predisposing factors or conditions: antibacterial agents, indwelling intravascular catheters, hyperalimentation fluids, indwelling urinary catheters, parenteral glucocorticoids, respirators, neutropenia, abdominal and thoracic surgery, cytotoxic chemotherapy, and immunosuppressive agents for organ transplantation. Patients with severe burns, lowbirth- weight neonates, and persons using illicit IV drugs are also susceptible. HIV-infected patients with low CD4 T cell counts and patients with diabetes are susceptible to mucocutaneous infection, which may eventually develop into the disseminated form when other predisposing factors are encountered.Women who receive antibacterial agents may develop vaginal candidiasis. Innate immunity is the most important defense mechanism against hematogenously disseminated candidiasis, and the neutrophil is the most important component of this defense. Although many immunocompetent individuals have antibodies to Candida, the role of these antibodies in defense against the organism is not clear. 

CLINICAL MANIFESTATIONS 

Mucocutaneous Candidiasis Thrush is characterized by white, adherent, painless, discrete or confluent patches in the mouth, tongue, or esophagus, occasionally with fissuring at the corners of the mouth. This form of Candida disease may also occur at points of contact with dentures. Organisms are identifiable in gram-stained scrapings from lesions.The occurrence of thrush in a young, otherwise healthy-appearing person should prompt an investigation for underlying HIV infection. More commonly, thrush is seen as a nonspecific manifestation of severe debilitating illness. Vulvovaginal candidiasis is accompanied by pruritus, pain, and vaginal discharge that is usually thin but may contain whitish “curds” in severe cases. Other Candida skin infections include paronychia, a painful swelling at the nail-skin interface; onychomycosis, a fungal nail infection rarely caused by this genus; intertrigo, an erythematous irritation with redness and pustules in the skin folds; balanitis, an erythematous-pustular infection of the glans penis; erosio interdigitalis blastomycetica, an infection between the digits of the hands or toes; folliculitis, with pustules developing most frequently in the area of the beard; perianal candidiasis, a pruritic, erythematous, pustular infection surrounding the anus; and diaper rash, a common erythematous-pustular perineal infection in infants. Generalized disseminated cutaneous candidiasis, another form of infection that occurs primarily in infants, is characterized by widespread eruptions over the trunk, thorax, and extremities.The diagnostic macronodular lesions of hematogenously disseminated candidiasis (Fig. 107-1) indicate a high probability for dissemination to multiple organs as well as the skin.While the lesions are seen predominantly in immunocompromised patients treated with cytotoxic drugs, they may also develop in patients without neutropenia. 

Chronic mucocutaneous candidiasis is a heterogeneous infection of the hair, nails, skin, and mucous membranes that persists despite intermittent therapy. The onset of disease usually comes in infancy or within the first two decades of life but in rare cases can come in later life. The condition may be mild and limited to a specific area of the skin or nails, or it may take a severely disfiguring form (Candida granuloma) characterized by exophytic outgrowths on the skin.The condition is usually associated with specific immunologic dysfunction; most frequently reported is a failure of T lymphocytes to proliferate or to stimulate cytokines in response to stimulation by Candida antigens in vitro. Approximately half of patients have associated endocrine abnormalities that together are designated the autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome. This syndrome is due to mutations in the autoimmune regulator (AIRE) gene and is most prevalent among Finns, Iranian Jews, Sardinians, northern Italians, and Swedes. Conditions that usually follow the onset of the disease include hypoparathyroidism, adrenal insufficiency, autoimmune thyroiditis, Graves’ disease, chronic active hepatitis, alopecia, juvenile- onset pernicious anemia, malabsorption, and primary hypogonadism. In addition, dental enamel dysplasia, vitiligo, pitted nail dystrophy, and calcification of the tympanic membranes may occur. Patients with chronic mucocutaneous candidiasis rarely develop hematogenously disseminated candidiasis, probably because their neutrophil function remains intact. Deeply Invasive Candidiasis Deeply invasive Candida infections may or may not be due to hematogenous seeding. Deep esophageal infection may result from penetration by organisms from superficial esophageal erosions; joint or deep wound infection from contiguous spread of organisms from the skin; kidney infection from catheter-initiated spread of organisms through the urinary tract; infection of intraabdominal organs and the peritoneum from perforation of the gastrointestinal tract; and gallbladder infection from retrograde migration of organisms from the gastrointestinal tract into the biliary drainage system. However, far more commonly, deeply invasive candidiasis is a result of hematogenous seeding of various organs as a complication of candidemia. Once the organism gains access to the intravascular compartment (either from the gastrointestinal tract or, less often, from the skin through the site of an indwelling intravascular catheter), it may spread hematogenously to a variety of deep organs. The brain, chorioretina (Fig. 107-2), heart, and kidneys are most commonly infected and the liver and spleen less commonly so (most often in neutropenic patients). 

In fact, nearly any organ can become involved, including the endocrine glands, pancreas, heart valves (native or prosthetic), skeletal muscle, joints (native or prosthetic), bone, and meninges. Candida organisms may also spread hematogenously to the skin and cause classic macronodular lesions (Fig. 107-1). Frequently, painful muscular involvement is also evident beneath the area of affected skin. Chorioretinal involvement and skin involvement are highly significant, since both findings are associated with a very high probability of abscess formation in multiple deep organs as a result of generalized hematogenous seeding. Ocular involvement (Fig. 107-2) may require specific treatment, such as partial vitrectomy to prevent permanent blindness. An ocular examination is indicated for all patients with candidemia, whether or not they have ocular manifestations. DIAGNOSIS The diagnosis of Candida infection is established by visualization of pseudohyphae or hyphae on wet mount (saline and 10% KOH), tissue Gram’s stain, periodic acid–Schiff stain, or methenamine silver stain in the presence of inflammation. Absence of organisms on hematoxylineosin staining does not reliably exclude Candida infection. The most challenging aspect of diagnosis is determining which patients with Candida isolates have hematogenously disseminated candidiasis. For instance, recovery of Candida from sputum, urine, or peritoneal catheters may indicate mere colonization rather than deep-seated infection, and Candida isolation from the blood of patients with indwelling intravascular catheters may reflect inconsequential seeding of the blood from or growth of the organisms on the catheter. Despite extensive research into both antigen and antibody detection systems, there is currently no widely available and validated diagnostic test to distinguish patients with inconsequential seeding of the blood from those whose positive blood cultures represent hematogenous dissemination to multiple organs. Many studies are under way to establish the utility of the -glucan test. Meanwhile, the presence of ocular or macronodular skin lesions is highly suggestive of widespread infection of multiple deep organs.  Treatment:  

CANDIDEMIA AND SUSPECTED HEMATOGENOUSLY DISSEMINATED CANDIDIASIS 

All patients with candidemia are now treated with a systemic antifungal agent. A certain percentage of patients, including many of those who have candidemia associated with an indwelling intravascular catheter, probably have “benign” candidemia rather than deep-organ seeding. However, because there is no reliable way to distinguish benign candidemia from deep-organ infection, and because antifungal drugs less toxic than amphotericin B are available, it has become the standard of practice to treat all patients with candidemia, whether or not there is clinical evidence of deep-organ involvement. In addition, if an indwelling intravascular catheter may be involved, it is best to remove or replace the device whenever possible.  The drugs used for the treatment of candidemia and suspected disseminated candidiasis are listed in Table 107-2. Various lipid formulations of amphotericin B, three echinocandins, and the azoles fluconazole and voriconazole are used; no agent within a given class has been clearly identified as superior to the others. Most institutions choose an agent from each class on the basis of their own specific microbial epidemiology, strategies to minimize toxicities, and cost considerations. Unless azole resistance is considered likely, fluconazole is the agent of choice for the treatment of candidemia and suspected disseminated candidiasis in nonneutropenic, hemodynamically stable patients. Initial treatment in the context of likely azole resistance depends, as mentioned above, on the epidemiology of the individual hospital. For example, certain hospitals have a high rate of recovery of C. glabrata, while others do not. For hemodynamically unstable or neutropenic patients, initial treatment with broader-spectrum agents is desirable; these drugs include polyenes, echinocandins, or later-generation azoles such as voriconazole. Once the clinical response has been assessed and the pathogen specifically identified, the regimen can be altered accordingly. 

At present, the vast majority of C. albicans isolates are sensitive to fluconazole. Isolates of C. glabrata and C. krusei are less sensitive to fluconazole and more sensitive to polyenes and echinocandins. C. parapsilosis is less sensitive to echinocandins in vitro, although the clinical significance of this finding is not known. Some generalizations about the management of specific Candida infections are possible. Recovery of Candida from sputum is almost never indicative of underlying pulmonary candidiasis and does not by itself warrant antifungal treatment. Similarly, Candida in the urine of a patient with an indwelling bladder catheter may represent colonization only rather than bladder or kidney infection; however, the threshold for systemic treatment is lower in severely ill patients in this category since it is not possible to distinguish colonization from lower or upper urinary tract infection. If the isolate is C. albicans, most clinicians use oral fluconazole rather than a bladder washout with amphotericin, which was more commonly used in the past. The significance of the recovery of Candida from abdominal drains in postoperative patients is also unclear, but again, the threshold for treatment is generally low because most of the affected patients have been subjected to factors predisposing to disseminated candidiasis. Removal of the infected valve and long-term antifungal therapy constitute appropriate treatment for Candida endocarditis. Although definitive studies are not available, patients usually are treated for weeks with a systemic antifungal agent and then given chronic suppressive therapy for months or years (and sometimes indefinitely) with an oral azole. Hematogenous Candida endophthalmitis is a special problem requiring ophthalmologic consultation. In lesions that are expanding or that threaten the macula, an IV polyene combined with flucytosine has been the regimen of choice. However, as more data on the azoles and echinocandins become available, new strategies 1021 may evolve.Of paramount importance is the decision to perform a partial vitrectomy.This procedure debulks the infection and can preserve sight, which may otherwise be lost as a result of vitreal scarring. All patients with candidemia should undergo ophthalmologic examination because of the relatively high frequency of this ocular complication. Not only can this examination detect a developing eye lesion early in its course; in addition, identification of a lesion signifies a probability of ∼90% of deep-organ abscesses and may prompt prolongation of therapy for candidemia beyond the recommended 2 weeks after the last positive blood culture. Although the basis for the consensus is a very small data set, the recommended treatment for Candida meningitis is a polyene plus flucytosine. Successful treatment of Candida-infected prosthetic material (e.g., an artificial joint) nearly always requires removal of the infected material followed by long-term administration of an antifungal agent selected on the basis of the isolate’s sensitivity and the logistics of administration.  

PROPHYLAXIS 

The use of antifungal agents to prevent Candida infections has been controversial, but some general principles have emerged. Most centers administer prophylactic fluconazole (400 mg/d) to recipients of allogeneic stem cell transplants. High-risk liver transplant recipients are also given fluconazole prophylaxis in most centers. The use of prophylaxis for neutropenic patients has varied considerably from center to center; most centers that elect to give prophylaxis to this population use either fluconazole or a comparatively low dose of an IV polyene— either amphotericin B deoxycholate or a lipid formulation of this agent. Some centers have used itraconazole suspension. Prophylaxis is sometimes given to surgical patients at very high risk. The widespread use of prophylaxis in general surgical or medical intensive care units is not—and should not be—a common practice for three reasons: (1) the incidence of disseminated candidiasis is relatively low, (2) the cost-benefit ratio is suboptimal, and (3) increased resistance with widespread prophylaxis is a valid concern. Prophylaxis for oropharyngeal or esophageal candidiasis in HIV-infected patients is not recommended unless there are frequent recurrences.

Cryptococcosis

DEFINITION AND ETIOLOGY 

Cryptococcus neoformans, a yeast-like fungus, is the etiologic agent of cryptococcosis. Cryptococcal strains are antigenically and genetically diverse. Both C. neoformans and C. gattii are pathogenic for humans and can cause cryptococcosis. C. neoformans consists of serotypes A and D, and C. gattii consists of serotypes B and C. Currently, most authorities further subdivide C. neoformans into two varieties: grubii (serotype A) and neoformans (serotype D). Most clinical microbiology laboratories do not routinely distinguish among cryptococcal species and varieties but rather identify all isolates simply as C. neoformans.  

EPIDEMIOLOGY 

Cryptococcosis was first described in the 1890s but remained relatively rare until the mid-twentieth century, when advances in diagnosis and increases in the number of immunosuppressed individuals markedly raised its reported prevalence. The spectrum of disease caused by C. neoformans consists predominantly of meningoencephalitis and pneumonia, but skin and soft tissue infections also occur. Serologic studies have shown that, although cryptococcal infection is common among immunocompetent individuals, cryptococcal disease (cryptococcosis) is relatively rare in the absence of impaired immunity. Individuals at high risk for cryptococcosis include patients with hematologic malignancies, recipients of solid organ transplants who require ongoing immunosuppressive therapy, persons whose medical conditions necessitate glucocorticoid therapy, and patients with advanced HIV infection and CD4T-lymphocyte counts of 200/L. Since the onset of the HIV pandemic in the early 1980s, the overwhelming majority of cryptococcosis cases have occurred in patients with AIDS (Chap. 90).

To understand the impact of HIV infection on the epidemiology of cryptococcosis, it is instructive to note that in the early 1990s there were 1000 cases of cryptococcal meningitis each year in New York City—a figure far exceeding that for all cases of bacterial meningitis.With the advent of effective antiretroviral therapy, the incidence of AIDS-related cryptococcosis has been sharply reduced among treated individuals; however, the disease remains distressingly common in regions where antiretroviral therapy is not readily available, such as Africa and Asia, where up to one-third of patients with AIDS have cryptococcosis. Cryptococcal infection is acquired from the environment. C. neoformans and C. gattii inhabit different ecologic niches. C. neoformans is frequently found in soils contaminated with avian excreta and can easily be recovered from shaded and humid soils contaminated with pigeon droppings. In contrast, C. gattii is not found in bird feces. Instead, it inhabits a variety of arboreal species, including several types of eucalyptus tree. C. neoformans strains are found throughout the world; however, var. grubii (serotype A) strains are far more common than var. neoformans (serotype D) strains among both clinical and environmental isolates. The geographic distribution of C. gattii was thought to be largely limited to tropical regions until an outbreak of cryptococcosis caused by a new serotype B strain began in Vancouver in 1999. In addition to the different geographic distributions of the two cryptococcal species, individual susceptibility to these species affects epidemiology. Cryptococcosis caused by the C. neoformans varieties occurs mostly in individuals with AIDS (Chap. 90) and other forms of impaired immunity. In contrast, C. gattii–related disease is not associated with specific immune deficits and often occurs in immunocompetent individuals. 

PATHOGENESIS 

Cryptococcal infection is acquired by inhalation of aerosolized infectious particles.The exact nature of these particles is not known; the two leading candidate forms are small desiccated yeast cells and basidiospores. Little is known about the pathogenesis of initial infection. Serologic studies have shown that cryptococcal infection is acquired in childhood, but it is not known whether the initial infection is symptomatic. Given serologic documentation that cryptococcal infection is common yet cryptococcal disease is rare, the consensus is that pulmonary defense mechanisms in immunologically intact individuals are highly effective at containing C. neoformans. It is not clear whether initial infection leads to a state of immunity or whether most individuals are subject throughout life to frequent and recurrent infections that resolve without clinical disease. However, evidence indicates that some human cryptococcal infections lead to a state of latency in which viable organisms are harbored for prolonged periods, possibly in granulomas. Thus the inhalation of C. neoformans can be followed by clearance of the organism or establishment of the latent state. The consequences of prolonged harboring of C. neoformans in the lung are not known, but evidence from animal studies indicates that the organism’s prolonged presence could alter the immunologic milieu in the lung and predispose to allergic airway disease. Cryptococcosis usually presents clinically as chronic meningoencephalitis.The mechanisms by which C. neoformans undergoes extrapulmonary dissemination and enters the central nervous system (CNS) remain poorly understood. There is evidence that yeast cells can migrate directly across the endothelium by a mechanism that may be associated with changes in polysaccharide structure. C. neoformans has well-defined virulence factors that include the polysaccharide capsule, the ability to make melanin, and the elaboration of enzymes (e.g., phospholipase and urease) that enhance the survival of fungal cells in tissue. Among these virulence factors, the capsule and melanin production have been most extensively studied. The C. neoformans capsule is antiphagocytic, and the capsular polysaccharide has been associated with numerous deleterious effects on host immune function. Cryptococcal infections elicit little or no tissue inflammatory response.The immune dysfunction seen in cryptococcosis has been attributed to the release of copious amounts of capsular polysaccharide into tissues, where it probably interferes with local immune responses (Fig. 106-1). In clinical practice, the cryptococcal polysaccharide is the antigen that is measured as a diagnostic marker of C. neoformans infection. SECTION VII Fungal and Algal Infections 1014 Approach to the Patient: 

CRYPTOCOCCOSIS 

Cryptococcosis should be included in the differential diagnosis when any patient presents with findings suggestive of chronic meningitis. Concern about cryptococcosis is heightened by a history of headache and neurologic symptoms in a patient with an underlying immunosuppressive disorder or state that is associated with an increased incidence of cryptococcosis, such as advanced HIV infection or solid organ transplantation.  CLINICAL MANIFESTATIONS The clinical manifestations of cryptococcosis reflect the site of fungal infection. C. neoformans infection can affect any tissue or organ, but the majority of cases that come to clinical attention involve the CNS and/or the lungs. CNS involvement usually presents as signs and symptoms of chronic meningitis, such as headache, fever, lethargy, sensorium deficits, memory deficits, cranial nerve paresis, vision deficits, and meningismus. Cryptococcal meningitis differs from bacterial meningitis in that many Cryptococcus-infected patients present with symptoms of several weeks’ duration. In addition, classic characteristics of meningeal irritation, such as meningismus, may be absent in cryptococcal meningitis. Indolent cases can present as subacute dementia. Meningeal cryptococcosis can lead to sudden catastrophic vision loss. Pulmonary cryptococcosis usually presents as cough, increased sputum production, and chest pain. Patients infected with C. gattii can present with granulomatous pulmonary masses known as cryptococcomas. Fever develops in a minority of cases. Like CNS disease, pulmonary cryptococcosis can follow an indolent course, and the majority of cases probably do not come to clinical attention. In fact, many cases are discovered incidentally during the workup of an abnormal chest radiograph obtained for other diagnostic purposes. Pulmonary cryptococcosis is often associated with antecedent diseases such as malignancy, diabetes, and tuberculosis. Skin lesions are common in patients with disseminated cryptococcosis and can be highly variable, including papules, plaques, purpura, vesicles, tumor-like lesions, and rashes. The spectrum of cryptococcosis in HIV-infected patients is so varied and has changed so much since the advent of antiretroviral therapy that a distinction between HIV-related and HIV-unrelated cryptococcosis is no longer pertinent. In patients with AIDS and solid organ transplant recipients, the lesions of cutaneous cryptococcosis often resemble those of molluscum contagiosum (Fig. 106-2; Chaps. 84 and 90). 

DIAGNOSIS 

A diagnosis of cryptococcosis requires the demonstration of C. neoformans in normally sterile tissues.Visualization of the capsule of fungal cells in cerebrospinal fluid (CSF) mixed with India ink is a useful rapid diagnostic technique. C. neoformans cells in India ink have a distinctive appearance because their capsules exclude ink particles. However, the CSF India ink examination may yield negative results in patients with a low fungal burden. This examination should be performed by a trained individual, since leukocytes and fat globules can sometimes be mistaken for fungal cells. Cultures of CSF and blood that are positive for C. neoformans are diagnostic for cryptococcosis. In cryptococcal meningitis, CSF examination usually reveals evidence of chronic meningitis with mononuclear cell pleocytosis and increased protein levels. A particularly useful test is cryptococcal antigen (CRAg) detection in CSF and blood. The assay is based on serologic detection of cryptococcal polysaccharide and is both sensitive and specific. A positive cryptococcal antigen test provides strong presumptive evidence for cryptococcosis; however, because the result is often negative in pulmonary cryptococcosis, the test is less useful in the diagnosis of pulmonary disease.  Treatment: 

CRYPTOCOCCOSIS 

Both the site of infection and the immune status of the host must be considered in the selection of therapy for cryptococcosis. The disease has two general patterns of manifestation: (1) pulmonary cryptococcosis, with no evidence of extrapulmonary dissemination; and (2) extrapulmonary (systemic) cryptococcosis, with or without meningoencephalitis. Pulmonary cryptococcosis in an immunocompetent host sometimes resolves without therapy. However, given the propensity of C. neoformans to disseminate from the lung, the inability to gauge the host’s immune status precisely, and the availability of low-toxicity therapy in the form of fluconazole, the current recommendation is for pulmonary cryptococcosis in an immunocompetent individual to be treated with fluconazole (200–400 mg/d for 3–6 months). Extrapulmonary cryptococcosis without CNS involvement in an immunocompetent host can be treated with the same regimen, although amphotericin B (AmB; 0.5–1.0 mg/kg daily for 4–6 weeks) may be required for more severe cases. In general, extrapulmonary cryptococcosis without CNS involvement requires less intensive therapy— with the caveat that morbidity and death in cryptococcosis are associated with meningeal involvement. Thus the decision to categorize cryptococcosis as “extrapulmonary without CNS involvement” should be made only after careful evaluation of the CSF reveals no evidence of C. neoformans infection. For CNS involvement in a host without AIDS or obvious immune impairment, most authorities recommend initial therapy with AmB (0.5–1.0 mg/kg daily) during an induction phase, which is followed by prolonged therapy with fluconazole (400 mg/d) during a consolidation phase. For cryptococcal meningoencephalitis without a concomitant immunosuppressive condition, the recommended regimen is AmB (0.5–1.0 mg/kg) plus flucytosine (100 mg/kg) daily for 6–10 weeks. Alternatively, patients can be treated with AmB (0.5–1.0 mg/kg) plus flucytosine (100 mg/kg) daily for 2 weeks and then with fluconazole (400 mg/d) for at least 10 weeks. Patients with immunosuppression are treated with the same initial regimens except that consolidation therapy with fluconazole is given for a prolonged period to prevent relapse. Cryptococcosis in patients with HIV infection always requires aggressive therapy and is considered incurable unless immune function improves. Consequently, therapy for cryptococcosis in the setting of AIDS has two phases: induction therapy (intended to reduce the fungal burden and alleviate symptoms) and lifelong maintenance therapy (to prevent a symptomatic clinical relapse). Pulmonary and extrapulmonary cryptococcosis without evidence of CNS involvement can be treated with fluconazole (200–400 mg/d). In patients who have more extensive disease, flucytosine (100 mg/d) may be added to the fluconazole regimen for 10 weeks, with lifelong fluconazole maintenance therapy thereafter. For HIV-infected patients with evidence of CNS involvement, most authorities recommend induction therapy with AmB. An acceptable regimen is AmB (0.7–1.0 mg/kg) plus flucytosine (100 mg) daily for 2 weeks followed by fluconazole (400 mg/d) for at least 10 weeks and then by lifelong maintenance therapy with fluconazole (200 mg/d). Fluconazole (400–800 mg/d) plus flucytosine (150–100 mg/d) for 6–10 weeks followed by fluconazole (200 mg/d) as maintenance therapy can be used as an alternative. Lipid formulations of AmB can be substituted for AmB deoxycholate in patients with renal impairment. Neither caspofungin nor mycofungin is effective against C. neoformans, and neither drug has a role in the treatment of cryptococcosis. Cryptococcal meningoencephalitis is often associated with increased intracranial pressure, which is believed to be responsible for damage to the brain and cranial nerves. Appropriate management of CNS cryptococcosis requires careful attention to the management of intracranial pressure, including the reduction of pressure by repeated therapeutic lumbar puncture and the placement of shunts. In HIV-infected patients with previously treated cryptococcosis who are receiving fluconazole maintenance therapy, it may be possible to discontinue antifungal drug treatment if antiretroviral therapy results in immunologic improvement.However, certain recipients of maintenance therapy who have a history of successfully treated cryptococcosis can develop a troublesome immune reconstitution syndrome when antiretroviral therapy produces a rebound in immunologic function.  

PROGNOSIS AND COMPLICATIONS 

Even with antifungal therapy, cryptococcosis is associated with high rates of morbidity and death. For the majority of patients with cryptococcosis, the most important prognostic factor is the extent and the duration of the underlying immunologic deficits that predisposed them to develop the disease. Therefore, cryptococcosis is often curable with antifungal therapy in individuals with no apparent immunologic dysfunction, but, in patients with severe immunosuppression (e.g., those with AIDS), the best that can be hoped for is that antifungal therapy will induce remission, which can then be maintained with lifelong suppressive therapy. Before the advent of antiretroviral therapy, the median overall survival period for AIDS patients with cryptococcosis was 1 year. Cryptococcosis in patients with underlying neoplastic disease has a particularly poor prognosis. For CNS cryptococcosis, poor prognostic markers are a positive CSF assay for yeast cells by initial India ink examination (evidence of a heavy fungal burden), high CSF pressure, low CSF glucose levels, low CSF pleocytosis (2/L), recovery of yeast cells from extraneural sites, the absence of antibody to C. neoformans, a CSF or serum cryptococcal antigen level of ≥1:32, and concomitant glucocorticoid therapy or hematologic malignancy. A response to treatment does not guarantee cure since relapse of cryptococcosis is common even among patients with relatively intact immune systems. Complications of CNS cryptococcosis include cranial nerve deficits, vision loss, and cognitive impairment. 

PREVENTION 

No vaccine is available for cryptococcosis. In patients at high risk (e.g., those with advanced HIV infection and CD4T lymphocyte counts of 200/L), primary prophylaxis with fluconazole (200 mg/d) is effective in reducing the prevalence of disease. Since antiretroviral therapy raises the CD4T lymphocyte count, it constitutes an immunologic form of prophylaxis. However, cryptococcosis in the setting of immune reconstitution has been reported in patients with HIV infection and recipients of solid organ transplants.