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(European Blastomycosis; Torulosis)

by Sanjay G. Revankar, MD, Jack D. Sobel, MD

Cryptococcosis is a pulmonary or disseminated infection acquired by inhalation of soil contaminated with the encapsulated yeast Cryptococcus neoformans or C. gattii. Symptoms are those of pneumonia, meningitis, or involvement of skin, bones, or viscera. Diagnosis is clinical and microscopic, confirmed by culture or fixed-tissue staining. Treatment, when necessary, is with azoles or amphotericin B, with or without flucytosine.

(See also the Infectious Diseases Society of America’s Practice Guidelines for the Management of Cryptococcal Disease .)

Distribution of C. neoformans is worldwide; it is present in soil contaminated with bird droppings, particularly those of pigeons. Cryptococcosis is a defining opportunistic infection for AIDS (typically associated with CD4 counts < 100/µL), although patients with Hodgkin lymphoma, other lymphomas, or sarcoidosis and those taking long-term corticosteroid therapy are also at increased risk, as are recipients of a solid organ transplant.

C. gattii is primarily associated with trees, especially the eucalyptus and, unlike C. neoformans, is not associated with birds and is more likely to cause disease in immunocompetent hosts. Outbreaks have occurred in the Pacific Northwest and in Papua New Guinea and northern Australia.


Cryptococcosis is acquired by inhalation and thus typically affects the lungs. Many patients present with asymptomatic, self-limited primary lung lesions. In immunocompetent patients, the isolated pulmonary lesions usually heal spontaneously without disseminating, even without antifungal therapy.

After inhalation, Cryptococcus may disseminate, frequently to the brain and meninges, typically manifesting as microscopic multifocal intracerebral lesions. Meningeal granulomas and larger focal brain lesions may be evident. Although pulmonary involvement is rarely dangerous, meningitis is life threatening and requires aggressive therapy.

Focal sites of dissemination may also occur in skin, the ends of long bones, joints, liver, spleen, kidneys, prostate, and other tissues. Except for those in the skin, these lesions usually cause few or no symptoms. Rarely, pyelonephritis occurs with renal papillary necrosis.

Involved tissues typically contain cystic masses of yeasts that appear gelatinous because of accumulated cryptococcal capsular polysaccharide, but acute inflammatory changes are minimal or absent.

Symptoms and Signs

Manifestations depend on the affected area.


Because inflammation is not extensive, fever is usually low grade or absent, and meningismus is uncommon. In patients with AIDS, cryptococcal meningitis may cause minimal or no symptoms, but headache frequently occurs and sometimes slowly progressive altered mental status. Because most symptoms of cryptococcal meningitis result from cerebral edema, they are usually nonspecific (eg, headache, blurred vision, confusion, depression, agitation, other behavioral changes). Except for ocular or facial palsies, focal signs are rare until relatively late in the course. Blindness may develop because of cerebral edema or direct involvement of the optic tracts.


Many patients are asymptomatic. Those with pneumonia usually have cough and other nonspecific respiratory symptoms. However, AIDS-associated cryptococcal pulmonary infection may manifest as severe, progressive pneumonia with acute dyspnea and an x-ray pattern suggesting Pneumocystis infection.


Dermatologic spread can manifest as pustular, papular, nodular, or ulcerated lesions, which sometimes resemble acne, molluscum contagiosum, or basal cell carcinoma.


  • Culture of CSF, sputum, urine, and blood

  • Fixed-tissue specimen staining

  • Serum and CSF testing for cryptococcal antigen

Clinical diagnosis is suggested by symptoms of an indolent infection in immunocompetent patients and a more severe, progressive infection in immunocompromised patients. Chest x-ray, urine collection, and lumbar puncture are done first.

Culture of C. neoformans is definitive. CSF, sputum, and urine yield organisms most often, and blood cultures may be positive, particularly in patients with AIDS. In disseminated cryptococcosis with meningitis, C. neoformans is frequently cultured from urine (prostatic foci of infection sometimes persist despite successful clearance of organisms from the CNS). Diagnosis is strongly suggested if experienced observers identify encapsulated budding yeasts in smears of body fluids, secretions, exudates, or other specimens. In fixed tissue specimens, encapsulated yeasts may also be identified and confirmed as C. neoformans by positive mucicarmine or Masson-Fontana staining.

Elevated CSF protein and a mononuclear cell pleocytosis are usual in cryptococcal meningitis. Glucose is frequently low, and encapsulated yeasts forming narrow-based buds can be seen on India ink smears in most patients, especially in those who have AIDS (who typically have a higher fungal burden than those without HIV infection). In some patients with AIDS, CSF parameters are normal, except for the presence of numerous yeasts on India ink preparation. The latex test for cryptococcal capsular antigen is positive in CSF or blood specimens or both in > 90% of patients with meningitis and is generally specific, although false-positive results may occur, usually with titers 1:8, especially if rheumatoid factor is also present.


  • For meningitis, amphotericin B with or without flucytosine, followed by fluconazole

  • For nonmeningeal disease, fluconazole (which is usually effective)

Patients without AIDS

Patients may need no treatment for localized, asymptomatic pulmonary involvement, confirmed by normal CSF parameters, negative cultures of CSF and urine, and no evidence of cutaneous, bone, or other extrapulmonary lesions. Some experts give a course of fluconazole to prevent hematogenous dissemination and to shorten the course of the illness. Patients with pulmonary symptoms should be treated with fluconazole 200 to 400 mg po once/day for 6 to 12 mo.

In patients without meningitis, localized lesions in skin, bone, or other sites require systemic antifungal therapy, typically fluconazole 400 mg po once/day for 6 to 12 mo. For more severe disease, amphotericin B 0.5 to 1.0 mg/kg IV once/day with flucytosine 25 mg/kg po q 6 h is given for several weeks.

For meningitis, the standard regimen is induction with amphotericin B 0.7 mg/kg IV once/day plus flucytosine 25 mg/kg po q 6 h for 2 to 4 wk, followed by consolidation therapy with fluconazole 400 mg po once/day for 8 wk, then maintenance therapy with fluconazole 200 mg po once/day for 6 to 12 mo. Repeated lumbar puncture is important to manage elevated opening pressures.

Patients with AIDS

All patients require treatment. For meningitis or severe pulmonary disease, the standard regimen is amphotericin B 0.7 mg/kg IV once/day plus flucytosine 25 mg po q 6 h for the first 2 wk of treatment (longer induction therapy may be needed if clinical response is slow or cultures remain positive), followed by fluconazole 400 mg po once/day for 10 wk total. Once induction therapy is completed, long-term suppressive (maintenance) therapy is required. Repeated lumbar puncture is important to manage elevated opening pressures. Patients with mild to moderate symptoms of localized pulmonary involvement (confirmed by normal CSF parameters, negative cultures of CSF and urine, and no evidence of cutaneous, bone, or other extrapulmonary lesions) may be treated with fluconazole 400 mg po once/day for 6 to 12 mo.

Nearly all AIDS patients need maintenance therapy until CD4 cell counts are > 150. Fluconazole 200 mg po once/day is preferred, but itraconazole at the same dose is acceptable; however, itraconazole serum levels should be measured to make sure that patients are absorbing the drug.

Key Points

  • C. neoformans is present worldwide; it is acquired by inhaling dust from soil contaminated with bird droppings, particularly those of pigeons.

  • In immunocompetent patients, infection is typically asymptomatic and self-limited.

  • In immunocompromised patients, Cryptococcus may disseminate to many sites, commonly to the brain and meninges, and to the skin.

  • Diagnose using culture, staining, and/or serum and CSF testing for cryptococcal antigen.

  • For localized pulmonary disease, use fluconazole.

  • For meningitis or other severe infection, use amphotericin B with or without flucytosine, followed by fluconazole.

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