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(European Blastomycosis; Torulosis)


Sanjay G. Revankar

, MD, Wayne State University School of Medicine

Last full review/revision Apr 2021| Content last modified Apr 2021

Cryptococcosis is a pulmonary or disseminated infection acquired by inhalation of soil contaminated with the encapsulated yeasts 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 Overview of Fungal Infections.)

Distribution of C. neoformans is worldwide; it is present in soil contaminated with bird droppings, particularly those of pigeons.

Risk factors for cryptococcosis include

Cryptococcosis is a defining opportunistic infection for AIDS (typically associated with CD4 cell counts < 100/mcL).

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. However, in one small study of C. gattii infections in Canada, findings suggested that the disease was more likely to occur in immunocompromised people (eg, those who have HIV/AIDS, have a history of invasive cancer, or were treated with corticosteroids) or people who had other lung disorders, were ≥ 50 years, or smoked tobacco (1).

Outbreaks of C. gattii infection have occurred in the Pacific Northwest, Papua New Guinea, northern Australia, and in the Mediterranean region of Europe.

General reference

  • 1. MacDougall L, Fyfe M, Romney M, et al: Risk factors for Cryptococcus gattii infection, British Columbia, Canada. Emerg Infect Dis 17(2):193–199, 2011. doi: 10.3201/eid1702.101020

Pathophysiology of Cryptococcosis

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, cryptococcal 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 of Cryptococcosis

Manifestations of cryptococcosis depend on the affected area.

Central nervous system

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 progressively 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 with cryptococcal pulmonary infection 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.

Diagnosis of Cryptococcosis

  • Culture of cerebrospinal fluid (CSF), sputum, urine, and blood
  • Fixed-tissue specimen staining
  • Serum and CSF testing for cryptococcal antigen

Clinical diagnosis of cryptococcosis 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 central nervous system). 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.

Treatment of Cryptococcosis

  • For cryptococcal meningitis, amphotericin B with or without flucytosine, followed by fluconazole
  • For nonmeningeal cryptococcosis, fluconazole (which is usually effective)

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

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 orally once a day for 6 to 12 months.

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

For meningitis, the standard regimen consists of the following:

  • Induction with amphotericin B 0.7 mg/kg IV once a day plus flucytosine 25 mg/kg orally every 6 hours for 2 to 4 weeks
  • Followed by consolidation therapy with fluconazole 400 mg orally once a day for 8 weeks
  • Then maintenance therapy with fluconazole 200 mg orally once a day for 6 to 12 months

Repeated lumbar puncture is important to manage elevated opening pressures.

Patients with AIDS

All patients with AIDS require treatment.

For meningitis or severe pulmonary disease, the standard regimen consists of the following:

  • Amphotericin B 0.7 mg/kg IV (or liposomal amphotericin B 3 to 4 mg/kg IV) once a day plus flucytosine 25 mg orally every 6 hours for the first 2 weeks of treatment (longer induction therapy may be needed if clinical response is slow or cultures remain positive)
  • Followed by fluconazole 400 mg orally once a day for 10 weeks total
  • Once induction therapy is completed, long-term suppressive (maintenance) therapy (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 orally once a day for 6 to 12 months.

Nearly all AIDS patients need maintenance therapy until CD4 cell counts are > 150/mcL. Fluconazole 200 mg orally once a 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 cerebrospinal fluid 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.

More Information

The following is an English-language resource that may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

  • Infectious Diseases Society of America: Clinical Practice Guidelines for the Management of Cryptococcal Disease

Drugs Mentioned In This Article

Drug Name Select Trade
itraconazole SPORANOX
fluconazole DIFLUCAN
flucytosine ANCOBON

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