Merck Manual

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Paschalis Vergidis

, MD, MSc, Mayo Clinic College of Medicine & Science

Reviewed/Revised Sep 2023
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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.

Distribution of C. neoformans and C. gattii is worldwide. C. neoformans is present in soil contaminated with bird droppings, particularly those of pigeons. C. gattii has been isolated from decayed hollows of certain tree species.

Risk factors for cryptococcosis include

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

C. gattii is associated with more than 50 species of trees, especially the eucalyptus in Australia. Unlike C. neoformans, C. gattii 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 people who are immunocompromised (eg, those who have HIV/AIDS, have a history of invasive cancer, or were treated with corticosteroids) or in people who had other lung disorders, were ≥ 50 years, or smoked tobacco (1 General reference Cryptococcosis is a pulmonary or disseminated infection acquired by inhalation of soil contaminated with the encapsulated yeasts Cryptococcus neoformans or C. gattii. Symptoms... read more General reference ).

Outbreaks of C. gattii infection have occurred in the Canadian province of British Columbia, the U.S. Pacific Northwest, Papua New Guinea, northern Australia, and in the Mediterranean region of Europe.

General reference

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 Cryptococcal meningitis Subacute meningitis develops over days to a few weeks. Chronic meningitis lasts ≥ 4 weeks. Possible causes include fungi, Mycobacterium tuberculosis, rickettsiae, spirochetes, Toxoplasma... read more 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.


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 patients who are immunocompromised.

The diagnosis is confirmed by identification of the organism on sputum or CSF culture. Blood cultures may be positive, particularly in patients with AIDS. In disseminated cryptococcosis with meningitis, cryptococci are 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 cryptococci 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, especially in patients with 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 serum specimens or both in > 90% of patients with meningitis and is generally specific; however, 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)

Patients without AIDS

Asymptomatic patients incidentally diagnosed with cryptococcal infection after resection of a pulmonary nodule who have a negative serum cryptococcal antigen may not require antifungal therapy.

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 with fluconazole 400 mg orally once a day for 6 to 12 months. For more severe disease, liposomal amphotericin B 3 to 4 mg/kg IV once a day with flucytosine 25 mg/kg orally every 6 hours is given followed by consolidation with fluconazole.

For patients with meningitis, the standard regimen consists of the following:

  • Induction with liposomal amphotericin B 4 mg/kg IV once a day plus flucytosine 25 mg/kg orally every 6 hours for 2 to 4 weeks (If lipid formulations of amphotericin B are not available, amphotericin B deoxycholate (0.7 mg/kg/day) should be used.)

  • Induction should be 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

Serial lumbar punctures may be required to reduce intracranial pressure.

Patients with AIDS

All patients with AIDS require treatment.

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

Serial lumbar puncture may be required to reduce intracranial pressure.

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 medication.

Patients with AIDS reference

Key Points

  • C. neoformans and C. gattii are present worldwide.

  • Cryptococcosis is acquired by inhalation and thus typically affects the lungs.

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

  • In patients who are immunocompromised, 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 liposomal amphotericin B with flucytosine, followed by fluconazole.

More Information

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

Drugs Mentioned In This Article

Drug Name Select Trade
Amphocin, Fungizone
NOTE: This is the Professional Version. CONSUMERS: View Consumer Version
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