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. Disseminated disease and cryptococcal meningitis are treated with the combination of liposomal amphotericin B and flucytosine.. 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. Disseminated disease and cryptococcal meningitis are treated with the combination of liposomal amphotericin B and flucytosine.
C. neoformans has a global distribution, whereas C. gattii, while predominantly found in tropical and subtropical regions, has been sporadically documented in other regions (1). Sporadic outbreaks of C. gattii infection have also occurred in the Canadian province of British Columbia, the Pacific Northwest of the United States, Papua New Guinea, northern Australia, and in the Mediterranean region of Europe.
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. C. gattii is associated with more than 50 species of trees, especially eucalyptus trees in Australia. Unlike C. neoformans, C. gattii is not associated with birds and is more likely to cause disease in immunocompetent hosts (2).
Risk factors for cryptococcosis include:
Other lymphomas
Long-term glucocorticoid therapy
Solid organ transplantation
Hepatic cirrhosis
Cryptococcosis is a defining opportunistic infection for patients with advanced HIV infection (typically associated with CD4 cell counts < 100 cells/mcL). In patients without HIV, C. gattii infection has been associated with lower mortality compared to C. neoformans.
(See also Overview of Fungal Infections.)
General references
1. Centers for Disease Control and Prevention (CDC). Cryptococcosis Facts and Stats. April 24, 2024.
2. Coussement J, Heath CH, Roberts MB, et al. Current Epidemiology and Clinical Features of Cryptococcus Infection in Patients Without Human Immunodeficiency Virus: A Multicenter Study in 46 Hospitals in Australia and New Zealand. Clin Infect Dis. 2023;77(7):976-986. doi:10.1093/cid/ciad321
Pathophysiology of Cryptococcosis
Cryptococcosis is acquired by inhalation and 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. While pulmonary involvement is rarely severe, 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 may occur 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 organ system.
Central nervous system
Because inflammation is not extensive, fever is usually low grade or absent, and meningismus is uncommon.
In patients with advanced HIV infection, cryptococcal meningitis may cause minimal or no symptoms, but headache frequently occurs and sometimes slowly progressively altered mental status. Focal brain lesions called cryptococcomas may also occur.
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.
In an immunosuppressed host, cryptococcal infection may manifest as focal brain lesions called cryptococcomas.
Lungs
Many patients with cryptococcal pulmonary infection are asymptomatic. Those with pneumonia usually have cough and other nonspecific respiratory symptoms. However, advanced HIV-associated cryptococcal pulmonary infection may manifest as severe, progressive pneumonia with acute dyspnea and a radiographic pattern suggesting Pneumocystis infection.
Skin
Dermatologic spread (ie, in disseminated cryptococcosis) can manifest as pustular, papular, nodular, or ulcerated lesions, which sometimes resemble acne, molluscum contagiosum, or basal cell carcinoma.
Disseminated cryptococcosis may manifest as pustular, papular, nodular, or ulcerated skin lesions. Lesions can resemble those of acne, molluscum contagiosum, or basal cell carcinoma.
Diagnosis of Cryptococcosis
Fixed-tissue specimen staining
Culture of cerebrospinal fluid (CSF), sputum, urine, and blood
Serum and CSF testing for cryptococcal antigen
Rarely imaging studies
Clinical diagnosis of cryptococcosis is suggested by symptoms of an indolent infection in immunocompetent patients and a more severe, progressive infection in immunocompromised patients.
The 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.
The diagnosis can be confirmed by identification of the organism on sputum or CSF culture (1). Blood cultures may be positive, particularly in patients with advanced HIV infection. 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).
Elevated CSF protein and pleocytosis with lymphocytic predominance are usual in cryptococcal meningitis. CSF glucose is frequently low, encapsulated yeasts forming narrow-based buds can be seen on India ink smears, especially in patients with advanced HIV infection (who typically have a higher fungal burden than those without HIV infection). In some patients with advanced HIV infection, CSF parameters are normal, except for the presence of numerous yeasts on India ink preparation. Imaging studies (eg, brain MRI) can be a helpful adjunct and help identify focal lesions.
CDC/Brinkman/SCIENCE PHOTO LIBRARY
The lateral flow immunochromatographic assay (LFA) for cryptococcal capsular antigen is becoming the preferred diagnostic test worldwide because of its rapid turnaround, ease of use, and excellent performance characteristics (sensitivity and specificity > 99%) for both C. neoformans and C. gattii infections (2). This test can be performed on blood or CSF and is effective even in the absence of classic clinical or laboratory findings, making it the diagnostic method of choice for both screening and confirmation of cryptococcosis.
Diagnosis references
1. Chang CC, Harrison TS, Bicanic TA, et al. Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. Lancet Infect Dis. 2024;24(8):e495-e512. doi:10.1016/S1473-3099(23)00731-4
2. Meya DB, Williamson PR. Cryptococcal Disease in Diverse Hosts. N Engl J Med. 2024;390(17):1597-1610. doi:10.1056/NEJMra2311057
Treatment of Cryptococcosis
For cryptococcal meningitis, amphotericin B with flucytosine, followed by fluconazole
For nonmeningeal cryptococcosis, fluconazole (which is usually effective)
(See also Antifungal Medications.)
Patients without advanced HIV infection
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 oral fluconazole for 6 to 12 months.Patients with pulmonary symptoms should be treated with oral fluconazole for 6 to 12 months.
In patients without meningitis, localized lesions in skin, bone, or other sites require systemic antifungal therapy, typically with oral fluconazole for 6 to 12 months. For more severe disease, IV liposomal amphotericin B with oral flucytosine is given followed by consolidation therapy with In patients without meningitis, localized lesions in skin, bone, or other sites require systemic antifungal therapy, typically with oral fluconazole for 6 to 12 months. For more severe disease, IV liposomal amphotericin B with oral flucytosine is given followed by consolidation therapy withfluconazole.
For patients with meningitis, the standard regimen consists of the following:
Induction with IV liposomal amphotericin B plus oral flucytosine for 2 to 4 weeks (If lipid formulations of Induction with IV liposomal amphotericin B plus oral flucytosine for 2 to 4 weeks (If lipid formulations ofamphotericin B are not available, amphotericin B deoxycholate may be used.)
Induction should be followed by consolidation therapy with oral fluconazole for 8 weeksInduction should be followed by consolidation therapy with oral fluconazole for 8 weeks
Then maintenance therapy with oral fluconazole for 6 to 12 monthsThen maintenance therapy with oral fluconazole for 6 to 12 months
Serial lumbar punctures may also be required to reduce intracranial pressure.
Patients with advanced HIV infection
All patients with advanced HIV infection require treatment (1).
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 oral fluconazole for 6 to 12 months.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 oral fluconazole for 6 to 12 months.
For meningitis or severe pulmonary disease, the standard regimen consists of the following (2):
Induction therapy with IV liposomal amphotericin B once a day plus oral flucytosine for the first 2 weeks of treatment (longer induction therapy may be needed if clinical response is slow or cultures remain positive) (If lipid formulations of Induction therapy with IV liposomal amphotericin B once a day plus oral flucytosine for the first 2 weeks of treatment (longer induction therapy may be needed if clinical response is slow or cultures remain positive) (If lipid formulations ofamphotericin B are not available, amphotericin B deoxycholate should be used.)
Alternative induction therapy with single high-dose IV liposomal amphotericin B (on day 1) plus oral flucytosine and oral fluconazole (both oral medications for the first 2 weeks of treatment) (Alternative induction therapy with single high-dose IV liposomal amphotericin B (on day 1) plus oral flucytosine and oral fluconazole (both oral medications for the first 2 weeks of treatment) (3)
Induction therapy should be followed by consolidation therapy with oral fluconazole for 8 weeksInduction therapy should be followed by consolidation therapy with oral fluconazole for 8 weeks
Once induction and consolidation therapy are completed, long-term suppressive (maintenance) therapy is with oral fluconazoleOnce induction and consolidation therapy are completed, long-term suppressive (maintenance) therapy is with oral fluconazole
Serial lumbar punctures may be required to reduce intracranial pressure.
Nearly all patients with advanced HIV infection also need maintenance therapy until CD4 cell counts are > 100 cells/mcL on antiretroviral therapy (4). Oral fluconazole is preferred, but itraconazole at the same dose is acceptable; however, ). Oral fluconazole 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.
Treatment references
1. McHale TC, Boulware DR, Kasibante J, Ssebambulidde K, Skipper CP, Abassi M. Diagnosis and management of cryptococcal meningitis in HIV-infected adults. Clin Microbiol Rev. 2023;36(4):e0015622. doi:10.1128/cmr.00156-22
2. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010;50(3):291-322. doi:10.1086/649858
3. Jarvis JN, Lawrence DS, Meya DB, et al. Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis. N Engl J Med. 2022;386(12):1109-1120. doi:10.1056/NEJMoa2111904
4. ClinicalInfo.gov. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV: Cryptococcosis. Accessed July 22, 2025.
Key Points
C. neoformans is present worldwide; C. gattii is predominantly found in tropical and subtropical regions.
Cryptococcosis is acquired by inhalation and typically affects the lungs.
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.
The diagnosis is based on culture, staining, and/or serum and cerebrospinal fluid cryptococcal antigen.
For localized pulmonary disease, use fluconazole.For localized pulmonary disease, use fluconazole.
For meningitis or other severe infection, use liposomal amphotericin B (if not available, use amphotericin B deoxycholate) with flucytosine, followed by fluconazole.For meningitis or other severe infection, use liposomal amphotericin B (if not available, use amphotericin B deoxycholate) with flucytosine, followed by fluconazole.
Drugs Mentioned In This Article
