(See also Overview of Fungal Infections Overview of Fungal Infections Fungi are eukaryotic organisms that exist as yeast, molds, or both forms. Yeasts consist of solitary cells that reproduce by budding. Molds occur in filaments, also known as hyphae, which extend... read more .)
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
Other lymphomas
Long-term corticosteroid therapy
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 
).
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
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 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 
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.
Lungs
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.
Skin
Dermatologic spread can manifest as pustular, papular, nodular, or ulcerated lesions, which sometimes resemble acne Acne Vulgaris Acne vulgaris is the formation of comedones, papules, pustules, nodules, and/or cysts as a result of obstruction and inflammation of pilosebaceous units (hair follicles and their accompanying... read more 
, molluscum contagiosum Molluscum Contagiosum Molluscum contagiosum is characterized by clusters of pink, dome-shaped, smooth, waxy, or pearly and umbilicated papules 2 to 5 mm in diameter caused by molluscum contagiosum virus, a poxvirus... read more 
, or basal cell carcinoma Basal Cell Carcinoma Basal cell carcinoma is a superficial, slowly growing papule or nodule that derives from certain epidermal cells. Basal cell carcinomas arise from keratinocytes near the basal layer, which are... read more 
.
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)
(See also Antifungal Medications Antifungal Medications Medications for systemic antifungal treatment include the following (see also table ): Amphotericin B (and its lipid formulations) Various azole derivatives (fluconazole, isavuconazonium [also... read more .)
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:
Induction with liposomal amphotericin B 3 to 4 mg/kg IV) once a day plus flucytosine 25 mg/kg 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) (If lipid formulations of amphotericin B are not available, amphotericin B deoxycholate (0.7 mg/kg/day) should be used.)
Alternative induction with single high-dose liposomal amphotericin B 10 mg/kg IV (on day 1) plus flucytosine 25 mg/kg orally every 6 hours and fluconazole 1200 mg orally once a day (both oral medications for the first 2 weeks of treatment) (1 Patients with AIDS 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
)Induction should be followed by consolidation therapy with fluconazole 400 mg orally once a day for 8 weeks
Once induction and consolidation therapy are completed, long-term suppressive (maintenance) therapy is with fluconazole 200 mg orally once a day
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
1. Jarvis JN, Lawrence DS, Meya DB, et al: Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis. N Engl J Med 386(12):1109-1120, 2022. doi: 10.1056/NEJMoa2111904
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.
Infectious Diseases Society of America: Clinical Practice Guidelines for the Management of Cryptococcal Disease (2010)
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
fluconazole |
Diflucan |
amphotericin b |
Amphocin, Fungizone |
flucytosine |
Ancobon |
itraconazole |
ONMEL, Sporanox, TOLSURA |
