Cryptococcosis and Cryptococcal Meningitis Overview

Cryptococcosis is a potentially fatal fungal disease affecting more than 16,000 people worldwide each day or approximately one million people each year.

Extrapulmonary cryptococcosis (which includes cryptococcal meningitis) is classified by the U.S. Centers for Disease Control and Prevention as an AIDS-defining condition. Overall, cryptococcal meningitis is the most common infection of the central nervous system and the third most frequent complication in people with AIDS.

Coughing man being examined by a doctor

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With the advent of combination antiretroviral therapy (ART), cryptococcosis incidence has declined steadily in the developed world since the mid-1990s.

However, from a global perspective, the annual number of deaths attributed to cryptococcal meningitis is currently in excess of 625,000 with the highest prevalence occurring in sub-Saharan Africa, where mortality is estimated to be between 50% and 70%.

By contrast, mortality due to cryptococcosis in the U.S. and other developed nations is around 12%.

Causal Agents

Cryptococcosis is caused by the fungus Cryptococcus neoformans and Cryptococcus gattii. Previously, cryptococcosis was attributed solely to C. neoformans, but research has since isolated and identified both causative subspecies.

Among people with HIV, more than three-quarters of the cases of cryptococcosis are reported in individuals with CD4 counts below 50 cells/mL. Cryptococcosis can rarely occur in individuals with intact immune systems.

Modes of Transmission

It is postulated that cryptococcosis is acquired by inhaling the reproductive spores (basidiospores) of C. neoformans or C. gattii.

While C. neoformans is commonly found in soil that contains bird droppings, particularly pigeon, inhalation is still regarded as the predominant route of infection (as opposed to accidental ingestion or contact with skin).

By contrast, C. gattii is generally not found in avian feces, but rather in trees (most commonly the eucalyptus). The fungus is known to proliferate in debris around the bases of trees.

While cryptococcosis occurs frequently in animals, both mammal and avian, cases of animal-to-human transmission are extremely rare. Human-to-human transmission is also considered rare.


Clinical manifestations of Crytococcal infection generally begin anywhere from two to 11 months after exposure.

Pulmonary cryptococcal infection can often be asymptomatic in patients, or present with low-grade, non-specific respiratory symptoms. Patients with cryptococcal pneumonia often experience cough, chest pains, low-grade fever, malaise, and shortness of breath. In some cases, there may also be weight loss, swollen lymph glands (lymphadenopathy), rapid breathing (tachypnea), and audible crackles in the lung (rales).

If the infection is disseminated beyond the lungs (extrapulmonary), it most often presents in the central nervous system as cryptococcal meningitis. In these instances, patients may initially present with sub-acute symptoms such as headache, fever, or changes in mental state (e.g., loss of alertness, vagueness, lethargy). Symptoms are often sub-acute at the onset, worsening progressively over the course of several weeks.

Characteristic acute and chronic symptoms of cryptococcal meningitis can include:

  • Nausea and vomiting
  • Blurred vision
  • Sensitivity to light
  • Hearing impairment or loss
  • Increased cranial pressure
  • Severe headaches
  • Stiff neck
  • Personality changes
  • Difficulty speaking, reading or writing
  • Seizures or loss of muscular coordination
  • Hallucinations
  • Coma

Since some of the symptoms associated with classic meningitis (such as stiff neck and sensitivity to light) do not occur in many patients with cryptococcal meningitis, awareness of the condition is sometimes missed, delaying medical attention for weeks and even months until the emergence of acute symptoms.

Beyond the lungs and central nervous system, cryptococcal infection may also manifest on the skin as lesions, ulcers, plaques, abscesses, and any number of other cutaneous (or subcutaneous) conditions. It can also affect the adrenal glands, the prostate, and other organ systems.


Diagnosis of cryptococcosis is supported by the presentation of clinical features and symptomatology and confirmed by the analysis of blood, tissue, cerebrospinal fluid, or other bodily fluids. Methods of diagnosis may include:

  • Cryptococcal antigen testing of blood or cerebrospinal fluid
  • Microscopic examination and/or culture of tissue, blood or cerebrospinal fluid
  • Culture of bronchoalveolar lavage washings

While chest x-rays may reveal localized or diffuse infiltrates in the lungs in cases of pulmonary infection, they ultimately support rather than confirm diagnosis.


For immunocompetent patients with asymptomatic or mild-to-moderate cryptococcal disease, a course of antifungal therapy (fluconazole, itraconazole) may be prescribed until the fungal infection is resolved.

In the event of severe disease, treatment usually begins with amphotericin B, often in combination with flucytosine. This is generally followed by ongoing maintenance therapy using a daily dose of antifungal medication (as well as the initiation of ART if the patient is not yet on therapy).

Maintenance therapy should be continued until such time as the CD4 count is above 100 cells/mL and the patient's viral load is consistently suppressed to undetectable levels. If the CD4 falls below 100, therapy should be restarted to prevent recurrence of disease.

In the U.S. and most developed countries, primary (preventative) antifungal prophylaxis is not recommended, although preemptive antigen testing may be considered for patients at increased risk or in areas of high disease burden.


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Also Known As:

  • Crypto (slang)
  • Crypotococcal disease
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By James Myhre & Dennis Sifris, MD
Dennis Sifris, MD, is an HIV specialist and Medical Director of LifeSense Disease Management. James Myhre is an American journalist and HIV educator.