Cryptococcosis

Cryptococcosis

Anthony Febres-Aldana, MD

Department of Medicine, Division of Infectious Diseases, UT Health San Antonio, Texas, United States 

Jorge Cardenas-Alvarez, MD

Department of Medicine, Division of Infectious Diseases, Columbia University Irving Medical Center, New York, United States

Author: Anthony Febres-Aldana, Jorge Cardenas-Alvarez

Mónica Pachar, MD, MSc, DTM&H

Coordinator of tropical clinical teaching, Infectotrópico Group. Santo Tomás Hospital, Panamá. (En español: Coordinador de docencia clínica tropical, Grupo Infectotrópico. Hospital Santo Tomás, Panamá).

José Antonio Suárez, MD

Director of Research and Teaching, Infectotrópico Group. National Research System (SNI), Panamá (En español: Director de Investigación y Docencia, Grupo Infectotrópico. Sistema Nacional de Investigación (SNI), Panamá).

Laura Naranjo, MD

Scientific Director of Project Integration, Infectotrópico Group. National Research System (SNI), Panamá (En español: Director Científico de Integración de Proyectos, Grupo Infectotrópico. Sistema Nacional de Investigación (SNI), Panamá).

Editors: Mónica Pachar, José Antonio Suárez, Laura Naranjo

Section Contents

  1. Background
  2. Epidemiology
  3. Transmission
  4. Clinical Presentation
  5. Diagnosis
  6. Treatment & Management
  7. References

Background

Cryptococcosis is a fungal infection caused by the encapsulated yeasts Cryptococcus neoformans (~80%) and Cryptococcus gattii (~20%). As with other fungal infections, it is largely opportunistic and disproportionately affects immunosuppressed individuals - especially those with acquired immunodeficiency syndrome (AIDS). Although still present among immunosuppressed patients, C. gattii presents more frequently than C. neoformans among immunocompetent individuals.

Cryptococcosis can be life-threatening, and infection can range from asymptomatic to pulmonary, cutaneous, and/or meningeal involvement.

Epidemiology

Distribution: Cryptococcus spp. grows in soil enriched with bird droppings (e.g., pigeons, canaries); and found in tree bark (e.g. Eucalyptus trees) but is not naturally present in unenriched soil. C. neoformans has a global distribution whereas C. gatti inhabits tropical and subtropical areas, commonly in Australia and South America, and the Pacific Northwest region of Canada and the United States.

Risk factors: the main risk factor for cryptococcosis is the presence of any immunocompromising condition, such as AIDS with CD4 counts <100 cells/uL (more common), organ transplantation, immune suppressing medication, cirrhosis, diabetes, mellitus, among others. Although remember it can also occur (less frequently) in immunocompetent individuals.

Transmission

Cryptococcosis starts with inhalation of encapsulated yeast spores from an environmental source. The primary pulmonary infection can range from asymptomatic to acute pneumonia. From the lungs, the yeast can spread through blood and lymph to other organs, including the central nervous system (CNS) due to its ability to cross the blood-brain barrier, and the skin.

More commonly, following primary infection (can be asymptomatic), the yeast can remain dormant in lung-lymphatic reservoirs, and can reactivate once cellular immunity declines.

Clinical Presentation

Incubation period is variable and can range from a few weeks to years. Click below to learn more about the clinical spectrum of cryptococcosis:

CNS cryptococcosis
Pulmonary cryptococcosis
Others
What are the key highlights in C. gatti?

Answer

C. gatti is more commonly seen in immunocompetent individuals than C. neoformans, it is associated more frequently with cryptococcomas and pulmonary disease, and is causative of outbreaks. C-IRIS complicating C. gattii cryptococcosis is rarer in comparison with C. neoformans cryptococcosis. Suspect in individuals from endemic areas with cryptococcosis, especially those who are immunocompetent!

You’ll likely come across plenty of resources and information on C. neoformans, but much less on C. gatti. Below, we highlight the key differences for your review.

C. Gatti C. neoformans
Reservoir Tree bark (e.g., Eucalyptus) Soil enriched with bird droppings
Distribution Tropical and subtropical areas, mainly Australia, Papua New Guinea, and some areas in South America. AND
US/Canada: Pacific Northwest		 Widespread distribution
Immune status of the host More common in immunocompetent than C. neoformans More common in immunocompromised (especially AIDS)
Meningoencephalitis Less common More common
Cryptococcomas (CNS) More common Less common
Pulmonary involvement More common Less common

Table 1. Comparison between C. gatti and C. neoformans

Diagnosis

As with all diseases, diagnosis starts with a clinical suspicion in the right epidemiological context (ask yourself: what is the presentation? who is the host?). Definitive diagnosis can be supported through different modalities:

  1. Microbiologic diagnosis: relies on isolation and/or direct visualization of the yeast.
    1. Culture: gold standard.
    2. Staining (blood or cerebrospinal fluid): india Ink (sensitivity up to >85%) or gram stain.
    3. MALDI-TOF MS: allows accurate and reliable identification of Cryptococcus spp.
  2. Cryptococcal antigen (CrAg): it is a point of care test that can be detected in blood and CSF and is considered a first-line rapid diagnostic test due to sensitivity close to 99% (especially in CSF). Lateral flow assay (LFA) is preferred, but depending on your site of practice, may use other techniques such as latex agglutination or enzyme immunoassay. CrAg cannot differentiate between C. neoformans and C. gatti.
  3. PCR: typically used as part of a multiplex panel in blood or for research purposes. Not widely available.
  4. Imaging: crucial in the diagnosis of cryptococcosis.
    1. CNS cryptococcosis: look for lepto- or pachymeningeal enhancement, ring-enhancing lesions (cryptococcomas) with perilesional edema, signs of increased intracranial pressure (ICP).
    2. Pulmonary cryptococcosis: look for nodules (single or multiple), lobar infiltrates, masses, hilar lymphadenopathy, and, less frequently, pleural effusions.

Treatment & Management

Treating cryptococcosis is quite complex. In this module, we will give you the most high-yield concepts. However, for specific considerations, please consult the ECMM/ISHAM/ASM Global Guidelines.

As a general rule, treatment of Cryptococcus requires both antifungal therapy and management of intracranial hypertension. Antifungal therapy is summarized below. To manage intracranial hypertension, patients often require serial lumbar punctures to relieve elevated pressure and reduce disease burden.

Treatment is divided into three phases: (i) induction phase; (ii) consolidation phase; (iii) maintenance phase:

  1. Induction phase: the preferred regimen is IV liposomal amphotericin B PLUS flucytosine. Treatment duration is generally around 2 weeks but may be extended if persistently positive CSF cultures or based on clinical picture. For example, C. gattii and cryptococcomas typically require longer treatment (4-6 weeks). In low-income settings, an alternative regimen using single dose IV liposomal amphotericin followed by flucytosine and fluconazole is recommended. If liposomal amphotericin B and/or flucytosine are unavailable at your institution, as management can become quite complex.
  2. Consolidation phase: followed by fluconazole monotherapy for at least 8 weeks.
  3. Maintenance phase: continue fluconazole secondary prophylaxis for at least 1 year OR until CD4 >100 cells/uL and HIV RNA is suppressed while on antiretrovirals for 3 months.
At least 2 weeks*

Introducción

Resource-rich setting

L-Amphotericin B + Flucytosine

Resource-limited setting

Single-dose L-Amphotericin B followed by high-dose fluconazole AND flucytosine

→
8 Weeks

Consolidation

Fluconazole

→
At least 12 months

Maintenance

Fluconazole

*Longer if persistently positive CSF cultures or based on clinical picture. C. gattii and cryptococcomas typically require longer treatment

Figure 1. Phases of treatment in cryptococcomas

Want to know some management pearls about Cryptococcus?

Answer

  • Lumbar puncture is not only diagnostic, but also therapeutic. In the setting of increased ICP (≥ 20 cm of CSF), guidelines recommend proactive ICP management with therapeutic lumbar punctures. In clinical practice, that usually translates to daily LPs to decrease the ICP.
  • Consider lumbar puncture at the end of the induction phase to guarantee CSF sterility - DO NOT initiate antiretrovirals at first. Wait 4-6 weeks to reduce risk of IRIS.
  • Management in transplant recipients can become COMPLICATED. Call your transplant infectious diseases friend!
  • Be careful, because certain strains of C. gattii may have higher minimum inhibitory concentrations (MIC) to fluconazole #KeepAnEyeOnThoseCultures

References

This lesson was built in partnership with Infectotropico Group, Panama.

This lesson was built in partnership with Infectotropico and was last updated August 22 2025

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