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Cryptococcal meningitis

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Cryptococcal meningitis

Not to be confused with Cryptosporidiosis.
Classification and external resources
10 9 DiseasesDB MedlinePlus eMedicine MeSH D003453

Cryptococcosis, or cryptococcal disease, is a potentially fatal fungal disease. It is caused by one of two species; Cryptococcus neoformans and Cryptococcus gattii. These were all previously thought to be subspecies of C. neoformans, but have now been identified as distinct species.

Cryptococcosis is believed to be acquired by inhalation of the infectious propagule from the environment. Although the exact nature of the infectious propagule is unknown, the leading hypothesis is the basidiospore created through sexual or asexual reproduction.


Cryptococcosis is a defining opportunistic infection for AIDS, and is the second most common AIDS-defining illness in Africa. Other conditions which pose an increased risk include certain lymphomas (e.g. Hodgkin's lymphoma), sarcoidosis, liver cirrhosis and patients on long-term corticosteroid therapy.

Distribution is worldwide in soil.[1] The prevalence of cryptococcosis has been increasing over the past 20 years for many reasons, including the increase in incidence of AIDS and the expanded use of immunosuppressive drugs.

In humans, C. neoformans causes three types of infections:

Cryptococcal meningitis (infection of the meninges, the tissue covering the brain) is believed to result from dissemination of the fungus from either an observed or unappreciated pulmonary infection. Often there is also silent dissemination throughout the brain when meningitis is present. Cryptococcus gattii causes infections in immunocompetent people (fully functioning immune system), but C. neoformans v. grubii, and v. neoformans usually only cause clinically evident infections in persons who have some form of defect in their immune systems (immunocompromised persons). People who have defects in their cell-mediated immunity, for example, people with AIDS, are especially susceptible to disseminated cryptococcosis. Cryptococcosis is often fatal, even if treated. The 10-week survival averages near 70% with optimal therapy.

Although the most common presentation of cryptococcosis is of C. neoformans infection in an immunocompromised person (such as persons living with AIDS), the C. gattii is being increasingly recognised as a pathogen in presumptively immunocompetent hosts, especially in Canada and Australia. This may be due to rare exposure and high pathogenicity, or to unrecognised isolated defects in immunity, specific for this organism.


Dependent on the infectious syndrome, symptoms include fever, fatigue, chest pain, dry cough, swelling of abdomen, headache, blurred vision and confusion.[2] Symptom onset is often subacute, progressively worsened over several weeks.

Detection of cryptococcal antigen (capsular material) by culture of CSF, sputum and urine provides definitive diagnosis.[3] Blood cultures may be positive in heavy infections. India ink of the CSF is a traditional microscopic method of diagnosis,[4] although the sensitivity is poor in early infection, and may miss up to >=20% of patients with culture-positive cryptococcal meningitis. Unusual morphological forms are rarely seen.[5] Cryptococcal antigen from cerebrospinal fluid is the best test for diagnosis of cryptococcal meningitis in terms of sensitivity.[6] Apart from conventional methods of detection like direct microscopy and culture, rapid diagnostic methods to detect cryptococcal antigen by latex agglutination test, lateral flow immunochromatographic assay (LFA), or enzyme immunoassay (EIA). A new cryptococcal antigen LFA was FDA approved in July 2011.[7] Polymerase chain reaction (PCR) has been used on tissue specimens.

Cryptococcosis can rarely occur in the non-immunosuppressed people, particularly with Cryptococcus gattii.


Treatment options in persons without HIV-infection have not been well studied. Intravenous Amphotericin B combined with oral flucytosine is recommended.[8]

Persons living with AIDS often have a greater burden of disease and higher mortality (30-70% at 10-weeks), but recommended therapy is with Amphotericin B (0.7-1.0 mg/kg/day) and flucytosine. Where flucytosine (5FC) is not available, fluconazole 800–1200 mg/day should be used adjunctively with amphotericin.[9] Amphotericin-based induction therapy has much greater microbiologic activity than fluconazole monotherapy with 30% better survival at 10-weeks.[3][10] Based on a systematic review of existing data, the most cost-effective induction treatment in resource-limited settings appears to be one week of amphotericin B 1 mg/kg/day coupled with high dose fluconazole 1200 mg/day.[10] After initial induction treatment as above, consolidation therapy is typically with oral fluconazole 400-800 mg/day for at least 8 weeks is used with secondary prophylaxis with fluconazole 200mg/day thereafter.[9]

The decision on when to start treatment for HIV is not yet settled, although one small, under-powered trial (when restricting to a "per protocol analysis") suggested that delaying the start of treatment for several weeks may be beneficial in avoiding deaths from Cryptococcal Optimal ART Timing (COAT) Trial, will be completed in spring 2013.

Prevention of Cryptococcosis

Cryptococcosis is a very subacute infection with a prolonged subclinical phase lasting weeks to months in persons with HIV/AIDS before the onset of symptomatic meningitis. In Sub-Saharan Africa, the prevalence rates of detectable cryptococcal antigen in perpheral blood is often Cryptococcal antigen screen and preemptive treatment with fluconazole is cost saving to the health care system by avoiding cryptococcal meningitis.[13] The World Health Organization recommends cryptococcal antigen screening in HIV-infected persons entering care with CD4<100 cells/μL.[9] This undetected subclinical cryptococcal (if not preemptively treated with anti-fungal therapy) will often go on to develop cryptococcal meningitis, despite receiving HIV therapy.[12][14] Cryptococcosis accounts for 20-25% of the mortality after initiating HIV therapy in Africa. What is effective preemptive treatment is unknown, with the current recommendations on dose and duration based on expert opinion.

The U.S. Department of

IRIS in immunocompetent hosts

The immune reconstitution inflammatory syndrome (IRIS) has been described in immunocompetent hosts who have meningitis caused by C. gattii and C. grubii. Several weeks or even months into appropriate treatment, there is a sudden onset deterioration with worsening meningitis symptoms and progression or development of new neurological symptoms. IRIS is however much more common in immunocompromised hosts (~25% vs. ~8%).

Magnetic resonance imaging shows increase in the size of brain lesions, and CSF abnormalities (white cell count, protein, glucose) increase. CSF culture is sterile, and there is no increase in CSF cryptococcal antigen titre.

The increasing inflammation can cause brain injury or be fatal.[15][16][17]

The mechanism behind IRIS in cryptococcal meningitis is primarily immunologic. With reversal of immunosuppression, there is paradoxical increased inflammation as the recovering immune system recognises the fungus. In severe IRIS cases, treatment with systemic corticosteroids has been utilized.

In other animals

Cryptococcosis is also seen in cats and occasionally dogs. It is the most common deep fungal disease in cats, usually leading to chronic infection of the nose and sinuses, and skin ulcers. Cats may develop a bump over the bridge of the nose from local tissue inflammation. It can be associated with FeLV infection in cats. Cryptococcosis is most common in dogs and cats but cattle, sheep, goats, horses, wild animals and birds can also be infected. Soil, fowl manure and pigeon droppings are among the sources of infection.[18][19]


External links

  • is a clearinghouse for information as an international collaboration between government and non-governmental organizations, academic institutions, and private industry partners -- who are dedicated to reducing the global burden of cryptococcal disease.
  • Health AtoZ
  • Busse-Buschke disease at Who Named It?
  • Medscape entry on cryptococcosis
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