Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy

Key Points

  • In most clinical centres in Africa, despite access to antiretroviral therapies, cases of HIV-associated cryptococcal meningitis (CM) are not decreasing owing to challenges with retention and adherence to HIV care

  • CM in HIV-negative individuals is relatively rare, but carries a mortality at least as high as in HIV-associated disease; therefore, CM must be considered in all cases of lymphocytic meningitis — even in the apparently immunocompetent

  • A point-of-care, lateral flow 'dipstick' test to detect cryptococcal antigen in the blood or cerebrospinal fluid (CSF) is a significant advance: it is highly specific, sensitive, and easy to use

  • Amphotericin B (in conventional or liposomal formulation) combined with flucytosine remains the induction therapy of choice, and is associated with a survival advantage over amphotericin B alone

  • Measurement of CSF opening pressure and appropriate management of raised CSF pressure can reduce mortality

  • Any future attempts at adjunctive immunotherapies will need to be closely guided by the specific immune status of the host at the time of any intervention


HIV-associated cryptococcal meningitis is by far the most common cause of adult meningitis in many areas of the world that have high HIV seroprevalence. In most areas in Sub-Saharan Africa, the incidence of cryptococcal meningitis is not decreasing despite availability of antiretroviral therapy, because of issues of adherence and retention in HIV care. In addition, cryptococcal meningitis in HIV-seronegative individuals is a substantial problem: the risk of cryptococcal infection is increased in transplant recipients and other individuals with defects in cell-mediated immunity, and cryptococcosis is also reported in the apparently immunocompetent. Despite therapy, mortality rates in these groups are high. Over the past 5 years, advances have been made in rapid point-of-care diagnosis and early detection of cryptococcal antigen in the blood. These advances have enabled development of screening and pre-emptive treatment strategies aimed at preventing the development of clinical infection in patients with late-stage HIV infection. Progress in optimizing antifungal combinations has been aided by evaluation of the clearance rate of infection by using serial quantitative cultures of cerebrospinal fluid (CSF). Measurement and management of raised CSF pressure, a common complication, is a vital component of care. In addition, we now better understand protective immune responses in HIV-associated cases, immunogenetic predisposition to infection, and the role of immune-mediated pathology in patients with non-HIV associated infection and in the context of HIV-associated immune reconstitution reactions.

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Figure 1: Associations between baseline cerebrospinal fluid immune response profiles and clinical outcome in HIV-associated CM.
Figure 2: Systemic immune responses to cryptococcal antigen are associated with survival in HIV-associated cryptococcal meningitis.
Figure 3: Raised cerebrospinal fluid pressure in a patient with HIV-associated cryptococcal meningitis.
Figure 4: Host damage from infection-related inflammatory syndromes in HIV-positive and in HIV-negative cryptococcal meningitis.
Figure 5: Corticosteroid treatment can reduce brain oedema in patients with HIV-negative cryptococcal meningitis.


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Author information

P.R.W., J.N.J., A.A.P., M.C.F. and T.S.H. wrote the article. All authors participated in researching data for article, provided substantial contribution to discussion of content, and reviewed and edited the manuscript before submission.

Correspondence to Thomas S. Harrison.

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Competing interests

P.W. has a CRADA (cooperative research and development agreement) with Matinas BioPharma regarding an oral amphotericin formulation. J.J. has received an Investigator Award (to institution) from Gilead Sciences. T.H. has received an Investigator Award (to institution) from Gilead Sciences and has received a donation of cryptococcosis test kits for research purposes from Immuno-Mycologics, received honoraria from Pfizer, and is on the advisory board for Viamet.

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Idiopathic CD4+ lymphopenia

Repeated presence of a CD4+ T lymphocyte count of <300 cells/ml without a predisposing cause.

Hyperimmunoglobulin E recurrent infection syndrome

This syndrome, also known as Job syndrome, is caused by mutations in the signal transducer and activator of transcription (STAT3). Patients typically have eosinophilia, eczema, and recurrent skin and pulmonary infections.

Colony forming unit

A measure to quantify viable fungal cells on the basis of the cells' ability to grow to form visible colonies on an agar plate.

Rate of infection clearance

The rate of decrease in viable organisms in the cerebrospinal fluid (CSF) during treatment, derived from quantitative cultures of the CSF obtained from serial lumbar punctures done over the first 14 days of treatment. For a particular drug regimen, the early fungicidal activity is the mean rate of infection clearance for patients on that regimen.

ASSURED criteria

Originally developed by the WHO Sexually Transmitted Diseases Diagnostics Initiative as a benchmark to determine whether new diagnostic tests addressed the needs of their disease control programmes in resource-limited settings: the ASSURED criteria include the test being affordable, sensitive, specific, user-friendly, rapid and robust, equipment-free, and deliverable to end-users.

Paradoxical IRIS

Clinical deterioration in HIV-positive patients with cryptococcal meningitis who have responded to initial antifungal therapy, but then relapse after starting antiretroviral therapy owing to the resultant immune restoration and enhanced inflammatory immune response to residual cryptococcal antigens.

Unmasking IRIS

Individuals with HIV infection can present for the first time with cryptococcal meningitis after effective antiretroviral therapy (ART) has been initiated. These patients may have a mixture of active infection and immune-mediated pathology as a result of ART-mediated immune restoration.

Macrophage–T-cell dissociation

Despite appropriate T-cell signalling, macrophages fail to become classically activated and clear infection but rather remain in an alternatively activated state that is less effective at controlling infection and clearing antigen.

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Williamson, P., Jarvis, J., Panackal, A. et al. Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy. Nat Rev Neurol 13, 13–24 (2017).

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