Cryptococcal meningitis: epidemiology and therapeutic options

Abstract

Cryptococcal meningitis causes morbidity and mortality worldwide. The burden of disease is greatest in middle- and low-income countries with a high incidence of human immunodeficiency virus (HIV) infection. Patients taking immunosuppressive drugs and some immunocompetent hosts are also at risk. Treatment of cryptococcal meningitis consists of three phases: induction, consolidation, and maintenance. Effective induction therapy requires potent fungicidal drugs (amphotericin B and flucytosine), which are often unavailable in low-resource, high-endemicity settings. As a consequence, mortality is unacceptably high. Wider access to effective treatment is urgently required to improve outcomes. For human immunodeficiency virus-infected patients, judicious management of asymptomatic cryptococcal antigenemia and appropriately timed introduction of antiretroviral therapy are important.

Keywords: HIV; antifungal therapy; antiretroviral therapy; cryptococcosis; immune reconstitution inflammatory syndrome; immunosuppression.

Figure 1

Evolution of the incidence of cryptococcosis, by year of diagnosis in France (1985–2001), as reported to the National Reference Centre for Mycosis. Note: Reproduced with permission from Dromer F, Mathoulin-Pelissier S, Fontanet A, Ronin O, Dupont B, Lortholary O, Epidemiology of HIV-associated cryptococcosis in France (1985–2001): comparison of the pre-and post-HAART eras, AIDS, 18:555–562. Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Lippincott williams & wilkins. Please contact journalpermissions@lww.com for further information. Abbreviation: HIV, human immunodeficiency virus.

Figure 2

Global incidence and mortality from cryptococcal meningitis among United Nations global regions from 1997 to 2007. Notes: Figures in brackets and italics indicate human immunodeficiency virus prevalence in 1,000s from each region during the period studied. Data from Park et al.

Figure 3

(A–C) Diagnosis of cryptococcal meningitis. (A) Lumbar puncture being performed on a human immunodeficiency virus-infected patient with suspected meningitis in Malawi. (B) Lateral flow immunoassay test strips for cryptococcal antigen detection (the strip on the left shows a negative result, indicated by a single horizontal “control” band in the center; the strip on the right shows a positive result, indicated by adjacent horizontal “control” and “test” bands). (C) Cryptococcus neoformans growing on Sabouraud media. Images kindly supplied by Kate Gaskell, College of Medicine, University of Malawi, and Brigitte Denis, Malawi Liverpool wellcome Trust Clinical Research Programme.

Figure 4

Treatment options for cryptococcal meningitis (CM), summarized from infectious Diseases Society of America and world Health Organization guidelines. Notes: ^aIn HIV-infected patients with renal impairment or concern about nephrotoxicity, LAmB or ABLC should be used. ^bIn settings of limited AmB availability or difficulty with toxicity monitoring, an abbreviated 5- to 7-day induction course of AmB may be used. ^cNon-HIV, nontransplant patients are a heterogeneous group, including individuals with hematological malignancies and immunocompetent hosts with Cryptococcus gattii infection. There is no consensus on optimal treatment; some authors suggest identical induction and consolidation therapy as for HIV-associated CM. ^dUndetectable Hiv viral load and CD4 > 100/μL should be demonstrated on two occasions 6 months apart before stopping fluconazole. Abbreviations: HIV, human immunodeficiency virus; AmB, amphotericin B; LAmB, liposomal amphotericin B (3–6 mg/kg/day); ABLC, amphotericin B lipid complex (5 mg/kg/day); od, once daily; PO, per os (by mouth); ART, antiretroviral therapy.

Figure 5

A screening and management strategy for asymptomatic antigenemia. Notes: Undetectable HIV viral load and CD4 >100/μL should be demonstrated on two occasions 6 months apart before stopping fluconazole. Jarvis JN, Govender N, Chiller T, et al, J Int Assoc Physicians AIDS Care (Chic) (11), pp 374–379, copyright © 2012 by SAGE Publications. Adapted by permission of SAGE Publications. Abbreviations: HIV, human immunodeficiency virus; CrAg, cryptococcal antigen; LP, lumbar puncture; CM, cryptococcal meningitis; od, once daily; ART, antiretroviral therapy.

Figure 6

Types of immune restoration inflammatory syndrome (IRIS) in cryptococcal disease. Note: ^aHIV-associated CM IRIS should occur within 12 months of ART initiation. Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus; CM, cryptococcal meningitis.