Skip to main content

Advertisement

Log in

Management of Cryptococcal Meningitis in Sub-Saharan Africa

  • Published:
Current HIV/AIDS Reports Aims and scope Submit manuscript

Abstract

Cryptococcal meningitis (CM) is a common form of meningitis in sub-Saharan Africa due to the high prevalence of HIV/AIDS. This report outlines the management of CM with a focus on resource-limited settings. Sections covered include epidemiology and diagnosis, pharmacotherapy, management of complications, timing of antiretrovirals, and primary and secondary prevention of CM. Emphasis has been given to recent articles and landmark trials, and opinion is given from the authors’ own experiences.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Okongo M, Morgan D, Mayanja B, et al.: Causes of death in a rural, population-based human immunodeficiency virus type 1 (HIV-1) natural history cohort in Uganda. Int J Epidemiol 1998, 4:698–702.

    Article  Google Scholar 

  2. French N, Gray K, Watera C, et al.: Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS 2002, 16:1031–1038.

    Article  PubMed  Google Scholar 

  3. • Park BJ, Wannemuehler KA, Marston BJ, et al.: Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 2009, 23:525–530. This article highlights the devastating effect of this underappreciated disease in resource-limited areas.

    Article  PubMed  Google Scholar 

  4. Ellis DH, Pfeiffer TJ: Ecology, life cycle, and infectious propagule of Cryptococcus neoformans. Lancet 1990, 336:923–925.

    Article  CAS  PubMed  Google Scholar 

  5. Goldman DL, Khine H, Abadi J, et al.: Serologic evidence for Cryptococcus neoformans infection in early childhood. Pediatrics 2001, 107:E66.

    Article  CAS  PubMed  Google Scholar 

  6. Davis J, Zheng WY, Glatman-Freedman A, et al.: Serologic evidence for regional differences in pediatric cryptococcal infection. Pediatr Infect Dis J 2007, 26:549–551.

    Article  PubMed  Google Scholar 

  7. Scarborough M, Gordon SB, Whitty CJ, et al.: Corticosteroids for bacterial meningitis in adults in sub-Saharan Africa. N Engl J Med 2007, 357:2441–2450.

    Article  CAS  PubMed  Google Scholar 

  8. •• Bicanic T, Muzoora C, Brouwer AE, et al.: Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients. Clin Infect Dis 2009, 49:702–709. This article validates a useful tool for assessing efficacy of anticryptococcal regimens.

    Article  CAS  PubMed  Google Scholar 

  9. Graybill JR, Sobel J, Saag M, et al.: Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis 2000, 30:47–54.

    Article  CAS  PubMed  Google Scholar 

  10. van der Horst CM, Saag MS, Cloud GA, et al.: Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med 1997, 337:15–21.

    Article  PubMed  Google Scholar 

  11. Maher D, Mwandumba H: Cryptococcal meningitis in Lilongwe and Blantyre, Malawi. J Infect 1994, 28:59–64.

    Article  CAS  PubMed  Google Scholar 

  12. Robinson PA, Bauer M, Leal MA, et al.: Early mycological treatment failure in AIDS-associated cryptococcal meningitis. Clin Infect Dis 1999, 28:82–92.

    Article  CAS  PubMed  Google Scholar 

  13. Perfect JR, Dismukes WE, Dromer F, et al.: Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2010, 50:291–322.

    Article  PubMed  Google Scholar 

  14. • Bicanic T, Meintjes G, Wood R, et al.: Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis 2007, 45:76–80. This article supports the use of AmB when possible for CM and highlights the fact that lower doses of fluconazole are very ineffective at clearing disease.

    Article  CAS  PubMed  Google Scholar 

  15. Mwaba P, Mwansa J, Chintu C, et al.: Clinical presentation, natural history, and cumulative death rates of 230 adults with primary cryptococcal meningitis in Zambian AIDS patients treated under local conditions. Postgrad Med J 2001, 77:769–773.

    Article  CAS  PubMed  Google Scholar 

  16. Bicanic T, Harrison T, Niepieklo A, et al.: Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution. Clin Infect Dis 2006, 43:1069–1073.

    Article  CAS  PubMed  Google Scholar 

  17. Bicanic T, Wood R, Meintjes G, et al.: High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial. Clin Infect Dis 2008, 47:123–130.

    Article  CAS  PubMed  Google Scholar 

  18. Brouwer AE, Rajanuwong A, Chierakul W, et al.: Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004, 363:1764–1767.

    Article  CAS  PubMed  Google Scholar 

  19. •• Nussbaum JC, Jackson A, Namarika D, et al.: Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi. Clin Infect Dis 2010, 50:338–344. This article shows the most effective combination of oral therapies for CM to date, with EFA of fluconazole 1200 mg/day plus flucytosine approaching that of AmB alone. It lends weight to the call for flucytosine to be made available in resource-limited settings.

    Article  CAS  PubMed  Google Scholar 

  20. Dromer F, Mathoulin-Pelissier S, Launay O, Lortholary O: Determinants of disease presentation and outcome during cryptococcosis: the CryptoA/D study. PLoS Med 2007, 4:e21.

    Article  PubMed  Google Scholar 

  21. • Milefchik E, Leal MA, Haubrich R, et al.: Fluconazole alone or combined with flucytosine for the treatment of AIDS-associated cryptococcal meningitis. Med Mycol 2008, 46:393–395. This article supports the use of high-dose fluconazole with flucytosine.

    Article  CAS  PubMed  Google Scholar 

  22. • Longley N, Muzoora C, Taseera K, et al.: Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda. Clin Infect Dis 2008, 47:1556–1561. This article demonstrates the safety and efficacy of higher doses of fluconazole.

    Article  CAS  PubMed  Google Scholar 

  23. • Pappas PG, Chetchotisakd P, Larsen RA, et al.: A phase II randomized trial of amphotericin B alone or combined with fluconazole in the treatment of HIV-associated cryptococcal meningitis. Clin Infect Dis 2009, 48:1775–1783. This study shows improved efficacy of AmB combined with fluconazole 800 mg over AmB alone.

    Article  CAS  PubMed  Google Scholar 

  24. Sloan D, Dlamini S, Paul N, Dedicoat M: Treatment of acute cryptococcal meningitis in HIV infected adults, with an emphasis on resource-limited settings. Cochrane Database Syst Rev 2008, 4:CD005647.

    PubMed  Google Scholar 

  25. Apseloff G, Hilligoss DM, Gardner MJ, et al.: Induction of fluconazole metabolism by rifampin: in vivo study in humans. J Clin Pharmacol 1991, 31:358–361.

    CAS  PubMed  Google Scholar 

  26. Bozzette SA, Larsen RA, Chiu J, et al.: A placebo-controlled trial of maintenance therapy with fluconazole after treatment of cryptococcal meningitis in the acquired immunodeficiency syndrome. California Collaborative Treatment Group. N Engl J Med 1991, 324:580–584.

    CAS  PubMed  Google Scholar 

  27. Powderly WG, Saag MS, Cloud GA, et al.: A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. The NIAID AIDS Clinical Trials Group and Mycoses Study Group. N Engl J Med 1992, 326:793–798.

    CAS  PubMed  Google Scholar 

  28. Saag MS, Cloud GA, Graybill JR, et al.: A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 1999, 28:291–296.

    Article  CAS  PubMed  Google Scholar 

  29. Vibhagool A, Sungkanuparph S, Mootsikapun P, et al.: Discontinuation of secondary prophylaxis for cryptococcal meningitis in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy: a prospective, multicenter, randomized study. Clin Infect Dis 2003, 36:1329–1331.

    Article  PubMed  Google Scholar 

  30. Aberg JA, Price RW, Heeren DM, Bredt B: A pilot study of the discontinuation of antifungal therapy for disseminated cryptococcal disease in patients with acquired immunodeficiency syndrome, following immunologic response to antiretroviral therapy. J Infect Dis 2002, 185:1179–1782.

    Article  PubMed  Google Scholar 

  31. Bicanic T, Brouwer AE, Meintjes G, et al.: Relationship of cerebrospinal fluid pressure, fungal burden and outcome in patients with cryptococcal meningitis undergoing serial lumbar punctures. AIDS 2009, 23:701–706.

    PubMed  Google Scholar 

  32. Loyse A, Wainwright H, Jarvis JN, et al.: Histopathology of the arachnoid granulations and brain in HIV-associated cryptococcal meningitis: correlation with cerebrospinal fluid pressure. AIDS 2010, 24:405–410.

    Article  PubMed  Google Scholar 

  33. Manosuthi W, Sungkanuparph S, Chottanapund S, et al.: Temporary external lumbar drainage for reducing elevated intracranial pressure in HIV-infected patients with cryptococcal meningitis. Int J STD AIDS 2008, 19:268–271.

    Article  PubMed  Google Scholar 

  34. Park MK, Hospenthal DR, Bennett JE: Treatment of hydrocephalus secondary to cryptococcal meningitis by use of shunting. Clin Infect Dis 1999, 28:629–633.

    Article  CAS  PubMed  Google Scholar 

  35. Newton PN, Thai le H, Tip NQ, et al.: A randomized, double-blind, placebo-controlled trial of acetazolamide for the treatment of elevated intracranial pressure in cryptococcal meningitis. Clin Infect Dis 2002, 35:769–772.

    Article  CAS  PubMed  Google Scholar 

  36. Bisson GP, Nthobatsong R, Thakur R, et al.: The use of HAART is associated with decreased risk of death during initial treatment of cryptococcal meningitis in adults in Botswana. J Acquir Immune Defic Syndr 2008, 49:227–229.

    Article  PubMed  Google Scholar 

  37. Zolopa A, Andersen J, Powderly W, et al.: Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One 2009, 4:e5575.

    Article  PubMed  Google Scholar 

  38. Makadzange A, Ndhlovu CE, Takarinda K, et al.: Early vs delayed initation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis 2010, 50:1532–1538.

    Article  CAS  PubMed  Google Scholar 

  39. McCarthy K, Meintjes G: Guidelines for the prevention, diagnosis and management of cryptococcal meningitis and disseminated cryptococcosis in HIV-infected patients. Southern African J HIV Med 2007, 25–35.

  40. Wakeham K, Parkes-Ratanshi R, Watson V, et al.: Co-administration of fluconazole increases nevirapine concentrations in HIV-infected Ugandans. J Antimicrob Chemother 2010, 65:316–319.

    Article  CAS  PubMed  Google Scholar 

  41. Manosuthi W, Athichathanabadi C, Uttayamakul S, et al.: Plasma nevirapine levels, adverse events and efficacy of antiretroviral therapy among HIV-infected patients concurrently receiving nevirapine-based antiretroviral therapy and fluconazole. BMC Infect Dis 2007, 7:14.

    Article  PubMed  Google Scholar 

  42. Bicanic T, Meintjes G, Rebe K, et al.: Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J Acquir Immune Defic Syndr 2009, 51:130–134.

    Article  CAS  PubMed  Google Scholar 

  43. Lortholary O, Fontanet A, Memain N, et al.: Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France. AIDS 2005, 19:1043–1049.

    Article  PubMed  Google Scholar 

  44. Powderly WG, Finkelstein D, Feinberg J, et al.: A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. N Engl J Med 1995, 332:700–705.

    Article  CAS  PubMed  Google Scholar 

  45. Chariyalertsak S, Supparatpinyo K, Sirisanthana T, Nelson KE: A controlled trial of itraconazole as primary prophylaxis for systemic fungal infections in patients with advanced human immunodeficiency virus infection in Thailand. Clin Infect Dis 2002, 34:277–284.

    Article  CAS  PubMed  Google Scholar 

  46. Essential Prevention and Care Interventions for Adults and Adolescents Living With HIV in Resource-Limited Settings. World Health Organization; 2008.

  47. Parkes-Ratanshi R, Kamali A, Wakeham K, et al.: Successful primary prevention of cryptococcal meningitis using fluconazole prophylaxis in HIV-infected Ugandan adults [abstract]. Conference on Retroviruses and Opportunistic Infections. 2009, In press.

  48. Liechty CA, Solberg P, Were W, et al.: Asymptomatic serum cryptococcal antigenemia and early mortality during antiretroviral therapy in rural Uganda. Trop Med Int Health 2007, 12:929–935.

    PubMed  Google Scholar 

  49. •• Jarvis JN, Lawn SD, Vogt M, et al.: Screening for cryptococcal antigenemia in patients accessing an antiretroviral treatment program in South Africa. Clin Infect Dis 2009, 48:856–862. This study suggests an approach to reduce the incidence of clincial CM in resource-limited settings by screening for CrAg in at-risk individuals.

    Article  CAS  PubMed  Google Scholar 

  50. •• Meya DB, Castelnuovo B, Kambugu A, et al.: Serum cryptococcal antigen (CRAG) screening: Cost-effective method to prevent death in HIV-infected persons with CD4 ≤100/μL in sub-Saharan Africa. Cape Town, South Africa: International AIDS Society; 2009. This study shows the cost-benefit implications of a CrAg screening approach in resource-limited settings. It is shown to be a cost-effective method.

    Google Scholar 

Download references

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mina C. Hosseinipour.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jackson, A., Hosseinipour, M.C. Management of Cryptococcal Meningitis in Sub-Saharan Africa. Curr HIV/AIDS Rep 7, 134–142 (2010). https://doi.org/10.1007/s11904-010-0052-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11904-010-0052-6

Keywords

Navigation