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Journal of Tropical Pediatrics Advance Access originally published online on September 9, 2008
Journal of Tropical Pediatrics 2008 54(6):361-363; doi:10.1093/tropej/fmn072
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© The Author [2008]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Clinical Review

Evidence behind the WHO Guidelines: Hospital Care for Children: The Usefulness of Azole Prophylaxis against Cryptococcal Meningitis in HIV-positive children

Primary Reviewer: Jana Thurey

University of Edinburgh, Scotland

Secondary Reviewer: Elizabeth Molyneux

University of Malawi, Blantyre, Malawi

For more information on this project to evaluate the evidence behind the WHO Hospital Care for Children, see J Trop Pediatr 2006; 52: 1–2. If you would like suggest a topic or contribute a review, please contact Dr Julian Kelly. E-mail <julian.kelly{at}rch.org.au>.

The World Health Organization has produced guidelines for the management of common illnesses in hospitals with limited resources. This series reviews the scientific evidence behind WHO's recommendations. The WHO guidelines and more reviews are available at http://www.ichrc.org

This review addresses the question: The usefulness of azole prophylaxis against cryptococcal meningitis in HIV-positive children.

The WHO Pocketbook of Hospital Care for Children recommends that if a HIV positive child has cryptococcal meningitis then treat with amphotericin for 14 days then fluconazole for a further 8 weeks. Fluconazole prophylaxis is then started after treatment. (Pocketbook p. 218)


   Background
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Cryptococcal meningitis (CM) is a form of meningitis that is found in children and adults infected with the human immunodeficiency virus (HIV) [1, 2].

The causative organism for cryptococcal disease is Cryptococcus neoformans, an encapsulated yeast and the disease spectrum includes pneumonia, cutaneous lesions and most commonly and morbidly meningitis.

The most recent guidelines by the US Public Health Service and Infectious Disease society of America recommend that ‘antifungal prophylaxis not be used routinely to prevent cryptococcosis because of the relative infrequency of cryptococcal disease, lack of survival benefits associated with prophylaxis, possibility of drug interactions, potential antifungal drug resistance, and cost’. Life-long secondary prophylaxis, however, is recommended for patients who have completed initial therapy for cryptococcal infection [3]. No specific guidelines exist for children and all the current recommendations are based on adult data.

The development of highly active antiretroviral therapy (HAART) has reduced the need for prophylactic treatment for several opportunistic infections such as Pneumocysitis carinii pneumonia (PCP) [4] and disseminated Mycobacterium avium [5]. Low availability of HAART, higher incidences of CM in developing countries, however, have brought into question whether the current guidelines discouraging the routine use of fluconazole prophylaxis are indeed adequate for countries with low resources [6, 7].


   Methodology
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The Cochrane library, EMBASE and Medline were searched systematically using the keywords meningitis, cryptococcal, cryptococcus neoformans, crypto$.mp, cryptococcosis, HIV, acquired immunodeficiency syndrome, prophylaxis, fluconazole, itraconazole and azoles.


   Results
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Discussion and Summary
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No studies conducted in children, or with paediatric patients as a subset of the study sample were identified. The adult literature was therefore assessed. Three studies, including a Cochrane review, which assessed five randomized controlled trials, on the topic of primary fluconazole prophylaxis in HIV positive adults were identified [11–17]. Four studies investigating the need for secondary prophylaxis after the treatment for CM in HIV positive adults were also included in this review [18–21].

Research conducted in adults
Both fluconazole and itraconazole are effective at preventing CM in HIV-positive adults [3, 8–12] but are only associated with a survival benefit in patients with either very low CD4 counts (<100 cells/µl) or living in areas where CM has an increased incidence [3, 12]. Due to heterogeneity between the studies no definite conclusions can be drawn concerning which antifungal agent is superior or what dose/timing would be best.

Even though antifungal prophylaxis should not be prescribed routinely for all HIV-positive individuals it has a role in preventing CM in patients with very low CD4 counts, living in endemic areas, who are naïve to HAART or in the early stages of treatment. Once immune reconstitution has taken place to >200 cells/µl it appears safe to discontinue secondary prophylaxis when serum cryptococcal antigen is negative [13–17] but further randomized blinded studies with more participants are needed to confirm this finding. If HAART is not available, fluconazole prophylaxis should be used as an alternative means of preventing opportunistic cryptococcal infections.

Applicability of the research to children
In order to assess how applicable this research was to children the literature search was conducted to assess the safety of fluconazole in children. The safety profile of fluconazole has been studied in large paediatric trials and appears to be just as favourable as in adults [18, 19]. To reach equivalent levels of fluconazole exposure in children compared with adults the per kilogram dose has to be increased [20] due to differences in volume of distribution. Of note is also the decreased incidence of CM in children, which may reduce the efficacy of a prophylactic intervention. Accurate epidemiological data on the prevalence of CM in children does not exist, but limited data suggests that it is less prevalent than in adults [21]. Its prevalence may however be underestimated as some CM may be misdiagnosed as tuberculous meningitis. Furthermore, few hospitals are able to conduct Cryptococcus antigen tests and rely on India ink staining the cerebrospinal fluid for diagnosis of C. neoformans, which has a poorer sensitivity than antigen testing [22].


   Discussion and Summary
Top
 Notes
 Background
 Methodology
 Results
 Discussion and Summary
References
 
The issues surrounding antifungal prophylaxis against CM are complex and not fully elucidated, even in adults. Fundamental to deciding how useful azole prophylaxis against CM would be in HIV-positive children is accurate epidemiological data. Once the extent of the problem has been identified the need for prophylaxis can be assessed more accurately. Studies conducted in HIV-positive children aged 6–18 years assessing the usefulness of azole prophylaxis against CM are needed to clarify the question. These studies should be conducted in developing countries, as differences in access to health care and antifungal therapies as well as differences in the incidence of HIV and CM will affect the need and argument for prophylaxis. Care must be taken to evaluate the possibility of the development of resistant strains when azole prophylaxis use is being assessed.

International public health efforts to make HIV testing as well as HAART more available for children and adults in countries with low resources will almost certainly be the most effective measure to diminish the morbidity associated with CM. Further data on the epidemiology of CM in HIV-positive children is needed in order to assess more accurately the usefulness of azole prophylaxis.


   Notes
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 Notes
Background
 Methodology
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 Discussion and Summary
 References
 
Section Editors: Trevor Duke and Julian Kelly


   References
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 Methodology
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 Discussion and Summary
 References
 

  1. French N, Gray K, Watera C, et al. Cryptococcal infection in a cohort of HIV-1 infected Ugandan adults. AIDS (2002) 16:1031–8.[CrossRef][Web of Science][Medline]
  2. Moosa MY, Coovadia YM. Cryptococcal meningitis in Durban, South Africa: a comparison of clinical features, laboratory findings, and outcome for HIV-positive and HIV-negative patients. Clin Infect Dis (1997) 24:131–4.[Web of Science][Medline]
  3. Kaplan J, Masur H, Holmes KK. Guidelines for preventing of opportunistic infections among HIV-infected presons. Morb Mortal Wkly Rep (2002) 51:1–46.[Medline]
  4. Lopez JC, Miro JM, Pena JM, et al. A randomized controlled trial of the discontinuation of primary and secondary prophylaxis against Pneumocystic carinii pneumonia after HAART in patients with HIV infection. N Engl J Med (2001) 344:159–67.[Abstract/Free Full Text]
  5. El-Sadr WM, Burman WJ, Grant LB, et al. Discontinuation of prophylaxis for Mycobacterium avium complex disease in HIV-infected patients who have a response to antiretroviral therapy. N Engl J Med (2000) 342:1058–92.[Free Full Text]
  6. Chariyalertsak S, Supparatpinyo T, Nelson KE. A controlled trial of itraconazole as primary prophylaxis for systemic fungal infections in patients with advanced HIV infection in Thailand. Clin Infect Dis (2002) 34:277–84.[CrossRef][Web of Science][Medline]
  7. Mirza SA, Phelan M, Rimland D, et al. The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas 1992–2000. Clin Infect Dis (2003) 36:789–94.[CrossRef][Web of Science][Medline]
  8. Chang LW, Phipps WT, Kennedy GE, Rutherford GW. Antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV. Cochrane Database Syst Rev (2005) (3). Art. No.: CD004773.
  9. Powderly WG, Finkelstein DM, 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. N Engl J Med (1995) 332:700–5.[Abstract/Free Full Text]
  10. McKinsey DS, Wheat LJ, Cloud GA, et al. Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: randomised, placebo-controlled, double-blind study. Clin Infect Dis (1999) 28:1049–56.[Web of Science][Medline]
  11. Smith DE, Bell J, Johnson M, et al. A randomized, double-blind, placebo-controlled study of intraconazole capsules for the prevention of deep fungal infections in immunodeficient patients with HIV infection. HIV Med (2001) 2:78–83.[CrossRef][Medline]
  12. Chetchotisakd P, Sungkanuparph S, Thinkhamrop B, et al. A multicentre, randomized, double-blind, placebo-controlled trial of primary cryptococcal meningitis prophylaxis in HIV-infected patients with severe immune deficiency. HIV Med (2004) 5:140–3.[CrossRef][Web of Science][Medline]
  13. 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) 12:929–35.[Web of Science][Medline]
  14. Sun H-Y, Chen M-Y, Hsiao C-F, et al. Endemic fungal infections caused by Cryptococcus neoformans and Penicillium Marneffei in patients with human immunodeficiency virus and treated with highly active anti-retroviral therapy. Clin Microbiol Infect (2006) 12:381–8.[CrossRef][Web of Science][Medline]
  15. Mussini C, Pezzotti P, Miro JM, et al. Discontinuation of maintenance therapy for cryptococcal meningitis in patients with AIDS treated with highly active antiretroviral therapy: an international observational study. Clin Infect Dis (2004) 38:565–71.[CrossRef][Web of Science][Medline]
  16. 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 multicentre randomized study. Clin Infect Dis (2003) 36:1329–31.[CrossRef][Web of Science][Medline]
  17. Sheng WH, Hung CC, Chen MY, et al. Successful discontinuation of fluconazole as secondary prophylaxis for cryptococcosis in AIDS patients responding to highly active antiretroviral therapy. Int J STD AIDS (2002) 13:702–5.[Abstract/Free Full Text]
  18. Novelli V, Holzel H. Safety and tolerability of fluconazole in children. Antimicrob Agents Chemother (1999) 43:1955–60.[Abstract/Free Full Text]
  19. Lee JW, Seibel NL, Amantea M, et al. Safety and pharmacokinetics of fluconazole in children with neoplastic disease. J Pediatr (1992) 120:987–93.[CrossRef][Web of Science][Medline]
  20. Brammer KW, Coates PE. Pharmacokinetics of fluconazole in paediatric patients. Eur J Microbiol Infect Dis (1994) 13:325–9.[CrossRef]
  21. Adabi J, Nachman S, Kressel AB, et al. Cryptococcosis in children with AIDS. Clin Infect Dis (1999) 28:309–13.[Web of Science][Medline]
  22. Khanna N, Chandramuki A, Desai A, et al. Cryptococcal infections of the central nervous system: an analysis of predisposing factors, laboratory findings and outcome in patients from South India with special reference to HIV infection. J Med Microbiol (1996) 45:376–9.[Abstract/Free Full Text]

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