Fungal Infections
A recent clinical trial conducted in Zimbabwe determined median duration of survival to be worse among patients receiving ART within 72 hours of antifungal treatment compared to those receiving ART after 10 weeks of treatment with 800 mg of fluconazole per day (28 versus 637 days).84
The best interval
between initiation of antifungal therapy and ART remains unclear and necessitates further study.
Elevated ICP is also a major problem for patients with cryptococcal meningitis. One study found that of 221 HIV-positive patients, about
50 % had ICP ≥25 cm H2O, and over 25 % had an ICP ≥35 cm H2O.85 Furthermore, IRIS-associated cryptococcal meningitis was found to occur with higher ICPs, resulting from the inflammatory response.31.86 Aggressive management of CSF pressures in these patients is often not feasible in developing countries with limited clinical capacity. Limited use of lumbar punctures in these settings may result in high mortality despite antifungal availability and administration.
Prevention
Given the high burden on patients and healthcare systems related to cryptococcal meningitis, especially in developing countries with a large burden of HIV, public health officials should consider methods to reduce the incidence, mortality, and cost related to this disease.
Pre-emptive Treatment
This strategy is based on identifying persons early in the course of disease, and intervening with an oral agent such as fluconazole, in order to prevent morbidity and mortality related to severe sequelae. Cryptococcal antigen can be present in serum prior to symptom onset,87,88
and has been shown to precede clinical disease and independently predict poor outcomes. A study conducted in Uganda determined that CrAg positivity preceded clinical symptoms by a median of 22 days (range, 5–234 days) prior to symptom onset, with 11 % being positive for greater than 100 days.78
Performing serum CrAg screening among asymptomatic, or mildly symptomatic, individuals therefore has the potential to identify persons who may benefit from pre-emptive therapy. In another study in Uganda, CrAg screening and prompt initiation of fluconazole
1. Vandepitte J, Verwilghen R, Zachee P, AIDS and cryptococcosis (Zaire, 1977), Lancet, 1983;1(8330):925–6.
2. Schutte CM, Van der Meyden CH, Magazi DS, The impact of HIV on meningitis as seen at a South African Academic Hospital (1994 to 1998), Infection, 2000;28(1):3–7.
3. 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(6):789–94.
4. Hajjeh RA, Conn LA, Stephens DS, et al., Cryptococcosis: population-based multistate active surveillance and risk factors in human immunodeficiency virus-infected persons. Cryptococcal Active Surveillance Group, J Infect Dis, 1999;179(2):449–54.
5. Currie BP, Casadevall A, Estimation of the prevalence of cryptococcal infection among patients infected with the human immunodeficiency virus in New York City, Clin Infect Dis, 1994;19(6):1029–33.
6. Chuck SL, Sande MA, Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome,
However, using fluconazole as the mainstay of treatment can pose a higher risk of immune reconstitution inflammatory syndrome (IRIS). Fluconazole is fungistatic, and may require longer administration to achieve sterile CSF in the absence of a functional immune system.42–44 This suggests that rapid initiation of ART after fluconazole therapy commences may result in a higher fungal load, and therefore a high risk of IRIS. Indeed, many deaths after ART initiation occur during the first few months.83
therapy prevented cryptococcal meningitis and death in patients started on ART.89
In this study, 100 % of patients with CD4 counts <100 cells/µl and a positive CrAg who did not receive fluconazole therapy died within two months of ART initiation. With use of fluconazole, 71 % survived for >2.5 years. Initial cost-benefit analysis of integrating CrAg screening into HIV care by targeting patients with CD4 cell counts <100 cells/µl suggested a positive benefit. Further study of this ‘screen and treat’ strategy is urgently needed.
Primary Prophylaxis
Primary prophylaxis is another strategy that may also decrease the long-term risk of developing cryptococcal meningitis. In countries and areas with a high incidence of cryptococcal disease, the recently published IDSA guidelines recommend considering primary prophylaxis as a viable prevention strategy.41
While most primary prophylaxis trials
have shown a reduction or elimination of risk for development of cryptococcal infection, most did not clearly demonstrate an overall survival benefit,90–92 in Thailand.93
with the exception of a recent study conducted
Further published experience with primary prophylaxis to prevent cryptococcal meningitis is needed, particularly from countries with high burdens of HIV or from those that currently recommend prophylaxis policies. To date, most primary prophylaxis trials were performed in developed countries where the incidence and mortality from cryptococcal disease among the cohorts was likely fairly low. In resource-limited countries such as those in sub-Saharan Africa that experience a higher incidence and mortality associated with cryptococcal infection, the survival benefit of primary prophylaxis may be greater. Further studies are therefore necessary in developing countries, particularly where the burden of cryptococcal infection is high.
Conclusion
The large global burden of cryptococcal disease presents a number of challenges and opportunities to public health. The epidemiology and public health issues surrounding cryptococcal disease are currently changing, due to the changing practice and epidemiology of at-risk populations. Issues surrounding access to antifungal therapy and ability to manage complications of high intracranial pressure, as well as IRIS, can be formidable, particularly in resource-poor regions with a high HIV burden and limited treatment options. Multiple strategies are required to combat this public health challenge. In addition to expanding laboratory and clinical capacity in many of these countries, other efforts should focus on prevention of disease or the severe sequelae associated with this disease. n
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7. Dromer F, Mathoulin-Pélissier S, Fontanet A, et al., Epidemiology of HIV-associated cryptococcosis in France (1985-2001): comparison of the pre- and post-HAART eras. AIDS, 2004;18(3):555–62.
8. Kaplan JE, Hanson D, Dworkin MS, et al., Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy, Clin Infect Dis, 2000;30 (Suppl. 1):S5–14.
9. van Elden LJ, Walenkamp AM, Lipovsky MM, et al., Declining number of patients with cryptococcosis in the Netherlands in the era of highly active antiretroviral therapy, AIDS, 2000;14(17):2787–8.
10. Békondi C, Bernede C, Passone N, et al., Primary and opportunistic pathogens associated with meningitis in adults in Bangui, Central African Republic, in relation to human immunodeficiency virus serostatus, Int J Infect Dis, 2006;10(5):387–95.
11. Bogaerts J, Rouvroy D, Taelman H, et al., AIDS-associated cryptococcal meningitis in Rwanda (1983-1992): epidemiologic
and diagnostic features, J Infect, 1999;39(1):32–7.
12. Gordon SB, Walsh AL, Chaponda M, et al., Bacterial meningitis in Malawian adults: pneumococcal disease is common, severe, and seasonal. Clin Infect Dis, 2000;31(1):53–7.
13. Helbok R, Pongpakdee S, Yenjun S, et al., Chronic meningitis in Thailand. Clinical characteristics, laboratory data and outcome in patients with specific reference to tuberculosis and cryptococcosis, Neuroepidemiology, 2006;26(1):37–44.
14. Heyderman RS, Gangaidzo IT, Hakim JG, et al., Cryptococcal meningitis in human immunodeficiency virus-infected patients in Harare, Zimbabwe, Clin Infect Dis, 1998;26(2):284–9.
15. Hovette P, Soko TO, Raphenon G, et al., Cryptococcal meningitis in AIDS patients: an emerging opportunistic infection in Senegal, Trans R Soc Trop Med Hyg, 1999;93(4):368.
16. Aberg JA, Powderly WG, Cryptococcosis, Adv Pharmacol, 1997;37:215–51.
17. Bartlett KH, Kidd SE, Kronstad JW, The emergence of Cryptococcus gattii in British Columbia and the Pacific Northwest, Curr Infect Dis Rep, 2008;10(1):58–65.
18. CDC, Emergence of Cryptococcus gattii-- Pacific Northwest,
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