Cryptococcal Meningitis – Global Public Health Challenges and Opportunities
a retrospective study of 2,125 cases of cryptococcosis in 135 French cities between 1985–2001, 17 % were not HIV-infected; cryptococcal meningitis was diagnosed in 51 % of the HIV-negative patients.7
Studies conducted in Shanghai reported that 72–76 % of cryptococcal meningitis occurred in apparently healthy patients;58
were immunocompetent.59–61 HIV-infected
The vast majority of disease caused by Cryptococcus neoformans is found in persons with advanced HIV-infection and varies geographically according to the burden of AIDS. As a result, the epidemiology of cryptococcosis among the HIV-infected population has seen a number of changes in the past several decades, concomitant with the introduction of ART.
Introduction of ART has led to a decline in the incidence of AIDS-associated cryptococcal meningitis in economically-developed countries. A population-based surveillance study conducted in Atlanta, Georgia and Houston, Texas during 1992–2000 observed a decline of HIV-associated cryptococcosis from 6.6 to 0.7 % in Atlanta and 2.4 to 0.2 % in Houston.3
The EuroSIDA Cohort conducted from
1994–2002 followed 9,803 persons with HIV/AIDS in 70 centres across Europe and documented a remarkable decrease in cryptococcal disease post-ART:62
from 1 % in 1995 to 0.1 % in 2001. Another study conducted in France documented a 46 % decrease in cryptococcosis cases in the post-ART era between 1997–2001 compared to the pre-ART era between 1985–1996.7
In economically developed countries,
cryptococcal meningitis is now primarily diagnosed in patients who have limited access to health care.3,7
In contrast, the burden of cryptococcal meningitis in less economically developed regions such as sub-Saharan Africa and southeast Asia remains elevated,63,64
Cryptococcal meningitis can also occur in the absence of underlying disease. In fact, in some areas, non-HIV associated cryptococcal meningitis may be more commonly observed in non-immunocompromised individuals. In one Ho Chi Minh City, Vietnam hospital, a prospective study determined that an underlying disease was absent in 81 % of non-HIV associated cryptococcal meningitis cases.57
in Taiwan, 79.7 % of persons with this disease
conducted by the South African National Institute for Communicable Diseases, suggests that cryptococcal meningitis incidence rates have actually increased in South Africa since the introduction of ART, possibly due to increasing numbers of persons with AIDS in South Africa.68
In a survey of over 100,000 persons with AIDS Studies in Vietnam and Cambodia indicate
In India, 3.1–9.4 million people are infected with HIV;69 1.7 to 4.7 % of this population is co-infected with Cryptococcus neoformans/gattii.70,71
in Thailand, almost 20 % had cryptococcal meningitis as their AIDS-defining illness.72
similarly high rates of cryptococcal meningitis.73–75
Likewise, case-fatality is also much higher in developing countries, likely due to the limited capability to manage complications of cryptococcal meningitis and poorer access to antifungal medications. AIDS-related cryptococcal mortality has been documented as <10 % in developed countries, and 36–54 % mortality in less economically developed countries.19,36,76
In sub-Saharan Africa, cohort studies have
shown that 13 to 44 % of deaths among persons with HIV/AIDS are due to cryptococcal disease.77–80
In one study of 230 AIDS patients
conducted in Lusaka, Zambia (1998), the mortality was 100 %, despite receipt of antifungal medications.81
Based on case-fatality rates from published clinical trials, case-series, surveillance reports, and studies on outcomes of cryptococcal meningitis, global burden of disease calculations estimated a total of 625,000 deaths/year, 500,000 of which occur in sub-Saharan Africa.65 These numbers indicate that cryptococcal meningitis is one of the main causes of mortality in HIV-infected individuals and may be more common than deaths due to infections such as tuberculosis. This is not surprising, especially given that treatment is resource-intensive, requiring frequent lumbar punctures to manage increased intracranial pressure and long-term secondary prophylaxis.
Public Health Challenges Laboratory Capacity
since these regions continue to have the
largest AIDS populations amidst limited (but increasing) access to ART. Estimation of the global burden of cryptococcal meningitis approximates 958,000 cases/year (range, 371, 700–1,544,000).65 The most afflicted geographical region is sub-Saharan Africa, with an estimated 720,000 cases/year, followed by South and Southeast Asia at 120,000 cases/year, and Latin America, at 54,400 cases/year. North America is estimated to have a yearly burden of 7,800 cases, while Western and Central Europe and Oceania were calculated to have the lowest burdens, at 500 cases/year and 100 cases/year respectively.
In sub-Saharan Africa alone, over 25,000,000 persons are infected with HIV. Cryptococcal meningitis is now the leading cause of meningitis in most areas of sub-Saharan Africa, accounting for up to 45 % of meningitis cases; cryptococcal meningitis is more common than meningitis due to either S. pneumoniae or N. meningitis.2,10–12,14,15,66 Incidence of cryptococcal disease has ranged from 1.4 to 12.2 %, but may be underestimated due to poor access to healthcare and unrecognised disease.63,67
Data from one surveillance network, EUROPEAN INFECTIOUS DISEASE
Currently, many of the countries with the highest burden of infection do not have laboratory capacity to reliably detect Cryptococcus neoformans/gattii. Some facilities may be poorly equipped and staffed by minimally trained individuals. Through the President’s Emergency Plan for AIDS Relief (PEPFAR), public health agencies such as CDC, in partnership with non-governmental organisations such as the American Society for Microbiology and academic partners, have been expanding laboratory capacity. This partnership has started to facilitate diagnosis of cryptococcal meningitis by improving capacity for India ink staining and diagnosis by cryptococcal antigen latex agglutination testing at central and provincial hospitals, but help in many countries is still needed.
Access to Treatment
Treatment of cryptococcal meningitis is intensive; administration of antifungal drugs and ART is lengthy and management of elevated intracranial pressure is difficult, especially for resource-poor countries. Many recommended agents, such as amphotericin B and flucytosine, are not available in countries with insufficient public health and medical infrastructure. The regimen is expensive, amphotericin B is difficult to administer, and monitoring of renal function is required. Fluconazole is safe and effective at doses ≥800 mg/day, and is often the only antifungal medication available for many patients with cryptococcal meningitis, due to its low price, or free availability through the Pfizer Diflucan Partnership programme.82
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