Preventing deaths from cryptococcal meningitis: from bench to bedside

Abstract

Cryptococcal meningitis (CM), a fungal disease caused by Cryptococcus spp., is the most common form of meningitis and a leading cause of death among persons with HIV/AIDS in sub-Saharan Africa. Detection of cryptococcal antigen, which is present several weeks before overt signs of meningitis develop, provides an opportunity to detect infection early. Screening persons with HIV for cryptococcal infection when they access healthcare can identify asymptomatic infected patients allowing for prompt treatment and prevention of death. A newly developed point-of-care assay for cryptococcal antigen, as well as growing evidence supporting the utility and cost–effectiveness of screening, are further reasons to consider broad implementation of cryptococcal screening in countries with a high burden of cryptococcal disease.

Keywords::

• AIDS
• cryptococcus
• fluconazole
• HIV

Cryptococcal meningitis is a fungal disease caused by Cryptococcus spp., which are found in soil contaminated with bird droppings. The fungus is usually inhaled through the lungs and is believed to remain dormant for many years. Reactivation, which occurs primarily among immunosuppressed individuals such as persons with HIV/AIDS, leads to infection, the most common of which is meningitis. Despite appropriate therapy and antiretroviral treatment (ART), mortality from cryptococcal meningitis (CM) remains high (>50% in sub-Saharan Africa) [1]. Various strategies, including prophylaxis and targeted screening, have been proposed to decrease CM-related deaths. A newly developed cryptococcal antigen assay, clinical strategies to prevent CM-related death and cost–effectiveness of screening were discussed at the 8th International Conference on Cryptococcus and Cryptococcosis.

Point-of-care immunoassay for diagnosis of cryptococcosis in HIV/AIDS

This session was presented by Tom Kozel (University of Nevada, Reno, NV, USA) and Sean Bauman (Immuno Mycologics).

Cryptococcal diagnostics currently focus on antigen detection using latex agglutination (LA) or enzyme immunoassay (EIA), direct examination (via India Ink), or culture. The LA assay is a relatively simple test that affords high sensitivity and specificity, but its use in low-income countries may be limited by the need for laboratory infrastructure [2]. A new point-of-care immunochromatographic assay, known as a lateral-flow immunoassay (LFA), has been developed for diagnosis of cryptococcosis (Immuno Mycologics). The assay functions similarly to the traditional LA, where antigen from the fluid being tested binds to antibodies in the test strip; however, all the materials for the LFA are stable at room temperature and do not require any additional equipment. The LFA is as simple to read as a pregnancy test, with one band indicating a negative and two bands indicating a positive result. This dipstick assay is highly sensitive, inexpensive, rapid and can be performed by untrained personnel in a point-of-care setting [3]. Data were presented demonstrating that it was effective with cerebrospinal fluid and serum samples, and that it is being evaluated for use with urine, plasma, and whole blood. Preliminary data suggest close correlation with LA and EIA assays and greater sensitivity than these other methods [3]. The assay has received a CE mark approval for marketing in Europe and is currently under review by the US FDA.

The WHO developed the ASSURED criteria (affordable, sensitive, specific, user-friendly, rapid and robust, equipment fee, deliverable to end users) as a benchmark for successful development of diagnostics in all income and resource settings. The LFA meets these criteria and shows promise for use in countries with a high burden of persons with HIV/AIDS cryptococcosis.

Clinical strategies to prevent disease & death

This session was presented by Tom Harrison (St George’s University of London & the Desmond Tutu HIV Centre, London, UK).

Cryptococcal meningitis is the most common cause of meningitis in much of sub-Saharan Africa and is an important cause of early death among patients initiating ART [1,4–6]. The majority of patients (>70%) that develop CM have already presented to the healthcare system and received an HIV diagnosis [7]. Thus, a high proportion of CM deaths are potentially preventable by screening for cryptococcal antigen at entry into HIV programs and providing pre-emptive treatment before symptoms of meningitis develop. The presence of cryptococcal antigen in blood several weeks prior to the development of overt symptoms presents an important opportunity to identify persons with early or asymptomatic disease [8]. In a retrospective study conducted in Cape Town, South Africa, 707 stored plasma samples of HIV patients initiating ART were retrospectively tested for the cryptococcal antigen [9]. Approximately 13% of those with CD4⁺ T-cell levels <100 tested antigen positive, 29% of whom developed CM. Of the 661 who tested antigen-negative, none developed meningitis; demonstrating a high negative predictive value of the cryptococcal antigen test.

Another strategy that has been proposed to prevent CM deaths is primary prophylaxis of all persons with HIV and CD4⁺ T-cell levels of <100. However, if only 10% are antigen positive, this would lead to the unnecessary prophylaxis of the other 90% of the population. A targeted screening approach would minimize drug costs, adverse drug events and possible development of azole resistance, and would potentially be more cost effective.

While the merits of cryptococcal screening are evident, there are several key questions that still need to be answered to determine the optimal screening strategy [1]: to minimize time to treatment and loss to follow-up, should testing be done at the laboratory (as part of reflex CD4⁺ T-cell testing) or at the point of care [2]? Should lumbar puncture be offered to all asymptomatic antigen-positive patients, those whose antigen titer exceeds a specific cutoff value, or not be offered at all [3]? What is the optimal time to initiate ART after starting antifungal therapy [4]? What is the appropriate dose of fluconazole that should be administered as part of pre-emptive treatment? Current prospective research studies are being conducted to answer some of these questions. Meanwhile, available evidence supports integration of cryptococcal screening into national ART programs in sub-Saharan Africa.

Cost–effectiveness in prevention of cryptococcal disease: what makes sense in Africa?

This session was presented by David B Meya (Makerere University, Uganda).

Cost–effectiveness of the cryptococcal screening strategy has been evaluated in a prospective study conducted in Kampala, Uganda [10]. A total of 609 ART-naive patients were screened for cryptococcal antigen at an outpatient, hospital-based clinic. No clinic-wide protocol was established for management of antigen-positive patients and intervention was dependent on clinician discretion. Among patients who tested antigen-positive, fluconazole use was associated with survival. This remained statistically significant in multivariate modeling that included a CD4⁺ T-cell count. The number that needed to be screened to detect one antigen-positive patient was 11.3. To prevent one death, 15.9 people needed to be screened and treated. Cost per disability-adjusted life year was calculated at US$21. Analyzing cost of screening versus cost of amphotericin B treatment, the authors found that, at an antigenemia prevalence of >3%, screening was more cost-effective than amphotericin B treatment. This study provides evidence that screening is both cost-effective and affordable in resource-limited settings.

Expert commentary

Cryptococcal meningitis is a significant cause of morbidity and mortality among persons with HIV/AIDS. Cryptococcus spp. infect an estimated 1,000,000 people per year and results in approximately 625,000 deaths annually [1]. In many countries in sub-Saharan Africa, where HIV infects up to 20% of the population, Cryptococcus is the most common cause of meningitis and, in fact, is estimated to cause more deaths than TB [1]. Preventing these deaths needs to be a high priority for public health. Fortunately, recent data demonstrating that this infection can be detected before symptoms are severe, along with advances in diagnostic testing have brought together experts in public health and HIV treatment to develop a strategy for screening and early treatment. With the development of a new point-of-care assay that can detect Cryptococcus spp. and growing evidence to support the utility and cost–effectiveness of a cryptococcal screening strategy, we are in an ideal environment to integrate screening into national ART programs. These programs will prevent deaths in countries with a high burden of cryptococcal disease. While further research is needed to determine optimal treatment strategies and to address anticipated operational issues with widespread screening, this should not delay countries from pursuing a phased-in implementation strategy. This would allow countries to gain evidence by practice and begin saving lives. Use of the new point-of-care assay will dramatically alter the way in which CM is diagnosed. Since this conference occurred, the US FDA has approved the LFA for use in serum. Pending validation in whole blood and urine, the new LFA assay will broaden access to cryptococcal diagnostics in low-resource settings with a high HIV/AIDS burden.

Disclaimer

The findings and conclusions of this article are those of the authors and do not necessarily represent the official position of the CDC. The use of product names in this manuscript does not imply their endorsement by the US Department of Health and Human Services.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.