2.1.1. Background

Early diagnosis and treatment of cryptococcal meningitis is key to reducing mortality from cryptococcal disease. Health-care professionals should have a low threshold for suspecting cryptococcal meningitis among people with advanced HIV disease. National programmes should give priority to reliable access to rapid diagnostic cryptococcal antigen assays, preferably lateral flow assays, for use in cerebrospinal fluid (CSF), serum, plasma or whole blood. In addition, health-care professionals need to have a low threshold for suspecting cryptococcal meningitis.

2.1.2. Rationale for the recommendations

Rapid cryptococcal antigen assay in CSF, serum, plasma or whole blood (depending on access to lumbar puncture) is preferred based on the much higher diagnostic accuracy of these rapid cryptococcal antigen assays versus the India ink test and the fact that these rapid assays depend less on the health-care provider’s skills. Advantages of the lateral-flow assay over the latex agglutination assay include its rapid (<10 minutes) turnaround time, cost–effectiveness, minimal training requirements and laboratory infrastructure, no need for refrigerated storage and higher clinical and analytical sensitivity.

A serum, plasma or whole-blood cryptococcal antigen test is recommended as an initial diagnostic option in settings in which access to lumbar puncture is limited or contraindicated. The use of serum, plasma or whole-blood cryptococcal antigen diagnosis does not replace the need for lumbar puncture with CSF examination where this is feasible, considering also the important survival benefit of facilitating control of intracranial pressure (17).

In low- and middle-income countries, the use of rapid low-cost assays that rely on limited technical skills and laboratory infrastructure facilitates prompt diagnosis and initiation of antifungal therapy. A low index of suspicion is needed for cryptococcal meningitis in regions with moderate to high HIV prevalence.

Limited data from retrospective cohorts suggest that diagnostic performance among children is similar to that of adults (18,19). The recommendations for adults have therefore been extended to children.

2.2.1. Background

Early diagnosis and initiation of antiretroviral therapy remains the most important preventive strategy to reduce the incidence of cryptococcal disease among people living with HIV and the associated high mortality.¹ Screening for cryptococcal antigenaemia is the optimal approach for guiding resources in a public health approach and is the preferred approach for identifying infection when managing people aged 10 years or older presenting with advanced HIV disease (20). There remains a role for fluconazole primary prophylaxis in settings in which cryptococcal antigen screening is not available.

2.2.2. Rationale for the recommendations

Since 2018, WHO guidelines have recommended that all adults and adolescents living with HIV who have a CD4 cell count <100 cells/mm³ be screened for cryptococcal antigen before ART initiation or reinitiation; cryptococcal antigen screening may also be considered for adults and adolescents living with HIV who have a CD4 cell count <200 cells/mm³. These recommendations were supported by evidence favouring the clinical benefit and cost–effectiveness of cryptococcal antigen screening (20,22,24–30). All individuals screening positive for cryptococcal antigen should be given pre-emptive antifungal therapy (fluconazole 800–1200 mg/day for adults and 12 mg/kg per day for adolescents for two weeks), followed by consolidation and maintenance fluconazole therapy, as for treatment. The 2019 guidelines from the Southern African HIV Clinicians Society recommend 1200 mg for first 2 weeks given safety and concerns over breakthrough infection (21).

Everyone testing positive for serum, plasma or whole-blood cryptococcal antigen during screening should be carefully evaluated for signs and symptoms of meningitis. Everyone with signs or symptoms of meningitis should have lumbar puncture and, where feasible, those without signs or symptoms of meningitis should also have lumbar puncture, with CSF examination and cryptococcal antigen assay (or India ink if cryptococcal antigen assay is not available) to exclude cryptococcal meningitis.

These recommendations would apply equally to people who present to care again after a period of disengagement from care with advanced HIV disease.

Cryptococcal antigen screening followed by pre-emptive therapy is preferred over providing fluconazole primary prophylaxis after considering cost, the potential for developing antifungal resistance and concerns about fetal safety among women of childbearing age without access to adequate contraception. Fluconazole primary prophylaxis should be made available in settings in which cryptococcal antigen screening is not available or there may be prolonged delays in receiving the result since cryptococcal disease and mortality peak in the first four weeks among people presenting with a CD4 cell count <100 cells/mm³ (31).

This recommendation is based on a systematic review that found a 70% reduction in mortality from cryptococcal disease among people living with HIV with low CD4 cell counts (95% confidence interval (CI) 12–89%); the review also found a 71% reduction in cryptococcal disease incidence; the incidence of serious adverse events did not differ, but some evidence indicated an increased risk of fluconazole-resistant Candida infection (23).

National guidelines should determine the optimal duration of prophylaxis based on available resources. Duration of fluconazole primary prophylaxis differed in the randomized trials that support the clinical benefit of this intervention. In the REALITY trial conducted in Kenya, Malawi, Uganda and Zimbabwe, fluconazole (100 mg once daily) was discontinued after 12 weeks (31). In another trial conducted in Uganda in the era of ART, fluconazole (200 mg three times per week) was discontinued when participants’ CD4 cell counts reached 200 cells/mm³ (32).

2.2.3. Recommendations for children

These recommendations apply to adults and adolescents with advanced HIV disease. The decision not to extend these recommendations to children was based on the recognition that cryptococcal disease in this age group is rare, even in countries with high incidence (4,10).