Late Neurological Sequelae after Cryptococcal Meningitis

Abstract Despite the success of Cryptococcal Antigen (CrAg) screening and the Test and Treat policy in reducing the prevalence of cryptococcal meningitis, it remains a leading cause of death among people living with HIV, contributing to approximately 19% of HIV-related deaths globally. This burden is particularly high in Africa, where roughly 73% of individuals with cryptococcosis reside. HIV-associated cryptococcal meningitis is also the most common cause of opportunistic neuro-infections worldwide, with Africa accounting for over 70% of all global cases. While cryptococcal meningitis survivors may experience significant short-term impairment, the long-term impact of these impairments on functional and neurocognitive outcomes remains unclear. Additionally, the role of persistent cryptococcal antigenemia following meningitis treatment is unknown. It is possible that persistent cryptococcal antigen could contribute to chronic CNS inflammation, a well-established risk factor for neurocognitive disorders. This proposal aims to determine the prevalence and risk factors for persistent neurological deficits after cryptococcal meningitis. This research will lay the foundation for future clinical trials aimed at improving survival and minimizing neurocognitive sequelae from HIV-associated neuro-infections. The specific aims include: 1. To determine the prevalence of sustained neurocognitive impairment by Quantitative Neurocognitive Performance Z-score (QNPZ-8) among survivors of HIV-associated cryptococcal meningitis at ≥1 year. 2. To identify clinical and immunologic risk factors for neurocognitive impairment in survivors of HIV- associated cryptococcal meningitis at ≥1 year. A new cohort will be recruited by re-consenting 200 survivors of cryptococcal meningitis who have previously participated in clinical trials or prospective cohorts in Uganda. Neurocognitive testing will have already been performed at 12 weeks in these participants. We will focus on re-consenting participants to collect annual neurocognitive outcome data thereafter. Biomarker immune profiling will be analyzed to determine whether chronic inflammation is a risk factor for poor neurocognitive outcomes and is associated with persistent cryptococcal antigenemia. Finally, we will compare neurocognitive outcomes between participants with persistently elevated cryptococcal antigenemia and those with low or undetected levels. This novel investigation into late neurocognitive outcomes, chronic inflammation, and persistent antigenemia will address major gaps in our understanding of the complications associated with meningitis.