Cryptococcal meningitis remains one of the leading causes of death among HIV-infected adults in the fourth decade of HIV era in sub-Saharan Africa, contributing to 10%-20% of global HIV-related deaths. Despite widespread use and early induction of ART among HIV-infected adults, incidence of
cryptococcosis remains significant in those with advanced HIV disease. Cryptococcus species that causes fatal
infection follows systemic spread from initial environmental acquired
infection in lungs to antigenaemia and fungaemia in circulation prior to establishment of often fatal disease,
cryptococcal meningitis in the CNS. Cryptococcus person-to-person transmission is uncommon, and deaths related to blood
infection without CNS involvement are rare. Keen to the persistent high mortality associated with HIV-
cryptococcal meningitis,
seizures are common among a third of the patients, altered mental status is frequent, anaemia is prevalent with ensuing
brain hypoxia and at autopsy, brain
fibrosis and
infarction are evident. In addition, fungal burden is 3-to-4-fold higher in those with
seizures. And high immune activation together with exacerbated
inflammation and elevated PD-1/PD-L immune checkpoint expression is immunomodulated phenotypes elevated in CSF relative to blood. Lastly, though multiple Cryptococcus species cause disease in this setting, observations are mostly generalised to cryptococcal
infection/
meningitis or regional dominant species (C neoformans or gattii complex) that may limit our understanding of interspecies differences in
infection, progression, treatment or recovery outcome. Together, these factors and underlying mechanisms are hypotheses generating for research to find targets to prevent
infection or adequate
therapy to prevent persistent high mortality with current optimal
therapy.