Symptomatic cryptococcal antigenemia presenting as early cryptococcal meningitis with negative CSF analysis

Background: Individuals with cryptococcal antigenemia are at high risk of developing cryptococcal meningitis if untreated. The progression and timing from asymptomatic infection to cryptococcal meningitis is unclear. We describe a sub-population of individuals with neurologic symptomatic cryptococcal antigenemia, but negative CSF studies. Methods: We evaluated 1201 HIV-seropositive individuals hospitalized with suspected meningitis in Kampala and Mbarara, Uganda. Baseline characteristics and clinical outcomes of participants with CNS-symptomatic cryptococcal antigenemia and negative CSF CrAg were compared to participants with confirmed CSF CrAg+ cryptococcal meningitis. Additional CSF testing included microscopy, fungal culture, bacterial culture, TB culture, multiplex FilmArray PCR (Biofire), and Xpert MTB/Rif (Cepheid). Results: We found 56% (671/1201) of participants had confirmed CSF CrAg+ cryptococcal meningitis, and 4% (54/1201) had neurologic symptomatic cryptococcal antigenemia with negative CSF CrAg. Of those with negative CSF CrAg, 9% (5/54) had Cryptococcus isolated on CSF culture (n=3) or PCR (n=2), and 11% (6/54) had confirmed tuberculous meningitis. CSF CrAg-negative patients had lower proportions with CSF pleocytosis (16% vs 26% with >=5 white cells/mcL) and CSF opening pressure >200mmH2O (16% vs 71%) compared with CSF CrAg+. No cases of bacterial or viral meningitis were detected by CSF PCR or culture. In-hospital mortality was similar between symptomatic cryptococcal antigenemia (32%) and cryptococcal meningitis (31%) (P=.91). Conclusions: Cryptococcal antigenemia with meningitis symptoms was the third most common meningitis etiology. We postulate this is early cryptococcal meningoencephalitis. Fluconazole monotherapy was suboptimal, despite Cryptococcus-negative CSF. Further studies are warranted to understand the clinical course and optimal management of this distinct entity.