Symptomatic Cryptococcal Antigenemia Presenting as Early Cryptococcal Meningitis With Negative Cerebral Spinal Fluid Analysis

Abstract

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 subpopulation of individuals with neurologic symptomatic cryptococcal antigenemia but negative cerebral spinal fluid (CSF) studies.

Methods: We evaluated 1201 human immunodeficiency virus-seropositive individuals hospitalized with suspected meningitis in Kampala and Mbarara, Uganda. Baseline characteristics and clinical outcomes of participants with neurologic-symptomatic cryptococcal antigenemia and negative CSF cryptococcal antigen (CrAg) were compared to participants with confirmed CSF CrAg+ cryptococcal meningitis. Additional CSF testing included microscopy, fungal culture, bacterial culture, tuberculosis culture, multiplex FilmArray polymerase chain reaction (PCR; Biofire), and Xpert MTB/Rif.

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/μL) and CSF opening pressure >200 mmH2O (16% vs 71%) compared with CSF CrAg-positive patients. 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.

Clinical trials registration: NCT01802385.

Keywords: HIV; aseptic meningitis; cryptococcal meningitis; diagnosis; fungal antigen.

Figure 1.

Study population: 1201 individuals with suspected meningitis were screened with a blood cryptococcal antigen (CrAg) test. Overall, 40% (476/1201) were CrAg negative in blood and excluded from this analysis, all of whom were also cerebral spinal fluid (CSF) CrAg negative. Overall, 671 individuals who were blood and CSF CrAg positive were diagnosed with cryptococcal meningitis. Of 574 with first-episode cryptococcal meningitis, 5 had tuberculous meningitis coinfection and were excluded from this analysis. Of the 54 blood CrAg positive and CSF CrAg negative, 3 were later diagnosed by CSF culture and 2 by polymerase chain reaction with cryptococcal meningitis, 6 were diagnosed with microbiologically confirmed tuberculous meningitis, and 43 had neurologic symptomatic cryptococcal antigenemia. Abbreviations: CrAg, cryptococcal antigen; CSF, cerebral spinal fluid; PCR, polymerase chain reaction; TB, tuberculosis; TBM, tuberculous meningitis.