Utility of Cerebrospinal Fluid Protein Levels as a Potential Predictive Biomarker of Disease Severity in HIV-Associated Cryptococcal Meningitis.

Background:Cerebrospinal fluid (CSF) protein levels exhibit high variability in HIV-associated cryptococcal meningitis from being normal to markedly elevated. However, the clinical implications of CSF protein levels in cryptococcal meningitis remain unclear. Methods:We analysed data from 890 adults with HIV-associated cryptococcal meningitis randomized into two clinical trials in Uganda between 2015 and 2021. CSF protein was grouped into ≥100 mg/dL (n=249) and <100 mg/dL (n=641). We described baseline clinical variables and mortality by CSF protein levels. Results:Approximately one-third of individuals had a baseline CSF protein ≥100 mg/dL. Those with CSF protein ≥100 mg/dL were more likely to present with Glasgow coma scale scores <15 (P<0.01), self-reported seizures at baseline (P=0.02), higher CD4 T-cells (p<0.001), and higher CSF white cells (p<0.001). Moreover, those with a baseline CSF protein ≥100 mg/dL also had a lower baseline CSF fungal burden (p<0.001) and a higher percentage of sterile CSF cultures at day 14 (p=0.02). Individuals with CSF protein ≥100 mg/dL demonstrated a more pronounced immune response consisting of upregulation of immune effector molecules pro-inflammatory cytokines, type-1 T-helper cell cytokines, type-3 chemokines, and immune-exhaustion marker (p<0.05). 18-week mortality risk in individuals with a CSF protein <100 mg/dL was 34% higher, (unadjusted Hazard Ratio 1.34; 95% CI, 1.05 to 1.70; p=0.02) than those with ≥100 mg/dL. Conclusion:In cryptococcal meningitis, individuals with CSF protein ≥100 mg/dL more frequently presented with seizures, altered mental status, immune activation, and favourable fungal outcomes. Baseline CSF protein levels may serve as a surrogate marker of immune activation and prognosis.