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Utility of Cerebrospinal Fluid Protein Levels as a Potential Predictive Biomarker of Disease Severity in
John Kasibante1, Eesha Irfanullah2, Abduljewad Wele2
1Infectious Diseases Institute, College of health sciences, Makerere University. P.O. Box 22418, Kampala, Uganda.
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.
Insights
Elevated cerebrospinal fluid (CSF) protein in HIV-associated cryptococcal meningitis indicates immune activation and better fungal outcomes. Lower CSF protein levels correlate with increased mortality risk.
Area of Science:
- Infectious Diseases
- Neuroscience
- Immunology
Background:
- HIV-associated cryptococcal meningitis presents with highly variable cerebrospinal fluid (CSF) protein levels.
- The clinical significance of these protein level variations in cryptococcal meningitis remains largely undetermined.
Approach:
- Analysis of data from 890 adults with HIV-associated cryptococcal meningitis from two clinical trials in Uganda (2015-2021).
- CSF protein levels were categorized as ≥100 mg/dL and <100 mg/dL.
- Baseline clinical variables, fungal burden, and 18-week mortality were compared between groups.
Key Points:
- Individuals with CSF protein ≥100 mg/dL were more likely to have seizures, altered mental status, higher CD4 T-cells, and elevated CSF white cells.
- Higher CSF protein was associated with lower fungal burden and higher rates of sterile CSF cultures at day 14.
- A pronounced immune response, including pro-inflammatory cytokines and immune-exhaustion markers, was observed in the higher protein group.
Conclusions:
- CSF protein levels ≥100 mg/dL are linked to increased immune activation and favorable fungal clearance in cryptococcal meningitis.
- Baseline CSF protein may serve as a prognostic biomarker for immune status and clinical outcomes.
