Inadequate diagnostics: the case to move beyond the bacilli for detection of meningitis due to Mycobacterium tuberculosis.

Tuberculosis (TB) meningitis is extremely difficult to diagnose due to its pauci-bacillary disease nature and new techniques are needed. Improved test sensitivity would allow for greater clinician confidence in diagnostic testing and has the potential to improve patient outcomes. Traditional microbiologic and molecular tests for TB meningitis focus on detection of TB bacilli and are inadequate. Smear microscopy is rapid but only ~10-15  % sensitive. Culture has 50-60  % sensitivity but is slow. Xpert MTB/Rif Ultra is a rapid, automated PCR-based assay with ~70  % sensitivity versus clinical case definition. Thus, even the best current testing may miss up to 30  % of cases. Clinicians are often left to treat empirically with prolonged regimens with significant side effects or risk a missed case that would result in death. Rather than relying strictly on microbiologic or molecular testing to diagnose TB meningitis, we propose that testing of CSF for biomarkers of host response may have an adjunctive role to play in improving the diagnosis of TB meningitis.