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

Abstract

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.

Keywords: Mycobacterium tuberculosis; delayed diagnosis; diagnostic techniques and procedures; opportunistic infection; tuberculosis meningitis.

Fig. 1.

Diagnostic framework for TB meningitis. The figure displays a modified damage response framework. Right to left shows increased immune response and thus decreased organism burden (requiring more sensitive, bacilli-based detection methods for diagnosis). At the extremes of immune response, poor clinical outcomes occur.

Fig. 2.

Venn diagram describing current TB meningitis diagnosis as related to bacillary burden and immune response. The figure shows increasing bacillary burden from right to left, reflective of an absent or dysfunctional immune response. From left to right, the response is more likely to be functional (Th1), thus, increasing levels of inflammation and lower organism burdens are seen. The dark circle on the left represents cases of TB meningitis able to be detected using microbiologic/molecular methods – higher bacillary burdens. The white circle represents cases that are more difficult to detect currently, with less bacillary burden and more inflammation. These cases may potentially be detectable by immunology-based diagnostic tests.