CSF Hypo-Inflammation Drives Mortality in HIV-Associated Tuberculous Meningitis

Abstract

Background: Outcomes in tuberculous meningitis (TBM) are closely linked to host inflammation. Anti-inflammatory corticosteroid therapy improves survival in HIV-negative TBM, but not in people with HIV. In people with HIV, TBM is fatal in 40-50% of cases. Therefore, we investigated how mortality is associated with the local immune response in people with HIV-associated TBM.

Methods: We measured baseline concentrations of immune signalling mediators in cerebrospinal fluid (CSF) of 149 adults with HIV in Uganda, who presented with definite or probable TBM. Participants received both antimycobacterial and corticosteroid therapy.

Results: At baseline, non-survivors had more severe TBM disease and lower blood CD4 T cells than survivors. Mortality at 90 days was strongly associated with CSF hypo-inflammation. CSF interferon gamma (IFN-γ) was most differentially expressed by survivors (2.2 log2-fold change higher, p=.003), and 90-day mortality was lower with increasing concentrations (Tertile-1=50%, Tertile-2=41%, Tertile-3=18%; p=.006). Even among people who successfully mounted a CSF cellular immune response (>5 white cells/μL CSF), those with low CSF IFN-γ had higher risk of death (Hazard Ratio =3.10 (1.44-6.68). Interleukin-13 had a more complex relationship, with lower mortality among people with intermediate CSF interleukin-13 concentrations but higher at the two extremes (Tertile-1=45%, Tertile-2=22%, Tertile-3=40%; p=.017). Of all sub-groups, those with both peripheral CD4 depletion and low CSF IFN-γ had the highest mortality (63%).

Conclusions: In adults with HIV-associated TBM receiving dexamethasone, mortality was strongly associated with CSF hypo-inflammation. Although steroids may be appropriate in those with high inflammation, personalized approaches to immunotherapy are likely necessary to improve outcomes.

Keywords: HIV; Tuberculosis; cerebrospinal fluid; cytokines; inflammation; tuberculous meningitis.