Presentation and outcome of tuberculous meningitis in a high HIV prevalence setting

Abstract

Background: Mycobacterium tuberculosis is a common, devastating cause of meningitis in HIV-infected persons. Due to international rollout programs, access to antiretroviral therapy (ART) is increasing globally. Starting patients with HIV-associated tuberculous meningitis (TBM) on ART during tuberculosis (TB) treatment may increase survival in these patients. We undertook this study to describe causes of meningitis at a secondary-level hospital in a high HIV/TB co-infection setting and to determine predictors of mortality in patients with TBM.

Methods: A retrospective review of cerebrospinal fluid findings and clinical records over a six-month period (March 2009-August 2009). Definite, probable and possible TBM were diagnosed according to published case definitions.

Results: TBM was diagnosed in 120/211 patients (57%) with meningitis. In 106 HIV-infected patients with TBM, six-month all-cause mortality was lower in those who received antiretroviral therapy (ART) during TB treatment; hazard ratio = 0.30 (95% CI = 0.08-0.82). Factors associated with inpatient mortality in HIV-infected patients were 1) low CD4(+) count at presentation; adjusted odds ratio (AOR) = 1.4 (95% confidence interval [CI] = 1.03-1.96) per 50 cells/µL drop in CD4(+) count and, 2) higher British Medical Research Council TBM disease grade (2 or 3 versus 1); AOR = 4.8 (95% CI = 1.45-15.87).

Interpretation: Starting ART prior to or during TB treatment may be associated with lower mortality in patients with HIV-associated TBM. Advanced HIV and worse stage of TBM disease predict in-hospital mortality in patients presenting with TBM.

Figure 1. Flow diagram of differential diagnoses in patients with ‘markedly abnormal’ CSF and/or microbiological-confirmed meningitis.

¹ Common alternative diagnoses include: hypoglycemia (n = 9), intracranial bleed (n = 7) and peripheral nerve disorders (n = 6). ² Including 5 patients with CSF culture-confirmed bacterial meningitis. Organisms isolated include: Streptococcus pneumonia (n = 3), beta-hemolytic Streptococcus (n = 1), Neisseria meningitides (n = 1). ³ Including 1 patient with positive CSF polymerase chain reaction for both cytomegalovirus and herpes simplex-1 virus. ⁴ Other causes of meningitis include: Acute HIV infection (n = 1), Toxoplasma gondii meningoencephalitis (n = 1), disseminated Burkitt's lymphoma (n = 1), disseminated large B-cell lymphoma (n = 1), chronic resolving TBM immune reconstitution inflammatory syndrome (n = 1). ⁵ Including patients with the following differential diagnoses: 1) TBM with tuberculoma or toxoplasmosis (n = 1); 2) partially treated bacterial meningitis, viral meningitis or TBM (n = 3); and 3) viral meningitis or TBM (n = 3). CSF, cerebrospinal fluid.

Figure 2. Kaplan-Meier survival curves of patients with definite, probable and possible tuberculous meningitis (TBM).

Survival probability at 6-months was similar between patients with definite TBM and those with probable TBM (log-rank test p = 0.69), and possible TBM (log-rank test p = 0.15).

Figure 3. Cox proportional hazard model survival curves.

ART: HIV-infected tuberculous meningitis (TBM) patients either on antiretroviral therapy (ART) at TBM presentation or started on ART during subsequent 6 months of antituberculosis (TB) treatment (n = 43). No ART: HIV-infected TBM patients not on ART at presentation nor started on ART during subsequent 6 months of TB treatment (n = 23). The model only included patients who survived hospitalization (n = 66). Hazard ratio for patients on ART = 0.30 (95% confidence interval 0.08–0.82, p-value = 0.03).