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Randomized Controlled Trial
. 2009 Sep 30;4(9):e7277.
doi: 10.1371/journal.pone.0007277.

Dexamethasone, cerebrospinal fluid matrix metalloproteinase concentrations and clinical outcomes in tuberculous meningitis

Justin A Green  1 , Chau T H Tran, Jeremy J Farrar, Mai T H Nguyen, Phu H Nguyen, Sinh X Dinh, Nghia D T Ho, Chuong V Ly, Hien T Tran, Jon S Friedland, Guy E Thwaites
Affiliations
Randomized Controlled Trial

Dexamethasone, cerebrospinal fluid matrix metalloproteinase concentrations and clinical outcomes in tuberculous meningitis

Justin A Green et al. PLoS One. .

Abstract

Background: Adjunctive dexamethasone reduces mortality from tuberculous meningitis, but how it produces this effect is not known. Matrix metalloproteinases (MMPs) are important in the immunopathology of many inflammatory CNS diseases thus we hypothesized that that their secretion is important in TBM and might be influenced by dexamethasone.

Methodology/principal findings: The kinetics of cerebrospinal fluid (CSF) MMP and tissue inhibitors of MMPs (TIMPs) concentrations were studied in a subset of HIV uninfected adults (n = 37) with TBM recruited to a randomized, placebo-controlled trial of adjuvant dexamethasone. Analysis followed a pre-defined plan. Dexamethasone significantly reduced CSF MMP-9 concentrations in early follow up samples (median 5 days (range 3-8) of treatment), but had no significant influence on other MMPs/TIMPs. Additionally CSF MMP-9 concentration was strongly correlated to concomitant CSF neutrophil count.

Conclusions/significance: Dexamethasone decreased CSF MMP-9 concentrations early in treatment and this may represent one mechanism by which corticosteroids improve outcome in TBM. The strong correlation between CSF MMP-9 and neutrophil count suggests that polymorphonuclear leukocytes may play a central role in the early pathogenesis of TBM.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Dexamethasone reduces CSF MMP-9 concentrations in early follow up samples.
Paired CSF samples from patients with tuberculous meningitis were taken pre-treatment and at early follow up, a median 5 days (range 3–8) into anti-tuberculosis therapy, and analyzed for MMP-1, -2, -3, -7, -8, -9 & -10 concentration by ELISA (MMP-6, -7 & -8 do not exist). Patients who received placebo (light grey bars, n = 11) had significantly higher MMP-9 concentrations in their early follow-up CSF samples than those who received dexamethasone (dark grey bars, n = 11). *, p = 0.01. The black line represents the median value and the box the interquartile range. Whiskers represent 1.5 times the interquartile range away from the box.
Figure 2
Figure 2. CSF TIMP concentrations in early follow up samples are not affected by dexamethasone.
Paired CSF samples from patients with tuberculous meningitis were taken pre-treatment and at early follow up, a median 5 days (range 3–8) into anti-tuberculosis therapy, and analyzed for TIMP-1, -2, & -4 concentrations by ELISA. The black line represents the median value and the box the interquartile range. Whiskers represent 1.5 times the interquartile range away from the box.
Figure 3
Figure 3. CSF MMP-9 concentration and CSF neutrophil count are significantly correlated in early follow up samples.
Early follow-up CSF samples, taken a median of 5 days (range 3–8, n = 29) into anti-tuberculosis treatment, from patients with tuberculous meningitis were analyzed for correlation between absolute neutrophil count and MMP-9 concentration (measured by ELISA). The R2 value for the correlation was 0.52 (p<0.001). Patients who received placebo are represented by light grey circles and dexamethasone by dark grey circles.
See this image and copyright information in PMC

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