Central Inflammatory Cytokines in Tuberculous Meningitis: A Systematic Review and Meta-analysis

No formal agreement exists regarding central inflammatory cytokine aberrations in tuberculosis (TB). We undertook a systematic review and meta-analysis of studies comparing cytokine levels in cerebrospinal fluid (CSF) from patients with TB compared with controls. We searched PubMed, Scopus, and Web of Science for articles published up to June 22, 2021. Studies were included in the meta-analysis if they assessed unadjusted levels of cytokines in unstimulated CSF samples and drew the comparison(s) between any of the following pairs: patients with TB versus controls without central nervous system (CNS) infection and meningitis, patients with TB versus patients with meningitis of etiologies other than Mycobacterium tuberculosis, HIV-infected patients with TB versus HIV-uninfected patients with TB, and HIV-infected patients with TB versus HIV-infected patients without TB. The primary outcome was the difference in mean CSF inflammatory cytokine levels between each of the 2 groups mentioned. The standardized mean difference was chosen to measure effect using a restricted maximum-likelihood estimator random-effects model. Of 1170 records identified, 40 studies were included in the meta-analysis. We calculated effect sizes for 30 different cytokines. About half of the studies took place in South Africa and India (18 out of 40 studies). Studies were mostly (92.5%) on patients with tuberculous meningitis (TBM), with only 3 articles of patients with neurotuberculosis and spinal TB. The quality of studies was rated as low to moderate and high with a 1.2:1 ratio. Compared with controls without CNS infection and meningitis, interferon-gamma (IFNγ), interleukin (IL)-12p40, IL-17F, IL-1β, IL-2, IL-4, IL-6, IL-8, sIL-2R, transforming growth factor beta (TGFβ), TGFβ1, and tumor necrosis factor alpha (TNFα) were increased in patients with TBM. Compared with patients with meningitis of etiologies other than M. tuberculosis or combined meningitis and nonmeningitis patients, patients with TBM had higher CSF concentrations of IFNγ, IL-13, and sIL-2R, whereas levels of IL-12p70, IL-15, IL-1Ra, IL-5, IL-7, IL-9, and sTNFR55 were decreased. Compared with patients with meningitis of bacterial etiologies other than M. tuberculosis, CSF levels of IFNγ and sIL-2R were increased in patients with TBM, whereas levels of IL-1Ra, IL-13, IL-17, and TNF R55-BP were decreased. Patients with TBM were not different from patients with CM for most CSF cytokines assessed, but IFNγ and IL-1β were increased. TNFα, IL-1β, IL-1Ra, IL-8, IFNγ, sIL-2R, IL-13, and IL-17 were higher in patients with TBM than those with viral or aseptic meningitis. Compared with HIV-negative patients with TBM, IFNγ, IL-10, IL-12p70, and IL-5 were decreased in HIV-positive patients with TBM, whereas IL-1β, TNFα, and IL-2 were increased. Elevated TNFα, IL-1β, IFNγ, IL-6, IL-17, and IFNα2 were found in HIV-positive patients with TBM compared with their counterparts without TBM. This study should be considered an explorative meta-analytic review, leading us to offer the best TBM-associated central inflammatory cytokines. Our study could prepare a panel of central cytokines as a potential aid in diagnosing TBM and its differentiation from meningitis of other etiologies.