Relationship between Intracranial Granulomas and Cerebrospinal Fluid Levels of Gamma Interferon and Interleukin-10 in Patients with Tuberculous Meningitis

Abstract

Cerebrospinal fluid gamma interferon (IFN-␥) and interleukin-10 levels in 39 patients with tuberculous meningitis were serially measured. Cytokine levels did not predict intracranial granuloma (IG) development, but IFN-␥ levels in the top quartile after 1 month of therapy were highly associated (odds ratio ‫؍‬ 18) with detection of an IG by computed tomography scanning.Cytokines such as gamma interferon (IFN-␥) and tumor necrosis factor alpha play a pivotal role in the development of granulomas in pulmonary tuberculosis (1,11,13). Similar mechanisms presumably mediate intracranial granuloma (IG) formation in patients with tuberculous meningitis (TBM), but as of yet, the relationship has not been well characterized. We therefore sought to determine whether IG formation could be predicted on the basis of cerebrospinal fluid levels of these two cytokines.Study patients were a subset of a TBM treatment trial conducted at the Abbassia Fever Hospital in Cairo, Egypt. For the treatment trial, patients received daily isoniazid (INH) (10 mg/kg of body weight/day; maximum, 300 mg/day), rifampin (20 mg/kg/day; maximum, 600 mg/day), pyrazinamide (40 mg/ kg/day; maximum, 1,000 mg), and streptomycin (15 mg/kg/day; maximum, 1,000 mg) for 2 months followed by daily INH and rifampin. Oral dexamethasone (0.4 mg/kg/day) was administered for the first month of therapy, and then the dosage was tapered over the next month.Inclusion in the present study required a pretreatment cerebrospinal fluid (CSF) culture positive for Mycobacteria tuberculosis plus an aliquot of CSF collected prior to initiation of antituberculous therapy and 1 month later. When available, CSF collected 6 months after initiation of therapy was also tested for cytokines. CSF IFN-␥ and interleukin-10 (IL-10) concentrations were determined at the University of Arkansas by use of enzyme-linked immunoassay kits (R and D Systems, Minneapolis, Minn.). The detection limits of the assays were 8 pg/ml for IFN-␥ and 4 pg/ml for IL-10. All samples were analyzed undiluted in duplicate according to the manufacturer's instructions and reanalyzed when variability between duplicates was greater than 20%, which occurred in Ͻ3% of the samples tested.Computed tomography (CT) brain scans, obtained prior to and after administration of urographin contrast material, were performed on all patients before initiation of antituberculous therapy and repeated 1 month and 6 months later with a Toshiba TCT 600 HQ CT scanner (Toshiba Company, Tokyo, Japan). A single experienced radiologist, blinded to the diagnosis of the patient, evaluated all CT scan results.Clinical characteristics and cytokine levels were compared between patients who did and did not develop IG after completing 1 month and 6 months of therapy. Differences in proportions of categorical variables were evaluated using chisquare or Fisher's exact test when expected cell values were lower than 5. Continuous variables were analyzed using either two-sample Wilcoxon rank-sum (Mann-Whitney) testing for unmatched data or Wilcoxon sign...

Overview of Brain-to-Gut Axis Exposed to Chronic CNS Bacterial Infection(s) and a Predictive Urinary Metabolic Profile of a Brain Infected by Mycobacterium tuberculosis

“…Lu et al also determined that in 10 of these TBM patients the average CSF IFN-γ levels were 500.48 pg/mL before treatment and 103.62 pg/mL following 4 weeks of treatment, indicating that while IFN-γ decreased significantly (5-fold), it still remained elevated compared to the norm, after 4 weeks of treatment (that is, inflammation in the brain persisted). Mansour et al (2005) reported a highly elevated mean concentration of CSF IFNγ (794 ± 530 pg/mL) in 39 patients with TBM (all of whom were HIV negative) prior to receiving medication, which was correlated with markers of neuroinflamation in these individuals. Mansour et al (2005) also showed that the CSF IFN-γ remained elevated for many weeks after treatment was begun in patients with TBM, whereas in those cases diagnosed with VM and BM the CSF IFN-γ returned to undetectable concentrations within a couple of days post-treatment.…”

“…Mansour et al (2005) reported a highly elevated mean concentration of CSF IFNγ (794 ± 530 pg/mL) in 39 patients with TBM (all of whom were HIV negative) prior to receiving medication, which was correlated with markers of neuroinflamation in these individuals. Mansour et al (2005) also showed that the CSF IFN-γ remained elevated for many weeks after treatment was begun in patients with TBM, whereas in those cases diagnosed with VM and BM the CSF IFN-γ returned to undetectable concentrations within a couple of days post-treatment. Considering all of the above, patients with VM and TBM exhibit a similar increase in CSF IFN-γ levels, both far greater than in patients with BM.…”

Stroke in tuberculous meningitis

“…CSF IL6 concentration at the time of presentation was independently associated with severity of disease [49]. Levels of IFNγ and IL10 did not predict the development of intracranial granuloma in TBM [50]. In a recent study IL1β, IL6, IL8 and IL10 were expressed in the initial stage of TBM and declined significantly with therapy but were not related to the stage of meningitis and its outcome [51].…”

Worsening CSF parameters after the start of anti-tuberculosis treatment predicts intracerebral tuberculoma development

“…The mechanism behind the progression or development of intracranial tuberculomas after treatment remains a subject of speculation. It has been reported that the paradoxical tuberculomas were attributable to several factors such as exaggerated immune responses occurring on ATT, the virulence of the tubercle bacilli, the site of infection, the antigen load, hypersensitivity to tuberculosis, and chemotherapeutic regimen (Afghani and Lieberman, 1994;Ranjan et al, 2003;Cheng et al, 2003;Unal and Sutlas, 2005;Gupta et al, 2003;Mansour et al, 2005;Davis and Ramakrishnan, 2009). A therapy-induced transient worsening of cerebrospinal fluid (CSF) parameters is also frequently observed during treatment, such as an initial lymphocytic reaction may change in the direction of neutrophil predominance (Singh et al, 2016;Sutlas et al, 2003;Tai et al, 2016;Cheng et al, 2003;Garcia-Monco et al, 2005;Teoh et al, 1986).…”