Diagnostic value of cytokine measurement in cerebrospinal fluid in children with central nervous system tuberculosis.

Abstract

To the Editor. The prevalence of tuberculous meningitis (TBM) in developing countries remains high in developing areas of the world, and recently increased in developed countries.1 Distinguishing TBM from other causes of bacterial meningitis is a frequent clinical problem. The inflammatory response and the production of cytokines in the cerebrospinal fluid (CSF) of patients with purulent bacterial meningitis are well-documented.2 Conversely, little is known about the production of proinflammatory cytokines in the CSF during the course of TBM. The purpose of this study was to estimate the diagnostic value of CSF tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-8 levels during the course of TBM in children.The levels of TNF-α, IL-6, and IL-8 in CSF were analyzed in 37 cases with highly probable TBM according to Doer et al's3criteria admitted to the Unit of Pediatric Infectious Diseases of Dicle University Hospital, Diyarbakir, Turkey, from July 1998 through February 1999, and 13 control subjects with noninfectious neurologic diseases, including epilepsy and cerebrovascular disease. The ages of patients ranged from 8 months to 10 years (mean: 3.7 years) in the TBM group (21 boys, 16 girls) and 10 months to 12 years (mean: 4.1 years) in the control group (8 boys, 5 girls). Of 37 patients (21 boys, 16 girls) with TBM, 16 were in stage II and 21 in stage III. The duration of symptoms before admission varied from 9 to 63 days (average 25 days). Fever (94%), vomiting (83%), unconscious (78%), neck stiffness (74%), and changes in personality (57%) were the most common presenting signs and symptoms.All patients were treated with Isoniazid, rifampin, pyrazinamide, and streptomycin for 2 months, followed by 10 months of Isoniazid and rifampin alone. Steroids were used as adjunctive therapy in all patients for 4 weeks and then gradually tapered as tolerated over a period of 7 to 10 days. All patients responded to treatment clinically. Of the 37 CSF pretreatment specimens, 7 (19%) were by Bactec, 3 (8%) were by growth in Löwenstein-Jensen medium, and 1 (3%) was by acid-fast staining. On the second CSF examination after the eighth week of treatment, none of patients were positive by culture and direct smear. Hydrocephalus was seen on cranial computed tomography in 95% of patients. Concentrations of TNF-α, IL-6, and IL-8 in the lumbar CSF of all children were determined by chemiluminescent enzyme immunometric assay (Immulite, DPC, Los Angeles, CA) in the first week of therapy and in the second, fourth, sixth, and 12th months of therapy.The median CSF concentrations of TNF-α in TBM patients was 134.7 pg/mL in the first week of therapy and 85.3 pg/mL, 53.8 pg/mL, 38.1 pg/mL, and 16.8 pg/mL in the second, fourth, sixth, and 12th months, respectively. These values were significantly higher than the control group (median: <5.6 pg/mL) (P < .0001–.001). The median CSF concentrations of IL-6 in TBM patients was 504.9 pg/mL in the first week of therapy and 128.4 pg/mL, 26.3 pg/mL, 5.2 pg/mL, and 5.1 pg/mL in the second, fourth, sixth, and 12th months of therapy. All except the 6- and 12-month levels were significantly higher than in the control group (median: <5.4 pg/mL) (P < .0001–.001). The median CSF concentration of IL-8 in TBM patients was 1931.7 pg/mL in the first week of therapy and 431.6 pg/mL, 112.9 pg/mL, 68.1 pg/mL, and 60.2 pg/mL in the second, fourth, sixth, and 12th months. Again, all except the 6- and 12-month levels were significantly higher than in the control group (medians <62 pg/mL) (P < .0001–.001).In this study, CSF concentrations of IL-6 and IL-8 were elevated in patients with TBM and remained detectable for a long time. By contrast, TNF-α was present at lower levels but over a longer period of time (12 months). In addition, cytokine concentration in the CSF was related neither to the TBM stage nor to the clinical outcome of the disease. Previous studies reported very high levels of proinflammatory cytokines (TNF-α, IL-6, and IL-8) in the purulent bacterial meningitis at the onset of the disease and a rapid decrease 6 to 24 hours after the beginning of treatment.4 Mastroianni et al5showed that the CSF concentration of TNF-α was moderately high in their patients with TBM and was detectable for a remarkably long time (16 months). Donald et al6 also reported the presence of TNF-α in the CSF of children with complicated forms of TBM and its persistent presence throughout the first month of treatment.Because cytokine levels were not related to the stage or the clinical outcome of TBM, we think they support the presence of continuous inflammatory activity5 rather than playing a role in the pathogenesis and course of TBM. The persistence of TNF-α for 12 months suggests that the duration of treatment with antituberculous agents in TBM should be at least 12 months.