Performance of immune-based and microbiological tests in children with tuberculosis meningitis in Europe: a multicentre Paediatric Tuberculosis Network European Trials Group (ptbnet) study

Abstract

Introduction Tuberculous meningitis (TBM) is often diagnostically challenging. Only limited data exist on the performance of interferon-gamma release assays (IGRA) and molecular assays in children with TBM in routine clinical practice, particularly in the European setting. Methods Multicenter, retrospective study involving 27 healthcare institutions providing care for children with tuberculosis (TB) in nine European countries. Results Of 118 children included, 54 (45.8%) had definite, 38 (32.2%) probable and 26 (22.0%) possible TBM; 39 (33.1%) had TBM grade 1, 68 (57.6%) grade 2 and 11 (9.3%) grade 3. Of 108 patients who underwent cranial imaging 90 (83.3%) had ≥1 abnormal finding consistent with TBM. At the 5 mm cut-off the tuberculin skin test had a sensitivity of 61.9% (95%CI: 51.2–71.6%); at the 10 mm cut-off 50.0% (95%CI: 40.0–60.0%). The test sensitivities of QuantiFERON-TB and T-SPOT.TB assays were 71.7% (95%CI: 58.4–82.1%) and 82.5% (95%CI: 58.2–94.6%), respectively (p=0.53). Indeterminate results were common, occurring in 17.0% of QuantiFERON-TB assays performed. Cerebrospinal fluid (CSF) cultures were positive in 50.0% (95%CI: 40.1–59.9%), and CSF polymerase-chain-reaction (PCR) in 34.8% (95%CI: 22.9–43.7%). In the subgroup of children who had TST, IGRA, CSF culture and CSF PCR performed simultaneously, 84.4% had at least one positive test result (95%CI: 67.8%–93.6%). Conclusions Existing immunological and microbiological TB tests have suboptimal sensitivity in children with TBM, with each test producing false-negative results in a substantial proportion of patients. Combining immune-based tests with CSF culture and CSF PCR results in considerably higher positive diagnostic yields, and should therefore be standard clinical practice in high-resource settings.