Xpert MTB/Rif Ultra for the Diagnosis of HIV-Associated Tuberculous Meningitis: A Prospective Validation

Abstract

Introduction: Tuberculous meningitis accounts for 1-5% of tuberculosis (TB) cases. Diagnostic delay contributes to poor outcomes. We evaluated the performance of the new Xpert MTB/Rif Ultra (Ultra) for TB meningitis diagnosis. Methods: In a prospective diagnostic accuracy study, we tested the cerebrospinal fluid (CSF) of adults presenting with sub-acute meningitis to Mulago and Mbarara Hospitals, Uganda. We centrifuged the CSF, resuspended the cell pellet in 2mL CSF and tested 0.5ml aliquots with Ultra, Xpert, and mycobacterial growth indicator tube (MGIT) culture. We quantified diagnostic performance against 1) the uniform case definition of probable or definite TB meningitis and 2) a composite microbiological reference standard. Findings: From November 2016 to January 2019, we screened 466 adults with suspected meningitis and tested 204 for TB meningitis. Uniform clinical case definition classified 51 participants as probable/definite TB meningitis. Against this uniform case definition, Ultra had 76% sensitivity (39/51) compared with Xpert 56% (25/45; P=0·001) or culture 61% (27/44; P=0·02). Against the composite reference standard, Ultra had sensitivity of 93% (39/42), higher than Xpert at 66% (25/38; p=0·006) or culture at 72% (27/37; p=0·09). Ultra detected nine TB meningitis cases missed by Xpert and culture. In multivariate analysis, decreasing CSF glucose was a predictor of definite TB meningitis (P=0.001). Interpretation: Ultra detects TB meningitis with higher sensitivity than Xpert and culture in this HIV-positive population. However, with a negative predictive value of 93% Ultra cannot be used as a 'rule out' test. Clinical judgement and novel highly sensitive point of care tests are still required. Funding Statement: This research was made possible through support from the National Institute of Neurologic Disorders and Stroke (R01NS086312), the Fogarty International Center (K01TW010268, K43TW010718), and National Institute of Allergy and Infectious Diseases (T32AI055433). Declaration of Interests: FVC is supported through a Wellcome Trust Clinical PhD Fellowship (Grant no. 210772/Z/18/Z). FVC is an honorary fellow of the Makerere University – Uganda Virus Research Institute Centre of Excellence for Infection and Immunity Research and Training (MUII-plus). MUII-plus is supported through the DELTAS Africa Initiative (Grant no. 107743). The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS), Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (Grant no. 107743) and the UK Government. The MRC/UVRI and LSHTM Uganda Research Unit is jointly funded by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the EDCTP2 programme supported by the European Union. All other authors have nothing to disclose. Ethics Approval Statement: Institutional review board and Uganda National Council of Science and Technology approvals were obtained and informed consent was obtained from participants or their surrogate (in patients with altered mental status). The study was conducted in line with the Standards for Reporting Diagnostic Accuracy Studies.