Abstract
SummaryIntroductionTuberculous meningitis accounts for 1–5% of tuberculosis cases. Diagnostic delay contributes to poor outcomes. We evaluated the performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis diagnosis.MethodsIn this prospective validation study, we tested the cerebrospinal fluid (CSF) of adults presenting with suspected meningitis (ie, headache or altered mental status with clinical signs of meningism) to the Mulago National Referral Hospital and Mbarara Regional Referral Hospital in Uganda. We centrifuged the CSF, resuspended the cell pellet in 2 mL CSF, and tested 0·5 mL aliquots with Xpert Ultra, Xpert MTB/RIF (Xpert), and mycobacterial growth indicator tube (MGIT) culture. We quantified diagnostic performance against the uniform case definition of probable or definite tuberculous meningitis and a composite microbiological reference standard.FindingsFrom Nov 25, 2016, to Jan 24, 2019, we screened 466 adults with suspected meningitis and tested 204 for tuberculous meningitis. Uniform clinical case definition classified 51 participants as having probable or definite tuberculous meningitis. Against this uniform case definition, Xpert Ultra had 76·5% sensitivity (95% CI 62·5–87·2; 39 of 51 patients) and a negative predictive value of 92·7% (87·6–96·2; 153 of 165), compared with 55·6% sensitivity (44·0–70·4; 25 of 45; p=0·0010) and a negative predictive value of 85·8% (78·9–91·1; 121 of 141) for Xpert and 61·4% sensitivity (45·5–75·6; 27 of 44; p=0·020) and negative predictive value of 85·2% (77·4–91·1; 98 of 115) for MGIT culture. Against the composite microbiological reference standard, Xpert Ultra had sensitivity of 92·9% (80·5–98·5; 39 of 42), higher than Xpert at 65·8% (48·6–80·4; 25 of 38; p=0·0063) and MGIT culture at 72·2% (55·9–86·2; 27 of 37; p=0·092). Xpert Ultra detected nine tuberculous meningitis cases missed by Xpert and MGIT culture.InterpretationXpert Ultra detected tuberculous meningitis with higher sensitivity than Xpert and MGIT culture in this HIV-positive population. However, with a negative predictive value of 93%, Xpert Ultra cannot be used as a rule-out test. Clinical judgment and novel highly sensitive point-of-care tests are still required.FundingWellcome Trust, National Institute of Health, National Institute of Neurologic Diseases and Stroke, Fogarty International Center, and National Institute of Allergy and Infectious Diseases.
Highlights
Worldwide, Mycobacterium tuberculosis affected more than 10 million people in 2018, with devastating consequences, including around 1·5 million deaths.[1]
262 participants were diagnosed with cryptococcal meningitis and had no suspicion for disseminated tuberculosis warranting cerebrospinal fluid (CSF) tuberculosis diagnostics, so were excluded from this study. 204 were tested for tuberculous meningitis with Xpert Ultra, of whom 195 (96%) were HIV positive with a median CD4 T cell count of 46 cells/μL (IQR 11–130)
This number included 39 (19%) patients who had a positive CSF cryptococcal antigen test but were still tested for tuberculous meningitis because of suspected tuberculosis coinfection, and an additional 31 (15%) of those tested for tuberculous meningitis tested positive for cryptococcal antigen in serum but negative in CSF
Summary
Mycobacterium tuberculosis affected more than 10 million people in 2018, with devastating consequences, including around 1·5 million deaths.[1]. Xpert has been deployed in 130 of 145 countries eligible for concessional pricing as of 2016.10 Xpert provides 45–67% sensitivity to detect microbiologically proven tuberculous meningitis, meaning a negative result does not provide adequate confidence that tuberculous meningitis is not present.[8,11] empirical antituberculous therapy for tuberculous meningitis, with its associated drug toxicities, drug– drug interactions, pill burden, and cost, is still commonly used, often unnecessarily
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