Xpert MTB/RIF Ultra for the diagnosis of HIV-associated tuberculous meningitis: a prospective validation study

ASTRO-CM Team

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26 Scopus citations

Abstract

Introduction: Tuberculous 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. Methods: In 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. Findings: From 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. Interpretation: Xpert 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. Funding: Wellcome Trust, National Institute of Health, National Institute of Neurologic Diseases and Stroke, Fogarty International Center, and National Institute of Allergy and Infectious Diseases.

Original languageEnglish (US)
Pages (from-to)308-317
Number of pages10
JournalThe Lancet Infectious Diseases
Volume20
Issue number3
DOIs
StatePublished - Mar 2020

Bibliographical note

Funding Information:
This research was made possible through support from the National Institute of Neurologic Disorders and Stroke (R01NS086312, K23NS110470), the Fogarty International Center (K01TW010268, K43TW010718), and National Institute of Allergy and Infectious Diseases (T32AI055433). FVC is supported through a Wellcome Trust Clinical PhD Fellowship (grant number 210772/Z/18/Z). FVC is an honorary fellow of the Makerere University?Uganda Virus Research Institute (UVRI) Centre of Excellence for Infection and Immunity Research and Training (MUII-plus). MUII-plus is supported through the Developing Excellence in Leadership, Training and Science Africa Initiative (grant number 107743), which is an independent funding scheme of the African Academy of Sciences and the Alliance for Accelerating Excellence in Science in Africa, and is supported by the New Partnership for Africa's Development Planning and Coordinating Agency, with funding from the Wellcome Trust (grant number 107743) and the UK Government. The MRC/UVRI & LSHTM Uganda Research Unit is jointly funded by the UK MRC and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the European & Developing Countries Clinical Trials Partnership 2 programme supported by the EU. We would like to acknowledge the technologists at Makerere University Microbiology Laboratory and MSF Epicentre Laboratory and the study participants and their caregivers. We thank Joshua Matovu for assisting with the running of some of the assays in the Infectious Diseases Institute Translational Laboratory.

Funding Information:
This research was made possible through support from the National Institute of Neurologic Disorders and Stroke ( R01NS086312 , K23NS110470 ), the Fogarty International Center ( K01TW010268 , K43TW010718 ), and National Institute of Allergy and Infectious Diseases ( T32AI055433 ). FVC is supported through a Wellcome Trust Clinical PhD Fellowship ( grant number 210772/Z/18/Z ). FVC is an honorary fellow of the Makerere University—Uganda Virus Research Institute (UVRI) Centre of Excellence for Infection and Immunity Research and Training (MUII-plus). MUII-plus is supported through the Developing Excellence in Leadership, Training and Science Africa Initiative (grant number 107743), which is an independent funding scheme of the African Academy of Sciences and the Alliance for Accelerating Excellence in Science in Africa, and is supported by the New Partnership for Africa's Development Planning and Coordinating Agency, with funding from the Wellcome Trust (grant number 107743) and the UK Government. The MRC/UVRI & LSHTM Uganda Research Unit is jointly funded by the UK MRC and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the European & Developing Countries Clinical Trials Partnership 2 programme supported by the EU. We would like to acknowledge the technologists at Makerere University Microbiology Laboratory and MSF Epicentre Laboratory and the study participants and their caregivers. We thank Joshua Matovu for assisting with the running of some of the assays in the Infectious Diseases Institute Translational Laboratory.

Publisher Copyright:
© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

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