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

28 Pages Posted: 22 May 2019

See all articles by Fiona Cresswell

Fiona Cresswell

London School of Hygiene and Tropical Medicine - Department of Clinical Research; Makerere University - Infectious Diseases Institute; London School of Hygiene and Tropical Medicine - Uganda Research Unit; Government of Uganda - Uganda Virus Research Institute

Lillian Tugume

Makerere University - Infectious Diseases Institute

Nathan C. Bahr

University of Kansas - University of Kansas Medical Center

Richard Kwizera

Makerere University - Infectious Diseases Institute

Ananta S. Bangdiwala

University of Minnesota - Minneapolis

Abdu K. Musubire

Makerere University - Infectious Diseases Institute

Morris Rutakingirwa

Makerere University - Infectious Diseases Institute

Enock Kagimu

Makerere University - Infectious Diseases Institute

Edwin Nuwagira

Mbarara University of Science and Technology

Edward Mpoza

Makerere University - Infectious Diseases Institute

Joshua Rhein

Makerere University - Infectious Diseases Institute

Darlisha A. Williams

Makerere University - Infectious Diseases Institute

Conrad Muzoora

Mbarara University of Science and Technology

Daniel Grint

London School of Hygiene and Tropical Medicine - MRC Tropical Epidemiology Group (TEG)

Alison M. Elliott

London School of Hygiene and Tropical Medicine; Government of Uganda - Uganda Virus Research Institute

David B. Meya

Makerere University - Infectious Diseases Institute

David R. Boulware

University of Minnesota - Minneapolis

ASTRO-CM Team

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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.

Keywords: Xpert MTB/Rif Ultra, Tuberculous meningitis, TBM, diagnostic tests, extrapulmonary tuberculosis

Suggested Citation

Cresswell, Fiona and Tugume, Lillian and Bahr, Nathan C. and Kwizera, Richard and Bangdiwala, Ananta S. and Musubire, Abdu K. and Rutakingirwa, Morris and Kagimu, Enock and Nuwagira, Edwin and Mpoza, Edward and Rhein, Joshua and Williams, Darlisha A. and Muzoora, Conrad and Grint, Daniel and Elliott, Alison M. and Meya, David B. and Boulware, David R. and Team, ASTRO-CM, Xpert MTB/Rif Ultra for the Diagnosis of HIV-Associated Tuberculous Meningitis: A Prospective Validation (05/13/2019 18:27:11). The Lancet Infectious Diseases, Volume 20, Issue 3, March 2020, Pages 308-317, https://doi.org/10.1016/S1473-3099(19)30550-X, Available at SSRN: https://ssrn.com/abstract=3388827 or http://dx.doi.org/10.2139/ssrn.3388827

Fiona Cresswell (Contact Author)

London School of Hygiene and Tropical Medicine - Department of Clinical Research ( email )

London
United Kingdom

Makerere University - Infectious Diseases Institute ( email )

Kampala
Uganda

London School of Hygiene and Tropical Medicine - Uganda Research Unit ( email )

United Kingdom

Government of Uganda - Uganda Virus Research Institute ( email )

Uganda

Lillian Tugume

Makerere University - Infectious Diseases Institute

Kampala
Uganda

Nathan C. Bahr

University of Kansas - University of Kansas Medical Center

3901 Rainbow Boulevard
Kansas City, KS 66160
United States

Richard Kwizera

Makerere University - Infectious Diseases Institute

Kampala
Uganda

Ananta S. Bangdiwala

University of Minnesota - Minneapolis

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Abdu K. Musubire

Makerere University - Infectious Diseases Institute

Kampala
Uganda

Morris Rutakingirwa

Makerere University - Infectious Diseases Institute

Kampala
Uganda

Enock Kagimu

Makerere University - Infectious Diseases Institute

Kampala
Uganda

Edwin Nuwagira

Mbarara University of Science and Technology

Uganda

Edward Mpoza

Makerere University - Infectious Diseases Institute

Kampala
Uganda

Joshua Rhein

Makerere University - Infectious Diseases Institute

Kampala
Uganda

Darlisha A. Williams

Makerere University - Infectious Diseases Institute

Kampala
Uganda

Conrad Muzoora

Mbarara University of Science and Technology

Uganda

Daniel Grint

London School of Hygiene and Tropical Medicine - MRC Tropical Epidemiology Group (TEG)

London
United Kingdom

Alison M. Elliott

London School of Hygiene and Tropical Medicine ( email )

Keppel Street
London, WC1E 7HT
United Kingdom

Government of Uganda - Uganda Virus Research Institute ( email )

Uganda

David B. Meya

Makerere University - Infectious Diseases Institute

Kampala
Uganda

David R. Boulware

University of Minnesota - Minneapolis

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

No contact information is available for ASTRO-CM Team

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