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Cited by 310Infectious Diseases and TuberculosisTuberculosis Research and EpidemiologyBacterial Infections and Vaccines

Diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculous meningitis in HIV-infected adults: a prospective cohort study

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Bahr, Nathan C, Nuwagira, Edwin, Evans, Emily E, Cresswell, Fiona V, Bystrom, Philip V, Byamukama, Adolf, Bridge, Sarah C, Bangdiwala, Ananta S +16 more·2018·The Lancet Infectious Diseases
DOI 10.1016/s1473-3099(17)30474-7PMC PMC5739874
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Abstract

BACKGROUND: WHO recommends Xpert MTB/RIF as initial diagnostic testing for tuberculous meningitis. However, diagnosis remains difficult, with Xpert sensitivity of about 50-70% and culture sensitivity of about 60%. We evaluated the diagnostic performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis. METHODS: We prospectively obtained diagnostic cerebrospinal fluid (CSF) specimens during screening for a trial on the treatment of HIV-associated cryptococcal meningitis in Mbarara, Uganda. HIV-infected adults with suspected meningitis (eg, headache, nuchal rigidity, altered mental status) were screened consecutively at Mbarara Regional Referral Hospital. We centrifuged CSF, resuspended the pellet in 2 mL of CSF, and tested 0·5 mL with mycobacteria growth indicator tube culture, 1 mL with Xpert, and cryopreserved 0·5 mL, later tested with Xpert Ultra. We assessed diagnostic performance against uniform clinical case definition or a composite reference standard of any positive CSF tuberculous test. FINDINGS: From Feb 27, 2015, to Nov 7, 2016, we prospectively evaluated 129 HIV-infected adults with suspected meningitis for tuberculosis. 23 participants were classified as probable or definite tuberculous meningitis by uniform case definition, excluding Xpert Ultra results. Xpert Ultra sensitivity was 70% (95% CI 47-87; 16 of 23 cases) for probable or definite tuberculous meningitis compared with 43% (23-66; 10/23) for Xpert and 43% (23-66; 10/23) for culture. With composite standard, we detected tuberculous meningitis in 22 (17%) of 129 participants. Xpert Ultra had 95% sensitivity (95% CI 77-99; 21 of 22 cases) for tuberculous meningitis, which was higher than either Xpert (45% [24-68]; 10/22; p=0·0010) or culture (45% [24-68]; 10/22; p=0·0034). Of 21 participants positive by Xpert Ultra, 13 were positive by culture, Xpert, or both, and eight were only positive by Xpert Ultra. Of those eight, three were categorised as probable tuberculous meningitis, three as possible tuberculous meningitis, and two as not tuberculous meningitis. Testing 6 mL or more of CSF was associated with more frequent detection of tuberculosis than with less than 6 mL (26% vs 7%; p=0·014). INTERPRETATION: Xpert Ultra detected significantly more tuberculous meningitis than did either Xpert or culture. WHO now recommends the use of Xpert Ultra as the initial diagnostic test for suspected tuberculous meningitis. FUNDING: National Institute of Neurologic Diseases and Stroke, Fogarty International Center, National Institute of Allergy and Infectious Disease, UK Medical Research Council/DfID/Wellcome Trust Global Health Trials, Doris Duke Charitable Foundation.

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  • In people living with HIV, Xpert Ultra specificity in Bahr 2017 was 90% (95% CI 83 to 95).

    “Specificity (95% CI) was 90% (83 to 95) (Bahr 2017) and 92% (86 to 95) (Cresswell 2020) for Xpert Ultra and 97% (95% CI 92 to 99) (Bahr 2017) and 97% (93 to 99) (Cresswell 2020) for Xpert MTB/RIF; Figure 11.”

    From Xpert MTB/RIF Ultra and Xpert MTB/RIF assays for extrapulmonary tuberculosis and rifampicin resistance in adults (2021) · cites this paper as Bahr 2017

    The Results report Xpert Ultra diagnostic specificity of 95% (101/106) among participants classified as having possible or non-tuberculous meningitis, under an assumption the authors consider improbable. They do not report the attributed specificity of 90% (95% CI 83–95); the 90% figure in the Results is a negative predictive value for Xpert and culture, not Xpert Ultra specificity. (LLM, conf=0.88)

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  • In people living with HIV, Xpert MTB/RIF specificity in Bahr 2017 was 97% (95% CI 92 to 99).

    “Specificity (95% CI) was 90% (83 to 95) (Bahr 2017) and 92% (86 to 95) (Cresswell 2020) for Xpert Ultra and 97% (95% CI 92 to 99) (Bahr 2017) and 97% (93 to 99) (Cresswell 2020) for Xpert MTB/RIF; Figure 11.”

    From Xpert MTB/RIF Ultra and Xpert MTB/RIF assays for extrapulmonary tuberculosis and rifampicin resistance in adults (2021) · cites this paper as Bahr 2017

    The Results (Table 3; page not available) report 10 Xpert-positive cases among the 23 definite or probable cases. The Results also identify 106 participants outside those categories; the reported counts imply no Xpert positives among them, or 100% specificity against that clinical case definition—not 97% (95% CI 92–99). (LLM, conf=0.82)

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  • In people living with HIV, Xpert Ultra sensitivity in Bahr 2017 was 90% (95% CI 55 to 100).

    “Sensitivity (95% CI) was 90% (55 to 100) (Bahr 2017) and 89% (71 to 98) (Cresswell 2020) for Xpert Ultra and 60% (26 to 88) (Bahr 2017) and 70% (50 to 86) (Cresswell 2020) for Xpert MTB/RIF.”

    From Xpert MTB/RIF Ultra and Xpert MTB/RIF assays for extrapulmonary tuberculosis and rifampicin resistance in adults (2021) · cites this paper as Bahr 2017

    Table 3 in the Results reports Xpert Ultra sensitivity in the HIV-infected cohort as 95% (95% CI 77–99) against the composite endpoint, or 70% (47–87) against the clinical case definition. Neither result matches the attributed 90% (55–100). (LLM, conf=0.90)

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    Experimental — accuracy not yet measured

  • In people living with HIV, Xpert MTB/RIF sensitivity in Bahr 2017 was 60% (95% CI 26 to 88).

    “Sensitivity (95% CI) was 90% (55 to 100) (Bahr 2017) and 89% (71 to 98) (Cresswell 2020) for Xpert Ultra and 60% (26 to 88) (Bahr 2017) and 70% (50 to 86) (Cresswell 2020) for Xpert MTB/RIF.”

    From Xpert MTB/RIF Ultra and Xpert MTB/RIF assays for extrapulmonary tuberculosis and rifampicin resistance in adults (2021) · cites this paper as Bahr 2017

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Research works printed but not linked: 1

  1. [7]WHO Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary tuberculous in adults and children. Policy update 2013 World Health Organization Geneva 25473701

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Authors
Bahr, N. C., Nuwagira, E., Evans, E. E., Cresswell, F. V., Bystrom, P. V., Byamukama, A., Bridge, S. C., Bangdiwala, A. S., Meya, D. B., Denkinger, C. M., Muzoora, C., Boulware, D. R., Williams, D. A., Taseera, K., Nyehangane, D., Ivan, M., Orikiriza, P., Rhein, J., Hullsiek, K. H., Musubire, A., Pastick, K., Nabeta, P., Mwesigye, J., & Rajasingham, R.
Affiliations
  • University of Minnesota (US)
  • Mbarara University of Science and Technology (UG)
  • London School of Hygiene & Tropical Medicine (GB)
  • FIND (CH)
Corresponding author
Boulware, David R
ORCID
Venue
The Lancet Infectious Diseases
Publisher
Elsevier BV
Published
2018-01
Volume
18
Issue
1
Pages
68-75
ISSN
1473-3099 (ISSN-L)
DOI
10.1016/s1473-3099(17)30474-7
PMC
PMC5739874
OpenAlex
W2753952100
Cited by
308
References
19
Citations by year
2026: 17 · 2025: 21 · 2024: 21 · 2023: 22 · 2022: 30 · 2021: 22 · 2020: 75 · 2019: 59 · 2018: 34 · 2017: 7
FWCI
49.88
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Infectious Diseases (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
Funders
  • Fogarty International Center
  • National Institutes of Health (R25TW009345, R01NS086312)
  • National Institute of Neurological Disorders and Stroke
  • Doris Duke Charitable Foundation
  • National Institute of Allergy and Infectious Diseases (T32AI055433)
Topics
  • Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
Keywords
tuberculous meningitis, Xpert MTB/RIF Ultra, Xpert MTB/RIF, HIV infection, diagnostic accuracy, cerebrospinal fluid, molecular tuberculosis diagnosis, sensitivity, Uganda, Mbarara, case definition, composite reference standard, HIV-associated tuberculosis
MeSH terms
Adult, Cerebrospinal Fluid, Female, Humans, Male, Mycobacterium, Prospective Studies, Sensitivity and Specificity, Tuberculosis, Meningeal, Uganda, HIV Infections, Tuberculosis, Multidrug-Resistant, Molecular Diagnostic Techniques

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