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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, Meya, David B, Denkinger, Claudia M, Muzoora, Conrad, Boulware, David R, Williams, Darlisha A, Taseera, Kabanda, Nyehangane, Dan, Ivan, Mugisha, Orikiriza, Patrick, Rhein, Joshua, Hullsiek, Kathy Huppler, Musubire, Abdu, Pastick, Katelyn, Nabeta, Pamela, Mwesigye, James, Rajasingham, Radha·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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Figure 1 Trial profile Composite reference standard was culture, Xpert, or Xpert Ultra. CSF=cerebrospinal fluid. Xpert=Xpert MTB/RIF. *Suspected meningitis with normal cerebrospinal fluid profile of <5 leucocytes per μL and protein <40 mg/dL.
Figure 1 Trial profile Composite reference standard was culture, Xpert, or Xpert Ultra. CSF=cerebrospinal fluid. Xpert=Xpert MTB/RIF. *Suspected meningitis with normal cerebrospinal fluid profile of <5 leucocytes per μL and protein <40 mg/dL.CC BY · PubMed Central
Figure 2 Venn diagram of overlap in tuberculous meningitis diagnostics The Venn diagram displays 22 participants with tuberculosis detected in CSF by each diagnostic test and the overlap between tests. Of eight participants positive by Xpert Ultra only, six had recently initiated HIV therapy, and all eight were negative by testing with cryptococcal antigen, India ink, Gram stain, culture, and multiplex PCR for 14 common meningitis pathogens. Xpert=Xpert MTB/RIF. MGIT=mycobacteria growth indicator tube. CSF=cerebrospinal fluid.
Figure 2 Venn diagram of overlap in tuberculous meningitis diagnostics The Venn diagram displays 22 participants with tuberculosis detected in CSF by each diagnostic test and the overlap between tests. Of eight participants positive by Xpert Ultra only, six had recently initiated HIV therapy, and all eight were negative by testing with cryptococcal antigen, India ink, Gram stain, culture, and multiplex PCR for 14 common meningitis pathogens. Xpert=Xpert MTB/RIF. MGIT=mycobacteria growth indicator tube. CSF=cerebrospinal fluid.CC BY · PubMed Central

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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
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 › Infectious Diseases › 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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