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Xpert MTB/RIF Ultra for the diagnosis of HIV-associated tuberculous meningitis: a prospective validation study
Open accessAbstract
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.
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“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 Cresswell 2020
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“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 Cresswell 2020
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In the citing paper
“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 Cresswell 2020
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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 Cresswell 2020
Experimental — accuracy not yet measured
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Citations
Cites
STARD 2015 guidelines for reporting diagnostic accuracy studies: explanation and elaboration
Cohen, J. F., Korevaar, D. A., Altman, D. G., Bruns, D. E., Gatsonis, C. A., Hooft, L., Irwig, L., Levine, D., Reitsma, J. B., de Vet, H. C. W., et al. (2016) · BMJ Open · doi:10.1136/bmjopen-2016-012799 · Cited by 2,570
Tuberculous meningitis: a uniform case definition for use in clinical research
Marais, S., Thwaites, G., Schoeman, J. F., Török, M. E., Misra, U. K., Prasad, K., Donald, P. R., Wilkinson, R. J., & Marais, B. J. (2010) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(10)70138-9 · Cited by 932
Anatomy and physiology of cerebrospinal fluid
Sakka, L. J., Coll, G., & Chazal, J. (2011) · European Annals of Otorhinolaryngology Head and Neck Diseases · doi:10.1016/j.anorl.2011.03.002 · Cited by 816
Dorman, S. E., Schumacher, S. G., Alland, D., Nabeta, P., Armstrong, D. T., King, B., Hall, S. L., Chakravorty, S., Cirillo, D. M., Tukvadze, N., et al. (2017) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(17)30691-6 · Cited by 705
Chakravorty, S., Simmons, A. M., Rowneki, M., Parmar, H., Cao, Y., Ryan, J., Banada, P. P., Deshpande, S., Shenai, S., Gall, A., et al. (2017) · mBio · doi:10.1128/mbio.00812-17 · Cited by 668
Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis
Heemskerk, D., Bang, N. D., Hoang, N. T., Chau, T. T. H., Phu, N. H., Loc, P. P., Châu, N. V. V., Hien, T. T., Dung, N. H., Lan, N. T. N., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1507062 · Cited by 308
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., et al. (2018) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(17)30474-7 · Cited by 308
Self-citationCazabon, D., Alsdurf, H., Satyanarayana, S., Nathavitharana, R. R., Subbaraman, R., Daftary, A., & Pai, M. (2016) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2016.10.016 · Cited by 173
Theron, G., Venter, R., Calligaro, G., Smith, L., Limberis, J. D., Meldau, R., Chanda, D. M., Esmail, A., Peter, J., & Dheda, K. U. J. (2016) · Clinical Infectious Diseases · doi:10.1093/cid/civ1223 · Cited by 152
GeneXpert MTB/Rif to Diagnose Tuberculous Meningitis: Perhaps the First Test but not the Last
Bahr, N. C., Marais, S., Caws, M., van Crevel, R., Wilkinson, R. J., Tyagi, J. S., Thwaites, G. E., & Boulware, D. R. (2016) · Clinical Infectious Diseases · doi:10.1093/cid/ciw083 · Cited by 120
Cited by
Sorted by citations
Advances in Molecular Diagnosis of Tuberculosis
MacLean, E. L.-H., Kohli, M., Weber, S. F., Suresh, A., Schumacher, S. G., Denkinger, C. M., & Pai, M. (2020) · Journal of Clinical Microbiology · doi:10.1128/jcm.01582-19 · Cited by 224
“Notably, even with sensitivity of 77%, as observed in another study of TB meningitis (26), the Ultra test’s negative predictive value is still too low for use as a rule-out test.”
BackgroundKohli, M., Schiller, I., Dendukuri, N., Yao, M., Dheda, K., Denkinger, C. M., Schumacher, S. G., & Steingart, K. R. (2021) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd012768.pub3 · Cited by 215
Tuberculous meningitis: progress and remaining questions
Huynh, J., Donovan, J., Phu, N. H., Nghia, H. D. T., Thương, N. T. T., & Thwaites, G. E. (2022) · The Lancet Neurology · doi:10.1016/s1474-4422(21)00435-x · Cited by 153
Challenges in the diagnosis of tuberculous meningitis
Palacios, C. F., & Saleeb, P. G. (2020) · Journal of Clinical Tuberculosis and Other Mycobacterial Diseases · doi:10.1016/j.jctube.2020.100164 · Cited by 66
“In this study, Xpert Ultra had a 93% negative predictive value for the diagnosis of TBM [102].”
Use of Xpert MTB/RIF and Xpert Ultra in extrapulmonary tuberculosis
Park, M., & Kon, O. M. (2020) · Expert Review of Anti-infective Therapy · doi:10.1080/14787210.2020.1810565 · Cited by 69
Metadata
- Authors
- Cresswell, F. V., Tugume, L., Bahr, N. C., Kwizera, R., Bangdiwala, A. S., Musubire, A. K., Rutakingirwa, M., Kagimu, E., Nuwagira, E., Mpoza, E., Rhein, J., Williams, D. A., Muzoora, C., Grint, D., Elliott, A. M., Meya, D. B., & Boulware, D. R.
- Affiliations
- London School of Hygiene & Tropical Medicine (GB)
- Infectious Diseases Institute (UG)
- University of Kansas (US)
- University of Minnesota (US)
- Mbarara University of Science and Technology (UG)
- Corresponding author
- Cresswell, Fiona V
- ORCID
- Venue
- The Lancet Infectious Diseases
- Publisher
- Elsevier BV
- Published
- 2020-03
- Volume
- 20
- Issue
- 3
- Pages
- 308-317
- ISSN
- 1473-3099 (ISSN-L)
- PMC
- PMC7045085
- OpenAlex
- W2998865775
- Cited by
- 124
- References
- 26
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 11 · 2023: 16 · 2022: 22 · 2021: 22 · 2020: 26
- FWCI
- 19.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Lancet Infectious Diseases (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (T32AI055433)
- Fogarty International Center (K01TW010268, K43TW010718)
- National Institute of Neurological Disorders and Stroke (K23NS110470, R01NS086312)
- Wellcome Trust (210772/Z/18/Z)
- European Commission
- European and Developing Countries Clinical Trials Partnership
- African Academy of Sciences
- Medical Research Council
- Department for International Development, UK Government
- 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, HIV-associated tuberculosis, Xpert MTB/RIF Ultra, Xpert MTB/RIF, cerebrospinal fluid, sensitivity and specificity, molecular diagnosis, delayed diagnosis, Uganda, meningitis diagnosis, case definition, negative predictive value, resource-limited settings
- MeSH terms
- Cerebrospinal Fluid, Hospitals, Humans, Mycobacterium tuberculosis, Predictive Value of Tests, Sensitivity and Specificity, Tuberculosis, Meningeal, Uganda, HIV Infections, Tuberculosis, Multidrug-Resistant, Molecular Diagnostic Techniques
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