Abstract
SummaryBackgroundXpert MTB/RIF Ultra (Xpert Ultra) might have higher sensitivity than its predecessor, Xpert MTB/RIF (Xpert), but its role in tuberculous meningitis diagnosis is uncertain. We aimed to compare Xpert Ultra with Xpert for the diagnosis of tuberculous meningitis in HIV-uninfected and HIV-infected adults.MethodsIn this prospective, randomised, diagnostic accuracy study, adults (≥16 years) with suspected tuberculous meningitis from a single centre in Vietnam were randomly assigned to cerebrospinal fluid testing by either Xpert Ultra or Xpert at baseline and, if treated for tuberculous meningitis, after 3–4 weeks of treatment. Test performance (sensitivity, specificity, and positive and negative predictive values) was calculated for Xpert Ultra and Xpert and compared against clinical and mycobacterial culture reference standards. Analyses were done for all patients and by HIV status.FindingsBetween Oct 16, 2017, and Feb 10, 2019, 205 patients were randomly assigned to Xpert Ultra (n=103) or Xpert (n=102). The sensitivities of Xpert Ultra and Xpert for tuberculous meningitis diagnosis against a reference standard of definite, probable, and possible tuberculous meningitis were 47·2% (95% CI 34·4–60·3; 25 of 53 patients) for Xpert Ultra and 39·6% (27·6–53·1; 21 of 53) for Xpert (p=0·56); specificities were 100·0% (95% CI 92·0–100·0; 44 of 44) and 100·0% (92·6–100·0; 48 of 48), respectively. In HIV-negative patients, the sensitivity of Xpert Ultra was 38·9% (24·8–55·1; 14 of 36) versus 22·9% (12·1–39·0; eight of 35) by Xpert (p=0·23). In HIV co-infected patients, the sensitivities were 64·3% (38·8–83·7; nine of 14) for Xpert Ultra and 76·9% (49·7–91·8; ten of 13) for Xpert (p=0·77). Negative predictive values were 61·1% (49·6–71·5) for Xpert Ultra and 60·0% (49·0–70·0) for Xpert. Against a reference standard of mycobacterial culture, sensitivities were 90·9% (72·2–97·5; 20 of 22 patients) for Xpert Ultra and 81·8% (61·5–92·7; 18 of 22) for Xpert (p=0·66); specificities were 93·9% (85·4–97·6; 62 of 66) and 96·9% (89·5–91·2; 63 of 65), respectively. Six (22%) of 27 patients had a positive test by Xpert Ultra after 4 weeks of treatment versus two (9%) of 22 patients by Xpert.InterpretationXpert Ultra was not statistically superior to Xpert for the diagnosis of tuberculous meningitis in HIV-uninfected and HIV-infected adults. A negative Xpert Ultra or Xpert test does not rule out tuberculous meningitis. New diagnostic strategies are urgently required.FundingWellcome Trust and the Foundation for Innovative New Diagnostics.
Highlights
Mycobacterium tuberculosis kills more people each year than any other infectious disease.[1]
Meta-analyses of the diagnostic perfor mance of Xpert for tuberculous meningitis showed pooled sensitivities of 79·5–80·5% compared with mycobacterial culture and specificities of 98·6–98·8% for M tuberculosis detection in Cerebrospinal fluid (CSF).[5,6]
We showed that Xpert Ultra was not superior to Xpert when compared against either clinical or mycobacterial culture reference standards
Summary
Mycobacterium tuberculosis kills more people each year than any other infectious disease.[1]. Xpert MTB/RIF (Xpert; Cepheid, Sunnyvale, CA, USA) offered a breakthrough in tuberculosis diagnostics: a rapid, highly sensitive nucleic acid amplification test (NAAT) with additional rifampicin susceptibility testing. Xpert uses a hemi-nested real-time PCR assay to detect and amplify an M tuberculosis-specific sequence of the bacterial rpoB gene.[4] Xpert is valuable when positive, yet it is insufficiently sensitive to exclude tuberculous meningitis when negative. Meta-analyses of the diagnostic perfor mance of Xpert for tuberculous meningitis showed pooled sensitivities of 79·5–80·5% compared with mycobacterial culture and specificities of 98·6–98·8% for M tuberculosis detection in CSF.[5,6] sensitivity is affected by the volume of CSF tested, whether CSF centrifugation was done before testing,[7] and the choice of diagnostic gold standard. Use of a clinical reference standard, wherein not Lancet Infect Dis 2020; 20: 299–307
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