Abstract
SummaryBackgroundWHO 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.MethodsWe 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.FindingsFrom 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).InterpretationXpert 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.FundingNational 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.
Highlights
Tuberculous meningitis is the second most common cause of adult meningitis in Africa.1–4 Meningitis from tuberculosis leads to fatality in more than 50% of cases, in large part due to difficulty and delay in diagnosis.5 Cerebrospinal fluid (CSF) smear microscopy for acid-fast bacilli has poor sensitivity (≤15%) in routine care.5 mycobacterial culture has higher sensitivity (50–60%), culture is too slow to be clinically useful.5In 2013, WHO endorsed the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA) as the preferred initial test to investigate tuberculous meningitis after a systematic review of 13 studies.6–8 The Xpert is cartridge-based fullyautomated PCR test
Added value of this study To our knowledge, we present the first evaluation of the diagnostic performance of Xpert Ultra in the diagnosis of tuberculous meningitis
Of 221 HIV-infected people presenting with suspected meningitis between Feb 27, 2015, and Nov 7, 2016, 129 participants underwent tuberculous testing with Xpert, culture, and Xpert Ultra on centrifuged cerebrospinal fluid (CSF)
Summary
Tuberculous meningitis is the second most common cause of adult meningitis in Africa. Meningitis from tuberculosis leads to fatality in more than 50% of cases, in large part due to difficulty and delay in diagnosis. Cerebrospinal fluid (CSF) smear microscopy for acid-fast bacilli has poor sensitivity (≤15%) in routine care. mycobacterial culture has higher sensitivity (50–60%), culture is too slow to be clinically useful.5In 2013, WHO endorsed the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA) as the preferred initial test to investigate tuberculous meningitis after a systematic review of 13 studies. The Xpert is cartridge-based fullyautomated PCR test. In 2013, WHO endorsed the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA) as the preferred initial test to investigate tuberculous meningitis after a systematic review of 13 studies.. The first reported 67% sensitivity using Xpert in microbiologically proven tuberculous meningitis in HIV-infected South Africans.. This study initially tested 1 mL of CSF but later found higher sensitivity (82%; 22 of 27 positive cases) when centrifuging 3 mL of CSF.. Sensitivity compared with consensus clinical case definition was only 36%.9,10. The second large cohort study, in Vietnam, measured Xpert against the same clinical case definition and found 59% sensitivity generally using 2 mL or less of centrifuged CSF.. The imperfect sensitivity has meant no test can exclude tuberculous meningitis. The first reported 67% sensitivity using Xpert in microbiologically proven tuberculous meningitis in HIV-infected South Africans. This study initially tested 1 mL of CSF but later found higher sensitivity (82%; 22 of 27 positive cases) when centrifuging 3 mL of CSF. Sensitivity compared with consensus clinical case definition was only 36%.9,10 The second large cohort study, in Vietnam, measured Xpert against the same clinical case definition and found 59% sensitivity generally using 2 mL or less of centrifuged CSF. A third Ugandan study reported 28% sensitivity with 2 mL of uncentrifuged CSF and 72% sensitivity when centrifuging a median volume of 6 mL (IQR 4–10) with Xpert. the imperfect sensitivity has meant no test can exclude tuberculous meningitis.
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