Improved diagnostic sensitivity for tuberculous meningitis with Xpert<SUP>®</SUP> MTB/RIF of centrifuged CSF

Abstract

Introduction TB meningitis (TBM) diagnosis is difficult and novel diagnostic methods are needed. The World Health Organization recommends Xpert MTB/RIF (Xpert) as the initial TBM diagnostic test, based on two studies reporting suboptimal sensitivity (~50–60%). Objective To study the effect of cerebrospinal fluid (CSF) centrifugation on Xpert performance for TBM detection. Design 107 predominantly HIV-infected adults with suspected meningitis were screened prospectively in Kampala, Uganda. CSF was tested by 1) microscopy for acid-fast bacilli; 2) Mycobacteria growth indicator tube culture; 3) Xpert of 2mL of unprocessed CSF; 4) Xpert of centrifuged CSF. Diagnostic performance was measured against an a priori composite reference standard of any positive CSF tuberculosis test. Results 17% (18/107) of participants had definite TBM. When CSF was centrifuged, Xpert had better sensitivity (72%, 13/18) than when using 2mL of unprocessed CSF (28%, 5/18; P=0.008). The median centrifuged CSF volume was 6mL (IQR 4–10mL). Mycobacterial culture yielded 71% (12/17) sensitivity at a median delay of 27 days. Only 39% were positive both by culture and centrifuged Xpert, with additional cases detected by Xpert and culture. Conclusions Centrifuging of CSF optimizes Xpert diagnostic performance for detection of TBM. A combination of culture and Xpert detected the largest number of cases.

Can improved diagnostics reduce mortality from Tuberculous meningitis? Findings from a 6.5-year cohort in Uganda

“…This is consistent with prior findings and is likely due to the relatively higher sensitivity of culture versus Xpert, and the ability of Xpert to detect dead TB bacilli 13, 27 . Neither test performed better than the other (P=0.42).…”

“…Subjects had comprehensive testing for TBM with CSF AFB smear (Mulago Hospital only), Xpert MTB/Rif on large volume centrifuged CSF 13 and CSF Mycobacteria Growth Inhibitor Tube culture (MGIT, Becton Dickinson, Franklin Lakes, USA). AFB smear was discontinued in Mbarara in 2013 as the sensitivity was deemed too low to justify further use.…”

“…Of the two major studies included in the meta-analysis, Patel and colleagues reported 67% sensitivity against microbiologically proven TBM and 36% against consensus clinical case definitions, while Nhu and colleagues showed 59% sensitivity against the same case definitions 10– 12 . Additionally, use of a larger volume of centrifuged CSF improves sensitivity of Xpert 10, 13 . Yet, inadequate negative predictive value means that Xpert cannot substitute for clinical judgement 14 .…”

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

“…Among participants without cryptococcal meningitis (who require large volume lumbar punctures for control of intracranial pressure), testing of at least 6 mL of CSF (median 10 mL [IQR [8][9][10][11][12]) was associated with a tuberculous meningitis diagnosis (19 [26%] of 73) compared with less than 6 mL (4 mL [3-5mL]; 3 [7%] of 43; p=0·014)].…”

“…11,12 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. 12 Thus, the imperfect sensitivity has meant no test can exclude tuberculous meningitis. 13,14 The Xpert MTB/RIF Ultra (Xpert Ultra) is a new, fully automated, nested real-time PCR assay for the GeneXpert platform.…”