title: Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous meningitis in a high burden setting: a prospective study.
abstract: BACKGROUND
  Tuberculous meningitis (TBM) is difficult to diagnose promptly. The utility of the Xpert MTB/RIF test for the diagnosis of TBM remains unclear, and the effect of host- and sample-related factors on test performance is unknown. This study sought to evaluate the sensitivity and specificity of Xpert MTB/RIF for the diagnosis of TBM.
  
  
  RESULTS
  235 South-African patients with a meningeal-like illness were categorised as having definite (culture or Amplicor PCR positive), probable (anti-TBM treatment initiated but microbiological confirmation lacking), or non-TBM. Xpert MTB/RIF accuracy was evaluated using 1 ml of uncentrifuged and, when available, 3 ml of centrifuged cerebrospinal fluid (CSF). To evaluate the incremental value of MTB/RIF over a clinically based diagnosis, test accuracy was compared to a clinical score (CS) derived using basic clinical and laboratory information. Of 204 evaluable patients (of whom 87% were HIV-infected), 59 had definite TBM, 64 probable TBM, and 81 non-TBM. Overall sensitivity and specificity (95% CI) were 62% (48%-75%) and 95% (87%-99%), respectively. The sensitivity of Xpert MTB/RIF was significantly better than that of smear microscopy (62% versus 12%; p = 0.001) and significantly better than that of the CS (62% versus 30%; p = 0.001; C statistic 85% [79%-92%]). Xpert MTB/RIF sensitivity was higher when centrifuged versus uncentrifuged samples were used (82% [62%-94%] versus 47% [31%-61%]; p = 0.004). The combination of CS and Xpert MTB/RIF (Xpert MTB/RIF performed if CS<8) performed as well as Xpert MTB/RIF alone but with a ∼10% reduction in test usage. This overall pattern of results remained unchanged when the definite and probable TBM groups were combined. Xpert MTB/RIF was not useful in identifying TBM among HIV-uninfected individuals, although the sample was small. There was no evidence of PCR inhibition, and the limit of detection was ∼80 colony forming units per millilitre. Study limitations included a predominantly HIV-infected cohort and the limited number of culture-positive CSF samples.
  
  
  CONCLUSIONS
  Xpert MTB/RIF may be a good rule-in test for the diagnosis of TBM in HIV-infected individuals from a tuberculosis-endemic setting, particularly when a centrifuged CSF pellet is used. Further studies are required to confirm these findings in different settings. Please see later in the article for the Editors' Summary.
authors.affiliation: Department of Neurology, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Vinod B
authors.initials: VB
authors.lastname: Patel
authors.forename: Grant
authors.initials: G
authors.lastname: Theron
authors.forename: Laura
authors.initials: L
authors.lastname: Lenders
authors.forename: Brian
authors.initials: B
authors.lastname: Matinyena
authors.forename: Cathy
authors.initials: C
authors.lastname: Connolly
authors.forename: Ravesh
authors.initials: R
authors.lastname: Singh
authors.forename: Yacoob
authors.initials: Y
authors.lastname: Coovadia
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.forename: Keertan
authors.initials: K
authors.lastname: Dheda
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction / Q000379:methods*; D011446:Prospective Studies; D014390:Tuberculosis, Meningeal / Q000175:diagnosis* / Q000235:genetics; D055815:Young Adult