Abstract
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. 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. 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.
Highlights
There are,10 million new cases and 1.7 million deaths from tuberculosis (TB) annually [1]
The impact of sample volume and how samples are processed, the limit of detection, the effect of cerebrospinal fluid (CSF)–related Amplicor Mycobacterium Tuberculosis PCR Test (PCR) inhibition, and the relationship between CSF bacterial load and Xpert MTB/RIF cycle threshold (CT) values have not been determined. To address these gaps in knowledge, we evaluated the accuracy of Xpert MTB/RIF in an unselected cohort of patients with suspected Tuberculous meningitis (TBM)
15 ml of CSF, obtained by lumbar puncture, was processed for the following tests: microscopy (Gram stain and fluorescent staining for acid-fast bacilli [auramine]); bacterial culture; Mycobacterium tuberculosis (M.tb.) culture (Bactec MGIT 960; BD); fungal culture; cryptococcal latex agglutination test; Roche Amplicor Mycobacterium Tuberculosis PCR Test (Roche Diagnostic Systems) (Amplicor PCR); routine chemistry; viral PCR for cytomegalovirus, varicella zoster virus, and herpes simplex; venereal disease research laboratory test; fluorescent treponemal antibody test; and test for cysticercus antibodies
Summary
There are ,10 million new cases and 1.7 million deaths from tuberculosis (TB) annually [1]. The incidence of TB is decreasing worldwide, it remains a significant cause of morbidity and mortality in sub-Saharan Africa, where, fuelled by the HIV epidemic, it is out of control [1,2]. In this region, up to 80% of patients infected with TB are co-infected with HIV. Up to 40% of co-infected patients have extrapulmonary TB, and ,10% of those with extrapulmonary TB have tuberculous meningitis (TBM) [3,4] These patients frequently require prolonged admission, they have high morbidity rates due to neuro-pathology, and mortality is substantial (,30%), if the diagnosis and follow-on therapy are delayed [5,6,7,8]. TB meningitis is a serious health concern in countries with high rates of HIV and TB co-infection
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