Improving the microbiological diagnosis of tuberculous meningitis: A prospective, international, multicentre comparison of conventional and modified Ziehl–Neelsen stain, GeneXpert, and culture of cerebrospinal fluid

Heemskerk, A Dorothee; Donovan, Joseph; Thu, Do Dang Anh; Marais, Suzaan; Chaidir, Lidya; Dung, Vu Thi Mong; Centner, Chad M.; Ha, Vu Thi Ngoc; Annisa, Jessi; Dian, Sofiati; Bovijn, Louise; Hoang, Nguyen Thi; Phu, Nguyen Hoan; Châu, Nguyễn Văn Vĩnh; Ganiem, Ahmad Rizal; Cao, Thao Van; Geskus, Ronald B.; Thuong, Nguyen Thuy Thuong; Ruslami, Rovina; Meintjes, Graeme; Crevel, Reinout van; Wilkinson, Robert J.; Thwaites, Guy

doi:10.1016/j.jinf.2018.09.003

Cited by 82 publications

(60 citation statements)

References 12 publications

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“…4 Cerebrospinal fluid (CSF) smear microscopy with Ziehl-Neelsen staining for acidfast bacilli is the cheapest and most widely available test for tuberculous meningitis diagnosis, but it is insensitive in most settings with out expert microscopists. [5][6][7] Culture takes a minimum of 2 weeks to provide results (too slow for clinical utility), has only moderate sensitivity (30-60%), and is not readily available in most settings within lowincome tuberculosisendemic countries. 8,6 Xpert MTB/RIF (Xpert; Cepheid, Sunnyvale, CA, USA)-a rapid, automated, cartridgebased mol ecular test-was endorsed by WHO in 2015 as the best initial test for tuberculous meningitis.…”

Section: Introductionmentioning

confidence: 99%

Xpert MTB/RIF Ultra for the diagnosis of HIV-associated tuberculous meningitis: a prospective validation study

Cresswell

Tugume

Bahr

et al. 2020

The Lancet Infectious Diseases

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Introduction Tuberculous meningitis accounts for 1-5% of tuberculosis cases. Diagnostic delay contributes to poor outcomes. We evaluated the performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis diagnosis. Methods In this prospective validation study, we tested the cerebrospinal fluid (CSF) of adults presenting with suspected meningitis (ie, headache or altered mental status with clinical signs of meningism) to the Mulago National Referral Hospital and Mbarara Regional Referral Hospital in Uganda. We centrifuged the CSF, resuspended the cell pellet in 2 mL CSF, and tested 0•5 mL aliquots with Xpert Ultra, Xpert MTB/RIF (Xpert), and mycobacterial growth indicator tube (MGIT) culture. We quantified diagnostic performance against the uniform case definition of probable or definite tuberculous meningitis and a composite microbiological reference standard. Findings From Nov 25, 2016, to Jan 24, 2019, we screened 466 adults with suspected meningitis and tested 204 for tuberculous meningitis. Uniform clinical case definition classified 51 participants as having probable or definite tuberculous meningitis. Against this uniform case definition, Xpert Ultra had 76•5% sensitivity (95% CI 62•5-87•2; 39 of 51 patients) and a negative predictive value of 92•7% (87•6-96•2; 153 of 165), compared with 55•6% sensitivity (44•0-70•4; 25 of 45; p=0•0010) and a negative predictive value of 85•8% (78•9-91•1; 121 of 141) for Xpert and 61•4% sensitivity (45•5-75•6; 27 of 44; p=0•020) and negative predictive value of 85•2% (77•4-91•1; 98 of 115) for MGIT culture. Against the composite microbiological reference standard, Xpert Ultra had sensitivity of 92•9% (80•5-98•5; 39 of 42), higher than Xpert at 65•8% (48•6-80•4; 25 of 38; p=0•0063) and MGIT culture at 72•2% (55•9-86•2; 27 of 37; p=0•092). Xpert Ultra detected nine tuberculous meningitis cases missed by Xpert and MGIT culture. Interpretation Xpert Ultra detected tuberculous meningitis with higher sensitivity than Xpert and MGIT culture in this HIV-positive population. However, with a negative predictive value of 93%, Xpert Ultra cannot be used as a ruleout test. Clinical judgment and novel highly sensitive point-of-care tests are still required.

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Section: Introductionmentioning

confidence: 99%

Xpert MTB/RIF Ultra for the diagnosis of HIV-associated tuberculous meningitis: a prospective validation study

Cresswell

Tugume

Bahr

et al. 2020

The Lancet Infectious Diseases

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“…In previous studies, the sensitivities of mycobacterial culture and the Xpert MTB/RIF assay in HIV-uninfected patients were lower than those in HIV-infected patients due to the paucibacillary nature of HIV-uninfected TBM patients (4,5). However, the previous study showed that HIV infection status was not independently associated with microbiologically confirmed (definite) TBM (odds ratio [OR], 2.07; 95% CI, 0.71 to 5.99; P ϭ 0.18) in multivariate analysis (15). Therefore, it is uncertain how much HIV-uninfected status contributed to low sensitivities of the conventional tests in our study.…”

Section: Discussionmentioning

confidence: 93%

“…Therefore, it is uncertain how much HIV-uninfected status contributed to low sensitivities of the conventional tests in our study. It is worth noting that we used 1 ml of noncentrifuged CSF for the Xpert MTB/RIF assay, while the previous studies used 0.2 ml -2.0 ml centrifuged CSF (6,15). Therefore, the low volume of noncentrifuged CSF may contribute to low sensitivity of the Xpert MTB/RIF assay, while the SLIM assay, which does not need bulky instruments, revealed promising results from the same volume of noncentrifuged CSF.…”

Section: Discussionmentioning

confidence: 95%

A Simple Microfluidic Assay for Diagnosing Tuberculous Meningitis in HIV-Uninfected Patients

et al. 2019

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We evaluated the diagnostic performance of a simple and label-free pathogen enrichment method using homobifunctional imidoesters (HI) and a microfluidic system, called the SLIM assay, followed by real-time PCR from cerebrospinal fluid (CSF) in human immunodeficiency virus (HIV)-uninfected patients with suspected tuberculous meningitis (TBM). Patients with suspected TBM were prospectively enrolled in a tertiary hospital in an intermediate tuberculosis (TB)-burden country during a 30-month period. TBM was classified according to the uniform case definition. Definite and probable TBM were regarded as the reference standards for TBM, and possible TBM and not-TBM as the reference standards for not-TBM. Of 72 HIV-uninfected patients with suspected TBM, 10 were diagnosed with definite (n ϭ 2) and probable (n ϭ 8) TBM by the uniform case definition. The sensitivity of the SLIM assay was 100% (95% confidence interval [CI], 69 to 100%) compared with definite or probable TBM, and it was superior to those of mycobacterial culture (20% [95% CI, 3 to 56%]) and the Xpert MTB/RIF assay (0% [95% CI, 0 to 31%]). Of 21 possible TBM and 41 not-TBM patients by the uniform case definition, 5 possible TBM and no not-TBM patients gave positive results in the SLIM assay. The specificity of the SLIM assay was 92% (95% CI, 82 to 97%; 5/62). We demonstrated that the SLIM assay had a very high sensitivity and specificity with small samples of 10 cases of definite or probable TBM. Further studies are needed to confirm this finding and to compare the SLIM assay with mycobacterial culture, Xpert MTB/RIF, and Xpert MTB/ RIF Ultra assays in a larger prospective cohort of patients with suspected TBM, including both HIV-infected and HIV-uninfected cases. KEYWORDS SLIM assay, Xpert MTB/RIF, tuberculous meningitis T uberculous meningitis (TBM) is the most severe form of Mycobacterium tuberculosis infection and accounts for about 1% of all tuberculosis cases (1). The clinical course of TBM can deteriorate rapidly, and the mortality rate is high in the absence of prompt diagnosis and treatment (2). The gold standard for diagnosing tuberculosis is mycobacterial culture, but it takes 2 to 8 weeks to get the results, and the sensitivity is relatively low because of the paucibacillary nature of TBM (2). In 2013, the World Health Organization (WHO) endorsed the Xpert MTB/RIF assay as the initial diagnostic test for suspected TBM patients in preference to other tests, such as mycobacterial culture and M. tuberculosis PCR (3). The 43 to 72% sensitivity of the Xpert MTB/RIF assay was still not high enough to rule out TBM (4-7). In a recent report, the sensitivity of the Xpert MTB/RIF Ultra assay (70 to 95%) was superior to those of the Xpert MTB/RIF assay (43 to 45%) and mycobacterial culture (43 to 45%) (7). However, only human immunodeficiency virus (HIV)-infected patients with suspected TBM were enrolled in that study.

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“…The clinical study #1 entitled “expanding the laboratory diagnosis of tuberculous meningitis and meningoencephalitis in Vietnam” was conducted during January 2015–September 2016 (10). As per the study protocol, any adult (≥ 18 years) with a suspected CNS infection and requirement for lumbar puncture was eligible for enrolment.…”

Section: Methodsmentioning

confidence: 99%

Diagnostic Cerebrospinal Fluid Biomarker Discovery and Validation in Patients with Central Nervous System Infections

Thanh

Casals-Pascual

Nth.

et al. 2020

Preprint

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Word counts: Abstract: 245, text: 2760 2 7 Keywords: Meningitis, central nervous system infections, mass-spectrometry, lipocalin 2, 2 8 biomarkers 2 9Running title: Diagnostic biomarker discovery in central nervous system infected patients 3 0 ABSTRACT 1 Background: Central nervous system (CNS) infections are common causes of morbidity and 2 mortality worldwide. Rapid, accurate identification of the likely cause is essential for clinical 3 management and the early initiation of antimicrobial therapy, which potentially improves clinical 4 outcome. 5Methods: We applied liquid chromatography tandem mass-spectrometry on 45 cerebrospinal 6 fluid (CSF) samples from a cohort of adults with/without CNS infections to discover potential 7 diagnostic protein biomarkers. We then validated the diagnostic performance of a selected 8 biomarker candidate in an independent cohort of 364 consecutively treated adults with CNS 9 infections admitted to a referral hospital in southern Vietnam. 0Results: In the discovery cohort, we identified lipocalin 2 (LCN2) as a potential biomarker of 1 1 bacterial meningitis. The analysis of the validation cohort showed that LCN2 could discriminate 1 2 bacterial meningitis from other CNS infections, including tuberculous meningitis, cryptococcal 1 3 meningitis and viral/antibody-mediated encephalitis (sensitivity: 0.88 (95% confident interval 1 4 (CI): 0.77-0.94), specificity: 0.91 (95%CI: 0.88-0.94) and diagnostic odd ratio: 73.8 (95%CI: 1 5 31.8-171.4)). LCN2 outperformed other CSF markers (leukocytes, glucose, protein and lactate) 1 6 commonly used in routine care worldwide. The combination of LCN2 and these four routine 1 7 CSF markers resulted in the highest diagnostic performance for bacterial meningitis (area under 1 8 receiver-operating-characteristic-curve 0.96; 95%CI: 0.93-0.99).1 9Conclusions: Our results suggest that LCN2 is a sensitive and specific biomarker for 2 0 discriminating bacterial meningitis from a broad spectrum of CNS infections. A prospective 2 1 study is needed to further assess the diagnostic utility of LCN2 in the diagnosis and management 2 2 of CNS infections. 2 3 1 Central nervous system (CNS) infections cause significant mortality and morbidity worldwide, 2 but especially in low-and middle-income countries (1). Common CNS infections include 3 bacterial meningitis (BM), viral encephalitis, tuberculous meningitis (TBM) and cryptococcal 4 meningitis (2), but there are >100 documented infectious causes of CNS infections (3). 5 Additionally, over the last decade, antibody-mediated causes of encephalitis (e.g. anti-N-methyl-6 D-aspartate receptor (anti-NMDAR) encephalitis) have been recognized (4), which further 7 challenges routine diagnostics. 8 Clinical features are often insufficient to discriminate the likely cause and standard laboratory 9 investigations identify the causative agent in <60% of cases (5, 6). Critically, the clinical We thank Le 1 logistic support, and Dr Nguyen Thi Hoang Mai for her help with material collection. We are 2 indebted to patients for the...

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Improving the microbiological diagnosis of tuberculous meningitis: A prospective, international, multicentre comparison of conventional and modified Ziehl–Neelsen stain, GeneXpert, and culture of cerebrospinal fluid

Abstract: Modified ZN stain does not improve diagnosis of TBM. Currently available tests are insensitive, but testing large CSF volumes improves performance. New diagnostic tests for TBM are urgently required.

Cited by 82 publications

References 12 publications

Xpert MTB/RIF Ultra for the diagnosis of HIV-associated tuberculous meningitis: a prospective validation study

Xpert MTB/RIF Ultra for the diagnosis of HIV-associated tuberculous meningitis: a prospective validation study

A Simple Microfluidic Assay for Diagnosing Tuberculous Meningitis in HIV-Uninfected Patients

Diagnostic Cerebrospinal Fluid Biomarker Discovery and Validation in Patients with Central Nervous System Infections

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