International Journal of Infectious Diseases 104 (2021) 92–96

Contents lists available at ScienceDirect

International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

A comparison of the accuracy of the CapitalBio Mycobacterium

real-time polymerase chain reaction and the Xpert MTB/RIF assay
for the diagnosis of tuberculous meningitis
Lihua Sun, Liwei Yao, Genlian Fu, Lihua Lin, Enlan Zhu, Jinpeng Huang
Zhejiang Tuberculosis Diagnosis and Treatment Center, Zhejiang Chinese Medicine and Western Medicine Integrated Hospital, Hangzhou, Zhejiang, China

A R T I C L E I N F O A B S T R A C T

Article history: Objectives: We aimed to compare the efficiency of the CapitalBioMycobacterium real-time polymerase
Received 16 July 2020 chain reaction (PCR) detection test with the standard Xpert MTB/RIF assay for the diagnosis of
Received in revised form 10 December 2020 tuberculous meningitis (TBM).
Accepted 15 December 2020
Methods: We analyzed cerebrospinal fluid (CSF) from 163 patients with suspected TBM that were
collected between January 1, 2018, and December 31, 2019. For both tests, we determined the sensitivity,
Keywords: specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve
Mycobacterium tuberculosis
(AUC). Next, we compared the diagnostic accuracy of the two techniques using clinical diagnosis as a
CapitalBio
Xpert MTB/RIF
reference standard.
Tuberculous meningitis Results: The sensitivity, specificity, PPV, NPV, and AUC, of the CapitalBio Mycobacterium detection test
Real-time polymerase chain reaction were 48.5%, 100%, 100%, 29.6%, and 0.74, respectively, when used for the diagnosis of TBM. In comparison,
the Xpert MTB/RIF assay returned values of 47.0%, 100%, 100%, 29.0%, and 0.74, respectively. Our analysis
showed that the diagnostic accuracies of the CapitalBio Mycobacterium detection test and the Xpert MTB/
RIF assay were very similar; the accuracy of both tests for detecting mycobacteria was significantly higher
than that associated with acidfast staining.
Conclusions: The CapitalBio Mycobacterium real-time PCR detection test has moderate sensitivity and
very high specificity for TBM; results are very similar to those generated by the Xpert MTB/RIF assay. We
recommend that the CapitalBio PCR test should be used as an initial screening method for TB.
© 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-
nd/4.0/).

Introduction
Approximately 9.96 million new cases of tuberculosis (TB)
were reported in 2019; these infections led to serious
consequences, including approximately 1.4 million deaths
(World Health Organization, 2020). TB remains the most lethal
of the infectious diseases and as such has a profound global
impact (Donovan et al., 2020). Tuberculous meningitis (TBM),
which accounts for 1%–5% of all new cases of TB, is among the
most serious manifestations of this disease and can result in
severe disability or death in nearly half of those infected
(Cresswell et al., 2020). Among the major causes of the poor
prognosis associated with TBM are delayed diagnosis and
treatment (Sheu et al., 2009). The traditional acid-fast bacilli
E-mail addresses: slh1113@126.com (L. Sun), 2557228490@qq.com (L. Yao),
fgl8n931@sina.com (G. Fu), 65366263@qq.com (L. Lin), lanen99@126.com (E. Zhu),
jinpenghuang@126.com (J. Huang).
(AFB) test for Mycobacterium tuberculosis (MTB) has very low
sensitivity; as such, this diagnostic strategy is not effective for
rapid and accurate diagnosis (Cresswell et al., 2020). Thus,
although AFB tests are simple, inexpensive and widely used, their
sensitivity is very low, especially in the absence of a professional
diagnostician (Heemskerk et al., 2018a). Similarly, MTB cultures,
while moderately sensitive, require 2 - 6 weeks to carry out and
therefore cannot be used to guide early diagnosis (Bahr et al.,
2018). Given these issues, empirical anti-tuberculosis therapy for
TBM is often prescribed, often unnecessarily.
Nucleic acid amplification tests (NAATs) play a profound role
with respect to the early diagnosis of TB (Kohli et al., 2018). Among
these, the Xpert MTB/RIF system (Cepheid, Sunnyvale, CA) is a
rapid, automated hemi-nested real-time polymerase chain reac-
tion (PCR) assay designed to detect MTB. The use of this modality
was supported by the World Health Organization from 2015 for the
initial detection and diagnosis of TBM (Bahr et al., 2016). The Xpert
MTB/RIF assay has resulted in marked improvements with respect
to the early detection of TB.

https://doi.org/10.1016/j.ijid.2020.12.044
1201-9712/© 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
L. Sun et al.
The CapitalBio Mycobacterium real-time PCR detection test
(CapitalBio Technology Inc., Beijing, China; http://www.capital-
biotech.com) is a duplex real-time fluorescence PCR assay that
facilitates the rapid and accurate screening of MTB and non-
tuberculous mycobacteria (NTM) infections within a single test (Yu
et al., 2020). The design of this assay permits the screening of a
larger number of Mycobacterium species. Current research on the
use of the CapitalBio Mycobacterium real-time PCR detection test
for the diagnosis of TBM is very limited; its diagnostic accuracy for
this specific disease manifestation remains unclear. As such, the
objective of this study was to evaluate the accuracy of the
CapitalBio Mycobacterium real-time PCR detection test when used
to detect MTB in samples of CSF using clinical diagnosis as a
reference standard; results were then compared to those obtained
using the Xpert MTB/RIF assay.
Materials and methods
Study design
This retrospective study was conducted at the Zhejiang Chinese
Medicine and Western Medicine Integrated Hospital; this is the TB
diagnosis and treatment center of Zhejiang Province, China. We
reviewed the medical records of suspected TBM patients who were
evaluated at this center from January 1, 2018, to December 31, 2019.
The criteria for suspected TBM include clinical symptoms such as
headache; findings on physical examination including Kernig’s
sign or neck stiffness; radiographic manifestations; and the
biochemical analysis of CSF. We tested the samples of CSF from
each patient using the Xpert MTB/RIF assay, the CapitalBio
Mycobacterium real-time PCR detection test, mycobacterial culture,
and by an AFB smear. Written informed consent was obtained in
order to perform lumbar puncture so that we can acquire samples
of CSF. Ethical approval was received from the Human Research
Ethics Committee of Zhejiang Chinese Medicine and Western
Medicine Integrated Hospital.
The patients were categorized into three diagnostic groups
according to the uniform case definition criteria developed by the
TBM cooperation group in 2010 (Marais et al., 2010). These groups
included:
(1) Confirmed TBM, in which MTB was detected by CSF AFB smear
and/or culture.
(2) Probable TBM, based on clinical presentation, radiographic
findings, CSF biochemistry, and positive responses to antitu-
berculosis therapy. Sputum AFB smear, sputum culture, and/or
other PCR tests were also positive and other potential causes of
meningitis were excluded.
(3) Non TBM, in which microbiological cultures were negative for
MTB and another diagnosis associated with meningitis was
established.
The clinical diagnosis of TBM included the confirmation of TBM
and probable TBM.
Diagnostic specimen collection and handling
CSF samples were collected via lumbar puncture. The samples
were divided into four parts to facilitate evaluation using the Xpert
MTB/RIF assay, the CapitalBio Mycobacterium real-time PCR
detection test, mycobacterial culture, and by AFB smear.
Direct microscopy and culture
The Ziehl–Neelsen method was used for AFB staining;
microscopy was performed on fresh CSF samples. Lowenstein–
93
International Journal of Infectious Diseases 104 (2021) 92–96
Jensen solid medium and liquid culture medium (BACTEC MGIT
960 Mycobacteria Culture System, BD Diagnostic Systems, Sparks,
MD) were used for Mycobacterium culture, in accordance with the
manufacturer’s instructions.
The CapitalBio Mycobacterium real-time PCR detection test
This test was performed in accordance with the manufacturer’s
instructions. In brief, 2 ml of CSF was centrifuged at 3000 g for 15
min. The supernatant was then removed and the nucleic acids
were extracted from the pellet. Next, the samples were vibrated
and incubated in a 95  C water bath for 10 min to allow the
extraction of mycobacterial DNA. The extracted DNA was used to
perform the CapitalBio Mycobacterium real-time PCR detection test
according to the manufacturer’s instructions. Amplification was
performed using a real-time fluorescence quantification PCR
instrument (SLAN-96S Real-Time PCR System ZEESAN Xiamen
CN) to detect IS6110 and HSP65 multicopy elements from MTB and
NTM, respectively. This test can be performed in 3 h (Shen et al.,
2020).
The Xpert MTB/RIF
At least 2 ml of CSF was used for the Xpert MTB/RIF assay (Chin
et al., 2019). CSF was centrifuged at 3000 g for 15 min. The excess
supernatant was then removed, leaving a final sample volume of
approximately 2 ml. The sample was then mixed by shaking and
added to the first generation Xpert MTB/RIF reaction box; this was
arrange in a module to facilitate automatic detection. This system
can report test results for MTB within 2 h (Yu et al., 2018). The
reaction box and detection modules were developed by Cepheid
(US).
Data processing and statistical analysis
Mean values, standard deviations, frequency calculations, and
cross-tabulations, were determined by SPSS version 24.0 (IBM
Corp., Armonk, NY, USA). MedCalc Statistical Software version
15.2.2 (MedCalc Software bvba, Ostend, Belgium; http://www.
medcalc.org) was used to analyze the sensitivity, specificity,
positive predictive value (PPV), negative predictive value (NPV),
and area under the curve (AUC) of the results obtained from both
the Xpert MTB/RIF assay and the CapitalBio Mycobacterium real-
time PCR detection test. This allowed us to evaluate and compare
the diagnostic accuracy of these assays using clinical diagnosis as
reference standard. Individuals were excluded from the final
analysis if they did not have a complete set of clinical data. Paired
data were evaluated by McNemar’s test, and a Chi-square test or
Fisher’s exact test was performed in order to compare proportions.
A Z-test was performed to compare AUCs. Differences with P-
values <0.05 were considered to be statistically significant.
Results
We collected CSF samples from 163 patients with suspected
TBM between January 1, 2018, and December 31, 2019. The median
age was 47.0 years and the interquartile range (IQR) was 26.0–63.0
years; 105 of the patients were men and 58 were women. Only one
patient was diagnosed with HIV infection. Among the 163 samples,
14 (8.9%) exhibited CSF smears that were AFB-positive, 28 (17.2%)
were MTB culture-positive, 63 (38.6%) tested positive with the
Xpert MTB/RIF assay, and 65 (39.9%) tested positive using the
CapitalBio Mycobacterium real-time PCR detection test. The culture
results of 2 smear-positive patients were negative. Based on
diagnostic classification criteria, 28/163 (17.2%) of the samples
were from patients with confirmed TBM, 106/163 (65.0%) samples
L. Sun et al.
were from patients considered to be probable TBM, and 29/163
(17.8%) samples were from those that received a diagnosis of non-
TBM (Figure 1). Among those with confirmed TBM, the frequencies
of positive results from the Xpert MTB/RIF assay and the CapitalBio
Mycobacterium real-time PCR detection test were 19/28 (67.9%)
and 20/28 (71.4%), respectively. Among those diagnosed with
probable TBM, the frequencies of positive results from the Xpert
MTB/RIF assay and the CapitalBio Mycobacterium real-time PCR
detection test were 44/106 (41.5%) and 45/106 (42.5%), respective-
ly. Among the 36 non-TBM patients, 11 were finally diagnosed with
cryptococcal meningitis, 10 with bacterial meningitis, 4 with
autoimmune encephalopathy, 8 with viral meningitis, and 3 with
lymphoma. None of these patients tested positive with either the
Xpert MTB/RIF assay or the CapitalBio Mycobacterium real-time
PCR detection test. The clinical characteristics of the patients are
shown in Table 1. Furthermore, no NTM infections were identified
in any of the patients in our study.
Using clinical diagnosis as the reference standard, the overall
sensitivity, specificity, PPV, NPV, and AUC, for the CSF AFB smear
were 10.5% (95% confidence interval [CI]: 5.8%–16.9%), 100% (CI:
88.1%–100%), 100% (CI: 76.8%–100%), 19.5% (CI: 13.4%–26.7%) and
0.55 (CI: 0.47–0.63), respectively. The sensitivity, specificity, PPV,
NPV, and AUC of the CapitalBio Mycobacterium real-time PCR
detection test for MTB were 48.5% (CI: 39.8–57.3%), 100% (CI: 88.1–
100%), 100% (CI: 94.5–100%), 29.6% (CI: 20.8–39.7%), and 0.74 (CI:
0.67–0.81), respectively. Those arising from the Xpert MTB/RIF
assay were 47.0% (CI: 38.3–55.8%), 100% (CI: 88.1–100%), 100% (CI:
94.3–100%), 29.0% (CI: 20.4–38.9%), and 0.74 (CI: 0.66–0.80),
respectively (Table 2). The sensitivities of the Xpert MTB/RIF and
CapitalBio Mycobacterium real-time PCR detection test were
significantly higher than that of AFB smear (P < 0.05; Table 3).
The AUCs of the Xpert MTB/RIF assay and CapitalBio Mycobacteri-
um real-time PCR detection test were also significantly higher than
that of the AFB smear (P < 0.001; Table 3). Interestingly, the
sensitivities and AUCs of the Xpert MTB/RIF assay and the
CapitalBio Mycobacterium real-time PCR detection test were
similar to one another; no statistically significant differences
were observed. These results suggested that the diagnostic
accuracy of these two NAATs was similar (P > 0.05). The NPVs
Figure 1. Diagnostic classification of the study participants.
TBM: tuberculous meningitis; AFB: acid-fast bacilli; CapitalBio test: CapitalBio Mycobacterium real-time PCR detection test; MTB: Mycobacterium tuberculosis.
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International Journal of Infectious Diseases 104 (2021) 92–96
of both the Xpert MTB/RIF assay and the CapitalBio Mycobacterium
real-time PCR detection test were higher than that of the AFB
smear, although the differences did not reach statistical signifi-
cance (P > 0.05). The NPVs of the Xpert MTB/RIF assay and the
CapitalBio Mycobacterium real-time PCR detection test were also
similar to one another (P = 0.927). The specificities and PPV of all
three tests were all 100%.
Discussion
In order to combat the overall poor prognosis among those
diagnosed with TBM, there is an urgent need to address issues
currently that prevent early diagnosis and treatment. The
prognosis of TBM in patients diagnosed with acquired immuno-
deficiency syndrome (AIDS) represents an even greater problem
(Cox et al., 2015). The early diagnosis of TBM is very difficult at
present (Houlihan et al., 2019). Although AFB smears are the most
convenient and least expensive, this sensitivity of this method is
very low and cannot provide a reliable early diagnosis of TBM
(Wang and Xie, 2018). In the present study, we found that the
sensitivity of the AFB smear was only 10.5%; most patients with
TBM could not be identified using this test alone. Our results are
consistent with those reported in previous studies (Mokrousov
et al., 2018). Mycobacterium culture can clarify the diagnosis of
TBM. Unfortunately, this approach is very time-consuming and as
such does not facilitate early diagnosis; furthermore, the frequency
of true positive tests remains low (Heemskerk et al., 2018b). This
may be because the absolute numbers of M. tuberculosis in CSF is
also very low. In this study, only 28 patients generated positive
MTB cultures. Given these issues, the diagnosis of TBM still
requires comprehensive evaluation of CSF biochemistry and relies
largely on the positive response with antituberculosis treatment.
A variety of NAATs, including real-time fluorescent PCR, are
playing an increasingly important role in the early and rapid
diagnosis of TB (Boulware et al., 2013; Yu et al., 2020). Real-time
fluorescent PCR has a key advantage in that it facilitates the
simultaneous amplification and detection of DNA using a fluores-
cence-based system (Santos et al., 2018). This method provides
precise and reproducible quantitation of specific microbial nucleic
L. Sun et al. International Journal of Infectious Diseases 104 (2021) 92–96

Table 1
Clinical characteristics of patients suspected of having tuberculous meningitis.

Characteristics All (n = 163) Confirmed TBM (n = 30) Probable TBM (n = 104) Non-TBM (n = 29)
Age year (Median, IQR) 47.0 (26.0–63.0) 48.0 (25.8–67.5) 39.5 (25.3–59.0) 52.0 (43.0–63.0)
Male (n, %) 105 (64.4%) 21 (70.0%) 64 (61.5%) 20 (69.0%)
Symptoms (n, %)
Fever 107 (65.6%) 26 (86.7%) 79 (76.0%) 2 (6.9%)
Headache 69 (42.3%) 13 (43.3%) 42 (40.4%) 14 (48.3)
Meningeal irritation 133 (81.6%) 30 (100%) 85 (81.7%) 18 (62.1%)
Seizure 21 (12.9%) 8 (26.7%) 12 (11.5%) 1 (3.4%)
Disturbance of consciousness 24 (14.7%) 10 (33.3%) 13 (12.5%) 1 (3.4%)
Pulmonary tuberculosis (n, %) 91 (55.8%) 18 (60.0%) 73 (70.2%) 0 (0%)
CSF examinations
CSF pressure (mmH2O, Median, IQR) 190.0 (120.0–260.0) 190.0 (140.0–292.5) 190.0 (120.0–260.0) 180.0 (112.5–245.0)
Leukocyte (*109/L, Median, IQR) 140 (40–290) 85 (15–230) 140 (40–287.5) 170.0 (32.5–440.0)
ADA (U/L, Median, IQR) 4.0 (2.0–6.0) 4.8 (2.2–8.3) 4.1 (2.0–6.6) 2.0 (1.0–3.7)
LDH (U/L, Median, IQR) 43.0 (27.0–74.0) 57.5 (32.0–123.5) 42.0 (27.0–75.5) 38.0 (21.0–54.5)
Total protein (g/L, Median, IQR) 1.2 (0.8–1.9) 1.6 (1.0–2.3) 1.2 (0.8–1.8) 1.0 (0.6–1.6)
Glucose (mmol/L, median, IQR) 2.7 (2.1–3.6) 2.8 (2.0–3.7) 2.6 (2.1–3.1) 3.5 (2.8–4.2)
Chloridion (mmol/L, median, IQR) 117.7 (111.2–122.1) 116.7 (108.9–122.9) 117.0 (110.7–120.9) 120.4 (116.3–123.2)

TBM: tuberculous meningitis, IQR: interquartile range, CSF: cerebrospinal fluid, ADA: Adenosine deaminase, LDH: lactate dehydrogenase.

Table 2
Accuracy of the AFB smear, the CapitalBio Mycobacterium real-time polymerase chain reaction detection test, and the Xpert MTB/RIF assay for the detection of tuberculous
meningitis compared with a composite reference standard.

Test Sensitivity Specificity PPV NPV AUC

AFB smear 10.5% (5.8–16.9%) 100% (88.1–100%) 100% (76.8–100%) 19.5% (13.4–26.7%) 0.55 (0.47–0.63)
CapitalBio test 48.5% (39.8–57.3%) 100% (88.1–100%) 100% (94.5–100%) 29.6% (20.8–39.7%) 0.74 (0.67–0.81)
Xpert MTB/RIF 47.0% (38.3–55.8%) 100% (88.1–100%) 100% (94.3–100%) 29.0% (20.4–38.9%) 0.74 (0.66–0.80)

PPV: positive predictive value; NPV: negative predictive value; AUC, area under the curve; AFB: acid-fast bacilli, CapitalBio test: CapitalBio Mycobacterium real-time PCR
detection test.

Table 3
A comparison of diagnostic performance between the CapitalBio Mycobacterium real-time PCR detection test and the Xpert MTB/RIF assay for the detection of tuberculous
meningitis.

Test Sensitivity (P-value) Specificity (P-value) PPV (P-value) NPV (P-value) AUC (P-value)
AFB vs. CapitalBio test <0.001 1.000 1.000 0.066 0.005
AFB vs. Xpert MTB/RIF <0.001 1.000 1.000 0.081 0.007
CapitalBio test vs. Xpert MTB/RIF 0.668 1.000 1.000 0.927 0.888

PPV: positive predictive value; NPV: negative predictive value; AUC: area under the curve; AFB: acid-fast bacilli; CapitalBio test: CapitalBio Mycobacterium real-time PCR
detection test.

acids via the ongoing detection of the amplification target
throughout the full exponential phase of the reaction (Santos
et al., 2018). The CapitalBio Mycobacterium real-time PCR detection
test is a relatively inexpensive commercial real-time fluorescent
PCR-TaqMan assay that amplifies IS6110 for MTB and HSP65 for
NTM; as such, this assay can detect both MTB and NTM
simultaneously (Shen et al., 2020). IS6110 has been used as a
validated MTB target gene with good levels of performance for the
diagnosis of TB in several studies (Raj et al., 2016). However, the
sensitivity and specificity of the CapitalBio Mycobacterium real-
time PCR detection test for the diagnosis of TBM was unclear. In
contrast, the Xpert MTB/RIF assay is currently recommended by
the World Health Organization guidelines for the initial diagnosis
of TBM; this assay is used widely in clinical practice and has
relatively strong diagnostic performance (Rufai et al., 2017;
Solomons et al., 2015). These two assays are both PCR-based
molecular assays: the Xpert MTB/RIF assay is a fully automated
assay while the CapitalBio Mycobacterium real-time PCR detection
test is a semi-automated assay that requires the manual extraction
of nucleic acids and running of the PCR. These practices may
increase the risk of contamination and errors. As such, the present
study compared the efficacy of these two tests for the diagnosis of
TBM using CSF samples in a side-by-side experimental design.
The sensitivity and AUC of the Xpert MTB/RIF assay was used to
diagnose TBM were 47.0% and 0.74 respectively; these values are
much higher than those associated with the AFB smear test.
Similarly, the sensitivity and AUC of the CapitalBio Mycobacterium
real-time PCR detection test were 48.5% and 0.74 respectively;
these values were also much higher than those from the AFB smear
test. Equally important, we detected no differences between the
sensitivities and AUCs of the CapitalBio Mycobacterium real-time
PCR detection test and those of the Xpert MTB/RIF assay. There
were no differences between the three tests for TBM with respect
to specificity, PPV, and NPV. On the whole, the diagnostic
efficiencies of the CapitalBio Mycobacterium real-time PCR
detection test and the Xpert MTB/RIF assay for TBM were similar
to one another; each was substantially better than the AFB smear.
The diagnostic validity of the Xpert MTB/RIF assay in this study was
similar to that reported in previous studies (Donovan et al., 2020).
As such, we conclude that the CapitalBio Mycobacterium real-time
PCR detection test might represent another method for the initial
screening of TBM.

95
L. Sun et al.
Based on these results, the CapitalBio Mycobacterium real-time
PCR detection test might become an important tool to be used for
the diagnosis of suspected TBM in the early stages. The use of this
assay may ultimately serve to reduce the number and extent of
serious complications associated with TBM.
There were also limitations to our research that need to be
considered. First, we cannot rule out the possibility of bias with
regards to patient selection given that this was designed as a
retrospective study. Second, the fact that the study took place in an
area with a high burden of TB might have influenced the
conclusions regarding universal applicability. Finally, this test
can only be used to detect MTB, and does not provide any insight
into drug resistance. As such, drug resistance was not considered in
this study.
Conclusions
The CapitalBio Mycobacterium real-time PCR detection test had
moderate levels of sensitivity and very high levels of specificity for
TBM. Moreover, this PCR detection test yielded results that were
similar to those arising from the Xpert MTB/RIF assay. As such, the
CapitalBio Mycobacterium real-time PCR detection test might be
used as another method for the initial screening of TBM.
Funding
Lihua Sun, 2018ZB097, Zhejiang Administration of Traditional
Chinese Medicine, http://www.zjtcm.gov.cn.
Declaration of interest
None.
Acknowledgements
We thank the patients and their families who were included in
this study, and our colleagues in the department.
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