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Evaluation of GeneXpert EV assay for the rapid diagnosis of enteroviral meningitis: a systematic review and meta-analysis

Evaluation of GeneXpert EV assay for the rapid diagnosis of enteroviral meningitis: a systematic... Background: GeneXpert enterovirus Assay is a PCR‑based assay for Enterovirus meningitis diagnosis. However, there is currently no research about the performance of GeneXpert enterovirus assay in the diagnosis of enterovirus menin‑ gitis. Thus, a systematic review and meta‑analysis is significant on the topic. Methods: Embase, Cochrane Library, Web of Science, and PubMed were systematically reviewed with retrieval types. Some criteria were used to filter the studies. Only studies published in English, that made a comparison between GeneXpert enterovirus assay and RT‑PCR, and could be formulated in a 2*2 table, were included. The quality of the included studies was evaluated by QUADAS‑2. The effect of the GeneXpert enterovirus assay was assessed by the Sen‑ sitivity, Specificity, Positive Likelihood Ratio, Negative Likelihood Ratio, Diagnosis Odds Ratio, and summary receiver operating characteristic (SROC) curve. Publication bias and heterogeneity were evaluated by the Deeks’ funnel test and Bivariate Box plot respectively. Results: 7 studies were recruited in the analysis. The Pooled Sensitivity was 0.96 [95% CI (0.94–0.97)], Pooled Speci‑ ficity was 0.99 [95% CI (0.98–0.99)], Positive Likelihood Ratio was 130.46 [95% CI (35.79–475.58)], Negative Likelihood Ratio was 0.04 [95% CI (0.02–0.10)], and Diagnostic Odds Ratio was 3648.23 (95% CI [963.99–13,806.72)]. In SROC Curve, Area Under Curve (AUC) was 0.9980, and Q*= 0.9849. In Deeks’ funnel test, the P‑ value was 0.807 (P > 0.05), indicating no publication bias. The Bivariate Box plot indicated no evident heterogeneity. Conclusions: The GeneXpert enterovirus assay demonstrated high diagnostic accuracy in diagnosing enterovirus meningitis. Keywords: GeneXpert EV, Enterovirus meningitis, PCR, Systematic‑review, Meta‑analysis 30 nm [2]. Meningitis contains bacterial meningitis and Introduction aseptic meningitis. As one of aseptic meningitis, which The Enterovirus genus is one of the most populous in is infected by an enterovirus, [3] Enterovirus menin- the family Picornaviridae [1], in which, human Entero- gitisis the most common non-bacterial meningitis and viruses (Human EVs) have been discovered with more accounts for 90% in children and adults. However, no than 250 subtypes and with a diameter between 28 and antiviral drugs have been approved for the treatment of EV infections [4]. In addition, most patients with *Correspondence: gysygxg@gmail.com enterovirus meningitis have no obvious symptoms after infection, with only less than 10 percent of patients Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China behave obvious symptoms and can receive treatment Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lin et al. Ann Clin Microbiol Antimicrob (2022) 21:25 Page 2 of 8 timely [2]. If it is hard to quickly and accurately diag- Study selection nose whether it’s enterovirus meningitis, patients might All researchers have received prior training in system- receive unnecessary treatment or hospitalization [5, 6]. atic reviews and meta-analysis. The Kappa test was Therefore, simple and reliable methods of identifying used to assess the agreement among the results given patients whether infected with enterovirus meningitis by the researchers. 50 citations are selected randomly are critical to the clinic. to screen and calculate the Kappa value. If Kappa was Nucleic acid amplification methods (NAATs) are less than 0.75, the second round of training will be widely used in the diagnosis of enterovirus meningitis carried out. Titles and abstracts are screened by two [7]. The real-time polymerase chain reaction (RT-PCR) researchers independently (YWC, XJC). The screening is a kind of NAATs. In 2003, the World Health Organi- of full texts will be screened by two other researchers zation (WHO) announced the adoption of RT-PCR to (ML, GYW). Disagreements were resolved by consen- detect enteroviruses meningitis. Compared with the sus of all researchers. Overall, studies eligible for inclu- traditional viral culture [8, 9], RT-PCR can make a diag- sion met all of the following criteria: (1) Published in nosis within a shorter time of 7 h, and with higher sen- English; (2) GeneXpert EV assay as an index text; (3) sitivity and specificity (approximately 100%) [10, 11]. RT-PCR as the reference standard; (4) Data in studies Nowadays, RT-PCR is considered the gold standard for could be formed a 2*2 table. The criteria for exclusion the diagnosis and identification of enterovirus meningi - were as follows: (1) Non-English pieces of literature; tis [12]. But RT-PCR assay has two evident limitations. (2) The index text was no GeneXpert EV assay; (3) The On the one hand, it is too expensive and couldn’t be reference standard was no RT-PCR; (4) The article data applied in budget-limited rural clinics in some regions. was not enough to formulate the 2*2 table; (5) Stud- On the other hand, when detecting CSF samples from ies included conference abstracts or reviews were also low viral load level, like the early phase of infection, its excluded. The Preferred Reporting Items for System - sensitivity is too low to detecting enteroviruses menin- atic Reviews and Meta-Analyses (PRISM) was used to gitis [13, 14]. describe the steps of the study selection in the system- The GeneXpert EV assay (GXEA, Cepheid, Sunny - atic review and meta-analysis. vale, CA) is a fully integrated automated nucleic acid sample preparation system that consists of instru- ments, computers, and disposable fluid boxes [9 ], with Data extraction a diagnostic turnaround time of 2.5  h [15]. What’s The name of the first author, year of publication, coun - more, because its test box is completely independent try, experiment type (prospective or retrospective), the and could conduct all the procedures, there is less FP source and quantity of samples, patient’s age and gen- in GeneXpert EV Assay in the diagnosis of enteroviral der, index test, gold standard, true-positive (TP), false- meningitis [9, 16]. However, so far, there is no com- positive (FP), true-negative (TN) and false-negative (FN) prehensive and systematic study for GeneXpert EV were extracted from each included study. Due to the limi- assay. Thus, in the present work, we conducted a sys - tation of datasets, the classification of RT-PCR couldn’t tematic review and meta-analysis to explore the diag- be extracted from the included studies. Data were nostic accuracy of GeneXpert EV assay in enteroviral extracted by 7 researchers of the study team (ML, YRL, meningitis. GYW, QWL, WHY, YPL, and JQL) independently. They were blinded to each other’s results. Disagreements were resolved by consensus. Methods Search methods Original studies published in English from the estab- Quality assessment lishment of the databases to January 30, 2021, were Quality assessment of each article was conducted inde- searched on PubMed, Embase, Cochrane Library, and pendently by 6 researchers (ML, YRL, JQL, YWC, XJC, Web of Science by two researchers (ML, YRL) indepen- YPL) according to the Quality Assessment of Studies of dently. In addition, the references of the included litera- Diagnostic Accuracy included in Systematic Reviews-2 ture and unpublished literature  were hand-searched by (QUADAS-2) [17]. The QUADAS-2 includes 4 parts: two researchers (JQL, ML) to make sure all the relevant indicator testing, reference criteria, patient selection, and articles are covered. Discrepancies were resolved by dis- process and time. And each section could be considered cussion among all the researchers. The MeSH terms as high, unclear, or low risk of bias independently. All and search strategies are reported in (Additional file  1): analyses were done with Excel and Review Manager 5.3.0 appendix S1. (The Cochrane Collaboration, Copenhagen, Denmark). Lin  et al. Ann Clin Microbiol Antimicrob (2022) 21:25 Page 3 of 8 Table 1 Summary of the characteristics of included studies First author Year Country Study design The Age of patients Patients Initial Research Test method specimen with sample involved source gender size Frederick S 2010 Georgia Prospective CSF 156neonates ALL 475 416 GXEA Nolte [16] and retrospec‑ 227Children tive 53Adults Katja Seme (a) 2008 The Republic of Prospective CSF UC UC 162 162 GXEA [19] Slovenia Katja Seme (b) 2008 The Republic of Prospective CSF UC UC 162 162 GXEA [19] Slovenia Marlowe, E. M. 2008 USA Retrospective CSF UC UC 138 136 GXEA [15] Ninove, L. [12] 2011 France Prospective CSF < 1 year,1–4 years,5– ALL 310 310 GXEA 14 years,15– 24 years,25– 49 years, > 50 years Ninove, Laetitia 2010 France Prospective CSF ALL UC 469 390 GXEA [12] S.C.M. de Crom 2011 Netherlands Retrospective CSF 0–84.10 ALL 116 232 GXEA [21] Slika, S. [22] 2012 USA Prospective CSF UC UC 220 220 GXEA First author Positive Negative Reference Positive Negative TP FP TN FN standard Frederick S Nolte 114 312 RT‑PCR 94 322 90 14 308 4 [16] Katja Seme (a) [19] 75 87 RT‑PCR 83 79 75 0 79 8 Katja Seme (b) 82 80 RT‑PCR 83 79 82 0 79 1 [19] Marlowe, E. M. [15] 25 111 RT‑PCR 25 111 25 0 111 0 Ninove, L. [12] 85 174 RT‑PCR 81 225 81 0 172 2 Ninove, Laetitia 109 289 RT‑PCR 108 352 105 2 283 0 [12] S.C.M. de Crom 32 185 RT‑PCR 40 192 32 0 178 7 [21] Slika, S. [22] 42 178 RT‑PCR 42 178 42 0 178 0 CSF, cerebrospinal fluid; UC, unclear; TP, ture positive; FP, false positive; TN, ture negative; FN, false negative In this search, preliminary results using RT-PCR and GeneXpert EV assay detection In this search, final results were obtained by reexamining the preliminary negative and uncertain results Disagreements will be discussed and decided by the Box plot by using Stata12.0. In the end, the table check- above 6 researchers. list of this systematic review and meta-analysis could be found in Additional file 2. Statistical analysis The Meta-Disc [18] was applied to analyze the pooled Results sensitivity, pooled specificity, diagnostic positive likeli - Eligible studies after systematic review hood ratio (+ LR), diagnostic negative LR (-LR), diagnos- 36 citations were obtained totally, including 33 citations tic odds ratio (DOR), and SROC curve with all the 95% from the systematic review, and 3 citations from hand- confidence intervals (95% CI). The publication bias of searched. According to the inclusion and exclusion items, sensitivity and specificity in the included studies was ana - 7 citations were left [12, 16, 19–22]. In Katja Seme’s work, lyzed in Stata12.0 with Deeks’ funnel plot. In addition, preliminary results were obtained by using RT-PCR and heterogeneity was evaluated according to the Bivariate GeneXpert EV assay detection. However, due to invalid Lin et al. Ann Clin Microbiol Antimicrob (2022) 21:25 Page 4 of 8 Fig. 1 Risk of bias and applicability concerns graph results existing (preliminary negative and uncertain), the only 4 articles provided the ages of the patients clearly authors reexamined and obtained the final results [19]. [12, 16, 20, 21]. All the studies did not use platforms. The u Th s, the datasets from Katja Seme were divided into two characteristics were summarized in Table 1. 2*2 tables. The search process and results according to PRISMA 2009 Flow Diagram are outlined in Additional Quality assessment of the included studies according file 3. to QUADAS‑2 In Patient Selection, all the studies were considered as Study characteristics of the included studies low risk of bias. In Index Text, 2 articles were consid- In all included studies, 2 articles were retrospective [21], ered as unclear risk of bias because the results of the gold and 1 article was both retrospective and prospective [16], standard and index test were given at the same time; 4 Lin  et al. Ann Clin Microbiol Antimicrob (2022) 21:25 Page 5 of 8 Fig. 2 Sensitivity (A), specificity (B), PLR (C) and NLR (D) Fig. 3 Diagnostic Odds Ratio (DOR) articles were likely to have a high risk of bias because (0.98 – 0.99)], Pooled Positive LR (C) was 130.46 the results of the index test were not carried out without [95% CI (35.79–475.58)], Pooled Negative LR (D) was knowing the results of the gold standard. In Reference 0.04 [95% CI (0.02–0.10)], and Pooled Diagnostic Standard, 2 studies were likely to have an unclear risk and Odds Ratio was 3648.23 (95% CI [963.99–13,806.72)] a high risk of bias, respectively. In Flow and Timing, all (Figs. 2A–D, 3.) studies were likely to have a low risk of bias. The results were plotted in Fig. 1. SROC curve of Xpert EV assay for enteroviral meningitis In SROC Curve (Fig.  4.), AUC was 0.9980, Q index Diagnostic accuracy of expert EV assay for enteroviral was 0.9849. Both results were close to 1, indicating the meningitis high accuracy of the GeneXpert EV in the diagnosis of The Pooled Sensitivity (A) was 0.96 [95% CI (0.94– enteroviral meningitis. 0.97)], Pooled Specificity(B) was 0.99 [95% CI Lin et al. Ann Clin Microbiol Antimicrob (2022) 21:25 Page 6 of 8 Fig. 4 SROC Curve AB Bivariate Boxplot 2 3 4 5 6 7 LOGIT_SPEC Fig. 5 Deeks’ funnel plot (A) and Bivariate box plot (B) 0 2 4 6 Lin  et al. Ann Clin Microbiol Antimicrob (2022) 21:25 Page 7 of 8 Publication bias of the included studies results could be obtained rapidly (only 2.5 h) within the Deeks’ funnel plot test was conducted to evaluate the spinal fluid collection when using GeneXpert EV assay publication bias. In the results, most of the points are [25]. Fourth, the GeneXpert EV assay is a fully auto- symmetrical and the P-value was 0.807 (P > 0.05), indi- matic method, that could be operated easily that spe- cating that no publication bias exists [23]. The Deeks’ cially trained laboratory staff were not required [16]. funnel plot result could be sought in Fig. 5A. There are several drawbacks to this systematic review. On the one hand, we only brought English studies into consideration in our study, omitting studies in different Heterogeneity analysis languages. On the other hand, there were only 8 sets of The Bivariate Box plot shows no evident heterogeneity data in this analysis due to the insufficiency of qualified among the included studies (Fig. 5B). The Pooled Diag - studies. Besides, we failed to extract part of the data nostic Odds Ratio shows no significant heterogeneity due to the limitation of data sources. through the random-effects model (I = 45.9% < 50%, Cochran-Q = 12.93, Fig . 3). Conclusions Discussion In general, the GeneXpert EV assay in diagnosing In this systematic review and meta-analysis, we eval- enteroviral meningitis has been further studied through uated the GeneXpert EV assay in the diagnosis of systematic review and meta-analysis in this work. The enterovirus meningitis. On the one hand, the results results demonstrate that the GeneXpert EV assay has demonstrate that GeneXpert EV assay has high sensi- shown good performance in the diagnosis of enterovi- tivity and specificity, although one outlier exists with rus meningitis. As a supplementary method for entero- a lower sensitivity of 0.82 [95% CI (0.66–0.92)]. The virus meningitis diagnosis, the GeneXpert EV assay is outlier may cause by the two-step PT-PCR, which worthy to be popularized in clinical practice. However, was considered with a higher diagnosis performance more clinical studies are needed to further explore its than one-step RT-PCR [21]. In Positive LR, a numeri- role in different viral loads and different patients. cal value is lower than others {22.02 [95% CI (13.17– 36.82)]}. The lower value can be explained by intricate operations of the equipment with the assumption of FP Abbreviations EV: Enteroviral; QUADAS: Quality assessment of diagnostic accuracy studies; results may not cause by a target and amplicon cross- NLR: Negative likelihood ratio; PLR: Positive likelihood ratio; CI: Confidence contamination [16]. interval; DOR: Diagnostic odds ratio; SROC: Summary receiver operating char‑ On the other hand, no evident heterogeneity exists in acteristic; AUC : Area under the curve. the Bivariate Box plot. In addition, there was no curve pattern (shoulder-arm pattern) in the SROC Curve [18], Supplementary Information indicating no evident heterogeneity. Furthermore, the The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s12941‑ 022‑ 00517‑3. inconsistency was 45.9% in the frost plot of Diagnostic Odds Ratio, which proved the above results once again. Additional file 1: S1. Search terms and search strategy. However, the inconsistency was 78.8% in the frost plot Additional file 2: S2. Table Checklist of this systematic review and of Sensitivity, which was prompting the high heteroge- meta‑analysis. neity in the study. Thus, we explored the sources of the Additional file 3: S3. Screening processes. heterogeneity: First, the lower sensitivity in the Gen- eXpert EV assay may be a result of lacking a 1:5 sam- Acknowledgements ple dilution of CSF in saline, or freezing and thawing We express our sincere gratitude to all the patients and clinical researchers the undiluted CSF [24]. Second, the performance of who were involved in the included studies for their wonderful work and valu‑ able participation. the GeneXpert EV assay may be influenced by the dif - ferent lumbar puncture practices in different regions Author contributions [19]. Unfortunately, since the lack of information, we ML, YRL, JQL, XJC, YWC, YPL, GYW, and XGG conceived and designed the experiments. ML, YRL, XJC, YWC, GYW, and JQL analyzed the studies and couldn’t extract this data from included studies. extracted data. ML and YRL contributed to making tables. ML, YRL, LJL, JQL, Undoubtedly, some advantages are represented in YPL, GYW, QWL and contributed to the production of figures. All authors par ‑ the GeneXpert EV assay. First, since the GeneXpert ticipated in the writing, reading, and revision of the manuscript and approved the final version of the manuscript. All authors read and approved the final EV assay cartridge is completely self-contained and manuscript. performs all assay steps including sample preparation, the false positive due to cross-contamination could Funding No funding was used to support this study. be avoided. Second, the GeneXpert EV assay is robust and not prone to operator error [16, 19]. Third, reliable Lin et al. Ann Clin Microbiol Antimicrob (2022) 21:25 Page 8 of 8 Availability of data and materials 10. 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Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, zhou 510150, China. Department of Laboratory Medicine, Key Laboratory Leeflang MM, Sterne JA, Bossuyt PM. QUADAS‑2: a revised tool for the of Reproduction and Genetics of Guangdong Higher Education Institutes, The quality assessment of diagnostic accuracy studies. Ann Intern Med. Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, 2011;155(8):529–36. China. 18. Zamora J, Abraira V, Muriel A, Khan K, Coomarasamy A. Meta‑DiSc: a software for meta‑analysis of test accuracy data. BMC Med Res Methodol. Received: 25 August 2021 Accepted: 26 May 2022 2006;6:31. 19. Seme K, Mocilnik T, Komlos KF, Doplihar A, Persing DH, Poljak M. Gen‑ eXpert enterovirus assay: one‑ year experience in a routine laboratory setting and evaluation on three proficiency panels. J Clin Microbiol. 2008;46(4):1510–3. References 20. Ninove L, Nougairede A, Gazin C, Zandotti C, Drancourt M, de Lamballerie 1. 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Evaluation of GeneXpert EV assay for the rapid diagnosis of enteroviral meningitis: a systematic review and meta-analysis

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Evaluation of GeneXpert EV assay for the rapid diagnosis of enteroviral meningitis: a systematic review and meta-analysis

Abstract

BackgroundGeneXpert enterovirus Assay is a PCR-based assay for Enterovirus meningitis diagnosis. However, there is currently no research about the performance of GeneXpert enterovirus assay in the diagnosis of enterovirus meningitis. Thus, a systematic review and meta-analysis is significant on the topic.MethodsEmbase, Cochrane Library, Web of Science, and PubMed were systematically reviewed with retrieval types. Some criteria were used to filter the studies. Only studies published in English, that made a comparison between GeneXpert enterovirus assay and RT-PCR, and could be formulated in a 2*2 table, were included. The quality of the included studies was evaluated by QUADAS-2. The effect of the GeneXpert enterovirus assay was assessed by the Sensitivity, Specificity, Positive Likelihood Ratio, Negative Likelihood Ratio, Diagnosis Odds Ratio, and summary receiver operating characteristic (SROC) curve. Publication bias and heterogeneity were evaluated by the Deeks' funnel test and Bivariate Box plot respectively.Results7 studies were recruited in the analysis. The Pooled Sensitivity was 0.96 [95% CI (0.94–0.97)], Pooled Specificity was 0.99 [95% CI (0.98–0.99)], Positive Likelihood Ratio was 130.46 [95% CI (35.79–475.58)], Negative Likelihood Ratio was 0.04 [95% CI (0.02–0.10)], and Diagnostic Odds Ratio was 3648.23 (95% CI [963.99–13,806.72)]. In SROC Curve, Area Under Curve (AUC) was 0.9980, and Q*= 0.9849. In Deeks' funnel test, the P-value was 0.807 (P > 0.05), indicating no publication bias. The Bivariate Box plot indicated no evident heterogeneity.ConclusionsThe GeneXpert enterovirus assay demonstrated high diagnostic accuracy in diagnosing enterovirus meningitis.

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Copyright © The Author(s) 2022
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DOI
10.1186/s12941-022-00517-3
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Abstract

Background: GeneXpert enterovirus Assay is a PCR‑based assay for Enterovirus meningitis diagnosis. However, there is currently no research about the performance of GeneXpert enterovirus assay in the diagnosis of enterovirus menin‑ gitis. Thus, a systematic review and meta‑analysis is significant on the topic. Methods: Embase, Cochrane Library, Web of Science, and PubMed were systematically reviewed with retrieval types. Some criteria were used to filter the studies. Only studies published in English, that made a comparison between GeneXpert enterovirus assay and RT‑PCR, and could be formulated in a 2*2 table, were included. The quality of the included studies was evaluated by QUADAS‑2. The effect of the GeneXpert enterovirus assay was assessed by the Sen‑ sitivity, Specificity, Positive Likelihood Ratio, Negative Likelihood Ratio, Diagnosis Odds Ratio, and summary receiver operating characteristic (SROC) curve. Publication bias and heterogeneity were evaluated by the Deeks’ funnel test and Bivariate Box plot respectively. Results: 7 studies were recruited in the analysis. The Pooled Sensitivity was 0.96 [95% CI (0.94–0.97)], Pooled Speci‑ ficity was 0.99 [95% CI (0.98–0.99)], Positive Likelihood Ratio was 130.46 [95% CI (35.79–475.58)], Negative Likelihood Ratio was 0.04 [95% CI (0.02–0.10)], and Diagnostic Odds Ratio was 3648.23 (95% CI [963.99–13,806.72)]. In SROC Curve, Area Under Curve (AUC) was 0.9980, and Q*= 0.9849. In Deeks’ funnel test, the P‑ value was 0.807 (P > 0.05), indicating no publication bias. The Bivariate Box plot indicated no evident heterogeneity. Conclusions: The GeneXpert enterovirus assay demonstrated high diagnostic accuracy in diagnosing enterovirus meningitis. Keywords: GeneXpert EV, Enterovirus meningitis, PCR, Systematic‑review, Meta‑analysis 30 nm [2]. Meningitis contains bacterial meningitis and Introduction aseptic meningitis. As one of aseptic meningitis, which The Enterovirus genus is one of the most populous in is infected by an enterovirus, [3] Enterovirus menin- the family Picornaviridae [1], in which, human Entero- gitisis the most common non-bacterial meningitis and viruses (Human EVs) have been discovered with more accounts for 90% in children and adults. However, no than 250 subtypes and with a diameter between 28 and antiviral drugs have been approved for the treatment of EV infections [4]. In addition, most patients with *Correspondence: gysygxg@gmail.com enterovirus meningitis have no obvious symptoms after infection, with only less than 10 percent of patients Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China behave obvious symptoms and can receive treatment Full list of author information is available at the end of the article © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lin et al. Ann Clin Microbiol Antimicrob (2022) 21:25 Page 2 of 8 timely [2]. If it is hard to quickly and accurately diag- Study selection nose whether it’s enterovirus meningitis, patients might All researchers have received prior training in system- receive unnecessary treatment or hospitalization [5, 6]. atic reviews and meta-analysis. The Kappa test was Therefore, simple and reliable methods of identifying used to assess the agreement among the results given patients whether infected with enterovirus meningitis by the researchers. 50 citations are selected randomly are critical to the clinic. to screen and calculate the Kappa value. If Kappa was Nucleic acid amplification methods (NAATs) are less than 0.75, the second round of training will be widely used in the diagnosis of enterovirus meningitis carried out. Titles and abstracts are screened by two [7]. The real-time polymerase chain reaction (RT-PCR) researchers independently (YWC, XJC). The screening is a kind of NAATs. In 2003, the World Health Organi- of full texts will be screened by two other researchers zation (WHO) announced the adoption of RT-PCR to (ML, GYW). Disagreements were resolved by consen- detect enteroviruses meningitis. Compared with the sus of all researchers. Overall, studies eligible for inclu- traditional viral culture [8, 9], RT-PCR can make a diag- sion met all of the following criteria: (1) Published in nosis within a shorter time of 7 h, and with higher sen- English; (2) GeneXpert EV assay as an index text; (3) sitivity and specificity (approximately 100%) [10, 11]. RT-PCR as the reference standard; (4) Data in studies Nowadays, RT-PCR is considered the gold standard for could be formed a 2*2 table. The criteria for exclusion the diagnosis and identification of enterovirus meningi - were as follows: (1) Non-English pieces of literature; tis [12]. But RT-PCR assay has two evident limitations. (2) The index text was no GeneXpert EV assay; (3) The On the one hand, it is too expensive and couldn’t be reference standard was no RT-PCR; (4) The article data applied in budget-limited rural clinics in some regions. was not enough to formulate the 2*2 table; (5) Stud- On the other hand, when detecting CSF samples from ies included conference abstracts or reviews were also low viral load level, like the early phase of infection, its excluded. The Preferred Reporting Items for System - sensitivity is too low to detecting enteroviruses menin- atic Reviews and Meta-Analyses (PRISM) was used to gitis [13, 14]. describe the steps of the study selection in the system- The GeneXpert EV assay (GXEA, Cepheid, Sunny - atic review and meta-analysis. vale, CA) is a fully integrated automated nucleic acid sample preparation system that consists of instru- ments, computers, and disposable fluid boxes [9 ], with Data extraction a diagnostic turnaround time of 2.5  h [15]. What’s The name of the first author, year of publication, coun - more, because its test box is completely independent try, experiment type (prospective or retrospective), the and could conduct all the procedures, there is less FP source and quantity of samples, patient’s age and gen- in GeneXpert EV Assay in the diagnosis of enteroviral der, index test, gold standard, true-positive (TP), false- meningitis [9, 16]. However, so far, there is no com- positive (FP), true-negative (TN) and false-negative (FN) prehensive and systematic study for GeneXpert EV were extracted from each included study. Due to the limi- assay. Thus, in the present work, we conducted a sys - tation of datasets, the classification of RT-PCR couldn’t tematic review and meta-analysis to explore the diag- be extracted from the included studies. Data were nostic accuracy of GeneXpert EV assay in enteroviral extracted by 7 researchers of the study team (ML, YRL, meningitis. GYW, QWL, WHY, YPL, and JQL) independently. They were blinded to each other’s results. Disagreements were resolved by consensus. Methods Search methods Original studies published in English from the estab- Quality assessment lishment of the databases to January 30, 2021, were Quality assessment of each article was conducted inde- searched on PubMed, Embase, Cochrane Library, and pendently by 6 researchers (ML, YRL, JQL, YWC, XJC, Web of Science by two researchers (ML, YRL) indepen- YPL) according to the Quality Assessment of Studies of dently. In addition, the references of the included litera- Diagnostic Accuracy included in Systematic Reviews-2 ture and unpublished literature  were hand-searched by (QUADAS-2) [17]. The QUADAS-2 includes 4 parts: two researchers (JQL, ML) to make sure all the relevant indicator testing, reference criteria, patient selection, and articles are covered. Discrepancies were resolved by dis- process and time. And each section could be considered cussion among all the researchers. The MeSH terms as high, unclear, or low risk of bias independently. All and search strategies are reported in (Additional file  1): analyses were done with Excel and Review Manager 5.3.0 appendix S1. (The Cochrane Collaboration, Copenhagen, Denmark). Lin  et al. Ann Clin Microbiol Antimicrob (2022) 21:25 Page 3 of 8 Table 1 Summary of the characteristics of included studies First author Year Country Study design The Age of patients Patients Initial Research Test method specimen with sample involved source gender size Frederick S 2010 Georgia Prospective CSF 156neonates ALL 475 416 GXEA Nolte [16] and retrospec‑ 227Children tive 53Adults Katja Seme (a) 2008 The Republic of Prospective CSF UC UC 162 162 GXEA [19] Slovenia Katja Seme (b) 2008 The Republic of Prospective CSF UC UC 162 162 GXEA [19] Slovenia Marlowe, E. M. 2008 USA Retrospective CSF UC UC 138 136 GXEA [15] Ninove, L. [12] 2011 France Prospective CSF < 1 year,1–4 years,5– ALL 310 310 GXEA 14 years,15– 24 years,25– 49 years, > 50 years Ninove, Laetitia 2010 France Prospective CSF ALL UC 469 390 GXEA [12] S.C.M. de Crom 2011 Netherlands Retrospective CSF 0–84.10 ALL 116 232 GXEA [21] Slika, S. [22] 2012 USA Prospective CSF UC UC 220 220 GXEA First author Positive Negative Reference Positive Negative TP FP TN FN standard Frederick S Nolte 114 312 RT‑PCR 94 322 90 14 308 4 [16] Katja Seme (a) [19] 75 87 RT‑PCR 83 79 75 0 79 8 Katja Seme (b) 82 80 RT‑PCR 83 79 82 0 79 1 [19] Marlowe, E. M. [15] 25 111 RT‑PCR 25 111 25 0 111 0 Ninove, L. [12] 85 174 RT‑PCR 81 225 81 0 172 2 Ninove, Laetitia 109 289 RT‑PCR 108 352 105 2 283 0 [12] S.C.M. de Crom 32 185 RT‑PCR 40 192 32 0 178 7 [21] Slika, S. [22] 42 178 RT‑PCR 42 178 42 0 178 0 CSF, cerebrospinal fluid; UC, unclear; TP, ture positive; FP, false positive; TN, ture negative; FN, false negative In this search, preliminary results using RT-PCR and GeneXpert EV assay detection In this search, final results were obtained by reexamining the preliminary negative and uncertain results Disagreements will be discussed and decided by the Box plot by using Stata12.0. In the end, the table check- above 6 researchers. list of this systematic review and meta-analysis could be found in Additional file 2. Statistical analysis The Meta-Disc [18] was applied to analyze the pooled Results sensitivity, pooled specificity, diagnostic positive likeli - Eligible studies after systematic review hood ratio (+ LR), diagnostic negative LR (-LR), diagnos- 36 citations were obtained totally, including 33 citations tic odds ratio (DOR), and SROC curve with all the 95% from the systematic review, and 3 citations from hand- confidence intervals (95% CI). The publication bias of searched. According to the inclusion and exclusion items, sensitivity and specificity in the included studies was ana - 7 citations were left [12, 16, 19–22]. In Katja Seme’s work, lyzed in Stata12.0 with Deeks’ funnel plot. In addition, preliminary results were obtained by using RT-PCR and heterogeneity was evaluated according to the Bivariate GeneXpert EV assay detection. However, due to invalid Lin et al. Ann Clin Microbiol Antimicrob (2022) 21:25 Page 4 of 8 Fig. 1 Risk of bias and applicability concerns graph results existing (preliminary negative and uncertain), the only 4 articles provided the ages of the patients clearly authors reexamined and obtained the final results [19]. [12, 16, 20, 21]. All the studies did not use platforms. The u Th s, the datasets from Katja Seme were divided into two characteristics were summarized in Table 1. 2*2 tables. The search process and results according to PRISMA 2009 Flow Diagram are outlined in Additional Quality assessment of the included studies according file 3. to QUADAS‑2 In Patient Selection, all the studies were considered as Study characteristics of the included studies low risk of bias. In Index Text, 2 articles were consid- In all included studies, 2 articles were retrospective [21], ered as unclear risk of bias because the results of the gold and 1 article was both retrospective and prospective [16], standard and index test were given at the same time; 4 Lin  et al. Ann Clin Microbiol Antimicrob (2022) 21:25 Page 5 of 8 Fig. 2 Sensitivity (A), specificity (B), PLR (C) and NLR (D) Fig. 3 Diagnostic Odds Ratio (DOR) articles were likely to have a high risk of bias because (0.98 – 0.99)], Pooled Positive LR (C) was 130.46 the results of the index test were not carried out without [95% CI (35.79–475.58)], Pooled Negative LR (D) was knowing the results of the gold standard. In Reference 0.04 [95% CI (0.02–0.10)], and Pooled Diagnostic Standard, 2 studies were likely to have an unclear risk and Odds Ratio was 3648.23 (95% CI [963.99–13,806.72)] a high risk of bias, respectively. In Flow and Timing, all (Figs. 2A–D, 3.) studies were likely to have a low risk of bias. The results were plotted in Fig. 1. SROC curve of Xpert EV assay for enteroviral meningitis In SROC Curve (Fig.  4.), AUC was 0.9980, Q index Diagnostic accuracy of expert EV assay for enteroviral was 0.9849. Both results were close to 1, indicating the meningitis high accuracy of the GeneXpert EV in the diagnosis of The Pooled Sensitivity (A) was 0.96 [95% CI (0.94– enteroviral meningitis. 0.97)], Pooled Specificity(B) was 0.99 [95% CI Lin et al. Ann Clin Microbiol Antimicrob (2022) 21:25 Page 6 of 8 Fig. 4 SROC Curve AB Bivariate Boxplot 2 3 4 5 6 7 LOGIT_SPEC Fig. 5 Deeks’ funnel plot (A) and Bivariate box plot (B) 0 2 4 6 Lin  et al. Ann Clin Microbiol Antimicrob (2022) 21:25 Page 7 of 8 Publication bias of the included studies results could be obtained rapidly (only 2.5 h) within the Deeks’ funnel plot test was conducted to evaluate the spinal fluid collection when using GeneXpert EV assay publication bias. In the results, most of the points are [25]. Fourth, the GeneXpert EV assay is a fully auto- symmetrical and the P-value was 0.807 (P > 0.05), indi- matic method, that could be operated easily that spe- cating that no publication bias exists [23]. The Deeks’ cially trained laboratory staff were not required [16]. funnel plot result could be sought in Fig. 5A. There are several drawbacks to this systematic review. On the one hand, we only brought English studies into consideration in our study, omitting studies in different Heterogeneity analysis languages. On the other hand, there were only 8 sets of The Bivariate Box plot shows no evident heterogeneity data in this analysis due to the insufficiency of qualified among the included studies (Fig. 5B). The Pooled Diag - studies. Besides, we failed to extract part of the data nostic Odds Ratio shows no significant heterogeneity due to the limitation of data sources. through the random-effects model (I = 45.9% < 50%, Cochran-Q = 12.93, Fig . 3). Conclusions Discussion In general, the GeneXpert EV assay in diagnosing In this systematic review and meta-analysis, we eval- enteroviral meningitis has been further studied through uated the GeneXpert EV assay in the diagnosis of systematic review and meta-analysis in this work. The enterovirus meningitis. On the one hand, the results results demonstrate that the GeneXpert EV assay has demonstrate that GeneXpert EV assay has high sensi- shown good performance in the diagnosis of enterovi- tivity and specificity, although one outlier exists with rus meningitis. As a supplementary method for entero- a lower sensitivity of 0.82 [95% CI (0.66–0.92)]. The virus meningitis diagnosis, the GeneXpert EV assay is outlier may cause by the two-step PT-PCR, which worthy to be popularized in clinical practice. However, was considered with a higher diagnosis performance more clinical studies are needed to further explore its than one-step RT-PCR [21]. In Positive LR, a numeri- role in different viral loads and different patients. cal value is lower than others {22.02 [95% CI (13.17– 36.82)]}. The lower value can be explained by intricate operations of the equipment with the assumption of FP Abbreviations EV: Enteroviral; QUADAS: Quality assessment of diagnostic accuracy studies; results may not cause by a target and amplicon cross- NLR: Negative likelihood ratio; PLR: Positive likelihood ratio; CI: Confidence contamination [16]. interval; DOR: Diagnostic odds ratio; SROC: Summary receiver operating char‑ On the other hand, no evident heterogeneity exists in acteristic; AUC : Area under the curve. the Bivariate Box plot. In addition, there was no curve pattern (shoulder-arm pattern) in the SROC Curve [18], Supplementary Information indicating no evident heterogeneity. Furthermore, the The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s12941‑ 022‑ 00517‑3. inconsistency was 45.9% in the frost plot of Diagnostic Odds Ratio, which proved the above results once again. Additional file 1: S1. Search terms and search strategy. However, the inconsistency was 78.8% in the frost plot Additional file 2: S2. Table Checklist of this systematic review and of Sensitivity, which was prompting the high heteroge- meta‑analysis. neity in the study. Thus, we explored the sources of the Additional file 3: S3. Screening processes. heterogeneity: First, the lower sensitivity in the Gen- eXpert EV assay may be a result of lacking a 1:5 sam- Acknowledgements ple dilution of CSF in saline, or freezing and thawing We express our sincere gratitude to all the patients and clinical researchers the undiluted CSF [24]. Second, the performance of who were involved in the included studies for their wonderful work and valu‑ able participation. the GeneXpert EV assay may be influenced by the dif - ferent lumbar puncture practices in different regions Author contributions [19]. Unfortunately, since the lack of information, we ML, YRL, JQL, XJC, YWC, YPL, GYW, and XGG conceived and designed the experiments. ML, YRL, XJC, YWC, GYW, and JQL analyzed the studies and couldn’t extract this data from included studies. extracted data. ML and YRL contributed to making tables. ML, YRL, LJL, JQL, Undoubtedly, some advantages are represented in YPL, GYW, QWL and contributed to the production of figures. All authors par ‑ the GeneXpert EV assay. First, since the GeneXpert ticipated in the writing, reading, and revision of the manuscript and approved the final version of the manuscript. All authors read and approved the final EV assay cartridge is completely self-contained and manuscript. performs all assay steps including sample preparation, the false positive due to cross-contamination could Funding No funding was used to support this study. be avoided. Second, the GeneXpert EV assay is robust and not prone to operator error [16, 19]. Third, reliable Lin et al. Ann Clin Microbiol Antimicrob (2022) 21:25 Page 8 of 8 Availability of data and materials 10. 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Journal

Annals of Clinical Microbiology and Antimicrobials – Springer Journals

Published: Jun 9, 2022

Keywords: GeneXpert EV; Enterovirus meningitis; PCR; Systematic-review; Meta-analysis

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