Elsevier

Journal of Infection

Volume 64, Issue 6, June 2012, Pages 580-588
Journal of Infection

Rapid and effective diagnosis of tuberculosis and rifampicin resistance with Xpert MTB/RIF assay: A meta-analysis

https://doi.org/10.1016/j.jinf.2012.02.012Get rights and content

Summary

Objectives

Xpert MTB/RIF (Cepheid) assay has been introduced for the diagnosis of tuberculosis (TB) and RIF-resistance. The meta-analysis was used to establish the overall accuracy of Xpert MTB/RIF assay for diagnosing TB and RIF-resistance.

Methods

Based on comprehensive searches of the Pubmed and Embase, we identified outcome data from all articles estimating diagnostic accuracy with Xpert MTB/RIF assay. A summary estimation for sensitivity, specificity, diagnostic odds ratios (DOR) and the area under the summary ROC curve (AUC) was calculated by using the bivariate random-effects approach.

Results

The meta-analysis included 18 studies (10,224 suspected specimens). The summary estimate was 90.4% (95%CI 89.2%–91.4%) for sensitivity, 98.4% (95%CI 98.0%–98.7%) for specificity and 328.3/0.9822 for DOR/AUC in pulmonary tuberculosis (PTB). The sensitivity, specificity and DOR/AUC of detecting RIF-resistance were 94.1%, 97.0% and 177.8/0.9832, respectively. For extrapulmonary tuberculosis, the overall pooled sensitivity was 80.4% and specificity was 86.1%. The findings in subgroup analysis were as follows: the accuracy of Xpert MTB/RIF assay is higher in smear-positive specimens and the sensitivity of diagnosing PTB in adults was higher than that in children (90.8% versus 74.3%).

Conclusions

TB and RIF-resistance can be rapidly and effectively diagnosed with Xpert MTB/RIF assay.

Introduction

Tuberculosis (TB) constitutes a serious threat to public health in the world, with nearly 10 million new cases and 1.7 million deaths annually.1 The incidence of multidrug resistant (MDR) TB is increasing with almost 0.5 million reported new cases in 2008.2 The global control of TB and MDR-TB has created an urgent need for timely and effectively diagnostic method.

Rapid and effective diagnosis of patients suspected of having TB remains a challenge. The conventional TB diagnosis techniques, including methods based on direct microscopic examination by Ziehl–Neelsen staining, culture, chest radiography and tuberculin skin testing3 have limitations and are thus not always helpful in diagnosing TB. Smear microscopy alone, although cheap and easy to perform, has a highly false-negative result and cannot identify drug-resistance.4, 5 Currently, only 28% of expected incident cases of tuberculosis are detected and reported as smear positive.1 Although the culture is more sensitive than the smear microscopy, culture generally provides results in at least 2–8 weeks6 requires biosafety measures, and needs specialized laboratory personnel.7 This leads to a diagnostic delay that impedes disease control, and increases healthcare costs.8 Since the discovery of the polymerase chain reaction (PCR), a large number of molecular techniques have been developed.9 However, their sensitivity is greatly dependent on the efficiency of the sample preparation, DNA extraction and the presence of PCR inhibitors.10, 11 Therefore, a simple, rapid and effective method for TB diagnosis remains to be developed.

One of latest assay, Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) assay, was evaluated in large studies recently. The assay detects Mycobacterium tuberculosis (Mtb) and RIF-resistance by PCR amplifying five overlapping probes complementary to the rifampin resistance-determining region (RRDR) of the Mtb rpoB gene,12 and subsequently probes this region for mutations that are associated with RIF-resistance.13, 14 The PCR amplification process is heminested to minimize cross-amplification of nontuberculosis mycobacterium (NTM) species, and to maximize mutation detection.14 RIF-resistance can serve as a marker for MDR-TB. Therefore, the assay may fulfill the requirement of diagnosing TB and MDR-TB. Compared to conventional diagnosis methods, the Xpert MTB/RIF assay could detect TB and RIF-resistance in one sputum sample within 2 h.14 In addition, the assay can diagnose TB with a nearly fully automated manner, including bacterial lysis, nucleic acid extraction and amplification, and amplicon detection. Furthermore, the assay requires minimal biosafety measures.15

The diagnostic performance of Xpert MTB/RIF assay has been investigated in several studies, which have variable results. The aim of this meta-analysis is to establish the overall diagnostic accuracy of Xpert MTB/RIF assay and identify potential confounders or effective modifiers of its value in TB, thus providing the important up-to-date information on Xpert MTB/RIF assay for TB diagnosis.

Section snippets

Data sources and search strategy

The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines for the conduct of meta-analyses of observational cohort studies was followed.16 Two investigators (K.C. and W.L.) independently performed a systematic electronic search of the Pubmed and Embase databases for original articles published until 1 October 2011 to identify potentially relevant articles and abstracts. The following search terms were used: “Xpert MTB/RIF Assay” OR “Xpert MTB” OR “Xpert MTB RIF” OR “Xpert”

Search result

A total of 90 studies were identified in the Pubmed and Embase databases. After we evaluated these citations and the bibliographies of the potential studies, 18 unique studies were eventually included in our meta-analysis. The main reasons of excluding 72 other studies were as follows: the study was a duplicate between the PubMed and Embase database, the study was not diagnostic, or the study cannot reconstruct the diagnostic 2 by 2 table.

Study characteristics and quality assessment

Overall, the selected 18 studies included 10,224

Discussion

In this study, we clarified the diagnostic accuracy of Xpert MTB/RIF assay for PTB and EPTB. We evaluated the diagnostic accuracy of Xpert MTB/RIF assay for RIF-resistant PTB and HIV-PTB co-infection. In addition, the diagnostic accuracy in different smear status and age were also explored. To our knowledge, this is the first systematic review and meta-analysis to estimate the diagnostic accuracy of Xpert MTB/RIF assay in TB.

The results of these 15 studies showed that Xpert MTB/RIF assay was

Conclusions

The Xpert MTB/RIF assay fulfills the requirements of rapidly and effectively diagnosing TB and RIF-resistance. The single Xpert MTB/RIF assay diagnosed 90.4% of culture-confirmed PTB patients (98.7% in smear-positive specimens, 75.0% in smear-negative specimens) and 80.4% of EPTB patients (95.2% in smear-positive specimens, 70.7% in smear-negative specimens). RIF-resistant PTB was diagnosed with 94.1% for sensitivity and 97.0% for specificity. In a word, the introduction of Xpert MTB/RIF assay

Conflict of interest

We have no conflict of interest for this article.

Acknowledgments

The authors would like to express thanks to Prof. Wei Sun to review the manuscript. This work was supported by the Major Project Chinese National Programs for High Technology Research and Development (863 Program, 2007AA02Z416), the Chinese National Natural Science Foundation (No. 81071428, 30400107) and the National Infectious Disease Prevention and Cure Special Project (No. 2008ZX10003-012).

References (43)

  • S. Honore-Bouakline et al.

    Rapid diagnosis of extrapulmonary tuberculosis by PCR: impact of sample preparation and DNA extraction

    J Clin Microbiol

    (2003)
  • S. Chakravorty et al.

    Diagnosis of extrapulmonary tuberculosis by smear, culture, and PCR using universal sample processing technology

    J Clin Microbiol

    (2005)
  • A. Van Rie et al.

    Xpert((R)) MTB/RIF for point-of-care diagnosis of TB in high-HIV burden, resource-limited countries: hype or hope?

    Expert Rev Mol Diagn

    (2010)
  • R. Blakemore et al.

    Evaluation of the analytical performance of the Xpert MTB/RIF assay

    J Clin Microbiol

    (2010)
  • D. Helb et al.

    Rapid detection of Mycobacterium tuberculosis and rifampin resistance by use of on-demand, near-patient technology

    J Clin Microbiol

    (2010)
  • P.P. Banada et al.

    Containment of bioaerosol infection risk by the Xpert MTB/RIF assay and its applicability to point-of-care settings

    J Clin Microbiol

    (2010)
  • D.F. Stroup et al.

    Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group

    J Am Med Assoc

    (2000)
  • P. Whiting et al.

    Development and validation of methods for assessing the quality of diagnostic accuracy studies

    Health Technol Assess

    (2004)
  • C. Gatsonis et al.

    Meta-analysis of diagnostic and screening test accuracy evaluations: methodologic primer

    AJR Am J Roentgenol

    (2006)
  • P. Antonelli et al.

    Statistical methods for evidence-based medicine: the diagnostic test. Part II

    Minerva Anestesiol

    (2008)
  • B.M. Cesana et al.

    Statistical methods for evidence-based medicine: the diagnostic test. Part I

    Minerva Anestesiol

    (2008)
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    These authors contributed equally to this work as the co-first author.

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