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. 2019 Jun 7;6(6):CD009593.
doi: 10.1002/14651858.CD009593.pub4.

Xpert MTB/RIF and Xpert MTB/RIF Ultra for pulmonary tuberculosis and rifampicin resistance in adults

David J Horne #  1 , Mikashmi Kohli #, Jerry S Zifodya, Ian Schiller, Nandini Dendukuri, Deanna Tollefson, Samuel G Schumacher, Eleanor A Ochodo, Madhukar Pai, Karen R Steingart
Affiliations

Xpert MTB/RIF and Xpert MTB/RIF Ultra for pulmonary tuberculosis and rifampicin resistance in adults

David J Horne et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Xpert MTB/RIF (Xpert MTB/RIF) and Xpert MTB/RIF Ultra (Xpert Ultra), the newest version, are the only World Health Organization (WHO)-recommended rapid tests that simultaneously detect tuberculosis and rifampicin resistance in persons with signs and symptoms of tuberculosis, at lower health system levels. A previous Cochrane Review found Xpert MTB/RIF sensitive and specific for tuberculosis (Steingart 2014). Since the previous review, new studies have been published. We performed a review update for an upcoming WHO policy review.

Objectives: To determine diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra for tuberculosis in adults with presumptive pulmonary tuberculosis (PTB) and for rifampicin resistance in adults with presumptive rifampicin-resistant tuberculosis.

Search methods: We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, to 11 October 2018, without language restriction.

Selection criteria: Randomized trials, cross-sectional, and cohort studies using respiratory specimens that evaluated Xpert MTB/RIF, Xpert Ultra, or both against the reference standard, culture for tuberculosis and culture-based drug susceptibility testing or MTBDRplus for rifampicin resistance.

Data collection and analysis: Four review authors independently extracted data using a standardized form. When possible, we also extracted data by smear and HIV status. We assessed study quality using QUADAS-2 and performed meta-analyses to estimate pooled sensitivity and specificity separately for tuberculosis and rifampicin resistance. We investigated potential sources of heterogeneity. Most analyses used a bivariate random-effects model. For tuberculosis detection, we first estimated accuracy using all included studies and then only the subset of studies where participants were unselected, i.e. not selected based on prior microscopy testing.

Main results: We identified in total 95 studies (77 new studies since the previous review): 86 studies (42,091 participants) evaluated Xpert MTB/RIF for tuberculosis and 57 studies (8287 participants) for rifampicin resistance. One study compared Xpert MTB/RIF and Xpert Ultra on the same participant specimen.Tuberculosis detectionOf the total 86 studies, 45 took place in high tuberculosis burden and 50 in high TB/HIV burden countries. Most studies had low risk of bias.Xpert MTB/RIF pooled sensitivity and specificity (95% credible Interval (CrI)) were 85% (82% to 88%) and 98% (97% to 98%), (70 studies, 37,237 unselected participants; high-certainty evidence). We found similar accuracy when we included all studies.For a population of 1000 people where 100 have tuberculosis on culture, 103 would be Xpert MTB/RIF-positive and 18 (17%) would not have tuberculosis (false-positives); 897 would be Xpert MTB/RIF-negative and 15 (2%) would have tuberculosis (false-negatives).Xpert Ultra sensitivity (95% confidence interval (CI)) was 88% (85% to 91%) versus Xpert MTB/RIF 83% (79% to 86%); Xpert Ultra specificity was 96% (94% to 97%) versus Xpert MTB/RIF 98% (97% to 99%), (1 study, 1439 participants; moderate-certainty evidence).Xpert MTB/RIF pooled sensitivity was 98% (97% to 98%) in smear-positive and 67% (62% to 72%) in smear-negative, culture-positive participants, (45 studies). Xpert MTB/RIF pooled sensitivity was 88% (83% to 92%) in HIV-negative and 81% (75% to 86%) in HIV-positive participants; specificities were similar 98% (97% to 99%), (14 studies).Rifampicin resistance detectionXpert MTB/RIF pooled sensitivity and specificity (95% Crl) were 96% (94% to 97%) and 98% (98% to 99%), (48 studies, 8020 participants; high-certainty evidence).For a population of 1000 people where 100 have rifampicin-resistant tuberculosis, 114 would be positive for rifampicin-resistant tuberculosis and 18 (16%) would not have rifampicin resistance (false-positives); 886 would be would be negative for rifampicin-resistant tuberculosis and four (0.4%) would have rifampicin resistance (false-negatives).Xpert Ultra sensitivity (95% CI) was 95% (90% to 98%) versus Xpert MTB/RIF 95% (91% to 98%); Xpert Ultra specificity was 98% (97% to 99%) versus Xpert MTB/RIF 98% (96% to 99%), (1 study, 551 participants; moderate-certainty evidence).

Authors' conclusions: We found Xpert MTB/RIF to be sensitive and specific for diagnosing PTB and rifampicin resistance, consistent with findings reported previously. Xpert MTB/RIF was more sensitive for tuberculosis in smear-positive than smear-negative participants and HIV-negative than HIV-positive participants. Compared with Xpert MTB/RIF, Xpert Ultra had higher sensitivity and lower specificity for tuberculosis and similar sensitivity and specificity for rifampicin resistance (1 study). Xpert MTB/RIF and Xpert Ultra provide accurate results and can allow rapid initiation of treatment for multidrug-resistant tuberculosis.

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Conflict of interest statement

DJH received financial support for the submitted work from McGill University.

MK has no known conflicts of interest.

JSZ has no known conflicts of interest.

IS has no known conflicts of interest.

ND has no known conflicts of interest.

DT has no known conflicts of interest.

SGS is employed by the Foundation for Innovative New Diagnostics (FIND). FIND has conducted studies and published on Xpert MTB/RIF as part of a collaborative project between FIND, a Swiss non‐profit, Cepheid, a US company, and academic partners. The product developed through this partnership was developed under a contract that obligated FIND to pay for development costs and trial costs and Cepheid to make the test available at specified preferential pricing to the public sector in low‐ and middle‐income countries. In addition, FIND conducted studies for the Xpert MTB/Rif Ultra assay, which have also been published.

EAC has no known conflicts of interest.

MP serves on the Scientific Advisory Committee of FIND, Geneva. FIND is a non‐profit agency that works on global health diagnostics.

KRS received financial support for the submitted work from McGill University, and has received financial support for the preparation of systematic reviews and educational materials, consultancy fees from FIND (for the preparation of systematic reviews), honoraria, and travel support to attend WHO guideline meetings.

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the review apart from those disclosed.

Figures

Figure 1
Figure 1
Readout of Xpert MTB/RIF assay for a tuberculosis positive, rifampicin‐susceptible specimen. Courtesy: Karin Weyer, the WHO Global TB Programme.
Figure 2
Figure 2
The clinical pathway describes how people might present and the point in the pathway at which they would be considered for testing with Xpert MTB/RIF or Xpert Ultra. A person with presumptive PTB may experience cough, chest pain, the coughing up of blood, fever, night sweats, fatigue, loss of appetite, and weight loss. When she presents to a health facility, she will undergo a health examination (history and physical examination) and usually a chest x‐ray. She will be tested with the index test, either Xpert MTB/RIF or Xpert Ultra, if available, as this test is recommended as the initial diagnostic test for all adults and children with signs and symptoms of tuberculosis. Abbreviations: DR‐TB: drug‐resistant tuberculosis; MDR‐TB: multidrug‐resistant tuberculosis; PTB: pulmonary tuberculosis; RIF: rifampicin; SL‐LPA: second‐line line probe assay; Xpert: either Xpert MTB/RIF of Xpert Ultra. Figure adapted from GLI 2018.
Figure 3
Figure 3
Flow diagram of studies in the review. To identify other systematic reviews, we performed an additional literature search on 26 March 2018 (Table 8).
Figure 4
Figure 4
Risk of bias and applicability concerns graph for pulmonary tuberculosis detection: review authors' judgements about each domain presented as percentages across included studies.
Figure 5
Figure 5
Risk of bias and applicability concerns summary for pulmonary tuberculosis detection: review authors' judgements about each domain for each included study, studies A through K.
Figure 6
Figure 6
Risk of bias and applicability concerns summary for pulmonary tuberculosis detection: review authors' judgements about each domain for each included study, studies L through Z.
Figure 7
Figure 7
Risk of bias and applicability concerns graph for rifampicin resistance detection: review authors' judgements about each domain presented as percentages across included studies.
Figure 8
Figure 8
Risk of bias and applicability concerns summary for rifampicin resistance detection: review authors' judgements about each domain for each included study.
Figure 9
Figure 9
Forest plots of Xpert sensitivity and specificity for detection of pulmonary tuberculosis. The individual studies are ordered by decreasing sensitivity. The squares represent the sensitivity and specificity of one study, the black line its confidence interval. FN: false‐negative; FP: false‐positive; TN: true‐negative; TP: true‐positive.
Figure 10
Figure 10
Forest plots of Xpert sensitivity and specificity for detection of pulmonary tuberculosis in studies with unselected participants. The individual studies are ordered by decreasing sensitivity. The squares represent the sensitivity and specificity of one study, the black line its confidence interval. FN: false‐negative; FP: false‐positive; TN: true‐negative; TP: true‐positive.
Figure 11
Figure 11
Summary plots of Xpert MTB/RIF sensitivity and specificity for detection of pulmonary tuberculosis. Each individual study is represented by an empty square. The size of the square is proportional to the sample size of the study such that larger studies are represented by larger squares. The filled circle is the median pooled estimate for sensitivity and specificity. The solid curves represent the 95% credible region around the summary estimate; the dashed curves represent the 95% prediction region.
Figure 12
Figure 12
Summary ROC plots for sensitivity and specificity of Xpert MTB/RIF and Xpert Ultra for detection of pulmonary tuberculosis.
Figure 13
Figure 13
Forest plots of Xpert MTB/RIF sensitivity and specificity for detection of pulmonary tuberculosis, participants with smear‐positive (culture‐positive) specimens. The individual studies are ordered by decreasing sensitivity. The squares represent the sensitivity and specificity of one study, the black line its confidence interval. FN: false‐negative; FP: false‐positive; TN: true‐negative; TP: true‐positive.
Figure 14
Figure 14
Forest plots of Xpert MTB/RIF sensitivity and specificity for detection of pulmonary tuberculosis, participants with smear‐negative (culture‐positive) specimens. The individual studies are ordered by decreasing sensitivity. The squares represent the sensitivity and specificity of one study, the black line its confidence interval. FN: false‐negative; FP: false‐positive; TN: true‐negative; TP: true‐positive.
Figure 15
Figure 15
Forest plots comparing Xpert MTB/RIF and Xpert Ultra sensitivity and specificity for detection of pulmonary tuberculosis in smear‐positive and smear‐negative participants. The individual studies are ordered by decreasing sensitivity. The squares represent the sensitivity and specificity of one study, the black line its CI. TP = true positive; FP = false positive; FN = false negative; TN = true negative.
Figure 16
Figure 16
Forest plots of Xpert MTB/RIF sensitivity and specificity for detection of pulmonary tuberculosis in HIV‐negative participants. The individual studies are ordered by decreasing sensitivity. The squares represent the sensitivity and specificity of one study, the black line its confidence interval. FN: false‐negative; FP: false‐positive; TN: true‐negative; TP: true‐positive.
Figure 17
Figure 17
Forest plots of Xpert MTB/RIF sensitivity and specificity for detection of pulmonary tuberculosis in HIV‐positive participants. The individual studies are ordered by decreasing sensitivity. The squares represent the sensitivity and specificity of one study, the black line its confidence interval. FN: false‐negative; FP: false‐positive; TN: true‐negative; TP: true‐positive.
Figure 18
Figure 18
Forest plots of Xpert MTB/RIF sensitivity and specificity for detection of pulmonary tuberculosis, HIV‐negative and HIV‐positive participants compared within the same study. The squares represent the sensitivity and specificity of one study, the black line its confidence interval. FN: false‐negative; FP: false‐positive; TN: true‐negative; TP: true‐positive.
Figure 19
Figure 19
Summary plots of Xpert MTB/RIF sensitivity and specificity for detection of pulmonary tuberculosis in HIV‐negative people (red) and HIV‐positive people (black). Each individual study is represented by an empty square. The of the square is proportional to the sample size of the study such that larger studies are represented by larger squares. The filled circle is the pooled median estimate for sensitivity and specificity. The solid curve represents the 95% credible region around the summary estimate; the dashed curves represent the 95% prediction region.
Figure 20
Figure 20
Forest plots comparing Xpert MTB/RIF and Xpert Ultra sensitivity and specificity for detection of pulmonary tuberculosis in HIV‐negative and HIV‐positive participants. The individual studies are ordered by decreasing sensitivity. The squares represent the sensitivity and specificity of one study, the black line its CI. TP = true positive; FP = false positive; FN = false negative; TN = true negative.
Figure 21
Figure 21
Forest plots of Xpert MTB/RIF sensitivity and specificity for detection of rifampicin resistance. The individual studies are ordered by decreasing sensitivity. The squares represent the sensitivity and specificity of one study, the black line its CI. TP = true positive; FP = false positive; FN = false negative; TN = true negative.
Figure 22
Figure 22
Bayesian bivariate hierarchical model, likelihood.
Figure 23
Figure 23
Bayesian bivariate hierarchical model, prior distributions.
Test 1
Test 1
Xpert MTB/RIF for detection of pulmonary tuberculosis (PTB).
Test 2
Test 2
Xpert Ultra for detection of PTB.
Test 3
Test 3
Smear‐positive, Xpert MTB/RIF.
Test 4
Test 4
Smear‐positive, Xpert MTB/RIF, direct comparison Xpert MTB/RIF vs Xpert Ultra.
Test 5
Test 5
Smear‐positive, Xpert Ultra, direct comparison Xpert MTB/RIF vs Xpert Ultra.
Test 6
Test 6
Smear‐negative, Xpert MTB/RIF.
Test 7
Test 7
Smear‐negative, Xpert MTB/RIF, direct comparison Xpert MTB/RIF vs Xpert Ultra.
Test 8
Test 8
Smear‐negative, Xpert Ultra, direct comparison Xpert MTB/RIF vs Xpert Ultra.
Test 9
Test 9
HIV‐negative, Xpert MTB/RIF.
Test 10
Test 10
HIV‐positive, Xpert MTB/RIF.
Test 11
Test 11
HIV‐negative, within study comparisons.
Test 12
Test 12
HIV‐positive, within study comparisons.
Test 13
Test 13
HIV‐negative, Xpert MTB/RIF, direct comparison Xpert MTB/RIF vs Xpert Ultra.
Test 14
Test 14
HIV‐negative, Xpert Ultra, direct comparison Xpert MTB/RIF vs Xpert Ultra.
Test 15
Test 15
HIV‐positive, Xpert MTB/RIF, direct comparison Xpert MTB/RIF vs Xpert Ultra.
Test 16
Test 16
HIV‐positive, Xpert Ultra, direct comparison Xpert MTB/RIF vs Xpert Ultra.
Test 17
Test 17
Xpert MTB/RIF for detection of rifampicin resistance.
Test 18
Test 18
Xpert Ultra for detection of rifampicin resistance.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

    1. Adelman MW, Tsegaye M, Kempker RR, Alebachew T, Haile K, Tesfaye A, et al. Intensified tuberculosis case finding among HIV‐infected persons using a WHO symptom screen and Xpert® MTB/RIF. International Journal of Tuberculosis and Lung Disease 2015;19(10):1197‐203. - PMC - PubMed
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References to studies excluded from this review

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References to ongoing studies

    1. A trial of same‐day testing and treatment to improve outcomes among symptomatic patients newly diagnosed with HIV. Ongoing study 16 May 2017.
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    1. Improving tuberculosis diagnosis and treatment through Basic, Applied and health systems Research (BAR). Ongoing study 29 November 2017.
    1. Xpert Ultra and Xpert HIV‐VL in people living with HIV (UltraHIV). Ongoing study 15 June 2017.
    1. Diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculous bronchoalveolar lavage fluid in HIV‐infected adults: a prospective cohort study. Ongoing study 12 February 2018. - PMC - PubMed

Additional references

    1. American Thoracic Society, the Centers for Disease Control and Prevention, Infectious Disease Society of America. Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. American Journal Respiratory and Critical Care Medicine 2000;161(4 Pt 1):1376‐95. - PubMed
    1. Auld AF, Fielding KL, Gupta‐Wright A, Lawn SD. Xpert MTB/RIF ‐ why the lack of morbidity and mortality impact in intervention trials?. Transactions of the Royal Society of Tropical Medicine and Hygiene 2016;110(8):432‐44. - PubMed
    1. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. Journal of Clinical Epidemiology 2011;64(4):401‐6. - PubMed
    1. Banada PP, Sivasubramani SK, Blakemore R, Boehme C, Perkins MD, Fennelly K, et al. Containment of bioaerosol infection risk by the Xpert MTB/RIF assay and its applicability to point‐of‐care settings. Journal of Clinical Microbiology 2010;48(10):3551‐7. - PMC - PubMed
    1. Berhanu RH, David A, Silva P, Shearer K, Sanne I, Stevens W, et al. Performance of Xpert MTB/RIF, Xpert Ultra, and Abbott RealTime MTB for diagnosis of pulmonary tuberculosis in a high‐HIV‐burden setting. Journal of Clinical Microbiology 2018;56(12):e00560‐18. - PMC - PubMed

References to other published versions of this review

    1. Sohn H, Pai M, Dendukuri N, Kloda LA, Boehme CC, Steingart KR. Xpert MTB/RIF test for detection of pulmonary tuberculosis and rifampicin resistance. Cochrane Database of Systematic Reviews 2012, Issue 1. [DOI: 10.1002/14651858.CD009593] - DOI - PMC - PubMed
    1. Steingart KR, Sohn H, Schiller I, Kloda LA, Boehme CC, Pai M, et al. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database of Systematic Reviews 2013, Issue 1. [DOI: 10.1002/14651858.CD009593.pub2] - DOI - PMC - PubMed
    1. Steingart KR, Schiller I, Horne DJ, Pai M, Boehme CC, Dendukuri N. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database of Systematic Reviews 2014, Issue 1. [DOI: 10.1002/14651858.CD009593.pub3] - DOI - PMC - PubMed

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