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Review
. 2018 Aug 27;8(8):CD012768.
doi: 10.1002/14651858.CD012768.pub2.

Xpert® MTB/RIF assay for extrapulmonary tuberculosis and rifampicin resistance

Mikashmi Kohli  1 , Ian Schiller, Nandini Dendukuri, Keertan Dheda, Claudia M Denkinger, Samuel G Schumacher, Karen R Steingart
Affiliations
Review

Xpert® MTB/RIF assay for extrapulmonary tuberculosis and rifampicin resistance

Mikashmi Kohli et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Tuberculosis (TB) is the world's leading infectious cause of death. Extrapulmonary TB accounts for 15% of TB cases, but the proportion is increasing, and over half a million people were newly diagnosed with rifampicin-resistant TB in 2016. Xpert® MTB/RIF (Xpert) is a World Health Organization (WHO)-recommended, rapid, automated, nucleic acid amplification assay that is used widely for simultaneous detection of Mycobacterium tuberculosis complex and rifampicin resistance in sputum specimens. This Cochrane Review assessed the accuracy of Xpert in extrapulmonary specimens.

Objectives: To determine the diagnostic accuracy of Xpert a) for extrapulmonary TB by site of disease in people presumed to have extrapulmonary TB; and b) for rifampicin resistance in people presumed to have extrapulmonary TB.

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 (LILACS), Scopus, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number (ISRCTN) Registry, and ProQuest up to 7 August 2017 without language restriction.

Selection criteria: We included diagnostic accuracy studies of Xpert in people presumed to have extrapulmonary TB. We included TB meningitis and pleural, lymph node, bone or joint, genitourinary, peritoneal, pericardial, and disseminated TB. We used culture as the reference standard. For pleural TB, we also included a composite reference standard, which defined a positive result as the presence of granulomatous inflammation or a positive culture result. For rifampicin resistance, we used culture-based drug susceptibility testing or MTBDRplus as the reference standard.

Data collection and analysis: Two review authors independently extracted data, assessed risk of bias and applicability using the QUADAS-2 tool. We determined pooled predicted sensitivity and specificity for TB, grouped by type of extrapulmonary specimen, and for rifampicin resistance. For TB detection, we used a bivariate random-effects model. Recognizing that use of culture may lead to misclassification of cases of extrapulmonary TB as 'not TB' owing to the paucibacillary nature of the disease, we adjusted accuracy estimates by applying a latent class meta-analysis model. For rifampicin resistance detection, we performed univariate meta-analyses for sensitivity and specificity separately to include studies in which no rifampicin resistance was detected. We used theoretical populations with an assumed prevalence to provide illustrative numbers of patients with false positive and false negative results.

Main results: We included 66 unique studies that evaluated 16,213 specimens for detection of extrapulmonary TB and rifampicin resistance. We identified only one study that evaluated the newest test version, Xpert MTB/RIF Ultra (Ultra), for TB meningitis. Fifty studies (76%) took place in low- or middle-income countries. Risk of bias was low for patient selection, index test, and flow and timing domains and was high or unclear for the reference standard domain (most of these studies decontaminated sterile specimens before culture inoculation). Regarding applicability, in the patient selection domain, we scored high or unclear concern for most studies because either patients were evaluated exclusively as inpatients at tertiary care centres, or we were not sure about the clinical settings.Pooled Xpert sensitivity (defined by culture) varied across different types of specimens (31% in pleural tissue to 97% in bone or joint fluid); Xpert sensitivity was > 80% in urine and bone or joint fluid and tissue. Pooled Xpert specificity (defined by culture) varied less than sensitivity (82% in bone or joint tissue to 99% in pleural fluid and urine). Xpert specificity was ≥ 98% in cerebrospinal fluid, pleural fluid, urine, and peritoneal fluid.Xpert testing in cerebrospinal fluidXpert pooled sensitivity and specificity (95% credible interval (CrI)) against culture were 71.1% (60.9% to 80.4%) and 98.0% (97.0% to 98.8%), respectively (29 studies, 3774 specimens; moderate-certainty evidence).For a population of 1000 people where 100 have TB meningitis on culture, 89 would be Xpert-positive: of these, 18 (20%) would not have TB (false-positives); and 911 would be Xpert-negative: of these, 29 (3%) would have TB (false-negatives).For TB meningitis, ultra sensitivity and specificity against culture (95% confidence interval (CI)) were 90% (55% to 100%) and 90% (83% to 95%), respectively (one study, 129 participants).Xpert testing in pleural fluidXpert pooled sensitivity and specificity (95% CrI) against culture were 50.9% (39.7% to 62.8%) and 99.2% (98.2% to 99.7%), respectively (27 studies, 4006 specimens; low-certainty evidence).For a population of 1000 people where 150 have pleural TB on culture, 83 would be Xpert-positive: of these, seven (8%) would not have TB (false-positives); and 917 would be Xpert-negative: of these, 74 (8%) would have TB (false-negatives).Xpert testing in urineXpert pooled sensitivity and specificity (95% CrI) against culture were 82.7% (69.6% to 91.1%) and 98.7% (94.8% to 99.7%), respectively (13 studies, 1199 specimens; moderate-certainty evidence).For a population of 1000 people where 70 have genitourinary TB on culture, 70 would be Xpert-positive: of these, 12 (17%) would not have TB (false-positives); and 930 would be Xpert-negative: of these, 12 (1%) would have TB (false-negatives).Xpert testing for rifampicin resistanceXpert pooled sensitivity (20 studies, 148 specimens) and specificity (39 studies, 1088 specimens) were 95.0% (89.7% to 97.9%) and 98.7% (97.8% to 99.4%), respectively (high-certainty evidence).For a population of 1000 people where 120 have rifampicin-resistant TB, 125 would be positive for rifampicin-resistant TB: of these, 11 (9%) would not have rifampicin resistance (false-positives); and 875 would be negative for rifampicin-resistant TB: of these, 6 (1%) would have rifampicin resistance (false-negatives).For lymph node TB, the accuracy of culture, the reference standard used, presented a greater concern for bias than in other forms of extrapulmonary TB.

Authors' conclusions: In people presumed to have extrapulmonary TB, Xpert may be helpful in confirming the diagnosis. Xpert sensitivity varies across different extrapulmonary specimens, while for most specimens, specificity is high, the test rarely yielding a positive result for people without TB (defined by culture). Xpert is accurate for detection of rifampicin resistance. For people with presumed TB meningitis, treatment should be based on clinical judgement, and not withheld solely on an Xpert result, as is common practice when culture results are negative.

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Conflict of interest statement

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

CMD and SGS work for FIND. FIND is a non‐for‐profit foundation whose mission is to find diagnostic solutions to overcome diseases of poverty in low‐ and middle‐income countries. FIND works closely with the private and public sectors and receives funding from donors and some of its industry partners. FIND has an independent Scientific Advisory Committee and organizational firewalls that protect it against any undue influences in its work or in publication of its findings. More information on FIND’s policy and guidelines for working with private sector partners can be found at www.finddx.org/business‐model.

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

ND received funding from the CIDG.

Figures

Figure 1
Figure 1
The clinical pathway describes how patients might present and the point in the pathway at which they would be considered for testing with Xpert. Before a specimen was tested with Xpert, patients presumed of having extrapulmonary TB would have undergone a health examination (history and physical examination) and possibly a chest radiograph. Presentation of extrapulmonary TB varies depending on the body site affected; this condition may imitate other diseases such as cancer and bacterial and fungal infections. Signs and symptoms of extrapulmonary TB are often non‐specific and may include fever, night sweats, fatigue, loss of appetite, and weight loss (as seen in pulmonary TB) or specific complaints related to the involved site (e.g. headache for TB meningitis, back pain for TB of the spine). The clinical presentation of extrapulmonary disease may be acute but is more often subacute (falling between acute and chronic) or chronic, meaning that patients may have symptoms for days to months before they seek care. Signs and symptoms for the forms of extrapulmonary TB included in this review are described in Table 6. Standard practice includes obtaining specimens for microscopy, culture, and histological examination. We adapted this algorithm for Xpert from the Global Laboratory Initiative (GLI 2018). Abbreviations: DR‐TB: drug‐resistant TB; MDR‐TB: multidrug‐resistant TB; RIF: rifampicin; SL‐LPA: line probe assay for second‐line drugs; TB: tuberculosis.
Figure 2
Figure 2
Study flow diagram. *See Table 8.
Figure 3
Figure 3
Risk of bias and applicability concerns graph: review authors' judgements about each domain presented as percentages across included studies.
Figure 4
Figure 4
Risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study.
Figure 5
Figure 5
Forest plots of Xpert® MTB/RIF sensitivity and specificity in cerebrospinal fluid. 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 6
Figure 6
Forest plots of Xpert® MTB/RIF sensitivity and specificity in pleural fluid with respect to a culture reference standard (upper plots) and a composite reference standard (lower plots). 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 7
Figure 7
Forest plot of Xpert® MTB/RIF sensitivity and specificity in lymph node aspirates with respect to a culture reference standard. 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 8
Figure 8
Forest plots of Xpert® MTB/RIF sensitivity and specificity in urine with respect to a culture reference standard. 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 9
Figure 9
Forest plot of Xpert® MTB/RIF sensitivity and specificity for rifampicin resistance. 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
Receiver operating characteristic plot for TB meningitis. The black curve corresponds to the model that assumes culture is a perfect reference standard. The black emptied circles are plotted at co‐ordinates corresponding to study sensitivity and specificity estimates obtained from the data. The filled black circle is the pooled estimate of sensitivity and specificity obtained from the bivariate model under the assumption that culture is a perfect reference standard. The red dashed line corresponds to the latent class meta‐analysis. The red emptied squares are plotted at sensitivity and specificity co‐ordinates corresponding to sensitivity and specificity estimates obtained from the latent class model. The filled red square has co‐ordinates corresponding to pooled sensitivity and specificity estimates from the latent class model. The size of the emptied circles and squares is proportionate to the size of the studies.
Figure 11
Figure 11
Receiver operating characteristic plot for pleural fluid. The black curve corresponds to the model that assumes culture is a perfect reference standard. The black emptied circles are plotted at co‐ordinates corresponding to study sensitivity and specificity estimates obtained from the data. The filled black circle is the pooled estimate of sensitivity and specificity obtained from the bivariate model under the assumption that culture is a perfect reference standard. The red dashed line corresponds to the latent class meta‐analysis. The red emptied squares are plotted at sensitivity and specificity co‐ordinates corresponding to sensitivity and specificity estimates obtained from the latent class model. The filled red square has co‐ordinates corresponding to pooled sensitivity and specificity estimates from the latent class model. The size of the emptied circles and squares is proportionate to the size of the studies.
Figure 12
Figure 12
Receiver operating characteristic plot for lymph node aspirate. The black curve corresponds to the model that assumes culture is a perfect reference standard. The red curve corresponds to the latent class meta‐analysis model with non‐informative priors. The green curve corresponds to the latent class meta‐analysis model with informative priors. The filled circles of each colour correspond to the pooled sensitivity and specificity of the respective model. The empty circles for each colour are plotted at sensitivity and specificity co‐ordinates corresponding to sensitivity and specificity estimates obtained from the respective models. The size of the emptied circles is proportionate to the size of the studies.
Figure 13
Figure 13
Receiver operating characteristic plot for urine. The black curve corresponds to the model that assumes culture is a perfect reference standard. The black emptied circles are plotted at co‐ordinates corresponding to study sensitivity and specificity estimates obtained from the data. The filled black circle is the pooled estimate of sensitivity and specificity obtained from the bivariate model under the assumption that culture is a perfect reference standard. The size of the emptied circles and squares is proportionate to the size of the studies.
Figure 14
Figure 14
Forest plots of Xpert® MTB/RIF sensitivity and specificity for bone or joint TB (fluid and tissue) with respect to a culture reference standard. 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 of Xpert® MTB/RIF sensitivity and specificity for peritoneal TB (fluid and tissue) with respect to a culture reference standard. 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 16
Figure 16
Forest plots of Xpert® MTB/RIF sensitivity and specificity in pericardial fluid with respect to a culture reference standard. 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 in blood with respect to a culture reference standard. 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.
Test 1
Test 1
Cerebrospinal fluid.
Test 2
Test 2
Cerebrospinal fluid, Ultra.
Test 3
Test 3
Pleural fluid, culture.
Test 4
Test 4
Pleural fluid, composite reference standard.
Test 5
Test 5
Pleural tissue, culture.
Test 6
Test 6
Pleural tissue, composite reference standard.
Test 7
Test 7
Lymph node aspirate.
Test 8
Test 8
Lymph node tissue.
Test 9
Test 9
Urine.
Test 10
Test 10
Bone or joint fluid.
Test 11
Test 11
Bone or joint tissue.
Test 12
Test 12
Peritoneal fluid.
Test 13
Test 13
Peritoneal tissue.
Test 14
Test 14
Pericardial fluid.
Test 15
Test 15
Blood.
Test 16
Test 16
Rifampicin resistance testing.
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References

References to studies included in this review

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    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
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References to other published versions of this review

    1. Kohli M, Schiller I, Dendukuri N, Ryan H, Dheda K, Denkinger CM, Schumacher SG, Steingart KR. Xpert® MTB/RIF assay for extrapulmonary tuberculosis and rifampicin resistance. Cochrane Database of Systematic Reviews 2017, Issue 8. [DOI: 10.1002/14651858.CD012768] - DOI - PMC - PubMed

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