Xpert® MTB/RIF test for diagnosing extrapulmonary tuberculosis and rifampicin resistance

Why is improving the diagnosis of extrapulmonary tuberculosis important?

Tuberculosis (TB) is the world’s leading infectious cause of death. It mainly affects the lungs (pulmonary TB) but may occur in other body parts than the lungs (extrapulmonary TB). In most people, TB can be cured if the disease is diagnosed and properly treated. One problem involved in treating TB is that the bacteria become resistant to antibiotics. Not recognizing TB early (false-negative result) may result in delayed diagnosis and treatment and increased illness and death. An incorrect TB diagnosis (false-positive result) may result in increased anxiety and unnecessary treatment.

What is the aim of this review?

To find out how accurate Xpert® MTB/RIF (Xpert) is for diagnosing extrapulmonary TB and drug resistance. We included eight forms of extrapulmonary TB: tuberculous meningitis and pleural, lymph node, bone or joint, genitourinary, peritoneal, pericardial, and disseminated TB.

What was studied in this review?

Xpert is a relatively new, automated, rapid test that detects TB and rifampicin resistance at the same time. Rifampicin is an important drug for treating people with TB. Another Cochrane Review showed that Xpert is accurate for diagnosing pulmonary TB. The current review assessed Xpert accuracy for detecting eight forms of extrapulmonary TB, as well as the different specimens that may be collected for diagnosis, for instance, cerebrospinal fluid, pleural fluid, and urine. Xpert results were measured against culture results (benchmark).

What are the main results reported in this review?

We included 66 studies that evaluated 16,213 specimens for extrapulmonary TB and rifampicin resistance. Only one study evaluated the newest test version, Xpert Ultra (Ultra), for tuberculous meningitis.

In urine and bone or joint fluid and tissue, Xpert was sensitive (more than 80%), that is, registered positive in people who actually had TB. In cerebrospinal fluid, pleural fluid, urine, and peritoneal fluid, Xpert was highly specific (98% or more), that is, did not register positive in people who were actually negative.

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; and 911 would be Xpert-negative: of these, 29 (3%) would have TB.

• where 150 have pleural TB on culture, 83 would be Xpert-positive: of these, seven (8%) would not have TB ; and 917 would be Xpert-negative: of these, 74 (8%) would have TB.

• where 70 have genitourinary TB on culture, 70 would be Xpert-positive: of these, 12 (17%) would not have TB; and 930 would be Xpert-negative: of these, 12 (1%) would have TB.

• where 120 have rifampicin-resistant TB, 125 would be positive for rifampicin-resistant TB: of these, 11 (9%) would not have rifampicin resistance; and 875 would be negative for rifampicin-resistant TB: of these, 6 (1%) would have rifampicin resistance.

How confident are we in the review's results?

The diagnosis of extrapulmonary TB was made by assessing patients with culture, generally considered to be the best reference standard. However, it appears that culture did not work well as a reference test for lymph node TB.

Who do the review's results apply to?

People presumed to have extrapulmonary TB. Most studies included only inpatients at tertiary care centres or did not report the clinical setting. Therefore, we could not say how the test would work in primary care.

What are the implications of this review?

Xpert may be helpful in diagnosing extrapulmonary TB. The ability of Xpert to detect TB varies when different specimens are used, while Xpert rarely yields a positive result for people without TB (defined by culture). Xpert is accurate for diagnosing rifampicin resistance. In patients thought to have TB meningitis, which is considered a medical emergency, providers should use clinical judgement and should not rely solely on an Xpert result when deciding to withhold treatment, as is common practice when culture results are negative.

How up-to-date is this review?

The review authors searched for studies published up to 7 August 2017.

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.

Read the full 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 strategy: 

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 fluid

Xpert 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 fluid

Xpert 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 urine

Xpert 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 resistance

Xpert 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.

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