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

Why is improving the diagnosis of pulmonary tuberculosis important?

Tuberculosis causes more deaths globally than any other infectious disease. When detected early and effectively treated, tuberculosis is largely curable, but in 2017, around 1.6 million people died of tuberculosis. Xpert MTB/RIF and Xpert Ultra, the newest version, are World Health Organization-recommended tests that simultaneously detect tuberculosis and rifampicin resistance in persons with tuberculosis symptoms. Rifampicin is an important anti-tuberculosis drug. Not recognizing tuberculosis early may result in delayed diagnosis and treatment, severe illness, and death. An incorrect tuberculosis diagnosis may result in anxiety and unnecessary treatment.

What is the aim of this review?

To determine how accurate Xpert MTB/RIF and Xpert Ultra are for diagnosing pulmonary tuberculosis (PTB) and rifampicin resistance in adults. This is an update of the 2014 Cochrane Review.

What was studied in this review?

Xpert MTB/RIF and Xpert Ultra, with results measured against culture (benchmark).

What are the main results in this review?

95 studies: 86 studies (42,091 participants) evaluated Xpert MTB/RIF for tuberculosis; 57 studies (8287 participants) for rifampicin resistance. One study compared Xpert Ultra and Xpert MTB/RIF.

For PTB, Xpert MTB/RIF was sensitive (85%), registering positive in people who actually had tuberculosis, and specific (98%), i.e. it did not register positive in people who were actually negative. Xpert Ultra had higher sensitivity than Xpert MTB/RIF (88% versus 83%) in one study.

For rifampicin resistance, Xpert MTB/RIF was highly sensitive (96%) and specific (98%). Xpert Ultra gave similar results.

Xpert MTB/RIF was better for diagnosing tuberculosis in HIV-negative than in HIV-positive people.

How confident are we in the results of this review?

Confident. We included many studies and used the best reference standards.

Who do the results of this review apply to?

People with presumed PTB or rifampicin resistance.

What are the implications of this review?

In theory, among 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).

Among 1000 people where 100 have rifampicin resistance, 114 would be positive for rifampicin resistance and 18 (16%) would not have rifampicin resistance (false-positives); 886 would be negative for rifampicin resistance and four (0.4%) would have rifampicin resistance (false-negatives).

How up-to-date is this review?

To 11 October 2018.

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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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 strategy: 

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 detection

Of 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 detection

Xpert 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).

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