Podcast: How accurate are tests (Xpert Ultra and Xpert MTB/RIF) for diagnosing tuberculosis outside the lungs (extrapulmonary tuberculosis) and rifampicin resistance?

More than 140 Cochrane Reviews investigate the accuracy of diagnostic tests, covering a very wide range of conditions. One of these reviews, on a test used to detect tuberculosis, was updated in January 2021. The first author, Mikashmi Kohli from McGill University in Montreal Canada, tells us about the updating of the review and what they found.

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Monaz: Hello, I'm Monaz Mehta, editor in the Cochrane Editorial and Methods department. More than 140 Cochrane Reviews investigate the accuracy of diagnostic tests, covering a very wide range of conditions. One of these reviews, on a test used to detect tuberculosis, was updated in January 2021. The first author, Mikashmi Kohli from McGill University in Montreal Canada, tells us about the updating of the review and what they found.

Mikashmi: Tuberculosis, or TB, is a leading cause of infectious disease-related death and a top ten cause of death worldwide. When it's detected early and effectively treated, TB is largely curable. However, in 2019, around 1.2 million HIV‐negative people and 208,000 HIV‐positive people still died from tuberculosis. This situation could worsen further if the challenges to healthcare systems arising from the COVID-19 pandemic and its associated measures reduce the number of people whose TB is detected and treated. For example, a modelling study by the World Health Organization has suggested that there could be 200,000 to 400,000 additional TB deaths per year if, over a period of three months, 25% to 50% fewer cases were detected and treated.
For about one in six people with tuberculosis, TB is outside of their lungs, and this 'extrapulmonary TB' is the focus of our Cochrane review.  Some forms of extrapulmonary TB, such as TB meningitis, are extremely dangerous, meaning that a rapid diagnosis can make all the difference to a patient. It is also important to find out if TB is likely to be resistant to rifampicin, one of the most important drugs used to treat TB.
In the 2018 version of the review, we assessed the diagnostic accuracy of a test called Xpert MTB/RIF for detecting extrapulmonary TB and rifampicin resistance. However, the increasing number of studies and the arrival of a newer version of the test, Xpert Ultra, prompted us to do this update. 
Xpert is a World Health Organization-recommended test that simultaneously detects Mycobacterium tuberculosis complex and rifampicin resistance. The test is automated and rapid, providing results within two hours. 
We evaluated both Xpert MTB/RIF and Xpert Ultra for eight common forms of extrapulmonary TB by including the relevant specimens used to microbiologically verify a TB diagnosis, such as cerebrospinal fluid for TB meningitis. We then compared results against those obtained from culture, which means taking a specimen and letting it grow in the laboratory. For this update, we limited the review to adults, aged 15 years and older. We also added in a composite reference standard alongside the culture reference standard we had used before. This is important because in a systematic review of diagnostic test accuracy studies, the reference standard is the best available test to determine the presence or absence of the target condition but, as is the case with culture and the composite reference standard in our review, these reference standards are not always perfect. We applied a statistical method called latent class meta-analysis to adjust for the imperfect accuracy of the reference standard and were able to improve the estimation of both the pooled sensitivity and specificity of Xpert MTB/RIF, as well as between‐study variability. However, we weren't able to do this for the accuracy of Xpert Ultra because there were too few studies for the newer test. 
We included 69 studies that evaluated more than 19,000 specimens. These included 67 studies for Xpert MTB/RIF and 11 for Xpert Ultra. 
Xpert Ultra sensitivity for tuberculosis varied across different types of specimens, ranging from 75% in pleural fluid to almost 90% in cerebrospinal fluid. While for Xpert MTB/RIF, the sensitivity ranged from just under 50% in pleural fluid to 71% in cerebrospinal fluid to 98% in bone or joint aspirate. In cerebrospinal fluid, Xpert Ultra had higher sensitivity and lower specificity than Xpert MTB/RIF, against culture. Xpert MTB/RIF had a specificity of more than 97% for most specimens, while for Xpert Ultra, specificities were lower against culture. However, specificities for both tests were similar against the composite reference standard. 
For rifampicin resistance, sensitivity and specificity for both Xpert MTB/RIF and Ultra were high and very similar.
In summary, we found that in people thought to have extrapulmonary TB, both Xpert MTB/RIF and Xpert Ultra may be helpful in obtaining the diagnosis. These tests rarely yield a positive result for people without TB by culture, but the ability to detect TB varies depending on the specimen used. Xpert is also accurate for diagnosing rifampicin resistance. However, given the severity TB meningitis, a cautious approach should be taken for people thought to have this type of TB and treatment should be based on clinical judgement and not withheld solely on an Xpert result, as is common practice when culture results are negative.

Monaz: If you would like to read more about the use of these Xpert tests for TB outside the lungs, the full review is available online at Cochrane Library dot com. It can be found there with a search for 'Xpert for extrapulmonary TB'

 

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