Key messages
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Xpert Ultra has high sensitivity (people with tuberculosis correctly diagnosed as having the condition) and specificity (people without tuberculosis correctly identified as not having the condition) for the diagnosis of lung (pulmonary) tuberculosis in people suspected of tuberculosis based on signs, symptoms, or abnormal chest x-ray.
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Xpert Ultra has high sensitivity (people with rifampicin resistance correctly diagnosed as having the resistance) and specificity (people without rifampicin resistance correctly identified as not having the resistance) for rifampicin resistance (an important treatment for tuberculosis).
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Xpert Ultra demonstrates reduced sensitivity among people with sputum-smear negative tuberculosis (mucous coughed up from the respiratory tract that is examined under a microscope and tuberculosis bacteria are not seen) and reduced specificity among people with prior tuberculosis.
Why is improving the diagnosis of pulmonary tuberculosis important?
Pulmonary tuberculosis is a lung disease caused by a bacterium (a germ) that spreads through the air via droplets from an infected person. In the early stages, it remains dormant (does not multiply) and presents symptoms like fever, cough, weight loss, and night sweats. Tuberculosis is one of the leading causes of death worldwide. When people receive proper and timely treatment, tuberculosis is usually curable. One problem involved in managing tuberculosis is that the bacteria become resistant to rifampicin (an antibiotic), meaning that the medicine no longer works. Tuberculosis control is threatened by delays in diagnosis and inappropriate tuberculosis treatment when people are resistant to rifampicin. People living with HIV infection are at increased risk of developing tuberculosis.
What is the Xpert Ultra test?
Xpert Ultra is recommended by the World Health Organization (a well-known international organisation focused on global health) as a rapid test that simultaneously detects tuberculosis and rifampicin resistance.
What did we want to find out?
We wanted to determine the accuracy of Xpert Ultra for diagnosing pulmonary tuberculosis and rifampicin resistance in adults (aged 15 years and older) and adolescents (aged 10 to 14 years).
What did we do?
We searched for studies that investigated the accuracy of Xpert Ultra in diagnosing pulmonary tuberculosis and rifampicin resistance.
What did we find?
We found 32 studies (12,529 people) that evaluated Xpert Ultra for diagnosing pulmonary tuberculosis, and 10 studies (1644 people) that evaluated Xpert Ultra for rifampicin resistance.
For detecting tuberculosis, Xpert Ultra had:
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high sensitivity (91 of 100 people with tuberculosis correctly diagnosed as having the condition; Xpert Ultra missed 9 cases);
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high specificity (95 of 100 people without tuberculosis correctly identified as not having the condition; Xpert Ultra missed 5 cases).
Xpert Ultra sensitivity was lower in people with sputum-smear negative tuberculosis (mucous coughed up from the respiratory tract that is negative for tuberculosis) and specificity was lower in people with a history of tuberculosis.
For the detection of rifampicin resistance, Xpert Ultra had:
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high sensitivity (96 of 100 people with rifampicin resistance correctly diagnosed as having resistance; Xpert Ultra missed 4 cases);
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high specificity (98 of 100 people without rifampicin resistance correctly identified as not having resistance; Xpert Ultra missed 2 cases).
What are the limitations of the evidence?
Six of the 32 studies that detected tuberculosis and three of the 10 studies that detected rifampicin resistance were set in specialist hospitals and so these results may not apply to people in community clinics and local hospitals.
The results for Xpert Ultra's detection of tuberculosis in adolescents were based on six studies with only 160 adolescents, which limits our findings.
We were unable to estimate the accuracy of Xpert Ultra for rifampicin resistance testing among people living with HIV as we found no studies.
How up to date is this evidence?
This review is based on a database search that was performed on 16 October 2023. These results were supplemented with results from a World Health Organization Public Call for ongoing and unpublished studies between 30 November 2023 and 15 February 2024. We also contacted experts working on new diagnostics for tuberculosis.
Read the full abstract
Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular World Health Organization (WHO)-recommended rapid diagnostic test that simultaneously detects tuberculosis and rifampicin resistance. This review updates a comparative accuracy Cochrane review of Xpert MTB/RIF and Xpert Ultra as Xpert Ultra has replaced Xpert MTB/RIF.
Objectives
To determine the diagnostic accuracy of Xpert MTB/RIF Ultra (Xpert Ultra) for detecting pulmonary tuberculosis and rifampicin resistance in adults and adolescents with presumptive tuberculosis based on signs or symptoms or with an abnormal chest x-ray suggestive of tuberculosis.
Search strategy
We searched seven databases including CENTRAL, MEDLINE, and Embase, plus two trial registers (ClinicalTrials.gov and the WHO ICTRP) to 16 October 2023 without language restrictions. A WHO Public Call for ongoing and unpublished studies was made between 30 November 2023 and 15 February 2024.
Selection criteria
We included cross-sectional studies, cohort studies, and randomised controlled trials that provided data on the diagnostic accuracy of Xpert Ultra using respiratory specimens in adolescents (aged 10 to 14 years) and adults (aged 15 years and older) with presumptive pulmonary tuberculosis. For pulmonary tuberculosis detection, the reference standards were culture and a composite reference standard. For rifampicin resistance, the reference standards were culture-based phenotypic drug susceptibility testing with or without whole genome sequencing.
Data collection and analysis
Two review authors independently extracted data using a standardised form. We assessed risk of bias using QUADAS-2. We performed meta-analyses using a bivariate model to produce summary sensitivities and specificities, separately for pulmonary tuberculosis detection and rifampicin resistance detection. We performed subgroup analyses by smear status, HIV status, and history of tuberculosis. We summarised Xpert Ultra trace-positive results.
Main results
Pulmonary tuberculosis detection
For detection of pulmonary tuberculosis, Xpert Ultra summary sensitivity and specificity against culture were 90.7% (95% confidence interval (CI) 88.2 to 92.7) and 94.8% (95% CI 92.8 to 96.3) (32 studies, 12,529 participants; high-certainty evidence). Most studies had low risk of bias in all QUADAS-2 domains. If the point estimates for Xpert Ultra are applied to a hypothetical cohort of 1000 people, where 100 of those presenting with symptoms have pulmonary tuberculosis, Xpert Ultra will miss nine cases. The number of people wrongly diagnosed with pulmonary tuberculosis would be 47.
In people living with HIV, Xpert Ultra summary sensitivity and specificity were 87.7% (82.0 to 91.7) and 95.3% (92.2 to 97.2) (11 studies, 1164 participants). Amongst people with smear-negative, culture-positive pulmonary tuberculosis, Xpert Ultra summary sensitivity and specificity were 80.7% (75.4 to 85.0) and 94.0% (91.3 to 95.9) (16 studies, 6460 participants). In people with a history of tuberculosis, Xpert Ultra summary sensitivity and specificity were 84.8% (78.2 to 89.7) and 86.2% (78.9 to 91.3) (9 studies, 809 participants).
The proportion of Ultra trace-positive results that were true positives compared to the microbiological reference standard was 38.8%. Reclassifying trace-positive results as Xpert Ultra-negative led to a reduction in sensitivity and modest increase in specificity.
Rifampicin resistance detection
For detection of rifampicin resistance, Xpert Ultra summary sensitivity and specificity were 95.8% (93.2 to 97.4) and 98.3% (97.0 to 99.0) (10 studies, 1644 participants; high-certainty evidence). Most studies had low risk of bias in all QUADAS-2 domains. If the point estimates for Xpert Ultra are applied to a hypothetical cohort of 1000 people, where 100 of those presenting with symptoms have rifampicin resistance, Xpert Ultra will miss four cases. The number of people wrongly diagnosed with rifampicin resistance would be 16 out of the 900 who do not have rifampicin resistance. Xpert Ultra performed similarly, for rifampicin resistance, in people with smear-positive and smear-negative tuberculosis.
Authors' conclusions
Xpert Ultra has high sensitivity and specificity for detection of pulmonary tuberculosis rifampicin resistance. Xpert Ultra for the detection of pulmonary tuberculosis has lower sensitivity in people with smear-negative/culture-positive tuberculosis and lower sensitivity and specificity in people with a history of tuberculosis. Xpert Ultra trace-positive results were common.
Strengths of this review include the approach to identifying relevant studies, the number of studies and participants included in this systematic review, and that most studies were at low risk of bias. The small number of studies (six) and participants who were adolescents is a limitation to our accuracy estimates in this age group.
Xpert Ultra testing provides accurate results and can allow rapid initiation of treatment for rifampicin-resistant and multiple-drug-resistant tuberculosis.
Funding
The WHO supported this systematic review. Liverpool School of Tropical Medicine hosted the Cochrane Infectious Diseases Group (CIDG) editorial base, which supported the authors in the development of this review update. The Foreign, Commonwealth and Development Office funded the CIDG.
Registration
Generic protocol available on Open Science Framework via https://osf.io/26wg7/wiki/home/. Previous protocol and review versions available via DOI 10.1002/14651858.CD009593 and DOI 10.1002/14651858.CD009593.pub5.
