Diagnostic Tests | Cochrane Equity

Xpert Ultra versus Xpert MTB/RIF for pulmonary tuberculosis and rifampicin resistance in adults with presumptive pulmonary tuberculosis

Why is improving the diagnosis of tuberculosis important?

Tuberculosis (TB), while one of the leading causes of death worldwide, is largely curable when detected early and treated properly. The World Health Organization-recommended rapid tests used for diagnosing TB in people with signs and symptoms of TB are called Xpert MTB/RIF and Xpert Ultra. A rapid, accurate diagnosis of TB may allow for prompt treatment and alleviate severe illness and death. An incorrect diagnosis may result in anxiety and unnecessary treatment.

How accurate are tests (Xpert Ultra vs. Xpert MTB/RIF) for diagnosing pulmonary TB?

Xpert Ultra has higher sensitivity and lower specificity than Xpert MTB/RIF for pulmonary TB. This is also the case in people living with HIV and in those with a history of TB.

In a diagnostic test, sensitivity (also known as the true positive rate) is defined as the proportion of people with the disease who will have a positive result. Specificity (also known as the true negative rate) is defined as the proportion of people without the disease who will have a negative result. The higher the sensitivity, the lower the number of false-negative results, which indicate that a condition is not present when it really is. Similarly, the higher the specificity, the lower the number of false-positive results, which indicate that a given condition exists when it does not.

Xpert Ultra pooled sensitivity and specificity against culture were 90.9% and 95.6% (7 studies, 2834 participants; high‐certainty evidence) versus Xpert MTB/RIF pooled sensitivity and specificity of 84.7% and 98.4% (7 studies, 2835 participants; high‐certainty evidence).
In people living with HIV, pooled sensitivity was 87.6% for Xpert Ultra versus 74.9% for Xpert MTB/RIF; pooled specificity was 92.8% for Xpert Ultra versus 99.7% for Xpert MTB/RIF (3 studies).
In participants with a history of tuberculosis, pooled sensitivity was 84.2% for Xpert Ultra versus 81.8% for Xpert MTB/RIF; pooled specificity was 88.2% for Xpert Ultra versus 97.4% for Xpert MTB/RIF (4 studies).

*To evaluate the accuracy of a diagnostic test, referred to as the index test (in this case, Xpert MTB/RIF and Xpert Ultra), it must be compared to a reference standard, which is used to categorize participants as having or not having a target condition. In this case, the reference standards for pulmonary TB were solid culture or automated liquid culture. Pulmonary tuberculosis present was defined as a positive M tuberculosis culture. Pulmonary tuberculosis absent was defined as a negative M tuberculosis culture.

Equity – Relevance to disadvantaged populations:

Of the total nine studies, seven were conducted in low‐ or middle‐income countries, and seven were mainly or exclusively conducted in high TB burden countries.
Studies included adults, aged 15 years or older, with presumptive pulmonary TB.
Trials including specific disadvantaged groups, such as those who are HIV+, were included in the review. Individuals with HIV have an increased risk of developing TB compared to HIV‐negative individuals. Furthermore, diagnosing TB in such individuals is considerably more challenging.
HIV and TB are often concentrated in areas with limited resources for diagnosis, treatment, and prevention of TB.
Identifying a rapid and accurate diagnostic test ensures that people receive proper and timely treatment. Earlier detection of TB may prevent complications and make it more likely that the disease can be successfully treated. This can reduce socioeconomic impacts of TB, such as reduced time off work and reduced loss of earnings.

Summary of Findings [SOF] Table: Xpert Ultra versus Xpert MTB/RIF for the detection of pulmonary tuberculosis

Review question: what is the diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF for the detection of pulmonary tuberculosis?
Patients/population: adults with presumptive pulmonary tuberculosis. Participants were unselected, meaning they were not enrolled in a study based on microscopy smear results or history of tuberculosis
Role: an initial test
Index tests: Xpert Ultra and Xpert MTB/RIF
Threshold for index tests: an automated result is provided
Reference standards: solid or liquid culture
Studies: cross‐sectional and cohort studies
Setting: primary care facilities and local hospitals

Test result	Number of results per 1000 patients tested (95% CrI)**						Number of participants*** (studies)	Certainty of the evidence (GRADE)
	Prevalence 2.5%		Prevalence 10%		Prevalence 30%
	Xpert Ultra	Xpert MTB/RIF	Xpert Ultra	Xpert MTB/RIF	Xpert Ultra	Xpert MTB/RIF
True positives (TP)	23 (22 to 24)	21 (20 to 22)	91 (86 to 95)	85 (79 to 90)	273 (259 to 284)	254 (236 to 270)	983 (7)	⊕⊕⊕⊕ High
	2 more TP in Xpert Ultra		6 more TP in Xpert Ultra		19 more TP in Xpert Ultra
False negatives (FN)	2 (1 to 3)	4 (3 to 5)	9 (5 to 14)	15 (10 to 21)	27 (16 to 41)	46 (30 to 64)
	2 fewer FN in Xpert Ultra		6 fewer FN in Xpert Ultra		19 fewer FN in Xpert Ultra
True negatives (TN)	932 (907 to 950)	959 (946 to 968)	860 (837 to 877)	886 (873 to 894)	669 (651 to 682)	689 (679 to 695)	1852 (7)	⊕⊕⊕⊕ High
	27 fewer TN in Xpert Ultra		26 fewer TN in Xpert Ultra		20 fewer TN in Xpert Ultra
False positives (FP)	43 (25 to 68)	16 (7 to 29)	40 (23 to 63)	14 (6 to 27)	31 (18 to 49)	11 (5 to 21)
	27 more FP in Xpert Ultra		26 more FP in Xpert Ultra		20 more FP in Xpert Ultra
Abbreviations: CrI: credible interval
GRADE certainty of the evidence High: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
The results presented in this table should not be interpreted in isolation from the results of individual included studies contributing to each summary test accuracy measure. 95% credible limits were estimated based on those around the point estimates for pooled sensitivity and specificity. Prevalence estimates were suggested by the World Health Organization Global Tuberculosis Programme. The median tuberculosis prevalence in the included studies was 30.1% (range 12.8% to 72.2%). **In the Xpert Ultra analysis there were 1851 participants. Piersimoni 2019 reported three non‐determinate results for Xpert Ultra and two for Xpert MTB/RIF, accounting for the small difference in the total number of participants.

Relevance of the review for disadvantaged communities

Findings	Interpretation
Equity – Which of the PROGRESS groups examined
The trials included in this review were conducted in a mix of low- and middle-income countries (Belarus, Brazil, China, Georgia, India, Kenya, South Africa, Uganda, Switzerland, and Italy), where TB is most prevalent.	TB is widespread in low- and middle-income countries. Rapid, accurate diagnosis ensures that patients receive proper and timely treatment, thus decreasing prevalence in these endemic areas. The study provides high-certainty evidence demonstrating that Xpert Ultra has higher sensitivity but lower specificity than Xpert MTB/RIF for pulmonary tuberculosis.
Equity Applicability
The review summarized trials analyzing the effectiveness of Xpert Ultra and Xpert MTB/RIF across individuals who are HIV+ and who have a history of TB. Other high-risk groups were not included in this review. Studies including patients who were on TB treatment were excluded from the study, given that treatment might interfere with the confirmation of TB on culture.	Studies including HIV+ patients are important to consider for the following reasons: the risk of developing TB is greater in people living with HIV; signs and symptoms of TB in people living with HIV vary, which makes it challenging to determine when to consider a diagnosis of TB; and many HIV‐positive people in low‐income countries develop TB as the first manifestation of AIDS. Future studies should assess the diagnostic accuracy of Xpert Ultra vs. Xpert MTB/RIF for TB in difficult‐to‐diagnose groups, such as children and people with extrapulmonary TB. Other priority populations for research include those in whom the consequences of a missed diagnosis of TB are particularly severe, such as pregnant women and people with co-morbid conditions. The reference standards for this review were solid culture or automated liquid culture. Pulmonary TB present was defined as a positive M tuberculosis culture. Pulmonary TB absent was defined as a negative M tuberculosis culture. Because anti-tuberculosis treatment can interfere with the confirmation of tuberculosis on culture, those on TB treatment for more than 7 days were excluded from the study.
Cost-equity
No studies contributed economic data	This review did not examine costs, cost‐effectiveness, and affordability of molecular tests for TB. Cost‐effectiveness of Xpert Ultra and Xpert MTB/RIF is dependent on several factors, including testing volume, TB prevalence, level of empirical TB treatment, and pre-treatment loss to follow‐up. Further economic analyses are needed to develop an understanding of the most cost-effective and efficient test.
Monitoring & Evaluation for PROGRESS Groups
	Future studies should perform comparisons of different diagnostic tests across high-risk groups to reveal which tests yield superior diagnostic accuracy. This will help countries make decisions about scaling up the tests for programmatic management of TB. Other factors such as resource allocation, cost-effectiveness, and feasibility are also important considerations.

Comments on this summary? Please contact Jennifer Petkovic.

This summary was prepared by Lama Dahroug