Tuberculosis (TB) causes tremendous suffering worldwide, especially in low-income and middle-income countries. In 2012, 8.6 million people developed TB disease (active TB) for the first time and around 1.3 million people died. Most people with TB can be cured if the disease is diagnosed and properly treated. One of the problems in treating TB is that the bacteria become resistant to antibiotics. Detecting TB and TB drug resistance quickly is important for improving health, reducing deaths, and decreasing the spread of TB in communities.
Xpert® MTB/RIF is a new test that quickly detects TB and rifampicin resistance at the same time. Rifampicin is an important drug for treating people with TB. Since the test is automated, it does not require expert staff or an advanced laboratory.
Our objectives were to determine the diagnostic accuracy (sensitivity and specificity) for TB detection and rifampicin resistance detection. Sensitivity shows how often the test gives a positive result in people who really have TB. Specificity shows how often the test gives a negative result in people who do not have TB.
We included studies of adults with or without HIV infection thought to have pulmonary TB (TB in the lungs) or rifampicin resistance, and were most interested in the use of Xpert® MTB/RIF outside of the most advanced laboratories.
We also compared the sensitivity of Xpert® MTB/RIF to that of smear microscopy, the test commonly used for TB diagnosis in low- and middle-income countries. Smear microscopy is low-cost and fairly easy to do, but requires trained staff and is a hassle for patients, who must provide at least two sputum samples. Also, microscopy gives no information about drug resistance.
We searched for publications in any language up to 7 February 2013 and considered the study's risk of giving biased results.
What the results say
We included 27 studies involving around 9500 people. Most studies were performed in low- or middle-income countries. We thought most studies had a low risk of bias.
The key findings were:
For TB detection, Xpert® MTB/RIF was accurate (it was highly sensitive (89%), detecting almost all cases; and specific (99%), that is, not registering positive in people who were actually negative).
For rifampicin resistance detection, Xpert® MTB/RIF was accurate that is sensitive (95%) and specific (98%).
Xpert® MTB/RIF appeared to have similar accuracy in people with and without HIV infection.
Applying the findings of the review to an imaginary group of 1000 people who go to their doctor with symptoms, but where only 100 of them (10%) actually have TB, Xpert® MTB/RIF would diagnose 88 cases and miss 12 cases, whereas smear microscopy would diagnose 65 cases and miss 35 cases.
To summarize, our review shows that Xpert® MTB/RIF is more accurate than smear microscopy for diagnosing TB and also accurate for detecting rifampicin resistance. Xpert® MTB/RIF may be useful in many countries, as it does not require advanced laboratory facilities or expert staff.
In adults thought to have TB, with or without HIV infection, Xpert® MTB/RIF is sensitive and specific. Compared with smear microscopy, Xpert® MTB/RIF substantially increases TB detection among culture-confirmed cases. Xpert® MTB/RIF has higher sensitivity for TB detection in smear-positive than smear-negative patients. Nonetheless, this test may be valuable as an add-on test following smear microscopy in patients previously found to be smear-negative. For rifampicin resistance detection, Xpert® MTB/RIF provides accurate results and can allow rapid initiation of MDR-TB treatment, pending results from conventional culture and DST. The tests are expensive, so current research evaluating the use of Xpert® MTB/RIF in TB programmes in high TB burden settings will help evaluate how this investment may help start treatment promptly and improve outcomes.
Accurate, rapid detection of tuberculosis (TB) and TB drug resistance is critical for improving patient care and decreasing TB transmission. Xpert® MTB/RIF assay is an automated test that can detect both TB and rifampicin resistance, generally within two hours after starting the test, with minimal hands-on technical time. The World Health Organization (WHO) issued initial recommendations on Xpert® MTB/RIF in early 2011. A Cochrane Review on the diagnostic accuracy of Xpert® MTB/RIF for pulmonary TB and rifampicin resistance was published January 2013. We performed this updated Cochrane Review as part of a WHO process to develop updated guidelines on the use of the test.
To assess the diagnostic accuracy of Xpert® MTB/RIF for pulmonary TB (TB detection), where Xpert® MTB/RIF was used as both an initial test replacing microscopy and an add-on test following a negative smear microscopy result.
To assess the diagnostic accuracy of Xpert® MTB/RIF for rifampicin resistance detection, where Xpert® MTB/RIF was used as the initial test replacing culture-based drug susceptibility testing (DST).
The populations of interest were adults presumed to have pulmonary, rifampicin-resistant or multidrug-resistant TB (MDR-TB), with or without HIV infection. The settings of interest were intermediate- and peripheral-level laboratories. The latter may be associated with primary health care facilities.
We searched for publications in any language up to 7 February 2013 in the following databases: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; ISI Web of Knowledge; MEDION; LILACS; BIOSIS; and SCOPUS. We also searched the metaRegister of Controlled Trials (mRCT) and the search portal of the WHO International Clinical Trials Registry Platform to identify ongoing trials.
We included randomized controlled trials, cross-sectional studies, and cohort studies using respiratory specimens that allowed for extraction of data evaluating Xpert® MTB/RIF against the reference standard. We excluded gastric fluid specimens. The reference standard for TB was culture and for rifampicin resistance was phenotypic culture-based DST.
For each study, two review authors independently extracted data using a standardized form. When possible, we extracted data for subgroups by smear and HIV status. We assessed the quality of studies using QUADAS-2 and carried out meta-analyses to estimate pooled sensitivity and specificity of Xpert® MTB/RIF separately for TB detection and rifampicin resistance detection. For TB detection, we performed the majority of analyses using a bivariate random-effects model and compared the sensitivity of Xpert® MTB/RIF and smear microscopy against culture as reference standard. For rifampicin resistance detection, we undertook univariate meta-analyses for sensitivity and specificity separately to include studies in which no rifampicin resistance was detected.
We included 27 unique studies (integrating nine new studies) involving 9557 participants. Sixteen studies (59%) were performed in low- or middle-income countries. For all QUADAS-2 domains, most studies were at low risk of bias and low concern regarding applicability.
As an initial test replacing smear microscopy, Xpert® MTB/RIF pooled sensitivity was 89% [95% Credible Interval (CrI) 85% to 92%] and pooled specificity 99% (95% CrI 98% to 99%), (22 studies, 8998 participants: 2953 confirmed TB, 6045 non-TB).
As an add-on test following a negative smear microscopy result, Xpert®MTB/RIF pooled sensitivity was 67% (95% CrI 60% to 74%) and pooled specificity 99% (95% CrI 98% to 99%; 21 studies, 6950 participants).
For smear-positive, culture-positive TB, Xpert® MTB/RIF pooled sensitivity was 98% (95% CrI 97% to 99%; 21 studies, 1936 participants).
For people with HIV infection, Xpert® MTB/RIF pooled sensitivity was 79% (95% CrI 70% to 86%; seven studies, 1789 participants), and for people without HIV infection, it was 86% (95% CrI 76% to 92%; seven studies, 1470 participants).
Among 180 specimens with nontuberculous mycobacteria (NTM), Xpert® MTB/RIF was positive in only one specimen that grew NTM (14 studies, 2626 participants).
Comparison with smear microscopy
In comparison with smear microscopy, Xpert® MTB/RIF increased TB detection among culture-confirmed cases by 23% (95% CrI 15% to 32%; 21 studies, 8880 participants).
For TB detection, if pooled sensitivity estimates for Xpert® MTB/RIF and smear microscopy are applied to a hypothetical cohort of 1000 patients where 10% of those with symptoms have TB, Xpert® MTB/RIF will diagnose 88 cases and miss 12 cases, whereas sputum microscopy will diagnose 65 cases and miss 35 cases.
For rifampicin resistance detection, Xpert® MTB/RIF pooled sensitivity was 95% (95% CrI 90% to 97%; 17 studies, 555 rifampicin resistance positives) and pooled specificity was 98% (95% CrI 97% to 99%; 24 studies, 2411 rifampicin resistance negatives).
For rifampicin resistance detection, if the pooled accuracy estimates for Xpert® MTB/RIF are applied to a hypothetical cohort of 1000 individuals where 15% of those with symptoms are rifampicin resistant, Xpert® MTB/RIF would correctly identify 143 individuals as rifampicin resistant and miss eight cases, and correctly identify 833 individuals as rifampicin susceptible and misclassify 17 individuals as resistant. Where 5% of those with symptoms are rifampicin resistant, Xpert® MTB/RIF would correctly identify 48 individuals as rifampicin resistant and miss three cases and correctly identify 931 individuals as rifampicin susceptible and misclassify 19 individuals as resistant.