Search

Additional file 1: Supplemental Figure S1. Pairwise residual correlation plots for tests run on A) lymph node, B) CSF, and C) pleural fluid. Test pair 1: culture and Xpert; 2: culture and smear microscopy; 3: culture and cytopathology/histopathology or ADA; 4: Xpert and smear microscopy; 5: Xpert and cytopathology/histopathology or ADA; 6: smear microscopy and cytopathology/histopathology or ADA. ADA – adenosine deaminase; CSF – cerebral spinal fluid; TB – tuberculosis. Supplemental Figure S2. Density plots. For each of the three models (one per form of extrapulmonary TB), density plots were generated for each parameter of interest. For test result parameters specificity, C, and sensitivity, S, the indices 1, …,4 indicate culture, Xpert, smear microscopy, and ADA or cytopathology/histopathology. Supplementary Table S1. Probabilities of the four latent classes, for each form of extrapulmonary TB as estimated by Bayesian latent class analysis. Supplementary Table S2. Diagnostic accuracies of tests for each form of extrapulmonary TB by latent class analysis. Supplementary Table S3. Prevalence of each form of extrapulmonary TB as estimated by the two-class latent class model

11 páginas, 2 figuras, 1 tabla, Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance., I. Comas was supported by PID2019-104477RB-I00 from the Spanish Science Ministry and by ERC (CoG 101001038)

Background\ud Xpert MTB/RIF and Xpert MTB/RIF Ultra (Xpert Ultra) are World Health Organization (WHO)‐recommended rapid tests that simultaneously detect tuberculosis and rifampicin resistance in people with signs and symptoms of tuberculosis. This review builds on our recent extensive Cochrane Review of Xpert MTB/RIF accuracy.\ud \ud Objectives\ud To compare the diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF for the detection of pulmonary tuberculosis and detection of rifampicin resistance in adults with presumptive pulmonary tuberculosis. For pulmonary tuberculosis and rifampicin resistance, we also investigated potential sources of heterogeneity.\ud \ud We also summarized the frequency of Xpert Ultra trace‐positive results, and estimated the accuracy of Xpert Ultra after repeat testing in those with trace‐positive results.\ud \ud Search methods\ud We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, LILACS, Scopus, the WHO ICTRP, the ISRCTN registry, and ProQuest to 28 January 2020 with no language restriction.\ud \ud Selection criteria\ud We included diagnostic accuracy studies using respiratory specimens in adults with presumptive pulmonary tuberculosis that directly compared the index tests. For pulmonary tuberculosis detection, the reference standards were culture and a composite reference standard. For rifampicin resistance, the reference standards were culture‐based drug susceptibility testing and line probe assays.\ud \ud Data collection and analysis\ud Two review authors independently extracted data using a standardized form, including data by smear and HIV status. We assessed risk of bias using QUADAS‐2 and QUADAS‐C. We performed meta‐analyses comparing pooled sensitivities and specificities, separately for pulmonary tuberculosis detection and rifampicin resistance detection, and separately by reference standard. Most analyses used a bivariate random‐effects model. For tuberculosis detection, we estimated accuracy in studies in participants who were not selected based on prior microscopy testing or history of tuberculosis. We performed subgroup analyses by smear status, HIV status, and history of tuberculosis. We summarized Xpert Ultra trace results.\ud \ud Main results\ud We identified nine studies (3500 participants): seven had unselected participants (2834 participants). All compared Xpert Ultra and Xpert MTB/RIF for pulmonary tuberculosis detection; seven studies used a paired comparative accuracy design, and two studies used a randomized design. Five studies compared Xpert Ultra and Xpert MTB/RIF for rifampicin resistance detection; four studies used a paired design, and one study used a randomized design. Of the nine included studies, seven (78%) were mainly or exclusively in high tuberculosis burden countries. For pulmonary tuberculosis detection, most studies had low risk of bias in all domains.\ud \ud Pulmonary tuberculosis detection\ud \ud Xpert Ultra pooled sensitivity and specificity (95% credible interval) against culture were 90.9% (86.2 to 94.7) and 95.6% (93.0 to 97.4) (7 studies, 2834 participants; high‐certainty evidence) versus Xpert MTB/RIF pooled sensitivity and specificity of 84.7% (78.6 to 89.9) and 98.4% (97.0 to 99.3) (7 studies, 2835 participants; high‐certainty evidence). The difference in the accuracy of Xpert Ultra minus Xpert MTB/RIF was estimated at 6.3% (0.1 to 12.8) for sensitivity and −2.7% (−5.7 to −0.5) for specificity. If the point estimates for Xpert Ultra and Xpert MTB/RIF are applied to a hypothetical cohort of 1000 patients, where 10% of those presenting with symptoms have pulmonary tuberculosis, Xpert Ultra will miss 9 cases, and Xpert MTB/RIF will miss 15 cases. The number of people wrongly diagnosed with pulmonary tuberculosis would be 40 with Xpert Ultra and 14 with Xpert MTB/RIF.\ud \ud In smear‐negative, culture‐positive participants, pooled sensitivity was 77.5% (67.6 to 85.6) for Xpert Ultra versus 60.6% (48.4 to 71.7) for Xpert MTB/RIF; pooled specificity was 95.8% (92.9 to 97.7) for Xpert Ultra versus 98.8% (97.7 to 99.5) for Xpert MTB/RIF (6 studies).\ud \ud In people living with HIV, pooled sensitivity was 87.6% (75.4 to 94.1) for Xpert Ultra versus 74.9% (58.7 to 86.2) for Xpert MTB/RIF; pooled specificity was 92.8% (82.3 to 97.0) for Xpert Ultra versus 99.7% (98.6 to 100.0) for Xpert MTB/RIF (3 studies).\ud \ud In participants with a history of tuberculosis, pooled sensitivity was 84.2% (72.5 to 91.7) for Xpert Ultra versus 81.8% (68.7 to 90.0) for Xpert MTB/RIF; pooled specificity was 88.2% (70.5 to 96.6) for Xpert Ultra versus 97.4% (91.7 to 99.5) for Xpert MTB/RIF (4 studies).\ud \ud The proportion of Ultra trace‐positive results ranged from 3.0% to 30.4%. Data were insufficient to estimate the accuracy of Xpert Ultra repeat testing in individuals with initial trace‐positive results.\ud \ud Rifampicin resistance detection\ud \ud Pooled sensitivity and specificity were 94.9% (88.9 to 97.9) and 99.1% (97.7 to 99.8) (5 studies, 921 participants; high‐certainty evidence) for Xpert Ultra versus 95.3% (90.0 to 98.1) and 98.8% (97.2 to 99.6) (5 studies, 930 participants; high‐certainty evidence) for Xpert MTB/RIF. The difference in the accuracy of Xpert Ultra minus Xpert MTB/RIF was estimated at −0.3% (−6.9 to 5.7) for sensitivity and 0.3% (−1.2 to 2.0) for specificity. If the point estimates for Xpert Ultra and Xpert MTB/RIF are applied to a hypothetical cohort of 1000 patients, where 10% of those presenting with symptoms have rifampicin resistance, Xpert Ultra will miss 5 cases, and Xpert MTB/RIF will miss 5 cases. The number of people wrongly diagnosed with rifampicin resistance would be 8 with Xpert Ultra and 11 with Xpert MTB/RIF.\ud \ud We identified a higher number of rifampicin resistance indeterminate results with Xpert Ultra, pooled proportion 7.6% (2.4 to 21.0) compared to Xpert MTB/RIF pooled proportion 0.8% (0.2 to 2.4). The estimated difference in the pooled proportion of indeterminate rifampicin resistance results for Xpert Ultra versus Xpert MTB/RIF was 6.7% (1.4 to 20.1).\ud \ud Authors' conclusions\ud Xpert Ultra has higher sensitivity and lower specificity than Xpert MTB/RIF for pulmonary tuberculosis, especially in smear‐negative participants and people living with HIV. Xpert Ultra specificity was lower than that of Xpert MTB/RIF in participants with a history of tuberculosis. The sensitivity and specificity trade‐off would be expected to vary by setting. For detection of rifampicin resistance, Xpert Ultra and Xpert MTB/RIF had similar sensitivity and specificity. Ultra trace‐positive results were common.\ud \ud Xpert Ultra and Xpert MTB/RIF provide accurate results and can allow rapid initiation of treatment for rifampicin‐resistant and multidrug‐resistant tuberculosis.

Background\ud Xpert MTB/RIF Ultra (Xpert Ultra) and Xpert MTB/RIF are World Health Organization (WHO)‐recommended rapid nucleic acid amplification tests (NAATs) widely used for simultaneous detection of Mycobacterium tuberculosis complex and rifampicin resistance in sputum. To extend our previous review on extrapulmonary tuberculosis (Kohli 2018), we performed this update to inform updated WHO policy (WHO Consolidated Guidelines (Module 3) 2020).\ud \ud Objectives\ud To estimate diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF for extrapulmonary tuberculosis and rifampicin resistance in adults with presumptive extrapulmonary tuberculosis.\ud \ud Search methods\ud Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, 2 August 2019 and 28 January 2020 (Xpert Ultra studies), without language restriction.\ud \ud Selection criteria\ud Cross‐sectional and cohort studies using non‐respiratory specimens. Forms of extrapulmonary tuberculosis: tuberculous meningitis and pleural, lymph node, bone or joint, genitourinary, peritoneal, pericardial, disseminated tuberculosis. Reference standards were culture and a study‐defined composite reference standard (tuberculosis detection); phenotypic drug susceptibility testing and line probe assays (rifampicin resistance detection).\ud \ud Data collection and analysis\ud Two review authors independently extracted data and assessed risk of bias and applicability using QUADAS‐2. For tuberculosis detection, we performed separate analyses by specimen type and reference standard using the bivariate model to estimate pooled sensitivity and specificity with 95% credible intervals (CrIs). We applied a latent class meta‐analysis model to three forms of extrapulmonary tuberculosis. We assessed certainty of evidence using GRADE.\ud \ud Main results\ud 69 studies: 67 evaluated Xpert MTB/RIF and 11 evaluated Xpert Ultra, of which nine evaluated both tests. Most studies were conducted in China, India, South Africa, and Uganda. Overall, risk of bias was low for patient selection, index test, and flow and timing domains, and low (49%) or unclear (43%) for the reference standard domain. Applicability for the patient selection domain was unclear for most studies because we were unsure of the clinical settings.\ud \ud Cerebrospinal fluid\ud \ud Xpert Ultra (6 studies)\ud \ud Xpert Ultra pooled sensitivity and specificity (95% CrI) against culture were 89.4% (79.1 to 95.6) (89 participants; low‐certainty evidence) and 91.2% (83.2 to 95.7) (386 participants; moderate‐certainty evidence). Of 1000 people where 100 have tuberculous meningitis, 168 would be Xpert Ultra‐positive: of these, 79 (47%) would not have tuberculosis (false‐positives) and 832 would be Xpert Ultra‐negative: of these, 11 (1%) would have tuberculosis (false‐negatives).\ud \ud Xpert MTB/RIF (30 studies)\ud \ud Xpert MTB/RIF pooled sensitivity and specificity against culture were 71.1% (62.8 to 79.1) (571 participants; moderate‐certainty evidence) and 96.9% (95.4 to 98.0) (2824 participants; high‐certainty evidence). Of 1000 people where 100 have tuberculous meningitis, 99 would be Xpert MTB/RIF‐positive: of these, 28 (28%) would not have tuberculosis; and 901 would be Xpert MTB/RIF‐negative: of these, 29 (3%) would have tuberculosis.\ud \ud Pleural fluid\ud \ud Xpert Ultra (4 studies)\ud \ud Xpert Ultra pooled sensitivity and specificity against culture were 75.0% (58.0 to 86.4) (158 participants; very low‐certainty evidence) and 87.0% (63.1 to 97.9) (240 participants; very low‐certainty evidence). Of 1000 people where 100 have pleural tuberculosis, 192 would be Xpert Ultra‐positive: of these, 117 (61%) would not have tuberculosis; and 808 would be Xpert Ultra‐negative: of these, 25 (3%) would have tuberculosis.\ud \ud Xpert MTB/RIF (25 studies)\ud \ud Xpert MTB/RIF pooled sensitivity and specificity against culture were 49.5% (39.8 to 59.9) (644 participants; low‐certainty evidence) and 98.9% (97.6 to 99.7) (2421 participants; high‐certainty evidence). Of 1000 people where 100 have pleural tuberculosis, 60 would be Xpert MTB/RIF‐positive: of these, 10 (17%) would not have tuberculosis; and 940 would be Xpert MTB/RIF‐negative: of these, 50 (5%) would have tuberculosis.\ud \ud Lymph node aspirate\ud \ud Xpert Ultra (1 study)\ud \ud Xpert Ultra sensitivity and specificity (95% confidence interval) against composite reference standard were 70% (51 to 85) (30 participants; very low‐certainty evidence) and 100% (92 to 100) (43 participants; low‐certainty evidence). Of 1000 people where 100 have lymph node tuberculosis, 70 would be Xpert Ultra‐positive and 0 (0%) would not have tuberculosis; 930 would be Xpert Ultra‐negative and 30 (3%) would have tuberculosis.\ud \ud Xpert MTB/RIF (4 studies)\ud \ud Xpert MTB/RIF pooled sensitivity and specificity against composite reference standard were 81.6% (61.9 to 93.3) (377 participants; low‐certainty evidence) and 96.4% (91.3 to 98.6) (302 participants; low‐certainty evidence). Of 1000 people where 100 have lymph node tuberculosis, 118 would be Xpert MTB/RIF‐positive and 37 (31%) would not have tuberculosis; 882 would be Xpert MTB/RIF‐negative and 19 (2%) would have tuberculosis.\ud \ud In lymph node aspirate, Xpert MTB/RIF pooled specificity against culture was 86.2% (78.0 to 92.3), lower than that against a composite reference standard. Using the latent class model, Xpert MTB/RIF pooled specificity was 99.5% (99.1 to 99.7), similar to that observed with a composite reference standard.\ud \ud Rifampicin resistance\ud \ud Xpert Ultra (4 studies)\ud \ud Xpert Ultra pooled sensitivity and specificity were 100.0% (95.1 to 100.0), (24 participants; low‐certainty evidence) and 100.0% (99.0 to 100.0) (105 participants; moderate‐certainty evidence). Of 1000 people where 100 have rifampicin resistance, 100 would be Xpert Ultra‐positive (resistant): of these, zero (0%) would not have rifampicin resistance; and 900 would be Xpert Ultra‐negative (susceptible): of these, zero (0%) would have rifampicin resistance.\ud \ud Xpert MTB/RIF (19 studies)\ud \ud Xpert MTB/RIF pooled sensitivity and specificity were 96.5% (91.9 to 98.8) (148 participants; high‐certainty evidence) and 99.1% (98.0 to 99.7) (822 participants; high‐certainty evidence). Of 1000 people where 100 have rifampicin resistance, 105 would be Xpert MTB/RIF‐positive (resistant): of these, 8 (8%) would not have rifampicin resistance; and 895 would be Xpert MTB/RIF‐negative (susceptible): of these, 3 (0.3%) would have rifampicin resistance.\ud \ud Authors' conclusions\ud Xpert Ultra and Xpert MTB/RIF may be helpful in diagnosing extrapulmonary tuberculosis. Sensitivity varies across different extrapulmonary specimens: while for most specimens specificity is high, the tests rarely yield a positive result for people without tuberculosis. For tuberculous meningitis, Xpert Ultra had higher sensitivity and lower specificity than Xpert MTB/RIF against culture. Xpert Ultra and Xpert MTB/RIF had similar sensitivity and specificity for rifampicin resistance. Future research should acknowledge the concern associated with culture as a reference standard in paucibacillary specimens and consider ways to address this limitation.

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows: \ud \ud To determine the diagnostic accuracy of abdominal ultrasound as a standalone test for detecting abdominal TB or disseminated TB with abdominal involvement in HIV‐positive adults.