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Since 2018, over 14 million people have been treated for tuberculosis (TB) globally. However, pre-treatment loss to follow-up (PTLFU) has been shown to contribute substantially to patient losses in the TB care cascade with subsequent high community transmission and mortality rates.To identify, appraise, and synthesise evidence on the perspectives of patients and healthcare workers on factors contributing to PTLFU in adults with pulmonary TB.We registered the title with PROSPERO (CRD42021253212). We searched nine relevant databases up to 24 May 2021 for qualitative studies. Two review authors independently reviewed records for eligibility and extracted data. We assessed methodological quality with the Evidence for Policy and Practice Information Centre tool and synthesised data using the Supporting the Use of Research Evidence framework. We assessed confidence in our findings using Confidence in the Evidence from Reviews of Qualitative Research (GRADE-CERQual).We reviewed a total of 1239 records and included five studies, all from low- and middle-income countries. Key themes reported by patients and healthcare workers were communication challenges among healthcare workers and between healthcare workers and patients; knowledge, attitudes, and behaviours about TB and its management; accessibility and availability of facilities for TB care; and human resource and financial constraints, weakness in management and leadership in TB programmes. Patients' change of residence, long waiting times, and poor referral systems were additional factors that contributed to patients disengaging from care. We had moderate confidence in most of our findings.Findings from our qualitative evidence synthesis highlight multiple factors that contribute to PTLFU. Central to addressing these factors will be the need to strengthen health systems and offer people-centred care.

IntroductionTuberculosis (TB) is one of the top causes of death worldwide with more than 90% of reported cases occurring in low- and middle-income countries according to the World Health Organization Global Tuberculosis Report 2021. Pre-treatment loss to follow-up is a key contributor to community transmission and deaths due to the disease. Breaking the transmission cycle will require timely diagnosis and prompt initiation of effective treatment. Therefore, in this protocol, we outline a scoping review to systematically map out available evidence on interventions to reduce pre-treatment loss to follow-up in adults with pulmonary TB and identify any existing gaps in knowledge. Thereafter, we will develop a conceptual framework based on the Practical, Robust Implementation, and Sustainability Model to provide a base to guide the implementation of the available interventions.Methods and analysisWe will use the framework proposed by Arksey and O’Malley to conduct our scoping review. We will search the following electronic databases: Cochrane Library, MEDLINE (OVID), EMBASE (OVID), CINAHL, Science Direct, Web of Science, Global Index Medicus, Health Research and Development Information Network, Turning Research into Practice, Latin American and Caribbean Health Sciences, SCOPUS, and EBSCOhost. We will also search the medRxiv database for pre-prints and review reference lists of included studies. We will perform the search without date restriction. We will utilize filters limiting search results to English studies. We will include any primary study that meets the eligibility criteria as guided by the population, concept, and context framework. To minimize selection bias, two review authors will independently screen and select eligible studies. We will resolve disagreements through discussion and consensus and, if necessary, consult a third review author. We will extract data using a predesigned form. We will analyze data descriptively and present findings in a narrative summary and tables. We will then develop a conceptual framework to map the various interventions and factors to consider for effective implementation. Ethics and disseminationFor this scoping review, we will not seek formal ethical approval since we will be using secondary data that is available in the public domain. We will use Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for scoping reviews (PRISMA-ScR) to guide the reporting of our findings. We will disseminate our findings through peer-reviewed publications, stakeholder meetings, and conference presentations.

Background Every year, at least one million children become ill with tuberculosis and around 200,000 children die. Xpert MTB/RIF and Xpert Ultra are World Health Organization (WHO)‐recommended rapid molecular tests that simultaneously detect tuberculosis and rifampicin resistance in adults and children with signs and symptoms of tuberculosis, at lower health system levels. To inform updated WHO guidelines on molecular assays, we performed a systematic review on the diagnostic accuracy of these tests in children presumed to have active tuberculosis. Objectives Primary objectives • To determine the diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra for (a) pulmonary tuberculosis in children presumed to have tuberculosis; (b) tuberculous meningitis in children presumed to have tuberculosis; (c) lymph node tuberculosis in children presumed to have tuberculosis; and (d) rifampicin resistance in children presumed to have tuberculosis ‐ For tuberculosis detection, index tests were used as the initial test, replacing standard practice (i.e. smear microscopy or culture) ‐ For detection of rifampicin resistance, index tests replaced culture‐based drug susceptibility testing as the initial test Secondary objectives • To compare the accuracy of Xpert MTB/RIF and Xpert Ultra for each of the four target conditions • To investigate potential sources of heterogeneity in accuracy estimates ‐ For tuberculosis detection, we considered age, disease severity, smear‐test status, HIV status, clinical setting, specimen type, high tuberculosis burden, and high tuberculosis/HIV burden ‐ For detection of rifampicin resistance, we considered multi‐drug‐resistant tuberculosis burden • To compare multiple Xpert MTB/RIF or Xpert Ultra results (repeated testing) with the initial Xpert MTB/RIF or Xpert Ultra result Search methods We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and the International Standard Randomized Controlled Trials Number (ISRCTN) Registry up to 29 April 2019, without language restrictions. Selection criteria Randomized trials, cross‐sectional trials, and cohort studies evaluating Xpert MTB/RIF or Xpert Ultra in HIV‐positive and HIV‐negative children younger than 15 years. Reference standards comprised culture or a composite reference standard for tuberculosis and drug susceptibility testing or MTBDRplus (molecular assay for detection of Mycobacterium tuberculosis and drug resistance) for rifampicin resistance. We included studies evaluating sputum, gastric aspirate, stool, nasopharyngeal or bronchial lavage specimens (pulmonary tuberculosis), cerebrospinal fluid (tuberculous meningitis), fine needle aspirates, or surgical biopsy tissue (lymph node tuberculosis). Data collection and analysis Two review authors independently extracted data and assessed study quality using the Quality Assessment of Studies of Diagnostic Accuracy ‐ Revised (QUADAS‐2). For each target condition, we used the bivariate model to estimate pooled sensitivity and specificity with 95% confidence intervals (CIs). We stratified all analyses by type of reference standard. We assessed certainty of evidence using the GRADE approach. Main results For pulmonary tuberculosis, 299 data sets (68,544 participants) were available for analysis; for tuberculous meningitis, 10 data sets (423 participants) were available; for lymph node tuberculosis, 10 data sets (318 participants) were available; and for rifampicin resistance, 14 data sets (326 participants) were available. Thirty‐nine studies (80%) took place in countries with high tuberculosis burden. Risk of bias was low except for the reference standard domain, for which risk of bias was unclear because many studies collected only one specimen for culture. Detection of pulmonary tuberculosis For sputum specimens, Xpert MTB/RIF pooled sensitivity (95% CI) and specificity (95% CI) verified by culture were 64.6% (55.3% to 72.9%) (23 studies, 493 participants; moderate‐certainty evidence) and 99.0% (98.1% to 99.5%) (23 studies, 6119 participants; moderate‐certainty evidence). For other specimen types (nasopharyngeal aspirate, 4 studies; gastric aspirate, 14 studies; stool, 11 studies), Xpert MTB/RIF pooled sensitivity ranged between 45.7% and 73.0%, and pooled specificity ranged between 98.1% and 99.6%. For sputum specimens, Xpert Ultra pooled sensitivity (95% CI) and specificity (95% CI) verified by culture were 72.8% (64.7% to 79.6%) (3 studies, 136 participants; low‐certainty evidence) and 97.5% (95.8% to 98.5%) (3 studies, 551 participants; high‐certainty evidence). For nasopharyngeal specimens, Xpert Ultra sensitivity (95% CI) and specificity (95% CI) were 45.7% (28.9% to 63.3%) and 97.5% (93.7% to 99.3%) (1 study, 195 participants). For all specimen types, Xpert MTB/RIF and Xpert Ultra sensitivity were lower against a composite reference standard than against culture. Detection of tuberculous meningitis For cerebrospinal fluid, Xpert MTB/RIF pooled sensitivity and specificity, verified by culture, were 54.0% (95% CI 27.8% to 78.2%) (6 studies, 28 participants; very low‐certainty evidence) and 93.8% (95% CI 84.5% to 97.6%) (6 studies, 213 participants; low‐certainty evidence). Detection of lymph node tuberculosis For lymph node aspirates or biopsies, Xpert MTB/RIF pooled sensitivity and specificity, verified by culture, were 90.4% (95% CI 55.7% to 98.6%) (6 studies, 68 participants; very low‐certainty evidence) and 89.8% (95% CI 71.5% to 96.8%) (6 studies, 142 participants; low‐certainty evidence). Detection of rifampicin resistance Xpert MTB/RIF pooled sensitivity and specificity were 90.0% (67.6% to 97.5%) (6 studies, 20 participants; low‐certainty evidence) and 98.3% (87.7% to 99.8%) (6 studies, 203 participants; moderate‐certainty evidence). Authors' conclusions We found Xpert MTB/RIF sensitivity to vary by specimen type, with gastric aspirate specimens having the highest sensitivity followed by sputum and stool, and nasopharyngeal specimens the lowest; specificity in all specimens was > 98%. Compared with Xpert MTB/RIF, Xpert Ultra sensitivity in sputum was higher and specificity slightly lower. Xpert MTB/RIF was accurate for detection of rifampicin resistance. Xpert MTB/RIF was sensitive for diagnosing lymph node tuberculosis. For children with presumed tuberculous meningitis, treatment decisions should be based on the entirety of clinical information and treatment should not be withheld based solely on an Xpert MTB/RIF result. The small numbers of studies and participants, particularly for Xpert Ultra, limits our confidence in the precision of these estimates., Plain language summary Xpert tests for active tuberculosis in children Why is improving the diagnosis of pulmonary tuberculosis important? In 2018, at least one million children became ill with tuberculosis and around 200,000 died. When detected early and effectively treated, tuberculosis is largely curable. Xpert MTB/RIF and Xpert Ultra are World Health Organization‐recommended tests that simultaneously detect tuberculosis and rifampicin resistance in adults and children with tuberculosis symptoms. Rifampicin is an important anti‐tuberculosis drug. Not recognizing tuberculosis early may result in delayed diagnosis and treatment, severe illness, and death. A false tuberculosis diagnosis may result in anxiety and unnecessary treatment. What is the aim of this review? To determine the accuracy of tests in symptomatic children for diagnosing pulmonary tuberculosis, tuberculous meningitis, lymph node tuberculosis, and rifampicin resistance. What was studied in this review? Xpert MTB/RIF and Xpert Ultra, with results measured against culture and a composite reference standard (benchmarks), recognizing that neither reference is perfect in children. What are the main results in this review? A total of 49 studies were included. For pulmonary tuberculosis, we analysed 299 data sets including information describing nearly 70,000 children. For a population of 1000 children: Xpert MTB/RIF ‐ where 100 have pulmonary tuberculosis in sputum (by culture), 74 would be Xpert MTB/RIF‐positive, of whom 9 (12%) would not have tuberculosis (false‐positives); 926 would be Xpert MTB/RIF‐negative; and 35 (4%) would have tuberculosis (false‐negatives) ‐ where 100 have tuberculous meningitis (by culture), 86 would be Xpert MTB/RIF‐positive, of whom 59 (69%) would not have tuberculosis (false‐positives); 914 would be Xpert MTB/RIF‐negative; and 23 (3%) would have tuberculosis (false‐negatives) ‐ where 100 people have lymph node tuberculosis (by culture), 142 would be Xpert MTB/RIF‐positive, of whom 97 (68%) would not have lymph node tuberculosis (false‐positives); 858 would be Xpert MTB/RIF‐negative; and 5 (1%) would have lymph node TB (false‐negatives) ‐ where 100 have rifampicin resistance, 108 would have Xpert MTB/RIF‐rifampicin resistance detected, of whom 18 (17%) would not have rifampicin resistance (false‐positives); 892 would have Xpert MTB/RIF‐rifampicin resistance NOT detected; and 10 (1%) would have rifampicin resistance (false‐negatives) Xpert Ultra ‐ where 100 have pulmonary tuberculosis in sputum (by culture), 100 would be Xpert Ultra‐positive, of whom 27 (27%) would not have tuberculosis (false‐positives); 900 would be Xpert Ultra‐negative; and 27 (3%) would have tuberculosis (false‐negatives) How confident are we in the results of this review? We are confident. We included many studies from different countries and settings and used two reference standards. Some studies included only children at referral centres or did not report the setting. Therefore, we could not assess how the tests would work in a primary care setting. What children do the results of this review apply to? Children with presumed pulmonary tuberculosis, tuberculous meningitis, lymph node tuberculosis, or rifampicin resistance. What are the implications of this review? The results of the review suggest Xpert tests have the potential to be used to detect tuberculosis and rifampicin resistance. ‐ The risk of missing a diagnosis of pulmonary tuberculosis confirmed by culture with Xpert MTB/RIF (in sputum) is low (4% of those whose Xpert MTB/RIF suggests they do not have tuberculosis) suggesting that only a small number of children with tuberculosis confirmed by culture will not receive treatment. The risk of wrongly diagnosing a child as having tuberculosis is slightly higher (12% of those whose Xpert MTB/RIF test suggests they do have tuberculosis). This may result in some of these children receiving unnecessary treatment. ‐ The risk of missing a diagnosis of rifampicin resistance with Xpert MTB/RIF is low (1% of those whose Xpert MTB/RIF suggests they do not have rifampicin resistance) suggesting that only a small number of children with tuberculosis will not receive the appropriate treatment. The risk of wrongly diagnosing a child as rifampicin resistance tuberculosis is higher (17% of those whose Xpert MTB/RIF test suggests they do have rifampicin resistance). This may result in some of these children receiving unnecessary treatment. How up‐to‐date is this review? To 29 April 2019.

Background\ud The World Health Organization (WHO) End TB Strategy stresses universal access to drug susceptibility testing (DST). DST determines whether Mycobacterium tuberculosis bacteria are susceptible or resistant to drugs. Xpert MTB/XDR is a rapid nucleic acid amplification test for detection of tuberculosis and drug resistance in one test suitable for use in peripheral and intermediate level laboratories. In specimens where tuberculosis is detected by Xpert MTB/XDR, Xpert MTB/XDR can also detect resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin.\ud \ud Objectives\ud To assess the diagnostic accuracy of Xpert MTB/XDR for pulmonary tuberculosis in people with presumptive pulmonary tuberculosis (having signs and symptoms suggestive of tuberculosis, including cough, fever, weight loss, night sweats).\ud \ud To assess the diagnostic accuracy of Xpert MTB/XDR for resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin in people with tuberculosis detected by Xpert MTB/XDR, irrespective of rifampicin resistance (whether or not rifampicin resistance status was known) and with known rifampicin resistance.\ud \ud Search methods\ud We searched multiple databases to 23 September 2021. We limited searches to 2015 onwards as Xpert MTB/XDR was launched in 2020.\ud \ud Selection criteria\ud Diagnostic accuracy studies using sputum in adults with presumptive or confirmed pulmonary tuberculosis. Reference standards were culture (pulmonary tuberculosis detection); phenotypic DST (pDST), genotypic DST (gDST),composite (pDST and gDST) (drug resistance detection).\ud \ud Data collection and analysis\ud Two review authors independently reviewed reports for eligibility and extracted data using a standardized form. For multicentre studies, we anticipated variability in the type and frequency of mutations associated with resistance to a given drug at the different centres and considered each centre as an independent study cohort for quality assessment and analysis. We assessed methodological quality with QUADAS‐2, judging risk of bias separately for each target condition and reference standard. For pulmonary tuberculosis detection, owing to heterogeneity in participant characteristics and observed specificity estimates, we reported a range of sensitivity and specificity estimates and did not perform a meta‐analysis. For drug resistance detection, we performed meta‐analyses by reference standard using bivariate random‐effects models. Using GRADE, we assessed certainty of evidence of Xpert MTB/XDR accuracy for detection of resistance to isoniazid and fluoroquinolones in people irrespective of rifampicin resistance and to ethionamide and amikacin in people with known rifampicin resistance, reflecting real‐world situations. We used pDST, except for ethionamide resistance where we considered gDST a better reference standard.\ud \ud Main results\ud We included two multicentre studies from high multidrug‐resistant/rifampicin‐resistant tuberculosis burden countries, reporting on six independent study cohorts, involving 1228 participants for pulmonary tuberculosis detection and 1141 participants for drug resistance detection. The proportion of participants with rifampicin resistance in the two studies was 47.9% and 80.9%. For tuberculosis detection, we judged high risk of bias for patient selection owing to selective recruitment. For ethionamide resistance detection, we judged high risk of bias for the reference standard, both pDST and gDST, though we considered gDST a better reference standard.\ud \ud Pulmonary tuberculosis detection\ud \ud ‐ Xpert MTB/XDR sensitivity range, 98.3% (96.1 to 99.5) to 98.9% (96.2 to 99.9) and specificity range, 22.5% (14.3 to 32.6) to 100.0% (86.3 to 100.0); median prevalence of pulmonary tuberculosis 91.3%, (interquartile range, 89.3% to 91.8%), (2 studies; 1 study reported on 2 cohorts, 1228 participants; very low‐certainty evidence, sensitivity and specificity).\ud \ud Drug resistance detection\ud \ud People irrespective of rifampicin resistance\ud \ud ‐ Isoniazid resistance: Xpert MTB/XDR summary sensitivity and specificity (95% confidence interval (CI)) were 94.2% (87.5 to 97.4) and 98.5% (92.6 to 99.7) against pDST, (6 cohorts, 1083 participants, moderate‐certainty evidence, sensitivity and specificity).\ud \ud ‐ Fluoroquinolone resistance: Xpert MTB/XDR summary sensitivity and specificity were 93.2% (88.1 to 96.2) and 98.0% (90.8 to 99.6) against pDST, (6 cohorts, 1021 participants; high‐certainty evidence, sensitivity; moderate‐certainty evidence, specificity).\ud \ud People with known rifampicin resistance\ud \ud ‐ Ethionamide resistance: Xpert MTB/XDR summary sensitivity and specificity were 98.0% (74.2 to 99.9) and 99.7% (83.5 to 100.0) against gDST, (4 cohorts, 434 participants; very low‐certainty evidence, sensitivity and specificity).\ud \ud ‐ Amikacin resistance: Xpert MTB/XDR summary sensitivity and specificity were 86.1% (75.0 to 92.7) and 98.9% (93.0 to 99.8) against pDST, (4 cohorts, 490 participants; low‐certainty evidence, sensitivity; high‐certainty evidence, specificity).\ud \ud Of 1000 people with pulmonary tuberculosis, detected as tuberculosis by Xpert MTB/XDR:\ud \ud ‐ where 50 have isoniazid resistance, 61 would have an Xpert MTB/XDR result indicating isoniazid resistance: of these, 14/61 (23%) would not have isoniazid resistance (FP); 939 (of 1000 people) would have a result indicating the absence of isoniazid resistance: of these, 3/939 (0%) would have isoniazid resistance (FN).\ud \ud ‐ where 50 have fluoroquinolone resistance, 66 would have an Xpert MTB/XDR result indicating fluoroquinolone resistance: of these, 19/66 (29%) would not have fluoroquinolone resistance (FP); 934 would have a result indicating the absence of fluoroquinolone resistance: of these, 3/934 (0%) would have fluoroquinolone resistance (FN).\ud \ud ‐ where 300 have ethionamide resistance, 296 would have an Xpert MTB/XDR result indicating ethionamide resistance: of these, 2/296 (1%) would not have ethionamide resistance (FP); 704 would have a result indicating the absence of ethionamide resistance: of these, 6/704 (1%) would have ethionamide resistance (FN).\ud \ud ‐ where 135 have amikacin resistance, 126 would have an Xpert MTB/XDR result indicating amikacin resistance: of these, 10/126 (8%) would not have amikacin resistance (FP); 874 would have a result indicating the absence of amikacin resistance: of these, 19/874 (2%) would have amikacin resistance (FN).\ud \ud Authors' conclusions\ud Review findings suggest that, in people determined by Xpert MTB/XDR to be tuberculosis‐positive, Xpert MTB/XDR provides accurate results for detection of isoniazid and fluoroquinolone resistance and can assist with selection of an optimised treatment regimen. Given that Xpert MTB/XDR targets a limited number of resistance variants in specific genes, the test may perform differently in different settings. Findings in this review should be interpreted with caution. Sensitivity for detection of ethionamide resistance was based only on Xpert MTB/XDR detection of mutations in the inhA promoter region, a known limitation. High risk of bias limits our confidence in Xpert MTB/XDR accuracy for pulmonary tuberculosis.\ud \ud Xpert MTB/XDR's impact will depend on its ability to detect tuberculosis (required for DST), prevalence of resistance to a given drug, health care infrastructure, and access to other tests.

Background\ud Programmes that introduce rapid molecular tests for tuberculosis and tuberculosis drug resistance aim to bring tests closer to the community, and thereby cut delay in diagnosis, ensure early treatment, and improve health outcomes, as well as overcome problems with poor laboratory infrastructure and inadequately trained personnel. Yet, diagnostic technologies only have an impact if they are put to use in a correct and timely manner. Views of the intended beneficiaries are important in uptake of diagnostics, and their effective use also depends on those implementing testing programmes, including providers, laboratory professionals, and staff in health ministries. Otherwise, there is a risk these technologies will not fit their intended use and setting, cannot be made to work and scale up, and are not used by, or not accessible to, those in need.\ud \ud Objectives\ud To synthesize end‐user and professional user perspectives and experiences with low‐complexity nucleic acid amplification tests (NAATs) for detection of tuberculosis and tuberculosis drug resistance; and to identify implications for effective implementation and health equity.\ud \ud Search methods\ud We searched MEDLINE, Embase, CINAHL, PsycInfo and Science Citation Index Expanded databases for eligible studies from 1 January 2007 up to 20 October 2021. We limited all searches to 2007 onward because the development of Xpert MTB/RIF, the first rapid molecular test in this review, was completed in 2009.\ud \ud Selection criteria\ud We included studies that used qualitative methods for data collection and analysis, and were focused on perspectives and experiences of users and potential users of low‐complexity NAATs to diagnose tuberculosis and drug‐resistant tuberculosis. NAATs included Xpert MTB/RIF, Xpert MTB/RIF Ultra, Xpert MTB/XDR, and the Truenat assays. Users were people with presumptive or confirmed tuberculosis and drug‐resistant tuberculosis (including multidrug‐resistant (MDR‐TB)) and their caregivers, healthcare providers, laboratory technicians and managers, and programme officers and staff; and were from any type of health facility and setting globally. MDR‐TB is tuberculosis caused by resistance to at least rifampicin and isoniazid, the two most effective first‐line drugs used to treat tuberculosis.\ud \ud Data collection and analysis\ud We used a thematic analysis approach for data extraction and synthesis, and assessed confidence in the findings using GRADE CERQual approach. We developed a conceptual framework to illustrate how the findings relate.\ud \ud Main results\ud We found 32 studies. All studies were conducted in low‐ and middle‐income countries. Twenty‐seven studies were conducted in high‐tuberculosis burden countries and 21 studies in high‐MDR‐TB burden countries. Only one study was from an Eastern European country. While the studies covered a diverse use of low‐complexity NAATs, in only a minority of studies was it used as the initial diagnostic test for all people with presumptive tuberculosis.\ud \ud We identified 18 review findings and grouped them into three overarching categories.\ud \ud Critical aspects users value\ud \ud People with tuberculosis valued reaching diagnostic closure with an accurate diagnosis, avoiding diagnostic delays, and keeping diagnostic‐associated cost low. Similarly, healthcare providers valued aspects of accuracy and the resulting confidence in low‐complexity NAAT results, rapid turnaround times, and keeping cost to people seeking a diagnosis low. In addition, providers valued diversity of sample types (for example, gastric aspirate specimens and stool in children) and drug resistance information. Laboratory professionals appreciated the improved ease of use, ergonomics, and biosafety of low‐complexity NAATs compared to sputum microscopy, and increased staff satisfaction.\ud \ud Challenges reported to realizing those values\ud \ud People with tuberculosis and healthcare workers were reluctant to test for tuberculosis (including MDR‐TB) due to fears, stigma, or cost concerns. Thus, low‐complexity NAAT testing is not implemented with sufficient support or discretion to overcome barriers that are common to other approaches to testing for tuberculosis. Delays were reported at many steps of the diagnostic pathway owing to poor sample quality; difficulties with transporting specimens; lack of sufficient resources; maintenance of low‐complexity NAATs; increased workload; inefficient work and patient flows; over‐reliance on low‐complexity NAAT results in lieu of clinical judgement; and lack of data‐driven and inclusive implementation processes. These challenges were reported to lead to underutilization. \ud \ud Concerns for access and equity\ud \ud The reported concerns included sustainable funding and maintenance and equitable use of resources to access low‐complexity NAATs, as well as conflicts of interest between donors and people implementing the tests. Also, lengthy diagnostic delays, underutilization of low‐complexity NAATs, lack of tuberculosis diagnostic facilities in the community, and too many eligibility restrictions hampered access to prompt and accurate testing and treatment. This was particularly the case for vulnerable groups, such as children, people with MDR‐TB, or people with limited ability to pay.\ud \ud We had high confidence in most of our findings.\ud \ud Authors' conclusions\ud Low‐complexity diagnostics have been presented as a solution to overcome deficiencies in laboratory infrastructure and lack of skilled professionals. This review indicates this is misleading. The lack of infrastructure and human resources undermine the added value new diagnostics of low complexity have for recipients and providers. We had high confidence in the evidence contributing to these review findings.\ud \ud Implementation of new diagnostic technologies, like those considered in this review, will need to tackle the challenges identified in this review including weak infrastructure and systems, and insufficient data on ground level realities prior and during implementation, as well as problems of conflicts of interest in order to ensure equitable use of resources.

Background and Objectives Rapid reviews provide an efficient alternative to standard systematic reviews in response to a high priority or urgent need. Although rapid reviews of interventions have been extensively evaluated, little is known about the characteristics of rapid reviews of diagnostic evidence. Study Design and Setting We performed a scoping review for rapid reviews of medical tests published from 2013 to 2018. We extracted information on review characteristics and methods used to assess the evidence. Results We identified 191 rapid reviews. All reviews were developed within a short time (less than 12 months) and were relatively concise (less than 10 pages). The reviews involved multiple index tests (44%), multiple outcomes (88%), and several test applications (29%). Well-known methodological tailoring strategies were infrequently used. Although reporting of several key features was limited, we found that, in general, rapid reviews have similar characteristics to broader knowledge syntheses. Conclusion Our scoping review is the first to describe the characteristics and methods of rapid reviews of diagnostic evidence. Future research should identify the most appropriate methods for performing rapid reviews of medical tests. Standards for reporting of rapid reviews are needed.

Tests that can replace sputum smear microscopy have been identified as a top priority diagnostic need for tuberculosis by the World Health Organization. High-quality evidence on diagnostic accuracy for tests that may meet this need is an essential requirement to inform decisions about policy and scale-up. However, test accuracy studies are often of low and inconsistent quality and poorly reported, leading to uncertainty about true test performance. Here we provide guidance for the design of diagnostic test accuracy studies of sputum smear-replacement tests. Such studies should have a cross-sectional or cohort design, enrolling either a consecutive series or a random sample of patients who require evaluation for tuberculosis. Adults with respiratory symptoms are the target population. The reference standard should at a minimum be a single, automated, liquid culture, but additional cultures, follow-up, clinical case definition, and specific measures to understand discordant results should also be included. Inclusion of smear microscopy and Xpert MTB/RIF (or MTB/RIF Ultra) as comparators is critical to allow broader comparability and generalizability of results, because disease spectrum can vary between studies and affects relative test performance. Given the complex nature of sputum (the primary specimen type used for pulmonary TB), careful design and reporting of the specimen flow is essential. Test characteristics other than accuracy (such as feasibility, implementation considerations, and data on impact on patient, population and health systems outcomes) are also important aspects.

BackgroundSince 2018, there has been substantial progress with over 14 million people being treated for tuberculosis globally. However, the disease incidence and mortality are not falling fast enough to meet global targets, and, in addition, the COVID-19 pandemic threatens to counter the gains made in recent years. Pre-treatment loss to follow up is one of the factors that has been shown to contribute substantially to patient losses in the TB care cascade with subsequent high community transmission and mortality rates. This could be due to factors related to the patients as well as the health care workers. Therefore, conducting this review will enable us to identify, appraise and synthesize evidence on perspectives and experiences of patients and health care workers on pre-treatment loss to follow up in adults with pulmonary tuberculosis.MethodsA search strategy will be developed using SPIDER (Sample, Phenomenon of interest, Design, Evaluation, Research Type) framework and the search will be conducted in relevant databases. Screening of titles, abstract and full articles will be done using pre-defined eligibility criteria. Purposeful sampling will be considered if there is a large volume of primary studies eligible for inclusion. Data will be extracted using a predesigned form and assessment of methodological limitations will be done using the Evidence for Policy and Practice Information (EPPI) center tool. Two of the review authors will independently do the screening, data extraction and assess methodological limitations. Any disagreements will be resolved through discussion and consensus. Data synthesis will be done using a pre-determined framework developed using Supporting the Use of Research Evidence (SURE) guidelines collaboration. Confidence of the review findings will be conducted using Confidence in the Evidence from Reviews of Qualitative Research (CERQual) approach and the findings presented in a summary table.Ethics and disseminationFindings of the qualitative evidence synthesis will be prepared using Enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) statement using relevant items for the qualitative synthesis. The findings will be published in a peer reviewed journal. The protocol will be registered with the International Prospective Register of Systematic Reviews (PROSPERO).Key words: Pre-treatment loss to follow up, pulmonary tuberculosis, perspectives, experiences, qualitative.

Background Tuberculosis is a leading cause of infectious disease‐related death and is one of the top 10 causes of death worldwide. The World Health Organization (WHO) recommends the use of specific rapid molecular tests, including Xpert MTB/RIF or Xpert Ultra, as initial diagnostic tests for the detection of tuberculosis and rifampicin resistance in people with signs and symptoms of tuberculosis. However, the WHO estimates that nearly one‐third of all active tuberculosis cases go undiagnosed and unreported. We were interested in whether a single test, Xpert MTB/RIF or Xpert Ultra, could be useful as a screening test to close this diagnostic gap and improve tuberculosis case detection. Objectives To estimate the accuracy of Xpert MTB/RIF and Xpert Ultra for screening for pulmonary tuberculosis in adults, irrespective of signs or symptoms of pulmonary tuberculosis in high‐risk groups and in the general population. Screening "irrespective of signs or symptoms" refers to screening of people who have not been assessed for the presence of tuberculosis symptoms (e.g. cough). To estimate the accuracy of Xpert MTB/RIF and Xpert Ultra for detecting rifampicin resistance in adults screened for tuberculosis, irrespective of signs and symptoms of pulmonary tuberculosis in high‐risk groups and in the general population. Search methods We searched 12 databases including the Cochrane Infectious Diseases Group Specialized Register, MEDLINE and Embase, on 19 March 2020 without language restrictions. We also reviewed reference lists of included articles and related Cochrane Reviews, and contacted researchers in the field to identify additional studies. Selection criteria Cross‐sectional and cohort studies in which adults (15 years and older) in high‐risk groups (e.g. people living with HIV, household contacts of people with tuberculosis) or in the general population were screened for pulmonary tuberculosis using Xpert MTB/RIF or Xpert Ultra. For tuberculosis detection, the reference standard was culture. For rifampicin resistance detection, the reference standards were culture‐based drug susceptibility testing and line probe assays. Data collection and analysis Two review authors independently extracted data using a standardized form and assessed risk of bias and applicability using QUADAS‐2. We used a bivariate random‐effects model to estimate pooled sensitivity and specificity with 95% credible intervals (CrIs) separately for tuberculosis detection and rifampicin resistance detection. We estimated all models using a Bayesian approach. For tuberculosis detection, we first estimated screening accuracy in distinct high‐risk groups, including people living with HIV, household contacts, people residing in prisons, and miners, and then in several high‐risk groups combined. Main results We included a total of 21 studies: 18 studies (13,114 participants) evaluated Xpert MTB/RIF as a screening test for pulmonary tuberculosis and one study (571 participants) evaluated both Xpert MTB/RIF and Xpert Ultra. Three studies (159 participants) evaluated Xpert MTB/RIF for rifampicin resistance. Fifteen studies (75%) were conducted in high tuberculosis burden and 16 (80%) in high TB/HIV‐burden countries. We judged most studies to have low risk of bias in all four QUADAS‐2 domains and low concern for applicability. Xpert MTB/RIF and Xpert Ultra as screening tests for pulmonary tuberculosis In people living with HIV (12 studies), Xpert MTB/RIF pooled sensitivity and specificity (95% CrI) were 61.8% (53.6 to 69.9) (602 participants; moderate‐certainty evidence) and 98.8% (98.0 to 99.4) (4173 participants; high‐certainty evidence). Of 1000 people where 50 have tuberculosis on culture, 40 would be Xpert MTB/RIF‐positive; of these, 9 (22%) would not have tuberculosis (false‐positives); and 960 would be Xpert MTB/RIF‐negative; of these, 19 (2%) would have tuberculosis (false‐negatives). In people living with HIV (1 study), Xpert Ultra sensitivity and specificity (95% CI) were 69% (57 to 80) (68 participants; very low‐certainty evidence) and 98% (97 to 99) (503 participants; moderate‐certainty evidence). Of 1000 people where 50 have tuberculosis on culture, 53 would be Xpert Ultra‐positive; of these, 19 (36%) would not have tuberculosis (false‐positives); and 947 would be Xpert Ultra‐negative; of these, 16 (2%) would have tuberculosis (false‐negatives). In non‐hospitalized people in high‐risk groups (5 studies), Xpert MTB/RIF pooled sensitivity and specificity were 69.4% (47.7 to 86.2) (337 participants, low‐certainty evidence) and 98.8% (97.2 to 99.5) (8619 participants, moderate‐certainty evidence). Of 1000 people where 10 have tuberculosis on culture, 19 would be Xpert MTB/RIF‐positive; of these, 12 (63%) would not have tuberculosis (false‐positives); and 981 would be Xpert MTB/RIF‐negative; of these, 3 (0%) would have tuberculosis (false‐negatives). We did not identify any studies using Xpert MTB/RIF or Xpert Ultra for screening in the general population. Xpert MTB/RIF as a screening test for rifampicin resistance Xpert MTB/RIF sensitivity was 81% and 100% (2 studies, 20 participants; very low‐certainty evidence), and specificity was 94% to 100%, (3 studies, 139 participants; moderate‐certainty evidence). Authors' conclusions Of the high‐risks groups evaluated, Xpert MTB/RIF applied as a screening test was accurate for tuberculosis in high tuberculosis burden settings. Sensitivity and specificity were similar in people living with HIV and non‐hospitalized people in high‐risk groups. In people living with HIV, Xpert Ultra sensitivity was slightly higher than that of Xpert MTB/RIF and specificity similar. As there was only one study of Xpert Ultra in this analysis, results should be interpreted with caution. There were no studies that evaluated the tests in people with diabetes mellitus and other groups considered at high‐risk for tuberculosis, or in the general population., Plain language summary How accurate are sputum Xpert tests for screening for active pulmonary tuberculosis and rifampicin resistance in adults whether or not they have tuberculosis symptoms? Why is using Xpert tests to screen for pulmonary tuberculosis important? Tuberculosis is the leading cause of infectious disease‐related death and one of the top 10 causes of death worldwide. The World Health Organization (WHO) recommends using specific rapid tests as initial tests for diagnosing tuberculosis and rifampicin resistance in people with signs and symptoms of tuberculosis. However, the WHO estimates that nearly one‐third of all active tuberculosis cases go undiagnosed and unreported. Not recognizing tuberculosis when it is present (a false negative test result) may result in illness and death and an increased risk of infecting others. An incorrect diagnosis of tuberculosis (false‐positive result) may mean that people are given antibiotics when there is no benefit to be gained. What is the aim of this review? To estimate the accuracy of Xpert MTB/RIF and Xpert Ultra as screening tests for pulmonary tuberculosis and rifampicin resistance in adults whether or not they have tuberculosis symptoms (such as cough, fever, weight loss, and night sweats). We were interested in how the tests worked in groups at high risk for tuberculosis, including people living with HIV (PLHIV), household contacts of people with tuberculosis, miners, people residing in prisons, people with diabetes, and in the general public. What was studied in this review? Xpert MTB/RIF and Xpert Ultra are rapid tests for simultaneously diagnosing tuberculosis and rifampicin resistance. We combined study results to determine: ‐ sensitivity: people with tuberculosis (rifampicin resistance) correctly diagnosed as having the condition. ‐ specificity: people without tuberculosis (rifampicin resistance) correctly identified as not having the condition. The closer sensitivity and specificity are to 100%, the better the test. What are the main results in this review? Twenty‐one studies: 18 studies (13,114 participants) evaluated Xpert MTB/RIF as a screening test for pulmonary tuberculosis and one study (571 participants) evaluated both Xpert MTB/RIF and Xpert Ultra. Three studies (159 participants) evaluated Xpert MTB/RIF for rifampicin resistance. For every 1000 people tested, if 50 had tuberculosis according to the reference standard: PLHIV ‐ Xpert MTB/RIF (12 studies): · 40 people would test positive, including 9 without tuberculosis (62% sensitivity) · 960 people would test negative, including 19 with tuberculosis (99% specificity) ‐ Xpert Ultra (1 study): · 53 people would test positive, including 19 without tuberculosis (69% sensitivity) · 947 people would test negative, including 16 with tuberculosis (98% specificity) For every 1000 people tested, if 10 had tuberculosis according to the reference standard: Other high‐risk groups combined ‐ Xpert MTB/RIF (5 studies): · 19 people would test positive, including 12 without tuberculosis (69% sensitivity) · 981 people would test negative, including 3 with tuberculosis (99% specificity) For detection of rifampicin resistance, Xpert MTB/RIF sensitivity was 81% and 100% (2 studies) and specificity was 94% to 100% (3 studies). How reliable are the results of the studies in this review? In the included studies, the reference standards for diagnosing pulmonary tuberculosis (culture) and rifampicin resistance (drug susceptibility testing) are likely to have been reliable methods for deciding whether patients really had the conditions. We were fairly confident in the results for Xpert MTB/RIF in PLHIV, and less so for other high‐risk groups. Not enough people have been studied to be confident about the results for Xpert Ultra or for detection of rifampicin resistance. Who do the results of this review apply to? Studies were mainly performed in high tuberculosis and high HIV burden settings. No studies evaluated the tests in people with diabetes mellitus or the general population. What are the implications of this review? In PLHIV, Xpert MTB/RIF as a screening test was accurate for tuberculosis in high tuberculosis burden settings. In high‐risk groups, Xpert MTB/RIF may assist in identifying tuberculosis, but the certainty of evidence is low. In PLHIV, Xpert Ultra sensitivity was slightly higher than that of Xpert MTB/RIF and specificity similar based on one study. There were few studies and few people tested for rifampicin resistance and no studies that evaluated the tests in people with diabetes or in the general population. How up‐to‐date is this review? 19 March 2020.

Background 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. Objectives 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. 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. Search methods 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. Selection criteria 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. Data collection and analysis 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. Main results 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. Pulmonary tuberculosis detection 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. 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). 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). 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). 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. Rifampicin resistance detection 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. 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). Authors' conclusions 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. Xpert Ultra and Xpert MTB/RIF provide accurate results and can allow rapid initiation of treatment for rifampicin-resistant and multidrug-resistant tuberculosis.

Background 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). Objectives To estimate diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF for extrapulmonary tuberculosis and rifampicin resistance in adults with presumptive extrapulmonary tuberculosis. Search methods 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. Selection criteria 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). Data collection and analysis 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. Main results 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. Cerebrospinal fluid Xpert Ultra (6 studies) 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). Xpert MTB/RIF (30 studies) 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. Pleural fluid Xpert Ultra (4 studies) 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. Xpert MTB/RIF (25 studies) 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. Lymph node aspirate Xpert Ultra (1 study) 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. Xpert MTB/RIF (4 studies) 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. 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. Rifampicin resistance Xpert Ultra (4 studies) 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. Xpert MTB/RIF (19 studies) 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. Authors' conclusions 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.

Background\ud Every year, at least one million children become ill with tuberculosis and around 200,000 children die. Xpert MTB/RIF and Xpert Ultra are World Health Organization (WHO)‐recommended rapid molecular tests that simultaneously detect tuberculosis and rifampicin resistance in adults and children with signs and symptoms of tuberculosis, at lower health system levels. To inform updated WHO guidelines on molecular assays, we performed a systematic review on the diagnostic accuracy of these tests in children presumed to have active tuberculosis.\ud \ud Objectives\ud Primary objectives\ud \ud • To determine the diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra for (a) pulmonary tuberculosis in children presumed to have tuberculosis; (b) tuberculous meningitis in children presumed to have tuberculosis; (c) lymph node tuberculosis in children presumed to have tuberculosis; and (d) rifampicin resistance in children presumed to have tuberculosis\ud \ud ‐ For tuberculosis detection, index tests were used as the initial test, replacing standard practice (i.e. smear microscopy or culture)\ud \ud ‐ For detection of rifampicin resistance, index tests replaced culture‐based drug susceptibility testing as the initial test\ud \ud Secondary objectives\ud \ud • To compare the accuracy of Xpert MTB/RIF and Xpert Ultra for each of the four target conditions\ud \ud • To investigate potential sources of heterogeneity in accuracy estimates\ud \ud ‐ For tuberculosis detection, we considered age, disease severity, smear‐test status, HIV status, clinical setting, specimen type, high tuberculosis burden, and high tuberculosis/HIV burden\ud \ud ‐ For detection of rifampicin resistance, we considered multi‐drug‐resistant tuberculosis burden\ud \ud • To compare multiple Xpert MTB/RIF or Xpert Ultra results (repeated testing) with the initial Xpert MTB/RIF or Xpert Ultra result\ud \ud Search methods\ud We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and the International Standard Randomized Controlled Trials Number (ISRCTN) Registry up to 29 April 2019, without language restrictions.\ud \ud Selection criteria\ud Randomized trials, cross‐sectional trials, and cohort studies evaluating Xpert MTB/RIF or Xpert Ultra in HIV‐positive and HIV‐negative children younger than 15 years. Reference standards comprised culture or a composite reference standard for tuberculosis and drug susceptibility testing or MTBDRplus (molecular assay for detection of Mycobacterium tuberculosis and drug resistance) for rifampicin resistance. We included studies evaluating sputum, gastric aspirate, stool, nasopharyngeal or bronchial lavage specimens (pulmonary tuberculosis), cerebrospinal fluid (tuberculous meningitis), fine needle aspirates, or surgical biopsy tissue (lymph node tuberculosis).\ud \ud Data collection and analysis\ud Two review authors independently extracted data and assessed study quality using the Quality Assessment of Studies of Diagnostic Accuracy ‐ Revised (QUADAS‐2). For each target condition, we used the bivariate model to estimate pooled sensitivity and specificity with 95% confidence intervals (CIs). We stratified all analyses by type of reference standard. We assessed certainty of evidence using the GRADE approach.\ud \ud Main results\ud For pulmonary tuberculosis, 299 data sets (68,544 participants) were available for analysis; for tuberculous meningitis, 10 data sets (423 participants) were available; for lymph node tuberculosis, 10 data sets (318 participants) were available; and for rifampicin resistance, 14 data sets (326 participants) were available. Thirty‐nine studies (80%) took place in countries with high tuberculosis burden. Risk of bias was low except for the reference standard domain, for which risk of bias was unclear because many studies collected only one specimen for culture.\ud \ud Detection of pulmonary tuberculosis\ud \ud For sputum specimens, Xpert MTB/RIF pooled sensitivity (95% CI) and specificity (95% CI) verified by culture were 64.6% (55.3% to 72.9%) (23 studies, 493 participants; moderate‐certainty evidence) and 99.0% (98.1% to 99.5%) (23 studies, 6119 participants; moderate‐certainty evidence). For other specimen types (nasopharyngeal aspirate, 4 studies; gastric aspirate, 14 studies; stool, 11 studies), Xpert MTB/RIF pooled sensitivity ranged between 45.7% and 73.0%, and pooled specificity ranged between 98.1% and 99.6%.\ud \ud For sputum specimens, Xpert Ultra pooled sensitivity (95% CI) and specificity (95% CI) verified by culture were 72.8% (64.7% to 79.6%) (3 studies, 136 participants; low‐certainty evidence) and 97.5% (95.8% to 98.5%) (3 studies, 551 participants; high‐certainty evidence). For nasopharyngeal specimens, Xpert Ultra sensitivity (95% CI) and specificity (95% CI) were 45.7% (28.9% to 63.3%) and 97.5% (93.7% to 99.3%) (1 study, 195 participants).\ud \ud For all specimen types, Xpert MTB/RIF and Xpert Ultra sensitivity were lower against a composite reference standard than against culture.\ud \ud Detection of tuberculous meningitis\ud \ud For cerebrospinal fluid, Xpert MTB/RIF pooled sensitivity and specificity, verified by culture, were 54.0% (95% CI 27.8% to 78.2%) (6 studies, 28 participants; very low‐certainty evidence) and 93.8% (95% CI 84.5% to 97.6%) (6 studies, 213 participants; low‐certainty evidence).\ud \ud Detection of lymph node tuberculosis\ud \ud For lymph node aspirates or biopsies, Xpert MTB/RIF pooled sensitivity and specificity, verified by culture, were 90.4% (95% CI 55.7% to 98.6%) (6 studies, 68 participants; very low‐certainty evidence) and 89.8% (95% CI 71.5% to 96.8%) (6 studies, 142 participants; low‐certainty evidence).\ud \ud Detection of rifampicin resistance\ud \ud Xpert MTB/RIF pooled sensitivity and specificity were 90.0% (67.6% to 97.5%) (6 studies, 20 participants; low‐certainty evidence) and 98.3% (87.7% to 99.8%) (6 studies, 203 participants; moderate‐certainty evidence).\ud \ud Authors' conclusions\ud We found Xpert MTB/RIF sensitivity to vary by specimen type, with gastric aspirate specimens having the highest sensitivity followed by sputum and stool, and nasopharyngeal specimens the lowest; specificity in all specimens was > 98%. Compared with Xpert MTB/RIF, Xpert Ultra sensitivity in sputum was higher and specificity slightly lower. Xpert MTB/RIF was accurate for detection of rifampicin resistance. Xpert MTB/RIF was sensitive for diagnosing lymph node tuberculosis. For children with presumed tuberculous meningitis, treatment decisions should be based on the entirety of clinical information and treatment should not be withheld based solely on an Xpert MTB/RIF result. The small numbers of studies and participants, particularly for Xpert Ultra, limits our confidence in the precision of these estimates.

Objectives\ud This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows:\ud \ud To determine the accuracy of Xpert MTB/RIF and Xpert Ultra for screening for tuberculosis in adults irrespective of signs or symptoms of pulmonary tuberculosis in the general population (i.e. low‐risk population).\ud \ud To determine the accuracy of Xpert MTB/RIF and Xpert Ultra for screening of pulmonary tuberculosis in adults in the following high‐risk groups.\ud \ud People living with HIV.\ud \ud Household contacts of people with tuberculosis.\ud \ud Patients residing in high‐tuberculosis‐burden settings attending primary health facilities.\ud \ud Homeless people.\ud \ud Miners.\ud \ud People with diabetes mellitus.\ud \ud People who abuse alcohol.\ud \ud Smokers.\ud \ud People residing in prisons.\ud \ud Healthcare workers.\ud \ud To determine the accuracy of Xpert MTB/RIF and Xpert Ultra for the detection of rifampicin resistance in the general population and in the high‐risk groups and settings described above.\ud \ud Secondary objectives\ud To compare the accuracy of Xpert MTB/RIF and Xpert Ultra in the above high‐risk groups and settings.\ud \ud To investigate potential sources of heterogeneity in accuracy estimates, including the percentage of participants with tuberculosis symptoms, tuberculosis burden, tuberculosis/HIV burden, and MDR‐TB burden.

Background The lateral flow urine lipoarabinomannan (LF‐LAM) assay Alere Determine™ TB LAM Ag is recommended by the World Health Organization (WHO) to help detect active tuberculosis in HIV‐positive people with severe HIV disease. This review update asks the question, "does new evidence justify the use of LF‐LAM in a broader group of people?”, and is part of the WHO process for updating guidance on the use of LF‐LAM. Objectives To assess the accuracy of LF‐LAM for the diagnosis of active tuberculosis among HIV‐positive adults with signs and symptoms of tuberculosis (symptomatic participants) and among HIV‐positive adults irrespective of signs and symptoms of tuberculosis (unselected participants not assessed for tuberculosis signs and symptoms). The proposed role for LF‐LAM is as an add on to clinical judgement and with other tests to assist in diagnosing tuberculosis. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, without language restriction to 11 May 2018. Selection criteria Randomized trials, cross‐sectional, and observational cohort studies that evaluated LF‐LAM for active tuberculosis (pulmonary and extrapulmonary) in HIV‐positive adults. We included studies that used the manufacturer's recommended threshold for test positivity, either the updated reference card with four bands (grade 1 of 4) or the corresponding prior reference card grade with five bands (grade 2 of 5). The reference standard was culture or nucleic acid amplification test from any body site (microbiological). We considered a higher quality reference standard to be one in which two or more specimen types were evaluated for tuberculosis diagnosis and a lower quality reference standard to be one in which only one specimen type was evaluated. Data collection and analysis Two review authors independently extracted data using a standardized form and REDCap electronic data capture tools. We appraised the quality of studies using the Quality Assessment of Diagnostic Accuracy Studies‐2 (QUADAS‐2) tool and performed meta‐analyses to estimate pooled sensitivity and specificity using a bivariate random‐effects model and a Bayesian approach. We analyzed studies enrolling strictly symptomatic participants separately from those enrolling unselected participants. We investigated pre‐defined sources of heterogeneity including the influence of CD4 count and clinical setting on the accuracy estimates. We assessed the certainty of the evidence using the GRADE approach. Main results We included 15 unique studies (nine new studies and six studies from the original review that met the inclusion criteria): eight studies among symptomatic adults and seven studies among unselected adults. All studies were conducted in low‐ or middle‐income countries. Risk of bias was high in the patient selection and reference standard domains, mainly because studies excluded participants unable to produce sputum and used a lower quality reference standard. Participants with tuberculosis symptoms LF‐LAM pooled sensitivity (95% credible interval (CrI) ) was 42% (31% to 55%) (moderate‐certainty evidence) and pooled specificity was 91% (85% to 95%) (very low‐certainty evidence), (8 studies, 3449 participants, 37% with tuberculosis). For a population of 1000 people where 300 have microbiologically‐confirmed tuberculosis, the utilization of LF‐LAM would result in: 189 to be LF‐LAM positive: of these, 63 (33%) would not have tuberculosis (false‐positives); and 811 to be LF‐LAM negative: of these, 174 (21%) would have tuberculosis (false‐negatives). By clinical setting, pooled sensitivity was 52% (40% to 64%) among inpatients versus 29% (17% to 47%) among outpatients; and pooled specificity was 87% (78% to 93%) among inpatients versus 96% (91% to 99%) among outpatients. Stratified by CD4 cell count, pooled sensitivity increased, and specificity decreased with lower CD4 cell count. Unselected participants not assessed for signs and symptoms of tuberculosis LF‐LAM pooled sensitivity was 35% (22% to 50%), (moderate‐certainty evidence) and pooled specificity was 95% (89% to 96%), (low‐certainty evidence), (7 studies, 3365 participants, 13% with tuberculosis). For a population of 1000 people where 100 have microbiologically‐confirmed tuberculosis, the utilization of LF‐LAM would result in: 80 to be LF‐LAM positive: of these, 45 (56%) would not have tuberculosis (false‐positives); and 920 to be LF‐LAM negative: of these, 65 (7%) would have tuberculosis (false‐negatives). By clinical setting, pooled sensitivity was 62% (41% to 83%) among inpatients versus 31% (18% to 47%) among outpatients; pooled specificity was 84% (48% to 96%) among inpatients versus 95% (87% to 99%) among outpatients. Stratified by CD4 cell count, pooled sensitivity increased, and specificity decreased with lower CD4 cell count. Authors' conclusions We found that LF‐LAM has a sensitivity of 42% to diagnose tuberculosis in HIV‐positive individuals with tuberculosis symptoms and 35% in HIV‐positive individuals not assessed for tuberculosis symptoms, consistent with findings reported previously. Regardless of how people are enrolled, sensitivity is higher in inpatients and those with lower CD4 cell, but a concomitant lower specificity. As a simple point‐of‐care test that does not depend upon sputum evaluation, LF‐LAM may assist with the diagnosis of tuberculosis, particularly when a sputum specimen cannot be produced., Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in people living with HIV Why is improving the diagnosis of tuberculosis important? Tuberculosis causes more deaths in people living with HIV than any other disease. The lateral flow urine lipoarabinomannan assay (LF‐LAM, Alere Determine™ TB LAM Ag assay) is a World Health Organization‐recommended rapid test to assist in detection of active tuberculosis in HIV‐positive people with severe HIV disease. Rapid and early tuberculosis diagnosis may allow for prompt treatment and alleviate severe illness and death. An incorrect tuberculosis diagnosis may result in anxiety and unnecessary treatment. What is the aim of this review? To find out how accurate LF‐LAM is for diagnosing tuberculosis in HIV‐positive people with tuberculosis symptoms (symptomatic participants) and those not assessed for tuberculosis symptoms (unselected participants). This is an update of the 2016 Cochrane Review. What was studied in this review? LF‐LAM is a commercially available point‐of‐care test that detects lipoarabinomannan (LAM), a component of the bacterial cell walls, present in some people with active tuberculosis. The test is simple and shows results in 25 minutes. LF‐LAM results were measured against culture or molecular tests (benchmark). What are the main results of this review? Fifteen studies: eight studies evaluated LF‐LAM for tuberculosis among symptomatic participants and seven studies among unselected participants. All studies were conducted in low‐ or middle‐income countries. Tuberculosis diagnosis among symptomatic participants: LF‐LAM registered positive in 42% (sensitivity) of people who actually had tuberculosis and did not register positive in 91% of people who were actually negative (specificity). Tuberculosis diagnosis among unselected participants: LF‐LAM sensitivity was 35% and specificity 95%. How confident are we in the review’s results? Several studies excluded participants who could not produce sputum and most studies relied on a lower quality benchmark. Few studies and participants were included in some analyses and only one study was conducted outside of sub‐Saharan Africa. Results should be interpreted with caution. What do the results mean? Among symptomatic participants, in theory, for a population of 1000 people where 300 have microbiologically‐confirmed tuberculosis, the utilization of LF‐LAM would result in: 189 to be LF‐LAM positive: of these, 63 (33%) would not have tuberculosis (false‐positives); and 811 to be LF‐LAM negative: of these, 174 (21%) would have tuberculosis (false‐negatives). Among unselected participants, in theory, for a population of 1000 people where 100 have microbiologically‐confirmed tuberculosis, the utilization of LF‐LAM would result in: 80 to be LF‐LAM positive: of these, 45 (56%) would not have tuberculosis (false‐positives); and 920 to be LF‐LAM negative: of these, 65 (7%) would have tuberculosis (false‐negatives). Who do the review’s results apply to? HIV‐positive people with tuberculosis symptoms and those not assessed for tuberculosis symptoms. What are the implications of this review? LF‐LAM has sensitivity around 40% to detect tuberculosis. As the test does not require sputum collection, LF‐LAM may be the only way to diagnose tuberculosis when sputum cannot be produced. How up‐to‐date is this review? To 11 May 2018.

Objectives\ud This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments (HTA) and guideline developers can assess the results and the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA).\ud Study Design and Setting\ud We present an overview of the GRADE approach and guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. Part 1 of the two parts in this 21st guidance article about how to apply GRADE focuses on understanding study design issues in test accuracy, provide an overiew of the domains and describe risk of bias and indirectness specifically.\ud Results\ud Supplemented by practical examples, we describe how raters of the evidence using GRADE can evaluate study designs focusing on tests and how they apply the GRADE domains risk of bias and indirectness to a body of evidence of TA studies.\ud Conclusions\ud Rating the certainty of a body of evidence using GRADE in Cochrane and other reviews and World Health Organization and other guidelines dealing with in TA studies helped refining our approach. The resulting guidance will help applying GRADE successfully for questions and recommendations focusing on tests.

Objectives This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments (HTA) and guideline developers can rate the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA) on the domains imprecision, inconsistency, publication bias and other domains. It also provides guidance for how to present synthesized information in evidence profiles and summary of findings tables. Study Design and Setting We present guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. Results Supplemented by practical examples, we describe how raters of the evidence can apply the GRADE domains inconsistency, imprecision, and publication bias to a body of evidence of TA studies. Conclusions Using GRADE in Cochrane and other reviews as well as World Health Organization and other guidelines helped refining the GRADE approach for rating the certainty of a body of evidence from TA studies. While several of the GRADE domains (e.g., imprecision and magnitude of the association) require further methodological research to help operationalize them, judgments need to be made on the basis of what is known so far.

Background Xpert MTB/RIF (Xpert MTB/RIF) and Xpert MTB/RIF Ultra (Xpert Ultra), the newest version, are the only World Health Organization (WHO)‐recommended rapid tests that simultaneously detect tuberculosis and rifampicin resistance in persons with signs and symptoms of tuberculosis, at lower health system levels. A previous Cochrane Review found Xpert MTB/RIF sensitive and specific for tuberculosis (Steingart 2014). Since the previous review, new studies have been published. We performed a review update for an upcoming WHO policy review. Objectives To determine diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra for tuberculosis in adults with presumptive pulmonary tuberculosis (PTB) and for rifampicin resistance in adults with presumptive rifampicin‐resistant tuberculosis. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, to 11 October 2018, without language restriction. Selection criteria Randomized trials, cross‐sectional, and cohort studies using respiratory specimens that evaluated Xpert MTB/RIF, Xpert Ultra, or both against the reference standard, culture for tuberculosis and culture‐based drug susceptibility testing or MTBDRplus for rifampicin resistance. Data collection and analysis Four review authors independently extracted data using a standardized form. When possible, we also extracted data by smear and HIV status. We assessed study quality using QUADAS‐2 and performed meta‐analyses to estimate pooled sensitivity and specificity separately for tuberculosis and rifampicin resistance. We investigated potential sources of heterogeneity. Most analyses used a bivariate random‐effects model. For tuberculosis detection, we first estimated accuracy using all included studies and then only the subset of studies where participants were unselected, i.e. not selected based on prior microscopy testing. Main results We identified in total 95 studies (77 new studies since the previous review): 86 studies (42,091 participants) evaluated Xpert MTB/RIF for tuberculosis and 57 studies (8287 participants) for rifampicin resistance. One study compared Xpert MTB/RIF and Xpert Ultra on the same participant specimen. Tuberculosis detection Of the total 86 studies, 45 took place in high tuberculosis burden and 50 in high TB/HIV burden countries. Most studies had low risk of bias. Xpert MTB/RIF pooled sensitivity and specificity (95% credible Interval (CrI)) were 85% (82% to 88%) and 98% (97% to 98%), (70 studies, 37,237 unselected participants; high‐certainty evidence). We found similar accuracy when we included all studies. For a population of 1000 people where 100 have tuberculosis on culture, 103 would be Xpert MTB/RIF‐positive and 18 (17%) would not have tuberculosis (false‐positives); 897 would be Xpert MTB/RIF‐negative and 15 (2%) would have tuberculosis (false‐negatives). Xpert Ultra sensitivity (95% confidence interval (CI)) was 88% (85% to 91%) versus Xpert MTB/RIF 83% (79% to 86%); Xpert Ultra specificity was 96% (94% to 97%) versus Xpert MTB/RIF 98% (97% to 99%), (1 study, 1439 participants; moderate‐certainty evidence). Xpert MTB/RIF pooled sensitivity was 98% (97% to 98%) in smear‐positive and 67% (62% to 72%) in smear‐negative, culture‐positive participants, (45 studies). Xpert MTB/RIF pooled sensitivity was 88% (83% to 92%) in HIV‐negative and 81% (75% to 86%) in HIV‐positive participants; specificities were similar 98% (97% to 99%), (14 studies). Rifampicin resistance detection Xpert MTB/RIF pooled sensitivity and specificity (95% Crl) were 96% (94% to 97%) and 98% (98% to 99%), (48 studies, 8020 participants; high‐certainty evidence). For a population of 1000 people where 100 have rifampicin‐resistant tuberculosis, 114 would be positive for rifampicin‐resistant tuberculosis and 18 (16%) would not have rifampicin resistance (false‐positives); 886 would be would be negative for rifampicin‐resistant tuberculosis and four (0.4%) would have rifampicin resistance (false‐negatives). Xpert Ultra sensitivity (95% CI) was 95% (90% to 98%) versus Xpert MTB/RIF 95% (91% to 98%); Xpert Ultra specificity was 98% (97% to 99%) versus Xpert MTB/RIF 98% (96% to 99%), (1 study, 551 participants; moderate‐certainty evidence). Authors' conclusions We found Xpert MTB/RIF to be sensitive and specific for diagnosing PTB and rifampicin resistance, consistent with findings reported previously. Xpert MTB/RIF was more sensitive for tuberculosis in smear‐positive than smear‐negative participants and HIV‐negative than HIV‐positive participants. Compared with Xpert MTB/RIF, Xpert Ultra had higher sensitivity and lower specificity for tuberculosis and similar sensitivity and specificity for rifampicin resistance (1 study). Xpert MTB/RIF and Xpert Ultra provide accurate results and can allow rapid initiation of treatment for multidrug‐resistant tuberculosis., Xpert MTB/RIF and Xpert Ultra for diagnosing pulmonary tuberculosis and rifampicin resistance in adults Why is improving the diagnosis of pulmonary tuberculosis important? Tuberculosis causes more deaths globally than any other infectious disease. When detected early and effectively treated, tuberculosis is largely curable, but in 2017, around 1.6 million people died of tuberculosis. Xpert MTB/RIF and Xpert Ultra, the newest version, are World Health Organization‐recommended tests that simultaneously detect tuberculosis and rifampicin resistance in persons with tuberculosis symptoms. Rifampicin is an important anti‐tuberculosis drug. Not recognizing tuberculosis early may result in delayed diagnosis and treatment, severe illness, and death. An incorrect tuberculosis diagnosis may result in anxiety and unnecessary treatment. What is the aim of this review? To determine how accurate Xpert MTB/RIF and Xpert Ultra are for diagnosing pulmonary tuberculosis (PTB) and rifampicin resistance in adults. This is an update of the 2014 Cochrane Review. What was studied in this review? Xpert MTB/RIF and Xpert Ultra, with results measured against culture (benchmark). What are the main results in this review? 95 studies: 86 studies (42,091 participants) evaluated Xpert MTB/RIF for tuberculosis; 57 studies (8287 participants) for rifampicin resistance. One study compared Xpert Ultra and Xpert MTB/RIF. For PTB, Xpert MTB/RIF was sensitive (85%), registering positive in people who actually had tuberculosis, and specific (98%), i.e. it did not register positive in people who were actually negative. Xpert Ultra had higher sensitivity than Xpert MTB/RIF (88% versus 83%) in one study. For rifampicin resistance, Xpert MTB/RIF was highly sensitive (96%) and specific (98%). Xpert Ultra gave similar results. Xpert MTB/RIF was better for diagnosing tuberculosis in HIV‐negative than in HIV‐positive people. How confident are we in the results of this review? Confident. We included many studies and used the best reference standards. Who do the results of this review apply to? People with presumed PTB or rifampicin resistance. What are the implications of this review? In theory, among 1000 people where 100 have tuberculosis on culture, 103 would be Xpert MTB/RIF‐positive and 18 (17%) would not have tuberculosis (false‐positives); 897 would be Xpert MTB/RIF‐negative and 15 (2%) would have tuberculosis (false‐negatives). Among 1000 people where 100 have rifampicin resistance, 114 would be positive for rifampicin resistance and 18 (16%) would not have rifampicin resistance (false‐positives); 886 would be negative for rifampicin resistance and four (0.4%) would have rifampicin resistance (false‐negatives). How up‐to‐date is this review? To 11 October 2018.

Background\ud Assessment of diagnostic tests, broadly defined as any element that aids in the collection of additional information for further clarification of a patient's health status, has increasingly become a critical issue in health policy and decision-making. Diagnostic evidence, including the accuracy of a medical test for a target condition, is commonly appraised using standard systematic review methodology. Owing to the considerable time and resources required to conduct these, rapid reviews have emerged as a pragmatic alternative by tailoring methods according to the decision maker's circumstances. However, it is not known if streamlining methodological aspects has an impact on the validity of evidence synthesis. Furthermore, due to the particular nature and complexity of the appraisal of diagnostic accuracy, there is need for detailed guidance on how to conduct rapid reviews of diagnostic tests. In this study, we aim to identify the methods currently used by rapid review developers to synthesize evidence on diagnostic test accuracy, as well as to analyze potential shortcomings and challenges related to these methods.\ud Methods\ud We will carry out a two-fold approach: (1) an international survey of professionals working in organizations that develop rapid reviews of diagnostic tests, in terms of the methods and resources used by these agencies when conducting rapid reviews, and (2) semi-structured interviews with senior-level individuals to further explore and validate the findings from the survey and to identify challenges in conducting rapid reviews. We will use STATA 15.0 for quantitative analyses and framework analysis for qualitative analyses. We will ensure protection of data during all stages.\ud Discussion\ud The main result of this research will be a map of methods and resources currently used for conducting rapid reviews of diagnostic test accuracy, as well as methodological shortcomings and potential solutions in diagnostic knowledge synthesis that require further research.

Summary Background Microbiological confirmation of childhood tuberculosis is rare because of the difficulty of collection of specimens, low sensitivity of smear microscopy, and poor access to culture. We aimed to establish summary estimates for sensitivity and specificity of of the Xpert MTB/RIF assay compared with microscopy in the diagnosis of pulmonary tuberculosis in children. Methods We searched for studies published up to Jan 6, 2015, that used Xpert in any setting in children with and without HIV infection. We systematically reviewed studies that compared the diagnostic accuracy of Xpert MTB/RIF (Xpert) with microscopy for detection of pulmonary tuberculosis and rifampicin resistance in children younger than 16 years against two reference standards—culture results and culture-negative children who were started on anti-tuberculosis therapy. We did meta-analyses using a bivariate random-effects model. Findings We identified 15 studies including 4768 respiratory specimens in 3640 children investigated for pulmonary tuberculosis. Culture tests were positive for tuberculosis in 12% (420 of 3640) of all children assessed and Xpert was positive in 11% (406 of 3640). Compared with culture, the pooled sensitivities and specificities of Xpert for tuberculosis detection were 62% (95% credible interval 51–73) and 98% (97–99), respectively, with use of expectorated or induced sputum samples and 66% (51–81) and 98% (96–99), respectively, with use of samples from gastric lavage. Xpert sensitivity was 36–44% higher than was sensitivity for microscopy. Xpert sensitivity in culture-negative children started on antituberculosis therapy was 2% (1–3) for expectorated or induced sputum. Xpert's pooled sensitivity and specificity to detect rifampicin resistance was 86% (95% credible interval 53–98) and 98% (94–100), respectively. Interpretation Compared with microscopy, Xpert offers better sensitivity for the diagnosis of pulmonary tuberculosis in children and its scale-up will improve access to tuberculosis diagnostics for children. Although Xpert helps to provide rapid confirmation of disease, its sensitivity remains suboptimum compared with culture tests. A negative Xpert result does not rule out tuberculosis. Good clinical acumen is still needed to decide when to start antituberculosis therapy and continued research for better diagnostics is crucial. Funding WHO, Global TB Program of Texas Children's Hospital.

Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) is endorsed for the detection of pulmonary tuberculosis (TB). We performed a systematic review and meta-analysis to assess the accuracy of Xpert for the detection of extrapulmonary TB. We searched multiple databases to October 15, 2013. We determined the accuracy of Xpert compared with culture and a composite reference standard (CRS). We grouped data by sample type and performed meta-analyses using a bivariate random-effects model. We assessed sources of heterogeneity using meta- regression for predefined covariates. We identified 18 studies involving 4461 samples. Sample processing varied greatly among the studies. Xpert sensitivity differed substantially between sample types. In lymph node tissues or aspirates, Xpert pooled sensitivity was 83.1% (95% CI 71.4-90.7%) versus culture and 81.2% (95% CI 72.4-87.7%) versus CRS. In cerebrospinal fluid, Xpert pooled sensitivity was 80.5% (95% CI 59.0-92.2%) against culture and 62.8% (95% CI 47.7-75.8%) against CRS. In pleural fluid, pooled sensitivity was 46.4% (95% CI 26.3-67.8%) against culture and 21.4% (95% CI 8.8-33.9%) against CRS. Xpert pooled specificity was consistently .98.7% against CRS across different sample types. Based on this systematic review, the World Health Organization now recommends Xpert over conventional tests for diagnosis of TB in lymph nodes and other tissues, and as the preferred initial test for diagnosis of TB meningitis.

Background: Studies evaluating the impact of Xpert MTB/RIF testing for tuberculosis (TB) have demonstrated varied effects on health outcomes with many studies showing inconclusive results. We explored perceptions among diverse stakeholders about studies evaluating the impact of TB diagnostic tests, and identified suggestions for improving these studies. Methods: We used purposive sampling with consideration for differing expertise and geographical balance and conducted in depth semi-structured interviews. We interviewed English-speaking participants, including TB patients, and others involved in research, care or decision-making about TB diagnostics. We used the thematic approach to code and analyse the interview transcripts. Results: We interviewed 31 participants. Our study showed that stakeholders had different expectations with regard to test impact and how it is measured. TB test impact studies were perceived to be important for supporting implementation of tests but there were concerns about the unrealistic expectations placed on tests to improve outcomes in health systems with many influencing factors. To improve TB test impact studies, respondents suggested conducting health system assessments prior to the study; developing clear guidance on the study methodology and interpretation; improving study design by describing questions and interventions that consider the influences of the health-care ecosystem on the diagnostic test; selecting the target population at the health-care level most likely to benefit from the test; setting realistic targets for effect sizes in the sample size calculations; and interpreting study results carefully and avoiding categorisation and interpretation of results based on statistical significance alone. Researchers should involve multiple stakeholders in the design of studies. Advocating for more funding to support robust studies is essential. Conclusion: TB test impact studies were perceived to be important to support implementation of tests but there were concerns about their complexity. Process evaluations of their health system context and guidance for their design and interpretation are recommended.

In an effort to update and clarify policies on tuberculosis drug susceptibility testing (DST), the World Health Organization (WHO) commissioned a systematic review evaluating WHO-endorsed diagnostic tests. We report the results of this systematic review and meta-analysis of the diagnostic accuracy and reproducibility of phenotypic DST for first-line and second-line antituberculosis drugs. This review provides support for recommended critical concentrations for isoniazid and rifampin in commercial broth-based systems. Further studies are needed to evaluate critical concentrations for ethambutol and streptomycin that accurately detect susceptibility to these drugs. Evidence is limited on the performance of DST for pyrazinamide and second-line drugs.

Background Genotype® MTBDRsl (MTBDRsl) is a rapid DNA-based test for detecting specific mutations associated with resistance to fluoroquinolones and second-line injectable drugs (SLIDs) in Mycobacterium tuberculosis complex. MTBDRsl version 2.0 (released in 2015) identifies the mutations detected by version 1.0, as well as additional mutations. The test may be performed on a culture isolate or a patient specimen, which eliminates delays associated with culture. Version 1.0 requires a smear-positive specimen, while version 2.0 may use a smear-positive or -negative specimen. We performed this updated review as part of a World Health Organization process to develop updated guidelines for using MTBDRsl. Objectives To assess and compare the diagnostic accuracy of MTBDRsl for: 1. fluoroquinolone resistance, 2. SLID resistance, and 3. extensively drug-resistant tuberculosis, indirectly on a M. tuberculosis isolate grown from culture or directly on a patient specimen. Participants were people with rifampicin-resistant or multidrug-resistant tuberculosis. The role of MTBDRsl would be as the initial test, replacing culture-based drug susceptibility testing (DST), for detecting second-line drug resistance. Search methods We searched the following databases without language restrictions up to 21 September 2015: the Cochrane Infectious Diseases Group Specialized Register; MEDLINE; Embase OVID; Science Citation Index Expanded, Conference Proceedings Citation Index-Science, and BIOSIS Previews (all three from Web of Science); LILACS; and SCOPUS; registers for ongoing trials; and ProQuest Dissertations & Theses A&I. We reviewed references from included studies and contacted specialists in the field. Selection criteria We included cross-sectional and case-control studies that determined MTBDRsl accuracy against a defined reference standard (culture-based DST, genetic sequencing, or both). Data collection and analysis Two review authors independently extracted data and assessed quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We synthesized data for versions 1.0 and 2.0 separately. We estimated MTBDRsl sensitivity and specificity for fluoroquinolone resistance, SLID resistance, and extensively drug-resistant tuberculosis when the test was performed indirectly or directly (smear-positive specimen for version 1.0, smear-positive or -negative specimen for version 2.0). We explored the influence on accuracy estimates of individual drugs within a drug class and of different reference standards. We performed most analyses using a bivariate random-effects model with culture-based DST as reference standard. Main results We included 27 studies. Twenty-six studies evaluated version 1.0, and one study version 2.0. Of 26 studies stating specimen country origin, 15 studies (58%) evaluated patients from low- or middle-income countries. Overall, we considered the studies to be of high methodological quality. However, only three studies (11%) had low risk of bias for the reference standard; these studies used World Health Organization (WHO)-recommended critical concentrations for all drugs in the culture-based DST reference standard. MTBDRsl version 1.0 Fluoroquinolone resistance: indirect testing, MTBDRsl pooled sensitivity and specificity (95% confidence interval (CI)) were 85.6% (79.2% to 90.4%) and 98.5% (95.7% to 99.5%), (19 studies, 2223 participants); direct testing (smear-positive specimen), pooled sensitivity and specificity were 86.2% (74.6% to 93.0%) and 98.6% (96.9% to 99.4%), (nine studies, 1771 participants, moderate quality evidence). SLID resistance: indirect testing, MTBDRsl pooled sensitivity and specificity were 76.5% (63.3% to 86.0%) and 99.1% (97.3% to 99.7%), (16 studies, 1921 participants); direct testing (smear-positive specimen), pooled sensitivity and specificity were 87.0% (38.1% to 98.6%) and 99.5% (93.6% to 100.0%), (eight studies, 1639 participants, low quality evidence). Extensively drug-resistant tuberculosis: indirect testing, MTBDRsl pooled sensitivity and specificity were 70.9% (42.9% to 88.8%) and 98.8% (96.1% to 99.6%), (eight studies, 880 participants); direct testing (smear-positive specimen), pooled sensitivity and specificity were 69.4% (38.8% to 89.0%) and 99.4% (95.0% to 99.3%), (six studies, 1420 participants, low quality evidence). Similar to the original Cochrane review, we found no evidence of a significant difference in MTBDRsl version 1.0 accuracy between indirect and direct testing for fluoroquinolone resistance, SLID resistance, and extensively drug-resistant tuberculosis. MTBDRsl version 2.0 Fluoroquinolone resistance: direct testing, MTBDRsl sensitivity and specificity were 97% (83% to 100%) and 98% (93% to 100%), smear-positive specimen; 80% (28% to 99%) and 100% (40% to 100%), smear-negative specimen. SLID resistance: direct testing, MTBDRsl sensitivity and specificity were 89% (72% to 98%) and 90% (84% to 95%), smear-positive specimen; 80% (28% to 99%) and 100% (40% to 100%), smear-negative specimen. Extensively drug-resistant tuberculosis: direct testing, MTBDRsl sensitivity and specificity were 79% (49% to 95%) and 97% (93% to 99%), smear-positive specimen; 50% (1% to 99%) and 100% (59% to 100%), smear-negative specimen. We had insufficient data to estimate summary sensitivity and specificity of version 2.0 (smear-positive and -negative specimens) or to compare accuracy of the two versions. A limitation was that most included studies did not consistently use the World Health Organization (WHO)-recommended concentrations for drugs in the culture-based DST reference standard. Authors' conclusions In people with rifampicin-resistant or multidrug-resistant tuberculosis, MTBDRsl performed on a culture isolate or smear-positive specimen may be useful in detecting second-line drug resistance. MTBDRsl (smear-positive specimen) correctly classified around six in seven people as having fluoroquinolone or SLID resistance, although the sensitivity estimates for SLID resistance varied. The test rarely gave a positive result for people without drug resistance. However, when second-line drug resistance is not detected (MTBDRsl result is negative), conventional DST can still be used to evaluate patients for resistance to the fluoroquinolones or SLIDs. We recommend that future work evaluate MTBDRsl version 2.0, in particular on smear-negative specimens and in different settings to account for different resistance-causing mutations that may vary by strain. Researchers should also consider incorporating WHO-recommended critical concentrations into their culture-based reference standards. PLAIN LANGUAGE SUMMARY The rapid test GenoType® MTBDRsl for testing resistance to second-line TB drugs Background Different drugs are available to treat tuberculosis (TB), but resistance to these drugs is a growing problem. People with drug-resistant TB require second-line TB drugs that, compared with first-line TB drugs, must be taken for longer and may be associated with more harms. Detecting TB drug resistance quickly is important for improving health, reducing deaths, and decreasing the spread of drug-resistant TB. Definitions Multidrug-resistant TB (MDR-TB) is caused by TB bacteria that are resistant to at least isoniazid and rifampicin, the two most potent TB drugs. Extensively drug-resistant TB (XDR-TB) is a type of MDR-TB that is resistant to nearly all TB drugs. What test is evaluated by this review? GenoType® MTBDRsl (MTBDRsl) is a rapid test for detecting resistance to second-line TB drugs. In people with MDR-TB, MTBDRsl is used to detect additional drug resistance. The test may be performed on TB bacteria grown in culture from a patient specimen (indirect testing) or on a patient specimen (direct testing), which eliminates delays associated with culture. MTBDRsl version 1.0 requires a specimen to be smear-positive by microscopy, while version 2.0 (released in 2015) may use a smear-positive or -negative specimen. What are the aims of the review? We wanted to find out how accurate MTBDRsl is for detecting drug resistance; to compare indirect and direct testing; and to compare the two test versions. How up-to-date is the review? We searched for and used studies that had been published up to 21 September 2015. What are the main results of the review? We found 27 studies; 26 studies evaluated MTBDRsl version 1.0 and one study evaluated version 2.0. Fluoroquinolone drugs MTBDRsl version 1.0 (smear-positive specimen) detected 86% of people with fluoroquinolone resistance and rarely gave a positive result for people without resistance (GRADE, moderate quality evidence). Second-line injectable drugs MTBDRsl version 1.0 (smear-positive specimen) detected 87% of people with second-line injectable drug resistance and rarely gave a positive result for people without resistance (GRADE, low quality evidence). XDR-TB MTBDRsl version 1.0 (smear-positive specimen) detected 69% of people with XDR-TB and rarely gave a positive result for people without resistance (GRADE, low quality evidence). For MTBDRsl version 1.0, we found similar results for indirect and direct testing (smear-positive specimen). As we identified only one study evaluating MTBDRsl version 2.0, we could not be sure of the diagnostic accuracy of version 2.0. Also, we could not compare accuracy of the two versions. What is the methodological quality of the evidence? We used the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool to assess study quality. Overall, we considered the included studies to be of high quality; however, we had concerns about how the reference standard (the benchmark against which MTBDRsl was measured) was applied. What are the authors' conclusions? MTBDRsl (smear-positive specimen) identified most of the patients with second-line drug resistance. When the test reports a negative result, conventional testing for drug resistance can still be used.

Background Genotype® MTBDRsl (MTBDRsl) is a rapid DNA-based test for detecting specific mutations associated with resistance to fluoroquinolones and second-line injectable drugs (SLIDs) in Mycobacterium tuberculosis complex. MTBDRsl version 2.0 (released in 2015) identifies the mutations detected by version 1.0, as well as additional mutations. The test may be performed on a culture isolate or a patient specimen, which eliminates delays associated with culture. Version 1.0 requires a smear-positive specimen, while version 2.0 may use a smear-positive or -negative specimen. We performed this updated review as part of a World Health Organization process to develop updated guidelines for using MTBDRsl. Objectives To assess and compare the diagnostic accuracy of MTBDRsl for: 1. fluoroquinolone resistance, 2. SLID resistance, and 3. extensively drug-resistant tuberculosis, indirectly on a M. tuberculosis isolate grown from culture or directly on a patient specimen. Participants were people with rifampicin-resistant or multidrug-resistant tuberculosis. The role of MTBDRsl would be as the initial test, replacing culture-based drug susceptibility testing (DST), for detecting second-line drug resistance. Search methods We searched the following databases without language restrictions up to 21 September 2015: the Cochrane Infectious Diseases Group Specialized Register; MEDLINE; Embase OVID; Science Citation Index Expanded, Conference Proceedings Citation Index-Science, and BIOSIS Previews (all three from Web of Science); LILACS; and SCOPUS; registers for ongoing trials; and ProQuest Dissertations & Theses A&I. We reviewed references from included studies and contacted specialists in the field. Selection criteria We included cross-sectional and case-control studies that determined MTBDRsl accuracy against a defined reference standard (culture-based DST, genetic sequencing, or both). Data collection and analysis Two review authors independently extracted data and assessed quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We synthesized data for versions 1.0 and 2.0 separately. We estimated MTBDRsl sensitivity and specificity for fluoroquinolone resistance, SLID resistance, and extensively drug-resistant tuberculosis when the test was performed indirectly or directly (smear-positive specimen for version 1.0, smear-positive or -negative specimen for version 2.0). We explored the influence on accuracy estimates of individual drugs within a drug class and of different reference standards. We performed most analyses using a bivariate random-effects model with culture-based DST as reference standard. Main results We included 27 studies. Twenty-six studies evaluated version 1.0, and one study version 2.0. Of 26 studies stating specimen country origin, 15 studies (58%) evaluated patients from low- or middle-income countries. Overall, we considered the studies to be of high methodological quality. However, only three studies (11%) had low risk of bias for the reference standard; these studies used World Health Organization (WHO)-recommended critical concentrations for all drugs in the culture-based DST reference standard. MTBDRsl version 1.0 Fluoroquinolone resistance: indirect testing, MTBDRsl pooled sensitivity and specificity (95% confidence interval (CI)) were 85.6% (79.2% to 90.4%) and 98.5% (95.7% to 99.5%), (19 studies, 2223 participants); direct testing (smear-positive specimen), pooled sensitivity and specificity were 86.2% (74.6% to 93.0%) and 98.6% (96.9% to 99.4%), (nine studies, 1771 participants, moderate quality evidence). SLID resistance: indirect testing, MTBDRsl pooled sensitivity and specificity were 76.5% (63.3% to 86.0%) and 99.1% (97.3% to 99.7%), (16 studies, 1921 participants); direct testing (smear-positive specimen), pooled sensitivity and specificity were 87.0% (38.1% to 98.6%) and 99.5% (93.6% to 100.0%), (eight studies, 1639 participants, low quality evidence). Extensively drug-resistant tuberculosis: indirect testing, MTBDRsl pooled sensitivity and specificity were 70.9% (42.9% to 88.8%) and 98.8% (96.1% to 99.6%), (eight studies, 880 participants); direct testing (smear-positive specimen), pooled sensitivity and specificity were 69.4% (38.8% to 89.0%) and 99.4% (95.0% to 99.3%), (six studies, 1420 participants, low quality evidence). Similar to the original Cochrane review, we found no evidence of a significant difference in MTBDRsl version 1.0 accuracy between indirect and direct testing for fluoroquinolone resistance, SLID resistance, and extensively drug-resistant tuberculosis. MTBDRsl version 2.0 Fluoroquinolone resistance: direct testing, MTBDRsl sensitivity and specificity were 97% (83% to 100%) and 98% (93% to 100%), smear-positive specimen; 80% (28% to 99%) and 100% (40% to 100%), smear-negative specimen. SLID resistance: direct testing, MTBDRsl sensitivity and specificity were 89% (72% to 98%) and 90% (84% to 95%), smear-positive specimen; 80% (28% to 99%) and 100% (40% to 100%), smear-negative specimen. Extensively drug-resistant tuberculosis: direct testing, MTBDRsl sensitivity and specificity were 79% (49% to 95%) and 97% (93% to 99%), smear-positive specimen; 50% (1% to 99%) and 100% (59% to 100%), smear-negative specimen. We had insufficient data to estimate summary sensitivity and specificity of version 2.0 (smear-positive and -negative specimens) or to compare accuracy of the two versions. A limitation was that most included studies did not consistently use the World Health Organization (WHO)-recommended concentrations for drugs in the culture-based DST reference standard. Authors' conclusions In people with rifampicin-resistant or multidrug-resistant tuberculosis, MTBDRsl performed on a culture isolate or smear-positive specimen may be useful in detecting second-line drug resistance. MTBDRsl (smear-positive specimen) correctly classified around six in seven people as having fluoroquinolone or SLID resistance, although the sensitivity estimates for SLID resistance varied. The test rarely gave a positive result for people without drug resistance. However, when second-line drug resistance is not detected (MTBDRsl result is negative), conventional DST can still be used to evaluate patients for resistance to the fluoroquinolones or SLIDs. We recommend that future work evaluate MTBDRsl version 2.0, in particular on smear-negative specimens and in different settings to account for different resistance-causing mutations that may vary by strain. Researchers should also consider incorporating WHO-recommended critical concentrations into their culture-based reference standards.

Background Rapid detection of tuberculosis (TB) among people living with human immunodeficiency virus (HIV) is a global health priority. HIV-associated TB may have different clinical presentations and is challenging to diagnose. Conventional sputum tests have reduced sensitivity in HIV-positive individuals, who have higher rates of extrapulmonary TB compared with HIV-negative individuals. The lateral flow urine lipoarabinomannan assay (LF-LAM) is a new, commercially available point-of-care test that detects lipoarabinomannan (LAM), a lipopolysaccharide present in mycobacterial cell walls, in people with active TB disease. Objectives To assess the accuracy of LF-LAM for the diagnosis of active TB disease in HIV-positive adults who have signs and symptoms suggestive of TB (TB diagnosis).To assess the accuracy of LF-LAM as a screening test for active TB disease in HIV-positive adults irrespective of signs and symptoms suggestive of TB (TB screening). Search methods We searched the following databases without language restriction on 5 February 2015: the Cochrane Infectious Diseases Group Specialized Register; MEDLINE (PubMed,1966); EMBASE (OVID, from 1980); Science Citation Index Expanded (SCI-EXPANDED, from 1900), Conference Proceedings Citation Index-Science (CPCI-S, from 1900), and BIOSIS Previews (from 1926) (all three using the Web of Science platform; MEDION; LILACS (BIREME, from 1982); SCOPUS (from 1995); the metaRegister of Controlled Trials (mRCT); the search portal of the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP); and ProQuest Dissertations & Theses A&l (from 1861). Selection criteria Eligible study types included randomized controlled trials, cross-sectional studies, and cohort studies that determined LF-LAM accuracy for TB against a microbiological reference standard (culture or nucleic acid amplification test from any body site). A higher quality reference standard was one in which two or more specimen types were evaluated for TB, and a lower quality reference standard was one in which only one specimen type was evaluated for TB. Participants were HIV-positive people aged 15 years and older. Data collection and analysis Two review authors independently extracted data from each included study using a standardized form. We appraised the quality of studies using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. We evaluated the test at two different cut-offs: (grade 1 or 2, based on the reference card scale of five intensity bands). Most analyses used grade 2, the manufacturer's currently recommended cut-off for positivity. We carried out meta-analyses to estimate pooled sensitivity and specificity using a bivariate random-effects model and estimated the models using a Bayesian approach. We determined accuracy of LF-LAM combined with sputum microscopy or Xpert® MTB/RIF. In addition, we explored the influence of CD4 count on the accuracy estimates. We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main results We included 12 studies: six studies evaluated LF-LAM for TB diagnosis and six studies evaluated the test for TB screening. All studies were cross-sectional or cohort studies. Studies for TB diagnosis were largely conducted among inpatients (median CD4 range 71 to 210 cells per µL) and studies for TB screening were largely conducted among outpatients (median CD4 range 127 to 437 cells per µL). All studies were conducted in low- or middle-income countries. Only two studies for TB diagnosis (33%) and one study for TB screening (17%) used a higher quality reference standard. LF-LAM for TB diagnosis (grade 2 cut-off): meta-analyses showed median pooled sensitivity and specificity (95% credible interval (CrI)) of 45% (29% to 63%) and 92% (80% to 97%), (five studies, 2313 participants, 35% with TB, low quality evidence). The pooled sensitivity of a combination of LF-LAM and sputum microscopy (either test positive) was 59% (47% to 70%), which represented a 19% (4% to 36%) increase over sputum microscopy alone, while the pooled specificity was 92% (73% to 97%), which represented a 6% (1% to 24%) decrease from sputum microscopy alone (four studies, 1876 participants, 38% with TB). The pooled sensitivity of a combination of LF-LAM and sputum Xpert® MTB/RIF (either test positive) was 75% (61% to 87%) and represented a 13% (1% to 37%) increase over Xpert® MTB/RIF alone. The pooled specificity was 93% (81% to 97%) and represented a 4% (1% to 16%) decrease from Xpert® MTB/RIF alone (three studies, 909 participants, 36% with TB). Pooled sensitivity and specificity of LF-LAM were 56% (41% to 70%) and 90% (81% to 95%) in participants with a CD4 count of less than or equal to 100 cells per µL (five studies, 859 participants, 47% with TB) versus 26% (16% to 46%) and 92% (78% to 97%) in participants with a CD4 count greater than 100 cells per µL (five studies, 1410 participants, 30% with TB). LF-LAM for TB screening (grade 2 cut-off): for individual studies, sensitivity estimates (95% CrI) were 44% (30% to 58%), 28% (16% to 42%), and 0% (0% to 71%) and corresponding specificity estimates were 95% (92% to 97%), 94% (90% to 97%), and 95% (92% to 97%) (three studies, 1055 participants, 11% with TB, very low quality evidence). There were limited data for additional analyses. The main limitations of the review were the use of a lower quality reference standard in most included studies, and the small number of studies and participants included in the analyses. The results should, therefore, be interpreted with caution. Authors' conclusions We found that LF-LAM has low sensitivity to detect TB in adults living with HIV whether the test is used for diagnosis or screening. For TB diagnosis, the combination of LF-LAM with sputum microscopy suggests an increase in sensitivity for TB compared to either test alone, but with a decrease in specificity. In HIV-positive individuals with low CD4 counts who are seriously ill, LF-LAM may help with the diagnosis of TB. PLAIN LANGUAGE SUMMARY The lateral flow urine lipoarabinomannan (LF-LAM) test for diagnosis of tuberculosis in people living with human immunodeficiency virus (HIV) Background Tuberculosis (TB) is a common cause of death in people with human immunodeficiency virus (HIV) infection, but diagnosis is difficult, and depends on testing for TB in the sputum and other sites, which may take weeks to give results. A rapid and accurate point-of-care test could reduce delays in diagnosis, allow treatment to start promptly, and improve linkage between diagnosis and treatment. Test evaluated by this review The lateral flow urine lipoarabinomannan assay (LF-LAM, Alere Determine™ TB LAM Ag, Alere Inc, Waltham, MA, USA) is a commercially available point-of-care test for active TB (pulmonary and extrapulmonary TB). The test detects lipoarabinomannan (LAM), a component of the bacterial cell walls, which is present in some people with active TB. The test is performed by placing urine on one end of a test strip, with results appearing as a line (that is, a band) on the strip if TB is present. The test is simple, requires no special equipment, and shows results in 25 minutes. During the period we conducted the review, the manufacturer issued new recommendations for defining a positive test. We collected data based on both the original and the new recommendations Objectives We aimed to see how accurately LF-LAM diagnosed TB in people living with HIV with TB symptoms, and how accurately LF-LAM diagnosed TB in people living with HIV being screened for TB whether or not they had TB symptoms. Main results We examined evidence up to 5 February 2015 and included 12 studies: six studies evaluated LF-LAM for TB diagnosis and six studies evaluated the test for TB screening. All studies were conducted in low- or middle-income countries. Quality of the evidence We assessed quality by describing how participants were selected for the studies, details of the test and reference standards (the benchmark test), and study flow and timing, using the standard QUADAS-2 approach. Few studies used multiple types of specimens for the reference standard (higher quality standard) and most relied on sputum culture alone (lower quality standard), which may have affected results. What do the results mean? In a population of 1000 HIV-positive individuals with TB symptoms, where 300 actually have TB, the test will correctly identify 135 people as having TB, but miss the remaining 165 people; for the 700 people who do not have TB, the test will correctly identify 644 people as not having TB, but will misclassify 56 as having TB. The sensitivity of the test is higher in people living with HIV with low CD4 cell counts who are at risk of life-threatening illnesses. In patients with a CD4 ≤ 100 cells per µL, LF-LAM sensitivity was 56% (41% to 70%) versus 26% (16% to 46%) in patients with a CD4 count = 100 cells per µL. If the test is used in screening HIV-positive people for TB, in a population of 1000 where 10 actually have TB, LF-LAM will correctly identify none of the 10, or up to four of the 10; on the other hand, the test will miss six to 10 people with TB; in the remaining 990 who do not have TB, the test will correctly identify 931 to 941 people as not having TB while misclassifying 49 to 59 as having TB. Limitations The main limitations of the review were the use of a lower quality reference standard in most included studies, and small number of studies and participants included in the analyses. The results should, therefore, be interpreted with caution. Conclusions In this Cochrane review, we found that LF-LAM, whether the test is used for diagnosis or screening, has low sensitivity to detect TB. However, in HIV-positive people with low CD4 counts who are seriously ill, LF-LAM may help with the diagnosis of TB.

Chest radiography for the diagnosis of active pulmonary tuberculosis (PTB) is limited by poor specificity and reader inconsistency. Scoring systems have been employed successfully for improving the performance of chest radiography for various pulmonary diseases. We conducted a systematic review to assess the diagnostic accuracy and reproducibility of scoring systems for PTB. We searched multiple databases for studies that evaluated the accuracy and reproducibility of chest radiograph scoring systems for PTB. We summarised results for specific radiographic features and scoring systems associated with PTB. Where appropriate, we estimated pooled performance of similar studies using a random effects model. 13 studies were included in the review, nine of which were in low tuberculosis (TB) burden settings. No scoring system was based solely on radiographic findings. All studies used systems with various combinations of clinical and radiological features. 11 studies involved scoring systems that were used for making decisions concerning hospital respiratory isolation. None of the included studies reported data on intra- or inter-reporter reproducibility. Upper lobe infiltrates (pooled diagnostic OR 3.57, 95% CI 2.38- 5.37, five studies) and cavities (diagnostic OR range 1.97-25.66, three studies) were significantly associated with PTB. Sensitivities of the scoring systems were high (median 96%, IQR 93-98%), but specificities were low (median 46%, IQR 35-50%). Chest radiograph scoring systems appear useful in ruling out PTB in hospitals, but their low specificity precludes ruling in PTB. There is a need to develop accurate scoring systems for people living with HIV and for outpatient settings, especially in high TB burden settings.

Undiagnosed and mismanaged tuberculosis (TB) continues to fuel the global TB epidemic. Rapid, accurate and early diagnosis of TB is therefore a priority to improve TB case detection and interrupt transmission. Although considerable improvements have been made in TB diagnostics, there are two major gaps in the existing diagnostics pipeline: (1) lack of a simple accurate point-of-care test that can be used for rapid diagnosis at the primary care level; (2) lack of a biomarker (or combination of biomarkers) that can be used to identify latently infected individuals who will benefit most from preventive therapy. Currently available commercial serological (antibody detection) tests are inaccurate and do not improve patient outcomes. Despite this evidence, dozens of serological tests are sold and used in countries (e.g. India) with weak regulatory systems, especially in the private sector. Recognizing the threat posed by these suboptimal tests, a World Health Organization (WHO) Expert Group has strongly recommended against the use of serological tests for the diagnosis of pulmonary and extra-pulmonary TB. Another WHO Expert Group has discouraged the use of interferon-γ release assays for active pulmonary TB diagnosis in low- and middle-income countries. All existing tests for latent TB infection appear to have only modest predictive value and further research is needed to identify highly predictive biomarkers.

Tests that detect Mycobacterium tuberculosis antigens in clinical specimens could provide rapid direct evidence of active disease. We performed a systematic review to assess the diagnostic accuracy of antigen detection tests for active tuberculosis (TB) according to standard methods and summarized test performance using bivariate random effects meta-analysis. Overall, study quality was a concern. For pulmonary TB (47 studies, 5,036 participants), sensitivity estimates ranged from 2% to 100% and specificity from 33% to 100%. Lipoarabinomannan (LAM) was the antigen most frequently targeted (23 studies, 49%). The pooled sensitivity of urine LAM was higher in HIV-infected than HIV-uninfected individuals (47%; 95% confidence interval [CI], 26 to 68% versus 14%; 95% CI, 4 to 38%); pooled specificity estimates were similar: 96%; 95% CI, 81 to 100% and 97%; 95% CI, 86 to 100%, respectively. For extrapulmonary TB (21 studies, 1,616 participants), sensitivity estimates ranged from 0% to 100% and specificity estimates from 62% to 100%. Five studies targeting LAM, ESAT-6, Ag85 complex, and the 65-kDa antigen in cerebrospinal fluid, when pooled, yielded the highest sensitivity (87%; 95% CI, 61 to 98%), but low specificity (84%; 95% CI, 60 to 95%). Because of the limited number of studies targeting any specific antigen other than LAM, we could not draw firm conclusions about the overall clinical usefulness of these tests. Further studies are warranted to determine the value of LAM detection for TB meningitis in high-HIV-prevalence settings. Considering that antigen detection tests could be translated into rapid point-of-care tests, research to improve their performance is urgently needed.

Childhood TB is difficult to diagnose, since disease tends to be paucibacillary and sputum specimens are not easy to obtain in children. Thus, blood-based immune assays are an attractive option. Systematic reviews of serological assays suggest that these tests produce highly inconsistent estimates of sensitivity and specificity, but much of the serology literature is based on adults. In children, there is insufficient evidence to recommend the use of serological tests for active TB diagnosis. Interferon-gamma release assays (IGRA) do not offer substantial improvements in sensitivity over the TST for the diagnosis of active disease. For latent TB infection, the IGRA correlates well with the exposure gradient and seems to have utility in reducing the number of children who undergo preventive therapy due to false-positive TST. Although IGRAs can be used as evidence of TB infection in children, appropriate specimen collection and microbiological confirmation of TB disease should remain a priority.

Objective To determine whether interferon-gamma release assays (IGRAs) improve the identification of HIV-infected individuals who could benefit from latent tuberculosis infection therapy. Design Systematic review and meta-analysis. Methods We searched multiple databases through May 2010 for studies evaluating the performance of the newest commercial IGRAs (QuantiFERON-TB Gold In-Tube [QFT-GIT] and T-SPOT.TB [TSPOT]) in HIV-infected individuals. We assessed the quality of all studies included in the review, summarized results in prespecified subgroups using forest plots, and where appropriate, calculated pooled estimates using random effects models. Results The search identified 37 studies that included 5736 HIV-infected individuals. In three longitudinal studies, the risk of active tuberculosis was higher in HIV-infected individuals with positive versus negative IGRA results. However, the risk difference was not statistically significant in the two studies that reported IGRA results according to manufacturer-recommended criteria. In persons with active tuberculosis (a surrogate reference standard for latent tuberculosis infection), pooled sensitivity estimates were heterogeneous but higher for TSPOT (72%; 95% confidence interval [CI], 62-81%) than for QFT-GIT (61%; 95% CI, 47-75%) in low-/middle-income countries. However, neither IGRA was consistently more sensitive than the tuberculin skin test in head-to-head comparisons. Although TSPOT appeared to be less affected by immunosuppression than QFT-GIT and the tuberculin skin test, overall, differences among the three tests were small or inconclusive. Conclusions Current evidence suggests that IGRAs perform similarly to the tuberculin skin test at identifying HIV-infected individuals with latent tuberculosis infection. Given that both tests have modest predictive value and suboptimal sensitivity, the decision to use either test should be based on country guidelines and resource and logistic considerations.

Karen R Steingart, Andrew Ramsay & Madhukar Pai† †Author for correspondence McGill University, Dept. of Epidemiology, Biostatistics & Occupational Health, Montreal, Canada and, Respiratory Epidemiology & Clinical Research Unit, Montreal Chest Institute 1020 Pine Avenue West, Montreal, Canada Tel.: +1 514 398 5422; Fax: +1 514 398 4503; madhukar.pai@mcgill.ca ‘Both pulmonary and extrapulmonary TB present diagnostic challenges.’

The global burden of disability and death due to tuberculosis (TB) is immense. In 2005 alone, an estimated 8.8 million people developed TB and almost 2 million died, including 195,000 HIV-infected ...

Most of the world's tuberculosis cases occur in low-income and middle-income countries, where sputum microscopy with a conventional light microscope is the primary method for diagnosing pulmonary tuberculosis. A major shortcoming of conventional microscopy is its relatively low sensitivity compared with culture, especially in patients co-infected with HIV. In high-income countries, fluorescence microscopy rather than conventional microscopy is the standard diagnostic method. Fluorescence microscopy is credited with increased sensitivity and lower work effort, but there is concern that specificity may be lower. We did a systematic review to summarise the accuracy of fluorescence microscopy compared with conventional microscopy. By searching many databases and contacting experts, we identified 45 relevant studies. Sensitivity, specificity, and incremental yield were the outcomes of interest. The results suggest that, overall, fluorescence microscopy is more sensitive than conventional microscopy, and has similar specificity. There is insufficient evidence to determine the value of fluorescence microscopy in HIV-infected individuals. The results of this review provide a point of reference, quantifying the potential benefit of fluorescence microscopy, with which the increased cost and technical complexity of the method can be compared to determine the possible value of the method under programme conditions.

Background Accurate and rapid tests for tuberculosis (TB) drug resistance are critical for improving patient care and decreasing the transmission of drug-resistant TB. Genotype®MTBDRsl (MTBDRsl) is the only commercially-available molecular test for detecting resistance in TB to the fluoroquinolones (FQs; ofloxacin, moxifloxacin and levofloxacin) and the second-line injectable drugs (SLIDs; amikacin, kanamycin and capreomycin), which are used to treat patients with multidrug-resistant (MDR-)TB. Objectives To obtain summary estimates of the diagnostic accuracy of MTBDRsl for FQ resistance, SLID resistance and extensively drug-resistant TB (XDR-TB; defined as MDR-TB plus resistance to a FQ and a SLID) when performed (1) indirectly (ie on culture isolates confirmed as TB positive) and (2) directly (ie on smear-positive sputum specimens). To compare summary estimates of the diagnostic accuracy of MTBDRsl for FQ resistance, SLID resistance and XDR-TB by type of testing (indirect versus direct testing). The populations of interest were adults with drug-susceptible TB or drug-resistant TB. The settings of interest were intermediate and central laboratories. Search methods We searched the following databases without any language restriction up to 30 January 2014: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; ISI Web of Knowledge; MEDION; LILACS; BIOSIS; SCOPUS; the metaRegister of Controlled Trials; the search portal of the World Health Organization International Clinical Trials Registry Platform; and ProQuest Dissertations & Theses A&I. Selection criteria We included all studies that determined MTBDRsl accuracy against a defined reference standard (culture-based drug susceptibility testing (DST), genetic testing or both). We included cross-sectional and diagnostic case-control studies. We excluded unpublished data and conference proceedings. Data collection and analysis For each study, two review authors independently extracted data using a standardized form and assessed study quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We performed meta-analyses to estimate the pooled sensitivity and specificity of MTBDRsl for FQ resistance, SLID resistance, and XDR-TB. We explored the influence of different reference standards. We performed the majority of analyses using a bivariate random-effects model against culture-based DST as the reference standard. Main results We included 21 unique studies: 14 studies reported the accuracy of MTBDRsl when done directly, five studies when done indirectly and two studies that did both. Of the 21 studies, 15 studies (71%) were cross-sectional and 11 studies (58%) were located in low-income or middle-income countries. All studies but two were written in English. Nine (43%) of the 21 included studies had a high risk of bias for patient selection. At least half of the studies had low risk of bias for the other QUADAS-2 domains. As a test for FQ resistance measured against culture-based DST, the pooled sensitivity of MTBDRsl when performed indirectly was 83.1% (95% confidence interval (CI) 78.7% to 86.7%) and the pooled specificity was 97.7% (95% CI 94.3% to 99.1%), respectively (16 studies, 1766 participants; 610 confirmed cases of FQ-resistant TB; moderate quality evidence). When performed directly, the pooled sensitivity was 85.1% (95% CI 71.9% to 92.7%) and the pooled specificity was 98.2% (95% CI 96.8% to 99.0%), respectively (seven studies, 1033 participants; 230 confirmed cases of FQ-resistant TB; moderate quality evidence). For indirect testing for FQ resistance, four (0.2%) of 1766 MTBDRsl results were indeterminate, whereas for direct testing 20 (1.9%) of 1033 were MTBDRsl indeterminate (P < 0.001). As a test for SLID resistance measured against culture-based DST, the pooled sensitivity of MTBDRsl when performed indirectly was 76.9% (95% CI 61.1% to 87.6%) and the pooled specificity was 99.5% (95% CI 97.1% to 99.9%), respectively (14 studies, 1637 participants; 414 confirmed cases of SLID-resistant TB; moderate quality evidence). For amikacin resistance, the pooled sensitivity and specificity were 87.9% (95% CI 82.1% to 92.0%) and 99.5% (95% CI 97.5% to 99.9%), respectively. For kanamycin resistance, the pooled sensitivity and specificity were 66.9% (95% CI 44.1% to 83.8%) and 98.6% (95% CI 96.1% to 99.5%), respectively. For capreomycin resistance, the pooled sensitivity and specificity were 79.5% (95% CI 58.3% to 91.4%) and 95.8% (95% CI 93.4% to 97.3%), respectively. When performed directly, the pooled sensitivity for SLID resistance was 94.4% (95% CI 25.2% to 99.9%) and the pooled specificity was 98.2% (95% CI 88.9% to 99.7%), respectively (six studies, 947 participants; 207 confirmed cases of SLID-resistant TB, 740 SLID susceptible cases of TB; very low quality evidence). For indirect testing for SLID resistance, three (0.4%) of 774 MTBDRsl results were indeterminate, whereas for direct testing 53 (6.1%) of 873 were MTBDRsl indeterminate (P < 0.001). As a test for XDR-TB measured against culture-based DST, the pooled sensitivity of MTBDRsl when performed indirectly was 70.9% (95% CI 42.9% to 88.8%) and the pooled specificity was 98.8% (95% CI 96.1% to 99.6%), respectively (eight studies, 880 participants; 173 confirmed cases of XDR-TB; low quality evidence). Authors' conclusions In adults with TB, a positive MTBDRsl result for FQ resistance, SLID resistance, or XDR-TB can be treated with confidence. However, MTBDRsl does not detect approximately one in five cases of FQ-resistant TB, and does not detect approximately one in four cases of SLID-resistant TB. Of the three SLIDs, MTBDRsl has the poorest sensitivity for kanamycin resistance. MTBDRsl will miss between one in four and one in three cases of XDR-TB. The diagnostic accuracy of MTBDRsl is similar when done using either culture isolates or smear-positive sputum. As the location of the resistance causing mutations can vary on a strain-by-strain basis, further research is required on test accuracy in different settings and, if genetic sequencing is used as a reference standard, it should examine all resistance-determining regions. Given the confidence one can have in a positive result, and the ability of the test to provide results within a matter of days, MTBDRsl may be used as an initial test for second-line drug resistance. However, when the test reports a negative result, clinicians may still wish to carry out conventional testing.

Objective:To describe the epidemiology of measles in medical settings and to evaluate the implementation and effectiveness of the 1989 Advisory Committee on Immunization Practices (ACIP) guidelines for measles immunization in healthcare workers (HCWs).Design:Confirmed cases of measles reported in Clark County, Washington, from March 14 to June 2,1996, were analyzed for characteristics of cases occurring in medical settings. A questionnaire was used to assess employee immunization (95% response rate).Setting and Participants:Reported measles cases and HCWs at community hospitals, primary-care medical facilities, a health-maintenance organization, and a multispecialty group practice.Results:Of 31 cases of measles, 8 (26%) occurred in HCWs, and 5 (16%) occurred in patients or visitors to medical facilities. Cases of measles occurred in HCWs who were not required to have proof of measles immunity as defined by the 1989 ACIP guidelines. The relative risk of measles in HCWs compared to Clark County adults was 18.6 (95% confidence interval, 7.4-45.8;PA survey of medical facilities revealed that 47% had an employee measles immunization policy; only 21% met ACIP recommendations and enforced their policies.Conclusions:HCWs were at higher risk of measles than the adult population. Transmission of measles in medical settings was related to both deficiencies in, and lack of implementation of, the ACIP guidelines.

Background 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. Objectives 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. Search methods 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. Selection criteria 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. Data collection and analysis 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. Main results 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. Rifampicin resistance 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. Authors' conclusions 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.

Background. Since 1992 the US Pacific Northwest has experienced a substantial increase in the incidence of serogroup B meningococcal disease. The current meningococcal polysaccharide vaccine is poorly immunogenic in young children and does not protect against N. meningitidis serogroup B. Defining alternative approaches to the prevention and control of meningococcal disease is of considerable public health importance. Methods. We performed a case-control study comparing 129 patients in Oregon and southwest Washington with 274 age- and area-matched controls. We used conditional logistic regression analysis to determine which exposures remained associated with disease after adjusting for other risk factors and confounders and calculated the proportion of disease attributable to modifiable exposures. Results. After adjustment for all other significant exposures identified, having a mother who smokes was the strongest independent risk factor for invasive meningococcal disease in children

Summary Background Sputum smear microscopy is the most widely available diagnostic test for pulmonary tuberculosis in countries with a high burden of the disease. Improving its accuracy is crucial to achievement of case-detection targets established by the Millennium Development Goals. Unfortunately, many patients are unable to submit all of the specimens needed for examination or to return for treatment because standard sputum collection and reporting requires several clinic visits. To inform policy recommendations by a WHO-convened Expert Group, we aimed to assess the accuracy of sputum smear examination with strategies for obtaining sputum on 1 day compared with strategies for obtaining sputum over 2 days. Methods We did a systematic review and meta-analysis of research articles comparing the accuracy of front-loaded or same-day microscopy and standard sputum smear microscopy for diagnosis of culture-confirmed pulmonary tuberculosis. We searched Medline, Embase, Biosis, and Web of Science for articles published between Jan 1, 2005, and Feb 14, 2012. Two investigators identified eligible articles and extracted data for individual study sites. We generated pooled summary estimates (95% CIs) for sensitivity and specificity by use of random-effects meta-analysis when four or more studies were available. Findings We identified eight relevant studies from five articles enrolling 7771 patients with suspected tuberculosis in low-income countries. Compared with the standard approach of examination of two smears with Ziehl-Neelsen light microscopy over 2 days, examination of two smears taken on the same day had much the same sensitivity (64% [95% CI 60 to 69] for standard microscopy vs 63% [58 to 68] for same-day microscopy) and specificity (98% [97 to 99] vs 98% [97 to 99]). We noted similar results for studies employing light-emitting diode fluorescence microscopy and for studies examining three smears, whether they were compared with two-smear strategies or with one another. Interpretation Same-day sputum smear microscopy is as accurate as standard smear microscopy. Data from tuberculosis programmes are needed to document the changes required in the health system to successfully implement the strategy and understand its effects. Funding WHO and US National Institutes of Health.

Diagnostic tests for active tuberculosis (TB) based on the detection of antibodies (serological tests) have been commercially available for decades, although no international guidelines have recommended their use. An estimated 1.5 million serological TB tests, mainly enzyme-linked immunosorbent assays, are performed in India alone every year, mostly in the private sector. The cost of serological tests in India is conservatively estimated at US $15 million (`825 million) per year. Findings from systematic reviews on the diagnostic accuracy of serological tests for both pulmonary and extra-pulmonary TB suggest that these tests are inaccurate and imprecise. A cost-effectiveness modelling study suggests that, if used as a replacement test for sputum microscopy, serology would increase costs to the Indian TB control sector approximately 4-fold and result in fewer disability-adjusted life years averted and more false-positive diagnoses. After considering all available evidence, the World Health Organization issued a strong recommendation against the use of currently available commercial serological tests for the diagnosis of TB disease. The expanding evidence base continues to demonstrate that the harms/risks of serological tests far outweigh the benefits. Greater engagement of the private sector is needed to discontinue the use of serological tests and to replace these tests with WHO-endorsed new diagnostics in India. The recent ban on import or sale of TB serological tests by the Indian health ministry is a welcome step in the right direction.

To the Editors: There is great excitement over the introduction of new tuberculosis (TB) diagnostics [1]. Since 2007, several TB diagnostics and approaches have been endorsed by the World Health Organization (WHO) [2],with Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) being the most recent [3]. Amidst this excitement, there is growing concern surrounding the use of inappropriate and suboptimal TB diagnostics [4, 5]. Currently available commercial serological (antibody detection) tests for TB are inaccurate and highly inconsistent [6–8]. The International Standards for TB Care explicitly discourage their use [9]. Even so, serological tests are known to be widely used in countries such as India [2, 4, 5]. In addition to posing an economic burden on patients and healthcare systems, use of serological tests also entails potential harm to patients ( e.g. unnecessary TB therapy because of false-positive results, or morbidity and mortality because of false-negative serology results). After reviewing the evidence, including the findings of an updated meta-analysis [10], the WHO recently announced its first negative policy in TB, against the use of current TB serological tests [5 …

Using the example of an international collaboration on tuberculosis (TB) diagnostics, we mapped the key stages and stakeholders involved in translating research into global policies. In our experience, the process begins with advocacy for high-quality, policy-relevant research and appropriate funding. Following the assessment of current policy and the identification of key study areas, policy-relevant research questions need to be formulated and prioritised. It is important that a framework for translating evidence into policy at the target policymaking level, in this case global, is available to researchers. This ensures that research questions, study designs and research standards are appropriate to the type and quality of evidence required. The framework may evolve during the period of research and, as evidence requirements may change, vigilance is required. Formal and informal multi-stakeholder partnerships, as well as information sharing through extensive networking, facilitate efficient building of a broad evidence base. Coordination of activities by an international, neutral body with strong convening powers is important, as is regular interaction with policy makers. It is recognised that studies on diagnostic accuracy provide weak evidence that a new diagnostic will improve patient care when implemented to scale in routine settings. This may be one reason why there has been poor uptake of new tools by national TB control programmes despite global policy recommendations. Stronger engagement with national policy makers and donors during the research-intopolicy process may be needed to ensure that their evidence requirements are met and that global policies translate into national policies. National policies are central to translating global policies into practice.

David Dowdy and colleagues discuss the complexities of costing new TB diagnostic tests, including GeneXpert, and argue that flexible analytic tools are needed for decision-makers to adapt large-sample cost-effectiveness data to local conditions.

To provide a narrative synthesis of evidence on interferon-gamma release assays (IGRAs) for the diagnosis of latent tuberculosis infection (LTBI) in individuals with immune-mediated inflammatory disorders (IMIDs).Only a few studies have evaluated IGRAs in IMIDs, and most were small and varied considerably with respect to the use of immunosuppressive medications and types of IMIDs. Current evidence does not clearly suggest that IGRAs are better than tuberculin skin test (TST) in identifying individuals with IMID who could benefit from LTBI treatment. To date, no studies have been done on the predictive value of IGRAs in IMID patients. Important questions remain unanswered as to the impact of immunosuppressive medications and the impact of type of IMID on IGRA performance.Despite the lack of clear evidence, there is an increasing tendency for guidelines to prefer IGRA over TST in IMIDs or to recommend both TST and IGRA to enhance sensitivity. We believe the use of either test is acceptable for LTBI screening. Clinicians could consider starting with IGRAs in individuals with a history of Bacille Calmette-Guérin (BCG) vaccination after infancy or with repeated BCG vaccinations. When the index of suspicion for LTBI is high, both IGRA and TST could be performed, especially prior to initiating TNF-α inhibitor therapy. Regardless of the test used, it is important to remember that in the face of immune-suppression, both IGRA and TST can be falsely negative and are thus only diagnostic aids - they will need to be interpreted with other clinical and risk factor data.