Accuracy of routine laboratory tests to predict mortality and deterioration to severe or critical COVID-19 in people with SARS-CoV-2.

BACKGROUND: Identifying patients with COVID-19 disease who will deteriorate can be useful to assess whether they should receive intensive care, or whether they can be treated in a less intensive way or through outpatient care. In clinical care, routine laboratory markers, such as C-reactive protein, are used to assess a person's health status. OBJECTIVES: To assess the accuracy of routine blood-based laboratory tests to predict mortality and deterioration to severe or critical (from mild or moderate) COVID-19 in people with SARS-CoV-2. SEARCH METHODS: On 25 August 2022, we searched the Cochrane COVID-19 Study Register, encompassing searches of various databases such as MEDLINE via PubMed, CENTRAL, Embase, medRxiv, and ClinicalTrials.gov. We did not apply any language restrictions. SELECTION CRITERIA: We included studies of all designs that produced estimates of prognostic accuracy in participants who presented to outpatient services, or were admitted to general hospital wards with confirmed SARS-CoV-2 infection, and studies that were based on serum banks of samples from people. All routine blood-based laboratory tests performed during the first encounter were included. We included any reference standard used to define deterioration to severe or critical disease that was provided by the authors. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from each included study, and independently assessed the methodological quality using the Quality Assessment of Prognostic Accuracy Studies tool. As studies reported different thresholds for the same test, we used the Hierarchical Summary Receiver Operator Curve model for meta-analyses to estimate summary curves in SAS 9.4. We estimated the sensitivity at points on the SROC curves that corresponded to the median and interquartile range boundaries of specificities in the included studies. Direct and indirect comparisons were exclusively conducted for biomarkers with an estimated sensitivity and 95% CI of ≥ 50% at a specificity of ≥ 50%. The relative diagnostic odds ratio was calculated as a summary of the relative accuracy of these biomarkers. MAIN RESULTS: We identified a total of 64 studies, including 71,170 participants, of which 8169 participants died, and 4031 participants deteriorated to severe/critical condition. The studies assessed 53 different laboratory tests. For some tests, both increases and decreases relative to the normal range were included. There was important heterogeneity between tests and their cut-off values. None of the included studies had a low risk of bias or low concern for applicability for all domains. None of the tests included in this review demonstrated high sensitivity or specificity, or both. The five tests with summary sensitivity and specificity above 50% were: C-reactive protein increase, neutrophil-to-lymphocyte ratio increase, lymphocyte count decrease, d-dimer increase, and lactate dehydrogenase increase. Inflammation For mortality, summary sensitivity of a C-reactive protein increase was 76% (95% CI 73% to 79%) at median specificity, 59% (low-certainty evidence). For deterioration, summary sensitivity was 78% (95% CI 67% to 86%) at median specificity, 72% (very low-certainty evidence). For the combined outcome of mortality or deterioration, or both, summary sensitivity was 70% (95% CI 49% to 85%) at median specificity, 60% (very low-certainty evidence). For mortality, summary sensitivity of an increase in neutrophil-to-lymphocyte ratio was 69% (95% CI 66% to 72%) at median specificity, 63% (very low-certainty evidence). For deterioration, summary sensitivity was 75% (95% CI 59% to 87%) at median specificity, 71% (very low-certainty evidence). For mortality, summary sensitivity of a decrease in lymphocyte count was 67% (95% CI 56% to 77%) at median specificity, 61% (very low-certainty evidence). For deterioration, summary sensitivity of a decrease in lymphocyte count was 69% (95% CI 60% to 76%) at median specificity, 67% (very low-certainty evidence). For the combined outcome, summary sensitivity was 83% (95% CI 67% to 92%) at median specificity, 29% (very low-certainty evidence). For mortality, summary sensitivity of a lactate dehydrogenase increase was 82% (95% CI 66% to 91%) at median specificity, 60% (very low-certainty evidence). For deterioration, summary sensitivity of a lactate dehydrogenase increase was 79% (95% CI 76% to 82%) at median specificity, 66% (low-certainty evidence). For the combined outcome, summary sensitivity was 69% (95% CI 51% to 82%) at median specificity, 62% (very low-certainty evidence). Hypercoagulability For mortality, summary sensitivity of a d-dimer increase was 70% (95% CI 64% to 76%) at median specificity of 56% (very low-certainty evidence). For deterioration, summary sensitivity was 65% (95% CI 56% to 74%) at median specificity of 63% (very low-certainty evidence). For the combined outcome, summary sensitivity was 65% (95% CI 52% to 76%) at median specificity of 54% (very low-certainty evidence). To predict mortality, neutrophil-to-lymphocyte ratio increase had higher accuracy compared to d-dimer increase (RDOR (diagnostic Odds Ratio) 2.05, 95% CI 1.30 to 3.24), C-reactive protein increase (RDOR 2.64, 95% CI 2.09 to 3.33), and lymphocyte count decrease (RDOR 2.63, 95% CI 1.55 to 4.46). D-dimer increase had higher accuracy compared to lymphocyte count decrease (RDOR 1.49, 95% CI 1.23 to 1.80), C-reactive protein increase (RDOR 1.31, 95% CI 1.03 to 1.65), and lactate dehydrogenase increase (RDOR 1.42, 95% CI 1.05 to 1.90). Additionally, lactate dehydrogenase increase had higher accuracy compared to lymphocyte count decrease (RDOR 1.30, 95% CI 1.13 to 1.49). To predict deterioration to severe disease, C-reactive protein increase had higher accuracy compared to d-dimer increase (RDOR 1.76, 95% CI 1.25 to 2.50). The neutrophil-to-lymphocyte ratio increase had higher accuracy compared to d-dimer increase (RDOR 2.77, 95% CI 1.58 to 4.84). Lastly, lymphocyte count decrease had higher accuracy compared to d-dimer increase (RDOR 2.10, 95% CI 1.44 to 3.07) and lactate dehydrogenase increase (RDOR 2.22, 95% CI 1.52 to 3.26). AUTHORS' CONCLUSIONS: Laboratory tests, associated with hypercoagulability and hyperinflammatory response, were better at predicting severe disease and mortality in patients with SARS-CoV-2 compared to other laboratory tests. However, to safely rule out severe disease, tests should have high sensitivity (> 90%), and none of the identified laboratory tests met this criterion. In clinical practice, a more comprehensive assessment of a patient's health status is usually required by, for example, incorporating these laboratory tests into clinical prediction rules together with clinical symptoms, radiological findings, and patient's characteristics.

Overuse of medications in low- and middle-income countries: a scoping review.

Objective: To identify and summarize the evidence about the extent of overuse of medications in low- and middle-income countries, its drivers, consequences and potential solutions. Methods: We conducted a scoping review by searching the databases PubMed®, Embase®, APA PsycINFO® and Global Index Medicus using a combination of MeSH terms and free text words around overuse of medications and overtreatment. We included studies in any language published before 25 October 2021 that reported on the extent of overuse, its drivers, consequences and solutions. Findings: We screened 3489 unique records and included 367 studies reporting on over 5.1 million prescriptions across 80 low- and middle-income countries - with studies from 58.6% (17/29) of all low-, 62.0% (31/50) of all lower-middle- and 60.0% (33/55) of all upper-middle-income countries. Of the included studies, 307 (83.7%) reported on the extent of overuse of medications, with estimates ranging from 7.3% to 98.2% (interquartile range: 30.2-64.5). Commonly overused classes included antimicrobials, psychotropic drugs, proton pump inhibitors and antihypertensive drugs. Drivers included limited knowledge of harms of overuse, polypharmacy, poor regulation and financial influences. Consequences were patient harm and cost. Only 11.4% (42/367) of studies evaluated solutions, which included regulatory reforms, educational, deprescribing and audit-feedback initiatives. Conclusion: Growing evidence suggests overuse of medications is widespread within low- and middle-income countries, across multiple drug classes, with few data of solutions from randomized trials. Opportunities exist to build collaborations to rigorously develop and evaluate potential solutions to reduce overuse of medications.

Healthcare provider and drug dispenser knowledge and adherence to guidelines for the case management of malaria in pregnancy in the context of multiple first-line artemisinin-based combination therapy in western Kenya.

BACKGROUND: Concerns about emerging resistance to artemether-lumefantrine (AL) in Africa prompted the pilot introduction of multiple first-line therapies (MFT) in Western Kenya, potentially exposing women-of-childbearing-age (WOCBA) to anti-malarials with unknown safety profiles in the first trimester. The study assessed healthcare provider knowledge and adherence to national guidelines for managing malaria in pregnancy in the context of the MFT pilot. METHODS: From March to April 2022, a cross-sectional study was conducted in 50 health facilities (HF) and 40 drug outlets (DO) using structured questionnaires to assess pregnancy detection, malaria diagnosis, and treatment choices by trimester. Differences between HF and DO providers and between MFT and non-MFT HFs were assessed using Chi-square tests. RESULTS: Of 174 providers (77% HF, 23% DO), 56% were from MFT pilot facilities. Most providers had tertiary education; 5% HF and 20% DO had only primary or secondary education. More HF than DO providers had knowledge of malaria treatment guidelines (62% vs. 40%, p = 0.023), received training in malaria in pregnancy (49% vs. 20%, p = 0.002), and reported assessing for pregnancy in WOCBA (98% vs. 78%, p < 0.001). Most providers insisted on parasitological diagnosis, with 59% HF using microscopy and 85% DO using rapid diagnostic tests. More HF than DO providers could correctly name the drugs for treating uncomplicated malaria in the first trimester (oral quinine, or AL if quinine is unavailable) (90% vs. 58%, p < 0.001), second and third trimesters (artemisinin-based combination therapy) (84% vs. 70%, p = 0.07), and for severe malaria (parenteral artesunate/artemether) (94% vs. 60%, p < 0.001). Among HF providers, those in the MFT pilot had more knowledge of malaria treatment guidelines (67% vs. 49%, p = 0.08) and had received training on treatment of malaria in pregnancy (56% vs. 32%, p = 0.03). Few providers (10% HF and 12% DO) had adequate knowledge of malaria treatment in pregnancy, defined as the correct drug and dose for uncomplicated and severe malaria in all trimesters. CONCLUSIONS: Knowledge of national malaria in pregnancy treatment guidelines among providers in Western Kenya is suboptimal. Robust training on appropriate anti-malarial and dosage is needed, particularly given the recent change in recommendation for artemether-lumefantrine use in the first trimester. Supervision of DO and HF practices is essential for correct treatment of malaria in pregnancy in the context of MFT programmes.

Perceptions and drivers of healthcare provider and drug dispenser practices for the treatment of malaria in pregnancy in the context of multiple first-line therapies in western Kenya: a qualitative study.

BACKGROUND: Emergence of Plasmodium falciparum resistance to artemether-lumefantrine in Africa prompted the pilot introduction of multiple first-line therapies (MFT) against malaria in Kenya, potentially exposing women-of-childbearing-age (WOCBAs) to anti-malarials with unknown safety profiles in the first trimester. This qualitative study explored knowledge and perceptions among healthcare providers providing malaria treatment to WOCBAs and pregnant women. METHODS: In-depth interviews were conducted with purposively selected public and private health facility (HF) and drug outlet (DO) providers within and outside the pilot-MFT area. County health managers were interviewed about their knowledge of the national treatment guidelines. Transcripts were coded by content analysis using the World Health Organization health system building blocks (leadership/governance, financing, health workforce, health information systems, access to medicines, and service delivery). RESULTS: Thirty providers (HF:21, DO:9) and three health managers were interviewed. Eighteen providers were from HFs in the pilot-MFT area; the remaining three and all nine DOs were outside the pilot-MFT area. The analysis revealed that providers had not been trained in malaria case management in the previous twelve months. DO providers were unfamiliar with national treatment guidelines in pregnancy and reported having no pregnancy tests. Health managers were unable to supervise DOs due to resource limitations. Providers from HFs and DOs noted poor sensitivity of malaria rapid diagnostic tests (RDTs) and hesitancy among patients who associated malaria-RDTs with HIV testing. Almost all providers reported anti-malarial stock-outs, with quinine most affected. Patient preference was a major factor in prescribing anti-malarials. Providers in HFs and DOs reported preferentially using artemether-lumefantrine in the first trimester due to the side effects and unavailability of quinine. CONCLUSION: Knowledge of malaria case management in drug outlets and health facilities remains poor. Improved regulation of DO providers is warranted. Optimizing treatment of malaria in pregnancy requires training, availability of malaria commodities, and pregnancy tests.

Point-of-care viral load tests to detect high HIV viral load in people living with HIV/AIDS attending health facilities.

BACKGROUND: Viral load (VL) testing in people living with HIV (PLHIV) helps to monitor antiretroviral therapy (ART). VL is still largely tested using central laboratory-based platforms, which have long test turnaround times and involve sophisticated equipment. VL tests with point-of-care (POC) platforms capable of being used near the patient are potentially easy to use, give quick results, are cost-effective, and could replace central or reference VL testing platforms. OBJECTIVES: To estimate the diagnostic accuracy of POC tests to detect high viral load levels in PLHIV attending healthcare facilities. SEARCH METHODS: We searched eight electronic databases using standard, extensive Cochrane search methods, and did not use any language, document type, or publication status limitations. We also searched the reference lists of included studies and relevant systematic reviews, and consulted an expert in the field from the World Health Organization (WHO) HIV Department for potentially relevant studies. The latest search was 23 November 2020. SELECTION CRITERIA: We included any primary study that compared the results of a VL test with a POC platform to that of a central laboratory-based reference test to detect high viral load in PLHIV on HIV/AIDS care or follow-up. We included all forms of POC tests for VL as defined by study authors, regardless of the healthcare facility in which the test was conducted. We excluded diagnostic case-control studies with healthy controls and studies that did not provide sufficient data to create the 2 × 2 tables to calculate sensitivity and specificity. We did not limit our study inclusion to age, gender, or geographical setting. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles, abstracts, and full texts of the search results to identify eligible articles. They also independently extracted data using a standardized data extraction form and conducted risk of bias assessment using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Using participants as the unit of analysis, we fitted simplified univariable models for sensitivity and specificity separately, employing a random-effects model to estimate the summary sensitivity and specificity at the current and commonly reported World Health Organization (WHO) threshold (≥ 1000 copies/mL). The bivariate models did not converge to give a model estimate. MAIN RESULTS: We identified 18 studies (24 evaluations, 10,034 participants) defining high viral loads at main thresholds ≥ 1000 copies/mL (n = 20), ≥ 5000 copies/mL (n = 1), and ≥ 40 copies/mL (n = 3). All evaluations were done on samples from PLHIV retrieved from routine HIV/AIDS care centres or health facilities. For clinical applicability, we included 14 studies (20 evaluations, 8659 participants) assessing high viral load at the clinical threshold of ≥ 1000 copies/mL in the meta-analyses. Of these, sub-Saharan Africa, Europe, and Asia contributed 16, three, and one evaluation respectively. All included participants were on ART in only nine evaluations; in the other 11 evaluations the proportion of participants on ART was either partial or not clearly stated. Thirteen evaluations included adults only (n = 13), five mixed populations of adults and children, whilst in the remaining two the age of included populations was not clearly stated. The majority of evaluations included commercially available tests (n = 18). Ten evaluations were POC VL tests conducted near the patient in a peripheral or onsite laboratory, whilst the other 10 were evaluations of POC VL tests in a central or reference laboratory setting. The test types evaluated as POC VL tests included Xpert HIV-1 Viral Load test (n = 8), SAMBA HIV-1 Semi-Q Test (n = 9), Alere Q NAT prototype assay for HIV-1 (n = 2) and m-PIMA HIV-1/2 Viral Load test (n = 1). The majority of evaluations (n = 17) used plasma samples, whilst the rest (n = 3) utilized whole blood samples. Pooled sensitivity (95% confidence interval (CI)) of POC VL at a threshold of ≥ 1000 copies/mL was 96.6% (94.8 to 97.8) (20 evaluations, 2522 participants), and pooled specificity (95% CI) was 95.7% (90.8 to 98.0) (20 evaluations, 6137 participants). Median prevalence for high viral load (≥ 1000 copies/mL) (n = 20) was 33.4% (range 6.9% to 88.5%). Limitations The risk of bias was mostly assessed as unclear across the four domains due to incomplete reporting. AUTHORS' CONCLUSIONS: We found POC VL to have high sensitivity and high specificity for the diagnosis of high HIV viral load in PLHIV attending healthcare facilities at a clinical threshold of ≥ 1000 copies/mL.

Rapid molecular tests for tuberculosis and tuberculosis drug resistance: a qualitative evidence synthesis of recipient and provider views.

BACKGROUND: 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. OBJECTIVES: 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. SEARCH METHODS: 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. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: 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. MAIN RESULTS: 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. We identified 18 review findings and grouped them into three overarching categories. Critical aspects users value 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. Challenges reported to realizing those values 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.  Concerns for access and equity 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. We had high confidence in most of our findings. AUTHORS' CONCLUSIONS: 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. 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.

Point-of-care tests detecting HIV nucleic acids for diagnosis of HIV-1 or HIV-2 infection in infants and children aged 18 months or less.

BACKGROUND: The standard method of diagnosing HIV in infants and children less than 18 months is with a nucleic acid amplification test reverse transcriptase polymerase chain reaction test (NAT RT-PCR) detecting viral ribonucleic acid (RNA). Laboratory testing using the RT-PCR platform for HIV infection is limited by poor access, logistical support, and delays in relaying test results and initiating therapy in low-resource settings. The use of rapid diagnostic tests at or near the point-of-care (POC) can increase access to early diagnosis of HIV infection in infants and children less than 18 months of age and timely initiation of antiretroviral therapy (ART). OBJECTIVES: To summarize the diagnostic accuracy of point-of-care nucleic acid-based testing (POC NAT) to detect HIV-1/HIV-2 infection in infants and children aged 18 months or less exposed to HIV infection. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (until 2 February 2021), MEDLINE and Embase (until 1 February 2021), and LILACS and Web of Science (until 2 February 2021) with no language or publication status restriction. We also searched conference websites and clinical trial registries, tracked reference lists of included studies and relevant systematic reviews, and consulted experts for potentially eligible studies. SELECTION CRITERIA: We defined POC tests as rapid diagnostic tests conducted at or near the patient site. We included any primary study that compared the results of a POC NAT to a reference standard of laboratory NAT RT-PCR or total nucleic acid testing to detect the presence or absence of HIV infection denoted by HIV viral nucleic acids in infants and children aged 18 months or less who were exposed to HIV-1/HIV-2 infection. We included cross-sectional, prospective, and retrospective study designs and those that provided sufficient data to create the 2 × 2 table to calculate sensitivity and specificity. We excluded diagnostic case control studies with healthy controls. DATA COLLECTION AND ANALYSIS: We extracted information on study characteristics using a pretested standardized data extraction form. We used the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) tool to assess the risk of bias and applicability concerns of the included studies. Two review authors independently selected and assessed the included studies, resolving any disagreements by consensus. The unit of analysis was the participant. We first conducted preliminary exploratory analyses by plotting estimates of sensitivity and specificity from each study on forest plots and in receiver operating characteristic (ROC) space. For the overall meta-analyses, we pooled estimates of sensitivity and specificity using the bivariate meta-analysis model at a common threshold (presence or absence of infection). MAIN RESULTS: We identified a total of 12 studies (15 evaluations, 15,120 participants). All studies were conducted in sub-Saharan Africa. The ages of included infants and children in the evaluations were as follows: at birth (n = 6), ≤ 12 months (n = 3), ≤ 18 months (n = 5), and ≤ 24 months (n = 1). Ten evaluations were field evaluations of the POC NAT test at the point of care, and five were laboratory evaluations of the POC NAT tests.The POC NAT tests evaluated included Alere q HIV-1/2 Detect qualitative test (recently renamed m-PIMA q HIV-1/2 Detect qualitative test) (n = 6), Xpert HIV-1 qualitative test (n = 6), and SAMBA HIV-1 qualitative test (n = 3). POC NAT pooled sensitivity and specificity (95% confidence interval (CI)) against laboratory reference standard tests were 98.6% (96.1 to 99.5) (15 evaluations, 1728 participants) and 99.9% (99.7 to 99.9) (15 evaluations, 13,392 participants) in infants and children ≤ 18 months. Risk of bias in the included studies was mostly low or unclear due to poor reporting. Five evaluations had some concerns for applicability for the index test, as they were POC tests evaluated in a laboratory setting, but there was no difference detected between settings in sensitivity (-1.3% (95% CI -4.1 to 1.5)); and specificity results were similar. AUTHORS' CONCLUSIONS: For the diagnosis of HIV-1/HIV-2 infection, we found the sensitivity and specificity of POC NAT tests to be high in infants and children aged 18 months or less who were exposed to HIV infection.

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

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.

Routine laboratory testing to determine if a patient has COVID-19.

BACKGROUND: Specific diagnostic tests to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and resulting COVID-19 disease are not always available and take time to obtain results. Routine laboratory markers such as white blood cell count, measures of anticoagulation, C-reactive protein (CRP) and procalcitonin, are used to assess the clinical status of a patient. These laboratory tests may be useful for the triage of people with potential COVID-19 to prioritize them for different levels of treatment, especially in situations where time and resources are limited. OBJECTIVES: To assess the diagnostic accuracy of routine laboratory testing as a triage test to determine if a person has COVID-19. SEARCH METHODS: On 4 May 2020 we undertook electronic searches in the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions. SELECTION CRITERIA: We included both case-control designs and consecutive series of patients that assessed the diagnostic accuracy of routine laboratory testing as a triage test to determine if a person has COVID-19. The reference standard could be reverse transcriptase polymerase chain reaction (RT-PCR) alone; RT-PCR plus clinical expertise or and imaging; repeated RT-PCR several days apart or from different samples; WHO and other case definitions; and any other reference standard used by the study authors. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from each included study. They also assessed the methodological quality of the studies, using QUADAS-2. We used the 'NLMIXED' procedure in SAS 9.4 for the hierarchical summary receiver operating characteristic (HSROC) meta-analyses of tests for which we included four or more studies. To facilitate interpretation of results, for each meta-analysis we estimated summary sensitivity at the points on the SROC curve that corresponded to the median and interquartile range boundaries of specificities in the included studies. MAIN RESULTS: We included 21 studies in this review, including 14,126 COVID-19 patients and 56,585 non-COVID-19 patients in total. Studies evaluated a total of 67 different laboratory tests. Although we were interested in the diagnotic accuracy of routine tests for COVID-19, the included studies used detection of SARS-CoV-2 infection through RT-PCR as reference standard. There was considerable heterogeneity between tests, threshold values and the settings in which they were applied. For some tests a positive result was defined as a decrease compared to normal vaues, for other tests a positive result was defined as an increase, and for some tests both increase and decrease may have indicated test positivity. None of the studies had either low risk of bias on all domains or low concerns for applicability for all domains. Only three of the tests evaluated had a summary sensitivity and specificity over 50%. These were: increase in interleukin-6, increase in C-reactive protein and lymphocyte count decrease. Blood count Eleven studies evaluated a decrease in white blood cell count, with a median specificity of 93% and a summary sensitivity of 25% (95% CI 8.0% to 27%; very low-certainty evidence). The 15 studies that evaluated an increase in white blood cell count had a lower median specificity and a lower corresponding sensitivity. Four studies evaluated a decrease in neutrophil count. Their median specificity was 93%, corresponding to a summary sensitivity of 10% (95% CI 1.0% to 56%; low-certainty evidence). The 11 studies that evaluated an increase in neutrophil count had a lower median specificity and a lower corresponding sensitivity. The summary sensitivity of an increase in neutrophil percentage (4 studies) was 59% (95% CI 1.0% to 100%) at median specificity (38%; very low-certainty evidence). The summary sensitivity of an increase in monocyte count (4 studies) was 13% (95% CI 6.0% to 26%) at median specificity (73%; very low-certainty evidence). The summary sensitivity of a decrease in lymphocyte count (13 studies) was 64% (95% CI 28% to 89%) at median specificity (53%; low-certainty evidence). Four studies that evaluated a decrease in lymphocyte percentage showed a lower median specificity and lower corresponding sensitivity. The summary sensitivity of a decrease in platelets (4 studies) was 19% (95% CI 10% to 32%) at median specificity (88%; low-certainty evidence). Liver function tests The summary sensitivity of an increase in alanine aminotransferase (9 studies) was 12% (95% CI 3% to 34%) at median specificity (92%; low-certainty evidence). The summary sensitivity of an increase in aspartate aminotransferase (7 studies) was 29% (95% CI 17% to 45%) at median specificity (81%) (low-certainty evidence). The summary sensitivity of a decrease in albumin (4 studies) was 21% (95% CI 3% to 67%) at median specificity (66%; low-certainty evidence). The summary sensitivity of an increase in total bilirubin (4 studies) was 12% (95% CI 3.0% to 34%) at median specificity (92%; very low-certainty evidence). Markers of inflammation The summary sensitivity of an increase in CRP (14 studies) was 66% (95% CI 55% to 75%) at median specificity (44%; very low-certainty evidence). The summary sensitivity of an increase in procalcitonin (6 studies) was 3% (95% CI 1% to 19%) at median specificity (86%; very low-certainty evidence). The summary sensitivity of an increase in IL-6 (four studies) was 73% (95% CI 36% to 93%) at median specificity (58%) (very low-certainty evidence). Other biomarkers The summary sensitivity of an increase in creatine kinase (5 studies) was 11% (95% CI 6% to 19%) at median specificity (94%) (low-certainty evidence). The summary sensitivity of an increase in serum creatinine (four studies) was 7% (95% CI 1% to 37%) at median specificity (91%; low-certainty evidence). The summary sensitivity of an increase in lactate dehydrogenase (4 studies) was 25% (95% CI 15% to 38%) at median specificity (72%; very low-certainty evidence). AUTHORS' CONCLUSIONS: Although these tests give an indication about the general health status of patients and some tests may be specific indicators for inflammatory processes, none of the tests we investigated are useful for accurately ruling in or ruling out COVID-19 on their own. Studies were done in specific hospitalized populations, and future studies should consider non-hospital settings to evaluate how these tests would perform in people with milder symptoms.

Abdominal ultrasound for diagnosing abdominal tuberculosis or disseminated tuberculosis with abdominal involvement in HIV-positive individuals.

BACKGROUND: Accurate diagnosis of tuberculosis in people living with HIV is difficult. HIV-positive individuals have higher rates of extrapulmonary tuberculosis and the diagnosis of tuberculosis is often limited to imaging results. Ultrasound is such an imaging test that is widely used as a diagnostic tool (including point-of-care) in people suspected of having abdominal tuberculosis or disseminated tuberculosis with abdominal involvement. OBJECTIVES: To determine the diagnostic accuracy of abdominal ultrasound for detecting abdominal tuberculosis or disseminated tuberculosis with abdominal involvement in HIV-positive individuals.To investigate potential sources of heterogeneity in test accuracy, including clinical setting, ultrasound training level, and type of reference standard. SEARCH METHODS: We searched for publications in any language up to 4 April 2019 in the following databases: MEDLINE, Embase, BIOSIS, Science Citation Index Expanded (SCI-EXPANDED), Social Sciences Citation Index (SSCI), Conference Proceedings Citation Index- Science (CPCI-S), and also ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform to identify ongoing trials. SELECTION CRITERIA: We included cross-sectional, cohort, and diagnostic case-control studies (prospective and retrospective) that compared the result of the index test (abdominal ultrasound) with one of the reference standards. We only included studies that allowed for extraction of numbers of true positives (TPs), true negatives (TNs), false positives (FPs), and false negatives (FNs). Participants were HIV-positive individuals aged 15 years and older. A higher-quality reference standard was the bacteriological confirmation of Mycobacterium tuberculosis from any clinical specimen, and a lower-quality reference standard was a clinical diagnosis of tuberculosis without microbiological confirmation. We excluded genitourinary tuberculosis. DATA COLLECTION AND ANALYSIS: For each study, two review authors independently extracted data using a standardized form. We assessed the quality of studies using a tailored Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. We used the bivariate model to estimate pooled sensitivity and specificity. When studies were few we simplified the bivariate model to separate univariate random-effects logistic regression models for sensitivity and specificity. We explored the influence of the type of reference standard on the accuracy estimates by conducting separate analyses for each type of reference standard. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 11 studies. The risks of bias and concern about applicability were often high or unclear in all domains. We included six studies in the main analyses of any abnormal finding on abdominal ultrasound; five studies reported only individual lesions.The six studies of any abnormal finding were cross-sectional or cohort studies. Five of these (83%) were conducted in low- or middle-income countries, and one in a high-income country. The proportion of participants on antiretroviral therapy was none (1 study), fewer then 50% (4 studies), more than 50% (1 study), and not reported (5 studies). The first main analysis, studies using a higher-quality reference standard (bacteriological confirmation), had a pooled sensitivity of 63% (95% confidence interval (CI) 43% to 79%; 5 studies, 368 participants; very low-certainty evidence) and a pooled specificity of 68% (95% CI 42% to 87%; 5 studies, 511 participants; very low-certainty evidence). If the results were to be applied to a hypothetical cohort of 1000 people with HIV where 200 (20%) have tuberculosis then:- About 382 individuals would have an ultrasound result indicating tuberculosis; of these, 256 (67%) would be incorrectly classified as having tuberculosis (false positives).- Of the 618 individuals with a result indicating that tuberculosis is not present, 74 (12%) would be incorrectly classified as not having tuberculosis (false negatives).In the second main analysis involving studies using a lower-quality reference standard (clinical diagnosis), the pooled sensitivity was 68% (95% CI 45% to 85%; 4 studies, 195 participants; very low-certainty evidence) and the pooled specificity was 73% (95% CI 41% to 91%; 4 studies, 202 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: In HIV-positive individuals thought to have abdominal tuberculosis or disseminated tuberculosis with abdominal involvement, abdominal ultrasound appears to have 63% sensitivity and 68% specificity when tuberculosis was bacteriologically confirmed. These estimates are based on data that is limited, varied, and low-certainty.The low sensitivity of abdominal ultrasound means clinicians should not use a negative test result to rule out the disease, but rather consider the result in combination with other diagnostic strategies (including clinical signs, chest x-ray, lateral flow urine lipoarabinomannan assay (LF-LAM), and Xpert MTB/RIF). Research incorporating the test into tuberculosis diagnostic algorithms will help in delineating more precisely its value in diagnosing abdominal tuberculosis or disseminated tuberculosis with abdominal involvement.

Xpert MTB/RIF and Xpert MTB/RIF Ultra for pulmonary tuberculosis and rifampicin resistance in adults.

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 detectionOf 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 detectionXpert 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.

Investigation of household contacts of pulmonary tuberculosis patients increases case detection in Mwanza City, Tanzania.

BACKGROUND: Tuberculosis (TB) contact tracing is a key strategy for containing TB and provides addition to the passive case finding approach. However, this practice has not been implemented in Tanzania, where there is unacceptably high treatment gap of 62.1% between cases estimated and cases detected. Therefore calls for more aggressive case finding for TB to close this gap. We aimed to determine the magnitude and predictors of bacteriologically-confirmed pulmonary TB among household contacts of bacteriologically-confirmed pulmonary TB index cases in the city of Mwanza, Tanzania. METHODS: This study was carried out from August to December 2016 in Mwanza city at the TB outpatient clinics of Tertiary Hospital of the Bugando Medical Centre, Sekou-Toure Regional Hospital, and Nyamagana District Hospital. Bacteriologically-confirmed TB index cases diagnosed between May and July 2016 were identified from the laboratory registers book. Contacts were traced by home visits by study TB nurses, and data were collected using a standardized TB screening questionnaire. To detect the bacterioriologically-confirmed pulmonary TB, two sputum samples per household contact were collected under supervision for all household contacts following standard operating procedures. Samples were transported to the Bugando Medical Centre TB laboratory for investigation for TB using fluorescent smear microscopy, GeneXpert MTB/RIF and Löwenstein-Jensen (LJ) culture. Logistic regression was used to determine predictors of bacteriologically-confirmed pulmonary TB among household contacts. RESULTS: During the study period, 456 household contacts from 93 TB index cases were identified. Among these 456 household contacts, 13 (2.9%) were GeneXpert MTB/RIF positive, 18 (3.9%) were MTB-culture positive and four (0.9%) were AFB-smear positive. Overall, 29 (6.4%) of contacts had bacteriologically-confirmed pulmonary TB. Predictors of bacteriologically-confirmed pulmonary TB among household contacts were7being married (Odds ratio [OR], 3.3; 95% confidence interval [CI], 1.4-8.0; p = 0.012) and consuming less than three meals a day (OR, 3.7; 95% CI, 1.6-8.7; p = 0.009). CONCLUSIONS: Our data suggest that in Mwanza, Tanzania, seven in 100 contacts living in the same house with a TB patient develop bacteriologically-confirmed pulmonary TB. These results therefore underscore the need to implement routine TB contact tracing to control tuberculosis in high TB burden countries such as Tanzania.

Assessing variability in results in systematic reviews of diagnostic studies.

BACKGROUND: To describe approaches used in systematic reviews of diagnostic test accuracy studies for assessing variability in estimates of accuracy between studies and to provide guidance in this area. METHODS: Meta-analyses of diagnostic test accuracy studies published between May and September 2012 were systematically identified. Information on how the variability in results was investigated was extracted. RESULTS: Of the 53 meta-analyses included in the review, most (n=48; 91%) presented variability in diagnostic accuracy estimates visually either through forest plots or ROC plots and the majority (n=40; 75%) presented a test or statistical measure for the variability. Twenty-eight reviews (53%) tested for variability beyond chance using Cochran's Q test and 31 (58%) reviews quantified it with I(2). 7 reviews (13%) presented between-study variance estimates (τ(2)) from random effects models and 3 of these presented a prediction interval or ellipse to facilitate interpretation. Half of all the meta-analyses specified what was considered a significant amount of variability (n=24; 49%). CONCLUSIONS: Approaches to assessing variability in estimates of accuracy varied widely between diagnostic test accuracy reviews and there is room for improvement. We provide initial guidance, complemented by an overview of the currently available approaches.

Guide to clinical practice guidelines: the current state of play.

INTRODUCTION: Extensive research has been undertaken over the last 30 years on the methods underpinning clinical practice guidelines (CPGs), including their development, updating, reporting, tailoring for specific purposes, implementation and evaluation. This has resulted in an increasing number of terms, tools and acronyms. Over time, CPGs have shifted from opinion-based to evidence-informed, including increasingly sophisticated methodologies and implementation strategies, and thus keeping abreast of evolution in this field of research can be challenging. METHODS: This article collates findings from an extensive document search, to provide a guide describing standards, methods and systems reported in the current CPG methodology and implementation literature. This guide is targeted at those working in health care quality and safety and responsible for either commissioning, researching or delivering health care. It is presented in a way that can be updated as the field expands. CONCLUSION: CPG development and implementation have attracted the most international interest and activity, whilst CPG updating, adopting (with or without contextualization), adapting and impact evaluation are less well addressed.

Circulating antigen tests and urine reagent strips for diagnosis of active schistosomiasis in endemic areas.

BACKGROUND: Point-of-care (POC) tests for diagnosing schistosomiasis include tests based on circulating antigen detection and urine reagent strip tests. If they had sufficient diagnostic accuracy they could replace conventional microscopy as they provide a quicker answer and are easier to use. OBJECTIVES: To summarise the diagnostic accuracy of: a) urine reagent strip tests in detecting active Schistosoma haematobium infection, with microscopy as the reference standard; and b) circulating antigen tests for detecting active Schistosoma infection in geographical regions endemic for Schistosoma mansoni or S. haematobium or both, with microscopy as the reference standard. SEARCH METHODS: We searched the electronic databases MEDLINE, EMBASE, BIOSIS, MEDION, and Health Technology Assessment (HTA) without language restriction up to 30 June 2014. SELECTION CRITERIA: We included studies that used microscopy as the reference standard: for S. haematobium, microscopy of urine prepared by filtration, centrifugation, or sedimentation methods; and for S. mansoni, microscopy of stool by Kato-Katz thick smear. We included studies on participants residing in endemic areas only. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, assessed quality of the data using QUADAS-2, and performed meta-analysis where appropriate. Using the variability of test thresholds, we used the hierarchical summary receiver operating characteristic (HSROC) model for all eligible tests (except the circulating cathodic antigen (CCA) POC for S. mansoni, where the bivariate random-effects model was more appropriate). We investigated heterogeneity, and carried out indirect comparisons where data were sufficient. Results for sensitivity and specificity are presented as percentages with 95% confidence intervals (CI). MAIN RESULTS: We included 90 studies; 88 from field settings in Africa. The median S. haematobium infection prevalence was 41% (range 1% to 89%) and 36% for S. mansoni (range 8% to 95%). Study design and conduct were poorly reported against current standards. Tests for S. haematobium Urine reagent test strips versus microscopyCompared to microscopy, the detection of microhaematuria on test strips had the highest sensitivity and specificity (sensitivity 75%, 95% CI 71% to 79%; specificity 87%, 95% CI 84% to 90%; 74 studies, 102,447 participants). For proteinuria, sensitivity was 61% and specificity was 82% (82,113 participants); and for leukocyturia, sensitivity was 58% and specificity 61% (1532 participants). However, the difference in overall test accuracy between the urine reagent strips for microhaematuria and proteinuria was not found to be different when we compared separate populations (P = 0.25), or when direct comparisons within the same individuals were performed (paired studies; P = 0.21).When tests were evaluated against the higher quality reference standard (when multiple samples were analysed), sensitivity was marginally lower for microhaematuria (71% vs 75%) and for proteinuria (49% vs 61%). The specificity of these tests was comparable. Antigen assayCompared to microscopy, the CCA test showed considerable heterogeneity; meta-analytic sensitivity estimate was 39%, 95% CI 6% to 73%; specificity 78%, 95% CI 55% to 100% (four studies, 901 participants). Tests for S. mansoni Compared to microscopy, the CCA test meta-analytic estimates for detecting S. mansoni at a single threshold of trace positive were: sensitivity 89% (95% CI 86% to 92%); and specificity 55% (95% CI 46% to 65%; 15 studies, 6091 participants) Against a higher quality reference standard, the sensitivity results were comparable (89% vs 88%) but specificity was higher (66% vs 55%). For the CAA test, sensitivity ranged from 47% to 94%, and specificity from 8% to 100% (4 studies, 1583 participants). AUTHORS' CONCLUSIONS: Among the evaluated tests for S. haematobium infection, microhaematuria correctly detected the largest proportions of infections and non-infections identified by microscopy.The CCA POC test for S. mansoni detects a very large proportion of infections identified by microscopy, but it misclassifies a large proportion of microscopy negatives as positives in endemic areas with a moderate to high prevalence of infection, possibly because the test is potentially more sensitive than microscopy.

Publication and reporting of test accuracy studies registered in ClinicalTrials.gov.

BACKGROUND: Failure to publish and selective reporting are recognized problems in the biomedical literature, but their extent in the field of diagnostic testing is unknown. We aimed to identify nonpublication and discrepancies between registered records and publications among registered test accuracy studies. METHODS: We identified studies evaluating a test's accuracy against a reference standard that were registered in ClinicalTrials.gov between January 2006 and December 2010. We included studies if their completion date was set before October 2011, allowing at least 18 months until publication. We searched PubMed, EMBASE, and Web of Science and contacted investigators for publications. RESULTS: We included 418 studies, of which 224 (54%) had been published by mid-2013. Among studies that had been completed at least 30 months before our analyses, 45% were published within 30 months after their completion. Publication rates were high in studies registered after study completion (76%) and low for studies with an unknown (rather than completed) study status (36%). After we excluded these 2 categories, study duration was the only characteristic significantly associated with publication, with lower rates in studies lasting up to 1 year (39%) compared to studies of 13-24 months (62%) or longer (67%) (P = 0.01). In the 153 published studies that had been registered before completion, 49 (32%) showed discrepancies between the registry and publication regarding inclusion criteria (n = 19), test/threshold (n = 9), and outcomes (n = 32). CONCLUSIONS: Failure to publish and selective reporting are prevalent in test accuracy studies. Their registration should be further promoted among researchers and journal editors.

Investigation of publication bias in meta-analyses of diagnostic test accuracy: a meta-epidemiological study.

BACKGROUND: The validity of a meta-analysis can be understood better in light of the possible impact of publication bias. The majority of the methods to investigate publication bias in terms of small study-effects are developed for meta-analyses of intervention studies, leaving authors of diagnostic test accuracy (DTA) systematic reviews with limited guidance. The aim of this study was to evaluate if and how publication bias was assessed in meta-analyses of DTA, and to compare the results of various statistical methods used to assess publication bias. METHODS: A systematic search was initiated to identify DTA reviews with a meta-analysis published between September 2011 and January 2012. We extracted all information about publication bias from the reviews and the two-by-two tables. Existing statistical methods for the detection of publication bias were applied on data from the included studies. RESULTS: Out of 1,335 references, 114 reviews could be included. Publication bias was explicitly mentioned in 75 reviews (65.8%) and 47 of these had performed statistical methods to investigate publication bias in terms of small study-effects: 6 by drawing funnel plots, 16 by statistical testing and 25 by applying both methods. The applied tests were Egger's test (n = 18), Deeks' test (n = 12), Begg's test (n = 5), both the Egger and Begg tests (n = 4), and other tests (n = 2). Our own comparison of the results of Begg's, Egger's and Deeks' test for 92 meta-analyses indicated that up to 34% of the results did not correspond with one another. CONCLUSIONS: The majority of DTA review authors mention or investigate publication bias. They mainly use suboptimal methods like the Begg and Egger tests that are not developed for DTA meta-analyses. Our comparison of the Begg, Egger and Deeks tests indicated that these tests do give different results and thus are not interchangeable. Deeks' test is recommended for DTA meta-analyses and should be preferred.

Incorporating quality assessments of primary studies in the conclusions of diagnostic accuracy reviews: a cross-sectional study.

BACKGROUND: Drawing conclusions from systematic reviews of test accuracy studies without considering the methodological quality (risk of bias) of included studies may lead to unwarranted optimism about the value of the test(s) under study. We sought to identify to what extent the results of quality assessment of included studies are incorporated in the conclusions of diagnostic accuracy reviews. METHODS: We searched MEDLINE and EMBASE for test accuracy reviews published between May and September 2012. We examined the abstracts and main texts of these reviews to see whether and how the results of quality assessment were linked to the accuracy estimates when drawing conclusions. RESULTS: We included 65 reviews of which 53 contained a meta-analysis. Sixty articles (92%) had formally assessed the methodological quality of included studies, most often using the original QUADAS tool (n = 44, 68%). Quality assessment was mentioned in 28 abstracts (43%); with a majority (n = 21) mentioning it in the methods section. In only 5 abstracts (8%) were results of quality assessment incorporated in the conclusions. Thirteen reviews (20%) presented results of quality assessment in the main text only, without further discussion. Forty-seven reviews (72%) discussed results of quality assessment; the most frequent form was as limitations in assessing quality (n = 28). Only 6 reviews (9%) further linked the results of quality assessment to their conclusions, 3 of which did not conduct a meta-analysis due to limitations in the quality of included studies. In the reviews with a meta-analysis, 19 (36%) incorporated quality in the analysis. Eight reported significant effects of quality on the pooled estimates; in none of them these effects were factored in the conclusions. CONCLUSION: While almost all recent diagnostic accuracy reviews evaluate the quality of included studies, very few consider results of quality assessment when drawing conclusions. The practice of reporting systematic reviews of test accuracy should improve if readers not only want to be informed about the limitations in the available evidence, but also on the associated implications for the performance of the evaluated tests.

Health Economics in a World of Uneconomic Growth.

Multiple, accelerating and interacting ecological crises are increasingly understood as constituting a major threat to human health and well-being. Unconstrained economic growth is strongly implicated in these growing crises, and it has been argued that this growth has now become "uneconomic growth", which is a situation where the size of the economy is still expanding, but this expansion is causing more harm than benefit. This article summarises the multiple pathways by which uneconomic growth can be expected to harm human health. It describes how health care systems-especially through overuse, low value and poor quality care-can themselves drive uneconomic growth. Health economists need to understand not only the consequences of environmental impacts on health care, but also the significance of uneconomic growth, and pay closer attention to the growing body of work by heterodox economists, especially in the fields of ecological and feminist economics. This will involve paying closer heed to the existence and consequences of diminishing marginal returns to health care consumption at high levels; the central importance of inequalities and injustice in health; and the need to remedy health economists' currently limited ability to deal effectively with low value care, overdiagnosis and overtreatment.

A synthesis of qualitative evidence of barriers and facilitators in implementing guidelines for TB testing in healthcare settings.

INTRODUCTION: The suboptimal case notification rates for tuberculosis (TB) globally could partly be due to the poor implementation of TB testing guidelines or policies. We identified, appraised and synthesized qualitative evidence exploring the barriers and facilitators to implementing TB testing guidelines. METHODS: We searched electronic databases and grey literature and included studies based on predefined inclusion criteria (PROSPERO registered protocol CRD42016039790) until 9th February 2023. We used the Critical Appraisal Skills Programme tool to assess the methodological quality of the included studies. Two authors reviewed the search output, extracted data and assessed methodological quality independently, resolving disagreements by consensus. We used the Supporting the Use of Research Evidence framework to identify themes and analyse and synthesize our data. We applied the Confidence in the Evidence from Reviews of Qualitative Research approach to assess the confidence of the review findings. RESULTS: Our search output was 6976 articles, from which we included 25 qualitative studies, mostly from low- and middle-income countries (n=19) and about national guidelines (n=22). All studies were from healthcare settings. Most barriers revolved around health system constraints involving the guidelines (low trust and adherence, ambiguous and poorly developed or adapted guidelines) and poorly resourced and organized health facilities to enable the implementation of the guidelines. Individual-level barriers included low trust and low awareness among recipients and providers of care. Donor dependence was the main socio-political constraint. These barriers were similar across all income settings except poorly resourced health facilities and social and political constraints which were only reported in low- and middle-income settings. The reported facilitators were improved trust and knowledge of guidelines, national leadership support and availability of training tools and opportunities for guidelines across all income settings. We had high confidence in most of the review findings. CONCLUSION: Limited guideline knowledge, trust and adherence related to poorly developed and disseminated guidelines in all income settings and poorly resourced facilities in low- and middle-income countries hinder the implementation of TB testing guidelines. This could be improved by better guideline training and adaptation and resourcing of health facilities. TRIAL REGISTRATION: The protocol of this review was registered with the International Prospective Register of Systematic Reviews (PROSPERO), registration number CRD42016039790, and published in a peer-reviewed journal.