Subclinical tuberculosis: a meta-analysis of prevalence and scoping review of definitions, prevalence and clinical characteristics.

BACKGROUND: This scoping review aimed to characterise definitions used to describe subclinical tuberculosis (TB), estimate the prevalence in different populations and describe the clinical characteristics and treatment outcomes in the scientific literature. METHODS: A systematic literature search was conducted using PubMed. We included studies published in English between January 1990 and August 2022 that defined "subclinical" or "asymptomatic" pulmonary TB disease, regardless of age, HIV status and comorbidities. We estimated the weighted pooled proportions of subclinical TB using a random-effects model by World Health Organization reported TB incidence, populations and settings. We also pooled the proportion of subclinical TB according to definitions described in published prevalence surveys. RESULTS: We identified 29 prevalence surveys and 71 other studies. Prevalence survey data (2002-2022) using "absence of cough of any duration" criteria reported higher subclinical TB prevalence than those using the stricter "completely asymptomatic" threshold. Prevalence estimates overlap in studies using other symptoms and cough duration. Subclinical TB in studies was commonly defined as asymptomatic TB disease. Higher prevalence was reported in high TB burden areas, community settings and immunocompetent populations. People with subclinical TB showed less extensive radiographic abnormalities, higher treatment success rates and lower mortality, although studies were few. CONCLUSION: A substantial proportion of TB is subclinical. However, prevalence estimates were highly heterogeneous between settings. Most published studies incompletely characterised the phenotype of people with subclinical TB. Standardised definitions and diagnostic criteria are needed to characterise this phenotype. Further research is required to enhance case finding, screening, diagnostics and treatment options for subclinical TB.

Tuberculosis treatment monitoring tests during routine practice: study design guidance.

SCOPE: The current tools for tuberculosis (TB) treatment monitoring, smear microscopy and culture, cannot accurately predict poor treatment outcomes. Research into new TB treatment monitoring tools (TMTs) is growing, but data are unreliable. In this article, we aim to provide guidance for studies investigating and evaluating TB TMT for use during routine clinical care. Here, a TB TMT would guide treatment during the course of therapy, rather than testing for a cure at the regimen's end. This article does not cover the use of TB TMTs as surrogate endpoints in the clinical trial context. METHODS: Guidelines were initially informed by experiences during a systematic review of TB TMTs. Subsequently, a small content expert group was consulted for feedback on initial recommendations. After revision, feedback from substantive experts across sectors was sought. QUESTIONS ADDRESSED BY THE GUIDELINE AND RECOMMENDATIONS: The proposed considerations and recommendations for studies evaluating TB TMTs for use during the treatment in routine clinical care fall into eight domains. We provide specific recommendations regarding study design and recruitment, outcome definitions, reference standards, participant follow-up, clinical setting, study population, treatment regimen reporting, and index tests and data presentation. Overall, TB TMTs should be evaluated in a manner similar to diagnostic tests, but TB TMT accuracy must be assessed at multiple timepoints throughout the treatment course, and TB TMTs should be evaluated in study populations who have already received a diagnosis of TB. Study design and outcome definitions must be aligned with the developmental phase of the TB TMT under evaluation. There is no reference standard for TB treatment response, so different reference standards and comparator tests have been proposed, the selection of which will vary depending on the developmental phase of the TMT under assessment. The use of comparator tests can assist in generating evidence. Clarity is required when reporting of timepoints, TMT read-outs, and analysis results. Implementing these recommendations will lead to higher quality TB TMT studies that will allow data to be meaningfully compared, thereby facilitating the development of novel tools to guide individual TB therapy and improve treatment outcomes.

Target product profiles: tests for tuberculosis treatment monitoring and optimization.

The World Health Organization has developed target product profiles containing minimum and optimum targets for key characteristics for tests for tuberculosis treatment monitoring and optimization. Tuberculosis treatment optimization refers to initiating or switching to an effective tuberculosis treatment regimen that results in a high likelihood of a good treatment outcome. The target product profiles also cover tests of cure conducted at the end of treatment. The development of the target product profiles was informed by a stakeholder survey, a cost-effectiveness analysis and a patient-care pathway analysis. Additional feedback from stakeholders was obtained by means of a Delphi-like process, a technical consultation and a call for public comment on a draft document. A scientific development group agreed on the final targets in a consensus meeting. For characteristics rated of highest importance, the document lists: (i) high diagnostic accuracy (sensitivity and specificity); (ii) time to result of optimally ≤ 2 hours and no more than 1 day; (iii) required sample type to be minimally invasive, easily obtainable, such as urine, breath, or capillary blood, or a respiratory sample that goes beyond sputum; (iv) ideally the test could be placed at a peripheral-level health facility without a laboratory; and (v) the test should be affordable to low- and middle-income countries, and allow wide and equitable access and scale-up. Use of these target product profiles should facilitate the development of new tuberculosis treatment monitoring and optimization tests that are accurate and accessible for all people being treated for tuberculosis.

L'Organisation mondiale de la santé a élaboré des profils de produits cibles contenant des cibles minimales et optimales pour les caractéristiques principales des essais destinés au suivi et à l'optimisation du traitement de la tuberculose. L'optimisation du traitement de la tuberculose fait référence à l'instauration d'un régime de traitement efficace de la tuberculose ou à l'adoption d'un tel régime, avec une probabilité élevée d'obtenir de bons résultats thérapeutiques. Les profils de produits cibles couvrent également les essais de guérison effectués à l'issue du traitement. Les profils de produits cibles ont été élaborés sur la base d'un sondage auprès des parties prenantes, d'une analyse coût-efficacité et d'une analyse du parcours de soins du patient. Des retours supplémentaires des parties prenantes ont été obtenus au moyen d'un processus créé selon la méthode Delphi, d'une consultation technique et d'un appel à commentaires publics sur un projet de document. Un groupe d'élaboration scientifique s'est mis d'accord sur les objectifs finaux lors d'une réunion de concertation. En ce qui concerne les caractéristiques jugées les plus importantes, le document énumère ce qui suit: (i) une grande précision diagnostique (sensibilité et spécificité); (ii) un délai idéal d'obtention des résultats ≤ 2 heures et au maximum de 1 jour; (iii) le type d'échantillon requis doit être peu invasif et facile à obtenir, comme l'urine, l'haleine ou le sang capillaire, ou bien un échantillon respiratoire au-delà des expectorations; (iv) idéalement, l'essai pourrait avoir lieu dans un établissement de santé périphérique sans laboratoire ; et (v) l'essai devrait être abordable pour les pays à revenu faible et intermédiaire et permettre un accès large et équitable ainsi qu'une mise à l'échelle. L'utilisation de ces profils de produits cibles devrait faciliter la mise au point de nouveaux essais de surveillance et d'optimisation du traitement de la tuberculose qui soient précis et accessibles à toutes les personnes suivant un traitement pour la tuberculose.

La Organización Mundial de la Salud ha elaborado perfiles de productos objetivo que contienen objetivos mínimos y óptimos para las características principales de las pruebas de seguimiento y optimización del tratamiento de la tuberculosis. La optimización del tratamiento de la tuberculosis consiste en iniciar o cambiar a un régimen eficaz de tratamiento de la tuberculosis que ofrezca una alta probabilidad de un buen resultado terapéutico. Los perfiles de productos objetivo también abarcan las pruebas de curación realizadas al final del tratamiento. La elaboración de los perfiles de los productos objetivo se basó en una encuesta a las partes interesadas, un análisis de rentabilidad y un análisis de la vía de atención al paciente. Se obtuvo información adicional de las partes interesadas mediante un proceso tipo Delphi, una consulta técnica y una convocatoria de comentarios públicos sobre un borrador del documento. Un grupo de desarrollo científico acordó los objetivos finales en una reunión de consenso. Para las características clasificadas de mayor importancia, el documento enumera: (i) alta precisión diagnóstica (sensibilidad y especificidad); (ii) tiempo hasta el resultado de óptimamente ≤ 2 horas y no más de 1 día; (iii) el tipo de muestra requerida debe ser mínimamente invasiva, fácil de obtener, como orina, aliento o sangre capilar, o una muestra respiratoria que vaya más allá del esputo; (iv) idealmente la prueba podría realizarse en un centro sanitario periférico sin laboratorio; y (v) la prueba debe ser asequible para los países de ingresos bajos y medios y permitir un acceso amplio y equitativo y su expansión. El uso de estos perfiles de producto objetivo debería facilitar el desarrollo de pruebas nuevas de seguimiento y optimización del tratamiento de la tuberculosis que sean precisas y accesibles para todas las personas que reciben tratamiento antituberculoso.

Accuracy of package inserts of SARS-CoV-2 rapid antigen tests: a secondary analysis of manufacturer versus systematic review data.

BACKGROUND: Rapid antigen tests (RATs) were crucial during the COVID-19 pandemic. Information provided by the test manufacturer in product package inserts, also known as instructions for use (IFUs), is often the only data available to clinicians, public health professionals, and individuals on the diagnostic accuracy of these tests. We aimed to assess whether manufacturer IFU accuracy data aligned with evidence from independent research. METHODS: We searched company websites for package inserts for RATs that were included in the July 2022 update of the Cochrane meta-analysis of SARS-CoV-2 RATs, which served as a benchmark for research evidence. We fitted bivariate hierarchical models to obtain absolute differences in sensitivity and specificity between IFU and Cochrane Review estimates for each test, as well as overall combined differences. FINDINGS: We found 22 (100%) of 22 IFUs of the RATs included in the Cochrane Review. IFUs for 12 (55%) of 22 RATs reported statistically significantly higher sensitivity estimates than the Cochrane Review, and none reported lower estimates. The mean difference between IFU and Cochrane Review sensitivity estimates across tests was 12·0% (95% CI 7·5-16·6). IFUs in three (14%) of 22 diagnostic tests had significantly higher specificity estimates than the Cochrane Review and two (9%) of 22 had lower estimates. The mean difference between IFU and Cochrane Review specificity estimates across tests was 0·3% (95% CI 0·1-0·5). If 100 people with SARS-CoV-2 infection were tested with each of the tests in this study, on average 12 fewer people would be correctly diagnosed than is suggested by the package inserts. INTERPRETATION: Health professionals and the public should be aware that package inserts for SARS-CoV-2 RATs might provide an overly optimistic picture of the sensitivity of a test. Regulatory bodies should strengthen their requirements for the reporting of diagnostic accuracy data in package inserts and policy makers should demand independent validation data for decision making. FUNDING: None.

Integrating tuberculosis and COVID-19 molecular testing in Lima, Peru: a cross-sectional, diagnostic accuracy study.

BACKGROUND: Integrated molecular testing could be an opportunity to detect and provide care for both tuberculosis and COVID-19. Many high tuberculosis burden countries, such as Peru, have existing GeneXpert systems for tuberculosis testing with GeneXpert Xpert MTB/RIF Ultra (Xpert Ultra), and a GeneXpert SARS-CoV-2 assay, GeneXpert Xpert Xpress SARS-CoV-2 (Xpert Xpress), is also available. We aimed to assess the feasibility of integrating tuberculosis and COVID-19 testing using one sputum specimen with Xpert Ultra and Xpert Xpress in Lima, Peru. METHODS: In this cross-sectional, diagnostic accuracy study, we recruited adults presenting with clinical symptoms or suggestive history of tuberculosis or COVID-19, or both. Participants were recruited from a total of 35 primary health facilities in Lima, Peru. Participants provided one nasopharyngeal swab and one sputum sample. For COVID-19, we tested nasopharyngeal swabs and sputum using Xpert Xpress; for tuberculosis, we tested sputum using culture and Xpert Ultra. We compared diagnostic accuracy of sputum testing using Xpert Xpress with nasopharyngeal swab testing using Xpert Xpress. Individuals with positive Xpert Xpress nasopharyngeal swab results were considered COVID-19 positive, and a positive culture indicated tuberculosis. To assess testing integration, the proportion of cases identified in sputum by Xpert Xpress was compared with Xpert Xpress on nasopharyngeal swabs, and sputum by Xpert Ultra was compared with culture. FINDINGS: Between Jan 11, 2021, and April 26, 2022, we recruited 600 participants (312 [52%] women and 288 [48%] men). In-study prevalence of tuberculosis was 13% (80 participants, 95% CI 11-16) and of SARS-CoV-2 was 35% (212 participants, 32-39). Among tuberculosis cases, 13 (2·2%, 1·2-3·7) participants were concurrently positive for SARS-CoV-2. Regarding the diagnostic yield of integrated testing, Xpert Ultra detected 96% (89-99) of culture-confirmed tuberculosis cases (n=77), and Xpert Xpress-sputum detected 67% (60-73) of COVID-19 cases (n=134). All five study staff reported that integrated molecular testing was easy and acceptable. INTERPRETATION: The diagnostic yield of Xpert Xpress on sputum was moderate, but integrated testing for tuberculosis and COVID-19 with GeneXpert was feasible. However, systematic testing for both diseases might not be the ideal approach for everyone presenting with presumptive tuberculosis or COVID-19, as concurrent positive cases were rare during the study period. Further research might help to identify when integrated testing is most worthwhile and its optimal implementation. FUNDING: Canadian Institutes of Health Research and International Development Research Centre. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Updating the WHO target product profile for next-generation Mycobacterium tuberculosis drug susceptibility testing at peripheral centres.

There were approximately 10 million tuberculosis (TB) cases in 2020, of which 500,000 were drug-resistant. Only one third of drug-resistant TB cases were diagnosed and enrolled on appropriate treatment, an issue partly driven by a lack of rapid, accurate drug-susceptibility testing (DST) tools deployable in peripheral settings. In 2014, World Health Organization (WHO) published target product profiles (TPPs) which detailed minimal and optimal criteria to address high-priority TB diagnostic needs, including DST. Since then, the TB community's needs have evolved; new treatment regimens, changes in TB definitions, further emergence of drug resistance, technological advances, and changing end-users requirements have necessitated an update. The DST TPP's revision was therefore undertaken by WHO with the Stop TB Partnership New Diagnostics Working Group. We describe the process of updating the TPP for next-generation TB DST for use at peripheral centres, highlight key updates, and discuss guidance regarding technical and operational specifications.

The diagnostic yield of nasopharyngeal aspirate for pediatric pulmonary tuberculosis: a systematic review and meta-analysis.

Background: Tuberculosis (TB) is a leading cause of death in children, but many cases are never diagnosed. Microbiological diagnosis of pulmonary TB is challenging in young children who cannot spontaneously expectorate sputum. Nasopharyngeal aspirates (NPA) may be more easily collected than gastric aspirate and induced sputum and can be obtained on demand, unlike stool. However, further information on its diagnostic yield is needed. Methods: We systematically reviewed and meta-analyzed the diagnostic yield of one NPA for testing by either culture or nucleic acid amplification testing (NAAT) to detect Mycobacterium tuberculosis from children. We searched three bibliographic databases and two trial registers up to 24th November 2022. Studies that reported the proportion of children diagnosed by NPA compared to a microbiological reference standard (MRS) were eligible. Culture and/or WHO-endorsed NAAT on at least one respiratory specimen served as the MRS. We also estimated the incremental yield of two NPA samples compared to one and summarized operational aspects of NPA collection and processing. Univariate random-effect meta-analyses were performed to calculate pooled diagnostic yield estimates. Results: From 1483 citations, 54 were selected for full-text review, and nine were included. Based on six studies including 256 children with microbiologically confirmed TB, the diagnostic yield of NAAT on one NPA ranged from 31 to 60% (summary estimate 44%, 95% CI 36-51%). From seven studies including 242 children with confirmed TB, the diagnostic yield of culture was 17-88% (summary estimate 58%, 95% CI 42-73%). Testing a second NPA increased the yield by 8-19% for NAAT and 4-35% for culture. NPA collection procedures varied between studies, although most children had NPA successfully obtained (96-100%), with a low rate of indeterminate results (< 5%). Data on NPA acceptability and specifically for children under 5 years were limited. Conclusions: NPA is a suitable and feasible specimen for diagnosing pediatric TB. The high rates of successful collection across different levels of healthcare improve access to microbiological testing, supporting its inclusion in diagnostic algorithms for TB, especially if sampling is repeated. Future research into the acceptability of NPA and how to standardize collection to optimize diagnostic yield is needed.

Bayesian latent class analysis produced diagnostic accuracy estimates that were more interpretable than composite reference standards for extrapulmonary tuberculosis tests.

BACKGROUND: Evaluating the accuracy of extrapulmonary tuberculosis (TB) tests is challenging due to lack of a gold standard. Latent class analysis (LCA), a statistical modeling approach, can adjust for reference tests' imperfect accuracies to produce less biased test accuracy estimates than those produced by commonly used methods like composite reference standards (CRSs). Our objective is to illustrate how Bayesian LCA can address the problem of an unavailable gold standard and demonstrate how it compares to using CRSs for extrapulmonary TB tests. METHODS: We re-analyzed a dataset of presumptive extrapulmonary TB cases in New Delhi, India, for three forms of extrapulmonary TB. Results were available for culture, smear microscopy, Xpert MTB/RIF, and a non-microbiological test, cytopathology/histopathology, or adenosine deaminase (ADA). A diagram was used to define assumed relationships between observed tests and underlying latent variables in the Bayesian LCA with input from an inter-disciplinary team. We compared the results to estimates obtained from a sequence of CRSs defined by increasing numbers of positive reference tests necessary for positive disease status. RESULTS: Data were available from 298, 388, and 230 individuals with presumptive TB lymphadenitis, meningitis, and pleuritis, respectively. Using Bayesian LCA, estimates were obtained for accuracy of all tests and for extrapulmonary TB prevalence. Xpert sensitivity neared that of culture for TB lymphadenitis and meningitis but was lower for TB pleuritis, and specificities of all microbiological tests approached 100%. Non-microbiological tests' sensitivities were high, but specificities were only moderate, preventing disease rule-in. CRSs' only provided estimates of Xpert and these varied widely per CRS definition. Accuracy of the CRSs also varied by definition, and no CRS was 100% accurate. CONCLUSION: Unlike CRSs, Bayesian LCA takes into account known information about test performance resulting in accuracy estimates that are easier to interpret. LCA should receive greater consideration for evaluating extrapulmonary TB diagnostic tests.

Integrated testing for TB and COVID-19.

Integrated testing for TB and COVID-19 may help find those TB patients who are not accessing care in the context of the COVID-19 pandemic. Some molecular platforms with assays for both diseases are already commercially available; however, integrated testing approaches need to be systematically evaluated to ensure their appropriate implementation.

Biomarkers That Correlate with Active Pulmonary Tuberculosis Treatment Response: a Systematic Review and Meta-analysis.

Current WHO recommendations for monitoring treatment response in adult pulmonary tuberculosis (TB) are sputum smear microscopy and/or culture conversion at the end of the intensive phase of treatment. These methods either have suboptimal accuracy or a long turnaround time. There is a need to identify alternative biomarkers to monitor TB treatment response. We conducted a systematic review of active pulmonary TB treatment monitoring biomarkers. We screened 9,739 articles published between 1 January 2008 and 31 December 2020, of which 77 met the inclusion criteria. When studies quantitatively reported biomarker levels, we meta-analyzed the average fold change in biomarkers from pretreatment to week 8 of treatment. We also performed a meta-analysis pooling the fold change since the previous time point collected. A total of 81 biomarkers were identified from 77 studies. Overall, these studies exhibited extensive heterogeneity with regard to TB treatment monitoring study design and data reporting. Among the biomarkers identified, C-reactive protein (CRP), interleukin-6 (IL-6), interferon gamma-induced protein 10 (IP-10), and tumor necrosis factor alpha (TNF-α) had sufficient data to analyze fold changes. All four biomarker levels decreased during the first 8 weeks of treatment relative to baseline and relative to previous time points collected. Based on limited data available, CRP, IL-6, IP-10, and TNF-α have been identified as biomarkers that should be further explored in the context of TB treatment monitoring. The extensive heterogeneity in TB treatment monitoring study design and reporting is a major barrier to evaluating the performance of novel biomarkers and tools for this use case. Guidance for designing and reporting treatment monitoring studies is urgently needed.

Most common reasons for primary care visits in low- and middle-income countries: A systematic review.

With the Covid-19 pandemic and the introduction of the WHO's Essential Diagnostics List (EDL), increasing global attention is focused on the crucial role of diagnostics in achieving universal health coverage. To create national EDLs and to aid health system planning, it is vital to understand the most common conditions with which people present at primary care health facilities. We undertook a systematic review of the most common reasons for primary care visits in low- and middle-income countries. Six databases were searched for articles published between January 2009 and December 2019, with the search updated on MEDLINE to January 2021. Data on the most common patient reasons for encounter (RFEs) and provider diagnoses were collected. 17 of 22,279 screened articles were included. Most studies used unvalidated diagnostic classification systems or presented provider diagnosis data grouped by organ system, rather than presenting specific diagnoses. No studies included data from low-income countries. Only four studies (from Brazil, India, Nigeria and South Africa) using the ICPC-2 classification system contained RFE and provider diagnosis data and could be pooled. The top five RFEs from the four studies were headache, fever, back or low back symptom, cough and pain general/multiple sites. The top five diagnoses were uncomplicated hypertension, upper respiratory tract infection, type 2 diabetes, malaria and health maintenance/prevention. No psychological symptoms were among the top 10 pooled RFEs. There was more variation in top diagnoses between studies than top RFEs, showing the importance of creating location-specific lists of essential diagnostics for primary care. Future studies should aim to sample primary care facilities from across their country of study and use ICPC-3 to report both patient RFEs and provider diagnoses.

Sandfly Fever Sicilian Virus-Leishmania major co-infection modulates innate inflammatory response favoring myeloid cell infections and skin hyperinflammation.

BACKGROUND: The leishmaniases are a group of sandfly-transmitted diseases caused by species of the protozoan parasite, Leishmania. With an annual incidence of 1 million cases, 1 billion people living in Leishmania-endemic regions, and nearly 30,000 deaths each year, leishmaniasis is a major global public health concern. While phlebotomine sandflies are well-known as vectors of Leishmania, they are also the vectors of various phleboviruses, including Sandfly Fever Sicilian Virus (SFSV). Cutaneous leishmaniasis (CL), caused by Leishmania major (L. major), among other species, results in development of skin lesions on the infected host. Importantly, there exists much variation in the clinical manifestation between individuals. We propose that phleboviruses, vectored by and found in the same sandfly guts as Leishmania, may be a factor in determining CL severity. It was reported by our group that Leishmania exosomes are released into the gut of the sandfly vector and co-inoculated during blood meals, where they exacerbate CL skin lesions. We hypothesized that, when taking a blood meal, the sandfly vector infects the host with Leishmania parasites and exosomes as well as phleboviruses, and that this viral co-infection results in a modulation of leishmaniasis. METHODOLOGY/PRINCIPAL FINDINGS: In vitro, we observed modulation by SFSV in MAP kinase signaling as well as in the IRF3 pathway that resulted in a pro-inflammatory phenotype. Additionally, we found that SFSV and L. major co-infection resulted in an exacerbation of leishmaniasis in vivo, and by using endosomal (Toll-like receptor) TLR3, and MAVS knock-out mice, deduced that SFSV's hyperinflammatory effect was TLR3- and MAVS-dependent. Critically, we observed that L. major and SFSV co-infected C57BL/6 mice demonstrated significantly higher parasite burden than mice solely infected with L. major. Furthermore, viral presence increased leukocyte influx in vivo. This influx was accompanied by elevated total extracellular vesicle numbers. Interestingly, L. major displayed higher infectiveness with coincident phleboviral infection compared to L. major infection alone. CONCLUSION/SIGNIFICANCE: Overall our work represents novel findings that contribute towards understanding the causal mechanisms governing cutaneous leishmaniasis pathology. Better comprehension of the potential role of viral co-infection could lead to treatment regimens with enhanced effectiveness.

Progress toward Developing Sensitive Non-Sputum-Based Tuberculosis Diagnostic Tests: the Promise of Urine Cell-Free DNA.

A highly accurate, non-sputum-based test for tuberculosis (TB) detection is a key priority for the field of TB diagnostics. A recent study in the Journal of Clinical Microbiology by Oreskovic and colleagues (J Clin Microbiol 59:e00074-21, 2021, https://doi.org/10.1128/JCM.00074-21) reports the performance of an optimized urine cell-free DNA (cfDNA) test using sequence-specific purification combined with short-target PCR to improve the accuracy of TB detection. Their retrospective clinical study utilized frozen urine samples (n = 73) from study participants diagnosed with active pulmonary TB in South Africa and compared results to non-TB patients in South Africa and the United States in an early-phase validation study. Overall, this cfDNA technique detected TB with a sensitivity of 83.7% (95% CI: 71.0 to 91.5) and specificity of 100% (95% CI: 86.2 to 100), which meet the World Health Organization's published performance criteria. Sensitivity was 73.3% in people without HIV (95% CI: 48.1 to 89.1) and 76% in people with smear-negative TB (95% CI: 56.5 to 88.5). In this commentary, we discuss the results of this optimized urine TB cfDNA assay within the larger context of TB diagnostics and pose additional questions for further research.

Diagnostic accuracy of point-of-care ultrasound for pulmonary tuberculosis: A systematic review.

The advent of affordable, portable ultrasound devices has led to increasing interest in the use of point-of-care ultrasound (POCUS) for the detection of pulmonary TB (PTB). We undertook a systematic review of the diagnostic accuracy of POCUS for PTB. Five databases were searched for articles published between January 2010 and June 2020. Risk of bias was assessed using QUADAS-2. Data on sensitivity and specificity of individual lung ultrasound findings were collected, with variable reference standards including PCR and sputum smear microscopy. Six of 3,919 reviewed articles were included: five in adults and one in children, with a total sample size of 564. Studies had high risk of bias in many domains. In adults, subpleural nodule and lung consolidation were the lung ultrasound findings with the highest sensitivities, ranging from 72.5% to 100.0% and 46.7% to 80.4%, respectively. Only one study reported specificity data. Variability in sensitivity may be due to variable reference standards or may imply operator dependence. There is insufficient evidence to judge the diagnostic accuracy of POCUS for PTB. There is also no consensus on the optimal protocols for acquiring and analysing POCUS images for PTB. New studies which minimise potential sources of bias are required to further assess the diagnostic accuracy of POCUS for PTB.

Distinguishing bacterial versus non-bacterial causes of febrile illness - A systematic review of host biomarkers.

BACKGROUND: Acute febrile illnesses (AFIs) represent a major disease burden globally; however, the paucity of reliable, rapid point-of-care testing makes their diagnosis difficult. A simple tool for distinguishing bacterial versus non-bacterial infections would radically improve patient management and reduce indiscriminate antibiotic use. Diagnostic tests based on host biomarkers can play an important role here, and a target product profile (TPP) was developed to guide development. OBJECTIVES: To qualitatively evaluate host biomarkers that can distinguish bacterial from non-bacterial causes of AFI. DATA SOURCES: The PubMed database was systematically searched for relevant studies published between 2015 and 2019. STUDY ELIGIBILITY CRITERIA: Studies comparing diagnostic performances of host biomarkers in patients with bacterial versus non-bacterial infections were included. PARTICIPANTS: Studies involving human participants and/or human samples were included. METHODS: We collected information following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A risk of bias assessment was performed, based on a modified QUADAS-2 (Quality Assessment of Diagnostic Accuracy Score 2). RESULTS: We identified 1107 publications. Following screening, 55 publications were included, with 265 biomarker entries. Entries mostly comprised protein biomarkers (58.9%), followed by haematological, RNA, and metabolite biomarkers (15.5%, 8.7%, 12.5%). Sensitivity/specificity was reported for 45.7% of biomarker entries. We assessed a high overall risk of bias for most entries (75.8%). In studies with low/medium risk of bias, four biomarker entries tested in blood samples had sensitivity/specificity of more than 0.90/0.80. Only 12 additional biomarker entries were identified with sensitivity/specificity of more than 0.65/0.65. CONCLUSIONS: Most recently assessed biomarkers represent well-known biomarkers, e.g. C-reactive protein and procalcitonin. Some protein biomarkers with the highest reported performances include a combined biomarker signature (CRP, IP-10, and TRAIL) and human neutrophil lipocalin (HNL). Few new biomarkers are in the pipeline; however, some RNA signatures show promise. Further high-quality studies are needed to confirm these findings.

Diagnostic accuracy of centralised assays for TB detection and detection of resistance to rifampicin and isoniazid: a systematic review and meta-analysis.

Various diagnostic companies have developed high throughput molecular assays for tuberculosis (TB) and resistance detection for rifampicin and isoniazid. We performed a systematic review and meta-analyses to assess the diagnostic accuracy of five of these tests for pulmonary specimens. The tests included were Abbott RealTime MTB, Abbott RealTime RIF/INH, FluoroType MTB, FluoroType MTDBR and BD Max MDR-TB assay.A comprehensive search of six databases for relevant citations was performed. Cross-sectional, case-control, cohort studies, and randomised controlled trials of any of the index tests were included. Respiratory specimens (such as sputum, bronchoalveolar lavage, tracheal aspirate, etc) or their culture isolates.A total of 21 included studies contributed 26 datasets. We could only meta-analyse data for three of the five assays identified, as data were limited for the remaining two. For TB detection, the included assays had a sensitivity of 91% or more and the specificity ranged from 97% to 100%. For rifampicin resistance detection, all the included assays had a sensitivity of more than 92%, with a specificity of 99-100%. Sensitivity for isoniazid resistance detection varied from 70 to 91%, with higher specificity of 99-100% across all index tests. Studies that included head-to-head comparisons of these assays with Xpert MTB/RIF for detection of TB and rifampicin resistance suggested comparable diagnostic accuracy.In people with symptoms of pulmonary TB, the centralised molecular assays demonstrate comparable diagnostic accuracy for detection of TB, rifampicin and isoniazid resistance to Xpert MTB/RIF assay, a WHO recommended molecular test.