Search

Non-sputum tests are needed to improve tuberculosis (TB) diagnosis and close the diagnostic gap. The World Health Organization's target product profile (TPP) for point-of-care (POC) screening tests requires a minimum sensitivity of 90% and a specificity of 70%. Our objective was to identify host blood protein biomarkers meeting TPP criteria. A systematic review was conducted and reported following PRISMA guidelines. Data extraction and quality assessment with Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) were completed for the included studies. Heterogeneity was assessed. For biomarkers reporting sensitivity and specificity in at least four studies, a random-effects meta-analysis was performed for biomarkers with similar cut-offs. We screened 4,651 citations and included 65 studies that enrolled 16,010 participants and evaluated 156 host proteins. Most (47/65) studies enrolled adult pulmonary TB (PTB), with 15 studies in adult extra-pulmonary TB and 5 in children. Small early-stage discovery studies with case-control design were common (24/65) and had a high risk of bias. For adult PTB, CRP, IP-10, NCAM-1, and SAA met TPP criteria in high-quality studies. There was a high degree of heterogeneity in biomarker cut-offs and study design. CRP at 10 mg/L cut-off was meta-analyzed from 10 studies; pooled sensitivity 86% [95% confidence interval (CI): 80-95] and pooled specificity 67% (95% CI: 54-79). In people living with HIV (six studies), CRP pooled sensitivity was 93% (95% CI: 90-95), and pooled specificity was 59% (95% CI: 40-78). We identified promising biomarkers that performed well in high-quality studies. Data overall are limited and highly heterogenous. Further standardized validation across subgroups in prospective studies is needed before translating into POC assays., Importance: To our knowledge, this is the first comprehensive systematic review of host blood protein biomarkers for tuberculosis (TB), and we identified promising biomarkers for a TB screening test., Competing Interests: The authors declare no conflict of interest.

The diagnosis of paediatric tuberculosis remains a challenge due to the non-specificity of symptoms and the paucibacillary nature of tuberculosis in children. However, in the development of new tuberculosis diagnostics, the unique needs of children and adolescents are rarely considered in the design process, with delays in evaluation and approval. No clear guidance is available on when and how to include children and adolescents in tuberculosis diagnostic development and evaluation. To address this gap, we conducted a Delphi consensus process with 42 stakeholders, including one qualitative and two quantitative rounds. Consensus was achieved on 20 statements, with agreement that the needs and perspectives of children, adolescents, and their caregivers should be incorporated throughout diagnostic design and evaluation. Opportunities exist for the early use of well characterised samples and prospective enrolment of children and adolescents in tuberculosis diagnostic evaluation, with consideration of the type of test, expected benefit, and potential risks. Pathogen-based tests might be initially optimised and assessed in adults and adolescents, but parallel evaluation in children is needed for host-based tests. Late-stage evaluation and implementation studies should examine combination testing and integration into clinical algorithms. The statements support collaboration between developers, researchers, regulators, and users to widen and accelerate the diagnostic pipeline for paediatric tuberculosis., Competing Interests: Declaration of interests SL receives royalties from UpToDate on the tuberculosis in Pregnancy topic; and receives funding from Merck for her institution for investigator-initiated SARS-CoV-2 related research. EMB and LO are supported by a fellowship from the European Society for Paediatric Infectious Diseases. ELM is supported by a Canadian Institutes of Health Research Fellowship (472823). MPN is supported by an Australian National Health and Medical Research Council Investigator Award 1174455. HJZ is supported by the South African Medical Research Council. All other authors declare no competing interests. This consensus process was supported by the National Institute of Allergy and Infectious Diseases Feasibility of Novel Diagnostics for TB in Endemic Countries for TB studies (U01AI152087, U01AI152084, and U01AI152075)., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: The large reservoir of tuberculosis (TB) infections is one of the main reasons for the persistent incidence of TB. Accurate diagnostic tests are crucial to correctly identify and treat people with TB infection, which is vital to eliminate TB globally. The rdESAT-6 and rCFP-10 (Cy-Tb) injection ('Cy-Tb'), a TB-specific antigen skin test and STANDARD F TB-Feron FIA ('Standard F TB') measuring interferon-gamma by fluorescence immunoassay assay are two novel tools for the diagnosis of TB infection which offer advantages compared with current tests in low-resource settings and reduced costs to both health systems and TB-affected people. The proposed study aims to evaluate the diagnostic accuracy of these two new tests for TB infection diagnosis., Methods and Analysis: This cross-sectional study aims to assess the diagnostic accuracy for TB infection of the Cy-Tb skin test and Standard F TB assay (investigational tests) compared with the QuantiFERON-TB Gold Plus (QFT-Plus) assay as the immunological reference standard. Three different cohorts of study participants will be recruited at the Vietnam National Lung Hospital: adults with bacteriologically confirmed pulmonary TB (n=100), household contacts of people with TB (n=200) and people without TB infection (n=50). All consenting participants will undergo simultaneous testing with Cy-Tb, Standard F TB and QFT-Plus. The primary endpoint is the diagnostic accuracy of the Cy-Tb skin test and Standard F TB assay, expressed as sensitivity and specificity against the reference standard., Ethics and Dissemination: Ethical approval was granted by the Vietnam National Lung Hospital Institutional Review Board (65/23/CN-HDDD-BVPTU) and the Swedish Ethical Review Authority (Dnr 2023-04271-01). Study results will be disseminated to the scientific community and policymakers through scientific publications., Trial Registration Number: NCT06221735., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Competing Interests: We declare no competing interests.

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., (Copyright © 2024 World Health Organization. Published by Elsevier Ltd.. All rights reserved.)

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., ((c) 2023 The authors; licensee World Health Organization.)

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., Competing Interests: Declaration of interests MP serves as an advisor to the following non-profit agencies in global health: Bill & Melinda Gates Foundation, Foundation for Innovative New Diagnostics, WHO, and Stop TB Partnership. CU-G reports receiving funding from the Foundation of Innovative New Diagnostics, US National Institutes of Health, Abbott, and National Research Council Canada for grants in tuberculosis or COVID research, or both; receiving payment or honoraria for lectures, presentations, or educational events from Abbott and Molbio; and participating on an advisory board for point-of-care testing in infectious diseases., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)