TYPE Editorial PUBLISHED 24 February 2023 DOI 10.3389/fimmu.2023.1092651 Editorial: Immuno-diagnosis of OPEN ACCESS active tuberculosis; are we EDITED AND REVIEWED BY Ian Marriott, University of North Carolina at Charlotte, making progress? United States *CORRESPONDENCE Harriet Mayanja-Kizza 1,2*, Pere-Joan Cardona 3,4,5,6 Harriet Mayanja-Kizza hmk@chs.mak.ac.ug and Novel N. Chegou 7,8 SPECIALTY SECTION 1 Makerere University, Kampala, Uganda, 2 Uganda CWRU Research Collaboration, Kampala, Uganda, This article was submitted to 3 Department of Microbiology, University of Barcelona, Barcelona, Spain, 4 Microbiology Department, Microbial Immunology, North Metropolitan Clinical Laboratory, ‘Germans Trias i Pujol’ University Hospital, Badalona, a section of the journal Catalonia, Spain, 5 Genetics and Microbiology Department, Universitat Autònoma de Barcelona, Frontiers in Immunology Cerdanyola del Vallès, Catalonia, Spain, 6 Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain, 7 DSI-NRF Centre of Excellence for Biomedical Tuberculosis RECEIVED 08 November 2022 Research South African Medical Research Council Centre for Tuberculosis Research, South ACCEPTED 17 February 2023 Afriacan, South Africa, 8 Division of Molecular Biology and Human Genetics, Department of PUBLISHED 24 February 2023 Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa CITATION Mayanja-Kizza H, Cardona P-J and KEYWORDS Chegou NN (2023) Editorial: Immuno- diagnosis of active tuberculosis; are we tuberculosis, immuno-diagnosis, current trends, potential markers, future directions making progress? Front. Immunol. 14:1092651. doi: 10.3389/fimmu.2023.1092651 COPYRIGHT © 2023 Mayanja-Kizza, Cardona and Editorial on the Research Topic Chegou. This is an open-access article Immuno-diagnosis of active tuberculosis distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are Active tuberculosis (ATB) diagnosis suffers from several knowledge gaps and challenges, credited and that the original publication in this journal is cited, in accordance with including the need for newer assays with faster turn-around-time (TAT), high sensitivity and accepted academic practice. No use, specificity, lower costs, and the potential for Point-of-Care (POC) use assays. Towards this goal, distribution or reproduction is permitted which does not comply with these terms. we need novel tests that can be used at the population level to screen and/or test high risk populations, including household contacts of sputum positive index patients and persons living with HIV/AIDS. In addition, tests that can be adaptable towards use in treatment follow-up (to predict cure or relapse/reinfection), and as potential surrogate markers of tuberculosis (TB) vaccination are important towards the global control of tuberculosis. A test using blood-based samples would have potential for future studies to “estimate” the mycobacterial load in the body (akin to the HIV viral load test), which would improve the treatment of ATB, and latent tuberculosis infection (LTBI). In addition, immune-based POC tests for ATB diagnosis have the potential for low invasiveness, being user friendly for staff and patients, minimal training needs, greater simplicity, and low cost; making immuno-diagnosis of active tuberculosis a promising approach. To date, a number of studies have been done in both high and low TB endemic settings to diagnose, or even predict, the evolution towards ATB. Much as some studies have shown high sensitivity and specificity (over 85%), there are still many challenges towards the ideal test, and more research needs to be done. Frontiers in Immunology 01 frontiersin.org Mayanja-Kizza et al. 10.3389/fimmu.2023.1092651 Studies for an Immune marker in to control subjects, which may diagnose other forms of extra-pulmonary tuberculosis. active tuberculosis diagnostics In Brazil, a study by Queiroz et al. of persons with advanced HIV disease indicates the diagnostic potential of an assay with two Immunodiagnostic studies to diagnose and/or predict the cytokines, IL-15 and IL-10, in plasmathat are lower in ATB possibility of pulmonary tuberculosis (PTB have recently been compared to those that received early anti ATB treatment. This conducted in different non sputum specimens, including serum, emphasizes the possible role of low-level biomarkers in certain plasma, unstimulated or stimulated Quantiferon supernatants, disease states, a fact that is often overlooked, or ignored as a peripheral blood mononuclear cells (PBMC), in addition to extra- “negative result” as increased levels in a biosignature are often sanguineous specimens, such as saliva, urine, pleural fluid, ascites, expected in diagnostic studies. cerebrospinal fluid as well as bronchio-alveolar lavage cells and Among pregnant women with active tuberculosis, fluids, and induced sputum. The current literature still shows Ranaivomanana et al.’s find lower IGRA responses, probably limited sensitivity and specificity in the diagnosis of ATB, with related to the protective reduction in inflammatory immunity studies showing variable markers predicting ATB, despite generally during pregnancy, a finding of relevance to studies in related assays and study populations; with few achieving optimal pregnant women. sensitivity and specificity. Namuganga and colleagues compared immune markers in saliva and sputum among patients with Genexpert confirmed ATB, and showed different significant markers between saliva and Serology tests serum, thus highlighting the potential for saliva-based ATB Serology has over the years been considered an attractive low diagnostic markers (1). Two multi-country studies in high ATB cost option for the detection of ATB, with a number of products on endemic African sites showed potential of Mtb host response the market, and used in low income high endemicity countries, markers in different combinations with varying levels of despite most not being validated, or recommended for use in the sensitivity and specificity (up to 94 and 73% respectively) either general population. However, it is thought that some serological in predicting ATB compared to healthy controls, (or better still) to tests can be used as adjunctive diagnostic tests in HIV-infected Non-MTB respiratory infections (2, 3). However, these studies patients with smear-negative PTB or extra-PTB, despite their required 7 and 4 host marker combinations, respectively, to attain current limitations (5). Although serum antibodies to ESAT-6 the high sensitivity observed, making them expensive to produce for and CFP-10 were considered an attractive option to differentiate population based ATB triage assays. Moreover, there was little between LTBI and ATB, a related study performed in high and low overlap of significant host markers (only CRP and IP-10) in these ATB endemic countries, failed to show an ability to differentiate 2 studies, indicating possible site, technique or individual variation, Mtb infection from PTB (6). Another sero-diagnostic study impacts on the results obtained for particular markers. combining four MTB antigens ESAT-6, CFP-10, CFP-21, and In this collection, Luo et al. show that a single candidate marker MPT-64 did not significantly differentiate PTB from LTBI (7). HLA-DR on Mtb responding specific cells could differentiate ATB However, an antibody study in South Africa shows promise when from LTBI with a high area under the ROC (receiver operating used in combination with cytokine markers (8). Recently, a new characteristic) curve, (0.901), and high sensitivity, but moderate promising serological lateral flow assay (LFA) has entered the specificity, a step towards a low cost potential triage test marker. market (LIODetect®TB-ST). This POC test detects IgG, IgA and Furthermore, the same group shows that HLA-DR on Mtb-specific IgM antibodies against purified recombinant protein antigens PstS1 cells, combined with TBAg/PHA ratio increased the ROC to 0.937. and PstS3 together with highly purified lipoglycan of Mtb cell wall However, not all markers are upregulated in ATB, as in the paper by in serum, plasma or whole blood within 20 min (9). Intrestingly, Garlant et al., where in a 6-molecule biosignature, transmembrane Nziza et al. show a serological multiplex assay including 7 MTB protein 49 (TMEM9) was downregulated in ATB compared to LTBI antigens and 3 novel antibodies that is able to discern LTBI and negative controls. In a meta-analysis, Meca et al. suggest that CRP ATB across HIV positive and negative populations. alone, above 8 mg/L has potential as a single molecule triage diagnostic test. Related to this, high sensitivity (hs) CRP alone may differentiate various forms of pediatric ATB compared to healthy children, making this a potentially lower cost, variable Other potential markers age, triage test (4). Another pediatric test by Tornheim et al. suggests plasma kynurenine levels could be useful as an ATB In a 16-article meta-analysis, the ovarian cancer tumor marker diagnostic marker in children, having high sensitivity (81.5), but CA-125 has shown promise for detection of ATB with a pooled low ROC (0.667). It, would, however, be of interest to determine the sensitivity of 0.85 (10). This highlights the importance of thinking performance of the combined assessment ofhsCRP and kynurenine outside the box, to identify novel biomarkers and the potential of levels in pediatric populations. Mann et al. show 4-5 high sensitivity usingbiomarkers associated with other disease conditions to biomarker signatures in patients with confirmed spine ATB relative diagnose ATB. Frontiers in Immunology 02 frontiersin.org Mayanja-Kizza et al. 10.3389/fimmu.2023.1092651 Future directions Author contributions Overall, there has been extensive research towards an ideal test All authors listed have made a substantial, direct, and for immunodiagnosis of ATB. However, there is a need for more intellectual contribution to the work and approved it research with innovative approaches. These could include further for publication. studies looking at cell-mediated responses, with various cytokine/ chemokine responses, in different combinations, and the possibility of combining these with antibody responses. In addition, costs Conflict of interest should be considered by developing tests with the lowest possible number of biomarkers, as well as considering the availability for The authors declare that the research was conducted in the POC assays at a population level. absence of any commercial or financial relationships that could be Other options could include blood transcriptomic signatures and construed as a potential conflict of interest. blood immune-profiling, immune metabolic markers (e.g. endocrine markers, and pro-inflammatory markers), the use of novel antigens, or combinations of different antigen stimulation responses. Also, studies Publisher’s note using body samples other than blood, like saliva, sputum, exudative fluids, bronco alveolar lavage (BAL), breath condensate, urine, and All claims expressed in this article are solely those of the authors pleural, ascitic or pericardial fluids, could lead to novel immune and do not necessarily represent those of their affiliated markers for ATB diagnosis(pulmonary and extra pulmonary). In organizations, or those of the publisher, the editors and the addition, different diagnostic approaches, such as LFA-POC tests, reviewers. Any product that may be evaluated in this article, or and other techniques that are faster and have lower costs, diagnosis claim that may be made by its manufacturer, is not guaranteed or lower cost test need to be further investigated. endorsed by the publisher. References 1. Namuganga AR, Chegou NN, Mubiri P, Walzl G, Mayanja-Kizza H. Suitability of 6. 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