Editorial: Addressing Tuberculosis Infection: An Essential Step in the Fight Against Tuberculosis Provisionally Accepted

Miguel Santin^{1, 2, 3*} Anete Trajman^{4, 5, 6} Delia Goletti⁷ Luis Anibarro^{8, 9}

• ¹Department of Infectious Diseases, Bellvitge University Hospital, Spain
• ²Department of Clinical Sciences, University of Barcelona, Spain
• ³Centro de Investigación Biomédica en Red Enfermedades Infecciosas (CIBERINFEC), Spain
• ⁴Department of Internal Medicine, Federal University of Rio de Janeiro, Brazil
• ⁵Brazilian Tuberculosis Research Network, Brazil
• ⁶International TB Centre, School of Biomedical Sciences, Faculty of Medicine and Health Sciences, McGill University, Canada
• ⁷Translational Research Unit, Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases Lazzaro Spallanzani (IRCCS), Italy
• ⁸Department of Infectious Diseases, Complejo Hospitalario de Pontevedra, Spain
• ⁹Instituto de Investigación Sanitaria Galicia Sur (IISGS), Spain

Tuberculosis (TB) still causes 1.3 million deaths each year, despite the availability of treatment for over 65 years. Latently infected people constitute the main reservoir of Mycobacterium tuberculosis (Mtb) worldwide. Recognising this, systematic testing, and treatment of TB infection (TBI) is central to the World Health Organisation's (WHO) "End TB Strategy" to eliminate TB (1). The United Nations General Assembly (UNGA) convened its second High-Level Meeting (UNGA-HLM) on the fight against TB in September 2023, to review the targets set at the first meeting for 2018-2022 and to develop new targets up to 2027, including coverage of TB preventive therapy (TPT) for 45 million household contacts (HHCs) and people living with HIV (PLHIV). However, the limitations of diagnostic tests for TBI in predicting the development of TB (2), the long duration and toxicity of TPT (3), and the lack of resources, hinder this strategy from moving forward. This Research Topic includes eight arecles addressing interveneons to improve TBI screening and treatment outcomes (Villarihno's, Orez-Laza's, Alsdurf's papers), and challenges to their implementaeon (Coleman's, Liu's papers); the poteneal uelity of anebodies to Mtb-specific anegens for the classificaeon of Mtb infeceon states (Ruiz-Tagle's, Tran's papers), and the feasibility of new approaches to detect viable bacilli across the spectrum of Mtb infeceon (Alebouyeh's paper).Increasing human resources, without reducing those available for aceve TB care, and expanding the use of shorter rifamycin-containing regimens can contribute to the control and eventual eliminaeon of TB. A mulecentre cohort study (Laza's paper) in Spain showed a sharp decline in TB incidence over the last two decades accompanying the implementaeon of a TPT program, with a specialist nurse and an electronic registry. Telemonitoring with educaeonal aceviees, together with the three months of rifampicin plus isoniazid therapy, improved TPT compleeon from less than 70% to over 85%. However, resources are needed. In a relaevely large eme and moeon study (Alsdurf's paper), a program to scale up TPT in five countries resulted in an average 9% increase in the amount of eme HCW's spent on TPT aceviees, resuleng in an 11% reduceon in eme spent on aceve disease management. Programs should therefore increase their workforce by 10% to improve TPT aceviees. New shorter and safer regimens are available, but its implementaeon is slow, and moreover, they are not enough; health system strengthening and training are needed to move things forward. In Brazil, (Villarihno's paper) 14 years ajer the publicaeon of the naeonal guidelines recommending TPT for contacts of all ages and for PLHIV, TPT is sell not fully implemented. The integraeon of the short-course rifapenene plus isoniazid regimen into the health system has been slow. Debate about extending the TPT to other at-risk populaeons. A systemaec review (Liu's paper) found that people with diabetes have an increased risk of LTBI. Although WHO does not consider diabetes for TB screening, there is evidence of its involvement as a synergisec risk factor for TB when combined with other immunosuppressive or lifestyle factors (4,5). The debate about whether people with diabetes should be treated for TBI revolves around balancing the increased risk of TB with the challenges in diagnosis, side effects of treatment, and the need for more evidence to inform guidelines. For now, while PLHIV and HHCs of TB are not reached, scaling up TPT for people with diabetes may not be a priority. A review (Coleman's paper) highlights the importance and cost-benefit of idenefying and treaeng people with latent infeceon, to prevent future cases, together with aceve case finding, to rapidly eliminate all infeceous cases. Indeed, WHO has confirmed the benefits and high return of investment of adding TPT to aceve case finding in countries with different epidemiologic scenarios (6).The authors also summarise the challenges and call for bold strategies to make progress towards TB eliminaeon.Biomarkers capable of recognising the early stages of infeceon would allow targeeng individuals with actual recent infeceon and put them on TPT. The humoral immune response profile of TB paeents and contacts with TBI could serve as a diagnosec tool to differeneate between long-standing and recently acquired TBI, as previously suggested (7). In this Research Topic, two studies address the performance of anebodies against Mtb-specific anegens to discriminate between different TB states. A prospeceve study invesegated Mtb-specific IgA against various anegens in saliva among household contacts of smearposieve pulmonary TB cases (Ruiz-Tagle's paper). They found that levels of some anegens were higher among TB-infected than in uninfected contacts. However, the discriminatory ability of these IgA anebodies specific for TB infeceon was very low. In contrast, an exploratory retrospeceve analysis of serum anebodies in a cohort of aceve TB paeents, infected household contacts and healthy controls (Tran's paper), reported a high sensievity and specificity of serological tests for TB state classificaeon. The authors found higher serum IgA anebodies to MPT64 anegen, followed by IgG anebodies to Ag85B and CFP, among TB paeents than among infected contacts. The results showed a high discriminaeve accuracy for the MPT64-IgA-based assay (95% sensievity and 97% specificity). These preliminary results need to be validated in prospeceve cohorts to formally establish their accuracy in discriminaeng aceve TB from TBI.Finally, admilng the drawbacks of current diagnosec tests for TBI, properly idenefying bacterial viability during silent human TBI is a major need. A review (Alebouyeh's paper) evaluated the feasibility of new approaches to detect viable bacilli across the spectrum from infeceon to disease. The authors recognised the limitaeons imposed by the extremely low bacterial burden in supposedly infected people. Intereseng approaches are under evaluaeon, such as those deteceng Mtb DNA in blood by the phage technology (8) or in peripheral CD34+ cells (9).While dealing with TBI presents challenges, it is esseneal to maintain an opemisec outlook. Amidst the complexiees of latent TB, we must focus on the remarkable progress that has been made and the promise of what lies ahead. Despite the hurdles, the colleceve commitment to research, innovaeon, and collaboraeon conenues to push the boundaries of what we can achieve in the fight against TB.