{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T08:02:33Z","timestamp":1782547353848,"version":"3.54.5"},"posted":{"date-parts":[[2025,7,15]]},"group-title":"Infectious Diseases (except HIV\/AIDS)","reference-count":19,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Highly sensitive molecular tests, like Xpert Ultra, are reshaping TB diagnosis\u2014detecting paucibacillary TB but sometimes creating uncertainty when they detect DNA in extremely low quantities that may not signal disease. This ambiguity also complicates the evaluation of novel diagnostic strategies. We sought to monitor adults with a \u2018Trace\u2019 result on an Xpert Ultra test to estimate the risk of tuberculosis disease up to 24 months later.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted a multi-site clinical observational study in South Africa and Uganda, where we enrolled ambulatory participants aged &gt;=15 years with a sputum Xpert Ultra Trace result who had not yet initiated TB treatment. All participants underwent comprehensive clinical evaluation and repeated, standard sputum TB testing. Clinicians deferred treatment recommendations if TB status remained uncertain after evaluation. Untreated participants were followed regularly until TB diagnosis and\/or treatment initiation. We estimated cumulative incidence of TB disease, defined by three reference standards.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Of 311 participants with Trace results (50% male, 57% PLHIV, 37% treated for TB within the last 5 years), 24% were positive for TB within 12 months by culture, 37% by sputum Xpert or culture, and 54% by culture or clinical diagnosis. After excluding those diagnosed with TB at baseline, patients identified at baseline as having recent TB history, abnormal chest x-ray, or positive tongue swab, had higher risk of TB diagnosis (hazard ratios: 2.6, 2.4, 4.5, respectively) during follow-up. This hazard was highest in the first three months after the negative baseline evaluation (0.22 [95% CI: 0.19-0.26] per person-month) and decreased to 0.01 [95% CI: 0-0.02] per person-month in both the 3-6 and 6-12-month intervals.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Approximately half of adults and adolescents with a sputum Trace result were diagnosed with TB disease within twelve months. Although most TB diagnoses were made within 3 months, risk remained higher than estimated population incidence rates through the follow-up period. Individuals with sputum Trace results should receive close clinical monitoring, despite initial clinical treatment decision.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Summary results<\/jats:title>\n                  <jats:p>Xpert Ultra \u201cTrace\u201d results detect low quantities of TB DNA, creating diagnostic uncertainty that complicates both clinical decisions and diagnostics evaluation. This clinical observational cohort study followed untreated patients with Trace results for twelve or more months, using survival analysis to estimate actual tuberculosis disease risk and identify risk factors.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.14.25331384","type":"posted-content","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T21:42:02Z","timestamp":1752615722000},"source":"Crossref","is-referenced-by-count":5,"title":["Cumulative TB disease burden following sputum Xpert Ultra \u2018Trace\u2019 results in clinical settings: Results from a multi-site observational clinical study"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6959-0817","authenticated-orcid":false,"given":"Ronit R","family":"Dalmat","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin","family":"Visek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvira","family":"Budiawan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Stein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annet","family":"Nalutaaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Mukiibi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam","family":"Nantale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Bich\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4726-9651","authenticated-orcid":false,"given":"Joowhan","family":"Sung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zanele","family":"Magcaba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nompumelelo","family":"Ngcobo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer F.","family":"Morton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meena","family":"Lenn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Aucock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3106-1258","authenticated-orcid":false,"given":"Adrienne E.","family":"Shapiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5605-1240","authenticated-orcid":false,"given":"Amy","family":"Steadman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Draper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Ganguloo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achilles","family":"Katamba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily A","family":"Kendall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul K","family":"Drain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025071708400705000_2025.07.14.25331384v1.1","unstructured":"World Health O. Global tuberculosis report 2024. Geneva: World Health Organization; 2024."},{"key":"2025071708400705000_2025.07.14.25331384v1.2","first-page":"Cd009593","article-title":"Xpert\u00ae MTB\/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults","volume":"2014","year":"2014","journal-title":"The Cochrane database of systematic reviews"},{"key":"2025071708400705000_2025.07.14.25331384v1.3","first-page":"001737","article-title":"Long-Term GeneXpert Positivity after Treatment for Pulmonary Tuberculosis","volume":"7","year":"2020","journal-title":"European journal of case reports in internal medicine"},{"key":"2025071708400705000_2025.07.14.25331384v1.4","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/civ1223"},{"key":"2025071708400705000_2025.07.14.25331384v1.5","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.01696-17"},{"key":"2025071708400705000_2025.07.14.25331384v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(17)30691-6"},{"key":"2025071708400705000_2025.07.14.25331384v1.7","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.00812-17"},{"key":"2025071708400705000_2025.07.14.25331384v1.8","unstructured":"World Health O. WHO consolidated guidelines on tuberculosis: Module 3: Diagnosis Rapid diagnostics for tuberculosis detection: World Health Organization; 2021."},{"key":"2025071708400705000_2025.07.14.25331384v1.9","doi-asserted-by":"crossref","first-page":"e0272997","DOI":"10.1371\/journal.pone.0272997","article-title":"Evaluation of trace calls by Xpert MTB\/RIF ultra for clinical management in low TB burden settings","volume":"17","year":"2022","journal-title":"PLoS One"},{"key":"2025071708400705000_2025.07.14.25331384v1.10","doi-asserted-by":"crossref","first-page":"101","DOI":"10.4103\/ijmy.ijmy_200_20","article-title":"Multicenter evaluation of xpert MTB\/RIF ultra tests reporting detection of \u201cTrace\u201d of Mycobacterium tuberculosis DNA","volume":"10","year":"2021","journal-title":"International journal of mycobacteriology"},{"key":"2025071708400705000_2025.07.14.25331384v1.11","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ijid.2021.10.056","article-title":"Tracing TB: Are there predictors for active TB disease in patients with Xpert Ultra trace results?","volume":"114","year":"2022","journal-title":"International Journal of Infectious Diseases"},{"key":"2025071708400705000_2025.07.14.25331384v1.12","doi-asserted-by":"crossref","first-page":"28","DOI":"10.5588\/pha.21.0066","article-title":"Prevalence and interpretation of Xpert(\u00ae) Ultra trace results among presumptive TB patients","volume":"12","year":"2022","journal-title":"Public health action"},{"key":"2025071708400705000_2025.07.14.25331384v1.13","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1093\/cid\/ciac965","article-title":"Yield of Facility-based Targeted Universal Testing for Tuberculosis With Xpert and Mycobacterial Culture in High-Risk Groups Attending Primary Care Facilities in South Africa","volume":"76","year":"2023","journal-title":"Clin Infect Dis"},{"key":"2025071708400705000_2025.07.14.25331384v1.14","unstructured":"Visek Cea . 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Consensus standard operating procedure for collection of tongue swabs for TB diagnostics. Protocolsio 2024.","DOI":"10.17504\/protocols.io.kxygxyw54l8j\/v1"},{"key":"2025071708400705000_2025.07.14.25331384v1.18","doi-asserted-by":"crossref","unstructured":"Steadman A , Andama A , Ball A , et al. New manual qPCR assay validated on tongue swabs collected and processed in Uganda shows sensitivity that rivals sputum-based molecular TB diagnostics. Clinical Infectious Diseases 2024:ciae041.","DOI":"10.1101\/2023.08.10.23293680"},{"key":"2025071708400705000_2025.07.14.25331384v1.19","doi-asserted-by":"crossref","unstructured":"Drain PK , Bajema KL , Dowdy D , et al. Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection. Clin Microbiol Rev 2018;31.","DOI":"10.1128\/CMR.00021-18"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.07.14.25331384","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:40:44Z","timestamp":1768509644000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.07.14.25331384"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,15]]},"references-count":19,"URL":"https:\/\/doi.org\/10.1101\/2025.07.14.25331384","relation":{},"subject":[],"published":{"date-parts":[[2025,7,15]]},"subtype":"preprint"}}