{"doi":"10.1016/j.jiph.2025.102791","title":"Prominence of Mycobacterium tuberculosis biomarkers among sputum culture-negative clinic attendees, independent of Ultra status","abstract":"BACKGROUND: Highly-sensitive molecular tests like GeneXpert MTB/RIF Ultra improve detection of paucibacillary pulmonary tuberculosis (TB) but occasionally detect Mycobacterium tuberculosis (Mtb) DNA in sputum from culture-negative individuals, with unclear significance. We hypothesized that Ultra may be detecting culture-negative TB, and manifest in a higher prevalence of TB biomarkers compared to Ultra-negative/culture-negative ('sputum-negative') individuals. METHODS: From 1200 symptomatic African adults undergoing evaluation for TB, we identified 66 with discordant results (Ultra-positive, culture-negative), and matched 52 sputum-negative (Ultra-negative, culture-negative) and 30 sputum-positive (Ultra-positive, culture-positive) participants. Over 12 months, participants were assessed for Mtb biomarkers (Mtb growth in augmented or follow-up sputum cultures, Mtb mRNA in baseline sputum, and symptomatic Ultra-positive after baseline) and TB-associated host transcriptional signatures. RESULTS: At baseline, TB-associated biomarker(s) were detected in 51.5 % of sputum-discordant versus 59.6 % of sputum-negative participants (p = 0.46), with at least one Mtb biomarker in 16.7 % versus 26.9 % respectively (p = 0.26). Longitudinally, 26.5 % of untreated sputum-discordant versus 41.7 % of untreated sputum-negative participants had Mtb biomarkers (p = 0.17) despite most reporting symptom improvement. Notably, 30 % of untreated sputum-negative participants converted to Ultra-positive at month 2. One sputum-discordant and one sputum-negative participant developed culture-confirmed TB at follow-up. CONCLUSION: TB bacterial and host biomarkers were prevalent and no different between sputum-discordant and sputum-negative participants, raising concern for a considerable population of undiagnosed culture-negative TB. These findings parallel new evidence of Mtb aerosolization from sputum-negative individuals and highlight a need for more comprehensive diagnostics that detect sputum culture-negative TB with respect to infectiousness, pathology, and risk of progression.","journal":"Journal of Infection and Public Health","year":2025,"id":525594,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9612,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1067935,"name":"Nisha Modi","orcid":"0000-0002-8332-6078","position":1,"is_corresponding":false},{"id":483812,"name":"Kattya Lopez","orcid":null,"position":2,"is_corresponding":false},{"id":999483,"name":"Robert Reiss","orcid":"0000-0002-1131-0907","position":3,"is_corresponding":false},{"id":1400745,"name":"Jorge Robledo","orcid":null,"position":4,"is_corresponding":false},{"id":777254,"name":"Christie Eichberg","orcid":"0000-0002-6501-6295","position":5,"is_corresponding":false},{"id":1221046,"name":"Nchimunya Hapeela","orcid":null,"position":6,"is_corresponding":false},{"id":1221047,"name":"Elizabeth Nakabugo","orcid":null,"position":7,"is_corresponding":false},{"id":795692,"name":"Irene Anyango","orcid":null,"position":8,"is_corresponding":false},{"id":1005970,"name":"Kiranjot Arora","orcid":null,"position":9,"is_corresponding":false},{"id":1221048,"name":"Ronald Odero","orcid":null,"position":10,"is_corresponding":false},{"id":332905,"name":"Judi van Heerden","orcid":null,"position":11,"is_corresponding":false},{"id":866773,"name":"Widaad Zemanay","orcid":null,"position":12,"is_corresponding":false},{"id":854805,"name":"Vaishnavi Kaipilyawar","orcid":"0000-0002-8940-8509","position":13,"is_corresponding":false},{"id":777252,"name":"Samuel Kennedy","orcid":"0000-0001-8088-6339","position":14,"is_corresponding":false},{"id":659992,"name":"Padmapriya P. 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