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Background: Pulmonary tuberculosis due to Mycobacterium tuberculosis can be challenging to diagnose when sputum samples cannot be obtained, which is especially problematic in children and older people. We systematically appraised the performance characteristics and diagnostic accuracy of upper respiratory tract sampling for diagnosing active pulmonary tuberculosis., Methods: In this systematic review and meta-analysis, we searched MEDLINE, Cinahl, Web of Science, Global Health, and Global Health Archive databases for studies published between database inception and Dec 6, 2022 that reported on the accuracy of upper respiratory tract sampling for tuberculosis diagnosis compared with microbiological testing of sputum or gastric aspirate reference standard. We included studies that evaluated the accuracy of upper respiratory tract sampling (laryngeal swabs, nasopharyngeal aspirate, oral swabs, saliva, mouth wash, nasal swabs, plaque samples, and nasopharyngeal swabs) to be tested for microbiological diagnosis of tuberculous (by culture and nucleic acid amplification tests) compared with a reference standard using either sputum or gastric lavage for a microbiological test. We included cohort, case-control, cross-sectional, and randomised controlled studies that recruited participants from any community or clinical setting. We excluded post-mortem studies. We used a random-effects meta-analysis with a bivariate hierarchical model to estimate pooled sensitivity, specificity, and diagnostics odds ratio (DOR; odds of a positive test with disease relative to without), stratified by sampling method. We assessed bias using QUADAS-2 criteria. This study is registered with PROSPERO (CRD42021262392)., Findings: We screened 10 159 titles for inclusion, reviewed 274 full texts, and included 71, comprising 119 test comparisons published between May 13, 1933, and Dec 19, 2022, in the systematic review (53 in the meta-analysis). For laryngeal swabs, pooled sensitivity was 57·8% (95% CI 50·5-65·0), specificity was 93·8% (88·4-96·8), and DOR was 20·7 (11·1-38·8). Nasopharyngeal aspirate sensitivity was 65·2% (52·0-76·4), specificity was 97·9% (96·0-99·0), and DOR was 91·0 (37·8-218·8). Oral swabs sensitivity was 56·7% (44·3-68·2), specificity was 91·3% (CI 81·0-96·3), and DOR was 13·8 (5·6-34·0). Substantial heterogeneity in diagnostic accuracy was found, probably due to differences in reference and index standards., Interpretation: Upper respiratory tract sampling holds promise to expand access to tuberculosis diagnosis. Exploring historical methods using modern microbiological techniques might further increase options for alternative sample types. Prospective studies are needed to optimise accuracy and utility of sampling methods in clinical practice., Funding: UK Medical Research Council, Wellcome, and UK Foreign, Commonwealth and Development Office., Competing Interests: Declaration of interests We declare no competing interests., (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.)