{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T08:03:47Z","timestamp":1792742627202,"version":"4.5.0"},"posted":{"date-parts":[[2025,11,4]]},"group-title":"Infectious Diseases (except HIV\/AIDS)","reference-count":27,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,4]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The diagnosis of tuberculosis (TB) typically relies on being able to produce a sputum sample for microbiological testing. However, sputum scarcity, the inability to self-expectorate an adequate sputum sample for TB testing, is a well-known concern. Our systematic review and meta-analysis investigated the proportion of sputum scarcity among adolescents and adults being evaluated for presumptive TB in healthcare facilities.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We searched PubMed, Embase, Cochrane Library, Web of Science, and clinical trials databases with no language restrictions from January 2010 to October 2023 using terms for \u2018TB\u2019, sputum, and diagnostic studies. We excluded studies with participants aged &lt;15 years, that enrolled patients already providing sputum, or not adequately reporting information on sputum collection. Published summary data was extracted, and the risk of bias was assessed. Summary estimates for the proportion of sputum scarcity were calculated overall and by pre-specified sub-groups. The pooled proportion of sputum scarcity was calculated by random effects meta-analysis. The review protocol was registered on PROSPERO (CRD42023473882).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Findings<\/jats:title>\n                  <jats:p>Our search identified 9895 records, of which 114 studies were included and 81 were rated as a low risk of bias. The median proportion of sputum scarcity across all 114 studies was 6.0% (95% CI: 2.9-9.1%, IQR: 0-19.9%). In subgroup meta-analyses limited to studies collecting one or two self-expectorated spot sputum samples, the pooled estimate of sputum scarcity was 23% (95%CI: 14-33%, n=27). Sputum scarcity was higher in PLHIV sub-groups. The pooled estimate of sputum scarcity in studies enrolling only PLHIV was 24% (95% CI: 15-33%, n=9) for collection of one or two self-expectorated spot sputum samples. Sputum scarcity was the highest in PLHIV inpatients or with advanced disease, with 32% (95% CI: 22-41%, n=5) unable to provide one or two self-expectorated samples. Patients without HIV had the lowest pooled estimate of scarcity, with 12% (95% CI: 3-21%, n=5) unable to provide a self-expectorated sample of any number or collection time. And studies using sputum induction to collect one or two spot samples had a pooled scarcity of 10% (95% CI: 0-21%, n=12).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interpretation<\/jats:title>\n                  <jats:p>Sputum scarcity is seen in nearly a quarter of patients being evaluated for TB and this compromises TB detection. These findings support the ongoing work to develop non-sputum TB tests.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Funding<\/jats:title>\n                  <jats:p>Gates Foundation (INV-069540)<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Research in Context<\/jats:title>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Evidence before this study<\/jats:title>\n                  <jats:p>Current diagnostics for tuberculosis (TB) rely on testing sputum samples, and patients unable to produce sputum at the time of evaluation may have a delayed or missed diagnosis. However, there are no reliable estimates about how many patients being evaluted for presumptive TB are unable to produce a sputum sample (sputum scarce) and how this varies in different settings and populations.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Added value of this study<\/jats:title>\n                  <jats:p>This systematic review included data from 114 studies, and found approximately 24% of patients with presumed TB could not produce one or two sputum samples at the time of evaluation. We found higher proportions of sputum scarcity in people living with HIV, and in people living with HIV who were hospital inpatients. We found sputum scarcity was lowest in people without HIV.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Implications of all the available evidence<\/jats:title>\n                  <jats:p>Sputum scarcity can impact nearly a quarter of patients being evaluated for TB and is more common in people living with HIV. These data support the need for non-sputum diagnostics.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.02.25339326","type":"posted-content","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T21:10:20Z","timestamp":1762290620000},"source":"Crossref","is-referenced-by-count":6,"title":["Sputum scarcity among adolescents and adults with presumptive tuberculosis: a systematic review and meta-analysis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6713-3495","authenticated-orcid":false,"given":"Mary","family":"Gaeddert","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penelope","family":"Papadopoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Habbes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Niederegger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Schik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Meister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Grilli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashlyn","family":"Beecroft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikashmi","family":"Kohli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhukar","family":"Pai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia M.","family":"Denkinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian M.","family":"Marx","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankur","family":"Gupta-Wright","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025110602000875000_2025.11.02.25339326v1.1","unstructured":"World Health Organization. Global tuberculosis report 2024. 2024."},{"key":"2025110602000875000_2025.11.02.25339326v1.2","doi-asserted-by":"crossref","first-page":"103251","DOI":"10.1016\/j.eclinm.2025.103251","article-title":"Clinically diagnosed tuberculosis and mortality in high burden settings: a systematic review and meta-analysis","volume":"84","year":"2025","journal-title":"eClinicalMedicine"},{"key":"2025110602000875000_2025.11.02.25339326v1.3","unstructured":"Farzan S. Clinical Methods: The History, Physical, and Laboratory Examinations.1990."},{"key":"2025110602000875000_2025.11.02.25339326v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)17705-8"},{"key":"2025110602000875000_2025.11.02.25339326v1.5","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2018-315453"},{"key":"2025110602000875000_2025.11.02.25339326v1.6","unstructured":"World Health Organization. WHO operational handbook on tuberculosis: module 3: diagnosis: rapid diagnostics for tuberculosis detection. 2021."},{"issue":"10","key":"2025110602000875000_2025.11.02.25339326v1.7","doi-asserted-by":"crossref","first-page":"e1002149","DOI":"10.1371\/journal.pmed.1002149","article-title":"The Tuberculosis Cascade of Care in India\u2019s Public Sector: A Systematic Review and Meta-analysis","volume":"13","year":"2016","journal-title":"PLOS Medicine"},{"key":"2025110602000875000_2025.11.02.25339326v1.8","doi-asserted-by":"publisher","DOI":"10.5588\/ijtld.11.0816"},{"key":"2025110602000875000_2025.11.02.25339326v1.9","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1186\/s12879-014-0638-5","article-title":"Male Gender is independently associated with pulmonary tuberculosis among sputum and non-sputum producers people with presumptive tuberculosis in Southwestern Uganda","volume":"14","year":"2014","journal-title":"BMC Infect Dis"},{"key":"2025110602000875000_2025.11.02.25339326v1.10","doi-asserted-by":"crossref","unstructured":"Aparna L M , S A, I S, D R. Assessment of Sputum Quality and Its Importance in the Rapid Diagnosis of Pulmonary Tuberculosis. Archives of Clinical Microbiology. 2017;08(04).","DOI":"10.4172\/1989-8436.100053"},{"key":"2025110602000875000_2025.11.02.25339326v1.11","doi-asserted-by":"publisher","DOI":"10.5588\/ijtld.14.0798"},{"key":"2025110602000875000_2025.11.02.25339326v1.12","first-page":"446","article-title":"Effect of sputum quality on Xpert\u00ae MTB\/RIF results in the detection of Mycobacterium tuberculosis from persons presumed to have Tuberculosis in EAPHLN project Operational Research study sites in Kenya","volume":"27","year":"2014","journal-title":"African journal of health sciences"},{"issue":"6","key":"2025110602000875000_2025.11.02.25339326v1.13","doi-asserted-by":"crossref","first-page":"e0004612","DOI":"10.1371\/journal.pgph.0004612","article-title":"WHO target product profile for TB detection at peripheral settings: 2024 update","volume":"5","year":"2025","journal-title":"PLOS Global Public Health"},{"issue":"6","key":"2025110602000875000_2025.11.02.25339326v1.14","first-page":"e02057","article-title":"Diagnostic Accuracy of Stool Xpert MTB\/RIF for Detection of Pulmonary Tuberculosis in Children: a Systematic Review and Meta-analysis","volume":"57","year":"2019","journal-title":"Journal of Clinical Microbiology"},{"key":"2025110602000875000_2025.11.02.25339326v1.15","doi-asserted-by":"crossref","unstructured":"Shah M , Hanrahan C , Wang ZY , Dendukuri N , Lawn SD , Denkinger CM , et al. Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in HIV-positive adults. Cochrane Database of Systematic Reviews. 2016.","DOI":"10.1002\/14651858.CD011420.pub2"},{"issue":"5","key":"2025110602000875000_2025.11.02.25339326v1.16","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/S1473-3099(19)30707-8","article-title":"Exhaled Mycobacterium tuberculosis output and detection of subclinical disease by face-mask sampling: prospective observational studies","volume":"20","year":"2020","journal-title":"The Lancet Infectious Diseases"},{"key":"2025110602000875000_2025.11.02.25339326v1.17","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.00421-22"},{"issue":"7","key":"2025110602000875000_2025.11.02.25339326v1.18","doi-asserted-by":"crossref","first-page":"e1184","DOI":"10.1016\/S2214-109X(24)00148-7","article-title":"Diagnostic yield as an important metric for the evaluation of novel tuberculosis tests: rationale and guidance for future research","volume":"12","year":"2024","journal-title":"Lancet Glob Health"},{"key":"2025110602000875000_2025.11.02.25339326v1.19","unstructured":"World Health Organization. WHO ENDORSES NEW RAPID TUBERCULOSIS TEST 2010 [Available from: https:\/\/www.who.int\/news\/item\/08-12-2010-who-endorses-new-rapid-tuberculosis-test."},{"key":"2025110602000875000_2025.11.02.25339326v1.20","doi-asserted-by":"crossref","unstructured":"Munn Z MS , Lisy K , Riitano D , Tufanaru C. Chapter 5: Systematic reviews of prevalence and incidence. JBI Manual for Evidence Synthesis; 2020.","DOI":"10.46658\/JBIRM-17-05"},{"issue":"5","key":"2025110602000875000_2025.11.02.25339326v1.21","doi-asserted-by":"crossref","first-page":"636","DOI":"10.5588\/ijtld.12.0811","article-title":"Diagnostic and prognostic value of serum C-reactive protein for screening for HIV-associated tuberculosis","volume":"17","year":"2013","journal-title":"Int J Tuberc Lung Dis"},{"key":"2025110602000875000_2025.11.02.25339326v1.22","doi-asserted-by":"crossref","unstructured":"Page MJ , McKenzie JE , Bossuyt PM , Boutron I , Hoffmann TC , Mulrow CD , et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.","DOI":"10.1136\/bmj.n71"},{"key":"2025110602000875000_2025.11.02.25339326v1.23","unstructured":"World Health Organization. WHO releases new global lists of high-burden countries for TB, HIV-associated TB and drug-resistant TB 2021 [Available from: https:\/\/www.who.int\/news\/item\/17-06-2021-who-releases-new-global-lists-of-high-burden-countries-for-tb-hiv-associated-tb-and-drug-resistant-tb."},{"issue":"2","key":"2025110602000875000_2025.11.02.25339326v1.24","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1055\/s-0036-1572553","article-title":"Human Immunodeficiency Virus Infection and Host Defense in the Lungs","volume":"37","year":"2016","journal-title":"Semin Respir Crit Care Med"},{"issue":"4","key":"2025110602000875000_2025.11.02.25339326v1.25","doi-asserted-by":"crossref","first-page":"389","DOI":"10.5588\/ijtld.16.0785","article-title":"Effect of previous treatment and sputum quality on diagnostic accuracy of Xpert(\u00ae) MTB\/RIF","volume":"21","year":"2017","journal-title":"Int J Tuberc Lung Dis"},{"issue":"1","key":"2025110602000875000_2025.11.02.25339326v1.26","doi-asserted-by":"crossref","first-page":"29","DOI":"10.5588\/ijtld.23.0244","article-title":"The impact of sputum quality on Xpert positivity in active case-finding for TB","volume":"28","year":"2024","journal-title":"Int J Tuberc Lung Dis"},{"issue":"1","key":"2025110602000875000_2025.11.02.25339326v1.27","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1016\/S2214-109X(23)00469-2","article-title":"Oral swabs with a rapid molecular diagnostic test for pulmonary tuberculosis in adults and children: a systematic review","volume":"12","year":"2024","journal-title":"Lancet Glob Health"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.11.02.25339326","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:50:23Z","timestamp":1768510223000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.11.02.25339326"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,4]]},"references-count":27,"URL":"https:\/\/doi.org\/10.1101\/2025.11.02.25339326","relation":{},"subject":[],"published":{"date-parts":[[2025,11,4]]},"subtype":"preprint"}}