@article{Sossen2022,
abstract = {BACKGROUND Key stages in TB disease can be delineated by radiology, microbiology and symptoms, but transition between relevant stages remains unclear. We sought to quantify progression and regression across the spectrum of TB disease by systematically reviewing studies of individuals with untreated TB undergoing follow up. METHODS We searched PubMED, EMBASE and Web of Science until December 31st 1960, the Index Medicus between 1895 and 1945, and extensive investigator collections without date restriction - in English and German. Eligible studies were observational cohorts and clinical trials, presenting adults/adolescents with TB or recent TB exposure, undergoing follow-up for at least 12 months without therapeutic intervention. Two authors independently reviewed titles/abstracts and full texts for inclusion. Quality was assessed with a modified Newcastle-Ottawa Score, excluding highly biased studies. Summary estimates were extracted to align with TB disease transitions in a conceptual model, and we used meta-analysis of proportions with random-effects to synthesise the extracted data. This study is registered with PROSPERO (CRD42019152585). FINDINGS 10477 titles were screened and 1648 full texts reviewed. 223 met inclusion criteria. 109 were excluded for high risk of bias and 90 did not have extractable data. 24 studies (34 cohorts) were included. Progression from microbiologically negative to positive disease in those with radiographic TB evidence occurred at an annualized rate of 9.71{\%} (95{\%} CI:6.17-13.34) with active TB imaging, and 1.06{\%} (95{\%} CI:0.31-1.82) with inactive TB imaging. Reversion from microbiologically-positive to -undetectable in prospective cohorts occurred at an annualized rate of 12.40{\%} (95{\%} CI: 6.81-17.99). Studies reported symptoms poorly not allowing for direct estimation of transitions for subclinical (asymptomatic, culture positive) disease. INTERPRETATION We present the risk of progression in those with radiographic evidence of disease and the rate of self-cure for microbiologically positive disease to inform global disease burden estimates, clinical guidelines and policy decisions. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Clinical Protocols {\textless}https://www.crd.york.ac.uk/prospero/display{\_}record.php?RecordID=152585{\textgreater} {\#}{\#}{\#} Funding Statement This study was funded by Bill and Melinda Gates Foundation via a grant to the TB Modelling and Analysis Consortium {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript},
author = {Sossen, Bianca and Richards, Alexandra and Heinsohn, Torben and Frascella, Beatrice and Balzarini, Federica and Oradini--Alacreu, Aurea and Odone, Anna and Rogozinska, Ewelina and Hacker, Brit and Cobelens, Frank and Kranzer, Katharina and Houben, Rein M G J and Esmail, Hanif},
doi = {10.1101/2022.08.30.22279374},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sossen et al. - 2022 - The natural history of untreated pulmonary tuberculosis in adults a systematic review and meta-analysis.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {aug},
pages = {2022.08.30.22279374},
pmid = {36966795},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{The natural history of untreated pulmonary tuberculosis in adults: a systematic review and meta-analysis}},
url = {https://www.medrxiv.org/content/10.1101/2022.08.30.22279374v1 https://www.medrxiv.org/content/10.1101/2022.08.30.22279374v1.abstract},
year = {2022}
}

{"_id":"SkmAbtz34vRDF63qJ","bibbaseid":"sossen-richards-heinsohn-frascella-balzarini-oradinialacreu-odone-rogozinska-etal-thenaturalhistoryofuntreatedpulmonarytuberculosisinadultsasystematicreviewandmetaanalysis-2022","author_short":["Sossen, B.","Richards, A.","Heinsohn, T.","Frascella, B.","Balzarini, F.","Oradini–Alacreu, A.","Odone, A.","Rogozinska, E.","Hacker, B.","Cobelens, F.","Kranzer, K.","Houben, R. M G J","Esmail, H."],"bibdata":{"bibtype":"article","type":"article","abstract":"BACKGROUND Key stages in TB disease can be delineated by radiology, microbiology and symptoms, but transition between relevant stages remains unclear. We sought to quantify progression and regression across the spectrum of TB disease by systematically reviewing studies of individuals with untreated TB undergoing follow up. METHODS We searched PubMED, EMBASE and Web of Science until December 31st 1960, the Index Medicus between 1895 and 1945, and extensive investigator collections without date restriction - in English and German. Eligible studies were observational cohorts and clinical trials, presenting adults/adolescents with TB or recent TB exposure, undergoing follow-up for at least 12 months without therapeutic intervention. Two authors independently reviewed titles/abstracts and full texts for inclusion. Quality was assessed with a modified Newcastle-Ottawa Score, excluding highly biased studies. Summary estimates were extracted to align with TB disease transitions in a conceptual model, and we used meta-analysis of proportions with random-effects to synthesise the extracted data. This study is registered with PROSPERO (CRD42019152585). FINDINGS 10477 titles were screened and 1648 full texts reviewed. 223 met inclusion criteria. 109 were excluded for high risk of bias and 90 did not have extractable data. 24 studies (34 cohorts) were included. Progression from microbiologically negative to positive disease in those with radiographic TB evidence occurred at an annualized rate of 9.71% (95% CI:6.17-13.34) with active TB imaging, and 1.06% (95% CI:0.31-1.82) with inactive TB imaging. Reversion from microbiologically-positive to -undetectable in prospective cohorts occurred at an annualized rate of 12.40% (95% CI: 6.81-17.99). Studies reported symptoms poorly not allowing for direct estimation of transitions for subclinical (asymptomatic, culture positive) disease. INTERPRETATION We present the risk of progression in those with radiographic evidence of disease and the rate of self-cure for microbiologically positive disease to inform global disease burden estimates, clinical guidelines and policy decisions. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols \\textlesshttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=152585\\textgreater ### Funding Statement This study was funded by Bill and Melinda Gates Foundation via a grant to the TB Modelling and Analysis Consortium ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript","author":[{"propositions":[],"lastnames":["Sossen"],"firstnames":["Bianca"],"suffixes":[]},{"propositions":[],"lastnames":["Richards"],"firstnames":["Alexandra"],"suffixes":[]},{"propositions":[],"lastnames":["Heinsohn"],"firstnames":["Torben"],"suffixes":[]},{"propositions":[],"lastnames":["Frascella"],"firstnames":["Beatrice"],"suffixes":[]},{"propositions":[],"lastnames":["Balzarini"],"firstnames":["Federica"],"suffixes":[]},{"propositions":[],"lastnames":["Oradini–Alacreu"],"firstnames":["Aurea"],"suffixes":[]},{"propositions":[],"lastnames":["Odone"],"firstnames":["Anna"],"suffixes":[]},{"propositions":[],"lastnames":["Rogozinska"],"firstnames":["Ewelina"],"suffixes":[]},{"propositions":[],"lastnames":["Hacker"],"firstnames":["Brit"],"suffixes":[]},{"propositions":[],"lastnames":["Cobelens"],"firstnames":["Frank"],"suffixes":[]},{"propositions":[],"lastnames":["Kranzer"],"firstnames":["Katharina"],"suffixes":[]},{"propositions":[],"lastnames":["Houben"],"firstnames":["Rein","M","G","J"],"suffixes":[]},{"propositions":[],"lastnames":["Esmail"],"firstnames":["Hanif"],"suffixes":[]}],"doi":"10.1101/2022.08.30.22279374","file":":C$\\$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sossen et al. - 2022 - The natural history of untreated pulmonary tuberculosis in adults a systematic review and meta-analysis.pdf:pdf","journal":"medRxiv","keywords":"OA,fund_not_ack,original","mendeley-tags":"OA,fund_not_ack,original","month":"aug","pages":"2022.08.30.22279374","pmid":"36966795","publisher":"Cold Spring Harbor Laboratory Press","title":"The natural history of untreated pulmonary tuberculosis in adults: a systematic review and meta-analysis","url":"https://www.medrxiv.org/content/10.1101/2022.08.30.22279374v1 https://www.medrxiv.org/content/10.1101/2022.08.30.22279374v1.abstract","year":"2022","bibtex":"@article{Sossen2022,\r\nabstract = {BACKGROUND Key stages in TB disease can be delineated by radiology, microbiology and symptoms, but transition between relevant stages remains unclear. We sought to quantify progression and regression across the spectrum of TB disease by systematically reviewing studies of individuals with untreated TB undergoing follow up. METHODS We searched PubMED, EMBASE and Web of Science until December 31st 1960, the Index Medicus between 1895 and 1945, and extensive investigator collections without date restriction - in English and German. Eligible studies were observational cohorts and clinical trials, presenting adults/adolescents with TB or recent TB exposure, undergoing follow-up for at least 12 months without therapeutic intervention. Two authors independently reviewed titles/abstracts and full texts for inclusion. Quality was assessed with a modified Newcastle-Ottawa Score, excluding highly biased studies. Summary estimates were extracted to align with TB disease transitions in a conceptual model, and we used meta-analysis of proportions with random-effects to synthesise the extracted data. This study is registered with PROSPERO (CRD42019152585). FINDINGS 10477 titles were screened and 1648 full texts reviewed. 223 met inclusion criteria. 109 were excluded for high risk of bias and 90 did not have extractable data. 24 studies (34 cohorts) were included. Progression from microbiologically negative to positive disease in those with radiographic TB evidence occurred at an annualized rate of 9.71{\\%} (95{\\%} CI:6.17-13.34) with active TB imaging, and 1.06{\\%} (95{\\%} CI:0.31-1.82) with inactive TB imaging. Reversion from microbiologically-positive to -undetectable in prospective cohorts occurred at an annualized rate of 12.40{\\%} (95{\\%} CI: 6.81-17.99). Studies reported symptoms poorly not allowing for direct estimation of transitions for subclinical (asymptomatic, culture positive) disease. INTERPRETATION We present the risk of progression in those with radiographic evidence of disease and the rate of self-cure for microbiologically positive disease to inform global disease burden estimates, clinical guidelines and policy decisions. {\\#}{\\#}{\\#} Competing Interest Statement The authors have declared no competing interest. {\\#}{\\#}{\\#} Clinical Protocols {\\textless}https://www.crd.york.ac.uk/prospero/display{\\_}record.php?RecordID=152585{\\textgreater} {\\#}{\\#}{\\#} Funding Statement This study was funded by Bill and Melinda Gates Foundation via a grant to the TB Modelling and Analysis Consortium {\\#}{\\#}{\\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. 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