@article{Gray2023,
abstract = {INTRODUCTION People with radiographic evidence for pulmonary tuberculosis (TB), but negative sputum cultures, have increased risk of developing culture-positive TB. Recent expansion of X-ray screening is leading to increased identification of this group. We set out to synthesise the evidence for treatment to prevent progression to culture-positive disease. METHODS We searched for prospective trials evaluating the efficacy of TB regimens against placebo, observation, or alternative regimens, for the treatment of adults and children with radiographic evidence of TB but culture-negative respiratory samples. Databases were searched up to 18 Oct 2022. Study quality was assessed using ROB 2.0 and ROBINS-I. The primary outcome was progression to culture-positive TB. Meta-analysis with a random effects model was conducted to estimate pooled efficacy. RESULTS We included 13 trials (32,568 individuals) conducted between 1955 and 2018. Radiographic and bacteriological criteria for inclusion varied. 19.1{\%} to 57.9{\%} of participants with active x-ray changes and no treatment progressed to culture-positive disease. Progression was reduced with any treatment (6 studies, risk ratio [RR] 0.27, 95{\%}CI 0.13-0.56); multi-drug TB treatment (RR 0.11, 95{\%}CI 0.05 - 0.23), was significantly more effective than isoniazid treatment (RR 0.63, 95{\%}CI 0.35-1.13) (p=0.0002). DISCUSSION Multi-drug regimens were associated with significantly reduced risk of progression to TB disease for individuals with radiographically apparent, but culture-negative TB. However, most studies were old, conducted prior to the HIV epidemic and with outdated regimens. New clinical trials are required to identify the optimal treatment approach. STUDY REGISTRATION CRD42021248486Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was funded by an MRC grant (MR/V00476X/1) awarded to HE. HE, ER and MQ are partially supported through MRC unit grants (MC UU 00004/04, MC UU 00004/06, MC UU 00004/07, and MC UU 00004/09). RMGJH and ASR were funded by the European Research Council (Action number 757699). ASR was also supported by the UK FCDO (Leaving no-one behind: transforming gendered pathways to health for TB). This research has been partially funded by UK aid from the UK government (to ASR), however the views expressed do not necessarily reflect the UK governments official policies. SVK is affiliated with FIND. FIND conducts multiple clinical research projects to evaluate new diagnostic tests against published target product profiles that have been defined through consensus processes. These include studies of diagnostic products developed by private sector companies who provide access to know-how, equipment/reagents, and may contribute through unrestricted donations according to FIND policies and in line with guidance from the organisations external scientific advisory council. PM is funded by Wellcome (206575/Z/17/Z).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesI 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.YesI 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.YesAll data produced in the present study are available upon reasonable request to the authors},
author = {Gray, Adam Thorburn and Macpherson, Liana and Carlin, Ffion and Sossen, Bianca and Richards, Alexandra and Kik, Sandra Vivian and Houben, Rein M G J and MacPherson, Peter and Quartagno, Matteo and Rogozinska, Ewelina and Esmail, Hanif},
doi = {10.1101/2023.01.27.23285085},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gray et al. - 2023 - Treatment for radiographically active, sputum culture-negative pulmonary tuberculosis a systematic review and meta-.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}not{\_}ack,review},
mendeley-tags = {OA,fund{\_}not{\_}ack,review},
month = {jan},
pages = {2023.01.27.23285085},
title = {{Treatment for radiographically active, sputum culture-negative pulmonary tuberculosis: a systematic review and meta-analysis}},
url = {http://medrxiv.org/content/early/2023/01/28/2023.01.27.23285085.abstract},
year = {2023}
}

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METHODS We searched for prospective trials evaluating the efficacy of TB regimens against placebo, observation, or alternative regimens, for the treatment of adults and children with radiographic evidence of TB but culture-negative respiratory samples. Databases were searched up to 18 Oct 2022. Study quality was assessed using ROB 2.0 and ROBINS-I. The primary outcome was progression to culture-positive TB. Meta-analysis with a random effects model was conducted to estimate pooled efficacy. RESULTS We included 13 trials (32,568 individuals) conducted between 1955 and 2018. Radiographic and bacteriological criteria for inclusion varied. 19.1% to 57.9% of participants with active x-ray changes and no treatment progressed to culture-positive disease. Progression was reduced with any treatment (6 studies, risk ratio [RR] 0.27, 95%CI 0.13-0.56); multi-drug TB treatment (RR 0.11, 95%CI 0.05 - 0.23), was significantly more effective than isoniazid treatment (RR 0.63, 95%CI 0.35-1.13) (p=0.0002). DISCUSSION Multi-drug regimens were associated with significantly reduced risk of progression to TB disease for individuals with radiographically apparent, but culture-negative TB. However, most studies were old, conducted prior to the HIV epidemic and with outdated regimens. New clinical trials are required to identify the optimal treatment approach. STUDY REGISTRATION CRD42021248486Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was funded by an MRC grant (MR/V00476X/1) awarded to HE. HE, ER and MQ are partially supported through MRC unit grants (MC UU 00004/04, MC UU 00004/06, MC UU 00004/07, and MC UU 00004/09). RMGJH and ASR were funded by the European Research Council (Action number 757699). ASR was also supported by the UK FCDO (Leaving no-one behind: transforming gendered pathways to health for TB). This research has been partially funded by UK aid from the UK government (to ASR), however the views expressed do not necessarily reflect the UK governments official policies. SVK is affiliated with FIND. FIND conducts multiple clinical research projects to evaluate new diagnostic tests against published target product profiles that have been defined through consensus processes. These include studies of diagnostic products developed by private sector companies who provide access to know-how, equipment/reagents, and may contribute through unrestricted donations according to FIND policies and in line with guidance from the organisations external scientific advisory council. PM is funded by Wellcome (206575/Z/17/Z).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesI 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.YesI 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.YesAll data produced in the present study are available upon reasonable request to the authors","author":[{"propositions":[],"lastnames":["Gray"],"firstnames":["Adam","Thorburn"],"suffixes":[]},{"propositions":[],"lastnames":["Macpherson"],"firstnames":["Liana"],"suffixes":[]},{"propositions":[],"lastnames":["Carlin"],"firstnames":["Ffion"],"suffixes":[]},{"propositions":[],"lastnames":["Sossen"],"firstnames":["Bianca"],"suffixes":[]},{"propositions":[],"lastnames":["Richards"],"firstnames":["Alexandra"],"suffixes":[]},{"propositions":[],"lastnames":["Kik"],"firstnames":["Sandra","Vivian"],"suffixes":[]},{"propositions":[],"lastnames":["Houben"],"firstnames":["Rein","M","G","J"],"suffixes":[]},{"propositions":[],"lastnames":["MacPherson"],"firstnames":["Peter"],"suffixes":[]},{"propositions":[],"lastnames":["Quartagno"],"firstnames":["Matteo"],"suffixes":[]},{"propositions":[],"lastnames":["Rogozinska"],"firstnames":["Ewelina"],"suffixes":[]},{"propositions":[],"lastnames":["Esmail"],"firstnames":["Hanif"],"suffixes":[]}],"doi":"10.1101/2023.01.27.23285085","file":":C$\\$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gray et al. - 2023 - Treatment for radiographically active, sputum culture-negative pulmonary tuberculosis a systematic review and meta-.pdf:pdf","journal":"medRxiv","keywords":"OA,fund_not_ack,review","mendeley-tags":"OA,fund_not_ack,review","month":"jan","pages":"2023.01.27.23285085","title":"Treatment for radiographically active, sputum culture-negative pulmonary tuberculosis: a systematic review and meta-analysis","url":"http://medrxiv.org/content/early/2023/01/28/2023.01.27.23285085.abstract","year":"2023","bibtex":"@article{Gray2023,\r\nabstract = {INTRODUCTION People with radiographic evidence for pulmonary tuberculosis (TB), but negative sputum cultures, have increased risk of developing culture-positive TB. Recent expansion of X-ray screening is leading to increased identification of this group. We set out to synthesise the evidence for treatment to prevent progression to culture-positive disease. METHODS We searched for prospective trials evaluating the efficacy of TB regimens against placebo, observation, or alternative regimens, for the treatment of adults and children with radiographic evidence of TB but culture-negative respiratory samples. Databases were searched up to 18 Oct 2022. Study quality was assessed using ROB 2.0 and ROBINS-I. The primary outcome was progression to culture-positive TB. Meta-analysis with a random effects model was conducted to estimate pooled efficacy. RESULTS We included 13 trials (32,568 individuals) conducted between 1955 and 2018. Radiographic and bacteriological criteria for inclusion varied. 19.1{\\%} to 57.9{\\%} of participants with active x-ray changes and no treatment progressed to culture-positive disease. 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PM is funded by Wellcome (206575/Z/17/Z).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesI 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.YesI 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.YesAll data produced in the present study are available upon reasonable request to the authors},\r\nauthor = {Gray, Adam Thorburn and Macpherson, Liana and Carlin, Ffion and Sossen, Bianca and Richards, Alexandra and Kik, Sandra Vivian and Houben, Rein M G J and MacPherson, Peter and Quartagno, Matteo and Rogozinska, Ewelina and Esmail, Hanif},\r\ndoi = {10.1101/2023.01.27.23285085},\r\nfile = {:C$\\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gray et al. - 2023 - Treatment for radiographically active, sputum culture-negative pulmonary tuberculosis a systematic review and meta-.pdf:pdf},\r\njournal = {medRxiv},\r\nkeywords = {OA,fund{\\_}not{\\_}ack,review},\r\nmendeley-tags = {OA,fund{\\_}not{\\_}ack,review},\r\nmonth = {jan},\r\npages = {2023.01.27.23285085},\r\ntitle = {{Treatment for radiographically active, sputum culture-negative pulmonary tuberculosis: a systematic review and meta-analysis}},\r\nurl = {http://medrxiv.org/content/early/2023/01/28/2023.01.27.23285085.abstract},\r\nyear = {2023}\r\n}\r\n","author_short":["Gray, A. 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