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[Preprint]. 2024 Apr 8:2024.04.07.24305445.

doi: 10.1101/2024.04.07.24305445.

Factors associated with tuberculosis treatment initiation among bacteriologically negative individuals evaluated for tuberculosis: an individual patient data meta-analysis

Sun Kim¹, Melike Hazal Can¹, Tefera B Agizew², Andrew F Auld³, Maria Elvira Balcells⁴, Stephanie Bjerrum^{5

6}, Keertan Dheda^{7

8

9}, Susan E Dorman¹⁰, Aliasgar Esmail^{7

8}, Katherine Fielding¹¹, Alberto L Garcia-Basteiro^{12

13

14}, Colleen F Hanrahan¹⁵, Wakjira Kebede^{16

17}, Mikashmi Kohli¹⁸, Anne F Luetkemeyer¹⁹, Carol Mita²⁰, Byron W P Reeve²¹, Denise Rossato Silva²², Sedona Sweeney²³, Grant Theron²¹, Anete Trajman^{24

25}, Anna Vassall²⁶, Joshua L Warren²⁷, Marcel Yotebieng²⁸, Ted Cohen²⁹, Nicolas A Menzies^{1

30}

Affiliations

¹ Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
² U.S. Centers for Disease Control and Prevention, Botswana.
³ U.S. Centers for Disease Control and Prevention, Lusaka, Zambia.
⁴ Infectious Disease Department, School of Medicine, Pontificia Universidad Católica de Chile.
⁵ Department of Clinical Research, University of Southern Denmark, Odense Denmark.
⁶ Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁷ Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and UCT Lung Institute, Cape Town, South Africa.
⁸ South African MRC Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town, South Africa.
⁹ Faculty of Infectious and Tropical Diseases, Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, UK.
¹⁰ Medical University of South Carolina, Charleston, SC, USA.
¹¹ TB Centre, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
¹² ISGlobal, Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.
¹³ Centro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique.
¹⁴ Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Barcelona, Spain.
¹⁵ Epidemiology Department, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁶ School of Medical Laboratory Sciences, Jimma University, Jimma Ethiopia.
¹⁷ Mycobacteriology Research Center of Jimma University, Ethiopia.
¹⁸ FIND, Geneva, Switzerland.
¹⁹ University of California San Francisco, San Francisco, CA, USA.
²⁰ Countway Library of Medicine, Harvard University, Boston, MA, USA.
²¹ DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research and SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
²² Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
²³ Faculty of Public Health and Policy, London School of Hygiene & Tropical Medicine, London, UK.
²⁴ Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
²⁵ McGill University, Montreal, QC, Canada.
²⁶ Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK.
²⁷ Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
²⁸ Division of General Internal Medicine, Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA.
²⁹ Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.
³⁰ Center for Health Decision Science, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

PMID: 38645191
PMCID: PMC11030305
DOI: 10.1101/2024.04.07.24305445

Factors associated with tuberculosis treatment initiation among bacteriologically negative individuals evaluated for tuberculosis: an individual patient data meta-analysis

Sun Kim et al. medRxiv. 2024.

[Preprint]. 2024 Apr 8:2024.04.07.24305445.

doi: 10.1101/2024.04.07.24305445.

Authors

Affiliations

¹ Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
² U.S. Centers for Disease Control and Prevention, Botswana.
³ U.S. Centers for Disease Control and Prevention, Lusaka, Zambia.
⁴ Infectious Disease Department, School of Medicine, Pontificia Universidad Católica de Chile.
⁵ Department of Clinical Research, University of Southern Denmark, Odense Denmark.
⁶ Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁷ Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and UCT Lung Institute, Cape Town, South Africa.
⁸ South African MRC Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town, South Africa.
⁹ Faculty of Infectious and Tropical Diseases, Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, UK.
¹⁰ Medical University of South Carolina, Charleston, SC, USA.
¹¹ TB Centre, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
¹² ISGlobal, Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.
¹³ Centro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique.
¹⁴ Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Barcelona, Spain.
¹⁵ Epidemiology Department, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁶ School of Medical Laboratory Sciences, Jimma University, Jimma Ethiopia.
¹⁷ Mycobacteriology Research Center of Jimma University, Ethiopia.
¹⁸ FIND, Geneva, Switzerland.
¹⁹ University of California San Francisco, San Francisco, CA, USA.
²⁰ Countway Library of Medicine, Harvard University, Boston, MA, USA.
²¹ DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research and SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
²² Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
²³ Faculty of Public Health and Policy, London School of Hygiene & Tropical Medicine, London, UK.
²⁴ Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
²⁵ McGill University, Montreal, QC, Canada.
²⁶ Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK.
²⁷ Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
²⁸ Division of General Internal Medicine, Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA.
²⁹ Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.
³⁰ Center for Health Decision Science, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

PMID: 38645191
PMCID: PMC11030305
DOI: 10.1101/2024.04.07.24305445

Update in

Factors associated with tuberculosis treatment initiation among bacteriologically negative individuals evaluated for tuberculosis: An individual patient data meta-analysis.
Kim S, Can MH, Agizew TB, Auld AF, Balcells ME, Bjerrum S, Dheda K, Dorman SE, Esmail A, Fielding K, Garcia-Basteiro AL, Hanrahan CF, Kebede W, Kohli M, Luetkemeyer AF, Mita C, Reeve BWP, Silva DR, Sweeney S, Theron G, Trajman A, Vassall A, Warren JL, Yotebieng M, Cohen T, Menzies NA. Kim S, et al. PLoS Med. 2025 Jan 13;22(1):e1004502. doi: 10.1371/journal.pmed.1004502. eCollection 2025 Jan. PLoS Med. 2025. PMID: 39804959 Free PMC article.

Abstract

Background: Globally, over one-third of pulmonary tuberculosis (TB) disease diagnoses are made based on clinical criteria after a negative diagnostic test result. Understanding factors associated with clinicians' decisions to initiate treatment for individuals with negative test results is critical for predicting the potential impact of new diagnostics.

Methods: We performed a systematic review and individual patient data meta-analysis using studies conducted between January/2010 and December/2022 (PROSPERO: CRD42022287613). We included trials or cohort studies that enrolled individuals evaluated for TB in routine settings. In these studies participants were evaluated based on clinical examination and routinely-used diagnostics, and were followed for ≥1 week after the initial test result. We used hierarchical Bayesian logistic regression to identify factors associated with treatment initiation following a negative result on an initial bacteriological test (e.g., sputum smear microscopy, Xpert MTB/RIF).

Findings: Multiple factors were positively associated with treatment initiation: male sex [adjusted Odds Ratio (aOR) 1.61 (1.31-1.95)], history of prior TB [aOR 1.36 (1.06-1.73)], reported cough [aOR 4.62 (3.42-6.27)], reported night sweats [aOR 1.50 (1.21-1.90)], and having HIV infection but not on ART [aOR 1.68 (1.23-2.32)]. Treatment initiation was substantially less likely for individuals testing negative with Xpert [aOR 0.77 (0.62-0.96)] compared to smear microscopy and declined in more recent years.

Interpretation: Multiple factors influenced decisions to initiate TB treatment despite negative test results. Clinicians were substantially less likely to treat in the absence of a positive test result when using more sensitive, PCR-based diagnostics.

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Figures

**Figure 1.. Identification of studies and data to include in the meta-analysis.**

**Figure 2.. Odds ratios of TB treatment initiation following negative diagnostic test result: secondary analysis for datasets including duration of symptoms for cough, fever, and night sweats*.**
* Reference group: Age 18–30 years old, female sex, no history of prior TB, no reported cough, no reported fever, no reported night sweats, HIV-negative, tested negative with sputum smear microscopy. Blue symbols signify odds ratios >1.0, red symbols signify odds ratios <1.0.

See this image and copyright information in PMC

References

1. World Health Organization. Global Tuberculosis Report 2023 [Internet]. 2023. [cited 2024 Jan 15]. Available from: https://www.who.int/teams/global-tuberculosis-programme/tb-reports/globa...
1. World Health Organization. The end TB strategy [Internet]. 2015. Available from: https://www.who.int/publications-detail-redirect/WHO-HTM-TB-2015.19
1. World Health Organization. WHO consolidated guidelines on tuberculosis. Module 3: Diagnosis - Rapid diagnostics for tuberculosis detection 2021 update [Internet]. 2021. Available from: https://www.who.int/publications-detail-redirect/9789240029415 - PubMed
1. Hong JM, Lee H, Menon NV, Lim CT, Lee LP, Ong CWM. Point-of-care diagnostic tests for tuberculosis disease. Science Translational Medicine. 2022. Apr 6;14(639):eabj4124. - PubMed
1. Calligaro GL, Theron G, Khalfey H, Peter J, Meldau R, Matinyenya B, et al. Burden of tuberculosis in intensive care units in Cape Town, South Africa, and assessment of the accuracy and effect on patient outcomes of the Xpert MTB/RIF test on tracheal aspirate samples for diagnosis of pulmonary tuberculosis: a prospective burden of disease study with a nested randomised controlled trial. Lancet Respir Med. 2015. Aug;3(8):621–30. - PubMed

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This is a preprint.

Factors associated with tuberculosis treatment initiation among bacteriologically negative individuals evaluated for tuberculosis: an individual patient data meta-analysis

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Factors associated with tuberculosis treatment initiation among bacteriologically negative individuals evaluated for tuberculosis: an individual patient data meta-analysis

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