Factors associated with tuberculosis treatment initiation among bacteriologically negative individuals evaluated for tuberculosis: an individual patient data meta-analysis
Authors: Kim Sun , Can Melike Hazal , Agizew Tefera B. , Auld Andrew F. , Balcells Maria Elvira , Bjerrum Stephanie , Dheda Keertan , Dorman Susan E. , Esmail Aliasgar , Fielding Katherine , Garcia-Basteiro Alberto L. , Hanrahan Colleen F. , Kebede Wakjira , Kohli Mikashmi , Luetkemeyer Anne F. , Mita Carol , Reeve Byron W. P. , Silva Denise Rossato , Sweeney Sedona , Theron Grant , Trajman Anete , Vassall Anna , Warren Joshua L. , Yotebieng Marcel , Cohen Ted , Menzies Nicolas A. 
Published: April 2024

SUMMARYBackgroundGlobally, 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.MethodsWe 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).FindingsMultiple 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.InterpretationMultiple 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.FundingNational Institutes of HealthResearch in contextEvidence before this studyIn countries with a high burden of tuberculosis, over one-third of notified cases for pulmonary TB are diagnosed based on clinical criteria, without bacteriological confirmation of disease (‘clinical diagnosis’). For these individuals with negative bacteriological test results, there is limited evidence on the factors associated with higher or lower rates of clinical diagnosis. In the context of individual clinical trials, some analyses have reported lower rates of treatment initiation for individuals testing negative on new cartridge-based PCR tests (e.g., Xpert MTB-RIF), as compared to individuals testing negative in sputum smear microscopy.Added value of this studyThis study conducted a systematic review of studies that collected data on patient characteristics and treatment initiation decisions for individuals receiving a negative bacteriological test result as part of initial evaluation for TB. Patient-level data from 13 countries across 12 studies (n=15121) were analyzed in an individual patient data meta-analysis, to describe factors associated with clinicians’ decisions to treat for TB disease. We identified significant associations between multiple clinical factors and the probability that a patient would be initiated on TB treatment, including sex, history of prior TB, reported symptoms (cough and night sweats), and HIV status. Controlling for other factors, patients testing negative on PCR-based diagnostics (e.g., Xpert MTB/RIF) were less likely to be initiated on treatment than those testing negative with smear microscopy.Implications of all the available evidenceRates of clinical diagnosis for TB differ systematically as a function of multiple clinical factors and are lower for patients who test negative with new PCR-based diagnostics compared to earlier smear-based methods. This evidence can be used to refine diagnostic algorithms and better understand the implications of introducing new diagnostic tests for TB.