The Natural History of Untreated Pulmonary Tuberculosis in Adults: A Systematic Review and Meta-Analysis

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.