Host and pathogen factors modulate tuberculosis clinical severity independent of molecular bacterial burden: insights from a multicenter Ghanaian cohort

Introduction Tuberculosis exhibits marked clinical heterogeneity, complicating prognosis and disease management. Identifying reliable predictors of disease trajectory and severity could improve risk stratification. Methodology We investigated determinants of tuberculosis severity in 727 sputum-positive individuals recruited from five health facilities in Ghana. Participants were classified as tuberculosis-only, tuberculosis–HIV, or tuberculosis–diabetes mellitus. Disease severity was assessed using the Bandim TB score II. Bacterial burden was quantified using GeneXpert MTB/RIF Ultra cycle threshold (Ct) values, sputum smear microscopy grades, and time to culture positivity. Multivariable regression models were used to evaluate host, pathogen, and clinical determinants of severity. Results Bacterial load differed modestly across comorbidity groups, but GeneXpert Ct values showed no significant correlation with clinical severity (Spearman’s ρ = –0.006, p = 0.894). Lower BMI was consistently associated with increased odds of severe TB (OR = 0.639, 95% CI 0.566–0.714; p = 3.7 × 10 −14 ). Self-reported Ewe ethnicity was associated with milder clinical severity. Higher sputum smear grade was independently associated with more severe disease. Conclusion Host nutritional status, socio-demographic factors, and pathogen genotype were more consistently associated with tuberculosis severity than molecular bacterial burden alone, supporting a host–pathogen interaction framework to explain clinical heterogeneity and improve management.