Host and pathogen factors modulate tuberculosis clinical severity independent of molecular bacterial burden: insights...

Tuberculosis (TB) exhibits marked clinical heterogeneity, complicating prognosis, and disease management. Identifying reliable predictors of disease trajectory and severity could improve risk stratification.

We investigated determinants of TB severity in 727 sputum-positive individuals recruited from five health facilities in Ghana. Participants were classified as TB-only, TB-human immunodeficiency virus, or TB-diabetes mellitus. Disease severity was assessed using the Bandim TB score II. Bacterial burden was quantified using GeneXpert Mycobacterium tuberculosis/rifampicin Ultra cycle threshold values, sputum smear microscopy grades, and time to culture positivity. Multivariable regression models were used to evaluate host, pathogen, and clinical determinants of severity.

Bacterial load differed modestly across comorbidity groups, but GeneXpert cycle threshold values showed no significant correlation with clinical severity (Spearman's ρ = -0.006, P = 0.894). Lower body mass index was consistently associated with increased odds of severe TB (odds ratio = 0.639, 95% confidence interval 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.

Host nutritional status, socio-demographic factors, and pathogen genotype were more consistently associated with TB severity than molecular bacterial burden alone, supporting a host-pathogen interaction framework to explain clinical heterogeneity and improve management.