Host And Pathogen Factors Modulate Tuberculosis Clinical Severity Independent Of Molecular Bacterial Burden: Insights From A Multicenter Ghanaian Cohort

Abstract

Objectives: Tuberculosis (TB) exhibits marked clinical heterogeneity, complicating prognosis, and disease man- agement. Identifying reliable predictors of disease trajectory and severity could improve risk stratification. Methodology: 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. Results: 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. Conclusion: 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 frame- work to explain clinical heterogeneity and improve management.