Combining ADA, IFN-γ, and IL-6 as host biomarkers enhances diagnosis of paucibacillary and extrapulmonary tuberculosis

BACKGROUND: Accurate diagnosis of paucibacillary and extrapulmonary tuberculosis remains a major global challenge, as conventional pathogen-focused methods often lack sensitivity. This study aimed to evaluate whether combining host-derived immune biomarkers could improve diagnostic accuracy. METHODS: In a retrospective diagnostic accuracy study of 605 participants, nucleic acid amplification tests served as the reference standard. We assessed the performance of adenosine deaminase, interferon-gamma, and interleukin-6 individually and in combination using receiver operating characteristic analysis. Serial (rule-in) and parallel (rule-out) testing algorithms were compared to define strategies for confirmation or exclusion of disease. RESULTS: Here we show that while interferon-gamma was the strongest single discriminator, combinations of biomarkers significantly outperform any single marker. The dual-panel of interferon-gamma and interleukin-6 achieves the highest overall accuracy. Serial testing of adenosine deaminase and interferon-gamma maximizes specificity to 97.4% (95% CI: 95.6-98.7%), providing a reliable rule-in tool. Conversely, parallel testing of all three biomarkers achieves 94.9% (95% CI: 95.6-98.7%)sensitivity, enabling an effective rule-out strategy. CONCLUSIONS: The integration of complementary host biomarkers overcomes the inherent limitations of single analyte tests. By enabling adaptable, context-specific algorithms tailored for either high-specificity confirmation or high-sensitivity screening, this approach provides a scalable and cost-effective diagnostic approach, tailored for resource-constrained settings.