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

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. 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. 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. 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. Tuberculosis (TB) remains a major global health crisis. Some forms of the disease are particularly hard to detect using standard tests because they have very few bacteria or occur outside the lungs. This study aimed to see if combining three specific markers from the body’s immune system could improve diagnostic accuracy. Researchers analyzed data from 605 participants, testing these markers both individually and in different combinations. The results showed that using markers together is much more effective than using just one. Specifically, certain combinations can either accurately confirm the disease or safely rule it out. This finding is significant because it provides a fast, low-cost solution for diagnosing difficult TB cases. It is especially valuable for clinics with limited resources, helping patients receive life-saving treatment sooner. Mao et al., evaluate whether combining host immune biomarkers, including adenosine deaminase, interferon gamma, and interleukin six, improves diagnosis of paucibacillary and extrapulmonary tuberculosis. Using these combined biomarkers together increases accuracy and supports both confirmation and screening.