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External validation in different cohorts is a key step in the translational development of new biomarkers. We previously described three host mRNA whose expression in peripheral blood is significantly higher (<i>NPC2</i>) or lower (<i>DOCK9</i> and <i>EPHA4</i>) in individuals with TB compared to latent TB infection (LTBI) and controls. We have now conducted an independent validation of these genes by re-analyzing publicly available transcriptomic datasets from Brazil, China, Haiti, India, South Africa, and the United Kingdom. Comparisons between TB and control/LTBI showed significant differential expression of all three genes (<i>NPC2^high</i> <i>p</i> < 0.01, <i>DOCK9^low</i> <i>p</i> < 0.01, and <i>EPHA4^low</i> <i>p</i> < 0.05). <i>NPC2^high</i> had the highest mean area under the ROC curve (AUROC) for the differentiation of TB vs. controls (0.95) and LTBI (0.94). In addition, <i>NPC2</i> accurately distinguished TB from the clinically similar conditions pneumonia (AUROC, 0.88), non-active sarcoidosis (0.87), and lung cancer (0.86), but not from active sarcoidosis (0.66). Interestingly, individuals progressing from LTBI to TB showed a constant increase in <i>NPC2</i> expression with time when compared to non-progressors (<i>p</i> < 0.05), with a significant change closer to manifestation of active disease (≤3 months, <i>p</i> = 0.003). Moreover, <i>NPC2</i> expression normalized with completion of anti-TB treatment. Taken together, these results validate <i>NPC2</i> mRNA as a diagnostic host biomarker for active TB independent of host genetic background. Moreover, they reveal its potential to predict progression from latent to active infection and to indicate a response to anti-TB treatment.