AUTHOR=Delemarre Eveline M. , van Hoorn Laura , Bossink Aik W. J. , Drylewicz Julia , Joosten Simone A. , Ottenhoff Tom H. M. , Akkerman Onno W. , Goletti Delia , Petruccioli Elisa , Navarra Assunta , van den Broek Brigitte T. A. , Paardekooper Sanne P. A. , van Haeften Ineke , Koenderman Leo , Lammers Jan-Willem J. , Thijsen Steven F. T. , Hofland Regina W. , Nierkens Stefan 

TITLE=Serum Biomarker Profile Including CCL1, CXCL10, VEGF, and Adenosine Deaminase Activity Distinguishes Active From Remotely Acquired Latent Tuberculosis

JOURNAL=Frontiers in Immunology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.725447

DOI=10.3389/fimmu.2021.725447

ISSN=1664-3224

ABSTRACT=Introduction: There is an urgent medical need to differentiate active (ATB) from latent tuberculosis (LTBI) and prevent under- and overtreatment. The aim of this study was to identify biomarker profiles that may support in the differentiation between ATB and LTBI and to validate these signatures. 
Material and Methods: The discovery cohort included adult individuals, classified in four groups: ATB (n=20), LTBI without prophylaxis (untreated-LTBI; n=20), LTBI after completion of prophylaxis (treated-LTBI; n=20) and healthy controls (HC; n=20). Their sera were analyzed for 40 cytokines/chemokines and activity of adenosine deaminase (ADA) isozymes. A prediction model was designed to differentiate ATB from untreated-LTBI using Sparse Partial Least Squares (sPLS) and logistic regression analyses. Serum samples of two independent cohorts (national and international) were used for validation.
Results: SPLS regression analyses identified CCL1, CRP, CXCL10 and VEGF as the most discriminating biomarkers. These markers and ADA(2) activity were significantly increased in ATB compared to untreated-LTBI (p≤0.007). Combining CCL1, CXCL10, VEGF and ADA2 activity yielded a sensitivity and specificity of 95% and 90%, respectively, in differentiating ATB from untreated-LTBI. These findings were confirmed in the validation cohort including remotely acquired untreated-LTBI participants. 
Conclusion: The biomarker signature of CCL1, CXCL10, VEGF and ADA2 activity provides a promising tool for differentiating patients with ATB from non-treated LTBI individuals.