Plasma chemokines are baseline predictors of unfavorable treatment outcomes in pulmonary tuberculosis
Authors: Nathella Pavan Kumar 3, Kadar Moideen 1, Arul Nancy 1,2, Vijay Viswanathan 2, Kannan Thiruvengadam3, Dina Nair3, Vaithilingam V. Banurekha3, Shanmugam Sivakumar 3, Syed Hissar 3, Hardy Kornfeld 4 and Subash Babu 1,5
Affiliations: 1 National Institutes of Health—NIRT— International Center for Excellence in Research, Chennai, India; 2 Prof. M. Viswanathan Diabetes Research Center, Chennai, India; 3 ICMR-National Institute for Research in Tuberculosis, Chennai, India; 4 University of Massachusetts Medical School, Worcester, MA, USA and 5 LPD, NIAID, NIH, MD, USA.
Background: Plasma chemokines are biomarkers of greater disease severity, higher bacterial burden and delayed sputum culture conversion in pulmonary tuberculosis (PTB). Whether plasma chemokines could also serve as biomarkers of unfavorable treatment outcomes in PTB is not known.
Methods: A cohort of newly diagnosed, sputum smear and culture positive adult individuals with drug-sensitive PTB were recruited under the Effect of diabetes on Tuberculosis Severity study in Chennai, India. Plasma chemokine levels measured before treatment initiation were compared between 68 cases with unfavorable outcomes (treatment failure, death or recurrence) and 136 control individuals who had recurrence-free cure. A second validation cohort comprising of newly diagnosed, culture positive adults with drug-sensitive TB was used to measure plasma chemokine levels in 20 cases and 40 controls.
Findings: Chemokines such as CCL2 (OR [95% CI] 1.26 [1.03 - 1.54]; p=0.025), CCL3 (OR [95% CI] 4.41 [2.84 – 6.83]; p<0.001), CCL4 (OR [95% CI] 1.30 [1.11 - 1.52]; p=0.001), CXCL8 (OR [95% CI] 2.71 [1.99 – 3.68]; p<0.001), CXCL10 (OR [95% CI] 2.91 [2.10 – 4.03]; p<0.001) were associated with increased rates of unfavorable treatment outcomes, while CXCL1 (OR [95% CI] 0.50 [0.37 – 0.67]; p<0.001) was associated with a decreased rate of unfavorable outcome. Multivariate analysis showed that CCL2 (aOR [95% CI] 1.26 [1.02 – 1.56]; p=0.035), CCL3 (aOR [95% CI] 4.89 [2.99 – 7.99]; p<0.001), CCL4 (aOR [95% CI] 1.36 [1.15 - 1.61]; p<0.001), CXCL8 (aOR [95% CI] 2.84 [2.05 – 3.92]; p<0.001), CXCL10 (aOR [95% CI] 2.95 [2.10 – 4.15]; p<0.001) and CX3CL1 (aOR [95% CI] 1.70 [1.15 – 2.53]; p=0.008) were still associated with significantly increased risk of unfavorable treatment outcomes, while CXCL1 (aOR [95% CI] 0.45 [0.33 – 0.63]; p<0.001) was still associated with significantly decreased risk of unfavorable outcomes. Similarly, CCL3 (GM of 219.7 pg/ml in cases versus 73.7 pg/ml in controls), CXCL8 (GM of 281.3 pg/ml in cases versus 93.5 pg/ml in controls) and CXCL10 (GM of 131.1 pg/ml in cases versus 29.4 pg/ml in controls) were associated with increased risk of unfavorable treatment outcomes in the validation cohort. Receiver operating characteristic analysis revealed combinations of CCL3, CXCL8 and CXCL10 exhibited high AUC (0.937 to 0.969) with high sensitivity (82 – 96%) and specificity (87 – 92%) in differentiating cases versus controls.
Conclusions: Our study reveals a plasma chemokine signature that can be used as a novel biomarker for predicting adverse treatment outcomes in PTB
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