Chitinase and indoleamine 2, 3-dioxygenase are prognostic biomarkers for unfavorable treatment outcomes in pulmonary tuberculosis

Abstract

Introduction: Chitinase, Indoleamine 2,3-dioxygenesae-1 (IDO-1) and heme oxygenase-1 (HO-1) are candidate diagnostic biomarkers for tuberculosis (TB). Whether these immune markers could also serve as predictive biomarkers of unfavorable treatment outcomes in pulmonary TB (PTB) is not known.

Methods: A cohort of newly diagnosed, sputum culture-positive adults with drug-sensitive PTB were recruited. Plasma chitinase protein, IDO protein and HO-1 levels measured before treatment initiation were compared between 68 cases with unfavorable outcomes (treatment failure, death, or recurrence) and 108 control individuals who had recurrence-free cure.

Results: Plasma chitinase and IDO protein levels but not HO-1 levels were lower in cases compared to controls. The low chitinase and IDO protein levels were associated with increased risk of unfavourable outcomes in unadjusted and adjusted analyses. Receiver operating characteristic analysis revealed that chitinase and IDO proteins exhibited high sensitivity and specificity in differentiating cases vs controls as well as in differentiating treatment failure vs controls and recurrence vs controls, respectively. Classification and regression trees (CART) were used to determine threshold values for these two immune markers.

Discussion: Our study revealed a plasma chitinase and IDO protein signature that may be used as a tool for predicting adverse treatment outcomes in PTB.

Keywords: 3-dioxygenesae-1; chitinase; heme oxygenase-1; indoleamine 2; pulmonary tuberculosis (PTB); unfavourable TB treatment.

Figure 1

Outline of participant categorization. A schematic of our study cohort showing new smear positive pulmonary TB patients with poor treatment outcome [Cases (n=68)] and recurrence free cure till the end of study [Control (n=108)]. Plasma samples were isolated from whole blood of both the study groups.

Figure 2

Baseline analysis of plasma levels of chitinase protein and IDO protein in cases. The baseline plasma levels of chitinase protein, IDO protein and HO-1 were measured in (A) cases (n=68) and controls (n=108) (B) TB treatment failure (n=16) and controls (n=35) and (C) TB recurrence (n=34) and controls (n=69). The data are represented as scatter plots with each circle representing a single individual. P values were calculated using the Mann-Whitney U test with Holm’s correction for multiple comparisons. NS : No significance.

Figure 3

ROC analysis of chitinase protein, IDO protein and HO-1 in discriminating treatment failure and disease recurrence versus controls. Receiver operator characteristic analysis to estimate the sensitivity, specificity, and AUC was performed using chitinase protein, IDO protein and HO-1 to estimate the capacity of these factors to distinguish cases vs controls. (A–C) Total cases (n=68) and controls (n=108) (A) Chitinase protein (B) IDO Protein (C) HO-1. (D–F) TB Treatment failure (n=16) and controls (n=35) (D) Chitinase protein (E) IDO Protein (F) HO-1. (G–I) TB recurrence (n=34) and controls (n=69) (G) Chitinase protein (H) IDO Protein (I) HO-1. NS : No significance.

Figure 4

Identification of biomarkers showing the strongest associations with bad treatment outcome in TB disease. CART model analysis shows that chitinase protein and IDO protein exhibited the highest accuracy in discriminating cases from controls and ROC curves were employed to quantify the accuracy of biomarkers Cut-off value of chitinase protein and IDO protein is determined by this model.