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Effect of standard tuberculosis treatment on plasma cytokine levels in patients with active pulmonary tuberculosis.

Riou C, Perez Peixoto B, Roberts L, Ronacher K, Walzl G, Manca C, Rustomjee R, Mthiyane T, Fallows D, Gray CM, Kaplan G - PLoS ONE (2012)

Bottom Line: Plasma concentrations of interferon-inducible protein-10 (IP-10) and vascular endothelial growth factor (VEGF) were significantly reduced upon TB treatment, regardless of HIV status.By the end of treatment, IP-10 concentrations were significantly lower in HIV negative individuals when compared to HIV-positive individuals (p = 0.02).No significant changes were observed in other studied immune mediators.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IIDMM), Clinical Laboratory Sciences, University of Cape Town, Cape Town, Western Cape, South Africa.

ABSTRACT

Background: Sputum Mycobacterium tuberculosis (Mtb) culture is commonly used to assess response to antibiotic treatment in individuals with pulmonary tuberculosis (TB). Such techniques are constrained by the slow growth rate of Mtb, and more sensitive methods to monitor Mtb clearance are needed. The goal of this study was to evaluate changes in plasma cytokines in patients undergoing treatment for TB as a means of identifying candidate host markers associated with microbiologic response to therapy.

Methods: Twenty-four plasma cytokines/chemokines were measured in 42 individuals diagnosed with active pulmonary TB, 52% were HIV co-infected. Individuals, undergoing a 26-week standard TB treatment, were followed longitudinally over 18 months and measurements were associated with HIV status and rates of sputum culture conversion.

Results: Plasma concentrations of interferon-inducible protein-10 (IP-10) and vascular endothelial growth factor (VEGF) were significantly reduced upon TB treatment, regardless of HIV status. By the end of treatment, IP-10 concentrations were significantly lower in HIV negative individuals when compared to HIV-positive individuals (p = 0.02). Moreover, in HIV negative patients, plasma VEGF concentrations, measured as early as 2-weeks post TB treatment initiation, positively correlated with the time of sputum conversion (p = 0.0017). No significant changes were observed in other studied immune mediators.

Conclusions: These data suggest that VEGF plasma concentration, measured during early TB treatment, could represent a surrogate marker to monitor sputum culture conversion in HIV uninfected individuals.

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Comparison of baseline expression levels of soluble plasma mediators between TB+HIV− and TB+HIV+ individuals. (A) Mediators endowed with pro- and anti-inflammatory functions. (B) Mediators endowed with pleiotropic, chemoattractant and growth functions. Results are expressed as pg/ml of plasma. Open circles represent TB+HIV− subjects (n = 20) and black circles correspond to TB+HIV+ subjects (n = 22). Dotted lines represent the average limit of detection for all cytokines. Statistical comparisons have been performed using non-parametric Mann-Whitney U test and corrected for multiple comparisons using a false discovery rate (FDR) step down procedure.
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pone-0036886-g001: Comparison of baseline expression levels of soluble plasma mediators between TB+HIV− and TB+HIV+ individuals. (A) Mediators endowed with pro- and anti-inflammatory functions. (B) Mediators endowed with pleiotropic, chemoattractant and growth functions. Results are expressed as pg/ml of plasma. Open circles represent TB+HIV− subjects (n = 20) and black circles correspond to TB+HIV+ subjects (n = 22). Dotted lines represent the average limit of detection for all cytokines. Statistical comparisons have been performed using non-parametric Mann-Whitney U test and corrected for multiple comparisons using a false discovery rate (FDR) step down procedure.

Mentions: Using the Luminex assay, we assessed the concentrations of 24 soluble plasma mediators at baseline and during treatment. Baseline was defined as the plasma sample collected before initiation of TB treatment. Comparison of baseline plasma concentrations of each of the 24 cytokines between TB+HIV− (n = 20) and TB+HIV+ (n = 22) individuals is shown in Figure 1. Significantly elevated concentrations of IL-4 (p = 0.033), G-CSF (p = 0.0048), IFN-γ (p = 0.0064) and TNF-α (p = 0.0072) and lower concentrations of IL-12(p70) (p = 0.0054) and IL-17 (p = 0.032) were observed in TB+HIV+ patients as compared to TB+HIV− patients. Of note, all reported p-values were adjusted for multiple comparisons, using a false discovery rate step-down procedure. The median absolute concentrations and interquartile range for each cytokine within the 2 groups are detailed in Table S1. To define if cytokine signature profiles were distinct between HIV+ and HIV− individuals, we performed unsupervised hierarchical clustering and principal component (PCA) analyses on log-transformed baseline cytokine concentrations. Figure 2A shows that 73% (16/22) of TB+HIV+ individuals grouped together, indicating that the majority of HIV infected individuals shared a specific cytokine expression pattern. The dendrogram (bottom of Figure 2A) shows the proximity between the different cytokines, suggesting that cytokines within each sub-cluster probably share the same origin, common transcriptional regulation and/or common function. These distinct cytokine profile signatures observed between TB+HIV− and TB+HIV+ individuals at baseline were further confirmed by PCA, based on the 24 studied cytokines (Figure 2B). PCA enables the discrimination and visual clustering of two or more classes, where individuals with similar patterns of cytokine expression are placed next to each other. As shown in Figure 2B, TB+HIV− and TB+HIV+ individuals visually segregate on a PCA plot, based on their baseline plasma cytokine expression patterns.


Effect of standard tuberculosis treatment on plasma cytokine levels in patients with active pulmonary tuberculosis.

Riou C, Perez Peixoto B, Roberts L, Ronacher K, Walzl G, Manca C, Rustomjee R, Mthiyane T, Fallows D, Gray CM, Kaplan G - PLoS ONE (2012)

Comparison of baseline expression levels of soluble plasma mediators between TB+HIV− and TB+HIV+ individuals. (A) Mediators endowed with pro- and anti-inflammatory functions. (B) Mediators endowed with pleiotropic, chemoattractant and growth functions. Results are expressed as pg/ml of plasma. Open circles represent TB+HIV− subjects (n = 20) and black circles correspond to TB+HIV+ subjects (n = 22). Dotted lines represent the average limit of detection for all cytokines. Statistical comparisons have been performed using non-parametric Mann-Whitney U test and corrected for multiple comparisons using a false discovery rate (FDR) step down procedure.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351475&req=5

pone-0036886-g001: Comparison of baseline expression levels of soluble plasma mediators between TB+HIV− and TB+HIV+ individuals. (A) Mediators endowed with pro- and anti-inflammatory functions. (B) Mediators endowed with pleiotropic, chemoattractant and growth functions. Results are expressed as pg/ml of plasma. Open circles represent TB+HIV− subjects (n = 20) and black circles correspond to TB+HIV+ subjects (n = 22). Dotted lines represent the average limit of detection for all cytokines. Statistical comparisons have been performed using non-parametric Mann-Whitney U test and corrected for multiple comparisons using a false discovery rate (FDR) step down procedure.
Mentions: Using the Luminex assay, we assessed the concentrations of 24 soluble plasma mediators at baseline and during treatment. Baseline was defined as the plasma sample collected before initiation of TB treatment. Comparison of baseline plasma concentrations of each of the 24 cytokines between TB+HIV− (n = 20) and TB+HIV+ (n = 22) individuals is shown in Figure 1. Significantly elevated concentrations of IL-4 (p = 0.033), G-CSF (p = 0.0048), IFN-γ (p = 0.0064) and TNF-α (p = 0.0072) and lower concentrations of IL-12(p70) (p = 0.0054) and IL-17 (p = 0.032) were observed in TB+HIV+ patients as compared to TB+HIV− patients. Of note, all reported p-values were adjusted for multiple comparisons, using a false discovery rate step-down procedure. The median absolute concentrations and interquartile range for each cytokine within the 2 groups are detailed in Table S1. To define if cytokine signature profiles were distinct between HIV+ and HIV− individuals, we performed unsupervised hierarchical clustering and principal component (PCA) analyses on log-transformed baseline cytokine concentrations. Figure 2A shows that 73% (16/22) of TB+HIV+ individuals grouped together, indicating that the majority of HIV infected individuals shared a specific cytokine expression pattern. The dendrogram (bottom of Figure 2A) shows the proximity between the different cytokines, suggesting that cytokines within each sub-cluster probably share the same origin, common transcriptional regulation and/or common function. These distinct cytokine profile signatures observed between TB+HIV− and TB+HIV+ individuals at baseline were further confirmed by PCA, based on the 24 studied cytokines (Figure 2B). PCA enables the discrimination and visual clustering of two or more classes, where individuals with similar patterns of cytokine expression are placed next to each other. As shown in Figure 2B, TB+HIV− and TB+HIV+ individuals visually segregate on a PCA plot, based on their baseline plasma cytokine expression patterns.

Bottom Line: Plasma concentrations of interferon-inducible protein-10 (IP-10) and vascular endothelial growth factor (VEGF) were significantly reduced upon TB treatment, regardless of HIV status.By the end of treatment, IP-10 concentrations were significantly lower in HIV negative individuals when compared to HIV-positive individuals (p = 0.02).No significant changes were observed in other studied immune mediators.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IIDMM), Clinical Laboratory Sciences, University of Cape Town, Cape Town, Western Cape, South Africa.

ABSTRACT

Background: Sputum Mycobacterium tuberculosis (Mtb) culture is commonly used to assess response to antibiotic treatment in individuals with pulmonary tuberculosis (TB). Such techniques are constrained by the slow growth rate of Mtb, and more sensitive methods to monitor Mtb clearance are needed. The goal of this study was to evaluate changes in plasma cytokines in patients undergoing treatment for TB as a means of identifying candidate host markers associated with microbiologic response to therapy.

Methods: Twenty-four plasma cytokines/chemokines were measured in 42 individuals diagnosed with active pulmonary TB, 52% were HIV co-infected. Individuals, undergoing a 26-week standard TB treatment, were followed longitudinally over 18 months and measurements were associated with HIV status and rates of sputum culture conversion.

Results: Plasma concentrations of interferon-inducible protein-10 (IP-10) and vascular endothelial growth factor (VEGF) were significantly reduced upon TB treatment, regardless of HIV status. By the end of treatment, IP-10 concentrations were significantly lower in HIV negative individuals when compared to HIV-positive individuals (p = 0.02). Moreover, in HIV negative patients, plasma VEGF concentrations, measured as early as 2-weeks post TB treatment initiation, positively correlated with the time of sputum conversion (p = 0.0017). No significant changes were observed in other studied immune mediators.

Conclusions: These data suggest that VEGF plasma concentration, measured during early TB treatment, could represent a surrogate marker to monitor sputum culture conversion in HIV uninfected individuals.

Show MeSH
Related in: MedlinePlus