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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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Related in: MedlinePlus

Longitudinal assessment of plasma cytokine expression levels before, during and after TB therapy in TB+HIV− individuals. The concentration of each cytokine has been measured at baseline, 2, 4, 8, 12, 26, 52, 78 weeks after the initiation of a 26- week treatment period. Individuals who presented with sputum conversion at ≤8 weeks are depicted in red, individual who presented with sputum culture conversion between 12 and 26 weeks are depicted in blue and individuals where sputum culture conversion occurred after 26 weeks of TB therapy are shown in green. (A) Plasma cytokine levels (IL-2, IL-5, IL-13, G-CSF, IL-12, PDGF-BB, IL-7, IL-9, IFN-γ, MIP-1β, IL-4 and IL-10) showing no significant change overtime. (B) Plasma cytokine levels (IL-1RA, IL-6, Eotaxin, FGF-basic, IL-17, TNF-α, GM-CSF, MCP-1, IL-1β and IL-15) fluctuating overtime. (C) Plasma cytokines (IP-10 and VEGF) presenting significant changes over time. Each dot represents one individual (n = 20). Results are expressed as pg/ml of plasma. Dotted lines represent the limit of detection for each cytokine. Gray shaded box (on the first graph) represents the duration of TB therapy; dark gray box depicts the intensive phase of treatment, including rifampicin, isoniazid, pyrazinamide and ethambutol, while light gray box corresponds to the second phase of treatment with rifampicin and isoniazid. Statistical analyses were performed using non-parametric one-way ANOVA Kruskal-Wallis Tests (*: p<0.05, **: p<0.01, ***: P<0.001). Numerical p-values, reflecting the overall changes in IP-10 and VEGF expression levels, have been determined using random-effects linear regression. The x-axis (time after the initiation of treatment in weeks) has been logged to allow better visualization of cytokine expression levels at early time points.
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pone-0036886-g003: Longitudinal assessment of plasma cytokine expression levels before, during and after TB therapy in TB+HIV− individuals. The concentration of each cytokine has been measured at baseline, 2, 4, 8, 12, 26, 52, 78 weeks after the initiation of a 26- week treatment period. Individuals who presented with sputum conversion at ≤8 weeks are depicted in red, individual who presented with sputum culture conversion between 12 and 26 weeks are depicted in blue and individuals where sputum culture conversion occurred after 26 weeks of TB therapy are shown in green. (A) Plasma cytokine levels (IL-2, IL-5, IL-13, G-CSF, IL-12, PDGF-BB, IL-7, IL-9, IFN-γ, MIP-1β, IL-4 and IL-10) showing no significant change overtime. (B) Plasma cytokine levels (IL-1RA, IL-6, Eotaxin, FGF-basic, IL-17, TNF-α, GM-CSF, MCP-1, IL-1β and IL-15) fluctuating overtime. (C) Plasma cytokines (IP-10 and VEGF) presenting significant changes over time. Each dot represents one individual (n = 20). Results are expressed as pg/ml of plasma. Dotted lines represent the limit of detection for each cytokine. Gray shaded box (on the first graph) represents the duration of TB therapy; dark gray box depicts the intensive phase of treatment, including rifampicin, isoniazid, pyrazinamide and ethambutol, while light gray box corresponds to the second phase of treatment with rifampicin and isoniazid. Statistical analyses were performed using non-parametric one-way ANOVA Kruskal-Wallis Tests (*: p<0.05, **: p<0.01, ***: P<0.001). Numerical p-values, reflecting the overall changes in IP-10 and VEGF expression levels, have been determined using random-effects linear regression. The x-axis (time after the initiation of treatment in weeks) has been logged to allow better visualization of cytokine expression levels at early time points.

Mentions: To define the impact of a 26-week course of TB therapy on cytokine expression profiles, we compared the concentrations of cytokines before (BL: Baseline), during (2, 4, 8, 12 and 26 weeks) and after (52 and 78 weeks) TB therapy. When analyzing the profile of each cytokine separately in TB+HIV− individuals (Figure 3), we identified three distinct response patterns: (i) No significant changes of the median cytokine concentrations over the studied period. Twelve cytokines followed this pattern including IL-4, IL-10, IL-2, IL-5, IL-7, IL-9, IL-13, G-CSF, IFN-γ, MIP-1α, IL-12(p70) and PDGF-BB (Figure 3A); (ii) Fluctuations in cytokine concentrations over the studied period (IL-1β, IL-6, IL-1RA, IL-15, IL-17, TNF-α, Eotaxin, FGF-basic, GM-CSF and MCP-1) (Figure 3B) and (iii) Significant decrease of the median cytokine levels over time. This latter profile was observed for IP-10 (chemoattractant) and VEGF (growth factor) (Figure 3C). Significant declines in IP-10 and VEGF concentrations during the course of TB treatment were confirmed using two different types of statistical analyses: A non-parametric one-way ANOVA Kruskal-Wallis test, assessing the change in cytokine concentrations between individual time-points, and random-effects linear regression evaluating the overall trend in log-transformed cytokine concentrations over time, with study participants matched at each time-point.


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)

Longitudinal assessment of plasma cytokine expression levels before, during and after TB therapy in TB+HIV− individuals. The concentration of each cytokine has been measured at baseline, 2, 4, 8, 12, 26, 52, 78 weeks after the initiation of a 26- week treatment period. Individuals who presented with sputum conversion at ≤8 weeks are depicted in red, individual who presented with sputum culture conversion between 12 and 26 weeks are depicted in blue and individuals where sputum culture conversion occurred after 26 weeks of TB therapy are shown in green. (A) Plasma cytokine levels (IL-2, IL-5, IL-13, G-CSF, IL-12, PDGF-BB, IL-7, IL-9, IFN-γ, MIP-1β, IL-4 and IL-10) showing no significant change overtime. (B) Plasma cytokine levels (IL-1RA, IL-6, Eotaxin, FGF-basic, IL-17, TNF-α, GM-CSF, MCP-1, IL-1β and IL-15) fluctuating overtime. (C) Plasma cytokines (IP-10 and VEGF) presenting significant changes over time. Each dot represents one individual (n = 20). Results are expressed as pg/ml of plasma. Dotted lines represent the limit of detection for each cytokine. Gray shaded box (on the first graph) represents the duration of TB therapy; dark gray box depicts the intensive phase of treatment, including rifampicin, isoniazid, pyrazinamide and ethambutol, while light gray box corresponds to the second phase of treatment with rifampicin and isoniazid. Statistical analyses were performed using non-parametric one-way ANOVA Kruskal-Wallis Tests (*: p<0.05, **: p<0.01, ***: P<0.001). Numerical p-values, reflecting the overall changes in IP-10 and VEGF expression levels, have been determined using random-effects linear regression. The x-axis (time after the initiation of treatment in weeks) has been logged to allow better visualization of cytokine expression levels at early time points.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3351475&req=5

pone-0036886-g003: Longitudinal assessment of plasma cytokine expression levels before, during and after TB therapy in TB+HIV− individuals. The concentration of each cytokine has been measured at baseline, 2, 4, 8, 12, 26, 52, 78 weeks after the initiation of a 26- week treatment period. Individuals who presented with sputum conversion at ≤8 weeks are depicted in red, individual who presented with sputum culture conversion between 12 and 26 weeks are depicted in blue and individuals where sputum culture conversion occurred after 26 weeks of TB therapy are shown in green. (A) Plasma cytokine levels (IL-2, IL-5, IL-13, G-CSF, IL-12, PDGF-BB, IL-7, IL-9, IFN-γ, MIP-1β, IL-4 and IL-10) showing no significant change overtime. (B) Plasma cytokine levels (IL-1RA, IL-6, Eotaxin, FGF-basic, IL-17, TNF-α, GM-CSF, MCP-1, IL-1β and IL-15) fluctuating overtime. (C) Plasma cytokines (IP-10 and VEGF) presenting significant changes over time. Each dot represents one individual (n = 20). Results are expressed as pg/ml of plasma. Dotted lines represent the limit of detection for each cytokine. Gray shaded box (on the first graph) represents the duration of TB therapy; dark gray box depicts the intensive phase of treatment, including rifampicin, isoniazid, pyrazinamide and ethambutol, while light gray box corresponds to the second phase of treatment with rifampicin and isoniazid. Statistical analyses were performed using non-parametric one-way ANOVA Kruskal-Wallis Tests (*: p<0.05, **: p<0.01, ***: P<0.001). Numerical p-values, reflecting the overall changes in IP-10 and VEGF expression levels, have been determined using random-effects linear regression. The x-axis (time after the initiation of treatment in weeks) has been logged to allow better visualization of cytokine expression levels at early time points.
Mentions: To define the impact of a 26-week course of TB therapy on cytokine expression profiles, we compared the concentrations of cytokines before (BL: Baseline), during (2, 4, 8, 12 and 26 weeks) and after (52 and 78 weeks) TB therapy. When analyzing the profile of each cytokine separately in TB+HIV− individuals (Figure 3), we identified three distinct response patterns: (i) No significant changes of the median cytokine concentrations over the studied period. Twelve cytokines followed this pattern including IL-4, IL-10, IL-2, IL-5, IL-7, IL-9, IL-13, G-CSF, IFN-γ, MIP-1α, IL-12(p70) and PDGF-BB (Figure 3A); (ii) Fluctuations in cytokine concentrations over the studied period (IL-1β, IL-6, IL-1RA, IL-15, IL-17, TNF-α, Eotaxin, FGF-basic, GM-CSF and MCP-1) (Figure 3B) and (iii) Significant decrease of the median cytokine levels over time. This latter profile was observed for IP-10 (chemoattractant) and VEGF (growth factor) (Figure 3C). Significant declines in IP-10 and VEGF concentrations during the course of TB treatment were confirmed using two different types of statistical analyses: A non-parametric one-way ANOVA Kruskal-Wallis test, assessing the change in cytokine concentrations between individual time-points, and random-effects linear regression evaluating the overall trend in log-transformed cytokine concentrations over time, with study participants matched at each time-point.

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