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Sustained elevated levels of C-reactive protein and ferritin in pulmonary tuberculosis patients remaining culture positive upon treatment initiation

View Article: PubMed Central - PubMed

ABSTRACT

Background: Clinical trials that evaluate new anti-tubercular drugs and treatment regimens take years to complete due to the slow clearance of Mycobacterium tuberculosis infection and the lack of early biomarkers that predict treatment outcomes. Host Inflammation markers have been associated with tuberculosis (TB) pathogenesis. In the present study, we tested if circulating levels of C-reactive protein (CRP) and ferritin reflect mycobacterial loads and inflammation in pulmonary TB (PTB) patients undergoing anti-tuberculous therapy (ATT).

Methods: Prospective measurements of CRP and ferritin, used as readouts of systemic inflammation, were performed in cryopreserved serum samples from 165 Brazilian patients with active PTB initiating ATT. Associations between levels of these laboratory parameters with mycobacterial loads in sputum as well as with sputum conversion at day 60 of ATT were tested.

Results: Circulating levels of both ferritin and CRP gradually decreased over time on ATT. At pre-treatment, concentrations of these parameters were unable to distinguish patients with positive from those with negative acid-fast bacilli (AFB) in sputum cultures. However, patients who remained with positive cultures at day 60 of ATT exhibited heightened levels of these inflammatory markers compared to those with negative cultures at that time point.

Conclusions: CRP and Ferritin levels in serum may be useful to identify patients with positive cultures at day 60 of ATT.

No MeSH data available.


Related in: MedlinePlus

Pulmonary TB patients remaining with culture positive after 60 days of ATT displayed heightened levels of serum ferritin than those who had negative cultures.(A) Changes in hemoglobin levels following initiation of ATT are shown. (B) Hemoglobin levels upon ATT initiation in TB patients whose sputum cultures became negative at day 60 of ATT and in those who remained culture positive. (C) Serum concentrations of CRP and ferritin were compared between the indicated timepoints of ATT in the group of TB patients whose sputum cultures became negative at day 60 of ATT and in that of patients who remained culture positive. In (A), (B) and (C), data were compared using Kruskal Wallis test with non-parametric linear trend ad hoc test or Dunn’s multiple comparisons (for CRP). Statistically significant differences are highlighted. (D) CRP and Ferritin levels were compared between individuals with culture negative and those with culture positive at day 60 of ATT using the Mann-Whitney U test. (E) Performance of each marker in identifying patients who had positive cultures at day 60 of ATT was tested using Receiver Operator Characteristics (ROC) curve analysis.
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pone.0175278.g003: Pulmonary TB patients remaining with culture positive after 60 days of ATT displayed heightened levels of serum ferritin than those who had negative cultures.(A) Changes in hemoglobin levels following initiation of ATT are shown. (B) Hemoglobin levels upon ATT initiation in TB patients whose sputum cultures became negative at day 60 of ATT and in those who remained culture positive. (C) Serum concentrations of CRP and ferritin were compared between the indicated timepoints of ATT in the group of TB patients whose sputum cultures became negative at day 60 of ATT and in that of patients who remained culture positive. In (A), (B) and (C), data were compared using Kruskal Wallis test with non-parametric linear trend ad hoc test or Dunn’s multiple comparisons (for CRP). Statistically significant differences are highlighted. (D) CRP and Ferritin levels were compared between individuals with culture negative and those with culture positive at day 60 of ATT using the Mann-Whitney U test. (E) Performance of each marker in identifying patients who had positive cultures at day 60 of ATT was tested using Receiver Operator Characteristics (ROC) curve analysis.

Mentions: Considering that circulating levels of both CRP and ferritin usually reflect the degree of systemic inflammation, we tested the hypothesis that patients remaining with positive M. tuberculosis cultures at day 60 of ATT would persist with high levels of these markers, meaning residual inflammation. Of note, hemoglobin levels did not significantly change from pre-ATT to day 30 or 60 of treatment in the entire study population (Fig 3A). In addition, at these time points, hemoglobin levels could not distinguish patients remaining M. tuberculosis culture positive from those who exhibited negative cultures at day 60 (Fig 3B). These findings suggest that the effects of ATT on hemoglobin levels may require more time to happen, at least in the study population. Nevertheless, in the group of individuals who became culture negative at day 60 of treatment, both CRP and ferritin levels displayed a significant trend to gradually decrease after treatment initiation (Fig 3C). In patients who remained culture positive at day 60, ferritin levels also exhibited a gradual trend to decrease compared to pre-treatment measurements (Fig 3C). Intriguingly, in this group of patients, CRP concentrations significantly decreased by day 30 (p = 0.025), but were further unchanged by day 60 of ATT (Fig 3C). We next compared CRP and ferritin levels measured at day 60 of ATT between these groups of patients diverging in terms of M. tuberculosis culture conversion. Concentrations of both CRP and ferritin were found to be higher in patients who remained culture positive at day 60 than those who became culture negative (Fig 3D). Receiver Operator Characteristics (ROC) curve analysis revealed that both markers exhibited good performance in distinguishing patients with positive or negative cultures at day 60 of ATT (Fig 3E). In this discriminant analysis, CRP levels displayed higher sensitivity than ferritin concentrations (87.5% vs. 77.8%, respectively) while the latter exhibited increased specificity (81.1% vs. 72.9%) (Fig 3E). Interesting, a logistic regression model revealed that associations between heightened ferritin levels at day 60 and positive cultures at that time point (unadjusted Odds ratio [OR]: 2.05, 95% confidence interval [CI]: 1.15–3.58, p = 0.003) persisted after adjustment for age, gender, BMI, HIV infection status and CRP levels (adjusted OR: 1.54, 95% CI: 1.18–2.32, p = 0.025).


Sustained elevated levels of C-reactive protein and ferritin in pulmonary tuberculosis patients remaining culture positive upon treatment initiation
Pulmonary TB patients remaining with culture positive after 60 days of ATT displayed heightened levels of serum ferritin than those who had negative cultures.(A) Changes in hemoglobin levels following initiation of ATT are shown. (B) Hemoglobin levels upon ATT initiation in TB patients whose sputum cultures became negative at day 60 of ATT and in those who remained culture positive. (C) Serum concentrations of CRP and ferritin were compared between the indicated timepoints of ATT in the group of TB patients whose sputum cultures became negative at day 60 of ATT and in that of patients who remained culture positive. In (A), (B) and (C), data were compared using Kruskal Wallis test with non-parametric linear trend ad hoc test or Dunn’s multiple comparisons (for CRP). Statistically significant differences are highlighted. (D) CRP and Ferritin levels were compared between individuals with culture negative and those with culture positive at day 60 of ATT using the Mann-Whitney U test. (E) Performance of each marker in identifying patients who had positive cultures at day 60 of ATT was tested using Receiver Operator Characteristics (ROC) curve analysis.
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Related In: Results  -  Collection

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pone.0175278.g003: Pulmonary TB patients remaining with culture positive after 60 days of ATT displayed heightened levels of serum ferritin than those who had negative cultures.(A) Changes in hemoglobin levels following initiation of ATT are shown. (B) Hemoglobin levels upon ATT initiation in TB patients whose sputum cultures became negative at day 60 of ATT and in those who remained culture positive. (C) Serum concentrations of CRP and ferritin were compared between the indicated timepoints of ATT in the group of TB patients whose sputum cultures became negative at day 60 of ATT and in that of patients who remained culture positive. In (A), (B) and (C), data were compared using Kruskal Wallis test with non-parametric linear trend ad hoc test or Dunn’s multiple comparisons (for CRP). Statistically significant differences are highlighted. (D) CRP and Ferritin levels were compared between individuals with culture negative and those with culture positive at day 60 of ATT using the Mann-Whitney U test. (E) Performance of each marker in identifying patients who had positive cultures at day 60 of ATT was tested using Receiver Operator Characteristics (ROC) curve analysis.
Mentions: Considering that circulating levels of both CRP and ferritin usually reflect the degree of systemic inflammation, we tested the hypothesis that patients remaining with positive M. tuberculosis cultures at day 60 of ATT would persist with high levels of these markers, meaning residual inflammation. Of note, hemoglobin levels did not significantly change from pre-ATT to day 30 or 60 of treatment in the entire study population (Fig 3A). In addition, at these time points, hemoglobin levels could not distinguish patients remaining M. tuberculosis culture positive from those who exhibited negative cultures at day 60 (Fig 3B). These findings suggest that the effects of ATT on hemoglobin levels may require more time to happen, at least in the study population. Nevertheless, in the group of individuals who became culture negative at day 60 of treatment, both CRP and ferritin levels displayed a significant trend to gradually decrease after treatment initiation (Fig 3C). In patients who remained culture positive at day 60, ferritin levels also exhibited a gradual trend to decrease compared to pre-treatment measurements (Fig 3C). Intriguingly, in this group of patients, CRP concentrations significantly decreased by day 30 (p = 0.025), but were further unchanged by day 60 of ATT (Fig 3C). We next compared CRP and ferritin levels measured at day 60 of ATT between these groups of patients diverging in terms of M. tuberculosis culture conversion. Concentrations of both CRP and ferritin were found to be higher in patients who remained culture positive at day 60 than those who became culture negative (Fig 3D). Receiver Operator Characteristics (ROC) curve analysis revealed that both markers exhibited good performance in distinguishing patients with positive or negative cultures at day 60 of ATT (Fig 3E). In this discriminant analysis, CRP levels displayed higher sensitivity than ferritin concentrations (87.5% vs. 77.8%, respectively) while the latter exhibited increased specificity (81.1% vs. 72.9%) (Fig 3E). Interesting, a logistic regression model revealed that associations between heightened ferritin levels at day 60 and positive cultures at that time point (unadjusted Odds ratio [OR]: 2.05, 95% confidence interval [CI]: 1.15–3.58, p = 0.003) persisted after adjustment for age, gender, BMI, HIV infection status and CRP levels (adjusted OR: 1.54, 95% CI: 1.18–2.32, p = 0.025).

View Article: PubMed Central - PubMed

ABSTRACT

Background: Clinical trials that evaluate new anti-tubercular drugs and treatment regimens take years to complete due to the slow clearance of Mycobacterium tuberculosis infection and the lack of early biomarkers that predict treatment outcomes. Host Inflammation markers have been associated with tuberculosis (TB) pathogenesis. In the present study, we tested if circulating levels of C-reactive protein (CRP) and ferritin reflect mycobacterial loads and inflammation in pulmonary TB (PTB) patients undergoing anti-tuberculous therapy (ATT).

Methods: Prospective measurements of CRP and ferritin, used as readouts of systemic inflammation, were performed in cryopreserved serum samples from 165 Brazilian patients with active PTB initiating ATT. Associations between levels of these laboratory parameters with mycobacterial loads in sputum as well as with sputum conversion at day 60 of ATT were tested.

Results: Circulating levels of both ferritin and CRP gradually decreased over time on ATT. At pre-treatment, concentrations of these parameters were unable to distinguish patients with positive from those with negative acid-fast bacilli (AFB) in sputum cultures. However, patients who remained with positive cultures at day 60 of ATT exhibited heightened levels of these inflammatory markers compared to those with negative cultures at that time point.

Conclusions: CRP and Ferritin levels in serum may be useful to identify patients with positive cultures at day 60 of ATT.

No MeSH data available.


Related in: MedlinePlus