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Cytokine Kinetics in the First Week of Tuberculosis Therapy as a Tool to Confirm a Clinical Diagnosis and Guide Therapy.

den Hertog AL, Montero-Martín M, Saunders RL, Blakiston M, Menting S, Sherchand JB, Lawson L, Oladimeji O, Abdurrahman ST, Cuevas LE, Anthony RM - PLoS ONE (2015)

Bottom Line: Changes in concentrations of non-specific host biomarkers, particularly IP-10, in response to the first week of anti-TB therapy were strongly associated with bacteriological confirmation of TB.A decrease in IP-10 level of >300pg/ml between 0 and 7 days of treatment identified 75% of both smear-positive and smear-negative culture positive patients and correctly excluded TB in all nine culture negative patients.We believe this approach may be particularly appropriate for difficult to diagnose patients, e.g. smear-negative HIV-positive, or those with extra-pulmonary TB, often treated without bacterial confirmation.

View Article: PubMed Central - PubMed

Affiliation: Royal Tropical Institute (KIT), KIT Biomedical Research, Amsterdam, The Netherlands.

ABSTRACT

Background: Many patients treated for tuberculosis (TB) in low and middle income countries are treated based on clinical suspicion without bacteriological confirmation. This is often due to lack of rapid simple accurate diagnostics and low healthcare provider confidence in the predictive value of current tests. We previously reported in an animal TB model that levels of host markers rapidly change in response to treatment initiation.

Methods: We assessed the potential of host biomarker kinetics of TB patients during the first two weeks of therapy to identify patients responding to treatment. Adult patients clinically diagnosed with and treated for TB, 29 in Nigeria and 24 in Nepal, were analyzed.

Results: Changes in concentrations of non-specific host biomarkers, particularly IP-10, in response to the first week of anti-TB therapy were strongly associated with bacteriological confirmation of TB. A decrease in IP-10 level of >300pg/ml between 0 and 7 days of treatment identified 75% of both smear-positive and smear-negative culture positive patients and correctly excluded TB in all nine culture negative patients.

Conclusions: Monitoring of early IP-10 responses to treatment could form the basis of a simplified assay and could help identify patients who were erroneously clinically diagnosed with TB or those infected with drug resistant strains on inappropriate treatment. We believe this approach may be particularly appropriate for difficult to diagnose patients, e.g. smear-negative HIV-positive, or those with extra-pulmonary TB, often treated without bacterial confirmation.

No MeSH data available.


Related in: MedlinePlus

Serum IL-6 levels of TB patients at day 0 and day 7 of therapy.See legend Fig 2 for details on the panels and labels. Between day 0 and day 7, for culture/GeneXpert positive patients p<0.001; between day 0 and day 7, for culture/GeneXpert negative patients, p<0.05.
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pone.0129552.g004: Serum IL-6 levels of TB patients at day 0 and day 7 of therapy.See legend Fig 2 for details on the panels and labels. Between day 0 and day 7, for culture/GeneXpert positive patients p<0.001; between day 0 and day 7, for culture/GeneXpert negative patients, p<0.05.

Mentions: IFNγ, IL-6, and TNFα concentrations showed similar patterns as IP-10, although in a lower concentration range (Fig 3, Fig 4, Fig 5, S2 Fig, S3 Fig, S4 Fig, S5 Fig). TNFα decreased in culture/GeneXpert positive patients (p<0.001 for the overall difference between days 0 and day 7, p-values between 0.02 and 0.5 for individual smear positive and negative, HIV positive and negative subgroups), and no significant change was seen in culture/GeneXpert negative patients (p>0.05). IFNγ and IL-6 levels in culture/GeneXpert positive patients decreased between days 0 and 7 (overall both p<0.0001) and changes were weakly significant in culture/GeneXpert negative patients (p = 0.05 and 0.03, respectively). In ROC analysis of these cytokine shifts to identify patients receiving appropriate treatment, the areas under the curve (AUC) were 0.78 [95% CI 0.63–0.94], p>0.01 for IFNγ, 0.80 [95% CI 0.65–0.95], p<0.01 for IL-6, and 0.64 [95% CI 0.46 to 0.82], p>0.05 for TNFα, respectively (Panels B-D in S2 Fig). MIG serum levels in culture/GeneXpert positive patients decreased between days 0 and 5 to 7 (p<0.001; Fig 6, S6 Fig). However median concentrations had returned to enrolment values by day 14. This transient decrease in MIG was not observed in culture-negative patients (p>0.05). In ROC analysis performed as described above, AUC for the day 0-day7 change in MIG levels was 0.81 [95% CI 0.69 to 0.94], p<0.01 (Panel E in S2 Fig).


Cytokine Kinetics in the First Week of Tuberculosis Therapy as a Tool to Confirm a Clinical Diagnosis and Guide Therapy.

den Hertog AL, Montero-Martín M, Saunders RL, Blakiston M, Menting S, Sherchand JB, Lawson L, Oladimeji O, Abdurrahman ST, Cuevas LE, Anthony RM - PLoS ONE (2015)

Serum IL-6 levels of TB patients at day 0 and day 7 of therapy.See legend Fig 2 for details on the panels and labels. Between day 0 and day 7, for culture/GeneXpert positive patients p<0.001; between day 0 and day 7, for culture/GeneXpert negative patients, p<0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482639&req=5

pone.0129552.g004: Serum IL-6 levels of TB patients at day 0 and day 7 of therapy.See legend Fig 2 for details on the panels and labels. Between day 0 and day 7, for culture/GeneXpert positive patients p<0.001; between day 0 and day 7, for culture/GeneXpert negative patients, p<0.05.
Mentions: IFNγ, IL-6, and TNFα concentrations showed similar patterns as IP-10, although in a lower concentration range (Fig 3, Fig 4, Fig 5, S2 Fig, S3 Fig, S4 Fig, S5 Fig). TNFα decreased in culture/GeneXpert positive patients (p<0.001 for the overall difference between days 0 and day 7, p-values between 0.02 and 0.5 for individual smear positive and negative, HIV positive and negative subgroups), and no significant change was seen in culture/GeneXpert negative patients (p>0.05). IFNγ and IL-6 levels in culture/GeneXpert positive patients decreased between days 0 and 7 (overall both p<0.0001) and changes were weakly significant in culture/GeneXpert negative patients (p = 0.05 and 0.03, respectively). In ROC analysis of these cytokine shifts to identify patients receiving appropriate treatment, the areas under the curve (AUC) were 0.78 [95% CI 0.63–0.94], p>0.01 for IFNγ, 0.80 [95% CI 0.65–0.95], p<0.01 for IL-6, and 0.64 [95% CI 0.46 to 0.82], p>0.05 for TNFα, respectively (Panels B-D in S2 Fig). MIG serum levels in culture/GeneXpert positive patients decreased between days 0 and 5 to 7 (p<0.001; Fig 6, S6 Fig). However median concentrations had returned to enrolment values by day 14. This transient decrease in MIG was not observed in culture-negative patients (p>0.05). In ROC analysis performed as described above, AUC for the day 0-day7 change in MIG levels was 0.81 [95% CI 0.69 to 0.94], p<0.01 (Panel E in S2 Fig).

Bottom Line: Changes in concentrations of non-specific host biomarkers, particularly IP-10, in response to the first week of anti-TB therapy were strongly associated with bacteriological confirmation of TB.A decrease in IP-10 level of >300pg/ml between 0 and 7 days of treatment identified 75% of both smear-positive and smear-negative culture positive patients and correctly excluded TB in all nine culture negative patients.We believe this approach may be particularly appropriate for difficult to diagnose patients, e.g. smear-negative HIV-positive, or those with extra-pulmonary TB, often treated without bacterial confirmation.

View Article: PubMed Central - PubMed

Affiliation: Royal Tropical Institute (KIT), KIT Biomedical Research, Amsterdam, The Netherlands.

ABSTRACT

Background: Many patients treated for tuberculosis (TB) in low and middle income countries are treated based on clinical suspicion without bacteriological confirmation. This is often due to lack of rapid simple accurate diagnostics and low healthcare provider confidence in the predictive value of current tests. We previously reported in an animal TB model that levels of host markers rapidly change in response to treatment initiation.

Methods: We assessed the potential of host biomarker kinetics of TB patients during the first two weeks of therapy to identify patients responding to treatment. Adult patients clinically diagnosed with and treated for TB, 29 in Nigeria and 24 in Nepal, were analyzed.

Results: Changes in concentrations of non-specific host biomarkers, particularly IP-10, in response to the first week of anti-TB therapy were strongly associated with bacteriological confirmation of TB. A decrease in IP-10 level of >300pg/ml between 0 and 7 days of treatment identified 75% of both smear-positive and smear-negative culture positive patients and correctly excluded TB in all nine culture negative patients.

Conclusions: Monitoring of early IP-10 responses to treatment could form the basis of a simplified assay and could help identify patients who were erroneously clinically diagnosed with TB or those infected with drug resistant strains on inappropriate treatment. We believe this approach may be particularly appropriate for difficult to diagnose patients, e.g. smear-negative HIV-positive, or those with extra-pulmonary TB, often treated without bacterial confirmation.

No MeSH data available.


Related in: MedlinePlus