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

Abstract

BackgroundMany 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.MethodsWe 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.ResultsChanges 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.ConclusionsMonitoring 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.

Individualizing management of extensively drug-resistant tuberculosis: diagnostics, treatment, and biomarkers

“…Detailed studies focused on disclosure of patient biomarker with prognostic profiles to demonstrate the disease or treatment success, but remained elusive [76,77]. None the less, the kinetics of nonspecific disease-associated biomarkers are increasingly recognized as having potential for the monitoring of treatment success and could play a role in guiding the therapy of complex (M[X]DR-TB) cases [78,79]. Host-derived markers are universally present in healthy and disease individuals and the levels present in healthy individuals are in almost all cases already established.…”

“…Early evidence suggests that these responses will be informative before culture or microscopic conversion is currently detected [78,79,89,90]. Thus, as measuring the response of host biomarker kinetics has the potential to be both simple and rapid [91], measuring biomarkers deserve attention.…”

“…The kinetics of the most promising biomarkers are now being validated in independent studies and initial data suggest that at least some the associations identified are reproducible [78,79,90,97]. Differences in host marker responses between sensitive and MDR-TB patients have been observed.…”

Current status and opportunities for therapeutic drug monitoring in the treatment of tuberculosis

“…Some of these biomarkers have the potential for point-of-care measurement, notably IP-10. [63,64] The clinical value for treatment optimization and the predictive power of these markers needs to be established in larger trials in different patient populations. To date, no biomarkers have been included in treatment evaluation.…”

“…TB is associated with increased serum IP-10 levels [93,[95][96][97], and at completion of therapy, levels are significantly lower than before treatment/at diagnosis. [64,98,99] This decrease is also measurable in the first weeks of therapy, [63,93] and therefore measurement of the kinetics of this cytokine during treatment may provide useful information on whether patients are responding to the prescribed drugs. It is also notable that host markers are present and detectable in all individuals.…”