IP-10 Kinetics in the First Week of Therapy are Strongly Associated with Bacteriological Confirmation of Tuberculosis Diagnosis in HIV-Infected Patients

Abstract

Simple effective tools to monitor the long treatment of tuberculosis (TB) are lacking. Easily measured host derived biomarkers have been identified but need to be validated in larger studies and different population groups. Here we investigate the early response in IP-10 levels (between day 0 and day 7 of TB therapy) to identify bacteriological status at diagnosis among 127 HIV-infected patients starting TB treatment. All participants were then classified as responding or not responding to treatment blindly using a previously described IP-10 kinetic algorithm. There were 77 bacteriologically confirmed cases and 41 Xpert MTB/RIF® and culture negative cases. Most participants had a measurable decline in IP-10 during the first 7 days of therapy. Bacteriologically confirmed cases were more likely to have high IP-10 levels at D0 and had a steeper decline than clinically diagnosed cases (mean decline difference 2231 pg/dl, 95% CI: 897–3566, p = 0.0013). Bacteriologically confirmed cases were more likely to have a measurable decline in IP-10 at day 7 than clinically diagnosed cases (48/77 (62.3%) vs 13/41 (31.7%), p < 0.001). This study confirms the association between a decrease in IP-10 levels during the first week of treatment and a bacteriological confirmation at diagnosis in a large cohort of HIV positive patients.

Urine IP-10 as a biomarker of therapeutic response in patients with active pulmonary tuberculosis

“…However, this study also detected urine IP-10 levels after 2 months of an intensive anti-TB drug therapy, which is the point when clinicians routinely use radiological and bacteriological tests to determine treatment progress. Although recent studies have reported a decline in blood IP-10 levels after 2 weeks of efficient anti-TB drug therapy as an early biomarker for treatment response [ 21 , 22 ], this study demonstrated a peak in urine IP-10 levels after 2 months of treatment in HIV-negative patients with tuberculosis. Moreover, the same trend was observed in patients regardless of risk factors for TB relapse or treatment failure.…”

First description of agonist and antagonist IP-10 in urine of patients with active TB

“…Furthermore, the identification of new additional post-translational modifications of IP-10 and their role in TB pathogenesis may also be explored. Importantly, the "end therapy" time point differs between active TB and pneumonia patients (6 months vs 1 month), however, different drug regimens are expected for these diseases; shorter time courses during therapy, as previously described (Garcia-Basteiro et al, 2017), will better highlight the differences of IP-10 and its agonist/antagonist levels in urine.…”

“…Therefore, additional tests and new biomarkers for predicting treatment efficacy are needed. Blood IP-10 has been demonstrated as an early predictor of treatment response as its levels rapidly decrease in the first week of treatment, mainly in microbiologically confirmed active TB with or without HIV infection (Garcia-Basteiro et al, 2017;den Hertog et al, 2015;Chung et al, 2016). In this study we found declining levels of total and agonist/antagonist IP-10 forms in urine of patients with active TB during specific therapy but not in patients with pneumonia, suggesting that modifications of IP-10 forms during therapy may be associated to TB disease.…”

“…Indeed, IP-10 production by nonclassical CD14 dim monocytes strongly correlated with Bacillus Calmette-Guérin (BCG) growth reduction in the mycobacterial growth inhibition assay (MGIA) and pharmacological blockade of CXCR3 reverted mycobacterial growth control (Joosten et al, 2018). A prospective evaluation of IP-10 levels has been performed in Human Immunodeficiency Virus (HIV)-infected subjects with active TB where blood IP-10 levels have been demonstrated to be a useful early biomarker for treatment response, as it declines after 2 weeks of anti-TB specific treatment (Garcia-Basteiro et al, 2017).…”

IP-10 dried blood spots assay monitoring treatment efficacy in extrapulmonary tuberculosis in a low-resource setting

“…It has recently been demonstrated that IP-10 secretion during TB disease originates from infected macrophages and multinucleated giant cells located in the granulomas, and early inactivation of the secreted chemokine by antagonist form of IP-10 which binds to CXCR3 but does not induce signalling, may also play a role in the pathogenesis of TB 51,52 . Several studies show that IP-10 declines during efficient treatment of many diseases including TB 25,38,42,53,54 . Limited data also indicates that IP-10 increases in non-cured TB patients from baseline to 2 months of treatment, and in TB patients who relapse or develop active TB disease 25,55 .…”