Peripheral Blood Biomarkers Related To Preventive Treatment Of Latent Tuberculosis Infection In Middle-aged And Elderly People

Background:Latent tuberculosis infection(LTBI)testing and treatment among individuals at high-risk of developing active disease is a critical way to directly reduce the tuberculosis(TB)incidence.At present,directly observe the declined incidence is the standard method to evaluate the protective effect of preventive treatment,which usually requires a long follow-up time and huge resource investment.Recently,a large number of studies have been conducted to dynamically observe the changes of interferon gamma releasing assays(IGRAs)results,immunological methods for LTBI detection,during the preventive treatment.But the results of different studies were inconsistent.Few studies have been conducted to assess the performance of serum cytokines in monitoring the response to preventive treatment and predicting the development of active disease.Therefore,more studies are needed to identify potential biomarkers reflecting host responses to LTBI treatment.Methods:Based on a randomized controlled trial(RCT)for LTBI treatment in participants positive for a commercial IGRAs(QuantiFERON-TB Gold In-Tube,QFT-GIT),all eligible participants were randomly classified into three groups(Group A:treated with 8 weeks regimen of once-weekly RPT plus INH;Group B:treated with 6 weeks of twice-weekly RPT plus INH;Group C:untreated controls).During the 2-year follow-up to track active TB development,QFT-GIT tests were repeated three times in total:before treatment(TO),upon completion of treatment(T1),three months after completion of treatment(T2).Participants who completed the assigned regimes and with available QFT-GIT results at all three times were included in this analysis of the relationship between the dynamic changes of interferon-gamma(IFN-y)level in whole blood stimulated by the mycobacteria-specific antigens and preventive treatment.The dynamic changes of forty-eight serum cytokines were determined by bead-based multiplex assays for the participants who developed active TB during follow-up being matched with healthy controls on age and gender.Participants with available blood samples and who completed the assigned regimes were included in the analysis to identify potential cytokine biomarkers in unstimulated serum samples associated with prophylactic treatment which might also predict the development of TB from LTBI.Results:1)No significant difference was found in rates of persistent QFT-GIT reversion among Group A(19.0%,173/910),Group B(18.5%,165/890)and Group C(20.7%,169/818)(p=0.512).There was no significant difference in the dynamic changes of IFN-y levels among the three groups either.In treated participants,subjects with higher baseline IFN-y levels had an increased risk of TB occurrence(1.0%,9/896)than those with lower baseline levels(0.2%,2/904)(p=0.037).Similar trend was also observed in untreated controls,but it's not significant(p=0.100).When TB cases were matched with non-TB cases on baseline IFN-y levels,there were no significant differences being found with regard to the dynamic changes in IFN-y levels with time regardless if treated or not.2)A total of 21 individuals who were diagnosed with active TB during the 2-year follow-up(12 from treated participants and 9 from untreated controls)were matched with 42 healthy controls(24 from treated participants and 18 from untreated controls)on age and gender to analyze serum cytokines.At T0,the levels of the 16 cytokines(Eotaxin,MIP-1?,VEGF-A,Basic FGF,G-CSF,MCP-1(MCAF),SDF-1?,IFN-?,TNF-?,IL-1ra,TRAIL,IL-4,IL-l?,IL-8,IL-9 and IL-17A)were significantly higher in active TB patients than non-TB controls.In treated participants,the levels of IL-1ra were significantly reduced after preventive treatment in active TB group(p=0.002)and non-TB group(p=0.009).In untreated participants,there was no significant change in levels of IL-1ra after preventive treatment in active TB group(p=0.078)and non-TB group(p=0.265).Conclusions:Our results suggested that QFT-GIT reversion or decreased releasing of IFN-y should not be a biomarker to monitor host response to LTBI treatment.The serum level of IL-1ra decreased along with preventive treatment,which might also be a potential biomarker to evaluate the treatment efficacy.