Biomarkers that correlate with active pulmonary tuberculosis treatment response: a systematic review and meta-analysis

Abstract

Background Current WHO recommendations for monitoring treatment response in adult pulmonary tuberculosis (TB) are sputum smear microscopy and/or culture conversion at the end of the intensive phase of treatment. These methods either have sub-optimal accuracy or a long turn-around time. There is a need to identify alternative biomarkers to monitor TB treatment response. Methods We conducted a systematic review of active pulmonary TB treatment monitoring biomarkers. We screened 9,739 articles published between January 1 st 2008 and December 31 st 2020, of which 77 met the inclusion criteria. When studies quantitatively reported biomarker levels, we meta-analyzed the average fold change in biomarkers from pre-treatment to week 8 of treatment. We also performed a meta-analysis pooling the fold-change since previous time point collected. Results A total of 81 biomarkers were identified from 77 studies. Overall, these studies exhibited extensive heterogeneity with regard to TB treatment monitoring study design and data reporting. Among the biomarkers identified, CRP, IL-6, IP-10 and TNF-α had sufficient data to analyze fold-changes. All four biomarker levels decreased during the first 8 weeks of treatment relative to baseline and relative to previous time points collected. Conclusion Based on limited data available, CRP, IL-6, IP-10 and TNF-α have been identified as biomarkers that should be further explored in the context of TB treatment monitoring. The extensive heterogeneity in TB treatment monitoring study design and reporting is a major barrier to evaluating the performance of novel biomarkers and tools for this use case. Guidance for designing and reporting treatment monitoring studies are urgently needed.