Biomarkers That Correlate with Active Pulmonary Tuberculosis Treatment Response: a Systematic Review and Meta-analysis

Abstract

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 suboptimal accuracy or a long turnaround time. There is a need to identify alternative biomarkers to monitor TB treatment response. We conducted a systematic review of active pulmonary TB treatment monitoring biomarkers. We screened 9,739 articles published between 1 January 2008 and 31 December 2020, of which 77 met the inclusion criteria. When studies quantitatively reported biomarker levels, we meta-analyzed the average fold change in biomarkers from pretreatment to week 8 of treatment. We also performed a meta-analysis pooling the fold change since the previous time point collected. 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, C-reactive protein (CRP), interleukin-6 (IL-6), interferon gamma-induced protein 10 (IP-10), and tumor necrosis factor alpha (TNF-a) 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. Based on limited data available, CRP, IL-6, IP-10, and TNF-a 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 is urgently needed.