Biomarkers for diagnosis of childhood tuberculosis: A systematic review

Abstract

Introduction: As studies of biomarkers of tuberculosis (TB) disease provide hope for a simple, point-of-care test, we aimed to synthesize evidence on biomarkers for diagnosis of TB in children and compare their accuracy to published target product profiles (TPP).

Methods: We conducted a systematic review of biomarkers for diagnosis of pulmonary TB in exclusively paediatric populations, defined as age less than 15 years. PubMed, EMBASE and Web of Science were searched for relevant publications from January 1, 2000 to November 27, 2017. Studies using mixed adult and paediatric populations or reporting biomarkers for extrapulmonary TB were excluded. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) framework. No meta-analysis was done because the published childhood TB biomarkers studies were mostly early stage studies and highly heterogeneous.

Results: The 29 studies included in this systematic review comprise 20 case-control studies, six cohort studies and three cross-sectional studies. These studies reported diverse and heterogeneous forms of biomarkers requiring different types of clinical specimen and laboratory assays. Majority of the studies (27/29 [93%]) either did not meet the criteria in at least one of the four domains of the QUADAS-2 reporting framework or the assessment was unclear. However, the diagnostic performance of biomarkers reported in 22 studies met one or both of the WHO-recommended minimal targets of 66% sensitivity and 98% specificity for a new diagnostic test for TB disease in children, and/or 90% sensitivity and 70% specificity for a triage test.

Conclusion: We found that majority of the biomarkers for diagnosis of TB in children are promising but will need further refining and optimization to improve their performances. As new data are emerging, stronger emphasis should be placed on improving the design, quality and general reporting of future studies investigating TB biomarkers in children.

Fig 1. PRISMA flowchart.

Flow diagram of inclusion and exclusion of studies. Reasons for exclusion are: conference proceedings and abstracts only; language (not English or French); technique (imaging-based, culture-based, commercial IGRA); reviews (narrative review, systematic review, meta-analysis); or target of paper (epidemiological, molecular biology, cost effectiveness, vaccine or drug study; biomarkers for detection of LTBI, prediction of disease progression or treatment monitoring). Studies that only included adult patients were also excluded.

Fig 2. Quality assessment of childhood TB biomarker studies.

Results from assessment of the quality of each study in the systematic review using QUADAS-2 framework.