Host-Based Biomarkers in Saliva for the Diagnosis of Pulmonary Tuberculosis in Children: A Mini-Review.

Nisreen Khambati,Laura Olbrich,Rinn Song,Jerrold Ellner,Else Margreet Bijker,Padmini Salgame

doi:10.3389/fped.2021.756043

Abstract

The diagnosis of pulmonary tuberculosis (TB) in children remains a significant challenge due to its paucibacillary nature, non-specificity of symptoms and suboptimal sensitivity of available diagnostic methods. In young children particularly, it is difficult to obtain high-quality sputum specimens for testing, with this group the least likely to be diagnosed, while most at risk of severe disease. The World Health Organization (WHO) has prioritized research into rapid biomarker-based tests for TB using easily obtainable non-sputum samples, such as saliva. However, the role of biomarkers in saliva for diagnosing TB in children has not been fully explored. In this mini-review, we discuss the value of saliva as a diagnostic specimen in children given its ready availability and non-invasive nature of collection, and review the literature on the use of host-based biomarkers in saliva for diagnosing active pulmonary TB in adults and children. Based on available data from adult studies, we highlight that combinations of cytokines and other proteins show promise in reaching WHO-endorsed target product profiles for new TB triage tests. Given the lack of pediatric research on host biomarkers in saliva and the differing immune response to TB infection between children and adults, we recommend that pediatric studies are now performed to discover and validate salivary host biosignatures for diagnosing pulmonary TB in children. Future directions for pediatric saliva studies are discussed, with suggestions for technologies that can be applied for salivary biomarker discovery and point-of-care test development.

Highlights

THE CHALLENGES OF PEDIATRIC TB DIAGNOSISIn 2019, there were 192,000 deaths in children due to tuberculosis (TB), most experts agree this figure is underestimated [1]
An eight-marker biosignature involving salivary granzyme A, growth differentiation factor 15 (GDF-15), serum amyloid A (SAA), epithelial-neutrophil activating peptide 78 (ENA-78), IL-12(p40), interleukin 13 (IL-13), interleukin 21 (IL-21), and plasminogen activator inhibitor-1 (PAI-1) had a sensitivity of 93% and specificity of 100% [40]. This biosignature met target product profiles (TPP) for both a triage and diagnostic test. Another eight-marker biosignature involving extracellular matrix protein 1 (ECM1), myoglobulin, hemofiltrate CC chemokine 1 (HCC1), tissue plasminogen activator (TPA), ENA-78, IL-12 (p40), IL-13, and IL-21 had a sensitivity of 100% and a specificity of 95%, reaching TPP for a triage test [44]
We reviewed the current evidence on salivary host-based biomarkers for diagnosing pulmonary TB

Summary

INTRODUCTION

In 2019, there were 192,000 deaths in children due to tuberculosis (TB), most experts agree this figure is underestimated [1]. Molecular DNAbased methods such as GeneXpert R are faster but require a stable electricity supply, limiting useability in low resource settings [8] These tests require high-quality respiratory samples, which is problematic in young children who cannot expectorate sputum on demand, necessitating collection of gastric aspirates, nasopharyngeal aspirates, or induced sputum [9]. The development of non-sputum-based point-of-care (POC) tests on obtainable samples like blood, urine, stool, and saliva has been prioritized by the World Health Organization (WHO) [12] These diagnostic approaches ideally should be feasible in primary care settings with the purpose of starting therapy during the same clinical encounter [13]. Saliva is extracted from the absorbent device through centrifugation or compression [34]

Materials and Methods

DISCUSSION

Findings

CONCLUSION