Toward the Development of a Circulating Free DNA-Based In Vitro Diagnostic Test for Infectious Diseases: a Review of Evidence for Tuberculosis

B Leticia Fernández-Carballo, Tobias Broger, Romain Wyss, Niaz Banaei, Claudia M Denkinger, B Leticia Fernández-Carballo, Tobias Broger, Romain Wyss, Niaz Banaei, Claudia M Denkinger

Abstract

The detection of circulating free DNA (cfDNA) has transformed the field of oncology and prenatal diagnostics. Clinical application of cfDNA for disease diagnosis and monitoring, however, is relatively recent in the field of infectious disease. The potential of cfDNA as a noninvasive diagnostic and monitoring tool is especially promising for tuberculosis (TB), as it enables the detection of both pulmonary and extrapulmonary TB from easily accessible urine and/or blood samples from any age group. However, despite the potential of cfDNA detection to identify TB, very few studies are described in the literature to date. A comprehensive search of the literature identified 15 studies that report detecting Mycobacterium tuberculosis DNA in the blood and urine of TB patients with nongenitourinary disease, but in only six of them were the methodological steps considered suitable for cfDNA isolation and detection. The sensitivities and specificities for the diagnosis of pulmonary and extrapulmonary TB cases reported in these six studies are highly variable, falling in the range of 29% to 79% and 67% to 100%, respectively. While most studies could not meet the performance requirements of the high-priority target product profiles (TPP) published by the World Health Organization (WHO), the study results nonetheless show promise for a point-of-care detection assay. Better designed prospective studies, using appropriate samples, will be required to validate cfDNA as a TB biomarker.

Keywords: Mycobacterium tuberculosis; diagnosis; liquid biopsy.

Copyright © 2019 Fernández-Carballo et al.

Figures

FIG 1
FIG 1
Schematic drawing of the origin, release, and potential diagnostic use of M. tuberculosis cfDNA within the human host. M. tuberculosis within the lungs or in extrapulmonary sites release cell-free DNA into the blood circulation, which then may be redistributed in some other biological fluids that can serve as a sample for in vitro diagnostic (IVD) tests (2, 9, 56–62).
FIG 2
FIG 2
Performance (sensitivity versus specificity) of studies on blood and urine-based cfDNA detection of M. tuberculosis by nucleic acid amplification techniques in which the methodological steps are a priori considered suitable for cfDNA isolation and detection. Studies reporting only the sensitivity or specificity are excluded (23–25, 32–34). TPP, target product profile.

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