Towards Accurate Point-of-Care Tests for Tuberculosis in Children

Abstract

In childhood tuberculosis (TB), with an estimated 69% of missed cases in children under 5 years of age, the case detection gap is larger than in other age groups, mainly due to its paucibacillary nature and children's difficulties in delivering sputum specimens. Accurate and accessible point-of-care tests (POCTs) are needed to detect TB disease in children and, in turn, reduce TB-related morbidity and mortality in this vulnerable population. In recent years, several POCTs for TB have been developed. These include new tools to improve the detection of TB in respiratory and gastric samples, such as molecular detection of Mycobacterium tuberculosis using loop-mediated isothermal amplification (LAMP) and portable polymerase chain reaction (PCR)-based GeneXpert. In addition, the urine-based detection of lipoarabinomannan (LAM), as well as imaging modalities through point-of-care ultrasonography (POCUS), are currently the POCTs in use. Further to this, artificial intelligence-based interpretation of ultrasound imaging and radiography is now integrated into computer-aided detection products. In the future, portable radiography may become more widely available, and robotics-supported ultrasound imaging is currently being trialed. Finally, novel blood-based tests evaluating the immune response using "omic-"techniques are underway. This approach, including transcriptomics, metabolomic, proteomics, lipidomics and genomics, is still distant from being translated into POCT formats, but the digital development may rapidly enhance innovation in this field. Despite these significant advances, TB-POCT development and implementation remains challenged by the lack of standard ways to access non-sputum-based samples, the need to differentiate TB infection from disease and to gain acceptance for novel testing strategies specific to the conditions and settings of use.

Keywords: GeneXpert; LAM; LAMP; POCT; POCUS; Truenat; lipoarabinomannan; sonography.

Figure 1

Overview of current, future and ‘ideal’ point-of-care tests for the diagnosis of TB in children. Lipoarabinomannan (LAM) lateral flow assay detecting a component of the cell wall of M. tuberculosis in the urine. Sensitivity and specificity refer to PTB in children. TB-loop-mediated isothermal amplification (LAMP), a molecular POCT detecting M. tuberculosis. Sensitivity and specificity refer to PTB in adults. Xpert Omni, a PCR-based Xpert cartridge for detecting M. tuberculosis. * Commercialization of Gene Xpert Omni has been halted by Cepheid in 2021. TrueNat, based on real-time PCR chips for detecting M. tuberculosis. Point-of-care ultrasonography (POCUS) visualizing correlates of parenchymal pulmonary pathology in pulmonary TB as well as abnormalities in other anatomical locations in extra-pulmonary TB. It is only conditionally user-friendly, as it requires minimal skills acquisition. The “ideal” POCT for TB in children is cheap, fast and non-invasive. It should not harm the child via radiation or invasive procedures and be sputum-independent. The target can be based either on the host or on pathogen properties. According to the WHO Target Profile for a rapid biomarker-based non-sputum-based test, it should have at least a sensitivity of >66% and an optimal specificity of more than or equal to 98%. The health care provider should be able to perform the test without extensive training or skills.