Getting the Diagnosis Right: Approaches to New Diagnostics for Childhood Tuberculosis

Even though children account for an estimated 1 million new cases of TB every year, representing roughly 7% of the total disease burden, it remains a neglected problem. Every year, around 209 000 children die from TB, half of those cases are in Africa; it is believed that TB is among the top ten causes of mortality in children under five years of age. The main issue continues to be timely and accurate diagnosis, as treatment outcomes - even in thecase of drug resistance - are significantly better than in adults.

TB diagnosis remains a challenge in children, as both the tests themselves and the sampling/testing strategies are designed for TB among adults. Children tend to have paucibacillary and/or extrapulmonary disease and collection of adequate samples from children is difficult as well as time- and resource-consuming. Addressing the need for new diagnostic approaches implies the need for non-sputum based tests and improved sensitivity, while being more
feasible to conduct, particularly in resource-limited settings.

Recently, increased advocacy, political and funding support have led to an effort to develop new tests and testing strategies; as such, a number of potential candidates have been identified with the potential to substantially improve paediatric TB diagnosis.

RaPaed-TB is a prospective clinical study among children younger than 15 years in Sub-Sahara Africa, evaluating new tests and testing strategies with the ultimate goal of WHO endorsement. The study will be run on LMU' s AIDA TB platform (Assessment of Innovative Diagnostics and Algorithms for Early and Sensitive Detection of Acute and Incident TB in Adults and Children), which provides project management, scientific staffing support and valuable infrastructure in terms of data management for this project.

Most novel tests to be evaluated in this study use non-sputum samples and have different testing approaches:

- host response (i.e. a cytokione-based biomarker panel by the University of Stellenbosch and evaluation of host
RNA signatures)
- antigen-detection (incl. two novel urinary and one stool lipoarabinomannan [LAM] tests)
- cellular immunoresponse (T-cell activation marker-tuberculosis assay [TAM TB], LMU/Beckman Coulter)
- nucleic-acid amplification tests (Xpert Ultra on different specimen types, such as using a new stool processing
protocol and nasopharyngeal aspirates)

Importantly, these new tests have great potential to enhance paediatric case detection by circumventing the need for culture, which still represents a significant infrastructural challenge in most settings. The ultimate goal is to create novel triage algorithms, allowing to screen, confirm or rule out TB in children suspected of having TB, based on a study design that simultaneously evaluates multiple tests in a single patient cohort. The data on test performances will be significantly strengthened by subgroup analyses (e.g. sensitivity analyses based on HIV- or nutritional status) and the modeling of various successions of tests to identify novel algorithms.