Evaluating novel diagnostics and enabling preventive measures for childhood tuberculosis between the UK and partners in Sub-Saharan Africa

This project aims to develop and validate better diagnostic tools for children with TB (Find and Treat), as well as looking at implementation of preventive therapy for those already infected but not yet ill, but who might progress to disease if not receiving the recommended intervention- (Screen and Prevent).
Importance of TB in LMIC:
Around 1 million children fall ill from TB each year and 140 000 die. Many countries struggle to deliver the age-stratified notifications for TB in children to the WHO, and there is reluctance to engage in diagnosing and treating TB in children in many settings, as staff feel ill equipped to confirm a "gold standard" diagnosis, based on microbiological evidence. This
situation is pertinent in Africa and continues to lead to unnecessary morbidity and mortality and a reservoir of cases for the future. The roadmap for the elimination of TB sets priorities for achieving global TB control and within this effort, childhood TB has been identified as a neglected problem, but of great importance for overall TB control (WHO Global Plan for TB).
This requires two interventions: 1. to appropriately diagnose the cases and place on treatment -find and treat- and 2. to prevent secondary cases in TB-exposed children, which can be done successfully by delivering preventive medication-screen and prevent.
Why is it more difficult to diagnose TB in children?
Due to the limited number of mycobacteria contained in their sputa, conventional microbiological diagnostics perform poorly in children. Unless more sensitive diagnostics for paucibacillary disease can be developed, it is unlikely that the current situation of two thirds of children receiving treatment for TB without a confirmed diagnosis will change. Host-derived biosignatures in blood or urine therefore hold promise for development into point-of care tests for childhood TB.
What do we want to do?
We have considerable experience in the management of childhood TB in both the UK and The Gambia, and this project aims to involve new partners in Africa to find and treat children with TB using existing and new diagnostics. We have already developed such new tests but they need to be further validate also in children who have HIV or malnutrition. We will therefor recruit a large prospective court of children likely o have TB to validate the new diagnostics.
In addition, we want to work the National TB programs (NTP) in the partner countries to implement a preventive strategy, as supported by the WHO but not implemented on the ground. We want to understand the bottlenecks within the care path and train members of the NTP to recognise TB in children and take the necessary preventive steps to avoid secondary
cases in families. Based on the UK model, we have already established a screen-and-prevent- program of contact screening for children exposed to TB in their households in The Gambia, which has the support of the NTP. Our find and treat and screen and prevent activities have increased the case notifications by 50% over the last 3 years. This approach now requires full integration into the NTP programs in other countries and systematic evaluation to determine its long term
impact on national TB figures also in our partner countries. It could serve as an important model for the WHO strategy to improve prevention of TB worldwide but each country might have specific requirements and our project will deliver data from 4 different African settings to inform the recommendations.
We expect that our work can improve TB control and that we can create a network of excellence with specialist knowledge for childhood TB in Africa, as we have already done in Europe.

Tuberculosis causes significant morbidity and mortality in children worldwide. Bacteriological confirmation of TB in children is rare and lack of suitable alternative diagnostics is a major bottleneck to progress in identifying patients in need of treatment and for enrolment into clinical trials of new vaccines and therapies. As shown by our ongoing work, suitable
cohorts of children with TB disease, infected and controls can be reliably recruited and their specimens analysed, and our expertise can now be extended to the new sites in Africa. Supported by the state-of-the art technologies, bioinformatics and public health expertise available to the PI in the UK, our team of local and international investigators will further develop
and evaluate existing and new tools based on both host immune response and microbiology to build similar expertise in other LMIC where childhood TB remains a major problem.
Building on our previous MRC-supported work, we will test samples from children suspected to have TB by using a combined approach of cellular and molecular methods to validate protein and transcriptome -based diagnostic biosignatures. In this period of available funding, we will also set up pilot sites to administer preventive treatment to childhood contacts and translate our knowledge from the UK and the MRCG to the new partners in Africa. Translation into Policy: Integration of measurable host responses into diagnostic algorithms for patient care will not only secure the diagnosis of the individual patient but also facilitate clinical trials of new vaccines and drugs at participating sites. This project will build capacity for such future studies by creating a network of excellence for childhood TB. Epidemiological datasets that link TB exposure, infection and disease can serve as a model for public health and TB control and enable the wider roll out of IPT in the countries via the national TB programs with whom this proposal is engaging, as recommended by the WHO.