Development and validation of a quantitative point-of-care test for the measurement of severity biomarkers to improve risk stratification of fever syndromes and enhance child survival

Fever is the leading reason to seek healthcare globally, with over 1 billion cases of febrile illness occurring in children annually. The vast majority of infections are uncomplicated and self-limited and can be treated conservatively. A few (<1%) are life-threatening but are often challenging to identify early in the course of illness. Our project challenges the current status quo and inefficiencies of triaging practices. We propose to develop and validate a rapid triaging tool to determine, objectively, quantitatively and with high precision those patients at risk of dying, so as to prioritize their care. The breakthrough solution lies in the ENDOTHELIUM, a newly recognized in vivo biosensor, which plays a critical role in our defense against pathogens. Endothelial cell activation and subsequent loss of integrity is a common pathway of injury in several life-threatening infections, including sepsis, malaria, or even COVID-19. Measuring specific mediators of this pathway (sTREM-1, Ang2, etc.) at first clinical presentation can reliably identify individuals at risk of dying, irrespective of the disease causing the fever, and more robustly than previously known predictors such as clinical algorithms or ""classic"" biomarkers. Importantly, these pathways are also ""druggable"", thus allowing the testing or re-purposing of specific interventions to improve outcome. We will design and produce a RTT (glucometer-like) that quantitatively measures the two markers with best predictive performance (sTREM-1 and Ang2). We will then incorporate it into 2 clinical trials (to be done in Mozambique, Gabon and Ethiopia) to 1) verify the improved performance of the proposed PoC RTT in risk-stratifying and predicting mortality among paediatric patients when compared to standard of care, and 2) test whether a specific intervention (nutritional supplementation of L-Citrulline), guided by biomarker results, improves (vs. placebo) long-term outcomes and survival after hospital discharge. ""