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

“发烧是全球寻求医疗保健的主要原因，每年有超过10亿例发热性疾病发生在儿童中。绝大多数感染是不复杂的和自限性的，可以保守治疗。少数（<1%）是危及生命的，但在病程早期往往难以识别。我们的项目挑战了目前的现状和低效率的分类实践。我们建议开发并验证一种快速分诊工具，以客观、定量和高精度地确定有死亡风险的患者，从而优先考虑他们的护理。突破性的解决方案在于内皮细胞，这是一种新发现的体内生物传感器，在我们抵御病原体的过程中起着关键作用。内皮细胞激活和随后的完整性丧失是几种危及生命的感染（包括败血症、疟疾甚至COVID-19）的常见损伤途径。在首次临床表现时测量该途径的特定介质（sTREM-1， Ang2等）可以可靠地识别有死亡风险的个体，而不管引起发烧的疾病是什么，并且比以前已知的预测因素（如临床算法或“经典”生物标志物）更可靠。重要的是，这些途径也是“可药物化的”，从而允许测试或重新利用特定的干预措施来改善结果。我们将设计并生产一种RTT（类似血糖仪），定量测量具有最佳预测性能的两种标记（sTREM-1和Ang2）。然后，我们将其纳入两项临床试验（将在莫桑比克、加蓬和埃塞俄比亚进行），以1)验证与标准护理相比，所提出的PoC RTT在儿科患者风险分层和预测死亡率方面的改进性能，以及2)测试在生物标志物结果指导下的特定干预（l -瓜氨酸营养补充）是否改善（与安慰剂相比）出院后的长期结局和生存率。

"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.