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10亿例发烧疾病发生在儿童中。绝大多数感染并不复杂，而且是自限性的，可以保守治疗。少数(1%)有生命危险，但通常在病程早期识别具有挑战性。我们的项目挑战了分类实践的现状和低效。我们建议开发和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，以便优先处理他们的护理。突破的解决方案在于内皮，这是一种新的体内生物传感器，在我们防御病原体方面发挥着关键作用。内皮细胞的激活和随后的完整性丧失是几种威胁生命的感染中常见的损伤途径，包括败血症、疟疾，甚至新冠肺炎。检测该途径的特定介质(Strem-1、Ang2等)首先，临床表现可以可靠地识别有死亡风险的人，无论是什么疾病导致发烧，而且比之前已知的预测指标(如临床算法或“经典”生物标记物)更有力。重要的是，这些途径也是“可用药的”，从而允许测试或重新利用特定的干预措施来改善结果。我们将设计和生产一种RTT(类似血糖仪的)，定量测量两个具有最佳预测性能的标记物(Strem-1和Ang2)。然后，我们将把它纳入2项临床试验(将在莫桑比克、加蓬和埃塞俄比亚进行)，以1)验证拟议的PoC RTT在儿科患者风险分层和预测死亡率方面的改进性能，与护理标准相比，2)测试以生物标记物结果为指导的特定干预措施(L-瓜氨酸营养补充剂)是否改善(与安慰剂相比)出院后的长期结果和存活率。

"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.