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身上。绝大多数感染是简单的和自限性的，可以保守治疗。少数（<1%）是危及生命的，但往往是具有挑战性的，以确定在病程的早期。我们的项目挑战目前的现状和效率低下的分流做法。我们建议开发和验证一种快速的分类工具，以客观、定量和高精度地确定那些有死亡风险的患者，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，一种新认识的体内生物传感器，它在我们防御病原体方面起着至关重要的作用。内皮细胞活化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。测量该途径的特异性介质（斯特雷姆-1、Ang 2等）首先，临床表现可以可靠地识别处于死亡风险中的个体，而不管引起发烧的疾病，并且比先前已知的预测器（例如临床算法或“经典”生物标志物）更稳健。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。我们将设计和生产一种RTT（血糖仪样），其定量测量具有最佳预测性能的两种标志物（斯特雷姆-1和Ang 2）。然后我们将把它纳入2个临床试验（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，拟议的儿童死亡风险分层和预测儿童患者死亡率方面的改进性能，以及2）测试特定干预措施是否在生物标志物结果的指导下，补充L-瓜氨酸（营养补充剂）可改善（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.