RDT-undetectable Malaria in the DR Congo: Epidemiology and Development of Alternatives

摘要 与疟疾有关的死亡率正在下降，部分原因是实施了快速诊断检测(RDT)和 以青蒿素为基础的联合治疗(ACT)方案。RDT已经成为主要的方式 用于全球疟疾诊断，包括在撒哈拉以南非洲。最广泛使用的RDT依赖于检测 富组氨酸蛋白2(Hrp2)是一种针对恶性疟原虫​​的抗原，由​pfhrp2​基因编码。 然而，最近有报告称，在感染P-​的个人中出现了假阴性结果。恶性疟原虫​寄生虫 带有或不带有相关富含组氨酸的蛋白基因缺失的​​基因缺失， Pfhrp3​。这些寄生虫在南美洲被普遍描述，在其他地区也有零星描述， 包括非洲。直到最近，​pfhrp2​缺失在非洲的流行情况和影响还不得而知。 我们最近完成了对刚果民主共和国7000多名儿童的大型横断面调查 自2011年以来，在刚果(金)，RDTS一直是主要的诊断模式。我们发现，6.4%的 寄生虫病儿童由于p​fhrp2​缺失而出现假阴性RDT。在金沙萨省，超过20% 1例感染是由​基因缺失的​寄生虫引起的。类似的发现也出现在其他地区。 在撒哈拉以南非洲，增加了基于HRP2的区域发展援助正在变得无效的可能性。目前，我们的 合作者正在金沙萨进行一项纵向队列研究，以评估​pfhrp2/3的流行病学。 删除了寄生虫。我们的建议将利用这一群体来实现我们的短期目标，以(1)了解 这些缺失在刚果民主共和国的进化驱动因素，这个非洲疟疾第二高的国家 以及(2)建立一种简单的聚合酶链式反应检测​pfhrp2/3​缺失的方法，以便控制疟疾 程序可以在需要时实施替代诊断。我们的长期目标是开发替代产品 用于疟疾诊断的生物标志物和非侵入性诊断试验并在以HRP2为基础的地区进行试验 RDT失败。这项建议的独特之处在于，它将有助于描述一个正在出现的公共卫生问题，同时 同时寻求解决方案。因此，这项研究的结果很有可能将 对下一代医疗点疟疾诊断测试产生重大影响。

ABSTRACT Malaria-related mortality is falling, due in part to the implementation of rapid diagnostic tests (RDTs) and artemisinin-based combination therapy (ACT) treatment programs. RDTs have become the primary modality for diagnosis of malaria globally, including in Sub-Saharan Africa. Most widely used RDTs rely on the detection of histidine-rich protein 2 (HRP2), an antigen specific to P​ lasmodium falciparum​ encoded by the ​pfhrp2​ gene. However, false-negative results have recently been reported in individuals infected with P​ . falciparum ​parasites harboring a deletion of the ​pfhrp2​ gene with or without a deletion in a related histidine-rich protein gene, pfhrp3​. These parasites have been commonly described in South America and sporadically in other regions, including Africa. Until recently, the prevalence and impact of ​pfhrp2​ deletions deletions in Africa was unknown. We recently completed a large cross-sectional survey of more than 7,000 children in the Democratic Republic of Congo (DRC), where RDTs have been the primary mode of diagnosis since 2011. We found that 6.4% of parasitemic children had false-negative RDTs due to a p​ fhrp2​ deletion. In Kinshasa province, more than 20% of infections were due to ​pfhrp2​-deleted parasites. Similar findings are being made in other parts of Sub-Saharan Africa, raising the possibility that HRP2-based RDTs are becoming ineffective. Currently, our collaborators are conducting a longitudinal cohort study in Kinshasa to evaluate the epidemiology of ​pfhrp2/3 deleted parasites. Our proposal will leverage this cohort to achieve our short-term goals to (1) understand the evolutionary drivers of these deletions in the DRC, the country in Africa with the second-highest malaria burden; and (2) to develop a simple PCR assay for ​pfhrp2/3​ deletion surveillance so that malaria control programs can implement alternative diagnostics when needed. Our long-term goal is to develop alternate biomarkers and noninvasive diagnostic tests for malaria diagnosis and test them in an area of HRP2-based RDT failure. This proposal is unique in that it will help characterize an emerging public health problem while simultaneously seeking solutions. As a result, there is a high likelihood that the results of this research will significantly impact the next generation of point of care malaria diagnostic tests.