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测试， 青蒿素联合疗法（ACT）治疗方案。RDT已成为主要的方式 用于诊断全球疟疾，包括撒哈拉以南非洲。最广泛使用的RDT依赖于检测 富含组氨酸蛋白2（HRP 2），一种由pfhrp 2基因编码的恶性疟原虫特异性抗原。 然而，假阴性结果最近已被报道，在个人感染P。恶性寄生虫 携带pfhrp 2基因的缺失，在相关的富组氨酸蛋白基因中有或没有缺失， pfhrp3。这些寄生虫在南美洲常见，在其他地区也有零星的描述， 包括非洲。直到最近，非洲pfhrp 2缺失的患病率和影响尚不清楚。 我们最近完成了对刚果民主共和国7 000多名儿童的大型横断面调查 刚果（DRC），自2011年以来，RDTs一直是主要的诊断模式。我们发现，6.4%的 寄生虫血症儿童由于pfhrp 2缺失而具有假阴性RDT。在金沙萨省， 的感染是由于PFHRP 2缺失的寄生虫。类似的调查结果也在其他地区进行。 撒哈拉以南非洲，这增加了基于HRP 2的RDT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pfhrp 2/3的流行病学 删除寄生虫。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 刚果民主共和国是非洲疟疾发病率第二高的国家， 建立pfhrp 2/3基因缺失的PCR检测方法，为疟疾防治提供科学依据 程序可以在需要时实现替代诊断。我们的长期目标是开发替代 疟疾诊断的生物标志物和非侵入性诊断测试，并在基于HRP 2的区域进行测试。 RDT故障。这项建议的独特之处在于，它将有助于描述一个新出现的公共卫生问题， 同时寻求解决方案。因此，这项研究的结果很有可能 这将对下一代疟疾诊断检测产生重大影响。

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.