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

刚果民主共和国 RDT 检测不到的疟疾：流行病学和替代方案的开发

• 批准号: 10327684
• 负责人: Rhoel David Ramos Dinglasan
• 金额: $ 66.41万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-22 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327684
• 关键词: Adult; Africa; Africa South of the Sahara; Algorithms; Antigens; Area; Artemisinins; Biological Assay; Biological Markers; Blood specimen; Cameroon; Characteristics; Child; Clinical; Combined Modality Therapy; Congo; Country; Cross-Sectional Studies; Data; Democratic Republic of the Congo; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disasters; Epidemiology; Evolution; Failure; Future; Gene Proteins; Genes; Genome; Genotype; Goals; HRP-2 protein; Human; Immunoassay; Individual; Infection; Intervention; Lateral; Longitudinal cohort study; Malaria; Malaria Diagnosis; Malaria Diagnostic; Methods; Microsatellite Repeats; Microscopy; Modality; Molecular; Monitor; Parasites; Plasmodium falciparum; Prevalence; Proteins; Province; Public Health; Rapid diagnostics; Reporting; Research; Resistance; Saliva; Sampling; Severities; Site; South America; Test Result; Testing; Work; base; candidate marker; circulating biomarkers; cohort; detection limit; falls; histidine-rich proteins; mortality; next generation; noninvasive diagnosis; novel; novel marker; novel strategies; point of care; programs; prospective; prototype; rapid test; tool; treatment program

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.

抽象的 疟疾相关死亡率正在下降，部分原因是快速诊断测试（RDT）的实施和 基于青蒿素的联合疗法（ACT）治疗方案。 RDT 已成为主要方式 用于诊断全球疟疾，包括撒哈拉以南非洲地区。最广泛使用的 RDT 依赖于检测 富含组氨酸的蛋白 2 (HRP2)，这是由​pfhrp2​ 基因编码的恶性疟原虫​特异性抗原。 然而，最近报告了感染 P 的个体出现假阴性结果。恶性疟原虫 含有​pfhrp2​基因的删除，以及相关的富含组氨酸的蛋白质基因的删除或不删除， pfhrp3​。这些寄生虫在南美洲很常见，在其他地区也有零星的描述， 包括非洲。直到最近，pfhrp2 缺失在非洲的流行率和影响尚不清楚。 我们最近完成了一项针对民主共和国 7,000 多名儿童的大型横断面调查 刚果（金），自 2011 年以来，RDT 一直是主要的诊断方式。我们发现 6.4% 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% 的感染是由​pfhrp2​删除的寄生虫引起的。其他地区也有类似的发现 撒哈拉以南非洲地区，增加了基于 HRP2 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 pfhrp2/3 的流行病学 删除了寄生虫。我们的建议将利用这个群体来实现我们的短期目标：(1) 了解 刚果民主共和国是非洲疟疾第二严重的国家，这些缺失的进化驱动因素 负担; (2) 开发一种简单的 PCR 检测方法来监测 pfhrp2/3 缺失，从而控制疟疾 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品 用于疟疾诊断的生物标志物和无创诊断测试，并在基于 HRP2 的领域进行测试 RDT 失败。该提案的独特之处在于，它将有助于描述新出现的公共卫生问题，同时 同时寻求解决方案。因此，这项研究的结果很可能会 显着影响下一代护理点疟疾诊断测试。