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 与疟疾相关的死亡率正在下降，部分原因是实施快速诊断测试（RDTS）和 基于青蒿素的联合疗法（ACT）治疗计划。 RDT已成为主要方式 用于诊断全球疟疾，包括在撒哈拉以南非洲。最广泛使用的RDT依赖于检测 富含组氨酸的蛋白2（HRP2），这是一种由PFHRP2基因编码的恶性甲藻类特异的抗原。 但是，最近在感染恶性疟原虫的个体中报道了假阴性结果 在相关富组氨酸的蛋白基因中，有或没有缺失的PFHRP2基因的缺失， pfhrp3。这些寄生虫在南美通常是在其他地区偶发地描述的， 包括非洲。直到最近，非洲PFHRP2删除缺失的流行和影响尚不清楚。 我们最近完成了对民主共和国7,000多名儿童的大规模横断面调查 刚果（DRC），RDT自2011年以来一直是诊断的主要方式。我们发现6.4％ 由于P FHRP2缺失，寄生虫儿童具有错误的阴性RDT。在金沙萨省，超过20％ 感染是由于PFHRP2污染的寄生虫引起的。在其他部分也有类似的发现 撒哈拉以南非洲，增加了基于HRP2的RDT的可能性。目前，我们的 合作者正在金沙萨（Kinshasa）进行一项纵向队列研究，以评估PFHRP2/3的流行病学 删除的寄生虫。我们的建议将利用这一队列来实现我们的短期目标，以了解（1） 这些删除的进化驱动因素是刚果民主共和国，这是疟疾第二高的非洲国家 伯恩（2）为PFHRP2/3缺失监视开发简单的PCR分析，以使疟疾控制 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方案 生物标志物和疟疾诊断的无创诊断测试，并在基于HRP2的区域进行测试 RDT故障。该建议的独特之处在于，它将有助于表征新兴的公共卫生问题 同样寻求解决方案。结果，这项研究的结果很有可能 显着影响下一代护理点疟疾诊断测试。