False-negative malaria rapid diagnostic tests in Rwanda: impact of Plasmodium falciparum isolates lacking hrp2 and declining malaria transmission.
False-negative malaria rapid diagnostic tests in Rwanda: impact of Plasmodium falciparum isolates lacking hrp2 and declining malaria transmission.
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DOI：
10.1186/s12936-017-1768-1
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发表时间：
2017-03-20
期刊：
影响因子：
3
通讯作者：
Krogstad DJ
中科院分区：
文献类型：
--
作者：
Kozycki CT;Umulisa N;Rulisa S;Mwikarago EI;Musabyimana JP;Habimana JP;Karema C;Krogstad DJ
富含组氨酸的蛋白2（HRP 2）的快速诊断测试（RDTs）通常用于确定发烧的人是否应该用抗疟疾药物治疗。然而，缺失hrp 2基因的恶性疟原虫寄生虫产生假阴性RDT，并且当传播强度降低时，人们担心基于HRP 2的RDT的灵敏度可能会下降。这项观察性研究于2014年4月至2015年4月在卢旺达的三个健康中心招募了9226名患者。然后比较了基于HRP 2和疟原虫乳酸脱氢酶（pLDH）的RDTs与显微镜（厚涂片）诊断疟疾的灵敏度。PCR用于确定hrp 2基因（外显子2）的富含组氨酸的中央重复区域的缺失是否与基于HRP 2的RDT的假阴性相关。与显微镜相比，基于HRP 2和pLDH的RDT的灵敏度和特异性分别为89.5%和86.2%以及80.2%和94.3%。当两种RDT的结果相结合时，灵敏度上升到91.8%，特异性为85.7%。此外，当涂片阳性率从46%降至3%时，基于HRP 2的RDT的灵敏度从88%降至67%。在370例HRP 2 RDT结果为假阴性的样本中，140例（38%）通过PCR鉴定为恶性疟原虫。在PCR鉴定为恶性疟原虫的分离株中，32株（23%）基于PCR的hrp 2基因为阴性。在PCR检测hrp 2阴性的32株恶性疟原虫中，pLDH RDT检测阳性17株（53%）。这项RDT性能的前瞻性研究与Kibirizi疟疾传播强度的下降（载玻片阳性率从46%下降到3%）相吻合。这种下降与HRP 2 RDT敏感性降低（从88%降至67%）有关。虽然没有hrp 2基因的恶性疟原虫分离株是基于HRP 2的RDT假阴性的重要原因，但大多数是通过基于pLDH的RDT鉴定的。尽管世卫组织不建议在撒哈拉以南非洲使用HRP 2/pLDH联合检测，但这些结果表明，基于HRP 2/pLDH的RDT联合检测可以减少基于HRP 2的RDT假阴性对检测症状性恶性疟原虫疟疾的影响。本文的在线版本（doi：10.1186/s12936-017-1768-1）包含补充材料，可供授权用户使用。
Rapid diagnostic tests (RDTs) for histidine rich protein 2 (HRP2) are often used to determine whether persons with fever should be treated with anti-malarials. However, Plasmodium falciparum parasites with a deletion of the hrp2 gene yield false-negative RDTs and there are concerns the sensitivity of HRP2-based RDTs may fall when the intensity of transmission decreases. This observational study enrolled 9226 patients at three health centres in Rwanda from April 2014 to April 2015. It then compared the sensitivity of RDTs based on HRP2 and the Plasmodium lactate dehydrogenase (pLDH) to microscopy (thick smears) for the diagnosis of malaria. PCR was used to determine whether deletions of the histidine-rich central repeat region of the hrp2 gene (exon 2) were associated with false-negative HRP2-based RDTs. In comparison to microscopy, the sensitivity and specificity of HRP2- and pLDH-based RDTs were 89.5 and 86.2% and 80.2 and 94.3%, respectively. When the results for both RDTs were combined, sensitivity rose to 91.8% and specificity was 85.7%. Additionally, when smear positivity fell from 46 to 3%, the sensitivity of the HRP2-based RDT fell from 88 to 67%. Of 370 samples with false-negative HRP2 RDT results for which PCR was performed, 140 (38%) were identified as P. falciparum by PCR. Of the isolates identified as P. falciparum by PCR, 32 (23%) were negative for the hrp2 gene based on PCR. Of the 32 P. falciparum isolates negative for hrp2 by PCR, 17 (53%) were positive based on the pLDH RDT. This prospective study of RDT performance coincided with a decline in the intensity of malaria transmission in Kibirizi (fall in slide positivity from 46 to 3%). This decline was associated with a decrease in HRP2 RDT sensitivity (from 88 to 67%). While P. falciparum isolates without the hrp2 gene were an important cause of false-negative HRP2-based RDTs, most were identified by the pLDH-based RDT. Although WHO does not recommend the use of combined HRP2/pLDH testing in sub-Saharan Africa, these results suggest that combination HRP2/pLDH-based RDTs could reduce the impact of false-negative HRP2-based RDTs for detection of symptomatic P. falciparum malaria. The online version of this article (doi:10.1186/s12936-017-1768-1) contains supplementary material, which is available to authorized users.