Plasmodium falciparum parasites lacking histidine-rich protein 2 and 3: a review and recommendations for accurate reporting

Cheng, Qin; Gatton, Michelle L.; Barnwell, John W.; Chiodini, Peter L.; McCarthy, James S.; Bell, David A.; Cunningham, Jane

doi:10.1186/1475-2875-13-283

Cited by 200 publications

(303 citation statements)

References 30 publications

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“…While the primers used in this study amplified only exon 2 of the hrp2 gene, the hrp2 gene is also known to have chromosomal breaking points outside exon 2 [28]. …”

Section: Discussionmentioning

confidence: 99%

False-negative malaria rapid diagnostic tests in Rwanda: impact of Plasmodium falciparum isolates lacking hrp2 and declining malaria transmission

Kozycki

Umulisa

Rulisa

et al. 2017

Malar J

121

118

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BackgroundRapid 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.MethodsThis 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.ResultsIn 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.ConclusionThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-017-1768-1) contains supplementary material, which is available to authorized users.

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“…While the primers used in this study amplified only exon 2 of the hrp2 gene, the hrp2 gene is also known to have chromosomal breaking points outside exon 2 [28]. …”

Section: Discussionmentioning

confidence: 99%

False-negative malaria rapid diagnostic tests in Rwanda: impact of Plasmodium falciparum isolates lacking hrp2 and declining malaria transmission

Kozycki

Umulisa

Rulisa

et al. 2017

Malar J

121

118

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“…First, highly accurate tests are required for all malaria species affecting humans, but these panspecific tests are usually about 40% more expensive than RDTs that only detect Plasmodium falciparum. Most P. falciparum RDTs detect a malarial antigen, histidine-rich protein (HRP) 20 , and the discovery of parasites that have a deletion in this gene has raised concerns about false negative results and ongoing transmission. Also, the problems of providing adequate training and quality assurance of malaria tests and testing at remote POC sites are similar to those described for HIV RDTs 21,22 .…”

Section: Malariamentioning

confidence: 99%

REASSURED diagnostics to inform disease control strategies, strengthen health systems and improve patient outcomes

et al. 2018

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“…This phenomenon was first discovered in the Peruvian Amazon in 2010 (Gamboa et al, 2010). Since then, pfhrp2 deletion-associated poor performance of RDTs has been reported in many malaria-endemic regions (Cheng et al, 2014; Koita et al, 2012; Maltha et al, 2012; Pava et al, 2010; Wurtz et al, 2013). To date, unequivocal evidence for pfhrp2 and pfhrp3 gene deletions in P. falciparum isolates has been obtained in Peru (Gamboa et al, 2010; Maltha et al, 2012), Brazil (Houze et al, 2011), Senegal (Wurtz et al, 2013), and India (Kumar et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Apart from gene deletion, PfHRP2 sequences in different regions showed differences in the number of amino acid repeats and even some rare amino acid variants (Baker et al, 2010b; Baker et al, 2005; Deme et al, 2014; Kumar et al, 2012; Lee et al, 2006). Given the significance of PfHRP2-based RDTs in malaria diagnosis, systematic mapping of PfHRP2 diversity in global malaria endemic regions is highly demanded, especially in areas where poor performance or failure of PfHRP2-based RDTs have been reported (Cheng et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Genetic diversity of Plasmodium falciparum histidine-rich protein 2 in the China–Myanmar border area

Li¹,

Hua

Zhao³

et al. 2015

Acta Tropica

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Deletion of the Plasmodium falciparum histidine-rich protein 2 (pfhrp2) gene may affect the performance of PfHRP2-based rapid diagnostic tests (RDTs). Here we investigated the genetic diversity of the pfhrp2 gene in clinical parasite isolates collected in recent years from the China-Myanmar border area. Deletion of pfhrp2 has been identified in 4 out of 97 parasite isolates. Sequencing of the pfhrp2 exon 2 from 67 isolates revealed a high level of genetic diversity in pfhrp2, which is reflected in the presence of many repeat types and their variants, as well as variable copy numbers and different arrangements of these repeats in parasite isolates. In addition, we observed pfhrp3 deletion in three of the four parasites harboring pfhrp2 deletion, suggesting of double deletions of both genes in these three isolates. Analysis of two cases, which were P. falciparum-positive by microscopy and PCR but failed by two PfHRP2-based RDTs, did not find pfhrp2 deletion. Further correlational studies of pfhrp2 polymorphisms with detection sensitivity are needed to identify factors influencing the performance of RDTs in malaria-endemic areas.

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Plasmodium falciparum parasites lacking histidine-rich protein 2 and 3: a review and recommendations for accurate reporting

Cited by 200 publications

References 30 publications

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

REASSURED diagnostics to inform disease control strategies, strengthen health systems and improve patient outcomes

Genetic diversity of Plasmodium falciparum histidine-rich protein 2 in the China–Myanmar border area

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