Abstract
BackgroundAn accurate diagnosis is essential for the rapid and appropriate treatment of malaria. The accuracy of the histidine-rich protein 2 (PfHRP2)-based rapid diagnostic test (RDT) Palutop+4® was assessed here. One possible factor contributing to the failure to detect malaria by this test is the diversity of the parasite PfHRP2 antigens.MethodsPfHRP2 detection with the Palutop+4® RDT was carried out. The pfhrp2 and pfhrp3 genes were amplified and sequenced from 136 isolates of Plasmodium falciparum that were collected in Dakar, Senegal from 2009 to 2011. The DNA sequences were determined and statistical analyses of the variation observed between these two genes were conducted. The potential impact of PfHRP2 and PfHRP3 sequence variation on malaria diagnosis was examined.ResultsSeven P. falciparum isolates (5.9% of the total isolates, regardless of the parasitaemia; 10.7% of the isolates with parasitaemia ≤0.005% or ≤250 parasites/μl) were undetected by the PfHRP2 Palutop+4® RDT. Low parasite density is not sufficient to explain the PfHRP2 detection failure. Three of these seven samples showed pfhrp2 deletion (2.4%). The pfhrp3 gene was deleted in 12.8%. Of the 122 PfHRP2 sequences, 120 unique sequences were identified. Of the 109 PfHRP3 sequences, 64 unique sequences were identified. Using the Baker’s regression model, at least 7.4% of the P. falciparum isolates in Dakar were likely to be undetected by PfHRP2 at a parasite density of ≤250 parasites/μl (slightly lower than the evaluated prevalence of 10.7%). This predictive prevalence increased significantly between 2009 and 2011 (P = 0.0046).ConclusionIn the present work, 10.7% of the isolates with a parasitaemia ≤0.005% (≤250 parasites/μl) were undetected by the PfHRP2 Palutop+4® RDT (7.4% by the predictive Baker’model). In addition, all of the parasites with pfhrp2 deletion (2.4% of the total samples) and 2.1% of the parasites with parasitaemia >0.005% and presence of pfhrp2 were not detected by PfHRP2 RDT. PfHRP2 is highly polymorphic in Senegal. Efforts should be made to more accurately determine the prevalence of non-sensitive parasites to pfHRP2.
Highlights
An accurate diagnosis is essential for the rapid and appropriate treatment of malaria
There was no significant difference in term of sample numbers (p = 0.246, Chi-square test) or in term of parasitaemia between detected and undetected samples (p = 0.595, Wilcoxon rank sum test). One of these samples was detected by the pan-malaria-specific pLDH and the P. vivax-specific lactate dehydrogenase (LDH) (Table 1)
The World Health Organization (WHO) recently recommended adopting universal testing to confirm the presence of malaria parasites prior to the use of artemisinin-based combination therapy (ACT), and in the cases where microscopic examination cannot be performed, the rapid diagnostic test (RDT) would be the best alternative for confirmation
Summary
An accurate diagnosis is essential for the rapid and appropriate treatment of malaria. Many factors related either to the parasite or to the test may affect the performance of malaria RDTs. pALD and pLDH appear to be highly conserved [2,3], it has been reported that pfhrp sequence variations, with regard to certain amino acid repeats, can affect the sensitivity of HRP2-based RDTs [3,4,5,6,7]. PALD and pLDH appear to be highly conserved [2,3], it has been reported that pfhrp sequence variations, with regard to certain amino acid repeats, can affect the sensitivity of HRP2-based RDTs [3,4,5,6,7] These polymorphisms have been detected in the Asia-Pacific region [4,5], India [6], Madagascar [3] and in a clinical case in Uganda [7]. The deletions of pfhrp and pfhrp were reported as the causes of falsenegative diagnoses in populations from Peru [8,9], Mali [10], India [11] and in a clinical case from Brazil [12]
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