Abstract
ObjectivesOur objective was to systematically investigate false-negative histidine-rich protein 2 rapid diagnostic tests (HRP2-RDT) in imported Plasmodium falciparum malaria cases from travelers to the UK and the Republic of Ireland (RoI). MethodsFive imported malaria cases in travellers returning to the UK and RoI from East Africa were reported to the PHE Malaria Reference Laboratory as negative according to histidine-rich protein (HRP2)-RDT. The cases were systematically investigated using microscopic, RDT, molecular, genomic, and in in vitro approaches. ResultsIn each case, HRP2-RDT was negative, whereas microscopy confirmed the presence of P. falciparum. Further analysis revealed that the genes encoding HRP2 and HRP3 were deleted in three of the five cases. Whole-genome sequencing in one of these isolates confirmed deletions in P. falciparum chromosomes 8 and 13. Our study produced evidence that the fourth case, which had high parasitemia at clinical presentation, was a rare example of antigen saturation (‘prozone-like effect’), leading to a false negative in the HRP2-RDT, while the fifth case was due to low parasitemia. ConclusionsFalse-negative HRP2-RDT results with P. falciparum are concerning. Our findings emphasise the necessity of supporting the interpretation of RDT results with microscopy, in conjunction with clinical observations, and sets out a systematic approach to identifying parasites carrying pfhrp2 and pfhrp3 deletions.
Highlights
Malaria rapid diagnostic tests (RDTs) are point-of-care immunochromatographic lateral flow assays which detect malaria (Askling et al, 2012; Houze et al, 2013)
This study presents a systematic investigation of false-negative HRP2-RDT results in travelers to the UK and Republic of Ireland (RoI) with imported malaria due to P. falciparum infection
The study presents evidence that a false-negative RDT result obtained for a fourth patient was due to a prozone-like effect due to antigen saturation caused by high parasitemia, and for a fifth patient due to low parasitemia
Summary
Malaria rapid diagnostic tests (RDTs) are point-of-care immunochromatographic lateral flow assays which detect malaria (Askling et al, 2012; Houze et al, 2013) This is because RDT detection of P. falciparum has lower sensitivity than other methods, and the false-negative rate resulting from this is exacerbated by the emergence of P. falciparum parasites that do not express both HRP2 and HRP3 antigens (Berhane et al, 2018; Gamboa et al, 2010). While the global prevalence of parasites with the deletion remains low, and appears to be concentrated in certain populations, there is a growing recognition by WHO that these represent a potential threat to rapid diagnosis of falciparum malaria, a cornerstone of global control strategies (Gatton et al, 2017; Thomson et al, 2020)
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