Abstract
BackgroundMalaria rapid diagnostic tests (RDTs) have greatly improved access to diagnosis in endemic countries. Most RDTs detect Plasmodium falciparum histidine-rich protein 2 (HRP2), but their sensitivity is seriously threatened by the emergence of pfhrp2-deleted parasites. RDTs detecting P. falciparum or pan-lactate dehydrogenase (Pf- or pan-LDH) provide alternatives. The objective of this study was to systematically assess the performance of malaria RDTs against well-characterized pfhrp2-deleted P. falciparum parasites.MethodsThirty-two RDTs were tested against 100 wild-type clinical isolates (200 parasites/µL), and 40 samples from 10 culture-adapted and clinical isolates of pfhrp2-deleted parasites. Wild-type and pfhrp2-deleted parasites had comparable Pf-LDH concentrations. Pf-LDH-detecting RDTs were also tested against 18 clinical isolates at higher density (2,000 parasites/µL) lacking both pfhrp2 and pfhrp3.ResultsRDT positivity against pfhrp2-deleted parasites was highest (> 94%) for the two pan-LDH-only RDTs. The positivity rate for the nine Pf-LDH-detecting RDTs varied widely, with similar median positivity between double-deleted (pfhrp2/3 negative; 63.9%) and single-deleted (pfhrp2-negative/pfhrp3-positive; 59.1%) parasites, both lower than against wild-type P. falciparum (93.8%). Median positivity for HRP2-detecting RDTs against 22 single-deleted parasites was 69.9 and 35.2% for HRP2-only and HRP2-combination RDTs, respectively, compared to 96.0 and 92.5% for wild-type parasites. Eight of nine Pf-LDH RDTs detected all clinical, double-deleted samples at 2,000 parasites/µL.ConclusionsThe pan-LDH-only RDTs evaluated performed well. Performance of Pf-LDH-detecting RDTs against wild-type P. falciparum does not necessarily predict performance against pfhrp2-deleted parasites. Furthermore, many, but not all HRP2-based RDTs, detect pfhrp2-negative/pfhrp3-positive samples, with implications for the HRP2-based RDT screening approach for detection and surveillance of HRP2-negative parasites.
Highlights
Malaria rapid diagnostic tests (RDTs) have greatly improved access to diagnosis in endemic countries
RDT positivity rates against pfhrp2‐deleted panel compared to wild‐type panel The overall positivity of RDTs against pfhrp2-deleted parasites was 40.1%, differing by RDT group: 57.1% for Group 1 (Pf-Lactate dehy‐ drogenase (LDH)), 95.6% for Group 2, 43.4% for Group 3 (HRP2-only), and 23.7% for Group 4 (HRP2-combination)
Large differences in positivity were observed between the double-deleted, single-deleted and wild-type parasites for Group 3 (HRP2-only) and 4 (HRP2-combination) RDTs, and Group 4 RDTs showed large inter-product variation in Plasmodium falciparum (Pf) band positivity against single-deleted P. falciparum parasites (Table 3, Fig. 1)
Summary
Malaria rapid diagnostic tests (RDTs) have greatly improved access to diagnosis in endemic countries. Most RDTs detect Plasmodium falciparum histidine-rich protein 2 (HRP2), but their sensitivity is seriously threatened by the emergence of pfhrp2-deleted parasites. RDTs detecting P. falciparum or pan-lactate dehydrogenase (Pf- or panLDH) provide alternatives. The objective of this study was to systematically assess the performance of malaria RDTs against well-characterized pfhrp2-deleted P. falciparum parasites. Gatton et al Malar J (2020) 19:392 detect but do not differentiate between P. falciparum and non-P. falciparum species. Most P. falciparum-detecting RDTs use histidine-rich protein 2 (HRP2) as it is speciesspecific and abdundantly produced. Some HRP2-based RDTs may potentially detect P. falciparum histidine-rich protein 3 (HRP3) due to its structural similarity with HRP2 [3]. RDT bands detecting non-falciparum Plasmodium target Pan or species-specific lactate dehydrogenase (Pan-LDH, Plasmodium vivax (Pv)-LDH or P. vivax, Plasmodium ovale, Plasmodium malariae (Pvom)LDH), or aldolase. HRP2-based RDTs generally exhibit superior performance, at low parasite densities, and are more heat stable than non-HRP2-based RDTs [4]
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