Plasmodium falciparum Histidine-Rich Protein 2 and 3 Gene Deletions and Their Implications in Malaria Control

Abstract

Malaria remains the biggest threat to public health, especially among pregnant women and young children in sub-Saharan Africa. Prompt and accurate diagnosis is critical for effective case management and detection of drug resistance. Conventionally, microscopy and rapid diagnostic tests (RDTs) are the tools of choice for malaria diagnosis. RDTs are simple to use and have been extensively used in the diagnosis of malaria among travelers to malaria-endemic regions, routine case management, and surveillance studies. Most RDTs target the histidine-rich protein (PfHRP) which is exclusively found in Plasmodium falciparum and a metabolic enzyme Plasmodium lactate dehydrogenase (pLDH) which is common among all Plasmodium species. Other RDTs incorporate the enzyme aldolase that is produced by all Plasmodium species. Recently, studies have reported false-negative RDTs primarily due to the deletion of the histidine-rich protein (pfhrp2 and pfhrp3) genes in field isolates of P. falciparum. Herein, we review published literature to establish pfhrp2/pfhrp3 deletions, the extent of these deletions in different geographical regions, and the implication in malaria control. We searched for publications on pfhrp2/pfhrp3 deletions and retrieved all publications that reported on this subject. Overall, 20 publications reported on pfhrp2/pfhrp3 deletions, and most of these studies were done in Central and South America, with very few in Asia and Africa. The few studies in Africa that reported on the occurrence of pfhrp2/pfhrp3 deletions rarely evaluated deletions on the flanking genes. More studies are required to evaluate the existence and extent of these gene deletions, whose presence may lead to delayed or missed treatment. This information will guide appropriate diagnostic approaches in the respective areas.

Evaluation of Histidine-Rich Proteins 2 and 3 Gene Deletions in Plasmodium falciparum in Endemic Areas of the Brazilian Amazon

“…This exceeded the percentages found in the Peruvian Amazon, where the prevalence for this event was 41.0%, 1.3 times more than the frequency of 31.2% observed in the same municipality in a prospective study with samples collected in 2012 [ 5 , 7 ]. Although it was not possible to determine the prevalence of negative pfhrp2 isolates in the municipality of Cruzeiro do Sul, the data from this study confirm the evidence of this event, corroborating previous findings, and reinforce the need for attention in the area, in order to promote expansion and advancement of investigations for accurate and timely actions in public health [ 2 , 16 , 18 ].…”

“…However, it is necessary to continue the study, expanding the sampling in order to make it possible to determine the local prevalence and obtain information representative of each municipality as well the Amazon basin [ 16 ]. On the other hand, these studies support national malaria programs in strategic planning and operational actions for choosing the RDT that best meets the epidemiological and genetic characteristics of a certain area, since accurate mapping and enhanced monitoring of the prevalence of deletions of pfhrp2/3 are essential, together with the realization of harmonized methods that allow comparisons between studies [ 17 , 18 , 19 ].…”

Prevalence of <i>Plasmodium</i> spp. in symptomatic BaAka Pygmies inhabiting the rural Dzanga Sangha region of the Central African Republic

“…The Pfhrp2 gene is responsible for the production of the HRP2 protein, which is an antigen detected by the P. falciparum-specific RDTs. The rate of such infections has been estimated at approximately 5% in sub-Saharan Africa [31][32][33], up to 40% in Peru [34,35], and even over 80% in Eritrea, depending on the region [36]. As suggested by the WHO, the use of RDTs targeting the HRP2 protein for the diagnosis of malaria is questionable when the percentage of P. falciparum species with a Pfhrp2 deletion is over 5% in a given area [37,38].…”

Prevalence of Plasmodium spp. in Symptomatic BaAka Pygmies Inhabiting the Rural Dzanga Sangha Region, Central African Republic

“…Pfhrp2 gene is responsible for the production of HRP2 protein, which is an antigen detected by the P. falciparum-speci c RDTs. The rate of such infections has been estimated at approximately 5% in sub-Saharan Africa [37][38][39], up to 40% in Peru [40,41] and even over 80% in Eritrea depending on the region [42]. As suggested by the WHO, the use of RDTs targeting HRP2 protein for the diagnosis of malaria is questionable when the percentage of P. falciparum species with a Pfhrp2 deletion is over 5% in a given area [43,44].…”