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.

Keywords: Africa; Kenya; Plasmodium falciparum; control; deletions; epidemiology; histidine-rich proteins; malaria diagnosis.

Figure 1

Illustration of pfhrp2 and pfhrp3 genes and their flanking regions (green color), chromosome breakage and rejoining points (in red arrows) and the primer locations for the target genes (blue arrows).

Figure 2

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart showing the screening and retrieval process of publications that were eventually used in the analysis.

Figure 3

Bar chart showing the mean prevalence and distribution of pfhrp2, pfhrp3, and the corresponding flanking gene deletions in South America, Central America, Asia, and Africa.

Figure 4

Forest plot showing the prevalence of (A): (pfhrp2 exon1-2) (B): (Upstream MALP1.230) (C): (Downstream MALP1.228) (D): (pfhrp3 exon1-2), (E): (Upstream MAL13P1.475) (F): (Downstream MAL13P1.485), and (G): (Double negative for pfhrp2 and pfhrp3).

Figure 4

Forest plot showing the prevalence of (A): (pfhrp2 exon1-2) (B): (Upstream MALP1.230) (C): (Downstream MALP1.228) (D): (pfhrp3 exon1-2), (E): (Upstream MAL13P1.475) (F): (Downstream MAL13P1.485), and (G): (Double negative for pfhrp2 and pfhrp3).

Figure 4

Forest plot showing the prevalence of (A): (pfhrp2 exon1-2) (B): (Upstream MALP1.230) (C): (Downstream MALP1.228) (D): (pfhrp3 exon1-2), (E): (Upstream MAL13P1.475) (F): (Downstream MAL13P1.485), and (G): (Double negative for pfhrp2 and pfhrp3).

Figure 4

Forest plot showing the prevalence of (A): (pfhrp2 exon1-2) (B): (Upstream MALP1.230) (C): (Downstream MALP1.228) (D): (pfhrp3 exon1-2), (E): (Upstream MAL13P1.475) (F): (Downstream MAL13P1.485), and (G): (Double negative for pfhrp2 and pfhrp3).

Figure 4

Forest plot showing the prevalence of (A): (pfhrp2 exon1-2) (B): (Upstream MALP1.230) (C): (Downstream MALP1.228) (D): (pfhrp3 exon1-2), (E): (Upstream MAL13P1.475) (F): (Downstream MAL13P1.485), and (G): (Double negative for pfhrp2 and pfhrp3).

Figure 4

Forest plot showing the prevalence of (A): (pfhrp2 exon1-2) (B): (Upstream MALP1.230) (C): (Downstream MALP1.228) (D): (pfhrp3 exon1-2), (E): (Upstream MAL13P1.475) (F): (Downstream MAL13P1.485), and (G): (Double negative for pfhrp2 and pfhrp3).

Figure 4

Forest plot showing the prevalence of (A): (pfhrp2 exon1-2) (B): (Upstream MALP1.230) (C): (Downstream MALP1.228) (D): (pfhrp3 exon1-2), (E): (Upstream MAL13P1.475) (F): (Downstream MAL13P1.485), and (G): (Double negative for pfhrp2 and pfhrp3).