Abstract
BackgroundDeletion of pfhrp2 and/or pfhrp3 genes cause false negatives in malaria rapid diagnostic test (RDT) and threating malaria control strategies. This systematic review aims to assess the main methodological aspects in the study of pfhrp2 and pfhrp3 gene deletions and its global epidemiological status, with special focus on their distribution in Africa; and its possible impact in RDT.MethodsThe systematic review was conducted by examining the principal issues of study design and methodological workflow of studies addressing pfhrp2 deletion. Meta-analysis was applied to represent reported prevalences of pfhrp2 and pfhrp3 single and double deletion in the World Health Organization (WHO) region. Pooled-prevalence of deletions was calculated using DerSimonnian-Laird random effect model. Then, in-deep analysis focused on Africa was performed to assess possible variables related with these deletions. Finally, the impact of these deletions in RDT results was analysed combining reported information about RDT sensitivity and deletion prevalences.Results49 articles were included for the systematic review and 37 for the meta-analysis, 13 of them placed in Africa. Study design differs significantly, especially in terms of population sample and information reported, resulting in high heterogeneity between studies that difficulties comparisons and merged conclusions. Reported prevalences vary widely in all the WHO regions, significantly higher deletion were reported in South-Central America, following by Africa and Asia. Pfhrp3 deletion is more prevalent (43% in South-Central America; 3% in Africa; and 1% in Asia) than pfhrp2 deletion (18% in South-Central America; 4% in Africa; and 3% in Asia) worldwide. In Africa, there were not found differences in deletion prevalence by geographical or population origin of samples. The prevalence of deletion among false negatives ranged from 0 to 100% in Africa, but in Asia and South-Central America was only up to 90% and 48%, respectively, showing substantial relation between deletions and false negatives.ConclusionThe concerning prevalence of pfhrp2, pfhrp3 and pfhrp2/3 gene deletions, as its possible implications in malaria control, highlights the importance of regular and systematic surveillance of these deletions. This review has also outlined that a standardized methodology could play a key role to ensure comparability between studies to get global conclusions.
Highlights
Deletion of pfhrp2 and/or pfhrp3 genes cause false negatives in malaria rapid diagnostic test (RDT) and threating malaria control strategies
The majority of RDTs are based on detecting Histidine-rich protein 2 (HRP2), a specific protein from P. falciparum encoded by the pfhrp2 gene [6]
The review sought (1) to assess the main methodological aspects in the study of pfhrp2, pfhrp3 and pfhrp2/3 gene deletions; (2) to gather the epidemiological information reported for pfhrp2, pfhrp3 and pfhrp2/3 gene deletions worldwide; (3) to assess the epidemiological information reported for these genes in Africa; and (4) to evaluate the impact of these deletions on the results of PfHRP2-based malaria RDTs
Summary
Deletion of pfhrp and/or pfhrp genes cause false negatives in malaria rapid diagnostic test (RDT) and threating malaria control strategies. Plasmodium falciparum caused the majority of cases and deaths by malaria, followed by Plasmodium vivax (2.8% of cases). Africa, where the prevalent species is P. falciparum, reported more than 94% of cases and deaths [1]. Point-of-care testing is a good option in this regard, especially in resource-limited settings, which is typically the case for the majority of endemic malaria regions [3, 4]. The majority of RDTs are based on detecting HRP2 (histidine-rich protein 2), a specific protein from P. falciparum encoded by the pfhrp gene [6]. In addition to detecting HRP2, there are reports of cross-reactions with HRP3, a structural homologue of HRP2 encoded by the pfhrp gene [7].
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