Dataset Information

Plasmodium falciparum Histidine-Rich Protein 2 and 3 Gene Deletions in Strains from Nigeria, Sudan, and South Sudan.

ABSTRACT: Deletion of histidine-rich protein genes pfhrp2/3 in Plasmodium falciparum causes infections to go undetected by HRP2-based malaria rapid diagnostic tests. We analyzed P. falciparum malaria cases imported to Australia (n = 210, collected 2010-2018) for their pfhrp2/3 status. We detected gene deletions in patients from 12 of 25 countries. We found >10% pfhrp2-deletion levels in those from Nigeria (13.3%, n = 30), Sudan (11.2%, n = 39), and South Sudan (17.7%, n = 17) and low levels of pfhrp3 deletion from Sudan (3.6%) and South Sudan (5.9%). No parasites with pfhrp2/3 double deletions were detected. Microsatellite typing of parasites from Nigeria, Sudan, and South Sudan revealed low relatedness among gene-deleted parasites, indicating independent emergences. The gene deletion proportions signify a risk of false-negative HRP2-RDT results. This study's findings warrant surveillance to determine whether the prevalence of gene-deleted parasites justifies switching malaria rapid diagnostic tests in Nigeria, Sudan, and South Sudan.

SUBMITTER: Prosser C

PROVIDER: S-EPMC7853540 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Plasmodium falciparum Histidine-Rich Protein 2 and 3 Gene Deletions in Strains from Nigeria, Sudan, and South Sudan.

Prosser Christiane C Gresty Karryn K Ellis John J Meyer Wieland W Anderson Karen K Lee Rogan R Cheng Qin Q

Emerging infectious diseases 20210201 2

Deletion of histidine-rich protein genes pfhrp2/3 in Plasmodium falciparum causes infections to go undetected by HRP2-based malaria rapid diagnostic tests. We analyzed P. falciparum malaria cases imported to Australia (n = 210, collected 2010-2018) for their pfhrp2/3 status. We detected gene deletions in patients from 12 of 25 countries. We found >10% pfhrp2-deletion levels in those from Nigeria (13.3%, n = 30), Sudan (11.2%, n = 39), and South Sudan (17.7%, n = 17) and low levels of pfhrp3 dele ...[more]

PMID: 33496220

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Project description:BackgroundRapid diagnostic tests (RDTs) based on the detection of Plasmodium falciparum histidine rich protein 2 (PfHRP2) are widely used for the diagnostic of P. falciparum in Africa. However, deletions of the pfhrp2 and pfhrp3 genes can lead to false negative test results and compromise appropriate case management. Due to the high burden of malaria in Mozambique, it is crucial to monitor the potential emergence of parasites with pfhrp2/3 gene deletions in the country.MethodsThe presence of pfhrp2/3 deletions was assessed during the 2023 high transmission season in 34 health facilities from 9 districts across 6 provinces in Mozambique. Children between 2 and 10 years of age attending the health facility with fever were tested by both the routine HRP2-RDT and a P. falciparum lactate dehydrogenase (PfLDH)-RDT, and dried blood spots (DBS) were collected from those testing positive by one or both RDTs. DBS from children with a negative HRP2-RDT but positive PfLDH-RDT were tested for the presence of pfhrp2/3 deletions by multiplex real time quantitative polymerase chain reaction (qPCR).Results3208 children attended the health facilities during the study. 81.6% (2612/3208) participants were positive for at least one malaria RDT and, among them, 0.8% (210/2612) had discrepant RDT results (22 HRP2 - but LDH + and 188 HRP2 + but LDH -). The overall prevalence of suspected false-negative HRP2-RDT results in Mozambique was 0.91% (95% CI 0.58-1.39; 22/2424). pfhrp2/3 gene deletions were confirmed in 4 cases (1 in Nampula and 3 in Inhambane). Therefore, the prevalence of P. falciparum confirmed cases with pfhrp2/3 gene deletions in the six provinces sampled was 0.16% (95% CI 0.15-2.57; 4/2424), being 0.27% (95% CI 0.01-1.75; 1/367) in Nampula and 0.59% (95% CI 0.15-1.88; 3/503) in Inhambane.Conclusionpfhrp2/3 gene deletions were detected in 2 out of 6 provinces surveyed in Mozambique, but at a prevalence far below the 5% threshold recommended for a change in HRP2-based-RDT.

Project description:Peru was the first country where pfhrp2 and pfhrp3 gene deletions were detected despite the fact that rapid diagnostics tests are not commonly used for confirmatory malaria diagnosis. This context provides a unique scenario to study the dynamics of pfhrp2 and pfhrp3 gene deletions without apparent RDTs selection pressure. In this study we characterized the presence of pfhrp2 and pfhrp3 genes on 325 P. falciparum samples collected in Iquitos and surrounding communities between 2011 and 2018 in order to understand the dynamics of gene deletion prevalence, potential associations with clinical symptomatology and parasite genetic background. P. falciparum presence was confirmed by microscopy and PCR of 18 s rRNA, pfmsp1 and pfmsp2. Gene deletions were assessed by amplification of exon1 and exon2 of pfhrp2 and pfhrp3 using gene specific PCRs. Confirmation of absence of HRP2 expression was assessed by ELISA of HRP2 and pLDH. Genotyping of 254 samples were performed using a panel of seven neutral microsatellite markers. Overall, pfhrp2 and pfhrp3 dual gene deletions were detected in 67% (217/324) parasite samples. Concordance between pfhrp2 deletion and negligible HRP2 protein levels was observed (Cohen's Kappa = 0.842). Prevalence of gene deletions was heterogeneous across study sites (adjusted p < 0.005) but there is an overall tendency towards increase through time in the prevalence of dual pfhrp2/3-deleted parasites between 2011 (14.3%) and 2016 (88.39%) stabilizing around 65% in 2018. Dual deletions increase was associated with dominance of a single new parasite haplotype (H8) which rapidly spread to all study sites during the 8 study years. Interestingly, participants infected with dual pfhrp2/3-deleted parasites had a significantly lower parasitemias than those without gene deletions in this cohort. Our study showed the increase of pfhrp2/3 deletions in the absence of RDTs pressure and a clonal replacement of circulating lines in the Peruvian Amazon basin. These results suggest that other factors linked to the pfhrp2/3 deletion provide a selective advantage over non-deleted strains and highlight the need for additional studies and continuing surveillance.

Project description:In the thirteen years since the first report of pfhrp2-deleted parasites in 2010, the World Health Organization (WHO) has found that 40 of 47 countries surveyed worldwide have reported pfhrp2/3 gene deletions. Due to a high prevalence of pfhrp2/3 deletions causing false-negative HRP2 RDTs, in the last five years, Eritrea, Djibouti and Ethiopia have switched or started switching to using alternative RDTs, that target pan-specific-pLDH or P. falciparum specific-pLDH alone of in combination with HRP2. However, manufacturing of alternative RDTs has not been brought to scale and there are no WHO prequalified combination tests that use Pf-pLDH instead of HRP2 for P. falciparum detection. For these reasons, the continued spread of pfhrp2/3 deletions represents a growing public health crisis that threatens efforts to control and eliminate P. falciparum malaria. National malaria control programmes, their implementing partners and test developers desperately seek pfhrp2/3 deletion data that can inform their immediate and future resource allocation. In response, we use a mathematical modelling approach to evaluate the global risk posed by pfhrp2/3 deletions and explore scenarios for how deletions will continue to spread in Africa. We incorporate current best estimates of the prevalence of pfhrp2/3 deletions and conduct a literature review to estimate model parameters known to impact the selection of pfhrp2/3 deletions for each malaria endemic country. We identify 20 countries worldwide to prioritise for surveillance and future deployment of alternative RDT, based on quickly selecting for pfhrp2/3 deletions once established. In scenarios designed to explore the continued spread of deletions in Africa, we identify 10 high threat countries that are most at risk of deletions both spreading to and subsequently being rapidly selected for. If HRP2-based RDTs continue to be relied on for malaria case management, we predict that the major route for pfhrp2 deletions to spread is south out from the current hotspot in the Horn of Africa, moving through East Africa over the next 20 years. We explore the variation in modelled timelines through an extensive parameter sensitivity analysis and despite wide uncertainties, we identify three countries that have not yet switched RDTs (Senegal, Zambia and Kenya) that are robustly identified as high risk for pfhrp2/3 deletions. These results provide a refined and updated prediction model for the emergence of pfhrp2/3 deletions in an effort to help guide pfhrp2/3 policy and prioritise future surveillance efforts and innovation.

Project description:BackgroundRapid diagnostic tests (RDTs) targeting histidine rich protein 2(HRP2) are widely used for diagnosis of Plasmodium falciparum infections. Besides PfHRP2, the PfHRP3 antigen contributes to the detection of P. falciparum infections in PfHRP2 RDTs. However, the performance HRP2-based RDT is affected by pfhrp2/3 gene deletions resulting in false-negative test results. The objective of this study was to determine the presence and prevalence of pfhrp2/3 gene deletions including the respective flanking regions among symptomatic patients in Assosa zone, Northwest Ethiopia.MethodsA health-facility based cross-sectional study was conducted in febrile patients seeking a malaria diagnosis in 2018. Blood samples were collected by finger-prick for microscopic examination of blood smears, malaria RDT, and molecular analysis using dried blood spots (DBS) prepared on Whatman filter paper. A total of 218 P. falciparum positive samples confirmed by quantitative PCR were included for molecular assay of pfhrp2/3 target gene.ResultsOf 218 P. falciparum positive samples, exon 2 deletions were observed in 17.9% of pfhrp2 gene and in 9.2% of pfhrp3 gene. A high proportion of deletions in short segments of pfhrp2 exon1-2 (50%) was also detected while the deletions of the pfhrp3 exon1-2 gene were 4.1%. The deletions were extended to the downstream and upstream of the flanking regions in pfhrp2/3 gene (above 30%). Of eighty-six PfHRP2 RDT negative samples, thirty-six lacked pfhrp2 exon 2. Five PfHRP2 RDT negative samples had double deletions in pfhrp2 exon 2 and pfhrp3 exon2. Of these double deletions, only two of the samples with a parasite density above 2000 parasite/µl were positive by the microscopy. Three samples with intact pfhrp3 exon2 in the pfhrp2 exon2 deleted parasite isolates were found to be positive by PfHRP2 RDT and microscopy with a parasite density above 10,000/µl.ConclusionThis study confirms the presence of deletions of pfhrp2/3 gene including the flanking regions. Pfhrp2/3 gene deletions results in false-negative results undoubtedly affect the current malaria control and elimination effort in the country. However, further countrywide investigations are required to determine the magnitude of pfhrp2/3 gene deletions and its consequences on routine malaria diagnosis.

Dataset Information

Plasmodium falciparum Histidine-Rich Protein 2 and 3 Gene Deletions in Strains from Nigeria, Sudan, and South Sudan.

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Plasmodium falciparum Histidine-Rich Protein 2 and 3 Gene Deletions in Strains from Nigeria, Sudan, and South Sudan.

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