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Plasmodium falciparum pfhrp2 and pfhrp3 gene deletions among patients in the DRC enrolled from 2017 to 2018.

ABSTRACT: Rapid diagnostic tests (RDTs) detecting histidine-rich protein 2 (HRP2) and HRP3 are widely used throughout sub-Saharan Africa (SSA) to diagnose Plasmodium falciparum malaria. However, multiple SSA countries have reported pfhrp2 and pfhrp3 (pfhrp2/3) gene deletions. Blood samples (n = 1109) collected from patients with P. falciparum infection from six health facilities throughout the Democratic Republic of the Congo (DRC) from March 2017 to January 2018 were evaluated for pfhrp2/3 deletions. Samples were assayed for HRP2, pan-Plasmodium LDH (pLDH) and aldolase (pAldolase) antigens by bead-based multiplex antigen assay. Samples with low HRP2 concentration compared to pLDH and pAldolase antigens were selected for further pfhrp2/3 genotyping PCRs. The majority of blood samples (93.3%, 1035/1109) had high concentrations of the HRP2 antigen. Single deletions of pfhrp2 were identified in 0.27% (3/1109) of screened samples, with one sample from each of the Kapolowe, Mikalayi, and Rutshuru study sites. A pfhrp3 single deletion (0.09%, 1/1109) was found in the Kapolowe site. Dual pfhrp2 and pfhrp3 deletions were not observed. Due to, the low numbers of pfhrp2 deletions and the sporadic locations of these deletions, the use of HRP2-based RDTs appears to still be appropriate for these locations in DRC.

SUBMITTER: McCaffery JN

PROVIDER: S-EPMC8626453 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Plasmodium falciparum pfhrp2 and pfhrp3 gene deletions among patients in the DRC enrolled from 2017 to 2018.

McCaffery Jessica N JN Nace Douglas D Herman Camelia C Singh Balwan B Sompwe Eric Mukomena EM Nkoli Papy Mandoko PM Ngoyi Dieudonné Mumba DM Kahunu Gauthier Mesia GM Halsey Eric S ES Rogier Eric E

Scientific reports 20211126 1

Rapid diagnostic tests (RDTs) detecting histidine-rich protein 2 (HRP2) and HRP3 are widely used throughout sub-Saharan Africa (SSA) to diagnose Plasmodium falciparum malaria. However, multiple SSA countries have reported pfhrp2 and pfhrp3 (pfhrp2/3) gene deletions. Blood samples (n = 1109) collected from patients with P. falciparum infection from six health facilities throughout the Democratic Republic of the Congo (DRC) from March 2017 to January 2018 were evaluated for pfhrp2/3 deletions. Sam ...[more]

PMID: 34837020

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Project description:Plasmodium falciparum with the histidine rich protein 2 gene (pfhrp2) deleted from its genome can escape diagnosis by HRP2-based rapid diagnostic tests (HRP2-RDTs). The World Health Organization (WHO) recommends switching to a non-HRP2 RDT for P. falciparum clinical case diagnosis when pfhrp2 deletion prevalence causes ≥ 5% of RDTs to return false negative results. Tanzania is a country of heterogenous P. falciparum transmission, with some regions approaching elimination and others at varying levels of control. In concordance with the current recommended WHO pfhrp2 deletion surveillance strategy, 100 health facilities encompassing 10 regions of Tanzania enrolled malaria-suspected patients between February and July 2021. Of 7863 persons of all ages enrolled and providing RDT result and blood sample, 3777 (48.0%) were positive by the national RDT testing for Plasmodium lactate dehydrogenase (pLDH) and/or HRP2. A second RDT testing specifically for the P. falciparum LDH (Pf-pLDH) antigen found 95 persons (2.5% of all RDT positives) were positive, though negative by the national RDT for HRP2, and were selected for pfhrp2 and pfhrp3 (pfhrp2/3) genotyping. Multiplex antigen detection by laboratory bead assay found 135/7847 (1.7%) of all blood samples positive for Plasmodium antigens but very low or no HRP2, and these were selected for genotyping as well. Of the samples selected for genotyping based on RDT or laboratory multiplex result, 158 were P. falciparum DNA positive, and 140 had sufficient DNA to be genotyped for pfhrp2/3. Most of these (125/140) were found to be pfhrp2+/pfhrp3+, with smaller numbers deleted for only pfhrp2 (n = 9) or only pfhrp3 (n = 6). No dual pfhrp2/3 deleted parasites were observed. This survey found that parasites with these gene deletions are rare in Tanzania, and estimated that 0.24% (95% confidence interval: 0.08% to 0.39%) of false-negative HRP2-RDTs for symptomatic persons were due to pfhrp2 deletions in this 2021 Tanzania survey. These data provide evidence for HRP2-based diagnostics as currently accurate for P. falciparum diagnosis in Tanzania.

Project description:BackgroundHistidine-rich protein 2 (HRP2)-based malaria rapid diagnostic tests (RDTs) are effective and widely used for the detection of wild-type Plasmodium falciparum infections. Although recent studies have reported false negative HRP2 RDT results due to pfhrp2 and pfhrp3 gene deletions in different countries, there is a paucity of data on the deletions of these genes in Tanzania.MethodsA community-based cross-sectional survey was conducted between July and November 2017 in four regions: Geita, Kigoma, Mtwara and Ruvuma. All participants had microscopy and RDT performed in the field and provided a blood sample for laboratory multiplex antigen detection (for Plasmodium lactate dehydrogenase, aldolase, and P. falciparum HRP2). Samples showing RDT false negativity or aberrant relationship of HRP2 to pan-Plasmodium antigens were genotyped to detect the presence/absence of pfhrp2/3 genes.ResultsOf all samples screened by the multiplex antigen assay (n = 7543), 2417 (32.0%) were positive for any Plasmodium antigens while 5126 (68.0%) were negative for all antigens. The vast majority of the antigen positive samples contained HRP2 (2411, 99.8%), but 6 (0.2%) had only pLDH and/or aldolase without HRP2. Overall, 13 samples had an atypical relationship between a pan-Plasmodium antigen and HRP2, but were positive by PCR. An additional 16 samples with negative HRP2 RDT results but P. falciparum positive by microscopy were also chosen for pfhrp2/3 genotyping. The summation of false negative RDT results and laboratory antigen results provided 35 total samples with confirmed P. falciparum DNA for pfhrp2/3 genotyping. Of the 35 samples, 4 (11.4%) failed to consistently amplify positive control genes; pfmsp1 and pfmsp2 and were excluded from the analysis. The pfhrp2 and pfhrp3 genes were successfully amplified in the remaining 31 (88.6%) samples, confirming an absence of deletions in these genes.ConclusionsThis study provides evidence that P. falciparum parasites in the study area have no deletions of both pfhrp2 and pfhrp3 genes. Although single gene deletions could have been missed by the multiplex antigen assay, the findings support the continued use of HRP2-based RDTs in Tanzania for routine malaria diagnosis. There is a need for the surveillance to monitor the status of pfhrp2 and/or pfhrp3 deletions in the future.

Project description:Malaria rapid diagnostic tests (RDTs) targeting the Plasmodium falciparum histidine-rich protein 2 (PfHRP2) are widely used to diagnose P. falciparum infection. However, reports of P. falciparum strains lacking PfHRP2 and the structurally similar PfHRP3 have raised concerns about the utility and reliability of PfHRP2-based RDTs. This study investigated the presence of P. falciparum with pfhrp2 and/or pfhrp3 gene deletions among infected residents in the Lake Victoria region, Kenya. Four cross-sectional malaria, surveys were conducted in four sites (Suba South, Mfangano, Kibuogi, and Ngodhe) from September 2018 to January 2020. P. falciparum infections were detected using a PfHRP2-based RDT, microscopy, and PCR on 9120 finger-prick blood samples. Samples negative by RDT but positive by PCR were selected for PCR amplification of pfmsp1 and pfmsp2 to confirm the quality and quantity of P. falciparum DNA. Samples positive for both pfmsp1 and pfmsp2 were included for detection of deletions of exons 1 and 2 in pfhrp2 and pfhrp3 PCR. The multiplicity of infection (MOI) was determined as the higher allele count between pfmsp1 and pfmsp2. Logistic regression analysis was performed to analyze the association between pfhrp2 and/or pfhrp3 deletions and demographic and infection variables. Of the 445 RDT-negative and PCR-positive samples, 125 (28.1%) were analyzed for pfhrp2 and pfhrp3 deletions. Single pfhrp2 deletion, single pfhrp3 deletion, and pfhrp2/3 double deletions were detected in 13 (10.4%), 19 (15.2%), and 36 (28.8%) samples, respectively. Single pfhrp2 deletion was found in all sites while single pfhrp3 deletion was found in all sites except Kibuogi. The majority of samples with pfhrp2 and/or pfhrp3 deletions were submicroscopic (73.5%), asymptomatic (80.9%), and monoclonal (80.9%). Polyclonal infection was significantly (p = 0.022) associated with a lower odds of pfhrp2/3 double deletion, suggesting detection of intact pfhrp2/3 in mixed infections. We report the presence of P. falciparum with pfhrp2/pfhrp3 double deletions among asymptomatic and submicroscopic infections in Kenya. Our findings highlight the need for active monitoring of pfhrp2 and pfhrp3 deletions at the community level to improve malaria detection and control in the region.

Dataset Information

Plasmodium falciparum pfhrp2 and pfhrp3 gene deletions among patients in the DRC enrolled from 2017 to 2018.

Publications

Plasmodium falciparum pfhrp2 and pfhrp3 gene deletions among patients in the DRC enrolled from 2017 to 2018.

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