Analysis of false-negative rapid diagnostic tests for symptomatic malaria in the Democratic Republic of the Congo

The majority of Plasmodium falciparum malaria diagnoses in Africa are made using rapid diagnostic tests (RDTs) that detect histidine-rich protein 2. Increasing reports of false-negative RDT results due to parasites with deletions of the pfhrp2 and/or pfhrp3 genes ( pfhrp2/3 ) raise concern about exi...

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Published inScientific reports Vol. 11; no. 1; pp. 6495 - 12
Main Authors Parr, Jonathan B., Kieto, Eddy, Phanzu, Fernandine, Mansiangi, Paul, Mwandagalirwa, Kashamuka, Mvuama, Nono, Landela, Ange, Atibu, Joseph, Efundu, Solange Umesumbu, Olenga, Jean W., Thwai, Kyaw Lay, Morgan, Camille E., Denton, Madeline, Poffley, Alison, Juliano, Jonathan J., Mungala, Pomie, Likwela, Joris L., Sompwe, Eric M., Rogier, Eric, Tshefu, Antoinette K., N’Siala, Adrien, Kalonji, Albert
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 22.03.2021
Nature Publishing Group
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ISSN2045-2322
2045-2322
DOI10.1038/s41598-021-85913-z

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Abstract The majority of Plasmodium falciparum malaria diagnoses in Africa are made using rapid diagnostic tests (RDTs) that detect histidine-rich protein 2. Increasing reports of false-negative RDT results due to parasites with deletions of the pfhrp2 and/or pfhrp3 genes ( pfhrp2/3 ) raise concern about existing malaria diagnostic strategies. We previously identified pfhrp2 -negative parasites among asymptomatic children in the Democratic Republic of the Congo (DRC), but their impact on diagnosis of symptomatic malaria is unknown. We performed a cross-sectional study of false-negative RDTs in symptomatic subjects in 2017. Parasites were characterized by microscopy; RDT; pfhrp2/3 genotyping and species-specific PCR assays; a bead-based immunoassay for Plasmodium antigens; and/or whole-genome sequencing. Among 3627 symptomatic subjects, 427 (11.8%) had RDT-/microscopy + results. Parasites from eight (0.2%) samples were initially classified as putative pfhrp2/3 deletions by PCR, but antigen testing and whole-genome sequencing confirmed the presence of intact genes. 56.8% of subjects had PCR-confirmed malaria. Non-falciparum co-infection with P. falciparum was common (13.2%). Agreement between PCR and HRP2-based RDTs was satisfactory (Cohen’s kappa = 0.66) and superior to microscopy (0.33). Symptomatic malaria due to pfhrp2/3 -deleted P. falciparum was not observed. Ongoing HRP2-based RDT use is appropriate for the detection of falciparum malaria in the DRC.
AbstractList The majority of Plasmodium falciparum malaria diagnoses in Africa are made using rapid diagnostic tests (RDTs) that detect histidine-rich protein 2. Increasing reports of false-negative RDT results due to parasites with deletions of the pfhrp2 and/or pfhrp3 genes (pfhrp2/3) raise concern about existing malaria diagnostic strategies. We previously identified pfhrp2-negative parasites among asymptomatic children in the Democratic Republic of the Congo (DRC), but their impact on diagnosis of symptomatic malaria is unknown. We performed a cross-sectional study of false-negative RDTs in symptomatic subjects in 2017. Parasites were characterized by microscopy; RDT; pfhrp2/3 genotyping and species-specific PCR assays; a bead-based immunoassay for Plasmodium antigens; and/or whole-genome sequencing. Among 3627 symptomatic subjects, 427 (11.8%) had RDT-/microscopy + results. Parasites from eight (0.2%) samples were initially classified as putative pfhrp2/3 deletions by PCR, but antigen testing and whole-genome sequencing confirmed the presence of intact genes. 56.8% of subjects had PCR-confirmed malaria. Non-falciparum co-infection with P. falciparum was common (13.2%). Agreement between PCR and HRP2-based RDTs was satisfactory (Cohen’s kappa = 0.66) and superior to microscopy (0.33). Symptomatic malaria due to pfhrp2/3-deleted P. falciparum was not observed. Ongoing HRP2-based RDT use is appropriate for the detection of falciparum malaria in the DRC.
The majority of Plasmodium falciparum malaria diagnoses in Africa are made using rapid diagnostic tests (RDTs) that detect histidine-rich protein 2. Increasing reports of false-negative RDT results due to parasites with deletions of the pfhrp2 and/or pfhrp3 genes ( pfhrp2/3 ) raise concern about existing malaria diagnostic strategies. We previously identified pfhrp2 -negative parasites among asymptomatic children in the Democratic Republic of the Congo (DRC), but their impact on diagnosis of symptomatic malaria is unknown. We performed a cross-sectional study of false-negative RDTs in symptomatic subjects in 2017. Parasites were characterized by microscopy; RDT; pfhrp2/3 genotyping and species-specific PCR assays; a bead-based immunoassay for Plasmodium antigens; and/or whole-genome sequencing. Among 3627 symptomatic subjects, 427 (11.8%) had RDT-/microscopy + results. Parasites from eight (0.2%) samples were initially classified as putative pfhrp2/3 deletions by PCR, but antigen testing and whole-genome sequencing confirmed the presence of intact genes. 56.8% of subjects had PCR-confirmed malaria. Non-falciparum co-infection with P. falciparum was common (13.2%). Agreement between PCR and HRP2-based RDTs was satisfactory (Cohen’s kappa = 0.66) and superior to microscopy (0.33). Symptomatic malaria due to pfhrp2/3 -deleted P. falciparum was not observed. Ongoing HRP2-based RDT use is appropriate for the detection of falciparum malaria in the DRC.
Abstract The majority of Plasmodium falciparum malaria diagnoses in Africa are made using rapid diagnostic tests (RDTs) that detect histidine-rich protein 2. Increasing reports of false-negative RDT results due to parasites with deletions of the pfhrp2 and/or pfhrp3 genes (pfhrp2/3) raise concern about existing malaria diagnostic strategies. We previously identified pfhrp2-negative parasites among asymptomatic children in the Democratic Republic of the Congo (DRC), but their impact on diagnosis of symptomatic malaria is unknown. We performed a cross-sectional study of false-negative RDTs in symptomatic subjects in 2017. Parasites were characterized by microscopy; RDT; pfhrp2/3 genotyping and species-specific PCR assays; a bead-based immunoassay for Plasmodium antigens; and/or whole-genome sequencing. Among 3627 symptomatic subjects, 427 (11.8%) had RDT-/microscopy + results. Parasites from eight (0.2%) samples were initially classified as putative pfhrp2/3 deletions by PCR, but antigen testing and whole-genome sequencing confirmed the presence of intact genes. 56.8% of subjects had PCR-confirmed malaria. Non-falciparum co-infection with P. falciparum was common (13.2%). Agreement between PCR and HRP2-based RDTs was satisfactory (Cohen’s kappa = 0.66) and superior to microscopy (0.33). Symptomatic malaria due to pfhrp2/3-deleted P. falciparum was not observed. Ongoing HRP2-based RDT use is appropriate for the detection of falciparum malaria in the DRC.
The majority of Plasmodium falciparum malaria diagnoses in Africa are made using rapid diagnostic tests (RDTs) that detect histidine-rich protein 2. Increasing reports of false-negative RDT results due to parasites with deletions of the pfhrp2 and/or pfhrp3 genes (pfhrp2/3) raise concern about existing malaria diagnostic strategies. We previously identified pfhrp2-negative parasites among asymptomatic children in the Democratic Republic of the Congo (DRC), but their impact on diagnosis of symptomatic malaria is unknown. We performed a cross-sectional study of false-negative RDTs in symptomatic subjects in 2017. Parasites were characterized by microscopy; RDT; pfhrp2/3 genotyping and species-specific PCR assays; a bead-based immunoassay for Plasmodium antigens; and/or whole-genome sequencing. Among 3627 symptomatic subjects, 427 (11.8%) had RDT-/microscopy + results. Parasites from eight (0.2%) samples were initially classified as putative pfhrp2/3 deletions by PCR, but antigen testing and whole-genome sequencing confirmed the presence of intact genes. 56.8% of subjects had PCR-confirmed malaria. Non-falciparum co-infection with P. falciparum was common (13.2%). Agreement between PCR and HRP2-based RDTs was satisfactory (Cohen's kappa = 0.66) and superior to microscopy (0.33). Symptomatic malaria due to pfhrp2/3-deleted P. falciparum was not observed. Ongoing HRP2-based RDT use is appropriate for the detection of falciparum malaria in the DRC.The majority of Plasmodium falciparum malaria diagnoses in Africa are made using rapid diagnostic tests (RDTs) that detect histidine-rich protein 2. Increasing reports of false-negative RDT results due to parasites with deletions of the pfhrp2 and/or pfhrp3 genes (pfhrp2/3) raise concern about existing malaria diagnostic strategies. We previously identified pfhrp2-negative parasites among asymptomatic children in the Democratic Republic of the Congo (DRC), but their impact on diagnosis of symptomatic malaria is unknown. We performed a cross-sectional study of false-negative RDTs in symptomatic subjects in 2017. Parasites were characterized by microscopy; RDT; pfhrp2/3 genotyping and species-specific PCR assays; a bead-based immunoassay for Plasmodium antigens; and/or whole-genome sequencing. Among 3627 symptomatic subjects, 427 (11.8%) had RDT-/microscopy + results. Parasites from eight (0.2%) samples were initially classified as putative pfhrp2/3 deletions by PCR, but antigen testing and whole-genome sequencing confirmed the presence of intact genes. 56.8% of subjects had PCR-confirmed malaria. Non-falciparum co-infection with P. falciparum was common (13.2%). Agreement between PCR and HRP2-based RDTs was satisfactory (Cohen's kappa = 0.66) and superior to microscopy (0.33). Symptomatic malaria due to pfhrp2/3-deleted P. falciparum was not observed. Ongoing HRP2-based RDT use is appropriate for the detection of falciparum malaria in the DRC.
ArticleNumber 6495
Author Mwandagalirwa, Kashamuka
Parr, Jonathan B.
Rogier, Eric
Atibu, Joseph
Olenga, Jean W.
Poffley, Alison
Likwela, Joris L.
Tshefu, Antoinette K.
Mansiangi, Paul
Morgan, Camille E.
Juliano, Jonathan J.
Mvuama, Nono
Thwai, Kyaw Lay
N’Siala, Adrien
Denton, Madeline
Landela, Ange
Efundu, Solange Umesumbu
Sompwe, Eric M.
Phanzu, Fernandine
Kalonji, Albert
Kieto, Eddy
Mungala, Pomie
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Walker-JonahADolanSAGwadzRWPantonLJWellemsTEAn RFLP map of the Plasmodium falciparum genome, recombination rates and favored linkage groups in a genetic crossMol. Biochem. Parasitol.1992513133201:CAS:528:DyaK38XitVyqsbk%3D134942310.1016/0166-6851(92)90081-T
VerityRThe impact of antimalarial resistance on the genetic structure of Plasmodium falciparum in the DRCNat. Commun.20201121072020NatCo..11.2107V1:CAS:528:DC%2BB3cXosF2lu70%3D32355199719290610.1038/s41467-020-15779-8
WickhamHggplot2: Elegant graphics for data analysis2009BerlinSpringer1170.6200410.1007/978-0-387-98141-3
MorganAPFalciparum malaria from coastal Tanzania and Zanzibar remains highly connected despite effective control efforts on the archipelagoMalar. J.2020154710.1186/s12936-020-3137-8
WuLComparison of diagnostics for the detection of asymptomatic Plasmodium falciparum infections to inform control and elimination strategiesNature2015528S86932663377010.1038/nature16039
Li, H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv: 1303.3997 (2013).
PotiKESullivanDJDondorpAMWoodrowCJHRP2: Transforming malaria diagnosis, but with caveatsTrends Parasitol.2020361121263184811910.1016/j.pt.2019.12.004
Broad Institute. Picard tools. GitHub repository available at https://broadinstitute.github.io/picard/ (2016).
World Health OrganizationResponse Plan to pfhrp2 Gene Deletions2019WHO
WatsonOJModelling the drivers of the spread of Plasmodium falciparum hrp2 gene deletions in sub-Saharan AfricaElife201710.7554/eLife.25008291119745690282
Brazeau, N. F. et al. The Epidemiology of Plasmodium vivax Among Adults in the Democratic Republic of the Congo: A Nationally-Representative, Cross-Sectional Survey. Pre-print available on medRxiv at https://www.medrxiv.org/content/https://doi.org/10.1101/2020.02.17.20024190v1.abstract. (2020).
JonesSOne-step PCR: A novel protocol for determination of pfhrp2 deletion status in Plasmodium falciparumPLoS ONE202015e02363691:CAS:528:DC%2BB3cXhsFSktL7J32702040737746210.1371/journal.pone.0236369
RobinsonJTIntegrative genomics viewerNat. Biotechnol.20112924261:CAS:528:DC%2BC3MXjsFWrtg%3D%3D21221095334618210.1038/nbt.1754
LucchiNWA new single-step PCR assay for the detection of the zoonotic malaria parasite Plasmodium knowlesiPLoS ONE20127e318482012PLoSO...731848L1:CAS:528:DC%2BC38Xjt1Kqsbg%3D22363751328278210.1371/journal.pone.0031848
ParrJBPfhrp2-deleted Plasmodium falciparum parasites in the Democratic Republic of the Congo: A national cross-sectional surveyJ. Infect. Dis.201721636441:CAS:528:DC%2BC1cXitFGjsL3I2817750210.1093/infdis/jix347
SrisuthamSFour human Plasmodium species quantification using droplet digital PCRPLoS ONE201712e017577128423028539697110.1371/journal.pone.01757711:CAS:528:DC%2BC1cXhs1Wks7k%3D
PatiPDhangadamajhiGBalMRanjitMHigh proportions of pfhrp2 gene deletion and performance of HRP2-based rapid diagnostic test in Plasmodium falciparum field isolates of OdishaMalar. J.2018173941:CAS:528:DC%2BC1MXhtFCht7nI30373573620692510.1186/s12936-018-2502-3
TaylorSMMolecular malaria epidemiology: Mapping and burden estimates for the Democratic Republic of the Congo, 2007PLoS ONE20116e164202011PLoSO...616420T1:CAS:528:DC%2BC3MXhvVKrs7o%3D21305011303154910.1371/journal.pone.0016420
KoitaOAFalse-negative rapid diagnostic tests for malaria and deletion of the histidine-rich repeat region of the hrp2 geneAm. J. Trop. Med. Hyg.2012861941981:CAS:528:DC%2BC38Xjs1SitL8%3D22302847326926610.4269/ajtmh.2012.10-0665
ChengQPlasmodium falciparum parasites lacking histidine-rich protein 2 and 3: A review and recommendations for accurate reportingMalar. J.20141328325052298411547110.1186/1475-2875-13-2831:CAS:528:DC%2BC2cXhvVGmsL%2FN
WatsonOJImpact of seasonal variations in Plasmodium falciparum malaria transmission on the surveillance of pfhrp2 gene deletionsElife201982
PerandinFDevelopment of a real-time PCR assay for detection of Plasmodium falciparum, Plasmodium vivax, and Plasmodium ovale for routine clinical diagnosisJ. Clin. Microbiol.200442121412191:CAS:528:DC%2BD2cXivF2ktro%3D1500407835683410.1128/JCM.42.3.1214-1219.2004
QuinlanARHallIMBEDTools: A flexible suite of utilities for comparing genomic featuresBioinformatics201026210.1093/bioinformatics/btq0331:CAS:528:DC%2BC3cXivFGkurc%3D
GrignardLA novel multiplex qPCR assay for detection of Plasmodium falciparum with histidine-rich protein 2 and 3 (pfhrp2 and pfhrp3) deletions in polyclonal infectionsEBioMedicine20205510275732403083721825910.1016/j.ebiom.2020.102757
World Health OrganizationFalse-Negative RDT Results and Implications of New Reports of P. falciparum Histidine-Rich Protein 2/3 Gene Deletions2016WHO
VeronVSimonSCarmeBMultiplex real-time PCR detection of P. falciparum, P. vivax and P. malariae in human blood samplesExp. Parasitol.20091213463511:CAS:528:DC%2BD1MXisFKrsLY%3D1912402110.1016/j.exppara.2008.12.012
WoodrowCJFanelloCPfhrp2 deletions in the Democratic Republic of Congo: Evidence of absence, or absence of evidence?J. Infect. Dis.201721650450628931242585331410.1093/infdis/jix345
BakerJGlobal sequence variation in the histidine-rich proteins 2 and 3 of Plasmodium falciparum: Implications for the performance of malaria rapid diagnostic testsMalar. J.2010922010ikpm.book.....B10.1186/1475-2875-9-1291:CAS:528:DC%2BC3cXms1GgsLY%3D
McKennaAThe genome analysis toolkit: A MapReduce framework for analyzing next-generation DNA sequencing dataGenome Res.201020129713031:CAS:528:DC%2BC3cXhtFeru7jM20644199292850810.1101/gr.107524.110
SepúlvedaNGlobal analysis of Plasmodium falciparum histidine-rich protein-2 (pfhrp2) and pfhrp3 gene deletions using whole-genome sequencing data and meta-analysisInfect. Genet. Evol.2018622112192972938610.1016/j.meegid.2018.04.0391:CAS:528:DC%2BC1cXpt1Knt7g%3D
World Health OrganizationProtocol for Estimating the Prevalence of pfhrp2/pfhrp3 Gene Deletions Among Symptomatic Falciparum Patients with False-Negative RDT Results2018WHO
MitchellCLUnder the radar: Epidemiology of Plasmodium ovale in the Democratic Republic of the CongoJ. Infect. Dis.202010.1093/infdis/jiaa478322744998825215
ParrJBAndersonOJulianoJJMeshnickSRStreamlined, PCR-based testing for pfhrp2- and pfhrp3-negative Plasmodium falciparumMalar. J.20181713729609602587955510.1186/s12936-018-2287-41:CAS:528:DC%2BC1MXjt1OgtL0%3D
VermaAKBhartiPKDasAHRP-2 deletion: A hole in the ship of malaria eliminationLancet Infect. Dis.2018188268273006466710.1016/S1473-3099(18)30420-1
President's Malaria Initiative. Democratic Republic of the Congo Malaria Operational Plan FY 2018. Available at https://www.pmi.gov/docs/default-source/default-document-library/malaria-operational-plans/fy-2018/fy-2018-democratic-republic-of-the-congo-malaria-operational-plan.pdf?sfvrsn=5.
BakerJGenetic diversity of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) and its effect on the performance of PfHRP2-based rapid diagnostic testsJ. Infect. Dis.20051928708771:CAS:528:DC%2BD2MXhtVent77M1608883710.1086/432010
KamauEAlemayehuSFeghaliKCSaundersDOckenhouseCFMultiplex qPCR for detection and absolute quantification of malariaPLoS ONE20138e715392013PLoSO...871539K1:CAS:528:DC%2BC3sXhsVagtb%2FK24009663375697310.1371/journal.pone.0071539
MarkwalterCFCharacterization of Plasmodium lactate dehydrogenase and histidine-rich protein 2 clearance patterns via rapid on-bead detection from a single dried blood spotAm. J. Trop. Med. Hyg.201898138913961:CAS:528:DC%2BC1MXhs1ahsLw%3D29557342595339510.4269/ajtmh.17-0996
GattonMLImplications of parasites lacking Plasmodium falciparum histidine-rich protein 2 on malaria morbidity and control when rapid diagnostic tests are used for diagnosisJ. Infect. Dis.2017215115611662832903410.1093/infdis/jix094
BerhaneAMajor threat to malaria control programs by plasmodium falciparum lacking histidine-rich protein 2, EritreaEmerg. Infect. Dis.2018244624701:CAS:528:DC%2BC1cXisVKntLfJ29460730582335210.3201/eid2403.171723
MenegonMIdentification of Plasmodium falciparum isolates lacking histidine-rich protein 2 and 3 in EritreaInfect. Genet. Evol.2017551311341:CAS:528:DC%2BC2sXhsFWitLvP2888994410.1016/j.meegid.2017.09.004
PloweCVDjimdeABouareMDoumboOWellemsTEPyrimethamine and proguanil resistance-conferring mutations in Plasmodium falciparum dihydrofolate reductase: Polymerase chain reaction methods for surveillance in AfricaAm. J. Trop. Med. Hyg.1995525655681:CAS:528:DyaK2MXnslSqsr8%3D761156610.4269/ajtmh.1995.52.565
OyolaSOWhole genome sequencing of Plasmodium falciparum from dried blood spots using selective whole genome amplificationMalar. J.2016155971:CAS:528:DC%2BC1cXjsFCqu7k%3D10.1186/s12936-016-1641-7279982715175302
WatsonOJFalse-negative malaria rapid diagnostic test results and their impact on community-based malaria surveys in sub-Saharan AfricaBMJ Glob. Health201910.1136/bmjgh-2019-001582314065916666813
PriceRNMefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy numberLancet20043644384471:CAS:528:DC%2BD2cXmt1Wjurs%3D15288742433798710.1016/S0140-6736(04)16767-6
BolgerAMLohseMUsadelBTrimmomatic: A flexible trimmer for Illumina sequence dataBioinformatics201430211421201:CAS:528:DC%2BC2cXht1Sqt7nP24695404410359010.1093/bioinformatics/btu170
ThomsonRPrevalence of Plasmodium falciparum lacking histidine-rich proteins 2 and 3: A systematic reviewBull. World Health Organ.20209855856832773901741132410.2471/BLT.20.250621
ParrJBMeshnickSRResponse to woodrow and fanelloJ. Infect. Dis.201721650350428931243585368410.1093/infdis/jix347
PlucinskiMMScreening for Pfhrp2/3-deleted Plasmodium falciparum, non-falciparum, and low-density malaria infections by a multiplex antigen assayJ. Infect. Dis.20192194374471:CAS:528:DC%2BB3cXjslaqur8%3D3020297210.1093/infdis/jiy525
AfoninaIPrimers with 5’ flaps improve real-time PCRBiote
CV Plowe (85913_CR18) 1995; 52
JB Parr (85913_CR10) 2017; 216
NW Lucchi (85913_CR40) 2012; 7
85913_CR49
R Verity (85913_CR52) 2020; 11
CJ Woodrow (85913_CR11) 2017; 216
AR Quinlan (85913_CR30) 2010; 26
J Baker (85913_CR46) 2010; 9
M Menegon (85913_CR9) 2017; 55
S Jones (85913_CR14) 2020; 15
N Sepúlveda (85913_CR45) 2018; 62
AP Morgan (85913_CR24) 2020; 15
World Health Organization (85913_CR47) 2019
OJ Watson (85913_CR6) 2017
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AL Pickard (85913_CR19) 2003; 47
L Wu (85913_CR16) 2015; 528
SM Taylor (85913_CR48) 2011; 6
AK Verma (85913_CR2) 2018; 18
A Walker-Jonah (85913_CR44) 1992; 51
KE Poti (85913_CR3) 2020; 36
J Baker (85913_CR20) 2005; 192
World Health Organization (85913_CR41) 2018
OA Koita (85913_CR21) 2012; 86
S Srisutham (85913_CR37) 2017; 12
P Pati (85913_CR43) 2018; 17
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Q Cheng (85913_CR4) 2014; 13
A Berhane (85913_CR8) 2018; 24
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L Grignard (85913_CR51) 2020; 55
RN Price (85913_CR22) 2004; 364
CL Mitchell (85913_CR50) 2020
A McKenna (85913_CR29) 2010; 20
OJ Watson (85913_CR15) 2019
AM Bolger (85913_CR26) 2014; 30
World Health Organization (85913_CR1) 2016
JT Robinson (85913_CR32) 2011; 29
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JB Parr (85913_CR13) 2018; 17
JB Parr (85913_CR12) 2017; 216
MM Plucinski (85913_CR35) 2019; 219
F Perandin (85913_CR39) 2004; 42
H Wickham (85913_CR31) 2009
S Auburn (85913_CR33) 2012; 7
CF Markwalter (85913_CR42) 2018; 98
ML Gatton (85913_CR7) 2017; 215
V Veron (85913_CR38) 2009; 121
SO Oyola (85913_CR25) 2016; 15
I Afonina (85913_CR23) 2007; 43
R Thomson (85913_CR5) 2020; 98
E Kamau (85913_CR36) 2013; 8
OJ Watson (85913_CR53) 2019; 8
References_xml – reference: PotiKESullivanDJDondorpAMWoodrowCJHRP2: Transforming malaria diagnosis, but with caveatsTrends Parasitol.2020361121263184811910.1016/j.pt.2019.12.004
– reference: SepúlvedaNGlobal analysis of Plasmodium falciparum histidine-rich protein-2 (pfhrp2) and pfhrp3 gene deletions using whole-genome sequencing data and meta-analysisInfect. Genet. Evol.2018622112192972938610.1016/j.meegid.2018.04.0391:CAS:528:DC%2BC1cXpt1Knt7g%3D
– reference: LucchiNWA new single-step PCR assay for the detection of the zoonotic malaria parasite Plasmodium knowlesiPLoS ONE20127e318482012PLoSO...731848L1:CAS:528:DC%2BC38Xjt1Kqsbg%3D22363751328278210.1371/journal.pone.0031848
– reference: Li, H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv: 1303.3997 (2013).
– reference: BakerJGenetic diversity of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) and its effect on the performance of PfHRP2-based rapid diagnostic testsJ. Infect. Dis.20051928708771:CAS:528:DC%2BD2MXhtVent77M1608883710.1086/432010
– reference: AfoninaIPrimers with 5’ flaps improve real-time PCRBiotechniques2007437707741:CAS:528:DC%2BD1cXhsVCitA%3D%3D1825125310.2144/000112631
– reference: PlucinskiMMScreening for Pfhrp2/3-deleted Plasmodium falciparum, non-falciparum, and low-density malaria infections by a multiplex antigen assayJ. Infect. Dis.20192194374471:CAS:528:DC%2BB3cXjslaqur8%3D3020297210.1093/infdis/jiy525
– reference: ChengQPlasmodium falciparum parasites lacking histidine-rich protein 2 and 3: A review and recommendations for accurate reportingMalar. J.20141328325052298411547110.1186/1475-2875-13-2831:CAS:528:DC%2BC2cXhvVGmsL%2FN
– reference: BerhaneAMajor threat to malaria control programs by plasmodium falciparum lacking histidine-rich protein 2, EritreaEmerg. Infect. Dis.2018244624701:CAS:528:DC%2BC1cXisVKntLfJ29460730582335210.3201/eid2403.171723
– reference: RobinsonJTIntegrative genomics viewerNat. Biotechnol.20112924261:CAS:528:DC%2BC3MXjsFWrtg%3D%3D21221095334618210.1038/nbt.1754
– reference: McKennaAThe genome analysis toolkit: A MapReduce framework for analyzing next-generation DNA sequencing dataGenome Res.201020129713031:CAS:528:DC%2BC3cXhtFeru7jM20644199292850810.1101/gr.107524.110
– reference: MitchellCLUnder the radar: Epidemiology of Plasmodium ovale in the Democratic Republic of the CongoJ. Infect. Dis.202010.1093/infdis/jiaa478322744998825215
– reference: WickhamHggplot2: Elegant graphics for data analysis2009BerlinSpringer1170.6200410.1007/978-0-387-98141-3
– reference: BakerJGlobal sequence variation in the histidine-rich proteins 2 and 3 of Plasmodium falciparum: Implications for the performance of malaria rapid diagnostic testsMalar. J.2010922010ikpm.book.....B10.1186/1475-2875-9-1291:CAS:528:DC%2BC3cXms1GgsLY%3D
– reference: BolgerAMLohseMUsadelBTrimmomatic: A flexible trimmer for Illumina sequence dataBioinformatics201430211421201:CAS:528:DC%2BC2cXht1Sqt7nP24695404410359010.1093/bioinformatics/btu170
– reference: President's Malaria Initiative. Democratic Republic of the Congo Malaria Operational Plan FY 2018. Available at https://www.pmi.gov/docs/default-source/default-document-library/malaria-operational-plans/fy-2018/fy-2018-democratic-republic-of-the-congo-malaria-operational-plan.pdf?sfvrsn=5.
– reference: ThomsonRPrevalence of Plasmodium falciparum lacking histidine-rich proteins 2 and 3: A systematic reviewBull. World Health Organ.20209855856832773901741132410.2471/BLT.20.250621
– reference: WuLComparison of diagnostics for the detection of asymptomatic Plasmodium falciparum infections to inform control and elimination strategiesNature2015528S86932663377010.1038/nature16039
– reference: PriceRNMefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy numberLancet20043644384471:CAS:528:DC%2BD2cXmt1Wjurs%3D15288742433798710.1016/S0140-6736(04)16767-6
– reference: Broad Institute. Picard tools. GitHub repository available at https://broadinstitute.github.io/picard/ (2016).
– reference: World Health OrganizationFalse-Negative RDT Results and Implications of New Reports of P. falciparum Histidine-Rich Protein 2/3 Gene Deletions2016WHO
– reference: KamauEAlemayehuSFeghaliKCSaundersDOckenhouseCFMultiplex qPCR for detection and absolute quantification of malariaPLoS ONE20138e715392013PLoSO...871539K1:CAS:528:DC%2BC3sXhsVagtb%2FK24009663375697310.1371/journal.pone.0071539
– reference: PickardALResistance to antimalarials in southeast asia and genetic polymorphisms in pfmdr1Antimicrob. Agents Chemother.200347241824231:CAS:528:DC%2BD3sXlvFCmurs%3D1287849916605710.1128/AAC.47.8.2418-2423.2003
– reference: KoitaOAFalse-negative rapid diagnostic tests for malaria and deletion of the histidine-rich repeat region of the hrp2 geneAm. J. Trop. Med. Hyg.2012861941981:CAS:528:DC%2BC38Xjs1SitL8%3D22302847326926610.4269/ajtmh.2012.10-0665
– reference: QuinlanARHallIMBEDTools: A flexible suite of utilities for comparing genomic featuresBioinformatics201026210.1093/bioinformatics/btq0331:CAS:528:DC%2BC3cXivFGkurc%3D
– reference: SrisuthamSFour human Plasmodium species quantification using droplet digital PCRPLoS ONE201712e017577128423028539697110.1371/journal.pone.01757711:CAS:528:DC%2BC1cXhs1Wks7k%3D
– reference: WoodrowCJFanelloCPfhrp2 deletions in the Democratic Republic of Congo: Evidence of absence, or absence of evidence?J. Infect. Dis.201721650450628931242585331410.1093/infdis/jix345
– reference: OyolaSOWhole genome sequencing of Plasmodium falciparum from dried blood spots using selective whole genome amplificationMalar. J.2016155971:CAS:528:DC%2BC1cXjsFCqu7k%3D10.1186/s12936-016-1641-7279982715175302
– reference: VermaAKBhartiPKDasAHRP-2 deletion: A hole in the ship of malaria eliminationLancet Infect. Dis.2018188268273006466710.1016/S1473-3099(18)30420-1
– reference: Morgan A. P. vcfdo. Available at: https://github.com/IDEELResearch/vcfdo (2019).
– reference: WatsonOJModelling the drivers of the spread of Plasmodium falciparum hrp2 gene deletions in sub-Saharan AfricaElife201710.7554/eLife.25008291119745690282
– reference: GattonMLImplications of parasites lacking Plasmodium falciparum histidine-rich protein 2 on malaria morbidity and control when rapid diagnostic tests are used for diagnosisJ. Infect. Dis.2017215115611662832903410.1093/infdis/jix094
– reference: PatiPDhangadamajhiGBalMRanjitMHigh proportions of pfhrp2 gene deletion and performance of HRP2-based rapid diagnostic test in Plasmodium falciparum field isolates of OdishaMalar. J.2018173941:CAS:528:DC%2BC1MXhtFCht7nI30373573620692510.1186/s12936-018-2502-3
– reference: MarkwalterCFCharacterization of Plasmodium lactate dehydrogenase and histidine-rich protein 2 clearance patterns via rapid on-bead detection from a single dried blood spotAm. J. Trop. Med. Hyg.201898138913961:CAS:528:DC%2BC1MXhs1ahsLw%3D29557342595339510.4269/ajtmh.17-0996
– reference: Brazeau, N. F. et al. The Epidemiology of Plasmodium vivax Among Adults in the Democratic Republic of the Congo: A Nationally-Representative, Cross-Sectional Survey. Pre-print available on medRxiv at https://www.medrxiv.org/content/https://doi.org/10.1101/2020.02.17.20024190v1.abstract. (2020).
– reference: MorganAPFalciparum malaria from coastal Tanzania and Zanzibar remains highly connected despite effective control efforts on the archipelagoMalar. J.2020154710.1186/s12936-020-3137-8
– reference: ParrJBMeshnickSRResponse to woodrow and fanelloJ. Infect. Dis.201721650350428931243585368410.1093/infdis/jix347
– reference: GrignardLA novel multiplex qPCR assay for detection of Plasmodium falciparum with histidine-rich protein 2 and 3 (pfhrp2 and pfhrp3) deletions in polyclonal infectionsEBioMedicine20205510275732403083721825910.1016/j.ebiom.2020.102757
– reference: World Health OrganizationProtocol for Estimating the Prevalence of pfhrp2/pfhrp3 Gene Deletions Among Symptomatic Falciparum Patients with False-Negative RDT Results2018WHO
– reference: VerityRThe impact of antimalarial resistance on the genetic structure of Plasmodium falciparum in the DRCNat. Commun.20201121072020NatCo..11.2107V1:CAS:528:DC%2BB3cXosF2lu70%3D32355199719290610.1038/s41467-020-15779-8
– reference: JonesSOne-step PCR: A novel protocol for determination of pfhrp2 deletion status in Plasmodium falciparumPLoS ONE202015e02363691:CAS:528:DC%2BB3cXhsFSktL7J32702040737746210.1371/journal.pone.0236369
– reference: WatsonOJFalse-negative malaria rapid diagnostic test results and their impact on community-based malaria surveys in sub-Saharan AfricaBMJ Glob. Health201910.1136/bmjgh-2019-001582314065916666813
– reference: World Health OrganizationResponse Plan to pfhrp2 Gene Deletions2019WHO
– reference: PloweCVDjimdeABouareMDoumboOWellemsTEPyrimethamine and proguanil resistance-conferring mutations in Plasmodium falciparum dihydrofolate reductase: Polymerase chain reaction methods for surveillance in AfricaAm. J. Trop. Med. Hyg.1995525655681:CAS:528:DyaK2MXnslSqsr8%3D761156610.4269/ajtmh.1995.52.565
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Snippet The majority of Plasmodium falciparum malaria diagnoses in Africa are made using rapid diagnostic tests (RDTs) that detect histidine-rich protein 2. Increasing...
The majority of Plasmodium falciparum malaria diagnoses in Africa are made using rapid diagnostic tests (RDTs) that detect histidine-rich protein 2. Increasing...
Abstract The majority of Plasmodium falciparum malaria diagnoses in Africa are made using rapid diagnostic tests (RDTs) that detect histidine-rich protein 2....
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692/308/174
692/699/255/1629
Antigens
Diagnostic tests
Erythrocytes
Genomes
Genotyping
Histidine
Humanities and Social Sciences
Malaria
Microscopy
multidisciplinary
Parasites
Plasmodium falciparum
Science
Science (multidisciplinary)
Vector-borne diseases
Whole genome sequencing
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Title Analysis of false-negative rapid diagnostic tests for symptomatic malaria in the Democratic Republic of the Congo
URI https://link.springer.com/article/10.1038/s41598-021-85913-z
https://www.ncbi.nlm.nih.gov/pubmed/33753817
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https://pubmed.ncbi.nlm.nih.gov/PMC7985209
https://doaj.org/article/69b1915c79934da1b83f83083b3f0a84
Volume 11
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