Posttreatment HRP2 Clearance in Patients with Uncomplicated Plasmodium falciparum Malaria

Pluciński, Mateusz M.; Dimbu, Pedro Rafael; Fortes, Filomeno; Abdulla, Salim; Ahmed, Saumu; Gutman, Julie; Kachur, S. Patrick; Badiane, Aïda Sadikh; Ndiaye, Daouda; Talundzic, Eldin; Lucchi, Naomi W.; Aidoo, Michael; Udhayakumar, Venkatachalam; Halsey, Eric S.; Rogier, Eric

doi:10.1093/infdis/jix622

Cited by 59 publications

(74 citation statements)

References 15 publications

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“…The bead suspension array described here can successfully be used as for detection and quantification of PfHRP2 and pLDH in whole blood, eluted DBS and plasma or serum samples. The concentration of eluted PfHRP2 from DBS to be equivalent to approximately a 1:20 dilution from whole blood, similarly to previously reported data (40). Differently, for pLDH we found that antigen concentration in eluted DBS corresponds to a 1:60 whole blood dilution, which differs from previously published data showing no differences in antigen recovery between PfHRP2 and pLDH (20).…”

Section: Discussionsupporting

confidence: 90%

Quantification of malaria antigens PfHRP2 and pLDH by quantitative suspension array technology in whole blood, dried blood spot and plasma

Martiáñez–Vendrell

Jiménez

Vásquez

et al. 2019

Preprint

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BackgroundMalaria diagnostics by rapid diagnostic tests (RDTs) relies primarily on the qualitative detection of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) and Plasmodium sp lactate dehydrogenase (pLDH). As novel RDTs with increased sensitivity are being developed and implemented as point of care diagnostics, highly sensitive laboratory based assays are needed for evaluating RDTs performance. Here, a quantitative suspension array technology (qSAT) was developed, validated and applied for the simultaneous detection of PfHRP2 and pLDH in a variety of clinical samples (whole blood, plasma and dried blood spots) from different endemic countries.ResultsThe qSAT was specific for the target antigens, with analytical ranges of 6.8 to 762.8 pg/ml for PfHRP2 and 78.1 to 17076.6 pg/ml for P. falciparum (Pf-LDH). The assay detected P. vivax LDH (Pv-LDH) at a lower sensitivity than Pf-LDH (analytical range of 1093.20 to 187288.5 pg/ml). Both PfHRP2 and pLDH levels determined using the qSAT showed to positively correlate with parasite densities determined by quantitative PCR (Spearman r=0.59 and 0.75, respectively) as well as microscopy (Spearman r=0.40 and 0.75, respectively), suggesting the assay to be a good predictor of parasite density.ConclusionThis immunoassay can be used as a reference test for the detection and quantification of PfHRP2 and pLDH, and could serve for external validation of RDTs performance, to determine antigen persistence after parasite clearance, as well as a complementary tool to assess malaria burden in endemic settings.

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Section: Discussionsupporting

confidence: 90%

Quantification of malaria antigens PfHRP2 and pLDH by quantitative suspension array technology in whole blood, dried blood spot and plasma

Martiáñez–Vendrell

Jiménez

Vásquez

et al. 2019

Preprint

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“…Because it is a protein completely exogenous to the human body, with no known homology to other human proteins, the unique nature of HRP2 in sequence and structure may lead to delayed clearance from the human host. HRP2 is produced and excreted into the extracellular matrix in large quantities during the ring, trophozoite, and schizont stages (22), which is one of the reasons why it persists in the circulation (23). When HRP2 is used as a diagnostic marker for clinical cases, it may reflect the total parasite load, rather than current peripheral parasite densities.…”

Section: Discussionmentioning

confidence: 99%

“…If there is synchronization of the parasite cycle, then HRP2 levels might reflect the total load of parasites (including those that are sequestered) even better than a direct parasitological measure. This consideration has motivated the use of HRP2 levels as a measure of total parasite biomass (13,14) but is a disadvantage when HRP2 tests are used to estimate the point prevalence of active infections in population surveys, because HRP2 levels can persist for several weeks after parasites have been cleared (23).…”

Section: Discussionmentioning

confidence: 99%

Performance of Antigen Concentration Thresholds for Attributing Fever to Malaria among Outpatients in Angola

et al. 2019

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The density of malaria parasites is a key determinant of whether an infected individual develops fever. While the pyrogenic threshold for malaria parasite density has been well studied, there are no analogous data on the antigen levels associated with fever during infection. Samples from 797 afebrile and 457 febrile outpatients from two provinces in Angola with known concentrations of histidine-rich protein 2 (HRP2), aldolase, and lactate dehydrogenase (LDH) antigens were analyzed by Bayesian latent class modeling to attribute malarial etiology to the fevers and to estimate the sensitivity and specificity of different antigen thresholds for detection of malaria fevers. Among patients with aldolase or LDH levels detectable with a bead-based assay, the concentrations of these two antigens did not differ between afebrile and febrile patients. In contrast, the concentrations of HRP2 were substantially higher in febrile HRP2-positive patients than in afebrile HRP2-positive patients. When HRP2 concentrations were considered, the malaria-attributable fractions of fever cases were 0.092 in Huambo Province and 0.39 in Uíge Province. Diagnostic tests detecting HRP2 with limits of detection (LODs) in the range of 3,000 to 10,000 pg/µl would provide ideal sensitivity and specificity for determination of malarial etiology among febrile persons.

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“…Whilst repeated assessments of parasite density shortly after initiation of treatment provide the most conclusive evidence on (changes in) parasite responsiveness (16), alternative metrics are used to compare the early effects of antimalarials. These include the proportion of individuals with residual parasitemia by microscopy (17) or PCR (3,7) or the concentration of the histidine rich protein-2 parasite antigen (18). The current study, examining the kinetics of mRNA transcripts indicative of ring-stage parasitemia following treatment (10,19), explicitly does not aim to present this measure as a proxy for parasite clearance half-lives or direct evidence of reduced susceptibility of parasites to treatment.…”

Section: Discussionmentioning

confidence: 99%

Persistence of P. Falciparum Ring-Stage Parasites 42 Days After Artemisinin and Non-Artemisinin Combination Therapy in Naturally Infected Malians

Mahamar

Lanke²,

Graumans³

et al. 2020

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Background: Malaria control in sub-Saharan Africa relies upon prompt case management with artemisinin-based combination therapy (ACT). Ring-stage parasites, measured by sbp1 quantitative reverse-transcriptase PCR (qRT-PCR), were previously reported to persist after ACT treatment and hypothesized to reflect temporary arrest of the growth of ring-stage parasites (dormancy) following exposure to artemisinins. Here, we examined the persistence of ring-stage parasitemia following ACT and non-ACT treatment. Methods: We used samples from naturally infected Malian gametocyte carriers who received dihydroartemisinin-piperaquine (DP) or sulfadoxine-pyrimethamine (SP-AQ) with or without gametocytocidal drugs. Gametocytes and ring-stage parasites were quantified by qRT-PCR during 42 days of follow-up. Results: At baseline, 89% (64/73) of participants had measurable ring-stage parasites. Following treatment, the proportion of ring-stage parasite-positive individuals and ring-stage parasite densities declined for all four treatment groups. Participants who received DP had 81% lower post-treatment ring-stage parasite density compared to participants who received SP-AQ (p<0.001). Gametocytocidal drugs did not influence ring-stage parasite persistence. Ring-stage parasite densities on days 14 and 28 after initiation of treatment were higher among individuals who subsequently experienced recurrent parasitemia compared to those who remained free of parasites until day 42 after initiation of treatment (pday 14=0.011 and pday 28=0.068). We observed no association of ring-stage persistence with gametocyte carriage. Conclusions: Our findings of lower ring-stage persistence after ACT treatment without an effect of gametocytocidal partner drugs affirms the use of sbp1 as ring-stage marker and argues against preferential persistence of low densities of rings following ACT treatment. The implications of our findings for monitoring drug sensitivity require further study.

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Posttreatment HRP2 Clearance in Patients with Uncomplicated Plasmodium falciparum Malaria

Cited by 59 publications

References 15 publications

Quantification of malaria antigens PfHRP2 and pLDH by quantitative suspension array technology in whole blood, dried blood spot and plasma

Quantification of malaria antigens PfHRP2 and pLDH by quantitative suspension array technology in whole blood, dried blood spot and plasma

Performance of Antigen Concentration Thresholds for Attributing Fever to Malaria among Outpatients in Angola

Persistence of P. Falciparum Ring-Stage Parasites 42 Days After Artemisinin and Non-Artemisinin Combination Therapy in Naturally Infected Malians

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