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

Pluciński, Mateusz M.; Rogier, Eric; Dimbu, Pedro Rafael; Fortes, Filomeno; Halsey, Eric S.; Aidoo, Michael; Smith, T.

doi:10.1128/jcm.01901-18

Cited by 15 publications

(22 citation statements)

References 21 publications

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“…Moreover, the ratios of pre- and post-day 2 clearance rates for LDH and Aldo are very similar, suggesting the two antigens might share a similar mechanism of clearance. The link between LDH and Aldo concentration and the presence of the parasite itself is consistent with the previous observation that LDH and Aldo levels are more closely associated with current parasite density, compared to HRP2, which can be interpreted more accurately as a measure of cumulative parasite load over the course of the infection [4, 19, 20].…”

Section: Discussionsupporting

confidence: 88%

Clearance dynamics of lactate dehydrogenase and aldolase following antimalarial treatment for Plasmodium falciparum infection

et al. 2019

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Background Lingering post-treatment parasite antigen in blood complicates malaria diagnosis through antigen detection. Characterization of antigen clearance dynamics is important for interpretation of positive antigen detection tests. Results We used a bead-based serological assay to measure lactate dehydrogenase (LDH), aldolase (Aldo), and histidine-rich protein 2 (HRP2) levels in 196 children with Plasmodium falciparum malaria treated with effective antimalarials and followed for 28 to 42 days as part of therapeutic efficacy studies in Angola. Compared to pre-treatment levels, antigen concentrations two days after treatment declined by 99.7% for LDH, 96.3% for Aldo, and 54.6% for HRP2. After Day 2, assuming a first-order kinetics clearance model, half-lives of the antigens were 1.8 days (95% CI: 1.5–2.3) for LDH, 3.2 days (95% CI: 3.0–3.4) for Aldo, and 4.8 days (95% CI: 4.7–4.9) for HRP2. Conclusions LDH and Aldo show substantially different clearance rates than HRP2, and their presence is largely indicative of active infection. Electronic supplementary material The online version of this article (10.1186/s13071-019-3549-x) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 88%

Clearance dynamics of lactate dehydrogenase and aldolase following antimalarial treatment for Plasmodium falciparum infection

et al. 2019

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“…Point-of-care tests should be able to detect clinically relevant antigenemias (18) but not necessarily all antigenemias. A recent study showed that a PfHRP2-based RDT with an LOD in the range of 3 to 10 ng/ml would provide ideal sensitivity and specificity in diagnosing malaria infections at densities high enough to be the cause of fever (19). From this study, the LOD 50 estimates generally fall into this range, although the 75%, 90%, and 95% estimates exceed this range.…”

Section: Discussionmentioning

confidence: 62%

Assessing Performance of HRP2 Antigen Detection for Malaria Diagnosis in Mozambique

et al. 2019

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Rapid diagnostic tests (RDTs) that detect the Plasmodium falciparum-specific histidine-rich protein 2 (PfHRP2) antigen are the primary methods for malaria diagnosis in Mozambique. However, these tests do not detect infections with non-falciparum malaria or Pfhrp2- and Pfhrp3-deleted P. falciparum parasites. To assess the appropriateness of conventional PfHRP2-only RDTs for malaria diagnosis in Mozambique, samples collected during a health facility survey conducted in three provinces of Mozambique were screened using antigen detection methods and further characterized by molecular techniques. Samples from 1,861 outpatients of all ages and symptoms attending 117 randomly selected public health facilities in 2018 were analyzed with an ultrasensitive bead-based immunoassay for the presence of PfHRP2, pan-Plasmodium aldolase (pAldo), and pan-Plasmodium lactate dehydrogenase (pLDH). The presence of PfHRP2 in patient blood detected using the bead-based assay was compared to the results of PfHRP2-based RDTs performed during the routine health facility consult and during the survey reexamination at the exit interview. Samples with discordant antigen profiles (negative for PfHRP2 but positive for pAldo and/or pLDH) were further characterized by photoinduced electron transfer PCR (PET-PCR). Using the bead-based laboratory assay as the gold standard, the sensitivities of the conventional RDTs administered during the routine health facility consult and the exit interview were 90% and 83%, respectively, and the specificities were 91% and 97%, respectively. Of 710 samples positive for at least one antigen, 704 (99.2%) were positive for PfHRP2. Six (0.8% of total) discordant samples lacked PfHRP2 but were positive for pAldo and/or pLDH; 3 of these (0.4% of total) were Plasmodium ovale monoinfections or coinfections where P. ovale was the dominant species. The remaining 3 discordant samples were negative by PET-PCR. The sensitivity and specificity of the conventional RDTs performed in the routine health facility consults and survey exit interviews were acceptable, and there was no evidence of Pfhrp2- and Pfhrp3-deleted parasites. Monoinfections with non-falciparum malaria species comprised <1% of the total malaria infections. Nearly all malaria antigen-positive patients had detectable PfHRP2, confirming that this antigen remains an appropriate malaria diagnostic target in the surveyed provinces.

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“…Figure 2a shows the probability of detection by uRDT in relation to HRP2 concentration for Mali in comparison to the studies conducted in Uganda and Myanmar [7,8]. Differences emerged in uRDT detection limits among the three study populations: there was a 50% probability of testing positive by uRDT at HRP2 thresholds of 207 pg/mL [95% credible interval (CrI) 160-268] in Mali, 15 pg/mL (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) in Uganda, and 101 pg/mL (66-156) in Myanmar. The established limit of detection (LOD) for the commercial Alere Malaria Ag P.f uRDT is 80-100 pg/mL, per laboratory evaluation by Das et al [15].…”

Section: Performance Of the Ultra-sensitive Rdtmentioning

confidence: 99%

“…RDTs have been considered to perform equivalently to microscopy in terms of sensitivity and specificity [ 6 ], with a recognition that HRP2-based RDTs may provide false positives due to the long half-life of circulating HRP2 [ 1 , 2 ]. The advent of new RDTs, such as the ultra-sensitive HRP2-based Alere™ Malaria Ag P.f RDT (Abbott, South Korea) with a tenfold lower limit of detection for HRP2 than previous RDTs [ 7 , 8 ] has incentivized the research community to better understand antigen dynamics in infected populations [ 8 – 12 ]. Concurrently, new assays for antigen quantification have been developed both as research tools on the Luminex platform [ 13 , 14 ] and as the commercially available Q-Plex™ Human Malaria Array (Quansys Biosciences, USA) [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Ultra-sensitive RDT performance and antigen dynamics in a high-transmission Plasmodium falciparum setting in Mali

Reichert

Hume

Sagara³

et al. 2020

Malar J

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Background: The recent expansion of tools designed to accurately quantify malaria parasite-produced antigens has enabled us to evaluate the performance of rapid diagnostic tests (RDTs) as a function of the antigens they detecttypically histidine rich protein 2 (HRP2) or lactate dehydrogenase (LDH). Methods: For this analysis, whole blood specimens from a longitudinal study in Bancoumana, Mali were used to evaluate the performance of the ultra-sensitive HRP2-based Alere ™ Malaria Ag P.f RDT (uRDT). The samples were collected as part of a transmission-blocking vaccine trial in a high transmission region for Plasmodium falciparum malaria. Furthermore, antigen dynamics after successful anti-malarial drug treatment were evaluated in these samples using the Q-Plex Human Malaria Array (4-Plex) to quantify antigen concentrations. Results: The uRDT had a 50% probability of a positive result at 207 pg/mL HRP2 [95% credible interval (CrI) 160-268]. Individuals with symptomatic infection remained positive by uRDT for a median of 33 days [95% confidence interval (CI) 28-47] post anti-malarial drug treatment. Biphasic exponential decay models accurately captured the population level post-treatment dynamics of both HRP2 and Plasmodium LDH (pLDH), with the latter decaying more rapidly. Motivated by these differences in rates of decay, a novel algorithm that used HRP2:pLDH ratios to predict if an individual had active versus recently cleared P. falciparum infection was developed. The algorithm had 77.5% accuracy in correctly classifying antigen-positive individuals as those with and without active infection. Conclusions: These results characterize the performance of the ultra-sensitive RDT and demonstrate the potential for emerging antigen-quantifying technologies in the field of malaria diagnostics to be helpful tools in distinguishing between active versus recently cleared malaria infections.

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

Cited by 15 publications

References 21 publications

Clearance dynamics of lactate dehydrogenase and aldolase following antimalarial treatment for Plasmodium falciparum infection

Clearance dynamics of lactate dehydrogenase and aldolase following antimalarial treatment for Plasmodium falciparum infection

Assessing Performance of HRP2 Antigen Detection for Malaria Diagnosis in Mozambique

Ultra-sensitive RDT performance and antigen dynamics in a high-transmission Plasmodium falciparum setting in Mali

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