Malaria surveys using rapid diagnostic tests and validation of results using post hoc quantification of Plasmodium falciparum histidine-rich protein 2

Pluciński, Mateusz M.; Dimbu, Rafael; Candrinho, Baltazar; Colborn, James; Badiane, Aïda Sadikh; Ndiaye, Daouda; Mace, Kimberly E.; Chang, Michelle; Lemoine, Jean Frantz; Halsey, Eric S.; Barnwell, John W.; Udhayakumar, Venkatachalam; Aidoo, Michael; Rogier, Eric

doi:10.1186/s12936-017-2101-8

Cited by 28 publications

(35 citation statements)

References 16 publications

(17 reference statements)

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“…This study found substantial differences in LOD estimates between provinces, confirming earlier findings from other studies that showed estimated RDT LODs to be varied across settings, even within the same brand (15). Notably, while there were differences in the LODs between provinces, there generally was overlap between the LOD between the RDTs used during the routine health facility consult and those used in the exit interview.…”

Section: Discussionsupporting

confidence: 85%

“…Antigen concentrations were calculated from fluorescence intensity values using standard curves. Conventional RDT results from the routine health facility consults and from retesting during the survey exit interview were compared against the PfHRP2 concentration measured in the laboratory (15). Samples with discordant antigen results (as defined by presence of pAldo and/or pLDH but no PfHRP2 antigen) and a random selection of other samples were analyzed by PCR to confirm the antigen findings.…”

Section: Methodsmentioning

confidence: 99%

“…Sensitivity and specificity were calculated using the bead-based result as the gold standard. A logistic model was fit to estimate the level of detection at the 50% (LOD 50 ), 75%, 90%, and 95% levels (15), by province and separately for the RDT from the routine health facility consult and the exit interview. These estimates represent the PfHRP2 concentration at which 50%, 75%, 90%, and 95% of RDTs would be positive in a given site/test combination.…”

Section: Methodsmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 85%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Assessing Performance of HRP2 Antigen Detection for Malaria Diagnosis in Mozambique

et al. 2019

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“…The analysis was performed for antigen positivity for each of the three antigens. Three different definitions of HRP2 positivity were used, namely, any detectable HRP2 above the LOD of the ultrasensitive bead-based assay (152 pg/ml), an HRP2 concentration above 200 pg/ml (the practical LOD of ultrasensitive RDTs [14]), and an HRP2 concentration above 3,000 pg/ml, the estimated LOD of the conventional RDT used in the Angola survey (18). Next, the continuous values of the three antigen concentrations were characterized and plotted, and pairwise agreement in antigen positivity for the three antigens in patients was assessed using Cohen's kappa statistic (19).…”

Section: Methodsmentioning

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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“…Recent studies have highlighted the importance of using sensitive reference tests to provide empirical data on the performance of RDTs at parasite densities below 200 parasites/μL. 8,9 Here, we report the findings of a study in which we used qPCR to determine the malaria status of 491 patients compared with their RDT results.…”

mentioning

confidence: 99%

Using Reference Quantitative Polymerase Chain Reaction to Assess the Clinical Performance of the Paracheck-Pf® Rapid Diagnostic Test in a Field Setting in Uganda

Mitran

Mbonye

Hawkes

et al. 2018

The American Journal of Tropical Medicine and Hygiene

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Malaria rapid diagnostic tests (RDTs) are widely used in clinical and surveillance settings. However, the performance of most RDTs has not been characterized at parasite densities below detection by microscopy. We present findings from Uganda, where RDT results from 491 participants with suspected malaria were correlated with quantitative polymerase chain reaction (qPCR)-defined parasitemia. Compared with qPCR, the sensitivity and specificity of the RDT for mono-infections were 76% (95% confidence interval [CI]: 68-83%) and 95% (95% CI: 92-97%), respectively. The sensitivity of the RDT at parasite densities between 0.2 and 200 parasites/μL was surprisingly high (87%, 95% CI: 74-94%). The high sensitivity of the RDT is likely because of histidine-rich protein 2 from submicroscopic infections, gametocytes, or sequestered parasites. These findings underscore the importance of evaluating different RDTs in field studies against qPCR reference testing to better define the sensitivity and specificity, particularly at low parasite densities.

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Malaria surveys using rapid diagnostic tests and validation of results using post hoc quantification of Plasmodium falciparum histidine-rich protein 2

Cited by 28 publications

References 16 publications

Assessing Performance of HRP2 Antigen Detection for Malaria Diagnosis in Mozambique

Assessing Performance of HRP2 Antigen Detection for Malaria Diagnosis in Mozambique

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

Using Reference Quantitative Polymerase Chain Reaction to Assess the Clinical Performance of the Paracheck-Pf® Rapid Diagnostic Test in a Field Setting in Uganda

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