Factors Affecting the Performance of HRP2-Based Malaria Rapid Diagnostic Tests.
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SUBMITTER: Martianez-Vendrell X
PROVIDER: S-EPMC9611031 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
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Factors Affecting the Performance of HRP2-Based Malaria Rapid Diagnostic Tests.
Martiáñez-Vendrell Xavier X Skjefte Malia M Sikka Ruhi R Gupta Himanshu H
Tropical medicine and infectious disease 20220925 10
The recent COVID-19 pandemic has profoundly impacted global malaria elimination programs, resulting in a sharp increase in malaria morbidity and mortality. To reduce this impact, unmet needs in malaria diagnostics must be addressed while resuming malaria elimination activities. Rapid diagnostic tests (RDTs), the unsung hero in malaria diagnosis, work to eliminate the prevalence of <i>Plasmodium falciparum</i> malaria through their efficient, cost-effective, and user-friendly qualities in detecti ...[more]
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Project description:BackgroundMalaria rapid diagnostic tests (RDTs) based on the detection of the Plasmodium falciparum histidine-rich protein 2 (HRP2) antigen are widely used for detection of active infection with this parasite and are the only practical malaria diagnostic test in some endemic settings. External validation of RDT results from field surveys can confirm appropriate RDT performance.MethodsA community-based cross-sectional survey was conducted between July and November 2017 enrolling participants of all ages in households from 15 villages in four border regions of Tanzania: Geita, Kigoma, Mtwara and Ruvuma. All participants had an RDT performed in the field and provided a blood sample for later laboratory multiplex antigen detection of HRP2. In assessing the continuous HRP2 levels in participant blood versus RDT result, dose-response logistic regression provided quantitative estimates for HRP2 limit of detection (LOD).ResultsFrom the 15 study villages, 6941 persons were enrolled that had a RDT at time of enrollment and provided a DBS for later laboratory antigen detection. RDT positive prevalence for the HRP2 band by village ranged from 20.0 to 43.6%, but the magnitude of this prevalence did not have an effect on the estimated LOD of RDTs utilized in different villages. Overall, HRP2 single-target tests had a lower LOD at the 95% probability of positive RDT (4.3 ng/mL; 95% CI 3.4-5.4) when compared to pLDH/HRP2 dual target tests (5.4 ng/mL; 4.5-6.3), though this difference was not significant. With the exception of one village, all other 14 villages (93.3%) showed RDT LOD estimates at 90% probability of positive RDT between 0.5 and 12.0 ng/mL.ConclusionsBoth HRP2-only and pLDH/HRP2 combo RDTs utilized in a 2017 Tanzania cross-sectional survey of border regions generally performed well, and reliably detected HRP2 antigen in the low ng/mL range. Though single target tests had lower levels of HRP2 detection, both tests were within similar ranges among the 15 villages. Comparison of quantitative HRP2 detection limits among study sites can help interpret RDT testing results when generating population prevalence estimates for malaria infection.
| S-EPMC9714097 | biostudies-literature
Project description:BackgroundRapid diagnostic test (RDT) kits have been useful tools to screen for the presence of infection with malaria parasites. Despite the improvement, false results from RDTs present a greater challenge. The need for quality test kits is desirable. We evaluated the diagnostic accuracy of three malaria RDTs.MethodThe team consented and enrolled 754 participants from the two major public hospitals in Kintampo districts of Ghana from June 2014 to August 2014. Venous blood samples were obtained by trained personnel and samples were screened for malaria using CareStart and SD Bioline HRP2 and HRP2 with pLDH based RDTs with blood slides for malaria microscopy as "gold standard". Geometric mean parasite densities were estimated and parasite densities were used to estimate the quantitative limits of the RDTs. The sensitivities, specificities and other performance criteria were calculated using statistical analytical software.ResultThe median age of participants was 21 (range 5-31) years. There were 28.6% (215/752) were males and 71.4% (537/752) were females. Comparing with microscopy, the sensitivity, specificity, positive predictive value, negative predictive value and the ROC were for CareStart (HRP2), 98.2%, 66.5%, 82.6%, 95.6%, 0.82; for CareStart (HRP2/pLDH) 98.2%, 66.5%, 82.6%, 95.6%, 0.82 and for SD-Bioline (HRP2/pLDH) RDTs 98.2%, 69.2%, 84.2%, 96.0%, 0.84 respectively. The performance for all the kits were acceptable at a cut-off of 25 or more parasites/μl of blood.ConclusionsThe diagnostic performance of the three malaria RDTs was acceptable, according to the World Health Organisation criteria, to detect densities ≥25 parasite/μl of blood. The RDTs with HRP2/pLDH targets were comparable to those with only HRP2 and could successfully substitute current and commonly used HRP2-based RDTs.
| S-EPMC6128572 | biostudies-literature
Project description:BACKGROUND:Rapid diagnostic tests (RDT) for malaria are common, but their performance varies. Tests using histidine-rich protein 2 (HRP2) antigen are most common, and many have high sensitivity. HRP2 tests can remain positive for weeks after treatment, limiting their specificity and usefulness in high-transmission settings. Tests using Plasmodium lactate dehydrogenase (pLDH) have been less widely used but have higher specificity, mostly due to a much shorter time to become negative. METHODS:A prospective, health centre-based, diagnostic evaluation of two malaria RDTs was performed in rural Niger during the high malaria transmission season (3-28 October, 2017) and during the low transmission season (28 January-31 March, 2018). All children under 5 years of age presenting with fever (axillary temperature > 37.5 °C) or history of fever in the previous 24 h were eligible. Capillary blood was collected by finger prick. The SD Bioline HRP2 (catalog: 05FK50) and the CareStart pLDH(pan) (catalog: RMNM-02571) were performed in parallel, and thick and thin smears were prepared. Microscopy was performed at Epicentre, Maradi, Niger, with external quality control. The target sample size was 279 children with microscopy-confirmed malaria during each transmission season. RESULTS:In the high season, the sensitivity of both tests was estimated at > 99%, but the specificity of both tests was lower: 58.0% (95% CI 52.1-63.8) for the pLDH test and 57.4% (95% CI 51.5-63.1) for the HRP2 test. The positive predictive value was 66.3% (95% CI 61.1-71.2) for both tests. In the low season, the sensitivity of both tests dropped: 91.0% (95% CI 85.3-95.0) for the pLDH test and 85.8% (95% CI 79.3-90.9) for the HRP2 test. The positive predictive value remained low for both tests in the low season: 60.5% (95% CI 53.9-66.8) for the pLDH test and 61.9% (55.0-68.4) for the HRP2 test. Performance was similar across different production lots, gender, age of the children, and, during the high season, time since the most recent distribution of seasonal malaria chemoprevention. CONCLUSIONS:The low specificity of the pLDH RDT in this setting was unexpected and is not easily explained. As the pLDH test continues to be introduced into new settings, the questions raised by this study will need to be addressed.
| S-EPMC6933886 | biostudies-literature
Project description:BackgroundMalaria has a negative effect on the outcome of pregnancy. Pregnant women are at high risk of severe malaria and severe haemolytic anaemia, which contribute 60-70% of foetal and perinatal losses. Peripheral blood smear microscopy under-estimates sequestered placental infections, therefore malaria rapid diagnostic tests (RDTs) detecting histidine rich protein-2 antigen (HRP-2) in peripheral blood are a potential alternative.MethodsHRP-2 RDTs accuracy in detecting malaria in pregnancy (MIP >28 weeks gestation) and placental Plasmodium falciparum malaria (after childbirth) were conducted using Giemsa microscopy and placental histopathology respectively as the reference standard. The study was conducted in Mbale Hospital, using the midwives to perform and interpret the RDT results. Discordant results samples were spot checked using PCR techniques.ResultsAmong 433 febrile women tested, RDTs had a sensitivity of 96.8% (95% CI 92-98.8), specificity of 73.5% (95% CI 67.8-78.6), a positive predictive value (PPV) of 68.0% (95% CI 61.4-73.9), and negative predictive value (NPV) of 97.5% (95% CI 94.0-99.0) in detecting peripheral P. falciparum malaria during pregnancy. At delivery, in non-symptomatic women, RDTs had a 80.9% sensitivity (95% CI 57.4-93.7) and a 87.5% specificity (95%CI 80.9-92.1), PPV of 47.2% (95% CI 30.7-64.2) and NPV of 97.1% (95% CI 92.2-99.1) in detecting placental P. falciparum infections among 173 samples. At delivery, 41% of peripheral infections were detected by microscopy without concurrent placental infection. The combination of RDTs and microscopy improved the sensitivity to 90.5% and the specificity to 98.4% for detecting placental malaria infection (McNemar's X(2)> 3.84). RDTs were not superior to microscopy in detecting placental infection (McNemar's X(2)< 3.84). Presence of malaria in pregnancy and active placental malaria infection were 38% and 12% respectively. Placental infections were associated with poor pregnancy outcome [pre-term, still birth and low birth weight] (aOR = 37.9) and late pregnancy malaria infection (aOR = 20.9). Mosquito net use (aOR 2.1) and increasing parity (aOR 2.7) were associated with lower risk for malaria in pregnancy.ConclusionUse of HRP-2 RDTs to detect malaria in pregnancy in symptomatic women was accurate when performed by midwives. A combination of RDTs and microscopy provided the best means of detecting placental malaria. RDTs were not superior to microscopy in detecting placental infection. With a high sensitivity and specificity, RDTs could be a useful tool for assessing malaria in pregnancy, with further (cost-) effectiveness studies.
| S-EPMC3206496 | biostudies-literature
Project description:Malaria rapid diagnostic tests (RDTs) are dominated by products which use histidine-rich protein 2 (HRP2) to detect Plasmodium falciparum. The emergence of parasites lacking the pfhrp2 gene can lead to high rates of false-negative results amongst these RDTs. One solution to restore the ability to correctly diagnose falciparum malaria is to switch to an RDT which is not solely reliant on HRP2. This study used an agent-based stochastic simulation model to investigate the impact on prevalence and transmission caused by switching the type of RDT used once false-negative rates reached pre-defined thresholds within the treatment-seeking symptomatic population. The results show that low transmission settings were the first to reach the false-negative switch threshold, and that lower thresholds were typically associated with better long-term outcomes. Changing the diagnostic RDT away from a HRP2-only RDT is predicted to restore the ability to correctly diagnose symptomatic malaria infections, but often did not lead to the extinction of HRP2-negative parasites from the population which continued to circulate in low density infections, or return to the parasite prevalence and transmission levels seen prior to the introduction of the HRP2-negative parasite. In contrast, failure to move away from HRP2-only RDTs leads to near fixation of these parasites in the population, and the inability to correctly diagnose symptomatic cases. Overall, these results suggest pfhrp2-deleted parasites are likely to become a significant component of P. falciparum parasite populations, and that long-term strategies are needed for diagnosis and surveillance which do not rely solely on HRP2.
| S-EPMC10021339 | biostudies-literature
Project description:BackgroundRapid diagnostic tests (RDT) for malaria are the primary tool for malaria diagnosis in sub-Saharan Africa but the utility of the most commonly used histidine-rich protein 2 (HRP2) antigen-based tests is limited in high transmission settings due to the long duration of positivity after successful malaria treatment. HRP2 tests are also threatened by the emergence of Plasmodium that do not carry pfhrp2 or pfhrp 3 genes. Plasmodium lactate dehydrogenase (pLDH)-based tests are promising alternatives, but less available. This study assessed the performances of HRP2 and pLDH(pan) tests under field conditions.MethodsThe study performed a prospective facility-based diagnostic evaluation of two malaria RDTs in Aweil, South Sudan, during the high transmission season. Capillary blood by fingerprick was collected from 800 children under 15 years of age with fever and no signs of severity. SD Bioline HRP2 and CareStart pLDH(pan) RDTs were performed in parallel, thick and thin smears for microscopy were examined, and dried blood was used for PCR testing.ResultsUsing microscopy as the gold standard, the sensitivity of both tests was estimated at > 99%, but the specificity of each was lower: 55.0% for the pLDH test and 61.7% for the HRP2 test. When using PCR as the gold standard, the sensitivity of both tests was lower than the values assessed using microscopy (97.0% for pLDH and 96.5% for HRP2), but the specificity increased (65.1% for pLDH and 72.9% for HRP2). Performance was similar across different production lots, sex, and age. Specificity of both the pLDH and HRP2 tests was significantly lower in children who reported taking a therapeutic course of anti-malarials in the 2 months prior to enrollment. The prevalence of pfhrp2/3 deletions in the study population was 0.6%.ConclusionsThe low specificity of the pLDH RDT in this setting confirms previous results and suggests a problem with this specific test. The prevalence of pfhrp2/3 deletions in the study area warrants continued monitoring and underscores the relevance of assessing deletion prevalence nationally. Improved malaria RDTs for high-transmission environments are needed.
| S-EPMC9461093 | biostudies-literature
Project description:BackgroundThe Alere™ Malaria Ag P.f Ultra-sensitive RDT (UsmRDT) kit is an HRP2-based malaria rapid diagnostic test (RDT) with enhanced sensitivity relative to the SD Bioline Malaria Ag P.f RDT (mRDT) kit. However, the diagnostic performance of the UsmRDT kit has not been evaluated in Ghana.MethodsA total of 740 afebrile participants aged between 3 and 88 years old were recruited from the Central and Greater Accra Regions of Ghana during the off-peak malaria season. Axillary body temperature was measured, and a volume of 1 ml venous blood was drawn from each participant. Prior to separating the blood into plasma and packed cell pellets via centrifugation, the blood was spotted onto one UsmRDT and one mRDT kit and also used to prepare thick and thin blood smears as well as filter paper blood spots. Plasmodium falciparum specific polymerase chain reaction (PCR) was performed on gDNA extracted from 100 µl of the whole blood.ResultsThe overall positivity rate for microscopy, PCR, UsmRDT and mRDT kit were 20.4%, 40.8%, 31.3% and 30.8%, respectively. Overall, the UsmRDT identified 9.3% (28/302) more PCR positive samples than the mRDT kits. All samples that were negative by the UsmRDT kit were also negative by the mRDT kit. Overall, the sensitivity and specificity of the UsmRDT was 73% (221/302) and 89% (388/436), respectively, while that for the mRDT kit was 58% and 90%, respectively.ConclusionAlthough the UsmRDT kit was not as sensitive as PCR at detecting asymptomatic P. falciparum carriage, it correctly identified P. falciparum in 9.3% of the study participants that were not captured by the mRDT kit. In malaria endemic settings, the UsmRDT would provide an added advantage by identifying more asymptomatic P. falciparum carriers than the mRDT kit for targeted treatment interventions.
| S-EPMC7927401 | biostudies-literature
Project description:BackgroundRapid diagnostic tests (RDTs) that rely on the detection of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) have become key tools for diagnosing P. falciparum infection. The utility of RDTs can be limited by PfHRP2 persistence, however it can be a potential benefit in low transmission settings where detection of persistent PfHRP2 using newer ultra-sensitive PfHRP2 based RDTs can serve as a surveillance tool to identify recent exposure. Better understanding of the dynamics of PfHRP2 over the course of a malaria infection can inform optimal use of RDTs.MethodsA previously published mathematical model was refined to mimic the production and decay of PfHRP2 during a malaria infection. Data from 15 individuals from volunteer infection studies were used to update the original model and estimate key model parameters. The refined model was applied to a cohort of patients from Namibia who received treatment for clinical malaria infection for whom longitudinal PfHRP2 concentrations were measured.ResultsThe refinement of the PfHRP2 dynamic model indicated that in malaria naïve hosts, P. falciparum parasites of the 3D7 strain produce 33.6 × 10-15 g (95% CI 25.0-42.1 × 10-15 g) of PfHRP2 in vivo per parasite replication cycle, with an elimination half-life of 1.67 days (95% CI 1.11-3.40 days). The refined model included these updated parameters and incorporated individualized body fluid volume calculations, which improved predictive accuracy when compared to the original model. The performance of the model in predicting clearance of PfHRP2 post treatment in clinical samples from six adults with P. falciparum infection in Namibia improved when using a longer elimination half-life of 4.5 days, with 14% to 67% of observations for each individual within the predicted range.ConclusionsThe updated mathematical model can predict the growth and clearance of PfHRP2 during the production and decay of a mono-infection with P. falciparum, increasing the understanding of PfHRP2 antigen dynamics. This model can guide the optimal use of PfHRP2-based RDTs for reliable diagnosis of P. falciparum infection and re-infection in endemic settings, but also for malaria surveillance and elimination programmes in low transmission areas.
| S-EPMC9351188 | biostudies-literature
Project description:BackgroundA new more highly sensitive rapid diagnostic test (HS-RDT) for Plasmodium falciparum malaria (Alere™/Abbott Malaria Ag P.f RDT [05FK140], now called NxTek™ Eliminate Malaria Ag Pf) was launched in 2017. The test has already been used in many research studies in a wide range of geographies and use cases.MethodsIn this study, we collate all published and available unpublished studies that use the HS-RDT and assess its performance in (i) prevalence surveys, (ii) clinical diagnosis, (iii) screening pregnant women, and (iv) active case detection. Two individual-level data sets from asymptomatic populations are used to fit logistic regression models to estimate the probability of HS-RDT positivity based on histidine-rich protein 2 (HRP2) concentration and parasite density. The performance of the HS-RDT in prevalence surveys is estimated by calculating the sensitivity and positive proportion in comparison to polymerase chain reaction (PCR) and conventional malaria RDTs.ResultsWe find that across 18 studies, in prevalence surveys, the mean sensitivity of the HS-RDT is estimated to be 56.1% (95% confidence interval [CI] 46.9-65.4%) compared to 44.3% (95% CI 32.6-56.0%) for a conventional RDT (co-RDT) when using nucleic acid amplification techniques as the reference standard. In studies where prevalence was estimated using both the HS-RDT and a co-RDT, we found that prevalence was on average 46% higher using a HS-RDT compared to a co-RDT. For use in clinical diagnosis and screening pregnant women, the HS-RDT was not significantly more sensitive than a co-RDT.ConclusionsOverall, the evidence presented here suggests that the HS-RDT is more sensitive in asymptomatic populations and could provide a marginal improvement in clinical diagnosis and screening pregnant women. Although the HS-RDT has limited temperature stability and shelf-life claims compared to co-RDTs, there is no evidence to suggest, given this test has the same cost as current RDTs, it would have any negative impacts in terms of malaria misdiagnosis if it were widely used in all four population groups explored here.
| S-EPMC8815208 | biostudies-literature
Project description:BackgroundThe emergence of pfhrp2/3-deleted parasites threatens histidine-rich protein 2 (HRP2)-based malaria rapid diagnostic test (RDT) performance. RDTs targeting Plasmodium falciparum (Pf) lactate dehydrogenase (LDH) may address current product limitations and improve case management.ObjectivesTo evaluate the performance and usability of three LDH-based RDTs in febrile patients.MethodsA cross-sectional diagnostic accuracy study was conducted in Kédougou, Senegal. Capillary blood was tested using the SD Bioline Ag Pf (#05FK50) and three LDH-based RDTs: BIOCREDIT Malaria Ag Pf (pLDH), BIOCREDIT Pf (pLDH/HRPII), and BIOCREDIT Pf/Pv (pLDH/pLDH) (Rapigen Inc., Republic of Korea). Venous blood was collected to repeat the BIOCREDIT RDTs and conduct microscopy. Frozen venous specimens were tested using a reference PCR assay. A quantitative multiplex malaria antigen assay measured antigen concentration. RDT performance was determined and analyzed as a function of antigen concentration distribution. Usability of the Pf-only BIOCREDIT tests was evaluated using a questionnaire.Results154/220 participants (70%) were Pf-positive by PCR. The Pf (pLDH/HRPII) test demonstrated the highest sensitivity at 78% (70.9%-84.5%); specificity was 89% (79.4%-95.6%). All RDTs performed better than microscopy (53% sensitivity). RDTs performed better when compared to antigen concentration over PCR results. Improved sensitivity of the Pf (pLDH/HRPII) test was driven by the HRP2 line. Line intensity correlated with antigen concentration. Predicted sensitivity using the analytical limit of detection (LOD) was comparable to observed sensitivity. RDTs demonstrated acceptable usability.ConclusionsBoth HRP2 and LDH contributed to the sensitivity of the best-performing Pf-RDT. RDT analytical LODs can be used to predict performance in populations with known antigen concentrations.
| S-EPMC11661343 | biostudies-literature