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Assessing Performance of HRP2 Antigen Detection for Malaria Diagnosis in Mozambique.

ABSTRACT: 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.

SUBMITTER: Plucinski MM

PROVIDER: S-EPMC6711899 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Assessing Performance of HRP2 Antigen Detection for Malaria Diagnosis in Mozambique.

Plucinski Mateusz M MM Candrinho Baltazar B Dimene Mercia M Colborn James J Lu Austin A Nace Doug D Zulliger Rose R Rogier Eric E

Journal of clinical microbiology 20190826 9

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 ...[more]

PMID: 31270184

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Project description:Background An ultrasensitive malaria rapid diagnostic test (RDT) was recently developed for the improved detection of low-density Plasmodium falciparum infections. This study aimed to compare the diagnostic performance of the PfHRP2-based Abbott Malaria Ag P. falciparum ultrasensitive RDT (uRDT) to that of the conventional SD-Bioline Malaria Ag P. falciparum RDT (cRDT) when performed under field conditions. Methods Finger-prick blood samples were collected from adults and children in two cross-sectional surveys in May of 2017 in southern Mozambique. Using real-time quantitative PCR (RT-qPCR) as the reference method, the age-specific diagnostic performance indicators of the cRDT and uRDT were compared. The presence of histidine-rich protein 2 (HRP2) and Plasmodium lactate dehydrogenase (pLDH) antigens was evaluated in a subset from dried blood spots by a quantitative antigen assay. pfhrp2 and pfhrp3 gene deletions were assessed in samples positive by RT-qPCR and negative by both RDTs. Results Among the 4,396 participants with complete test results, the sensitivity of uRDTs (68.2; 95% CI 60.8 to 74.9) was marginally better than that of cRDTs (61.5; 95% CI 53.9 to 68.6) (p-value?=?0.004), while the specificities were similar (uRDT: 99.0 [95% CI 98.6 to 99.2], cRDT: 99.2 [95% CI 98.9 to 99.4], p-value?=?0.02). While the performance of both RDTs was lowest in???15-year-olds, driven by the higher prevalence of low parasite density infections in this group, the sensitivity of uRDTs was significantly higher in this age group (54.9, 95% CI 40.3 to 68.9) compared to the sensitivity of cRDTs (39.2, 95% CI 25.8 to 53.9) (p-value?=?0.008). Both RDTs detected P. falciparum infections at similar geometric mean parasite densities (112.9 parasites/?L for uRDTs and 145.5 parasites/?L for cRDTs). The presence of HRP2 antigen was similar among false positive (FP) samples of both tests (80.5% among uRDT-FPs and 84.4% among cRDT-FPs). Only one false negative sample was detected with a partial pfhrp2 deletion. Conclusion This study showed that the uRDTs developed by Abbott do not substantially outperform SD-Bioline Pf malaria RDTs in the community and are still not comparable to molecular methods to detect P. falciparum infections in this study setting.

Project description:BackgroundAlthough the clinical efficacy of antimalarial artemisinin-based combination therapies in Africa remains high, the recent emergence of partial resistance to artemisinin in Plasmodium falciparum on the continent is troubling, given the lack of alternative treatments.MethodsIn this study, we used data from drug-efficacy studies conducted between 2016 and 2019 that evaluated 3-day courses of artemisinin-based combination therapy (artesunate-amodiaquine or artemether-lumefantrine) for uncomplicated malaria in Eritrea to estimate the percentage of patients with day-3 positivity (i.e., persistent P. falciparum parasitemia 3 days after the initiation of therapy). We also assayed parasites for mutations in Pfkelch13 as predictive markers of partial resistance to artemisinin and screened for deletions in hrp2 and hrp3 that result in variable performance of histidine rich protein 2 (HRP2)-based rapid diagnostic tests for malaria.ResultsWe noted an increase in the percentage of patients with day-3 positivity from 0.4% (1 of 273) in 2016 to 1.9% (4 of 209) in 2017 and 4.2% (15 of 359) in 2019. An increase was also noted in the prevalence of the Pfkelch13 R622I mutation, which was detected in 109 of 818 isolates before treatment, from 8.6% (24 of 278) in 2016 to 21.0% (69 of 329) in 2019. The odds of day-3 positivity increased by a factor of 6.2 (95% confidence interval, 2.5 to 15.5) among the patients with Pfkelch13 622I variant parasites. Partial resistance to artemisinin, as defined by the World Health Organization, was observed in Eritrea. More than 5% of the patients younger than 15 years of age with day-3 positivity also had parasites that carried Pfkelch13 R622I. In vitro, the R622I mutation conferred a low level of resistance to artemisinin when edited into NF54 and Dd2 parasite lines. Deletions in both hrp2 and hrp3 were identified in 16.9% of the parasites that carried the Pfkelch13 R622I mutation, which made them potentially undetectable by HRP2-based rapid diagnostic tests.ConclusionsThe emergence and spread of P. falciparum lineages with both Pfkelch13-mediated partial resistance to artemisinin and deletions in hrp2 and hrp3 in Eritrea threaten to compromise regional malaria control and elimination campaigns. (Funded by the Bill and Melinda Gates Foundation and others; Australian New Zealand Clinical Trials Registry numbers, ACTRN12618001223224, ACTRN12618000353291, and ACTRN12619000859189.).

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.

Dataset Information

Assessing Performance of HRP2 Antigen Detection for Malaria Diagnosis in Mozambique.

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Assessing Performance of HRP2 Antigen Detection for Malaria Diagnosis in Mozambique.

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