Assessing Performance of HRP2 Antigen Detection for Malaria Diagnosis in Mozambique

Pluciński, Mateusz M.; Candrinho, Baltazar; Dimene, Mercia; Colborn, James; Lu, Austin; Nace, Doug; Zulliger, Rose; Rogier, Eric

doi:10.1128/jcm.00875-19

Cited by 23 publications

(21 citation statements)

References 21 publications

(32 reference statements)

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“…This study revealed that the sensitivity of both RDTs increased among febrile individuals, to 84.9 for uRDTs and 79.2 for cRDTs. This indicates that febrile cases which usually suffer from higher density infections as shown in this study (GMPD of 346.3 parasites/µL), are likely to be rightly diagnosed with both types of RDTs in southern Mozambique [32]. Therefore, this suggests that uRDTs do not provide added benefits to the detection of infections among febrile individuals in the community when compared to regular RDTs, a finding that has been similarly observed among febrile outpatients in Tanzania [27].…”

Section: Discussionsupporting

confidence: 53%

Field performance of ultrasensitive and conventional malaria rapid diagnostic tests in southern Mozambique

Galatas

Mayor

Gupta

et al. 2020

Malar J

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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/μL for uRDTs and 145.5 parasites/μL 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.

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Section: Discussionsupporting

confidence: 53%

Field performance of ultrasensitive and conventional malaria rapid diagnostic tests in southern Mozambique

Galatas

Mayor

Gupta

et al. 2020

Malar J

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“…As Uganda advances towards malaria elimination, false-negative RDT results due to low-parasite density infections will be a potential threat [61,62]. Efforts to address low-parasite density infections should consider the deployment of highly sensitive diagnostic tools, including nucleic acid amplification-based tests [61,[63][64][65][66][67][68]. However, the current WHO guidance does not recommend the use of ultrasensitive RDTs for routine diagnosis until additional evidence becomes available [67].…”

Section: Implication For Malaria Controlmentioning

confidence: 99%

Limitations of rapid diagnostic tests in malaria surveys in areas with varied transmission intensity in Uganda 2017-2019: Implications for selection and use of HRP2 RDTs

et al. 2020

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Background Plasmodium falciparum histidine-rich protein 2 (HRP2)-based rapid diagnostic tests (RDTs) are exclusively recommended for malaria diagnosis in Uganda; however, their functionality can be affected by parasite-related factors that have not been investigated in field settings. Methods Using a cross-sectional design, we analysed 219 RDT-/microscopy+ and 140 RDT+/microscopy+ dried blood spots obtained from symptomatic children aged 2–10 years from 48 districts in Uganda between 2017 and 2019. We aimed to investigate parasite-related factors contributing to false RDT results by molecular characterization of parasite isolates. ArcGIS software was used to map the geographical distribution of parasites. Statistical analysis was performed using chi-square or Fisher’s exact tests, with P ≤ 0.05 indicating significance. Odds ratios (ORs) were used to assess associations, while logistic regression was performed to explore possible factors associated with false RDT results. Results The presence of parasite DNA was confirmed in 92.5% (332/359) of the blood samples. The levels of agreement between the HRP2 RDT and PCR assay results in the (RDT+/microscopy+) and (RDT-/microscopy+) sample subsets were 97.8% (137/140) and 10.9% (24/219), respectively. Factors associated with false-negative RDT results in the (RDT-/microscopy+) samples were parasite density (<1,000/μl), pfhrp2/3 gene deletion and non-P. falciparum species (aOR 2.65, 95% CI: 1.62–4.38, P = 0.001; aOR 4.4, 95% CI 1.72–13.66, P = 0.004; and aOR 18.65, 95% CI: 5.3–38.7, P = 0.001, respectively). Overall, gene deletion and non-P. falciparum species contributed to 12.3% (24/195) and 19.0% (37/195) of false-negative RDT results, respectively. Of the false-negative RDTs results, 80.0% (156/195) were from subjects with low-density infections (< 25 parasites per 200 WBCs or <1,000/μl). Conclusion This is the first evaluation and report of the contributions of pfhrp2/3 gene deletion, non-P. falciparum species, and low-density infections to false-negative RDT results under field conditions in Uganda. In view of these findings, the use of HRP2 RDTs should be reconsidered; possibly, switching to combination RDTs that target alternative antigens, particularly in affected areas, may be beneficial. Future evaluations should consider larger and more representative surveys covering other regions of Uganda.

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“…A substantial proportion of parasite isolates with both pfhrp 2 and pfhrp 3 gene deletions have been reported across malaria endemic countries in Africa with the highest prevalence of deletion from Eritrea (62%) [ 14 ] and the lowest from Angola (0.4%) [ 19 ]. Indeed, in some hospitals in Eritrea the levels of gene deletions were as high as 80% [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

High prevalence and extended deletions in Plasmodium falciparum hrp2/3 genomic loci in Ethiopia

et al. 2020

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Deletions in Plasmodium falciparum histidine rich protein 2(pfhrp2) gene threaten the usefulness of the most widely used HRP2-based malaria rapid diagnostic tests (mRDTs) that cross react with its structural homologue, PfHRP3. Parasites with deleted pfhrp2/3 genes remain undetected and untreated due to ‘false-negative’ RDT results. As Ethiopia recently launched malaria elimination by 2030 in certain selected areas, the availability of RDTs and the scale of their use have rapidly increased in recent years. Thus, it is important to explore the presence and prevalence of deletion in the target genes, pfhrp2 and pfhrp3. From a total of 189 febrile patients visited Adama Malaria Diagnostic centre, sixty-four microscopically-and polymerase chain reaction (PCR)-confirmed P. falciparum clinical isolates were used to determine the frequency of pfhrp2/3 gene deletions. Established PCR assays were applied to DNA extracted from blood spotted onto filter papers to amplify across pfhrp2/3 exons and flanking regions. However, analysis of deletions in pfhrp2, pfhrp3 and flanking genomic regions was successful for 50 of the samples. The pfhrp2 gene deletion was fixed in the population with all 50(100%) isolates presenting a deletion variant. This deletion extended downstream towards the Pf3D7 0831900 (MAL7PI.230) gene in 11/50 (22%) cases. In contrast, only 2/50 (4%) of samples had deletions for the Pf3D7 0831700 (MALPI.228) gene, upstream of pfhrp2. Similarly, the pfhrp3 gene was deleted in all isolates (100%), while 40% of the isolates had an extension of the deletion to the downstream flanking region that codes for Pf3D7 13272400 (MAL13PI.485).The pfhrp3 deletion also extended upstream to Pf3D7 081372100 (MAL13PI.475) region in 49/50 (95%) of the isolates, exhibiting complete absence of the locus. Although all samples showed deletions of pfhrp2 exon regions, amplification of an intron region was successful in five cases. Two different repeat motifs in the intron regions were observed in the samples tested. Pfhrp2/3 gene deletions are fixed in Ethiopia and this will likely reduce the effectiveness of PfHRP2-based mRDTs. It will be important to determine the sensitivity PfHRP 2/3-based RDTs in these populations and conduct a countrywide survey to determine the extent of these deletions and its effect on routine RDT-based malaria diagnosis.

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Assessing Performance of HRP2 Antigen Detection for Malaria Diagnosis in Mozambique

Cited by 23 publications

References 21 publications

Field performance of ultrasensitive and conventional malaria rapid diagnostic tests in southern Mozambique

Field performance of ultrasensitive and conventional malaria rapid diagnostic tests in southern Mozambique

Limitations of rapid diagnostic tests in malaria surveys in areas with varied transmission intensity in Uganda 2017-2019: Implications for selection and use of HRP2 RDTs

High prevalence and extended deletions in Plasmodium falciparum hrp2/3 genomic loci in Ethiopia

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