article · Scientific Reports
Rapid diagnostic tests targeting histidine-rich protein 2 are widely used across Africa to diagnose Plasmodium falciparum malaria. However, gene deletions in pfhrp2 and pfhrp3 threaten diagnostic accuracy by causing false negatives. An investigation in the Democratic Republic of the Congo examined 3,627 symptomatic individuals to evaluate the prevalence of these deletions. Although 11.8 percent of subjects were negative by rapid tests but positive by microscopy, comprehensive testing using bead-based immunoassays and whole-genome sequencing revealed that suspected gene deletions were actually intact. Overall, 56.8 percent of participants had malaria confirmed by polymerase chain reaction, with frequent non-falciparum co-infections. The rapid tests demonstrated satisfactory agreement with polymerase chain reaction, outperforming microscopy. Because no symptomatic cases caused by gene-deleted parasites were detected, continuing the use of existing histidine-rich protein 2 rapid diagnostic tests remains an appropriate strategy for clinical diagnosis in the country.
Malaria rapid diagnostic tests rely on detecting specific parasite proteins to guide prompt treatment. Concerns that mutant malaria strains missing these target proteins could evade detection have raised questions about test reliability. This research provides evidence that current diagnostic tools remain effective for symptomatic patients in the Democratic Republic of the Congo, reassuring health programmes that standard rapid tests can continue to be deployed safely.
These findings directly inform diagnostic procurement and deployment decisions for public health authorities and non-governmental organisations operating malaria management programmes. The results validate the continued clinical use of existing, widely marketed histidine-rich protein 2 rapid diagnostic kits in the Democratic Republic of the Congo, showing that an immediate shift to alternative diagnostic products is not yet required for symptomatic populations.
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The majority of Plasmodium falciparum malaria diagnoses in Africa are made using rapid diagnostic tests (RDTs) that detect histidine-rich protein 2. Increasing reports of false-negative RDT results due to parasites with deletions of the pfhrp2 and/or pfhrp3 genes (pfhrp2/3) raise concern about existing malaria diagnostic strategies. We previously identified pfhrp2-negative parasites among asymptomatic children in the Democratic Republic of the Congo (DRC), but their impact on diagnosis of symptomatic malaria is unknown. We performed a cross-sectional study of false-negative RDTs in symptomatic subjects in 2017. Parasites were characterized by microscopy; RDT; pfhrp2/3 genotyping and species-specific PCR assays; a bead-based immunoassay for Plasmodium antigens; and/or whole-genome sequencing. Among 3627 symptomatic subjects, 427 (11.8%) had RDT-/microscopy + results. Parasites from eight (0.2%) samples were initially classified as putative pfhrp2/3 deletions by PCR, but antigen testing and whole-genome sequencing confirmed the presence of intact genes. 56.8% of subjects had PCR-confirmed malaria. Non-falciparum co-infection with P. falciparum was common (13.2%). Agreement between PCR and HRP2-based RDTs was satisfactory (Cohen's kappa = 0.66) and superior to microscopy (0.33). Symptomatic malaria due to pfhrp2/3-deleted P. falciparum was not observed. Ongoing HRP2-based RDT use is appropriate for the detection of falciparum malaria in the DRC.
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DOI: 10.1038/s41598-021-85913-z
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