Are HRP2/3 deletions silently crippling malaria rapid diagnostic tests?

Background and objectives The gold standard for diagnosing malaria is peripheral smear. Histidine-rich protein 2 (HRP2)-based rapid diagnostic tests (RDTs) are particularly used for P. falciparum (pf) infections. These tests are easily accessible and are simple to use. The rising incidence of pfhrp2 and pfhrp3 gene deletions has put malaria diagnostics through RDT kit at risk, leading to false-negative results that may affect patient management. Methods The search string used was: 'pfhrp2' OR 'pfhrp3' OR 'HRP2' OR 'HRP3' OR 'hrp2/3' AND 'malaria' OR 'Plasmodium falciparum' AND deletion OR 'deletion rate' OR prevalence OR 'RDT failure'. A total of 148 studies were gathered from PubMed and Google scholar. After screening, a total of 28 published studies and the WHO documents were included. Results High rates of gene deletion have been reported, ranging from 2.4 to 57.8%, with low range in Chhattisgarh, India (3.8%) and Brazil (∼18.3% dual deletions), to extreme levels in Southern Ethiopia (57.8%). These deletions are believed to be the result due to the widespread use of HRP2-based RDTs. The diagnostic performance of RDTs considerably declines in regions where the WHO-recommended 5% threshold for deletion prevalence is exceeded. Surveillance techniques like PCR, whole-genome sequencing, and digital droplet PCR (ddPCR) are needed for effective detection and monitoring in these regions. Interpretation and conclusions The widespread and regional variation of pfhrp 2/3 gene deletions stance a serious challenge to malaria diagnosis using HRP-based RDTs. Alternatives to HRP-based tests in high-deletion areas and adopting novel diagnostic tools are essential for effective malaria detection and elimination strategies.