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Background <p>Histidine Rich Protein 2-based rapid diagnostic tests (HRP2-based RDTs) are widely used for malaria diagnosis in Malawi, but their accuracy may be compromised by <i>Plasmodium falciparum</i> parasites lacking the <i>P. falciparum histidine rich protein 2</i> (<i>pfhrp2</i>)&#xa0;and <i>P. falciparum histidine rich protein 3</i> (<i>pfhrp3</i>) genes. While such deletions have been reported in other malaria-endemic countries, their presence and diagnostic impact in Malawi remain unknown. This study aimed to determine the prevalence of <i>pfhrp2/pfhrp3</i> gene deletions in Malawi and their effect on the diagnostic accuracy of HRP2-based RDTs relative to light microscopy and qPCR.</p> Methods <p>A cross-sectional study was conducted between December 2020 and June 2021, enrolling 1582 participants from referral hospitals in Mzuzu (<i>n</i> = 1186) and Lilongwe (<i>n</i> = 396). Malaria diagnosis was performed using RDTs, microscopy, and qPCR. A total of 391 <i>P. falciparum</i> positive samples were analyzed for <i>pfhrp2/pfhrp3</i> gene deletions using multiplex qPCR. Diagnostic accuracy metrics, such as sensitivity and specificity, were calculated with 95% confidence intervals. Spearman correlation was applied to assess associations involving log-transformed parasitemia, unpaired <i>t</i>-tests were used to compare diagnostic methods, and Mann–Whitney tests were used to compare symptomatic and asymptomatic groups.</p> Results <p>Malaria prevalence was higher in Lilongwe (45.2%) than in Mzuzu (22.9%). Infections in Lilongwe were predominantly asymptomatic (94.2%), whereas Mzuzu had mostly symptomatic cases (97.1%) (<i>P</i> &lt; 0.0002). RDTs demonstrated higher sensitivity of&#xa0;78.5% (95% <i>CI</i>: 74.6–82.1%) than microscopy 64.8% (95% <i>CI</i>: 60.3–69.1), but slightly lower specificity, with 93.6% (95% <i>CI</i>: 92.0–95.0%) for RDT compared to 95.4% (95% <i>CI</i>: 94.0–96.6%) for microscopy. Dual <i>pfhrp2/3</i> gene deletions were found in 24 (15.0%) isolates from Lilongwe and 24 (10.4%) from Mzuzu. All dual-deleted samples were false negative by RDT but were positive by microscopy and qPCR.</p> Conclusions <p>This study is the first to report <i>pfhrp2/3</i> gene deletions in Malawi. The presence of these deletions may compromise the performance of HRP2-based RDTs, indicating the need to reassess diagnostic strategies in affected regions.</p>

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First report of pfhrp2 and pfhrp3 gene deletions compromising HRP2-based malaria rapid diagnostic tests in Malawi

  • 期刊论文

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  • 发表日期：

    2025年10月9日

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  • Johnsy Mary Louis,
  • Ernest Mazigo,
  • Hojong Jun,
  • Wang-Jong Lee,
  • Jadidan Hada Syahada,
  • Fadhila Fitriana,
  • Fauzi Muh,
  • Wanjoo Chun,
  • Won Sun Park,
  • Se Jin Lee,
  • Sunghun Na,
  • Feng Lu,
  • Eun-Teak Han,
  • Jin-Hee Han

摘要

Background

Histidine Rich Protein 2-based rapid diagnostic tests (HRP2-based RDTs) are widely used for malaria diagnosis in Malawi, but their accuracy may be compromised by Plasmodium falciparum parasites lacking the P. falciparum histidine rich protein 2 (pfhrp2) and P. falciparum histidine rich protein 3 (pfhrp3) genes. While such deletions have been reported in other malaria-endemic countries, their presence and diagnostic impact in Malawi remain unknown. This study aimed to determine the prevalence of pfhrp2/pfhrp3 gene deletions in Malawi and their effect on the diagnostic accuracy of HRP2-based RDTs relative to light microscopy and qPCR.

Methods

A cross-sectional study was conducted between December 2020 and June 2021, enrolling 1582 participants from referral hospitals in Mzuzu (n = 1186) and Lilongwe (n = 396). Malaria diagnosis was performed using RDTs, microscopy, and qPCR. A total of 391 P. falciparum positive samples were analyzed for pfhrp2/pfhrp3 gene deletions using multiplex qPCR. Diagnostic accuracy metrics, such as sensitivity and specificity, were calculated with 95% confidence intervals. Spearman correlation was applied to assess associations involving log-transformed parasitemia, unpaired t-tests were used to compare diagnostic methods, and Mann–Whitney tests were used to compare symptomatic and asymptomatic groups.

Results

Malaria prevalence was higher in Lilongwe (45.2%) than in Mzuzu (22.9%). Infections in Lilongwe were predominantly asymptomatic (94.2%), whereas Mzuzu had mostly symptomatic cases (97.1%) (P < 0.0002). RDTs demonstrated higher sensitivity of 78.5% (95% CI: 74.6–82.1%) than microscopy 64.8% (95% CI: 60.3–69.1), but slightly lower specificity, with 93.6% (95% CI: 92.0–95.0%) for RDT compared to 95.4% (95% CI: 94.0–96.6%) for microscopy. Dual pfhrp2/3 gene deletions were found in 24 (15.0%) isolates from Lilongwe and 24 (10.4%) from Mzuzu. All dual-deleted samples were false negative by RDT but were positive by microscopy and qPCR.

Conclusions

This study is the first to report pfhrp2/3 gene deletions in Malawi. The presence of these deletions may compromise the performance of HRP2-based RDTs, indicating the need to reassess diagnostic strategies in affected regions.