Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement

Ilse Hendriksen, Juliet Mwanga-Amumpaire, Lorenz Von Seidlein, George Mtove, Lisa White, Rasaq Olaosebikan, Sue J Lee, Antoinette K Tshefu, Charles Woodrow, Ben Amos, Corine Karema, s Saiwaew, Kathryn Maitland, Ermelinda Gomes, W Pan-Ngum, Samwel Gesase, Kamolrat Silamut, Hugh Reyburn, S Joseph, ChotivanichCaterina Fanello, N Day, Nicholas J White, Arjen Dondorp

    Research output: Contribution to journalArticle

    3 Downloads (Pure)

    Abstract

    Background: In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria. 

    Methods and Findings: Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350-1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991-1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log10 plasma PfHRP2 and risk of death. Mortality increased 20% per log10 increase in PfHRP2 above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95%CI 1.05-1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50% with plasma PfHRP2?174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95%CI 0.44-0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95%CI 0.69-1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings. 

    Conclusions: Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of "true" severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children. 
    Original languageEnglish
    Article numbere1001297
    Pages (from-to)1-10
    Number of pages10
    JournalPLoS Medicine
    Volume9
    Issue number8
    DOIs
    Publication statusPublished - 2012

    Fingerprint Dive into the research topics of 'Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement'. Together they form a unique fingerprint.

  • Cite this

    Hendriksen, I., Mwanga-Amumpaire, J., Von Seidlein, L., Mtove, G., White, L., Olaosebikan, R., Lee, S. J., Tshefu, A. K., Woodrow, C., Amos, B., Karema, C., Saiwaew, S., Maitland, K., Gomes, E., Pan-Ngum, W., Gesase, S., Silamut, K., Reyburn, H., Joseph, S., ... Dondorp, A. (2012). Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement. PLoS Medicine, 9(8), 1-10. [e1001297]. https://doi.org/10.1371/journal.pmed.1001297