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Title: Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement
Authors: Ilse C.E. Hendriksen
Juliet Mwanga-Amumpaire
Lorenz von Seidlein
George Mtove
Lisa J. White
Rasaq Olaosebikan
Sue J. Lee
Antoinette K. Tshefu
Charles Woodrow
Ben Amos
Corine Karema
Somporn Saiwaew
Kathryn Maitland
Ermelinda Gomes
Wirichada Pan-Ngum
Samwel Gesase
Kamolrat Silamut
Hugh Reyburn
Sarah Joseph
Kesinee Chotivanich
Caterina I. Fanello
Nicholas P.J. Day
Nicholas J. White
Arjen M. Dondorp
Mahidol University
University of Oxford
Mbarara University of Science and Technology
Menzies School of Health Research
National Institute for Medical Research Tanga
Medical Research Council Laboratories Gambia
Kingasani Research Centre
Teule Hospital
Ministry of Health
Kenya Medical Research Institute
Hospital Central da Beira
London School of Hygiene & Tropical Medicine
Medical Research Council
Keywords: Medicine
Issue Date: 1-Aug-2012
Citation: PLoS Medicine. Vol.9, No.8 (2012)
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 log 10 plasma PfHRP2 and risk of death. Mortality increased 20% per log 10 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 malar ia-attributable disease as opposed to other severe illnesses in parasitaemic African children. Please see later in the article for the Editors' Summary. © 2012 Hendriksen et al.
ISSN: 15491676
Appears in Collections:Scopus 2011-2015

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