Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom; Mbarara University of Science and Technology and Epicentre Research Base, Mbarara, Uganda; Menzies School of Health Research, Casuarina, NT, Australia; National Institute for Medical Research, Amani Centre, Tanga, Tanzania; Medical Research Council Laboratories, Banjul, Gambia; Kinshasa School of Public Health, Kingasani Research Centre, Kinshasa, Congo; Teule Hospital, Muheza, Tanzania; Malaria Control Program, Ministry of Health, Kigali, Rwanda; Kenya Medical Research Institute (KEMRI)-Wellcome Trust Research Programme, Kilifi, Kenya; Hospital Central da Beira, Beira, Mozambique; National Institute for Medical Research, Tanga Medical Research Centre, Tanga, Tanzania; London School of Tropical Medicine and Hygiene, London, United Kingdom; Medical Research Council, London, United Kingdom
Hendriksen, I.C.E., Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, Centre for Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom; Mwanga-Amumpaire, J., Mbarara University of Science and Technology and Epicentre Research Base, Mbarara, Uganda; von Seidlein, L., Menzies School of Health Research, Casuarina, NT, Australia; Mtove, G., National Institute for Medical Research, Amani Centre, Tanga, Tanzania; White, L.J., Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, Centre for Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom; Olaosebikan, R., Medical Research Council Laboratories, Banjul, Gambia; Lee, S.J., Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, Centre for Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom; Tshefu, A.K., Kinshasa School of Public Health, Kingasani Research Centre, Kinshasa, Congo; Woodrow, C., Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, Centre for Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom; Amos, B., Teule Hospital, Muheza, Tanzania; Karema, C., Malaria Control Program, Ministry of Health, Kigali, Rwanda; Saiwaew, S., Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Maitland, K., Kenya Medical Research Institute (KEMRI)-Wellcome Trust Research Programme, Kilifi, Kenya; Gomes, E., Hospital Central da Beira, Beira, Mozambique; Pan-Ngum, W., Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Gesase, S., National Institute for Medical Research, Tanga Medical Research Centre, Tanga, Tanzania; Silamut, K., Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Reyburn, H., London School of Tropical Medicine and Hygiene, London, United Kingdom; Joseph, S., Medical Research Council, London, United Kingdom; Chotivanich, K., Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Fanello, C.I., Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, Centre for Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom; Day, N.P.J., Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, Centre for Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom; White, N.J., Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, Centre for Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom; Dondorp, A.M., Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, Centre for Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom
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. Please see later in the article for the Editors' Summary. © 2012 Hendriksen et al.