Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement
Author(s)
Hendriksen, AM
Type
Journal Article
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.
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.
Date Issued
2012-08-21
Date Acceptance
2012-07-13
Citation
PLOS Medicine, 2012, 9 (8)
ISSN
1549-1277
Publisher
Public Library of Science
Journal / Book Title
PLOS Medicine
Volume
9
Issue
8
Copyright Statement
© 2012 Hendriksen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
License URL
Publication Status
Published
Article Number
e1001297