title: Diagnosing severe falciparum malaria in parasitaemic African children: a prospective evaluation of plasma PfHRP2 measurement.
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.
  
  
  RESULTS
  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 malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children.
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Ilse C E
authors.initials: IC
authors.lastname: Hendriksen
authors.forename: Juliet
authors.initials: J
authors.lastname: Mwanga-Amumpaire
authors.forename: Lorenz
authors.initials: L
authors.lastname: von Seidlein
authors.forename: George
authors.initials: G
authors.lastname: Mtove
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: White
authors.forename: Rasaq
authors.initials: R
authors.lastname: Olaosebikan
authors.forename: Sue J
authors.initials: SJ
authors.lastname: Lee
authors.forename: Antoinette K
authors.initials: AK
authors.lastname: Tshefu
authors.forename: Charles
authors.initials: C
authors.lastname: Woodrow
authors.forename: Ben
authors.initials: B
authors.lastname: Amos
authors.forename: Corine
authors.initials: C
authors.lastname: Karema
authors.forename: Somporn
authors.initials: S
authors.lastname: Saiwaew
authors.forename: Kathryn
authors.initials: K
authors.lastname: Maitland
authors.forename: Ermelinda
authors.initials: E
authors.lastname: Gomes
authors.forename: Wirichada
authors.initials: W
authors.lastname: Pan-Ngum
authors.forename: Samwel
authors.initials: S
authors.lastname: Gesase
authors.forename: Kamolrat
authors.initials: K
authors.lastname: Silamut
authors.forename: Hugh
authors.initials: H
authors.lastname: Reyburn
authors.forename: Sarah
authors.initials: S
authors.lastname: Joseph
authors.forename: Kesinee
authors.initials: K
authors.lastname: Chotivanich
authors.forename: Caterina I
authors.initials: CI
authors.lastname: Fanello
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
mesh_terms: D000293:Adolescent; D000349:Africa / Q000453:epidemiology; D000953:Antigens, Protozoan / Q000097:blood*; D037621:Artemisinins / Q000627:therapeutic use; D000077332:Artesunate; D002648:Child; D002675:Child, Preschool; D003710:Demography; D005260:Female; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000097:blood* / Q000175:diagnosis* / Q000401:mortality / Q000469:parasitology; D008297:Male; D008954:Models, Biological; D016017:Odds Ratio; D018512:Parasitemia / Q000097:blood* / Q000150:complications / Q000175:diagnosis*; D011446:Prospective Studies; D015800:Protozoan Proteins / Q000097:blood*; D011803:Quinine / Q000627:therapeutic use; D012307:Risk Factors; D012720:Severity of Illness Index
chemical_list: D000953:Antigens, Protozoan; D037621:Artemisinins; C514457:HRP-2 antigen, Plasmodium falciparum; D015800:Protozoan Proteins; D000077332:Artesunate; D011803:Quinine