title: Defining falciparum-malaria-attributable severe febrile illness in moderate-to-high transmission settings on the basis of plasma PfHRP2 concentration.
abstract: BACKGROUND
  In malaria-endemic settings, asymptomatic parasitemia complicates the diagnosis of malaria. Histidine-rich protein 2 (HRP2) is produced by Plasmodium falciparum, and its plasma concentration reflects the total body parasite burden. We aimed to define the malaria-attributable fraction of severe febrile illness, using the distributions of plasma P. falciparum HRP2 (PfHRP2) concentrations from parasitemic children with different clinical presentations.
  
  
  METHODS
  Plasma samples were collected from and peripheral blood slides prepared for 1435 children aged 6-60 months in communities and a nearby hospital in northeastern Tanzania. The study population included children with severe or uncomplicated malaria, asymptomatic carriers, and healthy control subjects who had negative results of rapid diagnostic tests. The distributions of plasma PfHRP2 concentrations among the different groups were used to model severe malaria-attributable disease.
  
  
  RESULTS
  The plasma PfHRP2 concentration showed a close correlation with the severity of infection. PfHRP2 concentrations of >1000 ng/mL denoted a malaria-attributable fraction of severe disease of 99% (95% credible interval [CI], 96%-100%), with a sensitivity of 74% (95% CI, 72%-77%), whereas a concentration of <200 ng/mL denoted severe febrile illness of an alternative diagnosis in >10% (95% CI, 3%-27%) of patients. Bacteremia was more common among patients in the lowest and highest PfHRP2 concentration quintiles.
  
  
  CONCLUSIONS
  The plasma PfHRP2 concentration defines malaria-attributable disease and distinguishes severe malaria from coincidental parasitemia in African children in a moderate-to-high transmission setting.
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. ilse.h@tropmedres.ac
authors.forename: Ilse C E
authors.initials: IC
authors.lastname: Hendriksen
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: White
authors.forename: Jacobien
authors.initials: J
authors.lastname: Veenemans
authors.forename: George
authors.initials: G
authors.lastname: Mtove
authors.forename: Charles
authors.initials: C
authors.lastname: Woodrow
authors.forename: Ben
authors.initials: B
authors.lastname: Amos
authors.forename: Somporn
authors.initials: S
authors.lastname: Saiwaew
authors.forename: Samwel
authors.initials: S
authors.lastname: Gesase
authors.forename: Behzad
authors.initials: B
authors.lastname: Nadjm
authors.forename: Kamolrat
authors.initials: K
authors.lastname: Silamut
authors.forename: Sarah
authors.initials: S
authors.lastname: Joseph
authors.forename: Kesinee
authors.initials: K
authors.lastname: Chotivanich
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.forename: Lorenz
authors.initials: L
authors.lastname: von Seidlein
authors.forename: Hans
authors.initials: H
authors.lastname: Verhoef
authors.forename: Hugh
authors.initials: H
authors.lastname: Reyburn
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
mesh_terms: D000953:Antigens, Protozoan / Q000097:blood*; D002675:Child, Preschool; D005260:Female; D005334:Fever / Q000453:epidemiology / Q000209:etiology* / Q000469:parasitology; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000453:epidemiology* / Q000469:parasitology / Q000503:physiopathology* / Q000635:transmission*; D008297:Male; D018512:Parasitemia / Q000453:epidemiology / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D015800:Protozoan Proteins / Q000097:blood*; D012720:Severity of Illness Index; D013636:Tanzania / Q000453:epidemiology
chemical_list: D000953:Antigens, Protozoan; C514457:HRP-2 antigen, Plasmodium falciparum; D015800:Protozoan Proteins