title: Dysregulation of the haem-haemopexin axis is associated with severe malaria in a case-control study of Ugandan children.
abstract: BACKGROUND
  Malaria is associated with haemolysis and the release of plasma haem. Plasma haem can cause endothelial injury and organ dysfunction, and is normally scavenged by haemopexin to limit toxicity. It was hypothesized that dysregulation of the haem-haemopexin pathway contributes to severe and fatal malaria infections.
  
  
  METHODS
  Plasma levels of haemin (oxidized haem), haemopexin, haptoglobin, and haemoglobin were quantified in a case-control study of Ugandan children with Plasmodium falciparum malaria. Levels at presentation were compared in children with uncomplicated malaria (UM; n = 29), severe malarial anaemia (SMA; n = 27) or cerebral malaria (CM; n = 31), and evaluated for utility in predicting fatal (n = 19) vs non-fatal (n = 39) outcomes in severe disease. A causal role for haemopexin was assessed in a pre-clinical model of experimental cerebral malaria (ECM), following disruption of mouse haemopexin gene (hpx). Analysis was done using Kruskall Wallis tests, Mann-Whitney tests, log-rank tests for survival, and repeated measures ANOVA.
  
  
  RESULTS
  In Ugandan children presenting with P. falciparum malaria, haemin levels were higher and haemopexin levels were lower in SMA and CM compared to children with UM (haemin, p < 0.01; haemopexin, p < 0.0001). Among all cases of severe malaria, elevated levels of haemin and cell-free haemoglobin at presentation were associated with subsequent mortality (p < 0.05). Compared to ECM-resistant BALB/c mice, susceptible C57BL/6 mice had lower circulating levels of haemopexin (p < 0.01), and targeted deletion of the haemopexin gene, hpx, resulted in increased mortality compared to their wild type littermates (p < 0.05).
  
  
  CONCLUSIONS
  These data indicate that plasma levels of haemin and haemopexin measured at presentation correlate with malaria severity and levels of haemin and cell-free haemoglobin predict outcome in paediatric severe malaria. Mechanistic studies in the ECM model support a causal role for the haem-haemopexin axis in ECM pathobiology.
authors.affiliation: Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, ON, Canada. robyn.elphinstone@mail.utoronto.ca.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. robyn.elphinstone@mail.utoronto.ca.|Tropical Disease Unit, Department of Medicine, University of Toronto, Toronto, ON, Canada. robyn.elphinstone@mail.utoronto.ca.
authors.forename: Robyn E
authors.initials: RE
authors.lastname: Elphinstone
authors.affiliation: Infectious Disease Unit, Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA. friley@mgh.harvard.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: Riley
authors.affiliation: Infectious Disease Unit, Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA. tlin7@mgh.harvard.edu.
authors.forename: Tian
authors.initials: T
authors.lastname: Lin
authors.affiliation: Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, ON, Canada. sjhiggin@bidmc.harvard.edu.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. sjhiggin@bidmc.harvard.edu.|Tropical Disease Unit, Department of Medicine, University of Toronto, Toronto, ON, Canada. sjhiggin@bidmc.harvard.edu.
authors.forename: Sarah
authors.initials: S
authors.lastname: Higgins
authors.affiliation: Makerere University College of Health Sciences, Kampala, Uganda. adhabangi@gmail.com.
authors.forename: Aggrey
authors.initials: A
authors.lastname: Dhabangi
authors.affiliation: Makerere University College of Health Sciences, Kampala, Uganda. jxyug@yahoo.com.
authors.forename: Charles
authors.initials: C
authors.lastname: Musoke
authors.affiliation: Laboratory Medicine Program (Transfusion Medicine), University Health Network/University of Toronto, Toronto, ON, Canada. christine.cserti@uhn.ca.
authors.forename: Christine
authors.initials: C
authors.lastname: Cserti-Gazdewich
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, USA. raymond.regan@jefferson.edu.
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Regan
authors.affiliation: Infectious Disease Unit, Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA. warren@helix.mgh.harvard.edu.
authors.forename: H Shaw
authors.initials: HS
authors.lastname: Warren
authors.affiliation: Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, Toronto, ON, Canada. kevin.kain@uhn.ca.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. kevin.kain@uhn.ca.|Tropical Disease Unit, Department of Medicine, University of Toronto, Toronto, ON, Canada. kevin.kain@uhn.ca.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D006242:Haptoglobins / Q000032:analysis; D006418:Heme / Q000032:analysis*; D006454:Hemoglobins / Q000032:analysis; D006466:Hemopexin / Q000032:analysis*; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010949:Plasma / Q000737:chemistry; D011446:Prospective Studies; D016019:Survival Analysis; D014454:Uganda / Q000453:epidemiology
chemical_list: D006242:Haptoglobins; D006454:Hemoglobins; D006418:Heme; D006466:Hemopexin