Authors

Robyn E Elphinstone, Sandra Rotman Centre for Global Health, University Health Network-Toronto, General Hospital, Toronto, ON; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON; Tropical Disease Unit, Department of Medicine, University of Toronto, Toronto, ON
Frank Riley, Infectious Disease Unit, Department of Pediatrics, Massachusetts General Hospital, Boston, MA
Tian Lin, Infectious Disease Unit, Department of Pediatrics, Massachusetts General Hospital, Boston, MA
Sarah Higgins, Sandra Rotman Centre for Global Health, University Health Network-Toronto, General Hospital, Toronto, ON; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON; Tropical Disease Unit, Department of Medicine, University of Toronto, Toronto, ON
Aggrey Dhabangi, Makerere University, College of Health Sciences, Kampala, Uganda
Charles Musoke, Makerere University, College of Health Sciences, Kampala, Uganda
Christine Cserti-Gazdewich, Laboratory Medicine Program (Transfusion Medicine), University Health Network, University of Toronto, Toronto, ON
Raymond F. Regan, Department of Emergency Medicine, Thomas Jefferson UniversityFollow
H Shaw Warren, Infectious Disease Unit, Department of Pediatrics, Massachusetts General Hospital, Boston, MA
Kevin C Kain, Sandra Rotman Centre for Global Health, University Health Network-Toronto, General Hospital, Toronto, ON; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON; Tropical Disease Unit, Department of Medicine, University of Toronto, Toronto, ON

Document Type

Article

Publication Date

12-21-2015

Comments

This article has been peer reviewed. It was published in: Malaria Journal.

Volume 14, Issue 1, 21 December 2015, Article number 511.

The published version is available at DOI: 10.1186/s12936-015-1028-1

Copyright © 2015 Elphinstone et al.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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.

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