Identification of inflammatory biomarkers for pediatric malarial: Anemia severity using novel statistical methods

Abstract

Areas where Plasmodium falciparum transmission is holoendemic are characterized by high rates of pediatric severe malarial anemia (SMA) and associated mortality. Although the etiology of SMA is complex and multifactorial, perturbations in inflammatory mediator production play an important role in the pathogenic process. As such, the current study focused on identification of inflammatory biomarkers in children with malarial anemia. Febrile children (3 to 30 months of age) presenting at Siaya District Hospital in western Kenya underwent a complete clinical and hematological evaluation. Children with falciparum malaria and no additional identifiable anemia-promoting coinfections were stratified into three groups: uncomplicated malaria (hemoglobin [Hb] levels of >11.0 g/dl; n = 31), non-SMA (Hb levels of 6.0 to 10.9 g/dl; n = 37), and SMA (Hb levels of <6.0 g/dl; n = 80). A Luminex hu25-plex array was used to determine potential biomarkers (i.e., interleukin 1β [IL-1β], IL-1 receptor antagonist [IL-1Ra], IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-15, IL-17, tumor necrosis factor alpha [TNF-α], alpha interferon [IFN-γ], IFN-γ, granulocyte-macrophage colony-stimulating factor [GM-CSF], macrophage inflammatory protein 1 alpha [MIP-1α], MIP-1β, IFN-inducible protein of 10 kDa [IP-10], monokine induced by IFN-γ-[MIG],-eotaxin,-RANTES,-and-monocyte-chemoattractant-protein-1-[MCP-1])-in-samples-obtained-prior-to-any-treatment-interventions.-To-determine-the-strongest-biomarkers-of-anemia,-a-parsimonious-set-of-predictor-variables-for-Hb-was-generated-by-least-angle-regression-(LAR)-analysis,-controlling-for-the-confounding-effects-of-age,-gender,-glucose-6-phosphate-dehydrogenase-(G6PD)-deficiency,-and-sickle-cell-trait,-followed-by-multiple-linear-regression-analyses.-IL-12p70-and-IFN-γ-emerged-as-positive-predictors-of-Hb,-while-IL-2R,-IL-13,-and-eotaxin-were-negatively-associated-with-Hb.-The-results-presented-here-demonstrate-that-the-IL-12p70/IFN-γ-pathway-represents-a-set-of-biomarkers-that-predicts-elevated-Hb-levels-in-children-with-falciparum-malaria,-while-activation-of-the-IL-13/eotaxin-pathway-favors-more-profound-anemia. © 2011, American Society for Microbiology.