Identification of inflammatory biomarkers for pediatric malarial anemia severity using novel statistical methods
John M Ong'echa1, Gregory C Davenport, John M Vulule
1University of New Mexico Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kenya Medical Research Institute, P.O. Box 1578, 40100, Kisumu, Kenya. michaelongecha@yahoo.com
Insights
Severe malarial anemia (SMA) in children is linked to inflammation. Interleukin-12p70 (IL-12p70) and Interferon-gamma (IFN-γ) predict higher hemoglobin, while IL-13 and eotaxin indicate more severe anemia in Plasmodium falciparum malaria.
Area of Science:
- Immunology
- Pediatrics
- Infectious Diseases
Background:
- Pediatric severe malarial anemia (SMA) is a major cause of mortality in holoendemic Plasmodium falciparum transmission areas.
- Inflammatory mediator production is implicated in the pathogenesis of SMA.
- Identifying reliable biomarkers for SMA is crucial for understanding and managing the condition.
Purpose of the Study:
- To identify inflammatory biomarkers associated with malarial anemia in children.
- To investigate the relationship between specific inflammatory mediators and hemoglobin levels in children with Plasmodium falciparum malaria.
Main Methods:
- A Luminex hu25-plex array was used to quantify 25 inflammatory mediators in children with uncomplicated malaria, non-SMA, and SMA.
- Least-angle regression (LAR) and multiple linear regression analyses were employed to identify predictive biomarkers for hemoglobin levels, controlling for confounding factors.
Main Results:
- Interleukin-12p70 (IL-12p70) and Interferon-gamma (IFN-γ) were identified as positive predictors of hemoglobin levels.
- Interleukin-2 receptor (IL-2R), IL-13, and eotaxin were negatively associated with hemoglobin levels, indicating a role in promoting anemia.
- The IL-12p70/IFN-γ pathway predicted elevated Hb, while the IL-13/eotaxin pathway was linked to more profound anemia.
Conclusions:
- The IL-12p70/IFN-γ pathway serves as a biomarker for predicting higher hemoglobin levels in children with falciparum malaria.
- The IL-13/eotaxin pathway is associated with the development of more severe anemia in this population.
- These findings highlight distinct inflammatory pathways influencing anemia severity in pediatric malaria.
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-α], 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.