How Severe Anaemia Might Influence the Risk of Invasive Bacterial Infections in African Children

Abstract

Severe anaemia and invasive bacterial infections are common causes of childhood sickness and death in sub-Saharan Africa. Accumulating evidence suggests that severely anaemic African children may have a higher risk of invasive bacterial infections. However, the mechanisms underlying this association remain poorly described. Severe anaemia is characterized by increased haemolysis, erythropoietic drive, gut permeability, and disruption of immune regulatory systems. These pathways are associated with dysregulation of iron homeostasis, including the downregulation of the hepatic hormone hepcidin. Increased haemolysis and low hepcidin levels potentially increase plasma, tissue and intracellular iron levels. Pathogenic bacteria require iron and/or haem to proliferate and have evolved numerous strategies to acquire labile and protein-bound iron/haem. In this review, we discuss how severe anaemia may mediate the risk of invasive bacterial infections through dysregulation of hepcidin and/or iron homeostasis, and potential studies that could be conducted to test this hypothesis.

Keywords: E. coli; Haemophilus; Mendelian randomization; Salmonella; Staphylococcus; Streptococcus; bacteraemia; hepcidin; iron; severe anaemia.

Figure 1

The link between severe anaemia and bacteraemia. Severe anaemia may increase the risk of invasive bacterial infections through several interlinking pathways including increased erythropoietic drive, haemolysis, immune dysfunction, and gut permeability. In both haemolytic and non-haemolytic severe anaemia, elevated erythropoietic drive increases erythroferrone levels, reducing hepcidin, and altering macrophage iron sequestration. This increases iron availability for invading bacterial pathogens. Haemolysis increases the levels of non-transferrin-bound iron, free haem, and haem oxygenase-1 (HO-1), which are associated with immune dysfunction and dysregulation of iron homeostasis.

Figure 2

The severe anaemia-bacteraemia hypothesis. Children with severe anaemia may have increased gut permeability promoting the invasion of pathogenic bacteria from the gut lumen (1); haemolysis, which increases the availability of haem and non-transferrin bound iron (NTBI) for extracellular and intracellular organisms (2); increased erythropoietic drive, which inhibits the antimicrobial hepcidin allowing increased availability of iron for extracellular bacteria and movement of iron into the Salmonella containing vacuole (SCV) (3); and immune dysregulation including the inhibition of recruitment and effector function of immune cells such as neutrophils or production of pro-inflammatory cytokines such as interferon-gamma (IFN-γ) (4). TfR denotes transferrin receptor; ERFE: Erythroferrone; HO-1: Haem oxygenase-1; Cp: Ceruloplasmin; ROS: Reactive oxygen species; FPN: Ferroportin; IL-10: Interleukin-10; FR: Ferric reductase; Heph: Hephaestin; HCP-1: Haem carrier protein-1; and DMT-1: Divalent metal transporter-1. Black arrows indicate increased activity; red arrows, inhibitory pathways; and dotted lines, suppressed activity.