Abstract
BackgroundChildren presenting to hospital with recent or current Plasmodium falciparum malaria are at increased the risk of invasive bacterial disease, largely enteric gram-negative organisms (ENGO), which is associated with increased mortality and recurrent morbidity. Although incompletely understood, the most likely source of EGNO is the bowel. We hypothesised that as a result of impaired gut-barrier function endotoxin (lipopolysaccharide), present in the cell-wall of EGNO and in substantial quantities in the gut, is translocated into the bloodstream, and contributes to the pathophysiology of children with severe malaria.MethodsWe conducted a prospective study in 257 children presenting with malaria to two hospitals in Kenya and Uganda. We analysed the clinical presentation, endotoxin and cytokine concentration.ResultsEndotoxaemia (endotoxin activity ≥0.4 EAA Units) was observed in 71 (27.6%) children but its presence was independent of both disease severity and outcome. Endotoxaemia was more frequent in children with severe anaemia but not specifically associated with other complications of malaria. Endotoxaemia was associated with a depressed inflammatory and anti-inflammatory cytokine response. Plasma endotoxin levels in severe malaria negatively correlated with IL6, IL10 and TGFβ (Spearman rho: TNFα: r=−0.122, p=0.121; IL6: r=−0.330, p<0.0001; IL10: r=−0.461, p<0.0001; TGFβ: r=−0.173, p<0.027).ConclusionsEndotoxaemia is common in malaria and results in temporary immune paralysis, similar to that observed in patients with sepsis and experimentally-induced endotoxaemia. Intense sequestration of P. falciparum-infected erythrocytes within the endothelial bed of the gut has been observed in pathological studies and may lead to gut-barrier dysfuction. The association of endotoxaemia with the anaemia phenotype implies that it may contribute to the dyserythropoesis accompanying malaria through inflammation. Both of these factors feasibly underpin the susceptibility to EGNO co-infection. Further research is required to investigate this initial finding, with a view to future treatment trials targeting mechanism and appropriate antimicrobial treatment.
Highlights
Children presenting to hospital with recent or current Plasmodium falciparum malaria are at increased the risk of invasive bacterial disease, largely enteric gram-negative organisms (ENGO), which is associated with increased mortality and recurrent morbidity
In the group with severe malaria, Kenyan children were older, had a higher prevalence of impaired consciousness and a lower prevalence of severe anaemia or respiratory distress compared to children recruited from Mbale Regional Referral Hospital (MRRH), as expected in areas of lower transmission intensity (Table 2)
Children with malaria have elevated concentration of endotoxin in their blood Endotoxaemia (EAA≥0.4) was detected in 16 (31.4%) children with non-severe malaria, 15 (28.3%) children with severe malaria but not detected in any of the 25 healthy children recruited as a control group
Summary
Children presenting to hospital with recent or current Plasmodium falciparum malaria are at increased the risk of invasive bacterial disease, largely enteric gram-negative organisms (ENGO), which is associated with increased mortality and recurrent morbidity. We hypothesised that as a result of impaired gut-barrier function endotoxin (lipopolysaccharide), present in the cell-wall of EGNO and in substantial quantities in the gut, is translocated into the bloodstream, and contributes to the pathophysiology of children with severe malaria. Endotoxin is a complex lipopolysaccharide (LPS) present in the cell walls of gram-negative bacteria and in substantial quantities in the bowel, and a potent trigger of innate immunity due to activation of Toll Like Receptor (TLR) signalling [1]. In adults with critical illness, recent studies have shown that endotoxaemia is associated with mortality, organ failure and prolonged intensive care unit admission [4]. Endotoxaemia has been associated with more severe illness requiring admission to intensive care, severity or duration of illness but not mortality [5,6]
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