Endotoxaemia is common in children with Plasmodium falciparummalaria

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.

Invasive bacterial co-infection in African children with Plasmodium falciparum malaria: a systematic review

“…This may precipitate injury and impaired gut barrier function either directly or indirectly through local cytokine production, with the subsequent transfer of endotoxin and/or pathogenic bacteria into the blood stream. We have recently shown that endotoxemia is common in SM (28%) and results in temporary immune paralysis similar to that observed in patients with sepsis and experimentally-induced endotoxemia [63]. We hypothesized that the most likely origin of endotoxin was from the gut.…”

Mast cells and histamine alter intestinal permeability during malaria parasite infection

“…Further, our observations of ileal mastocytosis in a non-human primate model suggest that mast cells may be cause-and-effect with GI permeability in human malaria. Antihistamine therapy showed a trend toward reduced GI permeability and bacterial translocation in the mouse, suggesting that other mast cell-derived factors likely contribute to GI permeability to resident microbiota, bacterial pathogens, and perhaps ligands such as lipopolysaccharide or peptidoglycan in malaria (Olupot-Olupot et al, 2013). …”

Malaria Prevalence among Young Infants in Different Transmission Settings, Africa

“…Thus, the challenge is that young infants are not adequately protected against malaria because of their limited coverage by current preventive strategies, such as seasonal malaria chemoprevention and intermittent preventive treatment during infancy, which are not widely implemented. This inadequate coverage is critical because our findings show that young infants can be affected by malaria and subsequently become anemic, which would also potentially increase their vulnerability to other pathogens ( 32 ). Other interventions, such as the RTS,S/AS01 malaria vaccine, which will soon be registered for use, resulted in modest protection against clinical malaria in this age group and did not have any effect on preventing anemia ( 33 ).…”