40 We did not assess the presence of malarial retinopathy, which

increases the specificity of the diagnosis of CM, 21 however CM subjects were a relatively small subgroup and amongst those with highest sequestered biomass estimates. Finally, the mortality rate in our study was only 3.9% in SM cases, which might indicate that the children were ‘less’ seriously ill than our SM definitions suggest, but is also consistent with the lower risk of mortality in children, 27 the proportions of Anticancer Compound Library manufacturer different SM syndromes in our study, 2 exclusion of children suspected to have non-malarial illness, 28 and with our subjects living relatively close to the health-care facilities. 28 and 49 After considering methodological issues and these sources of bias we believe our findings are robust. How should our results be interpreted? Although the number of children with SA was small, the association with high PfHRP2 concentration is consistent with other studies,30 and 40 and extensive sequestration could be a causative factor in SA. This would not necessarily require

sequestration in the microvasculature, since retention of parasites in the slow open circulation of the spleen would also remove pRBCs from Carfilzomib purchase Grape seed extract the systemic circulation,50 and could explain this observation. Furthermore, we speculate that the role of microvascular obstruction by sequestered pRBCs in SM pathophysiology may differ between

the SM syndromes of LA, CM, and SA, and possibly between children and adults. Differences in the pathophysiology of LA and CM are consistent with distinct patterns of risk relative to exposure and age,51 additive effects on the risk of mortality,16 and differences in the associated pRBC adhesion phenotypes.52 LA in malaria is thought to be due to microcirculatory impairment and consequent tissue hypoxia.6 and 11 A recent study demonstrated impairment of the ability of the microvasculature to increase tissue oxygen delivery to match demand in severe malaria, and the severity of this impairment correlated strongly with blood lactate.53 Different host and parasite factors may pre-dispose to sequestration-independent microcirculatory dysfunction in LA (perhaps mediated by inflammatory cytokines, hypoargininemia and nitric oxide depletion),11 and 26 whereas pRBC sequestration may be more important in CM. Both mechanisms may have synergistic effects when LA and CM co-exist.