The systemic pathology of cerebral malaria in African children

Abstract

Pediatric cerebral malaria carries a high mortality rate in sub-Saharan Africa. We present our systematic analysis of the descriptive and quantitative histopathology of all organs sampled from a series of 103 autopsies performed between 1996 and 2010 in Blantyre, Malawi on pediatric cerebral malaria patients and control patients (without coma, or without malaria infection) who were clinically well characterized prior to death. We found brain swelling in all cerebral malaria patients and the majority of controls. The histopathology in patients with sequestration of parasites in the brain demonstrated two patterns: (a) the “classic” appearance (i.e., ring hemorrhages, dense sequestration, and extra-erythrocytic pigment) which was associated with evidence of systemic activation of coagulation and (b) the “sequestration only” appearance associated with shorter duration of illness and higher total burden of parasites in all organs including the spleen. Sequestration of parasites was most intense in the gastrointestinal tract in all parasitemic patients (those with cerebral malarial and those without).

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

“…However, in a small autopsy series of pediatric and adult with CM, cleaved caspase-3, the terminal effector of apoptosis pathways, was seen in >70% of brain endothelial cells examined. 136 The presence of ring hemorrhages around cerebral microvessels at autopsy, 53 or as part of the retinopathy observed in patients 137 would also be compatible with the occurrence of endothelial cell death. Indeed, the high levels of circulating nucleosomes of both parasite and human origins detected in the plasma of patients with severe falciparum malaria, compared with the much lower levels detected in septic patients, 138 would suggest that cell death in this infection may be more extensive than previously appreciated.…”

“…Based on histopathological 53 and transmission electron microscopy 26 studies of postmortem tissues, generalized endothelial cell death is not a prominent feature of acute falciparum malaria, consistent with the largely reversible nature of neurologic dysfunction in those that survive the infection. However, in a small autopsy series of pediatric and adult with CM, cleaved caspase-3, the terminal effector of apoptosis pathways, was seen in >70% of brain endothelial cells examined.…”

“…50 Detailed histopathological studies of human postmortem tissues performed in the past 3 decades show that sequestration is in fact widespread in infected patients, and the degree and organ specificity of sequestration correlated with clinical manifestations. [50][51][52][53] More recently, obstruction of the microcirculation that is reversed after anti-malarial therapy has also been documented in vivo in acutely infected patients. 25 Sequestration results from the adhesion, or cytoadherence, of IRBC to vascular endothelial cells, and the process is mediated by the variant parasite ligand Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on the surface of IRBC, and endothelial receptors, of which a number have been implicated.…”

Cerebrospinal fluid markers to distinguish bacterial meningitis from cerebral malaria in children

“…Definition of CM: although archive CSF samples were used, i have strong reservation with the criteria used in defining CM cases. They may need to include this as a limitation and cite recent papers on CM classification in addition to Milner 2014(Beare , 2011, Severe Malaria, et al, et al 2014, Seydel , 2015 Overlap of the figures removed in Figure S1 -the CM group has been excluded for clarity …”

“…They may need to include this as a limitation and cite recent papers on CM classification in addition to Milner 2014(Beare , 2011, Severe Malaria, et al, et al 2014, Seydel , 2015 ) et al , KEMRI-Wellcome Trust, Kenya James Njunge…”