Abstract
BackgroundCerebral malaria (CM) causes a rapidly developing coma, and remains a major contributor to morbidity and mortality in malaria-endemic regions. This study sought to determine the relationship between cerebrospinal fluid (CSF) Plasmodium falciparum histidine rich protein-2 (PfHRP-2) and clinical, laboratory and radiographic features in a cohort of children with retinopathy-positive CM.MethodsPatients included in the study were admitted (2009–2013) to the Pediatric Research Ward (Queen Elizabeth Central Hospital, Blantyre, Malawi) meeting World Health Organization criteria for CM with findings of malarial retinopathy. Enzyme-linked immunosorbent assay was used to determine plasma and CSF PfHRP-2 levels. Wilcoxon rank-sum tests and multivariable logistic regression analysis assessed the association of clinical and radiographic characteristics with the primary outcome of death during hospitalization.ResultsIn this cohort of 94 patients, median age was 44 (interquartile range 29–62) months, 53 (56.4%) patients were male, 6 (7%) were HIV-infected, and 10 (11%) died during hospitalization. Elevated concentrations of plasma lactate (p = 0.005) and CSF PfHRP-2 (p = 0.04) were significantly associated with death. On multivariable analysis, higher PfHRP-2 in the CSF was associated with death (odds ratio 9.00, 95% confidence interval 1.44–56.42) while plasma PfHRP-2 was not (odds ratio 2.05, 95% confidence interval 0.45–9.35).ConclusionsElevation of CSF, but not plasma PfHRP-2, is associated with death in this paediatric CM cohort. PfHRP-2 egress into the CSF may represent alteration of blood brain barrier permeability related to the sequestration of parasitized erythrocytes in the cerebral microvasculature.
Highlights
Cerebral malaria (CM) causes a rapidly developing coma, and remains a major contributor to morbidity and mortality in malaria-endemic regions
Additional pathological findings include concentrated intravascular haemozoin in regions of sequestration, and evidence of blood brain barrier (BBB) breakdown, associated with perivascular ring haemorrhages distributed in the subcortical white matter, corpus callosum, basal ganglia and the cerebellum [12]
After adjusting for age, abnormal white blood cell (WBC) count on admission, and abnormal lactate, higher levels of cerebrospinal fluid (CSF) Plasmodium falciparum histidine rich protein-2 (PfHRP-2) were associated with increased odds of in-hospital death while plasma PfHRP-2 and the CSF/plasma PfHRP-2 ratio were not associated with mortality (Table 4)
Summary
Cerebral malaria (CM) causes a rapidly developing coma, and remains a major contributor to morbidity and mortality in malaria-endemic regions. In an autopsy study of paediatric patients with CM, diffuse axonal and myelin damage in the brain parenchyma was present in cases where there was prominent infected erythrocyte sequestration [11]. Additional pathological findings include concentrated intravascular haemozoin in regions of sequestration, and evidence of blood brain barrier (BBB) breakdown, associated with perivascular ring haemorrhages distributed in the subcortical white matter, corpus callosum, basal ganglia and the cerebellum [12]. Neuroimaging studies have shown evidence of various patterns of parenchymal damage in CM patients, involving the basal ganglia, supratentorial white matter, brainstem and cerebral cortex [13,14,15,16]. Parasites are not seen within the brain parenchyma, and the cause of changes that lead to brain swelling, with neurological damage and death in some patients, is incompletely understood. Identification of Plasmodium-specific biological markers in the cerebrospinal fluid (CSF) may further elucidate mechanisms underlying the pathogenesis of CM
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