Pediatric Cerebral Malaria

Kazura

Front. Cell. Infect. Microbiol.

2023

Malaria is a parasitic disease of global health significance and a leading cause of death in children living in endemic regions. Although various Plasmodium species are responsible for the disease, Plasmodium falciparum infection accounts for most severe cases of the disease in humans. The mechanisms of cerebral malaria pathogenesis have been studied extensively in humans and animal malaria models; however, it is far from being fully understood. Recent discoveries indicate a potential role of bradykinin and the kallikrein kinin system in the pathogenesis of cerebral malaria. The aim of this review is to highlight how bradykinin is formed in cerebral malaria and how it may impact cerebral blood-brain barrier function. Areas of interest in this context include Plasmodium parasite enzymes that directly generate bradykinin from plasma protein precursors, cytoadhesion of P. falciparum infected red blood cells to brain endothelial cells, and endothelial cell blood-brain barrier disruption.

Section: Influence Of Bradykinin On Plasmodium Growthmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Is there a role for bradykinin in cerebral malaria pathogenesis?

Kazura

Front. Cell. Infect. Microbiol.

2023

“…Multiple rosettes cause the blockage of small blood vessels in the brain [ 9 , 10 ], known as cerebral malaria. In fact, most malaria deaths amongst children in Africa are due to cerebral malaria [ 11 , 12 ]. The pathogenesis of this severe form of malaria remains poorly understood, and treatment options are lacking [ 5 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Population-specific positive selection on low CR1 expression in malaria-endemic regions

et al. 2023

Complement Receptor Type 1 (CR1) is a malaria-associated gene that encodes a transmembrane receptor of erythrocytes and is crucial for malaria parasite invasion. The expression of CR1 contributes to the rosetting of erythrocytes in the brain bloodstream, causing cerebral malaria, the most severe form of the disease. Here, we study the history of adaptation against malaria by analyzing selection signals in the CR1 gene. We used whole-genome sequencing datasets of 907 healthy individuals from malaria-endemic and non-endemic populations. We detected robust positive selection in populations from the hyperendemic regions of East India and Papua New Guinea. Importantly, we identified a new adaptive variant, rs12034598, which is associated with a slower rate of erythrocyte sedimentation and is linked with a variant associated with low levels of CR1 expression. The combination of the variants likely drives natural selection. In addition, we identified a variant rs3886100 under positive selection in West Africans, which is also related to a low level of CR1 expression in the brain. Our study shows the fine-resolution history of positive selection in the CR1 gene and suggests a population-specific history of CR1 adaptation to malaria. Notably, our novel approach using population genomic analyses allows the identification of protective variants that reduce the risk of malaria infection without the need for patient samples or malaria individual medical records. Our findings contribute to understanding of human adaptation against cerebral malaria.

“…Clinical disease is classi ed as either uncomplicated or severe (2). Cerebral malaria (CM) is the severe malaria syndrome with the highest mortality risk (3). CM is clinically de ned as an otherwise unexplained coma in someone with asexual Plasmodium parasitemia.…”

Section: Introductionmentioning

confidence: 99%

Repeated blood lactate measurements during clinical care of children with cerebral malaria

Olowojesiku

Sherman

Mukadam

et al. 2023

Preprint

Background Admission blood lactate has previously guided therapy and is a valid estimator of prognosis in children with cerebral malaria (CM). Since bolus intravenous fluid administration to children with febrile coma and signs of hypovolemia (including high blood lactate) may be harmful, the use of blood lactate to guide therapy has waned. Its utility as a prognostic biomarker, either at admission or during hospitalization, remains unclear. Methods We performed a retrospective cohort study of 1674 Malawian children with CM hospitalized from 2000–2018 who had blood lactate measurements every 6 hours for the first 24 hours. We evaluated the strength of association between admission lactate or values measured at any time point in the first 24 hours post-admission, and outcomes (death or neurologic disability in survivors). We assessed the optimal duration of lactate monitoring of children with CM. Results When lactate is analyzed as a continuous variable, children with CM who have higher values at admission have a 1.05-fold higher odds (95% CI: 0.99–1.11) of death compared to those with lower lactate values. Children with higher blood lactate at 6 hours have 1.16-fold higher odds (95% CI: 1.09–1.23) of death, compared to those with lower values. If lactate levels are dichotomized into hyperlactatemic (lactate > 5.0 mmol/L) or not, the strength of association between admission lactate and death increases (OR = 2.49, 95% CI: 1.47–4.22). Neither blood lactate levels obtained after 18 hours post-admission nor trends in lactate concentrations during the first 24 hours of admission are associated with outcomes. Blood lactate during hospitalization is not associated with adverse neurologic outcomes in CM survivors. Conclusions In children with CM, blood lactate is associated with death but not neurologic morbidity in survivors. To comprehensively estimate prognosis, blood lactate in children with CM should be assessed at admission and for 18 hours afterwards.