Determinants of brain swelling in pediatric and adult cerebral malaria.

Praveen K Sahu,Rajyabardhan Pattnaik,Sanjib Mohanty,Sameer Maharana,Anita Mohanty,Selasi Dankwa,Samuel C Wassmer,Jabamani Bage,Kami Kim,Megharay Majhi,Terrie E Taylor,Joseph D Smith,Stephen J Rogerson,Maria Vishnyakova,Lukas Pirpamer,Maria Bernabeu,John D Aitchison,Karl B Seydel,Angelika Hoffman,Fergal J Duffy,D Noah Sather,Wilson L Mandala ,Akshaya Kumar Mohanty ,Rashmi Ranjan Mohanty ,В И Вигдорович

doi:10.1172/jci.insight.145823

Abstract

Cerebral malaria (CM) affects children and adults, but brain swelling is more severe in children. To investigate features associated with brain swelling in malaria, we performed blood profiling and brain MRI in a cohort of pediatric and adult patients with CM in Rourkela, India, and compared them with an African pediatric CM cohort in Malawi. We determined that higher plasma Plasmodium falciparum histidine rich protein 2 (PfHRP2) levels and elevated var transcripts that encode for binding to endothelial protein C receptor (EPCR) were linked to CM at both sites. Machine learning models trained on the African pediatric cohort could classify brain swelling in Indian children CM cases but had weaker performance for adult classification, due to overall lower parasite var transcript levels in this age group and more severe thrombocytopenia in Rourkela adults. Subgrouping of patients with CM revealed higher parasite biomass linked to severe thrombocytopenia and higher Group A–EPCR var transcripts in mild thrombocytopenia. Overall, these findings provide evidence that higher parasite biomass and a subset of Group A–EPCR binding variants are common features in children and adult CM cases, despite age differences in brain swelling.

Highlights

Cerebral malaria (CM) is a severe neurovascular complication of Plasmodium falciparum infection characterized by impaired consciousness and seizures, as well as a fatality rate up to 20% even when appropriate clinical management is provided [1]
We previously studied a malaria cohort in Blantyre, Malawi, that had undergone MRI brain scans and found that comatose children presented with higher plasma levels of Plasmodium falciparum histidine rich protein 2 (PfHRP2), a biomarker of parasite biomass [38], and var transcripts encoding endothelial protein C receptor (EPCR) binders compared with children with UM [36]
Our findings indicate that patients with CM with mild or severe thrombocytopenia were distinguished by parasite biomass and Group A–EPCR binding var transcripts from patients with UM, both features were elevated in all patients with CM compared with UM cases

Summary

Introduction

Cerebral malaria (CM) is a severe neurovascular complication of Plasmodium falciparum infection characterized by impaired consciousness and seizures, as well as a fatality rate up to 20% even when appropriate clinical management is provided [1]. Brain autopsy studies in African children have revealed microvascular leak, fibrin deposits, and thrombosis associated with sequestered pRBCs [7,8,9,10]. MRI studies in both children and adults have provided evidence for vasogenic edema resulting from a breakdown of the blood-brain barrier [14,15,16,17]. These autopsy and neuroimaging findings reveal heterogeneity in CM features between children and adults, despite having in common abundant sequestration of pRBCs within the brain microvasculature

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Conclusion