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Determinants of brain swelling in pediatric and adult cerebral malaria
Praveen K. Sahu, … , Maria Bernabeu, Samuel C. Wassmer
Praveen K. Sahu, … , Maria Bernabeu, Samuel C. Wassmer
Published September 22, 2021
Citation Information: JCI Insight. 2021;6(18):e145823. https://doi.org/10.1172/jci.insight.145823.
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Research Article Infectious disease Microbiology

Determinants of brain swelling in pediatric and adult cerebral malaria

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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.

Authors

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

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Figure 3

Characterization of parasite var transcript profiles by qPCR analysis.

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Characterization of parasite var transcript profiles by qPCR analysis.
(...
(A) Tukey box and whisker plots showing var domain transcript expression in CM (n = 19) and UM (n = 8) patients (top), brain swelling patients (BS+, score > 1, n = 16) (middle), as well as pediatric (n = 9) and adult (n = 12) CM and/or BS cases. Individual or summed primer groups (#) are shown: DC8# (CIDRα1) = CIDRα1.1, CIDRα1.8a, and CIDRα1.8b (n = 3); Group A# (CIDRα1) = CIDRα1.4/6, CIDRα1.5a, CIDRα1.5b, CIDRα1.6, CIDRα1.7 (n = 5); Group B/C# = DBLα0.1, DBLα0.6/9, CIDRα2/3/5/6/7/9/10, CIDRα2.2, and DBLα0.16 (n = 5). The horizontal line is the median, and boxes indicate quartiles. Outliers are indicated as circles. Significance was determined by Mann-Whitney U test. *P < 0.05. (B) Stacked bar graph showing functional annotation of DBLα tags in pediatric and adult patients measured by NGS. See also Figure 2. (C) Left: Proportion of var subgroup abundance in 7 annotated reference genomes (28). Right: Proportional expression of var subgroups measured by qPCR and NGS across patient subgroups in CMBS+ (n = 8), adult CM (n = 8), adult BS+ (n = 5). (D) Average of the summed var transcript levels measured by qPCR (var Tu) for each var subtype across patients in (C).

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