Plasma cell-free DNA predicts pediatric cerebral malaria severity

Vera, Iset Medina; Kessler, Anne; Ting, Li-Min; Harawa, Visopo; Keller, Thomas H.; Allen, D M; Njie, Madi; Moss, McKenze; Soko, Monica; Ahmadu, A. A.; Kadwala, Innocent; Ray, Stephen; Nyirenda, Tonney S.; Mandala, Wilson L.; Taylor, Terrie E.; Rogerson, Stephen J.; Seydel, Karl B.; Kim, Kami

doi:10.1172/jci.insight.136279

Cited by 15 publications

(15 citation statements)

References 62 publications

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“…However, in this study, samples were collected after death. Finally, a recent study reported higher levels of IL-8 in retinopathy-positive CM children who died than in survivors and UM children, similar to our results [ 51 ]. The authors claim that retinopathy diagnosis improves clinical CM specificity, as it is related to iRBC sequestration in brain.…”

Section: Discussionsupporting

confidence: 92%

Elevated plasma interleukin-8 as a risk factor for mortality in children presenting with cerebral malaria

Royo

Vianou²,

Kinkpé³

et al. 2023

Infect Dis Poverty

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Background Cerebral malaria (CM) is a neuropathology which remains one of the deadliest forms of malaria among African children. The kinetics of the pathophysiological mechanisms leading to neuroinflammation and the death or survival of patients during CM are still poorly understood. The increasing production of cytokines, chemokines and other actors of the inflammatory and oxidative response by various local actors in response to neuroinflammation plays a major role during CM, participating in both the amplification of the neuroinflammation phenomenon and its resolution. In this study, we aimed to identify risk factors for CM death among specific variables of inflammatory and oxidative responses to improve our understanding of CM pathogenesis. Methods Children presenting with CM (n = 70) due to P. falciparum infection were included in southern Benin and divided according to the clinical outcome into 50 children who survived and 20 who died. Clinical examination was complemented by fundoscopic examination and extensive blood biochemical analysis associated with molecular diagnosis by multiplex PCR targeting 14 pathogens in the patients’ cerebrospinal fluid to rule out coinfections. Luminex technology and enzyme immunoassay kits were used to measure 17 plasma and 7 urinary biomarker levels, respectively. Data were analysed by univariate analysis using the nonparametric Mann‒Whitney U test and Pearson’s Chi2 test. Adjusted and multivariate analyses were conducted separately for plasma and urinary biomarkers to identify CM mortality risk factors. Results Univariate analysis revealed higher plasma levels of tumour necrosis factor (TNF), interleukin-1beta (IL-1β), IL-10, IL-8, C-X-C motif chemokine ligand 9 (CXCL9), granzyme B, and angiopoietin-2 and lower urinary levels of prostanglandine E2 metabolite (PGEM) in children who died compared to those who survived CM (Mann–Whitney U-test, P-values between 0.03 and < 0.0001). The multivariate logistic analysis highlighted elevated plasma levels of IL-8 as the main risk factor for death during CM (adjusted odd ratio = 14.2, P-value = 0.002). Values obtained during follow-up at D3 and D30 revealed immune factors associated with disease resolution, including plasma CXCL5, C–C motif chemokine ligand 17 (CCL17), CCL22, and urinary 15-F2t-isoprostane. Conclusions The main risk factor of death during CM was thus elevated plasma levels of IL-8 at inclusion. Follow-up of patients until D30 revealed marker profiles of disease aggravation and resolution for markers implicated in neutrophil activation, endothelium activation and damage, inflammatory and oxidative response. These results provide important insight into our understanding of CM pathogenesis and clinical outcome and may have important therapeutic implications. Graphical Abstract

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Section: Discussionsupporting

confidence: 92%

Elevated plasma interleukin-8 as a risk factor for mortality in children presenting with cerebral malaria

Royo

Vianou²,

Kinkpé³

et al. 2023

Infect Dis Poverty

View full text Add to dashboard Cite

show abstract

“…However, in this study, samples were collected after death. Finally, a recent study reported higher levels of IL-8 in retinopathy-positive CM children who died than in survivors and UM children, similar to our results [51]. The authors claim that retinopathy diagnosis improves clinical CM speci city, as it is related to iRBC sequestration in brain.…”

Section: Discussionsupporting

confidence: 90%

Elevated plasma IL-8 as a risk factor for mortality in children presenting with cerebral malaria (NeuroCM study)

Royo

Vianou

Kinkpé

et al. 2022

Preprint

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Background: Cerebral malaria (CM) is a neuropathology which remains one of the deadliest forms of malaria among African children. The kinetics of the pathophysiological mechanisms leading to neuroinflammation and the death or survival of patients during CM are still poorly understood. The increasing production of cytokines, chemokines and other actors of the inflammatory and oxidative response by various local actors in response to neuroinflammation plays a major role during CM, participating in both the amplification of the neuroinflammation phenomenon and its resolution. In this study, we aimed to identify risk factors for CM death among specific variables of inflammatory and oxidative responses to improve our understanding of CM pathogenesis. Methods: Children presenting with CM (n = 70) due to P. falciparuminfection were included in southern Benin and divided according to the clinical outcome into 50 children who survived and 20 who died. Clinical examinationwas complemented by fundoscopic examination and extensive blood biochemical analysis associated with molecular diagnosis by multiplex PCR targeting 14 pathogens in the patients’ cerebrospinal fluid to rule out coinfections. Luminex technology and enzyme immunoassay kits were used to measure 17 plasma and 7 urinary biomarker levels, respectively. Data were analysedby univariate analysis using the nonparametric Mann‒Whitney U test and Chi2 Pearson test. Adjusted and multivariate analyses were conducted separately for plasma and urinary biomarkers to identify CM mortality risk factors. Results: Univariate analysis revealed that higher plasma levels of TNF, IL-1β, IL-10, IL-8, CXCL9, granzyme B, and angiopoietin-2 and lower urinary levels of PGEM were associated with CM mortality. The multivariate logistic analysis highlighted elevated plasma levels of IL-8 as the main risk factor for death during CM. Values obtained during follow-up at D3 and D30 revealed immune factors associated with disease resolution, including plasma CXCL5, CCL17, CCL22, and urinary 15-F2t-isoprostane. Conclusions: These results provide important insight into our understanding of CM pathogenesis and clinical outcome and may have important therapeutic implications.

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“…For instance, platelet counts are inversely correlated with extracellular histone levels in the Malawi cohort, and extracellular histones promote both procoagulant and barrier-disruptive pathways ( 22 ). Additionally, activated neutrophils, a source of extracellular histones, are linked to CM severity in the Malawi cohort ( 73 , 74 ). The phenotypes and effector functions of platelets are modified by microvesicles and extracellular histones released by injured cells ( 75 , 76 ) and neutrophils ( 77 ).…”

Section: Discussionmentioning

confidence: 99%

Determinants of brain swelling in pediatric and adult cerebral malaria

Sahu

Duffy²,

Dankwa³

et al. 2021

JCI Insight

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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.

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Plasma cell-free DNA predicts pediatric cerebral malaria severity

Abstract: Role of funding:The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Cited by 15 publications

References 62 publications

Elevated plasma interleukin-8 as a risk factor for mortality in children presenting with cerebral malaria

Elevated plasma interleukin-8 as a risk factor for mortality in children presenting with cerebral malaria

Elevated plasma IL-8 as a risk factor for mortality in children presenting with cerebral malaria (NeuroCM study)

Determinants of brain swelling in pediatric and adult cerebral malaria

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