<i>In Vivo</i>
            Imaging of the Buccal Mucosa Shows Loss of the Endothelial Glycocalyx and Perivascular Hemorrhages in Pediatric Plasmodium falciparum Malaria

Lyimo, Eric; Haslund, Lars Emil; Ramsing, Thomas; Wang, Christian W.; Efunshile, Akinwale Michael; Manjurano, Alphaxard; Makene, Victor A.; Lusingu, John; Theander, Thor G.; Kurtzhals, Jørgen A. L.; Paulsen, Rasmus Reinhold; Hempel, Casper

doi:10.1128/iai.00679-19

Cited by 12 publications

(28 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with previous reports in falciparum malaria 15 , 16 , we found that in both knowlesi and vivax malaria, syndecan-1 was associated with the endothelial activation marker angiopoietin-2, likely reflecting the known role of angiopoietin-2 in mediating glycocalyx breakdown 30 . Syndecan-1 was also associated with the adhesion molecule ICAM-1 in both knowlesi and vivax malaria.…”

Section: Discussionsupporting

confidence: 91%

Endothelial glycocalyx degradation and disease severity in Plasmodium vivax and Plasmodium knowlesi malaria

Barber

Grigg

Piera

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Degradation of the endothelial glycocalyx is associated with mortality in adult falciparum malaria. However, its role in the pathogenesis of non-falciparum malaria is unknown. In Malaysian patients with knowlesi (n = 200) and vivax (n = 61) malaria, and in healthy controls (n = 50), we measured glycocalyx breakdown products plasma syndecan-1 and urinary glycosaminoglycans, and evaluated correlations with biomarkers of disease severity. Urinary glycosaminoglycans were increased in patients with knowlesi and vivax malaria compared to healthy controls, and in knowlesi malaria were highest in those with severe disease. In knowlesi malaria, plasma syndecan-1 was also highest in those with severe disease, and correlated with markers of endothelial activation (angiopoietin-2, osteoprotegerin, ICAM-1), asymmetric dimethylarginine (ADMA) and impaired microvascular reactivity. Syndecan-1 also correlated with endothelial activation (ICAM-1, angiopoietin-2) and ADMA in vivax malaria. In knowlesi malaria increased syndecan-1 was associated with acute kidney injury, after controlling for age and parasitemia. In knowlesi malaria, the difference in median syndecan-1 between severe and non-severe disease was more marked in females than males. Endothelial glycocalyx degradation is increased in knowlesi and vivax malaria, and associated with disease severity and acute kidney injury in knowlesi malaria. Agents that inhibit glycocalyx breakdown may represent adjunctive therapeutics for severe non-falciparum malaria.

show abstract

Section: Discussionsupporting

confidence: 91%

Endothelial glycocalyx degradation and disease severity in Plasmodium vivax and Plasmodium knowlesi malaria

Barber

Grigg

Piera

et al. 2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Elevation of plasma syndecan-1 and/or GAG have been reported previously in adults and African children with malaria. [19][20][21]35 Results of non-invasive imaging showing an increase in the PBR further support the presence of eGC degradation in MSM. Decrement in microvascular reactivity was detected particularly in children with SM.…”

Section: Discussionmentioning

confidence: 60%

Degradation of endothelial glycocalyx in Tanzanian children with falciparum malaria

et al. 2021

View full text Add to dashboard Cite

A layer of glycocalyx covers the vascular endothelium serving important protective and homeostatic functions. The objective of this study was to determine if breakdown of the endothelial glycocalyx (eGC) occurs during malaria infection in children. Measures of eGC integrity, endothelial activation, and microvascular reactivity were prospectively evaluated in 146 children: 44 with moderately severe malaria (MSM), 42 with severe malaria (SM), and 60 healthy controls (HC). Biochemical measures of eGC integrity included plasma syndecan‐1 and total urinary glycosaminoglycans (GAG). Side‐stream dark field imaging was used to quantitatively assess integrity of eGC. Plasma angiopoietin‐2 (Ang‐2) was measured as a marker of endothelial activation and also as a possible mediator of eGC breakdown. Our results show that urinary GAG, syndecan‐1, and Ang‐2 were elevated in patients with MSM and SM compared with HC. Syndecan‐1 and GAG levels correlated significantly with each other and with plasma Ang‐2. The eGC breakdown products also inversely correlated significantly with hemoglobin and platelet count. In the MSM group, imaging results provided further evidence for eGC degradation. Although not correlated with markers of eGC degradation, vascular function (assessed by non‐invasive near infrared spectroscopy [NIRS]) demonstrated reduced microvascular reactivity, particularly affecting the SM group. Our findings provide further evidence for breakdown of eGC in falciparum malaria that may contribute to endothelial activation and adhesion of parasitized red blood cells, with reduced nitric oxide formation, and vascular dysfunction.

show abstract

“…We did not observe any change from baseline in any of the specific measures of glycocalyx degradation in this study. While glycocalyx degradation has been observed in proportion to disease severity in adult (8) and pediatric (20) patients with falciparum malaria and in P. berghei-infected mice with experimental cerebral malaria (19), no change from baseline in plasma syndecan-1 or urinary glycosaminoglycan levels or videomicroscopy quantitation of glycocalyx thickness was observed in the study par- ticipants. Sphingosine-1-phosphate has a hypothesized upstream role modulating glycocalyx integrity, and reduced levels have been observed in both P. falciparum and P. vivax infection, with the levels being associated with disease severity in patients with P. falciparum malaria (8,28,29).…”

Section: Discussionmentioning

confidence: 75%

“…It modulates interactions between vascular contents and endothelial cells, mediates flow-dependent NO production, and protects against the cytoadhesion of parasitized red cells, leukocytes, and platelets (19). The glycocalyx is degraded in falciparum malaria and is significantly associated with endothelial activation (9,20) and with disease severity and mortality (8). How early this glycocalyx degradation occurs in infection has not been studied.…”

mentioning

confidence: 99%

Early Endothelial Activation Precedes Glycocalyx Degradation and Microvascular Dysfunction in Experimentally Induced Plasmodium falciparum and Plasmodium vivax Infection

et al. 2020

View full text Add to dashboard Cite

Endothelial activation and microvascular dysfunction are key pathogenic processes in severe malaria. We evaluated the early role of these processes in experimentally induced Plasmodium falciparum and P. vivax infection. Participants were enrolled in induced blood-stage malaria clinical trials. Plasma osteoprotegerin, angiopoietin-2, and von Willebrand Factor (vWF) levels were measured as biomarkers of endothelial activation. Microvascular function was assessed using peripheral arterial tonometry and near-infrared spectroscopy, and the endothelial glycocalyx was assessed by sublingual videomicroscopy and measurement of biomarkers of degradation. Forty-five healthy, malaria-naive participants were recruited from 5 studies. Osteoprotegerin and vWF levels increased in participants following inoculation with P. vivax (n = 16) or P. falciparum (n = 15), with the angiopoietin-2 level also increasing in participants following inoculation with P. falciparum. For both species, the most pronounced increase was seen in osteoprotegerin. This was particularly marked in participants inoculated with P. vivax, where the osteoprotegerin level correlated with the levels of parasitemia and the malaria clinical score. There were no changes in measures of endothelial glycocalyx or microvascular function. Plasma biomarkers of endothelial activation increased in early P. falciparum and P. vivax infection and preceded changes in the endothelial glycocalyx or microvascular function. The more pronounced increase in osteoprotegerin suggests that this biomarker may play a role in disease pathogenesis.

show abstract

In Vivo Imaging of the Buccal Mucosa Shows Loss of the Endothelial Glycocalyx and Perivascular Hemorrhages in Pediatric Plasmodium falciparum Malaria

Cited by 12 publications

References 55 publications

Endothelial glycocalyx degradation and disease severity in Plasmodium vivax and Plasmodium knowlesi malaria

Endothelial glycocalyx degradation and disease severity in Plasmodium vivax and Plasmodium knowlesi malaria

Degradation of endothelial glycocalyx in Tanzanian children with falciparum malaria

Early Endothelial Activation Precedes Glycocalyx Degradation and Microvascular Dysfunction in Experimentally Induced Plasmodium falciparum and Plasmodium vivax Infection

Contact Info

Product

Resources

About