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dc.contributor.authorYeo, Tsin Wenen_US
dc.contributor.authorWeinberg, J. Briceen_US
dc.contributor.authorLampah, Daniel A.en_US
dc.contributor.authorKenangalem, Ennyen_US
dc.contributor.authorBush, Peggyen_US
dc.contributor.authorChen, Youweien_US
dc.contributor.authorPrice, Richard N.en_US
dc.contributor.authorYoung, Sarahen_US
dc.contributor.authorZhang, Hao Y.en_US
dc.contributor.authorMillington, Daviden_US
dc.contributor.authorGranger, Donald L.en_US
dc.contributor.authorAnstey, Nicholas M.en_US
dc.identifier.citationYeo, T. W., Weinberg, J. B., Lampah, D. A., Kenangalem, E., Bush, P., Chen, Y., Price, R. N., Young, S., Zhang, H. Y., Millington, D., Granger, D. L. & Anstey, N. M. (2019). Glycocalyx breakdown is associated With severe disease and fatal outcome in Plasmodium falciparum malaria. Clinical Infectious Diseases, 69(10), 1712-1720.
dc.description.abstractBackground: Interactions between the endothelium and infected erythrocytes play a major role in the pathogenesis of falciparum malaria, with microvascular dysfunction and parasite sequestration associated with worsening outcomes. The glycocalyx is a carbohydrate-rich layer that lines the endothelium, with multiple roles in vascular homeostasis. The role of the glycocalyx in falciparum malaria and the association with disease severity has not been investigated. Methods: We prospectively enrolled Indonesian inpatients (aged ≥18 years) with severe (SM) or moderately severe (MSM) falciparum malaria, as defined by World Health Organization criteria, and healthy controls (HCs). On enrollment, blood and urine samples were collected concurrently with measurements of vascular nitric oxide (NO) bioavailability. Urine was assayed for glycocalyx breakdown products (glycosaminoglycans) using a dimethylmethylene blue (GAG-DMMB) and liquid chromatography-tandem mass spectrometry (GAG-MS) assay. Results: A total of 129 patients (SM = 43, MSM = 57, HC=29) were recruited. GAG-DMMB and GAG-MS (g/mol creatinine) were increased in SM (mean, 95% confidence interval: 3.98, 2.44–5.53 and 6.82, 5.19–8.44) compared to MSM patients (1.78, 1.27–2.29 and 4.87, 4.27–5.46) and HCs (0.22, 0.06–0.37 and 1.24, 0.89–1.59; P < 0.001). In SM patients, GAG-DMMB and GAG-MS were increased in those with a fatal outcome (n = 3; median, interquartile range: 6.72, 3.80–27.87 and 12.15, 7.88–17.20) compared to survivors (n = 39; 3.10, 0.46–4.5 and 4.64, 2.02–15.20; P = 0.03). Glycocalyx degradation was significantly associated with parasite biomass in both MSM (r = 0.48, GAG-DMMB and r = 0.43, GAG-MS; P < 0.001) and SM patients (r = 0.47, P = 0.002 and r = 0.33, P = 0.04) and inversely associated with endothelial NO bioavailability. Conclusions: Increased endothelial glycocalyx breakdown is associated with severe disease and a fatal outcome in adults with falciparum malaria.en_US
dc.description.sponsorshipNational Medical Research Council (NMRC)en_US
dc.relationCSA INV 15nov007en_US
dc.relation.ispartofClinical Infectious Diseasesen_US
dc.rights© 2019 The Author(s). Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact DOI: 10.1093/cid/ciz038.en_US
dc.titleGlycocalyx breakdown is associated With severe disease and fatal outcome in Plasmodium falciparum malariaen_US
dc.typeJournal Articleen
dc.contributor.schoolLee Kong Chian School of Medicine (LKCMedicine)en_US
dc.description.versionPublished versionen_US
dc.subject.keywordsPlasmodium Falciparumen_US
dc.subject.keywordsSevere Malariaen_US
dc.description.acknowledgementThe study was supported by the National Health and Medical Research Council of Australia (grants 1132975, International Collaborative Research Grant 283321, HOTNORTH 1131932 [E. K.] and Fellowship 1135820 [N. A.]), the National Institutes of Health (grant 1R01 HL130763-01), the Durham VA Research Service (2772), the Wellcome Trust (ICRG ME928457MES), and the Singapore National Medical Research Council (award to T. W. Y., CSA INV 15nov007).en_US
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