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Title: Glycocalyx breakdown is associated With severe disease and fatal outcome in Plasmodium falciparum malaria
Authors: Yeo, Tsin Wen
Weinberg, J. Brice
Lampah, Daniel A.
Kenangalem, Enny
Bush, Peggy
Chen, Youwei
Price, Richard N.
Young, Sarah
Zhang, Hao Y.
Millington, David
Granger, Donald L.
Anstey, Nicholas M.
Keywords: Science::Medicine
Issue Date: 2019
Source: Yeo, 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.
Project: CSA INV 15nov007
Journal: Clinical Infectious Diseases
Abstract: Background: 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.
ISSN: 1058-4838
DOI: 10.1093/cid/ciz038
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.
Fulltext Permission: open
Fulltext Availability: With Fulltext
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