Glycocalyx breakdown is associated With severe disease and fatal outcome in Plasmodium falciparum malaria

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 endotheliu...

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Main 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.
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
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Language:English
Published: 2021
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Online Access:https://hdl.handle.net/10356/149019
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spelling sg-ntu-dr.10356-1490192023-03-05T16:44:34Z Glycocalyx breakdown is associated With severe disease and fatal outcome in Plasmodium falciparum malaria 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. Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Plasmodium Falciparum Severe Malaria 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. National Medical Research Council (NMRC) Published version The 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). 2021-05-11T02:56:31Z 2021-05-11T02:56:31Z 2019 Journal Article 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. https://dx.doi.org/10.1093/cid/ciz038 1058-4838 https://hdl.handle.net/10356/149019 10.1093/cid/ciz038 30753363 2-s2.0-85074308728 10 69 1712 1720 en CSA INV 15nov007 Clinical Infectious Diseases © 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 (http://creativecommons.org/licenses/ 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 journals.permissions@oup.com DOI: 10.1093/cid/ciz038. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Plasmodium Falciparum
Severe Malaria
spellingShingle Science::Medicine
Plasmodium Falciparum
Severe Malaria
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.
Glycocalyx breakdown is associated With severe disease and fatal outcome in Plasmodium falciparum malaria
description 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.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
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.
format Article
author 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.
author_sort Yeo, Tsin Wen
title Glycocalyx breakdown is associated With severe disease and fatal outcome in Plasmodium falciparum malaria
title_short Glycocalyx breakdown is associated With severe disease and fatal outcome in Plasmodium falciparum malaria
title_full Glycocalyx breakdown is associated With severe disease and fatal outcome in Plasmodium falciparum malaria
title_fullStr Glycocalyx breakdown is associated With severe disease and fatal outcome in Plasmodium falciparum malaria
title_full_unstemmed Glycocalyx breakdown is associated With severe disease and fatal outcome in Plasmodium falciparum malaria
title_sort glycocalyx breakdown is associated with severe disease and fatal outcome in plasmodium falciparum malaria
publishDate 2021
url https://hdl.handle.net/10356/149019
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