Endothelial Nitric Oxide Pathways in the Pathophysiology of Dengue

A Prospective Observational Study

Sophie Yacoub, Phung Khanh Lam, Trieu Trung Huynh, Hong Hanh Nguyen Ho, Hoai Tam Dong Thi, Nguyen Van Thu, Le Thi Lien, Quyen Nguyen Than Ha, Duyen Huynh Thi Le, Juthathip Mongkolspaya, Abigail Culshaw, Tsin Wen Yeo, Heiman Wertheim, Cameron Simmons, Gavin Screaton, Bridget Wills

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Background: Dengue can cause increased vascular permeability that may lead to hypovolemic shock. Endothelial dysfunction may underlie this; however, the association of endothelial nitric oxide (NO) pathways with disease severity is unknown. 

    Methods: We performed a prospective observational study in 2 Vietnamese hospitals, assessing patients presenting early (<72 hours of fever) and patients hospitalized with warning signs or severe dengue. The reactive hyperemic index (RHI), which measures endothelium-dependent vasodilation and is a surrogate marker of endothelial function and NO bioavailability, was evaluated using peripheral artery tonometry (EndoPAT), and plasma levels of l-arginine, arginase-1, and asymmetric dimethylarginine were measured at serial time-points. The main outcome of interest was plasma leakage severity. 

    Results: Three hundred fourteen patients were enrolled; median age of the participants was 21(interquartile range, 13-30) years. No difference was found in the endothelial parameters between dengue and other febrile illness. Considering dengue patients, the RHI was significantly lower for patients with severe plasma leakage compared to those with no leakage (1.46 vs 2.00; P <.001), over acute time-points, apparent already in the early febrile phase (1.29 vs 1.75; P =.012). RHI correlated negatively with arginase-1 and positively with l-arginine (P =.001). 

    Conclusions: Endothelial dysfunction/NO bioavailability is associated with worse plasma leakage, occurs early in dengue illness and correlates with hypoargininemia and high arginase-1 levels.

    Original languageEnglish
    Pages (from-to)1453-1461
    Number of pages9
    JournalClinical Infectious Diseases
    Volume65
    Issue number9
    DOIs
    Publication statusPublished - 1 Nov 2017

    Fingerprint

    Dengue
    Observational Studies
    Nitric Oxide
    Arginase
    Prospective Studies
    Biological Availability
    Arginine
    Fever
    Severe Dengue
    Manometry
    Capillary Permeability
    Vasodilation
    Endothelium
    Shock
    Arteries
    Biomarkers

    Cite this

    Yacoub, S., Lam, P. K., Huynh, T. T., Nguyen Ho, H. H., Dong Thi, H. T., Van Thu, N., ... Wills, B. (2017). Endothelial Nitric Oxide Pathways in the Pathophysiology of Dengue: A Prospective Observational Study. Clinical Infectious Diseases, 65(9), 1453-1461. https://doi.org/10.1093/cid/cix567
    Yacoub, Sophie ; Lam, Phung Khanh ; Huynh, Trieu Trung ; Nguyen Ho, Hong Hanh ; Dong Thi, Hoai Tam ; Van Thu, Nguyen ; Lien, Le Thi ; Ha, Quyen Nguyen Than ; Le, Duyen Huynh Thi ; Mongkolspaya, Juthathip ; Culshaw, Abigail ; Yeo, Tsin Wen ; Wertheim, Heiman ; Simmons, Cameron ; Screaton, Gavin ; Wills, Bridget. / Endothelial Nitric Oxide Pathways in the Pathophysiology of Dengue : A Prospective Observational Study. In: Clinical Infectious Diseases. 2017 ; Vol. 65, No. 9. pp. 1453-1461.
    @article{bb0ea7b489114520abbd510d47220035,
    title = "Endothelial Nitric Oxide Pathways in the Pathophysiology of Dengue: A Prospective Observational Study",
    abstract = "Background: Dengue can cause increased vascular permeability that may lead to hypovolemic shock. Endothelial dysfunction may underlie this; however, the association of endothelial nitric oxide (NO) pathways with disease severity is unknown. Methods: We performed a prospective observational study in 2 Vietnamese hospitals, assessing patients presenting early (<72 hours of fever) and patients hospitalized with warning signs or severe dengue. The reactive hyperemic index (RHI), which measures endothelium-dependent vasodilation and is a surrogate marker of endothelial function and NO bioavailability, was evaluated using peripheral artery tonometry (EndoPAT), and plasma levels of l-arginine, arginase-1, and asymmetric dimethylarginine were measured at serial time-points. The main outcome of interest was plasma leakage severity. Results: Three hundred fourteen patients were enrolled; median age of the participants was 21(interquartile range, 13-30) years. No difference was found in the endothelial parameters between dengue and other febrile illness. Considering dengue patients, the RHI was significantly lower for patients with severe plasma leakage compared to those with no leakage (1.46 vs 2.00; P <.001), over acute time-points, apparent already in the early febrile phase (1.29 vs 1.75; P =.012). RHI correlated negatively with arginase-1 and positively with l-arginine (P =.001). Conclusions: Endothelial dysfunction/NO bioavailability is associated with worse plasma leakage, occurs early in dengue illness and correlates with hypoargininemia and high arginase-1 levels.",
    keywords = "arginase, dengue, endothelial function, l -arginine, nitric oxide",
    author = "Sophie Yacoub and Lam, {Phung Khanh} and Huynh, {Trieu Trung} and {Nguyen Ho}, {Hong Hanh} and {Dong Thi}, {Hoai Tam} and {Van Thu}, Nguyen and Lien, {Le Thi} and Ha, {Quyen Nguyen Than} and Le, {Duyen Huynh Thi} and Juthathip Mongkolspaya and Abigail Culshaw and Yeo, {Tsin Wen} and Heiman Wertheim and Cameron Simmons and Gavin Screaton and Bridget Wills",
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    Yacoub, S, Lam, PK, Huynh, TT, Nguyen Ho, HH, Dong Thi, HT, Van Thu, N, Lien, LT, Ha, QNT, Le, DHT, Mongkolspaya, J, Culshaw, A, Yeo, TW, Wertheim, H, Simmons, C, Screaton, G & Wills, B 2017, 'Endothelial Nitric Oxide Pathways in the Pathophysiology of Dengue: A Prospective Observational Study', Clinical Infectious Diseases, vol. 65, no. 9, pp. 1453-1461. https://doi.org/10.1093/cid/cix567

    Endothelial Nitric Oxide Pathways in the Pathophysiology of Dengue : A Prospective Observational Study. / Yacoub, Sophie; Lam, Phung Khanh; Huynh, Trieu Trung; Nguyen Ho, Hong Hanh; Dong Thi, Hoai Tam; Van Thu, Nguyen; Lien, Le Thi; Ha, Quyen Nguyen Than; Le, Duyen Huynh Thi; Mongkolspaya, Juthathip; Culshaw, Abigail; Yeo, Tsin Wen; Wertheim, Heiman; Simmons, Cameron; Screaton, Gavin; Wills, Bridget.

    In: Clinical Infectious Diseases, Vol. 65, No. 9, 01.11.2017, p. 1453-1461.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Endothelial Nitric Oxide Pathways in the Pathophysiology of Dengue

    T2 - A Prospective Observational Study

    AU - Yacoub, Sophie

    AU - Lam, Phung Khanh

    AU - Huynh, Trieu Trung

    AU - Nguyen Ho, Hong Hanh

    AU - Dong Thi, Hoai Tam

    AU - Van Thu, Nguyen

    AU - Lien, Le Thi

    AU - Ha, Quyen Nguyen Than

    AU - Le, Duyen Huynh Thi

    AU - Mongkolspaya, Juthathip

    AU - Culshaw, Abigail

    AU - Yeo, Tsin Wen

    AU - Wertheim, Heiman

    AU - Simmons, Cameron

    AU - Screaton, Gavin

    AU - Wills, Bridget

    PY - 2017/11/1

    Y1 - 2017/11/1

    N2 - Background: Dengue can cause increased vascular permeability that may lead to hypovolemic shock. Endothelial dysfunction may underlie this; however, the association of endothelial nitric oxide (NO) pathways with disease severity is unknown. Methods: We performed a prospective observational study in 2 Vietnamese hospitals, assessing patients presenting early (<72 hours of fever) and patients hospitalized with warning signs or severe dengue. The reactive hyperemic index (RHI), which measures endothelium-dependent vasodilation and is a surrogate marker of endothelial function and NO bioavailability, was evaluated using peripheral artery tonometry (EndoPAT), and plasma levels of l-arginine, arginase-1, and asymmetric dimethylarginine were measured at serial time-points. The main outcome of interest was plasma leakage severity. Results: Three hundred fourteen patients were enrolled; median age of the participants was 21(interquartile range, 13-30) years. No difference was found in the endothelial parameters between dengue and other febrile illness. Considering dengue patients, the RHI was significantly lower for patients with severe plasma leakage compared to those with no leakage (1.46 vs 2.00; P <.001), over acute time-points, apparent already in the early febrile phase (1.29 vs 1.75; P =.012). RHI correlated negatively with arginase-1 and positively with l-arginine (P =.001). Conclusions: Endothelial dysfunction/NO bioavailability is associated with worse plasma leakage, occurs early in dengue illness and correlates with hypoargininemia and high arginase-1 levels.

    AB - Background: Dengue can cause increased vascular permeability that may lead to hypovolemic shock. Endothelial dysfunction may underlie this; however, the association of endothelial nitric oxide (NO) pathways with disease severity is unknown. Methods: We performed a prospective observational study in 2 Vietnamese hospitals, assessing patients presenting early (<72 hours of fever) and patients hospitalized with warning signs or severe dengue. The reactive hyperemic index (RHI), which measures endothelium-dependent vasodilation and is a surrogate marker of endothelial function and NO bioavailability, was evaluated using peripheral artery tonometry (EndoPAT), and plasma levels of l-arginine, arginase-1, and asymmetric dimethylarginine were measured at serial time-points. The main outcome of interest was plasma leakage severity. Results: Three hundred fourteen patients were enrolled; median age of the participants was 21(interquartile range, 13-30) years. No difference was found in the endothelial parameters between dengue and other febrile illness. Considering dengue patients, the RHI was significantly lower for patients with severe plasma leakage compared to those with no leakage (1.46 vs 2.00; P <.001), over acute time-points, apparent already in the early febrile phase (1.29 vs 1.75; P =.012). RHI correlated negatively with arginase-1 and positively with l-arginine (P =.001). Conclusions: Endothelial dysfunction/NO bioavailability is associated with worse plasma leakage, occurs early in dengue illness and correlates with hypoargininemia and high arginase-1 levels.

    KW - arginase

    KW - dengue

    KW - endothelial function

    KW - l -arginine

    KW - nitric oxide

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    DO - 10.1093/cid/cix567

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    JO - Clinical Infectious Diseases

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    SN - 1058-4838

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