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 Thu Van, 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, Sophie Yacoub, Phung Khanh Lam, Trieu Trung Huynh, Hong Hanh Nguyen Ho, Hoai Tam Dong Thi, Nguyen Thu Van, 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

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.

© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Study flow chart. Contraindications included age 9/L, or clinically unstable as decided by attending clinician. A random selection of patients who had peripheral artery tonometry testing were chosen to have plasma l-arginine, asymmetric dimethylarginine, and arginase tests. Abbreviations: ADMA, asymmetric dimethylarginine; EndoPAT, peripheral artery tonometry; HCMC, Ho Chi Minh City; HTD, Hospital for Tropical Diseases; NHTD, National Hospital for Tropical Diseases; OFI, other febrile illness.
Figure 2.
Figure 2.
Scatterplot of l-arginine-to-asymmetric dimethylarginine (ADMA) ratios for dengue patients by plasma leakage severity and illness phase. Short gray line represents the median value of l-arginine-to-ADMA ratio for each illness phase. The number represents the number of patients that contributed to each group. These graphs are based on 54 patients with at least 1 measurement.
Figure 3.
Figure 3.
Scatterplot of endothelial function in dengue patients by plasma leakage severity and illness phase. Short gray line represents the median value of reactive hyperemic index (RHI) during each illness phase. The number represents the number of patients that contributed to each group. Redline represents the 1.67 cutoff, below which is defined as endothelial dysfunction. This graph is based on 109 patients with at least 1 measurement.

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