High Levels of Serum Angiopoietin 2 and Angiopoietin 2/1 Ratio at the Critical Stage of Dengue Hemorrhagic Fever in Patients and Association with Clinical and Biochemical Parameters

Abstract

Longitudinal changes of serum angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2) associated with endothelial stability in dengue patients with different disease stages were studied. Serum Ang-1 and Ang-2 levels were measured in confirmed dengue fever (DF) patients on admission (DFA, n = 40) and discharge (DFD, n = 20); in dengue hemorrhagic fever (DHF) patients on admission (DHFA, n = 40), at critical stage (DHFC, n = 36), and on discharge (DHFD, n = 20); and in healthy controls (HC, n = 25). DHFC had the highest serum Ang-2 and lowest Ang-1 levels compared to DFA, DHFA, and HC (P < 0.050). The ratio of serum Ang-2/Ang-1 in DHFC was the highest among all study categories tested (P < 0.001). Significant positive correlations were observed between serum Ang-1 and platelet count in DHFA (Pearson r = 0.653, P < 0.001) and between Ang-1 and pulse pressure in DHFC (r = 0.636, P = 0.001). Using a cutoff value of 1.01 for the Ang-2/Ang-1 ratio for DHFC, a sensitivity of 83.2% and a specificity of 81.2% discerning DF from DHF were obtained. Therefore, serum Ang-2/Ang-1 could be used as a biomarker for endothelial dysfunction in severe dengue at the critical stage.

The emerging role of perivascular cells (pericytes) in viral pathogenesis

“…A number of papers have correlated changes in serum angiopoietin levels with the severity of dengue disease [68–70]. Patients with severe dengue exhibit reduced Ang-1 levels and increased Ang-2 levels, and hence a significantly increased Ang-2/Ang-1 ratio, during the life-threatening critical stage of disease that is associated with vascular leakage and shock [68, 70]. Angiopoietin levels and the Ang-2/Ang-1 ratio return to baseline levels at the point of recovery and discharge from hospital [68, 69].…”

Combination of inflammatory and vascular markers in the febrile phase of dengue is associated with more severe outcomes

“…Acknowledging these characteristics, we selected 10 candidate biomarkers from the vascular, immunological, and inflammatory pathways with good evidence supporting their involvement in the pathogenesis of dengue infection – focusing on those likely to be increased early in the disease course. We included vascular cell adhesion molecule-1 (VCAM-1), syndecan-1 (SDC-1), and angiopoietin-2 (Ang-2) because they represent endothelial activation and glycocalyx integrity ( Han et al, 2019 ; Mapalagamage et al, 2020 ; Suwarto et al, 2017 ; Yacoub et al, 2016a ). For markers of immune activation, we measured interleukin-8 (IL-8) and interferon gamma-induced protein-10 (IP-10) as these are associated with disease severity ( Oliveira et al, 2017 ; Pandey et al, 2015 ; Rathakrishnan et al, 2012 ), and IL-1 receptor antagonist (IL-1RA), soluble cluster of differentiation 163 (sCD163), and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as these are activation markers of monocytes and macrophages, the major targets for dengue replication ( Ab-Rahman et al, 2016 ; John et al, 2015 ; S S et al, 2017 ).…”

Validation of a Novel Zebrafish Model of Dengue Virus (DENV-3) Pathology Using the Pentaherbal Medicine Denguenil Vati

“…Vascular leakage, which is a hallmark of DHF, has been found to be associated with derangement of the normal regulatory function of endothelial cells, rather than endothelial cell death, and underlies the hemorrhagic diathesis of dengue [ 70 ]. Numerous studies have established ANG-2 and CCL3 as biomarkers that serve as reference standards for sensitive and early indicators of disease [ 14 , 71 , 72 , 73 ]. Hence, even with minute onset of viral replication and pathology, these genes show changes in their steady-state mRNA levels.…”