Association DENV1 and DENV2 infection with high serum levels of soluble thrombomodulin and VEGF in patients with dengue fever and dengue hemorrhagic fever

Abstract

INFECTION BY DENGUE VIRUS (DENV) CAN BE ASYMPTOMATIC OR MANIFEST IN TWO CLINICALLY DIFFERENTIATED FORMS: dengue fever (DF) and denguehemorrhagic fever (DHF). The principal pathophysiological characteristic of DHF is the increase in vascular permeability and the loss of plasma caused by the malfunction of the vascular endothelium that induces the release of chemical mediators. However, so far there is nothing that allows for the identification the patients that are at risk of developing the more severe form of the illness. The objective of this study was to investigate the relationship between the serum levels of soluble thrombomodulin (sTM) and VEGF with the severity of dengue and the viral serotype. 231 serum samples were analyzed, 70 DF, 80 DHF and 81 control group, all were residents of Guerrero state in Mexico. The infection by dengue virus as well and the levels of sTM and VEGF were determined using the ELISA sandwich, while the serotype was determined by real time RT-PCR. Our results show that the concentrations of sTM correlate with the degree of severity of the disease given that they are significantly higher (p<0.001) in the DHF group (median = 10.2 ng/mL) than in the DF group (median = 7.2 ng/mL), and these in turn higher than those of the control group (median = 3.3 ng/mL). The concentration of sTM was significantly higher (p=0.0002) in the patients infected with DENV2. For the VEGF, the highest levels were found in DF (median = 291.3 pg/mL) and did not correlate with the severity of the disease. In conclusion, our results indicate that sTM is a good marker for the severity of the infection by DENV, better than VEGF, and with higher sensibility and specificity.

Keywords: DENV1; DENV2; Thrombomodulin; VEGF; dengue fever; dengue hemorrhagic fever.

Figure 1

Soluble thrombomodulin and VEGF levels in patients with dengue and control group. Dengue patients are grouped according to the clinical diagnosis, all were positive for NS1 and DENV1 or DENV2. Serum levels of soluble thrombomodulin correlate with disease severity (A) while the highest serum levels of VEGF were found in DF (B). Box-and-whisker plots shown median values (Horizontal line in the box), 25-75% interquartile range (upper-lower limits of the box).

Figure 2

Serum levels of soluble thrombomodulin and VEGF and its relationship with viral serotypes. Dengue patients are grouped according to viral serotype; all were positive for NS1 and were typed by Real Time RT-PCR. DENV2 patients had soluble thrombomodulin serum levels higher than those patients with DENV1 (A), while VEGF serum levels did not vary according to serotype (B). Box-and-whisker plots shown median values (Horizontal line in the box), 25-75% interquartile range (upper-lower limits of the box).