Depressed inflammatory mediators may suggest immunologic dysregulation in advanced venous disease.

Abstract

Objective: Venous ulcer disease is slow to heal, recurs frequently, and represents a significant burden to the global health care system. In similar diseases such as diabetic foot ulcers, a lack of a robust inflammatory response frustrates wound healing. We do not know if a similar phenomenon occurs in venous ulcer. In this study, we used circulating plasma cytokine concentrations to understand how inflammation might link with venous leg ulcer. We hypothesized that venous leg ulcers may be associated with a less robust inflammatory response in regard to T-cell activity, which could explain, in part, their refractory nature, acknowledging the influence of factors such as obesity, venous hypertension, and pelvic outflow obstruction.

Methods: Human subjects with Clinical, Etiology, Anatomy, and Pathophysiology clinical class C2 to C6 chronic venous disease undergoing treatment, and control subjects without venous insufficiency were included. Demographic information, including age, gender, race/ethnicity, and comorbidities, were recorded. Descriptive statistics were calculated for each group. Plasma was obtained from venipuncture in treated and control subjects for isolation of cytokines using enzyme-linked immunosorbent assay and multiplex techniques with a focus on interferon-gamma (IFN-γ), interleukin-12 (IL-12), and IL-2 levels, which are associated with T-cell activity. Multiple linear regression was used to correlate cytokine level with clinical disease status, focusing on correlations with IL-2, which can help determine T-cell fate.

Results: Subjects with C2 to C4 disease demonstrated significantly elevated plasma levels of the T-cell associated cytokines IFN-γ, IL-12p70, and IL-2 compared with both control subjects and those subjects with C5 to C6 disease. Multilinear regression suggested that presentation with C2 to C4 disease, IFN-γ, and IL-12p70 concentrations significantly predicted IL2 concentration, whereas Venous Clinical Severity Score scores, age, sex, diabetes mellitus, and smoking did not.

Conclusions: Higher cytokine levels were primarily seen in subjects with varicose veins (C2-C4) as opposed to those with chronic wounds (C5-C6) which supports a reason why venous leg ulcer healing may stall. IL-2 is a regulator of T-cell activity and as not only diminished in venous ulcer disease but was also correlated with other T-cell mediators such as IFN-γ and IL-12p70. T-cell exhaustion, characterized by a declining immune response in the setting of antigen hyperstimulation and a reduced ability to carry out essential immune functions, may be a reason, explain these findings. Targeting T helper cell activity may be a future therapeutic avenue for managing severe chronic venous disease.