Biological Profile of Primary and Secondary Lymphedema: Inflammatory, Endothelial, Metabolic, Lymphatic, and Fibrotic Markers

This observational, cross-sectional study aims to characterize the biological profile of primary and secondary lymphedema by investigating five interconnected biological domains: T helper 2 (Th2)-related inflammation, endothelial activation, metabolic dysfunction, lymphatic biology, and tissue fibrosis. Lymphedema is traditionally considered a disorder of impaired lymphatic drainage resulting in the accumulation of interstitial fluid. However, increasing evidence suggests that its development and progression involve chronic inflammation, endothelial dysfunction, metabolic alterations, abnormal lymphatic signaling, adipose tissue accumulation, and progressive tissue fibrosis. While these mechanisms have been investigated predominantly in secondary lymphedema, the systemic biological profile of primary lymphedema remains insufficiently characterized. The study will include approximately 90 participants aged 18-45 years: 30 participants with primary lymphedema, 30 participants with secondary lymphedema, and 30 healthy control participants matched by age and sex. Each participant will attend one study visit lasting approximately 45-60 minutes. Clinical assessment will include medical history, demographic characteristics, blood pressure, body measurements, assessment of lymphedema location and clinical stage, pitting edema, Stemmer sign, skin changes, limb volume measurement by perometry, and assessment of tissue firmness. Venous blood samples will be collected to assess routine laboratory parameters and a panel of inflammatory, endothelial, metabolic, lymphatic, and fibrotic biomarkers. A standardized skin swab will also be collected for exploratory skin microbiome analysis. For the primary analysis, one representative marker will be selected in advance for each of the five biological domains: interleukin-13 (IL-13) for Th2-related inflammatory activity, soluble vascular cell adhesion molecule-1 (sVCAM-1) for endothelial activation, homeostatic model assessment of i