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 insulin resistance (HOMA-IR) for metabolic dysfunction, vascular endothelial growth factor C (VEGF-C) for lymphatic biology, and transforming growth factor beta 1 (TGF-β1) for tissue fibrosis. These five variables will constitute the co-primary outcome measures.
Secondary analyses will evaluate additional biomarkers within each biological domain and their associations with clinical severity, including lymphedema stage, limb volume, pitting edema, Stemmer sign, and skin fibrosis. The study will also investigate relationships between the different biological domains and assess differences between primary and secondary lymphedema.
Exploratory analyses will characterize the skin microbiome of affected and standardized comparison sites and investigate associations between microbiome composition, clinical disease characteristics, and systemic biomarkers. In participants with primary lymphedema without a previously established genetic diagnosis, selected genetic variants associated with primary lymphedema will also be investigated.
The study will provide a comprehensive assessment of biological alterations associated with lymphedema and may help clarify differences between primary and secondary disease. The findings may contribute to a better understanding of lymphedema as a complex biological and tissue disorder and provide a basis for future studies of more targeted diagnostic and therapeutic approaches.
Adults aged 18 to 45 years.
Ability to understand the study information and provide written informed consent.
Willingness and ability to attend one study visit and undergo the planned clinical assessment, blood sampling, and skin swab collection.
Clinically and, where appropriate, imaging-confirmed primary lymphedema of an upper or lower extremity.
Other major causes of limb swelling, including heart failure, nephrotic syndrome, clinically significant thyroid disease, or medications likely to cause edema when the effect cannot be adequately accounted for.
Acute systemic infection or cellulitis/erysipelas within 4 weeks before study enrollment.
Pregnancy or breastfeeding.
Active oncological treatment.
The study will include approximately 90 adults aged 18-45 years, comprising three groups: 30 participants with primary lymphedema, 30 participants with secondary lymphedema, and 30 healthy controls without lymphedema. Participants with lymphedema will be recruited primarily from patients receiving care at the Department of Dermatovenereology, University Medical Centre Ljubljana. Healthy controls will be recruited through public or direct invitations without undue influence. The study groups will be comparable with respect to age and sex where feasible. Each participant will undergo a single study visit including clinical assessment, blood sampling, and standardized skin swab collection. The study is designed as an observational cross-sectional comparative study to characterize and compare biological and clinical features of primary and secondary lymphedema.
Case-control
Cross-sectional
Not listed
Serum IL-13 concentrations
Comparison of serum IL-13 concentrations among participants with primary lymphedema, secondary lymphedema, and healthy controls. IL-13 represents Th2-related inflammatory activity.
Serum sVCAM-1 concentration
Comparison of serum sVCAM-1 concentrations among the three study groups as a marker of endothelial activation.
HOMA-IR
Comparison of HOMA-IR among the three study groups as a measure of metabolic dysfunction.
Serum VEGF-C concentration
Comparison of serum VEGF-C concentrations among the three study groups as a marker of lymphatic biology.
Comparison of primary and secondary lymphedema
Comparison of clinical and biological characteristics between participants with primary and secondary lymphedema.
Skin microbiome composition
Exploratory assessment of skin microbiome composition and diversity and its associations with clinical and biological characteristics of lymphedema.
Genetic variants associated with primary lymphedema
Exploratory identification of selected genetic variants associated with primary lymphedema in participants without a previously established genetic diagnosis.
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