Diagnostic performance of vascular endothelial growth factor D in severity stratification of pediatric COVID-19 and multisystem inflammatory syndrome in children.

Introduction: In recent years, vascular endothelial growth factor D (VEGF-D) has been recognized as a promising biomarker for disease severity stratification in coronavirus disease, as well as an indicator of endothelial dysfunction, hypoxia, and pathological angiogenesis - all of which are hallmarks of severe COVID-19. However, there is limited evidence on the specific role of VEGF-D in children with COVID-19, and its relevance in multisystem inflammatory syndrome in children (MIS-C) has not been thoroughly explored. Methods: This study included 200 children with confirmed COVID-19 (through PCR or rapid antigen test), 40 children with MIS-C, and 24 healthy children without SARS-CoV-2 infection. Serum VEGF-D concentrations, acute-phase markers (C-reactive protein, procalcitonin, ferritin), and interleukin levels (IL-1β, IL-6, TNF-α) were measured using enzyme-linked immunosorbent assay (ELISA) with commercial kits. Results: The results showed that VEGF-D levels were significantly higher in children with COVID-19 (325.61 (189.93; 535.85) pg/ml) and MIS-C (920.92 (473.45; 1157.70) pg/ml) compared with the control group (195.88 (115.58; 256.70) pg/ml), with the highest levels observed in patients with MIS-C and severe COVID-19. The increase in VEGF-D was more prominent in boys infected by SARS-CoV-2, but there were no significant differences based on age within the groups. Multivariable logistic regression analysis showed that VEGF-D was independently associated with severe COVID-19 and MIS-C in children. Receiver operating characteristic (ROC) analysis established clinically relevant cut-off values for VEGF-D: 387.87 pg/mL for identifying severe COVID-19 and 461.96 pg/mL for differentiating MIS-C from acute COVID-19. In children with COVID-19, exceeding the VEGF-D cut-off was associated with more severe hypoxia and higher levels of C-reactive protein and ferritin, while in MIS-C it was associated with elevated CRP and IL-6. Principal component analysis showed that VEGF-D, along with acute-phase markers and pro-inflammatory cytokines, contributes to an integrated inflammatory-endothelial profile in both COVID-19 and MIS-C. Conclusion: VEGF-D is an independent marker associated with disease severity in pediatric COVID-19 and MIS-C and may be useful for severity stratification, differentiating clinical phenotypes, and informing patient management.