Endovascular profiles linked to neutrophil activation in children and young adults with long COVID.

BACKGROUND

Endovascular symptoms are among the most debilitating long COVID symptoms; however, underlying mechanisms are unclear. Children and young adults with long COVID, an understudied population, offer key insight into long COVID pathology.

METHODS

Eighty-four children and young adults ≤25 years from the U.S. and Canada were enrolled; 61 with long COVID and 23 healthy pediatric controls. We assessed symptom burden, quantified fibrin amyloid microclots, endovascular cytokines, cell-free DNA, and conducted in vitro assays to assess Spike-related neutrophil-mediated endothelial cell injury.

RESULTS

Cardiovascular symptoms were prevalent among participants with long COVID. Microclot burden was increased (p = 0.0003), as were markers of angiogenesis and endothelial remodeling, including FGF-2, which correlated with microclots (p = 0.04). Cytokines involved in leukocyte trafficking (sVCAM-1, L-selectin, α-2-macroglobulin) were reduced while cell-free DNA, a marker of intravascular neutrophil extracellular trap (NET) formation, was increased (p = 0.003) and positively correlated with microclot component serum amyloid A (p = 0.004). Co-culture assays revealed that NETosis, triggered by Spike immune complexes, contributes to endothelial injury in long COVID.

CONCLUSIONS

Children and young adults with long COVID with cardiovascular symptoms display increased microclots, endothelial injury, and neutrophil inflammation, which warrant further evaluation and suggest intravascular NETosis as a key driver of endovascular pathology in long COVID.

IMPACT: Children and young adults with long COVID display elevated endothelial biomarkers, underscoring disease-related rather than age-related endovascular profiles following SARS-CoV-2 infection. Children and young adults with long COVID exhibit increased microclot burden in blood. Neutrophil activation may contribute to ongoing endovascular injury in long COVID. A combination of microclots, neutrophil markers, and endothelial cytokines could serve as biomarkers for Long COVID.