Biomarkers of Endothelial Damage in Distinct Phases of Multisystem Inflammatory Syndrome in Children

Abstract

Endothelial hyperinflammation and vasculitis are known hallmarks of acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C). They are due to the direct effect of the virus on endothelial cells enhanced by pro-inflammatory modulators and may cause venous/arterial thrombosis. Therefore, it is essential to identify patients with endothelial damage early in order to establish specific therapies. We studied the monocyte chemoattractant protein 1 (MCP-1), the perinuclear anti-neutrophil cytoplasmic antibodies (pANCA), and the vascular endothelial growth factor A (VEGF-A) in serum from 45 MIS-C patients at hospital admission and 24 healthy controls (HC). For 13/45 MIS-C patients, we measured the three serum biomarkers also after one week from hospitalization. At admission, MIS-C patients had significantly higher levels of MCP-1 and VEGF-A than the HC, but no significant differences were observed for pANCA. While after one week, MCP-1 was significantly lower, pANCA was higher and VEGF-A levels were not significantly different from the admission values. These findings suggest an involvement of epithelium in MIS-C with an acute phase, showing high MCP-1 and VEGF-A, followed by an increase in pANCA that suggests a vasculitis development. The serum biomarker levels may help to drive personalized therapies in these phases with anticoagulant prophylaxis, immunomodulators, and/or anti-angiogenic drugs.

A protective erythropoietin evolutionary landscape, NLRP3 inflammasome regulation, and multisystem inflammatory syndrome in children

“…Kawasaki disease (KD), KD Shock Syndrome, and MIS-C appear to be on the same immunopathological continuum, in which host immune responses precipitate vascular endothelial inflammation and a cytokine storm that result in cardiomyopathy and enteropathy [ 4 ]. Indeed, endothelial hyperinflammation-endotheliitis is the pathophysiological hallmark of acute, severe COVID-19 and MIS-C [ 5 – 7 ]. MIS-C, however, displays an even greater degree of inflammation, increased levels of circulating SARS-CoV-2 spike (S) protein, dysregulated inflammasome activation with pyroptosis, and presence of autoantibodies [ 8 – 10 ].…”

Efficacy of sildenafil and high-dose anakinra in an MIS-C patient with pulmonary vasculitis: A case report

“…MIS-C is a post-infectious hyperinflammatory syndrome caused by a dysregulated immune response to SARS-CoV-2 infection with severe morbidity and mortality (15,(19)(20)(21)(22). Diffuse vascular-endothelial damage is likely to play a major role in cases with severe cardiac and neurological involvement (15,(19)(20)(21)(22).…”

“…MIS-C is a post-infectious hyperinflammatory syndrome caused by a dysregulated immune response to SARS-CoV-2 infection with severe morbidity and mortality ( 15 , 19 – 22 ). Diffuse vascular-endothelial damage is likely to play a major role in cases with severe cardiac and neurological involvement ( 15 , 19 – 22 ). The strong association between COVID-19 and coagulopathy suggests that multiple molecular pathways are involved and dysregulated through the disease progression, contributing to the development of thrombosis; this is true also for MIS-C ( 37 ).…”

“…One of the most intriguing theories hypothesizes that the SARS-CoV-2 spike protein can act as a “superantigen,” activating both T- and B-cells, leading to the hyperinflammatory state and a subsequent cytokine storm, similar to toxic shock syndrome (TSS) induced by the staphylococcal endotoxin B ( 14 ). Furthermore, it has been observed that patients affected by MIS-C develop vasculitis with endothelial damage, as shown by high levels of MCP-1 and VEGF-A, followed by an increase in pANCA ( 15 ). Among non-specific symptoms, severe complications including cardiovascular shock and multi-organ failure appear in most severe cases of MIS-C ( 16 – 18 ).…”

Circulating Serum Cystatin C as an Independent Risk Biomarker for Vascular Endothelial Dysfunction in Patients with COVID-19-Associated Multisystem Inflammatory Syndrome in Children (MIS-C): A Prospective Observational Study

“…According to Demirkol et al, Cys C levels should correlate with ED and inflammation indirectly through renal function [ 27 ]. A paper by Gelzo and co-workers adds potentially valuable information to the discussion [ 28 ]. The study group confirmed epithelial involvement in acute-phase MIS-C. We suggest that it could be potentially plausible that the unifying concept between Cys C as a potential inflammatory marker [ 29 ] and CVD might be micro-inflammation [ 9 , 30 , 31 ]; however, the role of Cys C and the possible connection of inflammatory pathways need to be further clarified before a definitive conclusion is made.…”