Experimental Evidence of Dexamethasone in Reversing Endothelial Dysfunction in COVID-19: Therapeutic Insights from...

Vascular endothelial dysfunction (ED) plays a critical role in the pathogenesis of severe COVID-19. Intranasal dexamethasone (IN-DXM) has been reported to improve clinical outcomes more efficiently than intravenous (IV-DXM) administration in hospitalized patients. This study compared the efficacy of both regimens in improving ED.

Hospitalized COVID-19 patients from the REVIVAL trial received either intranasal dexamethasone (IN-DXM) via a MAD-Nasal device (0.12 mg/kg for 3 days followed by 0.06 mg/kg for 7 days; n = 10) or intravenous dexamethasone (IV-DXM; 6 mg/day for 10 days; n = 7). Respiratory and inflammatory parameters were analyzed before and 10 days after treatment. Serum levels of IL-6, malondialdehyde (MDA), and nitric oxide (NO) metabolites (nitrites) were quantified, along with their effects on human microvascular endothelial cells (HMEC-1) incubated with patient or control sera.

COVID-19 infection significantly increased IL-6 and MDA and reduced NO levels. Only IN-DXM significantly improved respiratory parameters (FiO₂, SatO₂, pO₂) and reduced serum IL-6. Both regimens decreased peripheral inflammatory markers (C-reactive protein, neutrophil-to-lymphocyte ratio and fibrinogen) and increased NO approaching control levels, improving the vascular function. Notably, only sera from IN-DXM-treated patients normalized IL-6 levels in HMEC-1 supernatants to those of controls. Regardless of the administration route, supernatants from HMEC-1 cells incubated with sera from treated patients showed decreased MDA and increased NO compared with those obtained before treatment.

The IN-DXM regimen produced greater improvement in respiratory and inflammatory parameters than IV-DXM, supporting its potential as a practical and effective alternative for managing severe COVID-19-associated endothelial dysfunction.