To the Editor,

In a cross-sectional, single-center cohort study, Kuchler et al. [1]. found that the damaged microcirculation of static retinal vessel analysis may contribute to ongoing symptoms in COVID-19 patients, characterized by a narrower central retinal artery equivalent (178.1 μm vs. 189.1 μm) and a lower arteriolar venular ratio (0.84 vs. 0.88) when compared to healthy controls. Despite several known confounders, such as age, gender, obesity, arterial hypertension and nicotine abuse, have been adjusted, we note that information on the use of systemic glucocorticoids was absent in the article. Glucocorticoids exert broad immunomodulatory effects and are recommended by current guidelines as part of the standard medication for COVID-19. According to the worldwide data from the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial [2], glucocorticoids were used in 40.1% of COVID-19 patients, with the highest percentage in the Americas (88.9%) and the lowest percentage in Africa (17.1%). On this background, whether systemic glucocorticoids link to long-term microvascular injury is still under discussion in COVID-19.

The presence of glucocorticoid receptors on endothelial cells and vascular smooth muscle cells consolidate the direct actions of glucocorticoids on microcirculation through at least 3 pathways. First, glucocorticoids inhibit angiogenesis. In an isolated mouse aortic ring model [3], the number of new vessels was significantly decreased after 7-day incubation with 600 nM glucocorticoids and down to about 30% of the controls, whereas this angiostatic effect could be reversed by the glucocorticoid receptor antagonist RU38486. Second, glucocorticoids induce endothelial dysfunction. Schäfer et al. [4]. applied intravital microscopy in a dorsal skin-fold chamber implanted in striated skin muscle of C57BL/6J mice, and revealed that the ACh- induced vasodilation was significantly blunted by oral dexamethasone (3.0 mg/kg body weight) for 1 week along with a 37%- decreased expression of endothelial NO synthase and a 50%- decreased NO2−/NO3 − in the circulation. Third, glucocorticoids enhance the constrictive tone of vascular smooth muscle cells. Molnar et al. [5]. administered dexamethasone to pregnant ewes as 3 weekly courses of 4 injections of 2 mg at 12-hour intervals, and found that the maximum tension of arterial vascular smooth muscle to cellular depolarization significantly increased from 1.19 mN/mm in saline- exposed fetuses to 1.83 mN/mm in dexamethasone-exposed fetuses, due to the potassium-induced influx of calcium into cells via voltage-gated calcium channels.

It’s worth noting that systemic glucocorticoids may also strengthen the cumulative risks for long-term microvascular injury indirectly through metabolic disarrangements of blood glucose, lipids and coagulation profiles.