Reply to “Patient variability in severity of COVID-19 disease. Main suspect: vascular endothelium”

To the Editor:

We thank Drs Tricarico and Travagli¹ for their comments on our recent Rostrum publication.² Over the past year, we have learned much about the pathobiology and immunology of the disease caused by the SARS-CoV-2 virus. Vascular dysfunction, serum cytokines, and chemokines have important roles in the pathophysiology of COVID-19 disease, especially in severe cases. They raise an interesting comment regarding how severe COVID-19 can result from damage to the vascular endothelium and how this damage may induce thrombotic events that may correlate with ABO blood groups.

Although there is little question as to whether damage to the vascular endothelium has a role in COVID-19 progression and severity, there are questions regarding how this damage arises in SARS-CoV-2 infection. Certainly, studies have shown that patients with the non-O blood type have an elevated risk for thrombocytopathy and endotheliopathy. Cardiovascular risk factors such as diabetes,³ hypertensive disorders,⁴ and obesity⁵ have also been shown to increase susceptibility to endotheliopathy and thrombosis; they correlate with increased morbidity and mortality in COVID-19 patients presenting with these comorbidities. Aging also decreases endothelial cell function through increased oxidative and nitrative stress responses.⁶

However, thrombosis and endothelial dysfunction may result from the response to the virus itself, outside preexisting genetic and health factors. For instance, Wu et al⁷ recently showed that the receptor binding domain of the SARS-CoV-2 spike protein preferentially binds to cells expressing blood type A, potentially boosting the viral load. Thrombotic and endothelial dysfunction may result from an increased viral burden, because endothelial cells have also been shown to express the angiotensin-converting enzyme 2 receptor.⁸ As we discussed in our article,² hyperinflammatory responses precipitated by inflammatory cytokines to SARS-CoV-2 infection may themselves elicit endothelial cell damage. In addition, thrombocytopathy and endotheliopathy may result from an errant humoral response that leads to the development of antiphospholipid antibodies. The production of these autoantibodies may cause symptoms of antiphospholipid syndrome,⁹ of which vascular endothelial cell dysfunction is a key pathological hallmark.¹⁰

Nitric oxide (NO) has recently been addressed as an important component of vascular dysfunction in patients with COVID-19 (reviewed by Fang et al¹¹). It has been reported to have an antiviral effect against SARS CoV-2.¹² Several reports have shown beneficial responses using inhaled NO therapy in COVID-19 patients.^{13 , 14} Atopic asthmatic patients have higher inducible NO synthase and exhaled NO, which correlate with sputum eosinophil levels.¹⁵ Kimura et al¹⁶ reported reduction of angiotensin-converting enzyme 2 gene expression in asthmatic patients with the Th2 phenotype. Thus, could the connection between the T _H 2 phenotype and exhaled NO contribute to less severe COVID-19 in asthmatic patients?¹⁷

Contributions to endotheliopathy of factors antecedent to infection versus the infection itself remain inconclusive. Certainly, risk and genetic factors can increase susceptibility to endothelial damage upon infection. However, hyperinflammatory and a disordered humoral response to SARS-CoV-2 infection itself significantly contribute to severe COVID-19.