Auricular vagus nerve stimulation: a new option to treat inflammation in COVID-19?

INTRODUCTION COVID-19 is an infectious disease caused by the new coronavirus (SARS-CoV-2), which invades alveolar epithelial cells through angiotensin-2 converting enzyme (ACE2) receptors1,2. Infection is triggered by the binding of the spike protein (S) of SARS-CoV-1 or SARS-CoV-2 to ACE23 and, through this binding, the virus enters the host cell, where ACE2 is later inactivated. As this enzyme is abundantly found in alveolar epithelial cells and in the myocardium, potentially serious damage can occur in the lungs and heart2,4. COVID-19 can cause acute respiratory distress syndrome (ARDS), leading to severe hypoxemia, and is associated with thromboembolic events. In ARDS, small-sized pulmonary blood vessels become more permeable, which leads to fluid leakage into the alveoli, impairing pulmonary gas exchange5. ARDS is characterized by generalized inflammation in the lungs, inflammatory cytokine storms, and an imbalance in the sympathetic-parasympathetic activity of the autonomic nervous system (ANS)6. Several treatments have been tried for ARDS from COVID19, based on its pathophysiology using ACE-2 receptors, and some of the most feared complications such as pulmonary thromboembolism. Unfortunately, the results were not promising. The BRACE CORONA trial7 determined whether discontinuation compared with the continuation of ACE inhibitors (ACEIs) or angiotensin-2 receptor blockers (ARBs) changed the number of days alive and out of the hospital through 30 days in 659 patients hospitalized with mild or moderate COVID-19 who were taking ACEIs or ARBs, and there was no significant difference for those assigned to discontinue vs. continue these medications. The ACTION trial8 investigated whether patients hospitalized with mild to moderate COVID-19 and elevated D-dimer concentration benefited from therapeutic vs. prophylactic anticoagulation, and results at day 30 have shown that therapeutic anticoagulation did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. All that said and based on its preclinical effects and some initial clinical studies, auricular vagus nerve stimulation (aVNS) emerges as a promising therapy for the treatment of inflammation in COVID-19, especially its pulmonary manifestations, due to its positive effect on autonomic balance, as discussed in the following sections.