Non-invasive Auricular Vagus Nerve Stimulation as a Potential Treatment for Covid19-Originated Acute Respiratory Distress Syndrome

Abstract

Background: Covid-19 is an infectious disease caused by an invasion of the alveolar epithelial cells by coronavirus 19. The most severe outcome of the disease is the Acute Respiratory Distress Syndrome (ARDS) combined with hypoxemia and cardiovascular damage. ARDS and co-morbidities are associated with inflammatory cytokine storms, sympathetic hyperactivity, and respiratory dysfunction. Hypothesis: In the present paper, we present and justify a novel potential treatment for Covid19-originated ARDS and associated co-morbidities, based on the non-invasive stimulation of the auricular branch of the vagus nerve. Methods: Auricular vagus nerve stimulation activates the parasympathetic system including anti-inflammatory pathways (the cholinergic anti-inflammatory pathway and the hypothalamic pituitary adrenal axis) while regulating the abnormal sympatho-vagal balance and improving respiratory control. Results: Along the paper (1) we expose the role of the parasympathetic system and the vagus nerve in the control of inflammatory processes (2) we formulate our physiological and methodological hypotheses (3) we provide a large body of clinical and preclinical data that support the favorable effects of auricular vagus nerve stimulation in inflammation, sympatho-vagal balance as well as in respiratory and cardiac ailments, and (4) we list the (few) possible collateral effects of the treatment. Finally, we discuss auricular vagus nerve stimulation protective potential, especially in the elderly and co-morbid population with already reduced parasympathetic response. Conclusions: Auricular vagus nerve stimulation is a safe clinical procedure and it could be either an effective treatment for ARDS originated by Covid-19 and similar viruses or a supplementary treatment to actual ARDS therapeutic approaches.

Keywords: cholinergic anti-inflammatory pathway; hypothalamic pituitary adrenal axis; lung inflammation; parasympathetic system; sympatho-vagal balance.

Figure 1

Diagram of the vagus nerve mediated anti-inflammatory responses. The vagus nerve plays a key role in the neuro-endocrine-immune axis, having a dual anti-inflammatory role through its afferent and efferent fibers. In an infection, such as that caused by Covid-19, a primary immune response leads to a release of pro-inflammatory cytokines, generating an inflammatory process at the site of infection, in this case, in the lungs and heart. Released cytokines are recognized by afferent fibers of the vagus nerve (blue arrows; information about inflammation from lung, heart and blood) who transmit such information to the nucleus of the solitary tract (NST). Activation of NST neurons give origin of the anti-inflammatory response which is generated through two different pathways. The first, known as “hypothalamic-pituitary-adrenal axis,” NST efferents to the hypothalamus (orange arrows) stimulate the release of corticotrophin-releasing hormone (CRH) which stimulates the secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland. ACTH reaches the adrenal glands (purple arrow) where stimulates the production of glucocorticoids (cortisol in humans). Glucocorticoids act on the spleen (red arrow), which leads to reduced cytokine release by acting on cells of the immune system. The second, known as the “cholinergic anti-inflammatory reflex,” NST efferents to DMNV, the dorsal motor nucleus of the vagus nerve (black arrow, green nucleus), stimulate the cholinergic motoneurons that project to the splenic nerve in the celiac ganglion (yellow arrow). Acetylcholine (ACh), released from the preganglionic terminals, excites celiac neurons and provoke the release of norepinephrine in the spleen (NE, green arrow). Then, splenic response inhibits macrophages' cytokines release, decreasing inflammation.

Figure 2

Scheme of the anti-inflammatory activity of the vagal efferents. Vagal efferents arise from the dorsal motor nucleus of the vagus nerve (DMVN) and project to the celiac ganglion, where they synapse with the splenic nerve. DMNV efferents activity provokes stimulates the splenic nerve which release of norepinephrine (NE) over the spleen. NE binds on β2 adrenergic receptors (β2AR) expressed on splenic macrophages and splenic lymphocytes. NE binding on macrophages inhibits the release of pro-inflammatory cytokines of these cells. NE binding on lymphocytes provoke the release of acetylcholine (Ach) which is recognized by α7 acetylcholine receptors (α7nACh) on the membrane of the macrophages. α7nACh activation provokes a disruption of the cytokine release pathway.