Implications for Neuromodulation Therapy to Control Inflammation and Related Organ Dysfunction in COVID-19

Abstract

COVID-19 is a syndrome that includes more than just isolated respiratory disease, as severe acute respiratory syndromecoronavirus 2 (SARS-CoV2) also interacts with the cardiovascular, nervous, renal, and immune system at multiple levels, increasing morbidity in patients with underlying cardiometabolic conditions and inducing myocardial injury or dysfunction. Emerging evidence suggests that patients with the highest rate of morbidity and mortality following SARS-CoV2 infection have also developed a hyperinflammatory syndrome (also termed cytokine release syndrome). We lay out the potential contribution of a dysfunction in autonomic tone to the cytokine release syndrome and related multiorgan damage in COVID-19. We hypothesize that a cholinergic anti-inflammatory pathway could be targeted as a therapeutic avenue.

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

“…A large amount of experimental data provides evidence that aVNS activates the parasympathetic anti-inflammatory pathways, equilibrates the sympatho-vagal balance, and improves respiratory and cardiac (Fudim et al, 2020 ) ailments, making aVNS an excellent candidate for clinical treatment of Covid19-related ARDS and other co-morbidities, including apparently less related diseases, as for example Kawasaki disease, an acute childhood vasculitis of unknown etiology, but associated with viral respiratory infections [infants with classic Kawasaki disease displayed also Covid19-positive symptoms (Jones et al, 2020 )].…”

“…Furthermore, it has been postulated that the employment of renin–angiotensin–aldosterone system inhibitors could alter ACE2 expression, which in turn could contribute to the expansion of Covid-19 (Diaz, 2020 ; Fang et al, 2020 ). The dysregulation of renin–angiotensin–aldosterone system may have detrimental effects on cardiovascular regulation and parasympathetic tone (Fudim et al, 2020 ), so that aVNS re-equilibrium of the sympatho-vagal balance could possibly counteract these negative effects. Furthermore, hyperactivation of the vagus nerve downregulated the expression or activity of ACE2 which could even potentially prevent viral infection via the ACE2 entry point (Fudim et al, 2020 ) (see also Osterziel et al, 1994 ; Duprez et al, 1995 ; Cody, 1997 ; Karas et al, 2005 ; Zucker et al, 2014 ; Liu et al, 2015 ).…”

COVID-19 infection and cardiac arrhythmias

“…On the other hand, an anti-inflammatory mechanism has been ascribed to the parasympathetic system which is proposed to monitor systemic inflammation through a reflex system and to activate a neuronal anti-inflammatory signal to prevent deleterious inflammation [81] . In contradistinction to SNS hyperactivation, which appears to be of particular significance for injury to the CV system [82] , inflammatory cytokines can activate the afferent sensory vagus nerve that transmits the information to the central nervous system which then can activate the efferent vagus nerve to control inflammation via acetylcholine, its principal neurotransmitter, and a nicotinic anti-inflammatory pathway and modulate the immune system by inhibiting the production of inflammatory cytokines in macrophages and the spleen [ 83 , 84 ]. In this context, diminished cardiac vagal activity, found in patients with pulmonary and cardiometabolic disease, has been shown to adversely affect patients with critical illness, such as COVID-19 infection [85] .…”

The role of nicotinic receptors in SARS-CoV-2 receptor ACE2 expression in intestinal epithelia

“…Therefore, since the COVID-19 outbreak late 2019, several trials (e.g. ClinicalTrials.gov; NCT04341415, NCT04368156, NCT04382391) have been originated to study the efficacy of electrical VNS as treatment for this hyper-inflammatory disease (3,4). However, clear evidence supporting the value of VNS in treating COVID-19 is lacking.…”