A case study on COVID-19 related respiratory symptoms suggests that electrical non-invasive vagus nerve stimulation might provide clinical benefits in patients with COVID-19. It may ease chest tightness and shortness of breath. (1) It is a remarkable fact that the risk groups of the COVID-19 patients with poor outcome have a relatively low vagal tone measured by heart rate variability: patients with diabetes, cardiovascular disease, hypertension, cancer, pulmonary diseases, old age, etc. (2)
Pulmonary gas exchange problems are also improved by vagal nerve activity that may explain the benefits of the vagus nerve activation. (3)
The fatality of the disease is prognosticated by cytokine storm, that is, by elevated Il-6, TNF-alpha, CRP, and by elevated d-dimer that may indicate blood clot (thrombus) formation and by decreased lymphocytes, B and T cells. (4)
In experimentally induced inflammation, endotoxemia, electrical vagus nerve stimulation decreased d-dimer, Il-6, TNF-alpha, Il-1 and so inhibited activation of coagulation and fibrinolysis. (5)
In this context it is remarkable that centrally administered proinsulin c-peptide has also vagus nerve stimulating ability and may increase splenic lymphocyte proliferation affected by sympathetically mediated suppression. (6) (7)
C-peptide also improves heart rate variability and autonomic nerve function in diabetic patients. (8)

The concept that COVID-19 infection is harming the autonomic nervous system may explain also anomalies emerging in the disease course. Stroke incidents may be unusual in cases with otherwise a mild disease course. (9) According to anecdotal evidences stroke occurs also at a relatively young age and as an early symptom of the infection. (10) Interesting is that reduced parasympathetic activity may increase the risk of stroke by enhancing the risk of arrhythmias that is measured by decreased nighttime heart rate variability. (11)
Evidence is accumulating that balancing the autonomic nervous system by central/intranasal proinsulin c peptide may be a viable method for the prevention of severe outcomes of the COVID-19 infection. (12)

(1) Staats, Peter et al.: Use of Non-Invasive Vagus Nerve Stimulation to Treat Respiratory Symptoms Associated With COVID-19: A Theoretical Hypothesis and Early Clinical Experience, Neuromodulation. 2020 Apr 27.

(2) Greiser, K.H. et al.: Cardiovascular disease, risk factors and heart rate variability in the elderly general population: Design and objectives of the CARdiovascular disease, Living and Ageing in Halle (CARLA) Study, BMC Cardiovasc Disord. 2005; 5: 33.

(3) Ito, Shoji et al.: Vagal Nerve Activity Contributes to Improve the Efficiency of Pulmonary Gas Exchange in Hypoxic Humans, Exp Physiol. 2006 Sep;91(5):935-41.

(4) Cao, Wei et al.: COVID-19: Towards Understanding of Pathogenesis, Cell Res. 2020 May;30(5):367-369.

(5) Van Westerloo D.J. et al: Vagus Nerve Stimulation Inhibits Activation of Coagulation and Fibrinolysis During Endotoxemia in Rats, J Thromb Haemost. 2006 Sep;4(9):1997-2002.

(6) Okamoto, S. et al.: Proinsulin C Peptide Obviates Sympathetically Mediated Suppression of Splenic Lymphocyte Activity in Rats, Diabetologia. 2000 Dec;43(12):1512-7.

(7) Kimura, K. et al.: Proinsulin C-peptide Activates Vagus Efferent Output in Rats, Peptides. 2005 Dec;26(12):2547-53.

(8) Johansson, B.L. et al.: C-peptide Improves Autonomic Nerve Function in IDDM Patients, Diabetologia. 1996 Jun;39(6):687-95.

(9) Avula, Akshay et al.: COVID-19 presenting as stroke, Brain Behav Immun. 2020 Apr 28.

(10) Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young In: https://www.nejm.org/doi/full/10.1056/NEJMc2009787

(11) Binici, Zeynep et al.: Decreased Nighttime Heart Rate Variability Is Associated With Increased Stroke Risk, Stroke. 2011 Nov;42(11):3196-201.

(12) Derkach, K.V. et al.: Intranasal Administration of Proinsulin C-Peptide Enhances the Stimulating Effect of Insulin on Insulin System Activity in the Hypothalamus of Diabetic Rats, Bull Exp Biol Med. 2019 Jul;167(3):351-355.