Journal of Infectious Diseases & Preventive Medicine
Open Access

Role of the Vagal Autonomic Pathways in the Life-Threatening Forms of COVID-19: Proofs of Concept

Emmanuel Moyse^{* *}Correspondence: Emmanuel Moyse, EA4245 Transplantation, Immunology, Inflammation, University of Tours, Tours, France, Email:

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Description

COVID-19 is a highly infectious disease caused by the Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2). This disease consists primarily of acute respiratory distress and/or pneumonia, after a mean incubation period around 5 days [1]. In some cases, critical illness develops around one more week later with respiratory dysventilation along with cytokine storm, systemic inflammation, cardiac dysfunction and hypertension [1,2]. All the symptoms of this severe COVID-19 cases evocated malfunction of the vital reflexes mediated by the vagus nerve, i.e. the tenth (X) pair of cranial nerve that includes most of viscerosensory afferents and parasympathetic efferents to and from discrete brainstem nuclei [2]. Gathering published elements of neurophysiological knowledge led to suggest a “vagal pathway of severe COVID-19” [2].

First, the vagal sensory and motor centers of brainstem selectively express high tissue concentrations of Angiotensin- Converting Enzyme-2 (ACE2), which mediates negative feedback on physiologically-triggered rises of arterial pressure and heart rate [2]. Since ACE2 also is the functional receptor for SARSCoV- 2 entry into cells, the initial pulmonary phase of COVID-19 might hamper the brainstem feedback control of hypertension and heart rate rise if the vagal nerve afferents from lung alveolae pick up the virus and transport it up to the brainstem [2]. Proof of concept for this part of our previous hypothesis has been brought by i) the detailed characterization of SARS-CoV-2 neurotropism, reporting uptake of the virus by neurons and astrocytes in human iPS-derived neurospheres in vitro [3], ii) the detection of all molecular relays downstream of ACE2 [4] inside sensory and relay neurons of the vagus nerve, by immunohistochemistry on human post-mortem brain samples [5]. By contrast, the other classical route for viral neuroinvasion: the olfactory pathway, is devoid of the molecules that operate virus uptake in brain-projecting olfactory neurons [2].

Second, the COVID-19-induced dysautonomia has been precisely characterized by Heart Rate Variability (HRV) analysis, from 24-hour electrocardiogram recording in a cohort of patients, which yielded significantly lowered time-domain indexes and significantly higher low-frequency/high-frequency ratio [6]. This result indicates that severe forms of COVID-19 involve a decrease of the vagal parasympathetic tone which, via the vagal cholinergic “inflammatory reflex”, contributes to raise systemic inflammation as previously reviewed [2]. This proof-ofconcept also indicates, as previously suggested [2], that lifethreatening evolutions of COVID-19 can be diagnosed early by non-invasive HRV monitoring, which is accessible via commercial applications for smartphones and connected watches.

Third, such decrease of the vagal health-protecting parasympathetic tone can be counteracted by a well-established medical intervention: the vagal non-invasive stimulation at the external ear lobe, as previously reviewed [2]. Such intervention has now been demonstrated on patient cohorts to improve significantly recovery and health in the course of COVID-19 [7,8]. Therefore, as previously hypothesized [2], auricular vagal stimulation should allow preventing severe evolutions of COVID-19 if it is applied at early stages. It is urgent now to test this hypothesis on a novel cohort of patients. If it is confirmed, the risk of COVID-19 evolution to a severe, life-threatening form would be addressable by patients out of hospital, by assessing their HRV with relevant commercial applications for smartphones and, if required, consulting for auricular vagal stimulation. Such preventive medicine on early COVID-19 patients would alleviate the epidemic burden in hospitals.

References

1. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-1720.

   [Crossref][Google Scholar]

2. Rangon CM, Krantic S, Moyse E, Fougère B. The vagal autonomic pathway of COVID-19 at the crossroad of Alzheimer’s disease and aging: a review of knowledge. J Alzheimers Dis Rep. 2020;4(1):537-551.

   [Crossref][Google Scholar]

3. Wang C, Zhang M, Garcia Jr G, Tian E, Cui Q, Chen X, et al. ApoE-isoform-dependent SARS-CoV-2 neurotropism and cellular response. Cell Stem Cell. 2021;28(2):331-342.

   [Crossref][Google Scholar]

4. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. cell. 2020;181(2):271-280.

   [Crossref]

5. Vitale-Cross L, Szalayova I, Scoggins A, Palkovits M, Mezey E. SARS-CoV-2 entry sites are present in all structural elements of the human glossopharyngeal and vagal nerves: clinical implications. EBioMedicine. 2022;78:103981.

   [Crossref][Google Scholar]

6. Acanfora D, Nolano M, Acanfora C, Colella C, Provitera V, Caporaso G, et al. Impaired Vagal Activity in Long-COVID-19 Patients. Viruses. 2022;14(5):1035.

   [Crossref][Google Scholar]

7. Rangon CM, Barruet R, Mazouni A, Le Cossec C, Thevenin S, Guillaume J, et al. Auricular Neuromodulation for Mass Vagus Nerve Stimulation: Insights From SOS COVID-19 a Multicentric, Randomized, Controlled, Double-Blind French Pilot Study. Front Physiol. 2021;12.

   [Crossref][Google Scholar]

8. Tornero C, Pastor E, del Mar Garzando M, Orduña J, Forner MJ, Bocigas I, et al. Non-invasive Vagus Nerve Stimulation for COVID-19: Results From a Randomized Controlled Trial (SAVIOR I). Front Neurol. 2022;13.

   [Crossref][Google Scholar]