# Vagus Nerve Stimulation: A Potential Adjunct Therapy for COVID-19

Eric Azabou, Guillaume Bao, Rania Bounab, Nicholas Heming, Djillali Annane

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## ► To cite this version:

Eric Azabou, Guillaume Bao, Rania Bounab, Nicholas Heming, Djillali Annane. Vagus Nerve Stimulation: A Potential Adjunct Therapy for COVID-19. Frontiers in Medicine, 2021, 8, 10.3389/fmed.2021.625836. [https://doi.org/10.3389/fmed.2021.625836](https://doi.org/10.3389/fmed.2021.625836). [hal-04548844](https://HAL.science/hal-04548844)

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# Vagus Nerve Stimulation: A Potential Adjunct Therapy for COVID-19

Eric Azabou, Guillaume Bao, Rania Bounab, Nicholas Heming, Djillali Annane

► To cite this version:

Eric Azabou, Guillaume Bao, Rania Bounab, Nicholas Heming, Djillali Annane. Vagus Nerve Stimulation: A Potential Adjunct Therapy for COVID-19. Frontiers in Medicine, 2021, 8, 10.3389/fmed.2021.625836. [https://doi.org/10.3389/fmed.2021.625836](https://doi.org/10.3389/fmed.2021.625836). [CC-BY-4.0](https://creativecommons.org/licenses/by/4.0/)

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Submitted on 16 Apr 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
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Check for
updates

# Vagus Nerve Stimulation: A Potential Adjunct Therapy for COVID-19

Eric Azabou<fnref n="1" />*, Guillaume Bao<fnref n="1" />, Rania Bounab², Nicholas Heming² and Djillali Annane²

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through excessive end organ inflammation. Despite improved understanding of the pathophysiology, management, and the great efforts worldwide to produce effective drugs, death rates of COVID-19 patients remain unacceptably high, and effective treatment is unfortunately lacking. Pharmacological strategies aimed at modulating inflammation in COVID-19 are being evaluated worldwide. Several drug therapies targeting this excessive inflammation, such as tocilizumab, an interleukin (IL)-6 inhibitor, corticosteroids, programmed cell death protein (PD)-1/PD-L1 checkpoint inhibition, cytokine-adsorption devices, and intravenous immunoglobulin have been identified as potentially useful and reliable approaches to counteract the cytokine storm. However, little attention is currently paid for non-drug therapeutic strategies targeting inflammatory and immunological processes that may be useful for reducing COVID-19-induced complications and improving patient outcome. Vagus nerve stimulation attenuates inflammation both in experimental models and preliminary data in human. Modulating the activity of cholinergic anti-inflammatory pathways (CAPs) described by the group of KJ Tracey has indeed become an important target of therapeutic research strategies for inflammatory diseases and sepsis. Non-invasive transcutaneous vagal nerve stimulation (t-VNS), as a non-pharmacological adjuvant, may help reduce the burden of COVID-19 and deserve to be investigated. VNS as an adjunct therapy in COVID-19 patients should be investigated in clinical trials. Two clinical trials on this topic are currently underway (NCT04382391 and NCT04368156). The results of these trials will be informative, but additional larger studies are needed.

**Keywords:** COVID-19, cytokine storm, inflammation, non-drug therapy, vagus nerve stimulation, neuromodulation, outcome

## INTRODUCTION

The coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) faced currently worldwide includes in its pathophysiology an excessive inflammatory phase called “cytokine storm” that is closely linked to its high mortality (1, 2). During sepsis, the host response to a pathogen is mediated by the interaction between

**OPEN ACCESS**

**Edited by:**
Constantinos Tsioutis,
European University Cyprus, Cyprus

**Reviewed by:**
Bruno Bonaz,
Centre Hospitalier Universitaire de
Grenoble, France
Eric J. Liebler,
electroCore LLC, United States

**\*Correspondence:**
Eric Azabou
eric.azabou@aphp.fr;
eric.azabou@uvsq.fr

**Specialty section:**
This article was submitted to
Infectious Diseases - Surveillance,
Prevention and Treatment,
a section of the journal
Frontiers in Medicine

**Received:** 04 November 2020

**Accepted:** 23 March 2021

**Published:** 07 May 2021

**Citation:**
Azabou E, Bao G, Bounab R, Heming N and Annane D (2021)
Vagus Nerve Stimulation: A Potential
Adjunct Therapy for COVID-19.
Front. Med. 8:625836.
doi: 10.3389/fmed.2021.625836

<footnote n="1">¹Clinical Neurophysiology and Neuromodulation Unit, Departments of Physiology and Critical Care Medicine, Raymond Poincaré Hospital, Assistance Publique- Hôpitaux de Paris, Inserm UMR 1173, Infection and Inflammation (2l), University of Versailles Saint-Quentin en Yvelines (UVSQ), Paris-Saclay University, Paris, France, ²General Intensive Care Unit - Assistance Publique Hôpitaux de Paris, Raymond Poincaré Hospital, Assistance Publique- Hôpitaux de Paris, Inserm UMR 1173, Infection and Inflammation (2l), University of Versailles Saint-Quentin en Yvelines (UVSQ), Paris-Saclay University, Paris, France</footnote>
<figure><img src="image_2.png" /></figure>

Check for
updates

# Vagus Nerve Stimulation: A Potential Adjunct Therapy for COVID-19

Eric Azabou¹*, Guillaume Bao¹, Rania Bounab², Nicholas Heming² and Djillali Annane²

¹Clinical Neurophysiology and Neuromodulation Unit, Departments of Physiology and Critical Care Medicine, Raymond Poincaré Hospital, Assistance Publique- Hôpitaux de Paris, Inserm UMR 1173, Infection and Inflammation (2l), University of Versailles Saint-Quentin en Yvelines (UVSQ), Paris-Saclay University, Paris, France, ²General Intensive Care Unit - Assistance Publique Hôpitaux de Paris, Raymond Poincaré Hospital, Assistance Publique- Hôpitaux de Paris, Inserm UMR 1173, Infection and Inflammation (2l), University of Versailles Saint-Quentin en Yvelines (UVSQ), Paris-Saclay University, Paris, France

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through excessive end organ inflammation. Despite improved understanding of the pathophysiology, management, and the great efforts worldwide to produce effective drugs, death rates of COVID-19 patients remain unacceptably high, and effective treatment is unfortunately lacking. Pharmacological strategies aimed at modulating inflammation in COVID-19 are being evaluated worldwide. Several drug therapies targeting this excessive inflammation, such as tocilizumab, an interleukin (IL)-6 inhibitor, corticosteroids, programmed cell death protein (PD)-1/PD-L1 checkpoint inhibition, cytokine-adsorption devices, and intravenous immunoglobulin have been identified as potentially useful and reliable approaches to counteract the cytokine storm. However, little attention is currently paid for non-drug therapeutic strategies targeting inflammatory and immunological processes that may be useful for reducing COVID-19-induced complications and improving patient outcome. Vagus nerve stimulation attenuates inflammation both in experimental models and preliminary data in human. Modulating the activity of cholinergic anti-inflammatory pathways (CAPs) described by the group of KJ Tracey has indeed become an important target of therapeutic research strategies for inflammatory diseases and sepsis. Non-invasive transcutaneous vagal nerve stimulation (t-VNS), as a non-pharmacological adjuvant, may help reduce the burden of COVID-19 and deserve to be investigated. VNS as an adjunct therapy in COVID-19 patients should be investigated in clinical trials. Two clinical trials on this topic are currently underway (NCT04382391 and NCT04368156). The results of these trials will be informative, but additional larger studies are needed.

**Keywords:** COVID-19, cytokine storm, inflammation, non-drug therapy, vagus nerve stimulation, neuromodulation, outcome

## INTRODUCTION

The coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) faced currently worldwide includes in its pathophysiology an excessive inflammatory phase called “cytokine storm” that is closely linked to its high mortality (1, 2). During sepsis, the host response to a pathogen is mediated by the interaction between

**OPEN ACCESS**

**Edited by:**
Constantinos Tsioutis,
European University Cyprus, Cyprus

**Reviewed by:**
Bruno Bonaz,
Centre Hospitalier Universitaire de
Grenoble, France
Eric J. Liebler,
electroCore LLC, United States

**\*Correspondence:**
Eric Azabou
eric.azabou@aphp.fr;
eric.azabou@uvsq.fr

**Specialty section:**
This article was submitted to
Infectious Diseases - Surveillance,
Prevention and Treatment,
a section of the journal
Frontiers in Medicine

**Received:** 04 November 2020

**Accepted:** 23 March 2021

**Published:** 07 May 2021

**Citation:**
Azabou E, Bao G, Bounab R, Heming N and Annane D (2021)
Vagus Nerve Stimulation: A Potential
Adjunct Therapy for COVID-19.
Front. Med. 8:625836.
doi: 10.3389/fmed.2021.625836
pathogen-associated molecular pattern and their receptors located on innate immune cells (3). This interaction leads to activation of the innate immune cell, release of inflammatory cytokines, and recruitment of further cells of the immune system (4). When this immune response is exaggerated, excessive inflammation may lead to end tissue damage. All major organs may be affected during sepsis including altered hypothalamic-pituitary-adrenal and altered cardiovascular responses (5, 6). Disruption of the hypothalamic-pituitary-adrenal axis may translate in patients with sepsis into cardiovascular and organ dysfunction and an increase in the risk of death (5, 6). Impaired heart rate variability and high concentrations of circulating catecholamines and impaired sympathetic modulation are common findings of septic and septic shock patients, reflecting dysfunction of the medullary autonomic centers (7) and suggesting that central autonomic regulatory impairment contributes to circulatory failure (8–10). Clinical patterns concordant with these hypotheses have been documented in COVID-19 patients and support the hypothesis of a potential contribution of a dysfunction in autonomic tone to the cytokine release syndrome and related multiorgan damage in COVID-19 (11–17).

Specific treatment for COVID-19 is unfortunately lacking (18, 19). However, given the high mortality rate and economic damage to date, great efforts are being made worldwide to produce successful drugs (20). Particularly, pharmacological strategies that restore inflammatory control or inhibit cytokine release are being evaluated (21–23). Several drug therapies targeting this excessive inflammation, such as tocilizumab, an interleukin (IL)-6 inhibitor, corticosteroids, programmed cell death protein (PD)-1/PD-L1 checkpoint inhibition, cytokine-adsorption devices, and intravenous immunoglobulin have been identified as potentially useful and reliable approaches to counteract cytokine storm in COVID-19 patients (1, 2, 18, 24–32). Little attention is currently paid for non-drug therapeutic strategies targeting inflammatory and immunological processes that may be useful for reducing COVID-19-induced complications and improving patient outcome (33–35).

## VAGUS NERVE STIMULATION A POTENTIAL ADJUNCT THERAPY IN COVID-19

Modulating the activity of cholinergic anti-inflammatory pathways (CAPs) described by the group of KJ Tracey (36–44) has indeed become an important target of therapeutic research strategies for inflammatory diseases and sepsis (37, 38, 45–47). In fact, the CAP pathways innervate the spleen through the efferent vagus nerve and the splenic nerve relay and act on macrophages by transforming adrenergic stimulation into a cholinergic signal by the T cells of the spleen, which plays an anti-inflammatory effect (48).

About 80% of the vagus nerve is composed of afferent sensory fibers carrying information from the periphery to

the brain (49). Within the central nervous system, the vagus primarily projects to the nucleus of the solitary tract (NTS), releasing excitatory neurotransmitters (glutamate and aspartate), inhibitory neurotransmitter (gamma-aminobutyric acid), acetylcholine, norepinephrine, and neuropeptides implicated in signal transduction (49). In turn, the NTS has widespread efferent pathways to the parabrachial nucleus, reticular formation, basal forebrain, amygdala, hippocampus, hypothalamus, dorsal raphe, cerebellum, and spinal cord (50). NTS projections to brainstem nuclei (locus coeruleus and dorsal raphe magnus) modulate serotonin and norepinephrine release to the entire brain (51). Through efferent and afferent fibers, the vagus nerve plays a role in maintaining cardiovascular homeostasis and in modulating inflammation (52). The autonomic nervous system regulates the production of cytokines, through interactions with the hypothalamic-pituitary-adrenal axis, leading to the release of anti-inflammatory glucocorticoid hormones. Vagal efferent fibers also release acetylcholine (Ach), which, by interacting with α7-subunit-containing nicotinic receptors found in tissue macrophages, and dendritic cells, inhibit the release of proinflammatory cytokines such as tumor necrosis factor alpha (TNFα), IL-1β, IL-6, and IL-18 (36, 53). Inflammatory reflex signaling, which is enhanced by electrically stimulating the vagus nerve, significantly reduces cytokine production and attenuates disease severity in animal models of inflammatory diseases and in experimental models of sepsis (36, 54–57). Electrical stimulation of the vagus nerve attenuates inflammation in a variety of pathological conditions with little side effects (36, 58, 59). Recently, Meneses and colleagues demonstrated that vagus nerve stimulation attenuates the inflammatory response in the central nervous system induced by peripheral lipopolysaccharide challenge in rats (60). Kohoutova and colleagues recently demonstrated that vagus nerve stimulation attenuates multiple organ dysfunction in a porcine model of sepsis (61). These findings suggest that VNS could be a promising adjunctive therapy targeting inflammatory pathways in COVID-19 patients. VNS might attenuate sepsis-related inflammatory processes leading to endothelial activation, impaired microcirculation, multiorgan failure, and death. VNS may also exhibit favorable cardiovascular effects during sepsis, including antiarythmogen, decreased myocardial oxygen consumption, and improved diastole (62). Vagus nerve stimulation has a favorable safety track record. Implanted VNS devices have been used for decades to treat refractory partial-onset seizures and severe recurrent refractory depression with confirmed safety and only mild to moderate side effects that are predictable improve over time (63–65). More recently, non-invasive transcutaneous vagus nerve stimulation devices (t-VNS) have been developed and commercialized (66). Evidence from preclinical models (61, 67) as well as from several clinical reports (47, 68) is accumulating (68–72). Boezaart and Botha reported a drastic reduction of two COVID-19 patients treated with t-VNS (69). Non-invasive VNS as adjunct therapy in COVID-19 patients might alleviate organ dysfunction and improve patients’ outcome. Randomized controlled studies assessing the effectiveness of non-invasive vagus nerve stimulation as adjunct therapy to current best medical practice for COVID-19 are needed (72). Two studies
pathogen-associated molecular pattern and their receptors located on innate immune cells (3). This interaction leads to activation of the innate immune cell, release of inflammatory cytokines, and recruitment of further cells of the immune system (4). When this immune response is exaggerated, excessive inflammation may lead to end tissue damage. All major organs may be affected during sepsis including altered hypothalamic-pituitary-adrenal and altered cardiovascular responses (5, 6). Disruption of the hypothalamic-pituitary-adrenal axis may translate in patients with sepsis into cardiovascular and organ dysfunction and an increase in the risk of death (5, 6). Impaired heart rate variability and high concentrations of circulating catecholamines and impaired sympathetic modulation are common findings of septic and septic shock patients, reflecting dysfunction of the medullary autonomic centers (7) and suggesting that central autonomic regulatory impairment contributes to circulatory failure (8–10). Clinical patterns concordant with these hypotheses have been documented in COVID-19 patients and support the hypothesis of a potential contribution of a dysfunction in autonomic tone to the cytokine release syndrome and related multiorgan damage in COVID-19 (11–17).

Specific treatment for COVID-19 is unfortunately lacking (18, 19). However, given the high mortality rate and economic damage to date, great efforts are being made worldwide to produce successful drugs (20). Particularly, pharmacological strategies that restore inflammatory control or inhibit cytokine release are being evaluated (21–23). Several drug therapies targeting this excessive inflammation, such as tocilizumab, an interleukin (IL)-6 inhibitor, corticosteroids, programmed cell death protein (PD)-1/PD-L1 checkpoint inhibition, cytokine-adsorption devices, and intravenous immunoglobulin have been identified as potentially useful and reliable approaches to counteract cytokine storm in COVID-19 patients (1, 2, 18, 24–32). Little attention is currently paid for non-drug therapeutic strategies targeting inflammatory and immunological processes that may be useful for reducing COVID-19-induced complications and improving patient outcome (33–35).

## VAGUS NERVE STIMULATION A POTENTIAL ADJUNCT THERAPY IN COVID-19

Modulating the activity of cholinergic anti-inflammatory pathways (CAPs) described by the group of KJ Tracey (36–44) has indeed become an important target of therapeutic research strategies for inflammatory diseases and sepsis (37, 38, 45–47). In fact, the CAP pathways innervate the spleen through the efferent vagus nerve and the splenic nerve relay and act on macrophages by transforming adrenergic stimulation into a cholinergic signal by the T cells of the spleen, which plays an anti-inflammatory effect (48).

About 80% of the vagus nerve is composed of afferent sensory fibers carrying information from the periphery to

the brain (49). Within the central nervous system, the vagus primarily projects to the nucleus of the solitary tract (NTS), releasing excitatory neurotransmitters (glutamate and aspartate), inhibitory neurotransmitter (gamma-aminobutyric acid), acetylcholine, norepinephrine, and neuropeptides implicated in signal transduction (49). In turn, the NTS has widespread efferent pathways to the parabrachial nucleus, reticular formation, basal forebrain, amygdala, hippocampus, hypothalamus, dorsal raphe, cerebellum, and spinal cord (50). NTS projections to brainstem nuclei (locus coeruleus and dorsal raphe magnus) modulate serotonin and norepinephrine release to the entire brain (51). Through efferent and afferent fibers, the vagus nerve plays a role in maintaining cardiovascular homeostasis and in modulating inflammation (52). The autonomic nervous system regulates the production of cytokines, through interactions with the hypothalamic-pituitary-adrenal axis, leading to the release of anti-inflammatory glucocorticoid hormones. Vagal efferent fibers also release acetylcholine (Ach), which, by interacting with α7-subunit-containing nicotinic receptors found in tissue macrophages, and dendritic cells, inhibit the release of proinflammatory cytokines such as tumor necrosis factor alpha (TNFα), IL-1β, IL-6, and IL-18 (36, 53). Inflammatory reflex signaling, which is enhanced by electrically stimulating the vagus nerve, significantly reduces cytokine production and attenuates disease severity in animal models of inflammatory diseases and in experimental models of sepsis (36, 54–57). Electrical stimulation of the vagus nerve attenuates inflammation in a variety of pathological conditions with little side effects (36, 58, 59). Recently, Meneses and colleagues demonstrated that vagus nerve stimulation attenuates the inflammatory response in the central nervous system induced by peripheral lipopolysaccharide challenge in rats (60). Kohoutova and colleagues recently demonstrated that vagus nerve stimulation attenuates multiple organ dysfunction in a porcine model of sepsis (61). These findings suggest that VNS could be a promising adjunctive therapy targeting inflammatory pathways in COVID-19 patients. VNS might attenuate sepsis-related inflammatory processes leading to endothelial activation, impaired microcirculation, multiorgan failure, and death. VNS may also exhibit favorable cardiovascular effects during sepsis, including antiarythmogen, decreased myocardial oxygen consumption, and improved diastole (62). Vagus nerve stimulation has a favorable safety track record. Implanted VNS devices have been used for decades to treat refractory partial-onset seizures and severe recurrent refractory depression with confirmed safety and only mild to moderate side effects that are predictable improve over time (63–65). More recently, non-invasive transcutaneous vagus nerve stimulation devices (t-VNS) have been developed and commercialized (66). Evidence from preclinical models (61, 67) as well as from several clinical reports (47, 68) is accumulating (68–72). Boezaart and Botha reported a drastic reduction of two COVID-19 patients treated with t-VNS (69). Non-invasive VNS as adjunct therapy in COVID-19 patients might alleviate organ dysfunction and improve patients’ outcome. Randomized controlled studies assessing the effectiveness of non-invasive vagus nerve stimulation as adjunct therapy to current best medical practice for COVID-19 are needed (72). Two studies
evaluating the efficacy of non-invasive VNS in COVID-19 patients are now on going using the gammaCore® non-invasive vagal nerve stimulation device. The gammaCore® (electroCore, Inc., Basking Ridge, NJ) is handheld and requires no surgery or implants. The device is applied by healthcare providers or patients to the skin at the neck over the vagus nerve to deliver periodic doses of VNS non-invasively. Tariq Cheema and colleagues are conducting a prospective, randomized, controlled investigation designed to assess the reduction in respiratory distress in a COVID-19 population: the SAVIORII study NCT04382391. The primary objective is to reduce initiation of mechanical ventilation in patients with COVID-19 compared to the control group. Secondary objectives are to evaluate cytokine trends/prevent cytokine storms, evaluate supplemental oxygen requirements, decrease mortality of COVID-19 patients, and delay the onset of mechanical ventilation. The second ongoing clinical trial using the same device is conducted by Carlos Tornero and colleagues NCT04368156: the SAVIOR study. The SAVIOR study is a prospective, randomized, controlled study assessing vagus nerve stimulation in COVID-19 respiratory symptoms (72). The primary outcome measures were incidence of changes in specific clinical events such as the proportion of subjects requiring mechanical ventilation, days to onset of mechanical ventilation, oxygen support requirements, O₂ saturation, pain levels, PaO₂/FiO₂, coagulation, laboratory measurements related to circulating cytokines and inflammation, live discharge from the hospital, patient length of stay, mortality, need for intensive care, shortness of breath, device-related serious adverse events, and adverse events. The results of these trials will be informative, but additional, larger, studies are needed.

## REFERENCES

1. Soy M, Keser G, Atagunduz P, Tabak F, Atagunduz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. *Clin Rheumatol*. (2020) 39:2085-94. doi: 10.1007/s10067-020-05190-5

2. Vergallo C. Infusion of HLA-matched and static magnetic field-exposed allogenic lymphocytes treating lymphocytopenia and cytokine storm syndrome: a treatment proposal for COVID-19 patients. *Electromagn Biol Med*. (2020) 40:11-25. doi: 10.1080/15368378.2020.1830290

3. Klucinski P, Martirosian G. Role of cytokines and pathogen associated molecular pattern receptors in sepsis. *Przegl Epidemiol*. (2005) 59:695-701.

4. Angus DC, van der Poll T. Severe sepsis and septic shock. *N Engl J Med*. (2013) 369:2063. doi: 10.1056/NEJMc1312359

5. Annane D. The role of ACTH and corticosteroids for sepsis and septic shock: an update. *Front Endocrinol* (Lausanne). (2016) 7:70. doi: 10.3389/fendo.2016.00070

6. da Costa LH, Junior NN, Catalao CH, Sharshar T, Chretien F, da Rocha MJ. Vasopressin impairment during sepsis is associated with hypothalamic intrinsic apoptotic pathway and microglial activation. *Mol Neurobiol*. (2016) 54:5526-33. doi: 10.1007/s12035-016-0094-x

7. Aboab J, Polito A, Orlikowski D, Sharshar T, Castel M, Annane D. Hydrocortisone effects on cardiovascular variability in septic shock: a spectral analysis approach. *Crit Care Med*. (2008) 36:1481-6. doi: 10.1097/CCM.0b013e31816f48f2

## DISCUSSION

COVID-19 remains a major healthcare issue worldwide. Excessive inflammation and its end organ consequences are key elements in the pathogenesis of COVID-19-induced multiple organ dysfunction (19, 26, 32). Specific treatment for COVID-19 is unfortunately lacking. Several promising pharmacological strategies aimed at modulating inflammation in COVID-19 are being evaluated worldwide. However, little attention is currently paid for non-drug therapeutic strategies targeting inflammatory and immunological processes, which may be useful for reducing COVID-19-induced complications and improving patient outcome (33-35). Vagal neurostimulation has a wide field of therapeutic benefit for patients and should be combined with the best current medical strategies (15, 17, 69, 70). Vagus nerve stimulation attenuates inflammation both in experimental models and preliminary data in man. The development non-invasive vagal nerve stimulation (t-VNS), a non-pharmacological adjuvant, may help reduce the burden of COVID-19 and deserve to be investigated. The aim of this paper is to promote the emergence of original studies assessing non-invasive VNS as an adjuvant treatment for the management of COVID-19.

## AUTHOR CONTRIBUTIONS

EA and DA conceived the manuscript. EA, NH, GB, RB, and DA were involved in early discussions and mapping the concepts that led to this paper and wrote the first draft of the manuscript. All authors read and critically reviewed drafts of the manuscript.

8. Annane D, Trabold F, Sharshar T, Jarrin I, Blanc AS, Raphael JC, et al. Inappropriate sympathetic activation at onset of septic shock: a spectral analysis approach. *Am J Respir Crit Care Med*. (1999) 160:458-65. doi: 10.1164/ajrccm.160.2.9810073

9. Annane D. Adjunctive treatment in septic shock: what's next? *Presse Med*. (2016) 45:105-9. doi: 10.1016/j.lpm.2016.03.004

10. Annane D, Buisson CB, Cariou A, Martin C, Misset B, Renault A, et al. Design and conduct of the activated protein C and corticosteroids for human septic shock (APROCCHSS) trial. *Ann Intensive Care*. (2016) 6:43. doi: 10.1186/s13613-016-0165-1

11. Ghosh R, Roy D, Sengupta S, Benito-Leon J. Autonomic dysfunction heralding acute motor axonal neuropathy in COVID-19. *J Neurovirol*. (2020) 26:964-6. doi: 10.1007/s13365-020-00908-2

12. Goldstein DS. The extended autonomic system, dyshomeostasis, and COVID-19. *Clin Auton Res*. (2020) 30:299-315. doi: 10.1007/s10286-020-00714-0

13. Gonzalez-Duarte A, Norcliffe-Kaufmann L. Is 'happy hypoxia' in COVID-19 a disorder of autonomic interoception? A hypothesis. *Clin Auton Res*. (2020) 30:331-3. doi: 10.1007/s10286-020-00715-z

14. Guaraldi P, Barletta G, Baschieri F, Calandra-Buonaura G, Provini F, Cortelli P. Testing cardiovascular autonomic function in the COVID-19 era: lessons from Bologna's Autonomic Unit. *Clin Auton Res*. (2020) 30:325-30. doi: 10.1007/s10286-020-00710-4

15. Figueroa JJ, Cheshire WP, Claydon VE, Norcliffe-Kaufmann L, Peltier A, Singer W, et al. Autonomic function testing in the COVID-19 pandemic:
evaluating the efficacy of non-invasive VNS in COVID-19 patients are now on going using the gammaCore® non-invasive vagal nerve stimulation device. The gammaCore® (electroCore, Inc., Basking Ridge, NJ) is handheld and requires no surgery or implants. The device is applied by healthcare providers or patients to the skin at the neck over the vagus nerve to deliver periodic doses of VNS non-invasively. Tariq Cheema and colleagues are conducting a prospective, randomized, controlled investigation designed to assess the reduction in respiratory distress in a COVID-19 population: the SAVIORII study NCT04382391. The primary objective is to reduce initiation of mechanical ventilation in patients with COVID-19 compared to the control group. Secondary objectives are to evaluate cytokine trends/prevent cytokine storms, evaluate supplemental oxygen requirements, decrease mortality of COVID-19 patients, and delay the onset of mechanical ventilation. The second ongoing clinical trial using the same device is conducted by Carlos Tornero and colleagues NCT04368156: the SAVIOR study. The SAVIOR study is a prospective, randomized, controlled study assessing vagus nerve stimulation in COVID-19 respiratory symptoms (72). The primary outcome measures were incidence of changes in specific clinical events such as the proportion of subjects requiring mechanical ventilation, days to onset of mechanical ventilation, oxygen support requirements, O₂ saturation, pain levels, PaO₂/FiO₂, coagulation, laboratory measurements related to circulating cytokines and inflammation, live discharge from the hospital, patient length of stay, mortality, need for intensive care, shortness of breath, device-related serious adverse events, and adverse events. The results of these trials will be informative, but additional, larger, studies are needed.

## REFERENCES

1. Soy M, Keser G, Atagunduz P, Tabak F, Atagunduz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. *Clin Rheumatol*. (2020) 39:2085-94. doi: 10.1007/s10067-020-05190-5

2. Vergallo C. Infusion of HLA-matched and static magnetic field-exposed allogenic lymphocytes treating lymphocytopenia and cytokine storm syndrome: a treatment proposal for COVID-19 patients. *Electromagn Biol Med*. (2020) 40:11-25. doi: 10.1080/15368378.2020.1830290

3. Klucinski P, Martirosian G. Role of cytokines and pathogen associated molecular pattern receptors in sepsis. *Przegl Epidemiol*. (2005) 59:695-701.

4. Angus DC, van der Poll T. Severe sepsis and septic shock. *N Engl J Med*. (2013) 369:2063. doi: 10.1056/NEJMc1312359

5. Annane D. The role of ACTH and corticosteroids for sepsis and septic shock: an update. *Front Endocrinol* (Lausanne). (2016) 7:70. doi: 10.3389/fendo.2016.00070

6. da Costa LH, Junior NN, Catalao CH, Sharshar T, Chretien F, da Rocha MJ. Vasopressin impairment during sepsis is associated with hypothalamic intrinsic apoptotic pathway and microglial activation. *Mol Neurobiol*. (2016) 54:5526-33. doi: 10.1007/s12035-016-0094-x

7. Aboab J, Polito A, Orlikowski D, Sharshar T, Castel M, Annane D. Hydrocortisone effects on cardiovascular variability in septic shock: a spectral analysis approach. *Crit Care Med*. (2008) 36:1481-6. doi: 10.1097/CCM.0b013e31816f48f2

## DISCUSSION

COVID-19 remains a major healthcare issue worldwide. Excessive inflammation and its end organ consequences are key elements in the pathogenesis of COVID-19-induced multiple organ dysfunction (19, 26, 32). Specific treatment for COVID-19 is unfortunately lacking. Several promising pharmacological strategies aimed at modulating inflammation in COVID-19 are being evaluated worldwide. However, little attention is currently paid for non-drug therapeutic strategies targeting inflammatory and immunological processes, which may be useful for reducing COVID-19-induced complications and improving patient outcome (33-35). Vagal neurostimulation has a wide field of therapeutic benefit for patients and should be combined with the best current medical strategies (15, 17, 69, 70). Vagus nerve stimulation attenuates inflammation both in experimental models and preliminary data in man. The development non-invasive vagal nerve stimulation (t-VNS), a non-pharmacological adjuvant, may help reduce the burden of COVID-19 and deserve to be investigated. The aim of this paper is to promote the emergence of original studies assessing non-invasive VNS as an adjuvant treatment for the management of COVID-19.

## AUTHOR CONTRIBUTIONS

EA and DA conceived the manuscript. EA, NH, GB, RB, and DA were involved in early discussions and mapping the concepts that led to this paper and wrote the first draft of the manuscript. All authors read and critically reviewed drafts of the manuscript.

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10. Annane D, Buisson CB, Cariou A, Martin C, Misset B, Renault A, et al. Design and conduct of the activated protein C and corticosteroids for human septic shock (APROCCHSS) trial. *Ann Intensive Care*. (2016) 6:43. doi: 10.1186/s13613-016-0165-1

11. Ghosh R, Roy D, Sengupta S, Benito-Leon J. Autonomic dysfunction heralding acute motor axonal neuropathy in COVID-19. *J Neurovirol*. (2020) 26:964-6. doi: 10.1007/s13365-020-00908-2

12. Goldstein DS. The extended autonomic system, dyshomeostasis, and COVID-19. *Clin Auton Res*. (2020) 30:299-315. doi: 10.1007/s10286-020-00714-0

13. Gonzalez-Duarte A, Norcliffe-Kaufmann L. Is 'happy hypoxia' in COVID-19 a disorder of autonomic interoception? A hypothesis. *Clin Auton Res*. (2020) 30:331-3. doi: 10.1007/s10286-020-00715-z

14. Guaraldi P, Barletta G, Baschieri F, Calandra-Buonaura G, Provini F, Cortelli P. Testing cardiovascular autonomic function in the COVID-19 era: lessons from Bologna's Autonomic Unit. *Clin Auton Res*. (2020) 30:325-30. doi: 10.1007/s10286-020-00710-4

15. Figueroa JJ, Cheshire WP, Claydon VE, Norcliffe-Kaufmann L, Peltier A, Singer W, et al. Autonomic function testing in the COVID-19 pandemic:
an American Autonomic Society position statement. *Clin Auton Res.* (2020) 30:295-7. doi: 10.1007/s10286-020-00702-4

16. Logmin K, Karam M, Schichel T, Harmel J, Wojtecki L. Non-epileptic seizures in autonomic dysfunction as the initial symptom of COVID-19. *J Neurol.* (2020) 267:2490-1. doi: 10.1007/s00415-020-09904-2

17. Chigr F, Merzouki M, Najimi M. Autonomic brain centers and pathophysiology of COVID-19. *ACS Chem Neurosci.* (2020) 11:1520-2. doi: 10.1021/acschemneuro.0c00265

18. Tang Y, Liu J, Zhang D, Xu Z, Ji J, Wen C. Cytokine storm in COVID-19: the current evidence and treatment strategies. *Front Immunol.* (2020) 11:1708. doi: 10.3389/fimmu.2020.01708

19. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. *JAMA.* (2020) 324:782-93. doi: 10.1001/jama.2020.12839

20. Boregowda U, Perisetti A, Nanjappa A, Gajendran M, Kutti Sridharan G, Goyal H. Addition of tocilizumab to the standard of care reduces mortality in severe COVID-19: a systematic review and meta-analysis. *Front Med* (Lausanne). (2020) 7:586221. doi: 10.3389/fmed.2020.586221

21. Calabrese LH. Cytokine storm and the prospects for immunotherapy with COVID-19. *Cleve Clin J Med.* (2020) 87:389-93. doi: 10.3949/ccjm.87a.ccc008

22. Horowitz RI, Freeman PR. Three novel prevention, diagnostic, and treatment options for COVID-19 urgently necessitating controlled randomized trials. *Med Hypotheses.* (2020) 143:109851. doi: 10.1016/j.mehy.2020.109851

23. Wang J, Jiang M, Chen X, Montaner LJ. Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts. *J Leukoc Biol.* (2020) 108:17-41. doi: 10.1002/JLB.3COVR0520-272R

24. Gonzalez-Nicolas MA, Gonzalez-Guerrero C, Perez-Fernandez VA, Lazaro A. Cilastatin: a potential treatment strategy against COVID-19 that may decrease viral replication and protect from the cytokine storm. *Clin Kidney J.* (2020) 13:903-5. doi: 10.1093/ckj/sfaa193

25. Chitturi KR, Thacker S, Al-Saadi MA, Kassi M. Successful treatment of acute heart failure in COVID-19-induced cytokine storm with tocilizumab: a case report. *Eur Heart J Case Rep.* (2020) 4:1-6. doi: 10.1093/ehjcr/ytaa188

26. Mustafa MI, Abdelmoneim AH, Mahmoud EM, Makhawi AM. Cytokine storm in COVID-19 patients, its impact on organs and potential treatment by QTY code-designed detergent-free chemokine receptors. *Mediators Inflamm.* (2020) 2020:819896. doi: 10.21467/preprints.139

27. Bradshaw PC, Seeds WA, Miller AC, Mahajan VR, Curtis WM. COVID-19: proposing a ketone-based metabolic therapy as a treatment to blunt the cytokine storm. *Oxid Med Cell Longev.* (2020) 2020:6401341. doi: 10.1155/2020/6401341

28. Langer-Gould A, Smith JB, Gonzales EG, Castillo RD, Figueroa JG, Ramanathan A, et al. Early identification of COVID-19 cytokine storm and treatment with anakinra or tocilizumab. *Int J Infect Dis.* (2020) 99:291-7. doi: 10.1016/j.ijid.2020.07.081

29. Yessayan L, Szamosfalvi B, Napolitano L, Singer B, Kurabayashi K, Song Y, et al. Treatment of cytokine storm in COVID-19 patients with immunomodulatory therapy. *ASAIO J.* (2020) 66:1079-83. doi: 10.1097/MAT.0000000000001239

30. Farooqi F, Dhawan N, Morgan R, Dinh J, Nedd K, Yatzkan G. Treatment of severe COVID-19 with tocilizumab mitigates cytokine storm and averts mechanical ventilation during acute respiratory distress: a case report and literature review. *Trop Med Infect Dis.* (2020) 5:112. doi: 10.3390/tropicalmed5030112

31. Dalamaga M, Karampela I, Mantzoros CS. Commentary: Phosphodiesterase 4 inhibitors as potential adjunct treatment targeting the cytokine storm in COVID-19. *Metabolism.* (2020) 109:154282. doi: 10.1016/j.metabol.2020.154282

32. Saha A, Sharma AR, Bhattacharya M, Sharma G, Lee SS, Chakraborty C. Tocilizumab: a therapeutic option for the treatment of cytokine storm syndrome in COVID-19. *Arch Med Res.* (2020) 51:595-7. doi: 10.1016/j.arcmed.2020.05.009

33. Azabou E, Bao G, Heming N, Bounab R, Moine P, Chevallier S, et al. Randomized controlled study evaluating efficiency of low intensity transcranial direct current stimulation (tDCS) for dyspnea relief in mechanically ventilated COVID-19 patients in ICU: The tDCS-DYSP-COVID Protocol.

The tDCS-DYSP-COVID Protocol. *Front Med* (Lausanne). (2020) 7:372. doi: 10.3389/fmed.2020.000372

34. Fudim M, Qadri YJ, Ghadimi K, MacLeod DB, Molinger J, Piccini JP, et al. Implications for neuromodulation therapy to control inflammation and related organ dysfunction in COVID-19. *J Cardiovasc Transl Res.* (2020) 13:894-9. doi: 10.1007/s12265-020-10031-6

35. Pilloni G, Bikson M, Badran BW, George MS, Kautz SA, Okano AH, et al. Update on the use of transcranial electrical brain stimulation to manage acute and chronic COVID-19 symptoms. *Front Hum Neurosci.* (2020) 14:595567. doi: 10.3389/fnhum.2020.595567

36. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. *Nature.* (2000) 405:458-62. doi: 10.1038/35013070

37. Huston JM. The vagus nerve and the inflammatory reflex: wandering on a new treatment paradigm for systemic inflammation and sepsis. *Surg Infect* (Larchmt). (2012) 13:187-93. doi: 10.1089/sur.2012.126

38. Martelli D, McKinley MJ, McAllen RM. The cholinergic anti-inflammatory pathway: a critical review. *Auton Neurosci.* (2014) 182:65-9. doi: 10.1016/j.autneu.2013.12.007

39. Oke SL, Tracey KJ. The inflammatory reflex and the role of complementary and alternative medical therapies. *Ann N Y Acad Sci.* (2009) 1172:172-80. doi: 10.1196/annals.1393.013

40. Olofsson PS, Katz DA, Rosas-Ballina M, Levine YA, Ochani M, Valdes-Ferrer SI, et al. Alpha7 nicotinic acetylcholine receptor (alpha7nAChR) expression in bone marrow-derived non-T cells is required for the inflammatory reflex. *Mol Med.* (2012) 18:539-43. doi: 10.2119/molmed.2011.00405

41. Pavlov VA, Chavan SS. Tracey KJ. Bioelectronic medicine: from preclinical studies on the inflammatory reflex to new approaches in disease diagnosis and treatment. *Cold Spring Harb Perspect Med.* (2020) 10:a034140. doi: 10.1101/cshperspect.a034140

42. Pavlov VA, Tracey KJ. The vagus nerve and the inflammatory reflex-linking immunity and metabolism. *Nat Rev Endocrinol.* (2012) 8:743-54. doi: 10.1038/nrendo.2012.189

43. Tarnawski L, Reardon C, Caravaca AS, Rosas-Ballina M, Tusche MW, Drake AR, et al. Adenyllyl cyclase 6 mediates inhibition of TNF in the inflammatory reflex. *Front Immunol.* (2018) 9:2648. doi: 10.3389/fimmu.2018.02648

44. Tracey KJ. The inflammatory reflex. *Nature.* (2002) 420:853-9. doi: 10.1038/nature01321

45. Wu YJ, Wang L, Ji CF, Gu SF, Yin Q, Zuo J. The role of alpha7nAChR-mediated cholinergic anti-inflammatory pathway in immune cells. *Inflammation.* (2021). doi: 10.1007/s10753-020-01396-6. [Epub ahead of print].

46. Yin Q, Wu YJ, Pan S, Wang DD, Tao MQ, Pei WY, et al. Activation of cholinergic anti-inflammatory pathway in peripheral immune cells involved in therapeutic actions of alpha-mangostin on collagen-induced arthritis in rats. *Drug Des Devel Ther.* (2020) 14:1983-93. doi: 10.2147/DDDT.S249865

47. Zi S, Li J, Liu L, Liu F. Cholinergic anti-inflammatory pathway and its role in treatment of sepsis. *Zhong Nan Da Xue Xue Bao Yi Xue Ban.* (2020) 45:68-73. doi: 10.11817/j.issn.1672-7347.2020.180651

48. Hu J, Liu S, Ma T. Research progress of exploring the treatment of sepsis based on cholinergic anti-inflammatory pathway. *Zhonghua Wei Zhong Bing Ji Jiu Yi Xue.* (2021) 33:122-5. doi: 10.3760/cma.j.cn121430-20200421-00318

49. Lulic D, Ahmadian A, Baaj AA, Benbadis SR, Vale FL. Vagus nerve stimulation. *Neurosurg Focus.* (2009) 27:E5. doi: 10.3171/2009.6.FOCUS09126

50. Ansari S, Chaudhri K, Al Moutaery KA. Vagus nerve stimulation: indications and limitations. *Acta Neurochir Suppl.* (2007) 97:281-6. doi: 10.1007/978-3-211-33081-4_31

51. Henry TR. Therapeutic mechanisms of vagus nerve stimulation. *Neurology.* (2002) 59:S3-14. doi: 10.1212/WNL.59.6_suppl_4.S3

52. Berthoud HR, Neuhuber WL. Functional and chemical anatomy of the afferent vagal system. *Auton Neurosci.* (2000) 85:1-17. doi: 10.1016/S1566-0702(00)00215-0

53. Rosas-Ballina M, Ochani M, Parrish WR, Ochani K, Harris YT, Huston JM, et al. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. *Proc Natl Acad Sci USA.* (2008) 105:11008-13. doi: 10.1073/pnas.0803237105
an American Autonomic Society position statement. *Clin Auton Res.* (2020) 30:295-7. doi: 10.1007/s10286-020-00702-4

16. Logmin K, Karam M, Schichel T, Harmel J, Wojtecki L. Non-epileptic seizures in autonomic dysfunction as the initial symptom of COVID-19. *J Neurol.* (2020) 267:2490-1. doi: 10.1007/s00415-020-09904-2

17. Chigr F, Merzouki M, Najimi M. Autonomic brain centers and pathophysiology of COVID-19. *ACS Chem Neurosci.* (2020) 11:1520-2. doi: 10.1021/acschemneuro.0c00265

18. Tang Y, Liu J, Zhang D, Xu Z, Ji J, Wen C. Cytokine storm in COVID-19: the current evidence and treatment strategies. *Front Immunol.* (2020) 11:1708. doi: 10.3389/fimmu.2020.01708

19. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. *JAMA.* (2020) 324:782-93. doi: 10.1001/jama.2020.12839

20. Boregowda U, Perisetti A, Nanjappa A, Gajendran M, Kutti Sridharan G, Goyal H. Addition of tocilizumab to the standard of care reduces mortality in severe COVID-19: a systematic review and meta-analysis. *Front Med* (Lausanne). (2020) 7:586221. doi: 10.3389/fmed.2020.586221

21. Calabrese LH. Cytokine storm and the prospects for immunotherapy with COVID-19. *Cleve Clin J Med.* (2020) 87:389-93. doi: 10.3949/ccjm.87a.ccc008

22. Horowitz RI, Freeman PR. Three novel prevention, diagnostic, and treatment options for COVID-19 urgently necessitating controlled randomized trials. *Med Hypotheses.* (2020) 143:109851. doi: 10.1016/j.mehy.2020.109851

23. Wang J, Jiang M, Chen X, Montaner LJ. Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts. *J Leukoc Biol.* (2020) 108:17-41. doi: 10.1002/JLB.3COVR0520-272R

24. Gonzalez-Nicolas MA, Gonzalez-Guerrero C, Perez-Fernandez VA, Lazaro A. Cilastatin: a potential treatment strategy against COVID-19 that may decrease viral replication and protect from the cytokine storm. *Clin Kidney J.* (2020) 13:903-5. doi: 10.1093/ckj/sfaa193

25. Chitturi KR, Thacker S, Al-Saadi MA, Kassi M. Successful treatment of acute heart failure in COVID-19-induced cytokine storm with tocilizumab: a case report. *Eur Heart J Case Rep.* (2020) 4:1-6. doi: 10.1093/ehjcr/ytaa188

26. Mustafa MI, Abdelmoneim AH, Mahmoud EM, Makhawi AM. Cytokine storm in COVID-19 patients, its impact on organs and potential treatment by QTY code-designed detergent-free chemokine receptors. *Mediators Inflamm.* (2020) 2020:819896. doi: 10.21467/preprints.139

27. Bradshaw PC, Seeds WA, Miller AC, Mahajan VR, Curtis WM. COVID-19: proposing a ketone-based metabolic therapy as a treatment to blunt the cytokine storm. *Oxid Med Cell Longev.* (2020) 2020:6401341. doi: 10.1155/2020/6401341

28. Langer-Gould A, Smith JB, Gonzales EG, Castillo RD, Figueroa JG, Ramanathan A, et al. Early identification of COVID-19 cytokine storm and treatment with anakinra or tocilizumab. *Int J Infect Dis.* (2020) 99:291-7. doi: 10.1016/j.ijid.2020.07.081

29. Yessayan L, Szamosfalvi B, Napolitano L, Singer B, Kurabayashi K, Song Y, et al. Treatment of cytokine storm in COVID-19 patients with immunomodulatory therapy. *ASAIO J.* (2020) 66:1079-83. doi: 10.1097/MAT.0000000000001239

30. Farooqi F, Dhawan N, Morgan R, Dinh J, Nedd K, Yatzkan G. Treatment of severe COVID-19 with tocilizumab mitigates cytokine storm and averts mechanical ventilation during acute respiratory distress: a case report and literature review. *Trop Med Infect Dis.* (2020) 5:112. doi: 10.3390/tropicalmed5030112

31. Dalamaga M, Karampela I, Mantzoros CS. Commentary: Phosphodiesterase 4 inhibitors as potential adjunct treatment targeting the cytokine storm in COVID-19. *Metabolism.* (2020) 109:154282. doi: 10.1016/j.metabol.2020.154282

32. Saha A, Sharma AR, Bhattacharya M, Sharma G, Lee SS, Chakraborty C. Tocilizumab: a therapeutic option for the treatment of cytokine storm syndrome in COVID-19. *Arch Med Res.* (2020) 51:595-7. doi: 10.1016/j.arcmed.2020.05.009

33. Azabou E, Bao G, Heming N, Bounab R, Moine P, Chevallier S, et al. Randomized controlled study evaluating efficiency of low intensity transcranial direct current stimulation (tDCS) for dyspnea relief in mechanically ventilated COVID-19 patients in ICU: The tDCS-DYSP-COVID Protocol.

The tDCS-DYSP-COVID Protocol. *Front Med* (Lausanne). (2020) 7:372. doi: 10.3389/fmed.2020.000372

34. Fudim M, Qadri YJ, Ghadimi K, MacLeod DB, Molinger J, Piccini JP, et al. Implications for neuromodulation therapy to control inflammation and related organ dysfunction in COVID-19. *J Cardiovasc Transl Res.* (2020) 13:894-9. doi: 10.1007/s12265-020-10031-6

35. Pilloni G, Bikson M, Badran BW, George MS, Kautz SA, Okano AH, et al. Update on the use of transcranial electrical brain stimulation to manage acute and chronic COVID-19 symptoms. *Front Hum Neurosci.* (2020) 14:595567. doi: 10.3389/fnhum.2020.595567

36. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. *Nature.* (2000) 405:458-62. doi: 10.1038/35013070

37. Huston JM. The vagus nerve and the inflammatory reflex: wandering on a new treatment paradigm for systemic inflammation and sepsis. *Surg Infect* (Larchmt). (2012) 13:187-93. doi: 10.1089/sur.2012.126

38. Martelli D, McKinley MJ, McAllen RM. The cholinergic anti-inflammatory pathway: a critical review. *Auton Neurosci.* (2014) 182:65-9. doi: 10.1016/j.autneu.2013.12.007

39. Oke SL, Tracey KJ. The inflammatory reflex and the role of complementary and alternative medical therapies. *Ann N Y Acad Sci.* (2009) 1172:172-80. doi: 10.1196/annals.1393.013

40. Olofsson PS, Katz DA, Rosas-Ballina M, Levine YA, Ochani M, Valdes-Ferrer SI, et al. Alpha7 nicotinic acetylcholine receptor (alpha7nAChR) expression in bone marrow-derived non-T cells is required for the inflammatory reflex. *Mol Med.* (2012) 18:539-43. doi: 10.2119/molmed.2011.00405

41. Pavlov VA, Chavan SS. Tracey KJ. Bioelectronic medicine: from preclinical studies on the inflammatory reflex to new approaches in disease diagnosis and treatment. *Cold Spring Harb Perspect Med.* (2020) 10:a034140. doi: 10.1101/cshperspect.a034140

42. Pavlov VA, Tracey KJ. The vagus nerve and the inflammatory reflex-linking immunity and metabolism. *Nat Rev Endocrinol.* (2012) 8:743-54. doi: 10.1038/nrendo.2012.189

43. Tarnawski L, Reardon C, Caravaca AS, Rosas-Ballina M, Tusche MW, Drake AR, et al. Adenyllyl cyclase 6 mediates inhibition of TNF in the inflammatory reflex. *Front Immunol.* (2018) 9:2648. doi: 10.3389/fimmu.2018.02648

44. Tracey KJ. The inflammatory reflex. *Nature.* (2002) 420:853-9. doi: 10.1038/nature01321

45. Wu YJ, Wang L, Ji CF, Gu SF, Yin Q, Zuo J. The role of alpha7nAChR-mediated cholinergic anti-inflammatory pathway in immune cells. *Inflammation.* (2021). doi: 10.1007/s10753-020-01396-6. [Epub ahead of print].

46. Yin Q, Wu YJ, Pan S, Wang DD, Tao MQ, Pei WY, et al. Activation of cholinergic anti-inflammatory pathway in peripheral immune cells involved in therapeutic actions of alpha-mangostin on collagen-induced arthritis in rats. *Drug Des Devel Ther.* (2020) 14:1983-93. doi: 10.2147/DDDT.S249865

47. Zi S, Li J, Liu L, Liu F. Cholinergic anti-inflammatory pathway and its role in treatment of sepsis. *Zhong Nan Da Xue Xue Bao Yi Xue Ban.* (2020) 45:68-73. doi: 10.11817/j.issn.1672-7347.2020.180651

48. Hu J, Liu S, Ma T. Research progress of exploring the treatment of sepsis based on cholinergic anti-inflammatory pathway. *Zhonghua Wei Zhong Bing Ji Jiu Yi Xue.* (2021) 33:122-5. doi: 10.3760/cma.j.cn121430-20200421-00318

49. Lulic D, Ahmadian A, Baaj AA, Benbadis SR, Vale FL. Vagus nerve stimulation. *Neurosurg Focus.* (2009) 27:E5. doi: 10.3171/2009.6.FOCUS09126

50. Ansari S, Chaudhri K, Al Moutaery KA. Vagus nerve stimulation: indications and limitations. *Acta Neurochir Suppl.* (2007) 97:281-6. doi: 10.1007/978-3-211-33081-4_31

51. Henry TR. Therapeutic mechanisms of vagus nerve stimulation. *Neurology.* (2002) 59:S3-14. doi: 10.1212/WNL.59.6_suppl_4.S3

52. Berthoud HR, Neuhuber WL. Functional and chemical anatomy of the afferent vagal system. *Auton Neurosci.* (2000) 85:1-17. doi: 10.1016/S1566-0702(00)00215-0

53. Rosas-Ballina M, Ochani M, Parrish WR, Ochani K, Harris YT, Huston JM, et al. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. *Proc Natl Acad Sci USA.* (2008) 105:11008-13. doi: 10.1073/pnas.0803237105
54. Andersson U, Tracey KJ. Neural reflexes in inflammation and immunity. *J Exp Med.* (2012) 209:1057-68. doi: 10.1084/jem.20120571

55. Huston JM, Ochani M, Rosas-Ballina M, Liao H, Ochani K, Pavlov VA, et al. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. *J Exp Med.* (2006) 203:1623-8. doi: 10.1084/jem.20052362

56. Meregnani J, Clarencon D, Vivier M, Peinnequin A, Mouret C, Sinniger V, et al. Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease. *Auton Neurosci.* (2011) 160:82-9. doi: 10.1016/j.autneu.2010.10.007

57. van Maanen MA, Lebre MC, van der Poll T, LaRosa GJ, Elbaum D, Vervoordeldonk MJ, et al. Stimulation of nicotinic acetylcholine receptors attenuates collagen-induced arthritis in mice. *Arthritis Rheum.* (2009) 60:114-22. doi: 10.1002/art.24177

58. Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Schuurman PR, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. *Proc Natl Acad Sci USA.* (2016) 113:8284-9. doi: 10.1073/pnas.1605635113

59. Yamakawa K, Matsumoto N, Imamura Y, Muroya T, Yamada T, Nakagawa J, et al. Electrical vagus nerve stimulation attenuates systemic inflammation and improves survival in a rat heatstroke model. *PLoS ONE.* (2013) 8:e56728. doi: 10.1371/journal.pone.0056728

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**Conflict of Interest:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Azabou, Bao, Bounab, Heming and Annane. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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55. Huston JM, Ochani M, Rosas-Ballina M, Liao H, Ochani K, Pavlov VA, et al. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. *J Exp Med.* (2006) 203:1623–8. doi: 10.1084/jem.20052362

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**Conflict of Interest:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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