The causative agent of the current coronavirus disease 2019 (COVID-19) pandemic is the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
COVID-19 was initially described as lung inflammation, or pneumonia, in older adults. However, we now know that SARS-CoV-2 infections can cause a wide range of symptoms in people of all ages, ranging from no symptoms at all to systemic inflammation and even death.
An excessive inflammatory phase called “cytokine storm” can occur in severely infected patients. The cytokine storm is closely connected with the mortality of COVID-19 patients. As a result of sepsis, pathogen-associated molecular patterns and their receptors on innate immune cells mediate the host response. This interaction triggers the innate immune cell, and subsequently, inflammatory cytokines are released, and other cells associated with the immune response get deployed.
However, an overstated immune response results in the extreme release of inflammatory cytokines, leading to tissue damage, organ dysfunction, erratic cardiovascular response, and altered hypothalamic-pituitary-adrenal response. Hence, excessive cytokine release increases the risk of mortality.
In septic shock patients, an erratic heart rate and a high level of circulating catecholamines are commonly found. This reflects dysfunction of the medullary autonomic centers and, thereby, indicates central autonomic regulatory damages causing circulatory failure.
Such an occurrence has been noted in patients with severe COVID-19 disease, where researchers have noted a connection between cytokine release syndrome and multiorgan failure.
Although there is no specific treatment for COVID-19, drug repurposing has enabled the identification of drugs that might be effective against the disease. Mainly, drugs that can inhibit cytokine release and reinstate inflammatory control are being explored.
Tocilizumab has been identified as a potential drug to counteract cytokine storm in COVID-19 patients. This drug functions as an interleukin (IL)-6 inhibitor, programmed cell death protein (PD)-1/PD-L1 checkpoint inhibition, corticosteroid, cytokine-adsorption device, and intravenous immunoglobulin.
A research gap exists in terms of non-drug therapeutic strategies aimed at inflammatory and immunological processes. Such an approach could be effective for treating COVID-19 patients.
A new hypothesis and theory article has been published in the Frontiers in Medicine which focuses on the stimulation of the vagus nerve as a potential COVID-19 therapy.
In this approach, the activity of cholinergic anti-inflammatory pathways is manipulated, and, recently, this therapeutic strategy has become an important approach for the treatment of inflammatory diseases and sepsis.
This therapy exploits the cholinergic anti-inflammatory pathways (CAP) pathways that innervate the spleen via the efferent vagus nerve. The spleen nerve relays and acts on macrophages by altering adrenergic stimulation into a cholinergic signal by the T cells of the spleen, which in turn causes an anti-inflammatory effect.
Around 80% of the vagus nerve consists of afferent sensory fibers, which carry information from the periphery to the brain. In the central nervous system, the vagus nerve projects to the nucleus of the solitary tract (NTS) and releases excitatory neurotransmitters (glutamate and aspartate), norepinephrine, acetylcholine, an inhibitory neurotransmitter (gamma-aminobutyric acid), and neuropeptides, which are involved in signal transduction. NTS is associated with the basal forebrain, hippocampus, amygdala, hypothalamus, cerebellum, spinal cord, etc. NTS projections to brainstem nuclei alter the release of serotonin and norepinephrine in the brain. Using efferent and afferent fibers, the vagus nerve plays a crucial role in sustaining cardiovascular homeostasis and controlling inflammation.
Scientists have explained that the autonomic nervous system controls the production of cytokines. This is done by regulating interactions with the hypothalamic-pituitary-adrenal axis, which causes the release of anti-inflammatory hormones, i.e., glucocorticoid.
Additionally, acetylcholine (Ach) is released by vagal efferent fibers, which interacts with α7subunit-containing nicotinic receptors present in macrophages and dendritic cells. This integration results in the inhibition of the release of proinflammatory cytokines, i.e., tumor necrosis factor-alpha (TNFα), IL-1β, IL-6, and IL-18.
The electrical stimulation of the vagus nerve enhances the inflammatory reflex signaling and lowers the production of cytokine. This approach has successfully reduced disease severity in an animal study associated with inflammatory diseases and sepsis.
Scientists have revealed that the approach of electrical stimulation of the vagus nerve has minimal side effects. For instance, implanted vagus nerve stimulation devices are being used for decades to treat severe recurrent refractory depression and refractory partial-onset seizures.
Scientists have found that vagus nerve stimulation by peripheral lipopolysaccharide lowers the inflammatory response in the central nervous system of rats.
Further, in a porcine model of sepsis, this approach has successfully minimized multiple organ dysfunction. Thereby, researchers revealed that vagus nerve stimulation could be a promising adjunctive therapy for the treatment of COVID-19 patients.
This therapeutic strategy has also shown positive cardiovascular effects during sepsis, which includes antiarythmogen, lowering of myocardial oxygen consumption, and improved diastole.
Recently, scientists have revealed that the use of non-invasive transcutaneous vagus nerve stimulation devices (t-VNS) has shown significant results in two COVID-19 patients.
Researchers believe that the use of non-invasive VNS as adjunct therapy might reduce multiorgan dysfunction in COVID-19 patients.
At present, two studies are being conducted to assess the efficacy of non-invasive VNS in COVID-19 patients, where scientists are using the gammaCore® non-invasive vagal nerve stimulation device for their research. This device is applied to the patient’s skin at the neck region over the vagus nerve to dispense periodic doses of VNS in a non-invasive manner.
Researchers believe that this approach could minimize mechanical ventilation in COVID-19 patients.
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