Autonomic balance determines the severity of COVID-19 courses

Abstract

COVID-19 has left mankind desperately seeking how to manage dramatically rising infection rates associated with severe disease progressions. COVID-19 courses range from mild symptoms up to multiple organ failure and death, triggered by excessively high serum cytokine levels (IL 1β, IL 6, TNF α, IL 8). The vagally driven cholinergic anti-inflammatory pathway (CAP) stops the action of nuclear factor κB (NF-κB), the transcriptional factor of pro-inflammatory cytokines. Thus, well-balanced cytokine release depends on adequate vagal signaling. Coronaviruses replicate using NF-κB transcriptional factor as well. By degrading the cytoplasmatic inhibitor of NF-κB subunits (IκB), coronaviruses induce unrestricted NF-κB expression accelerating both, virus replication and cytokine transcription.We hypothesize that CAP detriment due to depressed vagal tone critically determines the severity of COVID-19.

Is the heart rate variability monitoring using the analgesia nociception index a predictor of illness severity and mortality in critically ill patients with COVID-19? A pilot study

“…Therefore, activation of the NTS and the cholinergic anti-inflammatory pathway, both pharmacologically, by activating the alpha 7 nicotinic receptors, and electrically, through non-invasive brain neuromodulation and vagus nerve stimulation (VNS), as also suggested by Baptista et al [ 39 ], appear to be promising therapeutic strategies to balance the ANS and produce a balanced autonomic response [ 40 – 42 ]. Besides, Leitzke et al [ 43 ] have recently reported that these therapeutic approaches for sympathovagal balance in severe courses of COVID-19 can be achieved diagnostically by measuring HRV.…”

Lower values of a novel index of Vagal-Neuroimmunomodulation are associated to higher all-cause mortality in two large general population samples with 18 year follow up

“…In consequence, the stimulation of the vagus nerve may prevent the damaging effects of cytokine release in experimental sepsis, endotoxemia, ischemia/reperfusion injury, hemorrhagic shock, arthritis, and other inflammatory syndromes. Several medical hypothesis papers address potential clinical usage of the CAP, particularly Leitzke et al detail the underlying mechanisms in the SARS-CoV-2 infections 6 . Therefore, assessing the NIM in COVID-19-patients at hospitalization might be an additional, useful risk indicator to identify patients at high risk for worsening COVID-19-symptoms such as CRS or co-infections.…”

“…The CAP modulates inflammation, e.g., by inhibiting the HMGB1 and cytokine release, via the macrophages' α7 nicotinic acetylcholine receptor (α7nAChR) 4,5 . This CAP has been identified as highly relevant in COVID-19-patients hypothetically with detailed mechanism 6,7 , in clinical practice 8 , and it´s modulation through indirect methods such as physical activity and neuromodulation 9,10 . However, the CAP has played an important role in the pre-covid era and outside an acute clinical setting.…”

A Translational Perspective of Maternal Immune Activation by SARS-CoV-2 on the Potential Prenatal Origin of Neurodevelopmental Disorders: The Role of the Cholinergic Anti-inflammatory Pathway

“…The CAP may be more relevant in a SARS-2-CoV infection compared with other physiological mechanisms because further evidence indicates that the vagus nerve plays a relevant role in pulmonary inflammation (dos Santos et al, 2011 ). A detailed description of the neuroimmune mechanisms related to a possible CAP and its impairment in the case of this infection can be found elsewhere (Leitzke et al, 2020 ; Liu W. et al, 2020 ). In SARS-CoV-2 infections, young patients generally experience mild symptoms, while fatal interstitial pneumonia is more frequently reported in older patients.…”