It is among the most severe effects of the coronavirus infection that the high risk patients may have breathing problems. The oxygen supply of their body decreases. Independently of the causes of this problem, the oxygen deficiency, hypoxia may decrease heart rate variability (HRV). (1) HRV or the parasympathetic nervous system and the cholinergic anti-inflammatory pathway are impaired at all risk groups of the COVID-19 infection. The elderly, diabetics or who are affected by cardiovascular diseases have lower HRV also without hypoxic conditions. If hypoxia decreases HRV it pushes inflammation and one the most important cytokines of this disease the Il-6 even higher, because the inflammation markers (CRP, Il-6, TNF-alpha) are in inverse correlation with HRV. (2) Because proinsulin c peptide may increase the HRV in all risk groups, it should be administered to the infected. Most importantly proinsulin c peptide production, pulmonary functions and the HRV may be decreased in smokers, elderly and most of the diabetics. (16)(17)(18)(19) The HRV increasing effect of proinsulin c peptide was proven by clinical trials. (3) Proinsulin c peptide can increase the oxygen supply of the tissues independently of its HRV increasing effect. (4) C-peptide can promote vagus nerve activity that may be measured by HRV values, and the vagus nerve facilitates the gas exchange processes of the lung. (5)(6)(20)
COVID-19 may induce a vicious circle: Inflammation, cytokine storm may lead to injuries of the central and peripheral nervous system, the vagus nerve, to decreased HRV and impaired gas exchange processes of the lung, to breathing problems. Breathing problems and hypoxia decrease further the HRV, increase inflammation and impair further the cholinergic anti-inflammatory pathway. Inflammation and hypoxia are strengthening each other and decrease the HRV and vagus nerve function until septic shock or sudden cardiac death happens for that low HRV has a significant prognostic value. (7)(8)
It is tragic that mechanical ventilation that is applied at most of the critically ill patients may lead to the so called ventilation induced lung injury (VILI) that can increase further cytokine storm (9). VILI and lung inflammation can be decreased and lung functions improved by the activation of the vagus nerve and the cholinergic anti-inflammatory pathway (10). It is also important to note that in clinical practice the ventilator weaning is successful only in patients with relatively high HRV components. (11)
The autonomic nervous system is injured at least in COPD and diabetics, that both are in the high risk group of COVID-19. The injury of the autonomic nervous system seems to be one of the most important reasons of the development of COPD. (12)(13)(14) In type 1 diabetic patients lacking proinsulin c peptide the lung functions are significantly impaired. After pancreatic transplantation and the restauration of c peptide production in the body, the lung functions also markedly improve. (15) Type 1 diabetic patients also experience the increase of parasympathetic functions and HRV with proinsulin c peptide administration. (3)
Taken together: Pulmonary functions, HRV, proinsulin c peptide seem to be the common denominators to push down the cytokine storm of COVID-19 infection. Central proinsulin c peptide administration may be the most effective method to improve autonomic, pulmonary and cholinergic anti-inflammatory functions that may break down the vicious circle of the cytokine storm and hypoxic condition caused by COVID-19 in the high risk groups.