It is an emerging concern that the virus may damage the CNS, the brainstem, particularly the part of it regulating cardiopulmonary functions. The medulla oblongata may be infected also but not exclusively by the neural pathways connecting the lung and the CNS leading to breathing difficulties and oxygen deficiency. (1) Lung inflammation may increase inflammatory cytokines in the medulla oblongata mediated by the vagal afferent nerve and lead to hypoxic ventilatory response. (2) According to clinical experiences some of the patients are not aware of being in oxygen deficiency indicating CNS involvement of the problem. Hypoxic conditions may aggravate injuries of the neural pathways in the brain causing overactivation of the sympathetic nervous system and retraction of the vagus nerve functions, lowering heart rate variability (HRV).(3)(4)(5) Overactivation of the sympathetic nerves may lead to a decrease of lymphocyte proliferation in the spleen. (6) Lymphopenia predicts the disease severity of COVID-19. (7) Increased inflammation of the CNS is sufficient to induce the activation of the sympathetic nerve pathways. If Il-6, one of the most important cytokines serving as a prognostic marker of poor outcome of the disease, is administered into the CNS, it causes splenic sympathoexcitation. (8) Hypertension is naturally a high-risk factor for severe disease outcomes because it is associated with elevated sympathetic activity. (9) Studies emphasize the importance of poor clinical course the role of lymphopenia in contrast to the cytokine storm. Especially CD4+ T, CD8+ T and CD19+ B cell counts are significantly lower in pneumonia-COVID-19 patients than those in non-COVID-19-infected pneumonia patients. (10) Lymphopenia is SARS-Coronavirus patients is likely to result from indirect mechanisms secondary to the viral infection. (11) Investigating triathlon athletes a positive correlation was found between total lymphocytes, CD4+, CD8+ and rMDDS, an HRV measure. A positive correlation was also found between CD19+ (B cells) and pNN50, another HRV measure indicating parasympathetic tone. The authors conclude that the autonomic nervous system is directly related to the immune system and maintains balance or body homeostasis and HRV provides useful information about the risk of disease of the immune system. (12) In elite swimmers was experienced the same phenomenon. The upper respiratory tract and pulmonary infections were characterized by a shift towards sympathetic predominance and a drop in parasympathetic drive. (13) Stress measured by HRV is negatively correlated with lymphocyte percentages. HRV – inversely correlated to stress – is not only a viable method for indexing stress but also predicting immune functions. (14)
The above associations highlight the fact that to effectively avert severe disease course of COVID-19 is only possible by restoring the autonomic balance subverted by the virus infection. The central regulation of cardiopulmonary functions, lymphocyte proliferation and systemic inflammation should be supported by decreasing CNS damages caused by cytokines or direct virus infection of the brain. For this purpose a centrally/intranasally administered peptide may be the most effective candidate that can correct autonomic imbalances, increase parasympathetic and decrease sympathetic tone. Proinsulin C-peptide is one of the most promising neurotrophic factors that can restore lowered HRV and increase splenic lymphocyte proliferation by modulating sympathetic and parasympathetic balance. Its effect has been investigated not only in animal studies but also in several placebo-controlled double-blind studies. (15)(16)(17)