Jukka Ylikoski, Marika Markkanen & Antti Mäkitie (2020) Pathophysiology of the COVID-19 – entry to the CNS through the nose, Acta Oto-Laryngologica, 140:10, 886-889, https://www.tandfonline.com/doi/full/10.1080/00016489.2020.1773533

Michigan State University

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- Anosmia has been recognized as early symptoms of COVID-19 in most patients.
     - may indicate that SARS-CoV-2 has a high affinity for olfactory epithelium and 
       can utilize the olfactory nerve to enter the CNS.
          - based on the fact that the Influenza virus and other SARS viruses utilize 
             this short-cut to enter the brain. 
          - early CNS symptoms include headaches, nausea, and vomiting in patients 
               - this further points to the idea that COVID is confined to the 
                  respiratory system and the CNS.
- SARS-CoV has been observed in animal brain tissue that has been infected with heavy viral load.
- Viral invasion to CNS:
     - Prior research has shown that the olfactory nerve is a shortcut for SARS-CoV-2 
        and that there are specific SARS-CoV-2, ACE2, receptors that are abundant in 
        the brain, which helps bind viral particles.
     - Extensive neuronal infections have been reported as the main cause of death in 
        some patients when they had a minor lung infection.


Pathophysiology of the COVID-19 – entry to the CNS through the nose

- Dysfunction of the Central automimic network:
     - Once the virus enters the CNS through the olfactory nerve, it can cause 
        inflammation and imbalance in brain structures that regulate the ANS. 
          - Since the parasympathetic nervous system regulates the respiration rate, 
            this can cause distress.
     - Some hospitalized patients presented with asymptomatic hypoxia with central 
        apnea, which further suggests the virus entry through the nose.
     - Several clinical and radiology studies of hospitalized patients, >1000 COVID-19 
        patients, have shown normal chest x-rays and scans despite having a severe 
        illness. 
     - Early dyspnea and hypoxia are due to central dysfunctions.

CNS Dysfunction Due to Viral Entrance Through The Olfactory Nerve

ACE2 expression was quantified in 21 regions of the human brain using multiple tissue expression (MTE) arrays (*p < 0.01 (ANOVA); error bars represent one standard deviation of the mean).  The highest expression was found in the pons, amygdala, and the medulla oblongata.  The pons and medulla oblongata are notably known to control breathing and respiration. 

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