The respiratory condition COVID-19 arises in a human host upon the infection with SARS-CoV-2, a coronavirus that was first acknowledged in Wuhan, China, at the end of December 2019 after its outbreak of viral pneumonia. The full-blown COVID-19 can lead, in susceptible individuals, to premature death because of the massive viral proliferation, hypoxia, misdirected host immunoresponse, microthrombosis, and drug toxicities. Alike other coronaviruses, SARS-CoV-2 has a neuroinvasive potential, which may be associated with early neurological symptoms. In the past, the nervous tissue of patients infected with other coronaviruses was shown to be heavily infiltrated. Patients with SARS-CoV-2 commonly report dysosmia, which has been related to the viral access in the olfactory bulb. However, this early symptom may reflect the nasal proliferation that should not be confused with the viral access in the central nervous system of the host, which can instead be allowed by means of other routes for spreading in most of the neuroanatomical districts. Axonal, trans-synaptic, perineural, blood, lymphatic, or Trojan routes can gain the virus multiples accesses from peripheral neuronal networks, thus ultimately invading the brain and brainstem. The death upon respiratory failure may be also associated with the local inflammation- and thrombi-derived damages to the respiratory reflexes in both the lung neuronal network and brainstem center. Beyond the infection-associated neurological symptoms, long-term neuropsychiatric consequences that could occur months after the host recovery are not to be excluded. While our article does not attempt to fully comprehend all accesses for host neuroinvasion, we aim at stimulating researchers and clinicians to fully consider the neuroinvasive potential of SARS-CoV-2, which is likely to affect the peripheral nervous system targets first, such as the enteric and pulmonary nervous networks. This acknowledgment may shed some light on the disease understanding further guiding public health preventive efforts and medical therapies to fight the pandemic that directly or indirectly affects healthy isolated individuals, quarantined subjects, sick hospitalized, and healthcare workers.
The travel of SARS-CoV-2 into the human host is likely to follow no specific route, but several in parallel. Considering the infiltration in distinct neuroanatomical sites, we can infer a model of symptom progression that is in line with our personal experience but also with other authors' reports about the early stages of the disease. The nasal mucosa of humans seems a perfect environment for SARS-CoV-2 proliferation making it a potential reservoir for infection, like the salivary glands. A possible implication of the glossopharyngeal and facial nerve fibers has not to be excluded though. All three hypotheses previously advanced may be partially true regarding the smell disorders of infected patients. A partial nasal blockage for co-viral infections, an inflammation of the olfactory epithelium, and a viral insult at the level of olfactory receptor cells may all be concomitantly present. However, some authors recently suggested that the primarily targeted cells appear to be not the neurons, but those cells that would have been in charge of its early airway clearance through sputum expectoration, being the secretory and ciliated epithelial cells. The third hypothesis may be postponed though, thus making the hypothesis of inflammation and mucosal swelling in the back of the nose of primary importance. It is therefore still too early to acknowledge the nasal-nervous pathway as a potential route for host access and the local immunocompetence of the olfactory bulb may be sufficient to block the SARS-CoV-2 entering. Moreover, there are many other neglected routes for neuroinvasion: the trigeminal nerve, the terminal nerve, the enteric and pulmonary nervous networks, the vagus nerve, the dorsal root ganglia, the hematogenous flow through the circumventricular organs of the brain and brainstem, the peripheral lymphatic vessels, the central glymphatic system, the cerebrospinal fluid, the migrating Trojan horses, and the conjunctiva. That is, no viral passage across the olfactory bulb of the host has been confirmed so far and how SARS-CoV-2 gain access to and spread in the central nervous system remains to be explored. On the contrary, if dysosmia was an early sign of infection it could be too late to avoid neuronal affections as viral transport along axons is possibly moving about 2 μm/s in the retrograde direction. Because of the spatial distribution at the level of the head, it is much more likely that the preferred retrograde pathway is the one involving the shortest nerves at the level of the head, rather than the more systemic ones, such as the vagus nerve.
The symptom progression during the invasion of the human host by the SARS-CoV-2 upon nasal (olfactory bulb) access. The severe acute respiratory syndrome coronavirus that was discovered in Hubei province, China at the end of December 2019 (SARS-CoV-2) is a single-strand positive-sense RNA virus with the encoding potential of four structural proteins: the spike, the envelope, the membrane, and the nucleocapsid. The human host presents many potential accesses, but the inhalation of infected respiratory droplets exposes the airways first. (N) Assuming a nasal access, the olfactory mucosa may represent the primary site of the host for viral proliferation. It is reasonable to believe that SARS-CoV-2 needs to replicate several times before it can reach a harmful potential to infiltrate in the olfactory bulb, with the smell alterations being reported as one of the earliest symptoms. (O) The terminal nerve fibers extend in the olfactory epithelium colonized by the coronavirus. Here, not only axons of the fila olfactoria can be used as routes for central access, but also the trigeminal branches, the terminal nerve, blood or lymphatic vessels, or the cleft under the ensheathing cells of olfactory axons. (P) Upon inhalation, alveoli get in close contact with the virus, and it is reasonable to assume that the local inflammation could affect the different nerve fiber populations comprising the neuroendocrine cells and the annexed vagal contacts. Lung infection, which might manifest even few days after the contagion, can therefore provide direct access to the solitary tract and other parts of the central nervous system. (E) Once the virus has been accessed the epithelial barrier of gut cells through mucus or other vector ingestion, it can colonize the intestines that are permeated with the lymphatic system that drains the villi, the blood capillaries, and both the extrinsic and intrinsic neural networks. A fluctuating but chronic symptomatic onset is easily found. (B) It is still not clear which is the main route for the central nervous system access that may have a critical role in SARS-CoV-2 nervous infiltration, but both the brain and brainstem are likely to be infiltrated. High temperature is one of the earliest symptom after infection when more robust immune response is triggered, thus subsequently being associated with a permeabilization of the blood-brain barrier and immune cell infiltration. Cardiorespiratory centers in the medulla are critical districts that, if affected by either direct viral damages or indirect neuroinflammation and hypoxia, can lead to irreversible damage and fatal outcome.
Italy is one of the worst-hit countries in Europe with a death rate of 13.9% (WHO, report of May 8th, 2020). Among the currently infected, 72,157 are quarantined at home, 14,636 hospitalized in acute COVID-19 wards, and 1,168 hospitalized in intensive care units. Deceased patients had a mean age of 80 years old, 60.9% were males, 60.9% had three or more comorbid conditions (most common had been hypertension in 68.2% and ischemic heart disease in 28.4% of cases). At admission, the main symptoms were fever (76%), dyspnea (73%), dry cough (38%), diarrhea (6%), and hemoptysis (1%). A mean of 5 days passed from the onset of symptoms to hospitalization and the other 5 days from hospitalization to death (SARS-CoV-2 Surveillance Group of Italy, report of May 7th, 2020). Our direct experience in managing COVID-19 patients is in line with the abovementioned records. In addition, we observed also dysosmia being reported by over 80% of our patients. However, symptom reports at admission should not be taken for granted but contextualized on the feverish subject. In fact, all patients admitted to our hospitals are being classified as level 2 or higher (internal classification of COVID-19 patients comprises -level 0: asymptomatic-, -level 1: mild symptoms, pharyngodynia, dry cough, mild fever, -level 2: moderate symptoms, high fever, persistent cough, asthenia, dyspnea, non-invasive oxygen therapy-, -level 3: severe symptoms, invasive oxygen therapy, intensive care). Our infected patients were all malnourished (Briguglio et al., 2020b) and disoriented in time and space, thus rendering it very difficult to make an exhaustive history about the dysfunction of the olfactory capacity and its onset in reference to the disease. These symptoms may also derive from excessive exposure to disinfectants due to the pandemic (Keyhan et al., 2020), but also from medicines that are known to interfere with the smelly sensations and the aftertaste. On the other hand, many of our front-line colleagues infected with SARS-CoV-2 often reported a loss of taste and smell, which preceded the systemic symptoms, such a fever, loss of appetite, and diarrhea. Since numerous microthrombi are also being observed on peripheral limbs of our hospitalized patients, being likely to occur in pulmonary and cerebral capillaries as well, the neuronal damages should be of great concern. Other than antibiotics, antivirals, or corticosteroids, a therapy with low-molecular-weight heparin at daily doses over 4,000 IU should be considered for hospitalized COVID-19 patients. Neuronal injuries in critical brain areas of patients that will survive may carry permanent consequences, as was observed for SARS-CoV-1 survivors. Moreover, the risk of an impaired sympatho-vagal signal is worrying since its proper functioning is important for the peripheral immune response and central microglial polarization. Some authors even suggested that neuronal cells could serve as reservoirs for the virus (Kabbani and Olds, 2020). To the best of our knowledge, SARS-CoV-2 has not been found in nervous tissues so far. In Italy, brain autopsies are currently suspended due to biohazard security concer. However, other authors reported the presence of the virus in the cerebrospinal fluid and others observed multiple cerebral infarcts in vascular territories (Zhang et al., 2020). Dead-end signs of the coronavirus cycle may reflect respiratory signs in the severe COVID-19 host, such as ataxic breathing, altered rate and synchrony, apnea, or hyperventilation. Overall, the survival of the virus in the nasal cavity plus its neuroinvasive potential is not a novel pathway of contagion among the infective agents. This double survival in two sites of the same host permits the virus to efficiently exploit its neurotropism while still preserving the host-to-host transmission (MacGibeny et al., 2018). The risk of contracting SARS-CoV-2, like any other infection, primarily depends on the degree of exposure to the pathogen. Whether the infected host protects himself and others from contact might contrariwise depend on the level of awareness and, currently, there is no recognition of smell disorders being an early symptom of SARS-CoV-2 infection nor it is established the association between dysosmia and SARS-CoV-2 olfactory bulb invasion. However, as the SARS-CoV-2 virus spreads, so changed the feature of its pandemic (Brussow, 2020) and the possibility that individuals can carry the virus without knowing is a risk that our society cannot take. Some individuals may show symptoms of SARS-CoV-2 infection 10 days after exposure, which is a remarkable amount of time during which asymptomatic individuals can be carriers without knowing. To conclude, we can say that:
Some infected individuals show dysosmia, which may imply nasal proliferation of SARS-CoV-2.
• Public health actions should consider smell disorders when defining social distancing criteria.
• Axonal, trans-synaptic, blood, lymphatic, or Trojan transport are routes for viral neuroinvasion.
• Viral access in the peripheral or central nervous system may affect brainstem function.
• Viral neuroinvasion does not rule out long-term neuropsychiatric consequences.
Reference & source information : https://www.frontiersin.org/
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