Section 3: COVID-19: Neuro-invasive potential of SARS-nCoV-2 as cause of delirium (from DOI: 10.1186/s13054-020-02882-x)
From publication: "COVID-19: ICU delirium management during SARS-CoV-2 pandemic" published as Crit Care; 2020 04 28 ; 24 (1) 176. DOI: https://doi.org/10.1186/s13054-020-02882-x
Section 3: COVID-19: Neuro-invasive potential of SARS-nCoV-2 as cause of delirium
Most CoVs share a common viral structure, infection potential, and neurotropism, CoVs are large, enveloped viruses with a large positive-sense, single-stranded RNA genome. Human pathogenic CoVs include those causing recent epidemics, severe acute respiratory syndrome CoV (SARS-CoV and SARS-CoV-2), Middle East respiratory syndrome CoV (MERS-CoV) HCoV-229E, and other identified coronaviruses, i.e. HCoV-OC43, HCoV-NL63, and HCoV-HKU1. CoVs have been associated with CNS diseases such as acute viral encephalopathy, acute disseminated encephalomyelitis, and multiple sclerosis and are increasingly recognized as presenting a neurologic crisis. In one series of 183 children hospitalized with acute encephalitis, 12% were associated with coronavirus infection. Such propensity of CoVs has been documented for several of the beta-CoVs, including SARS-CoV and MERS-CoV. Acute necrotizing encephalitis has also been described in one case of SARS-CoV-2. The patient presented with fever, cough, and altered mental status and was found to have hemorrhagic rim enhancing lesions in the deep gray matter of the cerebral cortex bilaterally. Animal studies suggest coronaviruses are delivered through the peripheral nerves and may access the central nervous system through retrograde synaptic transmission. SARS-CoV spreads in the brains of intranasally inoculated mice primarily via the olfactory bulb with subsequent infection of the hypothalamus and brainstem. Such neuro-invasive potential of SARS-CoV-2 has been postulated to contribute to respiratory failure observed in infected patients.
The exact mechanism for neurotoxicity may depend on the brain entry route, which has not been fully elucidated. The SARS-CoVs enter human host cells mainly via a cellular receptor angiotensin-converting enzyme (ACE2), expressed not only in the entire respiratory tract (which it destroys resulting in the leading cause of death), but also in the upper esophagus or enterocytes and showing very low expression level in the brain under normal conditions. The virus entry route may be respiratory, via oro-fecal route, but also directly intranasal. The possible brain entry routes for CoVs, including SARS-CoV-2, include either direct intranasal access to the brain via olfactory nerves (with anosmia as an early symptom) or indirect access to the brain by crossing the blood-brain barrier (BBB) via hematogenous or lymphatic spread.
There are several mechanisms of coronavirus-related brain damage. One of them is connected with the dysfunction of renin-angiotensin system in the brain. ACE is the major component of the cerebral renin-angiotensin system and is localized in the endothelia of cerebral vasculature. The use of ACE inhibitors for treatment of blood hypertension reduces cognitive dysfunction through their anti-inflammatory actions. Circulating renin-angiotensin components do not affect the brain with airtight BBB. However, general inflammatory response to virus infection impairs BBB integrity leading to massive infiltration of renin-angiotensin components to the brain. Uncontrolled infiltration of the brain with renin-angiotensin components induces neuroinflammatory cascades resulting in extensive neurodegradation followed by cognitive dysfunction. The SARS-CoVs can enter the brain via the BBB angiotensin-converting enzyme receptors and induce neurodegeneration, astrogliosis, and neuroinflammation. It is noteworthy that SARS-CoV particles have been found in the brain.
Inflammatory response of the CNS to viral infection seems to be another important reason for poor neurological outcome and occurrence of delirium. A few hours after infection, neutrophils and monocytes infiltrate CNS, and neutrophils seem to be crucial in disruption of BBB permeability The postmortem study documented a massive infiltration of the brain by immune cells, which was associated with neuronal edema and the scattered red degeneration Noteworthy, activated macrophages and microglia have been present in areas of demyelination and play a critical role in myelin destruction. The hypomyelinated axons were found in experimental animals with short- and long-term memory deficit, and the degree of myelin disorders was associated with memory dysfunction and short- and long-term cognitive dysfunction. A large amount of damaged myelin following neuroinflammation is potentially immunogenic and activates macrophages again, which initiate a vicious cycle sustaining further inflammation. This prolonged inflammation may be responsible for the higher incidence of neuropsychological abnormalities in patients with severe infection and sepsis; however, this hypothesis should be confirmed in further studies.
The median time from the onset of first symptoms to the diagnosis of respiratory compromise (dyspnea) is usually 5 days and 8 days from admission to the intensive care unit with severe respiratory failure requiring intubation and mechanical ventilation. The latency period indicates that there might be sufficient time for the coronavirus to enter and destroy CNS neurons.
Previous studies have shown that some patients infected with SARS-CoV-2 present with neurological symptoms such as headache (about 8% of cases) or centrally mediated nausea and vomiting (about 1% of cases). A retrospective study performed by Mao et al., reporting data from 214 COVID-19 patients, showed that neurological symptoms were present in 45% of severely ill patients, with symptoms including both acute cerebrovascular disease and impaired consciousness. Possibly the neuro-invasive potential of SARS-CoV-2 may be associated with centrally mediated respiratory failure. As a hypothesis, early identification of patients with delirium, being an early symptom of CNS involvement is critical in COVID-19 patients, as it may indicate impending respiratory failure due to the neuro-invasive potential of SARS-CoV-2.
Acute brain dysfunction, symptomatically presenting as delirium (also called encephalopathy), may be a feature of the neuro-invasive potential of SARS-CoV-2. Neurotropism of coronaviridae has been demonstrated during SARS and MERS epidemics. During the 2002-2003 SARS epidemic older subjects presented not only with respiratory symptoms and typical febrile response, but also with decreased general well-being, poor feeding, and delirium. Given the fact that SARS-CoV and SARS-CoV-2 are similar in terms of pathogenicity, it is quite likely that SARS-CoV-2 has a similar ability to cause delirium.
Most CoVs share a common viral structure, infection potential, and neurotropism, CoVs are large, enveloped viruses with a large positive-sense, single-stranded RNA genome. Human pathogenic CoVs include those causing recent epidemics, severe acute respiratory syndrome CoV (SARS-CoV and SARS-CoV-2), Middle East respiratory syndrome CoV (MERS-CoV) HCoV-229E, and other identified coronaviruses, i.e. HCoV-OC43, HCoV-NL63, and HCoV-HKU1. CoVs have been associated with CNS diseases such as acute viral encephalopathy, acute disseminated encephalomyelitis, and multiple sclerosis and are increasingly recognized as presenting a neurologic crisis. In one series of 183 children hospitalized with acute encephalitis, 12% were associated with coronavirus infection. Such propensity of CoVs has been documented for several of the beta-CoVs, including SARS-CoV and MERS-CoV. Acute necrotizing encephalitis has also been described in one case of SARS-CoV-2. The patient presented with fever, cough, and altered mental status and was found to have hemorrhagic rim enhancing lesions in the deep gray matter of the cerebral cortex bilaterally. Animal studies suggest coronaviruses are delivered through the peripheral nerves and may access the central nervous system through retrograde synaptic transmission. SARS-CoV spreads in the brains of intranasally inoculated mice primarily via the olfactory bulb with subsequent infection of the hypothalamus and brainstem. Such neuro-invasive potential of SARS-CoV-2 has been postulated to contribute to respiratory failure observed in infected patients.
The exact mechanism for neurotoxicity may depend on the brain entry route, which has not been fully elucidated. The SARS-CoVs enter human host cells mainly via a cellular receptor angiotensin-converting enzyme (ACE2), expressed not only in the entire respiratory tract (which it destroys resulting in the leading cause of death), but also in the upper esophagus or enterocytes and showing very low expression level in the brain under normal conditions. The virus entry route may be respiratory, via oro-fecal route, but also directly intranasal. The possible brain entry routes for CoVs, including SARS-CoV-2, include either direct intranasal access to the brain via olfactory nerves (with anosmia as an early symptom) or indirect access to the brain by crossing the blood-brain barrier (BBB) via hematogenous or lymphatic spread.
There are several mechanisms of coronavirus-related brain damage. One of them is connected with the dysfunction of renin-angiotensin system in the brain. ACE is the major component of the cerebral renin-angiotensin system and is localized in the endothelia of cerebral vasculature. The use of ACE inhibitors for treatment of blood hypertension reduces cognitive dysfunction through their anti-inflammatory actions. Circulating renin-angiotensin components do not affect the brain with airtight BBB. However, general inflammatory response to virus infection impairs BBB integrity leading to massive infiltration of renin-angiotensin components to the brain. Uncontrolled infiltration of the brain with renin-angiotensin components induces neuroinflammatory cascades resulting in extensive neurodegradation followed by cognitive dysfunction. The SARS-CoVs can enter the brain via the BBB angiotensin-converting enzyme receptors and induce neurodegeneration, astrogliosis, and neuroinflammation. It is noteworthy that SARS-CoV particles have been found in the brain.
Inflammatory response of the CNS to viral infection seems to be another important reason for poor neurological outcome and occurrence of delirium. A few hours after infection, neutrophils and monocytes infiltrate CNS, and neutrophils seem to be crucial in disruption of BBB permeability The postmortem study documented a massive infiltration of the brain by immune cells, which was associated with neuronal edema and the scattered red degeneration Noteworthy, activated macrophages and microglia have been present in areas of demyelination and play a critical role in myelin destruction. The hypomyelinated axons were found in experimental animals with short- and long-term memory deficit, and the degree of myelin disorders was associated with memory dysfunction and short- and long-term cognitive dysfunction. A large amount of damaged myelin following neuroinflammation is potentially immunogenic and activates macrophages again, which initiate a vicious cycle sustaining further inflammation. This prolonged inflammation may be responsible for the higher incidence of neuropsychological abnormalities in patients with severe infection and sepsis; however, this hypothesis should be confirmed in further studies.
The median time from the onset of first symptoms to the diagnosis of respiratory compromise (dyspnea) is usually 5 days and 8 days from admission to the intensive care unit with severe respiratory failure requiring intubation and mechanical ventilation. The latency period indicates that there might be sufficient time for the coronavirus to enter and destroy CNS neurons.
Previous studies have shown that some patients infected with SARS-CoV-2 present with neurological symptoms such as headache (about 8% of cases) or centrally mediated nausea and vomiting (about 1% of cases). A retrospective study performed by Mao et al., reporting data from 214 COVID-19 patients, showed that neurological symptoms were present in 45% of severely ill patients, with symptoms including both acute cerebrovascular disease and impaired consciousness. Possibly the neuro-invasive potential of SARS-CoV-2 may be associated with centrally mediated respiratory failure. As a hypothesis, early identification of patients with delirium, being an early symptom of CNS involvement is critical in COVID-19 patients, as it may indicate impending respiratory failure due to the neuro-invasive potential of SARS-CoV-2.
