key: cord-347516-linjv64o
authors: Abdelaziz, Osama S.; Waffa, Zuraiha
title: Neuropathogenic human coronaviruses: A review
date: 2020-07-20
journal: Rev Med Virol
DOI: 10.1002/rmv.2118
sha: 
doc_id: 347516
cord_uid: linjv64o

Human Coronaviruses (HCoVs) have long been known as respiratory viruses. However, there are reports of neurological findings in HCoV infections, particularly in patients infected with the novel severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) amid Coronavirus disease 2019 (COVID‐19) pandemic. Therefore, it is essential to interpret the interaction of HCoVs and the nervous system and apply this understanding to the COVID‐19 pandemic. This review of the literature analyses how HCoVs, in general, and SARS‐CoV‐2, in particular, affect the nervous system, highlights the various underlying mechanisms, addresses the associated neurological and psychiatric manifestations, and identifies the neurological risk factors involved. This review of literature shows the magnitude of neurological conditions associated with HCoV infections, including SARS‐CoV‐2. This review emphasises, that, during HCoV outbreaks, such as COVID‐19, a focus on early detection of neurotropism, alertness for the resulting neurological complications, and the recognition of neurological risk factors are crucial to reduce the workload on hospitals, particularly intensive‐care units and neurological departments.

articles. The search terms "coronavirus," "SARS-CoV" "SARS-CoV-2," "MERS-CoV," "COVID-19," "nervous system," "neuroinvasion," "brain," "autopsy," and "neurological disorders" were used. There were no language restrictions. The final reference list was created on the basis of relevance to the topics covered in this review Twenty-five articles, including a total of 334 cases, were found to be useful and relevant to the research topic, in particular, 13 case reports, five prospective studies, three autopsy studies, two retrospective studies, one retrospective multicentre case series, and one case series.

The 25 selected articles were chronologically tabulated to demonstrate the number of cases, HCoV strains, neurological presentations and findings, neurological diagnoses, and neurological outcomes.

Since viral pathologies depend on host-pathogen interaction, the nervous system demonstrates unique characteristics that invite direct injury by respiratory viruses like the HCoVs. The blood-brain barrier (BBB) is susceptible to become more permeable to HCoVs after viremia leading to neuroinvasion via the haematogenous route, in the late stages of the viral infection. 1 Within the blood stream, the virus triggers a profound systemic inflammatory storm with a massive release of cytokines and chemokines, which compromise the BBB and hence the virus passes through the disrupted BBB, by a trans-endothelial mechanism, resulting in neuroinvasion. Cytokines, chemokines, and other inflammatory signals also trigger a massive neuroinflammatory response. 2 More interestingly, the olfactory nerve communicates the nasal mucosa with the olfactory bulb, the gateway to the CNS, and the proximity of the olfactory nerve to the nasal inoculation of HCoV may promote neuroinvasion of HCoV via the transneural route, and therefore a direct early neural injury before disease progression is possible. 1, 3, 7 This route utilises axonal transport and synaptic transmission to allow the virus to travel across the nervous system in a retrograde fashion, 8 however, it is not well described if this neurotropic process can occur antegrade for HCoV. Neuroinvasion and subsequent neuropropagation lead to dissemination of the virus to several regions within the CNS, particularly the brain stem. 1, 2, 4 Neuronal cells possess trans-membrane binding receptors required for the cellular entry of HCoV, enhanced by the presence of HCoV spike proteins and envelope proteins. 9,10 Whilst the binding affinity of SARS-CoV to angiotensin-converting enzyme-2 (ACE-2) receptor is evident in in vitro studies, 11, 12 animal experiments show that MERS-CoV has an affinity to dipeptidyl peptidase-4 (DPP-4) receptor. 13 Recently, a genomic resemblance of SARS-CoV-2 to SARS-CoV has been identified 5 and expression of SARS-CoV-2 cell receptor gene ACE-2 in a wide variety of human tissues, including the brain, has been reported. 6 Apart from viral replication-induced direct neural damage (ie, virusinduced neuropathology), it is also possible that HCoV infections, as result of the misdirected host autoimmune responses in susceptible patients, promote indirect neural damage (ie, virus-induced neuroimmunopathology) [14] [15] [16] (Figure 1 ). On the other hand, pre-existing neurological disorders, particularly autoimmune diseases and the immunosuppressive or immunomodulatory therapies, may indirectly induce or exacerbate immune-mediated neural damage by HCoVs. 17,18

It is evident from the relatively large body of literature, shown in Table 1 , that various strains of HCoVs are indeed associated with a wide range of neurological findings and conditions.

The post-infectious phenomena in HCoV patients exhibiting late onset neurological manifestations seem to be more commonly reported. 19, [21] [22] [23] 25, 26, 29 It has been recently reported that more than one-third of patients with COVID-19 had neurological manifestations related to involvement of the CNS, PNS, and NMS. 19 Intracranial haemorrhages (ICH) or strokes, due to the systemic spread of HCoVs, are very serious post-infectious complications of HCoVs and these patients may require neurosurgical interventions. 19, 25, 29, 30 There is no explicit evidence to indicate if hypoxia from the impending acute respiratory distress syndrome (ARDS) in severe HCoV cases can induce brain ischemia, this is a reasonable assumption. 25 The polyneuropathies might be explained by prolonged hospitalisations hinting at the neurotoxins from the proceeding respiratory distress. 26, 29 Reports of neuromusculoskeletal disorders, complicating HCoV infections and COVID-19, postulate that myopathies and neuropathies are a result of the significantly elevated inflammatory cytokines in patients' sera leading to virus-induced immune damage. 19, 31, 34 This is further supported by evidence of immunemediated neurological conditions due to cytokine and chemokine release after HCoV infection as the disease progresses. 21, 24, 44, 45 Another explanation could be the development of chronic illness myopathy (CIM), particularly in patients requiring mechanical ventilation for long periods. 31 It is important to recognise the post-infectious neurological sequalae and complications of HCoVs in order to design appropriate management strategies.

On the other hand, if the patient with HCoV infection presents with an initial onset of neurological symptoms, with or without fever, before any respiratory involvement, this suggests that the nervous system is the primary focus of HCoV, which directly triggers neuronal injury. 20, 24, 32, 33 This primary neurotropism could be further supported by the recent reports of the occurrence of olfactory and/or taste disorders, as early atypical manifestations of SARS-CoV-2, which may precede the onset of full-blown clinical COVID-19 in more than onethird of patients. 19, 46 The convenient access of SARS-CoV-2 to the brainstem via the olfactory nerve may cause neuronal injury to the cardiorespiratory centre, leading to central respiratory failure. This could explain why some patients have a respiratory failure in the early stages of COVID-19, as opposed to ARDS manifesting during the later stages of the same disease from local respiratory aetiologies. 2, 3 Hence, it is of clinical significance to emphasise early detection of neurological symptoms of HCoVs, with a high index of suspicion to identify and isolate patients.

The detection of HCoV RNA in cerebrospinal fluid (CSF) samples of patients has been diagnostic for SARS-CoV 35,37 and HCoV-OC43. 36, 40 However, it is not always necessary to depend upon the detection of HCoV RNA in the CSF to diagnose nervous system involvement. 20, 24, 28 Reports on deep sequencing of brain biopsy samples show the presence of HCoV-OC43 in neuronal tissue of patients with fatal encephalitis and whose CSF analyses were negative for virus RNA. 23, 28 This could mean that HCoV RNA in CSF may only be detected in the early stages of the infection. Moreover, creatine kinase identified in CSF, has been utilized as a marker to recognise neuromuscular disorders in COVID-19 patients. 19 The misdirected immune response in neurological pathologies caused by HCoVs may have cytokine and interleukin levels detectable in CSF. 27 The detection of anti-HCoV antibodies in high titres in CSF samples of patients with underlying neurological diseases, such as encephalitis, Parkinson's disease, and multiple sclerosis, suggests that HCoVs may play an etiologic or pathogenic role in these diseases. 27, 41, 42 Despite the excellent overview of neurological aspects of HCoV infections displayed in Table 1 , this review has limitations. Some of the reported symptoms, such as nausea, myalgia, headache, dizziness, are common to any other viral infection. Many of the presented research articles were missing essential diagnostic studies, such as CSF analysis, MRI examination, electroencephalogram study, and polymerase chain reaction testing of CSF samples and nasopharyngeal swabs. Moreover, the study designs of many identified research reports were lacking the inclusion of control groups.

The neurological outcomes in patients with HCoV infections vary according to the part of nervous system involved. Fatalities and poor prognoses are more prominent when the brain is involved as indicated by COVID-19 encephalopathy, 20 encephalitis caused by HCoV-OC43, 23,28 ICH after MERS, 25, 29 and cerebritis due to SARS. 33 Nevertheless, sometimes HCoV-associated encephalitis can have a good prognosis. 24, 27, 30 Also, post-infectious acute myelitis in a COVID-19 patient had ameliorated and the patient was transferred to rehabilitation therapy. 21 MERS-induced acute disseminated encephalomyelitis (ADEM) was fatal, 30 whereas the patient with ADEM afterHCoV-OC43 infection had survived and showed improvement over several weeks. 36 Incontrast, MERS-induced neuropathies 26 it is hard to apply the same for SARS or COVID-19 patients and whether these deaths were due to irreversible brain damage.

Whilst immunosuppressive disorders and immunosuppressive drugs are known to provoke infections in general, this is also true for HCoV infections in cases of leukaemia 23 and severe combined immunodeficiency. 28 Old age, underlying comorbidities, and critical illness are identified as risk factors that are capable of producing serious neurological manifestations in COVID-19 patients. 19 HCoV infections, in more vulnerable patients,

can induce an exacerbation of underlying neurological conditions via virus-induced neuro-immunopathology. 14 

It is noteworthy to mention, in addition to the neurological impact, the psychological and the psychiatric impact of HCoV infections, not only on patients 2 but also on the health care workers providing treatment and nursing care to patients with HCoV infections, particularly during the pandemic of COVID-19. 47 SARS-CoV-2 induced neuroinflammation together with prolonged hypoxia may promote the development of acute and chronic cognitive and psychiatric impairments in COVID-19 patients. 2 Health care workers, particularly those providing medical care to COVID-19 patients in overwhelmed hospitals, frequently reported symptoms of depression (50.4%), anxiety (44.6%), insomnia (34%), and stress (71.5%). 47 Such mental health problems have to be recognised in order to provide the appropriate psychological support and psychiatric treatments or interventions.

Neurologic alterations due to respiratory virus infections

Neuroinfection may potentially contribute to pathophysiology and clinical manifestations of COVID-19. Acta Phys. 2020;e13473

Neuroinvasive and neurotropic human respiratory coronaviruses: potential neurovirulent agents in humans

The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients

Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms

Expression of SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues

Murine olfactory bulb interneurons survive infection with a neurotropic coronavirus

Axonal transport enables neuron-to-neuron propagation of human coronavirus OC43

Cleavage of a neuroinvasive human respiratory virus spike glycoprotein by proprotein convertases modulates neurovirulence and virus spread within the central nervous system

The OC43 human coronavirus envelope protein is critical for infectious virus production and propagation in neuronal cells and is a determinant of neurovirulence and CNS pathology

Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

Middle East respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4

Coronavirus infection of the central nervous system: host-virus stand-off

Chemokine CXCL10 and coronavirusinduced neurologic disease

Human coronaviruses and other respiratory viruses: underestimated opportunistic pathogens of the central nervous system? Viruses

Consensus for prevention and management of coronavirus disease 2019 (COVID-19) for neurologists

Guidance for the management of myasthenia gravis (MG) and Lambert-Eaton Myasthenic Syndrome (LEMS) during the COVID-19 pandemic

Neurologic manifestations of hospitalized patients with coronavirus disease 19 in Wuhan, China

Neurological complications of coronavirus disease (COVID-19): encephalopathy. Cureus

Acute myelitis after SARS-CoV-2 infection: a case report

COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI Features

Fatal encephalitis associated with coronavirus OC43 in an immunocompromised child

Human coronavirus NL63 and acute encephalitis

Spontaneous intracranial hemorrhage in a patient with middle east respiratory syndrome corona virus

Neurological complications during treatment of middle east respiratory syndrome

Coronavirus infections in the central nervous system and respiratory tract show distinct features in hospitalized children

Human coronavirus OC43 associated with fatal encephalitis

Neurological complications of middle east respiratory syndrome coronavirus: a report of two cases and review of the literature

Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV)

Neuromusculoskeletal disorders following SARS: a case series

Multiple organ infection and the pathogenesis of SARS

Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis

Neuromuscular disorders in severe acute respiratory syndrome

Possible central nervous system infection by SARS coronavirus

Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis

Detection of SARS coronavirus RNA in the cerebrospinal fluid of a patient with severe acute respiratory syndrome

Neuroinvasion by human respiratory coronaviruses

Coronaviruses in spinal fluid of patients with acute monosymptomatic optic neuritis

Human coronavirus polyadenylated RNA sequences in cerebrospinal fluid from multiple sclerosis patients

Cerebrospinal fluid antibodies to coronavirus in patients with Parkinson's disease

Antibodies to coronaviruses OC43 and 229E in multiple sclerosis patients

Two coronaviruses isolated from central nervous system tissue of two multiple sclerosis patients

COVID-19: consider cytokine storm syndromes and immunosuppression

Fine tuning the cytokine storm by IFN and IL-10 following neurotropic coronavirus encephalomyelitis

Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study

Factors associated with mental health outcomes among health care workers exposed to coronavirus disease 2019

The authors have no competing interest.

Osama S. Abdelaziz https://orcid.org/0000-0002-4767-4286Zuraiha Waffa https://orcid.org/0000-0001-6103-8924