ArticlePDF AvailableLiterature Review

The neuroinvasive potential of SARS-CoV2 may be at least partially responsible for the respiratory failure of COVID-19 patients

  • Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences


Following the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), another highly pathogenic coronavirus named SARS-CoV-2 (previously known as 2019-nCoV) emerged in December 2019 in Wuhan, China, and rapidly spreads around the world. This virus shares highly homological sequence with SARS-CoV, and causes acute, highly lethal pneumonia (COVID-19) with clinical symptoms similar to those reported for SARS-CoV and MERS-CoV. The most characteristic symptom of COVID-19 patients is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously. Additionally, some COVID-19 patients also showed neurologic signs such as headache, nausea and vomiting. Increasing evidence shows that coronavriruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases. The infection of SARS-CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Furthermore, some coronaviruses have been demonstrated able to spread via a synapse-connected route to the medullary cardiorespiratory center from the mechano- and chemoreceptors in the lung and lower respiratory airways. In light of the high similarity between SARS-CoV and SARS-CoV2, it is quite likely that the potential invasion of SARS-CoV2 is partially responsible for the acute respiratory failure of COVID-19 patients. Awareness of this will have important guiding significance for the prevention and treatment of the SARS-CoV-2-induced respiratory failure. (229 words) This article is protected by copyright. All rights reserved.
J Med Virol. 2020;14. © 2020 Wiley Periodicals, Inc.
Received: 14 February 2020
Accepted: 24 February 2020
DOI: 10.1002/jmv.25728
The neuroinvasive potential of SARSCoV2 may play a role
in the respiratory failure of COVID19 patients
YanChao Li
|WanZhu Bai
|Tsutomu Hashikawa
Department of Histology and Embryology,
College of Basic Medical Sciences, Norman
Bethune College of Medicine, Jilin University,
Changchun, Jilin, China
Institute of Acupuncture and Moxibustion,
China Academy of Chinese Medical Science,
Beijing, China
Neural Architecture, Advanced Technology
Development Group, RIKEN Brain Science
Institute, Saitama, Japan
YanChao Li, Department of Histology and
Embryology, College of Basic Medical Sciences,
Norman Bethune College of Medicine, Jilin
University, Changchun, 130021 Jilin, China.
Following the severe acute respiratory syndrome coronavirus (SARSCoV) and
Middle East respiratory syndrome coronavirus (MERSCoV), another highly patho-
genic coronavirus named SARSCoV2 (previously known as 2019nCoV) emerged in
December 2019 in Wuhan, China, and rapidly spreads around the world. This virus
shares highly homological sequence with SARSCoV, and causes acute, highly lethal
pneumonia coronavirus disease 2019 (COVID19) with clinical symptoms similar to
those reported for SARSCoV and MERSCoV. The most characteristic symptom of
patients with COVID19 is respiratory distress, and most of the patients admitted to
the intensive care could not breathe spontaneously. Additionally, some patients with
COVID19 also showed neurologic signs, such as headache, nausea, and vomiting.
Increasing evidence shows that coronaviruses are not always confined to the re-
spiratory tract and that they may also invade the central nervous system inducing
neurological diseases. The infection of SARSCoV has been reported in the brains
from both patients and experimental animals, where the brainstem was heavily
infected. Furthermore, some coronaviruses have been demonstrated able to spread via a
synapseconnected route to the medullary cardiorespiratory center from the mechan-
oreceptors and chemoreceptors in the lung and lower respiratory airways. Considering
the high similarity between SARSCoV and SARSCoV2, it remains to make clear whether
the potential invasion of SARSCoV2 is partially responsible for the acute respiratory
failure of patients with COVID19. Awareness of this may have a guiding significance for
the prevention and treatment of the SARSCoV2induced respiratory failure.
cell susceptibility, coronavirus, dissemination, nervous system
Coronaviruses (CoVs), which are large enveloped nonsegmented
positivesense RNA viruses, generally cause enteric and re-
spiratory diseases in animals and humans.
Most human CoVs,
such as hCoV229E, OC43, NL63, and HKU1 cause mild re-
spiratory diseases, but the worldwide spread of two previously
unrecognized CoVs, the severe acute respiratory syndrome
CoV (SARSCoV) and Middle East respiratory syndrome CoV
(MERSCo V) ha ve called global attention to the lethal potential of
human CoVs.
While MERSCoV is still not eliminated from the world,
another highly pathogenic CoV, currently named SARSCoV2 (previously
known as 2019nCoV), emerged in December 2019 in Wuhan, China.
This novel CoV has caused a national outbreak of severe pneumonia
(coronavirus disease 2019 [COVID19]) in China, and rapidly spreads
around the world.
[Correction added on March 17, 2020 after first online publication: Manuscript has been revised with author's latest changes]
Genomic analysis shows that SARSCoV2 is in the same beta-
coronavirus (βCoV) clade as MERSCoV and SARSCoV, and shares
highly homological sequence with SARSCoV.
The public evidence
shows that COVID19 shares similar pathogenesis with the pneu-
monia induced by SARSCoV or MERSCoV.
Moreover, the entry of
SARSCoV2 into human host cells has been identified to use the
same receptor as SARSCoV.
Most CoVs share a similar viral structure and infection
and therefore the infection mechanisms previously
found for other CoVs may also be applicable for SARSCoV2.
A growing body of evidence shows that neurotropism is one
common feature of CoVs.
Therefore, it is urgent to make
clear whether SARSCoV2 can gain access to the central nervous
system (CNS) and induce neuronal injury leading to the acute
respiratory distress.
SARSCoV2 causes acute, highly lethal pneumonia with clinical
symptoms similar to those reported for SARSCoV and MERSCoV.
Imaging examination revealed that most patients with fever, dry
cough, and dyspnea showed bilateral groundglass opacities on chest
computerized tomography scans.
However, different from SARS
CoV, SARSCoV2infected patients rarely showed prominent upper
respiratory tract signs and symptoms, indicating that the target cells of
SARSCoV2 may be located in the lower airway.
Based upon the firsthand evidence from Wuhan local
the common symptoms of COVID19 were fever
(83%99%) and dry cough (59.4%82%) at the onset of illness.
However, the most characteristic symptom of patients is re-
spiratory distress (~55%). Among the patients with dyspnea,
more than half needed intensive care. About 46% to 65% of the
patients in the intensive care worsened in a short period of time
and died due to respiratory failure. Among the 36 cases in the
intensive care reported by Wang et al,
11.1% received high
flow oxygen therapy, 41.7% received noninvasive ventilation, and
47.2% received invasive ventilation. These data suggest that most
(about 89%) of the patients in need of intensive care could not
breathe spontaneously.
It is now known that CoVs are not always confined to the
respiratory tract and that they may also invade the CNS inducing
neurological diseases. Such neuroinvasive propensity of CoVs has
been documented almost for all the βCoVs, including SARSCoV,
mouse hepatitis
and porcine hemagglutinating encephalomyelitis
coronavirus (HEV).
With respect to the high similarity between SARSCoV and
SARSCoV2, it remains to know whether the potential neuroinvasion
of SARSCoV2 plays a role in the acute respiratory failure of patients
with COVID19.
It is believed that the tissue distributions of host receptors are
generally consistent with the tropisms of viruses.
The entry of
SARSCoV into human host cells is mediated mainly by a cellular
receptor angiotensinconverting enzyme 2 (ACE2), which is ex-
pressed in human airway epithelia, lung parenchyma, vascular en-
dothelia, kidney cells, and small intestine cells.
Different from
SARSCoV, MERSCoV enters human host cells mainly via dipeptidyl
peptidase 4 (DPP4), which is present in the lower respiratory tract,
kidney, small intestine, liver, and the cells of the immune system.
However, the presence of ACE2 or DPP4 solely is not sufficient
to make host cells susceptible to infection. For example, some ACE2
expressing endothelial cells and human intestinal cell lines failed to
be infected by SARSCoV,
while some cells without a detectable
expression level of ACE2, such as hepatocytes could also be infected
Likewise, the infection of SARSCoV or MERSCoV
was also reported in the CNS, where the expression level of ACE2
or DDP4
is very low under normal conditions.
Early in 2002 and 2003, studies on the samples from patients
with SARS have demonstrated the presence of SARSCoV particles
in the brain, where they were located almost exclusively in the
Experimental studies using transgenic mice further
revealed that either SARSCoV
when given in-
tranasally, could enter the brain, possibly via the olfactory nerves,
and thereafter rapidly spread to some specific brain areas including
thalamus and brainstem. It is noteworthy that in the mice infected
with low inoculum doses of MERSCoV virus particles were de-
tected only in the brain, but not in the lung, which indicates that the
infection in the CNS was more important for the high mortality
observed in the infected mice.
Among the involved brain areas,
the brainstem has been demonstrated to be heavily infected by
The exact route by which SARSCoV or MERSCOV enters the
CNS is still not reported. However, hematogenous or lymphatic route
seems impossible, especially in the early stage of infection, since al-
most no virus particle was detected in the nonneuronal cells in the
infected brain areas.
On the other hand, increasing evidence
shows that CoVs may first invade peripheral nerve terminals, and
then gain access to the CNS via a synapseconnected route.
The transsynaptic transfer has been well documented for other
CoVs, such as HEV67
and avian bronchitis virus.
HEV 67N is the first CoV found to invade the porcine brain, and
it shares more than 91% homology with HCoVOC43.
HEV first
oronasally infects the nasal mucosa, tonsil, lung, and small intestine in
suckling piglets, and then is delivered retrogradely via peripheral
nerves to the medullary neurons in charge of peristaltic function of
the digestive tract, resulting in the socalled vomiting diseases.
The transfer of HEV 67N between neurons has been demonstrated
by our previous ultrastructural studies to use the clathrincoating
mediated endocytotic/exocytotic pathway.
Similarly, the transsynaptic transfer has been reported for avian
bronchitis virus.
Intranasal inoculation in mice with avian influ-
enza virus was reported to cause neural infection besides bronchitis
or pneumonia.
Of interest, viral antigens have been detected in the
brainstem, where the infected regions included the nucleus of the
solitary tract and nucleus ambiguus. The nucleus of the solitary tract
receives sensory information from the mechanoreceptors and che-
moreceptors in the lung and respiratory tracts,
while the effer-
ent fibers from the nucleus ambiguus and the nucleus of the solitary
tract provide innervation to airway smooth muscle, glands, and blood
vessels. Such neuroanatomic interconnections indicate that the death
of infected animals or patients may be due to the dysfunction of the
cardiorespiratory center in the brainstem.
Taken together, the neuroinvasive propensity has been demon-
strated as a common feature of CoVs. In light of the high similarity
between SARSCoV and SARSCoV2, it is quite likely that SARS
CoV2 also possesses a similar potential. Based on an epidemiological
survey on COVID19, the median time from the first symptom to
dyspnea was 5.0 days, to hospital admission was 7.0 days, and to the
intensive care was 8.0 days.
Therefore, the latency period may be
enough for the virus to enter and destroy the medullary neurons. As
a matter of fact, the previous studies
mentioned above has re-
ported that some patients infected with SARSCoV2 did show neurologic
signs such as headache (about 8%), nausea and vomiting (1%). More
recently, one study on 214 COVID19 patients by Mao et al.
found that about 88% (78/88) among the severe patients displayed
neurologic manifestations including acute cerebrovascular diseases and
impaired consciousness. Therefore, awareness of the possible neu-
roinvasion may have a guiding significance for the prevention and
treatment of the SARSCoV2induced respiratory failure.
YanChao Li
1. Glass WG, Subbarao K, Murphy B, Murphy PM. Mechanisms of host
defense following severe acute respiratory syndromecoronavirus (SARS
CoV) pulmonary infection of mice. J Immunol. 2004;173:40304039.
2. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with
2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497506.
3. Yu F, Du L, Ojcius DM, Pan C, Jiang S. Measures for diagnosing and
treating infections by a novel coronavirus responsible for a pneu-
monia outbreak originating in Wuhan, China. Microbes Infect. 2020.
4. Song Z, Xu Y, Bao L, et al. From SARS to MERS, thrusting cor-
onaviruses into the spotlight. Viruses. 2019;11:59.
5. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of
2019 novel coronavirus: implications for virus origins and receptor
binding. Lancet. 2020;395:565574.
6. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by
novel coronavirus from Wuhan: an analysis based on decadelong
structural studies of SARS. J Virol. 2020.
7. Yuan Y, Cao D, Zhang Y, et al. CryoEM structures of MERSCoV and
SARSCoV spike glycoproteins reveal the dynamic receptor binding
domains. Nat Commun. 2017;8:15092.
8. Hulswit RJ, de Haan CA, Bosch BJ. Coronavirus spike protein and
tropism changes. Adv Virus Res. 2016;96:2957.
9. Li YC, Bai WZ, Hirano N, Hayashida T, Hashikawa T. Coronavirus
infection of rat dorsal root ganglia: ultrastructural characterization of
viral replication, transfer, and the early response of satellite cells.
Virus Res. 2012;163:628635.
10. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized
patients with 2019 novel coronavirusinfected pneumonia in Wuhan,
China. JAMA. 2020.
11. Khan S, Ali A, Siddique R, Nabi G. Novel coronavirus is putting the
whole world on alert. J Hosp Infect. 2020.
12. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical
characteristics of 99 cases of 2019 novel coronavirus pneumonia
in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):
13. Li K, WohlfordLenane C, Perlman S, et al. Middle East respiratory
syndrome coronavirus causes multiple organ damage and lethal dis-
ease in mice transgenic for human dipeptidyl peptidase 4. J Infect Dis.
14. Talbot PJ, Ekandé S, Cashman NR, Mounir S, Stewart JN. Neurotropism
of human coronavirus 229E. Adv Exp Med Biol. 1993;342:339346.
15. Dubé M, Le Coupanec A, Wong AHM, Rini JM, Desforges M,
Talbot PJ. Axonal transport enables neurontoneuron propagation of
human coronavirus OC43. J Virol. 2018;92,
16. Zhou X, Huang F, Xu L, et al. Hepatitis E virus infects neurons and
brains. J Infect Dis. 2017;215(8):11971206.
17. Li YC, Bai WZ, Hirano N, et al. Neurotropic virus tracing suggests a
membranouscoatingmediated mechanism for transsynaptic com-
munication. J Comp Neurol. 2013;521:203212.
18. Mengeling WL, Boothe AD, Ritchie AE. Characteristics of a cor-
onavirus (strain 67N) of pigs. Am J Vet Res. 1972;33(2):297308.
19. Andries K, Pensaert MB. Immunofluorescence studies on the patho-
genesis of hemagglutinating encephalomyelitis virus infection in pigs
after oronasal inoculation. Am J Vet Res. 1980;41(9):13721378.
20. To KF, Lo AW. Exploring the pathogenesis of severe acute respiratory
syndrome (SARS): the tissue distribution of the coronavirus (SARS
CoV) and its putative receptor, angiotensinconverting enzyme 2
(ACE2). J Pathol. 2004;203:740743.
21. Tang JW, To KF, Lo AW, Sung JJ, Ng HK, Chan PK. Quantitative
temporalspatial distribution of severe acute respiratory syndrome
associated coronavirus (SARSCoV) in postmortem tissues. J Med
Virol. 2007;79:12451253.
22. Kam YW, Okumura Y, Kido H, Ng LF, Bruzzone R, Altmeyer R.
Cleavage of the SARS coronavirus spike glycoprotein by airway pro-
teases enhances virus entry into human bronchial epithelial cells in
vitro. PLoS One. 2009;4(11):e7870.
23. Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin
converting enzymerelated carboxypeptidase (ACE2) converts an-
giotensin I to angiotensin 19. Circ Res. 2000;87(5):E1E9.
24. Harmer D, Gilbert M, Borman R, Clark KL. Quantitative mRNA ex-
pression profiling of ACE 2, a novel homologue of angiotensin con-
verting enzyme. FEBS Lett. 2002;532:107110.
25. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H.
Tissue distribution of ACE2 protein, the functional receptor for SARS
coronavirus. A first step in understanding SARS pathogenesis. JPathol.
26. Mattern T, Scholz W, Feller AC, Flad HD, Ulmer AJ. Expression of
CD26 (dipeptidyl peptidase IV) on resting and activated human
Tlymphocytes. Scand J Immunol. 1991;33:737748.
27. Boonacker E, Van Noorden CJ. The multifunctional or moonlighting
protein CD26/DPPIV. Eur J Cell Biol. 2003;82:5373.
28. Chan PK, To KF, Lo AW, et al. Persistent infection of SARS cor-
onavirus in colonic cells in vitro. J Med Virol. 2004;74:17.
29. Ding Y, Wang H, Shen H, et al. The clinical pathology of severe acute
respiratory syndrome (SARS): a report from China. J Pathol. 2003;200:
30. Bernstein HG, Dobrowolny H, Keilhoff G, Steiner J. Dipeptidyl
peptidase IV, which probably plays important roles in alzheimer
disease (AD) pathology, is upregulated in AD brain neurons
and associates with amyloid plaques. Neurochem Int. 2018;114:
31. Ding Y, He L, Zhang Q, et al. Organ distribution of severe acute re-
spiratory syndrome (SARS) associated coronavirus (SARSCoV) in
SARS patients: implications for pathogenesis and virus transmission
pathways. J Pathol. 2004;203:622630.
32. Gu J, Gong E, Zhang B, et al. Multiple organ infection and the pa-
thogenesis of SARS. J Exp Med. 2005;202(3):415424.
33. Xu J, Zhong S, Liu J, et al. Detection of severe acute respiratory
syndrome coronavirus in the brain: potential role of the chemokine
mig in pathogenesis. Clin Infect Dis. 2005;41:10891096.
34. Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S. Severe
acute respiratory syndrome coronavirus infection causes neuronal
death in the absence of encephalitis in mice transgenic for human
ACE2. J Virol. 2008;82:72647275.
35. McCray PB Jr, Pewe L, WohlfordLenane C, et al. Lethal infection of
K18hACE2 mice infected with severe acute respiratory syndrome
coronavirus. J Virol. 2007;81:813821.
36. Matsuda K, Park CH, Sunden Y, et al. The vagus nerve is one route of
transneural invasion for intranasally inoculated influenza a virus in
mice. Vet Pathol. 2004;41:101107.
37. Chasey D, Alexander DJ. Morphogenesis of avian infectious bronchitis
virus in primary chick kidney cells. Arch Virol. 1976;52:101111.
38. González JM, GomezPuertas P, Cavanagh D, Gorbalenya AE, Enjuanes L.
A comparative sequence analysis to revise the current taxonomy of the
family coronaviridae. Arch Virol. 2003;148:22072235.
39. Li Z, He W, Lan Y, et al. The evidence of porcine hemagglutinating
encephalomyelitis virus induced nonsuppurative encephalitis as the
cause of death in piglets. Peer J. 2016;4:e2443.
40. Kalia M, Mesulam MM. Brain stem projections of sensory and motor
components of the vagus complex in the cat: II. Laryngeal, tracheo-
bronchial, pulmonary, cardiac, and gastrointestinal branches. J Comp
Neurol. 1980;193:467508.
41. Hadziefendic S, Haxhiu MA. CNS innervation of vagal preganglionic
neurons controlling peripheral airways: a transneuronal labeling study
using pseudorabies virus. J Auton Nerv Syst. 1999;76:135145.
42. Raux H, Flamand A, Blondel D. Interaction of the rabies virus P pro-
tein with the LC8 dynein light chain. J Virol. 2000;74:1021210216.
43. Mao L, Wang M, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D,
Li Y, Jin H, Hu B. Neurological Manifestations of Hospitalized Patients
with COVID-19 in Wuhan, China: a retrospective case series study.
Additional supporting information may be found online in the Sup-
porting Information section.
How to cite this article: Li YC, Bai WZ, Hashikawa T. The
neuroinvasive potential of SARSCoV2 may play a role in the
respiratory failure of COVID19 patients. J Med Virol.
... Taken together, these results suggest that Severe Acute Respiratory Syndrome COronaVirus 2 (SARS-CoV-2), causing severe COVID-19, may retain the potential to disrupt the activity of brain regions related to autobiographical memories, triggering EPs and dissociative symptoms that, in the long term, may disrupt cognitive performance, in the long-COVID period. In fact, it has been reported that SARS-CoV-2 shows a neuroinvasive potential (Li et al., 2020) that may contribute to respiratory failure of COVID-19 patients and may promote the disruption of the activity of brain regions related to autobiographical memories that will be further discussed in light of the polyvagal theory (Poli et al., 2020). ...
... Both of these ANPs may be mainly supported at the neurophysiological level by the VVC, though there may be no integration between them ( Figure 5). Interestingly, SARS-CoV-2 viral antigens have been detected in the brainstem, where the infected regions included the nucleus of the solitary tract (the main input source for both DMNX and NA in the polyvagal theory) and NA (Li et al., 2020), whose myelinated fibers contribute to VVC, health, and social engagement, potentially characterizing COVID-19 as a cardiorespiratory disease (Poli et al., 2020). Disrupting the activity of the nucleus of the solitary tract and NA in the brainstem through its neuroinvasive potential (Lahiri et al., 2020;Li et al., 2020;Yashavantha Rao and Jayabaskaran, 2020;Valizadeh et al., 2022), SARS-CoV-2 may foster the perturbation of the SES and promote the activation of the cortical regions supporting the emergence of autobiographical EPs, possibly supported by SNS or DVC, and dissociative symptoms. ...
... Interestingly, SARS-CoV-2 viral antigens have been detected in the brainstem, where the infected regions included the nucleus of the solitary tract (the main input source for both DMNX and NA in the polyvagal theory) and NA (Li et al., 2020), whose myelinated fibers contribute to VVC, health, and social engagement, potentially characterizing COVID-19 as a cardiorespiratory disease (Poli et al., 2020). Disrupting the activity of the nucleus of the solitary tract and NA in the brainstem through its neuroinvasive potential (Lahiri et al., 2020;Li et al., 2020;Yashavantha Rao and Jayabaskaran, 2020;Valizadeh et al., 2022), SARS-CoV-2 may foster the perturbation of the SES and promote the activation of the cortical regions supporting the emergence of autobiographical EPs, possibly supported by SNS or DVC, and dissociative symptoms. ...
Full-text available
Dissociative disorders (DDs) are characterized by a discontinuity in the normal integration of consciousness, memory, identity, emotion, perception, bodily representation, motor control, and action. The life-threatening coronavirus disease 2019 (COVID-19) pandemic has been identified as a potentially traumatic event and may produce a wide range of mental health problems, such as depression, anxiety disorders, sleep disorders, and DD, stemming from pandemic- related events, such as sickness, isolation, losing loved ones, and fear for one’s life. In our conceptual analysis, we introduce the contribution of the structural dissociation of personality (SDP) theory and polyvagal theory to the conceptualization of the COVID-19 pandemic-triggered DD and the importance of assessing perceived safety in DD through neurophysiologically informed psychometric tools. In addition, we analyzed the contribution of eye movement desensitization and reprocessing (EMDR) to the treatment of the COVID- 19 pandemic-triggered DD and suggest possible neurobiological mechanisms of action of the EMDR. In particular, we propose that, through slow eye movements, the EMDR may promote an initial non-rapid-eye-movement sleep stage 1-like activity, a subsequent access to a slow-wave sleep activity, and an oxytocinergic neurotransmission that, in turn, may foster the functional coupling between paraventricular nucleus and both sympathetic and parasympathetic cardioinhibitory nuclei. Neurophysiologically informed psychometric tools for safety evaluation in DDs are discussed. Furthermore, clinical and public health implications are considered, combining the EMDR, SDP theory, and polyvagal conceptualizations in light of the potential dissociative symptomatology triggered by the COVID-19 pandemic.
... Beyond being one of the symptoms of SARS-CoV-2, olfactory dysfunction serves as a precursing clinical sign of a developing infection (Li, Bai, & Hashikawa, 2020); difficulty detecting smells tends to appear prior to other symptoms such as cough and fever. Moreover, Li, Long, et al. (2020) found that olfactory impairments can hold for longer than 95 days with a median duration of 62 days. ...
... Given the similarities between SARS-CoV and the newer version of the virus (SARS-CoV-2), it is hypothesized that the latter could also impact the CNS. Characteristic clinical manifestations of SARS-CoV-2 -headaches, nausea, and vomiting -could indicate neurological impacts of the infection (Li, Bai, et al., 2020). Conversely, research by Mao et al. (2020) tentatively found that 36.4 % of SARS-CoV-2 infections came with neurological expressions. ...
Olfactory deficits are common among nonclinical and clinical patients, particularly in those with neuropsychological conditions. They are, however, often not diagnosed because standard assessments focus on superior cognitive domains and do not examine the senses. Olfactory function greatly impacts mental health and quality of life. It is also associated with the likelihood of developing neurological or psychological conditions and impacts the prognostic and rehabilitative outcomes of patients, particularly in regards to cognitive health. The purpose of this article is to (a) provide an overview of the olfactory sense and its unique characteristics, (b) discuss the scientific literature around olfaction and related neurological and psychological conditions, (c) present common olfactory assessment techniques, and (d) argue for the inclusion of olfactory measures to standard neuropsychological examinations. An olfactory measurement tool is currently being developed that is suitable to supplement neuropsychological examinations.
... Трій час тий нерв може бути потенційним джерелом ура ження ЦНС через ноцицептивні клітини носової порожнини та сенсорні волокна кон'юнктиви. Свідченням цього є виявлення РНК SARS-CoV-2 у пацієнтів із кон'юнктивітом [23,24,36]. ...
Full-text available
Мета роботи — дослідити наявність зв’язку між рівнем біомаркерів NSE, S100 та Е-селектину з ускладненим перебігом і симптомами з боку нервової системи при коронавірусній хворобі-2019 (COVID-19) у дітей. Матеріали та методи. Проведено пілотне когортне обсерваційне ретроспективне дослідження із залученням 88 дітей віком від 1 міс до 18 років із лабораторно підтвердженим методом полімеразної ланцюгової реакції діагнозом COVID-19, які перебували на стаціонарному лікуванні в Київській міській дитячій клінічній інфекційній лікарні у 2021—2022 рр. У першу добу після госпіталізації визначали рівень у сироватці крові біомаркерів (нейрон-специфічної енолази (NSE), білка S100 та Е-селектину) методом імуноферментного аналізу. Результати та обговорення. Ускладнений перебіг COVID-19 спостерігали у 42 (47,7 %) пацієнтів. Симптоми з боку нервової системи зареєстрували в 46 (52,0 %) хворих. У пацієнтів із неускладненим перебігом середній рівень NSE становив (12,1 ± 1,2) мкг/л, S100 — (164,0 ± 8,2) нг/л, Е-селектину — (12,02 ± 1,70) нг/мл, у хворих з ускладненим перебігом — відповідно (16,9 ± 1,5) мкг/л, (165,9 ± 6,9) нг/л і (15,04 ± 1,90) нг/мл. Величина NSE > 15 мкг/л та Е-селектину > 25 нг/мл асоціювалась зі статистично значущим зростанням ризику появи клінічних симптомів з боку нервової системи та ускладненого перебігу у дітей із COVID-19 (р < 0,05), значення показника S100 > 150 нг/л — з підвищенням ризику появи клінічних симптомів ураження нервової системи (p < 0,05) і тенденцією до виникнення ускладнень (р < 0,1). Зростання рівня всіх біомаркерів збільшувало тривалість стаціонарного лікування. Висновки. Ускладнений перебіг і поява симптомів з боку нервової системи у дітей, госпіталізованих із COVID-19, асоціюється з підвищенням рівня біомаркерів NSE, S100 та Е-селектину. Визначення цих біомаркерів можна використовувати для прогнозування перебігу та тяжкості хвороби у дітей, що перебувають на стаціонарному лікуванні з приводу COVID-19.
... There was no apparent anti-inflammatory impact observed on macrophages or dendritic cells, nor was there any depletion of quiescent naive or memory T cells. Similarly, in a study, the mice infected by SARS-CoV, monocyte-macrophage inflammation responses eventually led to fatal pneumonia, recommending the vital role of inhibiting such monocytes in labeling severe pneumonia which is related to SARS-CoV to understand the consequences or effects that can have an impact on the patient due to the introduction of the drug [81,82]. ...
Full-text available
The COVID-19 pandemic has become a global health crisis, inflicting substantial morbidity and mortality worldwide. A diverse range of symptoms, including fever, cough, dyspnea, and fatigue, characterizes COVID-19. A cytokine surge can exacerbate the disease's severity. This phenomenon involves an increased immune response, marked by the excessive release of inflammatory cytokines like IL-6, IL-8, TNF-α, and IFNγ, leading to tissue damage and organ dysfunction. Efforts to reduce the cytokine surge and its associated complications have garnered significant attention. Standardized management protocols have incorporated treatment strategies, with corticosteroids, chloroquine, and intravenous immunoglobulin taking the forefront. The recent therapeutic intervention has also assisted in novel strategies like repurposing existing medications and the utilization of in vitro drug screening methods to choose effective molecules against viral infections. Beyond acute management, the significance of comprehensive post-COVID-19 management strategies, like remedial measures including nutritional guidance, multidisciplinary care, and follow-up, has become increasingly evident. As the understanding of COVID-19 pathogenesis deepens, it is becoming increasingly evident that a tailored approach to therapy is imperative. This review focuses on effective treatment measures aimed at mitigating COVID-19 severity and highlights the significance of comprehensive COVID-19 management strategies that show promise in the battle against COVID-19.
... Research indicates that SARS-CoV-2 has the ability to directly attack the central nervous system (CNS), causing a range of neurological manifestations. (9) Around 70% of individuals with COVID-19 experience a reduction or complete loss of their sense of smell (anosmia) and taste (ageusia), which are among the most common neurological symptoms associated with SARS-CoV-2 infection. (10) Additional neurological symptoms that may occur as a result of SARS-CoV-2 infection include but are not limited to: headaches, dizziness, confusion, delirium, seizures, and strokes. ...
Full-text available
This article covers various aspects of COVID-19, also known as the new coronavirus. It is caused by the SARS-CoV-2 virus and was first identified in December 2019 in Wuhan, China. The virus has rapidly spread globally and caused a pandemic. The primary mode of transmission is through respiratory droplets when an infected person talks, coughs or sneezes. While most people will experience mild or moderate symptoms, the disease can be severe and even fatal, especially for older adults and those with underlying health conditions. Additionally, the article discusses the immunopathology of SARS-CoV-2 and its effects on the immune system, as well as the neurological manifestations of COVID-19 and its impact on cerebrovascular disease.
The recent outbreak of coronavirus disease 2019 (COVID-19) impacted the entire human population. This viral disease caused much morbidity and mortality as cancer has done over the years. The SARS-CoV-2 infection starts with the interaction of spike protein (S) and host cell surface receptor angiotensin-converting enzyme 2 (ACE2) to internalise the virus which is facilitated by transmembrane serine protease 2 (TMPRSS2). Comorbidity includes cancer associated with the severity of the infection, which may cause multiple organ failures and deaths. Individuals in vulnerable populations, patients with metabolic disorders, cancer and others are considered at a high risk of developing severe COVID-19 outcomes. However, cancer and COVID-19 have similar pathophysiological events like cytokine storm, increase oxidative stress and compromised redox. Moreover, the clinical relevance of cancer to COVID-19 is based on cytokines, type I interferons (IFN-I), androgen receptors and immune checkpoint signalling. Over the years, multiple studies have identified a diversity of molecular devices deployed by every known virus family to hijack, control or impair p53 functions. Furthermore, the hallmarks of cancer and COVID-19 have provided a useful conceptual framework for understanding their complex biology. COVID-19 pandemic imposed significant challenges for clinicians, especially for oncologists in diagnosis and therapy. Oncologists must carefully determine viral exposure, the need for ventilation, to continue treatment or provide a particular therapy is a major clinical challenge. This chapter critically reviews the synergistic mechanism of COVID-19 and cancer which can provide a lead to tackle current conceptual and clinical challenges.
Full-text available
Background SARS-CoV-2 was declared a global health emergency by WHO Emergency Committee based on growing case notification rates at Chinese and international locations. In this paper, we present an approach to understand the probable clinical origin of SARS-CoV-2. Methods A combination of citation network analysis, analysis of Medical Heading Subject (MeSH) terms, and quantitative content analysis of scientific literature, was employed to map the organization of the clinical origin of SARS-CoV-2 in this paper. Results According to the results of the study, a genome of the first 2019-nCoV strain in Hangzhou was obtained, and phylogenetic analysis showed the genome to be closest to the genome of a bat SARS-like coronavirus strain, RaTG13, with an identity of 96.11%. Conclusion The studies show that the dead Malayan pangolins found close to the outbreak of COVID-19 in China may have carried coronavirus closely related to SARS-CoV-2.
SARS-CoV-2, responsible for COVID-19, shares 79% and 50% of its identity with SARS-CoV-1 and MERS-CoV, respectively. It uses the same main cell attachment and entry receptor as SARS-CoV-1, which is the ACE-2 receptor. However, key residues in the receptor-binding domain of its S-protein seem to give it a stronger affinity for the receptor and a better ability to hide from the host immune system. Like SARS-CoV-1 and MERS-CoV, cytokine storms in critically ill COVID-19 patients cause ARDS, neurological pathology, multiorgan failure, and increased death. Though many issues remain, the global research effort and lessons from SARS-CoV-1 and MERS-CoV are hopeful. The emergence of novel SARS-CoV-2 variants and subvariants raised serious concerns among the scientific community amid the emergence of other viral diseases like monkeypox and Marburg virus, which are major concerns for healthcare settings worldwide. Hence, an updated review on the comparative analysis of various coronaviruses (CoVs) has been developed, which highlights the evolution of CoVs and their repercussions.
Full-text available
OBJECTIVE: To study the neurological manifestations of patients with coronavirus disease 2019 (COVID-19). DESIGN: Retrospective case series SETTING: Three designated COVID-19 care hospitals of the Union Hospital of Huazhong University of Science and Technology in Wuhan, China. PARTICIPANTS: Two hundred fourteen hospitalized patients with laboratory confirmed diagnosis of severe acute respiratory syndrome from coronavirus 2 (SARS-CoV-2) infection. Data were collected from 16 January 2020 to 19 February 2020. MAIN OUTCOME MEASURES: Clinical data were extracted from electronic medical records and reviewed by a trained team of physicians. Neurological symptoms fall into three categories: central nervous system (CNS) symptoms or diseases (headache, dizziness, impaired consciousness, ataxia, acute cerebrovascular disease, and epilepsy), peripheral nervous system (PNS) symptoms (hypogeusia, hyposmia, hypopsia, and neuralgia), and skeletal muscular symptoms. Data of all neurological symptoms were checked by two trained neurologists. RESULTS: Of 214 patients studied, 88 (41.1%) were severe and 126 (58.9%) were non-severe patients. Compared with non-severe patients, severe patients were older (58.7 ± 15.0 years vs 48.9 ± 14.7 years), had more underlying disorders (42 [47.7%] vs 41 [32.5%]), especially hypertension (32 [36.4%] vs 19 [15.1%]), and showed less typical symptoms such as fever (40 [45.5%] vs 92 [73%]) and cough (30 [34.1%] vs 77 [61.1%]). Seventy-eight (36.4%) patients had neurologic manifestations. More severe patients were likely to have neurologic symptoms (40 [45.5%] vs 38 [30.2%]), such as acute cerebrovascular diseases (5 [5.7%] vs 1 [0.8%]), impaired consciousness (13 [14.8%] vs 3 [2.4%]) and skeletal muscle injury (17 [19.3%] vs 6 [4.8%]). CONCLUSION: Compared with non-severe patients with COVID-19, severe patients commonly had neurologic symptoms manifested as acute cerebrovascular diseases, consciousness impairment and skeletal muscle symptoms.
Full-text available
Importance In December 2019, novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited. Objective To describe the epidemiological and clinical characteristics of NCIP. Design, Setting, and Participants Retrospective, single-center case series of the 138 consecutive hospitalized patients with confirmed NCIP at Zhongnan Hospital of Wuhan University in Wuhan, China, from January 1 to January 28, 2020; final date of follow-up was February 3, 2020. Exposures Documented NCIP. Main Outcomes and Measures Epidemiological, demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed. Outcomes of critically ill patients and noncritically ill patients were compared. Presumed hospital-related transmission was suspected if a cluster of health professionals or hospitalized patients in the same wards became infected and a possible source of infection could be tracked. Results Of 138 hospitalized patients with NCIP, the median age was 56 years (interquartile range, 42-68; range, 22-92 years) and 75 (54.3%) were men. Hospital-associated transmission was suspected as the presumed mechanism of infection for affected health professionals (40 [29%]) and hospitalized patients (17 [12.3%]). Common symptoms included fever (136 [98.6%]), fatigue (96 [69.6%]), and dry cough (82 [59.4%]). Lymphopenia (lymphocyte count, 0.8 × 10⁹/L [interquartile range {IQR}, 0.6-1.1]) occurred in 97 patients (70.3%), prolonged prothrombin time (13.0 seconds [IQR, 12.3-13.7]) in 80 patients (58%), and elevated lactate dehydrogenase (261 U/L [IQR, 182-403]) in 55 patients (39.9%). Chest computed tomographic scans showed bilateral patchy shadows or ground glass opacity in the lungs of all patients. Most patients received antiviral therapy (oseltamivir, 124 [89.9%]), and many received antibacterial therapy (moxifloxacin, 89 [64.4%]; ceftriaxone, 34 [24.6%]; azithromycin, 25 [18.1%]) and glucocorticoid therapy (62 [44.9%]). Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications, including acute respiratory distress syndrome (22 [61.1%]), arrhythmia (16 [44.4%]), and shock (11 [30.6%]). The median time from first symptom to dyspnea was 5.0 days, to hospital admission was 7.0 days, and to ARDS was 8.0 days. Patients treated in the ICU (n = 36), compared with patients not treated in the ICU (n = 102), were older (median age, 66 years vs 51 years), were more likely to have underlying comorbidities (26 [72.2%] vs 38 [37.3%]), and were more likely to have dyspnea (23 [63.9%] vs 20 [19.6%]), and anorexia (24 [66.7%] vs 31 [30.4%]). Of the 36 cases in the ICU, 4 (11.1%) received high-flow oxygen therapy, 15 (41.7%) received noninvasive ventilation, and 17 (47.2%) received invasive ventilation (4 were switched to extracorporeal membrane oxygenation). As of February 3, 47 patients (34.1%) were discharged and 6 died (overall mortality, 4.3%), but the remaining patients are still hospitalized. Among those discharged alive (n = 47), the median hospital stay was 10 days (IQR, 7.0-14.0). Conclusions and Relevance In this single-center case series of 138 hospitalized patients with confirmed NCIP in Wuhan, China, presumed hospital-related transmission of 2019-nCoV was suspected in 41% of patients, 26% of patients received ICU care, and mortality was 4.3%.
Full-text available
Background: A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods: All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings: By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0-58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0-13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation: The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding: Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
On 10 January 2020, a new coronavirus causing a pneumonia outbreak in Wuhan City in central China was denoted as 2019-nCoV by the World Health Organization (WHO). As of 24 January 2020, there were 887 confirmed cases of 2019-nCoV infection, including 26 deaths, reported in China and other countries. Therefore, combating this new virus and stopping the epidemic is a matter of urgency. Here, we focus on advances in research and development of fast diagnosis methods, as well as potential prophylactics and therapeutics to prevent or treat 2019-nCoV infection.
The recent emergence of Wuhan coronavirus (2019-nCoV) puts the world on alert. 2019-nCoV is reminiscent of the SARS-CoV outbreak in 2002 to 2003. Our decade-long structural studies on the receptor recognition by SARS-CoV have identified key interactions between SARS-CoV spike protein and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. One of the goals of SARS-CoV research was to build an atomic-level iterative framework of virus-receptor interactions to facilitate epidemic surveillance, predict species-specific receptor usage, and identify potential animal hosts and animal models of viruses. Based on the sequence of 2019-nCoV spike protein, we apply this predictive framework to provide novel insights into the receptor usage and likely host range of 2019-nCoV. This study provides a robust test of this reiterative framework, providing the basic, translational, and public health research communities with predictive insights that may help study and battle this novel 2019-nCoV.
Background: In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed. Methods: We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus. Findings: The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues. Interpretation: 2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation. Funding: National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.
Background: In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia. Methods: In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020. Findings: Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure. Interpretation: The 2019-nCoV infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In general, characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019-nCoV infection. Funding: National Key R&D Program of China.