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Cerebrovascular and Neurological Dysfunction under the Threat of COVID-19: Is There a Comorbid Role for Smoking and Vaping?

Authors:
  • Oakland University William Beaumont School of Medicine

Abstract and Figures

The recently discovered novel coronavirus, SARS-CoV-2 (COVID-19 virus), has brought the whole world to standstill with critical challenges, affecting both health and economic sectors worldwide. Although initially, this pandemic was associated with causing severe pulmonary and respiratory disorders, recent case studies reported the association of cerebrovascular-neurological dysfunction in COVID-19 patients, which is also life-threatening. Several SARS-CoV-2 positive case studies have been reported where there are mild or no symptoms of this virus. However, a selection of patients are suffering from large artery ischemic strokes. Although the pathophysiology of the SARS-CoV-2 virus affecting the cerebrovascular system has not been elucidated yet, researchers have identified several pathogenic mechanisms, including a role for the ACE2 receptor. Therefore, it is extremely crucial to identify the risk factors related to the progression and adverse outcome of cerebrovascular-neurological dysfunction in COVID-19 patients. Since many articles have reported the effect of smoking (tobacco and cannabis) and vaping in cerebrovascular and neurological systems, and considering that smokers are more prone to viral and bacterial infection compared to non-smokers, it is high time to explore the probable correlation of smoking in COVID-19 patients. Herein, we have reviewed the possible role of smoking and vaping on cerebrovascular and neurological dysfunction in COVID-19 patients, along with potential pathogenic mechanisms associated with it.
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International Journal of
Molecular Sciences
Review
Cerebrovascular and Neurological Dysfunction under
the Threat of COVID-19: Is There a Comorbid Role
for Smoking and Vaping?
Sabrina Rahman Archie 1and Luca Cucullo 1, 2, *
1Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center,
Amarillo, TX 79106, USA; Sabrina.Archie@ttuhsc.edu
2Center for Blood-Brain Barrier Research, Texas Tech University Health Sciences Center,
Amarillo, TX 79106, USA
*Correspondence: luca.cucullo@ttuhsc.edu; Tel.: +806-414-9237
Received: 10 May 2020; Accepted: 29 May 2020; Published: 30 May 2020


Abstract:
The recently discovered novel coronavirus, SARS-CoV-2 (COVID-19 virus), has brought
the whole world to standstill with critical challenges, aecting both health and economic sectors
worldwide. Although initially, this pandemic was associated with causing severe pulmonary and
respiratory disorders, recent case studies reported the association of cerebrovascular-neurological
dysfunction in COVID-19 patients, which is also life-threatening. Several SARS-CoV-2 positive case
studies have been reported where there are mild or no symptoms of this virus. However, a selection
of patients are suering from large artery ischemic strokes. Although the pathophysiology of the
SARS-CoV-2 virus aecting the cerebrovascular system has not been elucidated yet, researchers
have identified several pathogenic mechanisms, including a role for the ACE2 receptor. Therefore,
it is extremely crucial to identify the risk factors related to the progression and adverse outcome of
cerebrovascular-neurological dysfunction in COVID-19 patients. Since many articles have reported
the eect of smoking (tobacco and cannabis) and vaping in cerebrovascular and neurological systems,
and considering that smokers are more prone to viral and bacterial infection compared to non-smokers,
it is high time to explore the probable correlation of smoking in COVID-19 patients. Herein, we have
reviewed the possible role of smoking and vaping on cerebrovascular and neurological dysfunction
in COVID-19 patients, along with potential pathogenic mechanisms associated with it.
Keywords:
SARS-CoV-2; COVID-19; cerebrovascular; neurological; smoking; CNS; blood-brain
barrier
1. Introduction
Coronavirus disease 2019 or COVID-19 is an infectious disease caused by a recently discovered
form of coronavirus known as severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2) [
1
,
2
].
The outbreak of this virus first appeared in Wuhan city of Hubei province in China in December 2019 [
3
].
On March 11, 2020, it was declared as a pandemic by the World Health Organization (WHO) [
4
]. As of
May 28th 2020, a total number of 5,792,874 coronavirus cases, including 357,479 deaths, have been
reported all over the world [
5
]. This virus is spreading among all populations so rapidly that, in just
three months, the USA has become the epicenter, having 1,745,803 confirmed cases, including 102,107
deaths. The number of confirmed cases seems to indicate a steady increment over time and these
numbers can be forecasted using several mathematical models available for COVID-19 [58].
Coronaviruses belong to the subfamily Coronavirinae (family Coronaviridae; order
Nidovirales), containing four genera named, Alphacoronavirus,Betacoronavirus,Gammacoronavirus, and
Deltacoronavirus [
9
]. SARS-CoV-2 is a Betacoronavirus closely related to other human pathogenic
Int. J. Mol. Sci. 2020,21, 3916; doi:10.3390/ijms21113916 www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2020,21, 3916 2 of 18
coronaviruses SARS-CoV and MERS-CoV that also emerged in the 21st century [
10
]. SARS-CoV-2
is an enveloped and non-segmented single-stranded positive-sense RNA virus having crown like
spikes on the outer surface. The diameter and length of SARS-CoV-2 are about 65–125 nm and
29.9 kb respectively [
11
,
12
]. Structure of SARS-CoV-2 consists of 4 major proteins namely, spike (S)
glycoprotein, envelope (E) glycoprotein, membrane (M) glycoprotein, and nucleocapsid (N) protein,
as well as several non-structural and accessory proteins (see Figure 1). Among all the proteins, the
spike (S) protein plays a key role in viral attachment, fusion, entry, and transmission. This S protein is
responsible for the entry of SARS-CoV-2 into the host cell by attaching with angiotensin converting
enzyme 2 (ACE2), which acts as a receptor and is present in dierent organs of the body [13,14].
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 6 of 19
Figure 1. Illustrative view of the SARC-CoV-2 virus structural components and known modality of
viral entry into the cells. The scheme also provides a summary panel of the potential health impact
on the human body specific to lung and the CNS. (ACE2: Angiotensin converting enzyme 2, ER:
Endoplasmic reticulum)
Additionally, COVID-19 patients suffer from coagulopathy and prothrombin time prolongation,
which may contribute to secondary cerebral hemorrhage, although, as of today, no secondary
cerebral hemorrhage has been reported in COVID-19 patients [49]. Moreover, an increased level of
D-dimer has been found in COVID-19 patients, which may result in thrombotic vascular events
[49,73]. As SARS-CoV-2 has been found in cerebrospinal fluid, it is crucial to evaluate the protective
role of the BBB in preventing the virus from getting access to neural tissues [67]. This is of crucial
importance since comorbid pathologies (such as those promoted by chronic smoking and vaping
[28,31,74,75]) that negatively impact the integrity and function of the BBB may facilitate the virus
entry into the CNS.
Another important mechanism behind the cerebrovascular and neurological symptoms in
COVID-19 patients could be an immune injury. It has been found that viral infection may damage
the nervous system by altering the immune responses [76]. A CoV infection-mediated severe
pneumonia could promote systemic inflammatory response syndrome (SIRS). Studies suggested that
immune damage could be prevented by early anti-inflammatory intervention and could also decrease
the risk of nervous system injury [61,77]. Both SARS and COVID-19 have been found to cause
multiple organ failure-mediated fatalities through virus-induced SIRS or SIRS-like immune disorders
[62,78].
Cytokines play a pivotal role in regulating immunological and inflammatory function of the
body [79]. Additional studies confirmed the release of high level of inflammatory factors, such as
Figure 1.
Illustrative view of the SARC-CoV-2 virus structural components and known modality of
viral entry into the cells. The scheme also provides a summary panel of the potential health impact
on the human body specific to lung and the CNS. (ACE2: Angiotensin converting enzyme 2, ER:
Endoplasmic reticulum)
COVID-19 is easily transmitted through saliva droplets or discharge from the nose of an infected
person when he/she sneezes or coughs [
15
,
16
]. While most of the infected patients will show mild
to moderate respiratory distress/illness and recover with or without requiring special treatments,
the death toll number is shockingly high compared to other types of coronaviruses, SARS-CoV and
MERS-CoV. The symptoms include fever, dry cough, shortness of breath, sore throat, tiredness, and
aches and pains [
2
]. The Centers for Disease Control and Prevention (CDC) have identified some
severe symptoms which require emergency medical attention including, but not limited to, persistent
pain or pressure in the chest, trouble breathing, inability to wake or stay awake, new confusion, and
bluish lips or face [
17
]. Although COVID-19 primarily aects the respiratory system, recent reports
have revealed some neurological and cerebrovascular symptoms associated with the disease, including
Int. J. Mol. Sci. 2020,21, 3916 3 of 18
headache, disturbed consciousness, paresthesia [
1
], and, most recently, stroke [
18
]. Additionally, brain
tissue edema and partial neuronal degeneration, as well as viral encephalitis attacking the central
nervous system (CNS) have also been reported [
19
,
20
]. Therefore, it seems that COVID-19 can promote
harm of the cerebrovascular system and the CNS of infected patients.
Smoking (cigarettes and cannabis) and vaping are significant public health concerns in the USA
and around the globe. Ample studies have found that smoking is associated with dierent diseases
aecting dierent organs of the body, many of which are fatal. Smoking is considered a risk factor
for developing and progression of cancers and major forms of respiratory distress, including chronic
obstructive pulmonary disease (COPD), pulmonary fibrosis etc. [
21
]. It has been reported that smoking
is responsible for the development of squamous metaplasia in large airways, hypersecretion of mucus
and hyperplasia in smooth muscle, along with increased small airway fibrosis and thickening of the
airway wall which ultimately results in narrowing and destruction of the airway, accompanied by
bronchitis. Patients may also suer from airflow limitation due to emphysematous lung destruction [
22
].
Smoking is also considered a significant pro-immunogenic mix of substances impacting the immune
responses and promoting the onset of autoimmune disorders (such as rheumatoid arthritis and systemic
lupus) in genetically-susceptible individuals. Smoking severely impacts the vascular system promoting
the onset of neurological diseases as well as fatal cardiovascular diseases [
23
]. By comparison with
non-smokers, smokers are more prone to respiratory illness, including colds, increased rates of
influenza, bacterial pneumonia, and tuberculosis [
24
]. Smoking causes damage to the lungs which, in
turn, makes the patients more vulnerable to viral and bacterial pulmonary infections as well. Tobacco
smoke causes structural changes, including peri-bronchiolar inflammation and fibrosis, enhanced
mucosal permeability, impaired mucociliary clearance, changes in pathogen adherence, and disruption
of the respiratory epithelium, which ultimately dysregulate immune defenses of respiratory system.
Moreover, smoking is related to a wide range of alterations in cellular and humoral immune system
function [25].
In comparison to non-smokers, smokers have an increased risk of developing influenza [
25
]
and this infection can even exacerbate the comorbidities that are common in these populations [
26
].
It has also been reported that, after influenza infection, smokers are at higher risk of hospitalization
compared to non-smokers [
27
]. Tobacco smoke not only plays a crucial role in developing respiratory
distress but is also associated with an increased risk of cerebrovascular and neurological diseases, like
stroke, Alzheimer’s disease, multiple sclerosis, and vascular dementia by disrupting the blood-brain
barrier (BBB), inducing oxidative stress, inflammation, and the alteration of immune responses [
28
31
].
Noticeably, the negative eect of smoking on the progression of COVID-19 infection has been reported
in recent case studies and reports [
32
35
]. As smoking increases the risk and susceptibility of
SARS-CoV-2 infection, increasing the progression of COVID-19, and leading to severe respiratory
distress and cardiovascular disease, this review article aims to determine plausible comorbid CNS and
cerebrovascular roles of smoking and vaping in COVID-19 patients.
2. CoV Infection and CNS
Previous studies reported the disruption of the structure and function of the CNS due to viral
infection resulting in severe encephalitis, toxic encephalopathy, and severe acute demyelinating
lesions [
1
,
36
]. Some neurotropic viruses can cause infections of macrophages, microglia, and astrocytes
by invading nervous tissues [
37
,
38
]. It is evident from previous studies that respiratory-related
infections act as a critical factor for developing the acute cerebrovascular disease [
39
,
40
] Moreover, the
influenza virus has been found to exacerbate ischemic brain injury through initiating cytokine cascade,
thus increasing the probability of tissue-type plasminogen activator mediated cerebral hemorrhage [
41
].
SARS-CoV was found to cause dierent neurological diseases, including encephalitis,
polyneuropathy, and large artery ischemic stroke [
42
]. Subsequently, the occurrence of cerebral
edema and meningeal vasodilation along with the presence of the SARS-CoV genome sequence were
identified in the brain of several SARS cases from autopsy studies [
1
,
43
]. Moreover, monocyte and
Int. J. Mol. Sci. 2020,21, 3916 4 of 18
lymphocyte penetration in the vessel wall, ischemic changes of neurons, and nerve fiber demyelination
were also detected in autopsies of brain samples of the infected patients [43,44].
MERS-CoV, another coronavirus, causes Middle East Respiratory Syndrome or MERS and is known
as neuroinvasive. It has been found from dierent studies that MERS-CoV is also responsible for causing
dierent neurological complications, including insanity, seizures, ischemic stroke, paralysis, disturbed
consciousness, Guillain-Barre syndrome, and other poisoning or infectious neuropathy [45,46].
3. Neurological and Cerebrovascular Manifestations of COVID-19
SARS-CoV-2, the responsible virus for COVID-19, is 79.5% genetically similar to SARS-CoV and
96% similar to bat coronavirus [
47
]. The sequence homology of SARS-CoV-2 also showed a 50%
similarity to MERS-CoV virus [
48
]. Although the primary symptoms of COVID-19 include fever, dry
cough, and fatigue in most of the patients [
33
], some COVID-19 patients exhibited sole neurological
symptoms including headache, dizziness, languidness, unstable walking, malaise, cerebral hemorrhage,
and infarction without showing any of the typical COVID-19 symptoms [
49
]. Additional studies have
also reported a sudden loss of smell or taste in some COVID-19 patients as well [50,51].
A current study comprising 214 patients demonstrated that 36.45% of patients of the total cohort
showed neurological symptoms, including acute cerebrovascular disease, impairment of consciousness,
and skeletal muscle motor function disability; 18.7% of total admitted patients had these severe
neurological manifestations and required admission to the intensive care unit [
49
,
52
]. Other case
studies (shown in Table 1) also reported that acute cerebrovascular and neurological symptoms,
including headache, dizziness, impaired consciousness, olfactory disorders, have been found in
COVID-19 patients. Table 1summarizes recent case studies related to COVID-19 and neurological
dysfunction. However, one of the limitations of the case studies is that the analysis of cerebrospinal
fluid (CSF) and electroencephalography (EEG) was not performed to confirm the presence of the virus
in the CSF [53].
Another recent report has also shown COVID-19 to causes sudden stroke in patients aged between
30 and 40 years old. Although these COVID-19 infected patients had mild or no symptoms of
COVID-19, abnormal blood clotting in large arteries has been reported, which ultimately resulted in
severe stroke [18].
Another important finding is the detection of the genome sequence of SARS-CoV-2 in cerebrospinal
fluid, which opens up a direction towards the damage of CNS in COVID-19 patients causing viral
encephalitis [
1
]. Moreover, some of the COVID-19 patients were found to suer from viremia and
hypoxia [
59
], which play a crucial role in developing toxic encephalopathy. The occurrence of headache,
disturbance in consciousness, other neurological dysfunction is close to 40% of COVID-19 patients [
60
],
and the concurrent detection of brain tissue edema seems to suggest the existence of a possible link
between COVID-19 and infectious, toxic encephalopathy [
19
]. However, extensive studies need to
be conducted to validate this hypothesis further. Additionally, it has been reported that SARS-CoV-2
can initiate a cytokine storm mechanism, which may lead to a range of infectious and non-infectious
diseases, including pancreatitis, acute cerebrovascular disease, and multiple organ dysfunction [
61
63
].
Critically-infected patients also showed a high level of D dimer and severe reduction in platelets, which
may make the patients more vulnerable to acute cerebrovascular dysfunction [
60
,
64
]. Additionally, it
has been speculated that COVID-19 positive patients are vulnerable to other types of pathogenic bacteria,
which can damage the integrity of the blood-brain barrier (BBB). Subsequently, this secondary infection
may lead to headaches, vomiting, loss of vision, and limb convulsions in COVID-19 patients [1].
Focusing on current case studies and research on COVID-19 patients, it is evident that COVID-19
could be associated with neurological and cerebrovascular dysfunction, which can be life-threatening
as well.
Int. J. Mol. Sci. 2020,21, 3916 5 of 18
Table 1. Case studies on neurological and cerebrovascular symptoms in COVID-19 patients.
Study Type Time Study Design Outcome and Symptoms Reference
Retrospective
case series
13 January to 31
March
N=274,
admitted patients
Headache (11.31%),
Dizziness (7.66%) [54]
Retrospective
case series
16 January 2020 to
29 February 2020
N=221,
admitted patients
Acute ischemic stroke (5%),
CVST (0.5%), cerebral
hemorrhage (0.5%)
[55]
Retrospective
case series
16 January 2020 to
19 February 2020
N=214,
admitted patients
Nervous system symptoms
(36.4%) including CNS
symptoms (24.8%):
(Headache (13.1%), dizziness
(16.8%), impaired consciousness
(7.5%), acute cerebrovascular
disease (2.8%), ataxia (0.5%),
epilepsy (0.5%))
[52]
Retrospective
case series
1 January to 28
January, 2020
N=138 admitted
patients Headache (7%), dizziness (9%) [56]
Retrospective
case series
1 January to 20
January, 2020
N=99, admitted
patients Headache (8%), confusion (9%) [57]
Cross-sectional
survey 19 March, 2020 N=59, admitted
patients
Headache (3.4%)
Taste or olfactory disorder
(33.9%),
Taste and olfactory disorder
(18.6%)
[50]
Retrospective
case series
late December
2019- 26 Jan 2020
N=52, admitted
patients (critically
ill adults)
Headache (6%) [58]
Prospective
case series By 2 January 2020 N=41, admitted
patients Headache (8%) in 38 patients [33]
Case study
23 March to 7 April
N=5 Large-vessel stroke (100%) [18]
4. Pathophysiology of COVID-19 Related Cerebrovascular and Neurological Dysfunction
Although the underlying mechanism behind cerebrovascular and neurological dysfunction
in COVID-19 patients has not been elucidated yet, several potential mechanisms could be
non-exclusively responsible for the identified comorbidities. One of the critical targets of SARS-CoV-2
is Angiotensin-converting enzyme 2 (ACE2) [49], which is present in dierent organs including lung,
heart, kidney, testis as well neurons and glial cells of the brain [
13
,
65
67
]. ACE2 plays a pivotal
role in the regulation of blood pressure as well as anti-atherosclerosis mechanisms [
68
]. It has been
demonstrated from various studies that dierent types of CoV and influenza viruses may elevate blood
pressure and increase the potential risk of cerebral hemorrhage by binding to ACE2. A recent study
has also reported that SARS-CoV-2 enters into the host cell through the interaction of SARS-CoV-2 coat
protein SPIKE or (S protein) with ACE2 present on the host cell resulting in the internalization of the
virus [
69
71
]. The expression of ACE2 is found to be low in hypertensive patients, which increases the
chance of hemorrhagic occurrence. Since SARS-CoV-2 decreases the ACE2 expression [
72
] it can be
speculated that the SARS-CoV-2 infected patients are at high risk of hemorrhagic stroke (see Figure 1).
Additionally, COVID-19 patients suer from coagulopathy and prothrombin time prolongation,
which may contribute to secondary cerebral hemorrhage, although, as of today, no secondary cerebral
hemorrhage has been reported in COVID-19 patients [
49
]. Moreover, an increased level of D-dimer
has been found in COVID-19 patients, which may result in thrombotic vascular events [
49
,
73
]. As
SARS-CoV-2 has been found in cerebrospinal fluid, it is crucial to evaluate the protective role of the
BBB in preventing the virus from getting access to neural tissues [
67
]. This is of crucial importance
Int. J. Mol. Sci. 2020,21, 3916 6 of 18
since comorbid pathologies (such as those promoted by chronic smoking and vaping [
28
,
31
,
74
,
75
]) that
negatively impact the integrity and function of the BBB may facilitate the virus entry into the CNS.
Another important mechanism behind the cerebrovascular and neurological symptoms in
COVID-19 patients could be an immune injury. It has been found that viral infection may damage the
nervous system by altering the immune responses [
76
]. A CoV infection-mediated severe pneumonia
could promote systemic inflammatory response syndrome (SIRS). Studies suggested that immune
damage could be prevented by early anti-inflammatory intervention and could also decrease the risk
of nervous system injury [
61
,
77
]. Both SARS and COVID-19 have been found to cause multiple organ
failure-mediated fatalities through virus-induced SIRS or SIRS-like immune disorders [62,78].
Cytokines play a pivotal role in regulating immunological and inflammatory function of the
body [
79
]. Additional studies confirmed the release of high level of inflammatory factors, such as
interleukin-6 (IL-6), interleukin-12 (IL-12), interleukin-15 (IL-15), and tumor necrosis factor-
α
(TNF-
α
)
from primary glial cells infected with CoV [
80
]. Recently, Wan et al. reported the correlation of IL-6
with the severity of COVID-19 symptoms [
81
]. IL-6 may act as a potential biomarker of SARS-CoV-2
as IL-6 level has been found to be increased in COVID-19 patients [
79
] As CoV infection can infect
macrophages, microglia, and astrocytes in the CNS inducing pro-inflammatory conditions [
82
] and
activation of immune cells, it is crucial to find the probable correlation between COVID-19 and
neurological damage through immune injury.
Moreover, the proliferation of viruses in the lung tissue may lead to an impaired exchange of
alveolar gas, thus triggering hypoxia in CNS. This hypoxia causes anaerobic metabolism in brain cells,
which accumulates acid causing cerebral vasodilation, brain cells swelling, interstitial edema, blockage
of cerebral blood flow, and headache because of ischemia and congestion [
83
]. Untreated hypoxia
may induce acute cerebrovascular disease encompassing acute ischemic stroke in high-risk COVID-19
patients [
1
]. As COVID-19 patients often suer from fatal silent hypoxia, it requires substantial
examination and consideration [
84
]. Additionally, ACE2 also plays a role in controlling inflammatory
and atherosclerosis responses of vessels [
85
]. Thus, COVID-19 may promote atherosclerosis formation,
which ultimately may result in brain ischemic stroke by aecting brain microcapillaries.
A neurotrophic virus can also enter the CNS through neuronal pathways such as the olfactory
neuron transport system. Studies reported that, in the early stage of infection or nasal vaccination, CoV
could reach the brain through the olfactory tract, thus causing inflammation and demyelination [
1
,
86
,
87
].
Therefore, it is evident that CoV viruses can invade the brain by neuronal pathways, and this mechanism
should also be investigated in the case of SARS-CoV-2.
5. Smoking, COVID-19, and Cerebrovascular-Neurological Diseases
Tobacco smoking is responsible for a wide range of diseases aecting dierent organs of the body,
including cerebrovascular, cardiovascular, pulmonary systems, and this can be life-threatening as
well [
88
]. These diseases include, but are not limited to, lung cancer, chronic obstructive pulmonary
disease (COPD), cardiovascular diseases, stroke, and decreased immune function [
89
]. Yearly, tobacco
smoking (TS) kills around 6 million people in the world, and more than 0.48 million people in the
USA alone [90]. Although the main addictive component of TS is nicotine, it also contains more than
4700 toxic compounds encompassing carcinogens, mutagens, stable and unstable free radicals as well
as reactive oxygen species (ROS). Dierent studies demonstrated the association between tobacco
smoke and cerebrovascular-neurological dysfunction, including ischemic stroke, Alzheimer’s diseases,
multiple sclerosis, abnormal brain development, and vascular dementia [28,9092]. The mechanisms
behind the toxic eects of smoking include, but are not limited to, inflammation, oxidative stress,
atherosclerosis, disruption of the BBB, and hyperactive immune response [29,30].
The BBB plays a pivotal role in maintaining brain homeostasis and acts as a strong shield to
prevent the entrance of the potentially harmful substances from system blood circulating into the brain
parenchyma. Moreover, it protects the brain by limiting the body’s peripheral immune defense system
from entering inside the brain parenchyma [
74
]. Therefore, disruption of BBB integrity may expose the
Int. J. Mol. Sci. 2020,21, 3916 7 of 18
brain temporarily to potential hazardous components (both exogenous and endogenous) circulating
in the blood, which may aect neuronal activities both in the CNS and the periphery [
74
,
93
]. Loss
of BBB viability may, in turn, increase the risk for secondary brain damage and may progress the
pathogenesis of a variety of CNS diseases such as epilepsy, silent cerebral infarction, hemorrhagic
and non-hemorrhagic stroke, small vessel ischemic disease, and traumatic brain injury [
74
,
94
97
].
Dierent studies reported that TS causes endothelial dysfunction and damages the vascular system.
TS acts as an inflammatory agent causing oxidative stress, which may be responsible for impairment of
BBB [
98
101
]. Even at low concentrations, TS induces strong vascular pro-inflammatory responses.
These encompass the upregulation of endothelial pro-inflammatory genes, pro-inflammatory cytokines
such as Interleukin -1
β
(IL-1
β
), TNF-
α
, upregulation, and activation of matrix metalloproteinase-2 and
-9 (MMP-2, MMP-9), and monocyte dierentiation into macrophages [
31
,
74
]. MMP-2 and MMP-9 aect
BBB integrity by degrading basal laminal components and facilitating immune cell tracking into the
brain [
102
]. All of these pathogenic events promote BBB dysfunction and breakdown, which increases
the risk of cerebrovascular disease, including stroke and other neurological disorders [
31
,
74
]. Howkins
et al. reported the downregulation of zonula occludentes-1 (ZO-1; a tight junction—TJ—accessory
protein linking the TJs to the cellular actin cytoskeleton) at the BBB by nicotine, causing increased
BBB permeability [
103
]. Additionally, other scientific studies demonstrated the a7nAChR mediated
alteration of the function of BBB Na
+
K
+
2Cl
-
co-transporter by nicotine [
104
106
]. TS is also associated
with the progression of atherosclerosis and angiogenesis [
90
]. Signal transducer and activator of
transcription-3 (STAT-3) is an angiogenesis modulator that acts by IL-6/STAT-3 signaling mechanism
and can be upregulated by TS [
107
]. TS may also upregulate Apo-lipoprotein E genes, which regulate
the metabolism of lipoprotein and is related to increased cholesterol level [
90
]. This later can further
elevate the risk of ischemic stroke and atherosclerosis. Serum Amyloid A1 (SAA1) gene expression can
also be upregulated by TS, which may subsequently increase the BBB permeability [108,109].
Furthermore, tobacco smoke also generates a high amount of superoxide, hydrogen peroxide,
hydroxyl radical, and peroxynitrite, which exposes endothelial cells to highly reactive oxygen species
(ROS), leading to oxidative stress (OS) damage [
110
]. OS ultimately results in lipoperoxidation of
polyunsaturated fatty acids in membrane lipids, protein oxidation (backbone fragmentation), DNA
breakdown [
111
113
], mutations of the nuclear protein p53, carcinogen-mediated DNA damage, RNA
oxidation, mitochondrial depolarization, dysregulation of iron transporters and detoxifying enzymes,
and apoptosis [
28
,
114
]. These pathological eects may further impair the cerebrovascular integrity
and function, along with other factors or infectious agents that aect BBB [28,74,75,100,101].
Smokers are more vulnerable to bacterial and viral inflammatory neuropathologies compared
to non-smokers [
88
] and have been shown to promote cerebral vasodilation along with reduced BBB
integrity. Therefore, it is not surprising that chronic smokers are more susceptible to CNS disorders
and, overall, neuronal damage caused by infection [
115
,
116
]. It has also been shown that the post-deep
brain stimulation neuronal infection rate is higher in smoking patients compared to the non-smoking
patients [
117
]. These observed detrimental eects in smokers could be caused by several mechanisms
like increased inflammation and ROS, which leads to leaky BBB, and increased expression of receptors
that promote virus invasion into the brain parenchyma. Recently, Brake et al. reported that smoking
can upregulate the ACE2 receptor [
24
], which acts as a binding site for the S protein of SARS-CoV,
coronavirus NL63, and SARS-CoV-2. This is the first immunohistochemical human lung evidence for
ACE2 receptor expression in smokers and patients with COPD which identified the increased level of
ACE2 expression in resected lung tissue from patients with COPD and healthy lung function smokers
while entirely absent in healthy non-smoking individuals. As COPD patients showed significantly
higher levels of ACE2, suggesting that COPD further exaggerates ACE2 and potential SARS-CoV-2
adhesion site [
24
]. Another recent study demonstrated the dose-dependent upregulation of ACE2
in a subset of epithelial cells lining the respiratory tract which includes goblet cells, club cells, and
alveolar type 2 cells by cigarette smoke. This study also suggested that, smokers are more likely to
develop SARS-CoV-2 infection compared to non-smokers [
118
]. Moreover, a recent
in vitro
study has
Int. J. Mol. Sci. 2020,21, 3916 8 of 18
shown that SARS-CoV-2 can infect engineered human blood vessels organoids, and this interaction can
be inhibited by human recombinant soluble ACE2 (hrsACE2) antibody, thus highlighting a possible
venue to treat COVID-19 [119].
In addition to lung, kidney, heart, and intestine, this receptor is also expressed in endothelial
cells, glial cells, and neurons, which could increase the risk and progression of COVID-19 [
120
,
121
].
Thus the cerebral involvement of COVID-19 can result from the dissemination of the virus into the
systemic circulation from the infected organ, which has been reported in other SARS-CoV aected
patients [
122
]. Impaired BBB due to chronic smoking may facilitate the entry of the SARS-CoV-2 virus
into brain parenchyma. Later, this invading virus can interact with neuronal and glial ACE2 receptors
and start a viral proliferation cycle, which ultimately causes neuronal damage as previously observed
in SARS-CoV [
122
]. Therefore, it can be reasonably speculated that smoking may enhance the risk for
COVID-19 by upregulating the ACE2 [
24
] and promoting the loss of BBB integrity and viability (see
Figure 2).
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 9 of 19
Figure 2. Illustrative panel summarizing the SARS-CoV-2 entry into the human body and the
potential impact of comorbid smoking and/or vaping on the harmful effects of the viral infection to
the CNS. Pre-existing conditions that impairs the viability and function of the BBB (such as those
associated with chronic smoking and/or vaping) may facilitate viral entry into the brain, thus
increasing the risk of onset and severity of CNS disorders. (ROS: Reactive Oxygen Species, TS:
Tobacco Smoke, e-cig: electronic cigarette, BBB: Blood Brain Barrier, WBC: White Blood Cell, CNS:
Central Nervous System)
In addition to ACE2, another crucial pro-coagulant factor, von Willebrand factor (VWF), is
upregulated in COVID-19 patients [123,124]. On top of that, previous epidemiological studies have
shown that smoking increases the circulatory level of VWF. VWF is a glycoprotein and exclusively
synthesized by endothelial cells and megakaryocytes. Functionally, VWF is responsible for carrying
factor VIII in blood circulation and also mediates initial platelet adhesion to the subendothelium
through glycoprotein Ib-IX complex after inflammation and injury [125]. In addition to VWF
upregulation, smoking has been recently shown to promote the downregulation of thrombomodulin
[75,126]. Thrombomodulin acts as an anticoagulant factor by binding to thrombin and use its
enzymatic activities to degrade factor V, thus blocking the prothrombinase complex. The ultimate
effect is a significant alteration of the blood homeostasis with a significant propensity toward blood
coagulation and an increase in the risk of ischemic disorders like stroke [127,128]. Additionally,
microthrombi were found in the circulation of several organs in COVID-19 patients, which has been
claimed to be generated due to the dissemination of intravascular coagulation (DIC) [129–131]. Thus,
it is highly likely that these microthrombi can also reside inside the microvascular system of the CNS
and ultimately results in neurological complications. As smoking can increase the level of VWF and
Figure 2.
Illustrative panel summarizing the SARS-CoV-2 entry into the human body and the potential
impact of comorbid smoking and/or vaping on the harmful eects of the viral infection to the CNS.
Pre-existing conditions that impairs the viability and function of the BBB (such as those associated
with chronic smoking and/or vaping) may facilitate viral entry into the brain, thus increasing the risk
of onset and severity of CNS disorders. (ROS: Reactive Oxygen Species, TS: Tobacco Smoke, e-cig:
electronic cigarette, BBB: Blood Brain Barrier, WBC: White Blood Cell, CNS: Central Nervous System)
In addition to ACE2, another crucial pro-coagulant factor, von Willebrand factor (VWF), is
upregulated in COVID-19 patients [
123
,
124
]. On top of that, previous epidemiological studies have
shown that smoking increases the circulatory level of VWF. VWF is a glycoprotein and exclusively
Int. J. Mol. Sci. 2020,21, 3916 9 of 18
synthesized by endothelial cells and megakaryocytes. Functionally, VWF is responsible for carrying
factor VIII in blood circulation and also mediates initial platelet adhesion to the subendothelium through
glycoprotein Ib-IX complex after inflammation and injury [
125
]. In addition to VWF upregulation,
smoking has been recently shown to promote the downregulation of thrombomodulin [
75
,
126
].
Thrombomodulin acts as an anticoagulant factor by binding to thrombin and use its enzymatic
activities to degrade factor V, thus blocking the prothrombinase complex. The ultimate eect is a
significant alteration of the blood homeostasis with a significant propensity toward blood coagulation
and an increase in the risk of ischemic disorders like stroke [
127
,
128
]. Additionally, microthrombi were
found in the circulation of several organs in COVID-19 patients, which has been claimed to be generated
due to the dissemination of intravascular coagulation (DIC) [
129
131
]. Thus, it is highly likely that
these microthrombi can also reside inside the microvascular system of the CNS and ultimately results
in neurological complications. As smoking can increase the level of VWF and decrease the level of
thrombomodulin, there could be a correlation between smoking and stroke occurrence in COVID-19
patients. However, extensive well-designed and controlled animal experiments are required to confirm
this hypothesis.
Additionally, a recent study has suggested that smoking may promote cellular uptake of SARS
CoV-2 virus through
α
7nAChR signaling mechanism. As
α
7nAChR is present both in neuronal and
non-neuronal cells, therefore it can be said that, smoking may play a vital role in pathophysiology of
SARS-CoV-2 and may aect dierent organs of the body including brain [132].
6. Vaping (E-Cigarette), COVID-19, and Cerebrovascular-Neurological Diseases
At the present time, electronic cigarettes, or e-cigarettes, have become extremely popular among
youth on the pretense to be a safe alternative to tobacco smoke. It delivers nicotine by heating a vape
liquid containing nicotine, flavoring agents, and dierent solvents into an aerosol [
133
]. The aerosol
contains dierent harmful components including (but not limited) flavoring agents, humectants (such as
glycerin and propylene glycol), contaminants (such as heavy metals), and harmful solvent byproducts
(including formaldehyde and acrolein) in addition to tobacco specific nitrosamines [
133
,
134
]. All
these substances can harm the cerebrovascular systems and the BBB in a way not too dissimilar from
TS [
133
,
134
]. In fact, Kaisar et al. recently reported that chronic e-cigarette smoking is responsible
for disrupting the BBB integrity and promote vascular inflammation. Moreover, it may facilitate the
onset of stroke and worsen the condition of post-ischemic brain injury [
75
]. Another recent study
also reported that e-cigarette vaping may decrease neuronal glucose utilization, which could result in
increased risk for ischemic brain injury and stroke [
135
]. Recently, McAlinden et al. suggested that,
nicotine-based e-cigarettes or vaping may contribute to the upregulation of ACE2 which may also play
an important role in progression and outcome of COVID-19 [136].
7. Cannabis, COVID-19, and Cerebrovascular-Neurological Diseases
Cannabis, or marijuana, is the most widely abused recreational drug around the world, which is
associated with cerebrovascular and neurological diseases such as stroke, structural and functional
changes in the brain, cognitive and behavioral disorders [
137
]. Compared to TS and e-cigarette,
smoking cannabis can also generate ROS and
-9-tetrahydrocannabinol (THC), the main component
of cannabis which promotes OS as well as inflammation that may result in the onset of ischemic
stroke [
138
,
139
]. Other possible mechanisms behind cerebrovascular-neurological dysfunction related
to cannabis smoking include among others cerebral vasoconstriction, cerebral artery luminal stenosis,
cerebral auto-dysregulation, and angiopathy [
140
143
]. A recent report demonstrated that smoking
cannabis could deteriorate the condition of COVID-19 patients through airway inflammation [
144
].
Although no case has been reported on cerebrovascular dysfunction in COVID-19 patients and smoking
cannabis yet, cannabis could be a risk factor for developing neurological disorders in COVID-19
patients due to its detrimental eect on the cerebrovascular system.
Int. J. Mol. Sci. 2020,21, 3916 10 of 18
8. Conclusions
The COVID-19 pandemic has taken a tremendous hit on the individuals and family lives all
around the world within a short period. This has left health care providers and researchers unprepared
and with a plethora of questions to be answered. For instance, who are more vulnerable to this
infection? What are the risk factors associated with the severity of this infection? How to tackle the
severity and widespread of this kind of infection in the future?
Most importantly, what are the organs that could get aected by SARS-CoV-2 infection as we
need to take care of the current as well as recovered patients in the future. From the above-mentioned
case reports, it can be speculated that this virus can aect the CNS along with the lung, heart, and
gastrointestinal system. These case reports show the presence of neurological disorders in as high as
36.4% COVID-19 patients [
52
]. Yet, the mechanism of CNS invasion by COVID-19 is unknown. One of
the probable hypotheses is that it can reach the brain through the olfactory nerve system present in
the nasal cavity [
145
]. However, the presence of SARS-COV, a family member of Coronavirus, in the
CSF suggested an alternative mechanism of CNS invasion for this class of viruses [
146
]. Since the BBB
protects the brain parenchyma from viral and bacterial infection, damage to this biological barrier
could also lead to the accumulation of deadly viruses like SARS-CoV-2 in the CNS. Several studies,
including in our lab, have shown the detrimental eect of tobacco and e-cigarette smoking on BBB
integrity. Thus, it can be speculated that smoking could lead to the increased severity of SARS-CoV-2
infection by aecting the viability and integrity of the BBB while promoting the expression levels of
ACE2 (the responsible mediator of SARS-CoV-2 cell invasion and proliferation) in endothelial cells,
glia, and neurons. Furthermore, increased blood circulatory level of VWF and decrease levels of
thrombomodulin promoted by smoking and vaping can dysregulate the blood homeostasis promoting
blood coagulation and the formation of unwanted blood clot which severely increases the risk of stroke
and cardiovascular disorders. At this stage, it is clear that additional studies will be necessary to validate
these hypotheses, including further analyses of autopsy samples from smoking and non-smoking
COVID-19 patients or conducting
in vivo
studies. K18-hACE2 transgenic mouse developed by McCray
et al. for SARS-CoV studies along with tobacco smoke exposure rodent models could be useful available
animal models for studying pathogenesis of SARS-CoV-2 and evaluating the impact of smoking and
vaping on cerebrovascular and neurological dysfunction in COVID-19 patients [147,148].
Author Contributions:
S.R.A. conceived the study and prepared the drafting of the manuscript. L.C. assisted with
the drafting of the manuscript and preparation of the figures. L.C. also oversaw the entire project and provided
funding support. All authors reviewed the manuscript. All authors have read and agreed to the published version
of the manuscript.
Funding:
This work was supported by the National Institutes of Health/National Institute on Drug Abuse
2R01-DA029121 and 1R01-DA049737 to Luca Cucullo.
Conflicts of Interest: The authors declare no conflicts of interest.
Abbreviations
ACE2 Angiotensin-converting enzyme 2
BBB Blood–brain barrier
BMVEC Brain microvascular endothelial cells
CDC Centers for Disease Control and Prevention
CNS Central nervous system
COPD Chronic Obstructive Pulmonary Disease
DIC Dissemination of intravascular coagulation
e-cig Electronic cigarette
IL-1βInterleukin -1β
IL-6 Interleukin-6
IL-12 Interleukin-12
Int. J. Mol. Sci. 2020,21, 3916 11 of 18
IL-15 Interleukin-15
MERS Middle East Respiratory Syndrome
MMP-2 Matrix metalloproteinase-2
MMP-9 Matrix metalloproteinase-9
OS Oxidative stress
ROS Reactive oxygen species
SARS Severe acute respiratory syndrome-related coronavirus
SIRS Systemic inflammatory response syndrome
STAT-3 Signal Transducer and Activator of Transcription-3
TBI Traumatic brain injury
THC -9-tetrahydrocannabinol
TNF-αTumor necrosis factor-α
TJ Tight junction
TS Tobacco smoking
VWF Von Willebrand factor
WBC White blood cell
WHO World Health Organization
ZO-1 Zonulae occludentes-1
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2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
... O COVID-19 é uma doença infecciosa causada por uma forma recentemente descoberta de coronavírus conhecida como síndrome respiratória aguda grave coronavírus-2 (SARS-Cov-2) (Archie & Cucullo, 2020). ...
... O domínio S2 do envelope viral enriquecido tem alta afinidade para o receptor ACE2 no epitélio pulmonar. Não obstante, a expressão de ACE2 foi encontrada alta entre fumantes (possivelmente incluindo vapers de cigarros eletrônicos) e indivíduos em uso de inibidores da ACE (como hipertensos e diabéticos), sendo então um grupo de risco para a infecção e complicações (Archie & Cucullo, 2020). ...
... 8 . Além disso, a vaporização a base de nicotina pode contribuir para a regulação positiva da ECA2, que desempenha papel importante na progressão da COVID-19 (Archie & Cucullo, 2020). ...
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O uso de cigarros eletrônicos pode enfraquecer o sistema respiratório e comprometer a resposta imunológica, desse modo, há maior suscetibilidade a infecções respiratórias, como a causada pelo COVID-19. Nesse sentido, o objetivo deste estudo é analisar o impacto na infecção causada pela COVID-19 nos jovens que fazem uso de cigarros eletrônicos. Quanto à metodologia, trata-se de uma revisão sistemática da literatura que buscou artigos na Biblioteca Virtual de Saúde (BVS), U. S. National Library of Medicine (PubMed) e Google Acadêmico com os seguintes descritores: "Vaping" AND "COVID-19". Dos 321 artigos encontrados, foram excluídos 285 por fuga do tema, duplicidade e indisponibilidade do texto completo, sendo o corpus final constituído por 27 artigos, os quais foram categorizados em dois eixos: (I) Efeitos do cigarro eletrônico no aumento do risco de transmissão, infecção e complicações por COVID-19 e (II) Fisiopatologia das consequências do cigarro eletrônico no organismo. A vaporização está relacionada à ocorrência de lesões pulmonares graves que podem causar diminuição da resistência das vias aéreas a patógenos, aumentando a suscetibilidade a infecções e complicações por COVID-19. Portanto, é de extrema importância entender a relação entre o uso de vaporizadores e a COVID-19 para compreender seu impacto. Palavras-chave: COVID-19; Vaping; Avaliação do impacto na saúde; Ensino em saúde. Abstract E-cigarette use can weaken the respiratory system and compromise the immune response, thus, there is greater susceptibility to respiratory infections, such as that caused by COVID-19. In this sense, the objective of this study is to analyze the impact on the infection caused by COVID-19 in young people who use electronic cigarettes. As for the methodology, it is a systematic review of the literature that searched for articles in the Virtual Health Library (BVS), U.S. National Library of Medicine (PubMed) and Google Scholar with the following descriptors: "Vaping" AND "COVID-19". Of the 321 articles found, 285 were excluded due to escape from the topic, duplicity and unavailability of the full text, and the final corpus consisted of 27 articles, which were categorized into two axes: (I) Effects of electronic cigarettes in increasing the risk of transmission, infection and complications by COVID-19 and (II) Pathophysiology of the consequences of electronic cigarettes in the body. Vaporization is related to the occurrence of serious lung injuries that can cause decreased airway resistance to pathogens, increasing susceptibility to infections
... High Cerebrovascular and neurological dysfunction under the threat of COVID-19: Is there a comorbid role for smoking and vaping? (27) 2020 USA Review article. N=9 studies Objective: To summarize the possible role of smoking and vaporization in cerebrovascular and neurological dysfunction in patients with COVID-19. ...
... Studies (16,(27)(28) point to evidence that cannabis in the inhaled form causes important changes in the respiratory and in the vascular system, causing damage to the individuals' brain structure, reduction in the concentration of T CD4, CD8 and cytokines, which may result in inefficient activation of users' immune systems. Furthermore, the presence of a genetic risk factor for cannabis use disorder is correlated with COVID-19 and an increase in hospitalization cases (29) . ...
... Regardless of this controversy, the use of cannabis in the inhaled form causes concern when in the context of COVID-19. This PS has harmful consequences for lung health, reducing the effectiveness of the response to infection through airway inflammation, and may increase the risk of rapid progression to hypoxia in cases of SARS-CoV-2 infection (15,27) . Other alterations are chronic inflammation of the lungs and impairment of the vascular system, due to the large increase in THC levels (42) . ...
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Objective: to identify and synthesize studies on the effects of cannabis use and its relation with SARS-CoV-2, as well as the therapeutic possibilities of using cannabinoids in the prevention and treatment of COVID-19. Methods: scoping review, in the BVS, PubMed, SCIELO, CINAHL, SCOPUS, Web of Science, MedNar, CAPES and ProQuest databases, with no language restriction and year limitation. Narrative synthesis was performed. Results: cannabis use causes changes in the respiratory and vascular system, it reduces the production of cytokines, which affects the users' immune system, increasing the susceptibility to infection and progression of COVID-19. However, studies have suggested the use of cannabinoids in the prophylaxis and treatment of COVID-19, due to their anti-inflammatory effect. Conclusions: the use of inhaled cannabis increases the progression and severity of the infection. On the other hand, the benefits of cannabinoids seem promising to modulate the immune system, but it needs further studies.
... Smoking is a well-established risk factor for severe exacerbations or disease course in many respiratory infections, and may predispose to COVID-19 infection or worsen disease progression. With influenza and the MERS outbreak, patients who were smokers had an increased risk twice than that of non-smokers and were associated with higher mortality rates [3] [4], so it is necessary to investigate the relation to COVID-19. Current smokers also had a higher case fatality rate of 38.5% and were 1.45 times more likely to have morbid outcomes compared to their non-smoking counterparts [4]. ...
... With influenza and the MERS outbreak, patients who were smokers had an increased risk twice than that of non-smokers and were associated with higher mortality rates [3] [4], so it is necessary to investigate the relation to COVID-19. Current smokers also had a higher case fatality rate of 38.5% and were 1.45 times more likely to have morbid outcomes compared to their non-smoking counterparts [4]. As a modifiable risk factor, smoking is a very crucial consideration in COVID-19, so this literature review aims to understand the risk of COVID-19 with smoking, the relation of smoking to the progression of the disease and clinical course, and explore debating information regarding nicotine as well as its potential protective role due to competition of nicotinic acetylcholine receptor with SARS-CoV-2 binding sites. ...
... Permeability of BBB alteration and modification of Na + K + 2Cl − cotransporter causes neurological complications in smokers. In 214 patients in a study, of the smoker's studies, 36.5% showed neurological symptoms and 18.7% were admitted in ICU [4] ...
... In addition, it is also not clear by which route(s), such as blood brain barrier (BBB), blood-CSF barrier (BCSFB) or retrograde olfactory migration, SARS-CoV-2 might be more likely to invade into the CNS, particularly in patients without significant BBB impairment. Furthermore, smoking has been reported as a risk factor for COVID-19 severity in current smokers [38,39]. Previous studies have shown smoking upregulates pulmonary ACE2, which has been considered to contribute to the infection susceptibility, disease severity and treatment outcome in COVID-19 patients [40][41][42]. ...
... Several risk factors, including smoking, have been reported to be associated with disease severity in COVID-19 patients [38,39]. Smoking, including tobacco smoking and electronic nicotine vaping, upregulates pulmonary ACE2 expression which could attribute to worsened outcomes observed in smokers [40][41][42]. ...
Article
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Background Knowledge of the entry receptors responsible for SARS-CoV-2 is key to understand the neural transmission and pathogenesis of COVID-19 characterized by a neuroinflammatory scenario. Understanding the brain distribution of angiotensin converting enzyme 2 (ACE2), the primary entry receptor for SARS-CoV-2, remains mixed. Smoking has been shown as a risk factor for COVID-19 severity and it is not clear how smoking exacerbates the neural pathogenesis in smokers. Methods Immunohistochemistry, real-time PCR and western blot assays were used to systemically examine the spatial-, cell type- and isoform-specific expression of ACE2 in mouse brain and primary cultured brain cells. Experimental smoking exposure was conducted to evaluate the effect of smoking on brain expression. Results We observed ubiquitous expression of ACE2 but uneven brain distribution, with high expression in the cerebral microvasculature, medulla oblongata, hypothalamus, subventricular zones, and meninges around medulla oblongata and hypothalamus. Co-staining with cell type-specific markers demonstrates ACE2 is primarily expressed in astrocytes around the microvasculature, medulla oblongata, hypothalamus, ventricular and subventricular zones of cerebral ventricles, and subependymal zones in rhinoceles and rostral migratory streams, radial glial cells in the lateral ventricular zones, tanycytes in the third ventricle, epithelial cells and stroma in the cerebral choroid plexus, as well as cerebral pericytes, but rarely detected in neurons and cerebral endothelial cells. ACE2 expression in astrocytes is further confirmed in primary cultured cells. Furthermore, isoform-specific analysis shows astrocyte ACE2 has the peptidase domain responsible for SARS-CoV-2 entry, indicating astrocytes are indeed vulnerable to SARS-CoV-2 infection. Finally, our data show experimental tobacco smoking and electronic nicotine vaping exposure increase proinflammatory and/or immunomodulatory cytokine IL-1a, IL-6 and IL-5 without significantly affecting ACE2 expression in the brain, suggesting smoking may pre-condition a neuroinflammatory state in the brain. Conclusions The present study demonstrates a spatial- and cell type-specific expression of ACE2 in the brain, which might help to understand the acute and lasting post-infection neuropsychological manifestations in COVID-19 patients. Our data highlights a potential role of astrocyte ACE2 in the neural transmission and pathogenesis of COVID-19. This also suggests a pre-conditioned neuroinflammatory and immunocompromised scenario might attribute to exacerbated COVID-19 severity in the smokers.
... (3) Así lo constatan varias investigaciones originales (9,10,11,12) y revisiones sistemáticas. (4,6,13,14,15,16) En la literatura consultada, fueron identificados varios mecanismos fisiopatológicos que fundamentan el efecto deletéreo del tabaquismo en el contexto de la COVID-19: la regulación al alza de la ACE2; (17,18,19,20,21,22) el aumento de la expresión/actividad de la serina proteasa celular de transmembrana 2 (TMPRSS2), la catepsina B/L y la furina; (5,10,20) la inmunoinflamación e inmunosupresión; (1,5,18,21,23) la regulación al alza de la PDE4; (24) las alteraciones hemovasculares encefálicas; (23) y las modificaciones morfofuncionales del parénquima pulmonar. (1,5,7) ...
... (3) Así lo constatan varias investigaciones originales (9,10,11,12) y revisiones sistemáticas. (4,6,13,14,15,16) En la literatura consultada, fueron identificados varios mecanismos fisiopatológicos que fundamentan el efecto deletéreo del tabaquismo en el contexto de la COVID-19: la regulación al alza de la ACE2; (17,18,19,20,21,22) el aumento de la expresión/actividad de la serina proteasa celular de transmembrana 2 (TMPRSS2), la catepsina B/L y la furina; (5,10,20) la inmunoinflamación e inmunosupresión; (1,5,18,21,23) la regulación al alza de la PDE4; (24) las alteraciones hemovasculares encefálicas; (23) y las modificaciones morfofuncionales del parénquima pulmonar. (1,5,7) ...
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Introducción: Con la propagación del coronavirus tipo 2 causante del síndrome respiratorio agudo grave (SARS-CoV-2), han emergido interrogantes sobre los factores de riesgo que influyen en la enfermedad que este origina: la COVID-19. Una cuestión ampliamente debatida ha sido el efecto potencial del tabaquismo en las tasas de infección por SARS-CoV-2 y en las consecuencias clínicas de la COVID-19. Objetivo: Dilucidar las implicaciones del tabaquismo en el contexto de la COVID-19. Desarrollo: En la literatura consultada fueron identificados varios mecanismos fisiopatológicos que fundamentan el efecto deletéreo del tabaquismo en el contexto de la COVID-19: la regulación al alza de la enzima convertidora de angiotensina 2; el aumento de la expresión/actividad de la serina proteasa celular de transmembrana 2, la catepsina B/L y la furina; la inmunoinflamación e inmunosupresión; la regulación al alza de la fosfodiesterasa 4; las alteraciones hemovasculares encefálicas; y las modificaciones morfofuncionales del parénquima pulmonar. Conclusiones: El tabaquismo desempeña un efecto deletéreo en pacientes con la COVID-19. En esta nociva asociación concursan mecanismos fisiopatológicos que pudiesen hacer que los fumadores-2022;51(1): e02201457 http://scielo.sld.cu http://www.revmedmilitar.sld.cu Bajo licencia Creative Commons activos o pasivos-posean mayor vulnerabilidad ante la infección por SARS-CoV-2 o que expongan una evolución desfavorable una vez hayan desarrollado la COVID-19.
... Numerous studies revealed that the reported prevalence of smoking in hospitalized patients was significantly less than that in the respective demographics. Smoking may worsen the sternness of SARS-CoV-2 by reducing the BBB integrity and increasing the ACE2 expression (it is the main mediator of SARS-CoV-2 cell invasion and proliferation) in glia endothelial cells and neurons (36). ...
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Smoking status has been studied for a long time and proved to be a major cause of smokers' decreased immunity. In the present pandemic COVID-19 disease, there was an unclear belief about the effect of smoking on patients with COVID-19. Therefore, the current cross-sectional study aimed to evaluate the effect of cigarette smoking on the sequelae of COVID-19. This cross-sectional study involved 200 COVID-19 patients (114 males and 86 females) aged 13-77 years. A number of 87 patients were smokers, and the rest of them were non�smokers. All patients underwent a comprehensive laboratory assessment and diagnosis by full medical history by the physicians. The results indicated a significant difference (P<0.001) between smokers and non-smokers in terms of hypertension, anticoagulant, steroid therapy, pulmonary lesion, oxygen saturation, and duration of disease. As an overall conclusion, it can be stated that COVID-19 is less severe in smokers and they require less intensive treatment
... Additionally, a better understanding of the pathological role of SARS-CoV-2 in the CNS would be beneficial not only to develop effective treatments to protect the CNS from the harmful effects of SARS-CoV-2 infection but also to identify potential comorbidities and environmental clues that could worsen the neurological impact of COVID-19 itself (11,188). In conclusion, activation of the innate immune system associated with elevated levels of pro-inflammatory mediators seems a mainstream pathogenic occurrence in the COVID-19 pandemic. ...
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Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical manifestations of COVID-19 include dry cough, difficult breathing, fever, fatigue, and may lead to pneumonia and respiratory failure. There are significant gaps in the current understanding of whether SARS-CoV-2 attacks the CNS directly or through activation of the peripheral immune system and immune cell infiltration. Although the modality of neurological impairments associated with COVID-19 has not been thoroughly investigated, the latest studies have observed that SARS-CoV-2 induces neuroinflammation and may have severe long-term consequences. Here we review the literature on possible cellular and molecular mechanisms of SARS-CoV-2 induced-neuroinflammation. Activation of the innate immune system is associated with increased cytokine levels, chemokines, and free radicals in the SARS-CoV-2-induced pathogenic response at the blood-brain barrier (BBB). BBB disruption allows immune/inflammatory cell infiltration into the CNS activating immune resident cells (such as microglia and astrocytes). This review highlights the molecular and cellular mechanisms involved in COVID-19-induced neuroinflammation, which may lead to neuronal death. A better understanding of these mechanisms will help gain substantial knowledge about the potential role of SARS-CoV-2 in neurological changes and plan possible therapeutic intervention strategies.
... There is introductory evidence about the expected role of smoking as well as vaping on the infection and severity of COVID-19. And included investigations that showed that people who vape or smoke may be more likely to contract COVID-19 or need mechanical ventilation compared to nonsmokers (Kaur et al. 2020;Munzel et al. 2020;Archie and Cucullo 2020). There is a need to establish the effect of vaping on the lungs and whether this effect increases a person's susceptibility to COVID-19 infection and the severity of COVID-19 disease Lancet 2020;Galo et al. 2020). ...
Article
In this review, numerous analytical methods to quantify the heavy and trace elements emitted from electronic cigarettes, cigarettes liquid and atomizer. The selection of a method was dependent upon the purpose, e.g., quantification or identification of elements only. The introductory part of this review focuses on describing the importance of setting up an electronic cigarettes- associated safety profile. The review dealt with studies that assessed elements in sizes ranging from nano to micro. The formation of different degradation chemical substances as well as impurity trends can be indicated through chemical investigation of metals in electronic cigarettes. Some studies have been covered that show the uses and benefits of. It is noticeable from all the collected sources that the minerals emitted from the smoke of e- cigs do not constitute any significant damage, as the percentage is very small, with the exception of minerals that may be emitted from the components of the device after heating it if the components of the e- cig are of poor specifications, except in the case of long-term accumulation. For this reason, an electronic cigarette can help smokers to quit smoking tobacco and replace it with electronic cigarettes smoke with distinctive favors
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Purpose: Predisposition to acute illness from COVID-19 is suggested to correlate with cigarette smoking as it augments the risk of developing cardiovascular and respiratory illnesses, including infections. However, the effects of smoking on COVID-19 symptoms are not well described and controversial. In this study, we aim to explore the associations between smoking and COVID-19 symptoms. Subjects and Methods: A cross-sectional study using the Ministry of Public Health (MoPH), Qatar database was administered to a Qatari population with confirmed COVID-19 disease who filled in pre-defined phone-call questionnaire between 27th February 2020 and 31st December 2020. We analyzed 11,701 non-vaccinated COVID-19 individuals (2952 smokers and 8749 non-smokers) with confirmed RT-PCR test results. The association of smoking and the presence of symptoms as well as patient characteristics was calculated using Pearson’s Chi-square and Fisher’s exact tests, adjusting for potential covariates. Results: Compared with the non-smokers, symptomatic COVID-19 infection is significantly higher in smokers. In addition, we found fever as the most common symptom developed in COVID-19 patients followed by cough, headache, muscle ache, and sore throat. As compared to other symptoms, association of smoking with chills and abdominal pain was less evident (P < 0.05 and P < 0.001, respectively). However, both groups showed similar rates of developing cough. Conclusion: In conclusion, smoking is associated with COVID-19 symptoms frequency in non-vaccinated patients; nevertheless, further investigations are necessary to understand the mechanism of this association which could generate new targets for the management of COVID-19 in smoker patients. Keywords: COVID-19, smoking, frequency, Qatar, symptoms
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COVID-19 can appear with different manifestations including gastrointestinal, renal, cardiac, neurological, psychiatric, ENT, dermatological, and oral symptoms. Diagnosis and management of these manifestations has a crucial role for prevention of the spread of COVID-19. In this book, for the first time, we describe different manifestations of COVID-19 and their best treatments according to the suggestions of recent published papers in the databases such as PubMed and Scopus.
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Background: Traumatic brain injury (TBI) is among the most prevalent causes of cerebrovascular and neurological damage worldwide. To this end, tobacco smoke (TS) has been shown to promote vascular inflammation, neurovascular impairments, and risk of cerebrovascular and neurological disorders through oxidative stress (OS) stimuli targeting the blood-brain barrier (BBB) endothelium among others. It has been recently suggested that premorbid conditions such as TS may exacerbate post-TBI brain damage and impact recovery. Methods: Our study investigated the mechanisms underlying the exacerbation of TBI injury by TS using a weight drop model. For this purpose, male C57BL/6J mice, age range 6-8 weeks, were chronically exposed to premorbid TS for 3 weeks. Test animals were then subjected to TBI by guided vertical head weight drop using a 30 g metal weight free felling from an 80 cm distance before reaching the target. We analyzed the physical activity and body weight of the mice before TBI and 1 h, 24 h, and 72 h post-injury. Finally, mice were sacrificed to collect blood and brain samples for subsequent biochemical and molecular analysis. Western blotting was applied to assess the expression of Nrf2 (a critical antioxidant transcription factor) as well as tight junction proteins associated with BBB integrity including ZO-1, Occludin, and Claudin-5 from brain tissues homogenates. Levels of NF-kB (a pro-inflammatory transcript factor which antagonizes Nrf2 activity) and pro-inflammatory cytokines IL-6, IL-10, and TNF-α were assessed in blood samples. Results: Our data revealed that premorbid TS promoted significantly increased inflammation and loss of BBB integrity in TBI when compared to TS-Free test mice. Additionally, mice chronically exposed to TS before TBI experienced a more significant weight loss, behavioral and motor activity deficiency, and slower post-TBI recovery when compared to TS-free TBI mice. Conclusion: The effects of premorbid TS appear consequential to the abrogation of physiological antioxidative and anti-inflammatory response to TBI leading to worsening impairments of the BBB, OS damage, and inflammation. These factors are also likely responsible for the retardation of post-traumatic recovery observed in these animals.
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In this paper, we discuss an explicit model function that can estimate the total number of deaths in the population, and particularly, estimate the cumulative number of deaths in the United States due to the current Covid-19 virus. We compare the modeling results to two related existing models based on a new criteria and several existing criteria for model selection. The results show the proposed model fits significantly better than the other two related models based on the U.S. Covid-19 death data. We observe that the errors of the fitted data and the predicted data points on the total number of deaths in the U.S. on the last available data point and the next coming day are less than 0.5% and 2.0%, respectively. The results show very encouraging predictability for the model. The new model predicts that the maximum total number of deaths will be approximately 62,100 across the United States due to the Covid-19 virus, and with a 95% confidence that the expected total death toll will be between 60,951 and 63,249 deaths based on the data until 22 April, 2020. If there is a significant change in the coming days due to various testing strategies, social-distancing policies, the reopening of community strategies, or a stay-home policy, the predicted death tolls will definitely change. Future work can be explored further to apply the proposed model to global Covid-19 death data and to other applications, including human population mortality, the spread of disease, and different topics such as movie reviews in recommender systems.
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Since December 2019, a novel type of coronavirus disease (COVID-19) in Wuhan led to an outbreak throughout China and the rest of the world. To date, there have been more than 1,260,000 COVID-19 patients, with a mortality rate of approximately 5.44%. Studies have shown that coagulation dysfunction is a major cause of death in patients with severe COVID-19. Therefore, the People’s Liberation Army Professional Committee of Critical Care Medicine and Chinese Society on Thrombosis and Hemostasis grouped experts from the frontline of the Wuhan epidemic to come together and develop an expert consensus on diagnosis and treatment of coagulation dysfunction associated with a severe COVID-19 infection. This consensus includes an overview of COVID-19-related coagulation dysfunction, tests for coagulation, anticoagulation therapy, replacement therapy, supportive therapy and prevention. The consensus produced 18 recommendations which are being used to guide clinical work.
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In this report, we analyze historical and forecast infections for COVID-19 death based on Reduced-Space Gaussian Process Regression associated to chaotic Dynamical Systems with information obtained in 82 days with continuous learning, day by day, from January 21 th , 2020 to April 12 th . According last results, COVID-19 could be predicted with Gaussian models mean-field models can be meaning- fully used to gather a quantitative picture of the epidemic spreading, with infections, fatality and recovery rate. The forecast places the peak in USA around July 14 th 2020, with a peak number of 132,074 death with infected individuals of about 1,157,796 and a number of deaths at the end of the epidemics of about 132,800. Late on January, USA confirmed the first patient with COVID-19, who had recently traveled to China, however, an evaluation of states in USA have demonstrated a fatality rate in China (4%) is lower than New York (4.56%), but lower than Michigan (5.69%). Mean estimates and uncertainty bounds for both USA and his cities and other provinces have increased in the last three months, with focus on New York, New Jersey, Michigan, California, Massachusetts, ... (January e April 12 th ). Besides, we propose a Reduced-Space Gaussian Process Regression model predicts that the epidemic will reach saturation in USA on July 2020. Our findings suggest, new quarantine actions with more restrictions for containment strategies implemented in USA could be successfully, but in a late period, it could generate critical rate infections and death for the next 2 month.
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Background: The COVID-19 pandemic infected more than 200 countries and affected more than 28 lakhs people on date April 24, 2020. It was first identified at Wuhan City of China during December 2019. Objective: The study to identify top-15 countries with spatial mapping of the confirmed cases. The comparison between identified top-15 countries for confirmed, death and recovery of the cases and further advanced Auto-Regressive Integrated Moving Average Model (ARIMA) for predicting the spreading of COVID-19 disease trajectories of COVID-19 for next two months. Methods: The COVID-19 daily data collected and cumulatively represented as spatial map for more than 200 countries and territories. The spatial map useful to identify the intensity of COVID-19 infected people, top-15 countries and continent. The recent reported data for confirmed, death and recovery for last three months was represented and compared in between the top-15 infected countries. The advanced Auto-Regressive Integrated Moving Average Model (ARIMA) used for predicting the future data based on time-series data. The ARIMA model provide weight to past few values and error values to corrects it model prediction, so it better than other basic regression and exponential methods. The comparison of recent cumulative cases and predicted cases for top-15 countries for confirmed, death and recovery from COVID-19 disease. Results: The top-15 countries, with a high number of confirmed cases are stratified to include its data in mathematical model. The identified top-15 countries cumulative cases, death, and recovery of COVID-19 information were compared. The USA, UK, Turkey, China, Russia relatively fast spreading of disease. The fast recovery ratio in China, Switzerland, Germany, Iran, and Brazil and slow recovery ratio in USA, UK, Netherlands, Russia and Italy. The large number of death rate ratio in Italy, UK and less ratio in Russia, Turkey, China, USA. The ARIMA model used to predict estimated confirmed, death and recovery cases for the top-15 countries for 24 April to 07 July. Its value is represented with 95%, 80% and 70 % confidence interval values. The validation of ARIMA model using Akaike Information Criterion (AIC) value, its value in the range of 20, 14, and 16 for cumulative confirm cases, death and recovery COVID-19 cases, represents acceptable results. Conclusions: The observed predicted values represent the confirmed, death and recovery cases gets doubled in all the countries except China, Switzerland and Germany. It was also observed the death and recovery rate were faster as comparison to confirmed cases during next two months. The associated mortality rate will be much higher in USA, Spain, and Italy followed by France, Germany and UK. The forecast analysis of COVID-19 dynamics showed a different angle for the whole world, and it looks scarier than imagined, but recovery numbers also look promising by July 07, 2020. Clinicaltrial:
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We have previously provided the first genetic evi- dence that angiotensin converting enzyme 2 (ACE2) is the critical receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), and ACE2 pro- tects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 in- fections, and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2. Here, we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000–5,000. An equivalent mouse rsACE2 had no effect. We also show that SARS- CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections.