Cerebrovascular and Neurological Dysfunction
The recently discovered novel coronavirus, SARS-CoV-2 (COVID-19 virus), has brought the whole world to a 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 is 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.
1. 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 . The sequence homology of SARS-CoV-2 also showed a 50% similarity to MERS-CoV virus . Although the primary symptoms of COVID-19 include fever, dry cough, and fatigue in most of the patients , 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 . Additional studies have also reported a sudden loss of smell or taste in some COVID-19 patients as well .
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 . 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 1 summarizes 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 .
Table 1. Case studies on neurological and cerebrovascular symptoms in COVID-19 patients.
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 .
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 . Moreover, some of the COVID-19 patients were found to suffer from viremia and hypoxia , 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 , and the concurrent detection of brain tissue edema seems to suggest the existence of a possible link between COVID-19 and infectious, toxic encephalopathy . 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 . 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 . 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 .
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.
2. 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) , which is present in different organs including lung, heart, kidney, testis as well neurons and glial cells of the brain . ACE2 plays a pivotal role in the regulation of blood pressure as well as anti-atherosclerosis mechanisms . It has been demonstrated from various studies that different 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 . 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  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 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 . Moreover, an increased level of D-dimer has been found in COVID-19 patients, which may result in thrombotic vascular events . 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 . This is of crucial importance since comorbid pathologies (such as those promoted by chronic smoking and vaping ) 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 . 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 . Both SARS and COVID-19 have been found to cause multiple organ failure-mediated fatalities through virus-induced SIRS or SIRS-like immune disorders .
Cytokines play a pivotal role in regulating immunological and inflammatory function of the body . 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 . Recently, Wan et al. reported the correlation of IL-6 with the severity of COVID-19 symptoms . 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  As CoV infection can infect macrophages, microglia, and astrocytes in the CNS inducing pro-inflammatory conditions  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 . Untreated hypoxia may induce acute cerebrovascular disease encompassing acute ischemic stroke in high-risk COVID-19 patients . As COVID-19 patients often suffer from fatal silent hypoxia, it requires substantial examination and consideration . Additionally, ACE2 also plays a role in controlling inflammatory and atherosclerosis responses of vessels . Thus, COVID-19 may promote atherosclerosis formation, which ultimately may result in brain ischemic stroke by affecting 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 . 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.
The entry is from 10.3390/ijms21113916
- Wu, A.; Peng, Y.; Huang, B.; Ding, X.; Wang, X.; Niu, P.; Meng, J.; Zhu, Z.; Zhang, Z.; Wang, J.; et al. Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China. Cell Host Microbe 2020, 27, 325–328.
- Kim, J.M.; Chung, Y.S.; Jo, H.J.; Lee, N.J.; Kim, M.S.; Woo, S.H.; Park, S.; Kim, J.W.; Kim, H.M.; Han, M.G. Identification of coronavirus isolated from a patient in Korea with COVID-19. Osong Public Health Res. Perspect. 2020, 11, 3–7.
- Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395, 497–506.
- Wang, H.Y.; Li, X.L.; Yan, Z.R.; Sun, X.P.; Han, J.; Zhang, B.W. Potential neurological symptoms of COVID-19. Adv. Neurol. Disord. 2020, 13.
- Giacomelli, A.; Pezzati, L.; Conti, F.; Bernacchia, D.; Siano, M.; Oreni, L.; Rusconi, S.; Gervasoni, C.; Ridolfo, A.L.; Rizzardini, G.; et al. Self-reported olfactory and taste disorders in SARS-CoV-2 patients: A cross-sectional study. Clin. Infect. Dis. 2020.
- Miller, R.W. There’s a New Symptom of Coronavirus, Doctors Say: Sudden Loss of Smell or Taste. Available online: https://www.usatoday.com/story/news/health/2020/03/24/coronavirus-symptoms-loss-smell-taste/2897385001/ (accessed on 28 April 2020).
- Mao, L.; Wang, M.; Chen, S.; He, Q.; Chang, J.; Hong, C.; Zhou, Y.; Wang, D.; Jin, H.; Hu, B. Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: A retrospective case series study. medRxiv 2020.
- Asadi-Pooya, A.A.; Simani, L. Central nervous system manifestations of COVID-19: A systematic review. J. Neurol. Sci. 2020, 413, 116832.
- Chen, T.; Wu, D.; Chen, H.; Yan, W.; Yang, D.; Chen, G.; Ma, K.; Xu, D.; Yu, H.; Wang, H.; et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020, 368, m1091.
- Li, Y.; Wang, M.; Zhou, Y.; Chang, J.; Xian, Y.; Mao, L.; Hong, C.; Chen, S.; Wang, Y.; Wang, H.; et al. Acute cerebrovascular disease following COVID-19: A single center, retrospective, observational study. Lancet 2020.
- Wang, D.; Hu, B.; Hu, C.; Zhu, F.; Liu, X.; Zhang, J.; Wang, B.; Xiang, H.; Cheng, Z.; Xiong, Y.; et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020.
- Chen, N.; Zhou, M.; Dong, X.; Qu, J.; Gong, F.; Han, Y.; Qiu, Y.; Wang, J.; Liu, Y.; Wei, Y.; et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020, 395, 507–513.
- Yang, X.; Yu, Y.; Xu, J.; Shu, H.; Xia, J.; Liu, H.; Wu, Y.; Zhang, L.; Yu, Z.; Fang, M.; et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir. Med. 2020.
- Oxley, T.J.; Mocco, J.; Majidi, S.; Kellner, C.P.; Shoirah, H.; Singh, I.P.; De Leacy, R.A.; Shigematsu, T.; Ladner, T.R.; Yaeger, K.A.; et al. Large-vessel stroke as a presenting feature of covid-19 in the young. N. Engl. J. Med. 2020, e60.
- Wu, Y.; Xu, X.; Chen, Z.; Duan, J.; Hashimoto, K.; Yang, L.; Liu, C.; Yang, C. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav. Immun. 2020.
- Guo, Y.R.; Cao, Q.D.; Hong, Z.S.; Tan, Y.Y.; Chen, S.D.; Jin, H.J.; Tan, K.S.; Wang, D.Y.; Yan, Y. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak-an update on the status. Mil. Med. Res. 2020, 7, 11.
- Mao, L.; Jin, H.; Wang, M.; Hu, Y.; Chen, S.; He, Q.; Chang, J.; Hong, C.; Zhou, Y.; Wang, D.; et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020.
- Xu, Z.; Shi, L.; Wang, Y.; Zhang, J.; Huang, L.; Zhang, C.; Liu, S.; Zhao, P.; Liu, H.; Zhu, L.; et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med. 2020, 8, 420–422.
- Mehta, P.; McAuley, D.F.; Brown, M.; Sanchez, E.; Tattersall, R.S.; Manson, J.J. Hlh across speciality collaboration, U.K. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020, 395, 1033–1034.
- Chen, C.; Zhang, X.R.; Ju, Z.Y.; He, W.F. Advances in the research of cytokine storm mechanism induced by corona virus disease 2019 and the corresponding immunotherapies. Zhonghua Shao Shang Za Zhi 2020, 36, E005.
- Tisoncik, J.R.; Korth, M.J.; Simmons, C.P.; Farrar, J.; Martin, T.R.; Katze, M.G. Into the eye of the cytokine storm. Microbiol. Mol. Biol. Rev. 2012, 76, 16–32.
- Wang, Y.; Wang, Y.; Chen, Y.; Qin, Q. Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures. J. Med. Virol. 2020.
- Hamming, I.; Timens, W.; Bulthuis, M.L.; Lely, A.T.; Navis, G.; van Goor, H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J. Pathol. 2004, 203, 631–637.
- Donoghue, M.; Hsieh, F.; Baronas, E.; Godbout, K.; Gosselin, M.; Stagliano, N.; Donovan, M.; Woolf, B.; Robison, K.; Jeyaseelan, R.; et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ. Res. 2000, 87, E1–E9.
- Tipnis, S.R.; Hooper, N.M.; Hyde, R.; Karran, E.; Christie, G.; Turner, A.J. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J. Biol. Chem. 2000, 275, 33238–33243.
- Baig, A.M.; Khaleeq, A.; Ali, U.; Syeda, H. Evidence of the COVID-19 virus targeting the CNS: Tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem. Neurosci. 2020, 11, 995–998.
- Miller, A.J.; Arnold, A.C. The renin-angiotensin system in cardiovascular autonomic control: Recent developments and clinical implications. Clin. Auton. Res. 2019, 29, 231–243.
- Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Kruger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.H.; Nitsche, A.; et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020, 181, 271–280.
- Letko, M.; Marzi, A.; Munster, V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat. Microbiol. 2020, 5, 562–569.
- Williams, V.R.; Scholey, J.W. Angiotensin-converting enzyme 2 and renal disease. Curr. Opin. Nephrol. Hypertens. 2018, 27, 35–41.
- Verdecchia, P.; Cavallini, C.; Spanevello, A.; Angeli, F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur. J. Intern. Med. 2020, S0953–S6205.
- Chen, Z.M.; Fu, J.F.; Shu, Q.; Chen, Y.H.; Hua, C.Z.; Li, F.B.; Lin, R.; Tang, L.F.; Wang, T.L.; Wang, W.; et al. Diagnosis and treatment recommendations for pediatric respiratory infection caused by the 2019 novel coronavirus. World J. Pediatr. 2020.
- Kaisar, M.A.; Sivandzade, F.; Bhalerao, A.; Cucullo, L. Conventional and electronic cigarettes dysregulate the expression of iron transporters and detoxifying enzymes at the brain vascular endothelium: In vivo evidence of a gender-specific cellular response to chronic cigarette smoke exposure. Neurosci. Lett. 2018, 682, 1–9.
- Naik, P.; Cucullo, L. Pathobiology of tobacco smoking and neurovascular disorders: Untied strings and alternative products. Fluids Barriers CNS 2015, 12, 25.
- Hossain, M.; Sathe, T.; Fazio, V.; Mazzone, P.; Weksler, B.; Janigro, D.; Rapp, E.; Cucullo, L. Tobacco smoke: A critical etiological factor for vascular impairment at the blood-brain barrier. Brain Res. 2009, 1287, 192–205.
- Kaisar, M.A.; Villalba, H.; Prasad, S.; Liles, T.; Sifat, A.E.; Sajja, R.K.; Abbruscato, T.J.; Cucullo, L. Offsetting the impact of smoking and e-cigarette vaping on the cerebrovascular system and stroke injury: Is Metformin a viable countermeasure? Redox Biol. 2017, 13, 353–362.
- Klein, R.S.; Garber, C.; Howard, N. Infectious immunity in the central nervous system and brain function. Nat. Immunol. 2017, 18, 132–141.
- Fu, Y.; Cheng, Y.; Wu, Y. Understanding SARS-CoV-2-mediated inflammatory responses: From mechanisms to potential therapeutic tools. Virol. Sin. 2020.
- Yin, C.H.; Wang, C.; Tang, Z.; Wen, Y.; Zhang, S.W.; Wang, B.E. Clinical analysis of multiple organ dysfunction syndrome in patients suffering from SARS. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2004, 16, 646–650.
- Ulhaq, Z.S.; Soraya, G.V. Interleukin-6 as a potential biomarker of COVID-19 progression. Med. Mal. Infect. 2020, 50, 382–383.
- Bohmwald, K.; Galvez, N.M.S.; Rios, M.; Kalergis, A.M. Neurologic alterations due to respiratory virus infections. Front. Cell Neurosci. 2018, 12, 386.
- Wan, S.; Yi, Q.; Fan, S.; Lv, J.; Zhang, X.; Guo, L.; Lang, C.; Xiao, Q.; Xiao, K.; Yi, Z.; et al. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP). medRxiv 2020.
- Li, Y.; Fu, L.; Gonzales, D.M.; Lavi, E. Coronavirus neurovirulence correlates with the ability of the virus to induce proinflammatory cytokine signals from astrocytes and microglia. J. Virol. 2004, 78, 3398–3406.
- Abdennour, L.; Zeghal, C.; Deme, M.; Puybasset, L. Interaction brain-lungs. Ann. Fr. Anesth. Reanim. 2012, 31, e101–e107.
- Pappas, S. ’Silent Hypoxia’ May be Killing COVID-19 Patients. But There’s Hope. Available online: https://www.livescience.com/silent-hypoxia-killing-covid-19-coronavirus-patients.html (accessed on 2 May 2020).
- Ferrario, C.M.; Trask, A.J.; Jessup, J.A. Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function. Am. J. Physiol. Heart Circ. Physiol. 2005, 289, H2281–H2290.
- Mori, I. Transolfactory neuroinvasion by viruses threatens the human brain. Acta Virol. 2015, 59, 338–349.
- Desforges, M.; Le Coupanec, A.; Dubeau, P.; Bourgouin, A.; Lajoie, L.; Dube, M.; Talbot, P.J. Human coronaviruses and other respiratory viruses: Underestimated opportunistic pathogens of the central nervous system? Viruses 2019, 12, 14.
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