Dear Editor
Nicotine and COVID-19
Dear Editor
While SARS-CoV-2 is known to use angiotensin converting enzyme 2 (ACE2) as a receptor for cell entry [2], an intriguing hypothesis was recently presented about a potential interaction between SARS-CoV-2 and nicotinic acetylcholine receptors (nAChRs) [2]. It was initially observed that smokers were under-represented among hospitalized patients with COVID-19. While several limitations apply to this analysis, data from retrospective case series from China, the US, Italy and the UK have consistently shown that the proportion of hospitalized patients who were current smokers was substantially lower compared to the expected prevalence based on population smoking rates [3-8]. This represents a “paradox” considering that smoking increases the risk for respiratory infections susceptibility and severity [9].
Smoking was immediately and justifiably rejected as a viable protective measure for COVID-19 due to its well-established adverse health effects [4]. However, a protective role for nicotine was suggested based on the fact that cytokine storm is a hallmark of severe COVID-19 [10] while the cholinergic anti-inflammatory pathway, mediated mainly through nAChRs, can suppress the hyper-inflammatory response and promote immune homeostasis [11]. Nicotine is a cholinergic agonist that has been found to inhibit the release of pro-inflammatory cytokines, preventing the development of acute respiratory distress syndrome and sepsis in animal models [12,13]. Subsequently, an analysis of the clinical manifestations of COVID-19 identified that they could be linked to dysfunction of the nicotinic cholinergic system [2]. Additionally, an amino acid sequence on the receptor binding domain of SARS-CoV-2 spike glycoprotein was found to be homologous to a sequence of a snake venom neurotoxin [14]. In silico molecular modelling and docking experiments showed that this sequence may interact with the alpha9 and alpha7 subtypes of nAChRs [15]. These findings indicate that there may be a potential direct, adverse effect of SARS-CoV-2 on the nicotinic cholinergic system.
Studies have found that, once hospitalized, current smokers have higher risk for adverse outcome [16-18]. This is not contradictory to the above-mentioned hypothesis. Besides the higher likelihood for comorbidities that are risk factors for adverse COVID-19 outcome, such as cardiovascular and respiratory disease, smokers experience abrupt cessation of nicotine intake once hospitalized since it is highly unlikely that they would receive nicotine replacement therapies during hospitalization. As a result, their plasma nicotine levels would be reduced to non-detectable levels within hours from hospital admission. Therefore, although smokers should still be encouraged to quit as a general measure to reduce their health risk, physicians should consider prescribing pharmaceutical nicotine products as smoking substitutes. Additionally, pharmaceutical nicotine products could be considered for smokers hospitalized for COVID-19. Nicotine can be administered in the form of a patch, but could also be considered for inhalation through a nebulizer, which would deliver nicotine directly to the lungs and, thus, better address the local immunological cascade.
Another aspect of the interaction between nicotine and COVID-19 relates to its effects on ACE2. While previous studies have shown that smoking and nicotine down-regulate ACE2 [19], recent genetic studies report that smoking up-regulates ACE2 [20,21]. While this has been suggested to be detrimental in terms of susceptibility for infection and viral invasion, evidence suggests that ACE2 down-regulation has detrimental effects resulting due to unopposed activity of angiotensin II to AT1 receptors, which cause vasoconstriction, enhanced inflammation and thrombosis [22]. Studies on SARS-CoV also show that viral entry to the cells results in rapid depletion of ACE2 and severe inflammation [23]. Finally, common risk factors for severe COVID-19, such as age, male gender, diabetes and cardiovascular disease, are associated with lower levels of ACE2 [24-27]. Recently, an in vitro study found that nicotine increases ACE2 through the alpha7 subtype of nAChRs [28]. Still, it is currently unclear how ACE2, an enzyme which by definition has protective properties, affects SARS-CoV-2 virulence and disease severity.
In conclusion, the evidence suggests that nicotine or other nicotinic agonists could have beneficial effects against severe COVID-19. Potential mechanisms include modulation of the immune response through activation of the cholinergic anti-inflammatory pathway or prevention of an interaction between SARS-CoV-2 and nAChRs. Considering that pharmaceutical nicotine products have been available for years and have been administered for months, even in non-smoking patients, without significant side-effects [29,30], it is perhaps timely to propose a clinical trial of pharmaceutical nicotine in COVID-19 patients.
References
1. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052.
2. Farsalinos K, Niaura R, Le Houezec J, Barbouni A, Tsatsakis A, Kouretas D, Vantarakis A, Poulas K. Editorial: Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system. Toxicol Rep. 2020 Apr 30. doi: 10.1016/j.toxrep.2020.04.012.
3. Centers for Disease Control and Prevention. Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 — United States, February 12–March 28, 2020. MMWR Morb Mortal Wkly Rep 2020. doi: 10.15585/mmwr.mm6913e2.
4. Farsalinos K, Barbouni A, Niaura R. Systematic review of the prevalence of current smoking among hospitalized COVID-19 patients in China: could nicotine be a therapeutic option? Intern Emerg Med. 2020 May 9:1–8. doi: 10.1007/s11739-020-02355-7.
5. Petrilli CM, Jones SA, Yang J, Rajagopalan H, O'Donnell LF, Chernyak Y, Tobin K, Cerfolio RJ, Francois F, Horwitz LI. Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City. medRxiv 2020.04.08.20057794; doi: https://doi.org/10.1101/2020.04.08.20057794.
6. Rossato M, Russo L, Mazzocut S, Di Vincenzo A, Fioretto P, Vettor R. Current Smoking is Not Associated with COVID-19. Eur Respir J. 2020 Apr 29. pii: 2001290. doi: 10.1183/13993003.01290-2020.
7. Docherty AB, Harrison EM, Green CA, Hardwick HE, Pius R, Norman L, Holden KA, Read JM, Dondelinger F, Carson G, Merson L, Lee J, Plotkin D, Sigfrid L, Halpin S, Jackson C, Gamble C, Horby PW, Nguyen-Van-Tam JS, Ho A, Russell CD, Dunning J, Openshaw PJ, Baillie JK, Semple MG; ISARIC4C investigators. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. 2020 May 22;369:m1985. doi: 10.1136/bmj.m1985.
8. Farsalinos K, Angelopoulou A, Alexandris N, Poulas K. COVID-19 and the nicotinic cholinergic system. Eur Respir J. 2020 May 22:2001589. doi: 10.1183/13993003.01589-2020.
9. Arcavi L, Benowitz NL. Cigarette smoking and infection. Arch Intern Med. 2004 Nov 8;164(20):2206-16.
10. Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents. 2020 Mar 28:105954. doi: 10.1016/j.ijantimicag.2020.105954.
11. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007 Feb;117(2):289-96.
12. Mabley J, Gordon S, Pacher P. Nicotine exerts an anti-inflammatory effect in a murine model of acute lung injury. Inflammation. 2011;34(4):231-7. doi: 10.1007/s10753-010-9228-x.
13. van Westerloo DJ, Giebelen IA, Florquin S, Daalhuisen J, Bruno MJ, de Vos AF, Tracey KJ, van der Poll T. The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis. J. Infect. Dis. 2005;191:2138–2148.
14. Farsalinos K, Eliopoulos E, Tzartos S, Poulas K. Nicotinic Cholinergic System and COVID-19: Identification of a Potentially Crucial Snake Toxin-Like Sequence in the SARS-CoV-2 Spike Glycoprotein. Preprints 2020;2020050301. Doi. 10.20944/preprints202005.0301.v1.
15. Farsalinos K, Eliopoulos E, Leonidas D, Papadopoulos G, Tzartos S, Poulas, K. Molecular Modelling and Docking Experiments Examining the Interaction between SARS-CoV-2 Spike Glycoprotein and Neuronal Nicotinic Acetylcholine Receptors. Preprints 2020;2020050365. doi. 10.20944/preprints202005.0365.v1.
16. Vardavas CI, Nikitara K. COVID-19 and smoking: A systematic review of the evidence. Tob Induc Dis. 2020 Mar 20;18:20. doi: 10.18332/tid/119324. eCollection 2020.
17. Patanavanich R, Glantz SA. Smoking is Associated with COVID-19 Progression: A Meta-Analysis. Nicotine Tob Res. 2020 May 13:ntaa082. doi: 10.1093/ntr/ntaa082.
18. Farsalinos K, Poulas K, Polosa R, Barbouni A, Caponnetto P, Niaura R. Prevalence of Current Smoking and Association with Adverse Outcome in Hospitalized COVID-19 Patients: A Systematic Review and Meta-Analysis. Preprints 2020;2020050113. Doi. 10.20944/preprints202005.0113.v1.
19. Oakes JM, Fuchs RM, Gardner JD, Lazartigues E, Yue X. Nicotine and the renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol. 2018;315(5):R895-R906. doi: 10.1152/ajpregu.00099.2018.
20. Brake SJ, Barnsley K, Lu W, McAlinden KD, Eapen MS, Sohal SS. Smoking Upregulates Angiotensin-Converting Enzyme-2 Receptor: A Potential Adhesion Site for Novel Coronavirus SARS-CoV-2 (Covid-19). J Clin Med. 2020 Mar 20;9(3). pii: E841. doi: 10.3390/jcm9030841.
21. Smith JC, Sausville EL, Girish V, Yuan ML, Vasudevan A, John KM, Sheltzer JM. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract. Dev Cell. 2020 May 16. doi: 10.1016/j.devcel.2020.05.012.
22. Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med. 2020 Apr 20. pii: S0953-6205(20)30151-5. doi: 10.1016/j.ejim.2020.04.037.
23. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger JM. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005 Aug;11(8):875-9. doi: 10.1038/nm1267.
24. Xie X, Chen J, Wang X, Zhang F, Liu Y. Age- and gender-related difference of ACE2 expression in rat lung. Life Sci. 2006;78:2166–2171.
25. Pal R, Bhansali A. COVID-19, Diabetes Mellitus and ACE2: The conundrum. Diabetes Res Clin Pract. 2020 doi: 10.1016/j.diabres.2020.108132:108132.
26. Kassiri Z, Zhong J, Guo D, Basu R, Wang X, Liu PP, Scholey JW, Penninger JM, Oudit GY. Loss of angiotensin-converting enzyme 2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction. Circ Heart Fail. 2009;2:446–455.
27. Ciaglia E, Vecchione C, Puca AA. COVID-19 infection and the predictive ACE2 soluble levels: the favourable protection of children and women. Front. Pediatr 2020. doi: 10.3389/fped.2020.00206.
28. Leung JM, Yang CX, Tam A, Shaipanich T, Hackett TL, Singhera GK, Dorscheid DR, Sin DD. ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19. Eur Respir J. 2020 Apr 8. pii: 2000688. doi: 10.1183/13993003.00688-2020.
29. Villafane G, Thiriez C, Audureau E, Straczek C, Kerschen P, Cormier-Dequaire F, Van Der Gucht A, Gurruchaga JM, Quéré-Carne M, Evangelista E, Paul M, Defer G, Damier P, Remy P, Itti E, Fénelon G. High-dose transdermal nicotine in Parkinson's disease patients: a randomized, open-label, blinded-endpoint evaluation phase 2 study Eur J Neurol. 2018 Jan;25(1):120-127. doi: 10.1111/ene.13474.
30. Newhouse P, Kellar K, Aisen P, White H, Wesnes K, Coderre E, Pfaff A, Wilkins H, Howard D, Levin ED. Nicotine treatment of mild cognitive impairment: a 6-month double-blind pilot clinical trial. Neurology. 2012 Jan 10;78(2):91-101. doi: 10.1212/WNL.0b013e31823efcbb.
Competing interests:
No competing interests
30 May 2020
Konstantinos Farsalinos
MD, MPH
Konstantinos Poulas, PhD
Laboratory of Molecular Biology and Immunology, Department of Pharmacy, University of Patras
Rapid Response:
Nicotine and COVID-19
Dear Editor
Nicotine and COVID-19
Dear Editor
While SARS-CoV-2 is known to use angiotensin converting enzyme 2 (ACE2) as a receptor for cell entry [2], an intriguing hypothesis was recently presented about a potential interaction between SARS-CoV-2 and nicotinic acetylcholine receptors (nAChRs) [2]. It was initially observed that smokers were under-represented among hospitalized patients with COVID-19. While several limitations apply to this analysis, data from retrospective case series from China, the US, Italy and the UK have consistently shown that the proportion of hospitalized patients who were current smokers was substantially lower compared to the expected prevalence based on population smoking rates [3-8]. This represents a “paradox” considering that smoking increases the risk for respiratory infections susceptibility and severity [9].
Smoking was immediately and justifiably rejected as a viable protective measure for COVID-19 due to its well-established adverse health effects [4]. However, a protective role for nicotine was suggested based on the fact that cytokine storm is a hallmark of severe COVID-19 [10] while the cholinergic anti-inflammatory pathway, mediated mainly through nAChRs, can suppress the hyper-inflammatory response and promote immune homeostasis [11]. Nicotine is a cholinergic agonist that has been found to inhibit the release of pro-inflammatory cytokines, preventing the development of acute respiratory distress syndrome and sepsis in animal models [12,13]. Subsequently, an analysis of the clinical manifestations of COVID-19 identified that they could be linked to dysfunction of the nicotinic cholinergic system [2]. Additionally, an amino acid sequence on the receptor binding domain of SARS-CoV-2 spike glycoprotein was found to be homologous to a sequence of a snake venom neurotoxin [14]. In silico molecular modelling and docking experiments showed that this sequence may interact with the alpha9 and alpha7 subtypes of nAChRs [15]. These findings indicate that there may be a potential direct, adverse effect of SARS-CoV-2 on the nicotinic cholinergic system.
Studies have found that, once hospitalized, current smokers have higher risk for adverse outcome [16-18]. This is not contradictory to the above-mentioned hypothesis. Besides the higher likelihood for comorbidities that are risk factors for adverse COVID-19 outcome, such as cardiovascular and respiratory disease, smokers experience abrupt cessation of nicotine intake once hospitalized since it is highly unlikely that they would receive nicotine replacement therapies during hospitalization. As a result, their plasma nicotine levels would be reduced to non-detectable levels within hours from hospital admission. Therefore, although smokers should still be encouraged to quit as a general measure to reduce their health risk, physicians should consider prescribing pharmaceutical nicotine products as smoking substitutes. Additionally, pharmaceutical nicotine products could be considered for smokers hospitalized for COVID-19. Nicotine can be administered in the form of a patch, but could also be considered for inhalation through a nebulizer, which would deliver nicotine directly to the lungs and, thus, better address the local immunological cascade.
Another aspect of the interaction between nicotine and COVID-19 relates to its effects on ACE2. While previous studies have shown that smoking and nicotine down-regulate ACE2 [19], recent genetic studies report that smoking up-regulates ACE2 [20,21]. While this has been suggested to be detrimental in terms of susceptibility for infection and viral invasion, evidence suggests that ACE2 down-regulation has detrimental effects resulting due to unopposed activity of angiotensin II to AT1 receptors, which cause vasoconstriction, enhanced inflammation and thrombosis [22]. Studies on SARS-CoV also show that viral entry to the cells results in rapid depletion of ACE2 and severe inflammation [23]. Finally, common risk factors for severe COVID-19, such as age, male gender, diabetes and cardiovascular disease, are associated with lower levels of ACE2 [24-27]. Recently, an in vitro study found that nicotine increases ACE2 through the alpha7 subtype of nAChRs [28]. Still, it is currently unclear how ACE2, an enzyme which by definition has protective properties, affects SARS-CoV-2 virulence and disease severity.
In conclusion, the evidence suggests that nicotine or other nicotinic agonists could have beneficial effects against severe COVID-19. Potential mechanisms include modulation of the immune response through activation of the cholinergic anti-inflammatory pathway or prevention of an interaction between SARS-CoV-2 and nAChRs. Considering that pharmaceutical nicotine products have been available for years and have been administered for months, even in non-smoking patients, without significant side-effects [29,30], it is perhaps timely to propose a clinical trial of pharmaceutical nicotine in COVID-19 patients.
References
1. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052.
2. Farsalinos K, Niaura R, Le Houezec J, Barbouni A, Tsatsakis A, Kouretas D, Vantarakis A, Poulas K. Editorial: Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system. Toxicol Rep. 2020 Apr 30. doi: 10.1016/j.toxrep.2020.04.012.
3. Centers for Disease Control and Prevention. Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 — United States, February 12–March 28, 2020. MMWR Morb Mortal Wkly Rep 2020. doi: 10.15585/mmwr.mm6913e2.
4. Farsalinos K, Barbouni A, Niaura R. Systematic review of the prevalence of current smoking among hospitalized COVID-19 patients in China: could nicotine be a therapeutic option? Intern Emerg Med. 2020 May 9:1–8. doi: 10.1007/s11739-020-02355-7.
5. Petrilli CM, Jones SA, Yang J, Rajagopalan H, O'Donnell LF, Chernyak Y, Tobin K, Cerfolio RJ, Francois F, Horwitz LI. Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City. medRxiv 2020.04.08.20057794; doi: https://doi.org/10.1101/2020.04.08.20057794.
6. Rossato M, Russo L, Mazzocut S, Di Vincenzo A, Fioretto P, Vettor R. Current Smoking is Not Associated with COVID-19. Eur Respir J. 2020 Apr 29. pii: 2001290. doi: 10.1183/13993003.01290-2020.
7. Docherty AB, Harrison EM, Green CA, Hardwick HE, Pius R, Norman L, Holden KA, Read JM, Dondelinger F, Carson G, Merson L, Lee J, Plotkin D, Sigfrid L, Halpin S, Jackson C, Gamble C, Horby PW, Nguyen-Van-Tam JS, Ho A, Russell CD, Dunning J, Openshaw PJ, Baillie JK, Semple MG; ISARIC4C investigators. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. 2020 May 22;369:m1985. doi: 10.1136/bmj.m1985.
8. Farsalinos K, Angelopoulou A, Alexandris N, Poulas K. COVID-19 and the nicotinic cholinergic system. Eur Respir J. 2020 May 22:2001589. doi: 10.1183/13993003.01589-2020.
9. Arcavi L, Benowitz NL. Cigarette smoking and infection. Arch Intern Med. 2004 Nov 8;164(20):2206-16.
10. Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents. 2020 Mar 28:105954. doi: 10.1016/j.ijantimicag.2020.105954.
11. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007 Feb;117(2):289-96.
12. Mabley J, Gordon S, Pacher P. Nicotine exerts an anti-inflammatory effect in a murine model of acute lung injury. Inflammation. 2011;34(4):231-7. doi: 10.1007/s10753-010-9228-x.
13. van Westerloo DJ, Giebelen IA, Florquin S, Daalhuisen J, Bruno MJ, de Vos AF, Tracey KJ, van der Poll T. The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis. J. Infect. Dis. 2005;191:2138–2148.
14. Farsalinos K, Eliopoulos E, Tzartos S, Poulas K. Nicotinic Cholinergic System and COVID-19: Identification of a Potentially Crucial Snake Toxin-Like Sequence in the SARS-CoV-2 Spike Glycoprotein. Preprints 2020;2020050301. Doi. 10.20944/preprints202005.0301.v1.
15. Farsalinos K, Eliopoulos E, Leonidas D, Papadopoulos G, Tzartos S, Poulas, K. Molecular Modelling and Docking Experiments Examining the Interaction between SARS-CoV-2 Spike Glycoprotein and Neuronal Nicotinic Acetylcholine Receptors. Preprints 2020;2020050365. doi. 10.20944/preprints202005.0365.v1.
16. Vardavas CI, Nikitara K. COVID-19 and smoking: A systematic review of the evidence. Tob Induc Dis. 2020 Mar 20;18:20. doi: 10.18332/tid/119324. eCollection 2020.
17. Patanavanich R, Glantz SA. Smoking is Associated with COVID-19 Progression: A Meta-Analysis. Nicotine Tob Res. 2020 May 13:ntaa082. doi: 10.1093/ntr/ntaa082.
18. Farsalinos K, Poulas K, Polosa R, Barbouni A, Caponnetto P, Niaura R. Prevalence of Current Smoking and Association with Adverse Outcome in Hospitalized COVID-19 Patients: A Systematic Review and Meta-Analysis. Preprints 2020;2020050113. Doi. 10.20944/preprints202005.0113.v1.
19. Oakes JM, Fuchs RM, Gardner JD, Lazartigues E, Yue X. Nicotine and the renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol. 2018;315(5):R895-R906. doi: 10.1152/ajpregu.00099.2018.
20. Brake SJ, Barnsley K, Lu W, McAlinden KD, Eapen MS, Sohal SS. Smoking Upregulates Angiotensin-Converting Enzyme-2 Receptor: A Potential Adhesion Site for Novel Coronavirus SARS-CoV-2 (Covid-19). J Clin Med. 2020 Mar 20;9(3). pii: E841. doi: 10.3390/jcm9030841.
21. Smith JC, Sausville EL, Girish V, Yuan ML, Vasudevan A, John KM, Sheltzer JM. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract. Dev Cell. 2020 May 16. doi: 10.1016/j.devcel.2020.05.012.
22. Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med. 2020 Apr 20. pii: S0953-6205(20)30151-5. doi: 10.1016/j.ejim.2020.04.037.
23. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger JM. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005 Aug;11(8):875-9. doi: 10.1038/nm1267.
24. Xie X, Chen J, Wang X, Zhang F, Liu Y. Age- and gender-related difference of ACE2 expression in rat lung. Life Sci. 2006;78:2166–2171.
25. Pal R, Bhansali A. COVID-19, Diabetes Mellitus and ACE2: The conundrum. Diabetes Res Clin Pract. 2020 doi: 10.1016/j.diabres.2020.108132:108132.
26. Kassiri Z, Zhong J, Guo D, Basu R, Wang X, Liu PP, Scholey JW, Penninger JM, Oudit GY. Loss of angiotensin-converting enzyme 2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction. Circ Heart Fail. 2009;2:446–455.
27. Ciaglia E, Vecchione C, Puca AA. COVID-19 infection and the predictive ACE2 soluble levels: the favourable protection of children and women. Front. Pediatr 2020. doi: 10.3389/fped.2020.00206.
28. Leung JM, Yang CX, Tam A, Shaipanich T, Hackett TL, Singhera GK, Dorscheid DR, Sin DD. ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19. Eur Respir J. 2020 Apr 8. pii: 2000688. doi: 10.1183/13993003.00688-2020.
29. Villafane G, Thiriez C, Audureau E, Straczek C, Kerschen P, Cormier-Dequaire F, Van Der Gucht A, Gurruchaga JM, Quéré-Carne M, Evangelista E, Paul M, Defer G, Damier P, Remy P, Itti E, Fénelon G. High-dose transdermal nicotine in Parkinson's disease patients: a randomized, open-label, blinded-endpoint evaluation phase 2 study Eur J Neurol. 2018 Jan;25(1):120-127. doi: 10.1111/ene.13474.
30. Newhouse P, Kellar K, Aisen P, White H, Wesnes K, Coderre E, Pfaff A, Wilkins H, Howard D, Levin ED. Nicotine treatment of mild cognitive impairment: a 6-month double-blind pilot clinical trial. Neurology. 2012 Jan 10;78(2):91-101. doi: 10.1212/WNL.0b013e31823efcbb.
Competing interests: No competing interests