Response to the emerging novel coronavirus outbreakBMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m406 (Published 31 January 2020) Cite this as: BMJ 2020;368:m406
All rapid responses
Nicotine and COVID-19
While SARS-CoV-2 is known to use angiotensin converting enzyme 2 (ACE2) as a receptor for cell entry , an intriguing hypothesis was recently presented about a potential interaction between SARS-CoV-2 and nicotinic acetylcholine receptors (nAChRs) . 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 .
Smoking was immediately and justifiably rejected as a viable protective measure for COVID-19 due to its well-established adverse health effects . However, a protective role for nicotine was suggested based on the fact that cytokine storm is a hallmark of severe COVID-19  while the cholinergic anti-inflammatory pathway, mediated mainly through nAChRs, can suppress the hyper-inflammatory response and promote immune homeostasis . 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 . 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 . In silico molecular modelling and docking experiments showed that this sequence may interact with the alpha9 and alpha7 subtypes of nAChRs . 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 , 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 . Studies on SARS-CoV also show that viral entry to the cells results in rapid depletion of ACE2 and severe inflammation . 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 . 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.
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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.
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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.
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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
Re: Response to the emerging novel coronavirus outbreak: Dr Davies and Dr Kipshidze’s responses, and Dr Flachsbart’s idea a few weeks ago.
Dr Flachsbart’s idea - heparin to prevent micro thrombi - was, I think, way ahead of anything published.
Dr Davies suggests nicotine patches as an anti-virus treatment. Dr Kipshidze suggests the use of micro-catheters for instilling medicines into the smaller bronchioles.
Is someone, somewhere, trying the two things together? Flachsbartian heparin and nicotine insufflated into the bronchioles?
Maybe I am talking through my hat?
Competing interests: Might become a patient one day.
I strongly agree with Dr. Jonathan Davies that the use of Nicotine patches in the treatment of COVID-19, should be urgently considered and discussed.
Firstly, there is an increasing number of studies that show the negative correlation between smoking and the numbers of symptomatic COVID-19 patients (1).
There is a link between nicotine and other parameters that are essential for the survival of COVID-19, especially serious COVID-19 disease patients, e.g. Lymphocytes, CD4+ T cells and CD8+ T cells. Nicotine stimulates the Alpha 4 Beta 2 nicotinic receptor that promotes CD4+ T cell proliferation and helper T Cell immune response (2).
The Alpha 4 Beta 2 nicotinic receptor is also associated with Growth Hormone release (3), a factor that can be negatively correlated with serious COVID-19 disease, e.g. children and young adults have a higher growth hormone level than the elderly, women have a higher growth hormone level than men and some obese people have a lower growth hormone level.
This shows that somehow SARS-CoV2 is binding with the nicotinic receptors that activate the n-Acetylchonilergic Receptors and, lately, there is a study that suggested that SARS-CoV2 has a spike protein sequence that is similar to snake toxin (4). If this is true, then SARS-CoV2 may be some form of an antagonist for nicotinic (and possibly even muscarinic) receptors.
There are studies stating that the condition of smokers who were hospitalized for serious COVID-19 disease worsens more rapidly and has a higher mortality rate than that of non smokers. If we think of it from a competitive antagonist point of view, this is to be expected as habitual smokers will over time, develope some form of adaptation where the nicotinic receptors will be more tolerant towards stimulation (5).
Symptoms of serious COVID-19 disease, such as loss of speech and movement could also be down to the fact that when a patient's viral load become so high, the amount of nicotinic and/or muscarinic receptor antagonists become so high that it hampers muscle coordination. Some of these symptoms are very similar to symptoms of a well known nicotinic receptor antagonist, Dexthrometophan, toxicity (6).
The above corroborate with the hypothesis that nicotine and possibly other nicotinic receptor agonists can be used to treat COVID-19. While it is understandable that nicotine is treated more conservatively due to the undoubted damage of smoking, this should not stop, nor delay what has so far been the most sound treatment, in term of statistics. The statistics are there. The science is there. It is time to put nicotine to the litmus test.
Lim Kah Poh
Former chairman of the Community Pharmacy Chapter
Malaysian Pharmaceutical Society
1. M. Miyara et. al. Low incidence of daily active tobacco smoking in patients with symptomatic COVID-19. https://www.qeios.com/read/WPP19W.3
2. Jacob C. Nordman et. al. The alpha 4 nicotinic receptor promotes CD4+ T cell proliferation and a Helper T cell immune response. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868899/
3. Marco Feldi et. al. Association of a nicotinic receptor mutation with reduced height and blunted physiostigmine - stimulated growth hormone release. https://academic.oup.com/jcem/article/93/2/634/2598724
4. Konstantinos Farsalinos et. al. Nicotinic Cholinergic System and COVID-19: Identification of a potentially crucial snake toxin-like sequence in the SARS-CoV2 spike glycoprotein. https://www.preprints.org/manuscript/202004.0154/v1
5. Neal N. Benawitz. Pharmacology of Nicotine: Addiction, Smoking-Induced Disease and Therapeutics. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946180/
6. Jonathan D. Journey. Dextromethorphan toxicity. https://www.ncbi.nlm.nih.gov/books/NBK538502/
Competing interests: No competing interests
Re: Response to the emerging novel coronavirus outbreak : Placental and Umbilical Cord Stem Cell Therapies for the Treatment of COVID-19
Unfortunately until now there is no specific treatment for this severe condition. We hypothesize that placental and/or umbilical cord stem cells, based on their features could be used for treatment of different possible complications caused by COVID-19.
A number of authors have reported (1, 2) that mesenchymal stem cells produce anti-inflammatory cytokines, promote the maturation and function of dendritic cells, modulate macrophages and natural killer cells. Their paracrine factors provide repair and regeneration of injured tissue. Stem cells are also resistant to viral infections.
Wu et al. (2018) (3) show that stem cells express high levels of interferon stimulated genes (ISGs). ISGs have antiviral targets and protect stem cells from antiviral cytokine – interferon. This mechanism gives opportunity to stem cells (which are injected for treatment purposes) to survive in a viral environment.
There is very interesting information suggesting that interferon stimulated genes have specific antiviral activity, among them is antiviral action against Coronaviridae (human coronavirus OC43). Keaton M. Crosse (2018) (4) reported immune modulatory function of ISGs, which is triggered by virus entry and interferon production.
Interestingly, Hu C, et al. (2020) (5) reported that acute respiratory distress syndrome (ARDS), lung failure, and fulminant pneumonia are major lung diseases in H7N9 patients. Transplantation of mesenchymal stem cells (MSCs) in this patient population suggested that MSCs significantly improve survival rate of H7N9 induced ARDS and provide a theoretical basis for the treatment of H7N9 induced ARDS in both preclinical research and clinical studies. Because H7N9 and corona virus disease 2019 (COVID-19) share similar complications (such as ARDS and lung failure) and corresponding multi-organ dysfunction, MSC-based therapy could be a possible alternative for treating COVID-19.
As we reported earlier, (6) decellularized human placenta is mostly composed of type III collagen and glycoproteins. It also contains numerous growth factors, such as EGF, bFGF, KGF, VEGF, TGF-a, TGF-b, PDGF, HGF, and NGF. Decellularized human placenta also possesses immunomodulative and immune privilege, antimicrobial effect, anti-inflammatory properties and increases vascularization or revascularization.
We propose the use of an aqueous bioactive placenta extract containing freeze-dried Human Placental or Umbilical Cord blood stem cells (i) or decellularized human placenta as a sorbent (ii) for treatment of ARDS in COVID-19 patients. Recently conducted preclinical studies in small animal models showed that when using both methods, a significant decrease of endogenous intoxication, and an improvement in peripheral and central hemodynamics was noted. Reduction of lung tissue infiltration and inflammation may impede the progression of ARDS. We are continuing intensive research to understand these pathways and how they work.
In summary, freeze-dried placental and umbilical stem cells is a promising biomaterial that may be useful in treating COVID-19.
1. Kyurkchiev D. et al. Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cells. 2014 Nov 26; 6(5): 552–570.
2. Chae Woon Park. Cytokine Secretion Profiling of Human Mesenchymal Stem Cells by Antibody Array. Int J Stem Cells. 2009 May; 2(1): 59–68.
3. Wu et al. Intrinsic Immunity Shapes Viral Resistance of Stem Cells, Cell . 2018 January 25; 172(3): 423–438.e25. )
4. Crosse KM, Monson EA, Beard MR, Helbig KJ. Interferon-Stimulated Genes as Enhancers of Antiviral Innate Immune Signaling. J Innate Immun. 2018;10(2):85-93. doi: 10.1159/000484258. Epub 2017 Nov 30.
5. Chen J, Hu C, et al. Clinical study of mesenchymal stem cell treating acute respiratory distress syndrome induced by epidemic Influenza A (H7N9) infection, a hint for COVID-19 treatment. Engineering (Beijing). 2020 Feb 28. doi: 10.1016/j.eng.2020.02.006.
6. Kakabadze Z, Mardaleishvili K, Loladze G, Javakhishvili I, Chakhunasvili K, Karalashvili L, Sukhitashvili N, Chutkerashvili G, Kakabadze A, Chakhunasvili D. Clinical application of decellularized and lyophilized human amnion/chorion membrane grafts for closing post-laryngectomy pharyngocutaneous fistulas. J Surg Oncol. 2016 Apr;113(5):538-43.
Competing interests: No competing interests
The responses in this section (ibid) fall into two camps: on the one hand those suggesting strategies to downregulate Angiotensin II receptors since they are the means by which the COVID-19 virus enters cells; on the other hand recommendations to reduce Angiotensin II levels since raised amounts may be the pathway to severe disease. By and large they are achieved by opposite means so either strategy risks making matters worse for patients. It would be good to discover as soon as possible which, if either, is correct.
Competing interests: No competing interests
Given that the new viral pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has come to be an International Concern, there is a prompt necessity to come up with potential interventions to reduce morbidities and mortalities.
ARDS, the main death cause of COVID-19, is a common immunopathological event for SARS-CoV-2, SARS-CoV and MERS-CoV infections. Cytokine storm as one of the mechanisms for ARDS is associated with the release of huge amounts of inflammatory cytokines caused by SARS-CoV-2. Among these, bradykinin (BK) and IL-6 are stimulationg interest. Besides, because the entry pathway into the infected cells is mediated by ACE2 , loss of ACE2 catalytic function in association with infection ruffles the pulmonary RAS (Renin-Angiotensin System), increasing inflammation due to the activation of the ANG II/ AT1 axis .
Based on previous studies, three potential agents hypothesized to be effective in alleviating COVID-19-induced ARDS are Aliskiren, Deltibant, and Montelukast.
In research, Aliskiren (a renin inhibitor) prevents oxidative stress (increases superoxide dismutase (SOD) and glutathione (GSH) and decreases malondialdehyde in lung tissues of rats with sepsis-related acute lung injuries) and decreases levels of TNF-α, IL-1β, and IL-6. Also, it decreases serum angiotensin II level and increases serum renin level, as a result of RAS inhibition .
In-vivo, pulmonary ACE2 attenuation leads to impaired bradykinin active metabolite [des-Arg9]-BK (DABK) inactivation.2 BK surge mediates pro-inflammatory responses (vasodilation, increased permeability) and alterations in the hemodynamics seen in sepsis. BK activates the B2 receptor resulting in the activation of PLC/PKC/IKKαβ and NF-κB, leading to IL-6 expression up-regulation .
Deltibant, a bradykinin antagonist, has been previously revealed in a multicenter RCT to have no overall effect on the 28-day mortality rate in patients with septic shock but in a subset of patients with gram-negative infection, the mortality rate is reduced. However, data on the Deltibant effect in viral septic shock is scarce .
Montelukast (MLK), a LT-D4 receptor antagonist, in a model of septic shock potentially reduces mortality. MLK attenuates TNF-α and IL-6 levels, elevates lipid peroxide level and myeloperoxidase activity in the lung, heart, liver, and kidney tissues. Also, it increases GSH and SOD activity in the lung, liver, and kidney tissues. Under sepsis conditions the most protected tissue by MLK is the lung and kidney tissues, suggesting that MLK reverses the systemic inflammatory reaction to sepsis and thereby reduces multiple organ failure .
According to research, we hypothesize that Aliskiren, Deltibant, and Montelukast possibly have useful effects (therapeutic/ prophylactic) on ARDS in COVID-19 which further needs to be investigated.
1 Li X, Geng M, Peng Y, Meng L, Lu S. Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Biomed Anal 2020. DOI: https://doi.org/10.1016/j.jpha.2020.03.001.
2 Sodhi CP, Wohlford-Lenane C, YamaguchY i, et al. Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. Am J Physiol Lung Cell Mol Physiol 2018; 314: L17–31. DOI: https://doi.org/10.1152/ajplung.00498.2016.
3 Akpinar E, Halici Z, Cadirci E, et al. What is the role of renin inhibition during rat septic conditions: preventive effect of aliskiren on sepsis-induced lung injury. Naunyn Schmiedebergs Arch Pharmacol 2014; 387: 969–78. DOI: https://doi.org/10.1007/s00210-014-1014-0
4 Lee CH, Shieh DC, Tzeng CY, et al. Bradykinin-induced IL-6 expression through bradykinin B2 receptor, phospholipase C, protein kinase Cδ and NF-κB pathway in human synovial fibroblasts. Cell Mol Immunol 2008; 45: 3693–702. DOI: https://doi.org/10.1016/j.molimm.2008.06.007
5 Vincent JL, Sun Q, Dubois MJ. Clinical trials of immunomodulatory therapies in severe sepsis and septic shock. Clin Infect Dis 2002; 34: 1084–93. DOI: https://doi.org/10.1086/339549
6 Coskun AK, Yigiter M, Oral A, et al. The effects of Montelukast on antioxidant enzymes and proinflammatory cytokines on the heart, liver, lungs, and kidneys in a rat model of cecal ligation and puncture–induced sepsis. ScientificWorldJournal 2011; 11: 1341–56. DOI: https://doi.org/10.1100/tsw.2011.122
Competing interests: No competing interests
Several publications support the role of the ACE2 receptor is the entry point for COVID-19. At least two publications have provided information regarding ACE2 receptor antagonists. Besides avoiding ACE inhibitors and, perhaps more importantly, Angiotensin Receptor Blockers (ARBs), could ACE2 receptor antagonists be considered in the fight against COVID 19 to lung tissue?
Dales, N.A. et al. (2002) Substrate-based design of the first class of angiotensin-converting enzyme-related carboxypeptidase (ACE2) inhibitors. J. Am. Chem. Soc. 124, 11852–11853
Huang, L. et al. (2003) Novel peptide inhibitors of angiotensin converting enzyme 2. J. Biol. Chem. 278, 15532–15540
Competing interests: No competing interests
Re: Response to the emerging novel coronavirus outbreak: Renin angiotensin system blockade in COVID-19: ‘Primum non nocere’
Subsequent to an editorial published by Kickbusch and Leung, several letters and correspondences have appeared, including rapid responses on bmj.com, hypothesising that ACE inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs) could increase the risk of severe and fatal COVID-19 (1,2). While some proposed alternative antihypertensives such as calcium channel blockers others suggest switching ACEi to long acting ARBs.
It is unfortunate that this has raised major concerns among patients with diabetes and hypertension across the world. A simple google search of ACEi and COVID-19 yields more than 5 million hits. Similar high activity in social media raises concerns that patients might stop these drugs without consulting their health care professionals and come to significant harm. Within a week, various societies have quite rightly issued statements recommending not to discontinue these drugs without consulting their health care professionals; with some suggesting that these drugs should be reviewed on a case-by-case basis. The vast majority of these patients will be managed by general practitioners or general physicians and not by diabetes or hypertension specialists. We therefore strongly feel that it is important to summarise the nuances of the existing evidence to inform practice and suggest a potential alternative, if there is any, in cases where withdrawal of ACEi/ARB are clinically indicated.
It is true that Angiotensin Converting Enzyme 2 (ACE2) mRNA and protein expression is upregulated in early phases of hypertension and cardiovascular diseases (as a compensatory mechanism), it is reduced in later phases (3). This enables reduction of Angiotensin II (Ang-II) by ACE2, which converts it to the vasodilatory heptapeptide Ang-(1-7) (4). Indeed, Deshotels et al (3) also showed in rodents that ACE2 and Angiotensin Receptor 1 (AT1R) forms a complex which could be blocked by ARBs and excess Ang-II dissociates this complex resulting in ‘freeing up’ of ACE2 in the cell membrane. In addition to its anti-hypertensive, renal and cardiovascular benefits, Ang-(1-7) is also beneficial for pulmonary fibrosis, pulmonary hypertension and acute respiratory distress syndrome (ARDS), a common feature in COVID-19 and other corona virus infections. ACE2 knockout mouse shows severe ARDS, reversed by recombinant human ACE2 (rhACE2) (reviewed in 5). However, it is also true that COVID-19 utilises ACE2 as a receptor for host cell entry and has much higher affinity for COVID-19 compared to SARS (6). Studies in animal models investigating the relationship between ACEi/ARB and ACE2 have mainly been done on heart tissue, and the results are at best conflicting (7,8). Studies in humans do not show any correlation between ACEi/ARBs and circulating ACE2 levels (9,10)
It is important to remember that Renin-Angiotensin-Aldosterone axis (RAAS) is a very dynamic system and chronic ACE inhibition can result in poor control of hypertension (so called ACE escape), which in part may be due to Renin activation and subsequent increase in Ang-II and AT1R activation. It is therefore conceivable that direct renin inhibition using Aliskiren might offer better vasodilatory, renal and cardiac protection without the concern of possible increase in infective potential by COVID19. While it is not known what happens to ACE2 levels in Aliskiren use, we can at least be confident that the Ang-II-AT1R activation will not escape in comparison to the use of calcium channel blockers.
The evidence that RASS blocking agents increase the risk of developing severe disease and fatality due to COVID-19 is unconvincing. Therefore, we should await the results of the trials that are currently underway, one using rhACE2 and two using Losartan (https://clinicaltrials.gov/ct2/show/NCT04287686; https://clinicaltrials.gov/ct2/show/NCT04311177 and https://clinicaltrials.gov/ct2/show/NCT04312009) before making any firm recommendations about stopping or substituting these drugs. While it is highly tempting to ‘do something’ during this unprecedented global pandemic, we should follow the primary principle of the Hippocratic oath, ‘Primum non nocere’ – first, do no harm until we obtain more evidence.
1. Kickbusch I, Leung G. Response to the emerging novel coronavirus outbreak. BMJ 2020;368:m406. doi: 10.1136/bmj.m406 [published Online First: 2020/02/02]
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Competing interests: No competing interests
Loss of smell and taste in the course of COVID-19 infection may be related to angiotensin converting enzyme (ACE) inhibition
Very recently, there has been reports of loss of smell and taste in the course of COVID-19 infection. The report from the presidents of the British Association of Otorhinolaryngology and British Rhinological Society noted that there has been growing number of reports of a significant increase in COVID-19 patients presenting with loss of smell in the absence of other symptoms . Moreover, they suggested anosmia can be added to the current symptom criteria to trigger quarantine and/or self-isolation to limit dissemination of the COVID-19 .
In the former report , we suggested that there seems to be some ongoing ACE inhibition during COVID-19 infectious process because AngII is shown as increased in patients with COVID-19 and increased AngII causes decreased ACE mRNA levels in the lung and decrease in pulmonary ACE activity . The dry cough, which is a very common presentation of COVID-19 infection, may be related to this ACE inhibition . Of note, loss of smell and taste is a well-known effect of ACE inhibitors . While post-viral anosmia is a common causes of loss of smell sensation, loss of smell/taste may be more common in COVID-19 infections regarding this pathophysiological process. We suggest that the ACE inhibition that is present in COVID-19 infections may be the cause of the loss of smell/taste symptomatology, which seems to be specifically common in COVID-19 infections.
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Competing interests: No competing interests
What is the possible role of Nicotine in acute respiratory failure caused by COVID-19 Infection?
COVID 19 is understood to bind to ACE 2 receptors. It appears to have a disruptive effect on the homeostasis of the Renin Angiotensin System (1). Nicotine is an ACE-agonist. It has been shown to be protective in acute inflammatory reactions in ARDS probably by decreasing inflammatory cytokine production by macrophages and other mononuclear cells (2).
In this new disease smokers seem to have particularly poor outcomes (3). We postulate that at least in chronic smokers, the disruption of the normal Renin Angiotensin System is exacerbated by nicotine withdrawal leading to exacerbation of acute lung injury. We suggest that the simple use of Nicotine patches should be urgently considered and discussed.
1. Attila R Garami. Preventing a Covid-19 Pandemic.(Rapid Response). British Medical Journal 2020;368:m810. 12th of March 2020.
2. Mabley, Jay et al. Nicotine Excerpts and Anti-inflammatory Effect in a Murine Model of acute lung injury. Inflammation 2011, August; 34 (4): 231-237.
3. Chinese Medical Journal. Analysis of factors associated with disease outcomes in hospitalized patients with 2019 Novel Coronavirus DOI: 10.1097/cm90000000000000775
Dr Robert Davies Dr Nerys Conway Mr J P Davies
Dr Robert Davies MB BCh FRCA
Anaesthesia & Critical Care Consultant
Dr Nerys Conway MB BCh FRCP
Acute Medicine Consultant
Mr J.P. DAVIES MB BCh FRCS FRCS(Orth)
Trauma & Orthopaedic Consultant
19th of March 2020
The Royal Glamorgan Hospital
Conflict of Interest: None
Competing interests: No competing interests