Active smoking and COVID-19: a double-edged sword

We are thankful to Garufi et al [[1]Garufi G., Carbognin L., Orlandi A., Tortora G., Bria E.. Smoking habit and hospitalization for severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2)-related pneumonia: the unsolved paradox behind the evidence. Eur J Intern Med, in press.Google Scholar] for the comments on our recent article published in this journal [[2]Lippi G. Henry B.M. Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19).Eur J Intern Med. 2020; (Mar 16.Epub ahead of print)https://doi.org/10.1016/j.ejim.2020.03.014Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar], and we wish to add some further pieces to the intricate puzzle linking active cigarette smoking with severity of coronavirus disease 2019 (COVID-19). Information that has been garnered so far attests quite reasonably that cigarette smoking may significantly contribute to foster the expression of angiotensin-converting enzyme 2 (ACE2), the primary receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the surface of many cell types, including respiratory epithelia. This fact has been demonstrated by the seminal study of Leung et al [[3]Leung J.M. Yang C.X. Tam A. Shaipanich T. Hackett T.L. Singhera G.K. et al.ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19.Eur Respir J. 2020 Apr 8; (pii: 2000688Epub ahead of print)https://doi.org/10.1183/13993003.00688-2020Crossref Scopus (576) Google Scholar], and then confirmed by the preliminary investigation of Smith and Sheltzer [[4]Smith J.C., Sheltzer J.M.Cigarette smoke triggers the expansion of a subpopulation of respiratory epithelial cells that express the SARS-CoV-2 receptor ACE2 bioRxiv2020.03.28.013672; doi: 10.1101/2020.03.28.013672.Google Scholar]. Nevertheless, accumulating biological and clinical evidence suggests also that the relationship between active smoking and COVID-19 is not straightforward or unidirectional, and contributes to portray this intricate link as a double-edged sword, so that drawing definitive conclusions may be premature and even misleading, as we emphasized in our previous article [[2]Lippi G. Henry B.M. Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19).Eur J Intern Med. 2020; (Mar 16.Epub ahead of print)https://doi.org/10.1016/j.ejim.2020.03.014Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar]. On the one hand, whether cigarette smoking-induced up-regulation of the natural SARS-CoV-2 receptor ACE2 in human cells would increase the likelihood of being infected must be considered. However, to the contrary, increased expression of this enzyme may considerably attenuate the risk of developing the devastating lung and systemic injuries characterizing severe and critical forms of COVID-19 (Fig. 1). ACE2 plays a pivotal role in the pathogenesis of pulmonary disease and its evolution towards respiratory distress, whereby this enzyme catalyzes the conversion of angiotensin II (AngII) into angiotensin 1-7 (Ang1-7), a degradation peptide which strongly counteracts the unfavorable pro-inflammatory, vasoconstrictive, oxidative and fibrotic activity of the parental hormone AngII [[5]Sanchis-Gomar F. Lavie C.J. Perez-Quilis C. Henry B.M. Lippi G Angiotensin-converting enzyme 2 and antihypertensives (angiotensin receptor blockers and angiotensin-converting enzyme inhibitors) in coronavirus disease 2019.Mayo Clin Proc. 2020; (0.1016/j.mayocp.2020.03.026)Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar]. AngII levels have been shown to be elevated in COVID-19, correlating with lung injury. Therefore, it seems reasonable to conclude that enhanced expression of ACE2 on the cell surface of the lungs and other organs would cumulatively lower the risk of AngII-mediated tissue injury. This hypothesis finds some reliable epidemiological ground in a large report by Petrilli et al [[6]Petrilli C.M., Jones S.A., Yang J., Rajagopalan H., O'Donnell L.F., Chernyak Y., et al. Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City MedRxiv2020. 04.08.20057794; doi: 10.1101/2020.04.08.20057794.Google Scholar], showing that the prevalence of COVID-19 in tobacco users was significantly higher among patients with no critical COVID-19 illness who could be discharged than in COVID-19 patients who were instead classified as having severe disease (6.7% vs. 4.3%). Overall, this would translate into the evidence that current tobacco users have a nearly 40% lower risk of progressing towards critical COVID-19 illness (odds ratio (OR), 0.63; 95% confidence interval (95%CI), 0.40-1.00). Moreover, in multivariate logistic regression, tobacco use (former and current) was associated with reduced risk of hospitalization (OR, 0.71; 95%CI, 0.57-0.87). Importantly, recent data on approximately 1,500 US patients hospitalized for COVID-19 published by the Centers for Disease Control and Prevention (CDC) COVID-19 Response Team also shows that current smoking may be associated with a non-significant trend toward decreased disease severity [[7]CDC COVID-19 Response TeamPreliminary 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; 69: 382-386Crossref PubMed Google Scholar], whereby the percentage of current smokers was found to be nearly half in patients needing intensive care unit (ICU) admission than in those who do not (1.1% vs. 2.2%; odds ratio 0.51; 95% CI, 0.19-1.36). Indirect evidence of potential benefits from increasing ACE2 expression for ameliorating the prognosis of COVID-19 has then emerged from studies showing that recombinant ACE2 (rhACE2) is effective to rapidly decrease Ang II and interleukin 6 (IL-6) levels, thus mitigating the pro-inflammatory milieu that is commonplace in patients with acute respiratory distress syndrome [[8]Khan A. Benthin C. Zeno B. Albertson T.E. Boyd J. Christie J.D. et al.A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome.Crit Care. 2017; 21: 234Crossref PubMed Scopus (459) Google Scholar]. Additionally, interesting evidence has been published in the study of Monteil et al, who experimentally showed that not only could SARS-CoV-2 infection of human blood vessels and kidney organoids be efficiently inhibited by rhACE2, but the administration of this recombinant enzyme could also decrease viral load by a factor between 1,000–5,000 [[9]Monteil V. Kwon H. Prado P. Hagelkrüys A. Wimmer R.A. Stahl M. et al.Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2.Cell. 2020; https://doi.org/10.1016/j.cell.2020.04.004Abstract Full Text Full Text PDF PubMed Scopus (1547) Google Scholar]. In conclusion, far be it from recommending cigarette smoking to prevent evolution into severe or critical forms of COVID-19, since the many and multifaceted unhealthy effects of cigarette smoking are well established [[10]Onor I.O. Stirling D.L. Williams S.R. Bediako D. Borghol A. Harris M.B. et al.Clinical effects of cigarette smoking: epidemiologic impact and review of pharmacotherapy options.Int J Environ Res Public Health. 2017 Sep 28; 14 (pii: E1147)https://doi.org/10.3390/ijerph14101147Crossref PubMed Scopus (83) Google Scholar], we endorse the suggestion of Garufi et al [[1]Garufi G., Carbognin L., Orlandi A., Tortora G., Bria E.. Smoking habit and hospitalization for severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2)-related pneumonia: the unsolved paradox behind the evidence. Eur J Intern Med, in press.Google Scholar], that additional prospective studies and collaborative efforts are needed to clarify the complex relationship between smoking and COVID-19 (Fig. 1). All authors have no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence, their work.