key: cord-0683740-b1r6i0wq authors: Polverino, Francesca title: Cigarette Smoking and COVID-19: A Complex Interaction date: 2020-08-01 journal: Am J Respir Crit Care Med DOI: 10.1164/rccm.202005-1646le sha: d6fca836d3a86aa0530f13e81e8cee63e8021736 doc_id: 683740 cord_uid: b1r6i0wq nan To the Editor: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease (COVID-19), has expanded from Wuhan throughout China and is being exported to a growing number of countries worldwide. Despite the fact that the main complications of COVID-19 affect the lung, the prevalence of current smokers among hospitalized patients with COVID-19 has been reported consistently lower than the prevalence of smokers among the general population for that specific geographical area (1), even if one might have anticipated the opposite. Thus, the epidemiological data seem to question the role of coexisting active smoking as a risk factor for COVID-19 pneumonia. The data from Cai and colleagues, recently published in the Journal (2), report upregulation of pulmonary ACE2 (angiotensin-converting enzyme 2) gene expression in ever- smokers compared with nonsmokers in several transcriptomic data sets of lung samples from healthy never-and eversmokers and patients with chronic obstructive pulmonary disease. Also, they report an increase in ACE2-producing goblet cells in ever-smoker versus never-smoker lungs. These findings have putatively important implications for patients with COVID-19 because ACE2 has been shown to be the receptor used by SARS-CoV-2 to enter the host cells (3) and yet seem in contrast with the consolidated epidemiological data worldwide indicating a low prevalence of active smokers among patients with COVID-19. Cigarette smoke induces epigenetic modifications of the bronchial epithelium, leading to mucous (goblet) cell metaplasia. As goblet cells are a major source of ACE2 in the lung, this could, in part, justify the increased levels of ACE2 found by Cai and colleagues in lungs of smokers. However, goblet cells are also the main source of mucous, which provides an essential first host barrier to inhaled pathogens that can prevent pathogen invasion and subsequent infection. Additional factors could play a role in the interaction between active smoking and SARS-CoV-2. First, naturally occurring structural changes in the ACE2 allelic variants can interfere with the intermolecular interactions of such variants with SARS-CoV-2 spike protein (4). It is conceivable that, upon cigarette smoke (or nicotine?) stimulation, some ACE2 allelic variants that inhibit the SARS-CoV-2 binding may undergo positive selection. Second, nicotine interacts with many components of the RAS (renin-angiotensin system) in multiple organ systems. In the ACE/AT-II (angiotensin II)/AT 1 R (angiotensin 1 receptor) arm, nicotine increases the expression and/or activity of renin, ACE, and AT 1 R, whereas, in the compensatory ACE2/angiotensin (1-7) arm, nicotine downregulates the expression and/or activity of ACE2 and AT 2 R (5). How these findings fit with the ones from Cai and colleagues is worth investigation. Interestingly, activation of nicotinic receptors can lead to enhanced protease activation that may cleave and activate the spike protein of SARS-CoV for membrane fusion (5) . This effect may counterbalance the increase in ACE2 levels observed in the lungs of smokers by Cai and colleagues. Third, ACE2 knockout mice exposed to cigarette smoke exhibit increased pulmonary inflammation with activation of metalloproteinases (6) that could, in part, contribute to the inactivation or modification of ACE2 in the lungs of the smokers. Last, though it is possible that cigarette smoke increases the ACE2 expression by the bronchial epithelium, thus facilitating the entry of SARS-CoV-2, this does not necessarily translate into a higher risk for developing COVID-19 pneumonia. To conclude, what is unchallengeable is that cigarette smoke is detrimental for the lungs in several ways, and further studies are needed to clarify the reasons behind the reported low prevalence of current smokers among hospitalized patients with COVID-19. The effect of current smoking on SARS-CoV-2 infection is a delicate and complex topic that should be addressed meticulously before delivering messages that could be misinterpreted. n Covid-19 -a reminder to reason COVID-19 pneumonia: different respiratory treatments for different phenotypes? Intensive Care Med Respiratory pathophysiology of mechanically ventilated patients with COVID-19: a cohort study COVID-19 Lombardy ICU Network. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome Association between use of statins and mortality among patients hospitalized with laboratory-confirmed influenza virus infections: a multistate study Influenza Clinical Information Network (FLU-CIN). Pre-admission statin use and in-hospital severity of 2009 pandemic influenza A(H1N1) disease Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Tobacco smoking increases the lung gene expression of ACE2, the receptor of SARS-CoV-2 SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Structural variations in human ACE2 may influence its binding with SARS-CoV-2 spike protein Nicotine and the renin-angiotensin system Alternative roles of STAT3 and MAPK signaling pathways in the MMPs activation and progression of lung injury induced by cigarette smoke exposure in ACE2 knockout mice The overall lower-thanexpected prevalence of smoking reported in retrospective and/or observational databases is most likely because of incomplete or incorrect information about smoking patterns. Indeed, some early reports did not include smoking demographics in patients with severe COVID-19 (2, 3), suggesting that smoking history may be