Cigarette Smoking and COVID-19: A Complex Interaction

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 ever-smokers 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)/AT₁R (angiotensin₁ receptor) arm, nicotine increases the expression and/or activity of renin, ACE, and AT₁R, whereas, in the compensatory ACE2/angiotensin (1–7) arm, nicotine downregulates the expression and/or activity of ACE2 and AT₂R (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.