Reply to Polverino: Cigarette Smoking and COVID-19: A Complex Interaction.

From the Authors:

We thank our reader, Dr. Polverino, for the interest in our work and intriguing opinions. The major opinion of Dr. Polverino is that patients with coronavirus disease (COVID-19) include fewer than expected numbers of smokers. However, Dr. Polverino cites a recent study showing a 1.8-fold higher risk for death among current smokers (1). The overall lower-than-expected 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 overlooked in these patients. Therefore, “the consolidated epidemiological data worldwide” claimed by Dr. Polverino is not “consolidated” but probably instead the result of not recording or reporting smoking history correctly, as we indicated above. In our opinion, “a low prevalence of active smokers among patients with COVID-19” has been translated too quickly in public news with potentially harmful consequences. An alarming number of non–peer-reviewed and shoddy ecological studies of smoking and coronavirus have appeared online, which can be harmful. In contrast, an increased risk for severe COVID-19 is very well documented to be associated with a history of smoking (1, 4–6), although making a special distinction between former, active, or never-smokers is important because chronic obstructive pulmonary disease (COPD) remains highly underdiagnosed (7).

Our reader also raised a concern regarding the role of goblet cells in COPD, stating that mucus “…provides an essential first host barrier to inhaled pathogens…,” implying that the increased mucus seen in COPD protects from airway infections, especially viral infections. However, no citations are provided, and we know of no evidence to support this concept. In contrast to this opinion, increased mucus production is a common mechanism leading to alterations of the lung microbiota of smokers with chronic bronchitis, pulmonary function of whom regularly and highly predictably deteriorates after acute disease exacerbations that are precipitated by intercurrent infections caused by viruses, bacteria, and fungi (5, 8–10).

The concept that ACE2 (angiotensin-converting enzyme 2) variants that inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binding may be upregulated (positively selected) because of cigarette smoking is an interesting one, but it is one that is not supported by any direct data and, furthermore, not supported by any genetic regulatory mechanism that we are aware of.

Nicotine has been shown to downregulate expression of ACE2, but the concept that “…activation of nicotinic receptors can lead to enhanced protease activation that may cleave and activate S (the spike protein) of SARS-CoV for membrane fusion” is not supported by any scientific studies to our knowledge, and in our animal model of chronic exposure to nicotine via electronic cigarettes, we did not detect any changes in ACE2 expression (data not shown). Furthermore, the statement that lung metalloproteinases upregulated in the ACE2-deficient mouse can feed back to inactivate or modify ACE2 in smokers is a non sequitur.

Dr. Polverino also acknowledges that our careful interrogation of data sets revealed increased mRNA expression of ACE2 in former and active smokers but provides an opinion that was not claimed in our letter (11). Though we showed significant associations that we believe will provide one useful piece of the puzzle rather than speculations about COVID-19–related pneumonia, we did not state that increased ACE2 expression translates into worse or higher risk for COVID-19 pneumonia. It is now becoming clear that the presence of ACE2 marks tissues vulnerable to infection (12). We have thus discussed that smoking may increase risk for viral binding and entry of SARS-CoV-2 in lungs of smokers. Obviously, the pathway from discovery to guiding medical decisions or making public recommendations is usually not based on a single study. As indicated in our manuscript, further mechanistic studies are needed to understand the upregulation of ACE2 in lung tissues by smoking.

Finally, we agree with Dr. Polverino that cigarette smoking is detrimental. Investigators need to gauge the right level of evidence before delivering messages and aim for messages that will do more good than harm, which is the baseline for research studies as well as scientific responses. In terms of communicating research results to the public, if someone overstates our study finding and translates this into a message that smoking increases your chance of SARS-CoV-2 infection, then this will be just one more good reason to stop smoking.