Cigarette smoke and COVID-19

Some evidence suggests that cigarette smokers are more likely to develop severe COVID-19 disease than non-smokers. Chronic smoke exposure appears to trigger the expansion of cell types in the respiratory tract that produce ACE2, the receptor for SARS-CoV-2. This observation provides a plausible hypothesis to explain why cigarette smokers might experience more severe COVID-19.

A number of independent observations show that cigarette smoke increases expression of the ACE2 gene:

• Mice exposed to cigarette smoke daily for 5 months had up to 80% more ACE2 expression in the lung compared with control mice
• Human lung epithelial cells from the bronchi of smokers had 30-55% more ACE2 expression than cells from non-smokers
• Lung samples from patients who smoked more than 80 pack-years had 100% more ACE2 expression than those who smoked less than 20 pack-years
• Quitting smoking was associated with a 40% decrease in ACE2 expression
• In murine and human lung, ACE2 is expressed at high levels in secretory and goblet cells and alveolar type 2 cells. Chronic smoke exposure leads to expansion of mucus-secreting goblet cells, and consequently higher levels of ACE2.

There are two caveats to this study. In the observations listed above, ACE2 expression was assessed by quantifying RNA, not protein. While the authors show a correlation between ACE2 RNA and protein in selected cell lines, the same correlation might not extend to tissues. In other words, increased ACE2 RNA might not lead to increased ACE2 protein.

An important question not considered by the authors is how increased levels of ACE2 would lead to more severe COVID-19. One explanation is that the effect is mediated by increased susceptibility of cells to infection: more ACE2, more virus produced. Whether this situation holds true is unknown, as experiments to address it have not been done. Another issue is that severe COVID-19 typically occurs after a few weeks of virus multiplication in the upper tract, and is accompanied by decreasing viral loads in the respiratory tract. Furthermore, how increased ACE2 might affect the immune imbalance that contributes to severe disease is not known.

These observations make it clear that cigarette smoke increases ACE2 expression; however they do not provide an explanation for how smoking might exacerbate COVID-19. Despite this uncertainty, there are many other good reasons not to smoke cigarettes.