Smokers, COPD Patients’ Increased Levels of ACE2 Receptors Make Them More Vulnerable to SARS-CoV-2 Infection

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Senior male smoking cigarette on black background

The results of research by University of British Columbia scientists suggest that giving up smoking could lessen the chance that an infection with SARS-CoV-2 coronavirus will lead to severe COVID-19 disease. Their studies found that the lung cells of people who are current cigarette smokers, and individuals with chronic obstructive pulmonary disease (COPD), have increased levels of the angiotensin converting enzyme II (ACE-2) receptor that the SARS-CoV-2 virus uses to gain entry into host cells and cause infection.

“We found that patients with COPD and people who are still smoking have higher levels of ACE-2 in their airways, which might put them at an increased risk of developing severe COVID-19 infections,” commented research lead Janice Leung, PhD, clinical assistant professor at the University of British Columbia and St. Paul’s Hospital, Vancouver, Canada. “We also found that former smokers had similar levels of ACE-2 to people who had never smoked. This suggests that there has never been a better time to quit smoking to protect yourself from COVID-19 … Patients with COPD should be counseled to strictly abide by social distancing and proper hand hygiene to prevent infection.”

The team’s findings are reported in the European Respiratory Journal, in a paper titled, “ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19.”

SARS-CoV-2 uses the ACE-2 receptor as a cellular entry receptor, the authors wrote. While the virus can infect people of any age, most of the severe cases, to date, have been in individuals over the age of 55 years and with significant comorbidities, such as COPD. “The data emerging from China suggested that patients with COPD were at higher risk of having worse outcomes from COVID-19,” Leung noted. However, the authors further pointed out, what we don’t yet know is why most deaths occur in patients with major underlying chronic diseases such as lung and cardiovascular diseases.

“We hypothesized that this could be because the levels of ACE-2 in their airways might be increased compared to people without COPD, which could possibly make it easier for the virus to infect the airway,” Leung suggested. To look into this possibility the researchers analyzed lower respiratory tract bronchial epithelial cells obtained from the lungs of 21 COPD patients and 21 individuals without COPD, to determine ACE-2 expression. They looked at their resulting data in the context of factors, such as whether the samples were from people who had either never smoked, were current smokers, or former smokers.

The results confirmed higher ACE-2 expression levels in the samples from the COPD patients, and also in the samples from people who were current smokers. “ACE-2 expression in the epithelial cells was significantly increased in COPD versus non-COPD subjects,” the team noted. “Interestingly, smoking status was also significantly related to ACE-2 gene expression levels in airways of these participants with current smokers having a significantly higher gene expression than never smokers.”

The researchers then validated their findings against two existing study groups, which together contain data on a further 249 people—some non-smokers, some current smokers, and some former smokers. Again, they found that levels of ACE-2 were higher in current smokers, but lower in non-smokers and former smokers. “To our knowledge, our study is the first to demonstrate increased ACE-2 expression in airways of current (but not former) smokers and those with COPD,” the investigators stated. They noted that their study did have some limitations, but pointed out that the results are consistent with observations from previous studies in small animals, which found that smoke exposure upregulated both the expression and activity of ACE-2 in the airways.

The team noted that their findings indicate that active cigarette smoking and COPD upregulate ACE-2 expression in the lower airways, which may in part explain the increased risk of severe COVID-19 in these patients. “While the upregulation of ACE-2 may be useful in protecting the host against acute lung injury, chronically, this may predispose individuals to increased risk of coronavirus infections, which uses this receptor to gain entrance into epithelial cells,” the authors wrote. “This may in part explain the increased risk of viral respiratory tract infection in active smokers and virus-related exacerbations in those with COPD.”

They concluded, “These findings highlight the importance of smoking cessation for these individuals and increased surveillance of these risk subgroups for prevention and rapid diagnosis of this potentially deadly disease.”

“This study gives some interesting insight into why some people may be at risk of more severe COVID-19 symptoms than others,” said Tobias Welte, PhD, an infections expert from the European Respiratory Society, and a coordinator for the national German COVID-19 task force. Welte was not involved in the reported study. He further commented, “What it does not tell us is whether it’s possible to manipulate ACE-2 levels to improve survival in patients infected with COVID-19 or whether this would make a difference in COPD patients who contract the infection.”

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