By Sally Robertson, B.Sc.

Researchers at the University of California San Diego have conducted a study showing that both smoking and the use of e-cigarettes containing nicotine and flavorings may critically exacerbate inflammation in cases of coronavirus disease 2019 (COVID-19) and significantly worsen clinical outcomes.

The use of e-cigs that do not contain nicotine or flavorings, on the other hand may not lead to any significant increase in COVID-19-related inflammation.

The study also showed that tobacco smoking increased the expression of the host cell receptor angiotensin-converting enzyme 2 (ACE2) – the structure that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses to gain viral entry.

By contrast, the use of e-cigs did not upregulate ACE2 expression, irrespective of whether they contained nicotine and flavorings.

“Our study has demonstrated that tobacco and flavored or nicotine-containing e-cig use could both lead to increased inflammatory response, but only tobacco upregulates ACE2,” write Weg Ongkeko (University of California) and colleagues.

The authors believe their study represents an important early step in assessing the implications of smoking and vaping during the COVID-19 pandemic.

Since inflammation or ACE2 upregulation can increase susceptibility to COVID-19, further studies are needed to address the worrying findings, they say.

A pre-print version of the paper is available on the server bioRxiv*, while the article undergoes peer review.

Studies have sparked concerns about smoking and vaping
A growing body evidence suggests that smoking is a risk factor for more severe clinical outcomes following infection with SARS-CoV-2.

However, reports have so far been based on epidemiological data, and only a few studies reported data, say Ongkeko and colleagues.

“The lack of well-controlled laboratory experiments renders it extremely difficult to determine whether tobacco truly affects COVID-19 outcome and the mechanistic link between them,” writes the team.

Concerns have also arisen that the use of e-cigs, which has become increasingly popular over recent years, maybe linked to COVID-19 outcomes.

Detrimental effects associated with e-cig use, including inflamed airways, damaged lung epithelium, and increased mucus production have been reported, say the authors, but data relating to COVID-19 risks and outcomes are scarce.

“Complicating research on e-cig’s effects on COVID-19 is the fact that e-cig can be vaped with or without nicotine and with or without flavorings,” writes the team. “Flavors and nicotine in e-cig are frequently associated with more inflammation, epithelial barrier dysregulation, oxidative stress, and DNA damage than e-cig with only basic components.”

Potential mechanisms that could increase susceptibility to COVID-19
One potential mechanism through which either smoking or vaping could increase COVID-19 susceptibility is the upregulation of ACE2 (the receptor used by SAR-CoV-2 for viral entry).

Some animal studies have shown cigarette smoke increases ACE2 expression, but no such study has yet reported on the relationship between e-cig use and ACE2 expression.

potential

Another potential mechanism is increased inflammation. More severe outcomes have been associated with the hyperinflammatory state that can occur in COVID-19 called the cytokine storm.

“Although cigarette smoke has been associated with increased susceptibility to COVID-19, the effect of tobacco on the immune response to SARS-CoV-2 has not been studied,” writes the team.

• What did the current study involve?
• Related Stories
• Coronavirus immunity is higher than previously thought, study finds
• Sleep apnea may increase the risk of severe COVID-19, say researchers
• The approved dose of ivermectin alone not useful in treating COVID-19

Ongkeko and team mined three independent gene expression datasets available for tobacco smokers and e-cig users and compared between-group differences in the activation of key molecular pathways involved in COVID-19 pathogenesis.

Given that e-cig flavorings and nicotine have been implicated in promoting lung damage, the researchers analyzed one cohort who only vaped e-cigs without nicotine or flavorings and one cohort who vaped e-cigs containing nicotine and any flavorings.

What did the study find?
The team found that tobacco smoking increased the expression of ACE2, while e-cig use had no such effect, irrespective of whether products contained nicotine and flavorings.

The researchers also found that both tobacco smoking and the use of nicotine/flavor-containing e-cigs led to significant upregulation of pro-inflammatory cytokine production and genes involved in inflammasome activation.

However, the use of e-cigs that did not contain nicotine or flavorings had no such effect on either cytokine production or inflammasome activation.

The researchers say inflammasome activation can result in the release of cytokines such as interleukin 1 beta (IL-1β) and lead to a cytokine storm, both of which are hallmarks of COVID-19 infection, particularly in severe infection.

Further studies are needed to investigate the worrying links
“Our findings demonstrated that smoking or vaping, specifically use of flavored or nicotine-containing e-cigs, may critically exacerbate COVID-19-related inflammation or increase susceptibility to the disease,” write the researchers.

Ongkeko and colleagues say that although further experiments and epidemiologic studies would be required to clarify the findings, they believe the study is a critical early step in evaluating the implications of smoking and e-cig use during the COVID-19 pandemic.

“Further scientific and public health investigations should be undertaken to address these concerning links between COVID-19 and e-cig/smoking,” they conclude.

*Important Notice
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Ongkeko W, et al. Tobacco, but not nicotine and flavor-less electronic cigarettes, induces ACE2 and immune dysregulation. bioRxiv 2020. doi:https://doi.org/10.1101/2020.07.13.198630