Smoking, ACE-2, and COVID-19: Ongoing Controversies

Three recently published letters by Lutchman [1], McAlinden [2], and Farsalinos [3] together capture the divergence in opinion on the impact of smoking on COVID-19 and whether the angiotensin converting enzyme-2 (ACE-2) receptor mediates this relationship. At the heart of this controversy is whether smoking reduces or increases the risk of contracting COVID-19. Farsalinos et al. through analysis of the pooled prevalence of current smoking across 11 case series determined that current smoking status was significantly lower than expected gender and age-adjusted prevalence in COVID-19 patients [3]. That smoking could potentially be protective against COVID-19 has not gone unnoticed by the public. Since late April, multiple media outlets have reported on this possibility, prompting the World Health Organisation (WHO) to release a warning on May 4, 2020, on tobacco use during this pandemic [4]. While we do not dispute that the prevalence of smoking in COVID-19 cases has been surprisingly low across the world, we would echo the WHO's advice based on emerging evidence that outcomes in COVID-19 are worse in patients who do smoke. Mehra et al.'s analysis of 8910 COVID-19 patients across three continents, for instance, demonstrated that current smoking was an independent risk factor for in-hospital death, carrying an odds ratio of 1.79 (95% confidence interval 1.29–2.47) [5]. A recent meta-analysis has also shown that smokers have a relative risk of 1.45 (95% confidence interval 1.03–2.04) of having more severe disease [6]. While smoking may not necessarily increase one's risk for contracting COVID-19, the biologic and inflammatory cascade that occurs upon SARS-CoV-2 infection may be particularly devastating for a smoker.

McAlinden et al. raise the possibility that a similar effect could be occurring in patients who vape [2]. Certainly the risks of significant pulmonary injury with vaping are now well-described in the literature [7] and the multiple ways that vaping can cause cellular damage and impede the lung's response to infection are clearly delineated by the authors. The theoretical possibility that vaping could prime the lung for SARS-CoV-2 infection is still hypothetical, given that to date none of the epidemiologic studies have reported on vaping prevalence amongst their COVID-19 patients. Several demographic factors, however, make such estimates unlikely to be obtained with much precision. For instance, consider the landscape of e-cigarette use in China, the first epicenter of COVID-19. A 2018 survey of 10 233 individuals in five Chinese cities found that only 0.9% had used e-cigarettes within the past 30 days [8]. Only 0.2% of those 65 years and older reported e-cigarette use within the past 30 days compared to 1.5% of those in the 15–24 year age range. Similarly, in 2016, of 32 931 adults included in the United States National Health Interview Survey, 1.0% of those over 65 years reported current e-cigarette use compared to 4.6% of the 18–44 year age group [9]. Older age groups, the ones more likely to have severe COVID-19, present to a hospital, and therefore be captured by epidemiologists in their surveys, are therefore less likely to report current vaping. On the other hand, it may be difficult to ascertain the prevalence of vaping in younger age groups who are much more likely to vape, but also much more likely to have mild or asymptomatic COVID-19 infections that are not captured either for their failure to present to a health care provider or the constraints placed on available tests in resource-limited settings. Nonetheless, we would argue for hospitals to capture these data as best they can and hope that data for mild cases in younger outpatients begin to be reported from around the world. Similar to smoking, it is possible that vaping may still be associated with worse outcomes, if not necessarily being a risk factor for contracting infection in the first place.

Finally, as Lutchman notes, if the culprit player for worse outcomes in smokers in this pandemic is the heightened ACE-2 receptor in the airway epithelium, soluble ACE-2 might be a therapeutic option. Indeed, we would agree with the excitement for this approach as this was the subject of a recent study by Monteil et al. which showed that human recombinant soluble ACE-2 (hrsACE2) reduced SARS-CoV-2 viral loads in infected Vero-E6 cells by a factor of 1000–5000 [10]. hrsACE2 also inhibited SARS-CoV-2 infections of kidney and vascular organoids. hrsACE2 is now under Phase 2 investigation in Europe as a therapeutic agent for COVID-19 (ClinicalTrials.gov NCT04335136). Whether such a therapy will be helpful for the smokers and patients with chronic obstructive pulmonary disease who display higher levels of ACE-2 in their airways and may suffer worse outcomes from COVID-19 remains to be determined.