Smoking, ACE-2 and COVID-19: ongoing controversies

The three letters from D. Lutchman, K.D. McAlinden and co-workers, and K. Farsalinos and co-workers together capture the divergence in opinion on the impact of smoking on coronavirus disease 2019 (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. K. Farsalinos and co-workers, 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. 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 Organization (WHO) to release a warning on 4 May, 2020, on tobacco use during this pandemic [1]. While we do not dispute that the prevalence of smoking in COVID-19 cases has been surprisingly low across the world, we would echo WHO's advice, based on emerging evidence that outcomes in COVID-19 are worse in patients who do smoke. An analysis conducted by Killerby et al. [2], of 220 hospitalised and 311 nonhospitalised patients with COVID-19 patients across six acute care hospitals and associated outpatient clinics in metropolitan Atlanta, Georgia, for instance, demonstrated that smoking was an independent risk factor for COVID-19 hospitalisation, carrying an odds ratio of 2.3 (95% CI 1.2–4.5). A recent meta-analysis has also shown that smokers have a relative risk of 1.34 (95% CI 1.07–1.67) of having more severe disease or experiencing refractory or progressive disease [3]. While smoking may not necessarily increase one's risk for contracting COVID-19, the biological and inflammatory cascade that occurs upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may be particularly devastating for a smoker.

Short abstract

Smoking increases severity of COVID-19 https://bit.ly/2yWp3jb

From the authors:

The three letters from D. Lutchman, K.D. McAlinden and co-workers, and K. Farsalinos and co-workers together capture the divergence in opinion on the impact of smoking on coronavirus disease 2019 (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. K. Farsalinos and co-workers, 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. 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 Organization (WHO) to release a warning on 4 May, 2020, on tobacco use during this pandemic [1]. While we do not dispute that the prevalence of smoking in COVID-19 cases has been surprisingly low across the world, we would echo WHO's advice, based on emerging evidence that outcomes in COVID-19 are worse in patients who do smoke. An analysis conducted by Killerby et al. [2], of 220 hospitalised and 311 nonhospitalised patients with COVID-19 patients across six acute care hospitals and associated outpatient clinics in metropolitan Atlanta, Georgia, for instance, demonstrated that smoking was an independent risk factor for COVID-19 hospitalisation, carrying an odds ratio of 2.3 (95% CI 1.2–4.5). A recent meta-analysis has also shown that smokers have a relative risk of 1.34 (95% CI 1.07–1.67) of having more severe disease or experiencing refractory or progressive disease [3]. While smoking may not necessarily increase one's risk for contracting COVID-19, the biological and inflammatory cascade that occurs upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may be particularly devastating for a smoker.

K.D. McAlinden and co-workers raise the possibility that a similar effect could be occurring in patients who vape. Certainly, the risks of significant pulmonary injury with vaping are now well-described in the literature [4], 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 epidemiological 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 epicentre 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 [5]. 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 US 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 [6]. 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 healthcare 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 D. 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. [7], which showed that human recombinant soluble ACE-2 (hrsACE-2) reduced SARS-CoV-2 viral loads in infected Vero-E6 cells by a factor of 1000–5000. hrsACE-2 also inhibited SARS-CoV-2 infections of kidney and vascular organoids. hrsACE-2 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 COPD who display higher levels of ACE-2 in their airways and may suffer worse outcomes from COVID-19 remains to be determined.

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