Systematic review of the prevalence of current smoking among hospitalized COVID-19 patients in China: could nicotine be a therapeutic option?: Comment.

This is a comment on the low prevalence of smokers in hospitalized COVID-19 patients, citing the possible role of squamous cell metaplasia, which is commonly associated with smokers.

Dear Editor,

Konstantinos Farsalinos, Anastasia Barbouni, and Raymond Niaura have observed a consistent low prevalence of smoking among SARS-CoV-2-infected patients in China and the USA, almost 1/4th of the observed prevalence. The authors have credited this beneficial effect of smoking to nicotine, via its immunomodulatory effects and complex interactions with the renin–angiotensin system [1].

However, the effect or interactions of squamous cell metaplasia (SQM) as a possible deterrent to SARS-CoV-2 infection appears to be overlooked. Previous studies have noted that SQM is almost always present in smokers [2-4]. Alteration of the cell type, as seen in metaplasias, is known to alter its cell surface characteristics; in this case the squamous metaplasia might not allow the binding of SARS-CoV-2 virus as seen in normal pseudostratified epithelium, which might be one of the reasons of low prevalence of COVID-19 infection in smokers. Further, many studies have detailed about pathologic changes observed in SQM, such as

Replacement of single layer thick polarized, pseudostratified epithelium with multi-layered non-polarized, squamous epithelium [2].

Significant reduction of ciliated cells and proliferation of mucous cells [2, 4].

Acquisition of granular cell layer-like properties, as noted by expression of larger and a greater number of desmosomes [4], presence of keratohyalin-like granules [3], and expression of involucrin, especially in the superficial layers of SQM area [4].

Based on these findings, it can be construed that SARS-CoV-2 is unable to infect SQM areas—due to presence of cross-linked envelope (effect of keratohyalin-like granules [3], involucrin), which bars the entry of virus and related degeneration of nucleus [3], preventing the viral replication. Furthermore, as the superficial cells in SQM lose contact with basal lamina [4], it might reduce the cytokine-induced reactions, probably needing less hospitalization in smokers, as observed by the authors. In addition, due to its similar genetic makeup, this association should also be seen in SARS-CoV (2003) infection; however because of lesser number of reported cases and fewer studies elaborating on smoking statistics, it seems difficult to correlate. However, recently, Wrapp et al. [5] have shown that SARS-CoV-2 has 10- to 20-fold more affinity for angiotensin converting enzyme 2 (ACE2) receptors than SARS-CoV (2003). This fact indirectly proves the lesser incidence of SARS-CoV 2 infection in smokers, which could be attributed to squamous cell metaplasia, as cell surface characteristics are known to alter in it, probably including the ACE 2 receptors as well. It could also explain differences, if any, between the prevalence of SARS CoV 2003 infection and SARS CoV-2 Infection in smokers. Considering these above-mentioned facts, the probable link between squamous cell metaplasia in smokers and prevalence of SARS-CoV-2 infection should be assessed scientifically.