Cytokine Release Syndrome (CRS) and Nicotine in COVID-19 Patients: Trying to Calm the Storm

Abstract

SARS-CoV-2 is a new coronavirus that has caused a worldwide pandemic. It causes severe acute respiratory syndrome (COVID-19), which is fatal in many cases, and is characterized by a cytokine release syndrome (CRS). Great efforts are currently being made to block the signal transduction pathway of pro-inflammatory cytokines in order to control this "cytokine storm" and rescue severely affected patients. Consequently, possible treatments for cytokine-mediated hyperinflammation, preferably within approved safe therapies, are urgently being researched to reduce rising mortality. One approach to inhibit proinflammatory cytokine release is to activate the cholinergic anti-inflammatory pathway through nicotinic acetylcholine receptors (α7nAchR). Nicotine, an exogenous α7nAchR agonist, is clinically used in ulcerative colitis to counteract inflammation. We have found epidemiological evidence, based on recent clinical SARS-CoV-2 studies in China, that suggest that smokers are statistically less likely to be hospitalized. In conclusion, our hypothesis proposes that nicotine could constitute a novel potential CRS therapy in severe SARS-CoV-2 patients.

Derivation and Validation of Clinical Prediction Rules for COVID-19 Mortality in Ontario, Canada

“…The identification of nonsmoking as a predictor of mortality is likely to be controversial, and it is for this reason that we derived alternate rules that exclude nonsmoking. Apparent protective effects of smoking against COVID-19 acquisition [ 29 ] as well as under-representation of smokers among COVID-19 patients have been noted by others [ 30 ]. However, other investigators have suggested higher risk of progression of COVID-19 in smokers [ 30 , 31 ] and increased density of ACE-2 (a viral receptor) in the lungs of smokers [ 32 ], such that apparent protective effects might result from selection bias; individuals predisposed to very mild COVID-19 infection as a result of young age or good general health might be over-represented among those tested for COVID-19 due to smoking-related health concerns like cough.…”

Changes in Smoking Behaviour and Home-Smoking Rules during the Initial COVID-19 Lockdown Period in Israel

“…Several meta-analyses have suggested that former smokers are at increased risk for a severe disease [17,36,37], while other studies have shown that the proportion of smokers among infected patients was lower than expected [17,38]. This has raised the hypothesis that nicotine might play an immune-modulator protective role in the pathogenesis of the disease [39,40]. Claims based on this hypothesis were made on popular media outlets, which might impact smoking behavior [34,35].…”

Response to the Comment on “A Systematic Review and Meta-Analysis of Hospitalised Current Smokers and COVID-19”

“…It is likely that this association does not involve a causal relationship and, of course, as it is clearly indicated in the paper, smoking is not recommended as prevention or treatment of COVID-19. The association could be due to many factors that could include common smoking habits, increased likelihood of cross-immunity when smokers are infected by other coronavirus [ 3 ], anti-inflammatory effect of nicotine [ 4 , 5 , 6 ], increased hygienic habits, giving up smoking when became sick being considered non-smokers, the definition of “current smoker” is not always provided, etc. A detailed argumentation of all these potential issues is included in the discussion section of the paper.…”