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

This is a reply to the comment by Ivan Berlin and Daniel Thomas on our recently published work [...].

A Systematic Review and Meta-Analysis of Hospitalised Current Smokers and COVID-19.

SARS-CoV-2 is a new coronavirus that has caused a worldwide pandemic. It produces severe acute respiratory disease (COVID-19), which is fatal in many cases, characterised by the cytokine release syndrome (CRS). According to the World Health Organization, those who smoke are likely to be more vulnerable to infection. Here, in order to clarify the epidemiologic relationship between smoking and COVID-19, we present a systematic literature review until 28th April 2020 and a meta-analysis. We included 18 recent COVID-19 clinical and epidemiological studies based on smoking patient status from 720 initial studies in China, the USA, and Italy. The percentage of hospitalised current smokers was 7.7% (95% CI: 6.9-8.4) in China, 2.3% (95% CI: 1.7-2.9) in the USA and 7.6% (95% CI: 4.2-11.0) in Italy. These percentages were compared to the smoking prevalence of each country and statistically significant differences were found in them all (p < 0.0001). By means of the meta-analysis, we offer epidemiological evidence showing that smokers were statistically less likely to be hospitalised (OR = 0.18, 95% CI: 0.14-0.23, p < 0.01). In conclusion, the analysis of data from 18 studies shows a much lower percentage of hospitalised current smokers than expected. As more studies become available, this trend should be checked to obtain conclusive results and to explore, where appropriate, the underlying mechanism of the severe progression and adverse outcomes of COVID-19.

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

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.