sciencedirect | Nicotine could act as a
competitive agonist for the nAChRs that could restore the compromised
function of the nicotinic cholinergic system. This may be feasible
through repurposing already approved (for other indications)
pharmaceutical nicotine products such as nicotine patches for use by
non-smokers, or even by using these products as already indicated (i.e.
as smoking substitutes) among current smokers. These products are
available over-the-counter in most countries. They have been
administered therapeutically in non-smokers for neurological conditions
and inflammatory bowel disease for larger periods than would be needed
for COVID-19 [[81], [82], [83]]. No abuse liability was observed in non-smokers despite being administerd for several weeks [82,83].
Besides gums and patches, nicotine can be administered though
inhalation, with the use of a nebulizer or other aerosol systems, if
necessary. Nicotine administration could be added on top of antiviral or
other therapeutic options for COVID-19. By restoring and re-activating
the cholinergic anti-inflammatory pathway, a more universal suppression
of the cytokine storm could probably be achieved compared to
administering inhibitors of a single cytokine. The potential need to
provide pharmaceutical nicotine products to smokers and users of other
nicotine products who experience abrupt withdrawal symptoms of nicotine
when hospitalized for COVID-19 or aim to follow medical advice to quit
smoking, should also be examined. Additionally, if the hypothesis about
the beneficial effects of nicotine is valid, smokers who quit nicotine
use when hospitalized will be deprived from these benefits. In France,
the Addiction Prevention Network (RESPADD) officially recommends the use
of nicotine replacement therapies for smokers when hospitalized for any
illness [84].
Clinical trials will dictate future approaches and the role of nicotine
in COVID-19, while further experimental studies should examine the
affinity of the virus to nAChRs.
Conclusions
In
conclusion, we noticed that most of the clinical characteristics of
severe COVID-19 could be explained by dysregulation of the cholinergic
anti-inflammatory system. The observation that patients eventually
develop cytokine storm which results in rapid clinical deterioration,
led to the development of a hypothesis about the series of events
associated with adverse outcomes in COVID-19 (Fig. 2).
Once someone is infected with SARS-CoV-2, the immune system is
mobilized. As the virus replicates, cell and viral debris or virions may
interact with the nAChRs blocking the action of the cholinergic
anti-inflammatory pathway. If the initial immune response is not enough
to combat the viral invasion at an early stage, the extensive and
prolonged replication of the virus will eventually block a large part
the cholinergic anti-inflammatory pathway seriously compromising its
ability to control and regulate the immune response. The uncontrolled
action of pro-inflammatory cytokines will result in the development of
cytokine storm, with acute lung injury leading to ARDS, coagulation
disturbances and multiorgan failure. Based on this hypothesis, COVID-19
appears to eventually become a disease of the nicotinic cholinergic
system. Nicotine could maintain or restore the function of the
cholinergic anti-inflammatory system and thus control the release and
activity of pro-inflammatory cytokines. This could prevent or suppress
the cytokine storm. This hypothesis needs to be examined in the
laboratory and the clinical setting.
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