Welcome to The Plague Pit.

For issue number 39, I’m very grateful to Maria Solovyeva. Maria is a first-year medical undergraduate at Cambridge University. During the first wave of the pandemic, she was a sixth-former at St Swithun’s School, Winchester. There, she found time to write this fascinating article on COVID-19 and nicotine.

About two months ago I stumbled upon a whole thread of articles relating nicotine to the pandemic. Some headlines really struck me as vague, bold claims; others seemed to shine a glimmer of hope into the mechanism and potential treatment targets for the virus. I decided to dig a little deeper into the world of globalized research to discover the real source of such agitation in the media.

At time of writing, WHO still identifies tobacco smoking as a risk factor for Covid-19 [i]. It could lead to presenting with more severe cases of the illness due to its association with comorbidities, such as cardiovascular and respiratory conditions. Nonetheless, there have been numerous studies published to explore the positive effects of nicotine on disease susceptibility and progression. These hypotheses remain unproven, but here are the main concepts that have been outlined as potential targets:

ACE receptors

The main link between nicotine and the SARS-CoV-2 infection is the ACE-2 receptors that have been identified as likely host receptors for the coronavirus.

Some studies, published prior to the outbreak, highlight the fact that nicotine downregulates the ACE-2 expression [ii] whereas others suggest the contrary: ACE-2 is upregulated on the airway epithelium of smokers [iii]. No uniform conclusion has been reached yet, however the exploration of such an important receptor could uncover an important target for treatment for all coronaviruses.

Interestingly, as estrogens appear to have an upregulating effect on the ACE-2 receptors as well, there is a correlation with higher ACE2 levels and milder symptoms in younger adults and children compared to the older population.

Cytokine storms

Cytokine storms are a common complication of Covid-19 linked to high death rates and severe reactions to the virus. The phenomenon became widely known after the 2005 H5N1 influenza virus, also known as “bird flu”, when the high fatality rate raised questions about its effect on the immune system of the body.

 It is essentially a hyperinflammatory response that is necessary to guide macrophages to the infected site using cytokines (IL- 1b, IL-6 and tumor necrosis factor (TNF)). These provoke extreme physiological changes including long-lasting fever, blood pressure levels dropping, venous and arterial thrombosis, vascular permeability and organ failure as a result of an uncontrollable and irreversible change.

The cholinergic anti-inflammatory pathway is an important controlling mechanism in the body. It uses acetylcholine (parasympathetic nervous system’s principal neurotransmitter) to interact with the receptors on immune cells such as macrophages to suppress certain proinflammatory cytokines [iv].

The nervous system, through the vagus nerve, can significantly and rapidly inhibit the release of macrophage TNF and hence control the cytokine activity, however its stimulation through the use of electrical impulses is too invasive and risky to be considered.

The explanation for nicotine’s actions lies in its capacity to mimic acetylcholine. Nicotine, as part of a bigger group of compounds knows as α7-agonists, has proven to be effective in reducing macrophage cytokine production and inflammation in animal models of pancreatitis and peritonitis [v] and hence could be explored as a potential therapy for Covid-19.

Although there are other compounds that specifically target one or more of these cytokines and are used to treat inflammation, restoring and re-activating the cholinergic anti-inflammatory pathway with nicotine use may provide a more universal suppression of the cytokine storm compared to administering inhibitors of a single cytokine.

Interestingly, the cause of olfactory dysfunction, that has been pointed out before as a symptom of Covid-19, means impaired cholinergic transmission, suggesting this phenomenon as a potential target for further research and exploration.

Nicotine Withdrawal Therapy

Nicotine withdrawal therapy has been used previously to treat patients with nicotine withdrawal symptoms, so this virus is no different. During hospitalization it is essential to provide support for those who would struggle with abrupt nicotine cessation and hence nicotine patches continue to provide valuable support in management of this difficult condition.

However, it is important to distinguish between the effects of tobacco smoking and nicotine as a compound. Unfortunately, due to the contradictory research published and cited in the media it has been difficult to predict the extent of misinterpretation by people across the world. Meanwhile, the absurdity of headlines such “Smoking reduces the risk of coronavirus” is putting many lives at risk and France [vi] has had to place restrictions on the sale of nicotine replacement therapy to prevent self-medication and stockpiling.

For me, this phenomenon has highlighted the significance of news stories for the general public and the danger of bold claims in the media that are not supported by clear scientific evidence. I really hope that society will use the new globalized media platforms to stay safe and informed together, instead of fueling disarray amidst the pandemic panic through disinformation and fake news.

Maria Solovyeva

References

[i] https://www.who.int/news-room/detail/11-05-2020-who-statement-tobacco-use-and-covid-19

[ii] https://www.atsjournals.org/doi/abs/10.1513/AnnalsATS.201706-464MG

[iii] https://www.mdpi.com/2077-0383/9/3/841/htm?fbclid=IwAR2PZAnJ1L7ss1kdZ1jcszXywczWpA72W4xzz-HqRVLa5GSSwt_-J47ueBE

[iv] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3592351/

[v] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678737/

[vi] https://www.ft.com/content/1fe1dda2-bec5-426b-8cfc-a7c2e5a4b139