
A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications - Aissen
https://www.qeios.com/read/article/581
======
filleokus
The Swedish population might be an interesting demographic for studies about
this since we have the lowest rate of smoking in the EU [1], mostly due to our
high use of snus (tobacco under the lip).

Some quick glancing at the graphs: ≈ 10% smokes everyday and something like
20-30% uses snus every day.

Hence we have a large part of the population using strong nicotine products,
without smoking.

[1]: [https://ec.europa.eu/eurostat/statistics-
explained/index.php...](https://ec.europa.eu/eurostat/statistics-
explained/index.php/Tobacco_consumption_statistics)

[https://www.scb.se/hitta-statistik/artiklar/2018/farre-
roker...](https://www.scb.se/hitta-statistik/artiklar/2018/farre-roker-fler-
snusar/)

~~~
sktrdie
As an italian I can tell you there's LOTS of people smoking in italy... so
there's also that.

~~~
phkahler
That's actually good for testing this idea. If most of the people dying are
non-smokers that would be an indicator.

------
kens
The first sentence of the paper cites a reference for a claim, but the
reference doesn't support the claim at all. That's an immediate rejection of
the paper from me.

Specifically, the paper says "Symptomatic Covid-19 disease (as caused by SARS-
CoV-2 virus) is observed in 2.5 percent of infected individuals [2]". That's
an interesting claim, so I checked the reference.

Reference 2 explicitly says "All estimates are based on persons who developed
symptoms, and this work makes no inferences about asymptomatic infection with
SARS-CoV-2." In other words, the reference does not describe what percentage
of infected individuals show symptomatic disease. The 2.5% number apparently
comes from the reference's estimate that "fewer than 2.5% of infected persons
will display symptoms within 2.2 days of exposure." (Symptoms show up after a
median of 5.5 days.)

Thus, the paper claims 2.5% of infected individuals have symptomatic disease,
but the reference to support the claim says that 2.5% of infected individuals
with symptoms show symptoms _within 2.2 days_!

My conclusion is that the paper is misusing references, either carelessly or
maliciously. Reading a paper like that is a waste of time, since you can't
trust anything it says without checking every reference.

[2]: [https://annals.org/aim/fullarticle/2762808/incubation-
period...](https://annals.org/aim/fullarticle/2762808/incubation-period-
coronavirus-disease-2019-covid-19-from-publicly-reported)

~~~
Aissen
This is a preprint. This sentence could be modified and not change the core
claim of the paper. What's interesting is studying the data on which this is
based (some commenters yesterday said it made a few mistakes
[https://news.ycombinator.com/item?id=22935451](https://news.ycombinator.com/item?id=22935451)
; but without enough details to dismiss the paper entirely), and the other
papers (this is not the first) which have similar claims.

The doctors are rushing to share their core (incomplete) data to have others
study it. In normal times, this type of study would stay hidden for months
(I've heard up to two years for some niche domains) so that everything could
be checked, re-checked, and editors could fix the introduction mistakes. We
aren't in normal times.

------
juskrey
In countries where smoking is more prevalent, non-smokers are also more likely
those people who quit smoking because of other health problems.

~~~
fragsworth
Sometimes I think we can understand things. Then I read a (very astute)
comment like yours and I feel like we might as well give up trying to
understand anything at all. Everything is confounded.

~~~
abakker
This might not confound things if current consumption of Nicotine is the
protective element. people who quit previously are not currently consuming
nicotine.

------
fab1an
Anyone following the early data from China noticed this trend of PROFOUND
underrepresentation of smokers w COVID19.

Lots of theories why, but my latest (total ignoramus speculation) is that
smokers are more likely to have been exposed to the common endemic
coronaviruses, which seem to result in T-cells that are able to fight Sars2:
[https://www.youtube.com/watch?v=H07ukT8WkfY&feature=youtu.be](https://www.youtube.com/watch?v=H07ukT8WkfY&feature=youtu.be)

~~~
phkahler
I like that line of thinking. It leads me immediately to the question "do
smokers get more colds?". If the answer is yes, you may be on to something. If
the hypothesis in the paper is right the answer should be that they get fewer
colds.

For me this whole thing reminds me that nobody takes colds seriously. But now
it seems like there has actually been a lot of study on coronaviruses.

------
jkh1
This is prompted by the observation that in hospitals in Paris, the proportion
of smokers among COVID-19 patients is ~5 times lower than the proportion of
smokers in the population. The effect is big enough to merit some attention.
The challenge will be to disentangle a protective effect from the increased
vulnerability caused by smoking. The answer may be just a few nicotine patches
away.

~~~
cblades
Those hospitalized tend to be elderly. How many frequent smokers live to be
elderly?

~~~
jkh1
In the linked study[1] the effect is still there after controlling for age and
sex.

[1] [https://doi.org/10.32388/WPP19W.3](https://doi.org/10.32388/WPP19W.3)

------
htfu
For those nitpicking the preprint's (gasp!) lack of editing and clarity here's
an article with some further (rather convincing) background and stats. "French
researchers to test nicotine patches on coronavirus patients"[1]

> The results confirm a Chinese study published at the end of March in the New
> England Journal of Medicine that suggested only 12.6% of 1,000 people
> infected with the virus were smokers while the number of smokers in China is
> around 28%.

In France, figures from Paris hospitals showed that of 11,000 patients
admitted to hospital with Covid-19, 8.5% were smokers. The total number of
smokers in France is estimated at around 25.4%.

[1] [https://www.theguardian.com/world/2020/apr/22/french-
study-s...](https://www.theguardian.com/world/2020/apr/22/french-study-
suggests-smokers-at-lower-risk-of-getting-coronavirus)

~~~
sktrdie
This might simply be because the ones that require hospitalisation are usually
older. So the % of smokers must be taken within the older population, not the
entire population.

------
bjowen
Not an immunologist, but one claim that contradicts other published work
stands out to me — fn 7 and the assertion that ACE2 isn’t expressed in lung
tissue.

ACE2 has been shown as the target site for SARS-CoV [1] and expressed in
particular lung epithelial cells [2] and an important factor in infections
with the first SARS-CoV [3].

I wonder whether this nicotinic hypothesis is more important for understanding
the transmission and infection modes of the virus, rather than its involvement
in acute disease.

[1]
[https://science.sciencemag.org/content/367/6485/1444](https://science.sciencemag.org/content/367/6485/1444)

[2]
[https://www.biorxiv.org/content/10.1101/2020.01.26.919985v2](https://www.biorxiv.org/content/10.1101/2020.01.26.919985v2)

[3]
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1287568/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1287568/)

------
hcknwscommenter
Is it just me or is this entire article a bunch of junk? Right off the bat,
they give 2.5% as the symptomatic rate of those infected. As in, 87.5% are
asymptomatic? That seems completely bogus. Moreover, I don't see how they get
to the conclusion that hypothetical CNS involvement is "in contrast to" the
currently accepted view that ACE2 is the primary receptor. The significantly
weaker repesentation of smokers in the COVID patient population is intriguing,
but why are outpatients even more weakly smoker-proportioned as compared to in
patients? Also, doesn't this fly in the face of the Chinese data where smoking
is believed to be a major comorbidity? Their homology argument seems
particularly weak, since I see 6 non-conservative mutations in a 12 amino acid
stretch. Finally, I should note that this article is not peer reviewed at this
point in time.

------
fxj
We know (from RKI) that 86% of the fatalities in german ICUs were people with
an age of larger than 70. Compare that to the distribution of smokers vs age
in germany. 80% of the smokers are younger than 70.

[https://upload.wikimedia.org/wikipedia/commons/1/16/Percenta...](https://upload.wikimedia.org/wikipedia/commons/1/16/Percentage_of_smokers_by_age_and_gender_%28Germany%29.png)

[https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus...](https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Situationsberichte/2020-04-21-de.pdf?__blob=publicationFile)

------
gridlockd
We really need some data about vapers, some of them get way more nicotine than
smokers, directly into their lungs, but with less irritation.

The real protective factor may actually be the constant irritation provided by
the smoke, not the nicotine itself. What about Marijuana smokers?

Then we need to differentiate between long-time smokers with damaged lungs and
short-time smokers with more or less intact lungs.

In any case, we need to get over our confirmation bias that smoking is
universally bad.

~~~
stuntkite
My girlfriend and I vape and caught the bug in March. I had no idea the phat
cloudz were what saved us. Honestly, neither of us much felt like vaping when
the fever was bad. But I had to read this paper twice to make sure it wasn't
saying the opposite. This is interesting because the news and politicians have
been reporting that smokers and vapers are at risk. I never say any
information to back that up, especially vaping. I think I saw one study
recently where they concluded that vaping had basically no effect on outcome.
I should take a look at that study again if I can find it.

~~~
kerkeslager
> My girlfriend and I vape and caught the bug in March. I had no idea the phat
> cloudz were what saved us.

That is not a conclusion I would draw from this study, or any study I've come
across.

I do agree, however, that the conclusion that vaping is a risk factor is also
not backed up by any literature I've seen.

~~~
stuntkite
I was being glib about the vaping. Getting sick was awful and honestly I
didn't even think about my nicotine addiction for the 14 days we were ill. I
definitely didn't draw any conclusions about vaping being good for me. If this
hypothesis does turn out to be correct... I just don't even know. God has a
sense of humor or something.

~~~
gridlockd
Out of curiosity, did you have any risk factors such as (pre)diabetes/obesity?

~~~
stuntkite
No

------
JoeAltmaier
Can't see my way through all that.

But, just a thought, could a Nicotine patch be of any benefit? Would
introducing through that path provide any protection? If Nicotine provides any
protection at all, of course.

~~~
tsukurimashou
Clinical studies should answer that pretty quickly but yeah that's the idea,
to have medical staff put nicotine patches if Nicotine prevents Covid-19

------
sramsay
Forgive me, I am having trouble understanding what is being argued in this
paper. Could someone do a quick ELI5?

~~~
aaron695
Google Translate this - [https://www.franceinter.fr/la-nicotine-une-arme-
contre-le-co...](https://www.franceinter.fr/la-nicotine-une-arme-contre-le-
covid)

Proposed study - Hospital workers wear nicotine patches to protect themselves
from Covid-19.

~~~
sramsay
Just what I needed! (I read French, but not science ;)

Thank you so much.

------
el_don_almighty
Vaping at home during work hours has improved my performance and now it's
protecting me from the virus?!?!?

WINNING!

------
Someone1234
If that were true you'd be able to show it convincingly with COVID-19
demographic surveys. The fact this argues for an experimental treatment that
could be hazardous (even fatal) without first having reviewed available
demographic data or arguing for a study to obtain it makes me question the
ethics of what they're proposing.

For example other studies have looked at this question and found nicotine to
be a risk factor:

[https://www.cidrap.umn.edu/news-
perspective/2020/04/studies-...](https://www.cidrap.umn.edu/news-
perspective/2020/04/studies-smoking-age-other-factors-raise-risk-
covid-19-death)

~~~
dahfizz
The article you link shows _smoking_ to be a risk factor. That's why you can't
do this with demographic surveys: Smoking != tobacco != nicotine.

Nicotine has been shown to be a dangerous chemical all on its own, but that's
also true of almost any drug taken without medical regulation or supervision.
Whether this is safe to do or not should be left to the professionals.

~~~
Someone1234
From the thread's link:

> propose nicotine and nicotinic orthosteric and/or allosteric agents as a
> possible therapy for SARS-CoV-2 infection.

So nicotine's safety is absolutely relevant to the topic at hand.

> Whether this is safe to do or not should be left to the professionals.

Professionals have to consider the ethics and available data when proposing a
study. Considering this paper doesn't reference the available data (nor
propose gathering) it is reasonable to question that. There's a long history
of immoral science occurring during periods of national and international
strife, so I believe oversight, harm reduction, and due diligence remain
important considerations.

~~~
contravariant
Maybe I'm blinded by medical jargon, but where in that sentence are they
proposing administering nicotine through smoking tobacco?

------
aazaa
This paper has a deeply obfuscatory tone I tend to associate with liars.
Slogging through the words, here's the money shot:

> A potential protective effect of smoking and of nicotine on SARS-CoV-2
> infection has been noted. Until recently [39], no firm conclusions could be
> drawn from studies evaluating the rates of current smokers in Covid-19. All
> these studies [40-48], although reporting low rates of current smokers,
> ranging from 1.4% to 12.5%, did not take into account the main potential
> confounders of smoking including age and sex. In the study that two of us
> are reporting [1], the rates of current smoking remain below 5 % even when
> main confounders for tobacco consumption, i.e. age and sex, in- or
> outpatient status, were considered. Compared to the French general
> population, the Covid-19 population exhibited a significantly weaker current
> daily smoker rate by 80.3 % for outpatients and by 75.4 % for inpatients.
> Thus, current smoking status appears to be a protective factor against the
> infection by SARS-CoV-2. Although the chemistry of tobacco smoke is complex,
> these data are consistent with the hypothesis that its protective role takes
> place through direct action on various types of nAChRs expressed in neurons,
> immune cells (including macrophages), cardiac tissue, lungs, and blood
> vessels.

Notice how this mess of a paragraph starts with a passive voice claim.
Reference 39 is a meta-analysis that concludes that "active smoking does not
apparently seem to be signicantly [sic] associated with enhanced risk of
progressing towards severe disease in COVID-19." That's not a "firm"
conclusion.

At this point, I'm going to stop wasting my time. Do a controlled study or get
out.

~~~
m0llusk
With all respect, that isn't how science works. This article is about forming
a hypothesis based on limited available information. Such a hypothesis might
potentially be useful for designing studies for further investigation or the
hypothesis itself might be found to be fundamentally incorrect or
contradictory. This step of reviewing evidence for potential hypotheses is
essential in order to proceed to meaningful studies later. In this particular
case it should be obvious that the core ideas will be extremely controversial
as they point in the opposite direction of early advice that people should
stop smoking in order to avoid infection and disease progression.

~~~
aazaa
How do you think I think science works?

------
twomoretime
So I'm posting on mobile and can't find the link, but there was a literature
review posted on reddit a month or two ago. It was a collection of some 1-2
dozen papers regarding smoking and risk of infection for COVID19 as well as
SARS and MERS.

What was clear from multiple papers was that smokers were significantly less
likely than the general population to test positive for these viruses, though
their infections may be more severe. There is published evidence that nicotine
may downregulate ACE2 receptors - which means fewer binding sites for
potential infection.

I have a related pet theory that vaping may be doubly protective, considering
that some 60 years ago, propylene glycol was used as a surface disinfectant.
Since vape juice is some 30-70% PG, and because the virus infects lung cells
at the interface between air and blood, I'd bet good money that PG may have an
effect in reducing viral load, at least prophylactically. That's in addition
to the ACE downregulation, though we don't really know how long and how much
vaping one needs to do to see any benefit, if there is one...

~~~
gdubs
Interesting theory that reminds me of the Japanese researcher’s paper posted
around early April which proposed that shallow breaths of alcohol vapor (by
dissolving boiling water into whiskey or sake) could “disinfect” the lungs,
and provide relief from COVID-19.

[https://news.ycombinator.com/item?id=22742835](https://news.ycombinator.com/item?id=22742835)

[disclaimer: sharing for discussion/informational/entertainment purposes only]

------
scottlocklin
Classic Sleeper prediction:

[https://www.youtube.com/watch?v=kFxksNcLfcA](https://www.youtube.com/watch?v=kFxksNcLfcA)

I have a friend who studies the history of plagues; was telling me last summer
that smokers were viewed as more immune to historical plagues. I never asked
him for detailed evidence, as it was one of those conversations you have on
the balcony over a smoke. I enjoy entertaining wacky ideas, and figured
smokers might be fumigating the fleas, or in the case of pneumonic plague,
filtering the air. Never thought of the nicotinic hypothesis. Never really
took it real seriously; taking it seriously now. The evidence is pretty
overwhelming. A lot of people are going to lose their freaking minds over
this, as anti-smoker posturing has become a sort of substitute morality among
the upper middle classes (really it's just social class shitting on poor
people).

Of course, nicotine is known to statistically significantly reduce the risk of
Parkinson's disease, so it wouldn't be the first example of something like
this.

[https://www.reddit.com/r/COVID19/comments/faluhv/an_exhausti...](https://www.reddit.com/r/COVID19/comments/faluhv/an_exhaustive_lit_search_shows_that_only_585_sars/)

[https://www.medrxiv.org/content/10.1101/2020.04.13.20063669v...](https://www.medrxiv.org/content/10.1101/2020.04.13.20063669v1)

[https://www.qeios.com/read/article/561](https://www.qeios.com/read/article/561)

[https://www.qeios.com/read/article/574](https://www.qeios.com/read/article/574)

[https://www.qeios.com/read/article/581](https://www.qeios.com/read/article/581)

~~~
api
Nearly all the ill health effects of smoking come from other stuff in the
smoke, not nicotine. It's easy to get nicotine via gum, pill, patch, or
vaping.

~~~
jesuschroist
> It's easy to get nicotine via gum, pill, patch, or vaping.

.. or snuff! Which I think is one of the most elegant ways of delivering
nicotine to your body

~~~
detritus
'Elegant'? Have you ... ever tried it?

My experience of it decades ago was anything other than 'elegant', unless
having one's face scrunch up like a bulldog pissing on a nettle before
exploding into a sneezing fit can be considered 'elegant'.

~~~
lokedhs
The OP may be referring to Snus, which is often referred to as Snuff.

[https://en.wikipedia.org/wiki/Snus](https://en.wikipedia.org/wiki/Snus)

~~~
detritus
I had that stuff too, around the same time* - and re-visited it on a trip to
Sweden last year.. and, I'd still not consider it particularly 'elegant' :)

* we had a deal with our English teacher - my Swedish friend would supply him with little snus bundles, and we'd all get to sit in class using it ourselves. As a 17 year old, I thought it was the coolest thing, 'getting away with smoking in class with the teacher', even if i thought the actual process was utterly, utterly disgusting :)

</reddit>

