A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications | Hacker News Reader

A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications

qeios.com

46 pointsAissen64 comments

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://www.scb.se/hitta-statistik/artiklar/2018/farre-roker...

If the hypothesis is correct (unknown) then nicotine delivered through snus might also have a protective effect.

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

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

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...

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 ; 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.

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

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.

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

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

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.

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.

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

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

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

You can check the French distribution of smokers by age group here (could only find data from 2010, there has to be an updated dataset somewhere): https://www.statista.com/statistics/785664/consumption-daily...

Feeling cynical today. Perhaps folks in Paris don't tell their doctor that they've been smoking?

If so, vaporizers can be used to prevent infection.

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...

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.

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

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

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

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.

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://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus...

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.

Isn't it pretty much established science, not confirmation bias, that smoking is indeed universally bad? I mean, even if a handful of good things may come from it, it's still overwhelmingly bad for overall health. To be clear, I'm talking about the act of inhaling a combusted substance, smoke, not vapor.

The fact that there's so much data on the dangers of smoking causes confirmation bias. However, science is never complete.

It's not inconceivable that, say, smoking causes some changes that are protective/hormetic in some cases. That doesn't imply it's a worthy tradeoff to be a lifelong smoker, of course.

The question is, what are the fact that we aren't trying to find, because it goes completely against our expectations?

The USS Roosevelt data would be an amazing sample set-- vape and snuff use is very prevalent among sailors.

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.

> 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.

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.

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

I've always thought of smoking as a tradeoff:

Pros:

* Bumming/offering a cigarette is a low-key entrance into social groups, which is a big deal for people with social anxiety like me.

* Productivity: nicotine is absolutely the most effective nootripic I've found, and doesn't seem to lose this effect with time like coffee.

Cons:

* Health: even just nicotine from the patch is associated with heart and vascular issues--other methods of administration have worse effects (snuff seems to be actually the worst, as mouth cancer sets in faster/earlier than lung/throat cancer does from smoking, with similar mortality rates).

* Cost.

* Addiction.

The tradeoff never seemed worth it to me so I've never smoked beyond a cigarette/cigar here and there, but I can totally see why people do it.

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.

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

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

Google Translate this - https://www.franceinter.fr/la-nicotine-une-arme-contre-le-co...

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

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

Thank you so much.

TL;DR

> "Nicotine may be suggested as a potential preventive agent against Covid-19 infection."

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

WINNING!

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-...

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.

>Nicotine has been shown to be a dangerous chemical all on its own

Excluding overdose I've never come across a study which showed nicotine (not tobacco) was inherently harmful.

>but that's also true of almost any drug taken without medical regulation or supervision

The vast majority of prescription and over the counter drugs are safe for the vast majority of the population, regardless of supervision.

But I agree with your comment regarding demographic surveys.

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.

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

> I'm not sure if you read the thread's link before responding but they're proposing using smoking as a treatment vector

I did read it, at no point did I see them proposing smoking as treatment. Rather, they're proposing nicotine patches.

> 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.

Even if it was administered by smoking, nicotine would be about as safe a drug as you can find at that dose. You'd be hard pressed to find a case where somebody died upon smoking their first cigarette. Aspirin, Paracetamol or Ibuprofin are way more dangerous than that.

It would be undue diligence not to investigate this potential treatment vector, even if it turns out to be some weird statistical artifact.

"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."

Edit: here's another paper.

"The current study examined for the first time the prevalence of current smoking among hospitalized patients with COVID-19 in China. An unusually low prevalence of current smoking among hospitalized COVID-19 cases in China was observed when considering the population smoking prevalence. The pooled prevalence observed in the 13 studies analyzed was approximately 1/4th the population prevalence. Consistently low prevalence of current smoking was observed in all studies."

https://www.qeios.com/read/article/561

Of course the paper involves speculation (though, as others have pointed out, it is not as unsupported as you suggest), but there's nothing unusual, let alone wrong, about that. If the possible usefulness of nicotine could not be discussed until it was proven to be both an effective and safe treatment, we would never find out if it were either.

Nor is there anything wrong in considering whether it could lead to a feasible treatment, as that is an important consideration in how vigorously to follow up.

Your ethical concerns seem to be overblown and premature. By itself, this paper will have no effect on policy.

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.

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.

How do you think I think science works?

>Notice how this mess of a paragraph starts with a passive voice claim.

Welcome to scientific writing. Please stop wasting your time and see yourself out.

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...

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

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

Classic Sleeper prediction:

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.medrxiv.org/content/10.1101/2020.04.13.20063669v...

https://www.qeios.com/read/article/561

https://www.qeios.com/read/article/574

https://www.qeios.com/read/article/581

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.

yeah but I would argue that today most people benefiting from these effects are smokers, so it stays true?

> 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

'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'.

It's totally 17th century elegant. Take a sniff, scrunch up your face, blow snot on the ground, load up your elephant gun and head to Africa for King and Country! All you need is a monocle.

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

https://en.wikipedia.org/wiki/Snus

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>

What's your favorite? Big fan of Fribourg & Treyer brands here. Taking a sniff of something Lord Byron enjoyed hundreds of years ago can be a heady experience (I forget ... old paris or prince's)

I do feel like I should be wearing a powdered wig when I indulge in the stuff. Blowing my nose brings me down to earth; it's pretty gross!

Yep, I've looked into the health effects of nicotine independent of smoking. It definitely raises blood pressure; we know exactly how this works; there's a long term mechanism (I think involving aldosterone)and the short term stimulant mechanism. There's also a small but significant increase in pancreatic cancer[1], one shared by most stimulants (I think including caffeine). Otherwise, it's not a terrible thing. The parkinsons thing might make nic gum worthwhile.[2]

If you look at long term effects of snusers and people who use nasal snuff; it's pretty difficult to find any measurable negative health outcomes.

FWIIW the nicotinic hypothesis may not prove to be correct with respect to C19; Sweden will be a great test case, as there are more snus users than smokers there.

[1] https://academic.oup.com/carcin/article/30/3/506/2476826

[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430096/ -for example; too many papers to list

Some additives in cigarettes have been shown to dilate lung airways, suppress coughing, and disguise symptoms of illness:

https://www.verywellmind.com/cigarette-additives-2824737

Perhaps the additives are keeping COVID-19 patients alive by supporting breathing in difficult circumstances? There are hundreds of additives so figuring out if any of them help would be difficult:

https://ec.europa.eu/health/scientific_committees/emerging/d...

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