A new meta-analysis of studies on smoking and COVID-19 progression was released today as a preprint.* A meta-analysis is a study that pools together the data from many studies to look at the big picture.
One thing is quite straightforward: once diagnosed with COVID-19, smokers are more than twice as likely to develop a severe and life-threatening case. This doubling may, if anything, be an underestimate.
Please note that I have a PhD in Nutritional Sciences. I am not a medical doctor and none of this is medical advice.
The meta-analysis identified 12 relevant studies. Five of them looked at current smokers, three grouped current and former smokers together, and four asked about a “history of smoking,” which essentially is the same as grouping together current and former smokers. That we cannot distinguish between current and former smokers is an unfortunate limitation of this paper.
Two of the studies defined disease progression as the severity of shortness of breath and poor oxygenation of the blood; three defined it as getting worse over the study period rather than better; two defined it as moving to the intensive care unit (ICU); one defined it as ICU, ventilation, or death; two defined it as death; one defined it as deterioration during hospitalization and requiring supplemental oxygen; and one grouped severe cases and death together without defining “severe.”
Altogether, the analysis included 9,025 people with COVID-19, 878 (9.7%) of whom experienced one of the types of disease progression listed above, 88 (5.5%) of whom were current or former smokers.
A whopping 17.8% of the current and former smokers experienced disease progression, while only 9.3% of the never smokers did. Current and former smokers had 2.25 times the risk of progressing to a severe case or death.
The Probable Connection to ACE2
These results may be easily explained by the fact that smoking increases ACE2 expression in the lung. ACE2 is the protein that the virus binds to in order to enter the cell, and it is an absolute requirement for infection.
As I wrote about on April 2, the main cells that carry ACE2 on their surface within the lung are goblet cells, which are cells that make mucous; and ciliated cells, which have hairlike structures that move mucous and debris. Smoking increases the proportion of goblet cells in the lining of the lung from 17% to 47%. Thus, smoking almost triples the ACE2 on the surface of the lung.
While we cannot and should not rule out the role of general damage to the lung done by smoking, its ability to triple the ACE2 needed by this specific virus to enter the lung cells is likely a huge part of why smokers are more than twice as likely to develop a severe case or die.
With that said, there is a paradox. The prevalence of smokers included in the studies was far lower than the prevalence of smokers in the general population.
In Korea, the difference was small: 18.5% in the study, 21.1% in the population.
In China, the difference ranged from big to huge: 3.8% to 14.6% across ten studies; 27.7% in the population.
In US, the difference was huge: 3.6% in the study; 13.7% in the population.
They suggested that many smokers were misclassified as smokers, which would obscure the association of smoking with severe disease progression and make their 2.25-fold increased risk an underestimate.
While I do think it's possible that smokers were misclassified, and quite possible some smokers would lie about their smoking behavior, I think there are a few other explanations:
- Smokers are less likely to seek medical treatment.
- Smokers are less likely to participate in research.
- Smoking protects against infection, even though it makes an established infection worse.
Let's take this last hypothesis.
We know that coronaviruses are extremely vulnerable to oxidative stress (the wear and tear on tissues that occurs in response to normal metabolism, inflammation, heavy metals, and toxins). In fact, one hypothesis to explain why bats harbor thousands of coronaviruses and rarely if ever get sick from them is that bats, because of their high metabolism, generate a lot of oxidative stress. This is also why copper is toxic to coronaviruses, as I explained here. This is also why hydrogen peroxide kills coronaviruses.
Every puff of cigarette smoke contains massive numbers of chemicals that cause oxidative stress.
It is conceivable that the oxidants within cigarette smoke are directly toxic to SARS-CoV-2, the coronavirus that causes COVID-19.
Meanwhile, they are also toxic to the lungs, and the lungs react by making more goblet cells, which make more mucous and more ACE2.
Perhaps in between cigarettes, the greater ACE2 would give the virus more portals to entry, worsening the risk of infection; meanwhile, while a cigarette is being smoked, the smoke is killing the virus, at least when it is traveling from cell to cell, and perhaps also while it is inside a cell trying to replicate.
Smoking would then offer a tug-of-war between two conflicting effects. It would be a game of Russian roulette. It may prevent infection in some people, but if an infection is established, the virus has a much better ability to infect each new cell it takes on, replicating in large numbers. The greater viral load ultimately leads to a more severe case and possibly death.
What Does This Mean for ACE2?
If this interpretation is correct (and we are quite far from having the data to settle whether it is correct at this point), it underscores that high ACE2 expression may be a liability even for the progression from a mild disease to a severe disease.
This itself is a paradox, because it is widely believed that one of the ways the virus damages the lungs is to cause the cells to compensate for the infection by making less ACE2. ACE2 is needed to prevent the laying down of scar tissue in the lung and has other protective effects, so loss of ACE2 causes lung damage in severe cases.
Despite this, it is still the presence of ACE2 that enables viral infection, and greater ACE2 allows a greater degree of infection. Ultimately the infection itself is what drives the loss of ACE2 function and all the other means of damage.
ACE2 function is absolutely necessary in every case for the virus to infect the cell. However, loss of ACE2 is not the only way the virus can damage the lungs.
The initial stages of viral growth are exponential. That means a linear increase of ACE2 allows an exponential increase in viral replication. But a linear decrease of ACE2 only leads to a linear loss its protective physiological functions.
It is quite possible that the mathematics favor more ACE2 being a bad thing even for disease progression, despite the fact that loss of ACE2 function plays a role in disease progression. This is because a linear gain of ACE2 from something like smoking (or maybe vitamins A and D, as I outlined in The Food and Supplement Guide for the Coronavirus) leads to exponential growth of the very thing that causes loss of ACE2 function in later stages and the very thing that causes all the other mechanisms of lung damage: the virus.
This is supported by data from mice infected with the first SARS virus. Mice can only be infected if they are genetically engineered to have the human version of ACE2. When the mice were given doses of SARS-CoV that killed all of the ones expressing human ACE2 within seven days, the ones that had more copies of the human gene died faster. Among mice with four copies, half were dead by day 5, three quarters were dead by day 6, and the rest were dead by day 7. Among mice with 8 or 10 copies, all the mice were dead by day 5.
ACE2 didn't just get them infected; it killed them faster.
The Bottom Line
The exact role of ACE2 will remain controversial for quite some time, as will the explanation for lower rates of smokers among the COVID-19 patients included in these studies than in the general population, but the association between smoking and disease progression is clear: once the disease is established, smokers have at least double the risk of progressing to a severe case or death.
I suspect this association would be even stronger if we looked at current smokers, so most likely it is much more than a doubling.
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I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and my expertise is in conducting and interpreting research related to my field. Please consult your physician before doing anything for prevention or treatment of COVID-19, and please seek the help of a physician immediately if you believe you may have COVID-19.
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* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.