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The COVID Science Express: Smoking and Sex Differences

Giving nicotine to healthcare workers and thinking that testicles are the coronavirus’ playground? Just some of the more “out there” hypotheses that have come out of imperfect data.

A weekly explanation of the emerging science behind COVID-19 and its infectious agent, SARS-CoV-2.

The theory that smoking or nicotine protects people from catching the virus is based on questionable information

Where are all the smokers? It’s a question that many researchers are asking themselves after reports are coming out seemingly showing that fewer smokers than expected end up in the hospital because of COVID-19. If the virus infects everyone indiscriminately and, let’s say, 15% of the population smokes, shouldn’t 15% of COVID-19 cases be smokers? A review of studies coming out of China, the United States, Korea, France, and the United Kingdom concluded that “smoking rates in the included studies were generally lower than expected.” At a large Parisian hospital, the numbers being reported are quite mesmerizing: 4.4% of inpatients and 5.3% of outpatients with COVID-19 were daily smokers but in the French population that percentage rises to 25.4%. This association led the authors to quickly hypothesize a cause-and-effect phenomenon: maybe nicotine protects you from getting the virus. And because we act on every piece of evidence in the age of COVID, French researchers are planning to test nicotine patches on healthcare workers to see if they bestow protection against the coronavirus. Anticipating a chloroquine-like situation, France is now limiting the sale of nicotine patches in case desperate headline readers start stockpiling them.

Let’s take a step back and see if any of this holds up. First observation: the above reports are preprints. They have not been properly evaluated by other scientists and have not been formally published. They may contain errors that would be spotted by other scientists in the field. If we look at the Parisian study, some scientists have published comments that invite a skeptical outlook. The study was small: 343 inpatients and 139 outpatients, all from a single hospital. Generalizing based on patterns in the data is risky. Severe cases of the infection were excluded from this analysis, which can skew the data. Paris, as it turns out, has a smoking rate below that of France, so comparing Parisian patients to the French population with regards to smoking is misleading. The information on who smoked and who didn’t was based on self-reports: given that the socially desirable response is to say we don’t smoke, we can expect these numbers to be lower than they really are. Finally, a significant portion of the COVID-19 cases at this hospital were healthcare workers, a clue that is only mentioned once toward the end of the paper. It is possible that there are fewer smokers among Parisian healthcare workers than among the population at large. I was unable to find the right data to answer this question, though. The closest data set comes from a study published last year that reported that 25.4% of female healthcare workers in France report smoking (0.2% less than the general female population) and 27.8% of male healthcare workers do the same (2% less than the general male population). We will need better and larger studies to figure out what is going on here.

But what happens to smokers when they get the infection? Smoking is often associated with worse outcomes for COVID-19 and more deaths from it. And just because it bears repeating, smoking tobacco products like cigarettes is one of the worst things we can do to our health. The head of France’s national health agency recently warned that “smoking remains the number one killer in France”, while in Canada it causes one in five deaths. It shortens the lifespan of smokers, it is the most important risk factor for lung cancer (the leading cause of cancer deaths around the world for men and the second most common for women), and it is a major risk factor for a whole slew of diseases affecting the heart and the circulatory system. When exploring circumstantial and questionable evidence that smoking may protect us from catching the coronavirus, it is important to keep the big picture in mind.

As for vaping, there is at the moment no evidence of a connection between the use of e-cigarettes and getting COVID-19. Absence of evidence is not evidence of absence, and we will have to keep our eyes peeled for more information as it rolls in.

Men may be more at risk for complications and dying from COVID-19 and there are many potential reasons why

Men appear to be dying at a higher rate than women from COVID-19 (I am using the terms “men” and “women” as they are used in the data sets themselves). The rate disparity varies from country to country, with Canada reporting 1.3 men dying for every woman. This unequal effect on men led some researchers to hypothesize that testicles were to blame, but at this point it is a conjecture with little evidence behind it. The virus attaches itself to our cells via a receptor called ACE2, and previous studies have shown that testicles express a lot of it, but a team of Chinese scientists could not detect the virus in the sperm of 12 COVID-19 patients or in the testicular tissue of a recently diseased patient.

Before we explore why men may do worse, it bears mentioning that there are indirect effects of the pandemic that negatively impact women more than men. Pre- and post-natal care has been affected; domestic violence can worsen when couples are confined to their home; and given their prevalence in caregiving and healthcare professions, women may be closer to infectious people than men.

But why is this new coronavirus potentially nastier to men? It could be due to lifestyle factors like smoking and alcohol consumption, often seen more commonly in men, especially since these choices lead to health conditions like heart and lung problems that predispose to complications from COVID-19. And then there’s the hormone hypothesis.

When SARS, another severe respiratory infection caused by a coronavirus, hit in 2002-2003, we saw again that more men were severely affected by the disease. In 2017, scientists published a very interesting science experiment in which they showed that their male mice were more susceptible to the SARS virus when infected in the lab and many more of them died than female mice, imitating the situation with humans. When testosterone was blocked in these male mice, no difference was seen, but when estrogen was blocked in female mice, they became as susceptible to SARS as the male mice. In animals (and in humans as well), it has now been established that the male hormone testosterone suppresses part of the immune response, whereas the female hormone estrogen does the opposite in low enough concentrations. This idea that female hormones give women a sort of immunity boost is being tested at Cedars-Sinai and Stony Brook University in the context of COVID-19. Men will have the chance to receive an estrogen patch in one trial or a shot of progesterone (another female hormone) in the second trial. But before you plan on trying this at home, experts are warning people that hormone treatments require medical monitoring as there are contraindications. The risk of blood clots rises with the use of estrogen therapy, which could get compounded with COVID-19.

Finally, genetics may also help explain the sex gap. Men’s sex chromosomes are X and Y whereas women have two Xs. That second X is effectively silenced but some of its genes escape this inactivation, leading to a double dose of these genes compared to men. You will probably guess what some of these genes code for. That’s right. Proteins involved in the immune system. This can be a double-edged sword, however, as women are much more predisposed than men to having an autoimmune condition, a disease where the immune system fails to recognize part of you as you and attacks it.

I don’t want to oversimplify the picture, however. It’s not like women are spared viral infections. In fact, more women die of the flu than men, and viruses like herpes, HPV and HIV disproportionately affect women. But when it comes to COVID-19, the direct impact of the infection seems, at the moment, to be harder on men. It may be due to lifestyle factors, hormones or genetics, or quite possibly a combination of all of these factors. Or it might be an artefact of imperfect data. We will have to wait to find out.

Take-home message:
- Some studies are reporting that fewer smokers than expected end up in the hospital because of COVID-19
- The hypothesis that nicotine would protect people from catching the virus seems far-fetched but a team of French researchers want to test this by using nicotine patches on healthcare workers
- Men may be more at risk for complications and dying from COVID-19, and it may have to do with a combination of lifestyle factors, hormones and genetics


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