Even as the COVID-19 pandemic continues to spread over the world, scientists have had to come to terms with the fact that they don’t know much about the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or the disease it causes. Now, a new study by researchers at the University College Cork, Ireland, and published on the preprint server medRxiv* in June 2020 discusses the differences in COVID-19 risk between men and women who smoke.
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Risk Factors for Severe COVID-19
The coronavirus pneumonic illness called COVID-19 has caused over 9.17 million cases, with over 474,000 deaths so far. This makes it the worst pandemic of this century so far. The illness is known to be more severe in specific subgroups, such as those who are elderly, those who have certain chronic respiratory illnesses, and those with coexisting medical conditions like type 2 diabetes, obesity, and cardiovascular disease.
Smoking-Related Severity?
The role of smoking is not clear, with conflicting studies showing increased or decreased risk for COVID-19 in people who smoke. Smokers were described as being at higher risk of mortality in the earlier MERS outbreak compared to non-smokers. More recently, a review of 5 Chinese research papers found a 1.4 times increased risk of severe COVID-19 symptoms, and 2.4 times higher chances of intensive care unit (ICU) admission, mechanical ventilation, or death, following COVID-19 infection in smokers vs. non-smokers.
A third meta-analysis shows that males have worse outcomes than females, including higher mortality. This sex difference is partly explained by estrogen acting as a protective factor in females. At the same time, smoking is considered a risk factor for a poor outcome but is more prevalent among men.
Global Smoking Prevalence
A higher prevalence of smoking among men is a worldwide phenomenon, at 30% to 32%. However, women in developed countries have a higher prevalence of smoking compared to those in developing countries, at 17% vs. 3%. The current study aimed at finding out if this disparity is responsible for the difference in severity of COVID-19 between men and women.
The Study: Smoking vs. Severe COVID-19
The researchers made use of all studies relating to both COVID-19 and to smoking prevalence in China, published from January 1, 2020, to April 27, 2020. The reason for using only Chinese studies is explained as the origin of the pandemic in China, and the “extensive amount of research completed on COVID-19 in comparison to any other countries worldwide.”
They found six full-text studies that met their criteria. They extracted data on the total number of cases, the number of cases in males vs. females, the severity of the cases by sex, and history of smoking. Severe cases were those who met the criteria for severe COVID-19, were on mechanical ventilation, or died of the illness.
Quality assessment was performed with the Newcastle-Ottawa Quality Assessment Form for Cohort Studies, using the domains selection, comparability, and outcome.
The researchers report a twofold increase in the odds of severe clinical features of COVID-19 in smokers compared to never-smokers but without differentiation by sex or smoking rates. There was a total of over 1,300 males and 1,000 females in the six studies, but 158 more males suffered severe symptoms. This comprises 25% of the smoking males, compared to only 19% of female smokers.
The study also noted that the male smoking prevalence was at 54% vs. 2.6% for females. This, say the researchers, supports their conclusion that “a higher proportion of men suffer from severe manifestations, as compared to females, due to the higher prevalence of smoking amongst men in China.”
Other Supporting Evidence
They bolster their findings with a similarly higher prevalence of smoking among males in countries like Italy, at 23%, vs. 15% in females. An Irish study also showed a 24% male prevalence of smoking vs. a 21% female prevalence.
In Italy, almost 60% of COVID-19 cases were males, but an Italian study showed that a history of smoking was associated with a 0.35 times lower incidence of severe COVID-19 vs. non-smokers. This indicates the need to look for other factors that could explain this association.
On the other hand, data retrieved from the Health Protection Surveillance Centre shows that males make up less than half (46%) of confirmed cases but make up 71% of deaths. This could be an important factor in shaping public health policy, such as pushing through an amendment to the Irish Smoking Ban.
The ban disallows smoking in enclosed public spaces and in the workplace, but not in open public spaces, and does not apply to vaping. If COVID-19 is indeed aggravated by smoking, the ban would need to be extended to limit smoking in all public spaces and perhaps vaping as well, to bring down the number of severe cases of COVID-19 in Ireland. In addition, this could help reach the target of smoking prevalence of below 5% in Ireland by 2025.
Smoking and ACE2 Expression
In earlier outbreaks caused by SARS coronaviruses, the mortality among men was much higher, at 22% vs. 13%. These strains, like the currently circulating SARS-CoV-2, bind to the target cell via the angiotensin-converting enzyme (ACE) 2. Smoking is known to increase the expression of this receptor molecule, and this could explain why smokers may be more vulnerable to severe manifestations. The use of vaping devices, or electronic cigarettes, has also been thought to increase ACE2 expression.
Both the upregulation of the receptor and the difference in smoking prevalence between the sexes could help explain the greater overall severity of COVID-19 in males.
The study was limited by the small number of papers, while the variety of methods used to collect smoking data also introduced possible bias and heterogeneity. Without direct linkages between smoking prevalence and case severity on a sex-stratified basis, the researchers relied on known sex differences in population-based smoking trends for their analysis.
Moreover, the smoking history related to the overall lifespan and not recent smoking history, thus making it difficult to determine a cause-effect relationship. More research will be needed to verify this relationship.
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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