Update on the relationship between smoking and COVID-19| Tabaccologia

In mid-2021, after more than a year of pandemic, there were still great uncertainties about the role of tobacco smoking or nicotine on COVID-19 incidence, severity and mortality [1]. A large number of case series showed a low prevalence of smokers among patients with COVID-19. However, all these studies had an inadequate design to support any causal conclusion. On the contrary, the number of well-conducted longitudinal studies (i.e., cohort studies) on the issue was limited. This did not allow us to provide robust evidence on the relationship between tobacco smoking and COVID-19. Furthermore, little was known about the role of electronic cigarettes (e-cigarette) and heated tobacco products (HTP). During the last 12 months, the number of published studies on smoking and COVID-19 has more than doubled. The present article aims to provide an update of the scientific literature on the issue.

Smoking and SARS-CoV-2 infection

The most up-to-date systematic review of the literature on smoking and SARS-CoV-2 infection remains the living review by Simons and colleagues, updated to August 2021 [2]. This systematic review found a huge number of case series (over 170) showing relatively low smoking prevalence in COVID-19 patient samples, thus suggesting that nicotine may reduce the risk of incidence. As already mentioned, the case series have important limitations. In particular, they do not have a control group and therefore cannot be used to obtain causal conclusions. Furthermore, most of the studies suffered from major biases. Notably, many of these studies were based on selected populations with a low proportion of smokers (e.g., the elderly, health care workers), and others were not designed to test for smoking. In some studies, information on smoking was obtained from medical records (often with only partial information on smoking). Finally, seriously ill (or dead) patients were frequently excluded from studies.

Despite all these limitations, the results of these studies have been heavily emphasized by the lay press. For example, we recall a full-page headline in the Libero newspaper: “Those who smoke do not take Covid” [3]. Even in the scientific literature, some articles speculated that nicotine could protect against SARS-CoV-2 infection. It was later discovered that many of these articles were written by people possibly linked with the tobacco industry [4-7].

To evaluate the relationship between smoking and the incidence of COVID-19, we should rely on longitudinal studies based on the general population. The review by Simons e coll. [2] found 39 well-conducted longitudinal studies. Using meta-analytical approaches, the relative risk (RR) of COVID-19 incidence was 0.67 (95% confidence interval, CI: 0.60-0.75) for current compared to never smokers and 0.99 (95% CI: 0.94-1.05) for ex- versus never smokers. The apparent reduced risk by about 30% for current smokers might be totally or partially explained in terms of different characteristics of those who continue to smoke. For example, it is well known that current smokers have more limited social interactions compared with non-smokers [8,9], and consequently fewer chances of SARS-CoV-2 infection. Additionally, current smokers often experience symptoms similar to COVID-19 patients (such as cough or sore throat). Therefore, current smokers are tested more frequently than non-smokers. As a result, cohort studies based on symptomatic populations – i.e., the vast majority of available cohorts - have an excess of smokers. This generates a sampling bias resulting in an artificial - but not real - reduced risk of SARS-CoV-2 infection for smokers compared to non-smokers.

Tobacco smoking and COVID-19 hospitalization, severity and mortality

We conducted a systematic review of the literature on the association between cigarettes and the risk of COVID-19 hospitalization (among cohorts of SARS-CoV-2 positive subjects), severity and mortality (among cohorts of COVID-19 patients). This review, updated in March 2021, took advantage of an original and innovative research strategy involving the conduction of an umbrella review and a traditional review on the main scientific libraries (PubMed, MEDLINE and Web of Science). Compared to non-smokers, the odds ratios (ORs) of hospitalization among SARS-CoV-2 positive subjects were 1.11 (95% CI: 0.90-1.38; based on 17 studies) for current smokers and 1.22 (95% CI : 1.02-1.47; 12 studies) for ex-smokers. Among COVID-19 patients, ORs for severe disease course were 1.40 (95% CI: 1.20-1.64; 79 studies) for current smokers and 1.52 (95% CI: 1.30-1.76; 31 studies) for ex-smokers and ORs of mortality were 1.48 (95% CI: 1.30-1.68; 65 studies) for current and 1.32 (95% CI: 1.17-1.50; 25 studies) for ex-smokers. In practice, there is evidence of a substantial excess risk of disease progression (severity or mortality from COVID-19) for both current smokers and ex-smokers compared to those who have never smoked.

Novel nicotine containing products and COVID-19

Few studies have considered the role of e-cigarettes or HTPs on the risk of COVID-19 incidence or severity and mortality. As shown in Table 1, at least 6 studies were conducted to evaluate the role of electronic cigarette use on the incidence of COVID-19. None of these studies showed a favourable effect of e-cigarettes, and at least two articles showed a higher risk of incidence for e-cigarette users.

At least two other studies have shown that e-cigarette users had more frequent and persistent COVID-19 symptoms than non-users [16,17]. A large cohort study recently conducted in the UK found no statistically significant relationship between e-cigarette use and risk of COVID-19 hospitalization (OR 1.02; 95% CI: 0.81-1.29), severity (OR 1.20; 95% CI: 0.66-2.20) and mortality (OR 1.03; 95% CI: 0.69-1.54) [18]. The few cross-sectional studies that investigated the relationship between the use of heated tobacco products (HTP) and the incidence of COVID-19 found no statistically significant relationships [10].

Second-hand smoke and COVID-19

An article that appeared in 2021 in the authoritative Tobacco Control magazine highlighted the fact that an opportunity was missed in not having studied the role of second-hand smoke (SHS) on COVID-19 [19]. Indeed, knowledge on the issue is limited to a small study on paediatric patients positive for SARS-CoV-2, reporting more frequent symptoms among minors exposed to SHS [20]. Preliminary results of the COSMO-IT study (COvid19 and SMOking in ITaly) [21] showed no relationship between SHS exposure and COVID-19 severity, but a statistically significant 67% excess risk of mortality for patients exposed daily to SHS compared to non-exposed. There are still no studies in the literature that have investigated the effect of exposure to second-hand aerosols from electronic cigarettes on COVID-19 incidence, severity and mortality.

Conclusions

The update of the scientific literature between the role of tobacco smoking and COVID-19 led to the following conclusions: i) the apparent reduced risk of COVID-19 incidence for smokers compared to never smokers can be explained in terms of different characteristics of smokers compared to non-smokers; ii) there is robust evidence of a substantial excess risk of disease progression for smokers compared to non-smokers; iii) among the studies currently available on the association between novel nicotine containing products and COVID-19, no one found a protective role of these products on COVID-19. On the other hand, there are some studies that highlight a greater risk of incidence of COVID-19 for users vs. non-users of e-cigarettes; SHS exposure may play an unfavourable role in the progress of COVID-19 disease.

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