The association of smoking status with SARS-CoV-2 infection, hospitalisation and mortality from COVID-19: A living rapid evidence review with Bayesian meta-analyses (version 10)

Aims: To estimate the association of smoking status with rates of i) infection, ii) hospitalisation, iii) disease severity, and iv) mortality from SARS-CoV-2/COVID-19 disease. Design: Living rapid review of observational and experimental studies with random-effects hierarchical Bayesian metaanalyses. Published articles and pre-prints were identified via MEDLINE and medRxiv. Setting: Community or hospital. No restrictions on location. Participants: Adults who received a SARS-CoV-2 test or a COVID-19 diagnosis. Measurements: Outcomes were SARS-CoV-2 infection, hospitalisation, disease severity and mortality stratified by smoking status. Study quality was assessed (i.e. ‘good’, ‘fair’ and ‘poor’). Findings: Version 10 (searches up to 15 December 2020) included 345 studies with 52 ‘good’ and ‘fair’ quality studies included in unadjusted meta-analyses. One-hundred-and-one studies (29.3%) reported current, former and never smoking status with the remainder using broader categories. Recorded smoking prevalence among people with COVID19 was generally lower than national prevalence. Current compared with never smokers were at reduced risk of SARSCoV-2 infection (RR = 0.69, 95% Credible Interval (CrI) = 0.58-0.82, τ = 0.36). Data for former smokers were inconclusive (RR = 1.03, 95% CrI = 0.94-1.13, τ = 0.18) but favoured there being no important association (8% probability of RR ≥1.1). Former compared with never smokers were at increased risk of hospitalisation (RR = 1.18, CrI = 1.07-1.31, τ = 0.14), greater disease severity (RR = 1.52, CrI = 1.12-2.06, τ = 0.29) and mortality (RR = 1.40, 95% CrI = 1.20-1.64, τ = 0.19). Data for current smokers on hospitalisation, disease severity and mortality were inconclusive (RR = Qeios, CC-BY 4.0 · Article, January 11, 2021 Qeios ID: UJR2AW.11 · https://doi.org/10.32388/UJR2AW.11 1/71 1.08, CrI = 0.95-1.23, τ = 0.18; RR = 1.26, CrI = 0.85-1.93, τ = 0.34; RR = 1.05, 95% CrI = 0.77-1.41, τ = 0.39, respectively) but favoured there being no important associations with hospitalisation and mortality (31% and 38% probability of RR ≥1.1, respectively) and a small but important association with disease severity (80% probability of RR ≥1.1). Conclusions: Compared with never smokers, current smokers appear to be at reduced risk of SARS-CoV-2 infection while former smokers appear to be at increased risk of hospitalisation, greater disease severity and mortality from COVID-19. However, it is uncertain whether these associations are causal. v7 of this living review article has been published in Addiction and is available here https://doiorg.libproxy.ucl.ac.uk/10.1111/add.15276

intensive care beds), we deemed a 10% change in risk as small but important. Where data were inconclusive (as indicated by CrIs crossing RR = 1.0), to disambiguate whether data favoured no effect or there being a small but important association, we estimated whether there was ≥75% probability of RR ≥1.1 or RR ≤0.9.
Two sensitivity analyses were performed. First, a minimally informative prior for µ was specified as a normal distribution with a mean of 0 and standard deviation of 1 and τ as described above. Second, an informative prior as described above for µ was used with τ specified as a half-Cauchy distribution with a mean of 0.3 and standard deviation of 1 to reflect greater between-study heterogeneity.
To aid in the visualisation of smoking prevalence in the included studies, the weighted mean prevalence of current and former smoking was calculated for countries with ≥3 studies and plotted for comparison with national prevalence estimates. It should be noted that prevalence estimates in the included studies were not adjusted for age, sex, socioeconomic position, or geographic region within countries.

Results
In the current review version (v10) with searches up to 15 December 2020, a total of 874 records were identified, with 345 studies included in a narrative synthesis and 52 studies included in meta-analyses (see Figure 1).

Smoking prevalence by country
Unadjusted smoking prevalence compared with overall estimates for national adult smoking prevalence split by country and study setting is presented in Figure 2a and 2b. Lower than expected current smoking prevalence was generally observed, especially in studies with hospitalised samples. Former smoking prevalence was typically higher than expected prevalence when reported. National smoking prevalence estimates used for comparison are presented in Supplementary

SARS-CoV-2 testing by smoking status
Three studies provided data on access to SARS-CoV-2 diagnostic testing for those meeting local testing criteria by Sixty-three studies provided data on SARS-CoV-2 infection for people meeting local testing criteria by smoking status (see Table 2). Meta-analyses were performed for two 'good' and 23 'fair' quality studies (see Figure 3 and 4). Current smokers were at reduced risk of testing positive for SARS-CoV-2 compared with never smokers (RR = 0.69, 95% Credible Interval (CrI) = 0.58-0.82, τ = 0.36). The probability of current smokers being at reduced risk of infection compared with never smokers (RR ≤0.9) was 99.8%. Former compared with never smokers were at increased risk of testing positive, but data were inconclusive (RR = 1.03, 95% CrI = 0.94-1.13, τ = 0.18) and favoured there being no important association. The probability of former smokers being at increased risk of infection (RR ≥1.1) compared with never smokers was 7.8%.

Hospitalisation for COVID-19 by smoking status
The probability of current and former smokers being at increased risk of hospitalisation (RR ≥1.1) compared with never smokers was 31% and 89%, respectively. Results were materially unchanged in two sensitivity analyses.

Disease severity by smoking status
Sixty-five studies reported disease severity in hospitalised patients stratified by smoking status (see Table 4). Severe (as opposed to non-severe) disease was broadly defined as requiring intensive treatment unit (ITU) admission, requiring oxygen as a hospital inpatient or in-hospital death. Meta-analyses were performed for eight 'fair' quality studies (see Figure   7 and 8). Current (RR = 1.26, CrI = 0.86-1.94, τ = 0.34, 95% CI = 0.01-0.86) and former (RR = 1.52, CrI = 1.12-2.06, τ = 0.29, 95% CI = 0.05-0.65) compared with never smokers were at increased risk of greater disease severity; data for current smokers were inconclusive but favoured there being a small but important association. The probability of current and former smokers having increased risk of greater disease severity (RR ≥1.1) compared with never smokers was 80% and 98%, respectively. Results were materially unchanged in two sensitivity analyses.

Mortality by smoking status
Seventy-seven studies reported mortality from COVID-19 by smoking status (see Table 5), with 16 'fair' quality studies included in meta-analyses (see Figure 9 and 10). Current (RR = 1.05, 95% CrI = 0.77-1.41, τ = 0.39) and former (RR = 1.40, 95% CrI = 1.2-1.64, τ = 0.19) compared with never smokers were at increased risk of in-hospital mortality from COVID-19. However, data for current smokers were inconclusive and favoured there being no important association. The probability of current and former smokers being at greater risk of in-hospital mortality (RR ≥1.1) compared with never smokers was 38% and 99.8%, respectively. Results were materially unchanged in two sensitivity analyses.

Discussion
This living rapid review found uncertainty in the majority of 345 studies arising from the recording of smoking status.
Notwithstanding these uncertainties, compared with overall adult national prevalence estimates, recorded current smoking rates in most studies were lower than expected. In a subset of better-quality studies (n = 25), current but not former smokers had a reduced risk of testing positive for SARS-CoV-2 but current smokers appeared somewhat more likely to present for testing and/or receive a test. Data for current smokers on the risk of hospitalisation, disease severity and mortality were inconclusive, and favoured there being no important associations with hospitalisation and mortality and a small but important increase in the risk of severe disease. Former smokers were at increased risk of hospitalisation, disease severity and mortality compared with never smokers.

Issues complicating interpretation
Interpretation of results from studies conducted during the first phase of the SARS-CoV-2 pandemic is complicated by several factors (see Figure 11): 1) Exposure to SARS-CoV-2 Qeios, CC-BY 4.0 · Article,  1. Exposure to the SARS-CoV-2 virus is heterogeneous with different subgroups at heightened risk of infection at different stages of the pandemic, at least partly due to differential contact matrices by age, sex and socioeconomic position 36 , which are associated with smoking status.
2. The probability of viral exposure depends largely on local prevalence, which varies over time. This likely introduces bias in studies assessing the rate of infection by smoking status conducted in the early phase of the pandemic.
2) Infection with SARS-CoV-2 1. Infection following viral exposure depends on individual differences in, for example, genetic susceptibility or immunocompetence, which are poorly understood at present. For example, the household secondary attack rate for COVID-19 is estimated at 17% 37 .
2. Heated and humidified air may act to disrupt the ability of the virus to persist in the airway mucosa of smokers. There is some evidence that transient localised hyperthermia can inhibit replication of rhinoviruses, a non-enveloped virus that causes the common cold 38 . However, as SARS-CoV-2 is an enveloped virus 39 , it is unclear whether a similar protective effect against viral replication or invasion by heated and humidified air may occur.

3) Symptomatic COVID-19
1. An estimated 20% (95% CI = 17-25%) of COVID-19 cases are asymptomatic 40 , with some evidence suggesting younger people are more likely to be asymptomatic 41 . Testing is hence likely limited in some subgroups, with the potential for these groups to include an overrepresentation of current smokers.
2. Current and former smokers may be more likely to meet local criteria for community testing due to increased prevalence of symptoms consistent with SARS-CoV-2 infection, such as cough, increased sputum production or altered sense of smell or taste 42 . Evidence from a small number of studies indicates that current smokers may be more likely to present for testing, hence increasing the denominator in comparisons with never smokers and potentially inflating the rate of negative tests in current smokers. Infection positivity rates estimated among random samples are more informative. We identified one population study conducted in Hungary reporting on seroprevalence and smoking status 43  hospitalisation may lead to worse disease outcomes including death 12 .
3. During periods of heightened demand of limited healthcare resources, current and former smokers with extensive comorbidities may have reduced priority for intensive care admission, thus leading to higher in-hospital mortality.
COVID-19 outcomes are currently limited to in-hospital death or survival to discharge. This binary outcome does not capture potential long-term morbidity attributed to COVID-19, such as stroke, amputation or acute cardiac events, which may be moderated by smoking status. Figure 11. A schematic of some of the interpretation issues for the association of smoking status and COVID-19 infection, hospitalisation, disease severity and mortality. Numbers refer to the issues listed in the above section. Issues on the right-hand side relate explicitly to smoking status.
In addition, the emergence of new variants and strains of the SARS-CoV-2 virus may also change associations with risks factors, including smoking status.

Limitations
Qeios, CC-BY 4.0 · Article,  This living rapid evidence review was limited by having a single reviewer extracting data with a second independently verifying the data extracted to minimise errors, restricting the search to one electronic database and one pre-print server and by not including at least three large population surveys due to their reliance on self-reported suspected or confirmed SARS-CoV-2 infection (which means they do not meet our eligibility criteria) 42,54,55 . We also did not include a large, UKbased, representative seroprevalence study 56 in our meta-analyses as the odds of testing positive in former smokers was not reported. However, the odds of infection for current smokers (OR = 0.64, 95% CI = 0.58-0.71) was in concordance with the pooled estimate in our meta-analysis. Population surveys -particularly with linked data on confirmed infection or antibodies -will be included in future review versions to help mitigate some of the limitations of healthcare based observational studies. The comparisons of current and former smoking prevalence in the included studies with national prevalence estimates did not adjust observed prevalence for the demographic profile of those tested/admitted to hospital.
Other reviews focused on this comparison have applied adjustments for sex and age, and continue to find lower than expected prevalence -notwithstanding the issues complicating interpretation described above 17 .

Implications for research, policy and practice
Further scientific research is needed to resolve the mixed findings summarised in our review. First, clinical trials of the posited therapeutic effect of nicotine could have important implications both for smokers and for improved understanding of how the SARS-CoV-2 virus causes disease in humans. Such trials should focus on medicinal nicotine (as smoked tobacco is a dirty delivery mechanism that could mask beneficial effects) and potentially differentiate between different modes of delivery (i.e. inhaled vs. ingested) since this can affect pharmacokinetics 57 and potential therapeutic effects. A second research priority would be a large, representative (randomly sampled) population survey with a validated assessment of smoking status which distinguishes between recent and long-term ex-smokers -ideally biochemically verified -and assesses seroprevalence and links to health records.
In the meantime, public-facing messages about the possible protective effect of smoking or nicotine are premature. In our view, until there is further research, the quality of the evidence does not justify the huge risk associated with a message likely to reach millions of people that a lethal activity, such as smoking, may protect against COVID-19. It continues to be appropriate to recommend smoking cessation and emphasise the role of alternative nicotine products to support smokers to stop as part of public health efforts during COVID-19. At the very least, smoking cessation reduces acute risks from cardiovascular disease and could reduce demands on the healthcare system 58 . GPs and other healthcare providers can play a crucial role -brief, high-quality and free online training is available at National Centre for Smoking Cessation and Training.

Conclusion
Across 345 studies, recorded current but not past smoking prevalence was generally lower than national prevalence Qeios, CC-BY 4.0 · Article, January 11, 2021 Qeios ID: UJR2AW.11 · https://doi.org/10.32388/UJR2AW.11 46/71 estimates. Current smokers were at reduced risk of testing positive for SARS-CoV-2 and former smokers were at increased risk of hospitalisation, disease severity and mortality compared with never smokers.

Acknowledgements
An original short review for the Royal College of Physicians was converted to an extended living review after a request by Martin Dockrell, Tobacco Control Lead, Public Health England. All scientific decisions were made by the authors independently of funders and external organisations. The authors would like to thank Rosemary Koper for her assistance in running the electronic searches and data extraction up until v7, and all authors who responded to requests for additional data.