The association of smoking status with SARS-CoV-2 infection, hospitalisation and mortality from COVID-19: A living rapid evidence review (version 6)

Aims: T o 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 randomeffects hierarchical Bayesian meta-analyses. Published articles and pre-prints were identified via Ovid MEDLINE and medRxiv. Setting: Community or hospital with no restrictions on location. Participants: Adults who had received a test for SARS-CoV-2 infection or a diagnosis of COVID-19. Measurements: Outcomes were SARS-CoV-2 infection, hospitalisation, disease severity and mortality stratified by smoking status. Study quality was assessed. Findings: Version 6 with searches up to 17 July 2020 included 174 studies with 26 included in meta-analyses. T hirty-nine studies reported current, former and never smoking status. Notwithstanding recording uncertainties, compared with adult national prevalence estimates, recorded current smoking rates were generally lower than expected. Current compared with never smokers were at reduced risk of SARSQeios, CC-BY 4.0 · Article, August 2, 2020 Qeios ID: UJR2AW.7 · https://doi.org/10.32388/UJR2AW.7 1/47 CoV-2 infection (RR = 0.74, 95% Credible Interval (CrI) = 0.56-0.97, τ = 0.46). Former compared with never smokers were at somewhat increased risk of infection but data were inconclusive (RR = 1.06, 95% CrI = 0.94-1.20, τ = 0.19). Current (RR = 1.05, CrI = 0.82-1.34, τ = 0.29) and former (RR = 1.20, CrI = 1.03-1.44, τ = 0.19) compared with never smokers were both at somewhat increased risk of hospitalisation with COVID19, but data for current smokers were inconclusive. Current (RR = 1.15, CrI = 0.80-1.66, τ = 0.29) and former (RR = 1.51, CrI = 1.06-2.15, τ = 0.36) compared with never smokers were at increased risk of greater disease severity, but data for current smokers were inconclusive. Current (RR = 1.89, 95% CrI = 0.77-3.41, τ = 0.51) and former (RR = 1.93, 95% CrI = 1.33-2.66, τ = 0.19) compared with never smokers had increased risk of in-hospital death, but data for current smokers were inconclusive. Conclusions: T here is uncertainty about the associations of smoking with COVID-19 outcomes. Recorded smoking prevalence among people with COVID-19 was generally lower than national prevalence. Current smokers were at reduced risk of infection. Former smokers were at increased risk of hospitalisation, disease severity and mortality, while data for current smokers favoured no important associations but were inconclusive.


Introduction Introduction
COVID-19 is a respiratory disease caused by the emerging SARS-CoV-2 virus. Large age and gender differences in case severity and mortality have been observed in the ongoing COVID-19 pandemic 1 ; however, these differences are currently unexplained. SARS-CoV-2 enters epithelial cells through the angiotensin-converting enzyme 2 (ACE-2) receptor 2 .
Some evidence suggests that gene expression and subsequent receptor levels are elevated in the airway and oral epithelium of current smokers 3,4 , thus putting smokers at higher risk of contracting SARS-CoV-2. Other studies, however, suggest that nicotine downregulates the ACE-2 receptor 5 . T hese uncertainties notwithstanding, both former and current smoking is known to increase the risk of respiratory viral 6,7 and bacterial 8,9 infections and is associated with worse outcomes once infected. Cigarette smoke reduces the respiratory immune defence through peri-bronchiolar inflammation and fibrosis, impaired mucociliary clearance and disruption of the respiratory epithelium 10 .
T here is also reason to believe that behavioural factors (e.g. regular hand-to-mouth movements) involved in smoking may increase SARS-CoV-2 infection and transmission in current smokers. However, early data from the COVID-19 pandemic have not provided clear evidence for a negative impact of current or former smoking on SARS-CoV-2 Qeios, CC-BY 4.0 · Article, August 2, 2020 Qeios ID: UJR2AW.7 · https://doi.org/10.32388/UJR2AW.7 2/47 infection or COVID-19 disease outcomes, such as hospitalisation or mortality 11 . It has also been hypothesised that nicotine might protect against a hyper-inflammatory response to SARS-CoV-2 infection, which may lead to adverse outcomes in patients with COVID-19 disease 12 .
T here are several reviews that fall within the scope of smoking and COVID-19 11,13-18 .
We aimed to produce a rapid synthesis of available evidence pertaining to the rates of infection, hospitalisation, disease severity and mortality from SARS-CoV-2/COVID-19 stratified by smoking status. Given the increasing availability of data on this topic, this is a living review with regular updates. As evidence accumulates, the review will be expanded to include studies reporting COVID-19 outcomes by alternative nicotine use (e.g., nicotine replacement therapy or e-cigarettes).

M ethods M ethods
Study design T his is a living evidence review which is updated as new evidence becomes available 19 .
We adopted recommended best practice for rapid evidence reviews, which involved limiting the search to main databases and having one reviewer extract the data and another verify 20 . T his study was not pre-registered but evolved from a report written for a UK medical society 21 . T he most recent pre-print version is available here (version 6  reflect prior knowledge that high levels of between-study heterogeneity are more likely than lower levels. Markov Chain Monte Carlo methods (20,000 burn-ins followed by 80,000 iterations) were then used to generate a risk distribution for each study, in addition to a pooled effect for the posterior risk distribution. We report forest plots with the pooled effect for the posterior risk distribution displayed as the median relative risk with an accompanying 95% CrIs. We used the empirical cumulative distribution function (ECDF) to estimate the probability of there being a 10% reduction or 10% increase in relative risk (RR) (i.e. RR ≥1.1 or RR ≤0.9). Due to a lack of indication as to what constitutes a clinically or epidemiologically meaningful effect (e.g. with regards to onward disease transmission or requirements for 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.

Selection of studies
T wo 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.
T o aid in the visualisation of smoking prevalence in the included studies, 95% bootstrap percentile confidence intervals were calculated for each study. We performed 1,000 bootstrap replications, with the 2.5th and 97.5th percentiles of the empirical distribution forming the 95% bootstrap percentile confidence intervals25 (CIs). It should be noted that prevalence estimates in the included studies were not adjusted for age, sex, socioeconomic position, or region within countries.

Results Results
In the current review version (v6) with searches up to 17 July 2020, a total of 762 new records were identified, with 174 studies included in a narrative synthesis and 26 studies included in meta-analyses (see Figure 1).   Use of alternative nicotine products T wo studies recorded the use of alternative nicotine products in current and/or former smokers but did not report COVID-19 outcomes stratified by nicotine use 26,27 .

Quality appraisal
One study was performed in a random, representative population sample and was rated as 'good' quality. T hirty-three studies were rated as 'fair' quality. T he remaining 140 studies were rated as 'poor' quality (see T able 1).  Discussion Discussion T his living rapid review of 174 studies found substantial uncertainty arising from the recording of smoking status. Notwithstanding these uncertainties, compared with overall adult national prevalence estimates, recorded current smoking rates in most countries were lower than expected. Current smokers had a reduced risk of testing positive for SARS-CoV-2 but appeared more likely to present for testing and/or receive a test.

SARS-CoV-2 infection by smoking status
Current smokers were at increased risk of hospitalisation, disease severity and mortality but data were inconclusive. 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 12): 1) Exposure to SARS-CoV-2 is heterogeneous with different subgroups at heightened risk of infection at different stages of the pandemic. T his will likely introduce bias in studies assessing the rate of infection by smoking status conducted early on.
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 32 .
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 will be more informative than currently available data. We identified one population study conducted in Hungary reporting on seroprevalence and smoking status 33 ; however, the response rate was fairly low at 58.8% and the current smoking rate was 10 percentage points below national prevalence estimates, thus questioning the representativeness of the final sample.
Smoking status is being collected in at least two large representative infection and antibody surveys in the UK 34,35 .
3) T esting for acute infection requires swabbing of the mucosal epithelium, which may be disrupted in current smokers, potentially altering the sensitivity of assays 36 . Research shows large discrepancies between EHRs and actual behaviour 38  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 ingested) since this can affect pharmacokinetics 44 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.

4) Diagnostic criteria for SARS-CoV-2 infection and COVID
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 45 . 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 T raining.

Conclusion Conclusion
Across 174 studies, recorded smoking prevalence was generally lower than national prevalence 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. GeroScience 2020; published online July 17. DOI:10.1007/s11357-020-00226-9.