The association of smoking status with SARS-CoV-2 infection, hospitalisation and mortality from COVID-19: A living rapid evidence review (version 3)

Background: SARS-CoV-2 is the causative agent of COVID-19, an emergent zoonotic disease which has reached pandemic levels and is designated a public health emergency of international concern. It is plausible that former or current smoking status are associated with infection, hospitalisation and/or mortality from COVID-19. Objective: We aimed to estimate the association of smoking status with rates of i) infection, ii) hospitalisation, iii) disease severity, and iv) mortality from SARS-CoV2/COVID-19. Methods: We adopted recommended practice for rapid evidence reviews, which involved limiting the search to main databases and having one reviewer extract data and another verify. Published articles and pre-prints were identified via Ovid MEDLINE, medRxiv and expertise within the review team. We included observational studies with community-dwelling or hospitalised adults aged 16+ years who had been tested for SARS-CoV-2 infection or diagnosed with COVID-19, providing that data on smoking status were reported. T he National Institutes of Health’s Quality Assessment T ool for Observational Cohort and Cross-Sectional Studies was used to divide studies into ‘good’, ‘fair’ and ‘poor’ quality to address objectives of this review. Studies were judged as ‘good’ quality if they: i) had low levels of missing data on smoking status, ii) used a reliable self-report measure that distinguished between current, former and never smoking status, iii) used biochemical verification of smoking status and iv) adjusted Qeios, CC-BY 4.0 · Article, May 23, 2020 Qeios ID: UJR2AW.4 · https://doi.org/10.32388/UJR2AW.4 1/26 analyses for potential confounding variables. Results: Sixty-seven studies were included, 30 of which were conducted in China, 12 in the US, six in the UK, four in France, three in Mexico, three in Spain, two across multiple international sites, two in Italy, and one each from Iran, Israel, Korea, Kuwait and Switzerland. Eleven studies did not state the source for information on smoking status. Fifty-one studies reported current and/or former smoking status but had high levels of missing data and/or did not explicitly state whether the remaining participants were never smokers. Notwithstanding recording uncertainties, compared with national prevalence estimates, recorded current and former smoking rates in most studies were lower than expected. In six ‘fair’ quality studies, no significant difference was observed between current and never (RR = 0.78, 95% CI = 0.55-1.11, p = .17, I2 = 92%) or former and never smokers (RR = 1.07, 95% CI = 0.95-1.20, p = .24, I2 = 61%) in the risk of testing positive for SARS-CoV-2. In five ‘fair’ quality studies, there was no significant difference between current and never (RR = 1.12, 95% CI = 0.74-1.69, p = .48, I2 = 84%) or former and never smokers (RR = 1.21, 95% CI = 0.82-1.79, p = .24, I2 = 81%) in the risk of requiring admission to hospital following diagnosis of COVID-19. In three ‘fair’ quality studies, current smokers were at increased risk of greater disease severity compared with never smokers (RR = 1.37, 95% CI = 1.07-1.75, p = .01, I2 = 0%). No significant difference was observed between former and never smokers (RR = 1.51, 95% CI = 0.82-2.80, p = .19, I2 = 81%). In three ‘fair’ quality studies, there were inconsistent results on mortality from COVID-19 in current and former compared with never smokers. Conclusions: Across 67 observational studies, there is substantial uncertainty about the associations between smoking and COVID-19 outcomes. T he recorded smoking prevalence in hospitalised patients was lower than national estimates but this observation is inconsistent with there being no evidence of increased admission to hospital from five ‘fair’ quality studies of people who tested positive. T here was limited evidence from ‘fair’ quality studies that current compared with never smoking is associated with greater disease severity in those hospitalised for COVID-19. Implications: Unrelated to COVID-19, smokers are at a greater risk of a range of serious health problems, requiring them to be admitted to hospital. Given uncertainty around the association of smoking with COVID-19, smoking cessation remains a public health priority and high-quality smoking cessation advice including recommendations to use alternative nicotine should form part of public health efforts during this Qeios, CC-BY 4.0 · Article, May 23, 2020 Qeios ID: UJR2AW.4 · https://doi.org/10.32388/UJR2AW.4 2/26


pandemic.
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 ACE2 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 ACE2 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 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 (or "cytokine storm") to SARS-CoV-2 infection, which may lead to adverse outcomes in patients with COVID-19 disease 12 .
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 will be a 'living' review with fortnightly updates. As evidence accumulates, the review will be expanded to include studies reporting outcomes by alternative nicotine use (e.g., nicotine replacement therapy or e-cigarettes).

Study design
We adopted recommended practice for rapid evidence reviews, which involved limiting the search to main databases and having one reviewer extract the data and another were judged as 'good' quality if they: i) had low levels of missing data on smoking status, ii) used a reliable self-report measure that distinguished between current, former and never smoking status iii) used biochemical verification of smoking status; and iv) adjusted analyses for potential confounding variables (e.g. age, comorbidities). Studies were rated as 'fair' if they had low levels of missing data on smoking status and did one of either: i) used a reliable measure of current, former and never smoking status (e.g. self-report); or ii) adjusted analyses for potential confounding variables. Studies were otherwise rated as 'poor'. T he quality appraisal was conducted by one reviewer and verified by a second.

Evidence synthesis
A narrative synthesis was conducted. Where possible, data were pooled in R v.3.6.3 20 with the Mantel-Haenszel or inverse variance method using random or fixed effects, depending on heterogeneity, and presented as risk ratios (RRs) 21 . Heterogeneity between study outcomes was assessed using the I 2 statistic, suitable for smaller metaanalyses 22 . Results

Results
In the current review version (v3), a total of 143 new records were identified, with 67 studies included in a narrative synthesis and 12 studies included in meta-analyses (see Figure 1).

Study characteristics
Characteristics of included studies are presented in T able 1. T hirty studies were  Figure 7 and 8, respectively). with never smokers among those identified as testing positive in the community. T here was some limited evidence that current smokers are at increased risk of greater disease severity compared with never smokers.

Mortality by smoking status
In three 'fair' quality studies, there was inconsistent evidence on the association of smoking status and the risk of death from COVID-19. It should be noted that these early studies did not follow all patients for a sufficient period of time to report mortality outcomes.

Issues complicating interpretation
Interpretation of these early studies is complicated by several factors (see Figure 9). First, exposure to SARS-CoV-2 is heterogeneous with different subgroups being 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 in the pandemic. Second, current 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. T hird, testing for acute infection requires swabbing of the mucosal epithelium, which may be disrupted in current smokers, thus altering the sensitivity of the assay.
Fourth, most included studies relied on electronic health records (EHRs) as the source of information on smoking status. Research shows large discrepancies between EHRs and actual behaviour 90 . Known failings of EHRs include implausible longitudinal changes, such as former smokers being recorded as never smokers at subsequent hospital visits 90 .
Misreporting on the part of the patient (perhaps due to perceived stigmatisation) has also been observed, with biochemical measures showing higher rates of smoking behaviour compared with self-report in hospitalised patients in the US 91    CoV-2 virus. 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. not) since this can affect pharmacokinetics 95 (and thus 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 exsmokers -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 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 96 . GPs and other healthcare providers can play a crucial role -brief, high-quality and free online training is available from the National Centre for Smoking Cessation and T raining Conclusion Across 67 observational studies, there is substantial uncertainty arising from the recording of smoking status on whether current and/or former smoking status is associated with SARS-CoV-2 infection, hospitalisation or mortality. T here is limited evidence that current smoking compared with never is associated with greater disease severity in those hospitalised for COVID-19.