key: cord-1008886-c91ljght
authors: Simons, D.; Perski, O.; Shahab, L.; Brown, J.; Bailey, R.
title: The association of smoking status with hospitalisation for COVID-19 compared with other respiratory viruses a year previous: A case-control study at a single UK National Health Service trust
date: 2020-11-30
journal: nan
DOI: 10.1101/2020.11.26.20238469
sha: db5f899ee9bcda8be4479cbf8cbeae1149e06c9e
doc_id: 1008886
cord_uid: c91ljght

Abstract Background: It is unclear whether smoking increases the risk of COVID-19 hospitalisation. We aimed to i) examine the association of smoking status with hospitalisation for COVID-19 compared with hospitalisation for other respiratory virus infections a year previous; ii) compare current smoking in cases with age- and sex-matched London prevalence; and iii) examine concordance between smoking status recorded on the electronic health record (EHR) and the medical notes. Methods: This retrospective case-control study enrolled adult patients (446 cases and 211 controls) at a single National Health Service trust in London, UK. London smoking prevalence was obtained from the representative Annual Population Survey. The outcome variable was type of hospitalisation (COVID-19 vs. another respiratory virus). The exposure variable was smoking status (never/former/current smoker). Logistic regression analyses adjusted for age, sex, socioeconomic position and comorbidities were performed. The study protocol and analyses were pre-registered on the Open Science Framework. Findings: Patients hospitalised with COVID-19 had lower odds of being current smokers than patients admitted with other respiratory viruses (ORadj=0.55, 95% CI=0.31-0.96, p=.04). Odds were equivocal for former smokers (ORadj=1.08, 95% CI=0.72-1.65, p=.70). Current smoking in cases was significantly lower than expected from London prevalence (9.4% vs. 12.9%, p=.02). Smoking status recorded on the EHR deviated significantly from that recorded within the medical notes ({chi}2(3)=226.7, p<.001). Interpretation: In a single hospital trust in the UK, patients hospitalised with COVID-19 had reduced odds of being current smokers compared with patients admitted with other respiratory viruses a year previous. Funding: UK BBSRC, Cancer Research UK, UKPRP.

socioeconomic position and comorbidities were performed. The study protocol and analyses were 27 pre-registered on the Open Science Framework. 28 COVID-19 is a respiratory disease caused by the SARS-CoV-2 virus. There are in excess of 50 44 million confirmed COVID-19 cases globally, with over one million deaths reported [1] . Large age 45 and sex differences in case severity and mortality have been observed [2] , with hypertension, 46 diabetes and obesity identified as important risk factors [3] . There are a priori reasons to believe 47 that current smokers are at increased risk of contracting COVID-19 and experiencing greater 48 disease severity once infected. SARS-CoV-2 enters epithelial cells through the ACE-2 receptor [4] . 49

Evidence suggests that gene expression and subsequent ACE-2 receptor levels are elevated in 50 current smoking increase the risk of other respiratory viral[8] and bacterial [9] infections and are 55 associated with worse outcomes once infected. For example, a large observational study in the UK 56

found that former and current smokers had increased odds of being hospitalised with community-57 acquired pneumonia compared with never smokers [10] . However, early data from the ongoing 58 pandemic have not provided clear evidence for an independent association of smoking status with 59 COVID-19 outcomes [11, 12] . 60 61 A living evidence review of observational and experimental studies examining the association of 62 smoking status with COVID-19 infection, hospitalisation, disease severity and mortality has found 63 that, among 279 studies, current smoking (not adjusted for age, sex or comorbidities) was 64

generally lower than what would be expected from national smoking prevalence [12] . In addition, 65 current smokers were at reduced risk of testing positive for SARS-CoV-2 compared with never 66 smokers, and former smokers were at increased risk of hospitalisation, disease severity and in-67 hospital mortality compared with never smokers. However, the majority of included studies were 68 limited by the lack of appropriate controls, poor recording of smoking status and insufficient 69 adjustment for relevant covariates. Many studies relied on routine electronic health records (EHRs) 70 to obtain individual-level data on demographic characteristics, comorbidities and smoking status. 71

Previous research suggests that data on smoking status obtained via EHRs tend to be incomplete 72 or outright inaccurate, with implausible longitudinal changes observed [13] . In addition, as 73 hospitalised populations differ by age and sex from the general population, comparisons of current 74 and former smoking prevalence in hospitalised and non-hospitalised populations are likely limited. 75

There is hence an urgent need for alternative study designs with relevant comparator groups (e.g. 76 populations hospitalised with a similar type of respiratory viral infection) and adjustment for 77 covariates to better understand the association of smoking status with COVID-19 disease 78 outcomes. 79

We therefore aimed to i) examine, in a retrospective case-control study conducted at a single UK 81 hospital trust, the association of smoking status with hospitalisation for COVID-19 compared with 82 hospitalisation for other respiratory virus infections (e.g. influenza, respiratory syncytial virus) a 83 . CC-BY 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.26.20238469 doi: medRxiv preprint smokers' and 'never smokers'. For the primary analysis, patients categorised as a 'non-smoker' 167 were treated as 'never smokers'. Where possible, information on use of smokeless tobacco, 168 waterpipe and/or alternative nicotine products (e.g. e-cigarettes) was extracted. The joint first 169 authors searched within the contemporaneous medical records for free-text entries of smoking 170 status. The most recently available record of smoking status, obtained from either the summary 171 EHR or the medical notes, was extracted. Where available, data on pack-year history of smoking 172 were extracted. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.26.20238469 doi: medRxiv preprint were performed. First, those recorded as 'non-smokers' were removed from the analysis. Second, 196 those excluded from the analytic sample due to missing data on smoking status (see section above 197 on 'Exclusion criteria') were included and coded as i) 'never smokers' and then as ii) 'current 198 smokers'. 199 200 We then compared age-stratified current smoking prevalence in the case population with overall 201 London prevalence stratified by age and weighted by the sex distribution of the case population. 202

To examine the concordance between smoking status recorded on the summary EHR and within 204 the contemporaneous medical notes, Pearson's Chi-squared tests were performed for the entire 205 sample, and then separately for cases and controls. 206

A total of 610 potential cases and 514 potential controls were identified. A total of 446 cases and 208 211 controls were included in the analytic sample (see Figure 1 ). Thirteen potential controls and 60 209 potential cases were excluded due to not having a record of documented smoking status. This was 210 likely due to these patients having no prior contact with the selected NHS foundation trust. Notably, 211 37 (62%) of potential cases that were excluded because of missing smoking status did not survive 212 to hospital discharge, with no in-hospital mortality in potential controls, which suggests that data 213

were not missing at random. 214 . CC-BY 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.26.20238469 doi: medRxiv preprint 215 Figure 1 . Eligibility flow diagram for controls (left hand side) and cases (right hand side). 216 217 Compared with controls, cases were more likely to be male (55% vs. 35.9%) and older (64.9 years 218 vs 62.5 years) (see Table 1 ). Approximately 10% of cases and controls had missing data for 219 ethnicity. Compared with cases, controls were more likely to be admitted from more deprived areas 220 (IMD quintiles 1 and 2) (41.8% vs. 32.9%, p < 0.001) and have pre-existing metabolic (30.3% vs 221 13.3%) and cardiac comorbidities (53.4% vs 30.3%). A significantly larger proportion of cases 222 compared with controls did not survive to discharge (28.7% vs. 4.3%). Among 128 cases not 223 surviving to discharge, 53 (41.4%) were never smokers, 63 (49.2%) were former smokers and 12 224 (9.4%) were current smokers. For patients who survived to discharge, the median length of 225 hospital stay for cases and controls was 9 (IQR = 4-18) and 4 (IQR = 2-9) days, respectively (see 226 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.26.20238469 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The prevalence of former smoking was higher in cases compared with controls (38.6% vs. 31.8%). 241

Current smoking prevalence was lower in cases compared with controls (9.4% vs. 17.1%). A single 242 patient from the case cohort was recorded as a dual cigarette and e-cigarette user. Two patients, 243 one from each cohort, were recorded as dual cigarette and shisha/waterpipe users. Pack-year 244 history of smoking was only recorded for 40% of patients with a smoking history (see Table 1 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. Table 2 ). Current smokers were overrepresented in the 18-29 years age group and 273 underrepresented in the 45-59 years age group. Former smokers were consistently 274 overrepresented in cases compared with age-stratified London prevalence weighted by sex, except 275 for those aged 18-29 years. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.26.20238469 doi: medRxiv preprint 

Controls were more likely to have no record of smoking status on the summary EHR compared 284 with cases (75.4% vs. 7%) (see Figure 2 ). Smoking status on the summary EHR was incorrectly 285 recorded for 168 controls and 60 cases (χ 2 (3) = 226.7, p = < 0.001). In cases, six current smokers 286 were misclassified as former smokers, one current smoker as a never smoker and six current 287 smokers had no record of smoking status on the summary EHR. In controls, six current smokers 288 were misclassified as former smokers and 23 current smokers had no record of smoking status on 289 the summary EHR. There was greater discordance between smoking status recorded on the 290 summary EHR and within the medical notes in controls (χ 2 (3) = 256.5, p = < 0.001) than in cases 291 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. infections a year previous. The observed reduction in current smoking prevalence was robust to 303 adjustment for sex, age, socioeconomic position and comorbidities. The low prevalence of current 304 smoking in cases appeared driven by current smokers being underrepresented in those aged 45-305 59 years, with similar to expected current smoking prevalence in the other age groups. It should be 306 noted that cases aged 45-59 years were more likely to reside in less deprived areas than controls. 307

As smoking status is strongly associated with socioeconomic position [14] , this may partly explain 308 the lower smoking prevalence in this age group. 309 310 Further, we found that smoking status is typically poorly recorded in the summary EHR. This was 311 more prominent in controls than casesa difference that is likely explained by the observation that 312 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.26.20238469 doi: medRxiv preprint COVID-19 patients were followed up by the respiratory medicine team after discharge as part of a 313 COVID-19 follow-up clinic where they specifically asked about smoking status [22] . The observed 314 discrepancy between smoking status recorded on summary EHRs and the contemporaneous 315 medical notes is a concern, particularly for studies relying solely on EHRs as the source of 316 information on smoking status. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.26.20238469 doi: medRxiv preprint the course of the pandemic, at least partly due to improving knowledge and treatment of the 342 disease [27] . In addition, the risk of superadded bacterial infection in COVID-19 patients appears 343 lower than for those with influenza[28]] and COVID-19 patients have increased rates of 344 coagulopathies compared with other respiratory viruses [29] . Taken together, these emerging 345 observations may limit any direct comparison of risk profiles in cases and controls. Fourth, a 346 history of current or past cancer was high in both groups at greater than 20% and was significantly 347 greater in controls compared with cases. This reflects a bias in the population that regularly 348 interacts with the selected NHS hospital trust, which is a specialist cancer referral centre. We 349 visualised the geographic regions where patients were admitted from to examine any systemic 350 differences between cases and controls, and caution that the differing catchment areas of the two 351 cohorts may have led to important differences in the underlying populations. In addition, during the 352 peak of the first wave of the pandemic in the UK, many cases were transferred across hospital 353 sites due to bed pressures. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.26.20238469 doi: medRxiv preprint Consortium; ISARIC) collects smoking status but this is likely obtained from summary EHRs. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 

We gratefully acknowledge all funding listed above. The views expressed are those of the authors 407

and not necessarily those of the funders. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.26.20238469 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted November 30, 2020. ; https://doi.org/10.1101/2020.11.26.20238469 doi: medRxiv preprint

COVID-19 Map

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Are patients with hypertension and diabetes mellitus at 420 increased risk for COVID-19 infection?

Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease 423 Inhibitor

Enzyme-2 Receptor: A Potential Adhesion Site for Novel Coronavirus 426 SARS-CoV-2 (Covid-19

Bulk and Single-Cell Transcriptomics Identify Tobacco-Use Disparity in Lung Gene 428 Expression of ACE2, the Receptor of 2019-nCov

Nicotine and the renin-angiotensin 433 system

Risk factors associated with 435 hospitalisation for influenza-associated severe acute respiratory illness in South Africa: A case-436 population study

Cigarette smoking and mechanisms of susceptibility to infections of the 438 respiratory tract and other organ systems

Risk factors for hospital 440 admission in the 28 days following a community-acquired pneumonia diagnosis in older adults, and 441 their contribution to increasing hospitalisation rates over time: A cohort study

COVID-19 and smoking: A systematic review of the evidence. Tob 444 Induc Dis

The association of smoking status with SARS-CoV-2 446 infection, hospitalisation and mortality from COVID-19: A living rapid evidence review with 447 Bayesian meta-analyses

Challenges with Collecting Smoking 449 Status in Electronic Health Records

Adult smoking habits in the UK: 2019. Office for National Statistics

The Incubation Period of 455

COVID-19) From Publicly Reported Confirmed Cases: Estimation and 456 Application

Case-case comparisons to study causation of common infectious 458 diseases

Risk factors for disease severity among hospitalised patients with 2009 pandemic 461 influenza A (H1N1) in Spain

Syncytial Virus and Other Respiratory Viral Infections in Older Adults With Moderate to Severe 464 Influenza-like Illness

The English Indices of Deprivation

R 467 Foundation for Statistical Computing

Long-COVID': a cross-469 sectional study of persisting symptoms, biomarker and imaging abnormalities following 470 hospitalisation for COVID-19

How cigarette smoke skews immune responses to promote 472 infection, lung disease and cancer

Case-control studies: basic concepts

Measuring Neighbourhood Deprivation: A Critique of 476 the Index of Multiple Deprivation. Environ Plan C Gov Policy

Deaths due to coronavirus (COVID-19) compared with deaths from influenza and 478 pneumonia

483 ASSESSING THE AGE SPECIFICITY OF INFECTION FATALITY RATES FOR COVID-19: 484 SYSTEMATIC REVIEW

Co-infections in people with COVID-19: a systematic 487 review and meta-analysis

489 Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Covid-19: The role of smoking cessation during respiratory virus 492 epidemics. The BMJ