Researchers at the University of Oxford say they will be conducting the most extensive study to date linking primary and clinical data for the assessment of associations between smoking status and the severity of coronavirus disease 2019 (COVID-19).
“This representative population sample will, to our knowledge, present the first comprehensive examination of the association between smoking, nicotine use without smoking, respiratory disease, and severity of COVID-19,” write Julia Hippisley-Cox and colleagues.
The prospective cohort study will use anonymous data from 8.3 million people’s GP records linked to the Public Health England (PHE) database of tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, records of hospital and intensive care admissions and deaths due to COVID-19.
Novel Coronavirus SARS-CoV-2 Colorized scanning electron micrograph of an apoptotic cell (green) heavily infected with SARS-COV-2 virus particles (purple), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID
A pre-print version of the protocol is available in the server medRxiv*, while it undergoes peer review.
Evidence about smoking and COVID-19 severity is mixed
Smoking is presumed to increase the risk for more severe COVID-19, and the World Health Organization has recommended that people stop the habit.
However, the evidence for whether smoking is a risk factor for severe disease is mixed, with some studies suggesting that health outcomes among smokers may be better than among non-smokers.
“Taken together, the data suggest that smoking is associated with a somewhat higher risk of infection with SARS-CoV-2, but a lower risk of presenting for GP care, hospitalization, ICU admission, and death,” say Hippisley-Cox and team.
Although this suggests that smoking may be associated with less severe disease, the evidence is not reliable because research that confines samples to hospitalized cases produces bias that can mean the associations identified are distorted.
Possible reasons smoking may lower risk of severe disease
Some experiments have suggested that the reported reduced risk for the severe disease may involve nicotine, which downregulates the expression of the angiotensin-converting enzyme 2 (ACE2) receptor that SARS-CoV-2 binds to when it infects cells.
Human ACE2 receptor, 3D illustration. Image Credit: Kateryna Kon / Shutterstock
Nicotine has also been shown to demonstrate immunomodulatory effects that reduce disease severity in animal models of pancreatitis and peritonitis; it reduced immune cell influx and levels of pro-inflammatory cytokines - factors that may be relevant to COVID-19.
However, contrary to expectation, hospitalization rates for COVID-19 seem to be lower among people with chronic respiratory conditions, which some researchers suggest may be due to the use of inhaled corticosteroids among this subgroup.
“Laboratory experiments suggest that inhaled steroids could protect against severe COVID-19,” write Hippisley-Cox and colleagues.
What will the current study involve?
Hippisley-Cox and colleagues will link data from English GP records from the QResearch database to PHE data on SARS-CoV-2 test results, to Hospital Episode Statistics (HES) and data on intensive care unit (ICU) admission from the Intensive Care Research and Audit Centre (ICNARC) and data on COVID-19 deaths from the Office for National Statistics (ONS).
“To maximize precision and minimize selection bias, we will include all patients registered within the QResearch database on (01.01.2020),” writes the team.
The researchers will aim to assess whether smoking lowers the risk of severe disease and whether this risk is also lower among people who vape or use nicotine replacement therapy rather than smoking.
They will also examine whether respiratory diseases are associated with severe COVID-19 and whether inhaled corticosteroids reduce the risk of severe outcomes.
The team will perform sequential adjustment for potential confounding risk factors such as age, gender, and comorbidities, including smoking-related conditions.
The researchers say they will also analyze the data in several ways to ensure distortions such as those arising from patients’ and clinicians’ treatment decisions does not affect results: “We will be able to assess whether there is good evidence that people who smoke, use nicotine, have airway diseases, or use inhaled steroids have a different risk of experiencing serious COVID-19 when compared with the general population.”
The largest study of its kind
“This protocol describes what will be by far the largest linkage of primary and critical care data to investigate the associations between smoking, nicotine replacement, chronic respiratory disease (and drugs used to treat it), and severe COVID-19 disease,” write Hippisley-Cox and colleagues. “We will use four high quality, established large validated research databases (QResearch and ICNARC CMP, HES and ONS) and linked them to the national register of SARS-CoV-2 test results.”
The team says other strengths of the study include its size, representativeness, and its lack of selection, recall, and respondent bias.
The researchers also point out that UK general practices tend to keep accurate records of diagnoses and prescriptions and provide the option of updating analyses as data changes over time.
“It is, therefore, likely to be representative of the population of England. It has good face validity since it has been conducted in the setting where most patients in the UK are assessed, treated, and followed up,” concludes the team.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Hippisley-Cox J, et al. Associations between COVID-19 infection, tobacco smoking and nicotine use, common respiratory conditions, and inhaled corticosteroids: a prospective QResearch-Case Mix Programme data linkage study January-May 2020. medRxiv 2020. doi: https://doi.org/10.1101/2020.06.05.20116624