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COVID-19, smoking and respiratory conditions: a prospective QResearch-Case Mix Programme study

Title

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

What is the aim of the study and why is it important?

We aim to assess whether smoking reduces the risk of severe COVID-19 and whether the risk of severe COVID-19 is also reduced in people who use nicotine in the form of electronic cigarettes or nicotine replacement therapy (NRT), but do not currently smoke tobacco. We will also examine whether having airways disease is associated with severe COVID-19 and whether treatment for these diseases, particularly inhaled steroids, are associated with a reduced risk of serious outcomes.

This is important because COVID-19 is a disease of the airways and can lead to infection of the lungs (pneumonia), and smoking is a well-known cause of airway infections. This may be because smoking makes it harder for the body to remove infectious particles or because it changes the way that the body fights infection – its immune reaction. This immune reaction causes many of the symptoms we experience when we have infections. As a result, it would seem likely that the coronavirus that causes COVID-19 could worsen infections in people who smoke. However, emerging evidence suggests that this may not be the case, and that smokers may have better outcomes than non-smokers. Some laboratory experiments have suggested that this may be due to the nicotine in cigarettes. Nicotine is available as a cheap and safe drug that could provide a treatment option for COVID-19. People with diseases of the airways, like asthma, are at higher risk of serious lung infections. Data from China suggest that people admitted to hospital with COVID-19 are less likely to have diseases of the airways than might be expected given the rate of asthma in the general population. One reason for this could be that people with asthma or chronic obstructive pulmonary disease (COPD) take inhaled steroids as their treatment. Laboratory experiments suggest that inhaled steroids could protect against severe COVID-19.

How is the research being done?

We will use anonymous data from 8.3 million people’s GP records, linked to Public Health England’s database of tests for coronavirus, records of hospital admissions, records of admission to hospital intensive care units, and records of deaths due to COVID-19. We will use statistical methods to make sure we control for other factors that may cause more serious illness, resulting in admission to hospital, ICU, or death, like being older or having diabetes. Distortions in the answers we derive could result from distortions arising because of patients’ and doctors’ decision-making in who gets what kind of healthcare. We will analyse the data several ways to see if the main results are affected by these distortions that we cannot measure. These distortions can show up when the data are analysed differently.

Chief Investigator

Professor Paul Aveyard

Sponsor

University of Oxford

Location of research

Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK

Date on which research approved

11-Jun-2020

Project reference ID

OX86

Generic ethics approval reference

18/EM/0400

Are all data accessed are in anonymised form?

Yes

Brief summary of the dataset to be released (including any sensitive data)

QResearch data with linkage to ICNARCs intensive care data, PHE Covid-19 testing data, Hospital Episode Statistics, and ONS mortality data.
Data obtained specifically from QResearch will be:
• Demographic variables, including age, gender, ethnicity,
• Body mass index
• Smoking-related morbidity, divided into respiratory disease and smoking-related non-respiratory disease.
• Non-smoking-related morbidity, divided into respiratory disease and non-respiratory disease.
• Treatment for smoking-related morbidity: common treatments for cardiovascular disease, type 2 diabetes, and airways disease.
• Smoking status (current, former, never).
• Vaping (electronic cigarette use) status
• Prescription of nicotine replacement therapy or varenicline in the month before admission to hospital.

What were the main findings?

Why did you do this study?
It is important to know whether people with underlying respiratory diseases are at risk of severe covid and the previous research that had been done had not all agreed. Some research suggested that people with respiratory disease were at a very high risk from covid, while other research suggested no increased risk. It is severe covid, that is covid that needs treatment in hospital, intensive care units (ICU), or causes death that is threatening the UK.

Also, most research had been done on people admitted to hospital, which means that people were already severely ill with covid when they joined the study. Many people think of covid as a severe disease, but overall, the very large majority do not have illnesses severe enough to need treatment in hospital. A study run in Oxford found that only 3 in 100 people at highest risk of severe covid (aged over 65 years) with symptoms typical of covid were admitted to hospital. It’s likely that doctors use factors like whether a person already has respiratory disease to decide whether to recommend hospital admission or not. In this way, looking at only people admitted to hospital can distort the outcomes. For example, if doctors are more likely to recommend hospital admission in people who have respiratory disease, then people without respiratory disease will probably be more severely ill from their covid. Here we were able to study a representative group of people in the general population, not those already ill with covid, meaning our study was free of this possible distortion.

What did the research involve?
The research relied on a database called QResearch, which held 8 million adults’ GP records in an anonymous form. With approval, we were able to link these records to the database of covid test results and the information from hospitals that told us whether a person had been admitted to hospital and the reasons for that admission. We also had similar information on whether people went to ICU or died. In our case, we used only the records where people were ill enough to go to hospital with covid, be admitted to ICU with covid, and die from covid. We had these records from the end of January 2020 through to the end of April 2020, when the first wave of covid was at its peak. Deaths from covid peaked around the 6 April and hospital admissions a week earlier. Lockdown and shielding came into force from the 23 March.

GP records contained information about people- crucially in this case whether people had underlying respiratory diseases. GP records also contain information that either directly or indirectly tell us about factors like age, sex, social class, ethnic group, as well as the diseases and medications people were using. In this study, we looked at how likely people who had respiratory disease were to fall ill with severe covid if they had an underlying respiratory disease compared with people who did not have respiratory diseases. We used an approach that allowed us to ensure we were comparing like with like and removing distortions caused by factors like age, sex, ethnic group, social class, smoking, and other illnesses.

What did you find?
People with respiratory disease were at higher risk of getting severe covid, meaning they were more likely to need to go to hospital, go to ICU, or die from covid than people without such diseases. We looked at people with diseases of the airways, including asthma, chronic obstructive pulmonary disease (COPD, sometimes called chronic bronchitis or emphysema), and people with bronchiectasis. We also looked at people with diseases of the air exchange areas of the lung, conditions including sarcoidosis, extrinsic allergic alveolitis, idiopathic pulmonary fibrosis, and other interstitial lung diseases. We also included people with cystic fibrosis (CF), and who had had lung cancer.

Overall, people with asthma, particularly asthma severe enough to be needing 3 different medicines to control it, were at slightly higher risk of needing to go to hospital or ICU- around 10-30% higher, people with bronchiectasis also had similar sized increased risks. However, people with asthma or bronchiectasis were no more likely to die of covid. People with COPD were about 50% more likely to need hospital care and die from covid. People with interstitial lung diseases were also around 40-50% more likely to need hospital admission and die from covid. People with lung cancer were twice as likely to need hospital care or die from covid. There were too few people with CF to give accurate information, but their risk seemed to be around a 50% higher risk of going to hospital.

People with interstitial disease and the most severe forms of asthma, COPD, CF, and interstitial lung diseases were shielding after March 23. We found no evidence that the risk relative to everyone without these diseases changed after this time. This does not tell us about the success of shielding, but it perhaps suggests that the risk to people with respiratory diseases seen before it came in was not falsely lowered too much by people’s wariness of becoming infected in March and April 2020.

What does this mean- should I be worried?
Coronavirus has been anxiety provoking for us all, but it does seem that people with respiratory disease have felt especially anxious. These results may seem to justify that. We find an increased risk. While we don’t want to tell people how to feel, we tried in the research to put the increased risk into context. One way to look at this is to compare the risk of severe covid that having a respiratory illness gives a person with the risk that comes from having other types of illness. For example, having diabetes increases the risk of getting severe covid by 200-300%, while having respiratory disease increases the risk between 10-50%, so respiratory disease is much less of a risk. Likewise, one factor we can’t avoid is our sex. Being a man increases the risk as much as having a respiratory illness for hospitalisation, but men are at much greater risk of needing ICU care or dying of covid because they are a man than are people with respiratory illness. Of course, we add all our risk factors together- around half of people with respiratory illness are men, after all. But perhaps respiratory disease is not the biggest risk we face.

We calculated something called the normal risk of death. How confident do you feel you’ll still be alive in 3 months? The probability you won’t be alive is your ‘normal risk’ of death. During the period from end of January to end of April 2020, how did the risk of dying from covid because of underlying respiratory disease compare with the risk of death from all other causes of death? In the main, the risks of death from covid because of underlying respiratory disease were a small fraction of the normal risk of death. In other words, the ordinary risks of death we all face outweighed the increased risks from covid because of respiratory disease.

Implications and Impact

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. This has implications for the advice the public are given about their smoking and treatments to quit, guidance for tobacco smokers, nicotine users and those with airways disease during the coronavirus pandemic and treatment for tobacco smokers and those with airways disease infected with COVID-19.

Funding Source

NA

Research Team

Professor Paul Aveyard; (1) Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Observatory Quarter, Oxford, UK, OX2 6GG; (2) NIHR Oxford Biomedical Research Centre, Oxford University Hospitals, NHS Foundation Trust, Oxford, UK, OX2 6GG

Dr Nicola Lindson; Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Observatory Quarter, Oxford, UK, OX2 6GG

Min Gao; (1) Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Observatory Quarter, Oxford, UK, OX2 6GG; (2) NIHR Oxford Biomedical Research Centre, Oxford University Hospitals, NHS Foundation Trust, Oxford, UK, OX2 6GG

Dr Jamie Hartmann-Boyce;  (1) Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Observatory Quarter, Oxford, UK, OX2 6GG; (2) NIHR Oxford Biomedical Research Centre, Oxford University Hospitals, NHS Foundation Trust, Oxford, UK, OX2 6GG

Dr Margaret Smith;  (1) Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Observatory Quarter, Oxford, UK, OX2 6GG; (2) NIHR Oxford Biomedical Research Centre, Oxford University Hospitals, NHS Foundation Trust, Oxford, UK, OX2 6GG

Professor Duncan Young; Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK, OX3 9DU

Professor Carol Coupland; Faculty of Medicine & Health Sciences, University of Nottingham, University Park, Nottingham, UK, NG7 2RD 

Dr Pui San Tan; Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Observatory Quarter, Oxford, UK, OX2 6GG

Dr Ashley K. Clift; Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Observatory Quarter, Oxford, UK, OX2 6GG

Professor David Harrison; Intensive Care National Audit & Research Centre (ICNARC), Napier House, 24 High Holborn, London, UK, WC1V 6AZ 

Dr Doug Gould; Intensive Care National Audit & Research Centre (ICNARC), Napier House, 24 High Holborn, London, UK, WC1V 6AZ

Professor Ian D Pavord; University of Oxford, Nuffield Department of Medicine, Old Road Campus, Oxford, UK, OX3 7FZ   

Professor Peter Watkinson; Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK, OX3 9DU 

Professor Julia Hippisley-Cox; Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Observatory Quarter, Oxford, UK, OX2 6GG

Approval Letters

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Download Approval Letter amendment 1

Download Approval Letter amendment 2

Publications

  • 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
    Authors: Paul Aveyard, Nicola Lindson, Min Gao, Jamie Hartmann-Boyce, Margaret Smith, Duncan Young, Carol Coupland, Pui San Tan, Ashley K Clift, David Harrison, Doug W Gould, Ian Pavord, Peter Watkinson, Julia Hippisley-Cox
    Ref:
    https://www.medrxiv.org/content/10.1101/2020.06.05.20116624v1
  • Association between pre-existing respiratory disease and its treatment, and severe COVID-19: a population cohort study
    Authors: Paul Aveyard, Min Gao, Nicola Lindson, Jamie Hartmann-Boyce, Peter Watkinson, Duncan Young, Carol A C Coupland, Pui San Tan, Ashley K Clift, David Harrison, Doug W Gould, Ian D Pavord, Julia Hippisley-Cox
    Ref:
    https://pubmed.ncbi.nlm.nih.gov/33812494/
  • Association between pre-existing respiratory disease and its treatment, and severe COVID-19: a population cohort study. The Lancet
    Authors: Paul Aveyard, Min Gao, Nicola Lindson, Jamie Hartmann-Boyce, Peter Watkinson, Duncan Young, Carol A C Coupland, Pui San Tan, Ashley K Clift, David Harrison, Doug W Gould, Ian D Pavord, Julia Hippisley-Cox
    Ref:
    https://www.thelancet.com/action/showPdf?pii=S2213-2600%2821%2900095-3

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