Last updated: July 2021
Suggested citation: Winnall, WR, Bellew, B, Greenhalgh, EM, & Winstanley, MH. 3.9 Increased susceptibility to infection in smokers. In Greenhalgh, EM, Scollo, MM and Winstanley, MH [editors]. Tobacco tin Australia: Facts and issues. Melbourne: Cancer Council Victoria; 2021. Available from http://www.tobaccoinaustralia.org.au/3-9-increased-susceptibility-to-infection-in-smoke
Inhaling the complex chemical mixture of combustion compounds in tobacco smoke causes adverse health outcomes through mechanisms that include DNA damage, inflammation, impaired immune responses and oxidative stress.1 Smoking has substantial adverse effects on the immune system, both locally (such as in the respiratory tract and soft tissues in the lungs) and throughout the body. As a result, smokers are at increased risk of a wide range of infections.2, 3 Smoking causes diseases such as cancer (requiring chemotherapy)4 and chronic obstructive pulmonary disease,5 that also increase the risk of infections.
Smoking increases the risk of dying from an infectious disease. A longitudinal study of almost 500,000 people in the UK Biobank cohort found that current smokers had a 3.7-fold increased risk of dying from an infection compared to never-smokers, after multivariate adjustment for the effects of other risk factors.6
This Section examines the evidence with respect to acute infections: pneumonia, invasive pneumococcal disease, meningococcal disease, influenza, tuberculosis, HIV, coronaviruses and other viral and bacterial infections. Evidence regarding periodontitis is covered in Section 3.11.1 and surgical infection is discussed in Section 3.15.1. Chronic respiratory conditions such as chronic obstructive pulmonary disease and asthma are covered in Section 3.2.
3.9.1 Acute respiratory infections
An acute respiratory infection is a sudden-onset infectious disease of the respiratory tract that may interfere with normal breathing. Acute respiratory infections may occur in the upper respiratory tract or lower respiratory tract. The upper respiratory tract starts at the nose and sinuses and ends at the vocal cords (larynx). Common upper respiratory tract infections include tonsillitis, pharyngitis, laryngitis, sinusitis, otitis media and the common cold.7 Infections of the lower respiratory tract affect the region that starts at the vocal cords and ends at the lungs, including the trachea, bronchi, bronchioles and alveoli (air sacs) in the lungs. Acute infections of the lower respiratory tract include bronchitis, bronchiolitis and pneumonia. Most acute infections of the respiratory tract are caused by viruses or bacteria; however some rarer infections are fungal or parasitic.
The patient problems most commonly managed overall by Australian general practitioners are respiratory-related. These patient problems accounted for 22 problems per 100 encounters in 2009–10. This category also comprises the majority of new problems presented by patients; 39% of all problems, managed at a rate of 59 per 100 encounters.8
Exposure to tobacco smoke is a substantial risk factor for many acute respiratory infections. Both active and passive smoking increases the risk of many respiratory infections.2, 9 Smoking can increase the incidence, duration and/or severity of respiratory infections caused by numerous types of viruses and bacteria.10 The incidences of respiratory infections are higher in smokers, taking into account potential confounding from sources such as socioeconomic status, age, ethnicity, alcohol and some other risk-taking activities. It is therefore likely that smoking has a causal role in acquiring acute respiratory infections. An example is invasive pneumococcal disease in otherwise healthy young and middle-aged adults. Current smokers (up to the age of 64 years) in one major study had 2.6 times greater odds of infection compared to non-smokers, with an attributable risk of 31% of cases.2, 11 In other words, this study predicts 31% of pneumococcal disease cases could have been avoided if people in this population did not smoke. Cigarette smokers suffer more colds and worse colds, have several-fold higher rates and more severe cases of influenza and are at increased risk of bacterial pneumonia compared with non-smokers.2, 9
The mechanisms causing the enhanced susceptibility to respiratory infections in smokers are multifactorial and include alterations in structural and immune defences. A substantial report of immunologic effects of cigarette smoking was published in 2004 detailing these structural and immunological alternations.2 The structural changes caused by smoking include inflammation, fibrosis (formation of disruptive scar tissue), changes to pathogen adherence and disruption of the respiratory epithelium (cells lining the surface of the respiratory system). Immunological alternations are described below.
Numerous mechanisms have been investigated to explain the disruptive effects of smoking on the immune system. There is evidence that smoking disrupts innate immune responses (first-line defence) and adaptive immune responses (longer-term defence), changes the microbiota (living organisms) in the respiratory tract and has pathogen-related effects. Pathogen-related effects proposed to increase infection rates and impact on outcomes include an increase in the virulence (harmfulness) of bacteria with smoke exposure, increase in the ability of pathogens to adhere to respiratory tract membranes and increase in resistance to antibiotics.12 There is evidence that cigarette smokers have changes to the balance of normal microbial communities of the upper respiratory tract, which are thought to contribute to the prevalence of respiratory tract complications.13, 14
Cigarette smoking disrupts the normal functioning of the immune system that fights infection in the respiratory tract.2 Smoking may cause an increase in the numbers of white blood cells (immune cells) in the blood and lung fluids, consistent with harmful effects of inflammation. Smoking also causes impairment of the normal functioning of immune cells such as neutrophils, lymphocytes, macrophages and natural killer cells, reducing their ability to clear infections.12 Cigarette smoking leads to a decrease in circulating antibodies and a depression of antibody responses.2
A considerable research effort has examined the changes caused by tobacco exposure on a molecular level that may be contributing to disrupted immune responses. Some examples of these changes are: suppression of RIG-I-initiated immune responses to influenza,15 suppression of NLF IL-6 nasal inflammatory and anti-viral responses,16 repression of responses to bacteria through NF-kappaB (a master regulator of critical defence genes),17 inhibition of pulmonary T-lymphocyte responses to influenza and tuberculosis,18 inhibition of type II interferon responses (antiviral mechanisms) in airway epithelial cells10 and a decrease in the amount of intelectin 1 (an immune defence protein) in the airways.19
3.9.2 Chronic respiratory infections
For discussion of chronic respiratory diseases associated with infection such as chronic bronchitis and chronic obstructive pulmonary disease (COPD), see Section 3.2.5.
3.9.3 Pneumonia, pneumococcal disease and meningococcal disease
Pneumonia is an inflammatory disease of the lungs that is most often caused by acute infections. The pathogens causing pneumonia are usually bacteria or viruses, sometimes fungal and, rarely, parasites. Many cases are a combination of bacteria and viruses. Pathogens present in the nose, sinuses or mouth may spread to the lungs, causing pneumonia, or a person may breathe these pathogens directly into the lungs. The most common pathogen causing pneumonia in adults is the bacteria Streptococcus pneumoniae (pneumococcus). Viruses are a common cause of pneumonia, especially in infants and young children. Rhinoviruses, influenza viruses, coronaviruses, adenoviruses and respiratory syncytial viruses are common causes of viral pneumonia. Atypical pneumonia (sometimes called ‘walking pneumonia’) is caused by bacteria such as Legionella pneumophila, Mycoplasma pneumoniae, or Chlamydophila pneumoniae. Pneumocystis jiroveci pneumonia is sometimes seen in people whose immune system is impaired (due to HIV infection or immunosuppressive medications). Staphylococcus aureus, Moraxella catarrhalis, Klebsiella pneumoniae and Haemophilus influenzae are other examples of bacteria that cause pneumonia.20
Evidence from several studies confirms that smoking is significantly associated with the development of bacterial and viral pneumonia.2, 9, 21, 22 Exposure to tobacco smoke suppresses the activation of innate immune responses to bacterial infection; the front-line defence mechanism considered important in susceptibility to pneumonia.23, 24
Cigarette smoking is an especially prominent risk factor for pneumococcal pneumonia in patients with chronic obstructive pulmonary disease (COPD), but even without COPD, smoking remains a major risk factor. There are reported estimates of increased odds of pneumococcal pneumonia among smokers ranging from an almost two-fold to a four-fold increase in odds for active smoking. Exposure to secondhand smoke has been found to more than double the odds of this infection compared with non-exposed non-smokers.2 A 2010 review indicates active smoking,25 and other studies indicate secondhand smoke exposure26, 27 as factors that predispose the elderly population to pneumonia.25, 27 A 2019 meta-analysis showed that tobacco smoke exposure is significantly associated with the development of community-acquired pneumonia in current smokers and ex-smokers.26 Evidence from several longitudinal studies conducted in large populations confirms a significant increase in pneumonia-associated mortality in smokers compared with non-smokers (but other evidence to-date from cross-sectional studies and meta-analyses is inconsistent).3, 28 There is also strong evidence that smoking is an independent risk factor for Legionnaires disease, an atypical pneumonia that usually develops two to 14 days after exposure to L. pneumophila.22, 29
22.214.171.124 Invasive pneumococcal disease
Invasive pneumococcal disease, caused by S. pneumoniae, results in conditions such as pneumonia, bacteraemia (bacteria in the bloodstream) and meningitis (inflammation of the meninges, the membrane lining of the brain and spinal cord). A study from 2000 found an odds ratio of 4.1 of developing invasive pneumococcal disease for cigarette smokers compared to non-smokers. The odds ratio for passive smokers compared to non-smokers in this study was 2.5.30 There was also a dose–dependent association for pack-years of smoking and time since quitting, and an attributable risk of 51% for cigarette smokers. Approximately 50% of those with invasive pneumococcal disease are cigarette smokers.30
126.96.36.199 Meningococcal disease
Meningococcal disease describes infections caused by Neisseria meningitidis, also known as meningococcal bacteria. Like pneumococcal bacteria, meningococcal bacteria are a cause of meningitis (infection and inflammation of the meninges, the membrane lining of the brain and spinal cord). Meningococcal bacteria are also one of several pathogens that can cause septicaemia (blood poisoning) and sepsis (a serious infection that causes your immune system to attack your body). These bacteria are also a cause of other types of invasive infections worldwide, with major fluctuations in the incidence of endemic disease and the occurrence of outbreaks and epidemics.31
Although meningococcal disease is rare in Australia, it has a high mortality rate. There were 381 notifications of invasive meningococcal disease in Australian in 2017.32 Approximately 10% of infected people died from the disease, and 10–20% of survivors had long-term health problems.32 Australian has five common strains of meningococcal bacteria (A, B, C, W-135 and Y) that are all preventable by vaccines.33
There is evidence from case–control studies that tobacco smoke exposure independently increases the risk of developing meningococcal disease.3, 34 Children under 18 years of age have almost four times the odds of acquiring this disease if they are subjected to maternal smoking. All age groups have more than a doubling of odds from active smoking or from exposure to secondhand smoke compared to no exposure. There is a dose–response relationship between exposure to secondhand smoke and the risk of meningococcal disease in all age groups.34 Smoking also was found to be a risk factor for an outbreak of meningococcal disease in adults in Italy in 2015.35
Influenza is a highly contagious viral infection of the upper and lower respiratory tracts. In severe cases, it causes fluid build-up in the lungs that makes breathing difficult and inhibits oxygen reaching the blood.
The 1964 US Surgeon General’s report found that cigarette smokers had a modestly increased risk of death from influenza.36 The 2014 report of the US Surgeon General states that there is epidemiological evidence of increased risk of influenza in smokers.37 An increased risk for young smokers during influenza epidemics has been reported.38, 39 Whether smoking is a cause of this increased risk has not been assessed by Surgeon General reports.
More recently, two meta-analyses from 2019 have found an increased risk of influenza infection for smokers. In their meta-analysis of 9 studies, Lawrence (2019) found a higher chance of current smokers developing laboratory-confirmed influenza (OR 5.69, CI 2.79–11.60).40 Smokers also had 1.34-fold higher odds (CI 1.13–1.59) of developing influenza-like illness compared to non-smokers. Han (2019) found increased hospital admissions (OR 1.5, CI 1.3-1.7) and ICU admissions (OR 2.2, CI 1.4-3.4) after influenza infection for ever-smokers compared to never-smokers.41 This meta-analysis included 12 studies. It also found some evidence that children under 15 exposed to secondhand smoke had a higher chance being treated in hospital after influenza infection. Neither of these meta-analyses examined differences between current and former smokers, or a dose effect of tobacco exposure.
Tuberculosis is an infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. It typically attacks the lungs but can also affect other parts of the body. The highly infectious M. tuberculosis bacteria are transmitted through inhalation of tiny droplets (aerosols) that have been exhaled into the atmosphere by an infected person. The droplets are small enough to remain airborne for several hours.
Globally, tuberculosis is one of the top 10 causes of death and the leading cause from a single infectious agent.42 Approximately one-third of the human population are skin-test positive for the infection and are thus thought to harbour infection. However, most of these people have a latent infection that will remain indolent during their lifetime. In developed countries, tuberculosis is held in check by effective public health systems. However, in countries where symptomatic disease is endemic, control remains a huge challenge; one that is exacerbated as multidrug-resistant strains continue to evolve.43 Worldwide, an estimated 10 million people fell ill and 1.5 million people died due to tuberculosis in 2018.42 Overall, Australia has one of the lowest incident rates of tuberculosis in the world at 5.7 cases per 100,000 people in 2014.44 Most cases (86%) occurred in people born overseas.
Indigenous people from many different communities around the world are generally reported to have a higher prevalence of tuberculosis, and of risk factors for tuberculosis such as smoking rates, than non-Indigenous people.45 Aboriginal and Torres Strait Islander peoples have a 6-fold higher incidence of tuberculosis than non-Indigenous Australians.44 Looking at tuberculosis rates in countries with a comparable Indigenous population, Australia has a similar rate ratio between the Indigenous and non-Indigenous populations compared with New Zealand and the US, and a much lower rate ratio compared with Canada. There are no grounds for complacency given the probability of ongoing transmission of tuberculosis as well as the obvious need to address the ongoing inequalities.46
The US Surgeon General’s report in 2014 was the first in its series to address the evidence regarding smoking and tuberculosis. It concluded that smoking causes both an increased risk of tuberculosis illness (from M. tuberculosis infection) and increased risk of mortality from tuberculosis. Smoking was also suggested as causing an increased risk of recurrence of symptomatic tuberculosis.37
Subsequent reviews reported that active smoking is a risk factor for infection and that it increases the risk of progression to tuberculosis disease and death.47, 48 Some studies estimate that at least one in five deaths from tuberculosis could be avoided if patients were non-smokers.49-51 As with active smoking, exposure to secondhand smoke is also a risk factor for the development of tuberculosis,52 especially in children.48 Smoking also increased the risk of diagnosis with secondary multidrug-resistant tuberculosis.53
Quitting smoking and prevention of exposure to secondhand smoke are both important measures in the control of tuberculosis.22 These measures are underscored by the earlier information on incidence rates among Indigenous people, given that smoking prevalence is markedly higher in these communities than in the non-Indigenous population.54
3.9.6 Risks for and complications of HIV
Human Immunodeficiency Virus (HIV) infection causes Acquired Immunodeficiency Syndrome (AIDS) if untreated. HIV is transmitted via unsafe sex, sharing of contaminated needles, breast feeding or medical procedures using contaminated equipment or blood. By the end of 2018, there were an estimated 37.9 million people living with HIV, with over 32 million lives claimed by the disease in total.55 In developed countries, most people infected with HIV are successfully treated with antiretroviral drugs, preventing developed of AIDS and reducing transmission of the virus. The situation in developing countries is improving with international efforts to address the pandemic. In 2018, an estimated 62% of adults and 54% of children living with HIV in low- and middle-income countries were receiving lifelong treatment with antiretroviral drugs. An estimated 770,000 people died from HIV-related causes in 2018 and 1.7 million were infected.55 Australia’s incidence of HIV remains relatively low, with 4.2 notifications of infection per 100,000 people in 2016.56
People with HIV are known to have a higher prevalence of smoking than the general population. However, it does not necessarily follow that smoking is causally linked to HIV infection. Most of the studies demonstrating this association use observational methods that may be affected by bias or confounding, since smoking is also associated with other risk-taking activities.57 The authors of a 2007 systematic review suggest that smoking may be an independent risk factor for acquiring HIV infection58 but this finding is inconsistent with other reviews.3 Research into the association between smoking and HIV disease progression has produced inconsistent findings.59 Among people with HIV, smoking may increase the risk of developing COPD, cervical cancer (in those who also have human papillomavirus; HPV) and liver cancer.37 A review concluded that social class, intravenous drug use and compliance with the antiretroviral treatment program are factors that may interact with smoking behaviour, and the independent role of these factors may be difficult to assess in relation to the outcome of HIV infection.3
3.9.7 Other viral infections
Active and passive smoking increases the risks of otitis media (middle ear inflammation and infections). Both viral and bacterial infections are common in this condition.12
Smoking may also lead to indirect adverse outcomes such as the increased risk of hepatocellular carcinoma (cancer of the liver) due to smoking-related progression of chronic viral hepatitis.3
3.9.8 Infections of reproductive organs
A small but growing number of studies have investigated the association between cigarette smoking and infections of reproductive organs.
Bacterial vaginosis (a bacterial infection of the vagina) can cause considerable discomfort. It may lead to more serious infections such as septicaemia and increase the risk of poor pregnancy outcome. A review found that tobacco smoking is significantly associated with bacterial vaginosis, typically being around twice as common in smokers as non-smokers, with a greater prevalence noted in young women.60 Tobacco use was also independently associated with a higher prevalence of sexually transmitted chlamydia and gonorrhoea (both bacterial infections).22
Human papillomavirus (HPV) is a highly contagious virus spread by sexual contact. Most infected people do not have symptoms or long-term consequences. However, for some people, infection with HPV causes cancers of the cervix, vulva, vagina, penis and anus, or some head and neck cancers.61 Cervical cancer, caused by persistent oncogenic HPV infection, is a serious health burden, particularly in developing countries.62 The incidence and mortality rates from cervical cancer have halved in Australia since the introduction of a national screening program in 1991. Cervical cancer incidence in Australia has dropped from 14 cases per 100,000 females in 1982 to 7.2 per 100,000 females in 2019.63 Whilst HPV infection is the biggest risk factor for cervical cancer, smoking is also considered a major risk factor. Women who smoke have an increased risk of cervical cancer and cervical precancerous lesions.64, 65 Oral HPV infection, a risk factor for rare oropharyngeal cancer, is higher in people with past exposure to tobacco.66
3.9.10 Surgical infections (see 3.15.1)
3.9.11 Other bacterial infections
There is evidence that smoking may cause an increased risk of peptic ulcer disease owing to an increased rate of Helicobacter pylori infection.3 There is mixed evidence on the relationship between active smoking, bacteraemia (bloodstream infections) and sepsis (a life-threatening illness in which the bloodstream is overwhelmed by bacteria). About half of studies reviewed finding a positive association of smoking with adverse effects.3, 12 These mixed findings may reflect the wide-ranging causes for bacteraemia.
3.9.12 Coronaviruses and the COVID-19 pandemic
Coronaviruses are a group of related viruses that cause respiratory tract infections with varying severity. There are four strains of coronavirus that usually cause disease of low severity and three that have caused outbreaks with much greater morbidity and mortality. Coronaviruses with low virulence cause illnesses such as the common cold, whereas more dangerous forms cause severe respiratory syndromes such as Middle East Respiratory Syndrome (MERS), with a 35% mortality rate. Generally speaking, the less harmful coronaviruses infect the upper respiratory tract, whilst the more harmful infect the lower and upper respiratory tract, however exceptions exist.67 About 15% of common colds are estimated to result from coronavirus infections. Infection of the gastrointestinal tract by coronaviruses has also been observed. Symptoms caused by common cold coronaviruses include fever, runny nose, cough, malaise and headache.68 Aside from the common cold, the less virulent coronaviruses sometimes infect the lower respiratory tract, leading to pneumonia, bronchitis, bronchiolitis and croup.69 Three coronaviruses that infect both the upper and lower respiratory tracts have been responsible for serious outbreaks with high mortality rates: SARS-CoV-1, (causing the 2002-2004 Severe Acute Respiratory Syndrome (SARS) outbreak), MERs-CoV (causing MERS outbreaks from 2012) and SARS-CoV-2 (causing the 2019-2020 COVID-19 pandemic).67, 70 People infected with SARS or MERS have symptoms ranging from mild to severe.
Coronavirus transmission between people can occur when virus is expelled from the respiratory tract during breathing, coughing or sneezing, then breathed in by an uninfected person. Coronaviruses may also be transmitted by the touching of fomites: surfaces of inanimate object that temporarily harbour live viruses.71, 72
Coronaviruses are present worldwide. Of the four types that cause common colds, three are distributed globally and tend to be transmitted predominantly during the winter season in temperate-climate countries, while the NL63 virus has a spring-to-summer peak, at least in Hong Kong.68 These four coronaviruses are believed to have circulated in human populations for a long time, and are not known to infect animals. The three strains causing serious outbreaks are believed to have arisen from animal reservoirs, where humans are infected by new forms of virus found in animals.68, 73
188.8.131.52 SARS and MERS outbreaks since 2002
The pathogenic SARS-CoV, MERS-CoV and SARS-CoV-2 coronaviruses are predicted to have recent origins in animals such as bats (SARS) and camels (MERS).67, 74 Recombination events, that mix the genetic material of viruses, are predicted to have given rise to these newer forms of coronaviruses, causing serious outbreaks. The 2002-2004 SARS outbreak (caused by SARS-CoV) had a reported total of over 8,000 cases and 774 deaths. The outbreak had a case fatality rate of 9.6%. Cases were reported in 29 countries with the vast majority in China and Hong Kong.73 MERS outbreaks have occurred in 2012, 2015 and 2018, with most cases in the Middle East and South Korea. From 2012 to April 2020, 2,494 cases have been reported in over 27 countries, with 858 deaths. This is a case fatality rate of 34.4%.75 Strict public health measures, contract tracing and surveillance were used to control these epidemics.
Australia has been affected by a six suspected cases of SARS from the 2002–2004 outbreak but no cases of MERS as of 2020.76, 77 There have been no deaths from MERS or the SARS 2002–2004 outbreak reported in Australia.
Smoking is predicted to be a risk factor for MERS-CoV infection; it was independently associated with MERS-CoV infection as shown by multivariate regression analysis.78 Whether smoking was a risk factor for SARS-CoV during the 2002–2004 epidemic has not been definitively investigated.
184.108.40.206 COVID-19 pandemic
At the time of writing this section, Australia was in the midst of the COVID-19 pandemic. This pandemic was caused by an outbreak of the new SARS-CoV-2 virus, originating in China in late 2019.79, 80 Spreading worldwide, the COVID-19 pandemic has infected almost 190 million people and led to over 3.5 million deaths (as of 16th July 2021). The case fatality rate from SARS-CoV-2 infection during the COVID-19 pandemic is currently estimated to be approximately 3.7% (ranging from <0.1% in Singapore and Bhutan to 25% in Vanuatu).81, 82 The accuracy of this number depends on accurate and consistent global reporting of cases and deaths during the pandemic, complicated by the existence of asymptomatic and undetected cases. Australia has been fortunate that effective public health measures have limited the spread of COVID-19 cases, leading to a relatively low incidence and mortality. As of 16th July 2021, there have been 31,516 cases and 912 deaths from the COVID-19 pandemic in Australia.81
This section is being updated regularly to report important developments in the research field as they become available. The current version is from 16th July 2021.
Association of smoking with the incidence of COVID-19 cases
Whether people who smoke, or are otherwise exposed to tobacco, are more likely to be diagnosed with COVID-19 disease has been the subject of debate. Current evidence from observational studies indicates that smokers are less likely to be diagnosed with COVID-19 than non-smokers. However, these studies are potentially affected by bias, which may have distorted the results. In particular, there is evidence that smokers are more likely to be tested for COVID-19 infection than non-smokers.
Initial studies of COVID-19 patient characteristics were mostly case series from China. Some of these studies have estimated the proportion of hospitalised patients who had a history of smoking. Early meta-analyses of these studies estimated the rate of smoking in hospitalised patients to be 12.8%,83 6.4%84 or 14.5%.85 A pooled estimate of 7.3% patients being ever-smokers resulted from a systematic review of Chinese studies with a combined total of almost 6,000 patients.86 This estimate is lower than the WHO’s 2018 estimated prevalence of smoking in China (26.6%), interpreted by some to mean that smoking is not a risk factor for COVID-19 disease, and may even be a protective factor.87
A publication in the Lancet Infectious Diseases journal in May 2020 used multivariate modelling to determined risk factors for COVID-19 diagnosis.88 Among the factors associated with increased risk were age, ethnicity, obesity and living in urban and underprivileged areas. In this study, active smoking was associated with a lower odds of diagnosis. Smokers had approximately half the chance of testing positive. Several plausible explanations for this are proposed, including issues with study bias and accuracy of testing, as well as the possibility that smoking is protective against infection. The study authors state that their “findings should not be used to conclude that smoking prevents SARS-CoV-2 infection, or to encourage ongoing smoking, particularly given the well documented harms to overall health from smoking, the potential for smoking to increase COVID-19 disease severity, and the possible alternative explanations for these findings.”88
Two studies have examined smoking rates among Australians hospitalised with COVID-19. Among 172 critically ill COVID-19 patients, 12.2% reported a history of smoking.89 In this cohort, smokers were older and had a higher incidence of chronic comorbidities. Although this rate of smoking is lower than that among equivalent (COVID-19-negative) intensive care patients (20.3%), it’s similar to the current population prevalence of smoking in Australia. A second Australian study identifying COVID-19-positive people among those presenting to emergency departments also found a rate of smoking prevalence among those testing positive for SARS-CoV-2 that was similar to smoking prevalence among the total Australian population—about 10%.90 Interestingly, in this study of over 30,000 presentations, non-smoking status was reported to be a risk factor for COVID-19 infection. Smoking prevalence in those presenting with COVID-19 was 10%, compared to 38% for people presenting without the infection. Together, these studies indicate that the prevalence of smoking in people hospitalised with COVID-19 in Australia is very similar to the Australian population prevalence of smoking, but lower than expected for those admitted to hospital.
Multiple studies from at least 20 countries have similar findings, summarised in a living rapid evidence review.91 These studies generally support a lower-than-expected current smoking prevalence in people diagnosed or hospitalised with COVID-19 disease. The relative risk of COVID-19 diagnosis for current compared to never smokers was 0.71 (CI: 0.61 – 0.82). The prevalence of former smokers was more similar to population prevalence in these studies, with a relative risk of diagnosis for former compared to never smokers of 1.03 (CI: 0.95 -1.11).
Given the effects of smoking on lung damage, weakening the immune system and increasing susceptibility to lung infections, the lower prevalence of smokers in people diagnosed with COVID-19 indicated in these studies is unexpected. A number of issues complicate interpretation of the current results, as described by the living review authors.91 Certain groups of people, based on age, gender, geographical location and socioeconomic status, are more likely to be exposed to the virus at different times during the pandemic. These groups of people have different levels of smoking. It’s possible that people who were more likely to be exposed were less likely to smoke. Younger people, who in most countries in 2020, are less likely to be current smokers, may be less likely to have symptoms, meaning that they are less likely to be tested for infection. More than half of these studies have collected data from hospitalised patients only. This is a source of potential bias, such as collider bias (see Griffith et al 2020 and Tattan-Birth et al 2020)92, 93 which may have distorted the results indicating association of current and former smoking with COVID-19 diagnosis. It’s also possible that smoking status has not been accurately recorded for many people admitted to hospital with COVID-19, creating a bias that has skewed the results of these studies.
Many of the studies of COVID-19 diagnosis suffer from selection bias. This occurs because the people being tested are not usually chosen at random; they present at clinics for testing for a variety of reasons. One type of selection bias is that smokers are more likely to be tested than non-smokers, possibly because they tend to suffer more frequent coughs and other respiratory symptoms. This would mean that tests of current smokers are over-represented in the samples of these studies. This could increase the denominator in studies that measure the rate of positive tests, artificially decreasing the rate of testing positive for smokers. This hypothesis is supported by three studies. In a study of US military veterans an overall average of 23.8% of the sample received a COVID-19 test, but 42.3% of current smokers received the test.94 A study from the UK found that current (1.29-fold) and former smokers (1.44-fold) were more likely to receive a test in a multivariable analysis.95 In an Australian rapid assessment screening clinic, of all those who attended the clinic, current compared with former or never smokers may have been less likely to have met criteria for (i.e. to have been deemed sufficiently at risk to require) a test (RR = 0.93, 95% CI = 0.86-1.0, p = 0.045).96
A longitudinal cohort study should provide a less biased approach. Results from a large cohort study from the UK supported an increased risk of COVID-19 among smokers.97 Of 387,109 adults who completed a survey of lifestyle factors in years leading up to 2010, 760 people were hospitalised with COVID-19 in 2020. After adjusting for factors such as age, gender and other possible confounders, smokers had a significant 1.42-fold increased risk over never-smokers for hospitalisation with COVID-19.97 Further analysis of this cohort showed that among younger people (less than 69 years) current smokers were nearly twice as likely as never smokers to become infected with the COVID-19 virus. However among older people (aged 69 years and over) there was not difference in infection rates between smokers and non-smokers. Conversely, among older people, smokers were more likely to die from COVID-19 than non-smokers, whereas among young people, there was no difference in mortality risk for smokers compared to never smokers.98 A smaller cohort study from the China produced similar results.99 These two cohort studies provide evidence that smoking is a risk factor for COVID-19 incidence, not a protective factor. More studies that reduce the issues of bias are necessary to provide clarity on the effects of smoking on COVID-19 incidence.
Association of smoking with the severity of COVID-19 disease
Severity of COVID-19 disease is often measured as the need for hospitalisation, intensive care admission, use of ventilation, death or a combination of these measures. There is increasing evidence that a history of smoking is a risk factor for the severity of COVID-19 disease. However, a trend in the data indicates a greater risk for former smokers than current smokers.
Meta-analyses of studies from early in the pandemic generally found that a history of smoking was significantly associated with progression to more severe disease state and/or mortality.100, 101, 102
More recent meta-analyses of studies assessing the association of smoking with COVID-19 severity have had mixed results. A meta-analysis of 18 studies, including over 5,000 people, found that smokers with COVID-19 were less likely to be hospitalised (OR = 0.18).103 However, a meta-analysis of 60 studies, with over 50,000 people in 13 countries showed a higher in-hospital mortality risk for smoking (OR = 1.6).104 Smoking was more strongly associated with mortality for people 60 years of age and under. Current smokers also had an increased risk of severe COVID-19 disease (RR 1.80) in a meta-analysis of 47 studies, reporting on >32,000 hospitalised people with COVID-19 disease.105 People with a history of smoking had an increased risk of severe disease (RR = 1.29) and death (RR = 1.28) in a large meta-analysis of 77 studies, including almost 39,000 people. However, this meta-analysis did not consider current and former smokers separately and included many studies that did not perform multivariate analyses.106
Studies using longitudinal data rather than that collected upon testing or hospital admission should have less measurement bias. A study of 20,804 older Mexican people examined the effects of smoking and other risk factors on disease severity.107 Information came from a Government database updated daily with details of confirmed cases. Therefore, severity of disease was assessed in a broad range of people, not just those admitted to hospital. This study showed that smoking, as well as diabetes, hypertension, obesity and COPD, were all risk factors for hospitalisation for older people with confirmed COVD infection.107 A smaller study from the US compared 220 hospitalised and 311 non-hospitalised patients with COVID-19. Multi-variate analysis was used to show that smokers had a 2.3-fold higher chance of needing hospitalisation. Other risk factors independently associated with hospitalisation included diabetes, obesity and ethnicity.108 A similar study of over 500,000 people from the UK used pre-existing biobank information to show that being a current smoker was independently associated with COVID mortality.109
A living rapid evidence review combined data from multiple studies to assess COVID-19 disease severity in current, former and never-smokers.91 Current (RR 1.08) and former smokers (RR 1.18) were at increased risk of hospitalisation with COVID-19, but data for current smokers were inconclusive and favoured there being no important association. For severe disease, current (RR 1.26) and former smokers (RR 1.80) were at greater risk; these results showed a small but important increase in the risk of severe disease for current smokers. Results were similar for mortality with a relative risk for current smokers of 1.12 and former smokers of 1.56, with the results inconclusive for current smokers.91 As described above, numerous issues, such as potential collider bias, complicate the interpretation of these results.
The OpenSAFELY study examined factors associated with COVID-19-related mortality in over 17 million people in the UK.110 This study linked primary care health records with death records. Both current and former smoking were associated with a higher risk of death from COVID-19 when age and gender were taken into account. However, in a model fully adjusted for various cofactors, current smoking was associated with a lower risk of death from COVID-19 (HR 0.89 (0.82–0.97)). The authors examined issues that may have spuriously affected this result. They found that the change in risk was driven largely by adjustment for chronic respiratory disease. This and other comorbidities are possible consequences of smoking and likely to mediate the effects of smoking on disease severity. Therefore, it may be inappropriate to adjust for them when asking whether smoking is associated with severe disease. A model adjusted for demographic factors only showed no difference in risk of death between current smokers and never smokers (HR 1.07 (0.98–1.18)). This finding suggests that any risk from current smoking is likely to be small and will need to be clarified as the epidemic progresses and more data accumulate.110
Smoking and COVID-19 disease severity in people with other serious illnesses
Smoking appears to be associated with poor outcomes for people with COVID-19 together with other serious illnesses. A meta-analysis of 15 studies, including 2,473 COVID-19 patients, showed that current smokers with chronic obstructive pulmonary disease (COPD) were at greater risk of severe complications or death from COVID-19 compared to former or never smokers with COPD.111 COPD was also associated with poor outcomes in a pooled analysis of data from over 4,000 people.112 A study of 928 patients from the US, Canada and Spain with a range of cancers showed that smoking status was also associated with more severe COVID-19 disease or death.113 A registry-based study of people with thoracic cancer and COVID-19 infection showed that a history of smoking was independently associated with increased risk of death from COVID-19. People in this study with a history of smoking had a 3.18-fold higher odds of dying, compared to never smokers.114 People with lung cancer and COVID-19 were almost 3-fold more likely to have severe disease if they had a history of smoking, in a study from the US.115 Smoking was strongly associated with mortality for people with COVID-19 who had urgent surgery for hip fractures.116 Diabetes is consistently associated with poorer outcomes from COVID. A more recent meta-analysis of studies using multivariate analysis showed that diabetes and age were associated with death from COVID but that smoking was not.117 It is possible that—by statistically adjusting where a condition can be caused by smoking,—the researchers may be masking a real effect of smoking on disease outcomes.110
220.127.116.11 Potential mechanisms for the effect of smoking on COVID-19 infection and outcomes
As described in 18.104.22.168, smoking appears be a risk factor for COVID-19 disease severity, particularly mortality. There are numerous possible mechanisms by which smoking may be increasing risk, but none that have currently been investigated by high-quality experimental studies.
Older age and underlying health problems are common in those with more severe COVID-19 disease and mortality. Smoking causes several conditions that are independently associated with poor outcomes from COVID-19. These include COPD, diabetes and cardiovascular diseases.37 These pre-existing conditions seem to increase the vulnerability of patients to COVID-19 severity. By increasing the rates of COPD and cardiovascular diseases in smokers, smoking is likely to indirectly increase COVID-19 disease severity and mortality. Smoking has a strong negative effect on respiratory health, causing chronic inflammation and reducing immune responses. These conditions may increase the risk of COVID-19 infection or make the disease worse, but this is yet to be examined by researchers.
SARS-CoV-2, the virus causing COVID-19, is transmitted via inhalation of virus into the respiratory tract and possibly by contact with virus on fomites (objects and surfaces that may harbour the virus).71, 118 However, transmission via fomites is now considered to be rare.119 With the main route of viral transmission likely to be via the lungs, it is possible that the effects of smoking on the lungs may alter the infection process.
The SARS-CoV-2 virus gains entry into human cells by binding of the viral spike protein to ACE2 receptor proteins on the surface of alveolar cells.74 A number of researchers have speculated that smoking may increase the risk of SARS-CoV-2 infection by increasing the amount of the ACE2 receptors present in the lungs.120-124 However the evidence for this potential mechanism is indirect and inconsistent, with some researchers showing that nicotine may increase ACE2 receptor numbers.125 Numerous small studies indicate a small increase in ACE2 receptor mRNA or protein expression. However, a large-scale integration of ACE2 and TMPRSS2 gene expression across clinical and genetic data has shown no increase in ACE2 levels in smokers.126
Relevant news and research
For recent news items and research on this topic, click here. (Last updated May 2021)
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