|Last updated: August 2020
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 in Australia: Facts and issues. Melbourne: Cancer Council Victoria; 2020. 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 This Section examines the evidence with respect to acute infections: pneumonia, invasive pneumococcal disease, meningococcal disease, 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.4 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.5
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, 6 Smoking can increase the incidence, duration and/or severity of respiratory infections caused by numerous types of viruses and bacteria.7 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, 8 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, 6
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.9 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.10, 11
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.9 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,12 suppression of NLF IL-6 nasal inflammatory and anti-viral responses,13 repression of responses to bacteria through NF-kappaB (a master regulator of critical defence genes),14 inhibition of pulmonary T-lymphocyte responses to influenza and tuberculosis,15 inhibition of type II interferon responses (antiviral mechanisms) in airway epithelial cells7 and a decrease in the amount of intelectin 1 (an immune defence protein) in the airways.16
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.17
Evidence from several studies confirms that smoking is significantly associated with the development of bacterial and viral pneumonia.2, 6, 18, 19 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.20, 21
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,22 and other studies indicate secondhand smoke exposure23, 24 as factors that predispose the elderly population to pneumonia.22, 24 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.23 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, 25 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.19, 26
188.8.131.52 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 2.5.27 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.27
184.108.40.206 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.28
Although meningococcal disease is rare in Australia, it has a high mortality rate. There were 381 notifications of invasive meningococcal disease in Australian in 2017.29 Approximately 10% of infected people died from the disease, and 10–20% of survivors had long-term health problems.29 Australian has five common strains of meningococcal bacteria (A, B, C, W-135 and Y) that are all preventable by vaccines.30
There is evidence from case–control studies that tobacco smoke exposure independently increases the risk of developing meningococcal disease.3, 31 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.31 Smoking also was found to be a risk factor for an outbreak of meningococcal disease in adults in Italy in 2015.32
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.33 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.34 Worldwide, an estimated 10 million people fell ill and 1.5 million people died due to tuberculosis in 2018.33 Overall, Australia has one of the lowest incident rates of tuberculosis in the world at 5.7 cases per 100,000 people in 2014.35 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.36 Aboriginal and Torres Strait Islander peoples have a 6-fold higher incidence of tuberculosis than non-Indigenous Australians.35 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.37
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.38
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.39, 40 Some studies estimate that at least one in five deaths from tuberculosis could be avoided if patients were non-smokers.41-43 As with active smoking, exposure to secondhand smoke is also a risk factor for the development of tuberculosis,44 especially in children.40 Smoking also increased the risk of diagnosis with secondary multidrug-resistant tuberculosis.45
Quitting smoking and prevention of exposure to secondhand smoke are both important measures in the control of tuberculosis.19 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.46
3.9.5 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.47 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.47 Australia’s incidence of HIV remains relatively low, with 4.2 notifications of infection per 100,000 people in 2016.48
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.49 The authors of a 2007 systematic review suggest that smoking may be an independent risk factor for acquiring HIV infection50 but this finding is inconsistent with other reviews.3 Research into the association between smoking and HIV disease progression has produced inconsistent findings.51 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.38 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
3.9.6 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.9
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
3.9.7 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.52 Tobacco use was also independently associated with a higher prevalence of sexually transmitted chlamydia and gonorrhoea (both bacterial infections).19
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.53 Cervical cancer, caused by persistent oncogenic HPV infection, is a serious health burden, particularly in developing countries.54 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 2019.55 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.56, 57 Oral HPV infection, a risk factor for rare oropharyngeal cancer, is higher in people with past exposure to tobacco.58
3.9.9 Surgical infections (see 3.15.1)
3.9.10 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, 9 These mixed findings may reflect the wide-ranging causes for bacteraemia.
3.9.11 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.59 Around 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.60 Aside from the common cold, the less virulent coronaviruses sometimes infect the lower respiratory tract, leading to pneumonia, bronchitis, bronchiolitis and croup.61 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).59, 62 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 can also be transmitted by the touching of fomites: surfaces of inanimate object that temporarily harbour live viruses.63
Coronaviruses are present worldwide. Of the four types that cause common colds, three are 60distributed 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.60 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.60, 64
220.127.116.11 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).59, 65 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.64 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%.66 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 July 2020.67, 68 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.69 Whether smoking was a risk factor for SARS-CoV during the 2002–2004 epidemic has not been definitively investigated.
18.104.22.168 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 2019.70, 71 Spreading worldwide, the COVID-19 pandemic has infected over 19 million people and led to over 700 thousand deaths (as of 9th Aug 2020). The case fatality rate from SARS-CoV-2 infection during the COVID-19 pandemic was estimated to be approximately 3.7% (ranging from 0.1% in Singapore to 28.8% in the Yemen).72, 73 However, this number depends on accurate and consistent global reporting of cases and deaths during the pandemic, complicated by the existence of asymptomatic cases. Australia has been fortunate that effective public health measures have limited the spread of COVID cases, leading to a relatively low incidence and mortality. However, the state of Victoria is currently experiencing a second wave. As of 9th June 2020, there have been 20,893 cases and 295 deaths from the COVID-19 pandemic in Australia.72
This section is being updated regularly to report important developments in the research field as they become available. The current version is from 9th August 2020.
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 disease has been the subject of debate. Current evidence from observational studies indicates that smokers are less likely to be diagnosed with COVID 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 infection than non-smokers.
Initial studies of COVID 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%,74 6.4%75 or 14.5%.76 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.77 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 disease, and may even be a protective factor.78
Multiple studies from at least 20 countries have similar findings, summarised in a living rapid evidence review.79 These studies generally support a lower-than-expected current smoking prevalence in people diagnosed or hospitalised with COVID disease. The prevalence of former smokers was more similar to population prevalence in these studies. No studies from Australia have been included in this review.
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 indicated in these studies is unexpected. There are a number of potential issues with the current data.
In the living rapid evidence review, over half of these studies have collected data from hospitalised patients only. This is a source of potential bias, as it cannot be assumed that the prevalence of smoking among those who are hospitalised will be the same as the whole population of the country. Some of the reviewed studies included both community and hospitalised patients. Including data from the community had mixed effects on the estimated prevalence of smoking in people who are diagnosed with COVID. Studies of community and hospitalised people in the US produced a lower estimate of the smoking prevalence compared to hospital data. However, including community data increased the estimate of smoking prevalence in people with COVID in the UK. Overall, studies that included people in the community have led to estimates that remain lower than the current rate of smoking for each country, with only a couple of exceptions.79 Therefore the over-use of data for hospitalised people does not seem to have created a bias that could explain the unexpected low smoking prevalence in people with COVID.
It’s possible that smoking status has not been accurately recorded for people admitted to hospital with COVID, creating a bias that has skewed the results of these studies.
A publication in the Lancet Infectious Diseases journal in May 2020 used multivariate modelling to determined risk factors for COVID diagnosis.80 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.”80
One source of bias, that may have falsely indicated that smokers are less likely to be diagnosed with COVID, 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 current smokers are over-represented in the samples of studies in the living rapid review. 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 test, but 42.3% of current smokers received the test.81 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.82 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 require a test (RR = 0.93, 95% CI = 0.86-1.0, p = 0.045).83
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 among smokers.84 Of 387,109 adults who completed a survey of lifestyle factors by 2010, 760 people were hospitalised with COVID. 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.84 A smaller cohort study from the China produced similar results.85 These two cohort studies have provided 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 incidence.
Association of smoking with the severity of COVID-19 disease
Severity of COVID disease is often measured as the need for hospitalisation, intensive care admission, use of ventilation and/or death. Often a combination is used to indicate severe disease. There is increasing evidence that 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.
An early case series of 78 patients in China that adjusted for other potential risk factors showed that history of smoking was associated with progression to severe disease, with an adjusted odds ratio of 14.3. However there was a wide margin of error around this estimate.75 In this study, 27.3% of hospitalised COVID patients whose disease was classified as severe reported current smoking, compared to 3.0% of those hospitalised with non-severe disease. Consistent with these findings, a systematic review of early studies predicted that smoking was a risk factor for disease severity.86 However, meta-analyses of early studies have had mixed results.87-90 One meta-analysis reported no association of smoking and COVID severity,88 however, numerous subsequent publications claimed errors in their methodology and reasoning, and reported an association of smoking and disease severity when the same data were analysed correctly.91-96
Larger studies and meta-analyses have produced results consistent with smokers suffering more severe disease. A meta-analysis of 19 studies from China, Korea and the US, including 11,590 COVID patients, showed that a history of smoking was significantly associated with progression to more severe disease state or death, with an odds ratio of 1.91.97
A meta-analysis of 22 studies assessed the effect of smoking on COVID disease severity and mortality in 6,310 people.98 Active smoking was associated with a 1.34-fold higher odds of severe disease in hospitalised patients. There was no significant effect of smoking on mortality, but there was insufficient data to make conclusions in this regard. The authors noted that a poor quality of some studies used in this meta-analysis was a limitation of their study.98 Another meta-analysis of 12 studies examined the association of smoking with admission to intensive care in hospitalised patients. Requiring intensive care for COVID disease was associated with smoking history, as well as diseases caused by smoking, such as diabetes, hypertension and COPD.99
A study of 20,804 older Mexican people examined the effects of smoking and other risk factors on disease severity.100 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.100 A smaller study from the US compared 220 hospitalised and 311 non-hospitalised patients with COVID. 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.101
A living rapid evidence review combined data from multiple studies to assess COVID disease severity in current, former and never-smokers.79 Current and former smokers were at increased risk of hospitalisation with COVID-19, but data for current smokers were inconclusive and favoured there being no important association. Current and former smokers were at increased risk of in-hospital mortality compared to never-smokers. The data for current smokers were considered inconclusive but favoured there being a small but important association.79 All the studies in these meta-analyses were considered “fair” quality. There is a need for high-quality studies to better address the question of smoking as a risk factor for COVID disease severity.
Smoking and COVID disease severity in people with other serious illnesses
Smoking was associated with poor outcomes for people with COVID together with other serious illnesses. A meta-analysis of 15 studies, including 2,473 COVID patients, showed that current smokers with chronic obstructive pulmonary disease (COPD) were at greater risk of severe complications or death from COVID compared to former or never smokers with COPD.102 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 disease or death.103 A registry-based study of people with thoracic cancer and COVID infection showed that a history of smoking was independently associated with increased risk of death from COVID. People in this study with a history of smoking had a 3.18-fold higher odds of dying, compared to never smokers.104 People with lung cancer and COVID were almost 3-fold more likely to have severe disease if they had a history of smoking, in a study from the US.105 Smoking was strongly associated with mortality for people with COVID who had urgent surgery for hip fractures.106
22.214.171.124 Potential mechanisms for the effect of smoking on COVID infection and outcomes
As described in 126.96.36.199, smoking appears be a risk factor for COVID 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 disease and mortality. Smoking has a causal association for several conditions that are independently associated with poor outcomes from COVID. These include COPD, diabetes and cardiovascular diseases.38 These pre-existing conditions seem to increase the vulnerability of patients to COVID severity. By increasing the rates of COPD and cardiovascular diseases in smokers, smoking is likely to indirectly increase COVID 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 infection or make the disease worse, but this is yet to be examined by researchers.
SARS-CoV-2, the virus causing COVID, is transmitted via inhalation of virus into the lungs and possibly by contact with virus in fomites.63 Smoking has effects on people’s behaviour that may put them at greater risk of infection and transmission. Smoking and vaping increase hand-to-mouth activity that may increase the transmission of SARS-CoV-2 via exposure to virus on fomites (objects and surfaces). Addiction to nicotine may lead to people leaving their houses more often for smoking or purchasing nicotine products, increasing their risk of contact with an infected person. Whether these potential mechanisms have increased the risk for smokers needs to be addressed in future studies.
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.65 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.107-111 However the evidence for this potential mechanism is indirect and inconsistent, with some researchers showing that nicotine may increase ACE2 receptor numbers.112 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.113
Relevant news and research
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1. US Department of Health and Human Services. How tobacco smoke causes disease: the biology and behavioral basis for smoking-attributable disease. A report of the US Surgeon General, Atlanta, Georgia: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2010. Available from: http://www.surgeongeneral.gov/library/tobaccosmoke/report/index.html.
2. Arcavi L and Benowitz NL. Cigarette smoking and infection. Archives of Internal Medicine, 2004; 164(20):2206-16. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15534156
3. Huttunen R, Heikkinen T, and Syrjanen J. Smoking and the outcome of infection. Journal of Internal Medicine, 2011; 269(3):258-69. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21175903
4. Eccles MP, Grimshaw JM, Johnston M, Steen N, Pitts NB, et al. Applying psychological theories to evidence-based clinical practice: identifying factors predictive of managing upper respiratory tract infections without antibiotics. Implementation Science, 2007; 2:26. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17683558
5. Britt H, Miller GC, Charles J, Henderson J, Bayram C, et al. General practice activity in Australia 2009–10. Canberra, Australia: Australian Institute of Health and Welfare, 2010. Available from: https://www.aihw.gov.au/getmedia/ab96aa0b-a070-4026-a57e-bc96d329aae5/12118.pdf.aspx?inline=true.
6. Murin S and Bilello KS. Respiratory tract infections: another reason not to smoke. Cleveland Clinic Journal of Medicine, 2005; 72(10):916-20. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16231688
7. Modestou MA, Manzel LJ, El-Mahdy S, and Look DC. Inhibition of IFN-gamma-dependent antiviral airway epithelial defense by cigarette smoke. Respiratory Research, 2010; 11(1):64. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20504369
8. Pastor P, Medley F, and Murphy TV. Invasive pneumococcal disease in Dallas County, Texas: results from population-based surveillance in 1995. Clinical Infectious Diseases, 1998; 26(3):590-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/9524828
9. Feldman C and Anderson R. Cigarette smoking and mechanisms of susceptibility to infections of the respiratory tract and other organ systems. Journal of Infection, 2013; 67(3):169-84. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23707875
10. Charlson ES, Chen J, Custers-Allen R, Bittinger K, Li H, et al. Disordered microbial communities in the upper respiratory tract of cigarette smokers. PLoS ONE, 2010; 5(12):e15216. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21188149
11. Huang C and Shi G. Smoking and microbiome in oral, airway, gut and some systemic diseases. Journal of Translational Medicine, 2019; 17(1):225. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31307469
12. Wu W, Patel KB, Booth JL, Zhang W, and Metcalf JP. Cigarette smoke extract suppresses the RIG-I-initiated innate immune response to influenza virus in the human lung. American Journal of Physiology. Lung Cellular and Molecular Physiology, 2011; 300(6):L821-30. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21335520
13. Noah TL, Zhou H, Monaco J, Horvath K, Herbst M, et al. Tobacco smoke exposure and altered nasal responses to live attenuated influenza virus. Environmental Health Perspectives, 2011; 119(1):78-83. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20920950
14. Manzel LJ, Shi L, O'Shaughnessy PT, Thorne PS, and Look DC. Inhibition by cigarette smoke of nuclear factor-kappaB-dependent response to bacteria in the airway. American Journal of Respiratory Cell and Molecular Biology, 2011; 44(2):155-65. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20348206
15. Feng Y, Kong Y, Barnes PF, Huang FF, Klucar P, et al. Exposure to cigarette smoke inhibits the pulmonary T-cell response to influenza virus and Mycobacterium tuberculosis. Infection and Immunity, 2011; 79(1):229-37. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20974820
16. Carolan BJ, Harvey BG, De BP, Vanni H, and Crystal RG. Decreased expression of intelectin 1 in the human airway epithelium of smokers compared to nonsmokers. Journal of Immunology, 2008; 181(8):5760-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18832735
17. Sattar SBA and Sharma A, Bacterial Pneumonia. Treasure Island (FL), US: StatPearls Publishing LLC; 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK513321/.
18. Almirall J, Serra-Prat M, Bolibar I, and Balasso V. Risk Factors for Community-Acquired Pneumonia in Adults: A Systematic Review of Observational Studies. Respiration, 2017; 94(3):299-311. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28738364
19. Bagaitkar J, Demuth DR, and Scott DA. Tobacco use increases susceptibility to bacterial infection. Tobacco Induced Diseases, 2008; 4(1):12. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19094204
20. Herr C, Beisswenger C, Hess C, Kandler K, Suttorp N, et al. Suppression of pulmonary innate host defence in smokers. Thorax, 2009; 64(2):144-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18852155
21. Hwang JH, Lyes M, Sladewski K, Enany S, McEachern E, et al. Electronic cigarette inhalation alters innate immunity and airway cytokines while increasing the virulence of colonizing bacteria. Journal of Molecular Medicine, 2016; 94(6):667-79. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26804311
22. Fung HB and Monteagudo-Chu MO. Community-acquired pneumonia in the elderly. American Journal of Geriatric Pharmacotherapy, 2010; 8(1):47-62. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20226392
23. Baskaran V, Murray RL, Hunter A, Lim WS, and McKeever TM. Effect of tobacco smoking on the risk of developing community acquired pneumonia: A systematic review and meta-analysis. PLoS ONE, 2019; 14(7):e0220204. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31318967
24. Loeb M, Neupane B, Walter SD, Hanning R, Carusone SC, et al. Environmental risk factors for community-acquired pneumonia hospitalization in older adults. Journal of the American Geriatrics Society, 2009; 57(6):1036-40. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19467147
25. Jo BS, Lee J, Cho Y, Byun J, Kim HR, et al. Risk factors associated with mortality from pneumonia among patients with pneumoconiosis. Annals of Occupational and Environmental Medicine, 2016; 28:19. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27057317
26. Ginevra C, Duclos A, Vanhems P, Campese C, Forey F, et al. Host-related risk factors and clinical features of community-acquired legionnaires disease due to the Paris and Lorraine endemic strains, 1998-2007, France. Clinical Infectious Diseases, 2009; 49(2):184-91. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19508168
27. Nuorti JP, Butler JC, Farley MM, Harrison LH, McGeer A, et al. Cigarette smoking and invasive pneumococcal disease. Active Bacterial Core Surveillance Team. New England Journal of Medicine, 2000; 342(10):681-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/10706897
28. Harrison LH. Epidemiological profile of meningococcal disease in the United States. Clinical Infectious Diseases, 2010; 50 Suppl 2(S2):S37-44. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20144015
29. Australian Institute for Health and Welfare (AIHW). Meningococcal disease in Australia. Vaccine preventable disease fact sheets., Canberra, Australia: Australian Institute for Health and Welfare (AIHW). 2018. Available from: https://www.aihw.gov.au/reports/immunisation/vaccine-preventable-diseases/contents.
30. The Meningitis Centre. Meningitis. Available from: http://meningitis.com.au.
31. Fischer M, Hedberg K, Cardosi P, Plikaytis BD, Hoesly FC, et al. Tobacco smoke as a risk factor for meningococcal disease. Pediatric Infectious Disease Journal, 1997; 16(10):979-83. Available from: https://www.ncbi.nlm.nih.gov/pubmed/9380476
32. Miglietta A, Innocenti F, Pezzotti P, Riccobono E, Moriondo M, et al. Carriage rates and risk factors during an outbreak of invasive meningococcal disease due to Neisseria meningitidis serogroup C ST-11 (cc11) in Tuscany, Italy: a cross-sectional study. BMC Infectious Diseases, 2019; 19(1):29. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30621624
33. World Health Organization (WHO). Tuberculosis Fact Sheet.: World Health Organization (WHO), 2020. Available from: https://www.who.int/news-room/fact-sheets/detail/tuberculosis.
34. Russell DG, Barry CE, 3rd, and Flynn JL. Tuberculosis: what we don't know can, and does, hurt us. Science, 2010; 328(5980):852-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20466922
35. Toms C, Stapledon R, Coulter C, and Douglas P. Tuberculosis notifications in Australia, 2014. Communicable Diseases Intelligence Q Report, 2017; 41(3):E247-E63. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29720074
36. Cormier M, Schwartzman K, N'Diaye DS, Boone CE, Dos Santos AM, et al. Proximate determinants of tuberculosis in Indigenous peoples worldwide: a systematic review. Lancet Global Health, 2019; 7(1):e68-e80. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30554764
37. Robertus LM, Konstantinos A, Hayman NE, and Paterson DL. Tuberculosis in the Australian Indigenous population: history, current situation and future challenges. Australian and New Zealand Journal of Public Health, 2011; 35(1):6-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21299692
38. US Department of Health and Human Services. The health consequences of smoking - 50 years of progress. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014. Available from: https://www.ncbi.nlm.nih.gov/books/NBK179276/.
39. Bates MN, Khalakdina A, Pai M, Chang L, Lessa F, et al. Risk of tuberculosis from exposure to tobacco smoke: a systematic review and meta-analysis. Archives of Internal Medicine, 2007; 167(4):335-42. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17325294
40. Lin HH, Ezzati M, and Murray M. Tobacco smoke, indoor air pollution and tuberculosis: a systematic review and meta-analysis. PLoS Medicine, 2007; 4(1):e20. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17227135
41. Gajalakshmi V, Peto R, Kanaka TS, and Jha P. Smoking and mortality from tuberculosis and other diseases in India: retrospective study of 43000 adult male deaths and 35000 controls. Lancet, 2003; 362(9383):507-15. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12932381
42. Leung CC, Li T, Lam TH, Yew WW, Law WS, et al. Smoking and tuberculosis among the elderly in Hong Kong. American Journal of Respiratory and Critical Care Medicine, 2004; 170(9):1027-33. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15282201
43. Sitas F, Urban M, Bradshaw D, Kielkowski D, Bah S, et al. Tobacco attributable deaths in South Africa. Tobacco Control, 2004; 13(4):396-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15564624
44. Leung CC, Lam TH, Ho KS, Yew WW, Tam CM, et al. Passive smoking and tuberculosis. Archives of Internal Medicine, 2010; 170(3):287-92. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20142576
45. Sharma P, Lalwani J, Pandey P, and Thakur A. Factors Associated with the Development of Secondary Multidrug-resistant Tuberculosis. International Journal of Preventive Medicine, 2019; 10:67. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31198502
46. Centre for Excellence in Indigenous Tobacco Control. Just the facts: a fact sheet about tobacco use among Indigenous Australians. Parkville, Victoria, Australia: CEITC, 2010. Available from: http://www.ceitc.org.au/.
47. World Health Organization (WHO). HIV/AIDS fact sheet.: World Health Organization (WHO), 2019. Available from: https://www.who.int/news-room/fact-sheets/detail/hiv-aids.
48. Australian Institute of Health and Welfare. Australia’s health 2018. Australia’s health series no. 16. AUS 221, Canberra: AIHW, 2018. Available from: https://www.aihw.gov.au/reports/australias-health/australias-health-2018/contents/table-of-contents.
49. Marshall MM, McCormack MC, and Kirk GD. Effect of cigarette smoking on HIV acquisition, progression, and mortality. AIDS Education and Prevention, 2009; 21(3 Suppl):28-39. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19537952
50. Furber AS, Maheswaran R, Newell JN, and Carroll C. Is smoking tobacco an independent risk factor for HIV infection and progression to AIDS? A systemic review. Sexually Transmitted Infections, 2007; 83(1):41-6. Available from: https://pubmed.ncbi.nlm.nih.gov/16923740/
51. Kabali C, Cheng DM, Brooks DR, Bridden C, Horsburgh CR, Jr., et al. Recent cigarette smoking and HIV disease progression: no evidence of an association. AIDS Care, 2011; 23(8):947-56. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21400309
52. Hellberg D, Nilsson S, and Mardh PA. Bacterial vaginosis and smoking. International Journal of STD and AIDS, 2000; 11(9):603-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/10997505
53. Australian Government Department of Health. HPV (Human papillomavirus). Canberra, Australia: Australian Givernemnt Department of Health, 2020. Available from: https://www.health.gov.au/health-topics/hpv-human-papillomavirus.
54. Huh WK. Human papillomavirus infection: a concise review of natural history. Obstetrics and Gynecology, 2009; 114(1):139-43. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19546771
55. Australian Institute of Health and Welfare. Cancer in Australia 2019. Cancer series no.119, Cat. no. CAN 123 Canberra: AIHW, 2019. Available from: https://www.aihw.gov.au/getmedia/8c9fcf52-0055-41a0-96d9-f81b0feb98cf/aihw-can-123.pdf.aspx?inline=true.
56. Deacon JM, Evans CD, Yule R, Desai M, Binns W, et al. Sexual behaviour and smoking as determinants of cervical HPV infection and of CIN3 among those infected: a case-control study nested within the Manchester cohort. British Journal of Cancer, 2000; 83(11):1565-72. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11076670
57. Fang JH, Yu XM, Zhang SH, and Yang Y. Effect of smoking on high-grade cervical cancer in women on the basis of human papillomavirus infection studies. Journal of Cancer Research and Therapeutics, 2018; 14(Supplement):S184-S9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29578171
58. Hearnden V, Murdoch C, D'Apice K, Duthie S, Hayward NJ, et al. Oral human papillomavirus infection in England and associated risk factors: a case-control study. BMJ Open, 2018; 8(8):e022497. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30122664
59. Song Z, Xu Y, Bao L, Zhang L, Yu P, et al. From SARS to MERS, Thrusting Coronaviruses into the Spotlight. Viruses, 2019; 11(1). Available from: https://www.ncbi.nlm.nih.gov/pubmed/30646565
60. Su S, Wong G, Shi W, Liu J, Lai ACK, et al. Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses. Trends in Microbiology, 2016; 24(6):490-502. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27012512
61. Cecil RL, Goldman L, and Schafer AI, Goldman’s Cecil Medicine, Expert Consult. 24 ed Vol. 1. Philadelphia, USA: Elsevier Saunders; 2012. Available from: https://books.google.com.au/books?id=Qd-vvNh0ee0C&printsec=frontcover&source=gbs_ge_summary_r&cad=0#v=onepage&q&f=false.
62. Covid Investigation Team. Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States. Nature Medicine, 2020; 26(6):861-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32327757
63. van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, et al. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. New England Journal of Medicine, 2020; 382(16):1564-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32182409
64. World Health Organization (WHO). Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July 2003. Geneva, Switzerland: World Health Organization, 2020. Available from: https://www.who.int/csr/sars/country/table2004_04_21/en/.
65. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 2020; 579(7798):270-3. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32015507
66. World Health Organization (WHO). Middle East respiratory syndrome coronavirus (MERS-CoV). Geneva, Switzerland: World Health Organization, 2019. Available from: https://www.who.int/emergencies/mers-cov/en/.
67. The Australian Government Department of Health. Severe acute respiratory syndrome surveillance in Australia. 2004. Available from: https://www1.health.gov.au/internet/main/publishing.nsf/Content/cda-pubs-cdi-2004-cdi2802-htm-cdi2802f.htm.
68. The Australian Government Department of Health. Middle East Respiratory Syndrome (MERS). Canberra, Australia 2018. Available from: https://www1.health.gov.au/internet/main/publishing.nsf/Content/ohp-MERS.
69. Alraddadi BM, Watson JT, Almarashi A, Abedi GR, Turkistani A, et al. Risk Factors for Primary Middle East Respiratory Syndrome Coronavirus Illness in Humans, Saudi Arabia, 2014. Emerging Infectious Diseases, 2016; 22(1):49-55. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26692185
70. Munster VJ, Koopmans M, van Doremalen N, van Riel D, and de Wit E. A Novel Coronavirus Emerging in China - Key Questions for Impact Assessment. New England Journal of Medicine, 2020; 382(8):692-4. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31978293
71. Zhu N, Zhang D, Wang W, Li X, Yang B, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. New England Journal of Medicine, 2020; 382(8):727-33. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31978945
72. Johns Hopkins University. COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU). Baltimore, MA 2020. Available from: https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6.
73. Roser M, Ritchie H, Esteban Ortiz-Ospina E, and Hasell J. Coronavirus Pandemic (COVID-19). Global Change Data Lab. 2020. Available from: https://ourworldindata.org/grapher/coronavirus-cfr?year=2020-05-05&country=AUS+FRA+DEU+ISL+ITA+KOR+USA+OWID_WRL.
74. Wang R, Pan M, Zhang X, Han M, Fan X, et al. Epidemiological and clinical features of 125 Hospitalized Patients with COVID-19 in Fuyang, Anhui, China. International Journal of Infectious Diseases, 2020; 95:421-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32289565
75. Liu W, Tao ZW, Wang L, Yuan ML, Liu K, et al. Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease. Chinese Medical Journal, 2020; 133(9):1032-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32118640
76. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. New England Journal of Medicine, 2020; 382(18):1708-20. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32109013
77. Farsalinos K, Barbouni A, and Niaura R. Systematic review of the prevalence of current smoking among hospitalized COVID-19 patients in China: could nicotine be a therapeutic option? Internal and Emergency Medicine, 2020. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32385628
78. Farsalinos K, Niaura R, Le Houezec J, Barbouni A, Tsatsakis A, et al. Editorial: Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system. Toxicology Reports, 2020; 7:658-63. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32355638
79. Simons D, Shahab L, Brown J, and Perski O. The association of smoking status with SARS-CoV-2 infection, hospitalisation and mortality from COVID-19: A living rapid evidence review (version 6). Qeios, 2020. Available from: https://www.qeios.com/read/UJR2AW.7.
80. de Lusignan S, Dorward J, Correa A, Jones N, Akinyemi O, et al. Risk factors for SARS-CoV-2 among patients in the Oxford Royal College of General Practitioners Research and Surveillance Centre primary care network: a cross-sectional study. Lancet Infectious Diseases, 2020. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32422204
81. Rentsch CT, Kidwai-Khan F, Tate JP, Park LS, King JT, et al. Covid-19 Testing, Hospital Admission, and Intensive Care Among 2,026,227 United States Veterans Aged 54-75 Years. medRxiv, 2020. Available from: https://pubmed.ncbi.nlm.nih.gov/32511595/
82. Niedzwiedz CL, O'Donnell CA, Jani BD, Demou E, Ho FK, et al. Ethnic and socioeconomic differences in SARS-CoV-2 infection: prospective cohort study using UK Biobank. BMC Medicine, 2020; 18(1):160. Available from: https://pubmed.ncbi.nlm.nih.gov/32466757/
83. Trubiano JA, Vogrin S, Smibert OC, Marhoon N, Alexander AA, et al. COVID-MATCH65 - A prospectively derived clinical decision rule for severe acute respiratory syndrome coronavirus 2. medRxiv, 2020:2020.06.30.20143818. Available from: https://www.medrxiv.org/content/medrxiv/early/2020/07/02/2020.06.30.20143818.full.pdf
84. Hamer M, Kivimaki M, Gale CR, and Batty GD. Lifestyle risk factors, inflammatory mechanisms, and COVID-19 hospitalization: A community-based cohort study of 387,109 adults in UK. Brain, Behavior and Immunity, 2020; 87:184-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32454138
85. Zhu W, Xie K, Lu H, Xu L, Zhou S, et al. Initial clinical features of suspected coronavirus disease 2019 in two emergency departments outside of Hubei, China. Journal of Medical Virology, 2020. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32167181
86. Vardavas CI and Nikitara K. COVID-19 and smoking: A systematic review of the evidence. Tobacco Induced Diseases, 2020; 18:20. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32206052
87. Emami A, Javanmardi F, Pirbonyeh N, and Akbari A. Prevalence of Underlying Diseases in Hospitalized Patients with COVID-19: a Systematic Review and Meta-Analysis. Archives of Academic Emergency Medicine, 2020; 8(1):e35. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32232218
88. Lippi G and Henry BM. Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19). European Journal of Internal Medicine, 2020; 75:107-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32192856
89. Zhao Q, Meng M, Kumar R, Wu Y, Huang J, et al. The impact of COPD and smoking history on the severity of COVID-19: A systemic review and meta-analysis. Journal of Medical Virology, 2020. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32293753
90. Zheng Z, Peng F, Xu B, Zhao J, Liu H, et al. Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis. Journal of Infection, 2020. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32335169
91. Carmona-Bayonas A, Jimenez-Fonseca P, Sanchez Arraez A, Alvarez Mancenido F, and Castanon E. Does active smoking worsen Covid-19? European Journal of Internal Medicine, 2020; 77:129-31. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32507518
92. Gallus S, Lugo A, and Gorini G. No double-edged sword and no doubt about the relation between smoking and COVID-19 severity. European Journal of Internal Medicine, 2020; 77:33-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32564904
93. Guo FR. Active smoking is associated with severity of coronavirus disease 2019 (COVID-19): An update of a meta-analysis. Tobacco Induced Diseases, 2020; 18:37. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32382258
94. Guo FR. A flaw on a meta-analysis of smoking and the severity of COVID-19: the association should have been endorsed. Journal of Public Health, 2020. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32542369
95. Lo E and Lasnier B. Active smoking and severity of coronavirus disease 2019 (COVID-19): The use of significance testing leads to an erroneous conclusion. European Journal of Internal Medicine, 2020; 77:125-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32417144
96. Sanchez JJ, Acevedo N, and Guzman E. Active smoking and severity of coronavirus disease 2019 (COVID-19): Differences in measurement of variables could cause errors in the results. European Journal of Internal Medicine, 2020; 77:127-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32499172
97. Patanavanich R and Glantz SA. Smoking is Associated with COVID-19 Progression: A Meta-Analysis. Nicotine and Tobacco Research, 2020. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32399563
98. Karanasos A, Aznaouridis K, Latsios G, Synetos A, Plitaria S, et al. Impact of smoking status on disease severity and mortality of hospitalized patients with COVID-19 infection: a systematic review and meta-analysis. Nicotine and Tobacco Research, 2020. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32564072
99. Li J, He X, Yuanyuan, Zhang W, Li X, et al. Meta-analysis investigating the relationship between clinical features, outcomes, and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. American Journal of Infection Control, 2020. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32540370
100. Bello-Chavolla OY, Gonzalez-Diaz A, Antonio-Villa NE, Fermin-Martinez CA, Marquez-Salinas A, et al. Unequal impact of structural health determinants and comorbidity on COVID-19 severity and lethality in older Mexican adults: Considerations beyond chronological aging. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 2020. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32598450
101. Killerby ME, Link-Gelles R, Haight SC, Schrodt CA, England L, et al. Characteristics Associated with Hospitalization Among Patients with COVID-19 - Metropolitan Atlanta, Georgia, March-April 2020. MMWR; Morbidity and Mortality Weekly Report, 2020; 69(25):790-4. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32584797
102. Alqahtani JS, Oyelade T, Aldhahir AM, Alghamdi SM, Almehmadi M, et al. Prevalence, Severity and Mortality associated with COPD and Smoking in patients with COVID-19: A Rapid Systematic Review and Meta-Analysis. PLoS ONE, 2020; 15(5):e0233147. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32392262
103. Kuderer NM, Choueiri TK, Shah DP, Shyr Y, Rubinstein SM, et al. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. Lancet, 2020; 395(10241):1907-18. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32473681
104. Garassino MC, Whisenant JG, Huang LC, Trama A, Torri V, et al. COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study. Lancet Oncology, 2020; 21(7):914-22. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32539942
105. Luo J, Rizvi H, Preeshagul IR, Egger JV, Hoyos D, et al. COVID-19 in patients with lung cancer. Annals of Oncology, 2020. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32561401
106. Kayani B, Onochie E, Patil V, Begum F, Cuthbert R, et al. The effects of COVID-19 on perioperative morbidity and mortality in patients with hip fractures. The Bone & Joint Journal, 2020:1-10. Available from: https://pubmed.ncbi.nlm.nih.gov/32634023/
107. Brake SJ, Barnsley K, Lu W, McAlinden KD, Eapen MS, et al. Smoking Upregulates Angiotensin-Converting Enzyme-2 Receptor: A Potential Adhesion Site for Novel Coronavirus SARS-CoV-2 (Covid-19). Journal of Clinical Medicine, 2020; 9(3). Available from: https://www.ncbi.nlm.nih.gov/pubmed/32244852
108. Cai G, Bosse Y, Xiao F, Kheradmand F, and Amos CI. Tobacco Smoking Increases the Lung Gene Expression of ACE2, the Receptor of SARS-CoV-2. American Journal of Respiratory and Critical Care Medicine, 2020; 201(12):1557-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32329629
109. Kabbani N and Olds JL. Does COVID19 Infect the Brain? If So, Smokers Might Be at a Higher Risk. Molecular Pharmacology, 2020; 97(5):351-3. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32238438
110. Leung JM, Yang CX, Tam A, Shaipanich T, Hackett TL, et al. ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19. European Respiratory Journal, 2020; 55(5). Available from: https://www.ncbi.nlm.nih.gov/pubmed/32269089
111. Olds JL and Kabbani N. Is nicotine exposure linked to cardiopulmonary vulnerability to COVID-19 in the general population? FEBS Journal, 2020. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32189428
112. Oakes JM, Fuchs RM, Gardner JD, Lazartigues E, and Yue X. Nicotine and the renin-angiotensin system. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 2018; 315(5):R895-R906. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30088946
113. Bao R, Hernandez K, Huang L, and Luke JJ. ACE2 and TMPRSS2 expression by clinical, HLA, immune, and microbial correlates across 34 human cancers and matched normal tissues: implications for SARS-CoV-2 COVID-19. Journal for ImmunoTherapy of Cancer, 2020; 8(2). Available from: https://pubmed.ncbi.nlm.nih.gov/32675312/