key: cord-0864398-5tjw1f0r
authors: Besaratinia, Ahmad
title: COVID-19: a pandemic converged with global tobacco epidemic and widespread vaping – state of the evidence
date: 2021-07-05
journal: Carcinogenesis
DOI: 10.1093/carcin/bgab061
sha: c80f3234b3ebe9bec81f310c249b39db1bb66cb4
doc_id: 864398
cord_uid: 5tjw1f0r

This review highlights the convergence of three global health challenges at a crossroad where the pandemic of COVID-19 meets the tobacco epidemic and vaping. It begins with an overview of the current knowledge on the biology, pathophysiology, and epidemiology of COVID-19. It then presents the state of smoking and vaping during the pandemic by summarizing the published data on prevalence, use patterns, product availability/accessibility, sales records, and motivation to quit before- and after the start of the pandemic. It highlights the state of evidence on the association of tobacco product use with COVID-19 infection and transmission rates, symptom severity, and clinical outcomes. Also discussed are proposed biological mechanisms and behavioral factors that may modulate COVID-19 risk in tobacco product users. Furthermore, competing hypotheses on the protective effect of nicotine against COVID-19 as well as the claimed “smokers’ paradox” are discussed. Considerations and challenges of COVID-19 vaccination in tobacco product users are underscored. Collectively, the present data show an ‘incomplete’ but rapidly-shaping picture on the association of tobacco product use and COVID-19 infection, disease course, and clinical outcomes. Evidence is also growing on the mechanisms by which tobacco product use may contribute to COVID-19 pathophysiology. While we await definitive conclusions on the relative risk of COVID-19 infection in tobacco product users, compelling data confirm that many comorbidities associated with/caused by smoking predispose to COVID-19 infection, severe disease, and poor prognosis. Additionally, it is becoming increasing clear that should smokers get the disease, they are more likely to have serious health consequences.

With an unabating global tobacco epidemic, killing nearly 8 million people annually (1), the U.S.

Surgeon General declared, in December 2018, youth vaping an epidemic in the United States (2).

Earlier in September 2018, the U.S. Food and Drug Administration (FDA) had called JUUL, the preeminent electronic cigarette (e-cig) on the market (3), a particular cause for concern (4). On to 192 countries, and ravaged nations, causing infections and deaths at an unprecedented pace (6).

As of June 18, 2021, COVID-19 has infected over 177.7 million and killed more than 3.8 million people, worldwide (6). The U.S. holds the unenviable record of having roughly one-fifth of the global cases and one-sixth of all deaths related to this disease (6). The pandemic has wreaked havoc on almost all aspects of daily life, including lifestyle habits, such as substance use, e.g., smoking and vaping.

This review highlights the convergence of three global health challenges at a crossroad where the pandemic of COVID-19 meets the global tobacco epidemic and vaping. Firstly, it provides an overview of the current knowledge on the biology, pathophysiology, and epidemiology of COVID-19. It then summarizes the state of smoking and vaping during the pandemic by featuring the published data on prevalence, use patterns, product availability and accessibility, sales records, and motivation to quit before-and after the start of the pandemic. Moreover, it discusses the existing evidence on the association of tobacco product use with COVID-19 infection and transmission rates, symptom severity, and clinical outcomes. The unique-and overlapping clinical, laboratory, and radiologic features of COVID-19 and "e-cig, or vaping, product use-associated lung injury" (EVALI) (7)

are also described. Furthermore, competing hypotheses on the potential utility of nicotine for A c c e p t e d M a n u s c r i p t 5 prevention and treatment of COVID-19 as well as the claimed "smokers' paradox" are described.

Also highlighted are considerations and challenges of COVID-19 vaccination in tobacco product users. As the global pandemic of COVID-19 continues to evolve, unparalleled public health challenges and unique research opportunities have emerged that will be discussed in detail.

PubMed search was conducted to identify references using the following terms: "COVID-19", "SARS-CoV-2", "coronavirus", "smoking", "vaping", "tobacco", "cigarette", "electronic cigarette", and "ecigs". The search terms were used both individually and in combination with each other. All Englishwritten references, published on or before June 18, 2021, were considered. Where appropriate, publicly available databases and scientific reports from regulatory agencies and/or academia as well as news publications were considered; in all cases, cited sources were identified with a link to the published materials. To limit the number of citations, updated reviews were used rather than individual research articles, unless otherwise indicated.

Symptoms of COVID-19 are variable, but often include fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, and diarrhea (8) . COVID-19 most commonly spreads through close contact, from person to person, particularly when people are physically near each other in enclosed spaces (9) . According to the Centers for Disease Control and Prevention (CDC) guidelines, the principal mode by which COVID-19 infection occurs is through exposure to respiratory fluids, containing infectious virus (10) . There are three primary ways of exposure, including: (I) 'Inhalation' of air carrying very small fine droplets and aerosol particles that contain A c c e p t e d M a n u s c r i p t 6 infectious virus. Risk of transmission is greatest within three to six feet of an infectious source,

where the concentration of these very fine droplets and particles is highest; (II) 'Deposition' of virus carried in exhaled droplets and particles onto exposed mucous membranes, such as the mouth, nose, or eye (e.g., being coughed on by "splashes and sprays"). Risk of transmission is likewise greatest close to an infectious source, where the concentration of these exhaled droplets and particles is highest; and (III) 'Touching' mucous membranes with hands soiled by exhaled respiratory fluids containing virus, or from touching inanimate surfaces contaminated with virus (10) . Reinfection with COVID-19 has been reported but is relatively rare (10) .

Symptoms of COVID-19 infection may appear a few to several days after exposure to the virus (i.e., incubation period) (8) . The median incubation period for COVID-19 is four to five days (8) .

Most symptomatic people experience symptoms within two to seven days after exposure, and almost all symptomatic people will develop one or more symptoms before day twelve (8) . While most infected people have mild symptoms, some develop acute respiratory distress syndrome (ARDS) (11,12). COVID-19 can spread as early as two days before infected persons show symptoms, as well as from individuals who never experience any noticeable symptoms (i.e., asymptomatic carriers) (8) . The asymptomatic carriers tend not to get tested, and thus more likely to spread the disease (8) . Infected individuals remain contagious for up to ten days in moderate cases, and two weeks in severe cases (8) .

As COVID-19 progresses in its course, complications may follow and death may occur (13) . Common complications of the disease include respiratory complications, such as pneumonia and ARDS, cardiovascular complications, such as heart failure, arrhythmia, heart inflammation, and blood clots, multi-organ failure, kidney or liver injury, and septic shock (12, 13) . Children infected with COVID-19 may develop pediatric multisystem inflammatory syndrome, which has symptoms similar to

Kawasaki disease, that can be fatal (14) . Treatment options for COVID-19 have been summarized in elegant articles, including references (15, 16) .

A c c e p t e d M a n u s c r i p t Minister, prompting investigations into the utility of nicotine patches for COVID-19 prevention and/or treatment; clinical trials and observational studies in health care workers and patients are still underway (33). It is important to note that there is a clear distinction between "potential" therapeutic or preventive utility of nicotine, when administered transdermally through patches (i.e., nicotine replacement therapy (NRT)), as opposed to the known dangers of nicotine, when inhaled via smoking or vaping (35,36). It should be emphasized that smoking is a primary cause/risk factor for many comorbidities that make people susceptible to COVID-19 infection and poor outcomes (10).

These comorbidities include chronic obstructive pulmonary disease (COPD), cancer, cardiovascular disease (CVD) [e.g., cardiomyopathy, coronary artery disease, and heart failure], chronic kidney disease, type 2 diabetes mellitus, and obesity (see, Fig. 1 ) (10) .

A c c e p t e d M a n u s c r i p t 10 Subsequent systematic reviews and meta-analyses of data from considerably large populations have shown varying associations between smoking status and hospitalization rates, severity of symptoms, and mortality from COVID-19 (37, 38) . The strength of associations has varied in different studies, dependent on the characteristics of the study population (e.g., age, gender, race, socio-economic status) and their underlying health conditions and comorbidities (37, 38) . For example, existing comorbidities (as specified above), advanced age, male gender, being of minority races/ethnicities, working in service jobs, and having low income are shown to disproportionately affect the severity of illness, hospitalization, and death resulting from COVID-19 (37, 39) . The review found uncertainties in the majority of 233 studies, arisen from the recording of smoking status in the study subjects. More specifically, the vast majority of the analyzed studies either underreported or did not report smoking status of the study populations. As a result, recorded current smoking rates in most published studies from different countries were 'lower' than the corresponding national adults smoking prevalence estimates. So, under-reporting or not reporting smoking status proved to be a common problem in the overwhelming majority of the analyzed studies. In a subset of better-quality studies (n = 17), current smokers had a slightly reduced risk of testing positive for SARS-CoV-2, but appeared more likely to present for testing and/or receive a test as compared to never smokers. Data for current smokers on the risk of hospitalization, disease severity, and mortality were inconclusive, but favored a small but important increase in risk for severe disease. The data in current smokers, however, showed no trend of association between smoking status and hospitalization or mortality from the disease. Importantly, former smokers A c c e p t e d M a n u s c r i p t 11 showed increased risk of hospitalization, disease severity, and mortality from COVID-19 as compared to never smokers (27).

The findings of this living review underscore the need for better-designed studies with rigorous methodologies and adequate statistical power, which can produce reliable data and ensure reproducible results. Of high priority is collection of validated data on tobacco product use and frequency, e.g., by biochemical assays rather than self-reporting only. Equally important is the use of diagnostic tests with high sensitivity and specificity for COVID-19 diagnosis. As research groups around the world learn to navigate work in the midst of a global pandemic, we should aim to objectively investigate the relationship between tobacco product use and COVID-19 infection, transmission, and clinical outcomes.

SARS-CoV-2 can target both the upper respiratory tract (nose, nasal passages, pharynx, and larynx

[throat]) and the lower respiratory tract (trachea and bronchi, bronchioles, and alveoli [making up

the lungs]) (12) . The lungs are the most affected target organ for SARS-CoV-2 because the virus accesses host cells via ACE2, which is most abundant in type II alveolar cells of the lungs (40) . The virus uses a distinct surface glycoprotein, named "spike" protein (peplomer), to attach to ACE2 and enter the host cell; the ACE2 is interchangeably called 'ACE2 receptor' (Fig. 2) (40) . Using the spike protein on its surface, SARS-CoV-2 binds to ACE2 receptors -like a key being inserted into a lockprior to entry and infection of the host cells (40) . In addition to targeting the respiratory tract, SARS-CoV-2 can also affect gastrointestinal tract as ACE2 is abundantly present in the glandular cells of gastric, duodenal and rectal epithelium as well as endothelial cells and enterocytes of the small intestine (40) . ACE2 is also highly expressed in the heart and involved in heart function (40) . (11). Also, as mentioned above, the spike protein of SARS-CoV-2 binds specifically to ACE2 receptors in type II alveolar cells in the respiratory tract (40) . Of significance, ACE2 is over-expressed in smokers as compared to nonsmokers (42, 43) . Furthermore, chronic smoking is known to compromise mechanical barriers and other defence mechanisms in the respiratory system; these include filtration in the upper airway, mucociliary clearance of inhaled pathogens (e.g., diseasecausing bacteria and viruses, such as SARS-CoV-2), and phagocytosis by macrophages (35). In addition, behaviors, such as sharing e-cig devices, which is common among vapers (20) (although likely reduced due to 'stay-at-home' mandates and restrictions on social gatherings), may help spread the disease, especially by facilitating transmission from asymptomatic cases. 

The expression levels of ACE2 have been shown to be elevated in type-2 pneumocytes, alveolar macrophages, and small airway epithelium of smokers and subjects with COPD in comparison to healthy control cells (49, 50) . The upregulation of ACE2 is thought to involve nicotinic receptors, 

The abundant expression of ACE2 in type II alveolar cells facilitates rapid viral expansion and local alveolar wall destruction, resulting in fast and progressive severe diffuse alveolar damage and hyperinflammation, otherwise known as cytokine storm (11). Furthermore, SARS-CoV-2 infection can cause oxidative stress in the lung as a result of activation of resident cells or inflammatory cells recruited to the site of tissue injury (54) . Single-cell RNA sequencing of the human lungs has shown that specific components of the antioxidant defence system in the alveolar type II cells, such as superoxide dismutase 3 and activating transcription factor 4, are downregulated in healthy elderly donors as compared to young donors (55) . This may explain, in part, the observed severity of COVID-19 and its poor prognosis in older patients (37, 38) . Of significance, smoking and, to a lesser extent, vaping are known to induce oxidative stress and inflammation, and modulate antioxidant defence mechanisms in vivo (41, 56, 57 In a subset of COVID-19 patients, long-term lung impairment, including interstitial lung diseases, may follow after recovery from the disease (65) . Interstitial lung diseases comprise a broad range of diffuse parenchymal lung disorders that are characterized by widespread and heterogeneous parenchymal lung abnormalities, which can lead to irreversible fibrosis (66) .

Pulmonary fibrosis is caused by progressive and irreversible destruction of lung architecture due to scar formation, which may lead to disruption of gas exchange, organ malfunction, and ultimately death from respiratory failure (66) . To date, therapeutic options for pulmonary fibrosis are limited, treatment response is relatively low, and as such, the disease has high mortality rates (66) . The Since the early stages of the pandemic, concerns have been raised about the overlapping clinical, laboratory, and radiologic features of COVID-19 and EVALI, which can make accurate diagnosis a challenge, especially among e-cig users (69) . Also, the convergence of the two diseases and their possible synergistic effects have become a matter of concern (69). The shared clinical characteristics of EVALI and COVID-19, like many other respiratory illnesses, include fever (>100.4 °F), cough, shortness of breath, and gastrointestinal symptoms, such as nausea, vomiting, and diarrhea (70) . Both EVALI and COVID-19 can present as interstitial pneumonia leading to ARDS (70) .

Chest computed tomography (CT) imaging findings may considerably overlap, with ground glass opacities present in both EVALI and COVID-19, and organizing pneumonia as the imaging feature that is most common between the two diseases (71) . Laboratory findings in EVALI include nonspecific leukocytosis, elevated inflammatory markers, such as erythrocyte sedimentation rate and procalcitonin, and increased levels of liver enzymes (72) . Elevation of liver enzymes and A c c e p t e d M a n u s c r i p t 19 inflammatory markers can also be seen in COVID-19; however, patients with COVID-19 typically exhibit lymphopenia as opposed to lymphocytosis in EVALI (72) .

and EVALI, and considering the shared laboratory and imaging findings of the two diseases, clinicians are advised to pay particular attention during patients' history taking (69) . Specifically, physicians and nurses are encouraged to inquire about patients' vaping history, particularly use of e-cig products or marijuana vaping, as vaping is often a social activity during which wearing of masks and maintaining social distancing become less frequent, if not, unlikely (70) . Moreover, as the pandemicrelated restrictions on social gatherings are being lifted, and schools, colleges, and universities are re-opening, e-cigs users, specifically those who use VAE/THC-containing e-cig products, should be monitored for pneumonia-like symptoms, not only for COVID-19 diagnosis but also for EVALI evaluation (72). There may have been other barriers for smokers interested in quitting during the pandemic.

Non-emergency counseling appointments were canceled during the shutdowns, and loss of jobs for many smokers resulted in termination of employer-provided health insurance plans that often cover (wholly or in part) counseling fees and costs of smoking-cessation medications (76) . Furthermore, state and local health departments, which were overwhelmed during the early stages of the pandemic, might have redirected their resources, at least, temporarily and partially, from tobacco control intervention programs to other initiatives and campaigns, exclusively centered on COVID-19 (75, 76) .

Of significance, the rise in U.S. tobacco cigarette sales during the pandemic has coincided with a drop in vaping product sales (75, 76) . (20). Also, implementation of the pandemic rules and orders has led to retail store closures, disrupted supply chains, and restrictions on movement outside one's home to purchase tobacco products. This, in turn, has affected, to varying degrees, the availability and accessibility of tobacco products, as well as users' preference for source and location of purchase (e.g., online suppliers vs. vape shops or gas stations). Table 1 summarizes the results of selected studies on vaping and smoking prevalence, use frequency and patterns, product accessibility, and motivation to quit before-and after the start of COVID-19 pandemic. Detailed description of the studies and discussion of their findings are provided in Supplementary Materials.

As discussed in Section 5, numerous studies have investigated the incidence, symptom severity, and clinical outcomes of COVID-19 among tobacco product users. Table 2 infection in tobacco product users, the evidence is roundly growing on the severity of the disease in smokers as compared to nonsmokers (37, 38) . Evaluation of the overall published studies indicates that there is a need for high-quality investigations with improved study designs, rigorous methodologies, and high statistical power, which can generate reproducible and conclusive results.

Ideally, these investigations should use accurate diagnostic tests, clinical examination, histopathology, and imaging analysis to confirm cases of the disease, courses of its progress, and outcomes, while also validating smoking/vaping status by biochemical assays. Completion of these studies should help definitively demonstrate the influence of tobacco cigarette and e-cig use in M a n u s c r i p t 23 COVID-19 infection, transmission, and clinical outcomes, as well as uncover the mechanistic interactions between these lifestyle factors and the course, severity, and prognosis of this illness.

A pre-print study (79) has reported that smokers and vapers are more likely than nonsmokers to believe that smoking/vaping has 'no impact' or 'decreases risk' for severe COVID-19 symptoms. It is plausible that if tobacco product users become aware of a 'claimed' protective effect of smoking/vaping against COVID-19, and believe it to be true, they may feel a sense of enhanced immunity, which could make them less likely to take up a vaccine when offered. This might elevate their risk for contracting COVID-19, especially those who have a pre-existing comorbidity/comorbidities. At the same time, it could make it more difficult to achieve the vaccination coverage required for population immunity. Complicating matters further, smokers (by definition) are less likely to accept public health advice, and more prone to poor health choices, such as hesitancy for vaccination (e.g., against influenza), when compared to nonsmokers (80) . As discussed in Section 4, transparency and disclosure of competing interests for researchers claiming protection by smoking against COVID-19 (28) should not only facilitate non-biased evaluation of such claims, but also boost public trust and willingness for considering COVID-19 vaccination.

In a population survey of UK adults (n = 29,148), current smokers reported the greatest levels (and never smokers the lowest levels) of mistrust in the benefit of vaccines, worries about unforeseen future effects, concerns about commercial profiteering, and preference for natural immunity (81) . When asked whether they would take up the offer of a COVID-19 vaccine when one becomes available, current smokers were the most likely to report being uncertain or unwilling, with just 51% reporting an intention to vaccinate, compared with 66% of former smokers and never smokers. These differences were independent of age, gender, ethnicity, income, key worker status, or chronic physical health conditions. Of note, the data for this survey were collected during the period of September 7 to October 5, 2020, which precedes the reports of positive results for COVID-A c c e p t e d M a n u s c r i p t 24 19 vaccine trials and the announcement of first vaccine being approved for use in the UK (81) . With a disproportionately large number of smokers having comorbidities predisposing to COVID-19 (10), and also belonging to disadvantaged socioeconomic groups that have been hit hardest by the pandemic (82), vaccination hesitancy could further exacerbate the existing health disparities among tobacco product users.

Importantly, smokers/vapers are inclined to cluster in social networks whose members'

attitudes towards health choices could be influenced by other members (83) . It is prudent to adequately address issues related to vaccine hesitancy in the general population, although tobacco product users may require 'targeted' interventions and educational campaigns. These efforts should raise awareness of the greater benefits of vaccination against COVID-19 than any claimed protective effect by smoking against this illness. The accumulating data on the safety and excellent efficacy of COVID-19 vaccines against severe disease, hospitalization, and death (84) should persuade smokers, particularly those with pre-existing health conditions who are more vulnerable to those outcomes (10) , to take up a vaccine when it becomes available.

At this point in the pandemic, the evidence on the association of tobacco product use and COVID-19

infection, disease course, and clinical outcomes is 'incomplete', but rapidly growing. So is the knowledge on the mechanistic involvement of smoking and vaping in the pathophysiology of COVID- A c c e p t e d M a n u s c r i p t -Of those who reported on the type of change, nearly one-third quit vaping, another one-third cut down on vaping, and the reminder either increased e-cig-or cannabis use, or switched to other nicotine or cannabis products.

-Approximately one-fifth of the respondents reported changes in point of purchase of e-cigs, from retail stores to online sources, another one-fifth reported switching to alternative retail stores, and the remainder overwhelmingly reported no change in their point of purchase of e-cigs.

-Over a quarter of the underage respondents (13 -20 years) reported access to e-cigs without A c c e p t e d M a n u s c r i p t 38 age verification.

-Those who reported higher nicotine-dependence and more frequent use of e-cigs were less likely to quit vaping or reduce e-cig use.

-Compliance with the stay-athome mandates was significantly associated with quitting vaping or reduced e-cig use.

-Users of pod-based devices (e.g., JUUL) were less likely to quit vaping or reduce e-cig use. -Participants reported similar and positively correlated changes in motivation to quit smoking and vaping due to COVID-19 concerns.

-Participants reported similar and positively correlated changes in use of cigarettes and e-cigs.

-Nearly a quarter of participants reported decreased access to both cigarettes and e-cigs following the pandemic, half reported no change M a n u s c r i p t 39 in access to either product, and another quarter reported increased access to both products. -Over half of all respondents reported a form(s) of substance use, of whom one-third confirmed a change in use pattern during the stay-at-home period.

-Of those reporting changes in use pattern, 44% and 47% confirmed decreased vaping and smoking, respectively, and 69% acknowledged increased alcohol drinking. More than one-third of the respondents reported increased marijuana use, whereas another one-third reported decreased use.

-The extent of changes in substance use patterns was significantly and directly related to the self-reported levels of anxiety, depression, and loneliness. To assess associations between smoking status, e-cig use, and nicotine replacement therapy (NRT) use, and self-reported COVID-19 -Current smokers and long-term ex-smokers (> 1 year), but not vapers or NRT users, were more likely to report COVID-19 diagnosis as compared to never smokers, after controlling Arrows indicate that comorbidities shown within circles are associated with tobacco product use (smoking). These comorbidities include chronic obstructive pulmonary disease (COPD), cancer, cardiovascular disease (CVD), chronic kidney disease, type 2 diabetes mellitus, and obesity. The overlapping of "comorbidities" with "COVID-19 risk and disease course and clinical outcomes" represents "association", not "causality". . The proteolytic function of Transmembrane protease, serine 2 (TMPRSS2) cleaves the spike protein (i.e., activation), thus allowing entry and viral replication in the host cell, and subsequent release of the infectious virus into the intercellular meliu. This is a simplified diagram of the highly complex lifecyle of SARS-CoV-2, which causes COVID-19; interested readers are referd to elegant references (12, 40) for detailed information.

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A c c e p t e d M a n u s c r i p t