key: cord-0799073-pryunb9i
authors: Mahendra Bhatt, Jayesh; Ramphul, Manisha; Bush, Andrew
title: An update on controversies in e-cigarettes
date: 2020-09-26
journal: Paediatr Respir Rev
DOI: 10.1016/j.prrv.2020.09.003
sha: 8c7fbd4f9f143d2c048660c658db39408a709925
doc_id: 799073
cord_uid: pryunb9i

E-cigarettes are electronic nicotine delivery systems (ENDS) which mimic tobacco smoking without the combustion of tobacco. These devices have been misleadingly marketed as “less harmful” alternatives to conventional smoking tobacco products. The e-liquid in e-cigarettes include nicotine, a humectant and other additives including flavourings, colourants, or adulterants such as bacterial and fungal products. In this review, we discuss the contrasting views of the tobacco lobby and most professional societies. We describe the epidemiology of the use of these devices, with a widespread and significant rise in youth e-cigarette use seen in both the USA and Europe. We also describe what is known about the toxicity and mechanisms of EVALI (e-cigarette or vaping associated lung injury). This characterised by respiratory failure with an intense inflammatory response. The presentations are diverse and clinicians should consider vaping as a possible cause of any unusual respiratory illness in patients who have a history of vaping or other use of e-cigarette-related products. Second hand exposure to e-cigarettes is also harmful through respiration and transdermal absorption. E-cigarettes have a worse acute toxicity than tobacco and their long-term toxicity is unknown, and we advocate for the immediate, most vigorous anti-vaping legislation possible.

used tobacco (4) . Among US e-cigarette users aged 18-24 years in 2015, 40% had never been regular cigarette smokers. E-cigarette use among US youths is associated with intention to smoke but not with intention to quit smoking (5) .

By contrast, most paediatricians favour a much more cautious approach to e-cigarettes. This view places the protection of non-smokers, especially CYP as paramount and also focuses on the overall population impact, anticipating the ability of e-cigarettes to recruit a new generation of nicotine addicts, and almost certainly also, smokers. This is the stance adopted by the US National Academies of Science, Engineering, and Medicine (NASEM) (6) , Australian Commonwealth Scientific and Industrial Research Organization (7) FIRS has issued a position statement on e-cigarettes and ENDS use in youth which places protecting CYP at heart of the e-cigarettes debate (8) with stricter regulation and call for more research. The American Academy of Pediatrics also has castigated the use of e-cigarettes.

The WHO report on e-cigarettes suggested that regulations were needed to stop promotion of e-cigarettes to non-smokers and young people, minimise potential health risks to users and nonusers, stop unproven health claims about e-cigarettes, and protect existing tobacco control efforts This review will discuss the contrasting views of the tobacco lobby and most professional societies. We describe the epidemiology of uptake and use of these devices, and cover what is known about the toxicity and mechanisms of lung injury.

PHE acknowledge that there are some risks and uncertainties and that e-cigarettes could not be called "safe," but continues to maintain risks outweigh benefits (9) . UK Royal College of Physicians (RCP) report acknowledges that "e-cigarettes are not currently made to medicines standards and are probably more hazardous than nicotine replacement therapy "(10). It is also worth noting that the UK National Institute for Health and Care Excellence (NICE) excluded the use of e-cigarettes as an aid to smoking cessation in their guidelines.

The "at least 95% less harmful than conventional smoking" statement (above) is based on the outcome of a multi-criteria decision analysis (MCDA), in which a group of experts considered the harms to human health and well-being posed by using a wide range of tobacco products which was not based empirical data and did concede that the evidence was insufficient to reach a robust conclusion (11) . This did not stop robust conclusions being promulgated! Worryingly decreased use of smoking cessation services and medically tested pharmacotherapy has been observed in parallel with an increase in the use of e-cigarettes, indicating that alternative nicotine-containing products may be replacing evidence-based, effective smoking cessation tools (12) .

There are several limitations in concluding that e-cigarettes are safe (13-15) but we would highlight that decisions made during this MCDA exercises were based on value judgements not evidence. The MCDA approach cannot be a substitute for a formal risk-benefit analysis, that should be undertaken for new products to which the public are exposed (2) .

Transparency about the funding and organisation of this meeting have also been questioned (15) . PHE has argued that any evidence from RCTs do not capture the effects of e-cigarette use outside the specific conditions of a trial and so cannot be generalised to real life (thus at a stroke rubbishing all RCT evidence across the entire spectrum of medicine!). This does not stop them cherry picking evidence (16) to promote one of the very few trials that found that e-cigarettes, when administered in a highly controlled setting, in which subjects were also receiving an intensive behavioural intervention, achieved a higher quit rate than was seen with nicotine patches (17) . At one year, the rate of continuing e-cigarette use was fairly high as compared to nicotine replacement; effectively replacing one form of nicotine addiction with another. Switching to vaping is not solving the problem, merely substituting a new one.

That trial itself had many limitations, including not comparing e-cigarettes with the most effective pharmaceutical interventions and, obviously, saying nothing about the use of ecigarettes when used outside a structured behavioural programme (18) .

The "harm reduction" strategy hypothetically might be a gain for smokers reluctant to quit (although the evidence for this statement is zero), but ex-and never-smokers probably have an increased risk of harm by using e-cigarettes. There is a substantial risk of undermining smoking cessation programs and the renormalisation of smoking from widespread use of ecigarettes. Their use should at most be allowed in that minority of high-risk smokers unwilling or unable to quit (19) and not promoted as a population-based strategy. As well as being an aid to quitting, e-cigarettes are seen as having a role for people who do not want to quit, offering a substitute for some of the cigarettes they would otherwise smoke (15) . However, this introduces the risk of dual use which can be especially harmful, as dual users would be exposed to two sets of substances, having the worst of both worlds. Although some dual use is inevitable during the quitting process, if this persists long-term health concerns remain.

Dual use is popular (7) . A recent cohort study showed that dual use among daily "vapers" worryingly apparently remained above 80% after 12 months follow-up (20) . Of course, the best choice for these individuals is to quit tobacco and nicotine altogether. For those who have never smoked, especially youth, the best option is never to start using any tobacco or nicotine product.

Australia has banned nicotine-containing e-cigarettes and has had similar success to the UK in the area of smoking cessation by impressive tobacco control and not by the use of ecigarettes (21) .

This promotion of e-cigarettes by PHE has been described as "a reckless and irresponsible decision" (2) . England remains a global outlier on the question of e-cigarettes and this "English Exceptionalism" is from the perspective of using e-cigarettes as means to reduce the harm associated with smoking and bring potential benefits to existing smokers. This position has been hard to retreat from and has been referred to (14) as an example of what is termed "escalation of commitment" or, by economists and behavioural scientists, "sunk cost fallacy".

Once embarked on a course of action or line or argument, it is difficult to extract oneself. It leads to a situation in which evidence that supports the position being held is promoted, whereas that which challenges it is dismissed , probably due to underlying cognitive biases (14) .

The human lungs are created to breathe clean air, not "reduced levels of toxins and carcinogens", and the human body is not meant to be dependent on addictive drugs (22) , (23) .

We know the acute toxicity of e-cigarettes is greater than that of tobacco, there is no tobacco equivalent of EVALI (See Rubin et al Paed Resp Reviews 2020, this symposium); how therefore can any sane person confidently state that chronic toxicity is less? The question of whether vaping is safe or safer than smoking can only be answered if the total contents of each of the thousands of available vaping liquids are itemised and subjected to short-term and long-term toxicity testing; reassurances and extrapolations are no substitute for data.

Even the International CEO of Phillip Morris has written (24):

"To be clear, smoke-free alternatives are not risk-free and should never be used by youth or non-smokers.

To be clear, the commercialisation of smoke-free alternatives cannot come at the expense of youth or people who don't smoke.

Responsible marketing also plays a vital role: Tobacco and e-cigarette manufacturers should market their products only to adults who smoke or use smoke-free products".

We join in this increasing call that the sale of e-cigarettes to the public should also be banned to avoid placing them readily in the hands of young people. They should be available only on prescription from smoking cessation clinics (although NICE would challenge their use even in this case) (25) . Clearly there is a disconnect between the putative use of e-cigarettes in a smoking cessation clinic, and the way they are being marketed. Traditional quitting methods, such as nicotine patches and gum, are usually offered by a pharmacy where a pharmacist can provide advice. The medical quitting methods are also regulated as health products with controlled levels of nicotine and the user may also be referred to psychological services for support fighting their addiction. E-cigarettes can be purchased in shops on the high street and users will not usually access any wider therapies to help them to quit. The regulations that apply to tobacco should be applied to e-cigarettes, including those relating to advertising, packaging, taxation and where they can be used (26) . The tide however may be turning with declining public perception that e-cigarettes are less harmful than cigarettes as the new evidence on the harms of e-cigarettes continues to accumulate (27) .

The extremely effective marketing strategy by the e-cigarette industry has been associated with a very significant surge in the uptake of vaping by CYP as many believe that e-cigarettes are safer and more socially acceptable. Nicotine-free vaping devices also appear to act as a gateway product in addition to being unsafe even despite nicotine being absent (28) . Not only are more CYP are taking up vaping, there is substantial evidence that e-cigarette use increases risk of ever using CSTPs among CYP i.e. a likely gateway to CSTPs. Widespread and significant rises in youth e-cigarette use are seen in both the USA and Europe (29) . However, it must be stressed that, as argued elsewhere (26) , the dangers of nicotine addiction and other toxicity mean that whether they are a gateway to smoking is irrelevant. E-cigarettes are dangerous in their own right. Some of the factors related to e-cigarette use in CYP are listed in Table 1 . CSTPs are significantly more likely to report experimenting with e-cigarettes. Informing CYP about the lack of evidence that e-cigarettes aid smoking cessation, and the already known and the as yet unknown health risk of e-cigarettes may deter young adults from trying these products (30) . Indeed, for most smokers, using an e-cigarette is associated with lower odds of successfully quitting smoking (31) . Rather, they were more likely to switch from one tobacco product (cigarettes) to e-cigarettes rather than quit nicotine and tobacco altogether (17) . A recent study (32) has suggested that continued use of e-cigarettes by former smokers is associated with re-initiation of cigarette smoking.

Thus there is a strong, scientifically-based rationale that vaping is a risk factor for future smoking and for restricting youth access to e-cigarettes (33) despite suggestions by some that have downplayed the use of e-cigarettes and their link to CSTP use in adolescents (9,34);

continued surveillance is needed [ Table 2 ] (35).

The basic components are:

 a reservoir (a tank of different sizes, cartridge or pod) that contains the "e-liquid" . The lower electrical resistance but higher power in most recent generation devices increases the aerosol yield. The major portion of particle mass is well within the respirable size range to deposit in the alveoli and be rapidly absorbed into the blood stream (36, 37)  a wick typically made of cotton or silica that conducts the e-liquid to the metallic coil (the heating element)

 a battery (that generates electrical current to heat the metal coil) . There are substantial differences in efficiency of nicotine delivery, device voltage, and other variables (38) .

The e -liquid constituents are: heats the liquid, which can reach 250 °C to create the aerosol (40) . It is unsurprising that burn and blast injuries have resulted from malfunctioning of these devices (41, 42) .

Even though levels of some potentially harmful ingredients from e-cigarettes are significantly lower than combustible cigarettes, it does not mean that e-cigarette aerosols are "harmless vapour" as industry has claimed in the past. Differences between inhalation and oral toxicology should be borne in mind while promoting the "safety" of vaping that is based on theoretical grounds, rather than observational science. Thus there are legitimate concerns over the health effects of inhaling various substances in e liquids (43) (44) (45) .

These discussions about potentially harmful compounds in e-cigarettes should not shift the focus from the fact that these are primarily a very efficient nicotine delivery system.

Singly, or together, these factors may contribute to toxicity. Many different chemicals and particulate matter (PM) are inhaled at doses that vary with vaping techniques and user behaviour which impacts on the physics of aerosolisation and thus aerosol delivery to lungs.

The potential for adverse health effects is huge (46) .

Further, the mixing of primary active compounds with contaminants and / or pyrolysis of chemicals in the e-liquid (some of which are gases [e.g., ketene] and not easily measured in biologic samples) (47) is likely to produce a chemical milieu with its own unique toxicity [ Table   3 ] (47). The identification of a causative agent is also problematic given the extensive heterogeneity of compounds in vaping mixtures (48) . With regards to EVALI, no single product or substance has been linked to all cases; and given the very many different histopathologies, it would be surprising if this was the case.

Furthermore, there could be host factors/individual susceptibilities that contribute to toxicity

that have yet to be described (49) . Not only are e-cigarettes users exposed to nicotine, ultrafine particles, and other toxicants, but some pulmonary toxicants are in e-cigarette aerosols at higher levels than tobacco cigarettes, including PG, and some flavourings and metals (8) . Hence e-cigarette aerosol is far from innocuous water, and, as we will show, although there is overlap with toxicity from tobacco smoking, vaping introduces toxins not found in tobacco (50). In summary, e-cigarettes enable the ingestion of high concentrations of nicotine, mixed with potentially hundreds of other chemicals. The acute toxicity of most of these is little known, and even less is known about chronic, long-term toxicity. It should be noted that it took decades for the harm of tobacco to be appreciated, another cause to disallow premature acquittal of e-cigarettes. Furthermore, although there is overlap with the toxicity of tobacco, vaping introduces exposures and has effects which are not seen with tobacco (51, 52) . Thus the idea that vaping is a safer, watered-down version of smoking, is scientific nonsense.

The vast and growing global market brings in to focus the very successful marketing strategies [including use of social media / influencers] with young people which will be discussed next.

The hypocrisy of the vaping industry, most of which is controlled by the tobacco industry, those pillars of rectitude and transparency, is shown in their marketing strategy. Compare it with those of nicotine patches and gum; it is designed not to enable people to step down from smoking, but to attract a new generation of nicotine addicts.

Unlike eating or drinking, smoking is not a natural behaviour. The safety concerns of, flavourings have been addressed in liking and intent to try these products (59) . This relative product preference for sweet/fruit versus tobacco flavour e-cigarette advertisements in college-age youth, especially nonsmoking early experimenters (who otherwise have negative associations with tobacco)

suggests a potential impact of advertising for flavours on youth initiation and decreased knowledge of health risks of e-cigarette use (59) . Encouragement via online videos and social media portrays e-cigarettes as attractive experimentation and are a potential for covert use may reinforce traditional cigarette smoking in teenagers (60) .

The availability of multiple flavours (including fruit and sweet flavours that are the most popular in youths), the option to mix one's own flavourings, multimedia advertising that promotes 'natural' flavours and aromas, enhances the appeal to first-time users, encourages experimentation, maintains novelty, is associated with a higher likelihood, frequency and persistence of use (61) (62) (63) (64) . Sweet taste increases the desirability of all e-cigarettes and potentiates the reinforcement of nicotine-containing e-cigarettes on an addictive mesocorticolimbic mechanism (65) . The public health problem that e-cigarettes purportedly help solve -by helping people who are users of CSTPs stop smoking by switching to vaping -is adequately addressed by liquids that are not flavoured to appeal to adolescents (66) .

The fact that flavours are not needed for smoking cessation products is supported by the fact that evidence based (67) licensed forms of NRT (gum) can help people successfully stop smoking.

The marketing strategies are not restricted to flavours : online stores display implied and overt health claims and smoking cessation messages that are unsupported by scientific evidence, as well as celebrity endorsements, and collocate vaping products with Coronavirus medical supplies, creating an impression of safe space (39, 68) . The newer sleek fourth generation Pod or Pod-Mods devices mimic commonly used electronics such as USB memory sticks or devices resembling lipstick or inhalers making them easy to conceal and appealing to young consumers (1). Some have been referred to as the iPhone of e-cigarettes (69) . Ninetyfive percent of the websites make explicit or implicit health-related claims, 64% have a smoking cessation-related claim, 22% feature doctors, and 76% claim that the product does not produce second-hand smoke. Comparisons to cigarettes include claims that e-cigarettes were cleaner (95%) and cheaper (93%) (68) .

E-cigarettes are increasingly heavily promoted using social media (70) (71) (72) . This is concerning as teenagers often relate to social media influencers; posts featuring aesthetically pleasing images of male and female models that are known to alter young users' perceptions are frequent among the posts featuring vaping products. In the same study, pro-vaping Instagram hashtags like #vape were used up to 10,000 times more often than the FDA-sponsored hashtag #TheRealCost (50) . Worryingly, a considerable proportion of followers of vaping influencers on social media are underage (13) (14) (15) (16) (17) year-old) (50, 73) . Even Tobacco companies like JUUL have used social media to promote vaping and to brand their products as safe , discrete alternatives to conventional cigarettes and have changed their approach only when "caught red handed" recently (74) (75) (76) .

EVALI (also called vaping associated pulmonary injury [VAPI] or "vaping-associated respiratory distress syndrome" (VARDS) for symptomatic vaping-exposed hypoxemic patients who also have abnormal chest imaging (46) Histopathologic features described in EVALI include OP (organising pneumonia), DAD (diffuse alveolar damage), acute eosinophilic pneumonia, diffuse alveolar haemorrhage, acute fibrinous pneumonitis with organization, foamy or vacuolated macrophages, foamy or vacuolated pneumocytes, intra-alveolar fibrin, , bronchiolitis, bronchiolar mucosal ulceration, interstitial oedema, neutrophilic inflammation, chronic interstitial inflammation ,pigmented macrophages. As EVALI appears to reflect a spectrum of responses to lung injury, it is possible that the various presentations of EVALI will respond differently to glucocorticoids (82) .

Empirical treatment with glucocorticoids has been suggested as a treatment strategy (83) as experience from the EVALI epidemic has shown that patients who survived EVALI were more likely to have received glucocorticoids than those who died from the condition (84) .

We have no long-term health data on health hazards of e-cigarettes. However in addition to the catastrophic acute presentations of EVALI, there is also now emerging data that shows current use of e-cigarettes appears to be an independent risk factor for respiratory disease in addition to all CSTP smoking (31) over a three year follow up period.

There is a growing body of literature that e-cigarette (with or without nicotine), use may lead to effects that are not dissimilar to CSTP at a cellular, clinical, and population level. As well as some toxicities that are similar to CSTP, others seem to be unique to e-cigarettes. For example, human pulmonary epithelial cells from lung biopsy samples showed that about 300

proteins are differentially expressed in smoker and e-cigarette user airways, with only 78 proteins common to both groups. Acute pulmonary toxicity of e-cigarettes has been studied in cell culture, animal models, and human volunteers and are well described in detail in an excellent reviews (43, 85) . (91) . There is a potential health concern of SHA exposure via both respiration and dermal absorption. In particular, ultrafine particles formed from supersaturated 1,2-propanediol vapor can be deposited in the lung, and aerosolised nicotine seems capable of increasing the release of the inflammatory signalling molecule NO upon inhalation (92) . Non-smokers (exposed ≥2 h/day) have been found to absorb nicotine from SHA e-cigarette aerosol similar to second hand tobacco smoke exposure as measured by salivary cotinine concentrations (93) . Parents may perceive e-cigarette aerosol as safe for children (94) ; parents who were dual users of cigarettes and e-cigarettes were more likely to have strictly enforced smoke-free policies than vape-free policies for the home, were less likely to have strictly enforced smoke-free policies for the car and vape-free policies in the home and car than parents who only use traditional cigarettes. SHA exposure to vaping was described as the most likely cause of hypersensitivity pneumonitis in a 37 year old adult (95) .

Currently, the volume and pattern of adverse respiratory events reported in association with e-cigarette use or vaping in the UK do not seem to reflect the trends emerging from the USA.

This difference of magnitude may be due to differences in regulations, nicotine strengths available, chemical substances and devices used, and proportional use by younger populations. However, it may also be due to a lower index of suspicion among healthcare professionals in the UK. A proposed UK case definition for EVALI is similar to the CDC definition but requires use in the 30 days prior to symptom onset (as opposed to 90 days) (96).

We conducted a literature search on PubMed, MEDLINE and EMBASE from inception to 7 May 2020 (last search). Eligible case reports and case series relating to e-cigarette, or vaping, associated lung injury (EVALI) were included. The keywords for the search strategy were ("ecigarette" or "vaping") and ("lung injury" or "EVALI" or "pneumonitis" or "bronchiolitis " or "pneumonia" or "severe"). The search was restricted to articles in the English language. The reference lists of relevant papers were hand-searched to identify any further relevant studies.

Our inclusion criteria included the following: (a) age ≤35 year and (b) patient presenting to a hospital outside of the United States of America (USA). Our rationale for excluding cases presenting in USA is because these have been described at length in the existing literature.

Six papers (97,79,98-101) met our inclusion criteria and were considered in the analysis (Table 5a ,b,c,d); the papers were published between 2018 and 2020. The age range of the seven patients was between 16 to 34 years, presenting to hospital in 5 different countries including England, Canada, Belgium, Spain and Germany.

We looked at the contents of the e-cigarettes, including nicotine, cannabidiol, humeactant and flavourings, which are summarised in the Table 5 . We also reported on the clinical course of young people presenting to hospital with EVALI; the suspected mechanism of injury is varied and include hypersensitivity pneumonitis, bronchiolitis obliterans and lipoid pneumonia.

Three out of the seven patients required respiratory support with Extracorporeal Membrane Oxygenation (ECMO). Steroids were used in all of the reported cases. One patient died from EVALI and two had ongoing consequences of the EVALI in the medium term, as shown by clinical parameters and spirometry. 

In summary, e-cigarettes, largely promulgated by the tobacco industry, have worse acute toxicity than tobacco; their long-term toxicity is unknown. They have no documented benefits, but instead are acting as a 'nicotine trap' to ensnare a new generation of addicts.

The most vigorous anti-vaping legislation is mandatory.

 There is a need for continued vigilance to determine acute and long term toxicity  Monitor trends in the of use of e-cigarettes in children and young people, and how best to prevent experimentation and the slippery slope to addiction  Understand also the health effects of second hand exposure

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E-cigarettes and their impact on health: from pharmacology to clinical implications

Common household chemicals and the allergy risks in pre-school age children

Four hundred and sixty brands of e-cigarettes and counting: implications for product regulation

Evolution of Electronic Cigarette Brands From

Evaluation of Electronic Cigarette Liquids and Aerosol for the Presence of Selected Inhalation Toxins

From the Centers for Disease Control and Prevention. Fixed obstructive lung disease in workers at a microwave popcorn factory--Missouri

Flavorings-Related Lung Disease: A Brief Review and New Mechanistic Data

Respiratory symptoms and lung function abnormalities related to work at a flavouring manufacturing facility

Metal Concentrations in e-Cigarette Liquid and Aerosol Samples: The Contribution of Metallic Coils

High exposure to nicotine among adolescents who use Juul and other vape pod systems

Discrepancies in reported versus measured nicotine content of e-cigarette refill liquids across nine European countries before and after the implementation of the EU Tobacco Products Directive

Juul Will Stop Selling In Five European Countries, Including France And Spain [Internet]. Available from: Juul Will Stop Selling

Turbocharged Juul device challenges European tobacco regulators

The Effects of Nicotine on Development

E-cigarette Product Characteristics and Subsequent Frequency of Cigarette Smoking

Endotoxin and 1,3 Beta Glucan Contamination in Electronic Cigarette Products Sold in the United States

Characteristics of a Multistate Outbreak of Lung Injury Associated with E-cigarette Use, or Vaping -United States

An Animal Model of Inhaled Vitamin E Acetate and EVALI-like Lung Injury

Dose-Dependent Pulmonary Toxicity of Aerosolized Vitamin E Acetate