Introduction

In the last few months I have seen 2 patients who presented with significant respiratory symptoms, (cough, shortness of breath and chest pain) that they temporally associated with use of electronic cigarettes (e-cigarettes). They were relatively new to e-cigarette use: one was a former cigarette smoker and the other was a never smoker but had a history of asthma. The severity of their symptoms had abated but they still had residual symptoms and were worried about the long-term consequences. When I went to review the literature regarding the latest data on the long-term health risks of using e-cigarettes, I noted an explosion of information being published in just the past few years. It is clear there is a great deal of controversy and concern about the introduction of these products into the marketplace without sufficient information about potential health risks nor adequate regulation over their indications, contents, and the technology used to generate their aerosol. Currently there are regular advertisements for e-cigarettes promoting them as viable and safe alternatives to cigarette smoking. One of the key initial promotions for these devices was as a smoking cessation tool despite an absence of any large double-blinded, randomized placebo-controlled trials to prove any superior efficacy to conventional smoking cessation strategies (such as nicotine replacement, bupropion hydrochloride, or the nicotine receptor partial agonists such as varenicline and counseling). More recently however, since their entry into the marketplace in the United States in 2006, manufacturers, many users, and some tobacco control experts, advocate e-cigarettes as a viable long-term harm reduction alternative to cigarette smoking without any long-term safety data. E-cigarettes have become a multi-billion-dollar industry (U.S. $ 11.3 billion in 2018) and projections suggest that their sales will surpass combustible cigarettes by 2023.¹ There are few regulations concerning access to these devices and there is high utilization by teenagers and reports of use by middle school children.² The question has been raised of whether these companies are specifically targeting this population with flavors such as “bubble gum.” There is also data to suggest that rather than reducing the risk of teenagers smoking cigarettes, use of e-cigarettes may act as a gateway to young people transitioning to smoking tobacco cigarettes. Recent studies show that adolescents and young adult e-cigarette users are at a 3 times greater risk of starting cigarette smoking compared to those who had never used e-cigarettes.^3-8 (See abstracts below).

The essential design of e-cigarettes includes an atomizer that uses an electrical current, generated by a battery, to heat a metal coil which aerosolizes the e-liquid conducted from a reservoir to the coil via a wick, typically made of cotton or silica. The user presses a button on the device, inhales and a plume of droplets carry the aerosol to the oropharynx and respiratory tree. E-cigarettes have evolved from cigarette look-alikes to new industrial-looking devices that afford greater control with regard to the delivery, content and nature of aerosolization as well as heat of the e-liquid. The typical constituents in most e-liquids are vegetable glycerin, propylene glycol, nicotine, water, alcohol, flavoring agents and a variety of other substances. Some e-liquids actually do not have nicotine in them but still contain various flavoring agents. The assumption has been that the elimination of tobacco tar, smoke particulate and various chemical additives and their combustible by-products renders the e- cigarettes to be a safer alternative. While this may very well be true, it is important to appreciate that the various components of the e-cigarette are not benign and can potentially pose significant health risks and there is no regulation over the content and access to these devices.

Recent studies have outlined potential toxic effects from nicotine (see below) including increased airway hyper-reactivity, inflammation, reduction of host defenses and possible cardiovascular effects.^9-14 While nicotine is not considered a carcinogen, there are studies to suggest it may potentiate cancer.^15,16 There have also been recent studies suggesting that chronic obstructive pulmonary disease (COPD) patients may be more susceptible to potential harmful effects of e-cigarettes.^17,18 There are reports of fatalities in children as young as 5 in which the e-liquids were ingested.¹⁹ The nicotine content of the e-liquid cartridges continues to be increased and there is 1 brand that offers a single e-liquid cartridge that contains the equivalent nicotine (47 mg) of 20 cigarettes (1 pack).²⁰ Nicotine is highly addictive and with the increased stimulation of the central nervous system there is evidence not only that use of these e-cigarettes leads to some never cigarette smokerstransitioning to use of tobacco cigarettes (so called “gateway”)^3,21,22 but also to the use of illicit drugs such as cannabinoids.^14,23 Furthermore, studies of quality control have shown that there are inconsistencies between actual nicotine concentrations and those indicated on labeling.^{1,12,20,24-28}

There are reported to be over 8000 flavoring agents now used in e-cigarettes. Aromatic aldehyde compounds such as cinnamon flavor, (cinnamon aldehyde), almond flavor, (benzaldehyde), and vanilla flavors (vanilla and ethyl vanilla), as well as formaldehyde, have potential toxic effects when inhaled.^2,20,28-30 There are reports that some of these flavoring agents have already been associated with bronchiolitis, alveolitis and acute lung injury.^1,31-33Diacetyl flavoring has been reported as a cause for bronchiolitis in microwave popcorn manufacturing workers.^34,35 Despite the knowledge of this association between diacetyl and lung injury, a recent study identified its presence in 110 out of 159 tested “sweet” e- liquids.^36,37

The e-cigarette metal coils have been reported to contain variable amounts of chromium, manganese, nickel, lead, copper, silver, zinc, and tin and the wicks can be made of silica.^38,39 There are concerns that the higher heat settings that some devices offer can lead to the evolution of nanoparticles of these various metals³⁸ (see article abstract below)and acrolein¹⁵ (a known carcinogen) from the various additives in the e-liquids. There also have been several reports of these devices exploding and causing major injuries.⁴⁰

Hence, while e-cigarettes may indeed help some individuals to transition from the use of tobacco smoking to nicotine vaping, there is growing evidence that the ingredients, including nicotine itself, may have significant adverse health consequences. Yet there is very little information about the consequences of long-term use of these devices and they remain largely unregulated in terms of content, labeling and access.

The first paper reviewed in this Journal Club is from the European Respiratory Society (ERS) Tobacco Control Committee Statement regarding e-cigarettes. The Taskforce cautions that tobacco harm reduction strategies that endorse the use of alternative nicotine delivery products for smoking cessation have not been proven to be as or more effective than traditional smoking cessation strategies and have been based upon incorrect assumptions and unfounded or undocumented claims.¹³ The ERS Statement emphasizes that there is lack of proof supporting claims that nicotine delivery devices such as e-cigarettes and “heated not burned” tobacco products (which eliminates combustible particulates and other components that evolve from the high heat of the actual burning of tobacco cigarettes) are efficacious in helping people to quit smoking permanently and in fact there is growing evidence that they are actually harmful to health. The Taskforce urges policymakers and public health bodies to reevaluate smoking cessation programs that involve the use of e-cigarettes and heated tobacco products and states that the Taskforce cannot recommend this approach as an effective population-based strategy.

At the most recent American Thoracic Society International Conference in Dallas, Texas in May of this year, there were numerous posters and lectures on e-cigarettes and a large scientific symposium entitled, “Addicting a New Generation: JUULing, Vaping, Heat Not Burn, Flavorings and the Evidence for Why We Should Be Very Concerned.” Many of the topics outlined above were covered and the organizers emphasized the critical need for further research in several different areas.

In this Journal Club we review the ERS task force report and some of the most recent studies looking at e-cigarettes as a method of harm reduction in smoking cessation, the potential that these new devices may actually have significant health effects, the likelihood of e-cigarettes leading to never tobacco smokers becoming tobacco smokers and concerns regarding the urgent need for research studies that can lead to informed and appropriate subsequent policy and regulation of these products.

Note: Abstracts are presented in their original, published format and have not been edited to match JCOPDF style.

Abstract 1

Electronic Cigarettes: A Task Force Report from the European Respiratory Society

Bals R, Boyd J, Esposito S, et al. Eur Respir J. 2019;53(2):1801151. doi: https://doi.org/10.1183/13993003.01151-2018

Comments

The ERS Task Force report published in January of 2019 is an excellent distillation of the best and most relevant studies published up to 2016. Members of the Task Force were from Europe and the United States and they reviewed 2271 papers. There are over 290 references in the publication. While it is not a systematic literature review per se, the information is organized into several themes including epidemiology, design and operation of the devices, animal and human studies on health effects and toxicity of the various and variable constituents of e-cigarettes as well as the potential concerns about secondhand exposure. It also reviews the literature regarding e-cigarettes as a tool for smoking cessation and the behavioral and social impacts of e-cigarettes such as serving as a gateway for people to become tobacco smokers and the re-normalization of smoking in public. It is an excellent introduction to the field with excellent critique of the quality of studies and the key research questions that need to be addressed for each area. It provides an excellent framework of how to evaluate e-cigarettes going forward and most importantly presents a cogent argument for the need for further research to inform the proper utilization and regulation of e-cigarettes.

Abstract 2

A Randomized Trial of E-Cigarettes Versus Nicotine-Replacement Therapy

Hajek P, Phillips-Waller A, Przulj D, et al. N Engl J Med. 2019;380(7):629-637. doi: https://doi.org/10.1056/NEJMoa1808779

Comments

This is one of the most rigorous studies to demonstrate the potential benefit of e-cigarettes as a smoking cessation tool. Overall the abstinence results are fairly low for both the e-cigarette and nicotine replacement therapy groups, but it is almost twice as high for the e-cigarette group. It is worth noting that participants were not blinded in the study, but they had to claim no preference of one type of treatment over the other in order to enter the trial. Nonetheless, up to 75% of the participants had previously tried and failed to quit using nicotine replacement therapy in the past. This may select a group that is less responsive or has greater side effects and lower expectations from standard smoking cessation strategies and hence may not try to stay in trial. The nicotine replacement group did not have the option to use bupropion which has been shown to be more effective than nicotine replacement therapy alone especially for those with a history of depression.^41-43 There is a study planned that will be a double-blind double dummy trial comparing e-cigarettes versus varenicline; the protocol has been recently published.⁴⁴ It is also worth noting that most of the e-cigarette group participants were responsible for buying further refills after the initial starter pack. They could pick different devices and different flavors and different strengths of e-liquids after they used up the starter kit. The provided devices were also only second generation and lacked the variable controls of some 3^rd and 4^th generation devices. The newer devices are able to produce higher exposures to nicotine and other components and consequently potential side effects, (see Lechasseur et al abstract below).³⁸ Interestingly, more of the e-cigarette group reported serious respiratory adverse events but the e-cigarette group did have a lower respiratory infection rate. As the authors point out, while this study has relevance for the group of current nicotine dependent individuals who may be looking at using e-cigarettes to quit smoking, it is not likely generalizable to the population of smokers who are less dependent or those who try e-cigarettes for reasons besides smoking cessation. Further, it remains to be seen how generalizable the findings are considering that it was conducted within the United Kingdom National Health Stop Smoking Service setting and variable in terms of participants likely to utilize the service and the overall nature of the levels of support in the program.

Abstract 3

Nicotine Matters in Predicting Subsequent Smoking After E-Cigarette Experimentation: A Longitudinal Study Among Finnish Adolescents

Kinnunen JM, Ollila H, Minkkinen J, Lindfors PL, Timberlake DS, Rimpelä AH. Drug Alcohol Depend. 2019;201:182-187. doi: https://doi.org/10.1016/j.drugalcdep.2019.04.019

Comments

This is one of the largest cohorts that have been followed longitudinally and addresses a very important question. The Hajek et al study discussed above demonstrates that even if we accept the possibility that use of e-cigarettes for smoking cessation may have some slight advantages over conventional smoking cessation interventions, there is a much bigger concern about promoting the use of these devices long term as they may become a gateway for nicotine naïve adolescents to become long-term users of these devices or move on to smoke conventional cigarettes and beyond.

Abstract 4

E-Cigarette Use Causes a Unique Innate Immune Response in the Lung, Involving Increased Neutrophilic Activation and Altered Mucin Secretion

Reidel B, Radicioni G, Clapp PW, et al. Am J Respir Crit Care Med. 2018;197(4):492-501. doi: https://doi.org/10.1164/rccm.201708-1590OC

Comments

The findings from this study and others have raised serious concerns about the possible long- term health effects of e-cigarette use as a substitute for cigarette smoking rather than as a short- term alternative/bridge for smoking cessation. This is particularly important when considering already compromised individuals such as COPD patients and COPD/asthma overlap patients.⁴⁵ It reinforces the need for further longitudinal studies and the prudence of regulating these devices and e-liquids.

Abstract 5

Variations in Coil Temperature/Power and E-Liquid Constituents Change Size and Lung Deposition of Particles Emitted by an Electronic Cigarette

Lechasseur A, Altmejd S, Turgeon N, et al. Physiol Rep. 2019;7(10):e14093. doi: https://doi.org/10.14814/phy2.14093

Comments

As discussed in the review of the Hajek paper, the newer generation devices that afford greater ability for the user to modulate the aerosol generated can result in highly variable content and nature of the aerosol that is generated leading to differences in the deposition and possibly the health consequences.

Abstract 6

The Rise of E-Cigarettes, Pod Mod Devices, and JUUL Among Youth: Factors Influencing Use, Health Implications, and Downstream Effects

Fadus MC, Smith TT Squeglia LM. Drug Alcohol Depend. 2019;201:85-93. doi: https://doi.org/10.1016/j.drugalcdep.2019.04.011 .

Comments

JUUL has been the leading retailer of e-cigarette products in the United States and has developed the POD system of sleekly designed e-cigarettes that look like USB devices. In early July of this year, San Francisco, home of JUUL’s headquarters, imposed a city-wide ban on the sale of all vaping/e-cigarette products until they undergo Food and Drug Administration (FDA) reviews. Unfortunately, at the current time, the FDA has stated that e-cigarette companies have until 2022 before they will have to apply for regulatory approval. This currently is being challenged in court. It is worth noting that the JUUL website now restricts sales to those 21 years and above and potential buyers must agree to an age verification step (photo ID), and upload a photo that is analyzed using face recognition ID. They also state they have a “youth prevention effort” in place. In their statement they claim that they don’t want anyone who doesn’t smoke or already use nicotine to use JUUL products. The sentence, “we certainly don’t want youth using the product" is in this statement. They have also removed certain fruit flavors from retail distribution. This plan was initiated in November 2018.

Abstract 7

High-Nicotine Electronic Cigarette Products: Toxicity of JUUL Fluids and Aerosols Correlates Strongly with Nicotine and Some Flavor Chemical Concentrations

Omaiye EE, McWhirter KJ, Luo W, Pankow JF, Talbot P. Chem Res Toxicol. 2019;32(6):1058-1069. doi: https://doi.org/10.1021/acs.chemrestox.8b00381

Comments

This study highlights that the high levels of nicotine and flavoring agents that are being used in these devices may attract primarily young users and be highly addicting. They now sell a POD/cartridge that has a 59 mg/ml concentration that is purported to have the nicotine equivalent of 1 pack of cigarettes.⁴⁶ Each JUUL pod or cartridge contains 0.7 ml of liquid with about 45 mg of nicotine (or 50 mg nicotine salt) for a concentration of 59 mg/ml of liquid. This is supposed to provide up to the equivalent of 200 puffs. JUUL was the first producer to incorporate the use of nicotine salts and benzoic acid which increases the bioavailability of nicotine without causing the irritation to the back of the throat that a liquid form of nicotine would cause. It is important to note that even though each POD contains the equivalent of 1 pack of cigarettes the user is not obliged to use the contents of a POD all at one time. The user can stretch the use of a single POD out over time if so desired.

Bottom Line

While it is true that, relatively speaking, e-cigarettes have fewer potential toxic compounds than regular tobacco cigarettes, there is mounting evidence that they are not benign and may indeed have health effects that are not inconsequential. In fact, some individuals with the greatest incentives to stop smoking, COPD and/or asthma patients, may be more susceptible to the potential harmful effects of e-cigarettes. Furthermore, e-cigarettes are no longer being marketed solely as part of a temporary smoking cessation strategy but rather as an alternative nicotine delivery device that may be intended for long-term consumption. Particularly alarming is the evidence that substantial numbers of young people are trying e-cigarettes, and some are moving on to smoking tobacco cigarettes and other agents. Recently, various states and cities have already banned sales and imposed age restrictions, licensing requirements, taxation of e-cigarettes, indoor vaping bans, and banning of certain flavorings that may target youth until further research provides answers that will allow an informed and rational policy formulation and appropriate regulation. The ERS and the Forum of International Respiratory Societies have issued position statements on e- cigarettes stating that they cannot endorse these products as part of a public health “harm reduction” policy based on the evidence available at current time. They emphasize the critical need for more independent studies regarding the benefits and potential harms of e-cigarette use and a prudent restriction of the usage of these products at least until their safety and efficacy can be established. Hopefully other prominent respiratory societies globally will follow suit and render similar position statements.