Abstract: Electronic cigarettes (ECs) are being increasingly used as an attractive long-term alternative nicotine source to conventional tobacco cigarettes. This substitution is likely to improve health in regular EC users, and more and more respiratory patients using or intending to use ECs will be seeking professional medical advice. Unfortunately, the public's view of ECs is far from being clear with a great deal of ambiguity around the product and its intended use. Moreover, health-care professionals themselves do not seem to use an evidence-based approach when it comes to informing respiratory patients about ECs and many advise against their use. Evidence-based advice about ECs is provided here with the goal of improving counseling between physicians and their respiratory patients using or intending to use ECs. Regular EC use is unlikely to raise significant health concerns and can lead to health improvement in the respiratory patient who makes the switch from tobacco smoking.

Introduction

Cigarette smoke contains a mixture of over 7,000 chemicals, many of which harm the human body causing a broad range of diseases (USDHHS, 2014). Smoking is the leading cause of preventable premature mortality in the world; total tobacco attributable deaths are projected to increase from approximately 5 million per year today to over 8 million annually by 2030 (WHO, 2008). Death is mainly caused by ischemic heart disease, stroke, lung cancer and the catastrophic complications of advanced stage chronic obstructive pulmonary disease (COPD) (USDHHS, 2014; WHO, 2008; Doll et al., 2004). Besides lung cancer and COPD, inhalation of tobacco smoke has also been recognized to play a negative role in other pulmonary conditions, including asthma (Polosa and Thomson, 2013) and interstitial lung disease (ILD) (Travis et al., 2013).

Quitting is known to reduce the risk of lung cancer, ischemic heart disease, COPD, stroke, and other cancers (USDHHS, 2014; WHO, 2008; Doll et al., 2004). Moreover, abstaining from smoking may produce significant health gains also in the COPD, (Tønnesen, 2013), asthma (Polosa et al., 2012) and ILD (Caponnetto et al., 2012) patients who smoke. Irrespective of their specific respiratory condition, most smokers want to quit and many make attempts to do so, but the majority of these attempts fail largely because of the powerful addictive qualities of nicotine and non-nicotine sensory and behavioral cues (Buchhalter et al., 2005; Hughes et al., 2004). For those willing to quit, combination of pharmacotherapy and intensive behavioral intervention for smoking cessation can support quit attempts and can double or triple quit rates (Polosa and Benowitz, 2011; Stead and Lancaster, 2012). However, outside the context of rigorous randomized controlled trials, reported efficacy rates are disappointingly low (Alpert et al., 2013; Pierce et al., 2012; Zhu et al., 2012).

Figure 1. Examples of different designs of electronic cigarettes. The cigalikes ECs (also known as first generation devices) resemble very much tobacco cigarettes; they are lightweight, but have limited flavor assortments and are equipped with low-capacity batteries. The penlike ECs (also known as second generation devices) are equipped with high-capacity batteries and a more efficient vaporizing system that can be refilled with the e-liquid of choice. The more advanced devices (also known as third generation devices) can be personalized to achieve top performance; they do not resemble tobacco cigarettes and are heavyweight because of their larger-capacity batteries. (Adapted from Farsalinos and Polosa, Ther Adv Drug Saf, 2014.)

Electronic cigarettes (ECs) are electrically driven consumer products consisting of the battery part and a heating element (atomizer) that vaporizes a liquid (mainly consisting of propylene glycol, vegetable glycerin, distilled water, flavorings) that may or may not contain liquid nicotine. Vaporization allows for inhalation of vapor (referred to as vaping) and produces an aerosol similar in appearance but substantially different in substance to conventional cigarette smoke. Electronic cigarettes (ECs) are an attractive long-term alternative nicotine source to conventional cigarettes because of their many similarities with smoking behavior (Caponnetto et al., 2013a; Caponnetto et al., 2015). ECs come in a large variety of designs, shapes and sizes (Figure 1). Some resemble tobacco cigarettes (so-called cigalikes ECs) with a mouthpiece resembling a cigarette filter combining the e-liquid containing tank and the vaporizing system, a low-capacity disposable or re-chargeable battery and a LED that glows when the user inhales on the device. Others often resembling a pen (so-called penlike ECs) are equipped with high-capacity lithium batteries, a more efficient vaporizing system with a tank that can be refilled with a wide selection of e-liquid flavors and nicotine levels for a more fulfilling vaping experience. Most experienced users prefer more advanced devices (so-called MODs) that bear little visual resemblance to cigarettes, use larger-capacity batteries with adjustable and programmable power delivery, and allow replacement of heating coils and wicks in their vaporizing system. The growing popularity of ECs appears to be driven by a variety of factors: they can be used to reduce cigarette consumption or quit smoking; they are perceived as a much less harmful smoking alternative; their prices are competitive compared to conventional cigarettes; and they allow to continue having a “smoking experience without smoking” (Siegel et al., 2011; Farsalinos et al., 2014; Biener and Hargraves, 2015).

Confusion and concern is being generated by misreporting or misrepresentation or misinterpretation of scientific findings about EC safety and efficacy, and more and more respiratory patients using or intending to use ECs will be seeking professional medical advice about these products. Unfortunately, health professionals themselves do not seem to use an evidence-based approach when it comes to informing respiratory patients about ECs. This is not surprising given that healthcare professionals’ personal beliefs often conflict with the evidence-based research results and are more likely to influence practice (Michie et al., 2005). For example, previous research shows that healthcare professionals hold erroneous views about nicotine containing products and harm reduction generally, and that these beliefs are associated with the advice offered to smokers (Graham, 1996). By and large, similar erroneous views about ECs are being adopted and many may advise against their use (Borrelli and Novak, 2007; Patwardhan and Murphy, 2013).

The goal of this article is to provide healthcare professionals with appropriate interpretation of common safety concerns and with the emerging findings about potential benefits deriving from the regular use of ECs. This concise evidence-based guide is likely to improve counseling between physicians and their respiratory patients using or intending to use ECs.

Addressing Safety Concerns

Alarmist and deeply misleading stories about potential harm of these products have been increasingly fueled by irresponsible science, careless publishing, and credulous journalism. Although ECs are by and large perceived as a much less harmful smoking alternative (Caponnetto et al., 2015; Siegel et al., 2011; Farsalinos et al., 2014), these stories are now spreading fear and confusion by adversely changing the perceptions of the relative risks of smoking and vaping. Therefore, it is likely that more and more respiratory patients using or intending to use ECs will be seeking professional medical advice.

First of all, what about the nicotine? The damage done by conventional cigarettes comes not mainly from the nicotine, but from the process of burning tobacco and inhaling the smoke. Smoking-related diseases are pathophysiologically attributed to oxidative stress, activation of inflammatory pathways and direct toxic effect of thousands of chemicals and carcinogens present in tobacco smoke (EPA, 1992). All of these chemicals are emitted mostly during the combustion process, which is absent in ECs. Nicotine does not contribute to smoking-related diseases and it is not classified as a carcinogen by the International Agency for Research on Cancer (WHO-IARC, 2004). Up to 5 years of nicotine gum use in the Lung Health Study was unrelated to cardiovascular diseases or other serious side effects (Murray et al., 1996). A meta-analysis of 35 clinical trials found no evidence of cardiovascular or other life-threatening adverse effects caused by nicotine intake (Greenland et al., 1998). Even in patients with established cardiovascular disease, nicotine use in the form of nicotine replacement therapies (NRTs) does not increase cardiovascular risk (Benowitz and Gourlay, 1997; Woolf et al., 2012). The latest U.S. surgeon general’s report took a look at what harm nicotine itself can do and concluded that, although it may adversely affect fetuses and adolescents’ brain development, it does not contribute to smoking-related diseases (USDHHS, 2014). The delivery of nicotine without combustion is anticipated to significantly lower the risk associated with conventional cigarette consumption. Therefore, ECs have a large theoretical advantage in terms of health risks compared with conventional cigarettes due to the absence of toxic chemicals that are generated in vast quantities by combustion. Furthermore, nicotine delivery by ECs is unlikely to represent a significant safety issue, particularly when considering they are intended to replace conventional cigarettes, the most efficient and widely available nicotine delivery product. Nicotine is a powerful psychoactive substance and there is concern about the potential for ECs to lead non-smoking young people to develop an addictive behavior. However, first and second generation ECs seem to reduce conventional measures of dependence (Etter and Eissenberg, 2015; Foulds et al., 2015). Of note, it is a common trend among EC users to reduce the nicotine strength of their e-liquid over time (Dawkins et al., 2013; Farsalinos et al., 2013; Polosa et al., 2015). This is indication for decrease of nicotine dependence over time with regular EC use. Nonetheless, ECs should never be utilized in context of fetal or adolescent nicotine exposure.

What about heavy metals? Given that ECs have several metal parts in direct contact with the e-liquid, it is not unusual to detect some contamination with metals in the vapor generated by these products, particularly under experimental conditions that bear little relevance to their normal use. Goniewicz and colleagues examined samples for the presence of 12 metals and found trace levels of nickel, cadmium and lead emitted (few nanograms per 150 puffs) (Goniewicz et al., 2014). Williams et al. in 2013 tested poor quality first-generation cartomisers and found several metals emitted in the aerosol of the EC, specifying that in some cases the levels were higher compared with conventional cigarettes. However, it is unlikely that such small amounts pose a serious threat to users’ health. Even if all the aerosol was absorbed by the consumer an average user would be exposed to 4-40 times lower amounts for most metals than the maximum daily dose allowance from impurities in medicinal products (U.S. Pharmacopeia, 2013).

What about thermal degradation of propylene glycol and vegetable glycerin? Propylene glycol and vegetable glycerin are considered GRAS (Generally Recognized As Safe) by the U.S. Food and Drug Administration (FDA) and U.S. Environmental Protection Agency (EPA). There are limited data on the chronic exposure of these chemicals to humans, although the emerging evidence from cytotoxicity and toxicological animal studies is reassuring (reviewed in Farsalinos and Polosa, 2014). However, concern about thermal degradation of propylene glycol and vegetable glycerin is legitimate, because toxic aldehydes (including formaldehyde, acetaldehyde, acrolein) can be generated when vaping. Studies evaluating cigalike ECs found that formaldehyde, acetaldehyde and acrolein are found at much lower levels compared to cigarette smoke (Bekki et al., 2014; Goniewicz et al., 2014). Nevertheless, more recent studies examining aerosol generated from more advanced products at high power levels reported that the levels of aldehydes could approach or even exceed the levels found in cigarette smoke (Kosmider et al., 2014; Jensen et al., 2015). These latter studies generated concerns that EC use at high power levels is associated with significant exposure to harmful toxic chemicals. However, elevated aldehyde levels are known to be generated during overheating of these devices in the course of certain standardized experimental protocols that bear little relevance to normal use. Moreover, under these extreme conditions, the excess in aldehyde release is associated with the perception of a strong unpleasant taste by the user (so-called “dry puff phenomenon”) (Farsalinos et al., 2015). At dry puff conditions, EC users are not expected to be exposed to such high levels of aldehydes, because in practice it is impossible to tolerate such unpleasant aerosol. In any case, at normal vaping conditions, the levels of aldehyde emissions are by far lower than the levels of cigarette smoke.

Informing About Potential Benefits

Abstaining from smoking produces significant health gains in the respiratory patients with COPD asthma and ILD patients who smoke. ECs are increasingly being used also by smokers/ex-smokers with respiratory conditions (Farsalinos et al., 2014). Although these products have been shown to be effective conventional cigarette substitutes in clinical trials of healthy smokers (Caponnetto et al., 2013b; Bullen et al., 2013; Polosa et al., 2014a), only limited data is available regarding health effects of EC use among patients with preexisting respiratory diseases. Moreover, it is unknown if regular EC use could result in improved or worsened respiratory-related outcomes. The very few studies on respiratory health outcomes in EC users have shown minor acute effects on lung function (Vardavas et al., 2012; Flouris et al., 2013). The results of these small acute studies are consistent with the notion that a prompt defensive response against irritants from e-vapor inhalation may cause immediate physiologic changes detected with highly sensitive respiratory functional tests. The question of whether such an irritation could translate into clinically meaningful lung disease remains unanswered, and there certainly is no evidence to date to suggest that there are any clinically significant adverse lung effects, at least acutely. Long-term improvement has been described in a large group of ‘healthy’ smokers who were invited to quit or reduce their tobacco consumption by switching to a first generation EC. Significant early positive changes from baseline of a sensitive measure of obstruction in the more peripheral airways (i.e., forced expiratory flow measured between 25% and 75% of FVC) were already detected at 3 months after switching in those who completely gave up tobacco smoking, with steady progressive improvements being observed also at 6 and 12 months (Polosa R., unpublished observation).

As mentioned earlier, only limited data is available regarding health effects of EC use among users with preexisting pulmonary diseases. The only clinical study conducted to ascertain efficacy and safety of EC use in asthma failed to detect deterioration in respiratory physiology and subjective asthma outcomes (Polosa et al., 2014b). On the contrary, significant improvement in Juniper’s Asthma Control Questionnaire (ACQ), forced expiratory flow in 1 second (FEV1), forced vital capacity (FVC), forced expiratory flow at the middle half of the FVC (FEF25-75) and airways hyperresponsiveness (AHR) to inhaled methacholine was observed. Exposure to e-vapor in this vulnerable population did not trigger any asthma attacks. Likewise no formal efficacy and safety assessment of EC use has been conducted in patients with COPD or ILD. There is only evidence from a case series of three inveterate smokers with COPD, who eventually quit tobacco smoking on their own by switching to an EC (Caponnetto et al., 2011). Significant improvement in quality of life and reduction in the number of disease exacerbations were also noted. Findings from an internet survey of approximately 2,500 regular EC users diagnosed with asthma and COPD indicate clear clinical benefits (Farsalinos et al., 2014). An improvement in respiratory symptoms of asthma and COPD after switching was reported in 65.4% and 75.7% of the respondents, respectively. Of note, after switching, use of respiratory drugs was stopped in 460/2,498 (18.4%) respondents with asthma and COPD. Worsening after switching was only reported in 1.1% of the asthmatics and in 0.8% of the COPD respondents. Although only large prospective studies will provide a definite answer regarding the long-term impact on lung health, the current evidence is generally supportive of a beneficial effect of EC use in respiratory patients.

Concluding Remarks

Smoking cessation is the most important and cost-effective therapeutic option for smokers with respiratory conditions (Rigotti, 2013). Therefore, smoking cessation should be strongly encouraged in respiratory patients who smoke, and they should be offered effective personalized strategies. Besides pharmacotherapy and behavioral support, other options should be made available to manage smokers who frequently relapse, and for those who are unable or unwilling to quit. A realistic alternative is to encourage these smokers to switch to ECs, a much less harmful source of nicotine (Polosa et al., 2013).

Figure 2. Risk estimates for a wide range of nicotine containing products. Cigarettes, with an overall harm score of 99.6, is judged to be most harmful. Product related mortality, the upper dark red section, is a substantial contributor to tobacco cigarette's risk estimate. An overall risk estimate of 4 has been calculated for electronic cigarettes. (Adapted by Nutt et al., Eur J Addiction, 2014. With permission from Karger AG, Basel, Switzerland.)

Healthcare professionals need to recognize that it is not nicotine per se that causes the harm but tobacco combustion. While there is a trend to classify all nicotine containing products as being equally harmful, the reality is that there are major differences in their risk and relative risk, from the deadly tobacco cigarette to nicotine replacement therapy products. In between, we have a plethora of products including ECs (Figure 2). Compared to combustible cigarettes, e-vapor products are at least 96% less harmful and may substantially reduce individual risk and population harm (Nutt et al., 2014). Most importantly, product innovation will further reduce these residual risks from EC use to as low as possible by adopting new technologies and applying ad hoc product standards for safety and quality. Fast innovation in the e-vapor category is likely not only to further minimize residual health risks, but also to maximize health benefits in regular EC users. For example, by exploring diversities and similarities among different product designs, we are now beginning to learn that the extent of smoking abstinence is intimately connected with their role as smoking sensation products, where smoking cessation is the main “collateral benefit” for many smokers switching to regular EC use (Caponnetto et al., 2015).

The notion that under normal vaping conditions, EC toxicology is by far less problematic than tobacco cigarette toxicology and that there are beneficial effects associated with regular EC use, particularly in respiratory patients, will improve information exchange between physicians and their respiratory patients using or intending to use ECs. Physicians should accurately inform that regular EC use is unlikely to warrant significant health concerns and in fact may reap substantial health benefits for the respiratory patient who makes the switch. Of note, healthcare professionals dealing with smokers who frequently relapse, or facing smokers unable or unwilling to quit, may wish to recommend that they try several types of ECs to see if they can find one meeting their needs. Last but not least, patients should be reminded that the EC may also be used as a transitional tool to complete smoking/vaping cessation. In the ECLAT study, about 70% of participants who quit smoking by week 52 also quit EC use (Caponnetto et al., 2013b). It is possible that for these individuals, the EC may have facilitated a lingering need for a change in behavior as it might have been stimulated subconsciously the progression through the stages of change (from pre-contemplation to contemplation to determination to action, i.e., quitting).

Physicians should recommend the most effective ways for smokers to reduce their risk rapidly. While smoking cessation may be the most desirable final outcome from a health point of view, it may be the wrong goal if it leads to failure or relapse. The respiratory physician should consider all the pathways available to a smoking patient and select the ones that give the greatest probability of eliminating exposure to tobacco smoking. For some smokers, the best outcome may be a long-term switch to vaping — tolerating the small residual risk in return for a higher likelihood of success.

Acknowledgments

The authors wish to thank LIAF, Lega Italiana Anti Fumo (Italian acronym for Italian Anti Smoking League) for supporting our research in tobacco harm reduction.

Disclosure

R.P. received project grants from Pfizer and Boehringer Ingelheim; speaker fees from Novartis, GlaxoSmithKline, SFATA (Smoke-Free Alternatives Trade Association), and ECITA (Electronic Cigarette Industry Trade Association). He has served as a consultant for: Cancer Research UK; Italian Ministry of Health’s Technical Committee on electronic cigarette; UK All Party Parliamentary Group; Global Health Alliance for treatment of tobacco dependence, Arbi Group Srl (an Italian e-cigarette distributor), and ECITA (Electronic Cigarette Industry Trade Association). He serves as a Scientific Advisor for the Italian Antismoking League (LIAF) on a voluntary basis. His salary is entirely supported by University of Catania.

D.C. and P.C. have nothing to disclose.

Corresponding Author

Riccardo Polosa, M.D., Ph.D., Professor, UOC di Medicina Interna e d’Urgenza, Edificio 4, Piano 3, AOU ”Policlinico-V. Emanuele”, Universita’ di Catania, Via S. Sofia 78, 95123 Catania, Italy.

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