Riccardo Polosa

Persisting Long Term Benefits of Smoking Abstinence and Reduction in Asthmatic Smokers Who Have Switched to Electronic Cigarettes

r67r2pol — Tue, 23 Feb 2016 03:04:05 +0000

Introduction

The asthmatic smoker represents a distinct disease phenotype with increased susceptibility of exacerbations and poor asthma-specific health status (Polosa and Thomson, 2013a; Eisner and Iribarren, 2007). Increased disease severity and marked impairment in asthma control is more frequently reported in asthmatic smokers who have smoked more than 20 pack years (Polosa et al., 2011). Most studies show an accelerated decline in lung function and increased airflow obstruction (Lange et al., 1998) and asthma patients who smoke appear to have an impaired response to the beneficial effects of antiasthma drugs compared to asthmatics who do not (Tomlinson et al., 2005; Chaudhuri et al., 2003). Nonetheless, quitting smoking can reverse the negative impact of tobacco smoke on asthma symptoms and lung function (Polosa et al., 2012).

Electronic cigarettes (EC) are battery-operated devices designed to vaporize nicotine without burning tobacco. The growing popularity of ECs proves that many adult smokers are keen in using an alternative to combustible cigarettes to reduce tobacco consumption or quit smoking and to relieve withdrawal symptoms (Caponnetto et al., 2013b). Data from internet surveys (Farsalinos et al., 2014a; Siegel and Tanwar, 2011; Etter and Bullen, 2014) and clinical trials (Caponnetto et al., 2013a; Bullen et al., 2013; Polosa et al., 2014a) have shown that ECs may help smokers quitting or reducing their tobacco consumption. Given that vapor toxicology - under normal condition of use - is by far less problematic than that of conventional cigarettes (Farsalinos and Polosa, 2014b), and exclusive ECs users have significantly lower urine levels of tobacco smoke toxicants and carcinogens compared to cigarette smokers (Hecht et al., 2014), switching to ECs use is likely to produce significant health benefits.

Only limited data is available regarding health effects of ECs use among vulnerable populations, including people with asthma. Moreover, it is unknown if regular “vaping” (the act of inhaling vapor from ECs) could result in improved or worsening asthma-related outcomes. In a recent retrospective study regular EC use was associated with objective and subjective improvements in asthma outcomes (Polosa et al., 2014b). In particular, 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 were observed. Long term prospective assessment of objective and subjective asthma outcomes as well as safety and tolerability was undertaken in this group of asthmatic EC users and compared with earlier retrospective findings that have been published and presented before (Polosa et al., 2014b).

Methods

Patient population

Patients in the current study belong to an asthma cohort of adult daily EC users that were identified from medical records. Details of this patient population have been presented elsewhere (Polosa et al., 2014b). In the current study, eighteen daily ECs users with mild to moderate asthma were prospectively followed up for one additional year. This study was approved by the local institutional ERB and informed consent was obtained from each patient.

Study design and assessments

In the preliminary study (Polosa et al., 2014b), patients’ medical records were reviewed twice over one year, at 6 ±1 (follow-up visit 1; F/up 1) and 12 ±2 (follow-up visit 2; F/up 2) months) from baseline (when they first reported EC use) to acquire details about respiratory symptoms, asthma outcomes and tobacco consumption. We also included data from the clinic visit immediately prior to the baseline visit (pre-baseline visit). Pre-baseline data were acquired 6-12 months prior to the baseline visit; comparison of pre-baseline study outcomes with those obtained at baseline was used to demonstrate disease stability.

In the present study, the same daily EC users with asthma were prospectively re-evaluated for changes in respiratory symptoms, asthma outcomes and tobacco consumption for an additional year from October 2013 to January 2015 (follow-up visit 3; F/up 3). Re-evaluation also included (i) Juniper’s Asthma Control Questionnaire (ACQ) score; (ii) number of exacerbations from the previous follow up visit (an asthma exacerbation was defined as an increase in respiratory symptoms requiring a short course of oral or parenteral corticosteroids); (iii) simple spirometry with parameters of forced expiratory flow in 1 second (FEV1), forced vital capacity (FVC), and forced expiratory flow at the middle half of the FVC (FEF25-75); and (iv) in some subjects bronchial provocation tests assessing airway hyperresponsiveness (AHR) with methacholine were also conducted as previously described (Piccillo et al., 2008). Daily cigarette consumption, (biochemically verified by exhaled breath carbon monoxide - eCO monitoring), and review of EC use were also included in the re-evaluation. Findings obtained at F/up 3 were compared with those from baseline and from F/up 1 and 2.

Smoking/Vaping status

Smoking abstinence was defined as complete self-reported abstinence from tobacco smoking (not even a puff) since the previous study visit. This was also biochemically verified at F/up 3 by eCO levels of ≤7 ppm. Asthmatic EC users in this category are classified as Quitters (Single users).

Smoking reduction was defined as sustained self-reported reduction (at least >50%) in the number of cig/day from baseline. Asthmatic EC users in this category are classified as Reducers (Dual users).

EC users who were not categorized in the above categories were classified as Relapsers.

Analyses

Table 1. Patients characteristics at pre-baseline and baseline (before switching to electronic cigarettes).

All data obtained at the various time points were expressed as mean (±standard deviation (SD)) except for methacholine PC20 values expressed as geometric mean (data range). We also delineated data for single (exclusive EC use) and dual users (combined EC use with conventional cigarettes). Statistical comparisons of parameters assessed were carried out using student’s T-test and Wilcoxon-signed rank test depending on whether the data was parametric or not, respectively. Missing measurements were not included in the analyses. A two-tailed p value of less than 0.05 was considered to indicate statistical significance. All analyses were performed with the Statistical Package for Social Science (SPSS for windows version 18.0, Chicago, IL, USA).

Results

Characteristics of the patients and their EC use

Patient details are listed on Table 1. Of the starting 18 (11 male, 7 females) asthmatic EC users identified and evaluated in the preliminary study (Polosa et al., 2014b), two (1 dual user and, 1 single user) relapsed to exclusive tobacco smoking by the final follow up visit at 24 months. Of note, one dual user became single user by the end of the study. Thus, by the end of the follow-up we analyzed data from 10 single and 6 dual users. Dual users smoked less than 6 conventional cigarettes/day already at F/up 1, and less than 4 at F/up 2 and F/up 3.

Table 2. Changes in objective and subjective asthma parameters measured at baseline and at subsequent follow-up visits.

There were no significant differences in the measured parameters of lung function, methacholine PC20, number of respiratory exacerbations, or ACQ scores between the pre-baseline and baseline visits (except for a small but significant change in FEF25-75) (Table 1). All patients remained on a stable dose of ICS, LABA as well as on-demand SABA throughout the study.

Smoking consumption

Overall, there was a marked reduction in conventional cigarette use amongst EC users, the mean cigarette/day consumption of 21.9 at baseline decreasing to 2.3 at F/up 1 (p<0.001), 1.9 at F/up 2 (p<0.001), and 1.5 at F/up 3 (p<0.001) respectively (Table 2). Substantial reduction in conventional cigarette use was also observed in dual users; their mean cigarette/day consumption at baseline decreasing from 20.7 to 5.3 at F/up 1 (p<0.001), 3.7 at F/up 2 (p<0.001), and 3.5 at F/up 3 (p<0.001), respectively (Table 2). Importantly, 10 out of 16 asthmatics were still exclusively using EC at 24 months and not smoking conventional cigarettes throughout the study (single users).

ECs pattern of use

For all patients, first-time purchase was a “cig-alike” EC model, but the majority went on to adopt refillable “pen-like” ECs. Duration of regular EC use ranged from 20 to 26 months, with ten patients using them for at least 2 years. All participants were using standard refillable ECs by the end the study. The preferred nicotine strength of their e-liquid was 9 mg/ml and 18 mg/ml, which was consumed by 62.5% (10/16) and 18.8% (3/16) of EC users respectively. Most of the participants consistently preferred tobacco flavors over other flavors at final follow up visit.

Figure 1A. Dot plots representation of individual forced expiratory volume (FEV1) at the four timepoints of assessment for 16 EC users with asthma. The line in the figure shows the mean. * p≤0.05; ** p≤0.01; *** p≤0.001 compared to baseline.

Changes in lung function, methacholine PC20 and ACQ scores

Compared to baseline, at F/up 1 there were significant improvements in ACQ scores (Table 2; Figure 2); at F/up 2 and F/up 3 significant improvements were observed on ACQ scores, and all lung function parameters including methacholine PC20 (Table 2; Figures 1-3). Improvements detected at 12 months were still present at 24 months.

Similar improvements were also observed in the dual users (Table 2). At F/up 1, there were significant improvements in ACQ scores and FEF25-75. At F/up 2 and F/up 3 significant improvements from baseline (except for FVC at F/up 3) were observed on ACQ scores, lung function parameters, and methacholine PC20 (Table 2).

Of note, deterioration in objective and subjective asthma outcomes was noted in the two patients who relapsed to exclusive tobacco smoking. The normal FEV1/FVC of 79.5% at 12 months (F/up 2) decreased to 71.0% at 24 months (F/up 3), which indicates worsening obstructive disease. Their methacholine PC20 was reduced three-fold from 2.95 mg/ml to 1.05 mg/ml and their ACQ score increased substantially from 1.45 to 2.3.

Asthma exacerbations

Figure 1B. Dot plots representation of individual forced vital capacity (FVC) at the four timepoints of assessment for 16 EC users with asthma. The line in the figure shows the mean. * p≤0.05; ** p≤0.01; *** p≤0.001 compared to baseline. Abbreviations: F/up, follow-up; L, liters.

There were no significant differences in number of respiratory exacerbations throughout the study (Table 2). The average number of exacerbations at baseline of 1.13 not being significantly different from 0.93 exacerbations at F/up 1, 0.87 exacerbations at F/up 2, and 0.81 exacerbations at F/up 3, respectively. Of note, exacerbation rate increased from 0 at 12 months (F/up 2) to 2 at 24 months (F/up 3) in the two patients who relapsed to exclusive tobacco smoking.

Safety and tolerability

No severe adverse reactions or acute exacerbation of asthma symptoms (i.e., cough, wheeze) were noted during period of observation with EC use and none of the patients in the study cohort had a hospital or intensive care unit admission. EC use appears to be well tolerated in these asthmatic patients with dry mouth and throat irritation being occasionally reported.

Discussion

The negative impact of tobacco smoke on asthma symptoms and lung function has been thoroughly documented (Polosa and Thomson, 2013a; Eisner and Iribarren, 2007; Polosa et al., 2011). Emerging evidence now indicates that asthmatic smokers who quit or reduce substantially tobacco consumption by switching to ECs use are likely to gain significant health benefits. In a recent retrospective study, regular EC use was associated with significant improvement in lung function and asthma symptom scores (Polosa et al., 2014b). However, standard issues associated with retrospective studies do not allow establishing a causal relationship. Therefore, we followed up this group of EC users with asthma in the course of their regular visits at the outpatient clinic in order to document changes in asthma outcomes prospectively. Here we confirm that regular EC use ameliorates asthma outcomes and shows that these beneficial effects may persist in the long term. Moreover, it was shown that similar benefits could be also noted in the dual users and that regular EC use was well tolerated.

Figure 1C. Dot plots representation of individual forced expiratory flow at the middle half of the FVC (FEF25-75) at the four timepoints of assessment for 16 EC users with asthma. The line in the figure shows the mean. * p≤0.05; ** p≤0.01; *** p≤0.001 compared to baseline. Abbreviations: F/up, follow-up; L/sec, liters/second.

These confirmatory findings are of great importance considering that many asthmatic patients continue to smoke and seem uninterested in quitting (Polosa and Thomson, 2013a; Polosa et al., 2012), a paradox that may be explained by the highly addictive nature of tobacco smoking and the remitting clinical nature of asthma, particularly in its mild-to-moderate forms. The success in reducing cigarette consumption or quitting smoking with EC in these asthmatic patients may be explained by the combined compensatory effect at both physical and behavioral level (Caponnetto et al., 2013b). In agreement with this, nicotine-free plastic inhalators can improve quit rates only in smokers for whom cigarette handling and manipulation play a key role in their smoking ritual (Caponnetto et al., 2011).

This study confirms that lung function of smokers with asthma may improve when stopping smoking for a sufficient period of time. The improvement reported persisted in the long-term prospective follow up. These findings are in agreement with the positive results of prospective studies looking at the effect of stopping smoking on lung function in asthma (Tønnesen et al., 2005; Chaudhuri et al., 2006). Taken together, the evidence suggests that the harmful effects of smoking on the asthmatic airways can be reversed. It is plausible that the attenuation in pro-inflammatory effects of cigarette smoke on the airways after reducing smoking consumption by switching to EC use might have caused overall improvement in lung function (Polosa and Thomson, 2013; Chalmers et al., 2001).

Figure 2. Dot plots representation of individual Juniper's Asthma Control Questionnaire (ACQ) score at the four timepoints of assessment for 16 EC users with asthma. The line in the figure shows the mean. * p≤0.05; ** p≤0.01; *** p≤0.001 compared to baseline. Abbreviations: F/up, follow-up.

Given the close relationship between airway inflammation and airway hyperresponsiveness (AHR) in asthma (Joos et al., 2003) it is not surprising to observe significant and persistent improvements in methacholine PC20 in the asthmatic smokers who had been abstinent or reduced their tobacco consumption. The reported changes in methacholine PC20 are consistent with the results of prospective studies in allergic smokers for whom an objective proof of cessation was documented (Piccillo et al., 2008). The observed improvement in AHR may have important clinical implications because it is a risk factor for asthma symptoms and attenuated pulmonary function levels (Sparrow et al., 1987; Tashkin et al., 1996). Thus, improvement AHR is likely to confer some clinical benefit as documented by the early and stable reduction in asthma symptoms (i.e., ACQ scores). In support of this view, deterioration in methacholine PC20, lung function, and ACQ scores was noted in the two patients who relapsed to exclusive tobacco smoking.

In spite of significant improvement in lung function, AHR and asthma control, no significant change in disease exacerbations was observed. This discrepancy can be explained by the low baseline values for exacerbations in our mild-to-moderate asthmatic patient cohort (hence it is possible that scope for further improvement was limited). Nonetheless, EC use in this vulnerable population did not trigger any acute exacerbation of asthma symptoms.

Figure 3. Dot plots representation of individual Methacholine PC20 at the four timepoints of assessment for a group of EC users with asthma. The line in the figure shows the geometric mean. * p≤0.05; ** p≤0.01; *** p≤0.001 compared to baseline. Abbreviation: F/up, follow-up.

Consistent improvements in subjective and objective asthma outcomes were also observed in dual users with no real difference in dual compared to single users by the end of the follow up. This could be due to the fact that dual users in this study substantially reduced their daily tobacco consumption by 70-80% (i.e., heavy reducers).

The observed positive findings in asthma patients who have become regular ECs users are consistent with results from a large internet survey of EC users diagnosed with asthma (Farsalinos et al., 2014a). An improvement in symptoms of asthma after switching was reported in 65.4% of the respondents. Although improved asthma symptoms were more often noted in exclusive EC users, improvement was also often reported by dual users. Worsening after switching was only reported in 1.1% of the asthmatics. Taken together, these findings provide emerging evidence that EC use can reverse harm from tobacco smoking in exclusive EC users as well as in dual users when their level of reduction in cigarette consumption is substantial (i.e., heavy reducers).

In theory, EC use might induce people to introduce higher nicotine doses than those from tobacco cigarettes. However, there is no evidence to suggest that EC promotes higher nicotine consumption. In fact, the opposite is true because ECs are generally much less efficient than conventional cigarettes at delivering nicotine to the body (Nides et al., 2014; Dawkins et al., 2014; Farsalinos et al., 2014). Although compensatory puffing behaviors may contribute to higher nicotine intake both in exclusive EC users and in dual (combined cigarette smoking and vaping) users, overall level of plasma nicotine/cotinine (cotinine is a stable metabolite of nicotine) is comparable (not higher) to that of their previous smoking behavior (Behar et al., 2015; Pacifici et al., 2015). Nonetheless, nicotine is a powerful psychoactive substance and EC use may perpetuate an addictive behavior. However, there is increasing evidence that ECs may reduce measures of nicotine dependence (Etter et al., 2015; Foulds et al., 2015). Moreover, it is a common trend among EC users to reduce the nicotine strength of their e-liquid over time (Farsalinos et al., 2013; Polosa et al., 2015), suggesting that regular EC use may reduce nicotine dependence in the long term.

By substantially reducing the number of cigarettes smoked per day and exposure to their numerous hazardous toxicants, e-Cigarettes may not only improve asthma symptoms and pulmonary function but may also confer an overall health advantage in smokers with asthma (Polosa et al., 2013b). Therefore, e-Cigarette use in asthmatic smokers who are unable or unwilling to quit should be exploited as a safer alternative approach to harm-reversal (i.e., specific reversal of asthma-related outcomes) and, in general, to harm-reduction (i.e., overall reduction of smoke-related diseases).

There are some limitations in this study. Firstly, this is a small uncontrolled study, hence results must be interpreted with caution. Nonetheless, despite being a small study, the beneficial effects were consistently documented for each and every asthma outcomes throughout the final follow up visit. Secondly, it is likely that patients in this study represent a self-selected sample, which is not representative of all asthmatic smokers who switch to ECs. Lastly, assessment of symptoms may be liable to recall bias and the good tolerability reported by these patients should be considered with prudence.

The present study confirms that regular EC use ameliorates objective and subjective disease outcomes in asthma and shows that these beneficial effects may persist in the long term. Large controlled studies are now warranted to elucidate the emerging role of the e-vapor category for smoking cessation and/or reversal of harm in asthma patients who smoke. Nonetheless, the notion that substitution of conventional cigarettes with EC is unlikely to raise significant respiratory concerns, can improve counseling between physicians and their asthmatic patients who are using or intend to use ECs.

Disclosure

R.P. has received grant support from anti-asthma drug manufacturers including CV Therapeutics, NeuroSearch A/S, Sandoz, Merck Sharp & Dohme, and Boehringer-Ingelheim; has served as a speaker for CV Therapeutics, Novartis, Merck Sharp & Dohme, Roche, and GlaxoSmithKline; has served as a consultant for CV Therapeutics, Duska Therapeutics, NeuroSearch A/S, Boehringer-Ingelheim, and Forest Laboratories; and has received payment for developing educational presentations from Merck Sharp & Dohme, Novartis, and Almirall.

R.P. has also received lecture fees and research funding from GlaxoSmithKline and Pfizer, manufacturers of stop smoking medications; he has also served as a consultant for Pfizer and Arbi Group Srl, an Italian e-cigarettes distributor. R.P.’s research on e-cigarettes, smoking, and asthma is supported by Lega Italiana AntiFumo (LIAF).

J.B.M. has received honoraria for speaking and financial support to attend meetings/advisory boards from anti-asthma drug manufacturers including Wyeth, Chiesi, Pfizer, Merck Sharp & Dohme, Boehringer-Ingelheim, Teva, GlaxoSmithKline/Allen & Hanburys, Napp, Almirall, and Novartis.

P.C., M.C., D.C., M.D.A., G.C., C.R., and A.F. have no relevant conflicts of interest to declare in relation to this work.

Author Contribution

R.P. and J.B.M. contributed equally to this article.

Corresponding Author

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

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What to Advise to Respiratory Patients Intending to Use Electronic Cigarettes

r67r2pol — Mon, 28 Sep 2015 20:25:01 +0000

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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