This small study, the first of its kind to date, found no detectable changes in lung health in never smokers who have been regularly vaping for at least 4 years. Daily exposure to ECs aerosol emissions caused no significant changes in any of the health outcomes investigated, including measures of lung function and lung inflammation. Moreover, no significant structural abnormalities could be identified on HRCT of the lungs and no respiratory symptoms were consistently reported. In spite of the small sample size and lack of comparison to smokers, careful examination of long-term health effects of EC use in a rare cohort of regular daily users who have never smoked in their life may contribute to the current understanding of the potential health risks associated with EC use.

Six of the nine EC users who completed the study were still consuming nicotine-containing e-liquids as reported on their last visit. Tobacco combustion products, not nicotine, cause most of the adverse health effects of smoking27. However, there is concern that some adverse cardiovascular effects may be related to nicotine per se due to its ability to cause hemodynamic changes (increase in heart rate, a transient rise in blood pressure, vasoconstriction of coronary and other vascular beds), adverse effects on lipids and induction of insulin resistance27. In this study, no significant changes in systolic BP, diastolic BP or HR were observed in the EC user group throughout the study. Moreover, no notable individual changes were observed in any of the vapers consuming nicotine-containing e-liquids. Thus, consumption of low dose nicotine did not seem to have significant adverse cardiovascular effects, as shown in recent EC studies of healthy smokers28 and smokers with arterial hypertension29. Also, the latest US Surgeon General’s report that examined harm from tobacco and nicotine has concluded that - although it may adversely affect foetus and adolescent brain development – nicotine does not contribute to smoking-related diseases30.

Given that particle size in ECs aerosols is well within the respiratory range31,32, these particles can penetrate deeply within the lungs; therefore the concern that long-term exposure to ECs aerosol emissions may carry some health risk is reasonable18,19,33. However, in this study no significant changes in lung function, respiratory symptoms, FeNO or eCO measurements were found. Furthermore, no noticeable individual changes were observed in any of the vapers including those with the most significant exposure history. Some acute EC trials in healthy smokers have reported transient changes in respiratory effects34, but others have not confirmed these observations35,36. Long-term studies in healthy smokers20,21 and smokers with asthma and COPD37,38 switching to EC use have shown not only no clinically significant adverse respiratory effects, but, to the contrary, a mitigation of the harmful effects of smoked tobacco on the lung.

In addition, substantial improvement in respiratory symptoms has been reported in a large internet survey of 19.000 smokers who switched to vaping1. In those diagnosed with asthma (n = 1173) or COPD (n = 1062) improvement in respiratory symptoms after switching was reported in 65.4% and in 75.7% of the respondents, respectively. Worsening after switching was reported only in 1.1% of the asthmatics and 0.8% of the respondents with COPD.

Lung function tests and self-reported respiratory symptoms may not be sensitive enough to detect early potential pathologic changes that may occur in response to chronic inhalation of EC aerosol emissions. HRCT can be used to better identify distribution and extent of early evidence of lung damage39. Early signs of lung damage, such as parenchymal micronodules, ground-glass attenuation and emphysematous changes, have been described in asymptomatic smokers with and without spirometric abnormalities40,41,42. However, in this study no CT features indicative of early signs of lung damage were present in any of the EC users.

Flavorings in the e-liquid are generally considered safe to eat, but have largely unknown effects on the lung when heated and inhaled. Chronic exposure to high levels of diacetyl - a flavoring substance commonly used in the food industry for its appealing buttery aroma - in microwave popcorn workers has been shown to be associated with cases of bronchiolitis obliterans (i.e. “popcorn lung”)43,44. Although many vaping liquids may contain high concentrations of diacetyl45,46, there is no report that this has caused bronchiolitis obliterans in EC users. In this study, no features consistent with early sign of bronchiolitis obliterans were described in any of the EC users undergoing HRCT.

In the present study, over a period of about 4 years, none of the EC users started smoking tobacco cigarettes (two stopped vaping completely) and two never smokers from the reference group (never smokers, not using ECs) started smoking. Whether the use of ECs is a gateway to (or out of) smoking remains matter of debate47.

Some of the strengths of this study include the relatively long follow up period, the detailed vaping history, careful characterization of the study participants and the use of a panel of different clinical, functional and inflammatory measures. But it has also some notable limitations.

In relation to health effects reporting, it is important to acknowledge that reasons for loss to follow up may include health problems. In our study, four EC users were lost to follow-up (no shows); these individuals may have quit ECs because they experienced negative health effects associated with their use. Hence, the risk for selection bias cannot be excluded.

The very small sample size minimizes the power to show both prevalent abnormalities at baseline and statistically significant changes from baseline over time. Nonetheless, it must be recognized that vapers who have never smoked are a very uncommon sub-population of ECs users; the 2014 Eurobarometer survey found about 0.1% of daily EC use in never smokers48. Hence, we were fortunate enough to recruit into the study such a carefully selected rare population of great importance to address the potential absolute risk of long term exposure to EC aerosol emissions disentangled from the effects of concomitant or former tobacco cigarette smoking. However, there is evidence of significant spirometry changes relatively early after initiation of smoking, even when analysing very small samples - as low as 13 smokers49. In any case, careful examination of the individual data on a case-by-case basis revealed no impairment in the health measures evaluated in any of the EC users in the study.

Another limitation is that the sample of relatively young subjects studied (mean age 27–28 years), who had had a generally short duration of regular EC use prior to entering the study (on average 8 months) and vaporized, on average, only a modest amount of e-liquid (about 4 ml/die), may not be representative of the general population of EC users who never smoked. Consequently, firm conclusions cannot be drawn from the results and additional studies in a larger and more diverse group of EC users are needed. On the other hand, vapers who have never smoked are likely to be relatively young1,50.

A related weakness is that since the age of our subjects was, on average, only in the mid-twenties, the normal age-related decline in lung function may not have yet commenced51, thus making it more difficult to show accelerated declines in response to any EC-related lung injury. Also, since duration and intensity of smoking are significant predictors of lung function decline among regular cigarette smokers52, the generally short duration and small amount of EC use by the vapers whom we studied may not have been sufficient to result in detectable lung damage. In any case, these deficiencies may guide other researchers to improve the design of similar studies.

Although no deterioration in lung health was detected during the 3.5 years follow-up, one could argue that no significant changes would have been detected among young healthy smokers during such a period as well. Comparison with a reference group of young smokers would have helped the interpretation of the results in EC users, thus making problematic to establish whether ECs are harmless or even less harmful than conventional cigarettes. Data documenting the effects of smoking on the lung over the first few years following initiation of smoking are limited. Tashkin and coll49 found that, over the five years between two visits at which spirometry was performed, those who initiated the smoking habit sometime during these 5 years (possibly, 2.5 years on average) had a relatively greater “negative” change in spirometric indices compared to those who never initiated the smoking habit. Niewoehner and coll52 found pathologic changes of the small airways at autopsy in young cigarette smokers who had died accidentally in motor vehicle accidents, indicating evidence of the harmful effects of smoking on the lung relatively early after initiation of smoking.

Another shortcoming is that HRCT scans were performed only at TLC, so that air-trapping (a sensitive measure of early lung damage in smokers with normal spirometry) could not be assessed53.