Current perspective on e-cigarette use and respiratory variables: mechanisms and messaging

ABSTRACT

Introduction

There has been an increasing amount of research on the consequences of e-cigarette use for respiratory variables, which is significant for public health and respiratory medicine. We discuss recent findings and lay out implications for prevention and treatment.

Areas covered

Based on literature searches using several databases (PubMed, Web of Science, Google Scholar) for keywords, including synonyms, ‘e-cigarettes,’ with ‘pulmonary function,’ ‘oxidative stress’ and ‘inflammation,’ we review studies on acute effects of e-cigarette use for measures of pulmonary function and discuss selected laboratory studies on mechanisms of effect with a focus on processes of known relation to respiratory disease; oxidative stress and inflammation. We discuss available studies that have tested the effectiveness of communication strategies for prevention of e-cigarette use oriented to different audiences, including nonsmoking adolescents and adult smokers.

Expert opinion

We conclude that the evidence presents a mixed picture. Some evidence is found for harm reduction while evidence is also found on adverse consequences of e-cigarette use for measures of lung function and two biological processes. How to best communicate these results to a complex audience of users, from younger susceptible adolescents to long-term adult smokers interested in quitting, is a question of significant interest and empirically-validated communication strategies are greatly needed.

KEYWORDS:

• E-cigarettes
• respiratory disease
• pulmonary function
• oxidative stress
• inflammation
• health communication

Disclaimer

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1. Introduction

Electronic nicotine delivery systems (hereafter, e-cigarettes) were introduced to the commercial market in 2007 and their prevalence began to increase several years later. The situation at the present time includes an expansion in the nicotine products market, a substantial prevalence of e-cigarette use among young people, and an ongoing debate about the role of e-cigarettes in respiratory outcomes and public health generally [1–5].

Over the past five years, there has been an accumulation of evidence on e-cigarettes from research by epidemiologists, toxicologists, and respiratory medicine physicians [6–8]. In this paper we present a review of current e-cigarette research, focusing on the effects of e-cigarettes for respiratory-tract processes and the implications of this research for health communication messaging related to e-cigarettes. We include both behavioral research and basic physiological research because we think this will be synergistic: clinical studies being informed by mechanistic research, and communication research being informed by studies on physiological effects, so that continuing development in each of these areas will be informed by developments in the other.

The present situation includes meta-analyses on the association of e-cigarette use with respiratory disease [8,9], analyses for smoking cessation [3], and position papers providing discussion about benefits and risks of e-cigarette use [2,4]. In this paper we discuss current knowledge (past five years) about effects of e-cigarettes, though discussing some frequently cited previous studies to illustrate the depth of the evidence in this area. Given the increase in prevalence among adolescent nonsmokers and continuing debates about smoking cessation [4, 10–12] we include data on both adolescents and adults. In turn we will discuss research about acute effects, longer-term physiological mechanisms, and communication strategies, concluding with our expert opinion about the current state and future directions for of the field.

2. Effect of e-cigarettes on lung function

Meta-analyses show that while some studies have found e-cigarette use associated with lower risk of respiratory disease (asthma or COPD) compared to combustible cigarettes, there are some cases where a similar level of effect is found [8,9]. Accordingly it is essential to understand the effects of e-cigarette on pulmonary function since the lungs are the primary organ of contact with e-cigarette aerosol. E-cigarettes release a diverse range of harmful chemicals, including heavy metals, volatile organic compounds (VOCs), and ultrafine particles [12–15]. These substances have the potential to cause damage to the respiratory system, through pathways that are sometimes similar to those previously found for cigarettes but sometimes different (e.g., 16-18].

For example, carbonyl chemicals, such as acrolein, which are detected in the aerosol of e-cigarettes, are a major class of toxicants in cigarette smoking that can induce mucus hypersecretion and damage airway epithelium [19]. However, the different levels and composition of these toxicants in e-cigarette aerosol compared to cigarettes, compounded by the different patterns of use of the two tobacco methods, precludes extrapolating the evidence from cigarette smoking into e-cigarettes. Generally speaking, because of the lack of combustion products, which are the major toxicants in cigarette smoke, e-cigarettes have been considered less harmful than cigarettes. Still, the spread of e-cigarette use among young people, whose respiratory tract is still developing, makes researching harmful effects on the respiratory system a priority [20,21].

2.1 Current research on e-cigarette use and lung function

Previous challenge studies exploring the effect of e-cigarettes on lung function assessed lung function (as measured by spirometry) before and after an e-cigarette use session. We conducted a literature review in July 2023 based on searches of PubMed, EMBAS, Web of Science, Google, Scholar using keywords “e-cigarette, vape, or ENDS” and “spirometry, pulmonary function, or lung function”). The results from these studies yielded mixed and inconclusive findings. Several studies have shown decreases in pulmonary function as a result of e-cigarette use [22,23] while others have failed to show significant effects on the same outcomes [24–26]. A recent systematic review considered seven studies investigating the acute respiratory effects of e-cigarette use [27] and concluded that the use of e-cigarettes leads to an increase in airway resistance while exhibiting no discernible effect on forced expiratory volume in one second (FEV1), forced vital capacity (FVC), or the FEV1/FVC ratio. It also highlighted limitations of the existing literature on this topic. For example, some of the reviewed studies used brief e-cigarette use sessions lasting between 10 to 15 minutes [24,25], which may be inadequate given the irregular and extended pattern of naturalistic e-cigarette use [28]. Related to this issue, some studies applied restrictions on number of puffs during the session [25,29], which does not represent the true puffing behavior of the participants. Moreover, some of these studies used cigarette smokers or e-cigarette naive participants rather than current e-cigarette users as participants. For example, Boulay et al. [25] and Staudt et al. [30] used e-cigarette naive participants, Palamidas et al. [24, 31] included both cigarette users and e-cigarette naive participants as two groups whereas Coppeta et al. [29] and Ferrari [22] did not define the e-cigarette use status of their participants. Furthermore, several studies relied on a self-reported nonvalidated abstinence period prior to the study, which can introduce bias due to nonreported use carryover.

A recent study by Roy et al. [32] was conducted among 58 current young (ages 21-35 years) e-cigarette users to address these limitations. In this within-subject study, after a 12-hour plasma nicotine-validated abstinence, participants underwent a laboratory session during which they were allowed to use e-cigarettes ad libitum for up to 60 minutes with their preferred flavor (menthol or tobacco) and concentration (5% or 3%). Pulmonary function testing (PFT) was performed before and immediately after (within 10 minutes) the session. A Wilcoxon signed-rank test was conducted to compare the pre-and post-session spirometry findings. This analysis revealed a statistically significant decrease in all lung function parameters after the e-cigarette use session.

Also, linear mixed models and Pearson’s correlation coefficients were used to examine the correlation between e-liquid consumption, dependence level, and lung function changes. This analysis showed a dose-response relationship between e-cigarette liquid consumption and decline in lung function. In short, a higher use of e-cigarette was associated with more decline in lung function. However, this study did not find any relationship between e-cigarette use and diffusing capacity of the lungs for carbon monoxide (DLCO), a measure of gas transfer ability; this is probably due to the shorter duration of exposure compared to the prolonged exposure to cigarette smoking needed to document changes in pulmonary diffusion capacity [33].

As evidence is accumulating about the long-term {34] and acute effects of e-cigarettes on lung function [35], their long-term effect physiological pathways are, by and large, underinvestigated [8,15]. This is partly because of the long period of tobacco use and the development of major respiratory consequences, such as COPD, compared to the short history of e-cigarettes. The long-term detrimental respiratory effects of e-cigarettes on lung function can be glimpsed from only a few studies of respiratory effects associated with e-cigarette use. For example, Joshi et al. [34] studied the relation between e-cigarette ever use in a large population sample of Canadian adults aged 45-85 years. Lung function, assessed from spirometry data, was measured in a clinic examination and standardized criteria were used for scoring severity of lung damage. Results showed e-cigarette use was significantly associated with obstructive lung function impairment, controlling for cigarette smoking history and other covariates. Tattersall et al.[35] studied acute effects of a 15-muinute e-cigarette use session on a range of outcomes in a sample of exclusive e-cigarette users, exclusive cigarette smokers, and controls (nonsmoker, nonvaper). Several significant effects were found for the e-cigarette group compared with other groups. For example, they showed worsening cardiovascular parameters and worsened exercise tolerance. In addition, epidemiological studies have consistently found an association between e-cigarette use and current respiratory symptoms such as coughing and phlegm production in young people [36,37] and this literature includes several prospective studies [38–40]. While these studies were mostly had self-reported outcomes, the consistency of findings across cross-sectional and longitudinal studies is suggestive of a cause-and-effect relationship [9].

2.2. Interim summary

Taken together, these studies highlight some limitations in the extant literature and gaps that require further research. Despite these limitations, high-quality challenge studies of acute respiratory response to e-cigarette use are beginning to draw a clear picture of a detrimental effect of e-cigarette use on lung function. This detrimental effect on the respiratory system has been corroborated by emerging longitudinal literature on the association of e-cigarette use with incident respiratory symptoms [38–40]. As the e-cigarette epidemic gathers more time, longitudinal studies should start answering critical questions about long-lasting effects on respiratory health of users.

3 Evidence on inflammation and oxidative stress processes

Clinical papers [2,4] have discussed risks and benefits of e-cigarettes with attention to possible benefits (e.g., smoking cessation) while also discussing possible risks such as increased exposure to toxicants for dual users and cytotoxic effects noted in laboratory studies of e-cigarette aerosol. These reviews have mentioned examples of laboratory studies but a focused review of biological processes relevant for respiratory disease is needed. One author (TAW) conducted a focused review of studies examining the relation of e-cigarette use to oxidative stress and inflammation, which have been studied intensively because of their relation to several different diseases, including asthma and COPD [20,21,41,42]. A focused search using the keywords “e-cigarettes” (or synonyms) with “oxidative stress” and “inflammation” was conducted in November 2023 using similar databases as for the Wills et al. [8] review (e.g., PubMed, Google Scholar). From a final set of 30 primary studies conducted after 2020 (the cutoff for the review), the author selected studies for relevance and innovative research methods. Several biological processes have been examined for studying the effects of e-cigarettes on the respiratory system, but the majority of studies have focused on two basic processes: inflammation [41] and oxidative stress [42]. These are known to underlie several different diseases including asthma and COPD. Representative in vitro studies, animal models, and human studies are discussed in the following section; with basic study characteristics summarized in Table 1. It is important to note that oxidative stress and inflammation aren’t independent processes and it is not uncommon that they are examined together in the same study [e.g., 43-45]. Detailed discussion about findings of DNA damage is beyond the scope of the present review but we note this when such evidence was observed and discuss this briefly in a later section

Table 1 Studies of Oxidative Stress and Inflammation

Study	Type	Exposure^A	Assay(s)	Main finding(s)	DNA damage
Scott 2018 [49]	In vitro (cells)	Aerosol (vaped or nonvaped)	Cell viability, IL-6, TNFα, MMP-9, phagocytosis	Viability reduced by vaped e-liquid Inflammatory factors ↑, phagocytosis ability ↓ in vaped condition	n.a.
Muthu- malage 2019 [50]	In vitro (Cells, 2 lines)	Aerosol (JUUL)	IL2, IL-8 Prostaglandin E2 ROS	Inflammatory factors ↑Oxidative stress	Yes
Sun 2021 [45]	In vivo (mice)	Aerosol (PG, G), TS	Fibronectin, CRP 8-oxodG	↑Inflammatory factors ↑Oxidative stress	Yes
Ma (2020) [43]	In vitro (cells), In vivo (mice)	Aerosol	IL-1b, IL-8, TNFα, ROS	Pro-inflammatory effect on different cell lines, evidence of oxidative stress. Heating e-liquid ↑oxidative stress.	n.a.
Roxlau 2022 [41]	In vitro (cell lines, in vivo (mice)	Aerosol	IL-5.IL-13, IL-16, MMP9, MMP12	↑ inflammatory changes for in vitro study. E-cig exposure caused structural alterations consistent with emphysema.	n.a.
Moshensky 2022 [52]	In vivo (mice)	Aerosol	IL-1β, IL-6, IL-8, TNFα	↑ Inflammatory gene expression. Changes noted in brain, lung, GI tract suggestive of ↑ inflammation, ↓ innate immunity.	n.a.
Rodriguez 2022 [57]	In vivo (mice)	Aerosol (e-cig, TS)	IL-6, IL-15, MMP-9, TBARS	↑proinflammatory cytokines, cell damage ↑ density of alveolar air space (∼emphysema) in e-cig group.	n.a.
Been 2022 [59]	In vivo (mice) vehicle)	Aerosol (e-cig,	IL-4, IL-10, IL-13, TNFα, 8-OHdG, Sod2, Nrf2	Significant ↑in proinflammatory cytokines and oxidative stress. for e-cig condition. Also observed ↑in antioxidants.	Yes
Song 2020 [61]	In vivo (Human)	Exptl (e-cig, ∼e-cig)	IL-8, IL-13, TNFα	E-cig use frequency correlated with levels of pro-inflammatory cytokines	n.a.
Tommasi (2022) [64]	In vivo (Humans)	Natural (smoker, vaper)	Gene expression (RNA-seq)	Small overlap between gene expression for smokers, vapers. Most common gene pathways involved inflammation, innate immunity)	Yes
Wetherill 2022 [65]	In vivo (humans)	Natural (smoker, vaper)	PET lung imaging (iNOS), IL-6, TNFα	E-cig users had more iNOS inflammation compared with controls and smokers. IL-6 level correlated with vaping frequency.	n.a.
Kelesidis (2021) [66]	In vivo (human)	Exptl (1 vape session)	Immune cells, neutrophils	Significant ↑in oxidative stress observed after 1 vaping session.	n.a.

Note. IL = interleukin; TNF = tumor necrosis factor; MMP = metalloprotease; ROS = reactive oxygen species; CRP = C-reactive protein; PG = propylene glycol; G = vegetable glycerin; TS = tobacco smoke; Exptl = experimental.

1.1. In vitro studies

Several recent studies have examined effects of exposure to e-cigarette aerosol using various cell lines, sometimes in conjunction with animal models. (For more detailed discussion of earlier studies see [8]. Unless otherwise noted, the control condition was exposure to room air.

Effects on alveolar macrophages

In the lungs, alveolar macrophages (AMs) are an important part of the body’s innate and adaptive defense systems through a multiplicity of roles including activating other parts of the immune system through the production of pro-inflammatory cytokines [46–48]. A classic in-vitro study by Scott et al. [49] exposed macrophages obtained from a sample of human never smokers either to e-cigarette vapor condensate derived from a machine that heated and puffed an e-liquid, simulating actual e-cigarette use conditions (“vaped”), or to e-liquid that had not been heated (non-vaped). They observed a dose-dependent reduction in cell viability, which was higher in the vaped condition than in the non-vaped condition, with greater effect when nicotine was present in the e-liquid. Additionally, levels of pro-inflammatory interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), and matrix metalloprotease 9 (MMP-9) were elevated in the vaped condition, while the ability of macrophages to destroy a pathogen (E. coli) was reduced. This study showed that the functioning of an important part of the innate defense system was adversely affected by exposure to e-cigarette aerosol; also, protection against pathogens was reduced.

Effects of flavored e-cigarette pods

Effects of aerosol from a recent generation of e-cigarettes (JUUL) were examined in vitro for two human cell lines from the bronchial epithelium [50]. The study showed that exposure to e-liquids and e-cigarette aerosols caused significant increases in inflammatory mediators (e.g., IL-8, IL-15 and Prostaglandin E2), and that exposure to e-cigarette aerosols produced an increase in reactive oxygen species (ROS), a marker for oxidative stress. Several pod flavors generated significantly higher levels of reactive oxygen species and some flavors (e.g., Cool Cucumber, Classic Menthol) produced differential inflammatory response. There was also evidence for significant DNA damage. While results varied across flavors and cell lines, the findings are consistent with other studies with animal models indicating that repeated inhalation of e-cigarette aerosols produced pro-inflammatory responses and lung damage in mice [e.g., 51].

3.2. Animal model studies

Effect of humectant in e-juice on biomarkers for inflammation

In an in vivo animal study, Sun et al. [45] studied the effect of exposure to aerosol from heated propylene glycol/vegetable glycerine (PG/VG), a humectant used to vaporize e-juice, which was prepared with or without nicotine. Mice received whole-body exposure for 8 weeks under 3 conditions: clean air (negative control), aerosol from an e-cigarette with PG/VG, or smoke from a standard research cigarette (positive control). Histology examination of lung tissue examined for lung injury was based on observations for capillary congestion, hemorrhage, interstitial and intra-alveolar neutrophils, and intra-alveolar macrophages. Levels of inflammatory biomarkers fibronectin and C-reactive protein were increased in the e-cigarette condition compared to the clean-air control, as were levels of 8-hydroxy-deoxy-guanosine (8-oxodG), a biomarker for DNA oxidative damage. Histology data indicated that 33% of the mice in the e-cigarette condition showed an elevated score for lung injury whereas none of the mice in the control condition showed lung injury. This study showed that simple exposure to a heated humectant could produce increased inflammation and oxidative stress, independent of nicotine exposure.

Pathways for cytotoxicity

Ma et al. [43] generated e-cigarette aerosols from custom-made and commercial e-liquids using a puffing machine that heated e-liquid, and they varied puff numbers and nicotine content. Effects of aerosols were studied using both human cell lines (monocyte-differentiated macrophages and bronchial epithelial cells) and animal models using two types of mice (wild-type and transgenic). Macrophages treated with e-cigarette aerosol with different puff numbers showed a puff-dependent increase in markers of cell toxicity and oxidative stress (e.g., glutathione). In addition, cells exposed to aerosols with higher nicotine levels showed higher levels of toxicity and oxidative stress. Generally, e-cigarette aerosols induced pro-inflammatory effects in different human cell lines, indexed by increased production of IL-1β, IL-8, and TNF-α. Lung samples from mice exposed to e-cigarette aerosol with different nicotine levels showed a dose-dependent acute inflammatory effect and this was linked to the generation of reactive oxygen species (ROS). This study provided more evidence that heating of e-cigarette liquid generates fine particulate matter and ROS, which were linked to lung cell damage. The authors noted that the study showed combustible cigarettes and e-cigarettes worked through similar pro-inflammatory pathways.

E-cigarette effects on inflammatory parameters and lung structure

A study of e-cigarette effects on inflammatory mediators and lung structure [41] used studies with cell lines (e.g., human bronchial epithelial cells) and mice who were exposed to e-cigarette aerosol or conventional cigarette smoke in an inhalation chamber every day for 8 months. While the cell line studies generally did not show evidence of cytotoxicity for the e-cigarette studied, some effects on gene expression and metabolic pathways were observed (e.g., upregulation of glutathione metabolism). Results for the animal model from assays of bronco-arterial lavage (BAL) or lung sections showed that e-cigarette exposure increased levels of pro-inflammatory cytokines that are implicated in asthma (IL-5, IL-13, and IL-16) and matrix metalloproteases that are implicated in COPD (MMP9 and MMP12). Concerning lung structural alteration, which was measured with in vivo micro-computed tomography, long-term e-cigarette exposure caused emphysema-like structural alterations, some similar to those induced by cigarette smoke but some different. Results for a composite score for lung airways and parenchyma based on several parameters from computed tomography (e.g., resistance, inspiratory capacity, airspace) indicated the nicotine-free e-cigarette exposure group was more affected than the control group but less affected than the cigarette group, and interaction analyses suggested that nicotine increased the effects of e-cigarette vapor on inflammation and airway parameters. The authors noted that while some effects were dependent on nicotine, they could not exclude an effect on acute and chronic lung damage derived from exposure to nicotine-free e-cigarette vapor.

Effects of e-cigarettes on the brain, heart, and lung

Extending previous research on lung effects, Moshensky et al. [52] examined the effects of e-cigarettes on other organs in an animal model study. Mice received whole-body exposure to aerosol from JUUL e-cigarettes 60 min/day for 4-12 weeks. An elevation of inflammatory mediators TNF-α and IL-1β was observed in brain regions responsible for drug reward and behavior modification. Examination of colon tissue showed inflammatory gene expression, with upregulation of TNF-α, IL-6, and IL-8 in the exposed mice relative to the air control. BAL showed significant differences in gene expression between the two groups, involving for example genes for mucin, which plays an important part in protecting the lungs from pathogens. The authors noted that exposure to flavored JUUL aerosol produced significant neuroinflammation in the brain as well as inflammatory modulation in the heart, lung, and GI tract. Though structural changes were not observed for lung alveolar tissue as in previous studies [e.g., 53], the gene expression changes were consistent with altering the lung response to challenges from bacterial and viral infections as observed in other research [54–56].

Impact of e-cigarettes on emphysema parameters in an animal model

A study by Rodriguez-Herrera et al. [57] randomly assigned 48 mice to three conditions of whole-body exposure in an inhalation chamber (72/min day for 60 consecutive days): conventional tobacco smoke (TS), e-cigarette aerosol (EC), or clean air. After a 60-day recovery period, assessments were conducted using a small-animal spirometer. Additionally, samples of blood and BAL were obtained for assays of biomarkers and histology measures for lung structure. Results showed mice in the e-cigarette condition had altered ventilatory parameters (e.g., higher respiration rate), higher number of neutrophils in the BAL, and more damage to lung cell membranes as indexed by the thiobarbituric acid reactive substances (TBARS) assay. In addition, there were higher levels of proinflammatory cytokines (IL-6 and IL-15) and matrix metalloprotease MMP-9. Histological analysis of lung parenchyma (thin-walled alveoli) showed a higher density of alveolar air space for the e-cigarette group. The authors concluded that long-term e-cigarette exposure promoted altered breathing patterns suggestive of airway restriction; greater influx of immune cells (macrophages and neutrophils) into the airways; redox imbalance (i.e., higher levels of oxidants and lower levels of antioxidants); and altered lung architecture (higher density of alveolar air space volume). All these changes are known to be associated with the pathological development of chronic diseases such as COPD. The authors noted their results were consistent with previous studies for animal models of COPD [e.g., 53,58] but covered a wider range of outcomes. There were several instances where the e-cigarette group scored higher on adverse effects than the cigarette group.

Impact on immune cells and oxidative stress responses

The effect of flavoring in the JUUL pod system was examined in an in vivo animal study [59]. Mice were randomly assigned to e-cig exposure (three 20-minute JUUL aerosol exposures per day for three days with one of three JUUL flavors), a vehicle control (PG/G alone), or a room-air control. Data were obtained from BAL, blood samples, and lung tissue. The primary effect of e-cigarette exposure was an increase in levels of neutrophils and inflammatory cytokines but with variation across flavors. The mRNA expression of several cytokines as analyzed from lung tissue. There was evidence for changes in expression of Il-4, Il-10, and Il-13 associated with mint flavor and mango flavor. Increases in oxidative stress were noted for the biomarker malondialdehyde (MDA, for tobacco flavor) and the biomarker for oxidative DNA damage 8-OHdG (for mint flavor). Regarding immune cells, there was a significant increase in the number of neutrophils in the BAL of mice exposed to mint-flavored aerosol. While results were not totally consistent across outcomes,

this study showed e-cigarette exposure could affect immune-system cells, alter levels of proinflammatory cytokines, and show evidence of oxidative stress and DNA damage [60].

3.3. Human studies

Bronchoscopy measures for assays

In a human experimental study [61], 30 nonsmokers were randomized to use flavor- and nicotine-free e-cigarettes over a 4-week period or to a control condition with no e-cigarette use. Data were obtained from bronchoscopies and bronchial brushings performed at the beginning and end of the study. Analyses showed that the frequency of e-cigarette use was related to levels of inflammatory cytokines including IL-8, IL-13, and TNF-α. However, analyses of DNA from bronchial brushings showed no significant changes in overall gene expression scores. While results for inflammatory markers were notable, the lack of changes in gene expression was puzzling given that these changes usually go together [58,62,63].

E-cigarettes and gene dysregulation

Tommasi et al.[64] recruited 37 current exclusive vapers (with or without a history of smoking), 22 current exclusive smokers, and 23 controls (nonvaper, nonsmoker), so that biological consequences of e-cigarette use could be distinguished from those of cigarette smoking. Results showed significant dysregulation of functionally important genes and molecular pathways in leukocytes of both e-cigarette users and smokers, similar to results from a prior study. The number of gene expression changes in smokers on average was 7 times higher than in e-cigarette users. The great majority of differentially expressed genes in e-cigarette users (79% to 88%) were associated in a dose-response relation to the frequency of past e-cigarette use; but were not associated with a past-smoking index. The most frequently affected gene expression changes among e-cigarette users were for functional pathways involved in innate immunity and inflammation. There was an impairment in innate immunity for both groups, but the results did suggest an increased susceptibility to infection, and more severe infections, among e-cigarette users. The authors emphasized the importance of the observed changes to the susceptibility to infection and later development of chronic inflammatory conditions such as COPD.

Direct imaging of lung inflammation

A different approach to assessment was taken by Wetherill et al. [65], who used PET imaging of the lungs of human participants. They used a marker for inducible nitric oxide synthase (iNOS) which is specifically associated with inflammatory diseases including asthma and COPD, using a radiotracer (18-F-NOS) that allows imaging of iNOS in human lungs to characterize oxidative stress and inflammation in the lungs. The study involved 5 exclusive e-cigarette users who had vaped daily in the past 6 months; 5 exclusive cigarette smokers (CO verified), and 5 sex/age matched nonsmoking controls. A test for absolute level indicated showed that e-cigarette users had higher iNOS binding levels compared with controls and also compared with smokers. Repeated measures on biomarkers for inflammation in blood and plasma (TNF-α, IL-6, and C-reactive protein) showed that the use frequencies for both cigarettes and e-cigarettes (cigarettes/day and vaping episodes/day) were correlated with IL-6 levels. Though the study had a small sample, the significant iNOS difference over multiple assessments provides a direct indication that e-cigarette use may alter pulmonary oxidative stress responses and hence predispose to lung injury.

Impact of a single session of vaping

There has been debate about how much exposure to e-cigarettes is necessary to produce health effects. An experimental study by Kelesidis et al. [66] tested the effect of one session for oxidative stress. The study had a sample of 12 exclusive long-term e-cigarette users, 22 exclusive long-term smokers, and 11 controls (never smoked or used e-cigarettes). All participants engaged in two sessions randomly ordered (i.e., crossover design) Participants in two conditions (e-cigarette users and nonusers) used a real e-cigarette (5% nicotine) in a 30-minute vaping session with 1 puff every 30 seconds; and also performed a sham-vaping procedure (puffing through a straw) with the same parameters. Participants in the smoker condition smoked a cigarette (own brand) in a 7-minute session; and also used an empty, unlit straw-control for the same period. Immune cells collected before and 4 hours after the session were assessed for cellular oxidative stress (COS). Baseline measures of COS were lowest in controls, intermediate in e-cigarette users, and highest in cigarette smokers. The single session of e-cigarette use significantly increased oxidative stress, primarily among nonusers. Evidence of significant trends for COS across the two assessments was found for five types of immune cells (e.g., CD14, T cells, natural killer cells) and marginally for 4 other cell types (e.g., neutrophils). The experimental session did not significantly increase study measures for participants who had already smoked or vaped, for whom measures of oxidative stress were already elevated at baseline [cf. 30,67]. The authors suggested that increases in oxidative stress among experimental users of e-cigarettes could increase future risk for pulmonary diseases.

3.4 Interim summary

The studies discussed here involved a wide variety of designs, participants, and procedures both in vitro and in vivo. Results sometimes varied across assays and cell lines and there are studies that have not shown associations with the disease markers used here [68]. However, it is noteworthy that across studies there is a consistent signal that e-cigarettes are associated with measures for inflammation and oxidative stress, which have been linked to human disease outcomes [40,41]. When comparisons with cigarette smoke were available, they tended to show e-cigarettes as having a lower level of harm, but comparisons with clean-air controls typically showed e-cigarettes related to elevated oxidative stress and inflammation. This is consistent with results from Glantz et al. [9], which consistently showed exclusive e-cigarette use associated with an elevated rate of disease outcomes compared with nonuse.

4. E-cigarettes and health communication

E-cigarettes represent an evolution of tobacco products, which has become an epidemic in the global market over the last decade [69–71]. The previous sections have discussed possible risks and benefits with respect to lung function and biological processes, and an umbrella review [6] has summarized knowledge about risks and benefits for other areas (e.g., smoking cessation). One authoritative report [72] has suggested that messages that e-cigarettes reduce harm promote youth use. However, where to go from there is not clear and empirical guidance about messaging is greatly needed. The adverse health outcomes of e-cigarettes are still the subject of ongoing debates in public health [6]. While their use among adults who smoke combustible cigarettes may aid smoking cessation and reduce harm [73,74], their uptake by youth, young adults, and other tobacco-naive persons continues to be a growing public health concern [75] and is contrary to the recommendation of clinical reviewers that nonsmokers should not use e-cigarettes [2,5]. For example, a cross-sectional study of 414,755 respondents to the 2021 Behavioral Risk Factor Surveillance System survey (BRFSS) noted that, within the group aged 18 to 20 years, 72% of those who reported current e-cigarette use had no history of combustible cigarette use [70]. The observed high prevalence among adolescents, together with the uncertain value for smoking cessation among adults, poses difficult questions for public health. In this section, we discuss the main challenges for formulating preventive communications about e-cigarettes to different audiences.

4.1. Lack of evidence about the full spectrum of e-cigarette health consequences

Although data about health outcomes of e-cigarette use have been expanding progressively, comparative data on quantitative assessments and appraisals of the clinical importance of e-cigarette exposure levels compared to combustible cigarettes, both short- and long-term, are still needed. Challenges for research in this area include the wide variety of e-cigarette products in the market (e.g., power output, construction materials, design features, liquid constituents, nicotine level) together with predominant dual and poly e-cigarette use patterns with other tobacco products, which makes it hard to isolate their effects. For example, according to a recent study, 42.2% of current e-cigarette users indicated former combustible cigarette use, 37.1% indicated current combustible cigarette use, and only 20.7% indicated never using combustible cigarettes [70]. Therefore, the development of potential health communication messaging for e-cigarette products faces the challenge of communicating emerging knowledge about their risks along with uncertainty about the likelihood of both short and long-term health effects. However, consistent with two previous reviews [8], our umbrella review [6] found strong evidence that e-cigarette has some adverse impacts on respiratory health. In particular, the increasing prevalence of e-cigarette use among adolescents and the growing evidence on health effects for e-cigarette, or vaping, products sold in the U.S. has sparked wide-ranging discussion about the harm of e-cigarettes, leading health authorities to pledge several prevention campaigns such as the “Real Cost” campaign for the U.S. Food and Drug Administration (FDA).

4.2. Communicating conflicting messages about the benefit and risk of e-cigarettes with various audiences

Framing e-cigarette health communications according to their beneficial and detrimental potential for different groups is challenging. E-cigarettes can potentially be a harm reduction pathway for adults who smoke and who are seeking to make the complete switch from cigarettes [e.g., 76]. However, promoting the benefits of e-cigarettes as a harm reduction strategy for smokers might contribute to the e-cigarette epidemic among young people who will bear mostly the downside of these products [77–80]. Empirical studies have demonstrated that pro e-cigarette content messaging can lead to less harm perception [81,82]. On the other hand, trying to prevent young people from taking up e-cigarettes by raising awareness about their risks could discourage some adult smokers from using them to try to reduce stop smoking [77]. Exposure to conflicting health information about e-cigarettes (e.g., pro- and anti-e-cigarette at the same time) can arouse confusion and create unwarranted expectancies that can affect behavior negatively [83]. This spillover effect of health communication messaging has been at the heart of the current debate about promoting and regulating harm-reducing products behavior. For example, one study found that adult cigarette smokers who viewed FDA youth-targeted anti-vaping messages were less likely to consider e-cigarettes for smoking cessation [84]. Yet, evidence about the spillover effect has been sparse and inconsistent for the most part [83–87]. For example, a study among young adult smokers found that their exposure to the FDA anti-vaping messaging showed a positive spillover effect by provoking lower interest in smoking [86], while such an effect was not seen in a more recent study looking at the effect of exposure to the FDA “Real Cost” smoking prevention messages among adolescents [87]. To date, no comprehensive assessment has been done about e-cigarette health massaging that considers its effect on the target group and potential spillover to other groups. For example, the study by Kowitt et al. [87] did not assess the spillover effect of anti-vaping messaging on older smokers, where the real spillover risk lies. More research is needed about how e-cigarette benefits and risk heath communication may potentially impact various audiences.

4.3. Conflicting attitude and beliefs towards e-cigarette health communication among public health experts

Various public health experts have conflicting views about how we should communicate the benefits and risks of e-cigarettes. While one some see e-cigarettes as a disruptive technology that will displace cigarette smoking, others sees them as catalysts for propagating addiction to tobacco products, particularly among young people [6]. While these debates are not likely to be resolved soon, evidence-based, consumer-centered approaches are recommended given the massive uptake of e-cigarette use among young people on the one hand and the emerging evidence that while e-cigarette products have a potential benefit in a clinical smoking cessation setting, they may have the opposite effect at the population level [88,89]. This approach emphasizes the right of consumers of any product to have full knowledge about potential harms associated with the product, and emphasizes that benefits to one group cannot justify harm to another, especially if the latter is a vulnerable group (e.g., adolescents) who lack agency [90].

4.4. Interim summary

In summary, e-cigarettes health communication should consider two main conflicting goals for three different audiences. First, using harm prevention strategies to discourage e-cigarette use among those who do not smoke or vape and to those currently using e-cigarettes, educating them with research findings to realize the risk of e-cigarettes for addiction or adverse health consequences. Second, using harm reduction strategies to encourage people who smoke to switch completely to e-cigarettes and, ideally, cease nicotine use entirely (to realize the potential benefits from the e-cigarettes). However, balancing the harm prevention and reduction strategies to achieve these goals represents a challenge for e-cigarette health communication. Research on identifying effective health communication messaging that holds the most promising effect for harm reduction for smokers and harm prevention for nonsmokers, but with the least spillover effect beyond the target group is needed.

5. Conclusion

The experimental data presented in this article support a conclusion that e-cigarette use has a relation to short-term reduction in some measures of pulmonary function, though not to diffusing capacity. Controlled laboratory research with animal models and human studies has consistently shown effects of e-cigarette use for increases in oxidative stress and inflammation processes, in a context where these two processes have been related to respiratory disease outcomes. Also, communication research to studying how to address different potential audiences has suggested messaging strategies that reduce harm perception could encourage e-cigarette use among youth but messaging about physical risk from e-cigarettes could discourage adults from including them in smoking cessation efforts. Determining how to balance these issues is the topic of the next generation of communication research

6. Expert opinion

We have presented a focused review of the current evidence in three areas that influence our perspective on e-cigarettes. We think the largest change in the field is that there are now more randomized trials testing the potential of e-cigarettes for facilitating smoking cessation [3], and there has been progress in working out the complex methodological issues for studying short-term effects of e-cigarette use on lung function. (Section 2). Meta-analyses with larger data bases now provide more detailed tests of how e-cigarette use is related to actual disease outcomes, both compared to cigarette smoking and compared to nonuse of any tobacco product [9]. Toxicological research has progressed and we now have a better understanding of physiological processes that may underly a relation of e-cigarettes to respiratory disease outcomes. [8,15,91,92]. We think the current evidence provides a more balanced view that recognizes known relations of e-cigarette use to respiratory disease as well as a role of e-cigarettes for helping some persons to achieve total abstinence from nicotine [2,3,6,11].

We think this area of study will be essential for future progress in tobacco control. While significant advances in tobacco control have occurred [93], at present there is a complex international environment. Some countries are enacting policies to severely restrict access to e-cigarettes [94] and some are adopting measured policy restrictions [95], while other countries have policies to encourage e-cigarette use as a harm-reduction measure [96]. Some countries have actually reversed course and repealed previous restrictive legislation in order to gain tax income from cigarettes [97]. Effective advocacy will require more sophisticated approaches, so as to communicate the advantages of an evidence-based approach while addressing concerns about the different audiences that must be addressed by legislatures and public health agencies, recognizing a need for h differential messaging oriented to nonsmoking adolescents who may be attracted to e-cigarette use [2,4]and for adult smokers who want to quit cigarette smoking [6].

6.1 Is the association of e-cigarettes with pulmonary disease a real one?

A key question for bringing an evidence-based approach to drug policy and clinical practice is whether observed associations between e-cigarette use and respiratory disease outcomes [8] reflect a real phenomenon or, instead, are attributable to methodological artifacts. Some debates over possible harm from e-cigarettes have suggested that observed associations of e-cigarette use with respiratory disease actually reflect reverse causation, that is, smokers who contract respiratory disease switching to e-cigarettes to reduce their exposure to carcinogens. While we cannot say that reverse causation never happens, prospective studies have shown e-cigarette use related to onset of disease over time among initially disease-free persons [8,9], evidence inconsistent with the reverse-causation hypothesis. Moreover, a number of studies have shown e-cigarette use related to respiratory disease among never smokers [98], which is inconsistent with a reverse-causation hypothesis. Another issue in debates about e-cigarettes approach has been whether observed associations with respiratory disease are actually attributable to confounding with cigarette smoking. It is true that e-cigarette use tends to be correlated with cigarette smoking, especially among adults. However, almost every epidemiological study conducted has controlled statistically for smoking [8], meta-analyses showing that across a wide variety of populations and ages, a significant association with respiratory disease is still observed for e-cigarettes [8] even among adolescents, who by definition have almost no smoking history [38, 99]. Findings of significant respiratory disease effects for e-cigarette use among nonsmokers pose additional difficulty for the confounding hypothesis. Because the epidemiological studies meet most of the Hill criteria for interpreting causality [8] and experimental studies show significant effects for lung function (Section 2) and biological processes with disease relevance (Section 3), our opinion is that the relation of e-cigarette use to respiratory disease is a real one.

6.2. E-cigarettes and cigarettes: Different pathways

Over this review period there has been a considerable amount of basic research on e-cigarettes by toxicologists and physiologists [15,21,92]. Although these studies contain some findings showing that e-cigarettes produce less harm than cigarettes, there are cases in which there are equivalent levels. This parallels the pattern of results for meta-analyses for respiratory disease outcomes, where there is some evidence for harm reduction (e.g., for asthma) but also findings of increased disease compared with nonuse [9]. We think this mixture of effects from a large body of studies is an issue that should be considered for clinical practice [2,4].

An important message from the toxicological studies, which we think tends to get lost in translation, is that exposure to e-cigarettes acts through somewhat different pathways than are found for combustible cigarettes. In many discussions, e-cigarettes tend to get treated as a junior cousin of combustible cigarettes, having some of the traditional biomarkers as combustibles but at much lower levels. In contrast, the current generation of studies (Section 3) is providing findings indicating that e-cigarettes operate through new pathways not frequently studied in combustible-cigarette research, in addition to pathways through oxidative stress and inflammation, which have been studied for several diseases [40,41]. Moreover, the traditional thinking that tobacco exposure takes a decade or more to have adverse effects is challenged by studies indicating that adverse effects on physiological processes and pulmonary function can be observed following relatively short exposures (Section 2, Section 3). These studies, and replicated findings showing e-cigarette use related to respiratory disease among younger populations without a long exposure history, [8] suggest a different view for conceptualizing research designs and population impact.

However the tendency in writing favoring e-cigarette use as a consumer product is for the toxicological research to be given little attention When it is, the tendency is to gloss over it, perhaps with a statement to the effect that it is difficult to extrapolate from exposure conditions in cells and animals to humans. Our opinion is that this inattention is not well supported, particularly in view of the high prevalence of adolescent use, because processes such as oxidative stress and inflammation have a long research history supporting their relevance for several human diseases [40,41].

We think a notable example is findings on DNA damage. Discussions about e-cigarettes tend to emphasize that because they do not involve combustion, they do not have typical combustion products that cause cancer. However, there are now a number of experimental studies showing e-cigarette exposure associated with DNA damage. In addition to findings outlined in Section 3, findings of DNA damage have been noted in cell studies [100,101], animal models [102–104], and human studies [105–107]. Because e-cigarette aerosol does not have high levels of traditional biomarkers associated with combustible cigarettes, these effects must be occurring through new pathways in addition to oxidative stress [e.g., 107]. Though it is many steps from DNA damage or DNA repair at the cellular level to development of a tumor, the prevalence of e-cigarette use among adolescents, which means a longer period of exposure, argues for a conservative approach to this question, possibly including information about DNA damage in in educational campaigns to show audiences an effect that, beyond nicotine, has not been widely emphasized.

We recognize that e-cigarettes may have a useful role for smoking cessation when administered under controlled conditions [e.g., 73]. However, data from real-world conditions show that e-cigarettes as a consumer product may reduce the likelihood of smoking cessation and increase the probability of relapse among former smokers [6]. Though transitioning from cigarette smoking to exclusive e-cigarette use has been argued as a means for harm reduction, data indicate that a common tendency is for persons to continue smoking and using e-cigarettes (i.e., dual use, [11]). Longitudinal studies have indicated that dual users are less likely to quit smoking entirely [108,109] and, exposing themselves to additive effects from e-cigarette use and smoking [8,9], are at increased risk from a physiological standpoint [9]. Furthermore, while it is true that cigarette smoking is decreasing in the population, the notion that this is attributable to displacement by e-cigarettes is not supported empirically [110]. Thus, our opinion is that while e-cigarettes may have a role in tobacco control, the mixed consequences of e-cigarette use also need to be recognized.

6.3. How Will the Field Have Evolved in the Next Five Years?

Based on the research we have discussed here we can foresee several ways in which the field will have evolved over the next five years. Given that knowledge about the mechanisms of effects on respiratory disease is better understood, we hope that studies will incorporate measures to test for such mechanisms (e.g., oxidative stress) and conduct analyses to test how effects of exogenous variables are mediated through these mechanisms [111]. Although findings on long-term health effects are now in hand, we hope that large prospective studies will be in progress to test for effects of e-cigarette use over time, testing for alternative explanations and including biological measures to clarify mechanisms of effects for respiratory disease. We anticipate that prevention research will incorporate current knowledge about health effects and will incorporate empirically tested communication strategies to address specific audiences (e.g., youth, minorities, smokers who want to quit). Anticipating the prevalence rates for both cigarette smoking and e-cigarette use will probably decline over the next five years, researchers will need to adapt their research designs so that studies will be adequately powered to detect clinically important effects. Finally, given observed effects of e-cigarette use for respiratory symptomatology among adults, we hope that adequate research attention will be given to younger populations, who have the potential for a longer of exposure to possible health effects.

Article Highlights

• Over the past 5 years there has been an accumulation of evidence on e-cigarettes and health outcomes from studies by epidemiologists, toxicologists, and respiratory medicine physicians. We review current research with a focus on effects for respiratory-tract processes.

• While previous challenge studies on lung function have produced mixed results, a new challenge study with spirometry measures collected before and after a 60-minute vaping session showed declines in all measures of lung function, consistent with evidence from some recent epidemiological research.

• A focused review of recent laboratory research notes that across a variety of animal models and human studies there is a consistent signal that e-cigarette exposure is related to biological processes of oxidative stress and inflammation, which have been linked to respiratory disease in previous research.

• A consideration of developing research on prevention implications outlines findings showing how health communication messaging should be carefully designed, seeking an appropriate balancing of benefit and risk that discourages initiation by younger nonusers while suggesting possible utility of e-cigarettes for cessation among adult smokers who want to quit.

• Our expert opinion is that current research provides a balanced picture, recognizing known relations of e-cigarette use to respiratory disease while noting a possible role for e-cigarettes in clinically-monitored smoking cessation designed to achieve total abstinence from nicotine and avoid continued nicotine dependence.

• Current research has revealed several new pathways for e-cigarettes to disease outcomes that are different from those previously studied for combustible cigarettes, and we think this will be an important influence on research over the next 5 years.

Declarations of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by Grant # P30 CA 071789 from the National Cancer Institute (TA Wills) and Grant # R01 DA051836 from the National Institute on Drug Abuse (W Maziak, T Asfar, S Roy). The funding sources had no role in the study design; analysis and interpretation of the data; writing of the report; and decision to submit the manuscript for publication.