Association between electronic cigarette use and respiratory outcomes among people with no established smoking history: a comprehensive review and critical appraisal

Vol.:(0123456789) Internal and Emergency Medicine (2025) 20:667–680 https://doi.org/10.1007/s11739-025-03894-7 IM - REVIEW Association betweenelectronic cigarette use andrespiratory outcomes amongpeople withnoestablished smoking history: acomprehensive review andcritical appraisal ArielleSelya1,2· GiusyRitaMariaLaRosa3· LuciaSpicuzza2,3,4· JayminB.Morjaria5· GraziaCaci6· RiccardoPolosa2,3,7,8 Received: 6 November 2024 / Accepted: 4 February 2025 / Published online: 24 February 2025 © The Author(s) 2025 Abstract Nicotine consumption in many countries is shifting away from combustible cigarettes and toward electronic cigarettes (ECs). Understanding the overall population-level impact requires weighing their possible benefits (e.g., for smoking cessation/ switching) vs harms (e.g., long-term health risks). However, current evidence on health risks is limited by the absence of long-term data and confounding by prior cigarette smoking history. Focusing on shortto medium-term respiratory outcomes associated with EC use among people who never smoked (PWNS) is informative. We perform a narrative review and critical appraisal of studies examining the prospective association between exclusive EC use and respiratory outcomes among PWNS (eithertrue never-smoking or never-established smoking). We included 12 studies with prospective designs that examine a range of respiratory outcomes subsequent to EC use among PWNS. Eight studies did not find statistically significant differences in respiratory risk associated with baseline EC use. The remaining five studies reported a significant association in at least one analysis, but in four of these studies, associations were not robust across models. Limitations included overreliance on data from the U.S. Population Assessment of Tobacco and Health, uncertain directionality (i.e., pre-existing respiratory conditions were not always ruled out), confounding by other combustible tobacco use, and small sample sizes. All but one study lacked clear and statistically significant evidence of self-reportedrespiratory diagnoses associated with EC use among PWNS, or showed a tenuous association with mild respiratory symptoms. This has favorable implications for ECs’ population health impact; however, small sample sizes and statistical biases limit this evidence. A formal systematic review on this topic is forthcoming. Keywords Asthma· Chronic obstructive pulmonary disease· Electronic cigarettes· Never-smoking· Respiratory illness· Respiratory symptoms Abbreviations AHR Adjusted hazard rate ASH Action on Smoking and Health AOR Adjusted odds ratio ARR Adjusted risk ratio CI Confidence interval * Riccardo Polosa [email protected] Arielle Selya [email protected] 1 Pinney Associates, Inc., 201 N. Craig St. Suite 320, Pittsburgh, PA15213, USA 2 Center ofExcellence fortheAcceleration ofHArm Reduction (CoEHAR), University ofCatania, Via S. Sofia, 78-Ed. 4, P. 2, 95123Catania, Italy 3 Department ofClinical andExperimental Medicine, University ofCatania, Catania, Italy 4 Respiratory Unit, University Teaching Hospital “Policlinico-S.Marco”, University ofCatania, Catania, Italy 5 Department ofRespiratory Medicine, Harefield Hospital, Guy’s & St Thomas’ NHS Foundation Trust, Harefield, UK 6 UOC MCAU, University Teaching Hospital “Policlinico-S. Marco”, University ofCatania, Catania, Italy 7 Institute ofInternal Medicine, University Teaching Hospital “Policlinico-S.Marco”, University ofCatania, Catania, Italy 8 Department ofMedicine andSurgery, “Kore” University ofEnna, Enna, Italy 668 Internal and Emergency Medicine (2025) 20:667–680 COPD Chronic obstructive pulmonary disease EC Electronic cigarette eCO Expired carbon monoxide eNO Expired nitric oxide EPA Environmental Protection Agency HRCT High-resolution computed tomography NHIS National Health Interview Survey PATH Population Assessment of Tobacco and Health PICO Population, intervention, comparator, outcomes PRISMA Preferred Reported Items for Systematic Reviews and Meta-Analyses RCT Randomized controlled trial VERITAS Study The Vaping Effects: Real-World International Surveillance Study WHO World Health Organization Introduction Combustible cigarette smoking remains the primary cause of preventable premature death in many countries worldwide. Electronic cigarettes (ECs) are a non-combustible nicotine product and as such are substantially less harmful than cigarettes [1–3]. Given that ECs are at the lower end of the risk continuum [3–6] and are effective smoking cessation aids [7] among people who are actively trying to quit smoking in the near future—or alternatively, an appealing and lower-risk alternative consumer product for those who are not immediately planning to quit [8]—ECs have the potential to substantially reduce smoking-attributable mortality in the population if they displace cigarette smoking, according to simulation modeling studies [9–13]. However, the ultimate population impacts of ECs also depend on their possible detrimental effects, especially from long-term and cumulative use. While ECs most likely pose substantially lower health risks relative to cigarettes, there may be some absolute level of risk from EC use alone (Fig.1). Such absolute risks could attenuate some of the projected benefits of switching completely from cigarettes to ECs, as well as increase risks of EC use among people who smoke (i.e., dual use) and among people who never smoked (PWNS). We focus here on respiratory health outcomes, as e-cigarettes have been around for sufficiently long to theoretically impact respiratory health. Current evidence on whether EC use uniquely poses measurable respiratory health risks has major limitations due to the nature of observational studies, which contain selection bias and confounding. In particular, since most people who use ECs have a history of smoking combustible cigarettes (either currently or formerly), any apparent association between EC use and a health outcome is likely confounded by smoking history. While many studies adjust for smoking status, this is often insufficient: adjusting for more detailed smoking history (e.g., using pack-years) is essential to account for the degree of smoking exposure [14, 15], yet most studies merely adjust for smoking status (current vs. former vs. never smoking; or even simply current vs. non-current smoking). The resulting residual confounding suggests that the apparent association between EC use and health outcomes could in reality be partly, or perhaps fully, explained by cumulative smoking history. Studies focusing on PWNS can avoid this confounding bias, and provide stronger evidence examining ECs’ possible direct health risks in humans; however, little is known about respiratory risks of EC use in this group, as EC use among PWNS is rare [16–18]. Fig. 1 Possible mechanisms by which e-cigarettes could affect respiratory health 669Internal and Emergency Medicine (2025) 20:667–680 Here, we conduct a narrative review of existing literature on EC use by PWNS and respiratory outcomes, defined as broadly as possible. We focused on studies with prospective designs to avoid a common bias in cross-sectional studies on this topic (i.e., due to cases with the reverse temporal sequence where the respiratory outcome preceded EC use) [19]. We also critically appraise each study with respect to strengths and weaknesses and make recommendations for future research. Materials andmethods We performed a literature review to identify peer-reviewed studies that examined EC use and respiratory symptoms among PWNS and used a prospective study design. PubMed and Scopus databases were searched in April 2024 using the search terms: (“never-smokers” OR “never smokers” OR “never smok*” OR “näive” OR “healthy”) AND (“e-cig*” OR “e-cigarette” OR ENDS OR “electronic cigarette*”) AND (“respir*” OR “lung”) AND (“cohort” or “observational” or “follow-up” OR “randomized controlled trial” OR “RCT”). Additional manual searching was done in reference lists of included articles and in relevant peer-reviewed journals on either respiratory disease research or tobacco research. All types of prospective study were included [e.g., clinical observational studies, randomized clinical trials (RCTs), and population surveys]. Cross-sectional studies were excluded due to uncertainty about the temporal sequence of exposure and outcome [19], as were laboratory studies, reviews, study protocols, case reports, conference abstracts, and articles not written in English. Due to the small number of eligible studies, we retained studies regardless of their definition of never-smoking, i.e.,either “true” never-smoking (i.e., never smoked even a puff in one’s lifetime) or never-established smoking (< 100 cigarettes/lifetime); see Limitations. Additionally, some studies were retained which analyzed people who currently or formerly smoke but which analyzed data in a way that allowed an approximate estimation of the effect among PWNS. First, titles and abstracts of all search results were screened independently by two reviewers (GRMLR and GC), and eligible or potentially eligible articles were reviewed in full by three reviewers (AS, GRMLR, and GC) to determine final eligibility. Disagreements were resolved through discussion, bringing in a fourth reviewer (AS, GRMLR, GC, and RP). Some articles that lacked one of the criteria were retained for discussion on a case-by-case basis if all reviewers agreed they were nevertheless informative. Critical appraisal was conducted through detailed reading of the full text and focused on the following considerations: (1) possible violations of the correct temporal sequence, e.g., if respiratory symptoms or conditions could have been present from baseline and therefore co-occurred or preceded EC use; (2) whether all relevant confounding factors were included in the model (e.g., other non-cigarette combustible tobacco use); (3) possible sample size limitations; (4) presence of sensitivity/supplementary analyses, and robustness of findings across different analyses; (5) plausibility of results in the model (e.g., whether available results align with a dose–response effect and are larger for current EC use than former-EC use); (6) how PWNS were handled in the model (i.e., subgroup analysis or adjustment for smoking status). Results After applying inclusion and exclusion criteria, a total of 12 studies were included (see Table1; see Table2 for excluded studies). In this section, we provide only basic characteristics and main findings of each study, and in Discussion provide a more thorough summary of each paper along with an integrated critical appraisal of each study. Respiratory outcomes varied across studies: three studies analyzed self-reported asthma (incidence/onset of selfreported asthma in Patel etal. [20], age of self-reported new onset in Perez etal. [21], and self-reported prevalence and past-year asthma attacks in To etal. [22]); two studies analyzed wheezing symptoms (self-reported past-year wheezing in Sanchez-Romero etal. [23] and onset of self-reported wheezing symptoms in Xie etal. [24]); four studies analyzed an index of self-reported respiratory symptoms, some which used cut-off values denoting functionally important symptoms (Karey etal. [25]; Reddy etal. [26]; Stevens etal. [27]; Sargent etal. [14]); one study analyzed any self-reported respiratory diagnoses (COPD, chronic bronchitis, emphysema, or asthma; Kenkel etal. [28]); one study analyzed lung function (using expired biomarkers, spirometry tests, and high-resolution computed tomography; Polosa etal. [29]); and one study was a review and commentary on youth EC use (Polosa etal. [30]). Seven studies focused on the general adult population, two focused on young adults (ages 18–24), and five (some of which also examined adults) focused on youth. A total of 5 studies were identified for adults and 2 for young people. Table3 presents the aggregate findings for each of the above outcome categories, along with notable limitations (discussed in detail in Discussion). Seven studies reported no significant association between baseline EC use and subsequent respiratory outcomes among PWNS. Five reported at least one significant association, but in four of these studies, this result was not robust across different models presented (see Table1). The majority of studies (n = 9) analyzed data from the Population Assessment of Tobacco and 670 Internal and Emergency Medicine (2025) 20:667–680 Table 1 Included studies and their characteristics Article Age group Data source No. of PWNS Exposure/control group Outcome Significant association among PWNS? Karey etal. [25]Adults (18 +) PATH, Waves 4–5 65 Current vs. former-EC use vs. never-EC use Respiratory symptoms (functionally important: cutoff of 2 on 0–9 scale; 7 symptoms) No; “Among never combustible tobacco smokers, no significant association was detected between e-cigarette use and important respiratory symptoms” Reddy etal. [26] Youth (12–17), Adults (18 +) PATH, Waves 3–4 Current (some days or everyday) EC use vs. non-current use Incidence/onset of self-reported respiratory symptoms in past year No; non-significant due to confidence interval containing 1.00: “exclusive [EC] users (adjusted odds ratio [AOR] vs. noncurrent users, 1.17; 95% CI, 0.79–1.74)” Sargent etal. [14] Young adults (18–24) PATH, Waves 1–3 Current (some days or everyday) EC use vs. non-current use Respiratory symptoms (functionally important: cutoff of 3 on 0–9 scale; 7 symptoms) Sometimes; prevalence outcome: “Compared to never users, the risk of functionally important respiratory symptoms were not significantly different for exclusive users of e-cigarette” worsening outcome: “…findings for exclusive e-cigarette use were sensitive to symptom severity, showing a significant association with worsening symptoms at a threshold of ≥ 2… but not at a symptom threshold of ≥ 3” improvement outcome: “…e-cigarette users at a threshold of ≥ 3… were also more likely [to] show symptom improvement compared to never users” [Note: these comparisons were not solelyamong PWNS and may be biased; see Discussion] Kenkel etal. [28]Adults (18 +) PATH, Waves 1–3 12 Current (some days or everyday) EC use and used ECs fairly regularly (vs. non-current or never regular) Self-reported diagnoses of respiratory disease (COPD, chronic bronchitis, emphysema, or asthma) No; “…among respondents who had never smoked combustible tobacco, we find no evidence that current or former e-cigarette use is associated with respiratory disease” 671Internal and Emergency Medicine (2025) 20:667–680 Table 1 (continued) Article Age group Data source No. of PWNS Exposure/control group Outcome Significant association among PWNS? Stevens etal. [27] Youth (12–17) PATH, Waves 3–4 2998 Current vs. former-EC use vs. never-EC use Respiratory symptoms (functionally important: cutoff of 2 on 0–9 scale; 7 symptoms) No; “Baseline e-cigarette use did not increase the odds of having functionally important respiratory symptoms at followup regardless of combustible tobacco use status” Polosa etal. [29]Adults (18 +) Bespoke sample of Italian adults, 3.5-year followup 9 Daily EC use of 3 + months vs. never-EC use Lung function, respiratory symptoms, eNO, eCO, and HRCT of lungs No; “this study did not demonstrate any health concerns associated with long-term use of EC in relatively young users who did not also smoke tobacco” Sanchez-Romero etal. [23]Adults (18 +) PATH, Waves 1–5 51 Current (some days or everyday) EC use vs. non-current use Self-reported wheezing in past 12months No; “Associations were small and not statistically significant for the odds of self-reported wheezing among never cigarette and current ENDS use when compared with never cigarette and noncurrent [EC] use” Polosa etal. [30] Youth (US middle and high school students) Review and commentary of US youth survey results and respiratory risks Sometimes; “Although vaping has been linked to respiratory symptoms, they tend to be transient and of uncertain significance” Patel etal. [20] Youth (12–17) PATH, Waves 1–5 142 P30D EC use vs. no P30D use Incidence/onset of self-reported asthma diagnosis No; “…adolescents using [EC] exclusively… did not [have a statistically significant higher risk of incident diagnosed asthma at follow-up]” 672 Internal and Emergency Medicine (2025) 20:667–680 Table 1 (continued) Article Age group Data source No. of PWNS Exposure/control group Outcome Significant association among PWNS? Perez etal. [21] Youth (12–17), Adults (18 +) PATH, Waves 1–6 96 youth 160 adults P30D EC use vs. no P30D use Age of asthma onset Sometimes; main analysis: “adults who reported never using cigarettes… and P30D ENDS use at the first wave of participation had increased risk of asthma incidence at earlier ages in comparison to adults who reported no P30D [EC] use” Supplementary analysis: Non-significant due to confidence interval containing 1.00: (never use of combustible TP and P30D [EC] use (vs. never use of combustible TP and no P30D [EC] use), AHR = 0.93 (0.70–1.22)) To etal. [22] Adults (15–60) CCHS with linkage to administrative health records 75 Current vs. non-current EC use Asthma attack in past 12months, among those with asthma Sometimes; asthma prevalence outcome: “EC users had increased odds of prevalent asthma compared with nonusers… but the association was not statistically significant” Asthma attacks outcome: “EC use… showed significant interaction with sex… Female EC users and nonusers had a significant twofold increase in odds of asthma attacks compared with male nonusers” [Note: these comparisons were not solely among PWNS and may be biased; see Discussion] Xie etal. [24] Young adults (18–24) PATH, Waves 1–5 312 Current vs. former-EC use vs. never-EC use Onset of respiratory symptoms (wheezing) Yes; “Current e-cigarette use was associated with higher odds for any respiratory symptom… and wheezing in the chest… Associations persisted among participants who never smoked combustible cigarettes” CCHS Canadian Community Health Survey, COPD chronic obstructive pulmonary disease, EC electronic cigarette, eCO expired carbon monoxide, eNO expired nitric oxide, HRCT highresolution computed tomography, P30D past 30-day, PATH Population Assessment of Tobacco and Health, PWNS people who never smoked (i.e., < 100 cigarettes/lifetime, including “not even a puff”), TP tobacco products. Bold text: overall conclusion about the presence of a significant association. Underlined text: subheadings for specific analyses, if applicable 673Internal and Emergency Medicine (2025) 20:667–680 Health (PATH), a nationally representative longitudinal US survey of youth and adults. With one exception (Polosa etal. [29]; see Discussion), none of the studies provided detailed EC device characteristics (e.g., nicotine concentration, flavor, or device type). Discussion We identified 12 relevant studies examining the association between EC use and subsequent respiratory outcomes among PWNS. Here, we discuss each paper’s findings in detail and critically appraise the strengths and weaknesses of each study, organized first by main finding (whether or not a significant association between EC use and respiratory outcome was found in at least one study) and next by age group. Studies reporting noassociation: summary andcritical appraisal Adults In adults, a 2-year study by Karey etal. [25] and a similar timeframe study by Reddy etal. [26] both found no significant association between baseline EC use and the development of functionally important respiratory symptoms (using a 7-item index of symptoms, with a cutoff of a mean score of 2+ on a 0–9 scale) in adults who never smoked. Both studies analyzed consecutive waves of the longitudinal Population Assessment on Tobacco and Health (PATH) survey in adults. A limitation of existing (predominantly cross-sectional) studies of e-cigarette use and health outcomes is bias due to the presence of participants whose respiratory symptoms preceded EC use [19]. To overcome this limitation, both Karey etal. [25] and Reddy etal. [26] excluded participants who already had a diagnosis of respiratory disease [25] or respiratory symptoms [26] at the baseline wave. This is a notable strength of both studies as it ensures the correct temporal sequence to examine whether e-cigarettes have a causal effect on the development of respiratory symptoms. An additional strength of Karey etal. [25] was to stratify by cigarette status (current, former, or never) which allowed an examination of respiratory symptoms uniquely associated with e-cigarette use (i.e., among never-smokers, whose respiratory symptoms cannot be attributed to smoking history). Reddy etal. [26] Table 2 Excluded studies and reason for exclusion a Study only examined current vs. non-current smoking and thus combines former and never-smokers b While some of the analyses were truly longitudinal, they were in the reverse direction of the research question (i.e., asthma predicting later cigarette and e-cigarette use) Article Truly longitudinal? Investigates neversmoking individuals? Zavala-Arciniega etal. 2024, Res Square https:// doi. org/ 10. 21203/ rs.3. rs37931 49/ v1 YES NOa Delmas etal. 2024, Respir Med https:// doi. org/ 10. 1016/j. rmed. 2023. 107496 NO YES Mukerjee etal. 2024, Am J Prev Med https:// doi. org/ 10. 1016/j. amepre. 2023. 12. 005 YES NOa Cheney etal. 2023, Prev Med Rep https:// doi. org/ 10. 1016/j. pmedr. 2023. 102473 NObNOa Tackett etal. 2024, Thorax https:// doi. org/ 10. 1136/ thorax2022218670 YES NOa Mattingly etal. 2023, Prev Med 10.1016/j.ypmed.2023.107512 YES NOa Chaiton etal. 2024, Tob Induc Dis https:// doi. org/ 10. 18332/ tid/ 156839 NO YES Berlowitz etal. 2023, Am J Prev Med https:// doi. org/ 10. 1016/j. amepre. 2022. 10. 006 YES NOa Cordova etal. 2022, Prev Med Rep https:// doi. org/ 10. 1016/j. pmedr. 2022. 102016 YES NOa Dai etal. 2020, NTR https:// doi. org/ 10. 1093/ ntr/ ntaa1 80 YES NOa Tackett etal. 2020, JAMA Netw Open https:// doi. org/ 10. 1001/ jaman etwor kopen. 2020. 20671 YES NOa Bhatta and Glantz 2020, Am J Prev Med https:// doi. org/ 10. 1016/j. amepre. 2019. 07. 028 YES NOa 674 Internal and Emergency Medicine (2025) 20:667–680 Table 3 Overview of aggregate results by type of outcome and notable limitations EC electronic cigarette, eCO expired carbon monoxide, eNO expired nitric oxide, HRCT high-resolution computed tomography, P30D past 30-day, PATH Population Assessment of Tobacco and Health, PWNS people who never smoked (i.e., < 100 cigarettes/lifetime, including “not even a puff”), TP tobacco products Type of outcome Studies Aggregate findings (see Table1 for detailed findings) Limitations (see Discussion for details) Self-reported asthma outcomes Patel etal. [20] Perez etal. [21] To etal. [22] No evidence for association with asthma incidence/ onset [20]; tenuous association with age of asthma onset [21] (see Limitations); No evidence for association with asthma prevalenceor past-year asthma attacks overall Annals ATS [39], but possible interaction with sex for past-year asthma attacks [22] (see Limitations) In Perez etal. [21], tenuous association with age of asthma onset may be due to residual confounding by other combustible tobacco use; N.S. after accounting for this In To etal. [22], interaction with sex may be entirely due to sex; no clear evidence of a unique association with EC use Wheezing symptoms Sanchez-Romero etal. [23] Xie etal. [24] No evidence association with self-reported past-year wheezing [23]; association with onset of wheezing [24] Xie etal. [24] have possible confounding by other combustible tobacco use, which was not accounted for Respiratory symptom index Karey etal. [25] Reddy etal. [26] Stevens etal. [27] Sargent etal. [14] No evidence for association with prevalence of functionally important symptoms [14, 25, 26]; tenuous association with both worsening and improvement of functionally important symptoms depending on cut-off value [14] Reddy etal. [26] did not account for prior smoking history and associations could be due to cumulative smoking history In Karey etal. [25], stronger association among former (vs current EC use) is not plausible, suggesting unaccounted-for confounding Sargent etal. [14] adjusted for smoking status rather than analyzing PWNS separately, which may introduce bias In all studies here, small numbers of PWNS who used ECs may limit statistical power Any self-reported respiratory diagnosis Kenkel etal. [28] No evidence for association with prevalence of any self-reported respiratory diagnosis Small sample size of PWNS who used ECs (n = 12) prevented reliable estimates Lung function, eNO, eCO, and HRCT of lungs Polosa etal. [29] No evidence for effects on lung function Small sample size of PWNS who used ECs (n = 9) prevented statistical analysis Review and commentary on youth EC use Polosa etal. [30] Some evidence for transient respiratory symptoms of uncertain clinical significance Reflects limitations of underlying studies, e.g., unaccounted-for confounding 675Internal and Emergency Medicine (2025) 20:667–680 on the other hand, only examined current e-cigarette use, without accounting for prior smoking history: had there been a significant association between e-cigarette use and onset of respiratory symptoms, it could be due to prior cigarette smoking, in which case adjusting for pack-years would be necessary (though not necessarily sufficient) to account for this [14]. Limitations still apply to both Karey etal. [25] and Reddy etal. [26] due to the nature of observational data. Specifically, there may be spurious associations due to other factors that were unadjusted for: for example, Karey etal. [25] showed that among adults who formerly smoked, former EC, but not current EC use, was associated with higher odds of developing respiratory symptoms. Since it is not biologically plausible that former-EC use could have a causal effect, while current use does not, this likely indicates the influence of additional confounding factors. Additionally, since there were few never-smoking adults who used ECs, the ability to detect significant associations with respiratory symptoms may have been limited, calling for future research to seek out larger samples of adults who use ECs but never-smoked cigarettes. Overall, nevertheless, these findings lack clear evidence for moderate or severe respiratory risks of EC use over the medium term among never-smoking adults. Similarly, Sargent etal. [14] analyzed adult PATH participants without a diagnosis of COPD at the baseline wave and found no significant differences in the prevalence of respiratory symptoms at the follow-up wave between adults who exclusively used ECs vs. did not use ECs at baseline. (This same study did, however, find significant associations between EC use and changes in respiratory symptoms— both worsening and improvement; see section below.) Similarly to the studies above, a notable strength of this study is including only participants without baseline diagnoses of respiratory disease, ensuring the correct temporal sequence for examining the possible effects of e-cigarette use. A limitation of this analysis [14] is that Sargent etal. did not run a dedicated analysis containing solely neversmoking adults, but rather statistically adjusted for smoking status (i.e., had smoking status as a control variable, using never-smoking as the reference group). In the context of a multivariate regression, each estimate is interpreted as the change in that variable with all other variables in the model held constant: i.e., the odds ratio for EC use should reflect the effect of exclusive EC use regardless of whether a participant never, formerly, or currently smoked (provided that all model assumptions are met). However, there still may be some bias (toward a positive association) from including all smoking status groups in the same model, especially if there is an unaccounted-for interactive effect between EC use and smoking history (such that those with longer smoking histories have higher health risks) which could falsely appear to carry over to PWNS. A study by Kenkel etal. [28] conducted a replication and extension of a prior cross-sectional study by Bhatta and Glantz [31], the latter of which reported that EC use was associated with significantlyhigher odds of developing respiratory symptoms among adults in PATH, despite excluding those who already had respiratory disease at baseline. However, Kenkel etal. [28] noted that in Bhatta and Glantz’s analysis [31], the majority of EC users currently or formerly smoked: only 12 participants out of 17,601 used ECs but had never smoked cigarettes, and none of these 12 developed respiratory symptoms in the PATH waves examined. Since this group was too small for a formal statistical analysis, Kenkel etal. [28] instead replicated Bhatta and Glantz’s analysis [31] but examined categories of e-cigarette and cigarette use. Results showed no evidence of respiratory disease over a 3-year period in never-smoking adults who used ECs. Further, among adults who formerly and currently smoked, there was no marginal independent association between EC use and respiratory outcomes over and above smoking status, which is consistent with Sargent etal.’s conclusion [14] that cigarette smoking largely explains onset of respiratory symptoms, with no additional risk introduced by ECs. Limitations also apply to Kenkel etal.’s analysis, however, due to the observational nature of the data and the small sample size of adults who used ECs but never smoked (N = 12) [28]. These studies collectively indicate that while some individuals who use ECs may experience mild respiratory symptoms, evidence is lacking for an overall medium-term impact of ECs on lung health in the absence of an established smoking history. Stevens etal. [27] examined e-cigarette use and respiratory symptoms among youth in PATH Waves 3–4. They focused on youth without asthma at baseline, which is a strength of the study as it excludes youth who may have pre-existing respiratory symptoms due to asthma. Stevens etal. [27] found that youth who exclusively used ECs at baseline did not have significantly higher odds of reporting functionally important (cutoff of 2 on a 0–9 scale) respiratory symptoms (7-item scale related to wheezing). This was true regardless of combustible tobacco history (i.e., there was no significant association specifically among neversmoking youth). Similarly, a 3.5-year prospective observational study of daily ECs’ users without a history of smoking by Polosa etal. [29] found no significant alterations in lung function, respiratory symptoms, or exhaled breath nitric oxide (eNO), and no structural abnormalities in high-resolution computed tomography (HRCT) scans. However, the study faced limitations, such as a small sample size, which diminished its power to detect abnormalities or significant changes over time, the potential for selection bias (as the study may have disproportionately included healthier e-cigarette users), and a medium-term follow-up duration. This was the only study