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Open Access

Peer-reviewed

Research Article

Fruit flavors in electronic cigarettes (ECIGs) are associated with nocturnal dry cough: A population longitudinal analysis

  • Zahira Quinones Tavarez ,

    Roles Conceptualization, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing

    zahira_quinonestavarez@urmc.rochester.edu

    Affiliations Clinical Translational Science Institute, University of Rochester Medical Center, Rochester, New York, United States of America, Department of Public Health Sciences, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America

    ⨯
  • Daniel P. Croft,

    Roles Supervision, Writing – original draft, Writing – review & editing

    Affiliation Department of Medicine, Pulmonary Diseases and Critical Care, University of Rochester Medical Center, Rochester, New York, United States of America

    ⨯
  • Dongmei Li,

    Roles Formal analysis, Writing – original draft, Writing – review & editing

    Affiliation Clinical Translational Science Institute, University of Rochester Medical Center, Rochester, New York, United States of America

    ⨯
  • Steven R. Gill,

    Roles Writing – original draft, Writing – review & editing

    Affiliation Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America

    ⨯
  • Andrew P. Wojtovich,

    Roles Writing – original draft, Writing – review & editing

    Affiliation Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, Rochester, New York, United States of America

    ⨯
  • Irfan Rahman,

    Roles Writing – original draft, Writing – review & editing

    Affiliation Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America

    ⨯
  • Deborah J. Ossip

    Roles Conceptualization, Formal analysis, Methodology, Supervision, Writing – original draft, Writing – review & editing

    Affiliation Department of Public Health Sciences, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America

    ⨯

Abstract

Evidence from in vitro and animal models has identified the pulmonary toxicity of flavors in electronic cigarettes (ECIGs); however, less is known from epidemiological studies about the effects of flavors in the respiratory health. This study examined the longitudinal association between exposure to ECIGs flavors and nocturnal dry cough among ECIGs users. A secondary analysis of data from the Population Assessment of Tobacco and Health Study (2014–2019) was conducted. The study population included adults who provided information (n = 18,925) for a total of 38,638 observations. Weighted-incidence estimates and weighted- generalized estimating equation models were performed to assess unadjusted and adjusted associations. The weighted incidence proportion (WIP) of nocturnal dry cough was significantly higher among current (WIP:16.6%; 95%CI 10.5, 21.2) and former fruit flavored ECIGs users (WIP:16.6%; 95%CI 11.3, 21.9) as compared to non-ECIGs users (WIP:11.1%; 95%CI 10.6, 11.6). Current ECIGs users of fruit flavors showed 40% higher risk of reporting cough than non-ECIGs users (aRR:1.40, 95%CI 1.01, 1.94). Former ECIGs users of multiple flavors and other flavors had 300% and 66% higher risk to develop cough, respectively (aRR:3.33, 95%CI 1.51, 7.34 and aRR:1.66, 95%CI 1.0.9, 2.51), relative to non-ECIGs users. We observed a significantly higher risk of developing nocturnal dry cough in the past 12 months in current and former ECIGs users of fruit flavors and in former ECIGs users of multiple flavors. To the extent that cough may serve as an early indicator of respiratory inflammation and potential disease risk, the association between ECIGs use and cough raises potential concerns.

Citation: Quinones Tavarez Z, Croft DP, Li D, Gill SR, Wojtovich AP, Rahman I, et al. (2024) Fruit flavors in electronic cigarettes (ECIGs) are associated with nocturnal dry cough: A population longitudinal analysis. PLoS ONE 19(6): e0306467. https://doi.org/10.1371/journal.pone.0306467

Editor: Muhammad Shahzad Aslam, Xiamen University - Malaysia Campus: Xiamen University - Malaysia, MALAYSIA

Received: December 21, 2023; Accepted: June 18, 2024; Published: June 28, 2024

Copyright: © 2024 Quinones Tavarez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The study included a de-identified open-source dataset, publicly available from the National Addiction & HIV Data Archive Program (NAHDAP) website. The final dataset used in the analysis is available as DOI 10.60593/ur.d.25274299.

Funding: This work was supported by the University of Rochester CTSA award number TL1 TR002000 from the National Center for Advancing Translational Sciences of the National Institutes of Health. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) Center for Tobacco Products under Award Number U54CA228110. This research was also supported by the University of Rochester CTSA award number UL1 TR002001 from the National Center for Advancing Translational Sciences of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Quiñones is additionally funded by grant #BWF1014095 from the Burroughs Wellcome Fund.

Competing interests: The authors have declared that no competing interests exist.

Introduction

The use of electronic cigarettes (ECIGs) among youth and young adults is now a serious public health concern [1]. ECIGs are non-combustible tobacco products that heat and aerosolize a liquid containing humectants and solvents, mainly propylene glycol (PG) with or without vegetable glycerin (VG), with added flavorings and often nicotine [2, 3]. The constituents in e-liquids and the aerosols are not inert and have been reported to be associated with negative health effects. Flavorings in flavored ECIG contribute to the toxicity of e-liquids and ECIG aerosols [4–6], including a major source of toxicants such as aldehydes (formaldehyde and acetaldehyde), carbonyl emissions, reactive species of oxygen, and other free radicals [7–10]. In vitro and animal studies of the toxicological effects of flavored ECIG have focused on the respiratory system. Strawberry, menthol, vanillin, and cinnamon are the flavors most commonly associated with negative effects in the lungs [11]. ECIG flavorings dysregulate the respiratory innate immunity and elicit inflammatory responses, which are associated with adverse health effects in the airways. Specifically, cinnamaldehyde and menthol might disrupt the airway’s epithelia, elicit oxidative stress, impair mucociliary clearance, and induce inflammatory responses by increasing the release of inflammatory cytokines and through the activation of transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanillin 1 (TRPV1) [11–14]. All of these pathological processes are associated with respiratory disease and symptoms, including wheezing and coughing [15, 16]. Despite assumptions that ECIGs are less harmful than combustible cigarettes, research suggests that ECIGs use has potential and actual health risks [17]. Evidence from in vitro, animal, and population-based studies supports the association of ECIGs use and addiction, [18, 19] cardiovascular disease, [20–23] cancer, [24–26] and respiratory disease, including acute and chronic lung damage [27–30].

The 2019 outbreak of electronic cigarettes, or vaping, product use-associated lung injury (EVALI) raised national concern in the US about the harmful effects of ECIGs products and constituents [31, 32]. As of February 2020, a total of 2807 patients were hospitalized with EVALI, and 69 deaths were reported in the United States (US) [31, 33]. Cases of EVALI in the US were linked to the presence of vitamin E acetate (VEA) in tetrahydrocannabinol containing products that were inhaled using ECIGs [31]. Though VEA is one potential cause of EVALI, more research is needed to understand the short- and long-term health effects of ECIGs constituents in e-liquids and aerosols, including the respiratory health effects [32]. There is currently a need for improved characterization of non-hospitalized ECIG users who may have subacute respiratory symptoms (e.g. mild cough or subtle dyspnea) related to their ECIGs use [32].

Monitoring respiratory symptoms among ECIGs users might help assess the potential risk of lung injury or pulmonary disease. ECIGs use among never tobacco users is associated with increased report of respiratory symptoms [34, 35]. The risk of wheezing and other respiratory symptoms has been shown to be greater among ECIGs users as compared to non-users though lower when contrasted with smokers [36]. A recent study showed that exclusive use of ECIGs was not associated with functionally important respiratory symptoms, including wheezing and coughing [37].

The National Academy of Sciences, Engineering, and Medicine reported that there is moderate evidence for increased cough and wheezing among adolescents who use ECIGs [38]. ECIGs users are more likely than non-users to report persistent cough [39] and to show inhibition of the cough reflex sensitivity [40] and transient inhibition of the urge-to-cough sensation [41, 42]. Few reports have focused on the effects of ECIGs use on coughing [40–42]. Briefly, coughing is one of the most common symptoms reported by ECIGs users. A recent report indicated a higher prevalence of respiratory symptoms among never tobacco youth and non-daily ever smokers in Canada, with 40.1% of daily ECIGs users and non-daily ever tobacco users reporting regular cough in the past 4 months [43]. Initially, concerns regarding ECIGs exposure were focused on the effects of nicotine; however, exposure to PG, VG, and flavorings from ECIGs are of special concern and merit further research to examine the harmful effects of ECIGs, including coughing. This study examined the longitudinal association between exposure to flavors in ECIGs and nocturnal dry cough among ECIGs users.

Materials and methods

This study involved a secondary analysis of publicly available longitudinal data from the Population Assessment of Tobacco and Health (PATH) Study (2014–2019) [44]. The current study utilized publicly available and unidentifiable data which qualifies as IRB exempt review.

Study design

The PATH Study has been described elsewhere [45]. Briefly, the PATH Study is a nationally representative, ongoing, prospective longitudinal cohort of non-institutionalized adults (aged 18 and older) and youth (aged 12–17) in the United States (US). The PATH Study uses a four-stage stratified area probability sample design to select individual participants. A total of 45,971 adults aged 18 and older were recruited in Wave 1 of the PATH Study. At the time of Wave 4, a replenishment sample was selected and combined with Wave 1 participants. Full sample weights are provided to account for the complex sample design and nonresponse. Replicate weights are also provided to improve statistical precision of the estimates. The PATH Study collects data on tobacco use and health outcomes to inform tobacco regulatory efforts. All adult participants provided informed consent. The PATH Study is conducted by Westat and ethically approved by the Westat Institutional Review Board. The current analyses include data collected from Wave (W) 1 (2013–2014), W2 (2014–2015), W3 (2015–2016), W4 (2016–2018), and W5 (2018–2019). Audio computer assisted surveys were conducted 1 year after the previous wave for all waves, except W5, which was conducted 2 years after W4. The PATH Study collects data on tobacco use and health outcomes to inform tobacco regulatory efforts.

Study sample

The study sample included W1 adult participants who were interviewed at all 5 waves to enable the study to generate weighted estimates based on the all-wave weights assigned to participants in W5. However, the baseline analytic sample was restricted to W2 participants due to lack of assessment of the outcome variable in W1 (n = 18,925 participants). Three 1-year interval exposure periods (P) were established for the study: P1 (W2-W3), P2 (W3-W4), and P3 (W4-W5). In each period, participants who did not report dry cough during baseline (W2 in P1, W3 in P2, and W4 in P3) were followed onto next wave to provide data equivalent to 1 observation. All observations from every participant provided a total analytical sample of 38,638 observations (Fig 1).

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Fig 1. Study design and sample.

The study included participants who were followed across five waves of the PATH Study and considered new cases of coughing across three period cohorts (P1-P3). Each period represents a one-year follow-up period per participant. In each period, participants with missing information about cough and cases of cough were excluded. Final sample included 18,925 participants who were followed across the five waves, who contributed to a total of 38,638 observations.

https://doi.org/10.1371/journal.pone.0306467.g001

Variables and measures

Dependent variable.

The outcome variable was self-reported dry cough in the past 12 month (P12M). Nocturnal cough is a common symptom associated with environmental exposure such as tobacco smoke and secondhand smoker exposure [46]. Among the functionally important respiratory symptoms assessed by the PATH Study, only one question examines cough, specifically, nocturnal dry cough [37]. Participants who responded yes to the question “In the past 12 months, have you had a dry cough at night, apart from a cough associated with a cold or chest infection?” were considered as having dry cough in the P12M. A slightly different wording was used from W3 onwards: “A dry cough is a cough without phlegm or mucus. In the past 12 months, have you had a dry cough at night?”

Independent variables.

Respondents reported if their regular or last brand of e-cigarette was flavored to taste like menthol, mint, clove, spice, fruit, chocolate, alcoholic drinks, candy or other sweets. Tobacco flavor was added to the list of options in W3. Six mutually exclusive categories of flavors used among current and former established e-cigarette users were created: menthol or mint flavors, tobacco, fruit, candy and sweet, multiple (two or more flavors reported), and others (clove or spice, chocolate, and alcoholic drinks flavors and other not specified in the question). Respondents were allowed to select more than one flavor. Based on the use of flavored ECIG products, participants were categorized as non-ECIG users, those who did not report established use of ECIG products, and those ECIG users reporting different flavor categories.

Potential confounders.

The following variables were included in all multivariable analyses to account for potential confounding: sex, age, race and ethnicity, educational level, household income, body mass index (BMI), disease status, overall tobacco use, marijuana use, and secondhand smoke exposure status; these variables were statistically associated with the independent and dependent study variables. Categories for variables are provided in Table 1. Disease status included any heart condition, any lung disease, gum disease, cancer, precancerous oral lesions, ulcer, gastrointestinal bleeding, cataract and glaucoma, or diabetes mellitus in the P12M. Overall tobacco use includes four mutually exclusive categories: 1) never tobacco users (adult respondents who have never smoked or used a tobacco product); 2) ever non-established tobacco users (adult respondents who have used tobacco products but do not meet the threshold for established tobacco use and/or currently do not use the product every day or some days); 3) current established, and 4) former established tobacco users.

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Table 1. Sociodemographic and health characteristics of participants included in the analysis, PATH study, Waves 1–5 (2013–2019), n = 18,925 individual participants and 38,638 observations.

https://doi.org/10.1371/journal.pone.0306467.t001

Data analyses

First, data analyses included weighted descriptive statistics to report baseline characteristics of the study population and the weighted incidence proportion (WIP) of nocturnal dry cough. Complex survey all-waves weights and 100 replicate weights from Wave 5 were used to generate weighted representative estimates of the US population. The balanced repeated replication method was used to construct replicate weights with Fay’s adjustment of 0.3 to improve the stability of estimates as recommended by the PATH Study. One hundred replicates were generated to obtain weighted percentages for all sample baseline characteristics and WIP of nocturnal dry cough. Second, weighted Rao-Scott chi-squared tests were conducted to examine associations among covariates by ECIG flavor exposure and nocturnal dry cough. Third, generalized estimating equations (GEE) models were used to quantify unadjusted and adjusted associations between ECIGs flavors use and dry cough P12M accounting for time-varying variables. Here, weighted percentages, unadjusted, and adjusted relative risks and their 95% confidence intervals (95% CIs) are reported. Our models used three clustered measurements of each follow-up period and from each subject. In this analysis, all variables represent time-varying measurements, with different values at each follow-up period. Rates of data missingness are low in The PATH Study. Most of the missing data in this analysis are due to variables being recoded to missing data when participant responses were “do not know” or “refused to answer”. Missing rates are reported. The models provided weighted estimates of relative risks for complete cases only. GEE provided estimates of associations from a single sample analysis, while allowing to control for interdependence among individual observations. Two-side p-values of <0.05 were considered statistically significant. Analyses were conducted using SAS v9.4 (SAS Institute Inc., Cary, NC).

Results

Sample description

Weighted estimates of the baseline sociodemographic and health characteristics of participants at Wave 2 are shown in Table 1. Briefly, 35.3% of the population were young adults, 34.6% were middle aged adults, 52.2% were females, 37.7% achieved high school level or less, 67.1% were non-Hispanic White, and 43.6% reported a health condition. In terms of overall tobacco use, 24.1% were never tobacco users; 20.7% and 25.6% were current and former established tobacco users, respectively. Among participants, 2.9% were classified as current established ECIGs users, 4% as former established ECIGs users, and 92.8%, as non-ECIGs users.

Incidence of nocturnal dry cough

Except for age and health insurance coverage, all potential confounders were associated with self-reported nocturnal dry cough as observed in Table 2. Among never tobacco users, the WIP was 10.2% (95%CI 9.1, 11.3); current and former established tobacco users showed WIP of 15.1% (95%CI 13.3, 16.9) and 11.9% (95%CI 10.0, 13.8), respectively. Among established ECIGs users, current users showed a higher WIP than former users, 14.8% (95%CI 13.1, 16.6) in contrast to 8.9% (95%C 8.2, 9.7). Table 3 shows the WIP of nocturnal dry cough by ECIGs flavors category. Compared to non-ECIGs users (WIP:11.1%; 95%CI 10.6, 11.6), the WIP of nocturnal dry cough was significantly higher among current (WIP:16.6%; 95%CI 10.5, 21.2) and former fruit flavored ECIGs users (WIP:16.6%; 95%CI 11.3, 21.9). Across all flavor categories in former ECIGs users, the WIP of cough was higher than the non-ECIGs counterpart.

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Table 2. Weighted Incidence Proportion (WIP) of nocturnal dry cough among current and former established e-cigarettes users by potential confounders, PATH study, Waves 1–5 (2013–2019), n = 38,638 observations.

https://doi.org/10.1371/journal.pone.0306467.t002

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Table 3. Weighted Incidence Proportion (WIP) of nocturnal dry cough among current and former established e-cigarettes users by flavors regular or last used, PATH study, Waves 1–5 (2013–2019), n = 38,638 observations.

https://doi.org/10.1371/journal.pone.0306467.t003

Longitudinal associations by ECIGs flavor use

In Table 4, after controlling for all sociodemographic variables, health status, marijuana and overall tobacco use, current ECIGs users of fruit flavors showed 40% higher risk of reporting nocturnal dry cough than non-ECIGs users (aRR:1.40, 95%CI 1.01, 1.94). Current menthol and mint ECIGs users showed adjusted relative risk of 1.26 (95%CI 0.77, 2.07) compared to non-ECIGs users. Former ECIGs users of multiple flavors and other flavors had 233% and 66% higher risk to develop cough, respectively (aRR:3.33, 95%CI 1.51, 7.34 and aRR:1.66, 95%CI 1.0.9, 2.51), relative to non-ECIGs users.

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Table 4. Association between type of regular flavor used and incident cases of self-reported nocturnal dry cough in the past 12 months, PATH study, Waves 1–5 (2013–2019).

https://doi.org/10.1371/journal.pone.0306467.t004

Discussion

Our findings underscore the contribution of fruit flavors in ECIGs to the development of nocturnal dry cough among current established ECIGs users, after controlling for sociodemographic variables (sex, age, race-ethnicity, educational level, household income), disease status (heart disease, pulmonary disease, gum disease, cancer, precancerous oral lesions, ulcer, gastrointestinal bleeding, cataract and glaucoma, or diabetes mellitus), marijuana use, overall tobacco use, and secondhand smoke exposure. Our results are consistent with previous research from our group showing that ECIGs users of fruit were more likely to report dry cough in the P12M, as compared to non-established ECIGs users. Initially, concerns regarding ECIGs exposure were focused on the effects of nicotine, as nicotine-containing ECIGs show a dual effect on cough: initial coughing and a delayed suppressive effect on coughing [40]. However, exposure to flavors and flavorings from ECIGs are of special concern for cough.

Flavors in ECIGs evoke chemosensory experiences that has been associated with initiation, progression and dependence or addiction to ECIGs products among youth, young adults, and never smokers [47, 48]. Flavors enhance the palatability of high concentrations of ECIGs constituents, such as nicotine, PG and VG [15, 49, 50]. Characterizing flavors are vastly available in the market and are grouped into 11 main categories, including the most popular “fruit”, “dessert-candy-sweets”, “tobacco”, and “mint/menthol” [51]. Fruit flavors are more likely to attract youth and young adults [52, 53]. Flavorings, the chemicals responsible for the perception of flavors, are derived from the food industry and generally recognized as safe for ingestion, but not inhalation [54]. However, some flavorings including benzaldehyde (cinnamon), cinnamaldehyde (cinnamon), ethyl methylphenylglycidate (fruit [strawberry]) diacetyl, ortho-vanillin (sweet), ethyl vanillin (sweet), and dl-menthol have shown to elicit oxidative stress and pro-inflammatory effects in the respiratory system when inhaled [15]. Evidence from in vitro and animal studies have shown that flavorings can elicit cytotoxic effects and abnormal activation for the airways epithelial cells, increased production of antimicrobial molecules, impaired mucociliary clearance, and damped immune responses [15]. These effects provide biological plausibility to support the association between ECIGs use and coughing. ECIGs flavorings can dysregulate the respiratory innate immunity and elicit inflammation, which are associated with coughing.

Cough, a component of the airway innate immunity, is a neuro-physiological response to noxious stimuli initiated by ion channels, mainly transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1) [55]. As our study observed the highest relative risk of nocturnal cough among current ECIG users vaping fruit flavors, we have to consider the ingredients of fruit flavors. Two popular flavorings present in fruit flavors, cinnamaldehyde and menthol, might disrupt the airway’s epithelia, elicit oxidative stress, impair mucociliary clearance, and induce inflammatory responses by increasing the release of inflammatory cytokines and through the activation of TRPA1 [15, 56, 57]. This would be potentially augmented by the inclusion of synthetic cooling/ice agents, such as WS-3 (N-Ethyl-2-isopropyl-5-methylcyclohexanecarboxamide), WS-23 (ethyl diisopropyl propionamide), and coolada, present in US-marketed fruit flavored refill e-liquids [58]. WS-3 and WS-23 have been shown to cause more oxidative and inflammatory responses in lung epithelial cells [58–60]. The presence of additives/adjuncts in the flavored products is an important consideration when evaluating the potential health effects from ECIGs.

Coughing is an unpleasant, disturbing, and distressing symptom, which is difficult to manage and requires considerable costs and health care utilization [61]. Further, coughing is the most common reason for medical visits in primary care [61]. Nocturnal cough is a common symptom of respiratory and non-respiratory disease with multiple etiologies, including asthma, allergies, and environmental exposures such as tobacco smoke and secondhand smoke. Though not all cough is associated with later adverse respiratory outcomes, cough is suspected to be “the canary in the coal mine” with regards to the toxicity of ECIGs in the respiratory system [62]. The “vaping cough”, as referred by the general public, is one of the most common symptoms reported by ECIGs users. The “vaping cough” is thought to be related to the throat hit, i.e., a harsh and irritating sensation in the throat, [63] caused by higher concentrations of nicotine in newer ECIG devices. However, symptoms like cough or dry throat were not different among ECIG users reporting strong throat hit as compared to those with weak throat hit [64]. In addition, ECIG users reporting cough as a frequent symptom associated to their ECIG use was related to high levels of VG in the e-liquids and the presence of the flavor cinnamon [65]. King and colleagues showed that among ECIGs users, 40% of the adults and 42.3% of the adolescents reported cough as the most frequent symptom attributed to ECIGs use [66]. Our report is one of the first studies examining the potential contribution of flavors in the production of cough.

Our population-level study focused on the association between ECIGs and cough, as an early marker of respiratory health. Our study used GEE models, a statistical method to provide estimates of a relative risk assessment in a prospective longitudinal analysis of a national representative sample of the US population. Though we have adjusted for the most relevant potential confounders described in the literature, including sociodemographic characteristics, health status, tobacco use, marijuana use, and second-hand smoke exposure, there is still potential for residual confounding from other variables. To account for confounding from tobacco use, our statistical models qualitatively assessed overall tobacco use and ECIGs flavor in all analyses. To minimize the impact of current or former tobacco use on studies of ECIGs, we recommend that future studies include quantitative estimations for tobacco use, e.g., frequency of smoking or cigarette packs per year. In addition, race and ethnicity specific statistical models were not conducted as sample sizes were too small for comparisons across ECIG flavor categories; however, future studies need to consider exploring the impact of these structural factors, particularly in light of the study by Connolly et al. which observed that Spanish-speaking participants were significantly less likely to be asked by providers about e-cigarette use compared to English speaking patients [67].

The toxicological profile for most of the flavors remains difficult to define [8, 68]. Our study did not perform a direct comparison among the different broad flavor categories assessed in the PATH Study. The 95% confidence intervals for the adjusted relative risk shown in the study suggest there is no statistical difference among the categories examined in the study. However, future research might address specific comparisons between flavor categories, considering potential confounders such as sociodemographic variables, behaviors associated with ECIG use, tobacco use history, secondhand smoke exposure, and marijuana use. The expanding evidence suggest that menthol, strawberry, cinnamon, and tobacco flavors might elicit biological changes associated with respiratory adverse effects [12]. There is emerging evidence for increased risk of respiratory disease in ECIGs users, though the observed risk is generally lower than that for cigarettes. However, the relatively short time that ECIGs have been on the market compared to cigarettes means that, even when controlling for length of use, the sample of ECIGs users with sufficiently long exposures to lead to respiratory disease will be smaller in comparison to their age-matched peers who smoke cigarettes. This discrepancy limits the ability to compare the relative risks between smoking and ECIGs. Thus, there is a need to characterize more proximal markers of later disease development, such as cough and other physiologically relevant respiratory symptoms. As the availability and types of flavors evolves in response to regulation, future studies will need to continue focusing on flavor-specific effects on respiratory health, including early indicators such as cough.

References

  1. 1. Kundu S, Shaw S, Khan J, Chattopadhyay A, Baptista EA, Paswan B. Age, gender and socioeconomic patterns of awareness and usage of e-cigarettes across selected WHO region countries: evidence from the Global Adult Tobacco Survey. BMJ Open. 2023;13(1):e070419. pmid:36657753
  2. 2. Cheng T. Chemical evaluation of electronic cigarettes. Tobacco control. 2014;23(suppl 2):ii11–ii7. pmid:24732157
  3. 3. Beauval N, Antherieu S, Soyez M, Gengler N, Grova N, Howsam M, et al. Chemical evaluation of electronic cigarettes: Multicomponent analysis of liquid refills and their corresponding aerosols. Journal of analytical toxicology. 2017;41(8):670–8. pmid:28985322
  4. 4. Behar RZ, Davis B, Wang Y, Bahl V, Lin S, Talbot P. Identification of toxicants in cinnamon-flavored electronic cigarette refill fluids. Toxicol In Vitro. 2014;28(2):198–208. pmid:24516877
  5. 5. Behar RZ, Luo W, Lin SC, Wang Y, Valle J, Pankow JF, et al. Distribution, quantification and toxicity of cinnamaldehyde in electronic cigarette refill fluids and aerosols. Tob Control. 2016;25(Suppl 2):ii94–ii102. pmid:27633763
  6. 6. Leigh NJ, Lawton RI, Hershberger PA, Goniewicz ML. Flavourings significantly affect inhalation toxicity of aerosol generated from electronic nicotine delivery systems (ENDS). Tob Control. 2016;25(Suppl 2):ii81–ii7. pmid:27633767
  7. 7. Qu Y, Kim KH, Szulejko JE. The effect of flavor content in e-liquids on e-cigarette emissions of carbonyl compounds. Environ Res. 2018;166:324–33. pmid:29909173
  8. 8. Bitzer ZT, Goel R, Reilly SM, Elias RJ, Silakov A, Foulds J, et al. Effect of flavoring chemicals on free radical formation in electronic cigarette aerosols. Free Radic Biol Med. 2018;120:72–9. pmid:29548792
  9. 9. Augustini A, Sielemann S, Telgheder U. Quantitation of Flavor Compounds in Refill Solutions for Electronic Cigarettes Using HS-GCxIMS and Internal Standards. Molecules. 2022;27(22). pmid:36432167
  10. 10. Kuehl PJ, McDonald JD, Weber DT, Khlystov A, Nystoriak MA, Conklin DJ. Composition of aerosols from thermal degradation of flavors used in ENDS and tobacco products. Inhal Toxicol. 2022;34(11–12):319–28. pmid:35913821
  11. 11. Effah F, Taiwo B, Baines D, Bailey A, Marczylo T. Pulmonary effects of e-liquid flavors: a systematic review. J Toxicol Environ Health B Crit Rev. 2022;25(7):343–71. pmid:36154615
  12. 12. Muthumalage T, Lamb T, Friedman MR, Rahman I. E-cigarette flavored pods induce inflammation, epithelial barrier dysfunction, and DNA damage in lung epithelial cells and monocytes. Scientific Reports. 2019;9(1):19035. pmid:31836726
  13. 13. Kaur G, Muthumalage T, Rahman I. Mechanisms of toxicity and biomarkers of flavoring and flavor enhancing chemicals in emerging tobacco and non-tobacco products. Toxicol Lett. 2018;288:143–55. pmid:29481849
  14. 14. Clapp PW, Lavrich KS, van Heusden CA, Lazarowski ER, Carson JL, Jaspers I. Cinnamaldehyde in flavored e-cigarette liquids temporarily suppresses bronchial epithelial cell ciliary motility by dysregulation of mitochondrial function. American Journal of Physiology-Lung Cellular and Molecular Physiology237. 2019;316(3):L470–L86. pmid:30604630
  15. 15. Quinones Tavarez Z, Li D, Croft DP, Gill SR, Ossip DJ, Rahman I. The Interplay Between Respiratory Microbiota and Innate Immunity in Flavor E-Cigarette Vaping Induced Lung Dysfunction. Front Microbiol. 2020;11:589501. pmid:33391205
  16. 16. Shi H, Quiñones Tavárez Z, Xie Z, Schneller LM, Croft DP, Goniewicz ML, et al. Association of flavored electronic nicotine delivery system (ENDS) use with self-reported chronic obstructive pulmonary disease (COPD): Results from the Population Assessment of Tobacco and Health (PATH) study, Wave 4. Tobacco Induced Diseases. 2020;18(October):1–9. pmid:33082739
  17. 17. Gordon T, Karey E, Rebuli ME, Escobar YH, Jaspers I, Chen LC. E-Cigarette Toxicology. Annu Rev Pharmacol Toxicol. 2022;62:301–22. pmid:34555289
  18. 18. Rapp JL, Alpert N, Flores RM, Taioli E. Serum cotinine levels and nicotine addiction potential of e-cigarettes: an NHANES analysis. Carcinogenesis. 2020;41(10):1454–9. pmid:32052011
  19. 19. Glantz S, Jeffers A, Winickoff JP. Nicotine Addiction and Intensity of e-Cigarette Use by Adolescents in the US, 2014 to 2021. JAMA Netw Open. 2022;5(11):e2240671. pmid:36342713
  20. 20. MacDonald A, Middlekauff HR. Electronic cigarettes and cardiovascular health: what do we know so far? Vascular health and risk management. 2019;15:159. pmid:31417268
  21. 21. Neczypor EW, Mears MJ, Ghosh A, Sassano MF, Gumina RJ, Wold LE, et al. E-Cigarettes and Cardiopulmonary Health: Review for Clinicians. Circulation. 2022;145(3):219–32. pmid:35041473
  22. 22. Yu X, Zeng X, Xiao F, Chen R, Sinharoy P, Gross ER. E-cigarette aerosol exacerbates cardiovascular oxidative stress in mice with an inactive aldehyde dehydrogenase 2 enzyme. Redox Biol. 2022;54:102369. pmid:35751982
  23. 23. Mahoney MC, Rivard C, Kimmel HL, Hammad HT, Sharma E, Halenar MJ, et al. Cardiovascular Outcomes among Combustible-Tobacco and Electronic Nicotine Delivery System (ENDS) Users in Waves 1 through 5 of the Population Assessment of Tobacco and Health (PATH) Study, 2013–2019. Int J Environ Res Public Health. 2022;19(7). pmid:35409819
  24. 24. Wu C-H, Chung W-M, Rahman I, Lee Y-F. PD42-11 Cigarette smoke, e-cigarettes and bladder cancer cell-derived extracellular vesicles induce bladder carcinogenesis. The Journal of Urology. 2020;203(Supplement 4):e831–e.
  25. 25. Tang M-s, Wu X-R, Lee H-W, Xia Y, Deng F-M, Moreira AL, et al. Electronic-cigarette smoke induces lung adenocarcinoma and bladder urothelial hyperplasia in mice. Proceedings of the National Academy of Sciences. 2019;116(43):21727–31.
  26. 26. Tang MS, Lee HW, Weng MW, Wang HT, Hu Y, Chen LC, et al. DNA damage, DNA repair and carcinogenicity: Tobacco smoke versus electronic cigarette aerosol. Mutat Res Rev Mutat Res. 2022;789:108409. pmid:35690412
  27. 27. Gotts JE, Jordt S-E, McConnell R, Tarran R. What are the respiratory effects of e-cigarettes? BMJ (Clinical research ed). 2019;366:l5275. pmid:31570493
  28. 28. Park JA, Crotty Alexander LE, Christiani DC. Vaping and Lung Inflammation and Injury. Annu Rev Physiol. 2022;84:611–29. pmid:34724436
  29. 29. Jonas A. Impact of vaping on respiratory health. Bmj. 2022;378:e065997. pmid:35851281
  30. 30. Novelli CE, Higginbotham EJ, Kapanke KA, Webber-Ritchey KJ, Parker CH, Simonovich SD. A systematic review examining the pulmonary effects of electronic vapor delivery systems. J Clin Anesth. 2022;82:110952. pmid:36007478
  31. 31. Krishnasamy VP. Update: Characteristics of a Nationwide Outbreak of E-cigarette, or Vaping, Product Use–Associated Lung Injury—United States, August 2019–January 2020. MMWR Morbidity and Mortality Weekly Report. 2020;69.
  32. 32. Rebuli ME, Rose JJ, Noël A, Croft DP, Benowitz NL, Cohen AH, et al. The E-cigarette or Vaping Product Use-Associated Lung Injury Epidemic: Pathogenesis, Management, and Future Directions: An Official American Thoracic Society Workshop Report. Annals of the American Thoracic Society. 2023;20(1):1–17. pmid:36584985
  33. 33. Navon L, Ghinai I, Layden J. Notes from the Field: Characteristics of Tetrahydrocannabinol-Containing E-cigarette, or Vaping, Products Used by Adults—Illinois, September-October 2019. MMWR Morb Mortal Wkly Rep. 2020;69(29):973–5. pmid:32701939
  34. 34. Berlowitz JB, Xie W, Harlow AF, Blaha MJ, Bhatnagar A, Benjamin EJ, et al. Cigarette‒E-cigarette Transitions and Respiratory Symptom Development. Am J Prev Med. 2022.
  35. 35. Varella MH, Andrade OA, Shaffer SM, Castro G, Rodriguez P, Barengo NC, et al. E-cigarette use and respiratory symptoms in residents of the United States: A BRFSS report. PLoS One. 2022;17(12):e0269760. pmid:36454742
  36. 36. Li D, Sundar IK, McIntosh S, Ossip DJ, Goniewicz ML, O’Connor RJ, et al. Association of smoking and electronic cigarette use with wheezing and related respiratory symptoms in adults: cross-sectional results from the Population Assessment of Tobacco and Health (PATH) study, wave 2. Tob Control. 2020;29(2):140–7. pmid:30760629
  37. 37. Sargent JD, Halenar MJ, Edwards KC, Woloshin S, Schwartz L, Emond J, et al. Tobacco use and respiratory symptoms among adults: Findings from the Longitudinal Population Assessment of Tobacco and Health (PATH) Study 2014–16. Nicotine Tob Res. 2022.
  38. 38. Stratton K, Kwan LY, Eaton DL. Public health consequences of e-cigarettes: consensus study report. Public health consequences of e-cigarettes: consensus study report. 2018.
  39. 39. Ashford K, McCubbin A, Rayens MK, Wiggins A, Dougherty K, Sturgill J, et al. ENDS Use among College Students: Salivary Biomarkers and Persistent Cough. Addictive Behaviors. 2020:106462. pmid:32442871
  40. 40. Dicpinigaitis PV, L Chang A, Dicpinigaitis AJ, Negassa A. Effect of e-cigarette use on cough reflex sensitivity. Chest. 2016;149(1):161–5. pmid:26291648
  41. 41. Dicpinigaitis PV, Lee Chang A, Dicpinigaitis AJ, Negassa A. Effect of electronic cigarette use on the urge-to-cough sensation. Nicotine & Tobacco Research. 2016;18(8):1763–5. pmid:26803150
  42. 42. Dicpinigaitis PV. Effect of tobacco and electronic cigarette use on cough reflex sensitivity. Pulmonary pharmacology & therapeutics. 2017;47:45–8. pmid:28185897
  43. 43. Chaiton M, Pienkowski M, Musani I, Bondy SJ, Cohen JE, Dubray J, et al. Smoking, e-cigarettes and the effect on respiratory symptoms among a population sample of youth: Retrospective cohort study. Tob Induc Dis. 2023;21:08. pmid:36721859
  44. 44. Health USDo, Abuse HSNIoHNIoD, Health USDo, Food HS, Products DACfT. Population Assessment of Tobacco and Health (PATH) Study [United States] Public-Use Files. Inter-university Consortium for Political and Social Research [distributor]; 2022.
    • 45. Hyland A, Ambrose BK, Conway KP, Borek N, Lambert E, Carusi C, et al. Design and methods of the Population Assessment of Tobacco and Health (PATH) Study. Tob Control. 2017;26(4):371–8. pmid:27507901
    • 46. Singh DP, Jamil RT, Mahajan K. Nocturnal cough. 2018.
    • 47. Alhadyan SK, Sivaraman V, Onyenwoke RU. E-cigarette Flavors, Sensory Perception, and Evoked Responses. Chem Res Toxicol. 2022;35(12):2194–209.
    • 48. Patten T, Dreier A, Herman RJ, Kimball BA, De Biasi M. Exposure to fruit-flavoring during adolescence increases nicotine consumption and promotes dose escalation. Neuropharmacology. 2021;195:108672. pmid:34153314
    • 49. DeVito EE, Jensen KP, O’Malley SS, Gueorguieva R, Krishnan-Sarin S, Valentine G, et al. Modulation of "Protective" Nicotine Perception and Use Profile by Flavorants: Preliminary Findings in E-cigarettes. Nicotine Tob Res. 2020;22(5):771–81. pmid:30995302
    • 50. Kim H, Lim J, Buehler SS, Brinkman MC, Johnson NM, Wilson L, et al. Role of sweet and other flavours in liking and disliking of electronic cigarettes. Tob Control. 2016;25(Suppl 2):ii55–ii61. pmid:27708124
    • 51. Ma S, Qiu Z, Yang Q, Bridges JFP, Chen J, Shang C. Expanding the E-Liquid Flavor Wheel: Classification of Emerging E-Liquid Flavors in Online Vape Shops. Int J Environ Res Public Health. 2022;19(21). pmid:36360834
    • 52. Landry RL, Groom AL, Vu TT, Stokes AC, Berry KM, Kesh A, et al. The role of flavors in vaping initiation and satisfaction among U.S. adults. Addict Behav. 2019;99:106077. pmid:31437770
    • 53. Schneller LM, Bansal-Travers M, Goniewicz ML, McIntosh S, Ossip D, O’Connor RJ. Use of flavored electronic cigarette refill liquids among adults and youth in the US-Results from Wave 2 of the Population Assessment of Tobacco and Health Study (2014–2015). PloS one. 2018;13(8):e0202744. pmid:30138412
    • 54. Sears CG, Hart JL, Walker KL, Robertson RM. Generally Recognized as Safe: Uncertainty Surrounding E-Cigarette Flavoring Safety. Int J Environ Res Public Health. 2017;14(10). pmid:29065549
    • 55. Canning BJ, Chang AB, Bolser DC, Smith JA, Mazzone SB, McGarvey L. Anatomy and neurophysiology of cough: CHEST Guideline and Expert Panel report. Chest. 2014;146(6):1633–48. pmid:25188530
    • 56. Omaiye EE, McWhirter KJ, Luo W, Tierney PA, Pankow JF, Talbot P. High concentrations of flavor chemicals are present in electronic cigarette refill fluids. Sci Rep. 2019;9(1):2468. pmid:30792477
    • 57. Hua M, Omaiye EE, Luo W, McWhirter KJ, Pankow JF, Talbot P. Identification of Cytotoxic Flavor Chemicals in Top-Selling Electronic Cigarette Refill Fluids. Sci Rep. 2019;9(1):2782. pmid:30808901
    • 58. Jabba SV, Erythropel HC, Torres DG, Delgado LA, Woodrow JG, Anastas PT, et al. Synthetic Cooling Agents in US-marketed E-cigarette Refill Liquids and Popular Disposable E-cigarettes: Chemical Analysis and Risk Assessment. Nicotine Tob Res. 2022;24(7):1037–46. pmid:35167696
    • 59. Manevski M, Yogeswaran S, Rahman I, Devadoss D, Chand HS. E-cigarette synthetic cooling agent WS-23 and nicotine aerosols differentially modulate airway epithelial cell responses. Toxicol Rep. 2022;9:1823–30. pmid:36518432
    • 60. Yogeswaran S, Shaikh SB, Manevski M, Chand HS, Rahman I. The role of Synthetic Coolants, WS-3 and WS-23, in modulating E-cigarette-induced Reactive Oxygen Species (ROS) in lung epithelial cells. Toxicology Reports. 2022. pmid:36518479
    • 61. On PC. Overview of chronic cough. Am J Manag Care. 2022;28(9 Suppl):S152–s8. pmid:36198073
    • 62. Moazed F, Calfee CS. The Canary in the Coal Mine Is Coughing: Electronic Cigarettes and Respiratory Symptoms in Adolescents. Am J Respir Crit Care Med. 2017;195(8):974–6. pmid:28409686
    • 63. Baassiri M, Talih S, Salman R, Karaoghlanian N, Saleh R, El Hage R, et al. Clouds and "throat hit": Effects of liquid composition on nicotine emissions and physical characteristics of electronic cigarette aerosols. Aerosol Sci Technol. 2017;51(11):1231–9. pmid:32863527
    • 64. Etter JF. Throat hit in users of the electronic cigarette: An exploratory study. Psychol Addict Behav. 2016;30(1):93–100. pmid:26653150
    • 65. Li Q, Zhan Y, Wang L, Leischow SJ, Zeng DD. Analysis of symptoms and their potential associations with e-liquids’ components: a social media study. BMC public health. 2016;16:674. pmid:27475060
    • 66. King JL, Reboussin BA, Wiseman KD, Ribisl KM, Seidenberg AB, Wagoner KG, et al. Adverse symptoms users attribute to e-cigarettes: Results from a national survey of US adults. Drug Alcohol Depend. 2019;196:9–13. pmid:30658221
    • 67. Connolly M, Croft D, Ramírez-Palacios P, Cai X, Hill B, Orfin RH, et al. Are Black and Latino adolescents being asked if they use electronic cigarettes and advised not to use them? Results from a community-based survey. Front Public Health. 2023;11:1222184. pmid:37637819
    • 68. Sciuscio D, Calvino-Martin F, Kumar A, Langston TB, Martin E, Marescotti D, et al. Toxicological Assessment of Flavor Ingredients in E-Vapor Products. Front Toxicol. 2022;4:878976. pmid:35516526