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Association Between E-Cigarettes and Asthma in Adolescents: A Systematic Review and Meta-Analysis

Open AccessPublished:March 22, 2022DOI:https://doi.org/10.1016/j.amepre.2022.01.015

      Introduction

      Numerous studies have revealed the relationship between E-cigarettes and asthma but have shown inconsistent results. This study systematically evaluated the potential association between E-cigarette use and asthma in adolescents.

      Methods

      PubMed, Embase (Ovid), Cochrane Library, and the China Biological Medicine Database were searched for relevant articles published between database inception and February 28, 2021. The quality of included studies was evaluated using the Agency for Healthcare Research and Quality assessment, and a quantitative meta-analysis was conducted to pool outcomes of ORs with 95% CIs.

      Results

      A total of 10 cross-sectional studies incorporating a total of 483,948 participants were included. All the study participants were middle- and high-school students with a mean age of 15–16 years. The median prevalence of ever E-cigarette use was 11.2% (range=2.2%, 45%), and that of current use was 7.5% (range=2.7%, 25%). Overall, E-cigarette use was associated with significantly higher odds of having asthma (pooled OR=1.31, 95% CI=1.22, 1.42) than nonuse, and both current use (OR=1.36, 95% CI=1.26, 1.48) and ever use (OR=1.20, 95% CI=1.12, 1.28) showed similar associations.

      Discussion

      This study shows that both current and ever E-cigarette use have significant associations with asthma in adolescents. This knowledge might provide potential evidence for developing primary prevention strategies and serve as a reference for public health policy.

      INTRODUCTION

      E-cigarettes are alternative, nonconventional tobacco products, which primarily use a rechargeable battery to heat disposable E-liquid cartridges, generating an inhalable aerosol consisting of nicotine, flavors, propylene glycol, and vegetable glycerin.
      • Gotts JE
      • Jordt SE
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      What are the respiratory effects of e-cigarettes? [published correction appears in BMJ. 2019;367:l5980].
      As an alternative product with a fashionable appearance, E-cigarettes are an attractive option for current smokers, former smokers, and young people who have never smoked. These E-cigarettes were initially designed and produced by a Chinese pharmacist in 2000 and, after further improvements, were exported throughout the world, gaining significant popularity since 2006.
      • Cahn Z
      • Siegel M.
      Electronic cigarettes as a harm reduction strategy for tobacco control: a step forward or a repeat of past mistakes?.
      Today, the global E-cigarette market has reached a multibillion-dollar value.
      • Walley SC
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      • Winickoff JP
      • Groner J
      A public health crisis: electronic cigarettes, vape, and JUUL.
      In South Korea, it has been introduced as a healthy alternative to conventional cigarettes and publicized as an effective device for smoking cessation.
      • Lee S
      • Kimm H
      • Yun JE
      • Jee SH.
      Public health challenges of electronic cigarettes in South Korea.
      However, no preclinical toxicology testing or long-term safety trials were conducted before E-cigarette marketing. In 2019, an outbreak of lung injury associated with E-cigarettes occurred in America, where >2,600 cases were reported, mainly involving young students.
      • Perrine CG
      • Pickens CM
      • Boehmer TK
      • et al.
      Characteristics of a multistate outbreak of lung injury associated with e-cigarette use, or vaping - United States, 2019 [published correction appears in MMWR Morb Mortal Wkly Rep. 2019;68(40):900].
      Thus, the potential adverse health effects of exposure to E-cigarettes need to be investigated further, especially in adolescents.
      Asthma is a chronic inflammatory airway disease characterized by variable airflow limitations secondary to airway narrowing and wall thickening, leading to shortness of breath, chest tightness, and cough.
      • Boonpiyathad T
      • Sözener ZC
      • Satitsuksanoa P
      • Akdis CA.
      Immunologic mechanisms in asthma.
      It has been reported to be predominantly caused by a combination of genetic and environmental factors. Diverse environmental factors, including smoking, outdoor air pollution, or dust mites, could trigger an asthma attack.
      • Beasley R
      • Semprini A
      • Mitchell EA.
      Risk factors for asthma: is prevention possible?.
      As an incurable disease, any effective measure might also involve minimal exposure to the various trigger factors present in the environment for patients with asthma. However, owing to low awareness of avoiding exposure to different environmental irritants, children have been found to exhibit a higher prevalence of asthma than adults.

      Dharmage SC, Perret JL, Custovic A. Epidemiology of asthma in children and adults. Front Pediatr. 2019;7:246. https://doi.org/10.3389/fped.2019.00246.

      At present, it is established that smoking tobacco can induce significant airway inflammation and further trigger asthma attacks.
      • Polosa R
      • Thomson NC.
      Smoking and asthma: dangerous liaisons.
      ,
      • Thomson NC
      • Chaudhuri R
      • Livingston E.
      Asthma and cigarette smoking.
      By contrast, the role of E-cigarettes in asthma attacks remains unclear. In recent years, with the rising public health concern about the widespread use of E-cigarettes among children globally,
      • Cruz TB
      • McConnell R
      • Low BW
      • et al.
      Tobacco marketing and subsequent use of cigarettes, e-cigarettes, and hookah in adolescents.
      ,
      • Kennedy RD
      • Awopegba A
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      Global approaches to regulating electronic cigarettes.
      many studies have been conducted to investigate the possible association between E-cigarettes and asthma. In this study, a meta-analysis was performed to examine the association between E-cigarettes and asthma among adolescents, thus providing a theoretical basis for further research.

      METHODS

      This study was conducted according to the PRISMA checklist.
      • Page MJ
      • McKenzie JE
      • Bossuyt PM
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      The protocol for this study has been registered in the International Prospective Register of Systematic Reviews (CRD42021239273).

      Search Strategy and Selection Criteria

      A total of 3 English databases (PubMed, Embase [Ovid], and Cochrane Library) and 1 Chinese database (China Biological Medicine Database) were searched for relevant articles from inception through August 30, 2020. To maximize search feasibility, the reference lists of selected studies were scrutinized manually. An updated search was carried out on February 28, 2021 to ensure that all recent studies were included. The database search was conducted by YZ, and construction of the retrieval strategy was based on the Patient/Population, Intervention, Comparison, Outcome, Study framework. The search strategy for PubMed is presented in Appendix Table 1 (available online).
      The inclusion criteria were as follows: (1) studies that investigated the association between E-cigarette use and asthma (i.e., cross-sectional or longitudinal studies), (2) participants aged ≤18 years, (3) reasonable measures of asthma, (4) appropriate method used to measure participants’ use of E-cigarettes, and (5) clear statistical indicators that reflected the strength of associations (i.e., OR). The exclusion criteria were as follows: (1) articles for which the data could not be obtained, (2) participants used E-cigarettes in combination with marijuana, and (3) studies that were not in English or Chinese and for those where full text was not available.

      Study Selection and Data Extraction

      After the studies were retrieved from the databases, duplicates were removed using Endnote (version X8). Then, the rest of the articles were screened further through 2 independent steps of selection by 2 independent reviewers (XCL and YZ), which included scanning the titles and abstracts, and full-text retrieval to determine whether a study was eligible for inclusion.
      After screening the relevant studies, the data and basic information were extracted from the eligible articles by XCL and YZ independently. A prespecified Excel form was used during the process of data extraction. Any discrepancies in the data extraction were settled through consensus with a third reviewer (LZ). The extracted information was as follows: (1) study characteristics (i.e., first author, publication year, country, study design, sample size), (2) participant characteristics (i.e., mean age, sex distribution), (3) definitions of E-cigarette use and asthma, (4) factors adjusted by statistical models, and (5) statistical measures of ORs with 95% CIs. However, if several ORs were reported for the same indicator, only the results with the most adjusted confounding factors were extracted.

      Assessment of Risk of Bias

      The quality of each included study was further appraised by 2 independent researchers (XCL and FC) using the Agency for Healthcare Research and Quality (AHRQ) assessment for cross-sectional studies,
      • Viswanathan M
      • Patnode CD
      • Berkman ND
      • et al.
      Assessing the risk of Bias in systematic reviews of health care interventions.
      and adjudication with input from a third reviewer (LZ) was used to resolve any potential discrepancies. The AHRQ assessment consisted of 11 items based on 3-dimensional selection, comparability, and outcomes. The scores of 8–11 were considered low risk, 4–7 were considered moderate risk, and 0–3 were considered high risk of bias.

      Statistical Analysis

      A meta-analysis was conducted for the ORs with associated 95% CIs. Statistical heterogeneity was examined using chi-square tests and quantified using statistics,
      • Higgins JP
      • Thompson SG.
      Quantifying heterogeneity in a meta-analysis.
      with an value threshold of 25% considered low, 50% considered moderate, and ≥75% considered substantial heterogeneity. However, if moderate or substantial heterogeneity was identified, random-effect models were used to pool outcomes. Otherwise, a fixed-effect model was used.
      • Borenstein M
      • Hedges LV
      • Higgins JP
      • Rothstein HR
      A basic introduction to fixed-effect and random-effects models for meta-analysis.
      Potential publication bias was gauged graphically through funnel plots and statistically through Egger linear regression tests. If the previous test was statistically significant, the trim-and-fill method was employed thereafter.
      • Egger M
      • Davey Smith G
      • Schneider M
      • Minder C
      Bias in meta-analysis detected by a simple, graphical test.
      To explore potential sources of heterogeneity and thereby obtain additional information wherever possible, subgroup analysis was performed on the basis of the types of E-cigarette use (exclusive E-cigarette use versus E-cigarette use), different regions where studies were conducted (North American versus Asian), sample size (≥50,000 vs <50,000), and participant populations (only high-school students versus middle and high-school students). All analyses were conducted in RevMan, version 5.4, and Stata SE, version 15.0, with a 2-sided p<0.05 considered statistically significant.

      RESULTS

      A PRISMA flow diagram summarizing the process of selecting the relevant studies is depicted in Figure 1. After the removal of duplicates, 3,992 relevant articles were reviewed, and 90 articles were considered potentially eligible after screening the titles and abstracts. After full-text review, 10 cross-sectional studies
      • Cho JH
      • Paik SY.
      Association between electronic cigarette use and asthma among high school students in South Korea.
      • Choi K
      • Bernat D.
      E-cigarette use among Florida youth with and without asthma.
      • Chung SJ
      • Kim BK
      • Oh JH
      • et al.
      Novel tobacco products including electronic cigarette and heated tobacco products increase risk of allergic rhinitis and asthma in adolescents: analysis of Korean youth survey.
      • Fedele DA
      • Barnett TE
      • Dekevich D
      • Gibson-Young LM
      • Martinasek M
      • Jagger MA.
      Prevalence of and beliefs about electronic cigarettes and hookah among high school students with asthma.
      • Han YY
      • Rosser FJ
      • Forno E
      • Celedón JC.
      Electronic vapor products, marijuana use, smoking, and asthma in U.S. adolescents.
      • Kim SY
      • Sim S
      • Choi HG.
      Active, passive, and electronic cigarette smoking is associated with asthma in adolescents.
      • Larsen K
      • Faulkner GEJ
      • Boak A
      • et al.
      Looking beyond cigarettes: are Ontario adolescents with asthma less likely to smoke e-cigarettes, marijuana, waterpipes or tobacco cigarettes?.
      • Lee A
      • Lee SY
      • Lee KS.
      The use of heated tobacco products is associated with asthma, allergic rhinitis, and atopic dermatitis in Korean adolescents.
      • Schweitzer RJ
      • Wills TA
      • Tam E
      • Pagano I
      • Choi K.
      E-cigarette use and asthma in a multiethnic sample of adolescents.
      • Wills TA
      • Choi K
      • Pagano I.
      E-cigarette use associated with asthma independent of cigarette smoking and marijuana in a 2017 national sample of adolescents.
      fulfilled the inclusion criteria and were subjected to final analysis.
      Figure 1
      Figure 1Flowchart of study selection.
      CBM, China Biological Medicine Database.
      The characteristics of the 10 included studies with a total of 483,948 participants are described in Table 1.
      • Cho JH
      • Paik SY.
      Association between electronic cigarette use and asthma among high school students in South Korea.
      • Choi K
      • Bernat D.
      E-cigarette use among Florida youth with and without asthma.
      • Chung SJ
      • Kim BK
      • Oh JH
      • et al.
      Novel tobacco products including electronic cigarette and heated tobacco products increase risk of allergic rhinitis and asthma in adolescents: analysis of Korean youth survey.
      • Fedele DA
      • Barnett TE
      • Dekevich D
      • Gibson-Young LM
      • Martinasek M
      • Jagger MA.
      Prevalence of and beliefs about electronic cigarettes and hookah among high school students with asthma.
      • Han YY
      • Rosser FJ
      • Forno E
      • Celedón JC.
      Electronic vapor products, marijuana use, smoking, and asthma in U.S. adolescents.
      • Kim SY
      • Sim S
      • Choi HG.
      Active, passive, and electronic cigarette smoking is associated with asthma in adolescents.
      • Larsen K
      • Faulkner GEJ
      • Boak A
      • et al.
      Looking beyond cigarettes: are Ontario adolescents with asthma less likely to smoke e-cigarettes, marijuana, waterpipes or tobacco cigarettes?.
      • Lee A
      • Lee SY
      • Lee KS.
      The use of heated tobacco products is associated with asthma, allergic rhinitis, and atopic dermatitis in Korean adolescents.
      • Schweitzer RJ
      • Wills TA
      • Tam E
      • Pagano I
      • Choi K.
      E-cigarette use and asthma in a multiethnic sample of adolescents.
      • Wills TA
      • Choi K
      • Pagano I.
      E-cigarette use associated with asthma independent of cigarette smoking and marijuana in a 2017 national sample of adolescents.
      All the participants were middle- or high-school students. However, 1 of the included studies
      • Fedele DA
      • Barnett TE
      • Dekevich D
      • Gibson-Young LM
      • Martinasek M
      • Jagger MA.
      Prevalence of and beliefs about electronic cigarettes and hookah among high school students with asthma.
      did not provide mean participant age, and another study
      • Wills TA
      • Choi K
      • Pagano I.
      E-cigarette use associated with asthma independent of cigarette smoking and marijuana in a 2017 national sample of adolescents.
      applied an age range rather than the mean age; the mean participant age in the remaining studies was 15–16 years. Of all the included eligible studies, 5 studies
      • Choi K
      • Bernat D.
      E-cigarette use among Florida youth with and without asthma.
      ,
      • Fedele DA
      • Barnett TE
      • Dekevich D
      • Gibson-Young LM
      • Martinasek M
      • Jagger MA.
      Prevalence of and beliefs about electronic cigarettes and hookah among high school students with asthma.
      ,
      • Han YY
      • Rosser FJ
      • Forno E
      • Celedón JC.
      Electronic vapor products, marijuana use, smoking, and asthma in U.S. adolescents.
      ,
      • Schweitzer RJ
      • Wills TA
      • Tam E
      • Pagano I
      • Choi K.
      E-cigarette use and asthma in a multiethnic sample of adolescents.
      ,
      • Wills TA
      • Choi K
      • Pagano I.
      E-cigarette use associated with asthma independent of cigarette smoking and marijuana in a 2017 national sample of adolescents.
      were conducted in the U.S., 4 studies
      • Cho JH
      • Paik SY.
      Association between electronic cigarette use and asthma among high school students in South Korea.
      ,
      • Chung SJ
      • Kim BK
      • Oh JH
      • et al.
      Novel tobacco products including electronic cigarette and heated tobacco products increase risk of allergic rhinitis and asthma in adolescents: analysis of Korean youth survey.
      ,
      • Kim SY
      • Sim S
      • Choi HG.
      Active, passive, and electronic cigarette smoking is associated with asthma in adolescents.
      ,
      • Lee A
      • Lee SY
      • Lee KS.
      The use of heated tobacco products is associated with asthma, allergic rhinitis, and atopic dermatitis in Korean adolescents.
      were conducted in South Korea, and 1 study
      • Chung SJ
      • Kim BK
      • Oh JH
      • et al.
      Novel tobacco products including electronic cigarette and heated tobacco products increase risk of allergic rhinitis and asthma in adolescents: analysis of Korean youth survey.
      was conducted in Canada.
      Table 1Basis Characteristics of Included Cross-Sectional Studies
      StudyCountrySample sizeMale (%)ParticipantsAge (mean ± SD)Definition of E-cigarette useDefinition of asthmaEffect sizeAdjusted factors
      Cho et al., 201618South Korea35,90449.87High-school students16.4±0.9 yearsDefinition 2
      Participants who answered YES to the question Have you ever used an E-cigarettes in your life? were defined as ever users, and those who answered YES to the question Have you used E-cigarettes in the past 30 days? were defined as Current users.
      Self-reportORGender, city size, multicultural family status, overweight status, secondhand smoking at home, atopic dermatitis history, and allergic rhinitis history
      Choi et al., 201619U.S.36,08549.2High-school students16.08±0.02 yearsDefinition 2
      Participants who answered YES to the question Have you ever used an E-cigarettes in your life? were defined as ever users, and those who answered YES to the question Have you used E-cigarettes in the past 30 days? were defined as Current users.
      Self-reportORNo adjusted factors
      Chung et al., 202020South Korea60,04050.74Middle and high schools15.2 yearsDefinition 2
      Participants who answered YES to the question Have you ever used an E-cigarettes in your life? were defined as ever users, and those who answered YES to the question Have you used E-cigarettes in the past 30 days? were defined as Current users.
      Self-reportORAge, sex, BMI, residential area, regular exercise, sedentary time, exposure to secondhand smoke, and SES
      Fedele et al., 201621U.S.32,41449.62High-school studentsNRDefinition 3
      If participants answer YES for the question In the last 30 days, have you smoked E-cigarettes?, they were considered Current users, and those who reported not using any substance of interest (cigarette, E-cigarettes, or water pipe) were considered as Never users.
      Self-reportORRace, and grade level
      Han et al.,202022U.S.21,53251.599th through 12th-grade students16.1±0.02 yearsDefinition 3
      If participants answer YES for the question In the last 30 days, have you smoked E-cigarettes?, they were considered Current users, and those who reported not using any substance of interest (cigarette, E-cigarettes, or water pipe) were considered as Never users.
      Self-reportORAge, sex, race, overweight or obese, and dental office visit in the previous year
      Kim et al., 201723South Korea216,05650.717th through 13th-grade students15.0±1.8 yearsDefinition 3
      If participants answer YES for the question In the last 30 days, have you smoked E-cigarettes?, they were considered Current users, and those who reported not using any substance of interest (cigarette, E-cigarettes, or water pipe) were considered as Never users.
      Self-reportORAge, physical exercise, sex, obesity, region of residence, economic level, educational level of father, education level of mother, active, passive smoking
      Larsen et al., 201624Canada2,84051.9High-school students15.86±1.27 yearsDefinition 1
      Participants were classified as ever users if they smoked E-cigarettes in their lives, and those who have never smoked E-cigarettes were considered never users. NR, no report.
      Self-reportORGrade, sex, and SES
      Lee et al., 201925South Korea58,33650.76Middle and high-school students15.0±1.8 yearsDefinition 1
      Participants were classified as ever users if they smoked E-cigarettes in their lives, and those who have never smoked E-cigarettes were considered never users. NR, no report.
      Self-reportORAge, sex, obesity, residential area, family economic status, and physical activity
      Schweitzer et al., 201726U.S.6,08950High-school students15.8±1.2 yearsDefinition 2
      Participants who answered YES to the question Have you ever used an E-cigarettes in your life? were defined as ever users, and those who answered YES to the question Have you used E-cigarettes in the past 30 days? were defined as Current users.
      Self-reportORCigarettes smoking, marijuana use, gender, age, race, Filipino/Pacific Islander, education intentions, overweight, school clustering
      Wills et al., 202027U.S.14,65249.39th through 12th-grade students14‒18 yearsDefinition 2
      Participants who answered YES to the question Have you ever used an E-cigarettes in your life? were defined as ever users, and those who answered YES to the question Have you used E-cigarettes in the past 30 days? were defined as Current users.
      Self-reportORGender, overweight, obese, age, race
      Note: Self-report: participants self-reported whether they had asthma diagnosed by a doctor within the past year.
      a Participants who answered YES to the question Have you ever used an E-cigarettes in your life? were defined as ever users, and those who answered YES to the question Have you used E-cigarettes in the past 30 days? were defined as Current users.
      b If participants answer YES for the question In the last 30 days, have you smoked E-cigarettes?, they were considered Current users, and those who reported not using any substance of interest (cigarette, E-cigarettes, or water pipe) were considered as Never users.
      c Participants were classified as ever users if they smoked E-cigarettes in their lives, and those who have never smoked E-cigarettes were considered never users.NR, no report.
      Use of E-cigarettes was assessed by a self-administrated questionnaire in all included studies. The association between E-cigarette use and asthma was investigated on the basis of ever use versus never use in 2 studies,
      • Larsen K
      • Faulkner GEJ
      • Boak A
      • et al.
      Looking beyond cigarettes: are Ontario adolescents with asthma less likely to smoke e-cigarettes, marijuana, waterpipes or tobacco cigarettes?.
      ,
      • Lee A
      • Lee SY
      • Lee KS.
      The use of heated tobacco products is associated with asthma, allergic rhinitis, and atopic dermatitis in Korean adolescents.
      current use versus never use in 3 studies,
      • Fedele DA
      • Barnett TE
      • Dekevich D
      • Gibson-Young LM
      • Martinasek M
      • Jagger MA.
      Prevalence of and beliefs about electronic cigarettes and hookah among high school students with asthma.
      • Han YY
      • Rosser FJ
      • Forno E
      • Celedón JC.
      Electronic vapor products, marijuana use, smoking, and asthma in U.S. adolescents.
      • Kim SY
      • Sim S
      • Choi HG.
      Active, passive, and electronic cigarette smoking is associated with asthma in adolescents.
      and current use and ever use versus never use in 5 studies.
      • Cho JH
      • Paik SY.
      Association between electronic cigarette use and asthma among high school students in South Korea.
      • Choi K
      • Bernat D.
      E-cigarette use among Florida youth with and without asthma.
      • Chung SJ
      • Kim BK
      • Oh JH
      • et al.
      Novel tobacco products including electronic cigarette and heated tobacco products increase risk of allergic rhinitis and asthma in adolescents: analysis of Korean youth survey.
      ,
      • Schweitzer RJ
      • Wills TA
      • Tam E
      • Pagano I
      • Choi K.
      E-cigarette use and asthma in a multiethnic sample of adolescents.
      ,
      • Wills TA
      • Choi K
      • Pagano I.
      E-cigarette use associated with asthma independent of cigarette smoking and marijuana in a 2017 national sample of adolescents.
      Asthma was identified on the basis of the participant's self-reported diagnosis that was confirmed by a doctor within the past year. Among the included studies, the prevalence of ever E-cigarette use ranged from 2.2% to 45%, with a median of 11.2%, whereas the prevalence of current E-cigarette use ranged from 2.7% to 25%, with a median of 7.5%.
      The detailed quality assessment of all included studies is shown in Appendix Figure 1 (available online). The overall quality of the studies was found to be above average, with a mean AHRQ score of 6.6 and a range of 5–7.
      As depicted in Figure 2, the meta-analysis clearly showed that E-cigarette use was associated with significantly higher odds of having asthma than nonuse (pooled OR=1.31, 95% CI=1.22, 1.42). Both current use
      • Cho JH
      • Paik SY.
      Association between electronic cigarette use and asthma among high school students in South Korea.
      • Choi K
      • Bernat D.
      E-cigarette use among Florida youth with and without asthma.
      • Chung SJ
      • Kim BK
      • Oh JH
      • et al.
      Novel tobacco products including electronic cigarette and heated tobacco products increase risk of allergic rhinitis and asthma in adolescents: analysis of Korean youth survey.
      • Fedele DA
      • Barnett TE
      • Dekevich D
      • Gibson-Young LM
      • Martinasek M
      • Jagger MA.
      Prevalence of and beliefs about electronic cigarettes and hookah among high school students with asthma.
      • Han YY
      • Rosser FJ
      • Forno E
      • Celedón JC.
      Electronic vapor products, marijuana use, smoking, and asthma in U.S. adolescents.
      • Kim SY
      • Sim S
      • Choi HG.
      Active, passive, and electronic cigarette smoking is associated with asthma in adolescents.
      ,
      • Schweitzer RJ
      • Wills TA
      • Tam E
      • Pagano I
      • Choi K.
      E-cigarette use and asthma in a multiethnic sample of adolescents.
      ,
      • Wills TA
      • Choi K
      • Pagano I.
      E-cigarette use associated with asthma independent of cigarette smoking and marijuana in a 2017 national sample of adolescents.
      (OR=1.36, 95% CI=1.26, 1.48) and ever use
      • Cho JH
      • Paik SY.
      Association between electronic cigarette use and asthma among high school students in South Korea.
      • Choi K
      • Bernat D.
      E-cigarette use among Florida youth with and without asthma.
      • Chung SJ
      • Kim BK
      • Oh JH
      • et al.
      Novel tobacco products including electronic cigarette and heated tobacco products increase risk of allergic rhinitis and asthma in adolescents: analysis of Korean youth survey.
      ,
      • Larsen K
      • Faulkner GEJ
      • Boak A
      • et al.
      Looking beyond cigarettes: are Ontario adolescents with asthma less likely to smoke e-cigarettes, marijuana, waterpipes or tobacco cigarettes?.
      • Lee A
      • Lee SY
      • Lee KS.
      The use of heated tobacco products is associated with asthma, allergic rhinitis, and atopic dermatitis in Korean adolescents.
      • Schweitzer RJ
      • Wills TA
      • Tam E
      • Pagano I
      • Choi K.
      E-cigarette use and asthma in a multiethnic sample of adolescents.
      • Wills TA
      • Choi K
      • Pagano I.
      E-cigarette use associated with asthma independent of cigarette smoking and marijuana in a 2017 national sample of adolescents.
      (OR=1.20, 95% CI=1.12, 1.28) showed similar associations.
      Figure 2
      Figure 2Forest plot of the associations between E-cigarettes use and asthma.
      IV, independent variable.
      The results of the subgroup analysis are presented in Table 2. For the types of E-cigarette use, the pooled ORs were 1.22 (95% CI=1.12, 1.33) in exclusive E-cigarette use
      • Cho JH
      • Paik SY.
      Association between electronic cigarette use and asthma among high school students in South Korea.
      ,
      • Chung SJ
      • Kim BK
      • Oh JH
      • et al.
      Novel tobacco products including electronic cigarette and heated tobacco products increase risk of allergic rhinitis and asthma in adolescents: analysis of Korean youth survey.
      ,
      • Han YY
      • Rosser FJ
      • Forno E
      • Celedón JC.
      Electronic vapor products, marijuana use, smoking, and asthma in U.S. adolescents.
      ,
      • Lee A
      • Lee SY
      • Lee KS.
      The use of heated tobacco products is associated with asthma, allergic rhinitis, and atopic dermatitis in Korean adolescents.
      ,
      • Wills TA
      • Choi K
      • Pagano I.
      E-cigarette use associated with asthma independent of cigarette smoking and marijuana in a 2017 national sample of adolescents.
      and 1.34 (95% CI=1.22, 1.48) in E-cigarette use
      • Choi K
      • Bernat D.
      E-cigarette use among Florida youth with and without asthma.
      ,
      • Fedele DA
      • Barnett TE
      • Dekevich D
      • Gibson-Young LM
      • Martinasek M
      • Jagger MA.
      Prevalence of and beliefs about electronic cigarettes and hookah among high school students with asthma.
      ,
      • Kim SY
      • Sim S
      • Choi HG.
      Active, passive, and electronic cigarette smoking is associated with asthma in adolescents.
      ,
      • Larsen K
      • Faulkner GEJ
      • Boak A
      • et al.
      Looking beyond cigarettes: are Ontario adolescents with asthma less likely to smoke e-cigarettes, marijuana, waterpipes or tobacco cigarettes?.
      ,
      • Schweitzer RJ
      • Wills TA
      • Tam E
      • Pagano I
      • Choi K.
      E-cigarette use and asthma in a multiethnic sample of adolescents.
      subgroups. On the basis of the different regions where the included studies were conducted, both North American
      • Choi K
      • Bernat D.
      E-cigarette use among Florida youth with and without asthma.
      ,
      • Fedele DA
      • Barnett TE
      • Dekevich D
      • Gibson-Young LM
      • Martinasek M
      • Jagger MA.
      Prevalence of and beliefs about electronic cigarettes and hookah among high school students with asthma.
      ,
      • Han YY
      • Rosser FJ
      • Forno E
      • Celedón JC.
      Electronic vapor products, marijuana use, smoking, and asthma in U.S. adolescents.
      ,
      • Larsen K
      • Faulkner GEJ
      • Boak A
      • et al.
      Looking beyond cigarettes: are Ontario adolescents with asthma less likely to smoke e-cigarettes, marijuana, waterpipes or tobacco cigarettes?.
      ,
      • Schweitzer RJ
      • Wills TA
      • Tam E
      • Pagano I
      • Choi K.
      E-cigarette use and asthma in a multiethnic sample of adolescents.
      ,
      • Wills TA
      • Choi K
      • Pagano I.
      E-cigarette use associated with asthma independent of cigarette smoking and marijuana in a 2017 national sample of adolescents.
      and Asian
      • Cho JH
      • Paik SY.
      Association between electronic cigarette use and asthma among high school students in South Korea.
      ,
      • Chung SJ
      • Kim BK
      • Oh JH
      • et al.
      Novel tobacco products including electronic cigarette and heated tobacco products increase risk of allergic rhinitis and asthma in adolescents: analysis of Korean youth survey.
      ,
      • Kim SY
      • Sim S
      • Choi HG.
      Active, passive, and electronic cigarette smoking is associated with asthma in adolescents.
      ,
      • Lee A
      • Lee SY
      • Lee KS.
      The use of heated tobacco products is associated with asthma, allergic rhinitis, and atopic dermatitis in Korean adolescents.
      subgroups yielded a significant relationship between E-cigarette use and asthma, with pooled ORs of 1.28 (95% CI=1.19, 1.37) and 1.54 (95% CI=1.42, 1.68), respectively. Similarly, those using E-cigarettes had higher odds of having asthma than nonusers in the sample size <50,000
      • Cho JH
      • Paik SY.
      Association between electronic cigarette use and asthma among high school students in South Korea.
      • Choi K
      • Bernat D.
      E-cigarette use among Florida youth with and without asthma.
      • Fedele DA
      • Barnett TE
      • Dekevich D
      • Gibson-Young LM
      • Martinasek M
      • Jagger MA.
      Prevalence of and beliefs about electronic cigarettes and hookah among high school students with asthma.
      • Han YY
      • Rosser FJ
      • Forno E
      • Celedón JC.
      Electronic vapor products, marijuana use, smoking, and asthma in U.S. adolescents.
      • Larsen K
      • Faulkner GEJ
      • Boak A
      • et al.
      Looking beyond cigarettes: are Ontario adolescents with asthma less likely to smoke e-cigarettes, marijuana, waterpipes or tobacco cigarettes?.
      • Schweitzer RJ
      • Wills TA
      • Tam E
      • Pagano I
      • Choi K.
      E-cigarette use and asthma in a multiethnic sample of adolescents.
      • Wills TA
      • Choi K
      • Pagano I.
      E-cigarette use associated with asthma independent of cigarette smoking and marijuana in a 2017 national sample of adolescents.
      and ≥50,000
      • Chung SJ
      • Kim BK
      • Oh JH
      • et al.
      Novel tobacco products including electronic cigarette and heated tobacco products increase risk of allergic rhinitis and asthma in adolescents: analysis of Korean youth survey.
      • Kim SY
      • Sim S
      • Choi HG.
      Active, passive, and electronic cigarette smoking is associated with asthma in adolescents.
      • Lee A
      • Lee SY
      • Lee KS.
      The use of heated tobacco products is associated with asthma, allergic rhinitis, and atopic dermatitis in Korean adolescents.
      subgroups, with respective pooled ORs of 1.28 (95% CI=1.19, 1.38) and 1.54 (95% CI=1.41, 1.68). Finally, statistically significant ORs for having asthma and E-cigarette use were also obtained in high-school student participants
      • Cho JH
      • Paik SY.
      Association between electronic cigarette use and asthma among high school students in South Korea.
      ,
      • Choi K
      • Bernat D.
      E-cigarette use among Florida youth with and without asthma.
      ,
      • Fedele DA
      • Barnett TE
      • Dekevich D
      • Gibson-Young LM
      • Martinasek M
      • Jagger MA.
      Prevalence of and beliefs about electronic cigarettes and hookah among high school students with asthma.
      ,
      • Larsen K
      • Faulkner GEJ
      • Boak A
      • et al.
      Looking beyond cigarettes: are Ontario adolescents with asthma less likely to smoke e-cigarettes, marijuana, waterpipes or tobacco cigarettes?.
      ,
      • Schweitzer RJ
      • Wills TA
      • Tam E
      • Pagano I
      • Choi K.
      E-cigarette use and asthma in a multiethnic sample of adolescents.
      and in middle- and high-school participants,
      • Chung SJ
      • Kim BK
      • Oh JH
      • et al.
      Novel tobacco products including electronic cigarette and heated tobacco products increase risk of allergic rhinitis and asthma in adolescents: analysis of Korean youth survey.
      ,
      • Han YY
      • Rosser FJ
      • Forno E
      • Celedón JC.
      Electronic vapor products, marijuana use, smoking, and asthma in U.S. adolescents.
      ,
      • Kim SY
      • Sim S
      • Choi HG.
      Active, passive, and electronic cigarette smoking is associated with asthma in adolescents.
      ,
      • Lee A
      • Lee SY
      • Lee KS.
      The use of heated tobacco products is associated with asthma, allergic rhinitis, and atopic dermatitis in Korean adolescents.
      ,
      • Wills TA
      • Choi K
      • Pagano I.
      E-cigarette use associated with asthma independent of cigarette smoking and marijuana in a 2017 national sample of adolescents.
      with pooled ORs of 1.32 (95% CI=1.21, 1.46) and 1.32 (95% CI=1.14, 1.53), respectively.
      Table 2Subgroup Analysis of the Association Between E-Cigarettes Use With Asthma
      SubgroupNumber of studiesHeterogeneity resultModelResults of meta-analysis
      I
      • Cahn Z
      • Siegel M.
      Electronic cigarettes as a harm reduction strategy for tobacco control: a step forward or a repeat of past mistakes?.
      , %
      p-valueEffect sizep-value
      Types of E-cigarettes use
       Exclusive E-cigarettes use
      Exclusive E-cigarettes use subgroup included those studies that explicitly differentiated between E-cigarettes use and smoking and reported the effect size (ORs) of comparing only E-cigarettes use with nonuse.
      5300.19Fixed1.22 (1.12, 1.33)<0.001
       E-cigarettes use
      E-cigarettes use subgroup included studies that merely reported E-cigarettes use versus nonuse, but whether E-cigarettes use combined with smoking was not to be clearly defined.
      590<0.001Random1.34 (1.22, 1.48)<0.001
      Region
       North America678<0.001Random1.28 (1.19, 1.37)<0.001
       Asia420.4Fixed1.54 (1.42, 1.68)<0.001
      Sample size
       <50,000775<0.001Random1.28 (1.19, 1.38)<0.001
       ≥50,000300.67Fixed1.54 (1.41, 1.68)<0.001
      Participants
       High-school students only581<0.001Random1.32 (1.21, 1.46)<0.001
       Middle and high school5700.003Random1.32 (1.14, 1.53)<0.001
      a Exclusive E-cigarettes use subgroup included those studies that explicitly differentiated between E-cigarettes use and smoking and reported the effect size (ORs) of comparing only E-cigarettes use with nonuse.
      b E-cigarettes use subgroup included studies that merely reported E-cigarettes use versus nonuse, but whether E-cigarettes use combined with smoking was not to be clearly defined.
      Potential publication bias was assessed through Begg's test, which revealed no significant bias (p=0.245). A similar result was obtained after Egger's test (p=0.25), clearly ruling out large publication bias effects in this meta-analysis (Appendix Figure 2, available online).

      DISCUSSION

      This meta-analysis synthesized the results of 10 cross-sectional studies, which provided integrative evidence about the association between E-cigarette use and asthma in adolescents. The results revealed that E-cigarette use (both current and ever use) was associated with asthma. To rule out possible confounding factors (i.e., smoking), the results from a subgroup analysis of exclusive E-cigarette use were found to be consistent with the main findings. In a similar review, Wills et al.
      • Wills TA
      • Soneji SS
      • Choi K
      • Jaspers I
      • Tam EK.
      E-cigarette use and respiratory disorders: an integrative review of converging evidence from epidemiological and laboratory studies.
      investigated the relationship between E-cigarettes and respiratory disorders, including asthma and chronic obstructive pulmonary disease, and also summarized laboratory studies. However, that review including studies on both adolescents (11 studies) and adults (4 studies) did not report a pooled OR only for adolescents and did not explore the potential source of heterogeneous results by subgroup analyses. In addition, the report by Wills and colleagues
      • Wills TA
      • Soneji SS
      • Choi K
      • Jaspers I
      • Tam EK.
      E-cigarette use and respiratory disorders: an integrative review of converging evidence from epidemiological and laboratory studies.
      did not assess the quality of included studies.
      Moreover, the findings of this meta-analysis were consistent with those of previous literature reviews
      • Clapp PW
      • Jaspers I.
      Electronic cigarettes: their constituents and potential links to asthma.
      • Hickman E
      • Jaspers I.
      Current e-cigarette research in the context of asthma.
      • Bozier J
      • Chivers EK
      • Chapman DG
      • et al.
      The evolving landscape of e-cigarettes: a systematic review of recent evidence.
      that summarized the relationship between E-cigarettes and asthma and those of experimental studies
      • Chun LF
      • Moazed F
      • Calfee CS
      • Matthay MA
      • Gotts JE.
      Pulmonary toxicity of e-cigarettes.
      • Crotty Alexander LE
      • Drummond CA
      • Hepokoski M
      • et al.
      Chronic inhalation of e-cigarette vapor containing nicotine disrupts airway barrier function and induces systemic inflammation and multiorgan fibrosis in mice.
      • Martin EM
      • Clapp PW
      • Rebuli ME
      • et al.
      E-cigarette use results in suppression of immune and inflammatory-response genes in nasal epithelial cells similar to cigarette smoke.
      that explored the biological impact of E-cigarettes. The use of E-cigarettes has increased sharply worldwide in recent years. For example, in the U.S., the prevalence of E-cigarette use was consecutively declining from 2004 but increased significantly during 2013–2014, especially among youth.
      • Creamer MR
      • Dutra LM
      • Sharapova SR
      • et al.
      Effects of e-cigarette use on cigarette smoking among U.S. youth, 2004-2018.
      The regulation of E-cigarettes varies across countries and states, ranging from no regulation to banning them entirely.
      • Kennedy RD
      • Awopegba A
      • De León E
      • Cohen JE.
      Global approaches to regulating electronic cigarettes.
      ,
      • Etter JF
      • Bullen C
      • Flouris AD
      • Laugesen M
      • Eissenberg T.
      Electronic nicotine delivery systems: a research agenda.
      In Japan, E-cigarettes containing nicotine are illegal and banned for use as cigarette alternatives. Some other countries have licensed E-cigarettes as medical devices such as in South Korea and the United Kingdom.
      • Beard E
      • Shahab L
      • Cummings DM
      • Michie S
      • West R.
      New pharmacological agents to aid smoking cessation and tobacco harm reduction: what has been investigated, and what is in the pipeline?.
      However, because of medical drug policies and the companies that manufacture E-cigarettes pushing for laws that support their interests,
      • Lempert LK
      • Grana R
      • Glantz SA.
      The importance of product definitions in US e-cigarette laws and regulations.
      E-cigarette legislation has been a subject of debate in many countries.
      • Kim KH
      • Kabir E
      • Jahan SA.
      Review of electronic cigarettes as tobacco cigarette substitutes: their potential human health impact.
      Hence, the ambiguity or lack of regulation on E-cigarettes should be settled, with more stringent supervision over E-cigarettes, especially for adolescents.
      At present, no available therapeutic regimens can cure asthma; however, associations have been reported between a wide range of environmental factors and asthma such as tobacco smoke, dust mites, and air pollution. These factors are called asthma triggers.
      • Gautier C
      • Charpin D.
      Environmental triggers and avoidance in the management of asthma.
      On the basis of the findings of this study, E-cigarette appears to serve as a potential trigger for asthma in adolescents. It is not clear why some people develop asthma and others do not, but it is probably due to a combination of environmental and genetic factors. Exposure to various irritants is known to trigger the symptoms of asthma. Thus, the diverse prevalence of asthma among countries or regions may be related to the different distribution of asthma triggers among them, such as different rates of smoking, obesity, or pollution.
      • To T
      • Stanojevic S
      • Moores G
      • et al.
      Global asthma prevalence in adults: findings from the cross-sectional world health survey [published correction appears in BMC Public Health. 2021;21(1):1809].
      ,
      • Enilari O
      • Sinha S.
      The global impact of asthma in adult populations.
      The study reported by Bhatta et al.
      • Bhatta DN
      • Glantz SA.
      Association of e-cigarette use with respiratory disease among adults: a longitudinal analysis.
      revealed that switching from conventional cigarettes to E-cigarettes would lower the risk of developing respiratory disease. This finding is relevant because the controversy continues over whether E-cigarettes should be promoted as a harm-reduction device for smokers. However, the subgroup analysis in this study indicated that exclusive use of E-cigarettes was still significantly associated with asthma in adolescents (pooled OR=1.22, 95% CI=1.12, 1.33). Smoking has been established as a powerful trigger of asthma,
      • Gilliland FD
      • Islam T
      • Berhane K
      • et al.
      Regular smoking and asthma incidence in adolescents.
      which can substantially irritate the lining of the airways, and in some countries, E-cigarettes have been suggested to be used for smoking cessation,
      • Lee S
      • Kimm H
      • Yun JE
      • Jee SH.
      Public health challenges of electronic cigarettes in South Korea.
      ,
      • Campus B
      • Fafard P
      • St Pierre J
      • Hoffman SJ.
      Comparing the regulation and incentivization of e-cigarettes across 97 countries.
      but their role was reported to be controversial.
      • Orellana-Barrios MA
      • Payne D
      • Medrano-Juarez RM
      • Yang S
      • Nugent K.
      Electronic cigarettes for smoking cessation.
      The results of this study suggest that if E-cigarettes are licensed as medical devices for promoting smoking cessation in adolescents, there should be more research conducted first to investigate their safety.
      In this study, except for the studies reported by Chung and colleagues
      • Chung SJ
      • Kim BK
      • Oh JH
      • et al.
      Novel tobacco products including electronic cigarette and heated tobacco products increase risk of allergic rhinitis and asthma in adolescents: analysis of Korean youth survey.
      and Cho et al.,
      • Cho JH
      • Paik SY.
      Association between electronic cigarette use and asthma among high school students in South Korea.
      all the studies of current use and ever use subgroups were consistent in finding that E-cigarette use was associated with asthma (Figure 2). Indeed, those 2 studies had much wider CIs than those of other studies (Figure 2), which probably caused comparatively significant heterogeneity.
      • Viechtbauer W.
      Confidence intervals for the amount of heterogeneity in meta-analysis.
      Although after carrying out a thorough investigation along with a subgroup analysis, it was found that the results were also consistent with the main finding, indicating that a significantly robust association was identified in this meta-analysis.

      Limitations

      Some limitations are associated with this review that should be noted. First, because all the studies that were included in the analysis did not directly compare current with ever E-cigarette use or daily with occasional E-cigarette use, the possible association of E-cigarette use with asthma in these patterns was not analyzed. Second, active asthma and nonactive asthma, an important classification, were not reported in the included studies. Therefore, the possible association between E-cigarettes and asthma stratified by active and nonactive asthma status was not included in this study. Third, this meta-analysis incorporated only 1 study
      • Choi K
      • Bernat D.
      E-cigarette use among Florida youth with and without asthma.
      that did not present adjusted ORs but only crude ORs; however, when this study was excluded from meta-analysis, the pooled OR and I2 statistics did not change significantly. Finally, this review only included English and Chinese literature. Consequently, the data published in other languages were missing from this analysis.

      CONCLUSIONS

      This meta-analysis clearly establishes that both current use and ever use of E-cigarettes have significant associations with asthma in adolescents. This knowledge could provide potential evidence for primary prevention as well as intervention strategies and form the basis of a novel reference for public health policy.

      ACKNOWLEDGMENTS

      The authors of this paper would like to thank all authors of the included studies as well as the reviewers and editors for their valuable comments. All authors have participated sufficiently in this work to take responsibility for all of its content. Xuechao Li and Yi Zhang contributed equally to this work.
      This work was funded by the Research Center of Traditional Chinese Medicine (TCM), Gansu Province (zyzx-2020-36), TCM evidence-based Capacity Building project, and Clinical practice of TCM comprehensive prevention and treatment of heart failure based on evidence-based research (2019 XZZX-XXG002).
      No financial disclosures were reported by the authors of this paper.

      CRediT AUTHOR STATEMENT

      Xuechao Li: Conceptualization, Literature screening, Data extraction, Formal analysis, Writing - Original Draft, Writing - review & editing. Yi Zhang: Literature screening, Data extraction, Data curation, Writing - Review and Editing. Rongqiang Zhang: Software, Visualization, Interpretation. Fei Chen: Quality assessment of included studies, Interpretation. Lihua Shao: Validation. Li Zhang: Conceptualization, Supervision, Funding acquisition.

      Appendix. SUPPLEMENTAL MATERIAL

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