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. 2022 Dec 1;17(12):e0269760. doi: 10.1371/journal.pone.0269760

E-cigarette use and respiratory symptoms in residents of the United States: A BRFSS report

Marcia H Varella 1,#, Olyn A Andrade 2,, Sydney M Shaffer 2,, Grettel Castro 1,, Pura Rodriguez 1,, Noël C Barengo 1,3,4,#, Juan M Acuna 5,6,*,#
Editor: Koustubh Panda7
PMCID: PMC9714717  PMID: 36454742

Abstract

Purpose

E-cigarettes are the most common type of electronic nicotine delivery system in the United States. E-cigarettes contain numerous toxic compounds that has been shown to induce severe structural damage to the airways. The objective of this study is to assess if there is an association between e-cigarette use and respiratory symptoms in adults in the US as reported in the BRFSS.

Methods

We analyzed data from 18,079 adults, 18–44 years, who participated at the Behavioral Risk Factor Surveillance System (BRFSS) in the year 2017. E-cigarette smoking status was categorized as current everyday user, current some days user, former smoker, and never smoker. The frequency of any respiratory symptoms (cough, phlegm, or shortness of breath) was compared. Unadjusted and adjusted logistic regression analysis were used to calculate odds ratios (OR) and 95% confidence intervals (CI).

Results

The BRFSS reported prevalence of smoking e-cigarettes was 6%. About 28% of the participants reported any of the respiratory symptoms assessed. The frequency of reported respiratory symptoms was highest among current some days e-cigarette users (45%). After adjusting for selected participant’s demographic, socio-economic, and behavioral characteristics, and asthma and COPD status, the odds of reporting respiratory symptoms increased by 49% among those who use e-cigarettes some days (OR 1.49; 95% CI: 1.06–2.11), and by 29% among those who were former users (OR 1.29; 95% CI: 1.07–1.55) compared with those who never used e-cigarettes. No statistically significant association was found for those who used e-cigarettes every day (OR 1.41; 95% CI 0.96–2.08).

Conclusion

E-cigarettes cannot be considered as a safe alternative to aid quitting use of combustible traditional cigarettes. Cohort studies may shed more evidence on the association between e-cigarette use and respiratory diseases.

Introduction

E-cigarettes use, or vaping, was promoted as a safer alternative to conventional cigarettes and a potential alternative in tobacco smoking cessation efforts [13]. It was introduced in the US marketplace in 2007 and since then its use has grown exponentially. Estimates based on the 2016–2017 Behavioral risk Factor Surveillance System (BRFSS) indicate a 4.4% prevalence of e-cigarette use for adults (18 years or older) [4, 5] According to the National Youth Tobacco Survey (NYTS) of 2021, about 2.8% and 11.3% of middle and high school students, respectively reported having used e-cigarette at least once in the past 30 days [6].

The increase in use of e-cigarettes is of concern E-cigarette aerosol contains several toxic chemical constituents. For instance, a systematic review published in 2019 listed 84 hazardous chemical compounds were identified in e-cigarettes. The hazardous effects of those compounds are varied and included cytotoxic, carcinogenic, behavioral, cardiovascular, and respiratory system effects [7, 8]. E-cigarette is also associated with wheeze, chronic cough, phlegm, or bronchitis in children and adults [911]. Result of a recently published systematic review estimated that the pooled OR associated with e-cigarette use for asthma was 1.39 (95% confidence interval (CI) 1.28–1.51) and for COPD was 1.49 (95% CI 1.36–1.65) [12].

While growing evidence points to detrimental respiratory effects of e-cigarettes use, just a few comparative studies assessed the effects of e-cigarettes in population based, community dwelling adults in the US [1315]. Additionally, the impact of e-cigarettes in the respiratory system has been assessed mainly by report of asthma and or COPD, which could have underestimated the magnitude of the respiratory effects caused by e-cigarettes.

In this study, we assessed the association between e-cigarette use and the occurrence of respiratory symptoms (namely cough, phlegm production, or shortness of breath) as reported in the BRFSS, to obtain a more comprehensive understanding of the previous potentially underestimated impact of e-cigarette use in adults in the United States.

Methods

Design and setting

We used data from the 2017 BRFSS. Briefly, the BRFSS is an ongoing national yearly cross-sectional survey, originally aimed to identify emerging health problems in order to modify public health programs and policies [16]. It consists of phone-based interviews regarding participants health-related risk behaviors, chronic health conditions, and use of preventive services. The inclusion criteria consisted of individuals between the ages of 18–44 and those living within Arizona, District of Columbia, Florida, Georgia, Minnesota, Nevada, Tennessee, and West Virginia. Only these states in the US collected information on the outcome of interest.

Study variables

E-cigarette usage (or vaping) was categorized as current everyday e-cigarette smokers, current someday e-cigarette smokers, former smokers, and those that never smoked, according to self-report. Outcome of interest was presence of respiratory symptoms, considered present if the participant reported any of the following: cough, phlegm production occurring daily in the past three months, or shortness of breath hurrying on level ground or when walking up a slight hill or stairs. No report of these three symptoms was considered as absence of the outcome. Covariates assessed included participant’s age (assessed as a continuous variable and also categorized as either 18–34 or 35–44 years-old), sex, race (White, Black, Hispanic, and “other”), employment status (employed, unemployed, student, and unable to work), education level (less than high school, high school graduate/General Educational Development exam completion, up to 3 years of college, and greater than 4 years of college), family yearly income (≤15,000, >15,000 to 25,000, >25,000 to 35,000, > 35,000–50,000, and > 50,000), marital status (married and unmarried), health insurance status (insured and uninsured), exercise reported in the past 30 days (yes, no), cigarette smoking status (current, former, never smoker), and history of ever being told to have asthma or chronic obstructive pulmonary disease.

Statistical analysis

A descriptive analysis was conducted to assess overall sample characteristics and to check for missing data patterns. Subsequently, bivariate analyses were done to further assess for potential confounders in the sample. Lastly, unadjusted and adjusted logistic regression analysis were conducted to estimate crude and adjusted odds ratios and corresponding 95% confidence intervals to explore and control for potential confounding variables and to determine potential interactions (effect modifiers). STATA v15 software was used for all analyses [11]. Further analyses restricted to participants who were never smokers and to those never reporting having asthma and COPD were performed.

This study uses publicly available data from the CDC BRFSS. The IRB of Florida International University considered the present study a “Non-Human Subject Research”.

Results

Of the 22,844 participants who completed the BRFSS questionnaire in the selected states in 2017, 18,079 participants met our study inclusion criteria and were assessed. Table 1 displays the characteristics of participants according to e-cigarette use categories. Overall, never users of e-cigarettes were more frequently older, females, of minority race/ethnicity (Blacks and Hispanics), married, of higher education achievement (> 4 years of college) and higher income compared to all other e-cigarette users categories. Never users also reported less frequently smoking of traditional (combustible) cigarettes. For most comparisons, differences were more striking between never users and every day e-cigarette users. The frequency of asthma and COPD report were highest for those who e-cigarettes use frequency was reported as “some days”. The overall frequency of the respiratory symptoms assessed was 27.6%, and it varied according to e-cigarette use categorization: it was highest for those reporting as someday current users and lowest for never users of e-cigarettes (44.6% and 23.3%, respectively, p-value <0.0001 for differences in at least one category) (Table 1).

Table 1. Selected characteristics of the sample of participants of the BRFSS according to e-cigarette use.

E-cigarette User category N (%)*
Current every day Current some days Former Never p-value
Age (median and IQR) 29 (23–36) 28 (22–36) 30 (25–36) 34 (27–39)
Age (in years, categories) 18–34 315 (73.1) 539 (74.9) 2868 (72.3) 6648 (59.1) <0.001
35–44 134 (26.9) 220 (25.1) 1406 (27.7) 5949 (40.9)
Sex Male 309 (72.7) 437 (60.5) 2371 (58.9) 5574 (45.0) 0.002
Female 140 (27.3) 322 (39.5) 1903 (41.1) 7019 (55.0)
Race/ethnicity White 359 (79.4) 525 (65.5) 2980 (63.8) 7632 (48.9) <0.001
Black 13 (3.2) 66 (13.0) 390 (11.3) 1745 (18.7)
Hispanic 34 (7.2) 105 (16.0) 580 (17.6) 2283 (24.6)
Other 43 (10.2) 63 (5.5) 324 (7.2) 937 (7.7)
Marital Status Married 187 (40.6) 264 (35.9) 1714 (38.1) 6767 (50.6) <0.001
Unmarried 258 (59.4) 493 (64.1) 2538 (61.9) 5752 (49.4)
Employment Status Employed 317 (72.6) 466 (58.2) 3028 (69.8) 9071 (70.5) 0.001
Unemployed 54 (10.1) 139 (20.3) 616 (14.0) 1821 (15.5)
Student 44 (12.7) 96 (15.8) 362 (11.5) 1018 (10.7)
Unable to Work 29 (4.6) 48 (5.4) 215 (4.4) 473 (3.0)
Education achievement Up to high school 27 (8.8) 75 (16.6) 345 (12.4) 1029 (12.4) <0.001
≥High school/GED 172 (43.2) 307 (41.3) 1341 (31.9) 3133 (27.3)
≤3 years of college 173 (38.5) 269 (33.8) 1558 (39.2) 3469 (31.8)
> 4 years of college 75 (9.5) 108 (8.3) 1023 (16.5) 4933 (28.5)
Annual family income ($) <15,000 33 (7.9) 78 (13.7) 364 (8.9) 972 (9.8) 0.001
15,000–25,000 84 (23.1) 181 (28.3) 767 (22.7) 1833 (19.5)
25,000–35,000 59 (9.5) 76 (11.3) 470 (12.3) 1112 (11.3)
35,000–50,000 68 (20.2) 89 (17.3) 566 (15.1) 1539 (14.3)
>50,000 144 (39.2) 194 (29.3) 1488 (41.0) 5342 (45.1)
Health insurance status Insured 363 (80.0) 584 (71.5) 3391 (76.8) 10379 (79.0) 0.017
Uninsured 83 (20.0) 163 (28.5) 857 (23.2) 2120 (21.0)
Exercised in past 30 days Yes 337 (70.5) 585 (80.3) 3208 (75.6) 9614 (75.8) 0.160
No 110 (29.5) 173 (19.7) 1058 (24.4) 2967 (24.2)
Cigarette smoker status Current 133 (29.4) 434 (53.4) 1838 (42.2) 1092 (7.7) <0.001
Former 225 (46.2) 105 (14.5) 927 (20.5) 6094 (12.0)
Never 86 (24.4) 217 (32.1) 1486 (37.3) 9749 (80.2)
History of asthma Yes 80 (16.4) 173 (24.3) 836 (19.8) 1613 (12.9) <0.001
No 368 (83.6) 580 (75.7) 3425 (80.2) 10946 (87.1)
History of COPD Yes 19 (3.5) 65 (7.6) 231 (4.7) 292 (2.5) <0.001
No 429 (96.5) 687 (92.4) 4026 (95.3) 12276 (97.5)
Report of respiratory symptoms** Yes 159 (32.6) 320 (44.6) 1627 (36.3) 2882 (23.3) <0.0001
No 290 (67.4) 439 (55.4) 2647 (63.7) 9715 (76.7)

*Variables are reported as absolute count and % unless specified. **Symptoms were self-reported and included cough, phlegm production, or shortness of breath. GED- general education diploma; COPD—Chronic Obstructive Pulmonary Disease. P-value corresponding to difference for at least one e-cigarette use categories

Table 2 displays the crude and adjusted odds ratios (ORs) for participant’s selected characteristics and reported respiratory symptoms. In the unadjusted analyses, compared to the never users, all e-cigarette users had significant increased odds of reporting respiratory symptoms. After controlling for confounding factors (participant’s demographic, socio-economic, behavioral -exercise and combustible cigarette use- asthma and COPD status), the associations were attenuated and significant only for those reporting some days of e-cigarette use and for former users compared to those who never used e-cigarettes (OR 1.49; 95% CI: 1.06–2.11and OR 1.29; 95% CI: 1.07–1.55, respectively). Other variables were also found independently associated with the occurrence of respiratory symptoms; Females, Blacks, those with lower education, being unable to work, family annual income lower than 50,000, being a current smoker, having no exercise reported in the past 30 days, and reporting asthma were associated with higher odds for respiratory symptoms in the adjusted analyses.

Table 2. Associations between E-cigarette use, selected participant’s characteristics and occurrence of respiratory symptoms in a sample of adults in the US participating at the BRFSS 2017.

Characteristics Unadjusted Adjusted
  OR (95% CI) p-value OR (95% CI) p-value
E-cigarette Use Never Reference Reference
Current—every day 1.59 (CI 1.15–2.21) 0.005 1.41 (CI 0.96–2.08) 0.080
Current—some days 2.65 (CI 2.04–3.46) <0.001 1.49 (CI 1.06–2.11) 0.022
Former user 1.88 (CI 1.64–2.16) <0.001 1.29 (CI 1.07–1.55) 0.009
Age (Years) 35–44 Reference Reference
18–34 1.04 (CI 0.92–1.17) 0.581 0.97 (CI 0.83–1.14) 0.754
Sex Female 1.23 (CI 1.09–1.38) 0.001 1.27 (CI 1.08–1.48) 0.003
Race White Reference Reference
Black 1.19 (CI 1.00–1.41) 0.054 1.26 (CI 1.01–1.59) 0.043
Hispanic 0.86 (CI 0.73–1.01) 0.066 0.87 (CI 0.70–1.07) 0.187
Other 0.89 (CI 0.70–1.12) 0.316 1.07 (CI 0.77–1.47) 0.699
Marital Married Reference Reference
Unmarried 1.36 (CI 1.21–1.54) <0.001 1.09 (CI 0.93–1.28) 0.262
Employment Status Employed Reference Reference
Unemployed 1.36 (CI 1.15–1.60) <0.001 1.17 (CI 0.93–1.46) 0.179
Unable to Work 4.26 (CI 3.27–5.56) <0.001 2.47 (CI 1.76–3.48) <0.001
Education achievement > 4 years of college Reference Reference
Less than high school 2.94 (CI 2.39–3.60) <0.001 1.72 (CI 1.28–2.30) <0.001
High school/GED 2.28 (CI 1.95–2.67) <0.001 1.41 (CI 1.15–1.74) 0.001
≤3 years of college 2.04 (CI 1.74–2.38) <0.001 1.46 (CI 1.21–1.76) <0.001
Annual family income ($) >50,000 Reference Reference
<15,000 2.67 (CI 2.13–3.36) <0.001 1.54 (CI 1.14–2.08) 0.005
15,000–25,000 2.26 (CI 1.89–2.69) <0.001 1.53 (CI 1.23–1.91) <0.001
25,000–35,000 1.61 (CI 1.30–2.00) <0.001 1.27 (CI 0.99–1.62) 0.060
35,000–50,000 1.85 (CI 1.50–2.27) <0.001 1.51 (CI 1.21–1.88) <0.001
Health insurance status Insured Reference Reference
Uninsured 1.20 (CI 1.04–1.39) 0.014 0.89 (CI 0.73–1.08) 0.237
No exercise in past 30 days 1.59 (CI 1.39–1.82) <0.001 1.41 (CI 1.20–1.67) <0.001
Cigarette Smokers status Never Reference Reference
Current 3.15 (2.72–3.66) <0.001 1.99 (CI 1.62–2.44) <0.001
Former 1.24 (CI 1.04–1.48) 0.015 1.03 (CI 0.83–1.28) 0.791
History of Asthma 3.22 (CI 2.76–3.77) <0.001 2.63 (CI 2.18–3.17) <0.001
History of COPD 0.22 (CI 0.14–0.34) <0.001 0.42 (CI 0.26–0.69) 0.001

BRFSS- Behavior Risk Factor Surveillance System; OR–odds ratio; CI–confidence interval. Adjusted model included all variables sown in the table

To study potential interactions, further analyses were conducted assessing the association between e-cigarette use, and respiratory symptoms occurrence in participants who were never smokers. The absolute number of participants who never smoked combustible cigarettes and were 86, 217, 1486, and 9749 for current every day, current some days, former, and never e-cigarette users, respectively. Lastly, exclusion of participants with prior history of asthma and COPD did not affect the estimates of the associations reported for e-cigarette and respiratory symptoms compared to the analyses where those conditions were adjusted for.

Discussion

Our data revealed that 2.5% and 4.2% of the sample subjects were every day or some days e-cigarette users, respectively. Overall, respiratory symptoms (cough, phlegm production, or shortness of breath) was reported in approximately 28% of the sample, much higher frequency than those symptoms previously reported [911]. Compared to never users, e-cigarette use was associated with up to 50% increased odds of respiratory symptoms; the highest odds were found for those using some day, followed by former users of e-cigarette.

While previous research demonstrated that even short-term exposure to e-cigarettes and their toxic compounds produced cough and phlegm in healthy individuals and individuals with a history of asthma [7], most of the previous cross-sectional and longitudinal studies in US adults that were published, assessed the detrimental effects of e-cigarettes focusing on outcomes such as asthma and COPD occurrence [12, 13, 15, 17, 18]. Our results of for someday e-cigarette users suggesting a 49% increase in odds outcome a composite of cough, phlegm production, or shortness of breath, were consistent in magnitude with the previous studies, despite assessing associations independently of COPD, asthma status, and demographic, socio-economic, and clinical characteristics. For instance, in the meta-analyses reported in the integrative review published in 2021 by Wills et al, the pooled odds of asthma and COPD were 39% (OR = 1.39, 95% CI 1.28–1.51) and 49% (OR1.49, 95% CI = 1.36–1.65) higher respectively, for e-cigarette users compared to never users (12). A less marked increase in the odds of cough or phlegm has been also reported in Chinese adolescents in 2012–2013, with e-cigarette users having 1.28 times higher odds to develop those symptoms compared to non-users (regardless of other combustible smoking habits). (11) Our results suggest that increases symptoms occur and are independent of asthma and COPD diagnosis. We also attempted to further assess for potential gradient in the risk according to the frequency of e-cigarette use and our findings indicate that—while for current everyday users the magnitude of the association seemed like the one found for some day users—results were no longer significant after adjustments. Potential reasons or the lack of a gradient effect include systematic misclassification of frequency of e-cigarette use (e.g., underreporting of every-day users), residual confounding (survey lack details combustible cigarette use and comorbidities), and potential power limitations (about 40% less participants in the everyday users than some days users), and lastly, potential threshold effect (symptoms occurring even at less frequent use). Thus, further studies using larger number of e-cigarette users that collect more detailed and valid information on these factors are needed to better understand whether a dose-response gradient exists for the risk of e-cigarettes use and respiratory symptoms.

E-cigarettes are designed to deliver nicotine throughout the body, without the combustion of tobacco. Through inhalation of water vapor to the lungs, numerous toxic compounds similar to those found within conventional cigarettes are released within the body. Examples of these compounds are aldehydes (formaldehyde and acrolein) and e-liquids (propylene glycol and glycerol) [7, 8, 19]. Overtime, these chemicals cause an elevated mucin concentration and result in failed mucus transport, hallmarks seen in patients of COPD (Chronic Obstructive Pulmonary Disease). The chemicals within e-cigarettes also stimulate neutrophils, resulting in the release of myeloperoxidase (MPO), neutrophil elastase (NE) and other granular proteins. The amount of proteins that are released in e-cigarettes is double to what was described for conventional cigarette smoking, and it causes massive structural damage to airways [20]. These changes could explain potential mechanism that contribute to the common symptoms of chronic cough, phlegm, and shortness of breath observed in e-cigarette users.

This study large sample size and the use of systematically collected and comprehensive information from participants from multiple states contribute to increase study’s generalizability when representing the adult population in the US. Yet, some limitations inherent to the cross-sectional and self-reported nature of the survey should be discussed. We lack detailed information on e-cigarette use characteristics such as the age when e-cigarette use was initiated and the daily frequency of e-cigarette use, as such information was not collected by the BRFSS participants in 2017. Additionally, the timing when e-cigarette use and the symptoms occurred is not clear. The BRFSS survey inquired about cough and phlegm occurring in the three months preceding the survey, while e-cigarettes use status referred to the use at the time of the survey. Therefore, the extent of which potential reverse causality accounts for the association described is unknown, and prospective studies are warranted. Furthermore, given the responses were based on self-report, misclassifications of both exposure to e-cigarettes and occurrence of symptoms are possible. While we do not have evidence to help us to estimate the directionality of the bias, we believe that both the frequency of symptoms and of e-cigarettes would be underreported, thus, most likely biasing the association towards the null hypothesis.

In conclusion, in line of previous findings, our results suggest that e-cigarettes may increase the risk of detrimental respiratory symptoms and thus, cannot be considered as a safe alternative to aid quitting use of combustible traditional cigarettes. Population-based cohort further assessing the potential dose-effect relationship between e-cigarettes use and respiratory symptoms are warranted.

Acknowledgments

We thank the Behavior Risk Factor Surveillance System (BRFSS) working group and the survey participants for their contribution.

Data Availability

Data for the study is available publicly at the CDC BRFSS site:https://www.cdc.gov/brfss/annual_data/annual_data.htm.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Koustubh Panda

22 Aug 2022

PONE-D-22-15106E-cigarette use and Respiratory Symptoms in Residents of the United States: A BRFSS ReportPLOS ONE

Dear Dr. Acuna,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: 

Introduction:

Line 44: I would hate to imply that e-cigs are a “safer alternative”. I would suggest instead of “considered a safer alternative …” to consider “promoted as a safer alternative …”

Line 48: Please update to the most recent data available (currently 2021 data).

Line 50: It is not at all clear that e-cig use reduces combustible tobacco use.

Line 51: E-cigs contain many toxins and carcinogens, full review of the topic is beyond the scope of this report, however authors should not imply that only a couple of toxins are there. I suggest that the authors look more deeply into this topic and produce a brief succinct sentence that accurately portrays the toxicity.

Line 96: Authors claim “This study does not require IRB clearance”, although this claim is probably correct, it would be best for author to have their IRB declare that it is exempt from review rather than to take it on themselves.

Results: It is interesting that some day e-cig use had greater impact than every day use. Why would that be? If there is causation I would expect a dose-response relation unless there is something else confounding …

Discussion should start with how results address specific aims, how results are biologically plausible, and then how results fit with existing research on the topic. Discussion is not a topic review, nor should it present findings not presented in results. Lines 157-167 seems tangential. I will leave it to the authors to identify and other tangential discussion.

Authors need to explain the lack of finding of dose response in e-cig use on respiratory symptoms. Could certain groups of daily users be motivated to under-report?? Could there be different levels of combustible tobacco use or exposure? Is there something else going on? Authors need to contrast their findings with other research on the same topic. For example, see Xie W et al JAMA Netw Open 2020;3:e2020816 and McConnell R Am J Respir Crit Care Med 2017;195:1043–1049

Conclusion should be clear and focused, what is the take home point? “adds to the growing body of literature” is not a conclusion.

Reviewer #2: 

1) About the E-cigarette usage - how long they use per day? AND how may years they have been using?

This will have an impact. Why was this confounder/variable not considered?

2) What is the reason 'someday current users' have more frequent respiratory symptoms compared to 'everyday current users'?

This has to be explained as well. Much of the discussion has been about 'someday users', ignoring the 'everyday users'.

**********

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Reviewer #1: No

Reviewer #2: No

**********

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PLoS One. 2022 Dec 1;17(12):e0269760. doi: 10.1371/journal.pone.0269760.r002

Author response to Decision Letter 0


19 Oct 2022

Responses to reviewer 1:

Comment#1: Line 44: I would hate to imply that e-cigs are a “safer alternative”. I would suggest instead of “considered a safer alternative …” to consider “promoted as a safer alternative …”

Response#1: Agreed with reviewer and changed accordingly. The new sentence reads now as follows: “E-cigarettes use, or vaping, was promoted as a safer alternative to conventional cigarettes…”

Comment#2: Line 48: Please update to the most recent data available (currently 2021 data).

Response#2: The reference was updated accordingly. Reference list was updated to reflect the updated information/citation. The new citations is the following

Gentzke AS, Wang TW, Cornelius M, et al. Tobacco Product Use and Associated Factors Among Middle and High School Students — National Youth Tobacco Survey, United States, 2021. MMWR Surveill Summ 2022;71 (5):1-29.

Comment#3: Line 50: It is not at all clear that e-cig use reduces combustible tobacco use.

Response#3: We agree with the reviewer and have removed that statement.

Comment#4: Line 51: E-cigs contain many toxins and carcinogens, full review of the topic is beyond the scope of this report, however authors should not imply that only a couple of toxins are there. I suggest that the authors look more deeply into this topic and produce a brief succinct sentence that accurately portrays the toxicity.

Response#4: The statement was adjusted to remove the potential emphasis to the two components listed. The statement now included note from a systematic review that listed 84 components of e-cigarettes that have been linked to hazardous effect. The sentence reads now as follows: “For instance, a systematic review published in 2019 listed 84 hazardous chemical compounds were identified in e-cigarettes. The hazardous effects of those compounds are varied and included cytotoxic, carcinogenic, behavioral, cardiovascular, and respiratory system effects”.

The following text was removed “…including diacetyl or benzaldehyde, that negatively affect the respiratory system.”

Comment#5: Line 96: Authors claim “This study does not require IRB clearance”, although this claim is probably correct, it would be best for author to have their IRB declare that it is exempt from review rather than to take it on themselves.

Response#5: The sentence was Revised to inform that the IRB of the Florida International University reviewed the proposed study for “Non-Human Subject research determination” and it was considered as Non-Human Subject Research.

It read now as “This study used publicly available data from the CDC BRFSS. The IRB of Florida International University considered the present study a “Non-Human Subject Research”.

Of note: The project received the approval by the FIU IRB to be performed as a Non-Human Subject Research. This is not considered an exempt category. Instead, it is considered as research that does not require IRB review and approval.

Comment#6: Results: It is interesting that some day e-cig use had greater impact than every day use. Why would that be? If there is causation I would expect a dose-response relation unless there is something else confounding …Discussion should start with how results address specific aims, how results are biologically plausible, and then how results fit with existing research on the topic. Discussion is not a topic review, nor should it present findings not presented in results. Lines 157-167 seems tangential. I will leave it to the authors to identify and other tangential discussion.

Authors need to explain the lack of finding of dose response in e-cig use on respiratory symptoms. Could certain groups of daily users be motivated to under-report?? Could there be different levels of combustible tobacco use or exposure? Is there something else going on? Authors need to contrast their findings with other research on the same topic. For example, see Xie W et al JAMA Netw Open 2020;3:e2020816 and McConnell R Am J Respir Crit Care Med 2017;195:1043–1049

Response#6: We agree with the reviewer. We expanded the discussion on the potential reasons for lack of findings of a dose-response association (lines 153-165 in the tracked version). Potential reasons including residual confounding due to lack of detailed information available for adjustments, misclassification bias and threshold effect were added.

The following text was added “Potential reasons or the lack of a gradient effect include systematic misclassification of frequency of e-cigarette use (e.g., underreporting of every-day users), residual confounding (survey lack details regarding combustible cigarette use and comorbidities), and potential power limitations (about 40% less participants in the everyday users than some days users), and lastly, potential threshold effect (symptoms occurring even at less frequent use). Thus, further studies using larger number of e-cigarette users that collect more detailed and valid information on these factors are needed to better understand whether a dose-response gradient exists for the risk of e-cigarettes use and respiratory symptoms. "

In addition, we added the citation by Xie as suggested by the reviewer. Of note the results from Xie et al 2020 were not discussed in further detail as it did not assess e-cigarette’s gradient (the categories some day and everyday users were merged into one) and the outcomes reported were COPD, chronic bronchitis, emphysema, and asthma diagnosis, thus, final endpoints contrasting with the outcomes of the present study (respiratory symptoms) which intended to focus on intermediary outcomes. We believed these intermediate outcomes to be affected at greater magnitude than the COPD and other chronic pulmonary diseases as these later would require longer lag time from expose to development of outcome. This difference in outcome choice was one motivation for doing the present study: to assess if there is a potential underestimation of the magnitude of the health risk of e-cigarette when assessing COPD and Asthma as outcomes. For that same last reason, while we alluded to the consistency of our findings with the studies including the one by MCCornell et al 20217, the discussion focused on highlighting the fact that those studies assessed more “final endpoints” (COPD and asthma) and we were interested in assessing how the magnitude could potentially differ when assessing more intermediate endpoints (Cough, phlegm, shortness of breath).

Comment#7: Conclusion should be clear and focused, what is the take home point? “adds to the growing body of literature” is not a conclusion.

Response#7: We provided a more directive take home point as suggested and the implication based on the findings/limitations

The conclusion now states:

“In conclusion, in line of previous findings, our results suggest that e-cigarettes may increase the risk of detrimental respiratory symptoms and thus, cannot be considered as a safe alternative to aid quitting use of combustible traditional cigarettes. Population-based cohort further assessing the potential dose-effect relationship between e-cigarettes use and respiratory symptoms are warranted.”

Responses to Reviewer #2:

Comment#1: About the E-cigarette usage - how long they use per day? AND how may years they have been using? This will have an impact. Why was this confounder/variable not considered?

Response#1: We agree with the reviewer that this is an important limitation. Unfortunately, the BRFSS does not include information on the time e-cigarettes have been used. We added that limitation in the discussion and it reads now as follows:

“We lack detailed information on e-cigarette use characteristics such as the age when e-cigarette use was initiated and the daily frequency of e-cigarette use, as such information was not collected by the BRFSS participants in 2017. Additionally, the timing when e-cigarette use and the symptoms occurred is not clear. The BRFSS survey inquired about cough and phlegm occurring in the three months preceding the survey, while e-cigarettes use status referred to the use at the time of the survey.”

Comment#2: What is the reason 'someday current users' have more frequent respiratory symptoms compared to 'everyday current users'? This has to be explained as well. Much of the discussion has been about 'someday users', ignoring the 'everyday users'.

Response#2: We expanded the discussion on the potential reasons for lack of findings of a dose-response association (lines 153-165 in the tracked version). Potential reasons including residual confounding due to lack of detailed information available for adjustments, misclassification bias and threshold effect were added. The following text was added:

“Potential reasons or the lack of a gradient effect include systematic misclassification of frequency of e-cigarette use (e.g., underreporting of every-day users), residual confounding (survey lack details regarding combustible cigarette use and comorbidities), and potential power limitations(about 40% less participants in the everyday users than some days users), and lastly, potential threshold effect (symptoms occurring even at less frequent use). Thus, further studies using larger number of e-cigarette users that collect more detailed and valid information on these factors are needed to better understand whether a dose-response gradient exists for the risk of e-cigarettes use and respiratory symptoms. "

Attachment

Submitted filename: Response_to_reviewers_D22_15106.docx

Decision Letter 1

Koustubh Panda

11 Nov 2022

E-cigarette use and Respiratory Symptoms in Residents of the United States: A BRFSS Report

PONE-D-22-15106R1

Dear Dr. Acuna,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Koustubh Panda, M. Tech., Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

**********

Acceptance letter

Koustubh Panda

18 Nov 2022

PONE-D-22-15106R1

E-cigarette use and Respiratory Symptoms in Residents of the United States: A BRFSS Report

Dear Dr. Acuna:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Koustubh Panda

Academic Editor

PLOS ONE


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